Biological antagonists containing aromatic ring systems, their preparation methods and applications

Abstract

Provided are biological antagonists containing an aromatic ring system, as shown in general formula (I), or stereoisomers thereof, methods for their preparation and pharmaceutical compositions containing said compounds, as well as their application in the manufacture of medicaments for treating diabetes, kidney disease or hypertension. [Formula 1] TIFF2024534111000213.tif40170

Description

[Technical Field]

[0001] The present invention relates to the field of biopharmaceuticals, specifically to biological antagonists containing aromatic ring systems, their preparation methods and applications. [Background technology]

[0002] Focal segmental glomerulosclerosis (FSGS), a phenotype of nephrotic syndrome and a major cause of end-stage renal disease, has a complex pathogenesis that remains incompletely understood. Current drug treatments, primarily glucocorticoids and immunosuppressants, have shown poor response rates, failed to effectively control the onset and progression of FSGS, and have significant side effects. Currently, there are no approved treatments for FSGS. The complete remission rate for FSGS treatment is less than 30%. One-third of patients progress to chronic renal failure within five years, requiring long-term dialysis or kidney transplantation to survive. This creates a significant economic burden on families and society, making the search for new treatment strategies a priority.

[0003] In addition to FSGS, other kidney diseases or conditions characterized by glomerular damage include IgA nephropathy and idiopathic membranous nephropathy. IgA nephropathy, also known as Berger's disease, is caused by the accumulation of immunoglobulin A (IgA) in the kidney. The presence of IgA in the kidney can cause renal dysfunction, including inflammation, glomerular damage, and proteinuria. In some cases, patients with IgA nephropathy progress to ESRD. IgA nephropathy is the most common glomerulonephritis worldwide. Approximately 30% of patients experience a 50% decline in glomerular filtration rate over a 10-year period. Patients with IgA nephropathy form IgG autoantibodies to counteract galactose-deficient IgA1 antibodies. These antibodies then deposit in the mesangium and activate complement. Primary treatment for patients with IgA nephropathy involves eliminating risk factors, particularly hypertension, by blocking the renin-angiotensin-aldosterone system (RAAS). Although immunosuppression has also been extensively studied, no significant advantages have been observed. Common side effects of hormone therapy include elevated blood glucose levels, osteoporosis, and infections. Therefore, there remains a need for compositions and methods for treating various kidney diseases or conditions (e.g., FSGS, IgA nephropathy, and IMN).

[0004] Angiotensin II (Ang II) and endothelin-1 (ET-1), two potent and effective endogenous vasoactive peptides, are thought to play a role in regulating vascular tone and pathological tissue remodeling in various diseases, including diabetic nephropathy, heart failure, and chronic or persistently elevated blood pressure. The renin-angiotensin-aldosterone system (RAAS) regulates blood pressure, fluid, and sodium balance. Excessive activation of the RAAS promotes systemic and local glomerular capillary hypertension, causing glomerular hemodynamic damage and leading to kidney injury and fibrosis via profibrotic and proinflammatory pathways. RAAS-dependent drugs, such as angiotensin receptor blockers (ARBs), are used to treat diabetic nephropathy, heart failure, and chronic or persistently elevated blood pressure. Increasing data have demonstrated the potential benefits of ETA receptor antagonists (ERAs) in the treatment of hypertension and diabetic nephropathy.

[0005] Studies have shown that the combination of an ARB and an ERA produces a synergistic effect, with Ang II and ET-1 acting cooperatively in blood pressure control and pathological tissue remodeling. Elevated Ang II levels promote the synthesis and vasoconstriction of ET-1, and ET receptor blockade with an ETA can attenuate Ang II-induced vasoconstriction and reduce plasma aldosterone. ARBs not only block the action of Ang II on its AT1 receptor but also limit ET-1 production. Therefore, simultaneous blockade of both Ang II and ET-1 activity may provide superior efficacy compared with blocking either agent alone. While ARBs are the standard treatment for patients with diabetic nephropathy, phase II clinical trials have shown that dual antagonists (ARBs and ERAs) can improve proteinuria in patients with FSGS. Therefore, drugs with a dual AT1 / ETA target antagonism mechanism have potential therapeutic potential for renal disease and are of interest for drug development.

[0006] International application WO 2018071784 reports that the AT1 / ETA dual-targeting antagonist Sparsentan, developed by Retrophin, has demonstrated good anti-glomerular fibrosis effects in preclinical studies, and has been shown to improve proteinuria levels in FSGS patients in Phase II clinical trials, with Phase III clinical trials demonstrating its efficacy in treating FSGS and IgA nephropathy. This project aims to develop an AT1 / ETA dual-targeting antagonist to better treat nephrotic syndrome (including FSGS, IgA nephropathy, diabetic nephropathy, etc.). Summary of the Invention

[0007] An object of the present invention is to provide a compound represented by general formula (I), its stereoisomer or a pharmaceutically acceptable salt thereof, whose structure is as follows: [ka] where: X1 is N or CR 1and X2 is N or CR 2 and X3 is N or CR 3 and R 1 , R 2 and R 3 are each independently selected from hydrogen, deuterium, halogen, amino, nitro, hydroxy, cyano, alkyl, deuterated alkyl, halogenated alkyl, hydroxyalkyl, alkoxy, halogenated alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl groups, and the amino, alkyl, deuterated alkyl, halogenated alkyl, hydroxyalkyl, alkoxy, halogenated alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl groups may optionally be further substituted; L1 is -(CR a R b ) n1 -, -(CR a R b ) n1 O-, -O(CR a R b ) n1 -, -(CR a R b ) n1 S-, -S(CR a R b ) n1 -, -(CH2) n1 C(O)NR a -, -(CH2) n1 NR a C(O)-, -(CH2) n1 S(O) m1 -, -(CH2) n1 S(O) m1 NR a -, -(CH2) n1 NR a S(O) m1 -or-(CH2) n1 NR a - selected from L2 is -(CH2) n2 -, -(CH2)n2 NR c -, -(CH2) n2 C(O)NR c -, -(CH2) n2 C(O)NR c S(O) m2 -, -(CH2) n2 NR c C(O)-, -(CH2) n2 S(O) m2 -, -(CH2) n2 S(O) m2 NR c -, -(CH2) n2 S(O) m2 NR c C(O)-, -(CH2) n2 S(O) m2 NR c C(O)NR d -, -(CH2) n2 S(O) m2 NR c C(O)O(CH2) n3 -, -(CH2) n2 NR c S(O) m2 -or-(CH2) n2 NR c S(O) m2 NR d C(O)-; Ring A is selected from a cycloalkyl group, a heterocyclyl group, an aryl group, or a heteroaryl group, which cycloalkyl group, heterocyclyl group, aryl group, and heteroaryl group may optionally be further substituted; R a are independently hydrogen, deuterium, halogen, amino group, nitro group, hydroxy group, cyano group, oxo group, thio group, alkyl group, deuterated alkyl group, halogenated alkyl group, hydroxyalkyl group, alkoxy group, halogenated alkoxy group, alkenyl group, alkynyl group, cycloalkyl group, heterocyclyl group, aryl group, heteroaryl group, -(CH2) n4 C(O)R A1 , -(CH2) n4 C(O)OR A1 , -(CH2) n4 C(O)NR A1R B1 or -(CH2) n4 C(=S)NR A1 R B1 wherein the amino group, alkyl group, deuterated alkyl group, halogenated alkyl group, hydroxyalkyl group, alkoxy group, halogenated alkoxy group, alkenyl group, alkynyl group, cycloalkyl group, heterocyclyl group, aryl group and heteroaryl group may optionally be further substituted; R1 is hydrogen, deuterium, halogen, amino group, nitro group, hydroxy group, cyano group, alkyl group, deuterated alkyl group, halogenated alkyl group, hydroxyalkyl group, alkoxy group, halogenated alkoxy group, alkenyl group, alkynyl group, cycloalkyl group, heterocyclyl group, aryl group, heteroaryl group, -(CH2) n5 R A2 -, -(CH2) n5 O(CH2) n6 R A2 -, -(CH2) n5 C(O)R A2 , -(CH2) n5 NR A2 C(O)R B2 , -(CH2) n5 C(O)NR A2 R B2 , -(CH2) n5 OC(O)NR A2 R B2 or -(CH2) n5 NR A2 C(O)OR B2 wherein the amino group, alkyl group, deuterated alkyl group, halogenated alkyl group, hydroxyalkyl group, alkoxy group, halogenated alkoxy group, alkenyl group, alkynyl group, cycloalkyl group, heterocyclyl group, aryl group and heteroaryl group may optionally be further substituted; Or, R1 and R a are joined to form a cycloalkyl group, a heterocyclyl group, an aryl group, or a heteroaryl group, which cycloalkyl groups, heterocyclyl groups, aryl groups, and heteroaryl groups may optionally be further substituted; R2, R3, R4 and R5 are each independently selected from hydrogen, deuterium, halogen, amino, nitro, hydroxy, cyano, alkyl, deuterated alkyl, halogenated alkyl, hydroxyalkyl, alkoxy, halogenated alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl or heteroaryl groups, wherein the amino, alkyl, deuterated alkyl, halogenated alkyl, hydroxyalkyl, alkoxy, halogenated alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl groups may optionally be further substituted; R6 is selected from hydrogen, deuterium, halogen, amino group, nitro group, hydroxy group, cyano group, alkyl group, deuterated alkyl group, halogenated alkyl group, hydroxyalkyl group, alkoxy group, halogenated alkoxy group, alkenyl group, alkynyl group, cycloalkyl group, heterocyclyl group, aryl group, or heteroaryl group, wherein the amino group, alkyl group, deuterated alkyl group, halogenated alkyl group, hydroxyalkyl group, alkoxy group, halogenated alkoxy group, alkenyl group, alkynyl group, cycloalkyl group, heterocyclyl group, aryl group, and heteroaryl group may optionally be further substituted; R a , R b , R c , R d , R A1 , R A2 , R B1 and R B2are each independently selected from hydrogen, deuterium, halogen, amino, nitro, hydroxy, cyano, alkyl, deuterated alkyl, halogenated alkyl, hydroxyalkyl, alkoxy, halogenated alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl groups, and the amino, alkyl, deuterated alkyl, halogenated alkyl, hydroxyalkyl, alkoxy, halogenated alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl groups may optionally be further substituted; x is 0, 1, 2, 3, 4 or 5; n1 to n6 are 0, 1, 2, 3, 4, or 5, and m1 and m2 are 0, 1 or 2.

[0008] In one embodiment of the present invention, R2 and R5 together with adjacent atoms form a heterocyclyl group, which may optionally be further substituted.

[0009] In a preferred embodiment of the present invention, the ring A is C 3-12 Cycloalkyl groups, 3- to 12-membered heterocyclyl groups, C 6-14 an aryl group or a 5- to 14-membered heteroaryl group, 3-12 Cycloalkyl groups, 3- to 12-membered heterocyclyl groups, C 6-14 The aryl group and the 5- to 14-membered heteroaryl group may optionally be substituted with deuterium, halogen, amino, hydroxy, cyano, oxo, thio, C 1-6 Alkyl group, C 2-6 Alkenyl group, C 2-6 Alkynyl group, C 1-6 Deuterated alkyl groups, C 1-6 Halogenated alkyl groups, C 1-6 Hydroxyalkyl group, C 1-6 Alkoxy group, C 1-6 Alkylthio group, C 1-6 Halogenated alkoxy groups, C 3-12 Cycloalkyl groups, 3- to 12-membered heterocyclyl groups, C6-14 It may be further substituted with one or more of the following substituents: an aryl group and a 5- to 14-membered heteroaryl group.

[0010] In a further preferred embodiment of the present invention, the ring A is selected from a 5- to 10-membered heterocyclyl group or a 5- to 10-membered heteroaryl group.

[0011] In a further preferred embodiment of the present invention, the ring A is selected from a 5- to 6-membered nitrogen-containing monocyclic heterocyclyl group, a 6- to 10-membered nitrogen-containing spiroheterocyclyl group, or a 5- to 6-membered nitrogen-containing heteroaryl group.

[0012] In a further preferred embodiment of the present invention, the ring A is a pyridyl group, a pyrazinyl group, a pyrimidinyl group, a pyridazinyl group, a pyrrolyl group, an imidazolyl group, a pyrazolyl group, [ka] is selected from.

[0013] R a are independently hydrogen, deuterium, halogen, amino group, nitro group, hydroxy group, cyano group, oxo group, thio group, C 1-6 Alkyl group, C 1-6 Deuterated alkyl groups, C 1-6 Halogenated alkyl groups, C 1-6 Hydroxyalkyl group, C 1-6 Alkoxy group, C 1-6 Halogenated alkoxy groups, C 2-6 Alkenyl group, C 2-6 Alkynyl group, C 3-12 Cycloalkyl groups, 3- to 12-membered heterocyclyl groups, C 6-14 Aryl group, 5- to 12-membered heteroaryl group, -(CH2) n4 C(O)R A1 , -(CH2) n4 C(O)OR A1 , -(CH2) n4 C(O)NR A1 R B1 or -(CH2) n4 C(=S)NRA1 R B1 wherein the amino group, C 1-6 Alkyl group, C 1-6 Deuterated alkyl groups, C 1-6 Halogenated alkyl groups, C 1-6 Hydroxyalkyl group, C 1-6 Alkoxy group, C 1-6 Halogenated alkoxy groups, C 2-6 Alkenyl group, C 2-6 Alkynyl group, C 3-12 Cycloalkyl groups, 3- to 12-membered heterocyclyl groups, C 6-14 The aryl group, the 5- to 12-membered heteroaryl group may be optionally further substituted, and R A1 and R B1 are each independently hydrogen, deuterium, halogen, amino group, nitro group, hydroxy group, cyano group, C 1-6 Alkyl group, C 1-6 Deuterated alkyl groups, C 1-6 Halogenated alkyl groups, C 1-6 Hydroxyalkyl group, C 1-6 Alkoxy group, C 1-6 Halogenated alkoxy groups, C 2-6 Alkenyl group, C 2-6 Alkynyl group, C 3-12 Cycloalkyl groups, 3- to 12-membered heterocyclyl groups, C 6-14 an aryl group, a 5- to 12-membered heteroaryl group, and the amino group, C 1-6 Alkyl group, C 1-6 Deuterated alkyl groups, C 1-6 Halogenated alkyl groups, C 1-6 Hydroxyalkyl group, C 1-6 Alkoxy group, C 1-6 Halogenated alkoxy groups, C 2-6 Alkenyl group, C 2-6 Alkynyl group, C 3-12 Cycloalkyl groups, 3- to 12-membered heterocyclyl groups, C 6-14 The aryl group and the 5- to 12-membered heteroaryl group may optionally be further substituted. Preferably, R a are independently an amino group, a nitro group, a hydroxy group, a cyano group, an oxo group, C1-6 Alkyl group, C 1-6 Hydroxyalkyl group, -(CH2) n4 C(O)OR A1 , and (CH2) n4 C(=S)NR A1 R B1 Selected from R A1 and R B1 are each independently hydrogen or C 1-6 alkyl groups, More preferably, R a are independently an oxo group, C 1-4 Alkyl group, C 1-3 Hydroxyalkyl group, -(CH2) n4 C(O)OR A1 , and (CH2) n4 C(=S)NR A1 R B1 Selected from R A1 and R B1 are each independently hydrogen, C 1-6 alkyl groups, Most preferably, R a are independently an oxo group, an n-propyl group, an n-butyl group, a carboxyl group, an ethyl group, -CH2OH, -C(O)NH2, -C(O)NHCH3, [ka] is selected from.

[0014] In a further preferred embodiment of the present invention, the compound, its stereoisomer or its pharmaceutically acceptable salt is further as shown in general formula (II): [ka] X1 is N or CR 1 and X2 is N or CR 2 and X3 is N or CR 3 and R 1 , R 2 and R 3are each independently hydrogen, deuterium, halogen, amino group, hydroxy group, cyano group, C 1-6 Alkyl group, C 2-6 Alkenyl group, C 2-6 Alkynyl group, C 1-6 Deuterated alkyl groups, C 1-6 Halogenated alkyl groups, C 1-6 Hydroxyalkyl group, C 1-6 Alkoxy group, C 1-6 Alkylthio group, C 1-6 Halogenated alkoxy groups, C 3-12 Cycloalkyl groups, 3- to 12-membered heterocyclyl groups, C 6-14 an aryl group or a 5- to 14-membered heteroaryl group, 1-6 Alkyl group, C 2-6 Alkenyl group, C 2-6 Alkynyl group, C 1-6 Deuterated alkyl groups, C 1-6 Halogenated alkyl groups, C 1-6 Hydroxyalkyl group, C 1-6 Alkoxy group, C 1-6 Alkylthio group, C 1-6 Halogenated alkoxy groups, C 3-12 Cycloalkyl groups, 3- to 12-membered heterocyclyl groups, C 6-14 The aryl group and the 5- to 14-membered heteroaryl group may optionally be substituted with deuterium, halogen, amino, hydroxy, cyano, oxo, thio, C 1-6 Alkyl group, C 2-6 Alkenyl group, C 2-6 Alkynyl group, C 1-6 Deuterated alkyl groups, C 1-6 Halogenated alkyl groups, C 1-6 Hydroxyalkyl group, C 1-6 Alkoxy group, C 1-6 Alkylthio group, C 1-6 Halogenated alkoxy groups, C 3-12 Cycloalkyl groups, 3- to 12-membered heterocyclyl groups, C 6-14 further substituted with one or more substituents selected from the group consisting of aryl groups and 5- to 14-membered heteroaryl groups; L1 is -(CR a R b )n1 -, -(CR a R b ) n1 O-, -O(CR a R b ) n1 -, -(CR a R b ) n1 S-, -S(CR a R b ) n1 -, -(CH2) n1 C(O)NR a -, -(CH2) n1 NR a C(O)-, -(CH2) n1 S(O) m1 -, -(CH2) n1 S(O) m1 NR a -, -(CH2) n1 NR a S(O) m1 -or-(CH2) n1 NR a - selected from R1 is hydrogen, deuterium, halogen, amino group, hydroxy group, cyano group, C 1-6 Alkyl group, C 2-6 Alkenyl group, C 2-6 Alkynyl group, C 1-6 Deuterated alkyl groups, C 1-6 Halogenated alkyl groups, C 1-6 Hydroxyalkyl group, C 1-6 Alkoxy group, C 1-6 Alkylthio group, C 1-6 Halogenated alkoxy groups, C 3-12 Cycloalkyl groups, 3- to 12-membered heterocyclyl groups, C 6-14 Aryl group, 5- to 14-membered heteroaryl group, -(CH2) n5 R A2 -, -(CH2) n5 O(CH2) n6 R A2 -, -(CH2) n5 C(O)R A2 , -(CH2) n5 NR A2 C(O)R B2 , -(CH2) n5 C(O)NRA2 R B2 , -(CH2) n5 OC(O)NR A2 R B2 or -(CH2) n5 NR A2 C(O)OR B2 wherein C is selected from 1-6 Alkyl group, C 2-6 Alkenyl group, C 2-6 Alkynyl group, C 1-6 Deuterated alkyl groups, C 1-6 Halogenated alkyl groups, C 1-6 Hydroxyalkyl group, C 1-6 Alkoxy group, C 1-6 Alkylthio group, C 1-6 Halogenated alkoxy groups, C 3-12 Cycloalkyl groups, 3- to 12-membered heterocyclyl groups, C 6-14 The aryl group and the 5- to 14-membered heteroaryl group may optionally be substituted with deuterium, halogen, amino, hydroxy, cyano, oxo, thio, C 1-6 Alkyl group, C 2-6 Alkenyl group, C 2-6 Alkynyl group, C 1-6 Deuterated alkyl groups, C 1-6 Halogenated alkyl groups, C 1-6 Hydroxyalkyl group, C 1-6 Alkoxy group, C 1-6 Alkylthio group, C 1-6 Halogenated alkoxy groups, C 3-12 Cycloalkyl groups, 3- to 12-membered heterocyclyl groups, C 6-14 further substituted with one or more substituents selected from the group consisting of aryl groups and 5- to 14-membered heteroaryl groups; R7 and R8 each independently represent hydrogen, deuterium, a halogen, an amino group, a hydroxy group, a cyano group, or C 1-6 Alkyl group, C 2-6 Alkenyl group, C 2-6 Alkynyl group, C 1-6 Deuterated alkyl groups, C 1-6 Halogenated alkyl groups, C 1-6 Hydroxyalkyl group, C 1-6 Alkoxy group, C 1-6 Alkylthio group, C1-6 Halogenated alkoxy groups, C 3-12 Cycloalkyl groups, 3- to 12-membered heterocyclyl groups, C 6-14 an aryl group or a 5- to 14-membered heteroaryl group, 1-6 Alkyl group, C 2-6 Alkenyl group, C 2-6 Alkynyl group, C 1-6 Deuterated alkyl groups, C 1-6 Halogenated alkyl groups, C 1-6 Hydroxyalkyl group, C 1-6 Alkoxy group, C 1-6 Alkylthio group, C 1-6 Halogenated alkoxy groups, C 3-12 Cycloalkyl groups, 3- to 12-membered heterocyclyl groups, C 6-14 The aryl group and the 5- to 14-membered heteroaryl group may optionally be substituted with deuterium, halogen, amino, hydroxy, cyano, oxo, thio, C 1-6 Alkyl group, C 2-6 Alkenyl group, C 2-6 Alkynyl group, C 1-6 Deuterated alkyl groups, C 1-6 Halogenated alkyl groups, C 1-6 Hydroxyalkyl group, C 1-6 Alkoxy group, C 1-6 Alkylthio group, C 1-6 Halogenated alkoxy groups, C 3-12 Cycloalkyl groups, 3- to 12-membered heterocyclyl groups, C 6-14 further substituted with one or more substituents selected from the group consisting of aryl groups and 5- to 14-membered heteroaryl groups; Or, R7 and R8 are bonded to form C 3-8 Cycloalkyl groups, 5- to 8-membered heterocyclyl groups, C 6-14 An aryl group or a 5- to 14-membered heteroaryl group is formed, and 3-8 Cycloalkyl groups, 5- to 8-membered heterocyclyl groups, C 6-14 The aryl group or 5- to 14-membered heteroaryl group may optionally be further substituted; R a and R bare each independently hydrogen, deuterium, halogen, amino group, hydroxy group, cyano group, C 1-6 Alkyl group, C 2-6 Alkenyl group, C 2-6 Alkynyl group, C 1-6 Deuterated alkyl groups, C 1-6 Halogenated alkyl groups, C 1-6 Hydroxyalkyl group, C 1-6 Alkoxy group, C 1-6 Alkylthio group, C 1-6 Halogenated alkoxy groups, C 3-12 Cycloalkyl groups, 3- to 12-membered heterocyclyl groups, C 6-14 an aryl group or a 5- to 14-membered heteroaryl group, 1-6 Alkyl group, C 2-6 Alkenyl group, C 2-6 Alkynyl group, C 1-6 Deuterated alkyl groups, C 1-6 Halogenated alkyl groups, C 1-6 Hydroxyalkyl group, C 1-6 Alkoxy group, C 1-6 Alkylthio group, C 1-6 Halogenated alkoxy groups, C 3-12 Cycloalkyl groups, 3- to 12-membered heterocyclyl groups, C 6-14 The aryl group and the 5- to 14-membered heteroaryl group may optionally be substituted with deuterium, halogen, amino, hydroxy, cyano, oxo, thio, C 1-6 Alkyl group, C 2-6 Alkenyl group, C 2-6 Alkynyl group, C 1-6 Deuterated alkyl groups, C 1-6 Halogenated alkyl groups, C 1-6 Hydroxyalkyl group, C 1-6 Alkoxy group, C 1-6 Alkylthio group, C 1-6 Halogenated alkoxy groups, C 3-12 Cycloalkyl groups, 3- to 12-membered heterocyclyl groups, C 6-14 further substituted with one or more substituents selected from the group consisting of aryl groups and 5- to 14-membered heteroaryl groups; R A2 and R B2are each independently hydrogen, deuterium, halogen, amino group, hydroxy group, cyano group, C 1-6 Alkyl group, C 2-6 Alkenyl group, C 2-6 Alkynyl group, C 1-6 Deuterated alkyl groups, C 1-6 Halogenated alkyl groups, C 1-6 Hydroxyalkyl group, C 1-6 Alkoxy group, C 1-6 Alkylthio group, C 1-6 Halogenated alkoxy groups, C 3-12 Cycloalkyl groups, 3- to 12-membered heterocyclyl groups, C 6-14 an aryl group or a 5- to 14-membered heteroaryl group, 1-6 Alkyl group, C 2-6 Alkenyl group, C 2-6 Alkynyl group, C 1-6 Deuterated alkyl groups, C 1-6 Halogenated alkyl groups, C 1-6 Hydroxyalkyl group, C 1-6 Alkoxy group, C 1-6 Alkylthio group, C 1-6 Halogenated alkoxy groups, C 3-12 Cycloalkyl groups, 3- to 12-membered heterocyclyl groups, C 6-14 The aryl group and the 5- to 14-membered heteroaryl group may optionally be substituted with deuterium, halogen, amino, hydroxy, cyano, oxo, thio, C 1-6 Alkyl group, C 2-6 Alkenyl group, C 2-6 Alkynyl group, C 1-6 Deuterated alkyl groups, C 1-6 Halogenated alkyl groups, C 1-6 Hydroxyalkyl group, C 1-6 Alkoxy group, C 1-6 Alkylthio group, C 1-6 Halogenated alkoxy groups, C 3-12 Cycloalkyl groups, 3- to 12-membered heterocyclyl groups, C 6-14 further substituted with one or more substituents selected from the group consisting of aryl groups and 5- to 14-membered heteroaryl groups; n1, n5 and n6 are 0, 1, 2 or 3, and m1 is 0, 1 or 2.

[0015] In a further preferred embodiment of the present invention, the compound is further represented by general formula (VIII-1) or general formula (VIII-2), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, [ka] wherein L1, X1, X2, X3, R7, and R8 are defined as in claim 2; In the general formula (VIII-1), L1 is CH2, R7 and R8 are both methyl groups, and R1 is [ka] When this is the case, at least one of X1, X2, and X3 is not CH.

[0016] In a preferred embodiment of the present invention, L1 is -CR a R b -, -CR a R b O-, -OCR a R b -, -CR a R b S- or -SCR a R b - is selected from.

[0017] In a further preferred embodiment of the present invention, L1 is selected from -CH2-, -CD2- or -CH2O-; R a and R b are each independently hydrogen, deuterium, halogen, amino group, hydroxy group, cyano group, C 1-3 Alkyl group, C 2-3 Alkenyl group, C 2-3 Alkynyl group, C 1-3 Deuterated alkyl groups, C 1-3 Halogenated alkyl groups, C 1-3 Hydroxyalkyl group, C 1-3 Alkoxy group, C 1-3 Alkylthio group, C1-3 Halogenated alkoxy groups, C 3-8 Cycloalkyl groups, 3- to 8-membered heterocyclyl groups, C 6-10 an aryl group or a 5- to 10-membered heteroaryl group, 1-3 Alkyl group, C 2-3 Alkenyl group, C 2-3 Alkynyl group, C 1-3 Deuterated alkyl groups, C 1-3 Halogenated alkyl groups, C 1-3 Hydroxyalkyl group, C 1-3 Alkoxy group, C 1-3 Alkylthio group, C 1-3 Halogenated alkoxy groups, C 3-8 Cycloalkyl groups, 3- to 8-membered heterocyclyl groups, C 6-10 The aryl group and the 5- to 10-membered heteroaryl group may optionally be substituted with deuterium, halogen, amino, hydroxy, cyano, oxo, thio, C 1-3 Alkyl group, C 2-3 Alkenyl group, C 2-3 Alkynyl group, C 1-3 Deuterated alkyl groups, C 1-3 Halogenated alkyl groups, C 1-3 Hydroxyalkyl group, C 1-3 Alkoxy group, C 1-3 Alkylthio group, C 1-3 Halogenated alkoxy groups, C 3-8 Cycloalkyl groups, 3- to 8-membered heterocyclyl groups, C 6-10 It may be further substituted with one or more substituents selected from the group consisting of aryl groups and 5- to 10-membered heteroaryl groups.

[0018] In a preferred embodiment of the present invention, R1 and R7 are bonded to form an 8- to 20-membered heterocyclyl group, and the heterocyclyl group optionally contains deuterium, halogen, amino group, hydroxy group, cyano group, oxo group, thio group, C 1-6 Alkyl group, C 2-6 Alkenyl group, C 2-6 Alkynyl group, C 1-6 Deuterated alkyl groups, C 1-6 Halogenated alkyl groups, C 1-6 Hydroxyalkyl group, C1-6 Alkoxy group, C 1-6 Alkylthio group, C 1-6 Halogenated alkoxy groups, C 3-12 Cycloalkyl groups, 3- to 12-membered heterocyclyl groups, C 6-14 It may be further substituted with one or more of the following substituents: an aryl group and a 5- to 14-membered heteroaryl group.

[0019] In a further preferred embodiment of the present invention, R1 and R7 combine to form an 8- to 14-membered heterocyclyl group.

[0020] In a further preferred embodiment of the invention, R1 and R7 combine to form an 8- to 14-membered oxygen-containing heterocyclyl group.

[0021] In a preferred embodiment of the present invention, X1, X2 and X3 are all CH, L1 is selected from -CH2- or -CD2-; R1 is hydrogen, deuterium, halogen, amino group, hydroxy group, cyano group, C 1-6 Alkyl group, C 2-6 Alkenyl group, C 2-6 Alkynyl group, C 1-6 Deuterated alkyl groups, C 1-6 Halogenated alkyl groups, C 1-6 Hydroxyalkyl group, C 1-6 Alkoxy group, C 1-6 Alkylthio group, C 1-6 Halogenated alkoxy groups, C 3-12 Cycloalkyl groups, 3- to 12-membered heterocyclyl groups, C 6-14 Aryl group, 5- to 14-membered heteroaryl group, -(CH2) n5 R A2 , -(CH2) n5 O(CH2) n6 R A2 , -(CH2) n5 C(O)R A2 , -(CH2) n5 NR A2 C(O)R B2 , -(CH2) n5 C(O)NR A2 RB2 , -(CH2) n5 OC(O)NR A2 R B2 or -(CH2) n5 NR A2 C(O)OR B2 wherein C is selected from 1-6 Alkyl group, C 2-6 Alkenyl group, C 2-6 Alkynyl group, C 1-6 Deuterated alkyl groups, C 1-6 Halogenated alkyl groups, C 1-6 Hydroxyalkyl group, C 1-6 Alkoxy group, C 1-6 Alkylthio group, C 1-6 Halogenated alkoxy groups, C 3-12 Cycloalkyl groups, 3- to 12-membered heterocyclyl groups, C 6-14 The aryl group and the 5- to 14-membered heteroaryl group may optionally be substituted with deuterium, halogen, amino, hydroxy, cyano, oxo, thio, C 1-6 Alkyl group, C 2-6 Alkenyl group, C 2-6 Alkynyl group, C 1-6 Deuterated alkyl groups, C 1-6 Halogenated alkyl groups, C 1-6 Hydroxyalkyl group, C 1-6 Alkoxy group, C 1-6 Alkylthio group, C 1-6 Halogenated alkoxy groups, C 3-12 Cycloalkyl groups, 3- to 12-membered heterocyclyl groups, C 6-14 further substituted with one or more substituents selected from the group consisting of aryl groups and 5- to 14-membered heteroaryl groups; Preferably, R1 is H, -CH3, -CH2CH3, [ka] is selected from R7 is hydrogen, deuterium, halogen, amino group, hydroxy group, cyano group, C 1-3 Alkyl group, C 2-3 Alkenyl group, C 2-3 Alkynyl group, C 1-3 Deuterated alkyl groups, C1-3 Halogenated alkyl groups, C 1-3 Hydroxyalkyl group, C 1-3 Alkoxy group, C 1-3 Alkylthio group, C 1-3 Halogenated alkoxy groups, C 3-8 Cycloalkyl groups, 3- to 8-membered heterocyclyl groups, C 6-10 an aryl group or a 5- to 10-membered heteroaryl group; Preferably, R7 is selected from deuterium, fluorine, chlorine, bromine or a methyl group; The R8 is hydrogen, deuterium, halogen, amino group, hydroxy group, cyano group, C 1-3 Alkyl group, C 2-3 Alkenyl group, C 2-3 Alkynyl group, C 1-3 Deuterated alkyl groups, C 1-3 Halogenated alkyl groups, C 1-3 Hydroxyalkyl group, C 1-3 Alkoxy group, C 1-3 Alkylthio group, C 1-3 Halogenated alkoxy groups, C 3-8 Cycloalkyl groups, 3- to 8-membered heterocyclyl groups, C 6-10 an aryl group or a 5- to 10-membered heteroaryl group; Preferably, R8 is selected from a methyl group, an ethyl group, or a cyclopropyl group.

[0022] In a further preferred embodiment of the present invention, the compound, its stereoisomer, or its pharmaceutically acceptable salt is further represented by general formula (II-1): [ka] L1 is selected from -CH2- or -CD2-; R1 is deuterium, halogen, amino group, hydroxy group, cyano group, C 1-6 Alkyl group, C 2-6 Alkenyl group, C 2-6 Alkynyl group, C 1-6 Deuterated alkyl groups, C 1-6 Halogenated alkyl groups, C 1-6Hydroxyalkyl group, C 1-6 Alkoxy group, C 1-6 Alkylthio group, C 1-6 Halogenated alkoxy groups, C 3-12 Cycloalkyl groups, 3- to 12-membered heterocyclyl groups, C 6-14 Aryl group, 5- to 14-membered heteroaryl group, -(CH2) n5 R A2 , -(CH2) n5 O(CH2) n6 R A2 , -(CH2) n5 C(O)R A2 , -(CH2) n5 NR A2 C(O)R B2 , -(CH2) n5 C(O)NR A2 R B2 , -(CH2) n5 OC(O)NR A2 R B2 or -(CH2) n5 NR A2 C(O)OR B2 wherein C is selected from 1-6 Alkyl group, C 2-6 Alkenyl group, C 2-6 Alkynyl group, C 1-6 Deuterated alkyl groups, C 1-6 Halogenated alkyl groups, C 1-6 Hydroxyalkyl group, C 1-6 Alkoxy group, C 1-6 Alkylthio group, C 1-6 Halogenated alkoxy groups, C 3-12 Cycloalkyl groups, 3- to 12-membered heterocyclyl groups, C 6-14 The aryl group and the 5- to 14-membered heteroaryl group may optionally be substituted with deuterium, halogen, amino, hydroxy, cyano, oxo, thio, C 1-6 Alkyl group, C 2-6 Alkenyl group, C 2-6 Alkynyl group, C 1-6 Deuterated alkyl groups, C 1-6 Halogenated alkyl groups, C 1-6 Hydroxyalkyl group, C 1-6 Alkoxy group, C 1-6 Alkylthio group, C1-6 Halogenated alkoxy groups, C 3-12 Cycloalkyl groups, 3- to 12-membered heterocyclyl groups, C 6-14 further substituted with one or more substituents selected from the group consisting of aryl groups and 5- to 14-membered heteroaryl groups; Furthermore, R1 is preferably -CH3, -CH2CH3, [ka] and more preferably selected from: [ka] and R7 is selected from halogen, preferably fluorine, chlorine, bromine, more preferably chlorine; R8 is hydrogen, deuterium, halogen, amino group, hydroxy group, cyano group, C 1-3 Alkyl group, C 2-3 Alkenyl group, C 2-3 Alkynyl group, C 1-3 Deuterated alkyl groups, C 1-3 Halogenated alkyl groups, C 1-3 Hydroxyalkyl group, C 1-3 Alkoxy group, C 1-3 Alkylthio group, C 1-3 Halogenated alkoxy groups, C 3-8 Cycloalkyl groups, 3- to 8-membered heterocyclyl groups, C 6-10 It is selected from an aryl group or a 5- to 10-membered heteroaryl group, and is preferably a methyl group, an ethyl group, or a cyclopropyl group, more preferably a methyl group.

[0023] In a further preferred embodiment of the present invention, in the general formula (II-1), L1 is selected from -CH2- or -CD2-; R1 is -(CH2) n5 O(CH2) n6 R A2 n5 is 1 or 2, n6 is 0, and R A2 is C 1-3 Alkyl group, C 1-3Deuterated alkyl group or C 1-3 selected from halogenated alkyl groups, R7 is selected from fluorine, chlorine, bromine, preferably chlorine; R8 is a methyl group, an ethyl group, or a cyclopropyl group, and is preferably a methyl group.

[0024] In a further preferred embodiment of the present invention, in the general formula (II-1), L1 is selected from -CH2- or -CD2-; R1 is [ka] and R7 is selected from fluorine, chlorine, bromine, preferably chlorine; R8 is a methyl group.

[0025] In a further preferred embodiment of the present invention, the compound, its stereoisomer or its pharmaceutically acceptable salt is further as shown in general formula (III): [ka] where: L2 is -(CH2) n2 C(O)NR c -, -(CH2) n2 C(O)NR c S(O) m2 -, -(CH2) n2 NR c C(O)-, -(CH2) n2 S(O) m2 -, -(CH2) n2 S(O) m2 NR c -, -(CH2) n2 S(O) m2 NR c C(O)-, -(CH2) n2 S(O) m2 NR c C(O)NR d -, -(CH2) n2 S(O) m2NR c C(O)O(CH2) n3 -, -(CH2) n2 NR c S(O) m2 -or-(CH2) n2 NR c S(O) m2 NR d C(O)-; R6 is hydrogen, deuterium, halogen, amino group, hydroxy group, cyano group, C 1-6 Alkyl group, C 2-6 Alkenyl group, C 2-6 Alkynyl group, C 1-6 Deuterated alkyl groups, C 1-6 Halogenated alkyl groups, C 1-6 Hydroxyalkyl group, C 1-6 Alkoxy group, C 1-6 Alkylthio group, C 1-6 Halogenated alkoxy groups, C 3-12 Cycloalkyl groups, 3- to 12-membered heterocyclyl groups, C 6-14 an aryl group or a 5- to 14-membered heteroaryl group, 1-6 Alkyl group, C 2-6 Alkenyl group, C 2-6 Alkynyl group, C 1-6 Deuterated alkyl groups, C 1-6 Halogenated alkyl groups, C 1-6 Hydroxyalkyl group, C 1-6 Alkoxy group, C 1-6 Alkylthio group, C 1-6 Halogenated alkoxy groups, C 3-12 Cycloalkyl groups, 3- to 12-membered heterocyclyl groups, C 6-14 The aryl group and the 5- to 14-membered heteroaryl group may optionally be substituted with deuterium, halogen, amino, hydroxy, cyano, oxo, thio, C 1-6 Alkyl group, C 2-6 Alkenyl group, C 2-6 Alkynyl group, C 1-6 Deuterated alkyl groups, C 1-6 Halogenated alkyl groups, C 1-6 Hydroxyalkyl group, C 1-6 Alkoxy group, C 1-6Alkylthio group, C 1-6 Halogenated alkoxy groups, C 3-12 Cycloalkyl groups, 3- to 12-membered heterocyclyl groups, C 6-14 further substituted with one or more substituents selected from the group consisting of aryl groups and 5- to 14-membered heteroaryl groups; R c and R d are each independently hydrogen, deuterium, halogen, amino group, hydroxy group, cyano group, C 1-6 Alkyl group, C 2-6 Alkenyl group, C 2-6 Alkynyl group, C 1-6 Deuterated alkyl groups, C 1-6 Halogenated alkyl groups, C 1-6 Hydroxyalkyl group, C 1-6 Alkoxy group, C 1-6 Alkylthio group, C 1-6 Halogenated alkoxy groups, C 3-12 Cycloalkyl groups, 3- to 12-membered heterocyclyl groups, C 6-14 an aryl group or a 5- to 14-membered heteroaryl group, 1-6 Alkyl group, C 2-6 Alkenyl group, C 2-6 Alkynyl group, C 1-6 Deuterated alkyl groups, C 1-6 Halogenated alkyl groups, C 1-6 Hydroxyalkyl group, C 1-6 Alkoxy group, C 1-6 Alkylthio group, C 1-6 Halogenated alkoxy groups, C 3-12 Cycloalkyl groups, 3- to 12-membered heterocyclyl groups, C 6-14 The aryl group and the 5- to 14-membered heteroaryl group may optionally be substituted with deuterium, halogen, amino, hydroxy, cyano, oxo, thio, C 1-6 Alkyl group, C 2-6 Alkenyl group, C 2-6 Alkynyl group, C 1-6 Deuterated alkyl groups, C 1-6 Halogenated alkyl groups, C 1-6 Hydroxyalkyl group, C 1-6 Alkoxy group, C 1-6 Alkylthio group, C1-6 Halogenated alkoxy groups, C 3-12 Cycloalkyl groups, 3- to 12-membered heterocyclyl groups, C 6-14 further substituted with one or more substituents selected from the group consisting of aryl groups and 5- to 14-membered heteroaryl groups; n2 and n3 are 0, 1, 2, or 3; m2 is 0, 1 or 2.

[0026] In a preferred embodiment of the present invention, L2 is -C(O)NR c -, -C(O)NR c S(O)2-, -NR c C(O)-, -S(O)2-, -S(O)2NR c -, -S(O)NR c C(O)-, -S(O)NR c C(O)NR d -, -S(O)NR c C(O)OCH2-, -NR c S(O)2- or -NR c S(O)NR d C(O)-; In a further preferred embodiment of the invention, L2 is selected from -C(O)NH-, -C(O)NHS(O)2-, -S(O)2NH-, -S(O)2NHC(O)-, -S(O)2NHC(O)NH-, -S(O)2NHC(O)O-, -S(O)2NHC(O)OCH2-, -NHS(O)2- or -NHS(O)2NHC(O)-; R c and R d are each independently hydrogen, deuterium, halogen, amino group, hydroxy group, cyano group, C 1-3 Alkyl group, C 2-3 Alkenyl group, C 2-3 Alkynyl group, C 1-3 Deuterated alkyl groups, C 1-3 Halogenated alkyl groups, C 1-3 Hydroxyalkyl group, C 1-3 Alkoxy group, C 1-3 Alkylthio group, C 1-3 Halogenated alkoxy groups, C 3-8Cycloalkyl groups, 3- to 8-membered heterocyclyl groups, C 6-10 an aryl group or a 5- to 10-membered heteroaryl group, 1-3 Alkyl group, C 2-3 Alkenyl group, C 2-3 Alkynyl group, C 1-3 Deuterated alkyl groups, C 1-3 Halogenated alkyl groups, C 1-3 Hydroxyalkyl group, C 1-3 Alkoxy group, C 1-3 Alkylthio group, C 1-3 Halogenated alkoxy groups, C 3-8 Cycloalkyl groups, 3- to 8-membered heterocyclyl groups, C 6-10 The aryl group and the 5- to 10-membered heteroaryl group may optionally be substituted with deuterium, halogen, amino, hydroxy, cyano, oxo, thio, C 1-3 Alkyl group, C 2-3 Alkenyl group, C 2-3 Alkynyl group, C 1-3 Deuterated alkyl groups, C 1-3 Halogenated alkyl groups, C 1-3 Hydroxyalkyl group, C 1-3 Alkoxy group, C 1-3 Alkylthio group, C 1-3 Halogenated alkoxy groups, C 3-8 Cycloalkyl groups, 3- to 8-membered heterocyclyl groups, C 6-10 It is further substituted with one or more substituents of an aryl group or a 5- to 10-membered heteroaryl group.

[0027] In a preferred embodiment of the present invention, R6 is an amino group, C 1-3 Alkyl group, C 2-3 Alkenyl group, C 2-3 Alkynyl group, C 1-3 Deuterated alkyl groups, C 1-3 Halogenated alkyl groups, C 1-3 Hydroxyalkyl group, C 1-3 Alkoxy group, C 1-3 Alkylthio group, C 1-3 Halogenated alkoxy groups, C 3-8 Cycloalkyl groups, 3- to 8-membered heterocyclyl groups, C6-10 an aryl group or a 5- to 10-membered heteroaryl group, 1-3 Alkyl group, C 2-3 Alkenyl group, C 2-3 Alkynyl group, C 1-3 Deuterated alkyl groups, C 1-3 Halogenated alkyl groups, C 1-3 Hydroxyalkyl group, C 1-3 Alkoxy group, C 1-3 Alkylthio group, C 1-3 Halogenated alkoxy groups, C 3-8 Cycloalkyl groups, 3- to 8-membered heterocyclyl groups, C 6-10 The aryl group and the 5- to 10-membered heteroaryl group may optionally be substituted with deuterium, halogen, amino, hydroxy, cyano, oxo, thio, C 1-3 Alkyl group, C 2-3 Alkenyl group, C 2-3 Alkynyl group, C 1-3 Deuterated alkyl groups, C 1-3 Halogenated alkyl groups, C 1-3 Hydroxyalkyl group, C 1-3 Alkoxy group, C 1-3 Alkylthio group, C 1-3 Halogenated alkoxy groups, C 3-8 Cycloalkyl groups, 3- to 8-membered heterocyclyl groups, C 6-10 further substituted with one or more substituents selected from the group consisting of an aryl group and a 5- to 10-membered heteroaryl group; In a further preferred embodiment of the present invention, R6 is selected from an amino group, a methyl group, an ethyl group, a propyl group, an isopropyl group, a cyclopropyl group, an oxazolyl group, an isoxazolyl group, a triazolyl group, a phenyl group, a pyridyl group, a pyrazinyl group, a tetrazolyl group, a dihydrotetrazolyl group, a 1,2,4-oxadiazole-5(2H)-ketone group, or a 5,6-dihydro-4H-cyclopenta[d]isoxazolyl group; and the amino group, the methyl group, the ethyl group, the oxazolyl group, the isoxazolyl group, the triazolyl group, the phenyl group, the pyridyl group, the pyrazinyl group, the tetrazolyl group, the dihydrotetrazolyl group, the 1,2,4-oxadiazole-5(2H)-ketone group, or the 5,6-dihydro-4H-cyclopenta[d]isoxazolyl group. , propyl group, isopropyl group, cyclopropyl group, oxazolyl group, isoxazolyl group, triazolyl group, phenyl group, pyridyl group, pyrazinyl group, tetrazolyl group, dihydrotetrazolyl group, 1,2,4-oxadiazole-5(2H)-ketone group or 5,6-dihydro-4H-cyclopenta[d]isoxazolyl group is optionally further substituted with one or more substituents of oxo group, methyl group, ethyl group, propyl group or cyclopropyl group.

[0028] In a further preferred embodiment of the present invention, the compound, its stereoisomer or its pharmaceutically acceptable salt is further represented by general formula (IV): [ka] R1 is hydrogen, deuterium, halogen, amino group, hydroxy group, cyano group, C 1-6 Alkyl group, C 2-6 Alkenyl group, C 2-6 Alkynyl group, C 1-6 Deuterated alkyl groups, C 1-6 Halogenated alkyl groups, C 1-6 Hydroxyalkyl group, C 1-6 Alkoxy group, C 1-6 Alkylthio group, C 1-6 Halogenated alkoxy groups, C 3-12 Cycloalkyl groups, 3- to 12-membered heterocyclyl groups, C 6-14 Aryl group, 5- to 14-membered heteroaryl group, -(CH2) n5 R A2 , -(CH2) n5 O(CH2) n6 R A2, -(CH2) n5 C(O)R A2 , -(CH2) n5 NR A2 C(O)R B2 , -(CH2) n5 C(O)NR A2 R B2 , -(CH2) n5 OC(O)NR A2 R B2 or -(CH2) n5 NR A2 C(O)OR B2 wherein C is selected from 1-6 Alkyl group, C 2-6 Alkenyl group, C 2-6 Alkynyl group, C 1-6 Deuterated alkyl groups, C 1-6 Halogenated alkyl groups, C 1-6 Hydroxyalkyl group, C 1-6 Alkoxy group, C 1-6 Alkylthio group, C 1-6 Halogenated alkoxy groups, C 3-12 Cycloalkyl groups, 3- to 12-membered heterocyclyl groups, C 6-14 The aryl group and the 5- to 14-membered heteroaryl group may optionally be substituted with deuterium, halogen, amino, hydroxy, cyano, oxo, thio, C 1-6 Alkyl group, C 2-6 Alkenyl group, C 2-6 Alkynyl group, C 1-6 Deuterated alkyl groups, C 1-6 Halogenated alkyl groups, C 1-6 Hydroxyalkyl group, C 1-6 Alkoxy group, C 1-6 Alkylthio group, C 1-6 Halogenated alkoxy groups, C 3-12 Cycloalkyl groups, 3- to 12-membered heterocyclyl groups, C 6-14 further substituted with one or more substituents selected from the group consisting of aryl groups and 5- to 14-membered heteroaryl groups; Preferably, hydrogen, -CH3, -CH2CH3, [ka] and R7 is selected from halogens, preferably fluorine, chlorine, and bromine.

