Compounds, pharmaceutical compositions and applications of complement factor D inhibitors

Abstract

This invention discloses a compound as an inhibitor of complement factor D, its pharmaceutical composition and application, and specifically discloses the compound represented by formula (I), its tautomer, its stereoisomer, its prodrug, or a pharmaceutically acceptable salt of any of the foregoing, or a solvate of any of the foregoing, which has good inhibitory activity against complement factor D and excellent pharmacokinetic and pharmacodynamic activities.

Description

Technical Field

[0001] This application claims priority to Chinese Patent Application No. 202111165838.2, filed on September 30, 2021, and Chinese Patent Application No. 202211160701.2, filed on September 22, 2022. The full text of the aforementioned Chinese patent applications is incorporated herein by reference.

[0002] This invention relates to the field of pharmaceuticals, and more particularly to compounds that can inhibit the activity of complement factor D, pharmaceutical compositions thereof, and applications. Prior Technology

[0003] Complement is a protein widely found in the serum, tissue fluid, and cell membrane surface of humans and vertebrates. It mediates immune and inflammatory responses, and is mostly a glycoprotein produced by various cells, including hepatocytes, macrophages, and intestinal mucosal epithelial cells. Complement is a necessary complement for antibodies to achieve their cytolytic effect, hence its name, but it actually mediates both specific and non-specific immunity. The complement system has three activation pathways: the classical pathway, the mannan-binding lectin pathway (MBL), and the alternative (bypass) pathway. Complement factor D plays an early and central role in the activation cascade of the complement bypass pathway. Activation of the complement bypass pathway is initiated by the spontaneous hydrolysis of the thioester bond in C3 to produce C3(H2O), which associates with factor B to form the C3(H2O)B complex. The role of complement factor D is to cleave factor B within the C3(H2O)B complex to form Ba and Bb. Besides binding with C3b to form C3 convertase, Bb also participates in the proliferation of pre-activated B lymphocytes, while Ba inhibits their proliferation. Factor D exhibits high locus in adipose tissue, stimulating glucose transport, promoting the accumulation of triglycerides in adipocytes, and inhibiting lipolysis.

[0004] Complement system dysregulation plays a crucial role in the pathogenesis of IgA nephropathy (IgAN), lupus nephritis (LN), and paroxysmal nocturnal hemoglobinuria (PNH). In the renal pathology of IgAN and LN, the deposition of complement components and immune complexes is frequently observed. Complement is a direct cause of hemolysis in PNH, while C5aR amplifies complement system damage. CFB and CFD are key components of the complement bypass pathway and directly participate in the regulation of complement activation. Therefore, C5aR, CFB, and CFD are closely related to the pathogenesis of IgAN, LN, and PNH.

[0005] Paroxysmal nocturnal hemoglobinuria (PNH) is a rare, life-threatening blood disorder characterized by complement-driven hemolysis, thrombosis, and bone marrow dysfunction, leading to anemia, fatigue, and other debilitating symptoms that severely impact patients' quality of life. Currently, the main drugs marketed for PNH are monoclonal antibodies, Soliris and Ultomiris. Soliris was first approved in 2007 and is now approved for several extremely rare diseases, including: paroxysmal nocturnal hemoglobinuria (PNH), atypical uremic hemolytic syndrome (aHUS), generalized myasthenia gravis (gMG), and neuromyelitis optica (NMOSD). Ultomiris is an upgraded version of Soliris, a second-generation, long-acting C5 complement inhibitor, first approved in late 2018, with approved indications including PNH and aHUS. Despite treatment with current anti-C5 standard of care, a large proportion of PNH patients remain anemic and dependent on blood transfusions.

[0006] Currently, there are no drugs on the market that are small molecule inhibitors of complement factor D. The target is the complement replacement pathway, which is a key driver of complement-driven kidney disease (CDRD). Therefore, developing small molecule inhibitors with good bioactivity is of positive significance for the treatment of the above-mentioned diseases. Summary of the Invention

[0007] The present invention addresses the technical problem of the limited variety of small molecule inhibitors of complement factor D. To this end, the present invention provides a compound as an inhibitor of complement factor D, its pharmaceutical composition, and its application. This compound exhibits excellent inhibitory activity against complement factor D, as well as superior pharmacokinetic and pharmacodynamic activity.

