Apols inhibitor

Abstract

The present invention provides a compound for inhibiting apolipoprotein L, as represented by molecular formula (I), in particular, a compound having an inhibitory function against an APOL1 protein expressed by APOL1 G1 and / or G2 allele variants, which can be used for treating diseases caused by an abnormal apolipoprotein L.

Description

An APOLs inhibitor Technical Field

[0001] This invention relates to a compound that inhibits apolipoprotein L, for the treatment of diseases with abnormal apolipoprotein L, and belongs to the field of biopharmaceutical manufacturing. Background Technology

[0002] The human apolipoprotein L (APOL) gene family was identified in 2001. This family encodes apolipoprotein L1-6 (APOL1-6) proteins. APOL1 was identified first, followed by APOLs (APOL2-6). One common characteristic of the APOL family is that their expression can be induced by inflammatory triggers, such as interferon or TNFα, suggesting that they are part of the innate immune system (Vanhollebeke and Pays 2006; Zhaorigetu et al. 2008, 2011; Liao et al., 2011; Nichols et al., 2015). These proteins are effectors of the innate immune response to viruses, bacteria, and protozoan parasites. Members of the APOL family share high homology. Due to the high similarity among APOL proteins, they are generally considered to have similar functions to the earliest discovered APOL1, which forms cation channels in planar lipid bilayers and membranes, thereby generating cytolytic activity. However, Jyoti Pant et al. found that APOL1, APOL3, and APOL6 have cytolytic activity, while APOL2, APOL4, and APOL5 do not (Apolipoproteins L1-6 share key cation channel-regulating residues but have different membrane insertion and ion conductance properties, 2021). Despite their structural conservatism, APOLs proteins are functionally different.

[0003] Of the six apolipoproteins (APOL1-6), APOL1 is the most studied and best characterized. APOL1 is expressed only in humans and some other higher primates and is the only protein secreted from cells. It circulates in serum as a subfraction of high-density lipoprotein (HDL), and the HDL complex containing APOL1 accounts for 1% of the total HDL in plasma. It is the only member of the APOLs family to contain an N-terminal signal peptide (SP), which mediates its secretion into the serum as a trypanolytic factor (TLF) (Duchateau et al., 1997; Pays et al., 2006; Friedman and Pollak, 2011), protecting humans from the trypanolytic parasites that cause African sleeping sickness (Hajduk et al., 1989; Raper et al., 1999; Vanhamme et al., 2003; Pays et al., 2014; Weckerle et al., 2016). Meanwhile, APOL1 is a cation channel-forming protein that can insert into the lipid bilayer and form closed ion channels under acidic pH conditions. These channels are pH-controlled, so they open when the pH is neutralized, allowing cations to pass through the bilayer. Numerous studies have provided evidence that the increased risk of kidney disease is caused by intracellular rather than circulating APOL1 pools (Chen et al., 2015; Heneghan et al., 2015; Khatua et al., 2015; Ma et al., 2017, 2020); Olabisi et al., 2016; Beckerman et al., 2017; Granado et al., 2017; Kruzel-Davila, Shemer et al., 2017; Madhavan et al., 2017; Shah et al., 2019; Uzureau et al., 2020).

[0004] Pays and colleagues initially proposed a concept for APOL1 (Perez-Morga et al., 2005; Pays et al., 2006), which was extended by Smith and Malik (2009) to all members of the APOL family. APOL proteins contain three functional parts: a pore-forming domain (PFD), a membrane addressing domain (MAD), and an SRA-interacting protein-like domain (SID).

[0005] Of the six conserved apolipoprotein L (APOL1-6) variants, APOL1 variants have been the most studied. Through co-evolutionary competition, two APOL1 variants—G1 (S342G / I384M) and G2 (D388N, D389Y)—re-established APOL1-associated protection against these parasites in sub-Saharan African ancestry (Pays et al., 2014; Capewell et al., 2015; Kruzel-Davila, Wasser et al., 2017). APOL1 variant G2 lyses *Trypanosoma rhodesianum* but not *Trypanosoma gambiae*, while APOL1 G1 is associated with latent, asymptomatic infection in patients infected with *Trypanosoma gambiae* (Cooper et al., 2017). Moreover, similar to the link between sickle cell anemia and human resistance to malaria, two copies of these variants lead to an increased risk of a variety of kidney diseases, primarily glomerular diseases (Freedman et al., 2010; Genovese et al., 2010; Kasembeli et al., 2015). These include HIV and hypertension-related nephropathy, focal segmental glomerulosclerosis, lupus nephritis, membranous nephropathy, and more recently, Covid-19-related renal failure (Tzur et al., 2010; Kopp et al., 2011; Papeta et al., 2011; Larsen et al., 2014; Velez et al., 2020). Common features of these diseases include proteinuria and rapidly progressive nephropathy, which often leads to end-stage renal disease (Wiggins 2007) (Evolution of Renal-Disease Factor APOL1 Results in Cis and Trans Orientations at the Endoplasmic Reticulum That Both Show Cytotoxic Effects, 2021).

[0006] The wild-type APOL1 allele is sometimes referred to as the non-risk allele, or "G0," but it actually comprises many different protein-coding sequences, or "haplotypes" (Apolipoprotein L1 (APOL1) risk variant toxicity depends on the haplotype background, 2019). Experimental differences exist in the behavior of wild-type G0 compared to risk variants G1 and G2. Herbert Lannon et al. observed that human APOL variants contain multiple coding variants organized into different haplotypes, including at least eight relatively common non-risk haplotypes with different coding sequences. There is no typical "wild-type" APOL1; instead, there are many non-risk haplotypes that differ from each other by at least one amino acid, and sometimes several. The two risk variants G1 (S342G and I384M, two amino acid substitutions) almost always occur together, and G2 (del388-9, two amino acid deletions) are inherited within a specific human haplotype background. Both of these two alleles in the APOL1 gene lead to alterations in the apolipoprotein-L1 protein sequence, resulting in a significantly increased risk of kidney disease in a recessive model of risk inheritance. In the currently used nomenclature, G1 is the first of these alleles, referring to a pair of coding polymorphisms (or cSNPs, p.S342 and p.I384M) that are almost always inherited together; G2 is the second disease-associated APOL1 allele, referring to a six-nucleotide deletion that results in the loss of two amino acid frames (p.N388 and p.Y389) (APOL1 and APOL1-Associated Kidney Disease: A Common Disease, an Unusual Disease Gene – Proceedings of the Henry Shavelle Professorship, 2022). Alleles lacking G1 or G2 can also be called G0, which is sometimes considered preferable to the term "wild type." Some research groups have named G3 another specific APOL1 haplotype that lacks the G1 or G2 defined variant—however, this allele is not associated with kidney disease.

[0007] In summary, APOL1 C-terminal variants G1 and G2 are associated with kidney disease, particularly chronic renal failure. Expression of these variants induces podocyte foot process loss, leading to the loss of these cells from the glomeruli and impairing renal blood filtration activity. A characteristic feature of G1 / G2-related diseases is the close correlation between glomerular pathology and type I IFN inflammatory responses (e.g., inflammatory responses induced by viral infections) (The Mechanism of Kidney Disease Due to APOL1 Risk Variants, 2020). Therefore, there is a clinical need for treatments targeting kidney diseases caused by APOLs. Summary of the Invention

[0008] This invention provides an inhibitor of APOLs, particularly an inhibitor of APOL1, and more specifically, an inhibitor of APOL1 protein expressed by G1 and / or G2 allele variants, said compound being selected from compounds of Formula I:

[0009] X1 is selected from N or CH;

[0010] Y1 is selected from divalent C1-C8 straight-chain or branched alkyl, divalent C1-C8 straight-chain or branched alkoxy, divalent C1-C8 straight-chain or branched aminoalkyl, or divalent C1-C8 straight-chain or branched thioalkyl, wherein the divalent alkyl, divalent alkoxy, divalent aminoalkyl or divalent thioalkyl is optionally substituted by at least one group selected from: C1-C6 alkyl, aryl, heteroaryl, halogen group, hydroxyl, or amino;

[0011] Y2 is selected from NH or O;

[0012] Z is selected from hydrogen, phosphate group, sodium phosphate group, and carbonate group;

[0013] Ar is selected from five- to ten-membered aromatic rings or aromatic heterocyclic groups, and is optionally substituted with R2;

[0014] Preferably, Ar is selected from phenyl, pyridyl, pyrimidinyl, naphthyl, pyrroleyl, N-methylpyrroleyl, thiophenyl, and optionally substituted with R2;

[0015] R1 and R2 can be one or more, each independently selected from: halogen groups, hydroxyl groups, thiol groups, amino groups, cyano groups, -OC(O)C1-C6 straight-chain, branched, and cyclic alkyl groups, -C(O)OC1-C6 straight-chain, branched, and cyclic alkyl groups, -NHC(O)C1-C6 straight-chain, branched, and cyclic alkyl groups, -C(O)NHC1-C6 straight-chain, branched, and cyclic alkyl groups, -NHC(O) aryl, -C(O)NH aryl, -NHC(O) heteroaryl, -C(O)NH heteroaryl, -NHS(O)2C1-C6 straight-chain, branched, and cyclic alkyl groups, -S(O)2NHC1-C6 straight-chain, branched, and cyclic alkyl groups, -NHS(O)2 aryl, -S(O)2NH aryl, -NHS(O)2 heteroaryl, -S(O)2NH heteroaryl, -NHC(O)NHC1-C6 Straight-chain, branched, and cyclic alkyl groups; -NHC(O)NH aryl; -NHC(O)NH heteroaryl; C1-C6 straight-chain, branched, and cyclic alkyl groups; C2-C6 straight-chain, branched, and cyclic alkenyl groups; C1-C6 straight-chain, branched, and cyclic hydroxyalkyl groups; C1-C6 straight-chain, branched, and cyclic alkoxy groups; C1-C6 straight-chain, branched, and cyclic thioalkyl groups; C1-C6 straight-chain, branched, and cyclic haloalkyl groups; C1- C6 straight-chain, branched, and cyclic haloaminoalkyl; C1-C6 straight-chain, branched, and cyclic halothioalkyl; C1-C6 straight-chain, branched, and cyclic haloalkoxy; benzyloxy, benzylamino, or benzylthio; 3- to 6-membered heterocyclic alkenyl; 3- to 6-membered heterocyclic alkyl; and 5- and 6-membered heteroaryl; or two adjacent R1 or R2 groups together with the carbon atom to which they are attached to form C4-C8 cycloalkyl, aryl, or heteroaryl groups.