[0029] In a further preferred embodiment of the present invention, the compound, its stereoisomer or its pharmaceutically acceptable salt is further represented by general formula (V): [ka] R9 and R 10 are each independently hydrogen, deuterium, halogen, amino group, nitro group, hydroxy group, cyano group, oxo group, thio group, C 1-6 Alkyl group, C 1-6 Deuterated alkyl groups, C 1-6 Halogenated alkyl groups, C 1-6 Hydroxyalkyl group, C 1-6 Alkoxy group, C 1-6 Halogenated alkoxy groups, C 2-6 Alkenyl group, C 2-6 Alkynyl group, C 3-12 Cycloalkyl groups, 3- to 12-membered heterocyclyl groups, C 6-14 Aryl group, 5- to 12-membered heteroaryl group, -(CH2) n4 C(O)R A1 , -(CH2) n4 C(O)OR A1 , -(CH2) n4 C(O)NR A1 R B1 or -(CH2) n4 C(=S)NR A1 R B1 wherein the amino group, C 1-6 Alkyl group, C 1-6 Deuterated alkyl groups, C 1-6 Halogenated alkyl groups, C 1-6 Hydroxyalkyl group, C 1-6 Alkoxy group, C 1-6 Halogenated alkoxy groups, C 2-6 Alkenyl group, C 2-6 Alkynyl group, C 3-12 Cycloalkyl groups, 3- to 12-membered heterocyclyl groups, C 6-14The aryl group, the 5- to 12-membered heteroaryl group may be optionally further substituted, and R A1 and R B1 are each independently hydrogen, deuterium, halogen, amino group, nitro group, hydroxy group, cyano group, C 1-6 Alkyl group, C 1-6 Deuterated alkyl groups, C 1-6 Halogenated alkyl groups, C 1-6 Hydroxyalkyl group, C 1-6 Alkoxy group, C 1-6 Halogenated alkoxy groups, C 2-6 Alkenyl group, C 2-6 Alkynyl group, C 3-12 Cycloalkyl groups, 3- to 12-membered heterocyclyl groups, C 6-14 an aryl group, a 5- to 12-membered heteroaryl group, and the amino group, C 1-6 Alkyl group, C 1-6 Deuterated alkyl groups, C 1-6 Halogenated alkyl groups, C 1-6 Hydroxyalkyl group, C 1-6 Alkoxy group, C 1-6 Halogenated alkoxy groups, C 2-6 Alkenyl group, C 2-6 Alkynyl group, C 3-12 Cycloalkyl groups, 3- to 12-membered heterocyclyl groups, C 6-14 The aryl group and the 5- to 12-membered heteroaryl group may optionally be further substituted. Preferably, an amino group, a nitro group, a hydroxy group, a cyano group, an oxo group, C 1-6 Alkyl group, C 1-6 Hydroxyalkyl group, -(CH2) n4 C(O)OR A1 , and (CH2) n4 C(=S)NR A1 R B1 Selected from R A1 and R B1 are each independently hydrogen, C 1-6 alkyl groups, More preferably, an oxo group, C 1-4 Alkyl group, C 1-3 Hydroxyalkyl group, -(CH2)n4 C(O)OR A1 , and (CH2) n4 C(=S)NR A1 R B1 Selected from R A1 and R B1 are each independently hydrogen, C 1-6 alkyl groups, Most preferably, it is a methyl group, an ethyl group, a propyl group, a carboxyl group, [ka] is selected from R1 is hydrogen, deuterium, halogen, amino group, hydroxy group, cyano group, C 1-6 Alkyl group, C 2-6 Alkenyl group, C 2-6 Alkynyl group, C 1-6 Deuterated alkyl groups, C 1-6 Halogenated alkyl groups, C 1-6 Hydroxyalkyl group, C 1-6 Alkoxy group, C 1-6 Alkylthio group, C 1-6 Halogenated alkoxy groups, C 3-12 Cycloalkyl groups, 3- to 12-membered heterocyclyl groups, C 6-14 Aryl group, 5- to 14-membered heteroaryl group, -(CH2) n5 R A2 , -(CH2) n5 O(CH2) n6 R A2 , -(CH2) n5 C(O)R A2 , -(CH2) n5 NR A2 C(O)R B2 , -(CH2) n5 C(O)NR A2 R B2 , -(CH2) n5 OC(O)NR A2 R B2 or -(CH2) n5 NR A2 C(O)OR B2 wherein C is selected from 1-6 Alkyl group, C 2-6 Alkenyl group, C2-6 Alkynyl group, C 1-6 Deuterated alkyl groups, C 1-6 Halogenated alkyl groups, C 1-6 Hydroxyalkyl group, C 1-6 Alkoxy group, C 1-6 Alkylthio group, C 1-6 Halogenated alkoxy groups, C 3-12 Cycloalkyl groups, 3- to 12-membered heterocyclyl groups, C 6-14 The aryl group and the 5- to 14-membered heteroaryl group may optionally be substituted with deuterium, halogen, amino, hydroxy, cyano, oxo, thio, C 1-6 Alkyl group, C 2-6 Alkenyl group, C 2-6 Alkynyl group, C 1-6 Deuterated alkyl groups, C 1-6 Halogenated alkyl groups, C 1-6 Hydroxyalkyl group, C 1-6 Alkoxy group, C 1-6 Alkylthio group, C 1-6 Halogenated alkoxy groups, C 3-12 Cycloalkyl groups, 3- to 12-membered heterocyclyl groups, C 6-14 further substituted with one or more substituents selected from the group consisting of aryl groups and 5- to 14-membered heteroaryl groups; Preferably, hydrogen, -CH3, -CH2CH3, [ka] and R7 is hydrogen, deuterium, halogen, amino group, hydroxy group, cyano group, C 1-3 Alkyl group, C 2-3 Alkenyl group, C 2-3 Alkynyl group, C 1-3 Deuterated alkyl groups, C 1-3 Halogenated alkyl groups, C 1-3 Hydroxyalkyl group, C 1-3 Alkoxy group, C 1-3 Alkylthio group, C 1-3 Halogenated alkoxy groups, C 3-8 Cycloalkyl groups, 3- to 8-membered heterocyclyl groups, C 6-10an aryl group or a 5- to 10-membered heteroaryl group; Preferably, it is a deuterium, a fluorine, a chlorine, a bromine or a methyl group; R8 is hydrogen, deuterium, halogen, amino group, hydroxy group, cyano group, C 1-3 Alkyl group, C 2-3 Alkenyl group, C 2-3 Alkynyl group, C 1-3 Deuterated alkyl groups, C 1-3 Halogenated alkyl groups, C 1-3 Hydroxyalkyl group, C 1-3 Alkoxy group, C 1-3 Alkylthio group, C 1-3 Halogenated alkoxy groups, C 3-8 Cycloalkyl groups, 3- to 8-membered heterocyclyl groups, C 6-10 an aryl group or a 5- to 10-membered heteroaryl group; Preferably, it is characterized by being a methyl group, an ethyl group, or a cyclopropyl group.

[0030] The present invention further provides a compound represented by general formula (VI), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof: [ka] L1 is -(CR a R b ) n1 -, -(CR a R b ) n1 O-, -O(CR a R b ) n1 -, -(CR a R b ) n1 S-, -S(CR a R b ) n1 -, -(CH2) n1 C(O)NR a -, -(CH2) n1 NR a C(O)-, -(CH2) n1 S(O) m1 -, -(CH2) n1 S(O) m1 NRa -, -(CH2) n1 NR a S(O) m1 -or-(CH2) n1 NR a - selected from -CRaRb-, -CRaRbO-, -OCRaRb-, -CRaRbS- or -SCRaRb- is preferred. More preferably, it is -CH2- or -CD2-. R1 is hydrogen, deuterium, halogen, amino group, hydroxy group, cyano group, C 1-6 Alkyl group, C 2-6 Alkenyl group, C 2-6 Alkynyl group, C 1-6 Deuterated alkyl groups, C 1-6 Halogenated alkyl groups, C 1-6 Hydroxyalkyl group, C 1-6 Alkoxy group, C 1-6 Alkylthio group, C 1-6 Halogenated alkoxy groups, C 3-12 Cycloalkyl groups, 3- to 12-membered heterocyclyl groups, C 6-14 Aryl group, 5- to 14-membered heteroaryl group, -(CH2) n5 R A2 , -(CH2) n5 O(CH2) n6 R A2 , -(CH2) n5 C(O)R A2 , -(CH2) n5 NR A2 C(O)R B2 , -(CH2) n5 C(O)NR A2 R B2 , -(CH2) n5 OC(O)NR A2 R B2 or -(CH2) n5 NR A2 C(O)OR B2 wherein C is selected from 1-6 Alkyl group, C 2-6 Alkenyl group, C 2-6 Alkynyl group, C 1-6 Deuterated alkyl groups, C 1-6 Halogenated alkyl groups, C1-6 Hydroxyalkyl group, C 1-6 Alkoxy group, C 1-6 Alkylthio group, C 1-6 Halogenated alkoxy groups, C 3-12 Cycloalkyl groups, 3- to 12-membered heterocyclyl groups, C 6-14 The aryl group and the 5- to 14-membered heteroaryl group may optionally be substituted with deuterium, halogen, amino, hydroxy, cyano, oxo, thio, C 1-6 Alkyl group, C 2-6 Alkenyl group, C 2-6 Alkynyl group, C 1-6 Deuterated alkyl groups, C 1-6 Halogenated alkyl groups, C 1-6 Hydroxyalkyl group, C 1-6 Alkoxy group, C 1-6 Alkylthio group, C 1-6 Halogenated alkoxy groups, C 3-12 Cycloalkyl groups, 3- to 12-membered heterocyclyl groups, C 6-14 further substituted with one or more substituents selected from the group consisting of aryl groups and 5- to 14-membered heteroaryl groups; Preferably, hydrogen, -CH3, -CH2CH3, [ka] and More preferably, hydrogen, -CH3, -CH2CH3 or [ka] and R7 is hydrogen, deuterium, halogen, amino group, hydroxy group, cyano group, C 1-3 Alkyl group, C 2-3 Alkenyl group, C 2-3 Alkynyl group, C 1-3 Deuterated alkyl groups, C 1-3 Halogenated alkyl groups, C 1-3 Hydroxyalkyl group, C 1-3 Alkoxy group, C 1-3 Alkylthio group, C 1-3 Halogenated alkoxy groups, C 3-8Cycloalkyl groups, 3- to 8-membered heterocyclyl groups, C 6-10 an aryl group or a 5- to 10-membered heteroaryl group; Preferably, it is a deuterium, a fluorine, a chlorine, a bromine or a methyl group; R8 is hydrogen, deuterium, halogen, amino group, hydroxy group, cyano group, C 1-3 Alkyl group, C 2-3 Alkenyl group, C 2-3 Alkynyl group, C 1-3 Deuterated alkyl groups, C 1-3 Halogenated alkyl groups, C 1-3 Hydroxyalkyl group, C 1-3 Alkoxy group, C 1-3 Alkylthio group, C 1-3 Halogenated alkoxy groups, C 3-8 Cycloalkyl groups, 3- to 8-membered heterocyclyl groups, C 6-10 an aryl group or a 5- to 10-membered heteroaryl group; Preferably, it is a methyl group, an ethyl group, or a cyclopropyl group.

[0031] The present invention further provides a compound represented by general formula (VII), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof: [ka] L1 is -(CR a R b ) n1 -, -(CR a R b ) n1 O-, -O(CR a R b ) n1 -, -(CR a R b ) n1 S-, -S(CR a R b ) n1 -, -(CH2) n1 C(O)NR a -, -(CH2) n1 NR a C(O)-, -(CH2) n1 S(O) m1 -, -(CH2)n1 S(O) m1 NR a -, -(CH2) n1 NR a S(O) m1 -or-(CH2) n1 NR a - selected from Preferably, -CR a R b -, -CR a R b O-, -OCR a R b -, -CR a R b S- or -SCR a R b - and More preferably, it is -CH2- or -CD2-. R1 is hydrogen, deuterium, halogen, amino group, hydroxy group, cyano group, C 1-6 Alkyl group, C 2-6 Alkenyl group, C 2-6 Alkynyl group, C 1-6 Deuterated alkyl groups, C 1-6 Halogenated alkyl groups, C 1-6 Hydroxyalkyl group, C 1-6 Alkoxy group, C 1-6 Alkylthio group, C 1-6 Halogenated alkoxy groups, C 3-12 Cycloalkyl groups, 3- to 12-membered heterocyclyl groups, C 6-14 Aryl group, 5- to 14-membered heteroaryl group, -(CH2) n5 R A2 , -(CH2) n5 O(CH2) n6 R A2 , -(CH2) n5 C(O)R A2 , -(CH2) n5 NR A2 C(O)R B2 , -(CH2) n5 C(O)NR A2 R B2 , -(CH2) n5 OC(O)NR A2 R B2 or -(CH2) n5 NRA2 C(O)OR B2 wherein C is selected from 1-6 Alkyl group, C 2-6 Alkenyl group, C 2-6 Alkynyl group, C 1-6 Deuterated alkyl groups, C 1-6 Halogenated alkyl groups, C 1-6 Hydroxyalkyl group, C 1-6 Alkoxy group, C 1-6 Alkylthio group, C 1-6 Halogenated alkoxy groups, C 3-12 Cycloalkyl groups, 3- to 12-membered heterocyclyl groups, C 6-14 The aryl group and the 5- to 14-membered heteroaryl group may optionally be substituted with deuterium, halogen, amino, hydroxy, cyano, oxo, thio, C 1-6 Alkyl group, C 2-6 Alkenyl group, C 2-6 Alkynyl group, C 1-6 Deuterated alkyl groups, C 1-6 Halogenated alkyl groups, C 1-6 Hydroxyalkyl group, C 1-6 Alkoxy group, C 1-6 Alkylthio group, C 1-6 Halogenated alkoxy groups, C 3-12 Cycloalkyl groups, 3- to 12-membered heterocyclyl groups, C 6-14 further substituted with one or more substituents selected from the group consisting of aryl groups and 5- to 14-membered heteroaryl groups; Preferably, hydrogen, -CH3, -CH2CH3, [ka] and More preferably, hydrogen, -CH3, -CH2CH3 or [ka] and R7 is hydrogen, deuterium, halogen, amino group, hydroxy group, cyano group, C 1-3 Alkyl group, C 2-3 Alkenyl group, C 2-3 Alkynyl group, C 1-3Deuterated alkyl groups, C 1-3 Halogenated alkyl groups, C 1-3 Hydroxyalkyl group, C 1-3 Alkoxy group, C 1-3 Alkylthio group, C 1-3 Halogenated alkoxy groups, C 3-8 Cycloalkyl groups, 3- to 8-membered heterocyclyl groups, C 6-10 an aryl group or a 5- to 10-membered heteroaryl group; Preferably, it is a deuterium, a fluorine, a chlorine, a bromine or a methyl group; R8 is hydrogen, deuterium, halogen, amino group, hydroxy group, cyano group, C 1-3 Alkyl group, C 2-3 Alkenyl group, C 2-3 Alkynyl group, C 1-3 Deuterated alkyl groups, C 1-3 Halogenated alkyl groups, C 1-3 Hydroxyalkyl group, C 1-3 Alkoxy group, C 1-3 Alkylthio group, C 1-3 Halogenated alkoxy groups, C 3-8 Cycloalkyl groups, 3- to 8-membered heterocyclyl groups, C 6-10 an aryl group or a 5- to 10-membered heteroaryl group; Preferably, it is a methyl group, an ethyl group, or a cyclopropyl group.

[0032] In some embodiments of the present invention, the compound, its stereoisomer, or its pharmaceutically acceptable salt is such that R7 and R8 are both methyl groups, and R1 is [ka] If not, then R1 [ka] is selected from R7 and R8 are both methyl groups, and R1 is [ka] In the case where L1 contains deuterium, or at least one of X1, X2, or X3 is N, or R 3 is not hydrogen.

[0033] In a further preferred embodiment of the present invention, the compound, its stereoisomer or a pharmaceutically acceptable salt thereof is [ka] [ka] [ka] [ka] [ka] The compound is selected from the following compounds:

[0034] The present invention further provides a compound represented by general formula (M-1) or (M-2), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof: [ka] wherein L1, X1, X2, X3, R1, R7, and R8 are as described above; R9 is a halogen or [ka] is selected from, preferably bromine, chlorine or [ka] and Pg is selected from amino protecting groups, preferably a (trimethylsilyl)ethoxymethyl group, a methoxymethyl ether group, an allyloxycarbonyl group, a trifluoroacetyl group, a 2,4-dimethoxybenzyl group, a nitrobenzenesulfonyl group, a trityl group, a fluorenemethoxycarbonyl group, a p-toluenesulfonyl group, a formate ester, an acetyl group, a benzyloxycarbonyl group, a tert-butoxycarbonyl group, a benzyl group, or a p-methoxyphenyl group, and more preferably a (trimethylsilyl)ethoxymethyl or a methoxymethyl ether group.

[0035] In one embodiment of the present invention, L1 is selected from -CH2- or -CD2- and R1 is [ka] and R9 is [ka] and Pg is selected from (trimethylsilyl)ethoxymethyl or methoxymethyl ether groups.

[0036] The present invention further provides a method for preparing the compound of general formula (II) or its stereoisomer and its pharmaceutically acceptable salt, comprising the steps of: [ka] General formula (M-1) is reacted with general formula (M-3) to obtain general formula (M-2), and general formula (M-2) is deprotected to obtain general formula (II), wherein L1, X1, X2, X3, R1, R7, and R8 are as described above; R 2’ teeth, [ka] or halogen, preferably [ka] , chlorine or bromine; R9 is [ka] or halogen, preferably [ka] , chlorine or bromine; Pg is selected from amino-protecting groups, preferably a (trimethylsilyl)ethoxymethyl group, a methoxymethyl ether group, an allyloxycarbonyl group, a trifluoroacetyl group, a 2,4-dimethoxybenzyl group, a nitrobenzenesulfonyl group, a trityl group, a fluorenemethoxycarbonyl group, a p-toluenesulfonyl group, a formate ester, an acetyl group, a benzyloxycarbonyl group, a tert-butoxycarbonyl group, a benzyl group, or a p-methoxyphenyl group, and more preferably a (trimethylsilyl)ethoxymethyl group or a methoxymethyl ether group.

[0037] The present invention further provides a method for preparing the compound of general formula (II) or its stereoisomer and its pharmaceutically acceptable salt, comprising the steps of: [ka] General formula (M-4) is reacted with general formula (M-5) to obtain general formula (M-2), and general formula (M-2) is deprotected to obtain general formula (II), wherein L1, X1, X2, X3, R1, R7, and R8 are as described above; R 1’ is selected from methanesulfonyloxy or halogen, preferably methanesulfonyloxy or bromine; Pg is selected from amino-protecting groups, preferably a (trimethylsilyl)ethoxymethyl group, a methoxymethyl ether group, an allyloxycarbonyl group, a trifluoroacetyl group, a 2,4-dimethoxybenzyl group, a nitrobenzenesulfonyl group, a trityl group, a fluorenemethoxycarbonyl group, a p-toluenesulfonyl group, a formate ester, an acetyl group, a benzyloxycarbonyl group, a tert-butoxycarbonyl group, a benzyl group, or a p-methoxyphenyl group, and more preferably a (trimethylsilyl)ethoxymethyl group or a methoxymethyl ether group.

[0038] The present invention further relates to pharmaceutical compositions, which comprise a therapeutically effective amount of a compound of general formula (I), its stereoisomer or a pharmaceutically acceptable salt thereof and one or more pharmaceutically acceptable carriers, diluents or excipients.

[0039] In another aspect, the object of the present invention is further to provide the use of a compound comprising the description of general formula (I), its stereoisomer or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, in the manufacture of a medicament for treating and / or preventing angiotensin II (AT)-dependent diseases.

[0040] In another aspect, the object of the present invention is further to provide the use of a compound comprising the description of general formula (I), its stereoisomer or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, in the manufacture of a medicament for treating and / or preventing an endothelin (ET)-dependent disease.

[0041] In another aspect, the object of the present invention is further to provide the use of a compound comprising the description of general formula (I), its stereoisomer or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, in the manufacture of a medicament for treating and / or preventing dual-acting angiotensin-dependent and endothelin (DARA)-dependent diseases.

[0042] In another aspect, it is a further object of the present invention to provide the use of a compound comprising the description of general formula (I), its stereoisomer or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, in the manufacture of a medicament for the treatment and / or prevention of pain, sexual dysfunction, hypoxic and ischemic diseases, dementia, neurological diseases, liver diseases, cancer, hypertension, diabetes or related diseases such as kidney diseases.

[0043] The present invention further relates to methods for treating and / or preventing pain, sexual dysfunction, hypoxic and ischemic diseases, dementia, neurological diseases, liver diseases, cancer, hypertension, diabetes or related diseases such as kidney diseases.

[0044] In another aspect, it is a further object of the present invention to provide the use of a compound comprising the description of general formula (I), its stereoisomer or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, in the treatment and / or prevention of pain, sexual dysfunction, hypoxic and ischemic diseases, dementia, neurological diseases, liver diseases, cancer, hypertension, diabetes or related diseases such as kidney diseases.

[0045] In the above technical solutions, the kidney-related disease is selected from diseases or conditions related to the function of the kidney, glomerulus, or glomerular system mesangial cells, and is more preferably focal segmental glomerulosclerosis or IgA nephropathy.

[0046] Unless stated to the contrary, terms used in the specification and claims have the following meanings.

[0047] The term "alkyl group" refers to a saturated aliphatic hydrocarbon group, which is a straight-chain or branched-chain group containing 1 to 20 carbon atoms, preferably an alkyl group containing 1 to 12 carbon atoms, more preferably an alkyl group containing 1 to 8 carbon atoms, even more preferably an alkyl group containing 1 to 6 carbon atoms, and most preferably an alkyl group containing 1 to 3 carbon atoms. Non-limiting examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2-methylpropyl, 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1,3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2,3-dimethylbutyl, n-heptyl, 4-heptyl, 1-propylbutyl, 2-methylhexyl, 3-methylhexyl, 4-methylhexyl, 5 ... -methylhexyl group, 2,3-dimethylpentyl group, 2,4-dimethylpentyl group, 2,2-dimethylpentyl group, 3,3-dimethylpentyl group, 2-ethylpentyl group, 3-ethylpentyl group, n-octyl group, 2,3-dimethylhexyl group, 2,4-dimethylhexyl group, 2,5-dimethylhexyl group, 2,2-dimethylhexyl group, 3,3-dimethylhexyl group, 4,4-dimethylhexyl group, Examples include 2-ethylhexyl, 3-ethylhexyl, 4-ethylhexyl, 2-methyl-2-ethylpentyl, 2-methyl-3-ethylpentyl, n-nonyl, 2-methyl-2-ethylhexyl, 2-methyl-3-ethylhexyl, 2,2-diethylpentyl, n-decyl, 3,3-diethylhexyl, 2,2-diethylhexyl, and various branched chain isomers thereof.More preferred are lower alkyl groups containing 1 to 6 carbon atoms, and non-limiting examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, n-heptyl, 4-heptyl, 1-propylbutyl, 1-ethyl-2-methylpropyl, 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1,3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, and 2,3-dimethylbutyl. The alkyl group may be substituted or unsubstituted. When substituted, the substituent may be substituted at any available bonding site, and the substituent is preferably one or more groups independently selected from alkyl groups, alkenyl groups, alkynyl groups, alkoxy groups, alkylthio groups, alkylamino groups, halogens, mercapto groups, hydroxy groups, nitro groups, cyano groups, cycloalkyl groups, heterocycloalkyl groups, aryl groups, heteroaryl groups, cycloalkoxy groups, heterocycloalkoxy groups, cycloalkylthio groups, heterocycloalkylthio groups, oxo groups, carboxyl groups, and carboxylate groups, and in the present invention, is preferably a methyl group, an ethyl group, an isopropyl group, a tert-butyl group, a halogenated alkyl group, a deuterated alkyl group, an alkyl group substituted with an alkoxy group, and an alkyl group substituted with a hydroxy group.

[0048] The term "cycloalkyl group" refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent, wherein the ring of the cycloalkyl group contains 3 to 20 carbon atoms, preferably 3 to 12 carbon atoms, and more preferably 3 to 6 carbon atoms. Non-limiting examples of monocyclic cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cycloheptatrienyl, cyclooctyl, etc. Polycyclic cycloalkyl groups include spirocyclic, fused-ring, and bridged-ring cycloalkyl groups, preferably cyclopropyl, cyclobutyl, cyclohexyl, cyclopentyl, and cycloheptyl.

[0049] The ring of the cycloalkyl group can be fused onto the ring of an aryl group, heteroaryl group, or heterocycloalkyl group, where the ring connected to the base skeleton is a cycloalkyl group, non-limiting examples include an indanyl group, a tetrahydronaphthyl group, a benzocycloheptyl group, etc. The cycloalkyl group can be optionally substituted or unsubstituted, and when substituted, the substituents are preferably one or more groups independently selected from alkyl groups, alkenyl groups, alkynyl groups, alkoxy groups, alkylthio groups, alkylamino groups, halogens, mercapto groups, hydroxy groups, nitro groups, cyano groups, cycloalkyl groups, heterocycloalkyl groups, aryl groups, heteroaryl groups, cycloalkoxy groups, heterocycloalkoxy groups, cycloalkylthio groups, heterocycloalkylthio groups, oxo groups, carboxyl groups, and carboxylate groups.

[0050] The term "heterocyclyl group" refers to a saturated or partially unsaturated mono- or polycyclic cyclic hydrocarbon substituent containing 3 to 20 ring atoms, wherein one or more of the ring atoms is nitrogen, oxygen, C(O), or S(O). m(where m is an integer of 0 to 2), but does not include the ring moiety -OO-, -OS-, or -SS-, and the other ring atoms are carbon. Preferably, the heterocyclyl group contains 3 to 12 ring atoms, of which 1 to 4 are heteroatoms, more preferably 3 to 8 ring atoms, most preferably 3 to 8 ring atoms, and even more preferably 3 to 8-membered heterocyclyl groups containing 1 to 3 nitrogen atoms, optionally substituted with 1 to 2 oxygen atoms, sulfur atoms, or oxo groups, and includes nitrogen-containing monocyclic heterocyclyl groups, nitrogen-containing spiroheterocyclyl groups, and nitrogen-containing fused heterocyclyl groups.

[0051] Non-limiting examples of monocyclic heterocyclyl groups include oxetanyl, azetidinyl, thietanyl, pyrrolidinyl, imidazolidinyl, tetrahydrofuryl, tetrahydrothienyl, tetrahydropyranyl, dihydroimidazolyl, dihydrofuryl, dihydropyrazolyl, dihydropyrrolyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, homopiperazinyl, azepanyl, 1,4-diazacycloheptyl, pyranyl, or tetrahydrothiopyran dioxide groups, and preferably oxetanyl, azetidinyl, thietanyl, tetrahydrofuryl, tetrahydrothienyl, or tetrahydropyranyl. Examples of the alkyl group include tetrahydropyranyl, tetrahydrothienyl, tetrahydrothiopyranyl, tetrahydrothiopyran dioxide, pyrrolidinyl, morpholinyl, piperidinyl, piperazinyl, hexahydropyrazinyl, hexahydropyrimidinyl, azepanyl, 1,4-diazacycloheptyl, and piperazinyl, and more preferably piperidinyl, piperazinyl, pyrrolidinyl, morpholinyl, azetidinyl, dihydrotetrazolyl, pyrimidin-4(3H)-one, 1,2,4-oxadiazol-5(2H)-one, and 5,6-dihydro-4H-cyclopenta[d]isoxazole. Polycyclic heterocyclyl groups include spirocyclic, fused-ring, and bridged-ring heterocyclyl groups, where such spirocyclic, fused-ring, and bridged-ring heterocyclyl groups are optionally linked to other groups via a single bond or further tandemly linked to other cycloalkyl, heterocyclyl, aryl, and heteroaryl groups via any two or more atoms on the ring.

[0052] Heterocyclyl groups may be optionally substituted or unsubstituted, and if substituted, the substituents are preferably one or more groups independently selected from alkyl groups, alkenyl groups, alkynyl groups, alkoxy groups, alkylthio groups, alkylamino groups, halogens, mercapto groups, hydroxy groups, nitro groups, cyano groups, cycloalkyl groups, heterocycloalkyl groups, aryl groups, heteroaryl groups, cycloalkoxy groups, heterocycloalkoxy groups, cycloalkylthio groups, heterocycloalkylthio groups, oxo groups, carboxyl groups, or carboxylate groups.

[0053] The term "aryl group" refers to a 6- to 14-membered all-carbon monocyclic or fused polycyclic (i.e., rings sharing adjacent pairs of carbon atoms) group having a conjugated π-electron system, preferably 6- to 12-membered, such as a phenyl group or a naphthyl group. A phenyl group is more preferred.

[0054] The aryl group may be substituted or unsubstituted, and if substituted, the substituents are preferably one or more groups independently selected from alkyl groups, alkenyl groups, alkynyl groups, alkoxy groups, alkylthio groups, alkylamino groups, halogens, mercapto groups, hydroxy groups, nitro groups, cyano groups, cycloalkyl groups, heterocycloalkyl groups, aryl groups, heteroaryl groups, cycloalkoxy groups, heterocycloalkoxy groups, cycloalkylthio groups, heterocycloalkylthio groups, carboxyl groups, or carboxylate groups.

[0055] The term "heteroaryl group" refers to a heteroaromatic system containing 1 to 4 heteroatoms and 5 to 14 ring atoms, where the heteroatoms are oxygen, sulfur, and nitrogen. The heteroaryl group is preferably 5- to 12-membered, and more preferably 5- or 6-membered, and examples thereof include an imidazolyl group, a furyl group, a thienyl group, a thiazolyl group, a pyrazolyl group, an oxazolyl group, a pyrrolyl group, a triazolyl group, a tetrazolyl group, a pyridyl group, a pyrimidinyl group, a thiadiazole group, and a pyrazinyl group. Preferred are a pyridyl group, a pyrazinyl group, an oxadiazolyl group, a triazolyl group, a tetrazolyl group, a thienyl group, an imidazolyl group, a pyrazolyl group, an oxazolyl group, a thiazolyl group, a pyrimidinyl group, and a thiazolyl group. More preferred are a pyridyl group, an oxadiazolyl group, a pyrazolyl group, a pyrazinyl group, an isoxazolyl group, a triazolyl group, a tetrazolyl group, a pyrrolyl group, a thiazolyl group, and an oxazolyl group.

[0056] Heteroaryl groups may be optionally substituted or unsubstituted, and if substituted, the substituents are preferably one or more groups independently selected from alkyl groups, alkenyl groups, alkynyl groups, alkoxy groups, alkylthio groups, alkylamino groups, halogens, mercapto groups, hydroxy groups, nitro groups, cyano groups, cycloalkyl groups, heterocycloalkyl groups, aryl groups, heteroaryl groups, cycloalkoxy groups, heterocycloalkoxy groups, cycloalkylthio groups, heterocycloalkylthio groups, carboxyl groups, or carboxylate groups.

[0057] The term "alkoxy group" refers to -O-(alkyl group) and -O-(unsubstituted cycloalkyl group), where alkyl group is as defined above. Non-limiting examples of alkoxy groups include methoxy, ethoxy, propoxy, butoxy, cyclopropoxy, cyclobutoxy, cyclopentyloxy, or cyclohexyloxy groups. An alkoxy group may be optionally substituted or unsubstituted, and if substituted, the substituents are preferably one or more groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, carboxyl, or carboxylate groups.

[0058] "Halogenated alkyl group" refers to an alkyl group that is substituted with one or more halogens, where alkyl group is as defined above.

[0059] A "halogenated alkoxy group" refers to an alkoxy group substituted with one or more halogens, where alkoxy groups are as defined above.

[0060] "Hydroxyalkyl group" refers to an alkyl group substituted with one or more hydroxy groups, where alkyl group is as defined above.

[0061] "Hydroxy" refers to an -OH group.

[0062] "Halogen" refers to fluorine, chlorine, bromine or iodine.

[0063] An "amino group" refers to -NH2.

[0064] A "cyano group" refers to -CN.

[0065] A "nitro group" refers to -NO2.

[0066] A "carbonyl group" refers to -C(O)-.

[0067] A "carboxyl group" refers to -C(O)OH.

[0068] "THF" refers to tetrahydrofuran.

[0069] "Ethyl acetate" refers to ethyl acetate.

[0070] "MeOH" refers to methanol.

[0071] "DMF" refers to N,N-dimethylcarboxamide.

[0072] "DIPEA" refers to diisopropylethylamine.

[0073] "TFA" refers to trifluoroacetic acid.

[0074] "TEA" refers to triethylamine.

[0075] "MeCN" refers to acetonitrile.

[0076] "DMA" refers to N,N-dimethylacetamide.

[0077] "Et2O" refers to ether.

[0078] "DCM" refers to dichloromethane;

[0079] "DMAP" refers to 4-dimethylaminopyridine.

[0080] "DCC" refers to dicyclohexylcarbodiimide.

[0081] "DCE" refers to 1,2 dichloroethane.

[0082] "DIPEA" refers to N,N-diisopropylethylamine.

[0083] "NBS" refers to N-bromosuccinimide.

[0084] "NIS" refers to N-iodosuccinimide.

[0085] "Cbz-Cl" refers to benzyl chloroformate.

[0086] "Pd2(dba)3" refers to tri(dibenzylideneacetone)dipalladium.

[0087] "Dppf" refers to 1,1'-bisdiphenylphosphinoferrocene.

[0088] "HATU" refers to 2-(7-azabenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate.

[0089] "KHMDS" refers to potassium hexamethyldisilazane.

[0090] "LiHMDS" refers to lithium bistrimethylsilylamide.

[0091] "MeLi" refers to methyllithium.

[0092] "n-BuLi" refers to n-butyllithium.

[0093] "NaBH(OAc)3" refers to sodium triacetoxyborohydride.

[0094] "SEM" refers to (trimethylsilyl)ethoxymethyl.

[0095] "MOM" refers to a methoxymethyl ether group.

[0096] "OMs" refers to a methanesulfonyloxy group.

[0097] Various terms such as "X is selected from A, B, or C," "X is selected from A, B, and C," "X is A, B, or C," and "X is A, B, and C" all mean the same thing, i.e., X can be one or more of A, B, and C.

[0098] Any hydrogen atom described in the present invention may be substituted with its isotope, deuterium, and any hydrogen atom in the compounds of the examples of the present invention may also be substituted with a deuterium atom.

[0099] "Optionally" or "optionally" means that the subsequently described event or circumstance may, but need not, occur, and the description includes cases where the event or circumstance has occurred or not occurred. For example, "a heterocyclyl group optionally substituted with an alkyl group" means that the alkyl group may, but need not, be present, and the description includes cases where the heterocyclyl group is substituted with an alkyl group and cases where the heterocyclyl group is not substituted with an alkyl group.

[0100] "Substituted" refers to the fact that one or more hydrogen atoms in a group, preferably up to 5, more preferably 1 to 3 hydrogen atoms, are independently replaced with the corresponding number of substituents. Needless to say, substituents are present only at their possible chemical positions, and a person skilled in the art can determine (experimentally or theoretically) possible or impossible substitutions without much effort. For example, an amino group or a hydroxy group having free hydrogen may be unstable if it is bound to a carbon atom having an unsaturated (e.g., olefinic) bond.

[0101] A "pharmaceutical composition" is meant to contain a mixture of one or more compounds described herein, or physiologically / pharmaceutically acceptable salts or prodrugs thereof, with other chemical components, as well as other components, such as physiologically / pharmaceutically acceptable carriers and excipients. The purpose of a pharmaceutical composition is to facilitate administration to an organism and promote absorption of the active ingredients, thereby exerting their biological activity.

[0102] "Pharmaceutically acceptable salt" refers to a salt of a compound of the present invention, which is safe and effective when used in a mammalian body and possesses the desired biological activity. DETAILED DESCRIPTION OF THE INVENTION

[0103] The present invention will be further described below in conjunction with examples, but these examples are not intended to limit the scope of the present invention.

[0104] Example The structures of the compounds of the present invention are confirmed by nuclear magnetic resonance (NMR) and / or liquid chromatography-mass spectrometry (LC-MS). NMR chemical shifts (δ) are given in parts per million (ppm). NMR measurements were performed using a Bruker AVANCE-400 nuclear magnetometer in deuterated dimethyl sulfoxide (DMSO-d), deuterated methanol (CD3OD), and deuterated chloroform (CDCl3). The internal standard was tetramethylsilane (TMS).

[0105] Liquid chromatography-mass spectrometry (LC-MS) was performed using an Agilent 1200 Infinity Series mass spectrometer. HPLC was performed using an Agilent 1200DAD high-pressure liquid chromatograph (Sunfire C18 150 × 4.6 mm chromatography column) and a Waters 2695-2996 high-pressure liquid chromatograph (Gimini C). 18 A 150 x 4.6 mm chromatography column is used.

[0106] Thin-layer chromatography silica gel plates are Yantai Yellow Sea HSGF254 or Qingdao GF254 silica gel plates, with TLC using 0.15mm to 0.20mm specifications, and thin-layer chromatography product separation and purification using 0.4mm to 0.5mm specifications. Column chromatography generally uses Yantai Yellow Sea silica gel 200-300 mesh silica gel as the carrier.

[0107] The starting materials in the embodiments of the present invention are either known and commercially available, or can be synthesized using or according to methods known in the art.

[0108] Unless otherwise specified, all reactions of the present invention are carried out under a dry nitrogen or argon atmosphere with continuous magnetic stirring, the solvents are dry solvents, and the reaction temperatures are in degrees Celsius.

[0109] Intermediate 1 2-Bromo-N-(4-chloro-5-methylisoxazol-3-yl)-N-((2-(trimethylsilyl)ethoxy)methyl)benzenesulfonamide [ka]

[0110] Step 1 Preparation of 2-bromo-N-(4-chloro-5-methylisoxazol-3-yl)benzenesulfonamide 4-Chloro-5-methylisoxazol-3-amine (5.0 g, 37.8 mmol) was dissolved in tetrahydrofuran (50 mL) and the reaction mixture was cooled to -78 °C. tert-Butoxide (8.43 g, 75.3 mmol) was then added to the reaction mixture, and the mixture was stirred at -78 °C for 0.5 h. Intermediate 1a (10.0 g, 39.4 mmol) was then added to the reaction mixture, and the mixture was stirred at room temperature for 1 h. Water and dichloromethane (3 × 20 mL) were added for extraction. The organic layers were combined, dried over anhydrous sodium sulfate, filtered, and concentrated to give the desired product, Intermediate 1b (12.5 g, 88.5% yield).

[0111] MS m / z (ESI): 351.2 [M+1] + .

[0112] Step 2 Preparation of 2-bromo-N-(4-chloro-5-methylisoxazol-3-yl)-N-((2-(trimethylsilyl)ethoxy)methyl)benzenesulfonamide N,N-Dimethylformamide (20 mL) was dissolved in Intermediate 1b (12.5 g, 35.7 mmol) and potassium carbonate (9.8 g, 71.4 mmol). 2-(Trimethylsilyl)ethoxymethyl chloride (8.9 g, 53.6 mmol) was then added to the reaction mixture, and the mixture was stirred at room temperature for 16 hours. Water and dichloromethane (3 x 20 mL) were added for extraction. The combined organic layer was dried over anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography (petroleum ether / ethyl acetate system) to give the desired product, Intermediate 1 (17.2 g, yield: 98.5%).

[0113] Example 1 4'-((2-butyl-4-oxo-1,3-diazaspiro[4.4]non-1-en-3-yl)methyl-d2)-N-(4,5-dimethylisoxazol-3-yl)-2'-(ethoxymethyl)-[1,1'-biphenyl]-2-sulfonamide [ka]

[0114] Step 1 Preparation of N-(4,5-dimethylisoxazol-3-yl)-2'-(ethoxymethyl)-4'-((hydroxy-d)-methyl-d2)-N-(methoxymethyl)-[1,1'-biphenyl]-2-sulfonamide Example 1-1 (80 mg, 0.17 mmol) (see WO 2010114801A1 for the preparation method) and lithium aluminum tetrahydrogen deuteride (11 mg, 0.26 mmol) were dissolved in tetrahydrofuran (5 mL), the reaction mixture was cooled to 0°C, and the mixture was stirred for 2 hours. Saturated brine (10 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (2 x 10 mL). The organic phases were combined, dried over anhydrous sodium sulfate, concentrated, and purified using a silica gel chromatography column (petroleum ether / ethyl acetate system) to obtain Example 1-2 (50 mg, 70%).

[0115] MS m / z (ESI): 464.2 [M+1] + .

[0116] Step 2 Preparation of (2'-(N-(4,5-dimethylisoxazol-3-yl)-N-(methoxymethyl)sulfamoyl)-2-(ethoxymethyl)-[1,1'-biphenyl]-4-yl)methyl-d2 methanesulfonic acid Methanesulfonyl chloride (14.8 mg, 0.13 mmol) and diisopropylethylamine (41.8 mg, 0.32 mmol) were added to a solution of Example 1-2 (50 mg, 0.11 mmol) in dichloromethane (4 mL) under ice bath conditions, and the reaction mixture was warmed to room temperature and stirred for 1 h. The reaction mixture was concentrated to give crude Example 1-3 (60 mg, 98%), which was used directly in the next step.

[0117] MS m / z (ESI): 541.2 [M+1] + .

[0118] Step 3 Preparation of 4'-((2-butyl-4-oxo-1,3-diazaspiro[4.4]non-1-en-3-yl)methyl-d2)-N-(4,5-dimethylisoxazol-3-yl)-2'-(ethoxymethyl)-N-(methoxymethyl)-[1,1'-biphenyl]-2-sulfonamide Example 1-3 (60 mg, 0.11 mmol) was dissolved in DMF (4 mL), and potassium carbonate (30.7 mg, 0.24 mmol) and 2-butyl-1,3-diazaspirocyclo[4,4]nonan-1-en-4-one (25.8 mg, 0.13 mmol) were added under ice bath conditions. The reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was concentrated, and the crude product was purified by HPLC to give Example 1-4 (42 mg, 72%).

[0119] MS m / z (ESI): 639.3 [M+1] + .

[0120] Step 4 Preparation of 4'-((2-butyl-4-oxo-1,3-diazaspiro[4.4]non-1-en-3-yl)methyl-d2)-N-(4,5-dimethylisoxazol-3-yl)-2'-(ethoxymethyl)-[1,1'-biphenyl]-2-sulfonamide Example 1-4 (42 mg, 0.07 mmol) was dissolved in ethanol (2 mL), 6N hydrochloric acid was added, heated to reflux for 1 h, adjusted to pH 8 with sodium carbonate, and then adjusted to pH 5 and extracted with ethyl acetate (2 x 10 mL). The organic phases were combined, dried over anhydrous sodium sulfate, concentrated, and purified by reverse-phase HPLC to give Example 1 (10 mg, 26%).

[0121] MS m / z (ESI): 595.3 [M+1] + .

[0122] Example 2 4'-((((2-butyl-1,3-diazaspiro[4.4]nonane-1,3-dien-4-yl)oxy]methyl)-N-(4,5-dimethylisoxazol-3-yl)-2'-(ethoxymethyl)-[1,1'-biphenyl]-2-sulfonamide [ka]

[0123] Step 1 Preparation of 4'-((((2-butyl-1,3-diazaspiro[4.4]nonane-1,3-dien-4-yl]oxy)methyl)-N-(4,5-dimethylisoxazol-3-yl)-2'-(ethoxymethyl)-N-(methoxymethyl)-[1,1'-biphenyl]-2-sulfonamide Example 2-1 (100 mg, 0.19 mmol) (see WO 2010114801A1 for preparation method) was dissolved in chloroform (4 mL), silver oxide (47.3 mg, 0.38 mmol) and 2-butyl-1,3-diazaspirocyclo-[4,4]nonan-1-en-4-one (44.5 mg, 0.23 mmol) were added, and the mixture was heated to reflux for 12 hours. The reaction mixture was concentrated, and the crude product was purified by reverse-phase HPLC to obtain Example 2-2 (56 mg, 46%).

[0124] MS m / z (ESI): 637.3 [M+1] + .

[0125] Step 2 Preparation of 4'-((((2-butyl-1,3-diazaspiro[4.4]nonane-1,3-dien-4-yl]oxy)methyl)-N-(4,5-dimethylisoxazol-3-yl)-2'-(ethoxymethyl)-[1,1'-biphenyl]-2-sulfonamide For the synthesis method of Example 2, please refer to the synthesis method of Example 1. Example 2 (30 mg, 57%) was obtained using Example 2-1 as the raw material.

[0126] MS m / z (ESI): 593.3 [M+1] + .

[0127] Example 4 1-((2'-(N-(4,5-dimethylisoxazol-3-yl)sulfamoyl)-2-(ethoxymethyl)-[1,1'-biphenyl]-4-yl)methyl)-4-(2-hydroxypropan-2-yl)-2-propyl-1H-imidazole-5-carboxylic acid [ka]

[0128] Step 1 Preparation of methyl 1-((2'-(N-(4,5-dimethylisoxazol-3-yl)-N-(methoxymethyl)sulfamoyl)-2-(ethoxymethyl)-[1,1'-biphenyl]-4-yl)methyl)-4-(2-hydroxypropan-2-yl)-2-propyl-1H-imidazole-5-carboxylate Example 2-1 (100 mg, 0.19 mmol) (see WO 2010114801A1 for preparation method) was dissolved in acetonitrile (4 mL), methyl 4-(2-hydroxypropan-2-yl)-2-propyl-1H-imidazole-5-carboxylate (51.9 mg, 0.23 mmol) and potassium carbonate (52.8 mg, 0.38 mmol) were added, and the reaction mixture was heated to reflux for 6 hours. The reaction mixture was concentrated, and the crude product was purified by reverse-phase HPLC to give Example 4-1 (86 mg, 67%).

[0129] MS m / z (ESI): 655.3 [M+1] + .

[0130] Step 2 Preparation of 1-((2'-(N-(4,5-dimethylisoxazol-3-yl)sulfamoyl)-2-(ethoxymethyl)-[1,1'-biphenyl]-4-yl)methyl)-4-(2-hydroxypropan-2-yl)-2-propyl-1H-imidazole-5-carboxylic acid For the synthesis method of Example 4, please refer to the synthesis method of Example 1, and Example 4 (31 mg, 40%) was obtained using Example 4-1 as the starting material.

[0131] MS m / z (ESI): 611.2 [M+1] + .

[0132] Example 5 2-(2-butyl-1-((2'-(N-(4,5-dimethylisoxazol-3-yl)sulfamoyl)-2-(ethoxymethyl)-[1,1'-biphenyl]-4-yl)methyl)-4-methyl-6-oxo-1,6-dihydropyrimidin-5-yl)-N,N-dimethylethylthioamide [ka]

[0133] For the synthesis method of Example 5, refer to the synthesis method of Example 4. Example 5 (21 mg, 56%) was obtained by substituting 2-(2-butyl-4-methyl-6-oxo-1,6-dihydropyrimidin-5-yl)-N,N-dimethylethylthioamide for methyl 4-(2-hydroxypropan-2-yl)-2-propyl-1H-imidazole-5-carboxylate.

[0134] MS m / z (ESI): 666.3 [M+1] + .

[0135] Example 6 2-(4-((2-butyl-4-oxo-1,3-diazaspiro[4.4]non-1-en-3-yl)methyl)-2-(ethoxymethyl)phenyl)-N-(4,5-dimethylisoxazol-3-yl)pyridine-3-sulfonamide [ka]

[0136] Step 1 Preparation of 3-(4-borate-3-(ethoxymethyl)benzyl)-2-butyl-1,3-diazaspiro[4.4]nonan-1-en-4-one To a solution of Example 6-1 (4.8 g, 11.6 mmol) (see WO 2010135350A2 for the synthesis method) and bis(pinacolato)diboron (4.4 g, 17.5 mmol) in dioxane (100 mL) were added potassium acetate (3.4 g, 35 mmol) and Pd(dppf)2Cl2 (0.95 g, 1.1 mmol). The mixture was purged with nitrogen gas and heated at 85 °C overnight. The reaction mixture was concentrated under reduced pressure to give the crude product, which was purified by column chromatography (petroleum ether / ethyl acetate, 15% v / v) to give Example 6-2 (4.3 g, 80%).

[0137] MS m / z (ESI): 469.3 [M+1] + .

[0138] Step 2 Preparation of 2-bromo-N-(4,5-dimethylisoxazol-3-yl)pyridine-3-sulfonamide 3-Amino-4,5-dimethylisoxazole (264 mg, 2.35 mmol) was dissolved in 10 mL of dichloromethane, and triethylamine (594 mg, 5.88 mmol) and 2-bromopyridine-3-sulfonyl chloride (500 mg, 1.96 mmol) were added. The mixture was allowed to react at room temperature for 2 hours. 50 mL of water was added, and the mixture was extracted with dichloromethane (40 mL × 2). The combined organic phases were washed with water (40 mL) and saturated sodium chloride solution (40 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate system) to give Example 6-3 (350 mg, 53.8%).

[0139] MS m / z (ESI): 332.0 [M+1] + .

[0140] Step 3 Preparation of 2-bromo-N-(4,5-dimethylisoxazol-3-yl)-N-(methoxymethyl)pyridine-3-sulfonamide Example 6-3 (350 mg, 1.05 mmol) was dissolved in dichloromethane (10 mL), and triethylamine (319 mg, 3.16 mmol), 4-dimethylaminopyridine (129 mg, 1.05 mmol), and bromomethyl methyl ether (158 mg, 1.26 mmol) were added sequentially. The mixture was stirred at room temperature for 2 h. 50 mL of water was added, and the mixture was extracted with dichloromethane (40 mL × 2). The combined organic phases were washed sequentially with water (40 mL) and saturated sodium chloride solution (40 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give Example 6-4 (280 mg, 71.1%).

[0141] MS m / z (ESI): 376.0 [M+1] + .