[0008] This invention provides a pharmaceutically acceptable salt of a compound of formula (I), its tautomers, its stereoisomers, its prodrugs, or any of the foregoing (referring to the compound of formula (I), its tautomers, its stereoisomers, or its prodrugs), or a solvate of any of the foregoing (referring to the compound of formula (I), its tautomers, its stereoisomers, its prodrugs, or any of the foregoing pharmaceutically acceptable salts): (I) in: R1 is H, D, C1-6 alkyl, or a C1-6 alkyl substituted with 1, 2, or 3 R1-1; each R1-1 is independently a halogen, -CN, -OH, C1-6 alkoxy, or -NH2; R2 and R3 are each independently H, D, halogen, C1-6 alkyl, or C1-6 alkyl substituted with 1, 2, or 3 R2-1; each R2-1 is independently halogen, -CN, -OH, C1-6 alkoxy, or -NH2; R4 is H or a halogen; m is 0, 1, 2 or 3; R5 and R7 are each independently H, halogen, -CN, C1-6 alkyl, or C1-6 alkoxy; R6 is a C7-12 cycloalkyl group, a C7-12 cycloalkyl group substituted with 1, 2, or 3 R6-1 atoms, a 7-12 membered heterocyclic alkyl group having 1, 2, or 3 heteroatoms selected from N, O, and S, or having 1, 2, or 3 heteroatoms; or a 7-12 membered heterocyclic alkyl group substituted with 1, 2, or 3 R6-2 atoms. R 6-1 and R 6-2 are each independently hydroxyl, oxo (=O), halogen, C1-6 alkyl, C1-6 alkoxy, C1-6 haloalkyl, C1-6 haloalkoxy, C3-6 cycloalkyl, or -(CH2)pC3-6 cycloalkyl; p is 1, 2, 3, or 4; In R 6, R 6-1, and R 6-2, the cycloalkyl group is independently a monocyclic, bridged, or spirocyclic ring; In R 6, the heterocyclic alkyl group is a monocyclic, bridged, or spirocyclic ring; R8 is H, halogen, or C1-6 alkyl; R9 is H, halogen, C1-6 alkyl, or a C1-6 alkyl substituted with 1, 2, or 3 R9-1 atoms; Each R 9-1 is independently a halogen, -CN, -OH, or -NH 2; n is 0, 1, 2, 3, or 4; L is -(CR aR b) q-; q is 0, 1, 2, or 3; Ra and Rb are each independently H, D, or halogen, or Ra and Rb are linked together to form a C3-6 cycloalkylene ring, which can be monocyclic, bridged, or spirocyclic. R 10 is -COOH or -C(=O)OR c; Rc is a C1-6 alkyl group or a C1-6 alkyl group substituted with 1, 2 or 3 Rc-1 groups; each Rc-1 group is independently a halogen, -OH or -C(=O)OC(CH3)3; X is CR d or N; R d is H, halogen, or C1-6 alkyl.

[0009] In one aspect of the present invention, the compound represented by formula (I) has the structure shown in formula (I-1): (I-1) The definitions of R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, Rd, L, m, and n are as described in any one of the present invention.

[0010] In one aspect of the present invention, the compound represented by formula (I) has the structure shown in formula (I-2): (I-2) The definitions of R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, L, m, and n are as described in any one of the present invention.

[0011] In one aspect of the present invention, the compound represented by formula (I) has the structure shown in formula (I-3): (I-3) Wherein, X, R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, L and n are defined as described in any one of the present invention.

[0012] In one aspect of the present invention, the compound represented by formula (I) has the structure shown in formula (I-4): (I-4) Wherein, X, R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, L, m, and n are defined as described in any one of the present invention; When the carbon atom marked is a chiral carbon atom, it indicates the R configuration, S configuration, or a mixture thereof.

[0013] In certain preferred embodiments of the present invention, certain groups in the compound of formula (I), its tautomers, its stereoisomers, its prodrugs, or pharmaceutically acceptable salts of any of the foregoing (referring to the compound of formula (I), its tautomers, its stereoisomers, or its prodrugs), or solvates of any of the foregoing (referring to the compound of formula (I), its tautomers, its stereoisomers, its prodrugs, or pharmaceutically acceptable salts of any of the foregoing) are defined as follows, and groups not mentioned are as described in any embodiment of the present invention (hereinafter referred to as "in a certain embodiment of the present invention").

[0014] In one embodiment of the present invention, R1 is H.

[0015] In one embodiment of the present invention, R2 and R3 are each independently H, C1-6 alkyl, or C1-6 alkyl substituted by 1, 2, or 3 R2-1; each R2-1 is independently a halogen or -OH, wherein the halogen is preferably F.

[0016] In one embodiment of the present invention, R2 and R3 are each independently H, C1-3 alkyl, or C1-3 alkyl substituted by 1, 2, or 3 R2-1; each R2-1 is independently a halogen or -OH, wherein the halogen is preferably F.

[0017] In one embodiment of the present invention, m is 0 or 1.

[0018] In one embodiment of the present invention, R6 is "an 8-11-membered heterocyclic alkyl group selected from one, two, or three of N, O, and S, with one, two, or three heteroatoms" or "an 8-11-membered heterocyclic alkyl group selected from one, two, or three of N, O, and S, with one, two, or three heteroatoms substituted by one, two, or three R6-2", wherein the 8-11-membered heterocyclic alkyl group is 6-azaspiro[2.5]octyl, 5-azaspiro[2.5]octyl, 6-azaspiro[3.4]octyl, 2-azaspiro[3.4]octyl, 2-oxa-6-azaspiro[3.4]octyl, 6-oxa-2-azaspiro[3.4]octyl, 4-oxa-7-azaspiro[2.5]octyl, 2-azaspiro[ 4.4] Nonyl, 2-azaspiro[3.5]nonyl, 2-oxa-7-azaspiro[3.5]nonyl, 1-oxa-7-azaspiro[3.5]nonyl, 7-azaspiro[3.5]nonyl, 2,7-diazaspiro[3.5]nonyl, 2-oxa-8-azaspiro[4.5]decyl, 3-oxa-9-azaspiro[5.5]undecyl, 2-oxa-9-azaspiro[5.5]undecyl, 3,9-diazaspiro[5.5]undecyl or 3-azabicyclo[3.2.1]octyl.