[0016] The compound, including its pharmaceutically acceptable salt, solvate, isomer, polymorph, or deuterated derivative, is characterized by:

[0017] X1 is selected from N;

[0018] Y1 is selected from divalent C1-C8 straight-chain or branched alkyl groups, and is optionally substituted by at least one group selected from the following: C1-C6 alkyl, aryl, heteroaryl, halogen group, hydroxyl, or amino.

[0019] Y2 is selected from NH or O;

[0020] Ar is selected from phenyl, pyridinyl, pyrimidinyl, naphthyl, pyrrolithyl, N-methylpyrrolithyl, thiophenyl, and optionally substituted with R2;

[0021] R1 and R2 can be one or more, each independently selected from: halogen groups, hydroxyl groups, thiol groups, amino groups, cyano groups, -OC(O)C1-C6 straight-chain, branched, and cyclic alkyl groups, -C(O)OC1-C6 straight-chain, branched, and cyclic alkyl groups, -NHC(O)C1-C6 straight-chain, branched, and cyclic alkyl groups, -C(O)NHC1-C6 straight-chain, branched, and cyclic alkyl groups, -NHC(O) aryl, -C(O)NH aryl, -NHC(O) heteroaryl, -C(O)NH heteroaryl, -NHS(O)2C1-C6 straight-chain, branched, and cyclic alkyl groups, -S(O)2NHC1-C6 straight-chain, branched, and cyclic alkyl groups, -NHS(O)2 aryl, -S(O)2NH aryl, -NHS(O)2 heteroaryl, -S(O)2NH heteroaryl, -NHC(O)NHC1-C6 Straight-chain, branched, and cyclic alkyl groups; -NHC(O)NH aryl; -NHC(O)NH heteroaryl; C1-C6 straight-chain, branched, and cyclic alkyl groups; C2-C6 straight-chain, branched, and cyclic alkenyl groups; C1-C6 straight-chain, branched, and cyclic hydroxyalkyl groups; C1-C6 straight-chain, branched, and cyclic alkoxy groups; C1-C6 straight-chain, branched, and cyclic thioalkyl groups; C1-C6 straight-chain, branched, and cyclic haloalkyl groups; C1- C6 straight-chain, branched, and cyclic haloaminoalkyl; C1-C6 straight-chain, branched, and cyclic halothioalkyl; C1-C6 straight-chain, branched, and cyclic haloalkoxy; benzyloxy, benzylamino, or benzylthio; 3- to 6-membered heterocyclic alkenyl; 3- to 6-membered heterocyclic alkyl; and 5- and 6-membered heteroaryl; or two adjacent R1 or R2 groups together with the carbon atom to which they are attached to form C4-C8 cycloalkyl, aryl, or heteroaryl groups.

[0022] The compound, including its pharmaceutically acceptable salt, solvate, isomer, polymorph, or deuterated derivative, is characterized by:

[0023] Y1 is selected from methylene, ethylene, propylene, butylene, pentylene, and hexylene;

[0024] Ar is selected from phenyl, pyridinyl, pyrimidinyl, naphthyl, pyrrolithyl, N-methylpyrrolithyl, thiophenyl, and optionally substituted with R2;

[0025] R1 and R2 can be one or more, and can be independently selected from: fluorine, chlorine, bromine, and iodine.

[0026] Further, the compound is selected from compounds represented by formula (Ia), including pharmaceutically acceptable salts, solvates, isomers, polymorphs, or deuterated derivatives, characterized in that:

[0027] The definition of a substituent is the same as that in equation (I) above.

[0028] The use of the compound, its pharmaceutically acceptable salts, solvates, isomers, polymorphs, or deuterated derivatives in the preparation of a medicament, is characterized in that the medicament is used to treat diseases in which the patient benefits from the treatment of human apolipoprotein L-1 (APOL1) protein. The disease is APOL1-mediated kidney disease (AMKD), or kidney disease caused by abnormalities in human apolipoprotein L, including, for example, focal segmental glomerulosclerosis (FSGS), chronic kidney disease (CKD), rapidly progressive proteinuric nephrophagy, renal insufficiency, nephrotic kidney failure, end-stage kidney disease (ESKD), HIV-associated nephropathy, and hypertension-associated ESKD. Or it could be caused by renal cell damage, cell death and glomerular injury (which filters blood in the kidneys) due to human apolipoprotein L abnormalities, or progressive glomerular dysfunction and proteinuria, or caused by human apolipoprotein L abnormalities resulting in abnormal protein levels in the urine (or proteinuria) and reduced kidney function, or other symptoms caused by human apolipoprotein L abnormalities, including fatigue, swelling of the legs and feet and weight gain.

[0029] Furthermore, and more specifically, this includes compounds with the following structures: Detailed Implementation

[0030] Example 1: Synthesis of Compound I-1

[0031] Step 1: Synthesis of intermediates 1-2

[0032] Compound 1-1 (2.83 g, 16.05 mmol, 1.65 mL, 1.2 eq) and compound 1-1a (1.5 g, 13.38 mmol, 1 eq) were dissolved in 4.5 mL of DMF. Cuprous iodide (254.78 mg, 1.34 mmol, 0.1 eq), Pd(dppf)Cl2 (489.43 mg, 668.89 μmol, 0.05 eq), and triethylamine (6.77 g, 66.89 mmol, 9.31 mL, 5 eq) were added sequentially to the system. The reaction mixture was evacuated and purged three times with nitrogen. The system was stirred at 90 °C for 1 hour. TLC (petroleum ether / ethyl acetate = 4 / 1) showed the formation of a new product spot. LCMS confirmed the reaction was complete. The reaction mixture was filtered, the filtrate was diluted with 10 mL of water, and extracted with ethyl acetate (10 mL * 3). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was evaporated to dryness under reduced pressure to obtain an oily residue, which was then subjected to silica gel column chromatography. 12g Intermediates 1-2 were prepared by Silica Flash Column (mobile phase gradient: 0-100% ethyl acetate / petroleum ether; flow rate: 30 mL / min), which were yellow oily substances (2.74 g, yield: 82.39%).

[0033] LCMS(ESI):m / z C 11 H 11 FNO2 + [M+H] + Calculated value = 208.08, measured value = 208.1.

[0034] 1 H NMR (400MHz, CD3Cl) δppm 8.28(br s,1H),7.88-7.71(m,1H),7.04-6.80(m,1H),3.76(s,3H),2.80-2.74(m,2H),2.70-2.63(m,2H).

[0035] Step 2: Synthesis of intermediates 1-3

[0036] Intermediate 1-2 (200 mg, 965.25 μmol, 1 eq) and compound 1-2a were dissolved in 1 mL of DMF. Pd(OAc)₂ (10.84 mg, 48.26 μmol, 0.05 eq), potassium carbonate (667.01 mg, 4.83 mmol, 5 eq), and lithium chloride (40.92 mg, 965.25 μmol, 19.79 μL, 1 eq) were added sequentially to the solution. The system was stirred at 100 °C for 1 hour under nitrogen protection. TLC (petroleum ether / ethyl acetate = 4 / 1) showed the formation of a new product spot, and LCMS confirmed the reaction was complete. The reaction mixture was filtered, the filtrate was diluted with 5 mL of water, and extracted with ethyl acetate (3 mL x 3). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was evaporated under reduced pressure to obtain an oily residue.

[0037] Intermediates 1-3 were prepared by reversed-phase column chromatography (column type: C18; size: 150×30mm; mobile phase: [phase A water (0.05% HCl) - phase B acetonitrile]; gradient: 52%-82% B, 7 minutes), which were white solids (90 mg, yield: 27.89%).

[0038] LCMS(ESI):m / z C 17 H 14 F3N2O2 + [M+H] + Calculated value = 335.10, measured value = 335.1.

[0039] 1 H NMR(400MHz,CD3OD)δppm 8.45(d,J=2.5Hz,1H),8.30-8.14(m,1H),7.22(dd,J=2.6,8.5Hz,1H),7.13(dd,J=2.1,9 .3Hz,1H),6.81-6.78(m,1H),3.55(s,3H),3.13(t,J=7.6Hz,2H),2.64(t,J=7.6Hz,2H).

[0040] Step 3: Synthesis of intermediates 1-4

[0041] Intermediates 1-3 (40 mg, 119.66 μmol, 1 eq) were dissolved in 1 mL of methanol, and sodium hydroxide solution (2 M, 119.66 μL, 2 eq) was added dropwise. The reaction system was stirred at 25 °C for 1 hour. LC-MS monitoring showed complete consumption of the starting material and formation of the main product. The reaction solution was diluted with 10 mL of water and washed with ethyl acetate (10 mL * 2). The pH of the aqueous phase was adjusted to 6 with 1 M hydrochloric acid solution. Extraction was then performed with ethyl acetate (6 mL * 3). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was evaporated under reduced pressure to obtain intermediates 1-4, a pale yellow oily substance (38 mg, crude product).

[0042] LCMS(ESI):m / z C 16 H 12 F3N2O2 + [M+H] + Calculated value = 321.08, measured value = 321.0.