[0142] Step 4 Preparation of 2-(4-((2-butyl-4-oxo-1,3-diazaspiro[4.4]non-1-en-3-yl)methyl)-2-(ethoxymethyl)phenyl)-N-(4,5-dimethylisoxazol-3-yl)-N-(methoxymethyl)pyridine-3-sulfonamide Example 6-4 (50 mg, 0.133 mmol) was dissolved in 1,4-dioxane (2 mL) and water (0.5 mL), and Example 6-2 (63 mg, 0.133 mmol), [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (10 mg, 0.0133 mmol), and cesium carbonate (65 mg, 0.200 mmol) were added. Nitrogen gas was purged three times, and the reaction was carried out in a microwave oven at 100 °C for 1 hour. The reaction mixture was cooled to room temperature, 30 mL of water was added, and the mixture was extracted with ethyl acetate (30 mL × 2). The organic phases were combined, washed successively with water (30 mL) and saturated sodium chloride solution (30 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give the crude title product, Example 6-5 (75 mg), which was used directly in the next step.

[0143] MS m / z(ESI):638.3[M+1] + .

[0144] Step 5 Preparation of 2-(4-((2-butyl-4-oxo-1,3-diazaspiro[4.4]non-1-en-3-yl)methyl)-2-(ethoxymethyl)phenyl)-N-(4,5-dimethylisoxazol-3-yl)pyridine-3-sulfonamide Example 6-5 (75 mg, 0.118 mmol) was dissolved in ethanol (3 mL), and hydrochloric acid (6 M, 1 mL) was added, followed by reaction at 80° C. for 3 hours. The reaction mixture was cooled to room temperature, concentrated under reduced pressure, and the residue was purified by reverse-phase HPLC to give the title product 2-(4-((2-butyl-4-oxo-1,3-diazaspiro[4.4]non-1-en-3-yl)methyl)-2-(ethoxymethyl)phenyl)-N-(4,5-dimethylisoxazol-3-yl)pyridine-3-sulfonamide 6 (30 mg, 42.8%).

[0145] MS m / z (ESI): 594.3 [M+1] + .

[0146] Example 7 2-(6-((2-butyl-4-oxo-1,3-diazaspiro[4.4]non-1-en-3-yl)methyl)-2-(ethoxymethyl)pyridin-3-yl)-N-(4,5-dimethylisoxazol-3-yl)benzenesulfonamide [ka]

[0147] Step 1 Preparation of 5-bromo-6-(bromomethyl)picolinic acid methyl ester 5-Bromo-6-methylpicolinic acid methyl ester (1.0 g, 4.35 mmol) was dissolved in carbon tetrachloride (30 mL), N-bromosuccinimide (851 mg, 4.78 mmol) and azobisisobutyronitrile (71 mg, 0.435 mmol) were added, and the mixture was purged with nitrogen gas three times. The mixture was refluxed and reacted for 5 hours. The reaction mixture was cooled to room temperature, concentrated under reduced pressure, and then 50 mL of water was added. The mixture was extracted with ethyl acetate (50 mL × 2). The organic phases were combined, washed successively with water (50 mL) and saturated sodium chloride solution (50 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give Example 7-1 (600 mg, 44.9%).

[0148] MS m / z (ESI): 308.9 [M+1] + .

[0149] Step 2 Preparation of 5-bromo-6-(ethoxymethyl)picolinic acid ethyl ester Example 7-1 (600 mg, 1.95 mmol) was dissolved in ethanol (20 mL), sodium ethoxide (399 mg, 5.86 mmol) was added, and the mixture was heated to reflux and reacted for 2 hours. The reaction mixture was cooled to room temperature, concentrated under reduced pressure, 50 mL of water was added, and the mixture was extracted with ethyl acetate (50 mL x 2). The organic phases were combined, washed successively with water (50 mL) and saturated sodium chloride solution (50 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give Example 7-2 (520 mg, 92.7%).

[0150] MS m / z (ESI): 288.0 [M+1] + .

[0151] Step 3 Preparation of (5-bromo-6-(ethoxymethyl)pyridin-2-yl)methanol Example 7-2 (520 mg, 1.80 mmol) was dissolved in tetrahydrofuran (15 mL), purged with nitrogen gas three times, cooled to -78 °C, and a toluene solution of diisobutylaluminum hydride (1.5 M, 3.6 mL, 5.42 mmol) was added dropwise. The mixture was then warmed to room temperature and reacted for 5 hours. The reaction mixture was poured into 100 mL of ice water and extracted with ethyl acetate (80 mL × 2). The combined organic phases were washed successively with water (80 mL) and saturated sodium chloride solution (80 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give Example 7-3 (260 mg, 58.7%).

[0152] MS m / z (ESI): 246.0 [M+1] + .

[0153] Step 4 Preparation of methyl (5-bromo-6-(ethoxymethyl)pyridin-2-yl)methanesulfonate Example 7-3 (260 mg, 1.06 mmol) was dissolved in dichloromethane (10 mL), and triethylamine (320 mg, 3.17 mmol) and methanesulfonyl chloride (242 mg, 2.11 mmol) were added. The mixture was allowed to react at room temperature for 2 hours. The reaction mixture was poured into 50 mL of ice water and extracted with ethyl acetate (50 mL x 2). The combined organic phases were washed with water (50 mL) and saturated sodium chloride solution (50 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give the crude title product, Example 7-4 (330 mg), which was used directly in the next step.

[0154] MS m / z (ESI): 324.0 [M+1] + .

[0155] Step 5 Preparation of 3-((5-bromo-6-(ethoxymethyl)pyridin-2-yl)methyl)-2-butyl-1,3-diazaspiro[4.4]non-1-en-4-one Example 7-4 (330 mg, 1.02 mmol) was dissolved in N,N-dimethylformamide (10 mL), and 2-butyl-1,3-diazaspirocyclo-[4,4]nonan-1-en-4-one (237 mg, 1.22 mmol) and potassium carbonate (422 mg, 3.05 mmol) were added. The mixture was heated to 80 °C and reacted for 5 hours. The reaction mixture was cooled to room temperature, 50 mL of water was added, and the mixture was extracted with ethyl acetate (50 mL × 2). The organic phases were combined, washed successively with water (50 mL) and saturated sodium chloride solution (50 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give Example 7-5 (180 mg, 41.9%).

[0156] MS m / z (ESI): 422.1 [M+1] + .

[0157] Step 6 Preparation of 2-(6-((2-butyl-4-oxo-1,3-diazaspiro[4.4]non-1-en-3-yl)methyl)-2-(ethoxymethyl)pyridin-3-yl)-N-(4,5-dimethylisoxazol-3-yl)-N-(methoxymethyl)benzenesulfonamide Example 7-5 (50 mg, 0.118 mmol) was dissolved in 1,4-dioxane (2 mL) and 0.5 mL of water, and (2-(N-(4,5-dimethylisoxazol-3-yl)-N-(methoxymethyl)sulfamoyl)phenyl)boronic acid (48 mg, 0.142 mmol) (see WO 2010135350A2 for the preparation method), [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (8.6 mg, 0.0118 mmol), and cesium carbonate (58 mg, 0.177 mmol) were added. The mixture was purged with nitrogen gas three times and reacted at 100°C for 1 hour using a microwave. The reaction mixture was cooled to room temperature, 30 mL of water was added, and the mixture was extracted with ethyl acetate (30 mL x 2). The organic phases were combined, washed successively with water (30 mL) and saturated sodium chloride solution (30 mL), dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography to give Example 7-6 (35 mg), which was used directly in the next step reaction.

[0158] MS m / z(ESI):638.3[M+1] + .

[0159] Step 7 Preparation of 2-(6-((2-butyl-4-oxo-1,3-diazaspiro[4.4]non-1-en-3-yl)methyl)-2-(ethoxymethyl)pyridin-3-yl)-N-(4,5-dimethylisoxazol-3-yl)benzenesulfonamide The protecting group was removed from Example 7-6 according to the synthesis method of Example 6 to obtain Example 7 (19 mg, 58.3%).

[0160] MS m / z (ESI): 594.3 [M+1] + .

[0161] Example 8 2-(6-((2-butyl-4-oxo-1,3-diazaspiro[4.4]non-1-en-3-yl)methyl)-4-(ethoxymethyl)pyridin-3-yl)-N-(4,5-dimethylisoxazol-3-yl)benzenesulfonamide [ka]

[0162] Following the route and method of Example 7, 5-bromo-4-methylpicolinic acid ethyl ester was used as the starting material instead of 5-bromo-6-methylpicolinic acid methyl ester to give Example 8 (11 mg, 39.4%).

[0163] MS m / z (ESI): 594.3 [M+1] + .

[0164] Example 9 2-(4-((2-butyl-4-oxo-1,3-diazaspiro[4.4]non-1-en-3-yl)methyl)-2-(ethoxymethyl)phenyl)-N-(3-methoxy-5-methylpyrazin-2-yl)pyridine-3-sulfonamide [ka]

[0165] Step 1 Preparation of 2-bromo-N-(3-methoxy-5-methylpyrazin-2-yl)pyridine-3-sulfonamide 3-Methoxy-5-methylpyrazin-2-amine (130 mg, 0.938 mmol) was dissolved in dichloromethane (5 mL), triethylamine (237 mg, 2.34 mmol) and 2-bromopyridine-3-sulfonyl chloride (200 mg, 0.781 mmol) were added, and the mixture was allowed to react at room temperature for 2 hours. 50 mL of water was added, and the mixture was extracted with dichloromethane (40 mL × 2). The combined organic phase was washed with water (40 mL) and saturated sodium chloride solution (40 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give Example 9-1 (110 mg, 32.7%).

[0166] MS m / z (ESI): 359.0 [M+1] + .

[0167] Step 2 Preparation of 2-bromo-N-(3-methoxy-5-methylpyrazin-2-yl)-N-(methoxymethyl)pyridine-3-sulfonamide Example 9-1 (110 mg, 0.306 mmol) was dissolved in dichloromethane (5 mL), and triethylamine (93 mg, 0.919 mmol), 4-dimethylaminopyridine (37 mg, 0.306 mmol), and bromomethyl methyl ether (46 mg, 0.368 mmol) were added sequentially. The mixture was allowed to react at room temperature for 2 hours. 50 mL of water was added, and the mixture was extracted with dichloromethane (40 mL × 2). The combined organic phases were washed with water (40 mL) and saturated sodium chloride solution (40 mL) sequentially, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give Example 9-2 (80 mg, 64.9%).

[0168] MS m / z (ESI): 403.0 [M+1] + .

[0169] Step 3 Preparation of 2-(4-((2-butyl-4-oxo-1,3-diazaspiro[4.4]non-1-en-3-yl)methyl)-2-(ethoxymethyl)phenyl)-N-(3-methoxy-5-methylpyrazin-2-yl-N-(methoxymethyl)pyridine-3-sulfonamide Using Example 9-2 as the starting material, Example 9-3 (81 mg, 61%) was obtained according to the route and method of Example 6-3.

[0170] MS m / z (ESI): 665.3 [M+1] + .

[0171] Step 4 Preparation of 2-(4-((2-butyl-4-oxo-1,3-diazaspiro[4.4]non-1-en-3-yl)methyl)-2-(ethoxymethyl)phenyl)-N-(3-methoxy-5-methylpyrazin-2-yl)pyridine-3-sulfonamide Using Example 9-3 as the starting material, Example 9 (30 mg, 40%) was obtained according to the route and method of Example 6.

[0172] MS m / z (ESI): 620.3 [M+1] + .

[0173] Example 10 4'-((2-butyl-4-oxo-1,3-diazaspiro[4.4]non-1-en-3-yl)methyl)-N-(4,5-dimethylisoxazol-3-yl)-2'-(ethoxymethyl)-6-fluoro-[1,1'-biphenyl]-2-sulfonamide [ka]

[0174] Step 1 Preparation of 2-bromo-N-(4,5-dimethylisoxazol-3-yl)-3-fluorobenzenesulfonamide 3-Amino-4,5-dimethylisoxazole (123 mg, 1.10 mmol) was dissolved in dichloromethane (10 mL), triethylamine (222 mg, 2.19 mmol) and 2-bromo-3-fluorobenzenesulfonyl chloride (200 mg, 0.731 mmol) were added, and the mixture was allowed to react at room temperature for 2 hours. 50 mL of water was added, and the mixture was extracted with dichloromethane (40 mL × 2). The combined organic phase was washed with water (40 mL) and saturated sodium chloride solution (40 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give Example 10-1 (120 mg, 31.3%).

[0175] MS m / z (ESI): 349.0 [M+1] + .

[0176] Step 2 Preparation of 2-bromo-N-(4,5-dimethylisoxazol-3-yl)-3-fluoro-N-(methoxymethyl)benzenesulfonamide Example 10-1 (120 mg, 0.344 mmol) was dissolved in dichloromethane (10 mL), and triethylamine (104 mg, 1.03 mmol), 4-dimethylaminopyridine (42 mg, 0.344 mmol), and bromomethyl methyl ether (86 mg, 0.688 mmol) were added sequentially. The mixture was allowed to react at room temperature for 2 hours. 50 mL of water was added, and the mixture was extracted with dichloromethane (40 mL × 2). The combined organic phases were washed with water (40 mL) and saturated sodium chloride solution (40 mL) sequentially, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give Example 10-2 (90 mg, 66.6%).

[0177] MS m / z (ESI): 393.0 [M+1] + .

[0178] Step 3 Preparation of 4'-(((2-butyl-4-oxo-1,3-diazaspiro[4.4]non-1-en-3-yl)methyl)-N-(4,5-dimethylisoxazol-3-yl)-2'-(ethoxymethyl)-6-fluoro-N-(methoxymethyl)-[1,1'-biphenyl]-2-sulfonamide Using Example 10-2 as the starting material, Example 10-3 (51 mg, 56%) was obtained according to the route and method of Example 6-3.

[0179] MS m / z (ESI): 655.3 [M+1] + .

[0180] Step 4 Preparation of 4'-((2-butyl-4-oxo-1,3-diazaspiro[4.4]non-1-en-3-yl)methyl)-N-(4,5-dimethylisoxazol-3-yl)-2'-(ethoxymethyl)-6-fluoro-[1,1'-biphenyl]-2-sulfonamide Using Example 10-3 as the starting material, Example 10 (18 mg, 55.2%) was obtained following the route and method of Steps 3 and 4 of Example 6.

[0181] MS m / z (ESI): 611.3 [M+1] + .

[0182] Example 11 4'-((2-butyl-4-oxo-1,3-diazaspiro[4.4]non-1-en-3-yl)methyl)-N-(4,5-dimethylisoxazol-3-yl)-6-(ethoxymethyl)-[1,1'-biphenyl]-2-sulfonamide [ka]

[0183] Step 1 Preparation of 2-bromo-1-(bromomethyl)-3-nitrophenyl 2-Bromo-3-nitrotoluene (1.0 g, 4.63 mmol) was dissolved in carbon tetrachloride (30 mL), N-bromosuccinimide (988 mg, 5.56 mmol) and azobisisobutyronitrile (76 mg, 0.463 mmol) were added, and the mixture was purged with nitrogen gas three times. The mixture was refluxed and reacted for 5 hours. The reaction mixture was cooled to room temperature, concentrated under reduced pressure, and then 50 mL of water was added. The mixture was extracted with ethyl acetate (50 mL × 2). The organic phases were combined, washed successively with water (50 mL) and saturated sodium chloride solution (50 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give Example 11-1 (630 mg, 46.4%).

[0184] MS m / z (ESI): 293.9 [M+1] + .

[0185] Step 2 Preparation of 2-bromo-1-(ethoxymethyl)-3-nitrophenyl Example 11-1 (630 mg, 2.15 mmol) was dissolved in ethanol (20 mL), sodium ethoxide (419 mg, 6.45 mmol) was added, and the mixture was reacted at 40° C. for 2 hours. The reaction mixture was cooled to room temperature, concentrated under reduced pressure, 50 mL of water was added, and the mixture was extracted with ethyl acetate (50 mL × 2). The organic phases were combined, washed with water (50 mL) and saturated sodium chloride solution (50 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain crude Example 11-2 (410 mg), which was used directly in the next step.

[0186] MS m / z (ESI): 260.0 [M+1] + .

[0187] Step 3 Preparation of 2-bromo-3-(ethoxymethyl)aniline 20 mL of acetic acid was heated to 80 °C, iron powder (880 mg, 15.8 mmol) was added, and Example 11-2 (410 mg, 1.58 mmol) was slowly added in small portions. The reaction was continued at 80 °C for 30 minutes. The reaction mixture was cooled to room temperature, filtered, and the filtrate was concentrated under reduced pressure. 50 mL of water was added and extracted with ethyl acetate (50 mL × 2). The organic phases were combined, washed successively with saturated sodium carbonate solution (50 mL) and saturated sodium chloride solution (50 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give Example 11-3 (300 mg), which was used directly in the next step.

[0188] MS m / z (ESI): 230.0 [M+1] + .

[0189] Step 4 Preparation of 2-bromo-3-(ethoxymethyl)benzenesulfonyl chloride Example 11-3 (300 mg, 1.30 mmol) was dissolved in hydrochloric acid solution (6 M, 5 mL) and cooled to 0 °C. 1 mL of sodium nitrite (108 mg, 1.57 mmol) solution was slowly added dropwise, and the reaction was continued at 0 °C for 1 hour. 3 mL of acetic acid, cuprous chloride (6.4 mg, 0.0650 mmol), copper(II) chloride dihydrate (22 mg, 0.130 mmol) were added sequentially, and thionyl chloride (774 mg, 6.50 mmol) was slowly added dropwise. The mixture was allowed to react at 0 °C for 1 hour. 50 mL of water was added, and the mixture was extracted with ethyl acetate (40 mL × 2). The organic phases were combined, washed with saturated sodium chloride solution (40 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain crude Example 11-4 (330 mg), which was used directly in the next step.

[0190] MS m / z (ESI): 312.9 [M+1] + .

[0191] Step 5 Preparation of 2-bromo-N-(4,5-dimethylisoxazol-3-yl)-3-(ethoxymethyl)benzenesulfonamide 3-Amino-4,5-dimethylisoxazole (177 mg, 1.58 mmol) was dissolved in 5 mL of dichloromethane, and triethylamine (319 mg, 3.16 mmol) and Example 11-4 (330 mg, 1.05 mmol) were added and reacted at room temperature for 2 hours. 40 mL of water was added, and the mixture was extracted with dichloromethane (40 mL × 2). The organic phases were combined, washed with water (40 mL) and saturated sodium chloride solution (40 mL) successively, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give Example 11-5 (350 mg).

[0192] MS m / z (ESI): 389.0 [M+1] + .

[0193] Step 6 Preparation of 2-bromo-N-(4,5-dimethylisoxazol-3-yl)-3-(ethoxymethyl)benzenesulfonamide Example 11-5 (350 mg, 0.900 mmol) was dissolved in dichloromethane (10 mL), and triethylamine (273 mg, 2.70 mmol), 4-dimethylaminopyridine (110 mg, 0.900 mmol), and bromomethyl methyl ether (169 mg, 1.35 mmol) were added sequentially. The mixture was reacted at room temperature for 2 hours. 50 mL of water was added, and the mixture was extracted with dichloromethane (40 mL × 2). The combined organic phases were washed with water (40 mL) and saturated sodium chloride solution (40 mL) sequentially, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give Example 11-6 (130 mg, 33.4%).

[0194] MS m / z (ESI): 433.0 [M+1] + .

[0195] Step 7 Preparation of 3-(4-bromobenzoyl)-2-butyl-1,3-diazaspiro[4.4]non-1-en-4-one p-Bromobenzyl bromide (200 mg, 0.800 mmol) was dissolved in N,N-dimethylformamide (5 mL), potassium carbonate (221 mg, 1.60 mmol) and 2-butyl-1,3-diazaspirocyclo[4,4]nonan-1-en-4-one (155 mg, 0.800 mmol) were added, and the mixture was heated to 80 °C and reacted for 4 hours. The reaction mixture was cooled to room temperature, 50 mL of water was added, and the mixture was extracted with ethyl acetate (40 mL × 2). The organic phases were combined, washed sequentially with water (40 mL × 2) and saturated sodium chloride solution (40 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure and purified by silica gel column chromatography to give Example 11-7 (130 mg, 44.8%).

[0196] MS m / z (ESI): 363.1 [M+1] + .

[0197] Step 8 Preparation of 2-butyl-3-(4-(4,4,5,5-tetramethyl-1,3,2-dioxanaphthalen-2-yl)benzyl)-1,3-diazaspiro[4.4]non-1-en-4-one Example 11-7 (130 mg, 0.358 mmol) was dissolved in 1,4-dioxane (5 mL), and bis(pinacolato)diboron (182 mg, 0.716 mmol), [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (26 mg, 0.0358 mmol), and potassium acetate (70 mg, 0.358 mmol) were added. The mixture was purged with nitrogen gas three times, heated to 100 °C, and reacted for 4 hours. The reaction mixture was cooled to room temperature, 40 mL of water was added, and the mixture was extracted with ethyl acetate (40 mL × 2). The organic phases were combined, washed successively with water (40 mL) and saturated sodium chloride solution (40 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give Example 11-8 (90 mg, 61.1%).

[0198] MS m / z(ESI):411.3[M+1] + .

[0199] Step 9 Preparation of 4'-((2-butyl-4-oxo-1,3-diazaspiro[4.4]non-1-en-3-yl)methyl)-N-(4,5-dimethylisoxazol-3-yl)-6-(ethoxymethyl)-N-(methoxymethyl)-[1,1'-biphenyl]-2-sulfonamide Example 11-7 (50 mg, 0.122 mmol) was dissolved in 1,4-dioxane (2 mL) and 0.5 mL of water. Example 11-8 (53 mg, 0.122 mmol), [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (8.9 mg, 0.0122 mmol), and cesium carbonate (79 mg, 0.243 mmol) were added. Nitrogen gas was purged three times, and the reaction was carried out under microwave conditions at 100 °C for 1 hour. The reaction mixture was cooled to room temperature, 30 mL of water was added, and the mixture was extracted with ethyl acetate (30 mL × 2). The organic phases were combined, washed successively with water (30 mL) and saturated sodium chloride solution (30 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give Example 11-9 (40 mg, 51.5%).

[0200] MS m / z (ESI): 637.3 [M+1] + .

[0201] Step 10 Preparation of 4'-((2-butyl-4-oxo-1,3-diazaspiro[4.4]non-1-en-3-yl)methyl)-N-(4,5-dimethylisoxazol-3-yl)-6-(ethoxymethyl)-[1,1'-biphenyl]-2-sulfonamide Example 11-9 (40 mg, 0.0628 mmol) was dissolved in 3 mL of ethanol, and hydrochloric acid (6 M, 1 mL) was added. The mixture was heated to 80° C. and reacted for 3 hours. The reaction mixture was cooled to room temperature and concentrated under reduced pressure. The residue was purified by reverse phase HPLC to give Example 11 (25 mg, 67.1%).

[0202] MS m / z (ESI): 593.3 [M+1] + .

[0203] Intermediate 2 3-(3-(bromomethyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborinan-2-yl)benzyl)-2-butyl-1,3-diazaspiro[4.4]non-1-en-4-one [ka]

[0204] Step 1 Preparation of 4-bromo-3-methylbenzyl methanesulfonate Intermediate 2a (2.0 g, 10.0 mmol) and triethylamine (1.4 g, 11.0 mmol) were dissolved in dichloromethane (5 mL). Methanesulfonyl chloride (1.24 g, 11.0 mmol) was added to the reaction mixture in an ice bath, and the mixture was stirred at room temperature for 1 hour. Water and dichloromethane (20 mL x 3) were added for extraction. The organic layers were combined, dried over anhydrous sodium sulfate, filtered, concentrated, and purified using a column chromatography (petroleum ether / ethyl acetate system) to obtain the desired product, 4-bromo-3-methylbenzyl methanesulfonate (2.6 g, yield: 93.8%).

[0205] MS m / z (ESI): 278.9 [M+1] + .

[0206] Step 2 Preparation of 3-(4-bromo-3-methylbenzyl)-2-butyl-1,3-diazaspiro[4.4]nonan-1-en-4-one Intermediate 2b (2.0 g, 7.2 mmol) was dissolved in N,N-dimethylformamide (5 mL). Sodium hydride (0.34 g, 8.6 mmol) was added to the reaction mixture in an ice bath, and the mixture was stirred for 1 hour. 2-Butyl-1,3-diazaspiro[4.4]nonan-1-en-4-one (1.63 g, 8.6 mmol) was added to the reaction mixture, and the mixture was stirred at room temperature for 1 hour. Water and dichloromethane (20 mL x 3) were added for extraction. The organic layers were combined, dried over anhydrous sodium sulfate, filtered, concentrated, and purified using a column chromatography (petroleum ether / ethyl acetate system) to obtain the desired product, 4-bromo-3-methylbenzyl methanesulfonate (2.3 g, yield: 87.8%).

[0207] MS m / z (ESI): 377.1 [M+1] + .

[0208] Step 3 Preparation of 2-butyl-3-(3-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl)-1,3-diazaspiro[4.4]nonan-1-en-4-one Intermediate 2c (2.0 g, 5.3 mmol), bis(pinacolato)diboron (1.6 g, 6.4 mmol), [1,1'-bis(diphenylphosphino)ferrocene] palladium dichloride dichloromethane complex (42 mg, 0.05 mmol), and potassium acetate (1.1 g, 10.6 mmol) were dissolved in dioxane (5 mL). The reaction mixture was stirred at 80 °C for 16 h under nitrogen gas protection. Water and dichloromethane (20 mL × 3) were added for extraction. The organic layers were combined, dried over anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography (petroleum ether / ethyl acetate system) to obtain the desired product, 2-butyl-3-(3-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl)-1,3-diazaspiro[4.4]nonan-1-en-4-one (1.8 g, yield: 52.4%).

[0209] MS m / z(ESI):425.3[M+1] + .

[0210] Step 4 Preparation of 3-(3-(bromomethyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborinan-2-yl)benzyl)-2-butyl-1,3-diazaspiro[4.4]non-1-en-4-one Intermediate 2d (1.5 g, 3.5 mmol) was dissolved in acetonitrile (5 mL). N-bromosuccinimide (0.75 g, 4.2 mmol) was added to the reaction mixture under ice-water bath conditions, and the mixture was stirred at room temperature for 1 hour. Water and dichloromethane (3 × 20 mL) were added for extraction. The combined organic layer was dried over anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography (petroleum ether / ethyl acetate system) to give the desired product, 3-(3-(bromomethyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborinan-2-yl)benzyl)-2-butyl-1,3-diazaspiro[4.4]non-1-en-4-one (1.62 g, yield: 91.8%).

[0211] MS m / z (ESI): 503.2 [M+1] + .

[0212] Example 12 4'-(((2-butyl-4-oxo-1,3-diazaspiro[4.4]non-1-en-3-yl)methyl)-N-(4,5-dimethylisoxazol-3-yl)-2'-((trifluoromethoxy)methyl)-[1,1'-biphenyl]-2-sulfonamide [ka]

[0213] Step 1 Preparation of 2'-(bromomethyl)-4'-(((2-butyl-4-oxo-1,3-diazaspiro[4.4]non-1-en-3-yl)methyl)-N-(4,5-dimethylisoxazol-3-yl)-N-(methoxymethyl)-[1,1'-biphenyl]-2-sulfonamide Intermediate 2 (100 mg, 0.2 mmol), (2-(N-(4,5-dimethylisoxazol-3-yl)-N-(methoxymethyl)sulfamoyl)phenyl)boronic acid (75 mg, 0.2 mmol) (see WO 2010135350A2 for the preparation method), [1,1'-bis(diphenylphosphino)ferrocene]dichloride palladium dichloromethane complex (16 mg, 0.02 mmol), and cesium carbonate (291 mg, 0.9 mmol) were stirred in dioxane (4 mL) and water (1 mL) at 100 °C for 1 hour using a microwave. Extraction was performed with water and dichloromethane (20 mL × 3). The organic layers were combined, dried over anhydrous sodium sulfate, filtered, concentrated, and purified using a column chromatography (petroleum ether / ethyl acetate system) to obtain Example 12-1 (110 mg, yield: 82.5%).

[0214] MS m / z (ESI): 671.2 [M+1] + .

[0215] Step 2 Preparation of 4'-((2-butyl-4-oxo-1,3-diazaspiro[4.4]non-1-en-3-yl)methyl)-N-(4,5-dimethylisoxazol-3-yl)-N-(methoxymethyl)-2'-((trifluoromethoxy)methyl)-[1,1'-biphenyl]-2-sulfonamide Trifluoromethyl trifluoromethanesulfonate (72 mg, 0.33 mmol) and silver fluoride (48 mg, 0.33 mmol) were dissolved in acetonitrile (5 mL). The reaction mixture was cooled to -30°C and stirred for 2 hours. Then, Example 12-1 (110 mg, 0.16 mmol) dissolved in 5 mL of acetonitrile was added to the reaction mixture, and the mixture was stirred at room temperature for 24 hours. Saturated brine (10 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (10 mL x 3). The organic phases were combined, dried, concentrated, and purified using a column (petroleum ether / ethyl acetate system) to obtain Example 12-2 (85 mg, 77.6%).

[0216] MS m / z (ESI): 676.3 [M+1] + .

[0217] Step 3 Preparation of 4'-(((2-butyl-4-oxo-1,3-diazaspiro[4.4]non-1-en-3-yl)methyl)-N-(4,5-dimethylisoxazol-3-yl)-2'-((trifluoromethoxy)methyl)-[1,1'-biphenyl]-2-sulfonamide Example 12-2 (85 mg, 0.13 mmol) was dissolved in dioxane (2 mL), and 6 mol / L hydrochloric acid dioxane solution (2 mL) was added to the reaction mixture under ice bath conditions, and the reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated, purified, and separated to obtain Example 12 (32 mg, 40.4%).

[0218] MS m / z (ESI): 633.2 [M+1] + .

[0219] Example 13 4'-((2-butyl-4-oxo-1,3-diazaspiro[4.4]non-1-en-3-yl)methyl)-2'-(cyclopropoxymethyl)-N-(4,5-dimethylisoxazol-3-yl)-[1,1'-biphenyl]-2-sulfonamide [ka]

[0220] Step 1 Preparation of 4'-((2-butyl-4-oxo-1,3-diazaspiro[4.4]non-1-en-3-yl)methyl)-2'-(cyclopropoxymethyl)-N-(4,5-dimethylisoxazol-3-yl)-N-(methoxymethyl)-[1,1'-biphenyl]-2-sulfonamide Example 12-1 (100 mg, 0.15 mmol) and potassium carbonate (42 mg, 0.3 mmol) were dissolved in dichloromethane (5 mL). Cyclopropanol (18 mg, 0.3 mmol) was then added to the reaction mixture, and the mixture was stirred at room temperature for 2 h. Saturated brine (10 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (10 mL x 3). The organic phases were combined, dried, concentrated, and purified using a column (petroleum ether / ethyl acetate system) to obtain Example 13-1 (62 mg, 78.6%).

[0221] MS m / z (ESI): 649.3 [M+1] + .

[0222] Step 2 Preparation of 4'-((2-butyl-4-oxo-1,3-diazaspiro[4.4]non-1-en-3-yl)methyl)-2'-(cyclopropoxymethyl)-N-(4,5-dimethylisoxazol-3-yl)-[1,1'-biphenyl]-2-sulfonamide The synthesis method of Example 13 was carried out in accordance with the synthesis method of Example 12, and the title compound Example 13 (22 mg, 52.7%) was obtained using Example 13-1 as the starting material.

[0223] MS m / z (ESI): 605.3 [M+1] + .

[0224] Example 14 4'-((2-butyl-4-oxo-1,3-diazaspiro[4.4]non-1-en-3-yl)methyl)-2'-((cyclopropylmethoxy)methyl)-N-(4,5-dimethylisoxazol-3-yl)-[1,1'-biphenyl]-2-sulfonamide [ka]

[0225] Step 1 Preparation of 4'-((2-butyl-4-oxo-1,3-diazaspiro[4.4]non-1-en-3-yl)methyl)-2'-((cyclopropylmethoxy)methyl)-N-(4,5-dimethylisoxazol-3-yl)-N-(methoxymethyl)-[1,1'-biphenyl]-2-sulfonamide Example 12-1 (100 mg, 0.15 mmol) and potassium carbonate (42 mg, 0.3 mmol) were dissolved in dichloromethane (5 mL). Cyclopropylmethanol (22 mg, 0.3 mmol) was then added to the reaction mixture, and the mixture was stirred at room temperature for 2 h. Saturated brine (10 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (10 mL x 3). The organic phases were combined, dried, concentrated, and purified using a column (petroleum ether / ethyl acetate system) to obtain Example 14-1 (66 mg, 77.5%).

[0226] MS m / z (ESI): 663.3 [M+1] + .

[0227] Step 2 Preparation of 4'-((2-butyl-4-oxo-1,3-diazaspiro[4.4]non-1-en-3-yl)methyl)-2'-((cyclopropylmethoxy)methyl)-N-(4,5-dimethylisoxazol-3-yl)-[1,1'-biphenyl]-2-sulfonamide The synthesis method of Example 14 was carried out in accordance with the synthesis method of Example 12, and the title compound Example 14 (28 mg, 48.8%) was obtained using Example 14-1 as the starting material.

[0228] MS m / z(ESI):619.3[M+1] + .

[0229] Example 15 4'-(((2-butyl-4-oxo-1,3-diazaspiro[4.4]non-1-en-3-yl)methyl)-2'-(((3,3-difluoroazetidin-1-yl)methyl)-N-(4,5-dimethylisoxazol-3-yl)-[1,1'-biphenyl]-2-sulfonamide [ka]

[0230] Step 1 Preparation of 4'-(((2-butyl-4-oxo-1,3-diazaspiro[4.4]non-1-en-3-yl)methyl)-2'-(((3,3-difluoroazetidin-1-yl)methyl)-N-(4,5-dimethylisoxazol-3-yl)-N-(methoxymethyl)-[1,1'-biphenyl]-2-sulfonamide Example 12-1 (100 mg, 0.15 mmol) and potassium carbonate (63 mg, 0.45 mmol) were dissolved in dichloromethane (5 mL). 3,3-Difluoroazetidine hydrochloride (39 mg, 0.3 mmol) was then added to the reaction mixture, and the mixture was stirred at room temperature for 2 hours. Saturated brine (10 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (10 mL x 3). The organic phases were combined, dried, concentrated, and purified using a column (petroleum ether / ethyl acetate system) to obtain Example 15-1 (66 mg, 77.5%).

[0231] MS m / z (ESI): 684.3 [M+1] + .

[0232] Step 2 Preparation of 4'-(((2-butyl-4-oxo-1,3-diazaspiro[4.4]non-1-en-3-yl)methyl)-2'-(((3,3-difluoroazetidin-1-yl)methyl)-N-(4,5-dimethylisoxazol-3-yl)-[1,1'-biphenyl]-2-sulfonamide The synthesis method of Example 15 was carried out in accordance with the synthesis method of Example 12, and the title compound Example 15 (33 mg, 62.8%) was obtained using Example 15-1 as the starting material.

[0233] MS m / z(ESI):640.3[M+1] + .

[0234] Example 16 Methyl ((4-((2-butyl-4-oxo-1,3-diazaspiro[4.4]non-1-en-3-yl)methyl)-2'-(N-(4,5-dimethylisoxazol-3-yl)sulfamoyl)-[1,1'-biphenyl]-2-yl)methyl)carbamate [ka]

[0235] Step 1 Preparation of methyl ((4-((2-butyl-4-oxo-1,3-diazaspiro[4.4]non-1-en-3-yl)methyl)-2'-(N-(4,5-dimethylisoxazol-3-yl)-N-(methoxymethyl)sulfamoyl)-[1,1'-biphenyl]-2-yl)methyl)carbamate Example 12-1 (100 mg, 0.15 mmol) and potassium carbonate (63 mg, 0.45 mmol) were dissolved in dichloromethane (5 mL). Methyl carbamate (22 mg, 0.3 mmol) was then added to the reaction mixture, and the mixture was stirred at room temperature for 2 h. Saturated brine (10 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (10 mL x 3). The organic phases were combined, dried, concentrated, and purified using a column (petroleum ether / ethyl acetate system) to obtain Example 16-1 (58 mg, 56.5%).

[0236] MS m / z (ESI): 666.3 [M+1] + .

[0237] Step 2 Preparation of methyl ((4-((2-butyl-4-oxo-1,3-diazaspiro[4.4]non-1-en-3-yl)methyl)-2'-(N-(4,5-dimethylisoxazol-3-yl)sulfamoyl)-[1,1'-biphenyl]-2-yl)methyl)carbamate The synthesis method of Example 16 was carried out in accordance with the synthesis method of Example 12, and the title compound Example 16 (26 mg, 55.8%) was obtained using Example 16-1 as the starting material.

[0238] MS m / z (ESI): 622.3 [M+1] + .

[0239] Example 17 (4-((2-butyl-4-oxo-1,3-diazaspiro[4.4]non-1-en-3-yl)methyl)-2'-(N-(4,5-dimethylisoxazol-3-yl)sulfamoyl)-[1,1'-biphenyl]-2-yl)methylcarbamate [ka]

[0240] Step 1 Preparation of 4'-(((2-butyl-4-oxo-1,3-diazaspiro[4.4]non-1-en-3-yl)methyl)-N-(4,5-dimethylisoxazol-3-yl)-2'-(hydroxymethyl)-N-(methoxymethyl)-[1,1'-biphenyl]-2-sulfonamide Example 12-1 (100 mg, 0.15 mmol) was dissolved in a mixture of 5 mL of ethanol and 5 mL of water, and then sodium hydroxide (18 mg, 0.45 mmol) was added to the reaction solution. The reaction solution was stirred overnight at room temperature. Saturated brine (10 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (10 mL x 3). The organic phases were combined, dried, concentrated, and purified using a column (petroleum ether / ethyl acetate system) to obtain Example 17-1 (70 mg, 78.4%).

[0241] MS m / z(ESI):609.3[M+1] + .

[0242] Step 2 Preparation of (4-((2-butyl-4-oxo-1,3-diazaspiro[4.4]non-1-en-3-yl)methyl)-2'-(N-(4,5-dimethylisoxazol-3-yl)-N-(methoxymethyl)sulfamoyl)-[1,1'-biphenyl]-2-yl)methylcarbamate Example 17-1 (100 mg, 0.16 mmol) was dissolved in 5 mL of dimethyl disulfide, and then methyl isocyanate (28 mg, 0.48 mmol) was added to the reaction solution. The reaction solution was stirred at 55°C for 2 hours. Saturated brine (10 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (10 mL). The organic phases were combined, dried, concentrated, and purified using a column (petroleum ether / ethyl acetate system) to obtain Example 17-2 (110 mg, 62.8%).

[0243] MS m / z (ESI): 666.3 [M+1] + .

[0244] Step 3 Preparation of (4-((2-butyl-4-oxo-1,3-diazaspiro[4.4]non-1-en-3-yl)methyl)-2'-(N-(4,5-dimethylisoxazol-3-yl)sulfamoyl)-[1,1'-biphenyl]-2-yl)methylcarbamate The synthesis method of Example 17 was carried out in accordance with the synthesis method of Example 12, and the title compound Example 17 (42 mg, 68.9%) was obtained using Example 17-2 as the starting material.

[0245] MS m / z (ESI): 622.3 [M+1] + .

[0246] Example 18 2'-(Azetidine-1-carbonyl)-4'-(((2-butyl-4-oxo-1,3-diazaspiro[4.4]non-1-en-3-yl)methyl)-N-(4,5-dimethylisoxazol-3-yl)-[1,1'-biphenyl]-2-sulfonamide [ka]

[0247] Step 1 Preparation of 2'-(azetidine-1-carbonyl)-4'-(((2-butyl-4-oxo-1,3-diazaspiro[4.4]non-1-en-3-yl)methyl)-N-(4,5-dimethylisoxazol-3-yl)-N-(methoxymethyl)-[1,1'-biphenyl]-2-sulfonamide Example 12-1 (100 mg, 0.15 mmol) and potassium carbonate (63 mg, 0.45 mmol) were dissolved in dichloromethane (5 mL). Cyclobutanamine (15 mg, 0.2 mmol) was then added to the reaction mixture, and the mixture was stirred at room temperature for 2 hours. Saturated brine (10 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (10 mL x 3). The organic phases were combined, dried, concentrated, and purified using a column (petroleum ether / ethyl acetate system) to obtain Example 18-1 (65 mg, 72.6%).

[0248] MS m / z (ESI): 648.3 [M+1] + .

[0249] Step 2 2'-(Azetidine-1-carbonyl)-4'-(((2-butyl-4-oxo-1,3-diazaspiro[4.4]non-1-en-3-yl)methyl)-N-(4,5-dimethylisoxazol-3-yl)-N-(methoxymethyl)-[1,1'-biphenyl]-2-sulfonamide Example 18-1 (65 mg, 0.1 mmol) was dissolved in dichloromethane (10 mL), and hexadecyltrimethylammonium bromide (51 mg, 0.14 mmol) and KMnO4 (22 mg, 0.14 mmol) were added to the reaction mixture. The reaction mixture was stirred under reflux for 2 hours. The reaction mixture was cooled to room temperature, and saturated aqueous sodium sulfite solution (5 mL) was added with vigorous stirring. Saturated brine (10 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (10 mL x 3). The organic phases were combined, dried, concentrated, and purified by column chromatography (petroleum ether / ethyl acetate system) to obtain Example 18-2 (45 mg, 73.4%).

[0250] MS m / z (ESI): 662.3 [M+1] + .

[0251] Step 3 2'-(Azetidine-1-carbonyl)-4'-(((2-butyl-4-oxo-1,3-diazaspiro[4.4]non-1-en-3-yl)methyl)-N-(4,5-dimethylisoxazol-3-yl)-[1,1'-biphenyl]-2-sulfonamide Preparation The synthesis method of Example 18 was carried out in accordance with the synthesis method of Example 12, and the title compound Example 18 (22 mg, 48.5%) was obtained using Example 18-2 as the starting material.

[0252] MS m / z(ESI):618.3[M+1] + .

[0253] Example 19 N-((4-((2-butyl-4-oxo-1,3-diazaspiro[4.4]non-1-en-3-yl)methyl)-2'-(N-(4,5-dimethylisoxazol-3-yl)sulfamoyl)-[1,1'-biphenyl-2-yl)methyl)-N,3,3-trimethylbutanamide [ka]

[0254] Step 1 Preparation of 4'-(((2-butyl-4-oxo-1,3-diazaspiro[4.4]non-1-en-3-yl)methyl)-N-(4-cyclopropyl-5-methylisoxazol-3-yl)-N-(methoxymethyl)-2'-((methylamino)methyl)-[1,1'-biphenyl]-2-sulfonamide Example 19-1 (104 mg, 0.15 mmol) (see Example 12-1 for the synthesis method) and potassium carbonate (63 mg, 0.45 mmol) were dissolved in dichloromethane (5 mL). Methylamine hydrochloride (30 mg, 0.45 mmol) was then added to the reaction solution, and the reaction solution was stirred at room temperature for 2 hours. Saturated brine (10 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (10 mL x 3). The organic phases were combined, dried, concentrated, and purified using a column (petroleum ether / ethyl acetate system) to obtain Example 19-2 (65 mg, 67.0%).

[0255] MS m / z (ESI): 648.3 [M+1] + .

[0256] Step 2 Preparation of N-((4-((2-butyl-4-oxo-1,3-diazaspiro[4.4]non-1-en-3-yl)methyl)-2'-(N-(4-cyclopropyl-5-methylisoxazol-3-yl)-N-(methoxymethyl)sulfamoyl)-[1,1'-biphenyl-2-yl)methyl)-N,3,3-trimethylbutanamide Example 19-2 (65 mg, 0.10 mmol), 3,3-dimethylbutyric acid (23 mg, 0.20 mmol), and 2-(7-azabenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (114 mg, 0.30 mmol) were dissolved in dichloromethane (5 mL). Triethylamine (38 mg, 0.30 mmol) was then added to the reaction mixture, and the mixture was stirred at room temperature for 2 h. Saturated brine (10 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (10 mL x 3). The organic phases were combined, dried, concentrated, and purified using a column (petroleum ether / ethyl acetate system) to obtain Example 19-3 (55 mg, 73.7%).

[0257] MS m / z(ESI):746.4[M+1] + .

[0258] Step 3 Preparation of N-((4-((2-butyl-4-oxo-1,3-diazaspiro[4.4]non-1-en-3-yl)methyl)-2'-(N-(4-cyclopropyl-5-methylisoxazol-3-yl)sulfamoyl)-[1,1'-biphenyl]-2-yl)methyl)-N,3,3-trimethylbutanamide The synthesis method of Example 19 was carried out in accordance with the synthesis method of Example 12, and the title compound Example 19 (36 mg, 58.5%) was obtained using Example 19-2 as the starting material.

[0259] MS m / z (ESI): 702.4 [M+1] + .

[0260] Example 20 N-((4'-((2-butyl-4-oxo-1,3-diazaspiro[4.4]non-1-en-3-yl)methyl)-2'-(ethoxymethyl)-[1,1'-biphenyl]-2-yl)sulfonyl)cyclopropanecarboxamide [ka]

[0261] Step 1 Preparation of 4'-((2-butyl-4-oxo-1,3-diazaspiro[4.4]non-1-en-3-yl)methyl)-2'-(ethoxymethyl)-[1,1'-biphenyl]-2-sulfonamide Ammonia gas was bubbled into a solution of Example 20-1 (2.35 g, 5 mmol) (see WO 2010135350A2 for the preparation method) in THF (30 mL) until saturated. The mixture was stirred at 25 ° C. for 12 hours. The organic phases were combined, dried, and concentrated. The residue was purified by silica gel column chromatography (dichloromethane / methanol system) to obtain Example 20-2 (2.05 g, 91%).

[0262] MS m / z (ESI): 498.2 [M+1] + .

[0263] Step 2 Preparation of N-((4'-((2-butyl-4-oxo-1,3-diazaspiro[4.4]non-1-en-3-yl)methyl)-2'-(ethoxymethyl)-[1,1'-biphenyl]-2-yl)sulfonyl)cyclopropanecarboxamide To a solution of Example 20-2 (100 mg, 0.2 mmol) in DCM (5 mL) were added cyclopropanecarboxylic acid chloride (88.2 mg, 0.84 mmol) and 1,8-diazabicycloundec-7-ene (756 mg, 3.01 mmol) at 25° C., and the mixture was stirred for 2 hours at 50° C. The reaction mixture was quenched by adding 5 mL of water, extracted with DCM (10 mL × 3), and the combined organic phases were dried, concentrated, and purified by preparative HPLC to obtain Example 20 (56 mg, 49.1%).

[0264] MS m / z (ESI): 566.3 [M+1] + .

[0265] Example 21 N-((4'-((2-butyl-4-oxo-1,3-diazaspiro[4.4]non-1-en-3-yl)methyl)-2'-(ethoxymethyl)-[1,1'-biphenyl]-2-yl)sulfonyl)picolinamide [ka]

[0266] The synthesis method of Example 21 was the same as that of Example 20, except that cyclopropanecarboxylic acid chloride was replaced with pyridinecarboxylic acid chloride to obtain Example 21 (65 mg, 60.4%).

[0267] MS m / z (ESI): 603.3 [M+1] + .

[0268] Example 22 N-((4'-((2-butyl-4-oxo-1,3-diazaspiro[4.4]non-1-en-3-yl)methyl)-2'-(ethoxymethyl)-[1,1'-biphenyl]-2-yl)sulfonyl)benzamide [ka]

[0269] The synthesis method of Example 22 was the same as that of Example 20, except that cyclopropanecarbonyl chloride was replaced with benzoyl chloride to obtain Example 22 (57 mg, 43.2%).

[0270] MS m / z (ESI): 602.3 [M+1] + .

[0271] Example 23 4'-((2-butyl-4-oxo-1,3-diazaspiro[4.4]non-1-en-3-yl)methyl)-2'-(ethoxymethyl)-N-(5-oxo-2,5-dihydro-1,2,4-oxadiazol-3-yl)-[1,1'-biphenyl]-2-sulfonamide [ka]

[0272] The synthesis method of Example 23 was the same as that of Example 20-2, except that 4-cyclopropyl-5-methylisoxazol-3-amine was used instead of ammonia gas to obtain Example 23 (45 mg, 39.5%).

[0273] MS m / z(ESI):619.3[M+1] + .

[0274] Example 24 4'-((2-butyl-4-oxo-1,3-diazaspiro[4.4]non-1-en-3-yl)methyl)-N-(5,6-dihydro-4H-cyclopenta[d]isoxazol-3-yl)-2'-(ethoxymethyl)-[1,1'-biphenyl]-2-sulfonamide [ka]

[0275] The synthesis method of Example 24 was the same as that of Example 20-2, except that 5,6-dihydro-4H-cyclopenta[d]isoxazol-3-amine was used instead of ammonia gas to obtain Example 24 (36 mg, 40.1%).

[0276] MS m / z (ESI): 605.3 [M+1] + .

[0277] Example 25 4'-((2-butyl-4-oxo-1,3-diazaspiro[4.4]non-1-en-3-yl)methyl)-2'-(ethoxymethyl)-N-(2H-tetrazol-5-yl)-[1,1'-biphenyl]-2-sulfonamide [ka]

[0278] Example 20-1 (100 mg, 0.19 mmol) was added dropwise to a solution of 1H-tetrazol-5-amine (16.5 mg, 0.19 mmol) and NaOH (15.5 mg, 0.38 mmol) in water (2 mL) at 70° C. The mixture was stirred for 3 hours. The mixture was acidified with concentrated hydrochloric acid in an ice bath and extracted with ethyl acetate (30 mL×3). The organic phases were combined, dried, and concentrated. The residue was purified by HPLC to give Example 25 (26 mg, 23.8%).

[0279] MS m / z (ESI): 566.7 [M + 1] + .