[0019] In one embodiment of the present invention, R6 is "an 8-11 membered heterocyclic alkyl group selected from one, two, or three of N, O, and S, with one, two, or three heteroatoms" or surrounded by one, two, or three R6 atoms. The 6-2 substituted "heteroatoms selected from one, two, or three of N, O, and S, and the number of heteroatoms being one, two, or three, of an 8-11-membered heterocyclic alkyl group", wherein the 8-11-membered heterocyclic alkyl group is 6-azaspiro[2.5]octyl, 5-azaspiro[2.5]octyl, 6-azaspiro[3.4]octyl, 2-azaspiro[3.4]octyl, 2-oxa-6-azaspiro[3.4]octyl, 6-oxa-2-azaspiro[3.4]octyl, 4-oxa-7-azaspiro[2.5]octyl, 2-azaspiro[4.4]nonyl, 2-azaspiro[3.5]nonyl, 2-oxa-7-azaspiro[2.5]octyl, 7-azaspiro[3.5]nonyl, 1-oxa-7-azaspiro[3.5]nonyl, 7-azaspiro[3.5]nonyl, 2,7-diazaspiro[3.5]nonyl, 2-oxa-8-azaspiro[4.5]decyl, 3-oxa-9-azaspiro[5.5]undecyl, 2-oxa-9-azaspiro[5.5]undecyl, 3,9-diazaspiro[5.5]undecyl, 3-azabicyclo[3.2.1]octyl, 3-azaspiro[5.5]undecyl, 8-azaspiro[4.5]decyl or 1-oxa-6-azaspiro[3.4]octyl.

[0020] In one embodiment of the present invention, R5 and R7 are each independently H or a halogen, wherein the halogen is preferably F.

[0021] In one embodiment of the present invention, each R6-2 is independently a hydroxyl group or a C1-6 alkyl group, wherein the C1-6 alkyl group is preferably a methyl group.

[0022] In one embodiment of the present invention, each R 6-2 is independently hydroxyl or C 1-3 alkyl, preferably, each R 6-2 is independently hydroxyl, methyl, ethyl, n-propyl or isopropyl.

[0023] In one embodiment of the present invention, R 8 is H.

[0024] In one embodiment of the present invention, R9 is H or a halogen, preferably F.

[0025] In one embodiment of the present invention, n is 0 or 1.

[0026] In one embodiment of the present invention, q is 1.

[0027] In one embodiment of the present invention, Ra and Rb are each independently H.

[0028] In one embodiment of the present invention, R 10 is -COOH.

[0029] In one embodiment of the present invention, Rd is H.

[0030] In one embodiment of the present invention, R6 is "an 8-10 membered heterocyclic alkyl group selected from 1, 2 or 3 of N, O and S, with 1, 2 or 3 heteroatoms" or "an 8-10 membered heterocyclic alkyl group selected from 1, 2 or 3 of N, O and S, with 1, 2 or 3 heteroatoms replaced by 1, 2 or 3 R6-2", wherein the heterocyclic alkyl group is a bridged ring or a spiro ring.

[0031] In one embodiment of the present invention, R6 is "an 8-11 membered heterocyclic alkyl group selected from 1, 2 or 3 of N, O and S, with 1, 2 or 3 heteroatoms" or "an 8-11 membered heterocyclic alkyl group selected from 1, 2 or 3 of N, O and S, with 1, 2 or 3 heteroatoms replaced by 1, 2 or 3 R6-2", wherein the heterocyclic alkyl group is a bridged ring or a spiro ring.

[0032] In one embodiment of the present invention, R1 is H; R2 and R3 are each independently H, a C1-3 alkyl group, or a C1-3 alkyl group substituted with 1, 2, or 3 R2-1 groups; each R2-1 group is independently a halogen or -OH. R4 represents H or a halogen; m represents 0 or 1; R5 and R7 are each independently H or halogen; R6 is "an 8-11 membered heterocyclic alkyl group selected from one, two, or three of N, O, and S, with one, two, or three heteroatoms" or "an 8-11 membered heterocyclic alkyl group selected from one, two, or three of N, O, and S, with one, two, or three heteroatoms substituted by one, two, or three R6-2", wherein the heterocyclic alkyl group is a bridged ring or a spiro ring; Each R 6-2 is independently a hydroxyl group or a C 1-3 alkyl group; R 8 is H; R9 represents H or a halogen; n represents 0 or 1; L is -(CR aR b) q-, q is 1; Ra and R b are each independently H; R 10 is -COOH; X is CR d or N; R d is H.

[0033] In one embodiment of the present invention, in R1, R2, R3, R5, R7, R6-1, R6-2, R8, R9, Rc and Rd, each of the alkyl groups is independently methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl or tributyl, preferably methyl or ethyl.

[0034] In one embodiment of the present invention, in R1-1, R2-1, R5, R7, R6-1 and R6-2, each of the alkoxy groups is independently methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy or tert-butoxy.

[0035] In one embodiment of the present invention, each of the halogens in R1-1, R2, R3, R2-1, R4, R5, R7, R6-1, R6-2, R8, R9, R9-1, Ra, Rb, Rc-1 and Rd is independently F, Cl, Br or I, preferably F.

[0036] In one embodiment of the present invention, in R6, each of the heterocyclic alkyl groups is independently "an 8-11 membered heterocyclic alkyl group whose heteroatoms are selected from one, two, or three of N, O, and S, and whose number of heteroatoms is one or two", and the heterocyclic alkyl group is a bridged ring or a spiro ring; preferably, the heterocyclic alkyl group is connected to the parent compound through an N atom; the heterocyclic alkyl group is preferably... , , , , , , , , , , , , , , , , , , , or .

[0037] In one embodiment of the present invention, R6 is... , , , , , , , , , , , , , , , , , , , , , , or .

[0038] In one embodiment of the present invention, R2 is H, and R3 is H, -CH3, -CH2OH, -CH2CH2OH, -CH2F, or -CF2H.