[0043] Step 4: Synthesis of Compound I-1

[0044] Intermediate 1-4 (38 mg, 118.65 μmol, 1.06 eq) and intermediate 1-4a (13 mg, 111.95 μmol, 1 eq) (prepared according to the method in WO2021 / 252849,2021,A1) were dissolved in 1 mL of DMF, and then N-methylmorpholine (33.97 mg, 335.86 μmol, 36.93 μL, 3 eq) and 2-chloro-4,6-dimethoxy-1,3,5-triazine (CDMT) (29.48 mg, 167.93 μmol, 1.5 eq) were added sequentially. The reaction system was stirred at 25 °C for 1 hour. LCMS monitoring showed complete consumption of the starting materials and formation of the main product. The reaction solution was concentrated under reduced pressure to the residue, and then subjected to reversed-phase column chromatography (column type: C18 150×30mm; mobile phase: [phase A: water (0.04% NH3H2O ​​+ 10mM NH4HCO3) - phase B: ACN]; gradient: 25%-55% B, 7 min) to prepare compound I-1 as a white solid (12 mg, yield: 25.62%).

[0045] LCMS(ESI):m / z C 20 H 18 F3N4O3 + [M+H] + Calculated value = 419.13, measured value = 419.2.

[0046] 1H NMR(400MHz,CD3OD)δppm 8.50-8.44(m,1H),8.27-8.16(m,1H),7.24-7.20(m,2H),6.83-6.71(m,1H),4.31(q,J=7.4Hz,1H ),4.24-4.16(m,1H),3.55(dd,J=7.6,9.8Hz,1H),3.19-3.06(m,3H),2.61(dd,J=7.0,9.1Hz,2H).

[0047] Example 2: Synthesis of Compound I-2

[0048] Following the synthesis method of Example 1, and replacing the corresponding raw materials, compound I-2 was prepared using 2-bromo-5-fluoropyridine as the raw material. It is a white solid.

[0049] LCMS(ESI):m / z C 20 H 18 F3N4O3 + [M+H] + Calculated value = 419.13, measured value = 419.2.

[0050] 1 H NMR (400MHz, CD3OD) δppm 8.61 (d, J=3.0Hz, 1H), 7.92 (dd, J=4.3, 8.8Hz, 1H), 7.74-7.67 (m, 1H), 7.24 (br d,J=7.0Hz,1H),6.84-6.75(m,1H),4.34-4.26(m,1H),4.24-4.19(m,1H),3.55(dd,J =7.6,10.0Hz,1H),3.41-3.34(m,2H),3.10(dd,J=6.8,9.9Hz,1H),2.70-2.63(m,2H).

[0051] Example 3: Synthesis of Compound I-3

[0052] Following the synthesis method of Example 1, and replacing the corresponding raw materials, compound I-3 was prepared using 3-fluoro-4-iodopyridine as the raw material. It is a white solid.

[0053] LCMS(ESI):m / z C 20 H 18 F3N4O3 + [M+H] + Calculated value = 419.13, measured value = 419.2.

[0054] 1 H NMR(400MHz,CD3OD)δppm 8.67-8.57(m,1H),8.52(br d,J=4.9Hz,1H),7.75-7.62(m,1H),7.37-7.23(m,1H),6.96-6.73(m,1H),4.43-4.29 (m,1H),4.26-4.13(m,1H),3.61-3.53(m,1H),3.18-3.07(m,3H),2.66-2.56(m,2H).

[0055] Example 4: Synthesis of Compound I-4

[0056] Step 1: Synthesis of intermediate 4-2

[0057] Intermediate 4-1 (900 mg, 5.62 mmol, 1 eq) was dissolved in 30 mL of ethyl acetate, and 10% palladium on carbon (598.32 mg, 0.1 eq) was added under a nitrogen atmosphere. The reaction system was evacuated and then purged three times with hydrogen. The reaction mixture was stirred at 25 °C for 12 hours under a hydrogen atmosphere (15 Psi). LC-MS monitoring showed complete consumption of the starting material and formation of the main product. The reaction mixture was filtered through diatomaceous earth, and the filtrate was concentrated to give intermediate 4-2 as a yellow solid (715 mg, yield: 97.75%).

[0058] LCMS(ESI):m / z C5H5F2N2 + [M+H] + Calculated value = 131.04, measured value = 131.0.

[0059] Step 2: Synthesis of intermediate 4-3

[0060] Intermediate 4-2 (580 mg, 4.46 mmol, 1 eq) was dissolved in 15 mL of acetonitrile, and NIS (1.20 g, 5.35 mmol, 1.2 eq) and trifluoroacetic acid (1.53 g, 13.37 mmol, 3.0 eq) were added. The reaction mixture was stirred at 25 °C for 1 hour. TLC (ethyl acetate / petroleum ether = 1:2) was used to monitor complete consumption of the starting material and formation of the main product. The solvent in the reaction mixture was evaporated to dryness under reduced pressure. The residue was dissolved in 10 mL of ethyl acetate, washed with water (5 mL * 2), washed with saturated brine (5 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the residue, which was then subjected to silica gel column chromatography. 12g Intermediate 4-3 was prepared by Silica Flash Column (mobile phase gradient: 0-50% ethyl acetate / petroleum ether; flow rate: 30 mL / min), and was a yellow oily substance (1.12 g, yield: 98.43%).

[0061] LCMS(ESI):m / z C5H4F2IN2 + [M+H] + Calculated value = 256.94, measured value = 256.9.

[0062] 1 H NMR (400MHz, CD3OD) δppm 6.64 (dd, J=3.0, 9.3Hz, 1H), 4.24-3.76 (brs, 2H).

[0063] Step 3: Synthesis of intermediate 4-4

[0064] Intermediate 4-3 (633.11 mg, 2.47 mmol, 1.7 eq) and compound 4-3a (preparation method reference (Journal of the American Chemical Society, 2013, vol. 135, #21, pp. 7926-7932) (300 mg, 1.45 mmol, 1 eq)) were dissolved in 5 mL of DMF. Pd(OAc)₂ (32.66 mg, 145.48 μmol, 0.1 eq), potassium carbonate (1.01 g, 7.27 mmol, 5 eq), and lithium chloride (92.50 mg, 2.18 mmol, 44.73 μL, 1.5 eq) were added sequentially to the above solution. The reaction system was evacuated and purged three times with nitrogen. The system was then stirred at 110°C for 1 hour under nitrogen protection. LCMS was used to monitor the reaction until complete. TLC (petroleum ether / ethyl acetate = 2 / 1) showed the formation of a new product spot. LCMS was used to monitor the reaction until complete. The reaction solution was filtered, the filtrate was diluted with 10 mL of water, and extracted with ethyl acetate (10 mL * 3). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was evaporated under reduced pressure to obtain an oily residue, which was then subjected to silica gel column chromatography (…). 12g Intermediate 4-4 crude product was prepared by Silica Flash Column (mobile phase gradient: 0-100% ethyl acetate / petroleum ether; flow rate: 30 mL / min). Further intermediate 4-4 was prepared by reversed-phase column chromatography (column type: C18; size: 150 × 30 mm; mobile phase: [phase A: water (0.225% formic acid) - phase B: acetonitrile]; gradient: 55%-85% B, 6 min) as a white solid (170 mg, yield: 35.07%).

[0065] LCMS(ESI):m / z C 17 H 14 F3N2O2 + [M+H] + Calculated value = 335.10, measured value = 335.1.

[0066] 1 H NMR (400MHz, CD3OD) δppm 7.78-7.57(m,2H),7.35-7.21(m,2H),6.66(d,J=10.5Hz,1H),3.56(s,3H),3.15(t,J=7.7Hz,2H),2.73(t,J=7.7Hz,2H).

[0067] Step 4: Synthesis of intermediates 4-5

[0068] Intermediate 4-4 (100 mg, 29.91 μmol, 1 eq) was dissolved in 2 mL of methanol, and sodium hydroxide solution (2 M, 448.7 μL, 3 eq) was added dropwise. The reaction system was stirred at 25 °C for 1 hour. LC-MS monitoring showed complete consumption of the starting material and formation of the main product. The reaction solution was diluted with 10 mL of water and washed with ethyl acetate (3 mL x 2). The pH of the aqueous phase was adjusted to 6 with 1 M hydrochloric acid solution. Extraction was then performed with ethyl acetate (6 mL x 3). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was evaporated under reduced pressure to obtain intermediate 4-5, a pale yellow oily substance (80 mg, crude product).

[0069] LCMS(ESI):m / z C 16 H 12 F3N2O2 + [M+H] + Calculated value = 321.08, measured value = 321.0.

[0070] Step 5: Synthesis of compound I-4

[0071] Intermediate 4-5 (40 mg, 124.90 μmol, 1.12 eq) and intermediate 1-4a (13 mg, 111.95 μmol, 1 eq) were dissolved in 1 mL of DMF, and then N-methylmorpholine (33.97 mg, 335.86 μmol, 36.93 μL, 3 eq) and 2-chloro-4,6-dimethoxy-1,3,5-triazine (CDMT) (29.48 mg, 167.93 μmol, 1.5 eq) were added sequentially. The reaction system was stirred at 25 °C for 1 hour. LCMS monitoring showed complete consumption of the starting materials and formation of the main product. The reaction solution was concentrated under reduced pressure to the residue, and then subjected to reversed-phase column chromatography (column type: C18 150×30mm; mobile phase: [phase A: water (0.04% NH3H2O ​​+ 10mM NH4HCO3) - phase B: ACN]; gradient: 25%-55% B, 7 min) to prepare compound I-4 as a white solid (12 mg, yield: 25.62%).

[0072] LCMS(ESI):m / z C 20 H 18 F3N4O3 + [M+H] + Calculated value = 419.13, measured value = 419.2.