[0280] Example 26 4'-((2-butyl-4-oxo-1,3-diazaspiro[4.4]non-1-en-3-yl)methyl)-2'-(ethoxymethyl)-N-(5-oxo-2,5-dihydro-1,2,4-oxadiazol-3-yl)-[1,1'-biphenyl]-2-sulfonamide [ka]

[0281] The synthesis method of Example 26 was the same as that of Example 25, except that 1H-tetrazol-5-amine was replaced with 3-amino-1,2,4-oxadiazol-5(2H)-one to obtain Example 26 (36 mg, 33.1%).

[0282] MS m / z (ESI): 582.2 [M+1] + .

[0283] Example 27 4'-((2-butyl-4-oxo-1,3-diazaspiro[4.4]non-1-en-3-yl)methyl)-N-(cyclopropylsulfonyl)-2'-(ethoxymethyl)-[1,1'-biphenyl]-2-carboxamide [ka]

[0284] Step 1 Preparation of 4'-((2-butyl-4-oxo-1,3-diazaspiro[4.4]non-1-en-3-yl)methyl)-2'-(ethoxymethyl)-[1,1'-biphenyl]-2-carboxylic acid A round-bottom flask was charged with Example 6-2 (2.35 g, 5 mmol), 2-bromobenzoic acid (0.99 g, 5 mmol), Pd(dppf)Cl*DCM (200 mg, 0.25 mmol), CsCO (3.26 g, 10 mmol), 1',4-dioxane (25 mL), and HO (5 mL). The mixture was stirred at 80 °C for 12 h under N protection. The reaction mixture was quenched by adding 20 mL of dilute hydrochloric acid (1 M) and extracted with ethyl acetate (30 mL × 3). The organic phases were combined, dried, and concentrated. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate system) to give Example 27-1 (1.69 g, 73.3%).

[0285] MS m / z(ESI):463.3[M+1] + .

[0286] Step 2 Preparation of 4'-((2-butyl-4-oxo-1,3-diazaspiro[4.4]non-1-en-3-yl)methyl)-N-(cyclopropylsulfonyl)-2'-(ethoxymethyl)-[1,1'-biphenyl]-2-carboxamide Cyclopropylmethanesulfonamide (36 mg, 0.3 mmol) was added to a solution of Example 27-1 (100 mg, 0.22 mmol), EDCI (58 mg, 0.3 mmol), and DMAP (37 mg, 0.3 mmol) in DCM (5 mL) at 25° C., and the mixture was stirred overnight for 12 hours at 25° C. The reaction mixture was quenched by adding 5 mL of water, extracted with DCM (10 mL × 3), and the combined organic phases were dried, concentrated, and purified by preparative HPLC to give the title product Example 27 (48 mg, 39.2%).

[0287] MS m / z (ESI): 566.3 [M+1] + .

[0288] Example 28 4'-((2-butyl-4-oxo-1,3-diazaspiro[4.4]non-1-en-3-yl)methyl)-2'-(ethoxymethyl)-N-(2H-tetrazol-5-yl)-[1,1'-biphenyl]-2-carboxamide [ka]

[0289] The synthesis method of Example 28 was the same as that of Example 27, except that cyclopropanesulfonamide was replaced with 2H-tetrazol-5-amine to obtain Example 28 (62 mg, 58.2%).

[0290] MS m / z (ESI): 530.3 [M+1] + .

[0291] Example 29 4'-(2-butyl-4-oxo-1,3-diazaspiro[4.4]non-1-en-3-yl)methyl)-2'-(ethoxymethyl)-N-(benzenesulfonyl)-[1,1'-biphenyl]-2-carboxamide [ka]

[0292] The synthesis method of Example 29 was the same as that of Example 27, except that cyclopropanesulfonamide was replaced with benzenesulfonamide to obtain Example 29 (62 mg, 58.2%).

[0293] MS m / z (ESI): 602.3 [M+1] + .

[0294] Example 30 Methyl ((4'-((2-butyl-4-oxo-1,3-diazaspiro[4.4]non-1-en-3-yl)methyl)-2'-(ethoxymethyl)-[1,1'-biphenyl]-2-yl)sulfonyl)carbamate [ka]

[0295] The synthesis method of Example 30 was the same as that of Example 20, except that cyclopropanecarbonyl chloride was replaced with methyl chloroformate to obtain Example 30 (66 mg, 52.2%).

[0296] MS m / z (ESI): 556.2 [M+1] + .

[0297] Example 31 Cyclopropyl((4'-((2-butyl-4-oxo-1,3-diazaspiro[4.4]non-1-en-3-yl)methyl)-2'-(ethoxymethyl)-[1,1'-biphenyl]-2-yl)sulfonyl)carbamate [ka]

[0298] The synthesis method of Example 31 was the same as that of Example 20, except that cyclopropanecarbonyl chloride was replaced with cyclopropyl chloroformate to obtain Example 31 (45 mg, 41.3%).

[0299] MS m / z (ESI): 582.3 [M+1] + .

[0300] Example 32 Benzyl ((4'-((2-butyl-4-oxo-1,3-diazaspiro[4.4]non-1-en-3-yl)methyl)-2'-(ethoxymethyl)-[1,1'-biphenyl]-2-yl)sulfonyl)carbamate [ka]

[0301] The synthesis method of Example 32 was the same as that of Example 20, except that cyclopropanecarbonyl chloride was replaced with benzyl chloroformate to obtain Example 32 (65 mg, 60.5%).

[0302] MS m / z (ESI): 632.3 [M+1] + .

[0303] Example 33 4'-(2-butyl-4-oxo-1,3-diazaspiro[4.4]non-1-en-3-yl)methyl)-2'-(ethoxymethyl)-N-(isopropylcarbamoyl)-[1,1'-biphenyl]-2-sulfonamide [ka]

[0304] Pyridine (32 μL, 0.39 mmol) and Example 20-1 (0.1 g, 0.19 mmol) were mixed and stirred for 5 minutes, followed by the addition of a solution of sodium cyanate (18.9 mg, 0.29 mmol) in acetonitrile (5 mL). The mixture was stirred at room temperature for 4 hours, and isopropylamine (17.2 mg, 0.29 mmol) was added, followed by stirring at room temperature for approximately 1 hour. The reaction mixture was acidified with dilute hydrochloric acid (pH 5-6) in an ice bath, and the aqueous layer was extracted three times with ethyl acetate. The organic layers were combined, washed with saturated brine, and dried over anhydrous sodium sulfate. The mixture was concentrated under reduced pressure and purified by HPLC to give Example 33 (59 mg, 52%).

[0305] MS m / z (ESI): 583.8 [M+1] + .

[0306] Example 34 4'-(2-butyl-4-oxo-1,3-diazaspiro[4.4]non-1-en-3-yl)methyl)-2'-(ethoxymethyl)-N-(propylcarbamoyl)-[1,1'-biphenyl]-2-sulfonamide [ka]

[0307] The synthesis method of Example 34 was the same as that of Example 33, except that isopropylamine was replaced with n-propylamine to obtain Example 34 (68 mg, 63.1%).

[0308] MS m / z (ESI): 583.3 [M+1] + .

[0309] Example 35 4'-(2-butyl-4-oxo-1,3-diazaspiro[4.4]non-1-en-3-yl)methyl)-2'-(ethoxymethyl)-N-(phenylcarbamoyl)-[1,1'-biphenyl]-2-sulfonamide [ka]

[0310] The synthesis method of Example 35 was the same as that of Example 33, except that isopropylamine was replaced with aniline to obtain Example 35 (58 mg, 45.2%).

[0311] MS m / z(ESI):617.3[M+1] + .

[0312] Example 36 4'-(2-butyl-4-oxo-1,3-diazaspiro[4.4]non-1-en-3-yl)methyl)-2'-(ethoxymethyl)-N-(cyclopropylcarbamoyl)-[1,1'-biphenyl]-2-sulfonamide [ka]

[0313] The synthesis method of Example 36 was the same as that of Example 33, except that cycloisopropylamine was replaced with cyclopropylamine to obtain Example 36 (53 mg, 48.3%).

[0314] MS m / z (ESI): 581.3 [M+1] + .

[0315] Example 37 4'-(2-butyl-4-oxo-1,3-diazaspiro[4.4]non-1-en-3-yl)methyl)-2'-(ethoxymethyl)-N-(ethylcarbamoyl)-[1,1'-biphenyl]-2-sulfonamide [ka]

[0316] The synthesis method of Example 37 was the same as that of Example 33, except that cyclopropanecarbonyl chloride was replaced with ethyl isocyanate to obtain Example 37 (64 mg, 60.5%).

[0317] MS m / z (ESI): 569.3 [M+1] +.

[0318] Example 38 N-(N-(4'-((2-butyl-4-oxo-1,3-diazaspiro[4.4]non-1-en-3-yl)methyl)-2'-(ethoxymethyl)-[1,1'-biphenyl]-2-yl)sulfonamido)benzamide [ka]

[0319] Step 1 Preparation of 3-((2'-amino-2-(ethoxymethyl)-[1,1'-biphenyl]-4-yl)methyl)-2-butyl-1,3-diazaspiro[4.4]non-1-en-4-one A round-bottom flask was charged with Example 6-2 (2.35 g, 5 mmol), 2-bromoaniline (0.86 g, 5 mmol), Pd(dppf)Cl*DCM (200 mg, 0.25 mmol), CsCO (3.26 g, 10 mmol), 1'4-Dioxane (25 mL), and HO (5 mL). The mixture was stirred at 80 °C for 12 h under N protection. The reaction mixture was quenched by adding 30 mL of water and extracted three times with 30 mL of ethyl acetate. The organic phases were combined, dried, and concentrated. The residue was purified by silica gel column chromatography (ethyl acetate / petroleum ether) to give Example 38-1 (1.61 g, 75.2%).

[0320] MS m / z(ESI):434.3[M+1] + .

[0321] Step 2 Preparation of 3-((2'-sulfonylurea-2-(ethoxymethyl)-[1,1'-biphenyl]-4-yl)methyl)-2-butyl-1,3-diazaspiro[4.4]non-1-en-4-one At 0°C, tert-butanol (0.85 g, 11.48 mmol) in anhydrous dichloromethane (10 mL) was added to a stirred solution of chlorosulfonyl isocyanate (1.62 g, 11.48 mmol) in anhydrous dichloromethane (10 mL). After 30 min, the resulting solution (1.75 mL, 0.91 mmol) was taken at 0°C and slowly added to a solution of Example 38-1 (0.36 g, 0.83 mmol) in anhydrous dichloromethane (5 mL). The reaction solution was allowed to warm to room temperature and stirred for 2 h. The reaction mixture was diluted with dichloromethane (30 mL). The mixture was washed sequentially with 0.1 N dilute hydrochloric acid (20 mL) and water (25 mL). The organic layer was dried over anhydrous sodium sulfate and concentrated in vacuo. The resulting crude product was refluxed in distilled water (30 mL) for 15-30 min. The reaction mixture was extracted with ethyl acetate (3 × 30 mL), and the organic phases were combined, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and then purified by silica gel column chromatography (ethyl acetate / petroleum ether system) to obtain Example 38-2 (0.31 g, 72.9%).

[0322] MS m / z (ESI): 513.3 [M+1] + .

[0323] Step 3 Preparation of N-(N-(4'-((2-butyl-4-oxo-1,3-diazaspiro[4.4]non-1-en-3-yl)methyl)-2'-(ethoxymethyl)-[1,1'-biphenyl]-2-yl)sulfamoyl benzamide The synthesis method of Example 38 was the same as that of Example 20, except that cyclopropanecarboxylic acid chloride was replaced with benzoyl chloride to obtain Example 38 (180 mg, 48.4%).

[0324] MS m / z(ESI):617.3[M+1] + .

[0325] Example 39 N-(4'-((2-butyl-4-oxo-1,3-diazaspiro[4.4]non-1-en-3-yl)methyl)-2'-(ethoxymethyl)-[1,1'-biphenyl]-2-yl)-5-methylpyridine-2-sulfonamide [ka]

[0326] The synthesis method of Example 39 was carried out in accordance with the synthesis method of Example 20, using Example 38-1 as the starting material and 5-methylpyridine-2-sulfonyl chloride instead of cyclopropanecarboxylic acid chloride to obtain Example 39 (80 mg, 56.2%).

[0327] MS m / z (ESI): 589.3 [M + 1] + .

[0328] Example 40 N-(4'-((2-butyl-4-oxo-1,3-diazaspiro[4.4]non-1-en-3-yl)methyl)-2'-(ethoxymethyl)-[1,1'-biphenyl]-2-yl)-4,5-dimethylisoxazole-3-sulfonamide [ka]

[0329] The synthesis method of Example 40 was carried out in accordance with the synthesis method of Example 20, using Example 38-1 as the starting material and 4,5-dimethylisoxazole-3-sulfonyl chloride instead of cyclopropanecarboxylic acid chloride to obtain Example 40 (53 mg, 62.1%).

[0330] MS m / z (ESI): 593.3 [M+1] + .

[0331] Example 41 2'-(Benzyloxy)-4'-(2-butyl-4-oxo-1,3-diazaspiro[4.4]nonan-1-en-3-yl)methyl)-N-(4,5-dimethylisoxazol-3-yl)-[1,1'-biphenyl]-2-sulfonamide [ka]

[0332] Step 1 Preparation of ethyl 3-(benzyloxy)-4-bromobenzoate To a solution of Example 41-1 (5 g, 20.40 mmol) in DMF (50 mL), benzyl bromide (3.5 g, 20.40 mmol) and potassium carbonate (5.63 g, 40.80 mmol) were slowly added, and the mixture was stirred at 80° C. for 2 hours. After cooling, the reaction mixture was diluted with 100 mL of ethyl acetate and washed with water (50 mL * 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by silica gel column chromatography using eluent system B to give the title product Example 41-2 (6.50 g, colorless liquid) in a 95.1% yield.

[0333] 1 H NMR(400MHz,Chloroform-d)δ 7.63(d,J=8.1Hz,2H),7.51(dd,J=9.3,7.5Hz,3H),7.44-7.37(m,2H),7.37-7.31(m,1H),5.21(s,2H),3.91(s,3H).

[0334] Step 2 Preparation of (3-(benzyloxy)-4-bromophenyl)methanol Under nitrogen gas protection, DIBAL-H (1M, 50.60 mL) was slowly added to a solution of Example 41-2 (6.5 g, 20.24 mmol) in DCM (60 mL) at 0 °C, and the mixture was stirred at 25 °C for 1 hour. The reaction mixture was quenched by adding ice-cold 5% NaOH (60 mL) and extracted with dichloromethane (50 mL * 3). The organic phases were combined, dried, and concentrated to give the title product Example 41-3 (6.50 g, colorless liquid), which was used directly in the next step.

[0335] Step 3 Preparation of 3-(3-(benzyloxy)-4-bromophenyl)-2-butyl-1,3-diazaspiro[4.4]nonan-1-en-4-one Under nitrogen gas protection, methanesulfonyl chloride (4.53 g, 39.57 mmol) and ethyldiisopropylamine (7.67 g, 59.35 mmol, 10.34 mL) were added to a solution of Example 41-3 (5.8 g, 19.78 mmol) in DCM (30 mL) at 0 ° C., and the mixture was stirred at room temperature for 1 hour. Subsequently, 10 mL of ice water was added to quench the reaction, and the lower organic phase solution was collected and added to a mixture of methyltributylammonium chloride (0.4 mL, 75% purity), 2-butyl-1,3-diazaspiro[4.4]nonan-1-en-4-one hydrochloride (4.57 g, 19.78 mmol), aqueous sodium hydroxide solution (10 M, 13.16 mL) and DCM (30 mL) at room temperature, and the reaction was continued for 2 hours. The reaction mixture was quenched by adding water (30 mL) and extracted with dichloromethane (30 mL*3). The organic layers were combined, dried and concentrated. The residue was purified by silica gel column chromatography using eluent system B to give the title product Example 41-4 (8.60 g, pale yellow oil) with a yield of 92.6%.

[0336] MS m / z (ESI): 469.0 [M+1] + . 1H NMR(400MHz,Chloroform-d)δ 7.51(d,J=8.0Hz,1H),7.45-7.41(m,2H),7.38(dd,J=8.3,6.5Hz,2H),7.3 4-7.29(m,1H),6.72(d,J=1.9Hz,1H),6.64(dd,J=8.0,1.9Hz,1H),5.12(s ,2H),4.60(s,2H),2.26(t,J=8.1Hz,2H),2.02-1.93(m,6H),1.82(d,J=9. 7Hz,2H),1.58-1.51(m,2H),1.31(t,J=7.5Hz,2H),0.87(t,J=7.3Hz,3H).

[0337] Step 4 Preparation of 3-(3-(benzyloxy)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborin-2-yl)benzyl)-2-butyl-1,3-diazaspirocyclo[4.4]nonan-1-en-4-one A reactor was charged with Example 41-4 (1 g, 2.13 mmol), Pd(dppf)Cl*DCM (174 mg, 213.03 μmol), potassium acetate (626 mg, 6.39 mmol), boronic acid pinacol ester (650 mg, 2.56 mmol), and 1',4-dioxane (10 mL). The mixture was stirred at 90 °C for 12 hours under nitrogen gas protection. After cooling, the reaction mixture was quenched by adding 10 mL of water and extracted with ethyl acetate (15 mL * 3). The organic phases were combined, dried, and concentrated to give the title product Example 41-5 (600 mg, reddish-brown oil), which was used directly in the next step.

[0338] Step 5 Preparation of 2'-(benzyloxy)-4'-(2-butyl-4-oxo-1,3-diazaspiro[4.4]nonan-1-en-3-yl)methyl)-N-(4,5-dimethylisoxazol-3-yl)-N-(methoxymethyl)-[1,1'-biphenyl]-2-sulfonamide A reactor was charged with Example 41-5 (0.6 g, 1.16 mmol), 2-bromo-N-(4,5-dimethylisoxazol-3-yl)-N-(methoxymethyl)benzenesulfonamide (436 mg, 1.16 mmol), Pd(dppf)Cl*DCM (94.80 mg, 116.17 μmol), potassium carbonate (320.63 mg, 2.32 mmol), 1′,4-dioxane (10 mL), and HO (2 mL). The mixture was stirred at 100° C. for 12 hours under nitrogen gas protection. After cooling, the reaction mixture was quenched by adding 8 mL of water and extracted with ethyl acetate (10 mL*3). The organic phases were combined, dried, and concentrated. The residue was purified by silica gel column chromatography using eluent system B to give the title product Example 41-6 (650 mg, light brown solid) in 81.7% yield.

[0339] MS m / z (ESI): 685.1 [M+1] + . 1 H NMR(400MHz,Chloroform-d)δ 8.02(d,J=8.0Hz,1H),7.56(td,J=7.6,1.3Hz,1H),7.47-7.43(m,1H),7.25-7.21(m,4H),7.19-7 .16(m,2H),7.15-7.10(m,1H),6.77-6.73(m,2H),5.01(d,J=6.0Hz,2H),4.70(d,J=6.4Hz,2H),4 .58(d,J=10.9Hz,1H),4.42(d,J=10.8Hz,1H),3.31(s,3H),2.34(s,2H),2.28(s,3H),1.96(d,J= 10.5Hz,6H),1.89(s,3H),1.83(s,2H),1.58(d,J=7.8Hz,2H),1.36(d,J=8.3Hz,2H),0.90(s,3H).

[0340] Step 6 Preparation of 2'-(benzyloxy)-4'-(2-butyl-4-oxo-1,3-diazaspiro[4.4]nonan-1-en-3-yl)methyl)-N-(4,5-dimethylisoxazol-3-yl)-[1,1'-biphenyl]-2-sulfonamide Example 41-6 (50 mg, 73.01 μmol) and HCl / Dioxane (4 M, 5.00 mL) were added to a round-bottom flask, and the mixture was stirred at 70° C. for 1 hour. After cooling, the reaction mixture was concentrated and purified by preparative HPLC to give the title product Example 41 (14 mg, white solid) in a yield of 29.6%.

[0341] MS m / z (ESI): 641.0 [M+1] + . 1 H NMR(400MHz,DMSO-d6)δ 10.40(s,1H),8.13-8.04(m,1H),7.56(d,J=11.9Hz,2H),7.22(q,J=4.8,4.4Hz,4H),7.15-7.06 (m,2H),6.98(d,J=7.7Hz,1H),6.82(s,1H),6.65(d,J=7.7Hz,1H),4.96(d,J=12.7Hz,1H),4.86 (d,J=12.6Hz,1H),4.68(s,2H),2.31(t,J=7.5Hz,2H),2.10(s,3H),1.83(d,J=8.6Hz,6H),1.66 (d,J=7.1Hz,2H),1.61(s,3H),1.48(q,J=7.6Hz,2H),1.31-1.26(m,2H),0.82(t,J=7.3Hz,3H).

[0342] Example 42 4'-(2-butyl-4-oxo-1,3-diazaspiro[4.4]nonan-1-en-3-yl)methyl)-N-(4,5-dimethylisoxazol-3-yl)-2'-(2,2,2-trifluoroethoxy)-[1,1'-biphenyl]-2-sulfonamide [ka]

[0343] Step 1 Preparation of 4'-((2-butyl-4-oxo-1,3-diazaspiro[4.4]nonan-1-en-3-yl)methyl)-N-(4,5-dimethylisoxazol-3-yl)-2'-hydroxy-N-(methoxymethyl)-[1,1'-biphenyl]-2-sulfonamide A round-bottom flask was charged with Example 41-6 (600 mg, 876.11 μmol), wet palladium on carbon (150 mg), and MeOH (10 mL). The mixture was stirred at 20° C. for 24 hours under a hydrogen gas atmosphere. The reaction mixture was filtered and concentrated to give the title product Example 42-1 (600 mg, pale yellow solid) in a yield of 96.0%.

[0344] MS m / z (ESI): 595.0 [M+1] + .

[0345] Step 2 Preparation of 4'-((2-butyl-4-oxo-1,3-diazaspiro[4.4]nonan-1-en-3-yl)methyl)-N-(4,5-dimethylisoxazol-3-yl)-N-(methoxymethyl)-2'-(2,2,2-trifluoroethoxy)-[1,1'-biphenyl]-2-sulfonamide To a solution of Example 42-1 (30 mg, 50.44 μmol) in DMF (1 mL) were added potassium carbonate (13.92 mg, 100.89 μmol) and trifluoromethyl trifluoromethanesulfonate (58.51 mg, 252.22 μmol), and the mixture was stirred at 80° C. for 1 hour. After the reaction was cooled, it was quenched by adding 5 mL of water and extracted with ethyl acetate (6 mL*3). The organic phases were combined, dried, and concentrated. The residue was purified by silica gel column chromatography using eluent system B to give the title product Example 42-2 (26 mg, light brown solid) in a yield of 73.2%.

[0346] MS m / z (ESI): 677.2 [M+1] + .

[0347] Step 3 Preparation of 4'-(2-butyl-4-oxo-1,3-diazaspiro[4.4]nonan-1-en-3-yl)methyl)-N-(4,5-dimethylisoxazol-3-yl)-2'-(2,2,2-trifluoroethoxy)-[1,1'-biphenyl]-2-sulfonamide Example 42-2 (26 mg, 38.53 μmol) and HCl / Dioxane (4 M, 5 mL) were added to a round-bottom flask, and the mixture was stirred at 70° C. for 1 hour. After cooling, the reaction mixture was concentrated and purified by preparative HPLC to give the title product Example 42 (14 mg, white solid) in a yield of 39.8%.

[0348] MS m / z (ESI): 633.1 [M+1] + . 1 H NMR(400MHz,DMSO-d6)δ 10.44(s,1H),8.04(dd,J=7.7,1.6Hz,1H),7.57(d,J=11.1Hz,2H),7.21-7.16(m,1H),6.9 9(s,2H),6.71(d,J=7.5Hz,1H),4.71(s,2H),4.57(d,J=11.3Hz,1H),4.38(t,J=10.4Hz,1H) ),2.36(t,J=7.5Hz,2H),2.18(s,3H),2.00(d,J=7.7Hz,1H),1.91-1.81(m,5H),1.69(d,J =8.5Hz,2H),1.63(s,3H),1.53(p,J=7.5Hz,2H),1.33-1.28(m,2H),0.83(t,J=7.5Hz,3H).

[0349] Example 43 2-(2-butyl-1-((2'-(N-(4,5-dimethylisoxazol-3-yl)sulfamoyl)-2-(ethoxymethyl)-[1,1'-biphenyl]-4-yl)methyl-d2)-4-methyl-6-oxo-1,6-dihydropyrimidin-5-yl)-N,N-dimethylethylthioamide [ka]

[0350] Step 1 Preparation of 4'-(bromomethyl-d2)-N-(4,5-dimethylisoxazol-3-yl)-2'-(ethoxymethyl)-N-(methoxymethyl)-[1,1'-biphenyl]-2-sulfonamide Under nitrogen gas protection, carbon tetrabromide (1.60 g, 4.86 mmol) and triphenylphosphine (1.02 g, 3.89 mmol) were added to a solution of Example 1-2 (900 mg, 1.95 mmol) in DCM (20 mL) at 0° C., and the mixture was stirred at 20° C. for 1 hour. The reaction mixture was quenched by adding water (30 mL), extracted with dichloromethane (30 mL*3), the organic phases were combined, dried and concentrated, and the residue was purified by silica gel column chromatography using eluent system B to obtain the title product Example 43-1 (1 g, white solid) in a yield of 97.8%.

[0351] MS m / z (ESI): 525.1 [M+1] + .

[0352] Step 2 Preparation of 2-(2-butyl-1-((2'-(N-(4,5-dimethylisoxazol-3-yl)-N-(methoxymethyl)sulfamoyl)-2-(ethoxymethyl)-[1,1'-biphenyl]-4-yl)methyl-d2)-4-methyl-6-oxo-1,6-dihydropyrimidin-5-yl)-N,N-dimethylacetamide To a solution of Example 43-1 (180 mg, 342.56 μmol) in MeCN (6 mL) were added potassium carbonate (94.55 mg, 685.13 μmol) and 2-(2-butyl-4-methyl-6-oxo-1H-pyrimidin-5-yl)-N,N-dimethylacetamide (86.09 mg, 342.56 μmol), and the mixture was stirred at 70° C. for 1 hour. The reaction was quenched by adding water (20 mL) and extracted with dichloromethane (20 mL*3). The organic phases were combined, dried, and concentrated. The residue was purified by silica gel column chromatography using eluent system B to give the title product Example 43-2 (80 mg, pale yellow solid) in a yield of 33.6%.

[0353] MS m / z (ESI): 696.3 [M+1] + .

[0354] Step 3 Preparation of 2-(2-butyl-1-((2'-(N-(4,5-dimethylisoxazol-3-yl)-N-(methoxymethyl)sulfamoyl)-2-(ethoxymethyl)-[1,1'-biphenyl]-4-yl)methyl-d2)-4-methyl-6-oxo-1,6-dihydropyrimidin-5-yl)-N,N-dimethylethylthioamide To a solution of Example 43-2 (80 mg, 114.97 μmol) in toluene (5 mL) was added Lawesson's reagent (139.34 mg, 344.90 μmol), and the mixture was stirred at 70° C. for 1 hour under nitrogen gas protection. After cooling, the reaction mixture was quenched by adding water (10 mL), extracted with dichloromethane (10 mL * 3), the organic phases were combined, dried and concentrated, and the residue was purified by silica gel column chromatography using eluent system B to obtain the title product Example 43-3 (50 mg, pale yellow solid) in a yield of 61.1%.

[0355] MS m / z (ESI): 712.0 [M+1] + .

[0356] Step 4 Preparation of 2-(2-butyl-1-((2'-(N-(4,5-dimethylisoxazol-3-yl)sulfamoyl)-2-(ethoxymethyl)-[1,1'-biphenyl]-4-yl)methyl-d2)-4-methyl-6-oxo-1,6-dihydropyrimidin-5-yl)-N,N-dimethylethylthioamide Example 43-3 (50 mg, 70.23 μmol) and HCl / Dioxane (4 M, 5 mL) were added to a round-bottom flask, and the mixture was stirred at 70° C. for 1 hour. After cooling, the reaction mixture was concentrated and purified by preparative HPLC to give the title product Example 43 (9 mg, white solid) in an 18.8% yield.

[0357] MS m / z (ESI): 668.1 [M+1] + . 1 H NMR(400MHz,DMSO-d6)δ 10.51(s,1H),8.04(dd,J=7.5,1.8Hz,1H),7.60(d,J=7.9Hz,2H),7.25(s,1H),7.17(d,J=7.1H z,1H),6.97(dd,J=8.3,1.7Hz,1H),6.89(d,J=7.8Hz,1H),4.02-3.93(m,2H),3.80(s,2H),3.47 (s,3H),3.42(s,3H),3.23-3.12(m,2H),2.65(d,J=8.1Hz,2H),2.18(d,J=5.1Hz,6H),1.64(s, 3H),1.58(q,J=7.7Hz,2H),1.30(d,J=7.5Hz,2H),0.98(t,J=7.0Hz,3H),0.84(t,J=7.4Hz,3H).

[0358] Example 44 4'-((2-butyl-4-oxo-1,3-diazaspiro[4.4]nonan-1-en-3-yl)methyl-d2)-N-(4-chloro-5-methylisoxazol-3-yl)-2'-(ethoxymethyl)-[1,1'-biphenyl]-2-sulfonamide [ka]

[0359] Method 1: The synthesis method of Example 44 was the same as that of Example 1, except that 4,5-dimethylisoxazoleamine was replaced with 4-chloro-5-methylisoxazoleamine to obtain Example 44 (51 mg, white solid), with a yield of 50.3%.

[0360] Method 2: [ka]

[0361] Step 1 Preparation of (4-bromo-3-(ethoxymethyl)phenyl)-d2methanol Example 44-1 (1.0 g, 3.48 mmol) (see WO 2010114801A1 for the preparation method) and lithium aluminum tetrahydrogen deuteride (219.3 mg, 5.22 mmol) were dissolved in tetrahydrofuran (20 mL), the reaction mixture was cooled to 0°C, and the mixture was stirred for 2 hours. Saturated brine (50 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (2 x 100 mL). The organic phases were combined, dried over anhydrous sodium sulfate, concentrated, and purified using a silica gel chromatography column (petroleum ether / ethyl acetate system) to obtain Example 44-2 (850 mg, 98%).

[0362] MS m / z (ESI): 248.1 [M+1] + .

[0363] Step 2 Preparation of 4-bromo-3-(ethoxymethyl)benzyl-d2 methanesulfonate Methanesulfonyl chloride (433.4 mg, 3.78 mmol) and diisopropylethylamine (1.33 g, 10.32 mmol) were added to a solution of Example 44-2 (50 mg, 3.44 mmol) in dichloromethane (20 mL) under ice bath conditions, and the reaction mixture was warmed to room temperature and stirred for 1 h. The reaction mixture was concentrated to give crude Example 44-3 (1.1 g, 98%), which was used directly in the next step.

[0364] MS m / z (ESI): 326.2 [M+1] + .

[0365] Step 3 Preparation of 3-(4-bromo-3-(ethoxymethyl)phenyl)methyl-d2)-2-butyl-1,3-diazaaspirin[4.4]non-1-en-4-one Example 44-3 (1.1 g, 3.38 mmol) was dissolved in DMF (15 mL), and potassium carbonate (1.03 g, 7.44 mmol) and 2-butyl-1,3-diazaspirocyclo[4,4]nonan-1-en-4-one (858.4 mg, 3.72 mmol) were added under ice bath conditions. The reaction mixture was stirred at room temperature for 2 h. The reaction mixture was concentrated, and the crude product was purified by HPLC to give Example 44-4 (1.2 g, 86%).

[0366] MS m / z(ESI):424.4[M+1] + .

[0367] Step 4 Preparation of 2-butyl-3-((3-(ethoxymethyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)methyl-d2)-1,3-diazaspiro[4.4]non-1-en-4-one Compound 44-4 (1.2 g, 2.86 mmol) was dissolved in 15 mL of 1,4-dioxane, and bis(pinacolato)diboron (0.87 g, 3.4 mmol), 1,1'-bis(diphenylphosphino)ferrocenepalladium dichloride (102.9 mg, 0.14 mmol), and potassium acetate (0.84 g, 8.56 mmol) were added. Under nitrogen gas protection, the mixture was heated to 80 °C and stirred for 3 h. The reaction mixture was cooled to room temperature, saturated sodium chloride solution (50 mL) was added, and the mixture was extracted with ethyl acetate (100 mL × 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified using silica gel chromatography with an eluent system (ethyl acetate / petroleum ether = 10-50%) to give Example 44-5 (1.0 g, 80.0%).

[0368] MS m / z (ESI): 471.5 [M+1] + .

[0369] Step 5 Preparation of 4'-(2-butyl-4-oxo-1,3-diazaspiro[4.4]non-1-en-3-ylmethyl-d2)-n-(4-chloro-5-methylisoxazol-3-yl)-2'-(ethoxymethyl)-n-(2-trimethylsilylethoxy)methyl)-[1,1'-biphenyl]-2-sulfonamide Example 44-5 (0.5 g, 1.07 mmol) was dissolved in 20 mL of 1,4-dioxane and water (2 mL), and Intermediate 1 (0.4 g, 1.07 mmol), 1,1'-bis(diphenylphosphino)ferrocene palladium dichloride (0.039 g, 0.053 mmol), and potassium carbonate (0.3 g, 3.2 mmol) were added. Under nitrogen gas protection, the mixture was heated to 90 °C and stirred for 16 hours. The reaction mixture was cooled to room temperature, saturated sodium chloride solution (50 mL) was added, and the mixture was extracted with ethyl acetate (100 mL × 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by silica gel chromatography using an eluent system (ethyl acetate / petroleum ether = 10-50%) to give Example 44-6 (0.45 g, gray solid) in 66.0% yield.

[0370] MS m / z(ESI):746.4[M+1] + .

[0371] Step 6 Preparation of 4'-(2-butyl-4-oxo-1,3-diazaspiro[4.4]non-1-en-3-ylmethyl-d2)-n-(4-chloro-5-methylisoxazol-3-yl)-2'-(ethoxymethyl)-[1,1'-biphenyl]-2-sulfonamide Example 44-6 (0.45 g, 0.7 mmol) was dissolved in 10 mL of 4 M HCl / dioxane, and the mixture was heated to 70 °C and stirred for 2 hours. The reaction mixture was cooled to room temperature, saturated sodium chloride solution (50 mL) was added, and the mixture was extracted with ethyl acetate (100 mL × 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated. Example 44 (0.2 g, 50.0%) was obtained from the residue using silica gel chromatography with eluent system p-HPLC (FA).

[0372] MS m / z(ESI):615.2[M+1] + . 1 H NMR (400 MHz, DMSO-d6) δ 8.05-7.97(m,1H),7.54(s,2H),7.22-7.12(m,2H),6.99(s,2H),4.08(d,J=13. 1Hz,1H),3.99(d,J=13.1Hz,1H),3.21(ddd,J=9.4,7.0,3.6Hz,2H),2.35(t,J=7 .5Hz,2H),2.25(s,3H),1.85(d,J=8.5Hz,6H),1.69(d,J=8.8Hz,2H),1.50(q,J= 7.7Hz,2H),1.28(d,J=7.6Hz,2H),1.01(t,J=6.9Hz,3H),0.82(t,J=7.3Hz,3H).

[0373] Example 45 2-[4-[(2-butyl-4-oxo-1,3-diazaspiro[4.4]nonan-1-en-3-yl)methyl]-2-(ethoxymethyl)phenyl]-N-(4-chloro-5-methyl-isoxazol-3-yl)benzenesulfonamide [ka]

[0374] Method 1: The synthesis method of Example 45 was the same as that of Example 1, except that 4,5-dimethylisoxazoleamine was replaced with 4-chloro-5-methylisoxazoleamine to obtain Example 45 (56.6 mg, white solid), with a yield of 45.8%.

[0375] Method 2: [ka] Step 1 Preparation of 4'-(2-butyl-4-oxo-1,3-diazaspiro[4.4]non-1-en-3-ylmethyl)-n-(4-chloro-5-methylisoxazol-3-yl)-2'-(ethoxymethyl)-n-(2-trimethylsilylethoxy)methyl)-[1,1'-biphenyl]-2-sulfonamide Example 45-1 (0.3 g, 0.64 mmol) (see WO 2010114801A1 for the preparation method) was dissolved in 10 mL of 1,4-dioxane and water (1 ml), and Intermediate 1 (0.24 g, 0.64 mmol), 1,1'-bis(diphenylphosphino)ferrocene palladium dichloride (0.023 g, 0.032 mmol), and potassium carbonate (0.18 g, 1.9 mmol) were added. Under nitrogen gas protection, the mixture was heated to 90 °C and reacted with stirring for 16 hours. The reaction mixture was cooled to room temperature, saturated sodium chloride solution (50 mL) was added, and the mixture was extracted with ethyl acetate (100 mL × 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by silica gel chromatography with an eluent system (ethyl acetate / petroleum ether=10-50%) to obtain Example 45-2 (0.27 g, gray solid), the yield was 66.0%.

[0376] MS m / z (ESI): 744.4 [M+1] + .

[0377] Step 2 Preparation of 4'-(2-butyl-4-oxo-1,3-diazaspiro[4.4]non-1-en-3-ylmethyl)-n-(4-chloro-5-methylisoxazol-3-yl)-2'-(ethoxymethyl)-[1,1'-biphenyl]-2-sulfonamide Example 45-2 (0.27 g, 0.7 mmol) was dissolved in 10 mL of 4 M HCl / dioxane, and the mixture was heated to 70 °C and stirred for 2 hours. The reaction mixture was cooled to room temperature, saturated sodium chloride solution (50 mL) was added, and the mixture was extracted with ethyl acetate (100 mL × 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated. Example 45 (0.12 g, 54.5%) was obtained from the residue using silica gel chromatography and eluent system p-HPLC (FA).

[0378] MS m / z (ESI): 612.8 [M+1] + . 1 H NMR(400MHz,DMSO-d6)δ 7.97-7.95(m,1H),7.37-7.31(m,2H),7.09(s,1H),6.97(d,J=7.6Hz,1H),6.93-6. 88(m,2H),4.70(s,2H),4.08(d,J=13.2Hz,1H),3.93(d,J=13.2Hz,1H),3.24-3.15 (m,2H),2.36(t,J=7.6Hz,2H),2.12(s,3H),1.88-1.81(m,6H),1.72-1.65(m,2H), 1.57-1.49(m,2H),1.33-1.27(m,2H),1.01(t,J=6.8Hz,3H),0.83(t,J=7.2Hz,3H).

[0379] Example 46 2-[4-[(2-butyl-4-oxo-1,3-diazaspiro[4.4]nonan-1-en-3-yl)methyl]-2-(ethoxymethyl)phenyl]-N-(4-bromo-5-methyl-isoxazol-3-yl)benzenesulfonamide [ka]

[0380] The synthesis method of Example 46 was the same as that of Example 1, except that 4,5-dimethylisoxazoleamine was replaced with 4-bromo-5-methylisoxazoleamine to obtain Example 46 (40.8 mg, white solid), with a yield of 31.1%.

[0381] MS m / z (ESI): 656.8 [M+1] + . 1 H NMR(400MHz,DMSO-d6)δ 7.98-7.95(m,1H),7.36-7.31(m,2H),7.09(s,1H),6.98(d,J=8.0Hz,1H),6.92-6. 89(m,2H),4.70(s,2H),4.08(d,J=13.2Hz,1H),3.93(d,J=13.2Hz,1H),3.22-3.17 (m,2H),2.37(t,J=7.2Hz,2H),2.12(s,3H),1.90-1.81(m,6H),1.73-1.65(m,2H), 1.57-1.49(m,2H),1.33-1.27(m,2H),1.01(t,J=7.2Hz,3H),0.83(t,J=7.2Hz,3H).

[0382] Example 47 4'-(2-butyl-4-chloro-5-(hydroxymethyl)-1H-imidazol-1-yl)methyl)-N-(4-chloro-5-methylisoxazol-3-yl)-2'-(ethoxymethyl)-[1,1'-biphenyl]-2-sulfonamide [ka]

[0383] The synthesis method of Example 47-1 is based on the synthesis method of Example 43-5, except that 2-bromo-N-(4-chloro-5-methylisoxazol-3-yl)-N-(methoxymethyl)benzenesulfonamide is used instead of 2-bromo-N-(4,5-dimethylisoxazol-3-yl)-N-(methoxymethyl)benzenesulfonamide, and 2-butyl-4-chloro-1H-imidazole-5-carbaldehyde is used instead of 2-(2-butyl-4-methyl-6-oxo-1H-pyrimidin-5-yl)-N,N-dimethylacetamide to obtain Example 47-1 (50 mg, white solid), with a yield of 44.1%.

[0384] MS m / z(ESI):615.2[M+1] + .

[0385] Step 1 Preparation of 4'-(2-butyl-4-chloro-5-formyl-1H-imidazol-1-yl)methyl)-N-(4-chloro-5-methylisoxazol-3-yl)-2'-(ethoxymethyl)-N-(methoxymethyl)-[1,1'-biphenyl]-2-sulfonamide To a solution of Example 47-1 (50 mg, 76.97 μmol) in MeOH (6 mL) was added sodium borohydride (6 mg, 153.94 μmol), and the mixture was stirred at 20° C. for 1 hour. The organic phases were combined, dried, and concentrated, and the residue was purified by silica gel column chromatography using eluent system B to give the title product 47-2 (45 mg, pale yellow solid), with a yield of 90.3%.

[0386] MS m / z (ESI): 651.1 [M+1] + .

[0387] Step 2 Preparation of 4'-(2-butyl-4-chloro-5-(hydroxymethyl)-1H-imidazol-1-yl)methyl)-N-(4-chloro-5-methylisoxazol-3-yl)-2'-(ethoxymethyl)-[1,1'-biphenyl]-2-sulfonamide A round-bottom flask was charged with 47-2 (50 mg, 76.73 μmol) and a solution of hydrogen chloride in dioxane (4 M, 5 mL), and the mixture was stirred at 70° C. for 1 h. After cooling, the reaction mixture was concentrated and purified by preparative HPLC to give the title example 47 (19 mg, white solid) in a yield of 40.8%.

[0388] MS m / z (ESI): 607.1 [M+1] + . 1 H NMR(400MHz,DMSO-d6)δ 11.14(s,1H),8.02(dd,J=7.5,1.9Hz,1H),7.58(s,2H),7.21(s,1H),7.14(s,1H),6.9 7(d,J=7.9Hz,1H),6.88(d,J=7.9Hz,1H),5.29(s,2H),5.27(s,1H),4.34(d,J=4.0Hz, 2H),4.09-3.97(m,2H),3.25-3.15(m,2H),2.54(dd,J=8.8,6.4Hz,2H),2.27(s,3H),1 .51(q,J=7.6Hz,2H),1.30-1.25(m,2H),0.98(t,J=7.0Hz,3H),0.83(t,J=7.4Hz,3H).

[0389] Example 48 4'-((2-butyl-4-oxo-1,3-diazaspiro[4.4]nonan-1-en-3-yl)methyl-d2)-N-(4-fluoro-5-methylisoxazol-3-yl)-2'-(ethoxymethyl)-[1,1'-biphenyl]-2-sulfonamide [ka]

[0390] The synthesis method of Example 48 was the same as that of Example 1, except that 4,5-dimethylisoxazoleamine was replaced with 4-fluoro-5-methylisoxazoleamine to obtain Example 48 (11 mg, white solid), with a yield of 40.3%.

[0391] MS m / z (ESI): 599.3 [M + 1]+ . 1 H NMR (400 MHz, DMSO-d6) δ 8.05-7.97(m,1H),7.54(s,2H),7.22-7.12(m,2H),6.99(s,2H),4.08(d,J=13. 1Hz,1H),3.99(d,J=13.1Hz,1H),3.21(ddd,J=9.4,7.0,3.6Hz,2H),2.35(t,J=7 .5Hz,2H),2.25(s,3H),1.85(d,J=8.5Hz,6H),1.69(d,J=8.8Hz,2H),1.50(q,J= 7.7Hz,2H),1.28(d,J=7.6Hz,2H),1.01(t,J=6.9Hz,3H),0.82(t,J=7.3Hz,3H).

[0392] Example 49 4'-((2-butyl-4-oxo-1,3-diazaspiro[4.4]nonan-1-en-3-yl)methyl)-N-(4-chloro-5-methylisoxazol-3-yl)-2'-(ethoxydeuteromethyl)-[1,1'-biphenyl]-2-sulfonamide [ka]

[0393] Step 1 Preparation of methyl 2-bromo-5-(bromomethyl)benzoate N-Bromosuccinimide (854.68 mg, 4.80 mmol) and Example 49-1 (1.0 g, 4.37 mmol) were dissolved in carbon tetrachloride (5 mL), followed by the addition of benzoyl peroxide (105.74 mg, 436.55 μmol). The reaction mixture was then stirred at 80 °C for 16 h, saturated sodium chloride (10 mL) was added to the mixture, and the mixture was extracted with dichloromethane (10 mL x 3). The organic phases were combined, dried, and concentrated to give a crude product. The crude product was purified by column chromatography (petroleum ether / ethyl acetate system) to give the target molecule of Example 49-2 (1.1 g, 3.57 mmol, 81.82% yield).

[0394] Step 2 Preparation of (2-bromo-5-(bromomethyl)phenyl)deuteromethane alcohol Lithium aluminum tetrahydrogen deuteride (104.72 mg, 2.44 mmol) was dissolved in tetrahydrofuran (3 mL), followed by the addition of Example 49-2 (500 mg, 1.62 mmol). The reaction mixture was stirred at room temperature for 1 h, and then water (0.1 mL), 15% sodium hydroxide solution (0.1 mL), and water (0.3 mL) were added sequentially to the reaction mixture. After stirring for 0.5 h, the mixture was filtered. The filter cake was washed with dichloromethane (10 mL x 3). The filtrate was dried and concentrated to give the target molecule of Example 49-3 (310 mg, 1.10 mmol, 67.72% yield).

[0395] Step 3 Preparation of 3-(4-bromo-3-(hydroxymethyl-2)benzyl)-2-butyl-1,3-diazaspiro[4.4]nonan-1-en-4-one 2-Butyl-1,3-diazaspiro[4.4]nonan-1-en-4-one (62.01 mg, 319.18 μmol) and Example 49-3 were dissolved in acetonitrile (2 mL), followed by the addition of potassium carbonate (29.36 mg, 212.79 μmol). The reaction mixture was stirred at 80°C for 3 hours. After the reaction was completed, saturated sodium chloride (10 mL) solution was added, and the mixture was extracted with dichloromethane (10 mL x 3). The organic phases were combined, dried, and concentrated to obtain a crude product. The crude product was purified by column chromatography (petroleum ether / ethyl acetate system) to obtain the target molecule of Example 49-4 (18 mg, 45.53 μmol, 21.40% yield).

[0396] MS m / z (ESI): 395.2 [M+1] + .

[0397] Step 4 Preparation of 3-(4-bromo-3-(ethoxymethyl-D2)benzyl)-2-butyl-1,3-diazaspiro[4.4]nonan-1-en-4-one Example 49-4 (500 mg, 1.26 mmol) was dissolved in tetrahydrofuran (2 mL). Sodium hydride (151.76 mg, 3.79 mmol, 60% purity) was added and the reaction mixture was stirred at room temperature for 0.5 h. Iodoethane (986.30 mg, 6.32 mmol) was then added and the reaction mixture was stirred at room temperature for 1.5 h. After the reaction was completed, saturated sodium chloride (10 mL) solution was added, and the mixture was extracted with dichloromethane (10 mL x 3). The organic phases were combined, dried, and concentrated to obtain the crude product. The crude product was purified by column chromatography (petroleum ether / ethyl acetate system) to obtain the target molecule of Example 49-5 (210 mg, 496.01 μmol, 39.22% yield).

[0398] MS m / z (ESI): 423.2 [M+1] + .

[0399] Step 5 Preparation of 2-butyl-3-(3-(ethoxymethyl-d2)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborinan-2-yl)benzyl)-1,3-diazaspiro[4.4]nonan-1-en-4-one Example 49-5 (100 mg, 236.19 μmol), bis(pinacolato)diboron (71.97 mg, 283.43 μmol), [1,1'-bis(diphenylphosphino)ferrocene]dichloride palladium dichloromethane complex (19.27 mg, 23.62 μmol), and potassium acetate (45.35 mg, 472.39 μmol) were dissolved in dioxane (5 mL) and stirred at 90 °C for 16 h. Saturated aqueous sodium chloride (10 mL) was added, and the mixture was extracted with dichloromethane (10 mL x 3). The combined organic phases were dried and concentrated to give the crude target molecule, Example 49-6 (105 mg, 223.19 μmol, 94.50% yield). The crude product was used directly in the next step without further purification.

[0400] MS m / z (ESI): 471.2 [M+1] + .

[0401] Step 6 Preparation of 4'-((2-butyl-4-oxo-1,3-diazaspiro[4.4]nonan-1-en-3-yl)methyl)-N-(4-chloro-5-methylisoxazol-3-yl)-2'-(ethoxymethyl-d2)-N-(((2-(trimethylsilyl)ethoxy)methyl)-[1,1'-biphenyl]-2-sulfonamide Intermediate 1 (93 mg, 235.05 μmol), Example 49-6 (110.58 mg, 235.05 μmol), [1,1'-bis(diphenylphosphino)ferrocene]dichloride palladium dichloromethane complex (21.53 mg, 23.51 μmol), and cesium carbonate (229.88 mg, 705.16 μmol) were dissolved in dioxane and water (2.5 mL, 4:1), and the reaction mixture was stirred at 100 °C for 1 h. Saturated aqueous sodium chloride (10 mL) was added, and the mixture was extracted with dichloromethane (10 mL x 3). The organic phases were combined, dried, and concentrated to give the crude product, which was purified by column chromatography (petroleum ether / ethyl acetate system) to give the target molecule, Example 49-7 (106 mg, 160.79 μmol, 68.41% yield).