[0039] In one embodiment of the present invention, R1 is H; R2 is H, R3 is H, -CH3, or -CH2F; R4 is H or a halogen, and m is 0 or 1; R5 and R7 are each independently H or F; R 6 is "an 8-11 membered heterocyclic alkyl group selected from one, two, or three of N, O, and S, with one, two, or three heteroatoms" or "an 8-11 membered heterocyclic alkyl group selected from one, two, or three of N, O, and S, with one, two, or three heteroatoms substituted by one, two, or three R 6-2"; Each R 6-2 is independently a hydroxyl group or a C 1-3 alkyl group; R 8 is H; R9 represents H or F; n represents 0 or 1; L is -(CR aR b) q-; q is 1; R a and R b are each independently H; R 10 is -COOH; X is CR d or N; R d is H.

[0040] In one embodiment of the present invention, R1 is H; R2 is H, R3 is H, -CH3, or -CH2F; R4 is H or a halogen, and m is 0 or 1; R5 and R7 are each independently H; R 6 is "an 8-10 membered heterocyclic alkyl group selected from one, two, or three of N, O, and S, with one, two, or three heteroatoms" or "an 8-10 membered heterocyclic alkyl group substituted with one, two, or three R 6-2 groups"; R 6-2 is a hydroxyl group; R 8 is H; R9 represents H or F; n represents 0 or 1; L is -(CR aR b) q-; q is 1; R a and R b are each independently H; R 10 is -COOH; X is CR d; R d is H.

[0041] In one embodiment of the present invention, R1 is H; R2 is H, R3 is H, -CH3, or -CH2F; R4 is H or a halogen, and m is 0 or 1; R5 and R7 are each independently H or F; R 6 is "an 8-10 membered heterocyclic alkyl group selected from one, two, or three of N, O, and S, with one, two, or three heteroatoms" or "an 8-10 membered heterocyclic alkyl group substituted with one, two, or three R 6-2 groups"; Each R 6-2 is independently a C 1-3 alkyl group; R 8 is H; R9 represents H or F; n represents 0 or 1; L is -(CR aR b) q-; q is 1; R a and R b are each independently H; R 10 is -COOH; X is CR d or N; R d is H.

[0042] In one embodiment of the present invention, R1 is H; R2 is H, R3 is H, -CH3, or -CH2F; R4 is H or a halogen, and m is 0 or 1; R5 and R7 are each independently H or F; R 6 is "an 8-10 membered heterocyclic alkyl group selected from one, two, or three of N, O, and S, with one, two, or three heteroatoms" or "an 8-10 membered heterocyclic alkyl group substituted with one, two, or three R 6-2 groups"; Each R 6-2 is independently a hydroxyl group or a C 1-3 alkyl group; R 8 is H; R9 represents H or F; n represents 0 or 1; L is -(CR aR b) q-; q is 1; R a and R b are each independently H; R 10 is -COOH; X is CR d or N; R d is H.

[0043] In one embodiment of the present invention, R1 is H; R2 is H, R3 is H, -CH3, or -CH2F; R4 is H or a halogen, and m is 0 or 1; R5 and R7 are each independently H; R 6 is , , , , , , , , , , , , , , , , , , , , Or the following groups may be substituted by one R 6-2: , , , , , , , , , , , , , , , , , , , or ; R 6-2 is a hydroxyl group; R 8 is H; R9 represents H or F; n represents 0 or 1; L is -(CR aR b) q-; q is 1; R a and R b are each independently H; R 10 is -COOH; X is CR d; R d is H.

[0044] In one embodiment of the present invention, R1 is H; R2 is H, R3 is H, -CH3, or -CH2F; R4 is H or a halogen, and m is 0 or 1; R5 and R7 are each independently H or F; R 6 is , , , , , , , , , , , , , , , , , , , , Or the following groups may be substituted by one R 6-2: , , , , , , , , , , , , , , , , , , , or ; R6-2 is methyl; R 8 is H; R9 represents H or F; n represents 0 or 1; L is -(CR aR b) q-; q is 1; R a and R b are each independently H; R 10 is -COOH; X is CR d or N; R d is H.

[0045] In one embodiment of the present invention, R1 is H; R2 is H, R3 is H, -CH3, or -CH2F; R4 is H or a halogen, and m is 0 or 1; R5 and R7 are each independently H or F; R 6 is , , , , , , , , , , , , , , , , , , , , Or the following groups may be substituted by one R 6-2: , , , , , , , , , , , , , , , , , , , or ; R 6-2 is a hydroxyl or methyl group; R 8 is H; R9 represents H or F; n represents 0 or 1; L is -(CR aR b) q-; q is 1; R a and R b are each independently H; R 10 is -COOH; X is CR d or N; R d is H.

[0046] In one embodiment of the present invention, R1 is H; R2 is H, R3 is H, -CH3, or -CH2F; R4 represents H or F, and m represents 0 or 1; R5 and R7 are each independently H or F; R 6 is , , , , , , , , , , , , , , , , , , , , or ; R 8 is H; R9 represents H or F; n represents 0 or 1; L is -(CR aR b) q-; q is 1; R a and R b are each independently H; R 10 is -COOH; X is CR d or N; R d is H.

[0047] In one aspect of the present invention, the compound represented by formula (I) is selected from any of the following compounds: , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , or .

[0048] In one aspect of the present invention, the compound represented by formula (I) is selected from any of the following compounds: , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , or .