[0073] 1 H NMR(400MHz,CD3OD)δppm 7.77-7.64(m,2H),7.34-7.22(m,2H),6.69(d,J=10.5Hz,1H),4.42-4.30(m,1H),4.27-4.18( m,1H),3.57(dd,J=7.6,9.9Hz,1H),3.23-3.14(m,2H),3.13-3.06(m,1H),2.76-2.64(m,2H).

[0074] Example 5: Synthesis of compound I-5

[0075] Step 1: Synthesis of intermediate 5-2

[0076] Compound 5-1 (5 g, 38.43 mmol, 1 eq) was dissolved in 200 mL of ethanol, and compound 5-1a (10.01 g, 46.12 mmol, 1.2 eq) was added. The reaction mixture was heated under reflux at 90 °C for 16 hours. LC-MS was used to monitor complete consumption of the starting material and the formation of products. The reaction mixture was concentrated under reduced pressure to the residue and then subjected to silica gel column chromatography. 40g Intermediate 5-2 was prepared by Silica Flash Column (mobile phase gradient: 0-50% ethyl acetate / petroleum ether; flow rate: 30 mL / min), and was a white solid (7.82 g, yield: 82.08%).

[0077] LCMS(ESI):m / z C 13 H8F3N2 + [M+H] + Calculated value = 249.06, measured value = 249.1.

[0078] Step 2: Synthesis of intermediate 5-3

[0079] Intermediate 5-2 (600 mg, 2.42 mmol, 1 eq) was dissolved in 5 mL of DMF, and NBS (516.29 mg, 2.90 mmol, 1.2 eq) was added. The reaction mixture was stirred at 25 °C for 1 hour. TLC (petroleum ether:ethyl acetate = 10:1) showed complete consumption of the starting material and the formation of a product spot. The reaction mixture was diluted with 15 mL of water and 15 mL of ethyl acetate, and the organic phase was separated. The aqueous phase was extracted with ethyl acetate (15 mL * 2). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to the residue, followed by silica gel column chromatography. 12g Intermediate 5-3 was prepared by Silica Flash Column (mobile phase gradient: 0-30% ethyl acetate / petroleum ether; flow rate: 35 mL / min), and was a white solid (300 mg, yield: 37.89%).

[0080] LCMS(ESI):m / z C 13 H7BrF3N2 + [M+H] + Calculated values ​​= 326.97, 328.97; Measured values ​​= 327.1, 329.0.

[0081] Step 3: Synthesis of intermediate 5-4

[0082] Intermediate 5-3 (800 mg, 2.45 mmol, 1 eq) and compound 5-3a (470.20 mg, 3.67 mmol, 1.5 eq) were dissolved in 8 mL of DMF, and Pd(OAc)2 (54.91 mg, 244.57 μmol, 0.1 eq) and potassium carbonate (1.01 g, 7.34 mmol, 1.37 mL, 3 eq) were added sequentially. The reaction system was evacuated and purged with nitrogen three times, followed by microwave reaction at 130 °C for 2 hours under nitrogen protection. LC-MS monitoring showed complete consumption of the starting materials and product formation. The reaction solution was filtered, and the filtrate was diluted with 20 mL of water and 20 mL of ethyl acetate. The organic phase was separated, and the aqueous phase was extracted with ethyl acetate (10 mL * 2). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to the residue and subjected to silica gel column chromatography. 12g Intermediate 5-4 was prepared by Silica Flash Column (mobile phase gradient: 0-50% ethyl acetate / petroleum ether; flow rate: 30 mL / min), which was a white solid (350 mg, yield: 38.16%).

[0083] LCMS(ESI):m / z C 20 H 18 F3N2O2 + [M+H] + Calculated value = 375.13, measured value = 375.1.

[0084] 1 H NMR(400MHz,CD3Cl)δppm 8.27-8.25(m,1H),7.86(d,J=16.5Hz,1H),7.79-7.71(m,2H),7.24-7.18(m,2H),7.12-7.03(m,1H),6.31(d,J=16.3Hz,1H),1.55(s,9H).

[0085] Step 4: Synthesis of intermediate 5-5

[0086] Intermediate 5-4 (350 mg, 934.94 μmol, 1 eq) was dissolved in 8 mL of ethanol, and triphenylphosphine rhodium chloride (865.02 mg, 934.94 μmol, 1 eq) was added. The reaction system was evacuated, purged with nitrogen three times, and then purged with hydrogen. The system was stirred at 25 °C for 16 hours under a hydrogen atmosphere (15 psi). LC-MS monitoring showed complete consumption of the starting material and product formation. The reaction solution was filtered, and the filtrate was concentrated under reduced pressure and then...

[0087] The intermediate 5-5 was obtained by slurrying appropriate amounts of ethyl acetate and petroleum ether, which was a white solid (258 mg, yield:

[0088] 73.32%.

[0089] LCMS(ESI):m / z C 20 H 20 F3N2O2 + [M+H] + Calculated value = 377.15, measured value = 377.2. 1 H NMR(400MHz,CD3Cl)δppm 7.96-7.91(m,1H),7.81-7.70(m,2H),7.22-7.14(m,2H),6.92(ddd,J=2.0,8.5,1 0.0Hz, 1H), 3.35 (dd, J=7.0, 8.5Hz, 2H), 2.59 (dd, J=7.0, 8.5Hz, 2H), 1.42 (s, 9H).

[0090] Step 5: Synthesis of intermediates 5-6

[0091] Intermediate 5-5 (100 mg, 265.69 μmol, 1 eq) was dissolved in 3 mL of dichloromethane, and 1.5 mL of trifluoroacetic acid was added dropwise. The reaction mixture was stirred at 25 °C for 1 hour. LC-MS monitoring showed complete consumption of the starting material and formation of product. The reaction solution was concentrated under reduced pressure to the residue and then subjected to silica gel column chromatography (…). 4g Intermediate 5-6 was prepared by Silica Flash Column (mobile phase gradient: 0-60% ethyl acetate / petroleum ether; flow rate: 30 mL / min), and was a white solid (80 mg, yield: 94.01%).

[0092] LCMS(ESI):m / z C 16 H 12 F3N2O2 + [M+H] + Calculated value = 321.08, measured value = 321.1.

[0093] Step 6: Synthesis of Compound I-5

[0094] Intermediates 5-6 (70 mg, 218.57 μmol, 1 eq) and 1-4a (27.92 mg, 240.43 μmol, 1 eq) were dissolved in 3 mL of DMF, and then N-methylmorpholine (88.43 mg, 874.27 μmol, 4 eq) and 2-chloro-4,6-dimethoxy-1,3,5-triazine (CDMT) (46.05 mg, 262.28 μmol, 1.2 eq) were added sequentially. The reaction mixture was stirred at 25 °C for 1 hour. LCMS monitoring showed complete consumption of the starting materials and formation of the main product. The reaction solution was concentrated under reduced pressure to the residue, and then subjected to reversed-phase column chromatography (column type: C18 150×30mm; mobile phase: [phase A: water (0.04% NH3H2O ​​+ 10mM NH4HCO3) - phase B: ACN]; gradient: 22%-52% B, 7 min) to prepare compound I-5, a white solid (63 mg,

[0095] Yield: 67.72%, Purity: 98.3%.

[0096] LCMS(ESI):m / z C 20 H 18 F3N4O3 + [M+H] + Calculated value = 419.13, measured value = 419.2.

[0097] 1 H NMR(400MHz,CD3OD)δppm 8.53-8.45(m,1H),7.81-7.73(m,2H),7.30-7.19(m,3H),4.35-4.29(m,1H),4.28-4.21(m,1H), 3.55(dd,J=7.6,9.8Hz,1H), 3.45-3.38(m,2H), 3.10(dd,J=7.0,9.8Hz,1H), 2.69-2.58(m,2H).

[0098] Example 6: Synthesis of Compound I-6

[0099] Step 1: Synthesis of intermediate 6-3

[0100] Referring to the synthesis methods in steps 1 and 2 of Example 1, and replacing the corresponding raw materials, intermediate 6-3 was prepared using intermediate 6-1 as the raw material. It is a white solid.

[0101] LCMS(ESI):m / z C 18 H 15 F3NO2 + [M+H] +Calculated value = 334.10, measured value = 334.1.

[0102] 1 H NMR(400MHz,CD3Cl)δppm 8.11(br s,1H),7.59-7.49(m,2H),7.24-7.16(m,2H),7.07(dd,J=2.1,9.1Hz,1H ),6.78-6.74(m,1H),3.64(s,3H),3.23-3.09(m,2H),2.72-2.56(m,2H).

[0103] Step 2: Synthesis of intermediate 6-4

[0104] Intermediate 6-3 (70 mg, 210.02 μmol, 1 eq) was dissolved in 2 mL of acetonitrile, and potassium carbonate (87 mg, 630.06 μmol, 3 eq) and iodomethane (44.72 mg, 315.03 μmol, 19.61 μL, 1.5 eq) were added sequentially. The reaction mixture was stirred at 25 °C for 2 hours. LC-MS monitoring showed complete consumption of the starting material and product formation. The reaction solution was filtered, and the filtrate was concentrated under reduced pressure to the residue, which was then subjected to silica gel column chromatography (…). 4g Intermediate 6-4 was prepared by Silica Flash Column (mobile phase gradient: 0-20% ethyl acetate / petroleum ether; flow rate: 30 mL / min), and was a white solid (48 mg, yield: 65.8%).

[0105] LCMS(ESI):m / z C 19 H 17 F3NO2 + [M+H] + Calculated value = 348.12, measured value = 348.1.

[0106] Step 3: Synthesis of Compound I-6

[0107] Referring to the synthesis methods in steps 3 and 4 of Example 1, and replacing the corresponding raw materials, using intermediate 6-4 as the raw material, compound I-6 was prepared as a white solid.