[0402] MS m / z(ESI):745.3[M+1] + .

[0403] Step 7 4'-((2-butyl-4-oxo-1,3-diazaspiro[4.4]nonan-1-en-3-yl)methyl)-N-(4-chloro-5-methylisoxazol-3-yl)-2'-(ethoxydeuteromethyl)-[1,1'-biphenyl]-2-sulfonamide The synthesis method of Example 49 was carried out in accordance with the synthesis method of Example 33, and the title compound Example 40 (32 mg, 33.5%) was obtained using Example 49-7 as the starting material.

[0404] MS m / z(ESI):615.2[M+1] + . 1H NMR(400MHz,DMSO)δ 8.01(dd,J=16.0,14.4Hz,1H),7.60(t,J=29.2Hz,2H),7.15(d,J=11.1Hz,2 H),7.00(s,2H),4.83-4.66(m,2H),3.28-3.13(m,2H),2.36(t,J=7.5Hz,2H ),2.28(s,3H),1.86(d,J=6.4Hz,6H),1.71(d,J=8.0Hz,2H),1.52(dt,J=15 .2,7.5Hz,2H),1.34-1.25(m,2H),1.01(t,J=7.0Hz,3H),0.88-0.75(m,3H).

[0405] Example 50 2-(5-((2-butyl-4-oxo-1,3-diazaspiro[4.4]nonan-1-en-3-yl)methyl)-3-(ethoxymethyl)pyridin-2-yl)-N-(4,5-dimethylisoxazol-3-yl)benzenesulfonamide [ka]

[0406] The synthesis method of Example 50 was carried out in accordance with the synthesis method of Example 1 to obtain Example 50 (51 mg, white solid) with a yield of 50.3%.

[0407] MS m / z (ESI): 594.1 [M+1] + . 1H NMR(400MHz,DMSO-d6)δ 8.25(s,1H),8.19(s,1H),8.01-7.97(m,1H),7.50(s,2H),7.16(d,J=26.4Hz,2H),4.80 (s,2H),4.30(d,J=14.9Hz,1H),4.05(d,J=14.4Hz,1H),3.25(d,J=7.1Hz,2H),2.38(t,J =7.4Hz,2H),2.11(s,3H),1.86(t,J=5.2Hz,6H),1.69(d,J=8.6Hz,2H),1.60(s,3H),1. 52(t,J=7.5Hz,2H),1.31(d,J=7.7Hz,2H),1.02(t,J=7.0Hz,3H),0.83(t,J=7.3Hz,3H).

[0408] Example 51 2-(5-((2-butyl-4-oxo-1,3-diazaspiro[4.4]nonan-1-en-3-yl)methyl)-3-methylpyridin-2-yl)-N-(4,5-dimethylisoxazol-3-yl)benzenesulfonamide [ka]

[0409] The synthesis method of Example 51 was the same as that of Example 41, except that 41b was replaced with methyl 6-bromo-5-methylnicotinate to obtain Example 51 (21 mg, white solid), with a yield of 50.3%.

[0410] MS m / z (ESI): 550.2 [M+1] + . 1H NMR(400MHz,DMSO-d6)δ 8.16(s,1H),8.00(d,J=7.8Hz,1H),7.58(dt,J=15.1,7.4Hz,2H),7.40(s,1H),7.21(d,J=7.6Hz,2H),4.74(s,2H),2.40(t,J=7.5Hz,2H),2.1 6(s,3H),2.01(s,3H),1.86(q,J=6.6Hz,6H),1.68(t,J=5.5Hz,2H),1. 65(s,3H),1.56-1.50(m,2H),1.33-1.28(m,2H),0.83(t,J=7.3Hz,3H).

[0411] Example 52 4'-((2-butyl-4-oxo-1,3-diazaspiro[4.4]nonan-1-en-3-yl)methyl)-N-(4-chloro-5-methylisoxazol-3-yl)-2'-(cyclopropoxymethyl)-[1,1'-biphenyl]-2-sulfonamide [ka]

[0412] Step 1 Preparation of 2-butyl-3-(3-(cyclopropoxymethyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl)-1,3-diazaspiro[4.4]nonan-1-en-4-one Example 52-1 (240 mg, 553.79 μmol) (see WO 2010135350A2 for synthetic methods), bis(pinacolato)diboron (168.8 mg, 664.54 μmol), [1,1'-bis(diphenylphosphino)ferrocene]dichloride palladium dichloromethane complex (45.19 mg, 55.38 μmol), and potassium acetate (162.8 mg, 1.66 mmol) were dissolved in dioxane (5 mL) and stirred at 90 °C for 16 h. Saturated aqueous sodium chloride (10 mL) was added, followed by extraction with dichloromethane (10 mL x 3). The combined organic phases were dried and concentrated to obtain the crude target molecule, Example 52-2 (240 mg, 499.54 μmol, 90.2% yield). The crude product was used directly in the next step without further purification.

[0413] MS m / z (ESI): 481.2 [M+1] + .

[0414] Step 2 4'-((2-butyl-4-oxo-1,3-diazaspiro[4.4]nonan-1-en-3-yl)methyl)-N-(4-chloro-5-methylisoxazol-3-yl)-2'-(cyclopropoxymethyl)-N-(((2-(trimethylsilyl)ethoxy)methyl)-[1,1'-biphenyl]-2-sulfonamide Intermediate 1 (240.71 mg, 499.54 μmol), Example 52-2 (240 mg, 499.54 μmol), [1,1'-bis(diphenylphosphino)ferrocene]dichloride palladium dichloromethane complex (40.76 mg, 49.95 μmol), and cesium carbonate (488.55 mg, 1.50 mmol) were dissolved in dioxane / water (2.5 mL, 4:1). The reaction mixture was stirred at 100 °C under microwave irradiation for 1 h. Saturated aqueous sodium chloride (10 mL) was added, and the mixture was extracted with dichloromethane (10 mL x 3). The organic phases were combined, dried, and concentrated to give the crude product. The crude product was purified by column chromatography (petroleum ether / ethyl acetate system) to give the target molecule, Example 52-3 (210 mg, 277.99 μmol, 55.65% yield).

[0415] MS m / z (ESI): 755.2 [M+1] + .

[0416] Step 3 4'-((2-butyl-4-oxo-1,3-diazaspiro[4.4]nonan-1-en-3-yl)methyl)-N-(4-chloro-5-methylisoxazol-3-yl)-2'-(cyclopropoxymethyl)-[1,1'-biphenyl]-2-sulfonamide Example 52-3 was dissolved in tetrahydrofuran (2 mL), followed by the addition of tetrabutylammonium fluoride (1 M, 2 mL). The reaction mixture was stirred at 70°C for 2 hours, saturated aqueous sodium chloride (10 mL) was added, and the mixture was extracted with dichloromethane (10 mL x 3). The organic phases were combined, dried, and concentrated to give a crude product. The crude product was separated and purified (HCOOH) to give the target molecule of Example 52 (78 mg, 124.76 μmol, 30.40% yield).

[0417] MS m / z (ESI): 625.2 [M+1] + . 1 H NMR (400 MHz, DMSO) δ 8.02(d,J=6.3Hz,1H),7.54(s,2H),7.11(s,2H),6.99(d,J=7.7Hz,2H),4.72(s, 2H),4.08(dd,J=44.2,12.4Hz,2H),3.09(s,1H),2.34(dd,J=20.3,12.7Hz,2H), 2.25(s,3H),1.85(d,J=7.4Hz,6H),1.69(d,J=6.6Hz,2H),1.52(dt,J=15.2,7.7 Hz,2H),1.29(dq,J=14.5,7.3Hz,2H),0.82(t,J=7.3Hz,3H),0.45-0.11(m,4H).

[0418] Example 53 4'-((2-butyl-4-oxo-1,3-diazaspiro[4.4]nonan-1-en-3-yl)methyl)-N-(4-chloro-5-methylisoxazol-3-yl)-2'-(methoxymethyl)-[1,1'-biphenyl]-2-sulfonamide [ka]

[0419] Step 1 Preparation of ethyl 4-bromo-3-(bromomethyl)benzoate N-Bromosuccinimide (854.68 mg, 4.80 mmol) and Example 53-1 (1.0 g, 4.37 mmol) were dissolved in carbon tetrachloride (5 mL), benzoyl peroxide (105.74 mg, 436.55 μmol) was added, and the reaction mixture was stirred at 80°C for 16 hours. Saturated aqueous sodium chloride (10 mL) was added, and the mixture was extracted with dichloromethane (10 mL x 3). The organic phases were combined, dried, and concentrated to obtain a crude product. The crude product was purified by column chromatography (petroleum ether / ethyl acetate system) to obtain the target molecule of Example 53-2 (1.1 g, 3.57 mmol, 81.82% yield).

[0420] Step 2 Preparation of ethyl 4-bromo-3-(methoxymethyl)benzoate Example 53-2 (1 g, 3.11 mmol) was dissolved in N,N-dimethylformamide (2 mL) and methanol (1 mL), and sodium methoxide (335.56 mg, 6.21 mmol) was added. The reaction mixture was stirred at 50°C for 16 hours, and then saturated aqueous sodium chloride (10 mL) was added. Extraction was performed with dichloromethane (10 mL x 3). The organic phases were combined, dried, and concentrated to give a crude product. The crude product was purified by column chromatography (petroleum ether / ethyl acetate system) to give the target molecule of Example 53-3 (610 mg, 2.35 mmol, 75.81% yield).

[0421] Step 3 Preparation of (4-bromo-3-(methoxymethyl)phenyl)methanol Example 53-3 (610 mg, 2.35 mmol) was dissolved in toluene (4.76 mL) and cooled to -10°C. Diisobutylaluminum hydride (1 M, 4.71 mL) was added, and the reaction mixture was stirred at -10°C for 0.5 h. 5% aqueous sodium hydroxide solution (5 mL) was added, and the mixture was extracted with dichloromethane (10 mL x 3). The organic phases were combined, dried, and concentrated to give a crude product. The crude product was purified by column chromatography (petroleum ether / ethyl acetate system) to give the target molecule Example 53-4 (480 mg, 2.08 mmol, 88.23% yield).

[0422] Step 4 Preparation of 1-bromo-4-(bromomethyl)-2-(methoxymethyl)benzene Example 53-4 (480 mg, 2.08 mmol) and triphenylphosphine (817.21 mg, 3.12 mmol) were dissolved in dichloromethane (3 mL), followed by the addition of carbon tetrabromide (1.02 g, 3.12 mmol). The reaction mixture was stirred at 30°C for 3 h, and then saturated aqueous sodium chloride (10 mL) was added. Extraction was performed with dichloromethane (10 mL x 3). The organic phases were combined, dried, and concentrated to obtain a crude product. The crude product was purified by column chromatography (petroleum ether / ethyl acetate system) to obtain the target molecule of Example 53-5 (430 mg, 1.46 mmol, 70.42% yield).

[0423] Step 5 Preparation of 3-(4-bromo-3-(methoxymethyl)benzyl)-2-butyl-1,3-diazaspiro[4.4]nonan-1-en-4-one Example 53-5 (430 mg, 1.46 mmol) and 2-butyl-1,3-diazaspiro[4.4]nonan-1-en-4-one (312.57 mg, 1.61 mmol) were dissolved in acetonitrile (5 mL), followed by the addition of potassium carbonate (605.55 mg, 4.39 mmol). The reaction mixture was stirred at 80 ° C. for 16 hours, saturated aqueous sodium chloride (10 mL) was added, and the mixture was extracted with dichloromethane (10 mL × 3). The organic phases were combined, dried, and concentrated to obtain a crude product. The crude product was purified by column chromatography (petroleum ether / ethyl acetate system) to obtain the target molecule of Example 53-6 (570 mg, 1.40 mmol, 95.67% yield).

[0424] MS m / z(ESI):407.2[M+1] + .

[0425] Step 6 Preparation of 2-butyl-3-(3-(methoxymethyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl)-1,3-diazaspiro[4.4]nonan-1-en-4-one Example 53-6 (570 mg, 1.40 mmol), bis(pinacolato)diboron (426.41 mg, 1.68 mmol), potassium acetate (411.40 mg, 4.20 mmol), and [1,1'-bis(diphenylphosphino)ferrocene]dichloride palladium dichloromethane complex (114.18 mg, 139.93 μmol) were dissolved in dioxane (5 mL), and the reaction mixture was stirred at 100 °C for 16 h. Saturated aqueous sodium chloride (10 mL) was added, and the mixture was extracted with dichloromethane (10 mL x 3). The organic phases were combined, dried, and concentrated to give the crude target molecule, Example 53-7 (610 mg, 1.34 mmol, 95.93% yield). The crude product was used directly in the next step without further purification.

[0426] MS m / z (ESI): 455.2 [M+1] + .

[0427] Step 7 Preparation of 4'-((2-butyl-4-oxo-1,3-diazaspiro[4.4]nonan-1-en-3-yl)methyl)-N-(4-chloro-5-methylisoxazol-3-yl)-2'-(methoxymethyl)-N-(((2-(trimethylsilyl)ethoxy)methyl)-[1,1'-biphenyl]-2-sulfonamide Intermediate 1 (1.23 g, 2.55 mmol), Example 53-7 (610 mg, 1.34 mmol), [1,1'-bis(diphenylphosphino)ferrocene] palladium dichloride dichloromethane complex (109.54 mg, 134.24 μmol), and cesium carbonate (1.31 g, 4.03 mmol) were dissolved in dioxane / water (2.5 mL, 4:1). The reaction mixture was stirred at 100 °C under microwave irradiation for 1 h. Saturated aqueous sodium chloride (10 mL) was added, and the mixture was extracted with dichloromethane (10 mL × 3). The organic phases were combined, dried, and concentrated to give the crude product, which was purified by column chromatography (petroleum ether / ethyl acetate system) to give the target molecule, Example 53-8 (550 mg, 754.05 μmol, 56.17% yield).

[0428] MS m / z (ESI): 729.2 [M+1] + .

[0429] Step 8 Preparation of 4'-((2-butyl-4-oxo-1,3-diazaspiro[4.4]nonan-1-en-3-yl)methyl)-N-(4-chloro-5-methylisoxazol-3-yl)-2'-(methoxymethyl)-[1,1'-biphenyl]-2-sulfonamide The synthesis method of Example 53 was similar to that of Example 33, and the title compound Example 53 (22 mg, 48.5%) was obtained using Example 53-8 as the starting material.

[0430] MS: m / z(ESI):599.3[M+1] + . 1H NMR (400 MHz, DMSO) δ 8.24(s,1H),8.05-7.89(m,1H),7.49-7.23(m,2H),7.10(s,1H),7.00-6.78(m ,3H),4.70(s,2H),4.04(d,J=12.9Hz,1H),3.90(d,J=13.0Hz,1H),3.06(s,3H ),2.37(t,J=7.5Hz,2H),2.12(s,3H),1.85(d,J=7.3Hz,6H),1.68(d,J=7.0Hz ,2H),1.53(dt,J=15.0,7.4Hz,2H),1.36-1.17(m,2H),0.83(t,J=7.3Hz,3H).

[0431] Example 54 4'-((2-butyl-4-oxo-1,3-diazaspiro[4.4]nonan-1-en-3-yl)methyl)-N-(4-chloro-5-methylisoxazol-3-yl)-2'-methyl-[1,1'-biphenyl]-2-sulfonamide [ka]

[0432] Step 1 Preparation of 3-(4-bromo-3-methylbenzyl)-2-butyl-1,3-diazaspiro[4.4]nonan-1-en-4-one Example 54-1 (0.5 g, 1.89 mmol) and 2-butyl-1,3-diazaspiro[4.4]nonan-1-en-4-one (404.80 mg, 2.08 mmol) were dissolved in acetonitrile (5 mL), potassium carbonate (784.22 mg, 5.68 mmol) was added, and the reaction mixture was stirred at 80 ° C. for 16 hours. A saturated aqueous solution of sodium chloride (10 mL) was added, and the mixture was extracted with dichloromethane (10 mL × 3). The organic phases were combined, dried, and concentrated to obtain a crude product. The crude product was purified by column chromatography (petroleum ether / ethyl acetate system) to obtain the target molecule of Example 54-2 (0.59 g, 1.56 mmol, 82.55% yield).

[0433] MS m / z (ESI): 377.3 [M+1]+ .

[0434] Step 2 Preparation of 2-butyl-3-(3-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl)-1,3-diazaspiro[4.4]nonan-1-en-4-one Example 54-2 (590 mg, 1.56 mmol), bis(pinacolato)diboron (476.49 mg, 1.88 mmol), potassium acetate (459.72 mg, 4.69 mmol), and [1,1'-bis(diphenylphosphino)ferrocene]dichloride palladium dichloromethane complex (127.60 mg, 156.37 μmol) were dissolved in dioxane (5 mL), and the reaction mixture was stirred at 100 °C for 16 h. Saturated aqueous sodium chloride (10 mL) was added, and the mixture was extracted with dichloromethane (10 mL x 3). The organic phases were combined, dried, and concentrated to give the crude target molecule, Example 54-3 (580 mg, 1.37 mmol, 87.40% yield). The crude product was used directly in the next step without further purification.

[0435] MS m / z(ESI):425.3[M+1] + .

[0436] Step 3 4'-((2-butyl-4-oxo-1,3-diazaspiro[4.4]nonan-1-en-3-yl)methyl)-N-(4-chloro-5-methylisoxazol-3-yl)-2'-methyl-N-(((2-(trimethylsilyl)ethoxy)methyl)-[1,1'-biphenyl]-2-sulfonamide Intermediate 1 (613.14 mg, 1.27 mmol), Example 54-3 (540 mg, 1.27 mmol), [1,1'-bis(diphenylphosphino)ferrocene] palladium dichloride dichloromethane complex (103.83 mg, 127.24 μmol), and cesium carbonate (1.24 g, 3.82 mmol) were dissolved in dioxane and water (2.5 mL, 4:1). The reaction mixture was stirred at 100 °C under microwave irradiation for 1 h. Saturated aqueous sodium chloride (10 mL) was added, and the mixture was extracted with dichloromethane (10 mL × 3). The organic phases were combined, dried, and concentrated to give the crude product. The crude product was purified by column chromatography (petroleum ether / ethyl acetate system) to give the target molecule, Example 54-4 (550 mg, 754.05 μmol, 56.17% yield).

[0437] MS m / z (ESI): 699.2 [M+1] + .

[0438] Step 4 Preparation of 4'-((2-butyl-4-oxo-1,3-diazaspiro[4.4]nonan-1-en-3-yl)methyl)-N-(4-chloro-5-methylisoxazol-3-yl)-2'-methyl-[1,1'-biphenyl]-2-sulfonamide The synthesis method of Example 54 was carried out in accordance with the synthesis method of Example 33, and the title compound Example 54 (27 mg, 33.5%) was obtained using Example 54-4 as the starting material.

[0439] MS m / z (ESI): 569.2 [M+1] + . 1H NMR(400MHz,DMSO)δ 7.97(dd,J=6.0,3.3Hz,1H),7.50-7.19(m,2H),6.96(d,J=7.8Hz,1H),6.9 2-6.83(m,2H),6.76(d,J=7.7Hz,1H),4.65(s,2H),2.37(t,J=7.5Hz,2H),2 .09(d,J=15.8Hz,3H),1.84(d,J=6.0Hz,9H),1.68(d,J=6.8Hz,2H),1.53( dt,J=15.1,7.4Hz,2H),1.31(dt,J=7.1,6.0Hz,2H),0.84(t,J=7.3Hz,3H).

[0440] Example 55 4'-((2-butyl-4-oxo-1,3-diazaspiro[4.4]nonan-1-en-3-yl)methyl)-N-(4-chloro-5-methylisoxazol-3-yl)-2'-propoxy-[1,1'-biphenyl]-2-sulfonamide [ka]

[0441] The synthesis method of Example 55 was based on the synthesis method of Example 41, except that iodopropane was used instead of benzyl bromide, and 2-bromo-N-(4-chloro-5-methylisoxazol-3-yl)-N-(methoxymethyl)benzenesulfonamide was used instead of 2-bromo-N-(4,5-dimethylisoxazol-3-yl)-N-(methoxymethyl)benzenesulfonamide to obtain Example 55 (27 mg, white solid), with a yield of 40.9%.

[0442] MS m / z (ESI): 613.1 [M+1] + . 1H NMR(400MHz,DMSO-d6)δ 10.90(s,1H),8.04(dd,J=7.8,1.5Hz,1H),7.62-7.47(m,2H),7.16(d,J=7.5Hz,1H),7.04(d,J= 7.7Hz,1H),6.73(s,1H),6.66-6.60(m,1H),4.70(s,2H),3.70(dt,J=12.9,6.8Hz,2H),2.38(t,J =7.5Hz,2H),2.27(s,3H),1.86(q,J=7.7,6.8Hz,6H),1.73-1.65(m,2H),1.52(p,J=7.5Hz,2H), 1.39(tt,J=9.6,4.7Hz,2H),1.29(q,J=7.4Hz,2H),0.83(t,J=7.3Hz,3H),0.68(t,J=7.4Hz,3H).

[0443] Example 56 2-[4-[(2-butyl-4-oxo-1,3-diazaspiro[4.4]nonan-1-en-3-yl)methyl]-2-(ethoxymethyl)phenyl]-N-(4-chloro-5-cyclopropyl-isoxazol-3-yl)benzenesulfonamide [ka]

[0444] The synthesis method of Example 56 was the same as that of Example 1, except that 4,5-dimethylisoxazoleamine was replaced with 4-chloro-5-cyclopropylisoxazoleamine to obtain Example 56 (29.5 mg, white solid), with a yield of 22.4%.

[0445] MS m / z (ESI): 638.8 [M+1] + . 1H NMR(400MHz,DMSO-d6)δ 7.96-7.94(m,1H),7.36-7.31(m,2H),7.08(s,1H),6.97(d,J=7.6Hz,1H),6.93-6. 89(m,2H),4.70(s,2H),4.05(d,J=13.2Hz,1H),3.91(d,J=13.2Hz,1H),3.23-3.15( m,2H),2.37(t,J=7.6Hz,2H),1.91-1.81(m,7H),1.73-1.64(m,2H),1.57-1.49(m,2 H),1.33-1.27(m,2H),1.01(t,J=7.2Hz,3H),0.95-0.90(m,2H),0.85-0.82(m,5H).

[0446] Example 57 2-[4-[(2-butyl-4-oxo-1,3-diazaspiro[4.4]nonan-1-en-3-yl)methyl]-2-(ethoxymethyl)phenyl]-N-(4-chloro-3-ethyl-isoxazol-5-yl)benzenesulfonamide [ka]

[0447] The synthesis method of Example 57 was the same as that of Example 1, except that 4,5-dimethylisoxazoleamine was replaced with 4-chloro-3-ethylisoxazoleamine to obtain Example 57 (3.3 mg, white solid), with a yield of 2.5%.

[0448] MS m / z (ESI): 627.0 [M+1] + . 1H NMR(400MHz,DMSO-d6)δ 8.01-7.99(m,1H),7.43-7.38(m,2H),7.10(s,1H),7.00-6.96(m,2H),6.93-6.91( m,1H),4.71(s,2H),4.04(d,J=12.8Hz,1H),3.92(d,J=13.2Hz,1H),3.24-3.16(m,2 H),2.38-3.31(m,4H),1.91-1.81(m,6H),1.72-1.65(m,2H),1.55-1.49(m,2H),1.3 2-1.27(m,2H),1.07(d,J=7.6Hz,3H),1.00(t,J=7.2Hz,3H),0.83(t,J=7.2Hz,3H).

[0449] Example 58 2-[4-[(2-butyl-4-oxo-1,3-diazaspiro[4.4]nonan-1-en-3-yl)methyl]-2-(ethoxymethyl)phenyl]-N-(3-ethyl-4-methyl-isoxazol-5-yl)benzenesulfonamide [ka]

[0450] The synthesis method of Example 58 was the same as that of Example 1, except that 4,5-dimethylisoxazoleamine was replaced with 4-chloro-3-ethylisoxazoleamine to obtain Example 58 (14.1 mg, white solid), with a yield of 11.1%.

[0451] MS m / z (ESI): 607.0 [M+1] + . 1H NMR(400MHz,DMSO-d6)δ 8.00-7.98(m,1H),7.39-7.33(m,2H),7.08(s,1H),6.99(d,J=8.0Hz,1H),6.96-6.90(m ,2H),4.71(s,2H),4.01(d,J=13.2Hz,1H),3.92(d,J=13.2Hz,1H),3.22-3.15(m,2H),2 .36(t,J=7.2Hz,2H),2.28(q,J=7.6Hz,2H),1.93-1.80(m,6H),1.73-1.65(m,2H),1.55 -1.51(m,2H),1.43(s,3H),1.32-1.27(m,2H),1.06-0.99(m,6H),0.83(t,J=7.2Hz,3H).

[0452] Example 59 N-(4-chloro-5-methylisoxazol-3-yl)-2'-(ethoxymethyl)-4'-(((4-ethyl-5-(hydroxymethyl)-2-propyl-1H-imidazol-1-yl)methyl)-[1,1'-biphenyl]-2-sulfonamide [ka]

[0453] Step 1 Preparation of methyl 1-((2'-(N-(4-chloro-5-methylisoxazol-3-yl)-N-((2-(trimethylsilyl)ethoxy)methyl)sulfamoyl)-2-(ethoxymethyl)-[1,1'-biphenyl]-4-yl)methyl)-4-ethyl-2-propyl-1H-imidazole-5-carboxylate Example 59-1 (500 mg, 0.8 mmol) (see WO 2010114801A1 for preparation method) was dissolved in MeCN (15 mL), potassium carbonate (220 mg, 1.6 mmol) and methyl 4-ethyl-2-propyl-1H-imidazole-5-carboxylate (156 mg, 0.8 mmol) were added at room temperature, and the reaction mixture was stirred at 70 °C for 3 hours. The reaction mixture was concentrated, and the crude product was purified to give 59-2 (500 mg, white solid) in an 85.0% yield.

[0454] MS m / z (ESI): 745.2 [M+1] + .

[0455] Step 2 Preparation of methyl 1-((2'-(N-(4-chloro-5-methylisoxazol-3-yl)sulfamoyl)-2-(ethoxymethyl)-[1,1'-biphenyl]-4-yl)methyl)-4-ethyl-2-propyl-1H-imidazole-5-carboxylate 59-2 (500 mg, 0.67 mmol) was dissolved in HCl / dioxane (10 mL), and the reaction mixture was stirred at 70° C. for 3 h. Concentration gave 59-3 (400 mg, white solid) in a yield of 97.0%.

[0456] MS m / z(ESI):615.2[M+1] + .

[0457] Step 3 Preparation of 4-fluoro-5-methylisoxazol-3-amine-2-bromo-N-(4-fluoro-5-methylisoxazol-3-yl)benzenesulfonamide Compound 59-3 (0.1 g, 0.16 mmol) was dissolved in 10 mL of THF, and lithium borohydride (10 mg, 0.48 mmol) was added. The reaction mixture was stirred at 25 °C for 4 hours. The reaction mixture was extracted with ethyl acetate, and the organic phase was concentrated. The crude product was purified to give 59 (50 mg, white solid) in 52.0% yield.

[0458] MS m / z (ESI): 587.2 [M+1] + .

[0459] Example 60 1-((2'-(N-(4-chloro-5-methylisoxazol-3-yl)sulfamoyl)-2-(ethoxymethyl)-[1,1'-biphenyl]-4-yl)methyl)-4-ethyl-2-propyl-1H-imidazole-5-carboxamide [ka]

[0460] Step 1 Preparation of 1-((2'-(N-(4-chloro-5-methylisoxazol-3-yl)sulfamoyl)-2-(ethoxymethyl)-[1,1'-biphenyl]-4-yl)methyl)-4-ethyl-2-propyl-1H-imidazole-5-carboxylic acid Example 59-3 (200 mg, 0.33 mmol) and sodium hydroxide (26 mg, 0.65 mmol) were dissolved in a mixture of THF (8 mL) and HO (8 mL) and stirred at 30 °C for 4 h. Aqueous hydrochloric acid (1 M, 14 mL) was added, and the mixture was extracted with dichloromethane (2 × 20 mL). The organic layers were combined, dried over anhydrous sodium sulfate, filtered, and concentrated to give the desired product 60-1 (120 mg, white solid) in a yield of 61.0%.

[0461] MS m / z (ESI): 601.1 [M+1] + .

[0462] Step 2 Preparation of 1-((2'-(N-(4-chloro-5-methylisoxazol-3-yl)sulfamoyl)-2-(ethoxymethyl)-[1,1'-biphenyl]-4-yl)methyl)-4-ethyl-2-propyl-1H-imidazole-5-carboxamide Example 60-1 (100 mg, 0.17 mmol) and ammonium chloride (18 mg, 0.34 mmol) were dissolved in DMF (5 mL), and 2-(7-azabenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (129 mg, 0.34 mmol) and ethyldiisopropylamine (44 mg, 0.34 mmol) were added. The reaction mixture was stirred at 25 °C for 1 h. Saturated brine (10 mL) was added, and the mixture was extracted with ethyl acetate (2 × 10 mL). The combined organic phases were dried, concentrated, and purified by column chromatography (petroleum ether / ethyl acetate system) to obtain the target product 60 (50 mg, white solid) in a 50.0% yield.

[0463] MS m / z (ESI): 600.2 [M+1] + .

[0464] Example 61 1-((2'-(N-(4-chloro-5-methylisoxazol-3-yl)sulfamoyl)-2-(ethoxymethyl)-[1,1'-biphenyl]-4-yl)methyl)-4-ethyl-N-methyl-2-propyl-1H-imidazole-5-carboxamide [ka]

[0465] The synthesis method of Example 61 was the same as that of Example 60, except that ammonium chloride was replaced with methylamine to obtain Example 61 (15 mg, 46.2% yield).

[0466] MS m / z (ESI): 614.2 [M+1] + .

[0467] Example 62 N-(4-chloro-5-methylisoxazol-3-yl)-4'-((4-ethyl-5-(hydroxymethyl)-2-propyl-1H-imidazol-1-yl)methyl)-2'-(methoxymethyl)-[1,1'-biphenyl]-2-sulfonamide [ka]

[0468] The synthesis method of Example 62 was the same as that of Example 59.

[0469] MS m / z (ESI): 573.2 [M+1] + .

[0470] Example 63 1-((2'-(N-(4-chloro-5-methylisoxazol-3-yl)sulfamoyl)-2-(methoxymethyl)-[1,1'-biphenyl]-4-yl)methyl)-4-ethyl-2-propyl-1H-imidazole-5-carboxamide [ka]

[0471] The synthesis method of Example 63 was the same as that of Example 60.

[0472] MS m / z (ESI): 586.2 [M+1] + .

[0473] Example 64 1-((2'-(N-(4-chloro-5-methylisoxazol-3-yl)sulfamoyl)-2-(methoxymethyl)-[1,1'-biphenyl]-4-yl)methyl)-4-ethyl-N-methyl-2-propyl-1H-imidazole-5-carboxamide [ka]

[0474] The synthesis method of Example 64 was the same as that of Example 60.

[0475] MS m / z (ESI): 600.2 [M+1] + .

[0476] Example 65 4'-((2'-butyl-5'-oxaspiro[bicyclo[3.1.0]hexane-3,4'-imidazol]-1'(5'H)-yl)methyl)-N-(4-chloro-5-methylisoxazol-3-yl)-2'-(ethoxymethyl)-[1,1'-biphenyl]-2-sulfonamide [ka] The synthesis method of Example 65 was similar to that of Example 2, except that 2-butyl-1,3-diazaspirocyclo-[4,4]nonan-1-en-4-one was replaced with 2'-butylspiro[bicyclo[3.1.0]hexane-3,4'-imidazol]-5'(1'H)-one to synthesize Example 65 (14 mg, yield 46%).

[0477] MS m / z (ESI): 625.22 [M+1] + .

[0478] Example 66 N-(4-chloro-5-methylisoxazol-3-yl)-4'-((2-(3-chloropropyl)-4-oxo-1,3-diazaspiro[4.4]non-1-en-3-yl)methyl)-2'-(ethoxymethyl)-[1,1'-biphenyl]-2-sulfonamide [ka]

[0479] The synthesis method of Example 66 was similar to that of Example 2, except that 2-chlorobutyl-1,3-diazaspirocyclo-[4,4]nonan-1-en-4-one was used instead of 2-butyl-1,3-diazaspirocyclo-[4,4]nonan-1-en-4-one to synthesize Example 66 (6 mg, yield 15%).

[0480] MS m / z (ESI): 633.2 [M+1] + .

[0481] Example 67 N-(4-chloro-5-methylisoxazol-3-yl)-2'-(ethoxymethyl)-4'-(((2-(2-(methylthio)ethyl)-4-oxo-1,3-diazaspiro][4.4]non-1-en-3-yl)methyl)-[1,1'-biphenyl]-2-sulfonamide [ka]

[0482] The synthesis method of Example 67 was similar to that of Example 59, except that 2-butyl-1,3-diazaspirocyclo-[4,4]nonan-1-en-4-one was replaced with 2-(2-(methylthio)ethyl)-1,3-diazaspirocyclo-[4,4]nonan-1-en-4-one to synthesize Example 67 (16 mg, yield 21%).

[0483] MS m / z (ESI): 631.2 [M+1] + .

[0484] Example 68 4'-((2-2-4-4-oxo-1,3-diazaspiro[4.5]dec-1-en-3-yl)methyl)-N-(4-chloro-5-methylisoxazol-3-yl)-2'-(ethoxymethyl)-[1,1'-biphenyl]-2-sulfonamide [ka]

[0485] The synthesis method of Example 68 was carried out in accordance with the synthesis method of Example 59, except that 2-butyl-1,3-diazaspiro[4.5]dec-1-en-4-one was used instead of 2-butyl-1,3-diazaspirocyclo-[4,4]nonan-1-en-4-one to synthesize Example 68 (21 mg, yield 52%).

[0486] MS m / z (ESI): 627.2 [M+1] + . 1H NMR(400MHz,DMSO-d6)δ 8.03(dd,J=7.5,1.8Hz,1H),7.59(t,J=7.7Hz,2H),7.16(d,J=9.5Hz,2H),7.00(s ,2H),4.73(s,2H),4.04(q,J=13.1Hz,2H),3.26-3.16(m,2H),2.35(d,J=7.6Hz,2H ),2.29(s,3H),1.68(dq,J=16.3,8.3,6.4Hz,7H),1.52(q,J=7.5Hz,2H),1.40(d,J =12.1Hz,3H),1.29(q,J=7.4Hz,2H),1.00(t,J=7.0Hz,3H),0.82(t,J=7.3Hz,3H).

[0487] Example 69 4'-((2-butyl-4-oxo-1,3-diazaspiro[4.4]nonan-1-en-3-yl)methyl)-N-(4-chloro-5-methylisoxazol-3-yl)-2'-((trifluoromethoxy)methyl)-[1,1'-biphenyl]-2-sulfonamide [ka]

[0488] Step 1 Preparation of methyl 2-bromo-5-(bromomethyl)benzoate Under nitrogen gas protection, bromosuccinimide (8.16 g, 45.84 mmol) was added to a solution of Example 69-1 (10 g, 43.65 mmol) in MeCN (80 mL), and the mixture was stirred overnight at 25° C. for 12 hours. The reaction mixture was concentrated, diluted with 100 mL of ethyl acetate, and washed three times with 50 mL of water. The organic phases were combined, dried, and concentrated. The residue was purified by silica gel column chromatography using eluent system B to give Example 69-2 (10 g, colorless liquid) in a yield of 74.3%.

[0489] 1H NMR(400MHz,Chloroform-d)δ 7.82(d,J=2.3Hz,1H),7.64(d,J=8.3Hz,1H),7.36(dd,J=8.3,2.4Hz,1H),4.44(s,2H),3.94(s,3H).

[0490] Step 2 Preparation of (2-bromo-5-(bromomethyl)phenyl)methanol Under nitrogen gas protection, diisobutylaluminum hydride (1M, 62.11 mL) was added to a DCM solution of Example 69-2 (10 g, 31.06 mmol) at 0 ° C., and the mixture was stirred at 20 ° C. for 1 hour. The reaction mixture was quenched by adding ice water (200 mL), extracted with dichloromethane (100 mL * 3), and the organic phases were combined, dried, and concentrated to give Example 69-3 (6.0 g, white solid), which was used directly in the next step.

[0491] Step 3 Preparation of 3-(4-bromo-3-(hydroxymethyl)benzyl)-2-butyl-1,3-diazaspiro[4.4]nonan-1-en-4-one To a solution of Example 69-3 (1.25 g, 4.46 mmol) and 2-butyl-1,3-diazaspiro[4.4]nonan-1-en-4-one hydrochloride (1.03 g, 4.46 mmol) in MeCN (15 mL) was added potassium carbonate (1.23 g, 8.93 mmol), and the mixture was stirred at 80 ° C. for 12 hours. The reaction mixture was quenched by adding water (10 mL), extracted with dichloromethane (10 mL * 3), the organic phases were combined, dried, and concentrated, and the residue was purified by silica gel column chromatography using eluent system B to give Example 69-4 (1.0 g, white solid) in a yield of 56.9%.

[0492] MS m / z (ESI): 493.0 [M+1] + .

[0493] Step 4 Preparation of 4'-((2-butyl-4-oxo-1,3-diazaspiro[4.4]nonan-1-en-3-yl)methyl)-N-(4-chloro-5-methylisoxazol-3-yl)-2'-(hydroxymethyl)-N-(methoxymethyl)-[1,1'-biphenyl]-2-sulfonamide A reactor was charged with Example 69-4 (400 mg, 1.05 mmol), (2-(N-(4-chloro-5-methylisoxazol-3-yl)-N-(methoxymethyl)sulfamoyl)phenyl)boronic acid (380 mg, 1.06 mmol), [1,1'-bis(diphenylphosphino)ferrocene] palladium dichloride dichloromethane complex (85 mg, 105.1 μmol), KCO (285 mg, 2.10 mmol), 1',4-dioxane (5 mL), and HO (1 mL). The mixture was stirred at 100 °C for 12 hours under nitrogen gas protection. After cooling the reaction mixture, 8 mL of water was added to quench it, and the mixture was extracted with ethyl acetate (10 mL*3). The organic phases were combined, dried and concentrated. The residue was purified by silica gel column chromatography using eluent system B to give Example 69-5 (500 mg, light brown solid) in a yield of 75.3%.

[0494] MS m / z(ESI):715.3[M+1] + .

[0495] Step 5 Preparation of 2'-(bromomethyl)-4'-(2-butyl-4-oxo-1,3-diazaspiro[4.4]nonan-1-en-3-yl)methyl)-N-(4-chloro-5-methylisoxazol-3-yl)-N-(methoxymethyl)-[1,1'-biphenyl]-2-sulfonamide Under nitrogen gas protection, carbon tetrabromide (525 mg, 1.58 mmol) and triphenylphosphine (310 mg, 1.18 mmol) were added to a solution of Example 69-5 (500 mg, 0.79 mmol) in DCM (10 mL) at 0° C., and the mixture was stirred at 20° C. for 1 hour. The reaction mixture was quenched by adding water (10 mL), extracted with dichloromethane (10 mL*3), the organic phases were combined, dried and concentrated, and the residue was purified by silica gel column chromatography using eluent system B to give Example 69-6 (520 mg, pale yellow solid) in a yield of 95.3%.

[0496] MS m / z (ESI): 778.2 [M+1] + .

[0497] Step 6 Preparation of 4'-((2-butyl-4-oxo-1,3-diazaspiro[4.4]nonan-1-en-3-yl)methyl)-N-(4-chloro-5-methylisoxazol-3-yl)-2'-(((trifluoromethoxy)methyl)-N-((2-(trimethylsilyl)ethoxy)methyl)-[1,1'-biphenyl]-2-sulfonamide Trifluoromethyl trifluoromethanesulfonate (72 mg, 0.33 mmol) and silver fluoride (48 mg, 0.33 mmol) were dissolved in acetonitrile (5 mL). The reaction mixture was cooled to -30 °C and stirred for 2 hours. Then, Example 69-6 (125 mg, 0.16 mmol) dissolved in 5 mL of acetonitrile was added to the reaction mixture, and the reaction mixture was stirred at room temperature for 24 hours. Saturated brine (10 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (3 x 10 mL). The organic phases were combined, dried, concentrated, and purified using a column (petroleum ether / ethyl acetate system) to obtain Example 69-7 (85 mg, 69.1%).

[0498] MS m / z (ESI): 783.2 [M+1] + .

[0499] Step 7 Preparation of 4'-((2-butyl-4-oxo-1,3-diazaspiro[4.4]nonan-1-en-3-yl)methyl)-N-(4-chloro-5-methylisoxazol-3-yl)-2'-((trifluoromethoxy)methyl)-[1,1'-biphenyl]-2-sulfonamide The synthesis method of Example 69 was carried out in accordance with the synthesis method of Example 33, and the title compound Example 69 (27 mg, 28.5%) was obtained using Example 69-7 as the starting material.

[0500] MS m / z (ESI): 653.2 [M+1] + .

[0501] Example 70 2-[4-[(2-butyl-4-oxo-1,3-diazaspiro[4.4]nonan-1-en-3-yl)methyl]-2-(cyclobutoxymethyl)phenyl]-N-(4-chloro-5-methyl-isoxazol-3-yl)benzenesulfonamide [ka]

[0502] Step 1 Preparation of 2-[4-[(2-butyl-4-oxo-1,3-diazaspiro[4.4]nonan-1-en-3-yl)methyl]-2-(cyclobutoxymethyl)phenyl]-N-(4-chloro-5-methyl-isoxazol-3-yl)-N-(2-trimethylsiloxymethyl)benzenesulfonamide Cyclobutanol (46 mg, 0.642 mmol) was dissolved in N,N-dimethylformamide (5 mL), and sodium hydride (25 mg, 60% wt, 0.642 mmol) was added. The mixture was allowed to react at room temperature for 30 minutes. Example 69-6 (100 mg, 0.128 mmol) was added, and the mixture was allowed to react at room temperature for 1 hour. The reaction mixture was poured into 30 mL of ice water and extracted with ethyl acetate (30 mL * 2). The organic phases were combined, washed with saturated sodium chloride solution (30 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give Example 70-1 (90 mg, yellow solid), with a yield of 91.0%, which was used directly in the next step.

[0503] MS m / z (ESI): 769.3 [M+1] + .

[0504] Step 2 Preparation of 2-[4-[(2-butyl-4-oxo-1,3-diazaspiro[4.4]nonan-1-en-3-yl)methyl]-2-(cyclobutoxymethyl)phenyl]-N-(4-chloro-5-methyl-isoxazol-3-yl)benzenesulfonamide Example 70-1 (90 mg, 0.117 mmol) was dissolved in 4 M hydrochloric acid dioxane solution (4 mL), heated to 60° C., and reacted for 4 hours. The reaction mixture was cooled to room temperature and concentrated under reduced pressure. The resulting crude product was purified by reverse phase HPLC to give Example 70 (35.5 mg, white solid) in a yield of 48.6%.

[0505] MS m / z (ESI): 639.2 [M+1] + .

[0506] Example 71 2-[4-[(2-butyl-4-oxo-1,3-diazaspiro[4.4]nonan-1-en-3-yl)methyl]-2-(oxoalkyl-3-oxymethyl)phenyl]-N-(4-chloro-5-methyl-isoxazol-3-yl)benzenesulfonamide [ka]

[0507] Step 1 2-[4-[(2-butyl-4-oxo-1,3-diazaspiro[4.4]nonan-1-en-3-yl)methyl]-2-(oxoalkyl-3-oxymethyl)phenyl]-N-(4-chloro-5-methyl-isoxazol-3-yl)-N-(2-trimethylsiloxymethyl)benzenesulfonamide Oxetan-3-ol (48 mg, 0.642 mmol) was dissolved in N,N-dimethylformamide (5 mL), and sodium hydride (26 mg, 60% wt, 0.642 mmol) was added. The mixture was allowed to react at room temperature for 30 minutes. Example 69-6 (100 mg, 0.128 mmol) was added, and the mixture was allowed to react at room temperature for 1 hour. The reaction mixture was poured into 30 mL of ice water and extracted with ethyl acetate (30 mL * 2). The organic phases were combined, washed with saturated sodium chloride solution (30 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give Example 71-1 (75 mg, yellow solid), with a yield of 75.7%, which was used directly in the next step.

[0508] MS m / z (ESI): 771.3 [M+1] + .

[0509] Step 2 2-[4-[(2-butyl-4-oxo-1,3-diazaspiro[4.4]nonan-1-en-3-yl)methyl]-2-(oxoalkyl-3-oxymethyl)phenyl]-N-(4-chloro-5-methyl-isoxazol-3-yl)benzenesulfonamide Example 71-1 (75 mg, 0.097 mmol) was dissolved in 1 M tetrabutylammonium fluoride in tetrahydrofuran (4 mL), heated to 60 ° C, and reacted for 2 hours. The reaction mixture was cooled to room temperature, concentrated under reduced pressure, and 40 mL of ethyl acetate was added. The mixture was washed with water (40 mL * 2) and saturated sodium chloride solution (40 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified by reverse-phase HPLC to give Example 71 (12.6 mg, white solid), with a yield of 20.3%.

[0510] MS m / z (ESI): 641.2 [M+1] + .

[0511] Example 72 4'-((2-butyl-4-oxo-1,3-diazaspiro[4.4]nonan-1-en-3-yl)methyl)-N-(4-chloro-5-methylisoxazol-3-yl)-2'-(isopropoxymethyl)-[1,1'-biphenyl]-2-sulfonamide [ka]

[0512] Step 1 Preparation of 4'-((2-butyl-4-oxo-1,3-diazaspiro[4.4]nonan-1-en-3-yl)methyl)-N-(4-chloro-5-methylisoxazol-3-yl)-2'-(isopropoxymethyl)-N-(((2-(trimethylsilyl)ethoxy)methyl)-[1,1'-biphenyl]-2-sulfonamide Sodium bicarbonate (13 mg, 0.32 mmol) was added to isopropanol (2 mL), and the reaction mixture was stirred at room temperature for 1 hour. Then, Example 69-6 (125 mg, 0.16 mmol) dissolved in N,N-dimethylformamide (2 mL) was added to the reaction mixture, and the reaction mixture was stirred at 50°C for 16 hours. Saturated sodium chloride (10 mL) was added to the reaction mixture, and the mixture was extracted with dichloromethane (10 mL x 3). The organic phases were combined, dried, and concentrated to obtain a crude product. The crude product was purified by column chromatography (petroleum ether / ethyl acetate system) to obtain Example 72-1 (610 mg, 75.81% yield).

[0513] MS m / z (ESI): 757.3 [M+1] + .

[0514] Step 2 Preparation of 4'-((2-butyl-4-oxo-1,3-diazaspiro[4.4]nonan-1-en-3-yl)methyl)-N-(4-chloro-5-methylisoxazol-3-yl)-2'-(isopropoxymethyl)-[1,1'-biphenyl]-2-sulfonamide The synthesis method of Example 72 was carried out in accordance with the synthesis method of Example 71, and the title compound Example 72 (31 mg, 36.5%) was obtained using Example 72-1 as the starting material.

[0515] MS m / z (ESI): 627.2 [M+1] + .

[0516] Example 73 N-(4-chloro-5-methylisoxazol-3-yl)-4'-((4-oxo-1,3-diazaspiro[4.4]non-1-en-3-yl)methyl)-2'-((pyridin-2-oxy)methyl)-[1,1'-biphenyl]-2-sulfonamide [ka]

[0517] Step 1 Preparation of 4'-((2-butyl-4-oxo-1,3-diazaspiro[4.4]nonan-1-en-3-yl)methyl)-N-(4-chloro-5-methylisoxazol-3-yl)-N-(methoxymethyl)-2'-((pyridin-2-oxy)methyl)-[1,1'-biphenyl]-2-sulfonamide To a solution of Example 69-6 (100 mg, 144.51 μmol) in DMF (2 mL) were added potassium carbonate (40 mg, 289.02 μmol) and 2-hydroxypyridine (27 mg, 289.02 μmol), and the mixture was stirred at 80° C. for 5 hours. The reaction mixture was quenched by adding water (10 mL), extracted with dichloromethane (10 mL*3), the organic phases were combined, dried, and concentrated, and the residue was purified by silica gel column chromatography using eluent system B to give the title product 73-1 (52 mg, pale yellow solid), with a yield of 50.8%.

[0518] MS m / z (ESI): 706.2 [M+1] + .

[0519] Step 2 Preparation of 4'-((2-butyl-4-oxo-1,3-diazaspiro[4.4]nonan-1-en-3-yl)methyl)-N-(4-chloro-5-methylisoxazol-3-yl)-2'-((pyridin-2-oxy)methyl)-[1,1'-biphenyl]-2-sulfonamide The synthesis method of Example 73 was carried out in accordance with the synthesis method of Example 71, and Example 73-1 was used as the starting material to obtain the title compound Example 73 (18 mg, white solid), with a yield of 36.9%.

[0520] MS m / z (ESI): 662.1 [M+1] + .