[0049] The present invention also provides a method for preparing the compound represented by formula (I), which includes the following steps: (1) The compound shown in formula II-3 undergoes a deprotection reaction to yield the compound shown in formula II-4; (2) The compound shown in formula II-4 is hydrolyzed to obtain the compound shown in formula (I); Wherein, R10 is -COOH, and the definitions of R1, R2, R3, R4, R5, R6, R7, R8, R9, Rc, X, L, m and n are as described in any embodiment of the present invention. The conditions and operations of the above deprotection reaction and hydrolysis reaction can be as common in the art for such reactions. Preferably, R1 is H.

[0050] In one aspect of the present invention, the method for preparing the compound represented by formula (I) includes the following steps: Wherein, R10 is -COOH, and the definitions of R1, R2, R3, R4, R5, R6, R7, R8, R9, Rc, X, L, m and n are as described in any embodiment of the present invention. The conditions and operations of the above reaction can be as common in the art for such reactions. Preferably, R1 is H.

[0051] The present invention also provides compounds as shown in Formula II-3 or Formula II-4: or The definitions of R1, R2, R3, R4, R5, R6, R7, R8, R9, X, L, Rc, m, and n are as described in any embodiment of the present invention.

[0052] In one embodiment of the present invention, in the compound represented by formula II-3 or formula II-4, R1 is H.

[0053] The present invention also provides any of the following compounds: , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , or .

[0054] The present invention also provides a pharmaceutical composition comprising: (1) A pharmaceutically acceptable salt of a compound of formula (I) as described in any of the preceding claims, its tautomers, its stereoisomers, its prodrugs, or any of the foregoing (referring to a compound of formula (I), its tautomers, its stereoisomers, or its prodrugs), or a solvate of any of the foregoing (referring to a compound of formula (I), its tautomers, its stereoisomers, its prodrugs, or any of the foregoing pharmaceutically acceptable salts); and (2) Pharmaceutically acceptable carrier.

[0055] The present invention also provides the use of a compound of formula (I) as described in any of the preceding claims, its tautomers, its stereoisomers, its prodrugs, or a pharmaceutically acceptable salt of any of the foregoing (referring to the compound of formula (I), its tautomers, its stereoisomers, or its prodrugs), or a solvate of any of the foregoing (referring to the compound of formula (I), its tautomers, its stereoisomers, its prodrugs, or a pharmaceutically acceptable salt of any of the foregoing), or a pharmaceutical composition as described in any of the preceding claims, in the preparation of a medicament for treating and / or preventing complement factor D-mediated diseases.

[0056] The present invention also provides a method for treating and / or preventing complement factor D-mediated diseases, comprising: administering to an individual in need a therapeutically effective amount of substance X or a pharmaceutical composition as described in any of the preceding claims, said substance X being a compound of formula (I) as described in any of the preceding claims, its tautomer, its stereoisomer, its prodrug, or a pharmaceutically acceptable salt of any of the foregoing (referring to the aforementioned compound of formula (I), its tautomer, its stereoisomer, or its prodrug), or a solvate of any of the foregoing (referring to the aforementioned compound of formula (I), its tautomer, its stereoisomer, its prodrug, or a pharmaceutically acceptable salt of any of the foregoing).

[0057] In one embodiment of the present invention, the diseases mediated by complement factor D include blood diseases, kidney diseases, cardiovascular diseases, immune disorders, central nervous system diseases, respiratory diseases, genitourinary system diseases, or eye diseases. Preferably, the diseases mediated by complement factor D are, for example, blood diseases, kidney diseases, cardiovascular diseases, immune disorders, central nervous system diseases, or eye diseases.

[0058] In one embodiment of the present invention, the complement factor D-mediated diseases include cold agglutinin disease, catastrophic antiphospholipid syndrome, hemolytic anemia, anti-neutrophil cell cytoplasmic antibody (ANCA)-associated vasculitis (AAV), warm antibody-type autoimmune hemolytic anemia, paroxysmal nocturnal hemoglobinuria, IgA nephropathy, lupus nephritis, atypical uremic hemolytic syndrome, membranous proliferative glomerulonephritis (MPGN), dense deposit disease, C3 glomerulonephritis, focal segmental glomerulosclerosis, diabetic nephropathy, systemic lupus erythematosus or lupus erythematosus, rheumatoid arthritis, inflammatory bowel disease, psoriasis, multiple sclerosis, organ transplant rejection, myasthenia gravis, Alzheimer's disease, respiratory distress syndrome, and asthma. Asthma, chronic obstructive pulmonary disease, emphysema, coronavirus infection (such as SARS-CoV, MERS-CoV, or SARS-CoV-2 infection), macular degeneration, age-related macular degeneration (AMD), macular edema, diabetic macular edema, choroidal neovascularization (CNV), uveitis, Behcet's uveitis, proliferative diabetic retinopathy, non-proliferative diabetic retinopathy, glaucoma, hypertensive retinopathy, corneal neovascularization, corneal transplant rejection, corneal dystrophy, autoimmune dry eye disease, Stephens-Johnson syndrome, Sjögren's syndrome, environmental dry eye disease, Fehling's endothelial dystrophy, retinal vein occlusion, or postoperative inflammation.

[0059] In other embodiments of the present invention, the immune diseases include: lupus, allogeneic transplant rejection, autoimmune thyroid diseases (such as Graves' disease and Hashimoto's thyroiditis), autoimmune uveitis, giant cell arteritis, inflammatory bowel diseases (including Crohn's disease, ulcerative colitis, regional enteritis, granulomatous enteritis, terminal ileitis, regional ileitis and terminal ileitis), diabetes, multiple sclerosis, pernicious anemia, psoriasis, rheumatoid arthritis, sarcoidosis and scleroderma, etc.