[0108] LCMS(ESI):m / z C 22 H 21 F3N3O3 + [M+H] + Calculated value = 432.15, measured value = 432.2. 1H NMR(400MHz,DMSO-d6)δppm 8.16(d,J=7.7Hz,1H),7.76(s,1H),7.57-7.50(m,2H),7.45-7.35(m,2H),7.30(dd,J=2.2,9.4Hz,1H),7.08-6.95(m,1H),5.73-5.2 5(m,1H),4.12-4.01(m,2H),3.66(d,J=1.4Hz,3H),3.34(m,1H),2.90(dd,J=6.8,9.4Hz,1H),2.82-2.73(m,2H),2.40-2.29(m,2H).

[0109] Example 7: Synthesis of compound I-7

[0110] Following the synthesis method of Example 1, and replacing the corresponding raw materials, compound I-7 was prepared using compound 7-1 as the raw material. It is a white solid.

[0111] LCMS(ESI):m / z C 19 H 18 F2N3O3S + [M+H] + Calculated value = 406.10, measured value = 406.3. 1 H NMR(400MHz,DMSO-d6)δppm 11.75(s,1H),8.22(d,J=7.6Hz,1H),7.77(s,1H),7.70(dd,J=1.0,5.1Hz,1H),7.61(dd,J=1.1,3.6Hz,1H),7.30-7.20(m,2H), 7.03-6.95(m,1H),5.59-5.39(m,1H),4.14-4.04(m,2H),3.40(m,1H),3.14-3.08(m,2H),2.95-2.88(m,1H),2.46-2.40(m,2H).

[0112] Example 8: Compound I-8

[0113] Following the synthesis method of Example 1, and replacing the corresponding raw materials, compound I-8 was prepared using compound 8-1 as the raw material. It is a white solid.

[0114] LCMS(ESI):m / z C 19 H 18 F2N3O3S + [M+H] +Calculated value = 406.10, measured value = 406.1. 1 H NMR(400MHz,DMSO-d6)δppm 11.62(s,1H),8.24(d,J=7.6Hz,1H),7.91(dd,J=1.3,2.9Hz,1H),7.77(s,1H),7.74(dd,J=2.9,5.1Hz,1H),7.59(dd,J=1.3,5.0Hz,1H),7.24(d d,J=2.1,9.5Hz,1H),7.00-6.95(m,1H),5.48(s,1H),4.15-4.05(m,2H) ,3.40(m,1H),3.10-3.02(m,2H),2.94-2.87(m,1H),2.48-2.42(m,2H).

[0115] Example 9: Synthesis of Compound I-9

[0116] Step 1: Synthesis of intermediate 9-2

[0117] Referring to the synthesis methods in steps 3 and 4 of Example 1, and replacing the corresponding raw materials, compound 9-2 was prepared using intermediate 6-3 as the raw material. It is a white solid.

[0118] LCMS(ESI):m / z C 21 H 19 F3N3O3 + [M+H] + Calculated value = 418.14, measured value = 418.1. 1 H NMR(400MHz,CD3OD)δppm 7.72-7.60(m,2H),7.29-7.15(m,3H),6.80-6.66(m,1H),4.43-4.28(m,1H), 4.24-4.18(m,1H),3.61-3.52(m,1H),3.18-3.07(m,3H),2.65-2.54(m,2H).

[0119] Step 2: Synthesis of Compound I-9

[0120] Intermediate 9-2 (113.90 mg, 239.59 μmol, 1 eq) was dissolved in 4 mL of pyridine, and compound 9-2a (225.85 mg, 2.39 mmol, 10 eq) was added dropwise. After the addition was complete, the reaction system was stirred at 25 °C for 1 hour. LC-MS monitoring showed that some starting material remained, and product was formed. The reaction solution was concentrated under reduced pressure to the residue, and then subjected to silica gel column chromatography (…). 12g Intermediate I-9 was prepared by Silica Flash Column (mobile phase gradient: 0-30% ethyl acetate / petroleum ether; flow rate: 30 mL / min), and was a white solid (42 mg, yield: 36.87%).

[0121] LCMS(ESI):m / z C 23 H 21 F3N3O5 + [M+H] + Calculated value = 476.14, measured value = 476.1.

[0122] 1 H NMR(400MHz,CD3OD)δppm 7.70-7.63(m,2H),7.28-7.17(m,3H),6.74-6.71(m,1H),5.25-5.10(m,1H),4.29(d,J=6.8Hz,1H),3.81(dd,J =8.0,10.6Hz,1H),3.77(s,3H),3.28(dd,J=5.8,10.6Hz,1H),3.14(dd,J=6.7,9.5Hz,2H),2.61-2.54(m,2H).

[0123] Example 10: Synthesis of Compound I-10

[0124] Step 1: Synthesis of intermediate 10-2

[0125] Compound 9-2 (60 mg, 143.75 μmol, 1 eq) was dissolved in 5 mL of acetonitrile, and tetrazolium (60.42 mg, 862.52 μmol, 6 eq) was added. Compound 10-1a (211.57 mg, 862.52 μmol, 6 eq) was added dropwise to the above solution at 25 °C. After the addition was complete, the reaction system was stirred at 25 °C for half an hour, followed by the addition of peroxytert-butanol (77.74 mg, 862.52 μmol, 6 eq). The system was stirred at 25 °C for another half hour. LC-MS monitoring showed complete consumption of the starting material and product formation. The reaction solution was concentrated under reduced pressure to the residue and then subjected to silica gel column chromatography. 12g Intermediate 10⁻² was prepared by Silica Flash Column (mobile phase gradient: 0-60% ethyl acetate / petroleum ether; flow rate: 25 mL / min), and was a white solid (65 mg, yield: 78.29%).

[0126] LCMS(ESI):m / z C 27 H 28 F3N3O6P+ [M+H] + Calculated value = 578.17, measured value = 578.2. 1 H NMR (400MHz, CD3OD) δppm 7.65 (dd, J=5.4, 8.6Hz, 2H), 7.32-7.15 (m, 3H), 6.82-6.65 (m, 1H), 5.03-4.97 (m, 1H), 4.35 (br d,J=7.0Hz,1H),3.77(dd,J=7.9,10.1Hz,1H),3.36(br dd,J=6.3,10.3Hz,1H),3.19-3.08(m,2H),2.63-2.50(m,2H).

[0127] Step 2: Synthesis of compound 10⁻³

[0128] Intermediate 10⁻² (60 mg, 103.90 μmol, 1 eq) was dissolved in 5 mL of dichloromethane, and morpholine (9.05 mg, 103.90 μmol, 1 eq) and tetrakis(triphenylphosphine)palladium (12.01 mg, 10.39 μmol, 0.1 eq) were added. The reaction mixture was stirred at 25 °C for 1 hour. LC-MS monitoring showed a small amount of starting material remaining, and the main product was formed. The reaction mixture was concentrated under reduced pressure to the residue, and then subjected to reversed-phase column chromatography (column type: C18 150 × 40 mm; mobile phase: [phase A: water (0.3% formic acid) - phase B: ACN]; gradient: 15%-45% B, 10 min) to prepare compound 10⁻³ as a white solid (25 mg, yield: 48.37%).

[0129] LCMS(ESI):m / z C 21 H 20 F3N3O6P + [M+H] + Calculated value = 498.10, measured value = 498.2. 1 H NMR(400MHz,CD3OD)δppm 7.65(dd,J=5.4,8.7Hz,2H),7.30-7.17(m,3H),6.80-6.67(m,1H),5.00-4.96(m,1H),4.35(d,J=7.3Hz ,1H),3.77(dd,J=7.7,10.3Hz,1H),3.35(dd,J=6.3,10.4Hz,1H),3.16-3.10(m,2H),2.62-2.55(m,2H).

[0130] Step 3: Synthesis of Compound I-10

[0131] Approximately 3g of activated sodium-type cation exchange resin Amberlite IR120 was packed into a chromatography column. Compound 10-3 (25mg, 50.26μmol, 1eq) was dissolved in an appropriate amount of methanol and slowly poured into the chromatography column. The column was then eluted with deionized water, and the eluent containing compound I-10 was collected. The eluents were combined and concentrated under reduced pressure at 45°C to a volume of 4mL. The eluent was then freeze-dried to obtain compound I-10 as a light yellow solid (23mg, yield: 80.77%).

[0132] LCMS(ESI):m / z C 21 H 20 F3N3O6P + [M+H] + Calculated value = 498.10, measured value = 498.1. 1 H NMR(400MHz,D2O)δppm 7.47-7.43(m,2H),7.15-7.10(m,2H),7.06(d,J=9.5Hz,1H),6.71-6.66(m 1H), 4.63-4.56 (m, 1H), 4.16 (d, J = 7.2Hz, 1H), 3.64-3.60 (m, 1H), 3.24-3.21 (m, 1H), 2.98-2.94 (m, 2H), 2.47-2.43 (m, 2H).

[0133] Example 11: Synthesis of Compound I-11

[0134] Step 1: Synthesis of intermediate 11-2

[0135] Compound 11-1 (3.7 g, 24.16 mmol, 1 eq) was dissolved in 90 mL of DMF and 10 mL of DMSO, and then compound 11-1a (9.29 g, 72.49 mmol, 10.52 mL, 3 eq), Pd(OAc)2 (542.47 mg, 2.42 mmol, 0.1 eq), and Cu(OAc)2 (10.97 g, 60.41 mmol, 2.5 eq) were added sequentially. The reaction system was stirred at 90 °C for 12 hours. LCMS was used to monitor complete consumption of the starting materials and the formation of products. The reaction solution was filtered, and the filtrate was diluted with 150 mL of ethyl acetate and 150 mL of water. The organic phase was separated, and the aqueous phase was extracted with ethyl acetate (50 mL * 2). The combined organic phases were washed sequentially with water (50 mL * 2) and saturated brine (50 mL * 2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to the residue, followed by silica gel column chromatography. 120g Intermediate 11-2 was prepared by Silica Flash Column (mobile phase gradient: 0-50% ethyl acetate / petroleum ether; flow rate: 90 mL / min), and was a white solid (6.4 g, yield: 94.84%).