[0521] Example 74 2'-((1H-imidazol-1-yl)methyl)-4'-((2-butyl-4-oxo-1,3-diazaspiro[4.4]nonan-1-en-3-yl)methyl)-N-(4-chloro-5-methylisoxazol-3-yl)-[1,1'-biphenyl]-2-sulfonamide [ka]

[0522] The synthesis method of Example 74 was the same as that of Example 73-1, except that imidazole was used instead of 2-hydroxypyridine to obtain Example 74 (26 mg, white solid), with a yield of 56.3%.

[0523] MS m / z(ESI):635.2[M+1] + .

[0524] Example 75 4'-((2-butyl-4-oxo-1,3-diazaspirocyclo[4.4]nonan-1-en-3-yl)methyl)-N-(4-chloro-5-methylisoxazol-3-yl)-2'-((4-oxo-5-azaspiro[2.4]heptan-5-yl)methyl)-[1,1'-biphenyl]-2-sulfonamide [ka]

[0525] The synthesis method of Example 75 was the same as that of Example 73-1, except that imidazole was used instead of 2-hydroxypyridine to obtain Example 75 (35 mg, white solid), with a yield of 45.2%.

[0526] MS m / z (ESI): 678.2 [M+1] + .

[0527] Example 76 N-[[5-[(2-butyl-4-oxo-1,3-diazaspiro[4.4]nonan-1-en-3-yl)methyl]-2-[(4-chloro-5-methyl-isoxazol-3-yl)sulfamoyl]phenyl]phenyl]methyl]-N,1-dimethyl-cyclopropanecarboxamide [ka]

[0528] Step 1 Preparation of N,1-dimethylcyclopropanecarboxamide 1-Methylcyclopropane-1-carboxylic acid (1.0 g, 10.0 mmol) was dissolved in anhydrous dichloromethane (20 mL), N,N-dimethylformamide (74 mg, 1.0 mmol) was added, and oxalyl chloride (1.91 g, 15.0 mmol) was added dropwise. The mixture was allowed to react at room temperature for 2 hours. The reaction mixture was concentrated under reduced pressure and redissolved in anhydrous dichloromethane (20 mL). Triethylamine (3.03 g, 30.0 mmol) and methylamine hydrochloride (1.35 g, 20.0 mmol) were added, and the mixture was allowed to react at room temperature for 2 hours. The reaction mixture was diluted with 50 mL of dichloromethane, washed successively with water (50 mL) and saturated sodium chloride solution (50 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The resulting mixture was purified by silica gel column chromatography (methanol / dichloromethane = 0 to 10%) to give Example 76-1 (730 mg, white solid) in a yield of 64.6%.

[0529] MS m / z (ESI): 114.1 [M+1] + .

[0530] Step 2 Preparation of N-[[5-[(2-butyl-4-oxo-1,3-diazaspiro[4.4]nonan-1-en-3-yl)methyl]-2-[(4-chloro-5-methyl-isoxazol-3-yl)-(2-trimethylsiloxymethyl)sulfamoyl]phenyl]phenyl]methyl]-N,1-dimethyl-cyclopropanecarboxamide Example 76-1 (73 mg, 0.642 mmol) was dissolved in N,N-dimethylformamide (5 mL), and sodium hydride (26 mg, 60% wt, 0.642 mmol) was added, followed by reaction at room temperature for 30 minutes. Example 69-6 (100 mg, 0.128 mmol) was added, followed by reaction at room temperature for 1 hour. The reaction solution was poured into 30 mL of ice water and extracted with ethyl acetate (30 mL * 2). The organic phases were combined, washed with saturated sodium chloride solution (30 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give Example 76-2 (105 mg, yellow solid), which was used crude directly in the next step.

[0531] MS m / z(ESI):810.3[M+1] + .

[0532] Step 3 N-[[5-[(2-butyl-4-oxo-1,3-diazaspiro[4.4]nonan-1-en-3-yl)methyl]-2-[(4-chloro-5-methyl-isoxazol-3-yl)sulfamoyl]phenyl]phenyl]methyl]-N,1-dimethyl-cyclopropanecarboxamide Example 76-2 (105 mg, 0.130 mmol) was dissolved in 4 M hydrochloric acid dioxane solution (4 mL), heated to 60° C., and reacted for 4 hours. The reaction mixture was cooled to room temperature and concentrated under reduced pressure. The resulting crude product was purified by reverse phase HPLC to give Example 76 (21.6 mg, white solid), with a yield of 24.4%.

[0533] MS m / z (ESI): 680.3 [M+1] + .

[0534] Example 77 4'-((2-butyl-4-oxo-1,3-diazaspiro[4.4]nonan-1-en-3-yl)methyl)-N-(4-chloro-5-methylisoxazol-3-yl)-2'-(cyanomethyl)-[1,1'-biphenyl]-2-sulfonamide [ka]

[0535] Step 1 Preparation of 4'-((2-butyl-4-oxo-1,3-diazaspiro[4.4]nonan-1-en-3-yl)methyl)-N-(4-chloro-5-methylisoxazol-3-yl)-2'-(cyanomethyl)-N-(((2-(trimethylsilyl)ethoxy)methyl)-[1,1'-biphenyl]-2-sulfonamide Trimethylsilyl cyanide (48 mg, 0.48 mmol) and Example 69-6 (125 mg, 0.16 mmol) were dissolved in CH3CN (5 mL). Tetrabutylammonium fluoride (1 M, 0.48 mL) was then added to the reaction mixture. The reaction mixture was then stirred at room temperature for 2 hours, saturated sodium chloride (10 mL) was added to the reaction mixture, and the mixture was extracted with dichloromethane (10 mL x 3). The organic phases were combined, dried, and concentrated to obtain a crude product. The crude product was purified by column chromatography (petroleum ether / ethyl acetate system) to obtain the target molecule of Example 77-1 (95 mg, 81.9% yield).

[0536] MS m / z (ESI): 724.2 [M+1] + .

[0537] Step 2 Preparation of 4'-((2-butyl-4-oxo-1,3-diazaspiro[4.4]nonan-1-en-3-yl)methyl)-N-(4-chloro-5-methylisoxazol-3-yl)-2'-(cyanomethyl)-[1,1'-biphenyl]-2-sulfonamide The synthesis method of Example 77 was carried out in accordance with the synthesis method of Example 52, and the title compound Example 77 (22 mg, 28.5%) was obtained using Example 77-1 as the starting material.

[0538] MS m / z (ESI): 594.2 [M+1] + .

[0539] Example 78 2-(4-((2-butyl-4-oxo-1,3-diazaspiro[4.4]nonan-1-en-3-yl)methyl)-2'-(N-(4-chloro-5-methylisoxazol-3-yl)sulfamoyl)-[1,1'-biphenyl]-2-yl)-N,N-dimethylacetamide [ka]

[0540] Step 1 Preparation of 2-(4-((2-butyl-4-oxo-1,3-diazaspiro[4.4]nonan-1-en-3-yl)methyl)-2'-(N-(4-chloro-5-methylisoxazol-3-yl)sulfamoyl)-[1,1'-biphenyl]-2-yl)acetic acid Water (4 mL), concentrated sulfuric acid (4 mL), and glacial acetic acid (4 mL) were added to Example 77-1 (200 mg, 0.28 mmol), and the reaction mixture was stirred at 100°C for 1 hour. Water (10 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (10 mL x 3). The organic phases were combined, dried, and concentrated to obtain a crude product. The crude product was purified by column chromatography (petroleum ether / ethyl acetate system) to obtain the target molecule of Example 78-1 (82 mg, 48.5% yield).

[0541] MS m / z(ESI):613.2[M+1] + .

[0542] Step 2 Preparation of 2-(4-((2-butyl-4-oxo-1,3-diazaspiro[4.4]nonan-1-en-3-yl)methyl)-2'-(N-(4-chloro-5-methylisoxazol-3-yl)sulfamoyl)-[1,1'-biphenyl]-2-yl)-N,N-dimethylacetamide Example 78-1 (100 mg, 0.16 mmol) was added to dimethylamine hydrochloride (26 mg, 0.32 mmol), and 2-(7-azabenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (122 mg, 0.32 mmol) was dissolved in dichloromethane (5 mL). Triethylamine (33 mg, 0.32 mmol) was then added to the reaction mixture, and the reaction mixture was stirred at room temperature for 1 hour. Water (10 mL) was added to the reaction mixture, and the mixture was extracted with dichloromethane (10 mL x 3). The organic phases were combined, dried, and concentrated to obtain the crude product. The crude product was purified by column chromatography (petroleum ether / ethyl acetate system) to obtain the target molecule of Example 78 (32 mg, 33.5% yield).

[0543] MS m / z (ESI): 640.2 [M+1] + .

[0544] Example 79 2-(4-((2-butyl-4-oxo-1,3-diazaspiro[4.4]nonan-1-en-3-yl)methyl)-2'-(N-(4-chloro-5-methylisoxazol-3-yl)sulfamoyl)-[1,1'-biphenyl]-2-yl)-N,N-diethylacetamide [ka]

[0545] Step 1 Preparation of 2-(4-((2-butyl-4-oxo-1,3-diazaspiro[4.4]nonan-1-en-3-yl)methyl)-2'-(N-(4-chloro-5-methylisoxazol-3-yl)sulfamoyl)-[1,1'-biphenyl]-2-yl)-N,N-diethylacetamide Example 78-1 (100 mg, 0.16 mmol) was added to diethylamino hydrochloride (35 mg, 0.32 mmol), and 2-(7-azabenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (122 mg, 0.32 mmol) was dissolved in dichloromethane (5 mL). Triethylamine (33 mg, 0.32 mmol) was then added to the reaction mixture, and the reaction mixture was stirred at room temperature for 1 hour. Water (10 mL) was added to the reaction mixture, and the mixture was extracted with dichloromethane (10 mL x 3). The organic phases were combined, dried, and concentrated to obtain the crude product. The crude product was purified by column chromatography (petroleum ether / ethyl acetate system) to obtain the target molecule of Example 79 (32 mg, 33.5% yield).

[0546] MS m / z (ESI): 668.2 [M+1] + .

[0547] Example 82 N-[[5-[(2-butyl-4-oxo-1,3-diazaspiro[4.4]nonan-1-en-3-yl)methyl]-2-[(4-chloro-5-methyl-isoxazol-3-yl)sulfamoyl]phenyl]phenyl]methyl]-N,1-dimethyl-cyclopropanecarboxamide [ka]

[0548] Step 1 Preparation of 2-(2-bromo-5-methylphenyl)propanol Methyl 2-bromo-5-methylbenzoate (3.0 g, 13.1 mmol) was dissolved in anhydrous tetrahydrofuran (50 mL) and cooled to -78 °C under nitrogen gas protection. 3 M methylmagnesium bromide tetrahydrofuran solution (17.5 mL, 52.4 mmol) was added dropwise, and the mixture was allowed to warm slowly to room temperature and react for 3 hours. The reaction mixture was cooled to 0 °C and quenched by the dropwise addition of saturated ammonium chloride. The mixture was extracted with ethyl acetate (100 mL * 2). The combined organic phase was washed successively with water (100 mL) and saturated sodium chloride solution (100 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The product was purified by silica gel column chromatography (ethyl acetate / petroleum ether = 0-30%) to give Example 82-1 (2.2 g, white solid) in 73.3% yield.

[0549] 1 H NMR(400MHz,CDCl3)δ 7.51-7.48(m,2H),6.96-6.91(m,1H),2.63(s,1H),2.33(s,3H),1.76(s,6H).

[0550] Step 2 Preparation of 1-bromo-2-(2-ethoxypropan-2-yl)-4-toluene Example 82-1 (2.2 g, 9.61 mmol) was dissolved in anhydrous tetrahydrofuran (30 mL), sodium hydride (576 mg, 60% wt, 14.4 mmol) was added, and the mixture was allowed to react at room temperature for 1 hour. Iodoethane (2.25 g, 14.4 mmol) was added, and the mixture was heated to 80°C and allowed to react for 4 hours. The reaction mixture was cooled to room temperature, poured into 100 mL of ice water, and extracted with ethyl acetate (80 mL * 2). The combined organic phase was washed with water (80 mL) and saturated sodium chloride solution (80 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. Example 82-2 (1.4 g, white solid) was obtained by silica gel column chromatography (ethyl acetate / petroleum ether = 0-20%) in a 54.9% yield.

[0551] MS m / z (ESI): 257.1 [M+1] + .

[0552] Step 3 Preparation of 1-bromo-4-(bromomethyl)-2-(2-ethoxypropan-2-yl)benzene Example 82-2 (1.4 g, 5.47 mmol) was dissolved in carbon tetrachloride (30 mL), azobisisobutyronitrile (90 mg, 0.547 mmol) and N-bromosuccinimide (1.07 g, 6.02 mmol) were added, and the mixture was refluxed under nitrogen gas protection for 4 hours. The reaction mixture was cooled to room temperature, washed with water (30 mL) and saturated sodium chloride solution (30 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (ethyl acetate / petroleum ether = 0 to 30%) to give Example 82-3 (850 mg, yellow solid) in 46.5% yield.

[0553] MS m / z (ESI): 335.0 [M+1] + .

[0554] Step 4 Preparation of 3-(4-bromo-3-(2-ethoxypropan-2-yl)benzyl)-2-butyl-1,3-diazaspiro[4.4]nonan-1-en-4-one 2-Butyl-1,3-diazaspiro[4.4]nonan-1-en-4-one (739 mg, 3.81 mmol) was dissolved in N,N-dimethylformamide (10 mL), cooled to 0 °C, and sodium hydride (152 mg, 60% wt, 3.81 mmol) was added. The mixture was warmed to room temperature and reacted for 30 minutes. Example 82-3 (850 mg, 2.54 mmol) was added, and the mixture was reacted at room temperature for 2 hours. The reaction mixture was cooled to 0 °C, and water was added dropwise to quench the reaction. The pH was adjusted to approximately 6 with dilute hydrochloric acid, and the mixture was extracted with ethyl acetate (50 mL * 2). The organic phases were combined, washed successively with water (50 mL) and saturated sodium chloride solution (50 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (methanol / dichloromethane = 0 to 10%) to obtain Example 82-4 (680 mg, yellow solid), with a yield of 59.7%.

[0555] MS m / z(ESI):449.2[M+1] + .

[0556] Step 5 Preparation of 2-[4-[(2-butyl-4-oxo-1,3-diazaspiro[4.4]nonan-1-en-3-yl)methyl]-2-(1-ethoxy-1-methyl-ethyl)phenyl]-N-(4-chloro-5-methyl-isoxazol-3-yl)-N-(2-trimethylsiloxymethyl)benzenesulfonamide Example 82-4 (100 mg, 0.223 mmol) was dissolved in 1,4-dioxane (2 mL) and water (0.5 mL), and (2-(N-(4-chloro-5-methylisoxazol-3-yl)-N-((2-(trimethylsilyl)ethoxy)methyl)sulfamoyl)phenyl)boronic acid (149 mg, 0.334 mmol), [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (16 mg, 0.0223 mmol), and sodium carbonate (35 mg, 0.334 mmol) were added. The atmosphere was purged with nitrogen gas three times, and the reaction was carried out at 100 °C for 1 hour using a microwave. The reaction solution was poured into 30 mL of water and extracted with ethyl acetate (30 mL * 2). The organic phases were combined, washed with saturated sodium chloride solution (30 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (methanol / dichloromethane = 0-10%) to obtain Example 82-5 (90 mg, yellow solid), with a yield of 52.4%.

[0557] MS m / z (ESI): 771.3 [M+1] + .

[0558] Step 6 Preparation of N-[[5-[(2-butyl-4-oxo-1,3-diazaspiro[4.4]nonan-1-en-3-yl)methyl]-2-[(4-chloro-5-methyl-isoxazol-3-yl)sulfamoyl]phenyl]phenyl]methyl]-N,1-dimethyl-cyclopropanecarboxamide Example 82-5 (90 mg, 0.117 mmol) was dissolved in 4 M hydrochloric acid dioxane solution (4 mL), heated to 60 ° C, and reacted for 4 hours. The reaction solution was cooled to room temperature and concentrated under reduced pressure. The resulting crude product was purified by reverse phase HPLC to give Example 82 (39.5 mg, white solid) in a yield of 52.7%.

[0559] MS: m / z(ESI):641.3[M+1] + .

[0560] Example 83 2-[4-[(2-butyl-4-oxo-1,3-diazaspiro[4.4]nonan-1-en-3-yl)methyl]-2-(1-ethoxycyclopropyl)phenyl]-N-(4-chloro-5-methyl-isoxazol-3-yl)benzenesulfonamide [ka]

[0561] Step 1 Preparation of 2-bromo-N-methoxy-N,5-dimethylbenzamide 2-Bromo-5-methylbenzoic acid (3.0 g, 14.0 mmol) was dissolved in anhydrous dichloromethane (50 mL), N,N-dimethylformamide (103 mg, 1.40 mmol) was added, and the mixture was cooled to 0 °C. Oxalyl chloride (3.54 g, 27.9 mmol) was added dropwise and reacted at room temperature for 3 hours. The reaction mixture was concentrated under reduced pressure and redissolved in anhydrous dichloromethane (50 mL). Triethylamine (4.23 g, 41.9 mmol) and dimethylhydroxylamine hydrochloride (2.72 g, 27.9 mmol) were added, and the mixture was reacted at room temperature for 2 hours. The reaction mixture was poured into 100 mL of water and extracted with dichloromethane (100 mL * 2). The organic phases were combined, washed with saturated sodium chloride solution (100 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (ethyl acetate / petroleum ether=0-60%) to obtain Example 83-1 (3.2 g, white solid), with a yield of 88.6%.

[0562] MS m / z (ESI): 258.0 [M+1] + .

[0563] Step 2 Preparation of 1-(2-bromo-5-methylphenyl)ethan-1-one Example 83-1 (3.2 g, 12.4 mmol) was dissolved in anhydrous tetrahydrofuran (50 mL) and cooled to -78 °C under nitrogen gas protection. 3 M methylmagnesium bromide tetrahydrofuran solution (6.2 mL, 18.6 mmol) was added dropwise, and the mixture was allowed to warm to room temperature and react for 3 hours. The reaction mixture was cooled to 0 °C and quenched by adding saturated ammonium chloride solution dropwise. The mixture was extracted with ethyl acetate (60 mL * 2). The combined organic phases were washed with water (60 mL) and saturated sodium chloride solution (60 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The product was purified by silica gel column chromatography (ethyl acetate / petroleum ether = 0 to 60%) to give Example 83-2 (2.1 g, white solid) in 79.5% yield.

[0564] MS m / z (ESI): 213.0 [M+1] + .

[0565] Step 3 Preparation of 1-bromo-2-(1-ethoxyvinyl)-4-toluene Example 83-2 (2.1 g, 9.86 mmol) was dissolved in anhydrous tetrahydrofuran (30 mL), and tert-butoxide (1.66 g, 14.8 mmol) was added. The mixture was allowed to react at room temperature for 1 hour. A 1 M solution of triethyloxonium tetrafluoroborate in dichloromethane (14.8 mL, 14.8 mmol) was added, and the mixture was allowed to react at room temperature for 2 hours. The reaction mixture was poured into 100 mL of water and extracted with ethyl acetate (60 mL * 2). The combined organic phases were washed with water (60 mL) and saturated sodium chloride solution (60 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (ethyl acetate / petroleum ether = 0-60%) to give Example 83-3 (1.7 g, white solid) in 71.5% yield.

[0566] MS m / z (ESI): 242.1 [M+1] + .

[0567] Step 4 Preparation of 1-bromo-2-(1-ethoxycyclopropyl)-4-toluene Example 83-3 (1.7 g, 7.05 mmol) and diiodomethane (2.83 g, 10.6 mmol) were dissolved in dichloromethane (30 mL) and cooled to -78 °C under nitrogen gas protection. 1 M diethylzinc in n-hexane (10.6 mL, 10.6 mmol) was added dropwise and reacted at -78 °C for 1 hour, then slowly warmed to room temperature and reacted for 4 hours. The reaction mixture was slowly poured into 100 mL of ice water and extracted with dichloromethane (100 mL * 2). The combined organic phases were washed with water (100 mL) and saturated sodium chloride solution (100 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (ethyl acetate / petroleum ether = 0-30%) to obtain Example 83-4 (800 mg, white solid) in 44.5% yield.

[0568] MS m / z (ESI): 255.0 [M+1] + .

[0569] Step 5 Preparation of 1-bromo-4-(bromomethyl)-2-(1-ethoxycyclopropyl)benzene Example 83-4 (800 mg, 3.14 mmol) was dissolved in carbon tetrachloride (15 mL), azobisisobutyronitrile (51 mg, 0.314 mmol) and N-bromosuccinimide (670 mg, 3.76 mmol) were added, and the mixture was refluxed under nitrogen gas protection for 4 hours. The reaction mixture was cooled to room temperature, washed with water (30 mL) and saturated sodium chloride solution (30 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (ethyl acetate / petroleum ether = 0 to 30%) to give Example 83-5 (620 mg, yellow solid) in 59.5% yield.

[0570] MS m / z (ESI): 332.9 [M+1] + .

[0571] Step 6 Preparation of 3-(4-bromo-3-(1-ethoxycyclopropyl)benzyl)-2-butyl-1,3-diazaspiro[4.4]nonan-1-en-4-one 2-Butyl-1,3-diazaspiro[4.4]nonan-1-en-4-one (542 mg, 2.79 mmol) was dissolved in N,N-dimethylformamide (10 mL), cooled to 0 °C, and sodium hydride (112 mg, 60% wt, 2.79 mmol) was added. The mixture was warmed to room temperature and reacted for 30 minutes. Example 83-5 (620 mg, 1.86 mmol) was added, and the mixture was reacted at room temperature for 2 hours. The reaction mixture was cooled to 0 °C, and water was added dropwise to quench the reaction. The pH was adjusted to approximately 6 with dilute hydrochloric acid, and the mixture was extracted with ethyl acetate (50 mL * 2). The organic phases were combined, washed successively with water (50 mL) and saturated sodium chloride solution (50 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (methanol / dichloromethane = 0 to 10%) to obtain Example 83-6 (430 mg, yellow solid), with a yield of 51.7%.

[0572] MS m / z(ESI):447.2[M+1] + .

[0573] Step 7 Preparation of 2-[4-[(2-butyl-4-oxo-1,3-diazaspiro[4.4]nonan-1-en-3-yl)methyl]-2-(1-ethoxycyclopropyl)phenyl]-N-(4-chloro-5-methyl-isoxazol-3-yl)-N-(2-trimethylsiloxymethyl)benzenesulfonamide Example 83-6 (100 mg, 0.224 mmol) was dissolved in 1,4-dioxane (2 mL) and water (0.5 mL), and (2-(N-(4-chloro-5-methylisoxazol-3-yl)-N-((2-(trimethylsilyl)ethoxy)methyl)sulfamoyl)phenyl)boronic acid xx (150 mg, 0.336 mmol), [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (16 mg, 0.0224 mmol), and sodium carbonate (36 mg, 0.336 mmol) were added. The atmosphere was purged with nitrogen gas three times, and the reaction was carried out at 100 °C for 1 hour using a microwave. The reaction solution was poured into 30 mL of water and extracted with ethyl acetate (30 mL * 2). The organic phases were combined, washed with saturated sodium chloride solution (30 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (methanol / dichloromethane = 0-10%) to obtain Example 83-7 (70 mg, yellow solid), with a yield of 40.6%.

[0574] MS m / z (ESI): 769.3 [M+1] + .

[0575] Step 8 Preparation of 2-[4-[(2-butyl-4-oxo-1,3-diazaspiro[4.4]nonan-1-en-3-yl)methyl]-2-(1-ethoxycyclopropyl)phenyl]-N-(4-chloro-5-methyl-isoxazol-3-yl)benzenesulfonamide Example 83-7 (70 mg, 0.091 mmol) was dissolved in 4 M hydrochloric acid dioxane solution (4 mL), heated to 60° C., and reacted for 4 hours. The reaction solution was cooled to room temperature and concentrated under reduced pressure. The resulting crude product was purified by reverse phase HPLC to give Example 83 (15.0 mg, yield: 25.8%).

[0576] MS m / z (ESI): 639.3 [M+1] + .

[0577] Example 84 4'-((2-butyl-4-oxo-1,3-diazaspiro[4.4]non-1-en-3-yl)methyl)-N-(4-chloro-5-methylisoxazol-3-yl)-2'-(((methoxy-d3)methyl)-[1,1'-biphenyl]-2-sulfonamide [ka]

[0578] The synthesis method of Example 84 was carried out in accordance with the synthesis method of Example 69, and deuterated methanol was used as the raw material to obtain Example 84 (26 mg, yield: 56.3%).

[0579] MS m / z (ESI): 602.2 [M+1] + . 1 H NMR(400MHz,DMSO)δ 8.09-7.93(m,1H),7.53(s,2H),7.14(d,J=21.2Hz,2H),6.98(dd,J=16.8 ,7.7Hz,2H),4.73(s,2H),4.00(dd,J=31.4,13.0Hz,2H),2.36(t,J=7.5Hz ,2H),2.25(s,3H),1.85(d,J=7.1Hz,6H),1.69(d,J=7.5Hz,2H),1.52(dt ,J=15.2,7.6Hz,2H),1.29(dt,J=22.4,7.5Hz,2H),0.82(t,J=7.3Hz,3H).

[0580] Example 85 4'-((2-butyl-4-oxo-1,3-diazaspiro[4.4]non-1-en-3-yl)methyl)-N-(4-chloro-5-methylisoxazol-3-yl)-2'-((cyclopropylmethoxy)methyl)-[1,1'-biphenyl]-2-sulfonamide [ka]

[0581] The synthesis method of Example 85 was similar to that of Example 69, and Example 85 (14 mg, yield: 43%) was obtained using cyclopropylmethanol as a starting material.

[0582] MS m / z (ESI): 639.2 [M+1] + .

[0583] Example 86 4'-((2-butyl-4-oxo-1,3-diazaspiro[4.4]non-1-en-3-yl)methyl)-N-(4-chloro-5-methylisoxazol-3-yl)-2'-(((2,2,2-trifluoroethoxy)methyl)-[1,1'-biphenyl]-2-sulfonamide [ka]

[0584] The synthesis method of Example 86 was carried out in accordance with the synthesis method of Example 69, and Example 86 (21 mg, yield: 46%) was obtained using trifluoroethanol as a raw material.

[0585] MS m / z (ESI): 667.2 [M+1] + .

[0586] Example 87 4'-((2'-butyl-5'-oxyspiro[bicyclo[3.1.0]hexane-3,4'-imidazol]-1'(5'H)-yl)methyl)-N-(4,5-dimethylisoxazol-3-yl)-2'-(ethoxymethyl)-[1,1'-biphenyl]-2-sulfonamide [ka]

[0587] The synthesis method of Example 87 was the same as that of Example 2, except that 2-butyl-1,3-diazaspirocyclo-[4,4]nonan-1-en-4-one was replaced with 2'-butylspiro[bicyclo[3.1.0]hexane-3,4'-imidazol]-5'(1'H)-one to obtain Synthesis Example 87 (11 mg, yield 36%).

[0588] MS m / z (ESI): 605.2 [M+1] + . 1 H NMR (400 MHz, DMSO) δ 8.06(dd,J=7.4,1.9Hz,1H),7.66-7.57(m,2H),7.21-7.14(m,2H),7.03-6.92(m ,2H),4.68(s,2H),4.00(s,2H),3.21(d,J=6.8Hz,2H),2.32(d,J=7.5Hz,2H),2. 20(s,4H),1.86(d,J=13.5Hz,2H),1.66(s,3H),1.50(dq,J=9.2,5.5Hz,5H),1.3 3-1.26(m,2H),1.08-0.98(m,4H),0.82(t,J=7.3Hz,3H),0.56(q,J=4.0Hz,1H).

[0589] Example 88 4'-((2-2-4-4-oxo-1,3-diazaspiro[4.5]dec-1-en-3-yl)methyl)-N-(4,5-dimethylisoxazol-3-yl)-2'-(methoxymethyl)-[1,1'-biphenyl]-2-sulfonamide [ka]

[0590] The synthesis method of Example 88 was carried out in accordance with the synthesis method of Example 54, except that 2-butyl-1,3-diazaspiro[4.5]dec-1-en-4-one was used instead of 2-butyl-1,3-diazaspirocyclo-[4,4]nonan-1-en-4-one to synthesize Example 88 (29 mg, yield 52%).

[0591] MS m / z (ESI): 593.3 [M+1]+ .

[0592] Example 89 4'-((2-2-4-4-oxo-1,3-diazaspiro[4.5]dec-1-en-3-yl)methyl)-N-(4,5-dimethylisoxazol-3-yl)-2'-(deuterated methoxymethyl)-[1,1'-biphenyl]-2-sulfonamide [ka]

[0593] The synthesis method of Example 89 was the same as that of Example 69, except that 2-butyl-1,3-diazaspiro[4.5]dec-1-en-4-one was used instead of 2-butyl-1,3-diazaspirocyclo-[4,4]nonan-1-en-4-one to synthesize Example 88 (31 mg, yield 42%).

[0594] MS m / z (ESI): 596.3 [M+1] + .

[0595] Example 91 1-((2'-(N-(4,5-dimethylisoxazol-3-yl)sulfamoyl)-2-(ethoxymethyl)-[1,1'-biphenyl]-4-yl)methyl)-4-(2-hydroxypropan-2-yl)-2-propyl-1H-imidazole-5-carboxylic acid ethyl ester [ka]

[0596] Step 1 Preparation of methyl 1-((2'-(N-(4,5-dimethylisoxazol-3-yl)-N-(methoxymethyl)sulfamoyl)-2-(ethoxymethyl)-[1,1'-biphenyl]-4-yl)methyl)-4-(2-hydroxypropan-2-yl)-2-propyl-1H-imidazole-5-carboxylic acid ethyl ester Example 2-1 (100 mg, 0.19 mmol) (see WO 2010114801A1 for preparation method) was dissolved in acetonitrile (4 mL), 4-(2-hydroxypropan-2-yl)-2-propyl-1H-imidazole-5-carboxylic acid ethyl ester (53 mg, 0.23 mmol) and potassium carbonate (52.8 mg, 0.38 mmol) were added, and the reaction mixture was heated to reflux for 6 hours. The reaction mixture was concentrated, and the crude product was purified by reverse-phase HPLC to give Example 91-1 (86 mg, yield: 66%).

[0597] MS m / z (ESI): 683.3 [M+1] + .

[0598] Step 2 Preparation of 1-((2'-(N-(4,5-dimethylisoxazol-3-yl)sulfamoyl)-2-(ethoxymethyl)-[1,1'-biphenyl]-4-yl)methyl)-4-(2-hydroxypropan-2-yl)-2-propyl-1H-imidazole-5-carboxylic acid ethyl ester The synthesis method of Example 91 was similar to that of Step 4 in Example 1, and Example 91-1 was used as the starting material to obtain Example 91 (31 mg, yield: 40%).

[0599] MS m / z (ESI): 639.3 [M+1] + . 1H NMR(400MHz,DMSO-d6)δ 8.99(s,1H),8.26(dd,J=7.4,1.4Hz,1H),7.65(dd,J=7.5,1.9Hz,1H),7.63(td,J=7.2,1.4Hz,1H),7.46(td,J=7.3 ,2.0Hz,1H),7.30(dq,J=2.0,1.0Hz,1H),7.21(d,J=7.4Hz,1H),7.00(dq,J=7.5,1.1Hz,1H),5.43(t,J=1.0Hz,2H), 4.97(s,1H),4.70(d,J=1.1Hz,2H),4.31(q,J=8.0Hz,2H),3.58(q,J=8.0Hz,2H),2.59(t,J=7.1Hz,3H),2.28(s,2H) ),1.81(s,2H),1.73(s,6H),1.76-1.65(m,2H),1.36(t,J=8.0Hz,3H),1.19(t,J=8.0Hz,4H),1.01(t,J=8.0Hz,3H).

[0600] Example 92 4'-(2-butyl-4-oxo-1,3-diazaspiro[4.4]non-1-en-3-yl)methyl)-N-(dimethylcarbamoyl)-2'-(ethoxymethyl)-[1,1'-biphenyl]-2-sulfonamide [ka]

[0601] The synthesis method of Example 92 was the same as that of Example 20, except that cyclopropanecarbonyl chloride was replaced with dimethylcarbamyl chloride to obtain Example 92 (18.8 mg, yield: 54.8%).

[0602] MS m / z (ESI): 569.3 [M+1] + . 1H NMR(400MHz,DMSO-d6)δ 10.16(s,1H),8.00(d,J=6.8Hz,1H),7.61-7.48(m,2H),7.20(s,1H),7.16-7.10(m,1H ),7.06-7.00(m,2H),4.73(s,2H),4.10(d,J=13.2Hz,1H),4.03(d,J=13.2Hz,1H),3.3 0-3.21(m,2H),2.61(s,6H),2.37(t,J=7.6Hz,2H),1.92-1.81(m,6H),1.72-1.66(m,2 H),1.57-1.50(m,2H),1.32-1.27(m,2H),1.04(t,J=6.8Hz,3H),0.84(t,J=7.2Hz,3H).

[0603] Example 93 4'-(2-butyl-4-oxo-1,3-diazaspiro[4.4]non-1-en-3-yl)methyl)-2'-(ethoxymethyl)-N-(ethylcarbamoyl)-[1,1'-biphenyl]-2-sulfonamide [ka]

[0604] Compound 20-2 (30 mg, 0.060 mmol) was dissolved in anhydrous tetrahydrofuran (2 mL), and ethyl isocyanate (86 mg, 1.21 mmol) and N,N-diisopropylethylamine (39 mg, 0.301 mmol) were added. The mixture was heated to 70° C. and reacted for 16 hours. After concentration under reduced pressure, the resulting residue was purified by reverse-phase pre-HPLC chromatography to give Example 93 (9.0 mg, yield: 25.6%).

[0605] MS m / z (ESI): 569.3 [M+1] + . 1H NMR(400MHz,DMSO-d6)δ 8.00(d,J=8.0Hz,1H),7.56-7.46(m,2H),7.17(s,1H),7.11-7.00(m,3H),5.94(s,1H),4 .74(s,2H),4.15(d,J=13.2Hz,1H),4.00(d,J=13.2Hz,1H),3.30-3.21(m,2H),2.91-2.8 7(m,2H),2.36(t,J=7.6Hz,2H),1.93-1.79(m,6H),1.72-1.65(m,2H),1.56-1.48(m,2H) ,1.33-1.24(m,2H),1.03(t,J=6.8Hz,3H),0.91(t,J=7.2Hz,3H),0.82(t,J=7.2Hz,3H).

[0606] Example 94 N-((4'-((2-butyl-4-oxo-1,3-diazaspiro[4.4]non-1-en-3-yl)methyl)-2'-(ethoxymethyl)-(1,1'-biphenyl)-2-yl)sulfonyl)pyrrolidine-1-carboxamide [ka]

[0607] The synthesis method of Example 94 was the same as that of Example 20, except that cyclopropanecarbonyl chloride was replaced with 1-pyrrolidinecarbonyl chloride to obtain Example 94 (8.2 mg, yield: 22.3%).

[0608] MS m / z (ESI): 595.3 [M+1] + . 1H NMR(400MHz,DMSO-d6)δ 8.01-7.97(m,1H),7.47-7.41(m,2H),7.14(s,1H),7.07(d,J=7.6Hz,1H),7.01-7.01(m, 1H),6.98-6.93(m,1H),4.72(s,2H),4.10(d,J=13.2Hz,1H),4.02(d,J=13.2Hz,1H),3.29 -3.25(m,2H),3.11-2.78(m,4H),2.36(t,J=7.6Hz,2H),1.91-1.82(m,6H),1.72-1.61(m ,6H),1.58-1.50(m,2H),1.33-1.27(m,2H),1.04(t,J=6.8Hz,3H),0.84(t,J=7.2Hz,3H).

[0609] Example 95 tert-Butyl ((4"-((2-butyl-4-oxo-1,3-diazaspiro[4.4]nonan-1-en-3-yl)methyl)-2"-(ethoxymethyl)-[1,1'-biphenyl]-2-yl)sulfonyl)carbamate [ka]

[0610] Step 1 Preparation of tert-butyl ((2-bromophenyl)sulfonyl)carbamate Tert-butyl carbamate (26 mg, 2.35 mmol) was dissolved in 5 mL of dichloromethane, and triethylamine (594 mg, 5.88 mmol) and 2-bromopyridine-3-sulfonyl chloride (500 mg, 1.96 mmol) were added. The mixture was allowed to react at room temperature for 2 hours. 50 mL of water was added, and the mixture was extracted with dichloromethane (40 mL × 2). The combined organic phases were washed with water (40 mL) and saturated sodium chloride solution (40 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate system) to give Example 95-1 (360 mg, yield: 45.8%).

[0611] MS m / z (ESI): 336.0 [M+1] + .

[0612] Step 2 Preparation of tert-butyl ((4"-((2-butyl-4-oxo-1,3-diazaspiro[4.4]nonan-1-en-3-yl)methyl)-2"-(ethoxymethyl)-[1,1'-biphenyl]-2-yl)sulfonyl)carbamate With reference to the synthesis method of Example 6-5, Example 95 (18 mg, yield: 29.6%) was obtained using Example 95-1 and Example 6-2 as raw materials.

[0613] MS m / z (ESI): 598.3 [M + 1] + .

[0614] Example 96 4'-((2-butyl-4-oxo-1,3-diazaspiro[4.4]non-1-en-3-yl)methyl)-2'-((cyclopropylmethoxy)methyl)-N-(3-methoxy)-5-methylpyrazin-2-yl)-[1,1'-biphenyl]-2-sulfonamide [ka]

[0615] Step 1 Preparation of 2-bromo-N-(3-methoxy-5-methylpyrazin-2-yl)pyridine-3-sulfonamide Example 96-1 (562 mg, yield: 55.6%) was obtained using 2-bromopyridine-3-sulfonyl chloride and 3-methoxy-5-methylpyrazin-2-amine as starting materials in accordance with the synthesis method of Example 6-3.

[0616] MS m / z (ESI): 359.0 [M+1] + .

[0617] Step 2 Preparation of 2-bromo-N-(3-methoxy-5-methylpyrazin-2-yl)-N-(methoxymethyl)pyridine-3-sulfonamide Example 96-2 (582 mg, yield: 85.6%) was obtained using Example 96-1 and bromomethyl methyl ether as raw materials, with reference to the synthesis method of Example 6-3.

[0618] MS m / z (ESI): 403.0 [M+1] + .

[0619] Step 3 Preparation of 2'-(bromomethyl)-4'-((2-butyl-4-oxo-1,3-diazaspiro[4.4]non-1-en-3-yl)methyl)-N-(3-methoxy-5-methylpyrazin-2-yl)-N-(methoxymethyl)-[1,1'-biphenyl]-2-sulfonamide Example 96-3 (380 mg, yield: 65.4%) was obtained using Example 96-2 and Intermediate 2 as raw materials, with reference to the synthesis method of Reference Example 12-1.

[0620] MS m / z (ESI): 698.2 [M+1] + .

[0621] Step 4 Preparation of 4'-((2-butyl-4-oxo-1,3-diazaspiro[4.4]non-1-en-3-yl)methyl)-2'-((cyclopropylmethoxy)methyl)-N-(3-methoxy)-5-methylpyrazin-2-yl)-N-(methoxymethyl)-[1,1'-biphenyl]-2-sulfonamide With reference to the synthesis method of Example 12-2, Example 96-4 (220 mg, yield: 45.4%) was obtained using Example 96-3 and cyclopropylmethanol as raw materials.

[0622] MS m / z (ESI): 690.4 [M+1] + .

[0623] Step 5 Preparation of 4'-((2-butyl-4-oxo-1,3-diazaspiro[4.4]non-1-en-3-yl)methyl)-2'-((cyclopropylmethoxy)methyl)-N-(3-methoxy)-5-methylpyrazin-2-yl)-[1,1'-biphenyl]-2-sulfonamide Following the synthesis method of Example 12, Example 96 (22 mg, yield: 15.4%) was obtained using Example 96-4 as the starting material.

[0624] MS m / z (ESI): 646.3 [M+1] + .

[0625] Example 97 Methyl 4-((2-butyl-4-oxo-1,3-diazaspiro[4.4]nonan-1-en-3-yl)methyl)-2'-(N-(4,5-dimethylisoxazol-3-yl)-N-(methoxymethyl)sulfamoyl)-[1,1'-biphenyl]-2-carboxylate [ka]

[0626] Step 1 Preparation of methyl 2-bromo-5-((2-butyl-4-oxo-1,3-diazaspiro[4.4]non-1-en-3-yl)methyl)benzoate By referring to the synthesis method of intermediate 2c, methyl 2-bromo-5-(bromomethyl)benzoate and 2-butyl-1,3-diazaspiro[4.4]nonan-1-en-4-one were used as raw materials to obtain Example 97-1 (652 mg, yield: 55.6%).

[0627] MS m / z (ESI): 421.0 [M+1] + .

[0628] Step 2 Preparation of methyl 5-((2-butyl-4-oxo-1,3-diazaspiro[4.4]nonan-1-en-3-yl)methyl)-2-(4,4,5,5-tetramethyl-1,3-,2-dioxaborolan-2-yl)benzoate By referring to the synthesis method of intermediate 2d, Example 97-2 (550 mg, yield: 85.6%) was obtained using Example 97-1 and bis(pinacolato)diboron as raw materials.

[0629] MS m / z (ESI): 469.3 [M+1] + .

[0630] Step 3 Preparation of methyl 4-((2-butyl-4-oxo-1,3-diazaspiro[4.4]nonan-1-en-3-yl)methyl)-2'-(N-(4,5-dimethylisoxazol-3-yl)-N-(methoxymethyl)sulfamoyl)-[1,1'-biphenyl]-2-carboxylate Example 97-3 (220 mg, yield: 35.6%) was obtained using Example 97-2 as the starting material, with reference to the synthesis method of Example 12-1.

[0631] MS m / z (ESI): 637.3 [M+1] + .

[0632] Step 4 Preparation of methyl 4-((2-butyl-4-oxo-1,3-diazaspiro[4.4]nonan-1-en-3-yl)methyl)-2'-(N-(4,5-dimethylisoxazol-3-yl)-N-(methoxymethyl)sulfamoyl)-[1,1'-biphenyl]-2-carboxylate Following the synthesis method of Example 12, Example 97 (28 mg, yield: 22.6%) was obtained using Example 97-3 as the starting material.

[0633] MS m / z (ESI): 593.2 [M+1] + . 1H NMR(400MHz,DMSO-d6)δ 8.29(d,J=3.7Hz,1H),7.95(dd,J=6.7,2.8Hz,1H),7.63(d,J=2.1Hz,1H),7.36(d,J=6.5Hz,2 H),7.18(d,J=8.3Hz,1H),7.04(d,J=7.9Hz,1H),6.95(d,J=6.4Hz,1H),4.77(s,2H),3.31(d,J =1.8Hz,3H),2.36(d,J=7.5Hz,2H),2.10-1.96(m,4H),1.87(q,J=7.2Hz,5H),1.70(d,J=8.5H z,2H),1.52(q,J=7.5Hz,2H),1.43(d,J=2.9Hz,3H),1.33-1.27(m,2H),0.83(t,J=7.3Hz,3H).

[0634] Example 98 1-(3-(ethoxymethyl)-4-(3-(N-(3-methoxy-5-methylpyrazin-2-yl)sulfamoyl)pyridin-2-yl)benzyl)-4-(2-hydroxypropan-2-yl)-2-propyl-1H-imidazole-5-carboxylic acid ethyl ester [ka]

[0635] Step 1 Preparation of 2-bromo-N-(3-methoxy-5-methylpyrazin-2-yl)pyridine-3-sulfonamide 2-Bromopyridine-3-sulfonyl chloride (1.0 g, 3.9 mmol) was dissolved in anhydrous dichloromethane (20 mL) and pyridine (5 mL), and 3-methoxy-5-methylpyrazin-2-amine (542 mg, 3.9 mmol) was added. The mixture was allowed to react at room temperature for 3 hours. The reaction mixture was poured into 50 mL of water, the pH was adjusted to 6 with dilute hydrochloric acid, and the mixture was extracted with dichloromethane (50 mL * 2). The combined organic phases were washed with water (50 mL) and saturated sodium chloride solution (50 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give the title product Example 98-1 (1.0 g, yield: 71.1%).

[0636] MS m / z (ESI): 358.9 [M+1] + .

[0637] Step 2 Preparation of 2-bromo-N-(3-methoxy-5-methylpyrazin-2-yl)-N-(methoxymethyl)pyridine-3-sulfonamide 98-1 (1 g, 2.78 mmol) was dissolved in anhydrous dichloromethane (10 mL), pyridine (1 mL) was added, the mixture was cooled to 0 °C, bromomethyl methyl ether (365 mg, 2.92 mmol) was slowly added dropwise, the mixture was warmed to room temperature, and the mixture was reacted for 2 hours. The reaction mixture was slowly poured into 50 mL of water and extracted with dichloromethane (40 mL * 2). The organic phases were combined, washed successively with water (40 mL) and saturated sodium chloride solution (40 mL), dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography to give the title product Example 98-2 (1 g, yield: 89%).

[0638] MS m / z (ESI): 403.0 [M+1] + .

[0639] Step 3 Preparation of 2-(4-((2-butyl-4-oxo-1,3-diazaspiro[4.4]non-1-en-3-yl)methyl)-2-(ethoxymethyl)phenyl)-N-(4-chloro-5-methylisoxazol-3-yl)-N-(methoxymethyl)pyridine-3-sulfonamide The synthesis method of Example 98-3 was similar to that of Example 6-5, except that 98-2 was used instead of 6-4 to obtain Example 98-3 (50 mg, yield: 39.7%).

[0640] MS m / z(ESI):711.3[M+1] + .

[0641] Step 4 Preparation of 2-(4-((2-butyl-4-oxo-1,3-diazaspiro[4.4]non-1-en-3-yl)methyl)-2-(ethoxymethyl)phenyl)-N-(4-chloro-5-methylisoxazol-3-yl)pyridine-3-sulfonamide The synthesis method of Example 98 was the same as that of Example 6, except that 98-3 was used instead of 6-5 to obtain Example 98 (20 mg, yield: 55%).

[0642] MS m / z (ESI): 667.3 [M+1] + 1 H NMR(400MHz,DMSO-d6)δ 8.50(d,J=4.8Hz,1H),8.29(dd,J=7.9,1.7Hz,1H),7.38(dd,J=8.0,4.7Hz,1H),7.11-7.02( m,2H),6.97(s,1H),6.76(d,J=7.9Hz,1H),5.49(s,2H),5.43(s,1H),4.20(q,J=7.1Hz,2H), 3.98(s,2H),3.67(s,3H),3.11(q,J=7.0Hz,2H),2.64(d,J=7.7Hz,2H),2.09(s,3H),1.98(d ,J=6.4Hz,1H),1.68(h,J=7.4Hz,2H),1.47(s,6H),1.19(d,J=7.1Hz,3H),0.98-0.92(m,5H).

[0643] Example 99 Ethyl 1-((2'-(N-(4,5-dimethylisoxazol-3-yl)sulfamoyl)-2-(ethoxymethyl)-(1,1'-biphenyl]-4-yl)methyl-d2)-4-(2-hydroxypropan-2-yl)-2-propyl-1H-imidazole-5-carboxylic acid ethyl ester [ka]

[0644] Compound 99 was synthesized in accordance with the synthesis method of Example 1, and 99 (30 mg, yield: 66%) was obtained.

[0645] MS m / z (ESI): 641.3 [M+1] + 1 H NMR(400MHz,DMSO-d6)δ 8.99(s,1H),8.26(dd,J=7.4,1.4Hz,1H),7.65(dd,J=7.5,1.9Hz,1H),7.63(td,J=7.2,1.4Hz,1H),7.46 (td,J=7.3,2.0Hz,1H),7.30(q,J=1.1Hz,1H),7.24-7.17(m,2H),4.97(s,1H),4.70(d,J=1.1Hz,2H),4. 31(q,J=8.0Hz,2H),3.58(q,J=8.0Hz,2H),2.59(t,J=7.1Hz,3H),2.28(s,3H),1.81(s,2H),1.73(s,6H) ,1.71(dtd,J=15.1,8.0,7.1Hz,2H),1.36(t,J=8.0Hz,3H),1.19(t,J=8.0Hz,3H),1.01(t,J=8.0Hz,3H).

[0646] Example 100 4'-(2-butyl-4-oxo-1,3-diazaspiro[4.4]non-1-en-3-yl)methyl)-2'-(ethoxymethyl)-N-(5-methyl-4-(methyl-d3)isoxazol-3-yl)-[1,1'-biphenyl]-2-sulfonamide [ka] The synthesis method of Example 100 was the same as that of Example 1, except that 5-methyl-4-(deuterated methyl)isoxazol-3-amine was used instead of 4,5-dimethylisoxazolamine to obtain Example 100 (6.8 mg, yield: 14.0%).

[0647] MS m / z (ESI): 596.3 [M+1] + .

[0648] Example 101 4'-(2-butyl-4-oxo-1,3-diazaspiro[4.4]non-1-en-3-yl)methyl)-2'-(ethoxymethyl)-N-(5-methyl-1,2,4-oxadiazol-3-yl)-[1,1'-biphenyl]-2-sulfonamide [ka]

[0649] The synthesis method of Example 101 was the same as that of Example 1, except that 5-methyl-3-amino-4-azaisoxazole was used instead of 4,5-dimethylisoxazolamine to obtain Example 101 (7.0 mg, yield: 15.0%).