[0060] Furthermore, the diseases mediated by complement factor D include, but are not limited to, paroxysmal nocturnal hemoglobinuria, IgA nephropathy, lupus nephritis, atypical uremic hemolytic syndrome, organ transplant rejection, myasthenia gravis, neuromyelitis optica, membranous proliferative glomerulonephritis, dense deposit disease, cold agglutinin disease and catastrophic antiphospholipid syndrome, C3 glomerulonephritis and focal segmental glomerulosclerosis, macular degeneration, age-related macular degeneration (AMD), macular edema, diabetic macular edema, etc.

[0061] The present invention also provides the use of a compound of formula (I) as described in any of the preceding claims, its tautomers, its stereoisomers, its prodrugs, or a pharmaceutically acceptable salt of any of the foregoing (referring to the compound of formula (I), its tautomers, its stereoisomers, or its prodrugs), or a solvate of any of the foregoing (referring to the compound of formula (I), its tautomers, its stereoisomers, its prodrugs, or a pharmaceutically acceptable salt of any of the foregoing), or a pharmaceutical composition as described in any of the preceding claims, in the preparation of a complement factor D inhibitor medicament.

[0062] In the aforementioned applications, the complement factor D inhibitor drug can be used in mammalian organisms; it can also be used in vitro, primarily for experimental purposes, such as providing a standard or control sample for comparison, or preparing kits according to conventional methods in the art to provide rapid detection of the complement factor D inhibition effect.

[0063] Unless otherwise specified, the terms used in this invention have the following meanings.

[0064] Those skilled in the art will understand that, according to conventions used in the art, the use of "" in the structural formulas describing the functional groups in this invention is appropriate. "" refers to the fact that the corresponding group is connected to other fragments or groups in the compound through this site.

[0065] In this document, a hyphen "-" may be added before the substituents used to indicate that the named substituent is linked to the parent moiety by a single bond. When the linking groups listed in this invention do not specify their linking direction, the linking direction is the same as the reading order from left to right.

[0066] The term "pharmaceutically acceptable" means that salts, solvents, adjuvants, etc., are generally non-toxic, safe, and suitable for patient use. The term "patient" preferably refers to a mammal, more preferably a human. The term "mammal" includes any mammal. Examples of mammals include, but are not limited to, cattle, horses, sheep, pigs, cats, dogs, mice, rats, rabbits, guinea pigs, monkeys, and humans.

[0067] The term "pharmaceutically acceptable salt" refers to a salt prepared from the compounds of the present invention with a relatively non-toxic, pharmaceutically acceptable acid or base. When the compounds of the present invention contain relatively acidic functional groups, base addition salts can be obtained by contacting a sufficient amount of a pharmaceutically acceptable base with the neutral form of such compounds in a pure solution or a suitable inert solvent. Pharmaceutically acceptable base addition salts include, but are not limited to: lithium salts, sodium salts, potassium salts, calcium salts, aluminum salts, magnesium salts, zinc salts, bismuth salts, ammonium salts, and diethanolamine salts. When the compounds of the present invention contain relatively basic functional groups, acid addition salts can be obtained by contacting a sufficient amount of a pharmaceutically acceptable acid with the neutral form of such compounds in a pure solution or a suitable inert solvent. The pharmaceutically acceptable acids include inorganic acids, including but not limited to: hydrochloric acid, hydrobromic acid, hydroiodic acid, nitric acid, carbonic acid, phosphoric acid, phosphorous acid, sulfuric acid, etc. The pharmaceutically acceptable acids include organic acids, including but not limited to: acetic acid, propionic acid, oxalic acid, isobutyric acid, maleic acid, malonic acid, benzoic acid, succinic acid, octanoic acid, fumaric acid, lactic acid, mandelic acid, phthalic acid, benzenesulfonic acid, p-toluenesulfonic acid, citric acid, salicylic acid, tartaric acid, methanesulfonic acid, isonicotinic acid, acidic citric acid, oleic acid, tannic acid, pantothenic acid, hydrogen tartrate, ascorbic acid, gentic acid, fumaric acid, gluconic acid, succinic acid, formic acid, ethanesulfonic acid, dihydroxynaphthyl acid (i.e., 4,4'-methylene-bis(3-hydroxy-2-naphthylcarboxylic acid)), amino acids (e.g., glutamic acid, arginine), etc. When the compounds of the present invention contain relatively acidic and relatively basic functional groups, they can be converted into base addition salts or acid addition salts. For details, see Berge et al., "Pharmaceutical Salts", Journal of Pharmaceutical Science 66: 1-19 (1977) or Handbook of Pharmaceutical Salts: Properties, Selection, and Use (P. Heinrich Stahl and Camille G. Wermuth, ed., Wiley-VCH, 2002).

[0068] The term "solvent" refers to a substance formed by the combination of the compound of this invention with a stoichiometric or non-stoichiometric solvent. Solvent molecules in a solvate can exist in an ordered or disordered arrangement. The solvents include, but are not limited to, water, methanol, and ethanol.

[0069] The terms "pharmaceutically acceptable salt" and "solvent" in the term "solvent of a pharmaceutically acceptable salt" refer, as described above, to substances formed by (1) the preparation of the compound of the present invention with a relatively non-toxic, pharmaceutically acceptable acid or base, and (2) by combination with a stoichiometric or non-stoichiometric solvent. The "solvent of a pharmaceutically acceptable salt" includes, but is not limited to, hydrochloric acid monohydrates of the compound of the present invention.