[0136] 1 H NMR(400MHz,DMSO-d6)δppm 12.34(br s,1H),8.08(d,J=2.5Hz,1H),7.74(d,J=16.0Hz,1H),7.53(dd,J=2.0,9.5Hz,1H),7.26-6.99(m,1H),6.30(d,J=16.0Hz,1H),1.49(s,9H).

[0137] Step 2: Synthesis of intermediate 11-3

[0138] Intermediate 11-2 (6.14 g, 21.98 mmol, 1 eq) was dissolved in 10 mL of ethanol. Under a nitrogen atmosphere, palladium on carbon (389.78 mg, 2.20 mmol, 60% purity, 0.1 eq) was added. The reaction system was evacuated, purged three times with nitrogen, and then purged once with hydrogen. The reaction mixture was stirred at 20 °C under a hydrogen atmosphere (15 psi) for 12 hours. TLC (petroleum ether:ethyl acetate = 5:1) was used to monitor complete consumption of the starting material and the formation of products. The reaction mixture was filtered through diatomaceous earth, and the filtrate was concentrated under reduced pressure and then subjected to silica gel column chromatography. 80g Intermediate 11-3 was prepared by Silica Flash Column (mobile phase gradient: 0-50% ethyl acetate / petroleum ether; flow rate: 35 mL / min), and was a white solid (5.4 g, yield: 87.39%).

[0139] 1 H NMR(400MHz,DMSO-d6)δppm 11.41(br s,1H),7.26(d,J=2.1Hz,1H),7.19(dd,J=2.1,9.5Hz,1H),6.95-6.92(m,1H),2.88(t,J=7.5Hz,2H),2.55(t,J=7.5Hz,2H),1.35(s,9H).

[0140] Step 3: Synthesis of intermediate 11-4

[0141] Dissolve intermediate 11-3 (1.5 g, 5.33 mmol, 1 eq) in 8 mL of tetrahydrofuran. Slowly add sodium hydrogen hydride (383.94 mg, 9.60 mmol, 60% purity, 1.8 eq) to the above solution at 0 °C. Stir the reaction mixture at 0 °C for 20 min, then add p-toluenesulfonyl chloride (1.32 g, 6.93 mmol, 1.3 eq). Continue stirring the reaction mixture at 0 °C for 40 min. LCMS monitoring showed that the starting material consumption was safe and that the main product was formed. Concentrate the reaction mixture under reduced pressure to the residue and then perform silica gel column chromatography (…). 80g Intermediate 11-4 was prepared by Silica Flash Column (mobile phase gradient: 0-60% ethyl acetate / petroleum ether; flow rate: 40 mL / min), and was a white solid (1.85 g, yield: 79.67%).

[0142] LCMS(ESI):m / z C 22 H 24 F2NO4S + [M+H] + Calculated value = 436.14, measured value [Mt-Bu+H] + =380.0. 1 H NMR(400MHz,DMSO-d6)δppm 7.79-7.71(m,3H),7.46-7.35(m,3H),7.19(br t,J=10.0Hz,1H),2.90-2.83(m,2H),2.63(t,J=7.2Hz,2H),2.35(s,3H),1.36(s,9H).

[0143] Step 4: Synthesis of intermediate 11-5

[0144] Intermediate 11-4 (2.5 g, 5.74 mmol, 1 eq) was dissolved in 10 mL of tetrahydrofuran, and LDA (2 M, 2.87 mL, 1 eq) was slowly added dropwise at -78 °C. After the addition was complete, the reaction mixture was stirred at 78 °C for 0.5 hours. Carbon tetrabromide (2.28 g, 6.89 mmol, 1.2 eq) was added to the system. The reaction mixture was diluted with 15 mL of water and 15 mL of ethyl acetate, and the organic phase was separated. The aqueous phase was extracted with ethyl acetate (5 mL * 2). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to the residue, followed by silica gel column chromatography. 40g Intermediate 11-5 was prepared by Silica Flash Column (mobile phase gradient: 0-80% ethyl acetate / petroleum ether; flow rate: 40 mL / min), and was a white solid (1.89 g, yield: 64.0%).

[0145] LCMS(ESI):m / z C 22 H 23 BrF2NO4S + [M+H] + Calculated values ​​= 514.05, 516.05. Measured value [Mt - Bu + H] + =458.0,460.0.

[0146] Step 5: Synthesis of intermediate 11-6

[0147] Intermediate 11-5 (50 mg, 97.20 μmol, 1 eq) and compound 10-5a (58.91 mg, 291.61 μmol, 3 eq) were reacted with 5 mL of dioxane and 1 mL of aqueous solution, followed by the addition of sodium bicarbonate (40.83 mg, 486.02 μmol, 5 eq) and Pd(PPh3)4 (11.23 mg, 9.72 μmol, 0.1 eq). The reaction system was protected under nitrogen and stirred at 130 °C for 1 hour. LC-MS monitoring showed complete consumption of the starting materials and product formation. The reaction solution was concentrated under reduced pressure to obtain the residue, dissolved in 10 mL of ethyl acetate, washed with saturated ammonium chloride solution (3 mL x 2), washed with water (3 mL), washed with saturated sodium chloride solution (3 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the residue, which was then subjected to silica gel column chromatography. 4g Intermediate 11-6 was prepared by Silica Flash Column (mobile phase gradient: 0-60% ethyl acetate / petroleum ether; flow rate: 30 mL / min), and was a white solid (42 mg, yield: 73.03%).

[0148] LCMS(ESI):m / z C 33 H 32 F2NO5S + [M+H] + Calculated value = 592.20. Measured value [M-tBu+H] + =536.1.

[0149] Step 6: Synthesis of intermediates 11-7

[0150] Intermediate 11-6 (35 mg, 59.16 μmol, 1 eq) was dissolved in 5 mL of ethanol, and sodium hydroxide solution (2 M, 591.55 μL, 20 eq) was added dropwise to the above system. The reaction system was stirred at 90 °C for 17 hours. LC-MS monitoring showed complete consumption of the starting material and product formation. The pH of the reaction solution was adjusted to 6 with 1 M dilute hydrochloric acid, and 5 mL of ethyl acetate was added. The organic phase was separated, and the aqueous phase was extracted with ethyl acetate (2 mL * 2). The combined organic phases were washed successively with water (4 mL), saturated brine (4 mL * 2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to the residue, and then subjected to silica gel column chromatography (…). 4g Intermediate 11-7 was prepared by Silica Flash Column (mobile phase gradient: 0-60% ethyl acetate / petroleum ether; flow rate: 25 mL / min), and was a white solid (18 mg, yield: 79.79%).

[0151] LCMS(ESI):m / z C 22 H 18 F2NO3 + [M+H] + Calculated value = 382.12, measured value = 382.0.

[0152] Step 6: Synthesis of compound I-11

[0153] Referring to the synthesis method in step 4 of Example 1, and replacing the corresponding raw materials, using intermediate 11-7 as the raw material, compound I-11 was prepared as a white solid.

[0154] LCMS(ESI):m / z C 26 H 24 F2N3O4 + [M+H] + Calculated value = 480.17, measured value = 480.2. 1¹H NMR (400MHz, DMSO-d⁶) δppm 8.29(d,J=7.7Hz,1H),8.11(s,1H),7.94(t,J=9.1Hz,2H),7.75(dd,J=1.5, 8.5Hz,1H),7.39(d,J=2.3Hz,1H),7.30(dd,J=2.0,9.5Hz,1H),7.23(dd,J=2 .4,8.9Hz,1H),7.02-6.92(m,1H),4.17-4.06(m,2H),3.90(s,3H),3.38(dd, J=7.1,9.6Hz,1H),3.13-3.04(m,2H),2.96-2.88(m,1H),2.54-2.52(m,2H).

[0155] Example 12: Synthesis of Compound I-12

[0156] Referring to the synthesis method in Example 11, and replacing the corresponding raw materials, using intermediate 12-1a as the raw material, compound I-12 was prepared as a white solid.

[0157] LCMS(ESI):m / z C 25 H 21 ClF2N3O3 + [M+H] + Calculated value = 484.12, measured value = 484.1. 1 ¹H NMR (400MHz, DMSO-d⁶) δppm 11.84(s,1H),8.31-8.22(m,2H),8.13(d,J=1.7Hz,1H),8.07(d,J=8.7Hz,2 H),7.89(dd,J=1.2,8.6Hz,1H),7.78(s,1H),7.61(dd,J=2.0,8.8Hz,1H),7. 32(dd,J=1.9,9.4Hz,1H),7.08-6.96(m,1H),5.48(d,J=4.9Hz,1H),4.16-4. 04(m,2H),3.35-3.35(m,1H),3.14-3.07(m,2H),2.95-2.90(m,1H),2.54(br s,2H).

[0158] Example 13: Synthesis of Compound I-13

[0159] Referring to the synthesis method in Example 11, and replacing the corresponding raw materials, using intermediate 13-1a as the raw material, compound I-13 was prepared as a white solid.