[0650] MS m / z (ESI): 580.3 [M + 1] + . 1 H NMR(400MHz,DMSO-d6)δ 7.96-7.94(m,1H),7.36-7.31(m,2H),7.08(s,1H),7.01(d,J=7.6Hz,1H),6.94-6. 91(m,2H),4.71(s,2H),4.14(d,J=13.2Hz,1H),3.95(d,J=13.2Hz,1H),3.23-3.19 (m,2H),2.36(t,J=7.6Hz,2H),2.22(s,3H),1.92-1.79(m,6H),1.74-1.65(m,2H), 1.56-1.48(m,2H),1.32-1.26(m,2H),1.01(t,J=6.8Hz,3H),0.82(t,J=7.2Hz,3H).

[0651] Example 102 1-(3-(ethoxymethyl)-4-(3-(N-(3-methoxy-5-methylpyrazin-2-yl)sulfamoyl)pyridin-2-yl)benzyl)-4-(2-hydroxypropan-2-yl)-2-propyl-1H-imidazole-5-carboxylic acid [ka]

[0652] Compound 98 (100 mg, 0.15 mmol) and NaOH (2 M, 1.5 mL) were added to tetrahydrofuran (10 mL). The reaction solution was stirred at 25 °C for 4 hours, 1 M HCl (10 mL) was added, and then extracted with dichloromethane (30 mL * 2). The combined extracts were dried over Na SO and spin-dried. The resulting crude product was purified by silica gel column chromatography to give the title compound 102 (60 mg, yield: 63%).

[0653] MS m / z (ESI): 639.3 [M+1] + 1 H NMR(400MHz,DMSO-d6)δ 8.94(s,1H),8.79(dd,J=7.5,1.5Hz,1H),8.29(dd,J=7.5,1.5Hz,1H),7.96(d,J=7.5Hz,1H),7.5 1-7.43(m,2H),7.36(dq,J=2.1,1.1Hz,1H),7.05(dq,J=7.5,1.1Hz,1H),5.42(t,J=1.0Hz,2H),4 .97(s,1H),4.77(d,J=1.1Hz,2H),4.09(s,2H),3.58(q,J=8.0Hz,2H),2.59(t,J=7.1Hz,2H),2.5 1(d,J=0.7Hz,3H),1.73(s,6H),1.76-1.65(m,2H),1.19(t,J=8.0Hz,4H),1.01(t,J=8.0Hz,3H).

[0654] Example 103 4'-(2-butyl-4-oxo-1,3-diazaspiro[4.4]non-1-en-3-yl)methyl)-2'-(ethoxymethyl)-N-(5-methylisoxazol-3-yl)-[1,1'-biphenyl]-2-sulfonamide [ka]

[0655] The synthesis method of Example 103 was the same as that of Example 1, except that 4,5-dimethylisoxazolamine was replaced with 3-amino-5-methylisoxazole to obtain Example 103 (18.6 mg, yield: 15.2%).

[0656] MS m / z (ESI): 579.3 [M+1] + . 1 H NMR(400MHz,DMSO-d6)δ 11.22(br s,1H),7.98(d,J=7.6Hz,1H),7.65-7.57(m,2H),7.24-7.17(m,2H),7.07-7.02(m,2 H),5.76(s,1H),4.76(s,2H),4.07(d,J=13.2Hz,1H),4.00(d,J=13.2Hz,1H),3.28-3 .16(m,2H),2.35(t,J=7.6Hz,2H),2.25(s,3H),1.92-1.79(m,6H),1.76-1.65(m,2H) ,1.54-1.47(m,2H),1.32-1.24(m,2H),1.01(t,J=6.8Hz,3H),0.81(t,J=7.2Hz,3H).

[0657] Example 104 4'-(2-butyl-4-oxo-1,3-diazaspiro[4.4]non-1-en-3-yl)methyl)-N-(3-cyclopropylisoxazol-5-yl)-2'-(ethoxymethyl)-[1,1'-biphenyl]-2-sulfonamide [ka]

[0658] The synthesis method of Example 104 was the same as that of Example 1, except that 4,5-dimethylisoxazolamine was replaced with (3-cyclopropylisoxazol-5-yl)amine to obtain Example 104 (18.4 mg, yield: 15.2%).

[0659] MS m / z (ESI): 605.3 [M+1] + . 1H NMR(400MHz,DMSO-d6)δ 8.00(d,J=8.0Hz,1H),7.68-7.60(m,2H),7.22(d,J=7.6Hz,1H),7.20(s,1H),7.06(d,J=8.4Hz,1H),7.0 1(d,J=7.6Hz,1H),5.19(s,1H),4.77(s,2H),4.03(d,J=13.2Hz,1H),3.97(d,J=13.2Hz,1H),3.27-3.21( m,2H),2.38(t,J=7.6Hz,2H),1.93-1.84(m,6H),1.83-1.79(m,1H),1.75-1.68(m,2H),1.55-1.47(m,2H) ),1.31-1.24(m,2H),1.01(t,J=6.8Hz,3H),0.95-0.90(m,2H),0.81(t,J=7.2Hz,3H),0.66-0.60(m,2H).

[0660] Example 105 4'-(2-butyl-4-oxo-1,3-diazaspiro[4.4]non-1-en-3-yl)methyl)-N-(2-chloro-5-methoxypyrimidin-4-yl)-2'-(ethoxymethyl)-[1,1'-biphenyl]-2-sulfonamide [ka]

[0661] The synthesis method of Example 105 was the same as that of Example 1, except that 2-chloro-4-amino-5-methoxypyrimidine was used instead of 4,5-dimethylisoxazolamine to obtain Example 105 (26.6 mg, yield: 21.4%).

[0662] MS m / z (ESI): 640.2 [M+1] + . 1H NMR (400 MHz, DMSO-d6) δ 8.08(d,J=7.6Hz,1H),8.05-7.98(m,1H),7.66-7.56(m,2H),7.23-7.13(m, 2H),7.02(s,2H),4.75(s,2H),4.01-3.93(m,2H),3.78(s,3H),3.24-3.16( m,3H),2.36(t,J=7.6Hz,2H),1.92-1.82(s,6H),1.76-1.66(m,2H),1.55-1 .47(m,2H),1.32-1.24(m,2H),1.00(t,J=6.8Hz,3H),0.81(t,J=7.2Hz,3H).

[0663] Example 106 N-(5-(tert-butyl)isoxazol-3-yl)-4'-(2-butyl-4-oxo-1,3-diazaspiro[4.4]non-1-en-3-yl)methyl)-2'-(ethoxymethyl)-(1,1'-biphenyl)-2-sulfonamide [ka]

[0664] Compound 106 was synthesized in accordance with the synthesis method of Example 1, and 106 (62 mg, yield: 66%) was obtained.

[0665] MS m / z (ESI): 621.3 [M+1] + 1H NMR(400MHz,DMSO-d6)δ 11.23(s,1H),8.02(dd,J=7.6,1.8Hz,1H),7.69-7.59(m,2H),7.33-7.11(m,3H),7. 03(t,J=6.5Hz,2H),5.68(s,2H),4.76(s,2H),4.09-3.96(m,2H),3.25-3.16(m,2H), 2.34(t,J=7.5Hz,2H),1.85(d,J=7.6Hz,4H),1.70(d,J=8.9Hz,2H),1.50(p,J=7.5H z,2H),1.31-1.25(m,2H),1.20(s,9H),1.00(t,J=7.0Hz,3H),0.80(t,J=7.3Hz,3H).

[0666] Example 107 4'-((2-butyl-4-oxo-1,3-diazaspiro[4.4]non-1-en-3-yl)methyl)-N-(4,5-dimethylisoxazol-3-yl)-2'-hydroxy-[1,1'-biphenyl]-2-sulfonamide [ka]

[0667] Step 1 3-(4-Bromo-3-hydroxybenzyl)-2-butyl-1,3-diazaspiro[4.4]nonan-1-en-4-one Production By referring to the synthesis method of intermediate 2c, 2-bromo-5-(bromomethyl)phenol and 2-butyl-1,3-diazaspiro[4.4]nonan-1-en-4-one were used as raw materials to obtain Example 107-1 (343 mg, yield: 45.3%).

[0668] MS m / z (ESI): 379.1 [M+1] + .

[0669] Step 2 Preparation of 2-butyl-3-(3-hydroxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl)-1,3-diazaspiro[4.4]nonan-1-en-4-one By referring to the synthesis method of intermediate 2d, Example 107-2 (252 mg, yield: 65.6%) was obtained using Example 107-1 and bis(pinacolato)diboron as raw materials.

[0670] MS m / z(ESI):427.3[M+1] + .

[0671] Step 3 Preparation of 4'-((2-butyl-4-oxo-1,3-diazaspiro[4.4]non-1-en-3-yl)methyl)-N-(4,5-dimethylisoxazol-3-yl)-2'-hydroxy-N-(methoxymethyl)-[1,1'-biphenyl]-2-sulfonamide Example 107-3 (120 mg, yield: 45.6%) was obtained using Example 107-2 as the starting material, with reference to the synthesis method of Example 12-1.

[0672] MS m / z (ESI): 595.3 [M+1] + .

[0673] Step 4 Preparation of 4'-((2-butyl-4-oxo-1,3-diazaspiro[4.4]non-1-en-3-yl)methyl)-N-(4,5-dimethylisoxazol-3-yl)-2'-hydroxy-[1,1'-biphenyl]-2-sulfonamide Following the synthesis method of Example 12, Example 107 (21 mg, yield: 24.6%) was obtained using Example 107-3 as the starting material.

[0674] MS m / z (ESI): 551.2 [M+1] + . 1H NMR (400 MHz, DMSO) δ 10.24(s,1H),9.37(s,1H),7.95(d,J=7.4Hz,1H),7.49(dt,J=26.6,7.1Hz,2H ),7.12(d,J=7.3Hz,1H),6.73(t,J=39.8Hz,1H),6.49(d,J=10.6Hz,2H),4.56( s,2H),2.28(t,J=7.5Hz,2H),2.13(s,3H),1.79(d,J=6.9Hz,5H),1.71-1.54( m,5H),1.46(dt,J=15.2,7.6Hz,2H),1.29-1.17(m,3H),0.77(t,J=7.4Hz,3H).

[0675] Example 108 4'-(2-butyl-4-oxo-1,3-diazaspiro[4.4]non-1-en-3-yl)methyl)-2'-(ethoxymethyl)-N-(4-isopropyl-5-methylisoxazol-3-yl)-[1,1'-biphenyl]-2-sulfonamide [ka]

[0676] The synthesis method of Example 108 was the same as that of Example 1, except that 4,5-dimethylisoxazolamine was replaced with 4-isopropyl-5-methylisoxazol-3-amine to obtain Example 108 (3.5 mg, yield: 5.4%).

[0677] MS m / z (ESI): 621.3 [M+1] + . 1H NMR(400MHz,DMSO-d6)δ 8.00(d,J=8.8Hz,1H),7.38-7.30(m,2H),7.09(s,1H),6.98(d,J=8.0Hz,1H),6.91-6. 86(m,2H),4.70(s,2H),4.03(d,J=13.2Hz,1H),3.97(d,J=13.2Hz,1H),3.22-3.17(m,2 H),2.37-2.33(m,2H),2.09(s,3H),2.03-1.97(m,1H),1.89-1.81(m,6H),1.72-1.65( m,2H),1.55-1.49(m,2H),1.33-1.27(m,2H),1.07-1.00(m,9H),0.83(t,J=7.2Hz,3H).

[0678] Example 109 2-(4-((2-butyl-4-oxo-1,3-diazaspiro[4.4]non-1-en-3-yl)methyl)-2-(ethoxymethyl)phenyl)-N-(4-chloro-5-methylisoxazol-3-yl)pyridine-3-sulfonamide [ka]

[0679] Step 1 Preparation of 2-bromo-N-(4-chloro-5-methylisoxazol-3-yl)pyridine-3-sulfonamide 2-Bromopyridine-3-sulfonyl chloride (1.0 g, 4.72 mmol) was dissolved in anhydrous dichloromethane (20 mL) and pyridine (5 mL), and 4-chloro-5-methylisoxazol-3-amine (625 mg, 4.72 mmol) was added and reacted at room temperature for 3 hours. The reaction mixture was poured into 50 mL of water, the pH was adjusted to 6 with dilute hydrochloric acid, and extracted with dichloromethane (50 mL * 2). The combined organic phase was washed with water (50 mL) and saturated sodium chloride solution (50 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography using eluent system B to give the title product Example 109-1 (1.0 g, yield: 55.1%).

[0680] MS m / z (ESI): 351.9 [M+1] + .

[0681] Step 2 Preparation of 2-bromo-N-(4-chloro-5-methylisoxazol-3-yl)-N-(methoxymethyl)pyridine-3-sulfonamide 2-Bromo-N-(4-chloro-5-methylisoxazol-3-yl)pyridine-3-sulfonamide (600 mg, 1.95 mmol) was dissolved in anhydrous dichloromethane (10 mL), pyridine (770 mg, 9.74 mmol) was added, the mixture was cooled to 0 °C, bromomethyl methyl ether (365 mg, 2.92 mmol) was slowly added dropwise, the mixture was warmed to room temperature, and the reaction was carried out for 2 hours. The reaction mixture was slowly poured into 50 mL of water and extracted with dichloromethane (40 mL * 2). The combined organic phases were washed with water (40 mL) and saturated sodium chloride solution (40 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give the title product Example 109-2 (500 mg, yield: 72.9%).

[0682] MS m / z (ESI): 395.9 [M+1] + .

[0683] Step 3 Preparation of 2-(4-((2-butyl-4-oxo-1,3-diazaspiro[4.4]non-1-en-3-yl)methyl)-2-(ethoxymethyl)phenyl)-N-(4-chloro-5-methylisoxazol-3-yl)-N-(methoxymethyl)pyridine-3-sulfonamide The synthesis method of Example 109-3 was similar to that of Example 6-5, except that 109-2 was used instead of 6-4 to obtain Example 109-3 (40 mg, yield: 35.7%).

[0684] MS m / z (ESI): 658.2 [M+1] + .

[0685] Step 4 Preparation of 2-(4-((2-butyl-4-oxo-1,3-diazaspiro[4.4]non-1-en-3-yl)methyl)-2-(ethoxymethyl)phenyl)-N-(4-chloro-5-methylisoxazol-3-yl)pyridine-3-sulfonamide The synthesis method of Example 109 was similar to that of Example 6, except that 109-3 was used instead of 6-5 to obtain Example 109 (18.1 mg, yield: 48.2%).

[0686] MS m / z (ESI): 614.2 [M+1] + . 1 H NMR(400MHz,DMSO-d6)δ 8.72-8.66(m,1H),8.37(d,J=8.0Hz,1H),7.58-7.55(m,1H),7.19(s,1H),7.09( d,J=7.6Hz,1H),7.01(d,J=8.0Hz,1H),4.75(s,2H),4.07(s,2H),3.25-3.19(m,2 H),2.37(t,J=7.6Hz,2H),2.24(s,3H),1.93-1.79(m,6H),1.74-1.67(m,2H),1. 57-1.50(m,2H),1.33-1.27(m,2H),1.00(t,J=6.8Hz,3H),0.84(t,J=7.2Hz,3H).

[0687] Example 110 2-(4-((2-butyl-4-oxo-1,3-diazaspiro[4.4]non-1-en-3-yl)methyl-d2)-2-(ethoxymethyl)phenyl)-N-(4-fluoro-5-methylisoxazol-3-yl)pyridine-3-sulfonamide [ka]

[0688] The synthesis method of Example 110 was similar to that of Example 1, except that 4,5-dimethylisoxazolamine was replaced with 4-fluoro-5-methylisoxazolamine to obtain Example 110 (19 mg, yield: 50.3%).

[0689] MS m / z (ESI): 600.3 [M+1] 1 H NMR(400MHz,DMSO)δ 8.79(t,J=9.8Hz,1H),8.41(d,J=8.1Hz,1H),7.64(dd,J=8.0,4.8Hz,1H),7.22(s ,1H),7.05(dt,J=42.2,21.0Hz,3H),4.09(s,2H),3.22(dd,J=13.9,7.0Hz,2H),2. 36(t,J=7.5Hz,2H),2.28(s,3H),1.87(s,6H),1.71(s,2H),1.52(dt,J=15.2,7.5H z,2H),1.30(dt,J=14.7,7.4Hz,2H),0.99(t,J=7.0Hz,3H),0.83(t,J=7.3Hz,3H).

[0690] Example 111 (2-(4-((2-butyl-4-oxo-1,3-diazaspiro[4.4]non-1-en-3-yl)methyl)-2-(ethoxymethyl)phenyl)-N-(4-fluoro-5-methylisoxazol-3-yl)pyridine-3-sulfonamide [ka] The synthesis method of Example 111 was similar to that of Example 1, except that 4,5-dimethylisoxazolamine was replaced with 4-fluoro-5-methylisoxazolamine to obtain Example 111 (29 mg, yield: 55.6%).

[0691] MS m / z (ESI): 598.3 [M + 1] 1H NMR(400MHz,DMSO-d6)δ 9.13(s,1H),8.79(dd,J=7.5,1.5Hz,1H),8.29(dd,J=7.5,1.5Hz,1H),8.03(d,J=7.4Hz,1H),7 .54(q,J=1.1Hz,1H),7.50-7.43(m,2H),5.00(t,J=1.0Hz,2H),4.77(d,J=1.1Hz,2H),3.58(q,J =8.0Hz,2H),2.55(t,J=7.1Hz,2H),2.30(s,2H),2.11-2.00(m,6H),1.99-1.89(m,2H),1.60(p, J=7.1Hz,2H),1.40(dtd,J=15.1,7.9,6.9Hz,2H),1.19(t,J=8.0Hz,3H),0.91(t,J=8.0Hz,3H).

[0692] Example 112 4'-(2-butyl-4-chloro-5-(hydroxymethyl)-1H-imidazol-1-yl)methyl)-2'-(ethoxymethyl)-N-(4-fluoro-5-methylisoxazol-3-yl)-(1,1'-biphenyl)-2-sulfonamide [ka]

[0693] The synthesis method of Example 112 was the same as that of Example 1, except that 4,5-dimethylisoxazolamine was replaced with 4-fluoro-5-methylisoxazolamine to obtain Example 112 (25 mg, yield: 52.6%).

[0694] MS m / z (ESI): 591.2 [M+1] 1H NMR(400MHz,DMSO-d6)δ 9.10(s,1H),8.26(dd,J=7.4,1.4Hz,1H),7.65(dd,J=7.5,1.9Hz,1H),7.63(td,J=7.2,1.4Hz,1H),7.46(td,J =7.3,2.0Hz,1H),7.31(dq,J=1.8,1.1Hz,1H),7.21(d,J=7.4Hz,1H),7.00(dt,J=7.6,1.3Hz,1H),5.09(t,J=1 .0Hz,2H),4.77(d,J=7.5Hz,2H),4.70(d,J=1.1Hz,2H),3.71(t,J=7.7Hz,1H),3.58(q,J=8.0Hz,2H),2.57(t, J=7.1Hz,2H),2.30(s,2H),1.73-1.63(m,2H),1.57-1.46(m,2H),1.19(t,J=8.0Hz,3H),0.94(t,J=8.0Hz,3H).

[0695] Example 113 4'-((2-butyl-4-oxo-1,3-diazaspiro[4.4]non-1-en-3-yl)methyl)-N-(4,5-dimethylisoxazol-3-yl)-2'-propoxy-[1,1'-biphenyl]-2-sulfonamide [ka]

[0696] Example 107 (100 mg, 0.18 mmol) and potassium carbonate (45 mg, 0.36 mmol) were dissolved in dichloromethane (5 mL). Bromine propane (44 mg, 0.36 mmol) was then added to the reaction mixture, and the reaction mixture was stirred at room temperature for 2 h. Saturated brine (10 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (10 mL x 3). The organic phases were combined, dried, concentrated, and purified to give Example 113 (52 mg, yield: 49.1%).

[0697] MS m / z (ESI): 593.3 [M+1] + . 1H NMR(400MHz,DMSO)δ 10.86(s,1H),7.96(d,J=7.1Hz,2H),7.63-7.15(m,2H),7.20-6.91(m,2H),6.75-6.45( m,2H),4.63(s,2H),3.75(dd,J=36.1,7.0Hz,2H),3.31(s,3H),2.29(dd,J=25.0,17.5Hz ,2H),2.18(s,3H),1.78(d,J=7.2Hz,6H),1.62(d,J=7.3Hz,2H),1.46(dt,J=15.2,7.5Hz ,2H),1.22(ddd,J=20.5,14.1,6.6Hz,3H),0.94(t,J=6.9Hz,3H),0.76(t,J=7.3Hz,3H).

[0698] Example 114 4'-(2-butyl-4-oxo-1,3-diazaspiro[4.4]non-1-en-3-yl)methyl)-2'-(ethoxymethyl)-N-(5-methyl-4-(trifluoromethyl)isoxazol-3-yl)-[1,1'-biphenyl]-2-sulfonamide [ka]

[0699] The synthesis method of Example 114 was the same as that of Example 1, except that 5-methyl-4-(trifluoromethyl)isoxazol-3-amine was used instead of 4,5-dimethylisoxazolamine to obtain Example 114 (12.5 mg, yield: 8.6%).

[0700] MS m / z (ESI): 647.2 [M+1] + . 1H NMR(400MHz,DMSO-d6)δ 8.00-7.98(m,1H),7.38-7.32(m,2H),7.10(s,1H),6.99(d,J=7.6Hz,1H),6.94-6.91(m, 1H),6.88(d,J=8.0Hz,1H),4.70(s,2H),4.08(d,J=13.2Hz,1H),3.98(d,J=13.2Hz,1H), 3.23-3.18(m,2H),2.37(t,J=7.6Hz,2H),2.26(s,3H),1.91-1.82(m,6H),1.72-1.66(m, 2H),1.57-1.50(m,2H),1.34-1.28(m,2H),1.02(t,J=6.8Hz,3H),0.84(t,J=7.2Hz,3H).

[0701] Example 115 4'-(2-butyl-4-oxo-1,3-diazaspiro[4.4]non-1-en-3-yl)methyl)-N-(4-cyano-3-methylisoxazol-5-yl)-2'-(ethoxymethyl)-[1,1'-biphenyl]-2-sulfonamide [ka]

[0702] The synthesis method of Example 115 was the same as that of Example 1, except that 5-amino-3-methylisoxazole-4-carbonitrile was used instead of 4,5-dimethylisoxazoleamine to obtain Example 115 (5.1 mg, yield: 6.6%).

[0703] MS m / z (ESI): 604.2 [M+1] + . 1H NMR(400MHz,DMSO-d6)δ 8.02-7.99(m,1H),7.49-7.45(m,2H),7.13(s,1H),7.07-7.05(m,1H),7.02(d,J=7.6Hz, 1H),6.95(d,J=8.0Hz,1H),4.72(s,2H),4.08(d,J=13.2Hz,1H),3.96(d,J=13.2Hz,1H), 3.26-3.18(m,2H),2.35(t,J=7.6Hz,2H),2.01(s,3H),1.91-1.82(m,6H),1.73-1.66(m, 2H),1.55-1.48(m,2H),1.32-1.24(m,2H),1.02(t,J=6.8Hz,3H),0.83(t,J=7.2Hz,3H).

[0704] Example 116 4'-(2-butyl-4-oxo-1,3-diazaspiro[4.4]non-1-en-3-yl)methyl)-N-(4-chloro-5-methylisoxazol-3-yl)-2'-ethoxy-[1,1'-biphenyl]-2-sulfonamide [ka]

[0705] The synthesis method of Example 116 was the same as that of Example 113, except that iodopropane was replaced with iodoethane to obtain Example 116 (27.0 mg, yield: 34.5%).

[0706] MS m / z (ESI): 599.0 [M + 1] + . 1H NMR(400MHz,DMSO-d6)δ 10.91(br s,1H),8.03(d,J=8.0Hz,1H),7.58-7.47(m,2H),7.20-6.97(m,2H),6.72(s,1 H),6.63(d,J=8.0Hz,1H),4.70(s,2H),3.91-3.83(m,1H),3.79-3.72(m,1H),2 .38(t,J=7.6Hz,2H),2.25(s,3H),1.92-1.82(m,6H),1.71-1.65(m,2H),1.56 -1.49(m,2H),1.33-1.27(m,2H),1.01(t,J=6.8Hz,3H),0.83(t,J=7.2Hz,3H).

[0707] Example 117 Methyl 1-((2'-(N-(4-chloro-5-methylisoxazol-3-yl)-N-(methoxymethyl)sulfamoyl)-2-(ethoxymethyl)-[1,1'-biphenyl]-4-yl)methyl)-4-ethyl-2-propyl-1H-imidazole-5-carboxylate [ka]

[0708] Example 117-1 (300 mg, 0.55 mmol) (see WO 2010114801A1 for preparation method) was dissolved in acetonitrile (15 mL), methyl 4-ethyl-2-propyl-1H-imidazole-5-carboxylate (108 mg, 0.55 mmol) and potassium carbonate (160 mg, 1.1 mmol) were added, and the reaction mixture was heated to reflux for 6 h. The reaction mixture was concentrated, and the crude product was purified by reverse-phase HPLC to give Example 117-2 (300 mg, yield: 82.5%).

[0709] MS m / z(ESI):659.2[M+1]+.

[0710] Step 2 Preparation of methyl 1-((2'-(N-(4-chloro-5-methylisoxazol-3-yl)-N-(methoxymethyl)sulfamoyl)-2-(ethoxymethyl)-[1,1'-biphenyl]-4-yl)methyl)-4-ethyl-2-propyl-1H-imidazole-5-carboxylate Example 117-2 (300 mg, 0.46 mmol) was dissolved in 4 M HCl / dioxane (5 mL), and the reaction mixture was heated to 70°C and reacted for 2 hours. The reaction mixture was concentrated, and the crude product was purified by reverse-phase HPLC to obtain Example 117 (200 mg, yield: 71.4%).

[0711] MS m / z(ESI):615.2[M+1]+. 1 H NMR(400MHz,DMSO-d6)δ 9.07(s,1H),8.26(dd,J=7.4,1.4Hz,1H),7.68-7.59(m,2H),7.46(td,J=7.3,2.0Hz,1H),7.30(dq,J =2.0,1.0Hz,1H),7.21(d,J=7.4Hz,1H),7.00(dq,J=7.5,1.1Hz,1H),5.43(t,J=1.0Hz,2H),4.70(d,J =1.1Hz,2H),3.94(s,3H),3.58(q,J=8.0Hz,2H),2.99(q,J=8.0Hz,2H),2.58(s,3H),2.29(s,2H),1. 71(dtd,J=15.1,8.0,7.1Hz,2H),1.37(t,J=8.0Hz,3H),1.19(t,J=8.0Hz,3H),1.01(t,J=8.0Hz,3H).

[0712] Example 118 4'-(2-butyl-4-oxo-1,3-diazaspiro[4.4]non-1-en-3-yl)methyl)-2'-(ethoxymethyl)-N-(5-methoxy-4-methylisoxazol-3-yl)-(1,1'-biphenyl)-2-sulfonamide [ka]

[0713] The synthesis method of Example 118 was the same as that of Example 1, except that 5-methoxy-4-methylisoxazol-3-amine was used instead of 4,5-dimethylisoxazolamine to obtain Example 118 (11.5 mg, yield: 8.3%).

[0714] MS m / z(ESI):609.3[M+1] + . 1 H NMR(400MHz,DMSO-d6)δ 7.98-7.96(m,1H),7.38-7.36(m,2H),7.09(s,1H),7.01(d,J=7.6Hz,1H),6.97-6.91( m,2H),4.71(s,2H),4.03(d,J=13.2Hz,1H),3.96(d,J=13.2Hz,1H),3.67(s,3H),3.25 -3.17(m,2H),2.35(t,J=7.6Hz,2H),1.90-1.81(m,6H),1.72-1.66(m,2H),1.54-1.48 (m,2H),1.35(s,3H),1.32-1.26(m,2H),1.01(t,J=6.8Hz,3H),0.83(t,J=7.2Hz,3H).

[0715] Example 119 4'-(2-butyl-4-oxo-1,3-diazaspiro[4.4]non-1-en-3-yl)methyl)-N-(5-cyclopropyl-4-methylisoxazol-3-yl)-2'-(ethoxymethyl)-[1,1'-biphenyl]-2-sulfonamide [ka]

[0716] The synthesis method of Example 119 was similar to that of Example 1, except that 5-cyclopropyl-4-methylisoxazol-3-amine was used instead of 4,5-dimethylisoxazolamine to obtain Example 119 (13.2 mg, yield: 9.6%).

[0717] MS m / z(ESI):619.3[M+1] + . 1 H NMR(400MHz,DMSO-d6)δ 8.02-7.99(m,1H),7.50-7.42(m,2H),7.12(s,1H),7.06-7.00(m,1H),6.95(s,2H) ,4.72(s,2H),4.00-3.91(m,2H),3.22-3.17(m,2H),2.36(t,J=7.6Hz,2H),1.92-1 .81(m,8H),1.74-1.65(m,2H),1.59(s,3H),1.55-1.51(m,2H),1.32-1.27(m,2H), 1.01(t,J=6.8Hz,3H),0.89-0.86(m,2H),0.83(t,J=7.6Hz,3H),0.77-0.74(m,2H).

[0718] Example 120 Methyl 1-((2'-(N-(4-chloro-5-methylisoxazol-3-yl)-N-(methoxymethyl)sulfamoyl)-2-(ethoxymethyl)-[1,1'-biphenyl]-4-yl)methyl)-4-ethyl-2-propyl-1H-imidazole-5-carboxylic acid [ka]

[0719] Compound 117 (100 mg, 0.16 mmol) and NaOH (2 M, 1.5 mL) were added to tetrahydrofuran (10 mL). The reaction solution was stirred at 25 °C for 4 hours, 1 M HCl (10 mL) was added, and then extracted with dichloromethane (30 mL * 2). The combined extracts were dried over Na SO and spin-dried. The resulting crude product was purified by silica gel column chromatography to give the title compound 120 (60 mg, yield: 61%).

[0720] MS m / z (ESI): 601.2 [M+1] + 1H NMR(400MHz,DMSO-d6)δ 11.07(s,1H),9.07(s,1H),8.26(dd,J=7.4,1.4Hz,1H),7.65(dd,J=7.5,1.9Hz,1H),7.63(td,J=7.2,1.4Hz,1H) ,7.46(td,J=7.3,2.0Hz,1H),7.31(dq,J=1.8,1.1Hz,1H),7.21(d,J=7.4Hz,1H),7.00(dt,J=7.6,1.2Hz,1H),5.4 2(t,J=1.0Hz,2H),4.70(d,J=1.1Hz,2H),3.58(q,J=8.0Hz,2H),2.96(q,J=8.0Hz,2H),2.58(t,J=7.1Hz,3H),2.2 9(s,2H),1.71(dtd,J=15.1,8.0,7.1Hz,2H),1.37(t,J=8.0Hz,3H),1.19(t,J=8.0Hz,3H),1.01(t,J=8.0Hz,3H).

[0721] Example 121 N-(4-chloro-5-methylisoxazol-3-yl)-2'-(ethoxymethyl)-4'-(4-oxy-2-(4,4,4-trifluorobutyl)-1,3-diazaspiro[4.4]non-1-en-3-yl)methyl)-[1,1'-biphenyl]-2-sulfonamide [ka]

[0722] The synthesis method of Example 121 was the same as that of Example 1, except that 4,5-dimethylisoxazolamine was replaced with 4-chloro-5-methylisoxazolamine to obtain Example 121 (27 mg, yield: 51.5%).

[0723] MS: m / z(ESI):667.2[M+1] + 1H NMR(400MHz,DMSO-d6)δ 9.07(s,1H),8.26(dd,J=7.4,1.4Hz,1H),7.65(dd,J=7.5,1.9Hz,1H),7.63(td,J=7.2,1.4Hz,1 H),7.51-7.43(m,2H),7.33(dq,J=7.5,1.1Hz,1H),7.28(d,J=7.5Hz,1H),5.00(t,J=1.0Hz,2H), 4.70(d,J=1.1Hz,2H),3.58(q,J=8.0Hz,2H),2.70(t,J=7.1Hz,2H),2.34(qt,J=9.0,7.1Hz,2H), 2.29(s,3H),2.11-2.00(m,6H),1.99-1.89(m,2H),1.74(p,J=7.1Hz,2H),1.19(t,J=8.0Hz,3H).

[0724] Example 122 4'-(2-butyl-4-oxo-1,3-diazaspiro[4.4]non-1-en-3-yl)methyl)-N-(4-chloro-5-methylisoxazol-3-yl)-2'-(phenoxymethyl)-[1,1'-biphenyl]-2-sulfonamide [ka]

[0725] Step 1 Preparation of 4'-(2-butyl-4-oxo-1,3-diazaspiro[4.4]non-1-en-3-yl)methyl)-N-(4-chloro-5-methylisoxazol-3-yl)-2'-(phenoxymethyl)-N-((2-(trimethylsilyl)ethoxy)methyl)-[1,1'-biphenyl]-2-sulfonamide Compound 69-6 (60 mg, 0.077 mmol) was dissolved in anhydrous acetonitrile (3 mL), and phenol (22 mg, 0.231 mmol) and cesium carbonate (75 mg, 0.231 mmol) were added. The mixture was heated to 50 °C and reacted for 2 hours. The reaction mixture was poured into 30 mL of water and extracted with ethyl acetate (30 mL * 2). The organic phases were combined, washed with saturated sodium chloride solution (30 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give the title product 122-1 (60 mg, yield: 98.3%).

[0726] MS: m / z(ESI):791.3[M+1]

[0727] Step 2 Preparation of 4'-(2-butyl-4-oxo-1,3-diazaspiro[4.4]non-1-en-3-yl)methyl)-N-(4-chloro-5-methylisoxazol-3-yl)-2'-(phenoxymethyl)-[1,1'-biphenyl]-2-sulfonamide Compound 122 was synthesized in accordance with the synthesis method of Example 12, and the title compound Example 122 (30.3 mg, yield: 60.1%) was obtained using compound 122-1 as the starting material.

[0728] MS m / z (ESI): 661.2 [M+1] + . 1 H NMR(400MHz,DMSO-d6)δ 12.70(br s,1H),8.01-7.99(m,1H),7.47-7.37(m,2H),7.20-7.15(m,3H),7.09-7.00(m,3 H),6.88-6.84(m,1H),6.70(d,J=8.0Hz,2H),4.73(d,J=13.2Hz,1H),4.71(s,2H) ),4.51(d,J=13.2Hz,1H),2.31(t,J=7.6Hz,2H),2.13(s,3H),1.90-1.79(m,6H) ,1.68-1.61(m,2H),1.52-1.45(m,2H),1.29-1.24(m,2H),0.82(t,J=7.2Hz,3H).

[0729] Intermediate 3 2'-(Bromomethyl)-4'-(2-butyl-4-oxo-1,3-diazaspiro[4.5]dec-1-en-3-yl)methyl)-N-(4,5-dimethylisoxazol-3-yl)-N-(methoxymethyl)-[1,1'-biphenyl]-2-sulfonamide [ka]

[0730] Step 1. Preparation of 1-pentaaminocyclohexane-1-carboxamide Valeryl chloride (7.2 g, 60 mmol) and triethylamine (17 mL, 120 mmol) were added to a solution of 1-amino-cyclohexanecarboxamide (8.0 g, 56 mmol) in dichloromethane (200 mL) under ice bath conditions, and the reaction mixture was stirred for 1 hour under ice bath conditions. After the reaction was complete, 50 mL of water was added and the mixture was extracted with DCM (80 mL x 3). The organic layer was dried over MgSO4. After filtration, the solvent was removed under reduced pressure. The desired product, 1-pentaaminocyclohexane-1-carboxamide (12 g, yield: 94.3%), was obtained.

[0731] MS m / z(ESI):227.1[M+1]+.

[0732] Step 2. Preparation of 2-butyl-1,3-diazaspirocyclo-[4,5]dec-1-en-4-one Sodium hydroxide (10 M, 50 ml) was slowly added to a solution of intermediate B (12.0 g, 53 mmol) in methanol (80 mL), and the reaction was stirred at 60° C. for 3 hours. After the reaction was completed, water (30 mL) and dichloromethane (60 mL × 3) were added and extracted. The organic layers were combined, dried over anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography (petroleum ether / ethyl acetate system) to obtain the desired product intermediate C (8 g, yield: 70.2%).

[0733] MS m / z(ESI):209.1[M+1]+.

[0734] Step 3 Preparation of 4-bromo-3-methylbenzyl methanesulfonate (4-Bromo-3-methylphenyl)methanol (2.0 g, 10.0 mmol) and triethylamine (1.4 g, 11.0 mmol) were dissolved in dichloromethane (5 mL), and methanesulfonyl chloride (1.24 g, 11.0 mmol) was added in an ice bath. The mixture was stirred at room temperature for 1 hour. Water and dichloromethane (20 mL × 3) were added for extraction. The organic layers were combined, dried over anhydrous sodium sulfate, filtered, concentrated, and purified using a column chromatography (petroleum ether / ethyl acetate system) to obtain the desired product, 4-bromo-3-methylbenzyl methanesulfonate (2.6 g, yield: 93.5%).

[0735] MS m / z(ESI):278.9[M+1]+.

[0736] Step 4. Preparation of 3-(4-bromo-3-methylbenzyl)-2-butyl-1,3-diazaspiro[4.5]dec-1-en-4-one Sodium hydride (0.34 g, 8.6 mmol) was added to a solution of intermediate 3b (2.0 g, 7.2 mmol) in N,N-dimethylformamide (5 mL) in an ice bath, and the reaction was stirred for 1 hour. 2-Butyl-1,3-diazaspiro[4.5]dec-1-en-4-one (1.7 g, 8.2 mmol) was added, and the reaction was stirred at room temperature for 1 hour. Water and dichloromethane (20 mL x 3) were added for extraction. The combined organic layer was dried over anhydrous sodium sulfate, filtered, concentrated, and purified using a column chromatography (petroleum ether / ethyl acetate system) to give the desired product, 3-(4-bromo-3-methylbenzyl)-2-butyl-1,3-diazaspiro[4.5]dec-1-en-4-one (2.3 g, 82.1% yield).

[0737] MS m / z(ESI):391.1[M+1]+.

[0738] Step 5. Preparation of 2-butyl-3-(3-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl)-1,3-diazaspiro[4.5]dec-1-en-4-one Intermediate 3c (2.07 g, 5.3 mmol), bis(pinacolato)diboron (1.6 g, 6.4 mmol), [1,1'-bis(diphenylphosphino)ferrocene] palladium dichloride dichloromethane complex (42 mg, 0.05 mmol), and potassium acetate (1.1 g, 10.6 mmol) were dissolved in dioxane (35 mL), and the reaction mixture was stirred at 80 °C for 16 hours under nitrogen gas protection. Water and dichloromethane (50 mL × 2) were added for extraction. The organic layers were combined, dried over anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography (petroleum ether / ethyl acetate system) to obtain the desired product, 2-butyl-3-(3-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl)-1,3-diazaspiro[4.5]dec-1-en-4-one (1.8 g, yield: 77.6%).

[0739] MS m / z(ESI):439.3[M+1]+.

[0740] Step 6. Preparation of 3-(3-(bromomethyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborinan-2-yl)benzyl)-2-butyl-1,3-diazaspiro[4.5]dec-1-en-4-one N-Bromosuccinimide (0.75 g, 4.2 mmol) was added to a solution of intermediate 3d (1.55 g, 3.5 mmol) in acetonitrile (5 mL) in an ice bath, and the reaction mixture was stirred at room temperature for 1 hour. Water and dichloromethane (3 × 20 mL) were added for extraction. The combined organic layer was dried over anhydrous sodium sulfate, filtered, concentrated, and purified using a column chromatography (petroleum ether / ethyl acetate system) to give the desired product, 3-(3-(bromomethyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborinan-2-yl)benzyl)-2-butyl-1,3-diazaspiro[4.5]dec-1-en-4-one (1.62 g, yield: 88.5%).

[0741] MS m / z(ESI):517.2[M+1]+.

[0742] Step 7 Preparation of 2'-(bromomethyl)-4'-(((2-butyl-4-oxo-1,3-diazaspiro[4.5]dec-1-en-3-yl)methyl)-N-(4,5-dimethylisoxazol-3-yl)-N-(methoxymethyl)-[1,1'-biphenyl]-2-sulfonamide Intermediate 3e (100 mg, 0.19 mmol), (2-(N-(4,5-dimethylisoxazol-3-yl)-N-(methoxymethyl)sulfamoyl)phenyl)boronic acid (75 mg, 0.2 mmol) (see WO 2010135350A2 for the preparation method), [1,1'-bis(diphenylphosphino)ferrocene]dichloride palladium dichloromethane complex (16 mg, 0.02 mmol), and cesium carbonate (291 mg, 0.9 mmol) were dissolved in dioxane (4 mL) and water (1 mL), and the reaction mixture was stirred in a microwave oven at 100 °C for 1 hour. Extraction was performed with water and dichloromethane (20 mL × 3). The organic layers were combined, dried over anhydrous sodium sulfate, filtered, concentrated, and purified using a column chromatography (petroleum ether / ethyl acetate system) to obtain Intermediate 3 (110 mg, yield: 83%).

[0743] MS m / z(ESI):685.2[M+1]+.

[0744] Intermediate 4 2'-Butylspiro[bicyclo[3.1.0]hexane-3,4'-imidazol]-5'(1'H)-one [ka]

[0745] Step 1. Preparation of bicyclo[3.1.0]hexan-3-ol Under ice bath and nitrogen gas protection, cyclopent-3-en-1-ol (2 g, 24 mmol) was dissolved in 200 mL of dichloromethane, diethylzinc (5.9 g, 48 mmol) and diiodomethane (12.7 mL, 48 mmol) were added, and the reaction was stirred in an ice bath for 3 hours. After the reaction was complete, 50 mL of water was added and extracted with DCM (80 mL x 3). The organic layer was dried over MgSO4. After filtration, the solvent was removed under reduced pressure. The desired product, intermediate 4b (2 g, yield: 86%), was obtained.

[0746] MS m / z(ESI):99.1[M+1]+.

[0747] Step 2. Preparation of bicyclo[3.1.0]hexan-3-one Intermediate 4b (2.0 g, 20 mmol) was dissolved in dichloromethane (40 mL), Dess-Martin (10 g, 24 mmol) was slowly added, and the reaction was stirred at 20 °C for 3 h. Water (30 mL) and dichloromethane (30 mL × 3) were added for extraction. The organic layers were combined, dried over anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography (petroleum ether / ethyl acetate system) to give the desired product, intermediate 4c (1.7 g, yield: 87%).

[0748] MS m / z(ESI):97.1[M+1]+.

[0749] Step 3: Preparation of 3-aminobicyclo[3.1.0]hexane-3-carbonitrile Intermediate 4c (1.7 g, 17.7 mmol) and ammonium chloride (1.42 g, 26.5 mmol) were dissolved in DMF (5 mL) and water (25 mL). Potassium cyanide (1.73 g, 26.5 mmol) was added in an ice bath, and the reaction mixture was stirred at room temperature for 2 hours. Water and dichloromethane (20 mL × 3) were added for extraction. The organic layers were combined, dried over anhydrous sodium sulfate, filtered, concentrated, and purified using a column chromatography (petroleum ether / ethyl acetate system) to give the desired product, intermediate 4d (1.5 g, yield: 69.4%).

[0750] MS m / z(ESI):123.1[M+1]+.

[0751] Step 4. Preparation of 3-aminobicyclo[3.1.0]hexane-3-carboxamide To a solution of intermediate 4d (1.5 g, 12.3 mmol) in dichloromethane (15 mL) was added sulfuric acid (5 mL) in an ice bath, and the reaction mixture was stirred for 3 hours. Water and dichloromethane (20 mL × 3) were added for extraction. The organic layers were combined, dried over anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography (petroleum ether / ethyl acetate system) to obtain the desired product intermediate 4e (1.6 g, yield: 93%).

[0752] MS m / z(ESI):141.1[M+1]+.

[0753] Step 5 Preparation of 3-pentamidobicyclo[3.1.0]hexane-3-carboxamide To a solution of intermediate 4e (1.6 g, 11.4 mmol) in 30 mL of dichloromethane, valeryl chloride (1.5 g, 12.55 mmol) and triethylamine (2.8 mL, 22.8 mmol) were added under ice bath conditions, and the reaction mixture was stirred for 1 hour under ice bath conditions. After the reaction was completed, 50 mL of water was added and the mixture was extracted with DCM (80 mL x 3). The organic layer was dried over MgSO4. After filtration, the solvent was removed under reduced pressure. The desired product, intermediate 4f (2.3 g, yield: 89.8%), was obtained.

[0754] MS m / z(ESI):225.1[M+1]+.

[0755] Step 6 Preparation of 2'-butylspiro[bicyclo[3.1.0]hexane-3,4'-imidazol]-5'(1'H)-one Sodium hydroxide (10 M, 30 ml) was slowly added to a solution of intermediate 4f (2.3 g, 10.25 mmol) in methanol (40 mL), and the reaction mixture was stirred at 60° C. for 3 hours. Water (30 mL) and dichloromethane (60 mL × 3) were added for extraction. The organic layers were combined, dried over anhydrous sodium sulfate, filtered, concentrated, and purified using a column chromatography (petroleum ether / ethyl acetate system) to obtain the target product, intermediate 4 (1.3 g, yield: 61.3%).

[0756] MS m / z(ESI):207.1[M+1]+. 1 H NMR(400MHz,DMSO-d6)δ 13.30(s,1H),2.71(t,J=7.7Hz,2H),2.37(dd,J=14.7,4.0Hz,2H),2.09(d,J=14.4Hz,2H),1.68(p,J=7.6Hz,2 H),1.53(dt,J=8.5,4.1Hz,2H),1.33(dt,J=14.6,7.4Hz,2H),0.99-0.81(m,4H),0.60(td,J=8.3,4.8Hz,1H).

[0757] Intermediate 5 [ka] The synthesis method of Intermediate 5 is similar to that of Steps 4 to 7 of Intermediate 3, except that 2-butyl-1,3-diazaspirocyclo-[4,5]dec-1-en-4-one is replaced with 2'-butylspiro[bicyclo[3.1.0]hexane-3,4'-imidazol]-5'(1'H)-one to obtain Intermediate 5 (2g), with a yield of 65.8%.

[0758] MS m / z(ESI):683.2[M+1]+.

[0759] Example 123 4'-((2'-butyl-5'-oxopyrrole[bicyclo[3.1.0]hexane-3,4'-imidazol]-1'(5'H)-yl)methyl)-2'-((cyclopropylmethoxy)methyl)-N-(4,5-dimethylisoxazol-3-yl)-[1,1'-biphenyl]-2-sulfonamide [ka]

[0760] Step 1 Preparation of 4'-((2'-butyl-5'-oxopyrrole[bicyclo[3.1.0]hexane-3,4'-imidazol]-1'(5'H)-yl)methyl)-2'-((cyclopropylmethoxy)methyl)-N-(4,5-dimethylisoxazol-3-yl)-N-(methoxymethyl)-[1,1'-biphenyl]-2-sulfonamide Cyclopropylmethanol (46 mg, 0.642 mmol) was dissolved in N,N-dimethylformamide (5 mL), and sodium hydride (25 mg, 60% wt, 0.642 mmol) was added. The mixture was allowed to react at room temperature for 30 minutes. Intermediate 5 (88 mg, 0.129 mmol) was added, and the mixture was allowed to react at room temperature for 1 hour. The reaction mixture was poured into 30 mL of ice water and extracted with ethyl acetate (30 mL * 2). The organic phases were combined, washed with saturated sodium chloride solution (30 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give Example 123-1 (70 mg). The yield was 80.6%, which was used directly in the next step.

[0761] MS m / z (ESI): 675.3 [M+1] + .

[0762] Step 2 Preparation of 4'-((2'-butyl-5'-oxopyrrole[bicyclo[3.1.0]hexane-3,4'-imidazol]-1'(5'H)-yl)methyl)-2'-((cyclopropylmethoxy)methyl)-N-(4,5-dimethylisoxazol-3-yl)-[1,1'-biphenyl]-2-sulfonamide Example 123-1 (70 mg, 0.104 mmol) was dissolved in 4 M hydrochloric acid dioxane solution (4 mL), heated to 60 ° C, and reacted for 4 hours. The reaction solution was cooled to room temperature and concentrated under reduced pressure. The resulting crude product was purified by reverse phase HPLC to give Example 123 (30 mg), with a yield of 45.8%.

[0763] MS m / z (ESI): 631.2 [M+1] + .

[0764] Example 124 4'-((2'-butyl-5'-oxopyrrole[bicyclo[3.1.0]hexane-3,4'-imidazol]-1'(5'H)-yl)methyl)-N-(4,5-dimethylisoxazol-3-yl)-2'-(methoxymethyl)-[1,1'-biphenyl]-2-sulfonamide [ka]

[0765] Step 1 Preparation of 4'-((2'-butyl-5'-oxopyrrole[bicyclo[3.1.0]hexane-3,4'-imidazol]-1'(5'H)-yl)methyl)-N-(4,5-dimethylisoxazol-3-yl)-N,2'-bis(methoxymethyl)-[1,1'-biphenyl]-2-sulfonamide Methanol (20.5 mg, 0.642 mmol) was dissolved in N,N-dimethylformamide (5 mL), and sodium hydride (25 mg, 60% wt, 0.642 mmol) was added. The mixture was allowed to react at room temperature for 30 minutes. Intermediate 5 (88 mg, 0.128 mmol) was added, and the mixture was allowed to react at room temperature for 1 hour. The reaction mixture was poured into 30 mL of ice water and extracted with ethyl acetate (30 mL * 2). The organic phases were combined, washed with saturated sodium chloride solution (30 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give Example 124-1 (65 mg). The yield was 79.6%, which was used directly in the next step.