[0070] When any variable (e.g., R1-1) appears multiple times in the definition of a compound, the definition of that variable at each position is independent of its definitions at other positions; their meanings are mutually independent and do not affect each other. Therefore, if a group is substituted by one, two, or three R1-1 groups—that is, if the group may be substituted by a maximum of three R1-1 groups—the definition of R1-1 at that position is independent of the definitions of R1-1 at other positions. Furthermore, combinations of substituents and / or variables are only permitted if the combination produces a stable compound.

[0071] The term "A-membered," where A is an integer, typically describes the number of ring-forming atoms in a cycloalkyl group. For example, piperidinyl is an example of a 6-membered heterocyclic alkyl group, cyclopropyl is an example of a 3-membered cycloalkyl group, and phenyl is an example of a 6-membered aryl group, etc.

[0072] The term "AB-ary", where A and B are integers, describes the number of cyclic atoms in a range from A to B.

[0073] The term "halogen" refers to fluorine, chlorine, bromine, or iodine.

[0074] The term "alkyl" refers to a straight-chain or branched saturated hydrocarbon group having a specified number of carbon atoms. In some embodiments, the alkyl group is a C1-6 alkyl group, such as a C1-5 alkyl group, a C1-4 alkyl group, a C1-3 alkyl group, a C1-2 alkyl group, etc.; in other embodiments, the alkyl group is a C1-3 alkyl group. Examples of alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, tributyl, isobutyl, dibutyl, n-pentyl, n-hexyl, and similar alkyl groups.

[0075] The term "alkoxy" refers to the group -OR X, where RX is an alkyl group as defined above.

[0076] The term "cycloalkyl" refers to a saturated, monocyclic, bridged, or spirocyclic group having a specified number of carbon atoms in the ring (e.g., C3-6, C7-12) and consisting only of carbon atoms. Monocyclic alkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.

[0077] The term "cycloalkylene" refers to a saturated, monocyclic, bridged, or spirocyclic cyclic alkane with a specified number of carbon atoms in the ring (e.g., C3-6, C7-12), consisting only of carbon atoms, formed by eliminating two hydrogen atoms. The two eliminated hydrogen atoms can be on the same atom or on different atoms. Monocyclic alkylene includes, but is not limited to, cyclopropylene (e.g., cycloalkylene). or ), cyclobutylene (e.g.) , or ), cyclopentylene (e.g.) , or ), cyclohexylene (e.g.) , , or )wait.

[0078] The term "heterocyclic alkyl" refers to a saturated cyclic group having a specified number of ring atoms (e.g., 7-12 ring atoms) and whose ring atoms contain at least one heteroatom independently selected from nitrogen, oxygen, and sulfur, and is a monocyclic, bridged, or spirocyclic system. Preferably, the number of heteroatoms in the heterocyclic alkyl group is one, two, or three. The carbon atoms and heteroatoms of the heterocyclic alkyl group may optionally be oxidized to form oxo groups or sulfide groups or other oxidized bonds (e.g., C(=O), S(=O), S(=O)₂, or N-oxides, etc.), or the nitrogen atom may be quaternized. Heterocyclic alkyl groups can be linked to other segments or groups in the compound through cyclic carbon atoms or cyclic heteroatoms. In some embodiments, the heterocyclic alkyl group is an 8-11 membered heterocyclic alkyl group with one, two, or three heteroatoms selected from N, O, and S, and having one or two heteroatoms; in other embodiments, the heterocyclic alkyl group is an 8-10 membered heterocyclic alkyl group with one, two, or three heteroatoms selected from N, O, and S, and having one or two heteroatoms. Heterocyclic alkyl groups include, but are not limited to, azirrobutyl, tetrahydropyrrolyl, tetrahydrofuranyl, morpholinyl, piperidinyl, 6-azaspiro[2.5]octyl, 5-azaspiro[2.5]octyl, 6-azaspiro[3.4]octyl, 2-azaspiro[3.4]octyl, 2-oxa-6-azaspiro[3.4]octyl, 6-oxa-2-azaspiro[3.4]octyl, 4-oxa-7-azaspiro[2.5]octyl, 2-azaspiro[4.4]nonyl, 2-azaspiro[3.5]nonyl, and 2-oxa-7-azaspiro[3.5]nonyl. , 1-oxa-7-azaspiro[3.5]nonyl, 7-azaspiro[3.5]nonyl, 2,7-diazaspiro[3.5]nonyl, 2-oxa-8-azaspiro[4.5]decyl, 3-oxa-9-azaspiro[5.5]undecyl, 2-oxa-9-azaspiro[5.5]undecyl, 3,9-diazaspiro[5.5]undecyl, 3-azabicyclo[3.2.1]octyl, 3-azaspiro[5.5]undecyl, 8-azaspiro[4.5]decyl, 1-oxa-6-azaspiro[3.4]octyl, etc.

[0079] The term "pharmaceuticalally acceptable carrier" refers to excipients and additives used in the manufacture and dispensing of pharmaceutical products; these are all substances contained in pharmaceutical preparations, excluding the active ingredient. See Volume IV of the Pharmacopoeia of the People's Republic of China (2015 Edition) or the Handbook of Pharmaceutical Excipients (Raymond C Rowe, 2009 Sixth Edition).