[0160] LCMS(ESI):m / z C 25 H 21 F3N3O3 + [M+H] + Calculated value = 468.15, measured value = 468.2. 1 H NMR(400MHz,CD3CN)δppm 9.85(br s,1H),8.20(s,1H),8.05(dd,J=5.8,9.0Hz,1H),7.99(d,J=8.5Hz,1H),7.84(d,J=8.5Hz,1H),7.64(dd, J=2.5,10.3Hz,1H),7.42(dt,J=2.8,8.9Hz,1H),7.25(dd,J=2.0,9.5Hz,1H),6.90-6.81(m,1H),6.78(br d,J=2.5Hz,1H),6.23(br s,1H),4.82(d,J=2.0Hz,1H),4.14-4.06(m,1H),4.05-3.98(m,1H),3.50-3. 40(m,1H),3.26-3.17(m,2H),3.00(dd,J=7.7,9.4Hz,1H),2.68-2.59(m,2H).

[0161] Example 14: Synthesis of Compound I-14

[0162] Referring to the synthesis method in Example 11, and replacing the corresponding raw materials, using intermediate 14-1a as the raw material, compound I-14 was prepared as a white solid.

[0163] LCMS(ESI):m / z C 20 H 21 F2N4O3 + [M+H] + Calculated value = 403.16, measured value = 403.4. 1 H NMR(400MHz,DMSO-d6)δppm 11.54(s,1H),8.19(d,J=7.6Hz,1H),7.76(s,1H),7.26(dd,J=2.1,9.5Hz,1H),7.06-6.87(m,2H),6.25(dd,J=1.8,3.6Hz,1H),6. 17-6.07(m,1H),5.47(d,J=5.2Hz,1H),4.22-3.97(m,2H),3.57(s,3H),3.29-3.21(m,1H),2.97-2.77(m,3H),2.42-2.30(m,2H).

[0164] Example 15: Synthesis of Compound I-15

[0165] Referring to the synthesis method in Example 11, and replacing the corresponding raw materials, using intermediate 15-1a as the raw material, compound I-15 was prepared as a white solid.

[0166] LCMS(ESI):m / z C 20 H 21 F2N4O3 + [M+H] + Calculated value = 403.16, measured value = 403.3. 1 H NMR(400MHz,CD3OD)δppm 7.14(t,J=1.8Hz,1H),7.06(dd,J=2.1,9.6Hz,1H),6.74(t,J=2.4Hz,1H),6.63-6.56(m,1H),6.53-6.50(m,1H),4.34(q,J=7.4Hz,1H ),4.22(d,J=7.6Hz,1H),3.73(s,3H),3.57(dd,J=7.6,9.9Hz,1H),3.19-3.14(m,2H),3.11(dd,J=6.8,9.9Hz,1H),2.60-2.53(m,2H).

[0167] Example 16: Synthesis of Compound I-16

[0168] Step 1: Synthesis of Intermediate 16-1

[0169] Intermediate 9-1 (400 mg, 1.25 mmol, 1 eq) and benzyl alcohol (406.43 mg, 3.76 mmol, 3 eq) were dissolved in 10 mL of dichloromethane, and dicyclohexylcarbodiimide (853.03 mg, 4.13 mmol, 3.3 eq) and DMAP (76.53 mg, 626.41 μmol, 0.5 eq) were added. The reaction system was stirred at 25 °C for 2 hours. LCMS monitoring showed complete consumption of the starting materials and product formation. The reaction solution was concentrated under reduced pressure to obtain the residue, dissolved in 40 mL of ethyl acetate, filtered, and the filtrate was washed with ammonium chloride solution (10 mL * 2), water (10 mL), and saturated sodium chloride solution (10 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the residue, which was then subjected to silica gel column chromatography. 20g Intermediate 16-1 was prepared by Silica Flash Column (mobile phase gradient: 0-50% ethyl acetate / petroleum ether; flow rate: 35 mL / min), and was a white solid (380 mg, yield: 74.25%).

[0170] LCMS(ESI):m / z C 24 H 19 F3NO2 + [M+H] + Calculated value = 410.14. Measured value [M+H] + =410.2.

[0171] Step 2: Synthesis of intermediate 16-2

[0172] Intermediate 16-1 (300.0 mg, 732.78 μmol, 1 eq) was dissolved in 5 mL of acetonitrile, and cesium carbonate (477.51 mg, 1.47 mmol, 2 eq), sodium iodide (32.95 mg, 219.83 μmol, 0.3 eq), and compound 16-1a (364.99 mg, 2.93 mmol, 4 eq) were added sequentially. The reaction mixture was stirred at 50 °C for 1 hour. LC-MS monitoring showed complete consumption of the starting material and product formation. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure to the residue. The residue was then subjected to silica gel column chromatography (…). 12g Intermediate 16-2 was prepared by Silica Flash Column (mobile phase gradient: 0-40% ethyl acetate / petroleum ether; flow rate: 25 mL / min), and was a white solid (350 mg, yield: 96.0%).

[0173] LCMS(ESI):m / z C 27 H 23 F3NO5 + [M+H] + Calculated value = 498.15. Measured value [M+H] + =498.2. 1 H NMR (400MHz, CDCl3) δppm 7.39-7.31(m,5H),7.26-7.23(m,2H),7.22-7.16(m,2H),7.06(dd,J=2.1,8.6Hz,1H),6.81(ddd,J= 2.1,9.4,11.8Hz,1H),5.97(s,2H),5.04(s,2H),3.75(s,3H),2.99-2.87(m,2H),2.59-2.49(m,2H).

[0174] Step 3: Synthesis of intermediate 16-3

[0175] Intermediate 16-2 (350 mg, 703.57 μmol, 1 eq) was dissolved in 8 mL of methanol. Under a nitrogen atmosphere, 100 mg of 10% palladium hydroxide on carbon was added. The reaction system was evacuated and then purged three times with hydrogen. The reaction solution was stirred at 30 °C under a hydrogen atmosphere (15 Psi) for 1 hour. LC-MS monitoring showed complete consumption of the starting material and formation of the main product. The reaction solution was filtered, and the filtrate was concentrated under reduced pressure to the residue. The residue was then subjected to silica gel column chromatography (…). 12g Intermediate 16-3 was prepared by Silica Flash Column (mobile phase gradient: 0-80% ethyl acetate / petroleum ether; flow rate: 25 mL / min), and was a white solid (235.86 mg, yield: 82.3%).

[0176] LCMS(ESI):m / z C 20 H 17 F3NO5 + [M+H] + Calculated value = 408.11. Measured value [M-C2H4O3+H] + =332.0. 1 H NMR (400MHz, CDCl3) δppm 7.39(dd,J=5.3,8.8Hz,2H),7.21(t,J=8.7Hz,2H),7.07(dd,J=2.1,8.7Hz,1H),6.82(ddd ,J=2.4,9.4,11.8Hz,1H),5.99(s,2H),3.76(s,3H),2.96-2.88(m,2H),2.56-2.52(m,2H).

[0177] Step 4: Synthesis of compound I-16

[0178] Referring to the synthesis method in step 4 of Example 1, and replacing the corresponding raw materials, using intermediate 16-3 as the raw material, compound I-16 was prepared as a white solid.

[0179] LCMS(ESI):m / z C 24 H 23 F3N3O6 + [M+H] + Calculated value = 506.15, measured value [M-C2H4O3+H] + =430.2. 1¹H NMR (400MHz, DMSO-d⁶) δppm 8.18(d,J=7.9Hz,1H),7.77(s,1H),7.65-7.54(m,2H),7.40(t,J=8.9Hz,2H),7 .32(dd,J=2.1,9.2Hz,1H),7.08(ddd,J=2.1,9.8,12.2Hz,1H),6.29(t,J=6.4Hz ,1H),5.46(d,J=5.1Hz,1H),5.32(s,2H),4.14-4.01(m,2H),3.70(s,3H),3.42- 3.36(m,1H),2.90(dd,J=6.8,9.4Hz,1H),2.82-2.73(m,2H),2.38-2.31(m,2H).

[0180] Example 17: Synthesis of Compound I-17

[0181] Referring to the synthesis method in Example 16, and replacing the corresponding raw materials, using intermediate 17-1a as the raw material, compound I-17 was prepared as a white solid.

[0182] LCMS(ESI):m / z C 25 H 25 F3N3O6 + [M+H] + Calculated value = 520.17, measured value [M-C3H6O3+H] + =430.2. 1 ¹H NMR (400MHz, CDCl₃) δppm 7.49-7.41(m,2H),7.23(t,J=8.7Hz,2H),7.09(dd,J=2.1,8.7Hz,1H),6.80(dd d,J=2.3,9.5,12.0Hz,1H),6.30(s,1H),5.73(s,1H),5.38(s,2H),4.24-4.20( m,1H),4.08-4.00(m,1H),3.68-3.60(m,1H),3.39-3.36(m,2H),3.26(dd,J=8. 3,9.5Hz,1H),2.99-2.96(m,2H),2.48(t,J=7.8Hz,2H),1.11(t,J=7.0Hz,3H).

[0183] In vitro biological testing

[0184] Biological test cases were used to evaluate the potential inhibitory effect of the compounds on the APOL1 G1 channel.

[0185] Detection type: FLIPR (fluorescence imaging plate reader) detection

[0186] Reagents and Materials

[0187] Instruments and Consumables

[0188] Experimental methods and procedures

[0189] 1. Culture the cells in 85% DMEM, 10% Tet FBS, 100 U / mL penicillin-streptomycin, 8 μg / mL blastidin, and 1 μg / mL puromycin.

[0190] 2. The day before the test, cells were separated using TrypLE™ Express and counted using a cell counter. Only cells with a viability of >85% were used for the test.

[0191] 3. Seed 20,000 cells / well into 384-well cell culture plates, each well containing 30 μl of medium with 1 μg / mL doxycyline, and incubate the cells overnight at 37°C and 5% (v / v) CO2.

[0192] 4. On the day of testing, in accordance with The manual for the potassium assay kit explains how to prepare a 2× dye solution:

[0193] (1) Dilute the dye with assay buffer (20 mM HEPES in 1 x HBSS, pH 7.4);

[0194] (2) Add probenecid to a final concentration of 5mM;

[0195] (3) Vigorous vortex for 1-2 minutes.