[0766] MS m / z(ESI):635.3[M+1] + .

[0767] Step 2 Preparation of 4'-((2'-butyl-5'-oxopyrrole[bicyclo[3.1.0]hexane-3,4'-imidazol]-1'(5'H)-yl)methyl)-N-(4,5-dimethylisoxazol-3-yl)-2'-(methoxymethyl)-[1,1'-biphenyl]-2-sulfonamide Example 124-1 (65 mg, 0.102 mmol) was dissolved in 4 M hydrochloric acid dioxane solution (4 mL), heated to 60 ° C. and reacted for 4 hours. The reaction solution was cooled to room temperature and concentrated under reduced pressure. The resulting crude product was purified by reverse phase HPLC to give Example 124 (38 mg), with a yield of 62.8%.

[0768] MS m / z (ESI): 591.2 [M+1] + .

[0769] Example 125 4'-((2'-butyl-5'-oxopyrrole[bicyclo[3.1.0]hexane-3,4'-imidazol]-1'(5'H)-yl)methyl)-2'-(cyclobutoxymethyl)-N-(4,5-dimethylisoxazol-3-yl)-[1,1'-biphenyl]-2-sulfonamide [ka]

[0770] Step 1 Preparation of 4'-(2'-butyl-5'-oxopyrrole[bicyclo[3.1.0]hexane-3,4'-imidazol]-1'(5'H)-yl)methyl)-2'-(cyclobutoxymethyl)-N-(4,5-dimethylisoxazol-3-yl)-N-(methoxymethyl)-[1,1'-biphenyl]-2-sulfonamide Cyclobutanol (46 mg, 0.642 mmol) was dissolved in N,N-dimethylformamide (5 mL), and sodium hydride (25 mg, 60% wt, 0.642 mmol) was added. The mixture was allowed to react at room temperature for 30 minutes. Intermediate 5 (88 mg, 0.129 mmol) was added, and the mixture was allowed to react at room temperature for 1 hour. The reaction mixture was poured into 30 mL of ice water and extracted with ethyl acetate (30 mL * 2). The organic phases were combined, washed with saturated sodium chloride solution (30 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give Example 125-1 (70 mg). The yield was 80.6%, which was used directly in the next step.

[0771] MS m / z (ESI): 675.3 [M+1] + .

[0772] Step 2 Preparation of 4'-((2'-butyl-5'-oxopyrrole[bicyclo[3.1.0]hexane-3,4'-imidazol]-1'(5'H)-yl)methyl)-2'-(cyclobutoxymethyl)-N-(4,5-dimethylisoxazol-3-yl)-[1,1'-biphenyl]-2-sulfonamide Example 125-1 (70 mg, 0.104 mmol) was dissolved in 4 M hydrochloric acid dioxane solution (4 mL), heated to 60 ° C, and reacted for 4 hours. The reaction solution was cooled to room temperature and concentrated under reduced pressure. The resulting crude product was purified by reverse phase HPLC to give Example 125 (40 mg), with a yield of 61.2%.

[0773] MS m / z (ESI): 631.2 [M+1] + .

[0774] Example 126 4'-((2'-butyl-5'-oxopyrrole[bicyclo[3.1.0]hexane-3,4'-imidazol]-1'(5'H)-yl)methyl)-N-(4,5-dimethylisoxazol-3-yl)-2'-(deuterated methoxymethyl)-[1,1'-biphenyl]-2-sulfonamide [ka]

[0775] Step 1 Preparation of 4'-((2'-butyl-5'-oxopyrrole[bicyclo[3.1.0]hexane-3,4'-imidazol]-1'(5'H)-yl)methyl)-N-(4,5-dimethylisoxazol-3-yl)-2'-((methoxy-d3)methyl)-N-(methoxymethyl)-[1,1'-biphenyl]-2-sulfonamide Deuterated methanol (22.5 mg, 0.644 mmol) was dissolved in N,N-dimethylformamide (5 mL), and sodium hydride (26 mg, 60% wt, 0.644 mmol) was added. The mixture was allowed to react at room temperature for 30 minutes. Intermediate 5 (88 mg, 0.129 mmol) was added, and the mixture was allowed to react at room temperature for 1 hour. The reaction mixture was poured into 30 mL of ice water and extracted with ethyl acetate (30 mL * 2). The organic phases were combined, washed with saturated sodium chloride solution (30 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give Example 126-1 (65 mg). The yield was 79.3%, which was used directly in the next step.

[0776] MS m / z(ESI):638.3[M+1] + .

[0777] Step 2 Preparation of 4'-((2'-butyl-5'-oxopyrrole[bicyclo[3.1.0]hexane-3,4'-imidazol]-1'(5'H)-yl)methyl)-N-(4,5-dimethylisoxazol-3-yl)-2'-(deuterated methoxymethyl)-[1,1'-biphenyl]-2-sulfonamide Example 126-1 (65 mg, 0.102 mmol) was dissolved in 4 M hydrochloric acid dioxane solution (4 mL), heated to 60 ° C, and reacted for 4 hours. The reaction solution was cooled to room temperature and concentrated under reduced pressure. The resulting crude product was purified by reverse phase HPLC to give Example 126 (42 mg), with a yield of 69.4%.

[0778] MS m / z (ESI): 594.2 [M+1]+ .

[0779] Example 127 4'-(2'-butyl-5'-oxopyrrole[bicyclo[3.1.0]hexane-3,4'-imidazol]-1'(5'H)-yl)methyl)-2'-(cyclopropoxymethyl)-N-(4,5-dimethylisoxazol-3-yl)-[1,1'-biphenyl]-2-sulfonamide [ka]

[0780] Step 1 Preparation of 4'-(2'-butyl-5'-oxopyrrole[bicyclo[3.1.0]hexane-3,4'-imidazol]-1'(5'H)-yl)methyl)-2'-(cyclopropoxymethyl)-N-(4,5-dimethylisoxazol-3-yl)-N-(methoxymethyl)-[1,1'-biphenyl]-2-sulfonamide Cyclopropanol (36 mg, 0.64 mmol) was dissolved in N,N-dimethylformamide (5 mL), sodium hydride (24 mg, 60% wt, 0.64 mmol) was added, and the mixture was allowed to react at room temperature for 30 minutes. Intermediate 5 (87.5 mg, 0.128 mmol) was added, and the mixture was allowed to react at room temperature for 1 hour. The reaction mixture was poured into 30 mL of ice water and extracted with ethyl acetate (30 mL * 2). The organic phases were combined, washed with saturated sodium chloride solution (30 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give Example 127-1 (60 mg), a yield of 70.9%, which was used directly in the next step.

[0781] MS m / z (ESI): 661.3 [M+1] + .

[0782] Step 2 Preparation of 4'-(2'-butyl-5'-oxopyrrole[bicyclo[3.1.0]hexane-3,4'-imidazol]-1'(5'H)-yl)methyl)-2'-(cyclopropoxymethyl)-N-(4,5-dimethylisoxazol-3-yl)-[1,1'-biphenyl]-2-sulfonamide Example 127-1 (60 mg, 0.91 mmol) was dissolved in 4 M hydrochloric acid dioxane solution (4 mL), heated to 60 ° C, and reacted for 4 hours. The reaction solution was cooled to room temperature and concentrated under reduced pressure. The resulting crude product was purified by reverse phase HPLC to give Example 127 (37 mg), with a yield of 66.1%.

[0783] MS m / z (ESI): 617.2 [M+1] + .

[0784] Example 128 4'-((2'-butyl-5'-oxopyrrole[bicyclo[3.1.0]hexane-3,4'-imidazol]-1'(5'H)-yl)methyl)-N-(4,5-dimethylisoxazol-3-yl)-2'-(isopropoxymethyl)-[1,1'-biphenyl]-2-sulfonamide [ka]

[0785] Step 1 Preparation of 4'-((2'-butyl-5'-oxopyrrole[bicyclo[3.1.0]hexane-3,4'-imidazol]-1'(5'H)-yl)methyl)-N-(4,5-dimethylisoxazol-3-yl)-2'-(isopropoxymethyl)-N-(methoxymethyl)-[1,1'-biphenyl]-2-sulfonamide Isopropanol (38.5 mg, 0.64 mmol) was dissolved in N,N-dimethylformamide (5 mL), and sodium hydride (24 mg, 60% wt, 0.642 mmol) was added. The mixture was allowed to react at room temperature for 30 minutes. Intermediate 5 (87.5 mg, 0.128 mmol) was added, and the mixture was allowed to react at room temperature for 1 hour. The reaction mixture was poured into 30 mL of ice water and extracted with ethyl acetate (30 mL * 2). The organic phases were combined, washed with saturated sodium chloride solution (30 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give Example 128-1 (65 mg). The yield was 76.6%, which was used directly in the next step.

[0786] MS m / z (ESI): 663.3 [M+1] + .

[0787] Step 2 Preparation of 4'-((2'-butyl-5'-oxopyrrole[bicyclo[3.1.0]hexane-3,4'-imidazol]-1'(5'H)-yl)methyl)-N-(4,5-dimethylisoxazol-3-yl)-2'-(isopropoxymethyl)-[1,1'-biphenyl]-2-sulfonamide Example 128-1 (65 mg, 0.098 mmol) was dissolved in 4 M hydrochloric acid in dioxane (4 mL), heated to 60° C., and reacted for 4 hours. The reaction mixture was cooled to room temperature and concentrated under reduced pressure. The resulting crude product was purified by reverse-phase HPLC to give Example 128 (43 mg), with a yield of 70.8%.

[0788] MS m / z (ESI): 619.2 [M+1] + .

[0789] Example 129 4'-((2-butyl-4-oxo-1,3-diazaspiro[4.5]dec-1-en-3-yl)methyl)-2'-((cyclopropylmethoxy)methyl)-N-(4,5-dimethylisoxazol-3-yl)-[1,1'-biphenyl]-2-sulfonamide [ka]

[0790] Step 1 Preparation of 4'-(2-butyl-4-oxo-1,3-diazaspiro[4.5]dec-1-en-3-yl)methyl)-2'-(cyclopropylmethoxy)methyl)-N-(4,5-dimethylisoxazol-3-yl)-N-(methoxymethyl)-[1,1'-biphenyl]-2-sulfonamide Cyclopropylmethanol (46 mg, 0.642 mmol) was dissolved in N,N-dimethylformamide (5 mL), and sodium hydride (25 mg, 60% wt, 0.642 mmol) was added. The mixture was allowed to react at room temperature for 30 minutes. Intermediate 3 (88 mg, 0.129 mmol) was added, and the mixture was allowed to react at room temperature for 1 hour. The reaction mixture was poured into 30 mL of ice water and extracted with ethyl acetate (30 mL * 2). The organic phases were combined, washed with saturated sodium chloride solution (30 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give Example 129-1 (70 mg). The yield was 80.6%, which was used directly in the next step.

[0791] MS m / z (ESI): 677.3 [M+1] + .

[0792] Step 2 Preparation of 4'-((2-butyl-4-oxo-1,3-diazaspiro[4.5]dec-1-en-3-yl)methyl)-2'-((cyclopropylmethoxy)methyl)-N-(4,5-dimethylisoxazol-3-yl)-[1,1'-biphenyl]-2-sulfonamide Example 129-1 (70 mg, 0.103 mmol) was dissolved in 4 M hydrochloric acid dioxane solution (4 mL), heated to 60 ° C, and reacted for 4 hours. The reaction solution was cooled to room temperature and concentrated under reduced pressure. The resulting crude product was purified by reverse phase HPLC to give Example 129 (35.5 mg), with a yield of 54.2%.

[0793] MS m / z (ESI): 633.3 [M+1] + .

[0794] Example 130 4'-(2-butyl-4-oxo-1,3-diazaspiro[4.5]dec-1-en-3-yl)methyl)-2'-(cyclobutoxymethyl)-N-(4,5-dimethylisoxazol-3-yl)-[1,1'-biphenyl]-2-sulfonamide [ka]

[0795] Step 1 Preparation of 4'-(2-butyl-4-oxo-1,3-diazaspiro[4.5]dec-1-en-3-yl)methyl)-2'-(cyclobutoxymethyl)-N-(4,5-dimethylisoxazol-3-yl)-N-(methoxymethyl)-[1,1'-biphenyl]-2-sulfonamide Cyclobutanol (46 mg, 0.642 mmol) was dissolved in N,N-dimethylformamide (5 mL), sodium hydride (25 mg, 60% wt, 0.642 mmol) was added, and the mixture was allowed to react at room temperature for 30 minutes. Intermediate 3 (88 mg, 0.129 mmol) was added, and the mixture was allowed to react at room temperature for 1 hour. The reaction mixture was poured into 30 mL of ice water and extracted with ethyl acetate (30 mL * 2). The organic phases were combined, washed with saturated sodium chloride solution (30 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain Example 130-1 (70 mg). The yield was 80.6%. Used directly in the next step reaction.

[0796] MS m / z (ESI): 677.3 [M+1] + .

[0797] Step 2 Preparation of 4'-(2-butyl-4-oxo-1,3-diazaspiro[4.5]dec-1-en-3-yl)methyl)-2'-(cyclobutoxymethyl)-N-(4,5-dimethylisoxazol-3-yl)-[1,1'-biphenyl]-2-sulfonamide Example 130-1 (70 mg, 0.103 mmol) was dissolved in 4 M hydrochloric acid dioxane solution (4 mL), heated to 60 ° C, and reacted for 4 hours. The reaction solution was cooled to room temperature and concentrated under reduced pressure. The resulting crude product was purified by reverse phase HPLC to give Example 130 (35.5 mg), with a yield of 54.3%.

[0798] MS m / z (ESI): 633.3 [M+1] + .

[0799] Example 131 4'-(2-butyl-4-oxo-1,3-diazaspiro[4.5]dec-1-en-3-yl)methyl)-2'-(cyclopropoxymethyl)-N-(4,5-dimethylisoxazol-3-yl)-[1,1'-biphenyl]-2-sulfonamide [ka]

[0800] Step 1 Preparation of 4'-(2-butyl-4-oxo-1,3-diazaspiro[4.5]dec-1-en-3-yl)methyl)-2'-(cyclopropoxymethyl)-N-(4,5-dimethylisoxazol-3-yl)-N-(methoxymethyl)-[1,1'-biphenyl]-2-sulfonamide Cyclopropanol (37 mg, 0.642 mmol) was dissolved in N,N-dimethylformamide (5 mL), sodium hydride (25 mg, 60% wt, 0.642 mmol) was added, and the mixture was allowed to react at room temperature for 30 minutes. Intermediate 3 (88 mg, 0.129 mmol) was added, and the mixture was allowed to react at room temperature for 1 hour. The reaction mixture was poured into 30 mL of ice water and extracted with ethyl acetate (30 mL * 2). The organic phases were combined, washed with saturated sodium chloride solution (30 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give Example 131-1 (65 mg), with a yield of 75.8%. Used directly in the next step reaction.

[0801] MS m / z (ESI): 663.3 [M+1] + .

[0802] Step 2 Preparation of 4'-(2-butyl-4-oxo-1,3-diazaspiro[4.5]dec-1-en-3-yl)methyl)-2'-(cyclopropoxymethyl)-N-(4,5-dimethylisoxazol-3-yl)-[1,1'-biphenyl]-2-sulfonamide Example 131-1 (65 mg, 0.1 mmol) was dissolved in 4 M hydrochloric acid dioxane solution (4 mL), heated to 60 ° C, and reacted for 4 hours. The reaction solution was cooled to room temperature and concentrated under reduced pressure. The resulting crude product was purified by reverse phase HPLC to give Example 131 (35 mg), with a yield of 57.7%.

[0803] MS m / z(ESI):619.3[M+1] + .

[0804] Example 132 4'-(2-butyl-4-oxo-1,3-diazaspiro[4.5]dec-1-en-3-yl)methyl)-2'-(isopropoxymethyl)-N-(4,5-dimethylisoxazol-3-yl)-[1,1'-biphenyl]-2-sulfonamide [ka]

[0805] Step 1 Preparation of 4'-(2-butyl-4-oxo-1,3-diazaspiro[4.5]dec-1-en-3-yl)methyl)-2'-(isopropoxymethyl)-N-(4,5-dimethylisoxazol-3-yl)-N-(methoxymethyl)-[1,1'-biphenyl]-2-sulfonamide Isopropanol (39 mg, 0.642 mmol) was dissolved in N,N-dimethylformamide (5 mL), sodium hydride (25 mg, 60% wt, 0.642 mmol) was added, and the mixture was allowed to react at room temperature for 30 minutes. Intermediate 3 (88 mg, 0.129 mmol) was added, and the mixture was allowed to react at room temperature for 1 hour. The reaction mixture was poured into 30 mL of ice water and extracted with ethyl acetate (30 mL * 2). The organic phases were combined, washed with saturated sodium chloride solution (30 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give Example 132-1 (65 mg), with a yield of 76.2%. Used directly in the next step reaction....

Claims

1. A compound represented by general formula (I), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein 【Chemical Formula 1】 X １ is N or CR １ and X ２ is N or CR ２ and X ３ is N or CR ３ and R １ , R ２ and R ３ are each independently selected from hydrogen, deuterium, halogen, amino group, nitro group, hydroxy group, cyano group, alkyl group, deuterated alkyl group, halogenated alkyl group, hydroxyalkyl group, alkoxy group, halogenated alkoxy group, alkenyl group, alkynyl group, cycloalkyl group, heterocyclyl group, aryl group or heteroaryl group, and the amino group, alkyl group, deuterated alkyl group, halogenated alkyl group, hydroxyalkyl group, alkoxy group, halogenated alkoxy group, alkenyl group, alkynyl group, cycloalkyl group, heterocyclyl group, aryl group and heteroaryl group may optionally be further substituted. L １ is selected from -(CR ａ R ｂ ), -(CR ｎ１ R ａ R ｂ ), -O(CR ｎ１ R ａ R ｂ ), -S(CR ｎ１ R ａ R ｂ ), -S(CR ｎ１ R ａ R ｂ ), -(CH ｎ１ R ２ ), C(O)NR ｎ１ R ａ ), -(CH ２ R ｎ１ NR ａ R ２ ), C(O)-, -(CH ｎ１ R ｍ１ ), S(O)R ２ R ｎ１ ), S(O)NR ｍ１ R ａ ), -(CH ２ R ｎ１ NR ａ ), S(O)R ｍ１ ), -(CH ２ R ｎ１ NR ａ R), and is selected from: L ２ is selected from -(CH ２ ) ｎ２ -, -(CH ２ ) ｎ２ NR ｃ -, -(CH ２ ) ｎ２ C(O)NR ｃ -, -(CH ２ ) ｎ２ C(O)NR ｃ S(O) ｍ２ -, -(CH ２ ) ｎ２ NR ｃ C(O)-, -(CH ２ ) ｎ２ S(O) ｍ２ -, -(CH ２ ) ｎ２ S(O) ｍ２ NR ｃ -, -(CH ２ ) ｎ２ S(O) ｍ２ NR ｃ C(O)-, -(CH ２ ) ｎ２ S(O) ｍ２ NR ｃ C(O)NR ｄ -, -(CH ２ ) ｎ２ S(O) ｍ２ NR ｃ C(O)O(CH ２ ) ｎ３ -, -(CH ２ ) ｎ２ NR ｃ S(O) ｍ２ - or -(CH ２ ) ｎ２ NR ｃ S(O) ｍ２ NR ｄ C(O)- and is selected from said ring A is [Chemical 2] selected from R ａ is independently hydrogen, deuterium, halogen, amino group, nitro group, hydroxy group, cyano group, oxo group, thio group, alkyl group, deuterated alkyl group, halogenated alkyl group, hydroxyalkyl group, alkoxy group, halogenated alkoxy group, alkenyl group, alkynyl group, cycloalkyl group, heterocyclyl group, aryl group, heteroaryl group, -(CH ２ ) ｎ４ C(O)R Ａ１ , -(CH ２ ) ｎ４ C(O)OR Ａ１ , -(CH ２ ) ｎ４ C(O)NR Ａ１ R Ｂ１ or -(CH ２ ) ｎ４ C(=S)NR Ａ１ R Ｂ１ selected from, and the amino group, alkyl group, deuterated alkyl group, halogenated alkyl group, hydroxyalkyl group, alkoxy group, halogenated alkoxy group, alkenyl group, alkynyl group, cycloalkyl group, heterocyclyl group, aryl group and heteroaryl group may optionally be further substituted. R １ is hydrogen, deuterium, halogen, amino group, nitro group, hydroxy group, cyano group, alkyl group, deuterated alkyl group, halogenated alkyl group, hydroxyalkyl group, alkoxy group, halogenated alkoxy group, alkenyl group, alkynyl group, cycloalkyl group, heterocyclyl group, aryl group, heteroaryl group, -(CH ２ ) ｎ５ R Ａ２ -, -(CH ２ ) ｎ５ O(CH ２ ) ｎ６ R Ａ２ -, -(CH ２ ) ｎ５ C(O)R Ａ２ , -(CH ２ ) ｎ５ NR Ａ２ C(O)R Ｂ２ , -(CH ２ ) ｎ５ C(O)NR Ａ２ R Ｂ２ , -(CH ２ ) ｎ５ OC(O)NR Ａ２ R Ｂ２ or -(CH ２ ) ｎ５ NR Ａ２ C(O)OR Ｂ２ selected from, and the amino group, alkyl group, deuterated alkyl group, halogenated alkyl group, hydroxyalkyl group, alkoxy group, halogenated alkoxy group, alkenyl group, alkynyl group, cycloalkyl group, heterocyclyl group, aryl group and heteroaryl group may optionally be further substituted, Or, R １ and R ａ together with an adjacent atom form a cycloalkyl group, a heterocyclyl group, an aryl group or a heteroaryl group, and the cycloalkyl group, heterocyclyl group, aryl group and heteroaryl group may optionally be further substituted. R ２ 、 R ３ 、 R ４ and R ５ are each independently selected from hydrogen, deuterium, halogen, amino group, nitro group, hydroxy group, cyano group, alkyl group, deuterated alkyl group, halogenated alkyl group, hydroxyalkyl group, alkoxy group, halogenated alkoxy group, alkenyl group, alkynyl group, cycloalkyl group, heterocyclyl group, aryl group or heteroaryl group, and the amino group, alkyl group, deuterated alkyl group, halogenated alkyl group, hydroxyalkyl group, alkoxy group, halogenated alkoxy group, alkenyl group, alkynyl group, cycloalkyl group, heterocyclyl group, aryl group and heteroaryl group may optionally be further substituted. or R ２ and R ５ together with an adjacent atom form a heterocyclyl group, which heterocyclyl group may optionally be further substituted, R ６ is selected from hydrogen, deuterium, halogen, amino group, nitro group, hydroxy group, cyano group, alkyl group, deuterated alkyl group, halogenated alkyl group, hydroxyalkyl group, alkoxy group, halogenated alkoxy group, alkenyl group, alkynyl group, cycloalkyl group, heterocyclyl group, aryl group or heteroaryl group, and the amino group, alkyl group, deuterated alkyl group, halogenated alkyl group, hydroxyalkyl group, alkoxy group, halogenated alkoxy group, alkenyl group, alkynyl group, cycloalkyl group, heterocyclyl group, aryl group and heteroaryl group may optionally be further substituted, R ａ 、R ｂ 、R ｃ 、R ｄ 、R Ａ１ 、R Ａ２ 、R Ｂ１ and R Ｂ２ are each independently selected from hydrogen, deuterium, halogen, amino group, nitro group, hydroxy group, cyano group, alkyl group, deuterated alkyl group, halogenated alkyl group, hydroxyalkyl group, alkoxy group, halogenated alkoxy group, alkenyl group, alkynyl group, cycloalkyl group, heterocyclyl group, aryl group or heteroaryl group, and the amino group, alkyl group, deuterated alkyl group, halogenated alkyl group, hydroxyalkyl group, alkoxy group, halogenated alkoxy group, alkenyl group, alkynyl group, cycloalkyl group, heterocyclyl group, aryl group and heteroaryl group may optionally be further substituted. x is 0, 1, 2, 3, 4 or 5, n1 to n6 are 0, 1, 2, 3, 4 or 5, and m1 and m2 are 0, 1 or 2, a compound, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof.

2. Said compound is further as shown in general formula (II), [Chemical Formula 3] X １ is N or CR １ and X ２ is N or CR ２ and X ３ is N or CR ３ and R １ 、R ２ and R ３ are each independently hydrogen, deuterium, halogen, amino group, hydroxy group, cyano group, C １－６ alkyl group, C ２－６ alkenyl group, C ２－６ alkynyl group, C １－６ deuterated alkyl group, C １－６ halogenated alkyl group, C １－６ hydroxyalkyl group, C １－６ alkoxy group, C １－６ alkylthio group, C １－６ halogenated alkoxy group, C ３－１２ cycloalkyl group, 3- to 12-membered heterocyclyl group, C ６－１４ aryl group or 5- to 14-membered heteroaryl group, and the C １－６ alkyl group, C ２－６ alkenyl group, C ２－６ alkynyl group, C １－６ deuterated alkyl group, C １－６ halogenated alkyl group, C １－６ hydroxyalkyl group, C １－６ alkoxy group, C １－６ alkylthio group, C １－６ halogenated alkoxy group, C ３－１２ cycloalkyl group, 3- to 12-membered heterocyclyl group, C ６－１４ aryl group and 5- to 14-membered heteroaryl group are optionally further substituted with one or more substituents selected from deuterium, halogen, amino group, hydroxy group, cyano group, oxo group, thio group, C １－６ alkyl group, C ２－６ alkenyl group, C ２－６ alkynyl group, C １－６ deuterated alkyl group, C １－６ halogenated alkyl group, C １－６ hydroxyalkyl group, C １－６ alkoxy group, C １－６ alkylthio group, C １－６ halogenated alkoxy group, C ３－１２ cycloalkyl group, 3- to 12-membered heterocyclyl group, C ６－１４ aryl group and 5- to 14-membered heteroaryl group, L １ is -(CR ａ R ｂ ) ｎ１ -, -(CR ａ R ｂ ) ｎ１ O-, -O(CR ａ R ｂ ) ｎ１ -, -(CR ａ R ｂ ) ｎ１ S-, -S(CR ａ R ｂ ) ｎ１ -, -(CH ２ ) ｎ１ C(O)NR ａ -, -(CH ２ ) ｎ１ NR ａ C(O)-, -(CH ２ ) ｎ１ S(O) ｍ１ -, -(CH ２ ) ｎ１ S(O) ｍ１ NR ａ -, -(CH ２ ) ｎ１ NR ａ S(O) ｍ１ - or -(CH ２ ) ｎ１ NR ａ - selected from, R １ is hydrogen, deuterium, halogen, amino group, hydroxy group, cyano group, C １－６ alkyl group, C ２－６ alkenyl group, C ２－６ alkynyl group, C １－６ deuterated alkyl group, C １－６ halogenated alkyl group, C １－６ hydroxyalkyl group, C １－６ alkoxy group, C １－６ alkylthio group, C １－６ halogenated alkoxy group, C ３－１２ cycloalkyl group, 3- to 12-membered heterocyclyl group, C ６－１４ aryl group, 5- to 14-membered heteroaryl group, -(CH ２ ) ｎ５ R Ａ２ , -(CH ２ ) ｎ５ O(CH ２ ) ｎ６ R Ａ２ , -(CH ２ ) ｎ５ C(O)R Ａ２ , -(CH ２ ) ｎ５ NR Ａ２ C(O)R Ｂ２ , -(CH ２ ) ｎ５ C(O)NR Ａ２ R Ｂ２ , -(CH ２ ) ｎ５ OC(O)NR Ａ２ R Ｂ２ or -(CH ２ ) ｎ５ NR Ａ２ C(O)OR Ｂ２ selected from, wherein said C １－６ alkyl group, C ２－６ alkenyl group, C ２－６ alkynyl group, C １－６ deuterated alkyl group, C １－６ halogenated alkyl group, C １－６ hydroxyalkyl group, C １－６ alkoxy group, C １－６ alkylthio group, C １－６ halogenated alkoxy group, C ３－１２ Cycloalkyl group, 3- to 12-membered heterocyclyl group, C ６－１４ The aryl group and 5- to 14-membered heteroaryl group are optionally deuterium, halogen, amino group, hydroxy group, cyano group, oxo group, thio group, C １－６ alkyl group, C ２－６ alkenyl group, C ２－６ alkynyl group, C １－６ deuterated alkyl group, C １－６ halogenated alkyl group, C １－６ hydroxyalkyl group, C １－６ alkoxy group, C １－６ alkylthio group, C １－６ halogenated alkoxy group, C ３－１２ cycloalkyl group, 3- to 12-membered heterocyclyl group, C ６－１４ and are further substituted with one or more substituents selected from the aryl group and 5- to 14-membered heteroaryl group, R ７ and R ８ is each independently hydrogen, deuterium, halogen, an amino group, a hydroxy group, a cyano group, C １－６ alkyl group, C ２－６ alkenyl group, C ２－６ alkynyl group, C １－６ deuterated alkyl group, C １－６ halogenated alkyl group, C １－６ hydroxyalkyl group, C １－６ alkoxy group, C １－６ alkylthio group, C １－６ halogenated alkoxy group, C ３－１２ cycloalkyl group, a 3- to 12-membered heterocyclyl group, C ６－１４ aryl group or a 5- to 14-membered heteroaryl group, and the C １－６ alkyl group, C ２－６ alkenyl group, C ２－６ alkynyl group, C １－６ deuterated alkyl group, C １－６ halogenated alkyl group, C １－６ hydroxyalkyl group, C １－６ alkoxy group, C １－６ alkylthio group, C １－６ halogenated alkoxy group, C ３－１２ cycloalkyl group, a 3- to 12-membered heterocyclyl group, C ６－１４ aryl group and a 5- to 14-membered heteroaryl group are optionally further substituted with one or more substituents selected from deuterium, halogen, an amino group, a hydroxy group, a cyano group, an oxo group, a thio group, C １－６ alkyl group, C ２－６ alkenyl group, C ２－６ alkynyl group, C １－６ deuterated alkyl group, C １－６ halogenated alkyl group, C １－６ hydroxyalkyl group, C １－６ alkoxy group, C １－６ alkylthio group, C １－６ halogenated alkoxy group, C ３－１２ cycloalkyl group, a 3- to 12-membered heterocyclyl group, C ６－１４ aryl group and a 5- to 14-membered heteroaryl group, Or, R ７ and R ８ are combined to form C ３－８ a cycloalkyl group, a 5- to 8-membered heterocyclyl group, C ６－１４ an aryl group or a 5- to 14-membered heteroaryl group, and the C ３－８ cycloalkyl group, 5- to 8-membered heterocyclyl group, C ６－１４ aryl group or 5- to 14-membered heteroaryl group may optionally be further substituted. R ａ and R ｂ are each independently hydrogen, deuterium, halogen, amino group, hydroxy group, cyano group, C １－６ alkyl group, C ２－６ alkenyl group, C ２－６ alkynyl group, C １－６ deuterated alkyl group, C １－６ halogenated alkyl group, C １－６ hydroxyalkyl group, C １－６ alkoxy group, C １－６ alkylthio group, C １－６ halogenated alkoxy group, C ３－１２ cycloalkyl group, 3- to 12-membered heterocyclyl group, C ６－１４ aryl group or 5- to 14-membered heteroaryl group, and the C １－６ alkyl group, C ２－６ alkenyl group, C ２－６ alkynyl group, C １－６ deuterated alkyl group, C １－６ halogenated alkyl group, C １－６ hydroxyalkyl group, C １－６ alkoxy group, C １－６ alkylthio group, C １－６ halogenated alkoxy group, C ３－１２ cycloalkyl group, 3- to 12-membered heterocyclyl group, C ６－１４ aryl group and 5- to 14-membered heteroaryl group are optionally further substituted with one or more substituents selected from deuterium, halogen, amino group, hydroxy group, cyano group, oxo group, thio group, C １－６ alkyl group, C ２－６ alkenyl group, C ２－６ alkynyl group, C １－６ deuterated alkyl group, C １－６ halogenated alkyl group, C １－６ hydroxyalkyl group, C １－６ alkoxy group, C １－６ alkylthio group, C １－６ halogenated alkoxy group, C ３－１２ cycloalkyl group, 3- to 12-membered heterocyclyl group, C ６－１４ aryl group and 5- to 14-membered heteroaryl group, R Ａ２ and R Ｂ２ are each independently hydrogen, deuterium, halogen, amino group, hydroxy group, cyano group, C １－６ alkyl group, C ２－６ alkenyl group, C ２－６ alkynyl group, C １－６ deuterated alkyl group, C １－６ halogenated alkyl group, C １－６ hydroxyalkyl group, C １－６ alkoxy group, C １－６ alkylthio group, C １－６ halogenated alkoxy group, C ３－１２ cycloalkyl group, 3- to 12-membered heterocyclyl group, C ６－１４ aryl group or 5- to 14-membered heteroaryl group, and the C １－６ alkyl group, C ２－６ alkenyl group, C ２－６ alkynyl group, C １－６ deuterated alkyl group, C １－６ halogenated alkyl group, C １－６ hydroxyalkyl group, C １－６ alkoxy group, C １－６ alkylthio group, C １－６ halogenated alkoxy group, C ３－１２ cycloalkyl group, 3- to 12-membered heterocyclyl group, C ６－１４ aryl group and 5- to 14-membered heteroaryl group are optionally further substituted with one or more substituents selected from deuterium, halogen, amino group, hydroxy group, cyano group, oxo group, thio group, C １－６ alkyl group, C ２－６ alkenyl group, C ２－６ alkynyl group, C １－６ deuterated alkyl group, C １－６ halogenated alkyl group, C １－６ hydroxyalkyl group, C １－６ alkoxy group, C １－６ alkylthio group, C １－６ halogenated alkoxy group, C ３－１２ cycloalkyl group, 3- to 12-membered heterocyclyl group, C ６－１４ aryl group and 5- to 14-membered heteroaryl group, n1, n5 and n6 are 0, 1, 2 or 3, and m1 is 0, 1 or 2, R ７ and R ８ are both methyl groups, and R １ is 【Chemical Formula 4】 If not, R １ is 【Chemical Formula 5】 selected from R ７ and R ８ are both methyl groups, and R １ is 【Chemical Formula 6】 When it is, L １ contains deuterium or X １ , X ２ or X ３ at least one of which is N, or R ３ is not hydrogen, the compound according to claim 1, its stereoisomer or its pharmaceutically acceptable salt.

3. Said compound is further as shown in (II-1), 【Chemical Formula 7】 L １ is selected from -CH ２ - or -CD ２ - and is R １ is deuterium, halogen, amino group, hydroxy group, cyano group, C １－６ alkyl group, C ２－６ alkenyl group, C ２－６ alkynyl group, C １－６ deuterated alkyl group, C １－６ halogenated alkyl group, C １－６ hydroxyalkyl group, C １－６ alkoxy group, C １－６ alkylthio group, C １－６ halogenated alkoxy group, C ３－１２ cycloalkyl group, 3- to 12-membered heterocyclyl group, C ６－１４ aryl group, 5- to 14-membered heteroaryl group, -(CH ２ ) ｎ５ R Ａ２ , -(CH ２ ) ｎ５ O(CH ２ ) ｎ６ R Ａ２ , -(CH ２ ) ｎ５ C(O)R Ａ２ , -(CH ２ ) ｎ５ NR Ａ２ C(O)R Ｂ２ , -(CH ２ ) ｎ５ C(O)NR Ａ２ R Ｂ２ , -(CH ２ ) ｎ５ OC(O)NR Ａ２ R Ｂ２ or -(CH ２ ) ｎ５ NR Ａ２ C(O)OR Ｂ２ selected from, and the C １－６ alkyl group, C ２－６ alkenyl group, C ２－６ alkynyl group, C １－６ deuterated alkyl group, C １－６ halogenated alkyl group, C １－６ hydroxyalkyl group, C １－６ alkoxy group, C １－６ alkylthio group, C １－６ halogenated alkoxy group, C ３－１２ A cycloalkyl group, a 3- to 12-membered heterocyclyl group, C ６－１４ The aryl group and the 5- to 14-membered heteroaryl group are optionally further substituted with one or more substituents selected from deuterium, halogen, amino group, hydroxy group, cyano group, oxo group, thio group, C １－６ alkyl group, C ２－６ alkenyl group, C ２－６ alkynyl group, C １－６ deuterated alkyl group, C １－６ halogenated alkyl group, C １－６ hydroxyalkyl group, C １－６ alkoxy group, C １－６ alkylthio group, C １－６ halogenated alkoxy group, C ３－１２ a cycloalkyl group, a 3- to 12-membered heterocyclyl group, C ６－１４ and are further substituted with one or more of the aryl group and the 5- to 14-membered heteroaryl group, R ７ is selected from a halogen, preferably fluorine, chlorine, or bromine, and R8 is hydrogen, deuterium, a halogen, an amino group, a hydroxy group, a cyano group, C １－３ alkyl group, C ２－３ alkenyl group, C ２－３ alkynyl group, C １－３ deuterated alkyl group, C １－３ halogenated alkyl group, C １－３ hydroxyalkyl group, C １－３ alkoxy group, C １－３ alkylthio group, C １－３ halogenated alkoxy group, C ３－８ cycloalkyl group, 3- to 8-membered heterocyclyl group, C ６－１０ aryl group or 5- to 10-membered heteroaryl group, and is preferably a methyl group, an ethyl group or a cyclopropyl group, The compound, stereoisomer or pharmaceutically acceptable salt thereof according to claim 2, characterized in that.

4. Said compound is further as shown in general formula (VIII-1) or general formula (VIII-2), 【Chemical 8】 Here, L １ , X １ , X ２ , X ３ , R ７ and R ８ are defined as described in claim 2, Regarding the general formula (VIII-1), L １ is CH ２ and R ７ and R ８ are both methyl groups, and R １ is 【Chemical Formula 9】 When it is, X １ , X ２ , X ３ The compound according to claim 1, its stereoisomer or its pharmaceutically acceptable salt, wherein at least one of X is not CH.

5. L １ is selected from -CR ａ R ｂ -, -CR ａ R ｂ O-, -OCR ａ R ｂ -, -CR ａ R ｂ S- or -SCR ａ R ｂ - and is selected from R ａ and R ｂ are each independently hydrogen, deuterium, halogen, an amino group, a hydroxy group, a cyano group, C １－３ alkyl group, C ２－３ alkenyl group, C ２－３ alkynyl group, C １－３ deuterated alkyl group, C １－３ halogenated alkyl group, C １－３ hydroxyalkyl group, C １－３ alkoxy group, C １－３ alkylthio group, C １－３ halogenated alkoxy group, C ３－８ cycloalkyl group, 3- to 8-membered heterocyclyl group, C ６－１０ aryl group or 5- to 10-membered heteroaryl group, and the C １－３ alkyl group, C ２－３ alkenyl group, C ２－３ alkynyl group, C １－３ deuterated alkyl group, C １－３ halogenated alkyl group, C １－３ hydroxyalkyl group, C １－３ alkoxy group, C １－３ alkylthio group, C １－３ halogenated alkoxy group, C ３－８ cycloalkyl group, 3- to 8-membered heterocyclyl group, C ６－１０ aryl group and 5- to 10-membered heteroaryl group are optionally further substituted with one or more substituents selected from deuterium, halogen, an amino group, a hydroxy group, a cyano group, an oxo group, a thio group, C １－３ alkyl group, C ２－３ alkenyl group, C ２－３ alkynyl group, C １－３ deuterated alkyl group, C １－３ halogenated alkyl group, C １－３ hydroxyalkyl group, C １－３ alkoxy group, C １－３ alkylthio group, C １－３ halogenated alkoxy group, C ３－８ cycloalkyl group, 3- to 8-membered heterocyclyl group, C ６－１０ aryl group and 5- to 10-membered heteroaryl group, Preferably, L １ is -CH ２ -, -CD ２ - or -CH ２ O-, and is selected from More preferably, L １ is selected from -CH ２ -, and the compound according to claim 1, its stereoisomer or its pharmaceutically acceptable salt, characterized in that.

6. X １ , X ２ and X ３ are all CH, L １ is selected from -CH ２ - or -CD ２ - and R １ is hydrogen, deuterium, halogen, amino group, hydroxy group, cyano group, C １－６ alkyl group, C ２－６ alkenyl group, C ２－６ alkynyl group, C １－６ deuterated alkyl group, C １－６ halogenated alkyl group, C １－６ hydroxyalkyl group, C １－６ alkoxy group, C １－６ alkylthio group, C １－６ halogenated alkoxy group, C ３－１２ cycloalkyl group, 3- to 12-membered heterocyclyl group, C ６－１４ aryl group, 5- to 14-membered heteroaryl group, -(CH ２ ) ｎ５ R Ａ２ , -(CH ２ ) ｎ５ O(CH ２ ) ｎ６ R Ａ２ , -(CH ２ ) ｎ５ C(O)R Ａ２ , -(CH ２ ) ｎ５ NR Ａ２ C(O)R Ｂ２ , -(CH ２ ) ｎ５ C(O)NR Ａ２ R Ｂ２ , -(CH ２ ) ｎ５ OC(O)NR Ａ２ R Ｂ２ or -(CH ２ ) ｎ５ NR Ａ２ C(O)OR Ｂ２ selected from, and the C １－６ alkyl group, C ２－６ alkenyl group, C ２－６ alkynyl group, C １－６ deuterated alkyl group, C １－６ halogenated alkyl group, C １－６ hydroxyalkyl group, C １－６ alkoxy group, C １－６ alkylthio group, C １－６ halogenated alkoxy group, C ３－１２ A cycloalkyl group, a 3- to 12-membered heterocyclyl group, C ６－１４ The aryl group and the 5- to 14-membered heteroaryl group are optionally further substituted with one or more substituents selected from deuterium, halogen, amino group, hydroxy group, cyano group, oxo group, thio group, C １－６ alkyl group, C ２－６ alkenyl group, C ２－６ alkynyl group, C １－６ deuterated alkyl group, C １－６ halogenated alkyl group, C １－６ hydroxyalkyl group, C １－６ alkoxy group, C １－６ alkylthio group, C １－６ halogenated alkoxy group, C ３－１２ a cycloalkyl group, a 3- to 12-membered heterocyclyl group, C ６－１４ and are further substituted with one or more of the aryl group and the 5- to 14-membered heteroaryl group R ７ is selected from hydrogen, deuterium, halogen, amino group, hydroxy group, cyano group, C １－３ alkyl group, C ２－３ alkenyl group, C ２－３ alkynyl group, C １－３ deuterated alkyl group, C １－３ halogenated alkyl group, C １－３ hydroxyalkyl group, C １－３ alkoxy group, C １－３ alkylthio group, C １－３ halogenated alkoxy group, C ３－８ cycloalkyl group, 3- to 8-membered heterocyclyl group, C ６－１０ aryl group or 5- to 10-membered heteroaryl group, R ８ is selected from hydrogen, deuterium, halogen, amino group, hydroxy group, cyano group, C １－３ alkyl group, C ２－３ alkenyl group, C ２－３ alkynyl group, C １－３ deuterated alkyl group, C １－３ halogenated alkyl group, C １－３ hydroxyalkyl group, C １－３ alkoxy group, C １－３ alkylthio group, C １－３ halogenated alkoxy group, C ３－８ cycloalkyl group, 3- to 8-membered heterocyclyl group, C ６－１０ aryl group or 5- to 10-membered heteroaryl group, and the compound according to claim 1, its stereoisomer or its pharmaceutically acceptable salt, characterized in that.

7. L １ is selected from -CH ２ and R １ is selected from C １－３ alkyl groups or -(CH ２ ) ｎ５ O(CH ２ ) ｎ６ R Ａ２ and the C １－３ alkyl group is optionally further substituted with one or more substituents selected from deuterium, halogen, amino group, hydroxy group, cyano group, oxo group, thio group, C １－３ alkyl group, C ２－４ alkenyl group, C ２－４ alkynyl group, C １－３ deuterated alkyl group, C １－３ halogenated alkyl group, C １－３ hydroxyalkyl group, C １－３ alkoxy group, C １－３ alkylthio group, C １－３ halogenated alkoxy group, C ３－６ cycloalkyl group R Ａ２ is a C １－３ alkyl group, a C １－３ deuterated alkyl group, a C １－３ halogenated alkyl group, a C ３－６ cycloalkyl group, a 4- to 7-membered heterocyclyl group, a C ３－６ cycloalkyl group C １－３ alkyl group or a 4- to 7-membered heterocyclyl group C １－３ selected from alkyl groups, R ７ is selected from deuterium, fluorine, chlorine, bromine or a C １－３ alkyl group, R ８ is selected from C １－３ alkyl groups, n5 is 0, 1, 2 or 3, and n6 is 0, 1 or 2, a compound, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof according to claim 6, characterized in that.

8. R １ is hydrogen, -CH ３ , -CH ２ CH ３ , 【Chemical 10】 selected from R ７ is selected from fluorine, chlorine, bromine or a methyl group, R ８ The compound according to claim 7, its stereoisomer or its pharmaceutically acceptable salt, wherein R is a methyl group.

9. 【Fig. 11】 【Chemical Formula 12】 【Chemical 13】 【Chemical 14】 【Chemical Formula 15】 a compound such as, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof.

10. A compound represented by general formula (M-1) or (M-2), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, 【Chemical Formula 16】 The above-mentioned L １ , X １ , X ２ , X ３ , R １ , R ７ , R ８ are as described in claim 2, R ９ is a halogen or 【Chemical 17】 selected from, preferably bromine, chlorine or 【Chemical 18】 and more preferably 【Chemical Formula 19】 is Pg is selected from amino protecting groups, preferably (trimethylsilyl)ethoxymethyl group, methoxymethyl ether group, allyloxycarbonyl group, trifluoroacetyl group, 2,4-dimethoxybenzyl group, nitrobenzenesulfonyl group, trityl group, fluorenylmethoxycarbonyl group, p-toluenesulfonyl group, formate ester, acetyl group, benzyloxycarbonyl group, tert-butoxycarbonyl group, benzyl group or p-methoxyphenyl group, and more preferably (trimethylsilyl)ethoxymethyl group or methoxymethyl ether group, a compound, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof.

11. A method for producing the compound, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof according to claim 2, comprising the following steps: 【Chemical 20】 reacting general formula (M-1) with general formula (M-3) to obtain general formula (M-2), and deprotecting general formula (M-2) to obtain general formula (II), The above-mentioned L １ , X １ , X ２ , X ３ , R １ , R ７ , R ８ are as described in claim 2, R ２’ is 【Chemical 21】 or selected from halogens, preferably 【Chemical 22】 , chlorine or bromine, R ９ is 【Chemical 23】 or selected from halogens, preferably 【Chemical 24】 , chlorine or bromine, Pg is selected from amino protecting groups, preferably a (trimethylsilyl)ethoxymethyl group, a methoxymethyl ether group, an allyloxycarbonyl group, a trifluoroacetyl group, a 2,4-dimethoxybenzyl group, a nitrobenzenesulfonyl group, a trityl group, a fluorenylmethoxycarbonyl group, a p-toluenesulfonyl group, a formate ester, an acetyl group, a benzyloxycarbonyl group, a tert-butoxycarbonyl group, a benzyl group or a p-methoxyphenyl group, more preferably a (trimethylsilyl)ethoxymethyl group or a methoxymethyl ether group, or, 【Chemical 25】 reacting the general formula (M-4) with the general formula (M-5) to obtain the general formula (M-2), and deprotecting the general formula (M-2) to obtain the general formula (II), The above-mentioned L １ , X １ , X ２ , X ３ , R １ , R ７ , R ８ are as described in claim 2, R １’ is selected from a methanesulfonyloxy group or a halogen, preferably a methanesulfonyloxy group or bromine, and Pg is selected from amino protecting groups, preferably a (trimethylsilyl)ethoxymethyl group, a methoxymethyl ether group, an allyloxycarbonyl group, a trifluoroacetyl group, a 2,4-dimethoxybenzyl group, a nitrobenzenesulfonyl group, a trityl group, a fluorenylmethoxycarbonyl group, a p-toluenesulfonyl group, a formate ester, an acetyl group, a benzyloxycarbonyl group, a tert-butoxycarbonyl group, a benzyl group or a p-methoxyphenyl group, more preferably a (trimethylsilyl)ethoxymethyl group or a methoxymethyl ether group, characterized by the method.

12. A pharmaceutical composition comprising a therapeutically effective amount of the compound according to any one of claims 1 to 9, a stereoisomer thereof or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers or excipients.

13. Use of the compound according to any one of claims 1 to 9, a stereoisomer thereof or a pharmaceutically acceptable salt thereof, and the pharmaceutical composition according to claim 12 in the manufacture of a medicament for treating an angiotensin II-dependent or endothelin-dependent disease, particularly in the manufacture of a medicament for treating a dual-action angiotensin-dependent and endothelin-dependent disease.

14. Use of a compound according to any one of claims 1 to 9, a stereoisomer thereof or a pharmaceutically acceptable salt thereof, and the pharmaceutical composition according to claim 12, in the manufacture of a medicament for treating pain, sexual dysfunction, hypoxic and ischemic diseases, dementia, neurological diseases, liver diseases, cancer, hypertension, diabetes or kidney diseases, wherein the kidney disease is selected from diseases or conditions related to the function of the kidney, glomerulus or glomerular mesangial cells.

15. The use according to claim 14, wherein the kidney disease is selected from focal segmental glomerulosclerosis or IgA nephropathy.

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