[0196] 5. Gently brush the cell culture plate onto a paper towel to remove the culture medium from the cell culture plate.

[0197] 6. Add 10 μl of assay buffer and 10 μl of 2× dye solution to each well of the cell plate.

[0198] 7. Place the cell plate on a plate shaker and stir the plate at 600 rpm for 2 minutes. Incubate the plate at 37°C for 1 hour, and then incubate it at 25°C for another 15 minutes.

[0199] 8. Prepare the 3× compound in the assay buffer:

[0200] (1) Dilute the reference compound to the desired concentration using DMSO. Add the compound to a 384-well compound plate;

[0201] (2) Perform a series of dilutions;

[0202] (3) Add 30mM to the composite plate and perform a 4-fold continuous dilution.

[0203] (4) Transfer the reference compound and test compound (90 nL / well) from the source plate to the 384-well compound plate.

[0204] (5) Add 30 μL / well of assay buffer to the composite plate;

[0205] (6) Place the plate on a shaker and mix for 2 minutes.

[0206] 9. Place the cell plate, compound plate, and pipette tip into the FLIPR, and use the FLIPR to transfer 10 μl of 3x compound into each well of the cell plate.

[0207] 10. Store the cell plate at 25°C in the dark for 30 minutes.

[0208] 11. Prepare 1X chloride-free buffer containing 4X 3mM Tl+ stimulation buffer.

[0209] 12. After incubating at 25°C in the dark for 30 minutes, place the cell plate, the composite plate containing the stimulation buffer, and the FLIPR pipette tip into the FLIPR. Transfer 10 μL of stimulation buffer to each well of the cell plate using the FLIPR.

[0210] 13. Read the board for 100 seconds at 1-second intervals to obtain data on the antagonistic mode.

[0211] Data Analysis

[0212] 1. Normalized fluorescence reading (RFU) is calculated as follows, where Fmax and Fmin represent the maximum and minimum values ​​of the calcium signal within the defined time window, respectively: RFU = Fmax - Fmin

[0213] 2. Calculate the inhibition percentage using the following formula:

[0214] 3. The IC50 was calculated using XLfit by fitting the logarithm of the compound concentration to the percentage of inhibition using the Hill equation.

[0215] Results of activity tests on a series of compounds

[0216] 0.1-10nM: +++++, 10-100nM: ++++, 100-1000nM: +++, 1μM-10μM: ++, >10μM: +

[0217] The compounds of this invention exhibit favorable pharmacokinetic characteristics whether administered orally or intravenously.

Claims

1. A compound according to formula (I), wherein the pharmaceutically acceptable salt, solvate, isomer, polymorph or deuterated derivative thereof is characterized in that: X1 is selected from N or CH; Y1 is selected from divalent C1-C8 straight-chain or branched alkyl, divalent C1-C8 straight-chain or branched alkoxy, divalent C1-C8 straight-chain or branched aminoalkyl, or divalent C1-C8 straight-chain or branched thioalkyl, wherein the divalent alkyl, divalent alkoxy, divalent aminoalkyl or divalent thioalkyl is optionally substituted by at least one group selected from: C1-C6 alkyl, aryl, heteroaryl, halogen group, hydroxyl, or amino; Y2 is selected from NH or O; Z is selected from hydrogen, phosphate group, sodium phosphate group, and carbonate group; Ar is selected from five- to ten-membered aromatic rings or aromatic heterocyclic groups, and is optionally substituted with R2; Preferably, Ar is selected from phenyl, pyridyl, pyrimidinyl, naphthyl, pyrroleyl, N-methylpyrroleyl, thiophenyl, and optionally substituted with R2; R1 and R2 can be one or more, each independently selected from: halogen groups, hydroxyl groups, thiol groups, amino groups, cyano groups, -OC(O)C1-C6 straight-chain, branched, and cyclic alkyl groups, -C(O)OC1-C6 straight-chain, branched, and cyclic alkyl groups, -NHC(O)C1-C6 straight-chain, branched, and cyclic alkyl groups, -C(O)NHC1-C6 straight-chain, branched, and cyclic alkyl groups, -NHC(O) aryl, -C(O)NH aryl, -NHC(O) heteroaryl, -C(O)NH heteroaryl, -NHS(O)2C1-C6 straight-chain, branched, and cyclic alkyl groups, -S(O)2NHC1-C6 straight-chain, branched, and cyclic alkyl groups, -NHS(O)2 aryl, -S(O)2NH aryl, -NHS(O)2 heteroaryl, -S(O)2NH heteroaryl, -NHC(O)NHC1-C6 Straight-chain, branched, and cyclic alkyl groups; -NHC(O)NH aryl; -NHC(O)NH heteroaryl; C1-C6 straight-chain, branched, and cyclic alkyl groups; C2-C6 straight-chain, branched, and cyclic alkenyl groups; C1-C6 straight-chain, branched, and cyclic hydroxyalkyl groups; C1-C6 straight-chain, branched, and cyclic alkoxy groups; C1-C6 straight-chain, branched, and cyclic thioalkyl groups; C1-C6 straight-chain, branched, and cyclic haloalkyl groups; C1- C6 straight-chain, branched, and cyclic haloaminoalkyl; C1-C6 straight-chain, branched, and cyclic halothioalkyl; C1-C6 straight-chain, branched, and cyclic haloalkoxy; benzyloxy, benzylamino, or benzylthio; 3- to 6-membered heterocyclic alkenyl; 3- to 6-membered heterocyclic alkyl; and 5- and 6-membered heteroaryl; or two adjacent R1 or R2 groups together with the carbon atom to which they are attached to form C4-C8 cycloalkyl, aryl, or heteroaryl groups.

2. The compound according to claim 1, wherein its pharmaceutically acceptable salt, solvate, or deuterated derivative is characterized in that: X1 is selected from N; Y1 is selected from divalent C1-C8 straight-chain or branched alkyl groups, and is optionally substituted by at least one group selected from the following: C1-C6 alkyl, aryl, heteroaryl, halogen group, hydroxyl, or amino. Y2 is selected from NH or O; R1 and R2 can be one or more, each independently selected from: halogen groups, hydroxyl groups, thiol groups, amino groups, cyano groups, -OC(O)C1-C6 straight-chain, branched, and cyclic alkyl groups, -C(O)OC1-C6 straight-chain, branched, and cyclic alkyl groups, -NHC(O)C1-C6 straight-chain, branched, and cyclic alkyl groups, -C(O)NHC1-C6 straight-chain, branched, and cyclic alkyl groups, -NHC(O) aryl, -C(O)NH aryl, -NHC(O) heteroaryl, -C(O)NH heteroaryl, -NHS(O)2C1-C6 straight-chain, branched, and cyclic alkyl groups, -S(O)2NHC1-C6 straight-chain, branched, and cyclic alkyl groups, -NHS(O)2 aryl, -S(O)2NH aryl, -NHS(O)2 heteroaryl, -S(O)2NH heteroaryl, -NHC(O)NHC1-C6 Straight-chain, branched, and cyclic alkyl groups; -NHC(O)NH aryl; -NHC(O)NH heteroaryl; C1-C6 straight-chain, branched, and cyclic alkyl groups; C2-C6 straight-chain, branched, and cyclic alkenyl groups; C1-C6 straight-chain, branched, and cyclic hydroxyalkyl groups; C1-C6 straight-chain, branched, and cyclic alkoxy groups; C1-C6 straight-chain, branched, and cyclic thioalkyl groups; C1-C6 straight-chain, branched, and cyclic haloalkyl groups; C1- C6 straight-chain, branched, and cyclic haloaminoalkyl; C1-C6 straight-chain, branched, and cyclic halothioalkyl; C1-C6 straight-chain, branched, and cyclic haloalkoxy; benzyloxy, benzylamino, or benzylthio; 3- to 6-membered heterocyclic alkenyl; 3- to 6-membered heterocyclic alkyl; and 5- and 6-membered heteroaryl; or two adjacent R1 or R2 groups together with the carbon atom to which they are attached to form C4-C8 cycloalkyl, aryl, or heteroaryl groups.

3. The compound according to claim 1, wherein its pharmaceutically acceptable salt, solvate, isomer, polymorph, or deuterated derivative is characterized in that: Y1 is selected from methylene, ethylene, propylene, butylene, pentylene, and hexylene; Ar is selected from phenyl, pyridinyl, pyrimidinyl, naphthyl, pyrroleyl, N-methylpyrroleyl, thiophenyl, and optionally substituted with R2.

4. The compound according to claim 1, wherein its pharmaceutically acceptable salt, solvate, or deuterated derivative is characterized in that: R1 and R2 can be one or more, and can be independently selected from: fluorine, chlorine, bromine, and iodine.

5. The compound according to any one of claims 2-4, wherein its pharmaceutically acceptable salt, The solvate or deuterated derivative is characterized by: Y1 is selected from methylene, ethylene, propylene, butylene, pentylene, and hexylene; R1 and R2 can be one or more, and can be independently selected from: fluorine, chlorine, bromine, and iodine.

6. A pharmaceutically acceptable salt, solvate, isomer, polymorph, or deuterated derivative of a compound according to formula (Ia), characterized in that: The definition of substituents is the same as that in claims 1-5.

7. The use of the compounds according to claims 1-6, specifically their pharmaceutically acceptable salts, solvates, isomers, polymorphs, or deuterated derivatives, in the preparation of pharmaceuticals, characterized in that... The drug is used to treat diseases in which patients can benefit from the inhibition of human apolipoprotein L (APOL) protein.

8. The use according to claim 7, characterized in that, The human apolipoprotein L is human apolipoprotein L1 (APOL1).

9. The use according to claim 8, characterized in that, The disease is a kidney disease caused by abnormal human apolipoprotein L.

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