[0080] The term “treatment” refers to a therapeutic approach. When a specific condition is involved, treatment means: (1) alleviating one or more biological manifestations of the disease or condition; (2) interfering with (a) one or more points in a biological cascade that causes or induces the condition or (b) one or more biological manifestations of the condition; (3) improving one or more symptoms, effects or side effects associated with the condition, or one or more symptoms, effects or side effects associated with the condition or its treatment; or (4) slowing the development of the condition or one or more biological manifestations of the condition.

[0081] The term "prevention" refers to the reduction of the risk of acquiring or developing a disease or disorder.

[0082] The term "therapeutic effective amount" refers to an amount of compound sufficient to effectively treat the disease or condition described herein when administered to a patient. The "therapeutic effective amount" will vary depending on the compound, the condition and its severity, and the age of the patient to be treated, but may be adjusted as needed by those skilled in the art.

[0083] Without violating common sense in the field, the above-mentioned preferred conditions can be combined arbitrarily to obtain various preferred embodiments of the present invention.

[0084] The reagents and raw materials used in this invention are all commercially available.

[0085] The positive and progressive effects of this invention are as follows: the compounds of this invention have excellent inhibitory activity against complement factor D (the IC50 values ​​of the compounds in the examples against C3b are 0.01-100 nM), excellent inhibitory effect on rabbit erythrocyte hemolysis (the IC50 values ​​of rabbit erythrocyte hemolysis are 0.1-500 nM), and excellent pharmacokinetic and pharmacodynamic activities. Implementation

[0086] The present invention is further illustrated below by way of embodiments, but the invention is not limited to the scope of the embodiments described herein. Experimental methods in the following embodiments that do not specify specific conditions were performed according to conventional methods and conditions, or as selected according to the product instructions.

[0087] The terms used in the following specific experimental descriptions represent (unless otherwise stated) the following reagents or procedures: (Boc)₂O: dibutyl dicarbonate; B₂Pin₂: pinacol diboronate; DIAD: diisopropyl azodicarbonate; DMF: N,N-dimethylformamide; DCM: dichloromethane; DIEA: N,N-diisopropylethylamine; Et₃N: triethylamine; EA: ethyl acetate; IV: intravenous injection; KOAc: potassium acetate; MeOH: methanol; MeCN: acetonitrile; PPh₃: triphenylphosphine; Pd₂(dba)₃: tris(dibenzylacetone)palladium; Pd(dppf)Cl₂: [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride; Pd(PPh₃) 4: Tetra(triphenylphosphine)palladium; PO: Oral administration; TEA: Triethylamine; TFA: Trifluoroacetic acid; THF: Tetrahydrofuran; X-Phos: 2-Dicyclohexylphosphine-2',4',6'-Triisopropylbiphenyl.

[0088] <Preparation Examples>

[0089] Example 1: Synthesis of 2-(2-((3'-(aminomethyl)-5-(6-azaspiro[2.5]octane-6-yl)-[1,1'-biphenyl]-3-yl)methoxy)phenyl)acetic acid (compound 001)

[0090] 1.1 Synthesis of Compound 001-1 001-a (11.16 g, 60 mmol), triethylamine (11.00 g, 108 mmol), and dichloromethane (120 mL) were added to a 500 mL reaction flask. Dibutyl dicarbonate (15.71 g, 72 mmol) was added to the system under ice bath conditions. The reaction mixture was reacted at 0 °C for 1 hour, then concentrated under reduced pressure. The solution was transferred to a 500 mL separatory funnel, and 150 mL of ethyl acetate and 200 mL of water were added. The mixture was extracted and separated to obtain the organic phase. The aqueous phase was then extracted again with ethyl acetate (50 mL × 2). The combined organic phases were washed with saturated sodium chloride solution, 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 = 10 / 1 (v / v)) to obtain compound 001-1, which was used directly in the next step.

[0091] 1.2 Synthesis of Compound 001-2 Compound 001-1 (18.02 g, 60 mmol) obtained in step 1.1, pinacol diboronate (18.28 g, 72 mmol), potassium acetate (11.78 g, 120 mmol), [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride (4.40 g, 6 mmol), and 1,4-dioxane (120 mL) were added sequentially to a 500 mL reaction flask. After purging with nitrogen three times, the resulting reaction solution was heated in an oil bath at 80 °C for 4 hours. The reaction solution was cooled to room temperature, filtered, and the filtrate was concentrated under reduced pressure. 150 mL of ethyl acetate and 200 mL of water were added, and the mixture was extracted and separated to obtain the organic phase. The aqueous phase was extracted again with ethyl acetate (50 mL × 2). The combined organic phases were washed with saturated sodium chloride solution, 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 = 8 / 1 (v / v)) to obtain compound 001-2, which can be used directly in the next step. LC / MS (ESI+) m / z: [M+Ht-Bu]+ = 278.15.

[0092] 1.3 Synthesis of Compound 001-3 Compounds 001-b (5.00 g, 18.8 mmol), 001-c (3.12 g, 18.8 mmol), and triphenylphosphine (9.87 g, 37.6 mmol) were dissolved sequentially in dichloromethane (70 mL). A solution of bis(4-chlorobenzyl) azodicarbonate (13.7 g, 37.6 mmol) in dichloromethane (70 mL) was added dropwise to the system under ice bath conditions. After the addition was complete, the reaction was continued at 0 °C for 2 hours. The reaction solution was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 20 / 1~10 / 1 (v / v)) to give compound 001-3. LC / MS (ESI+) m / z: [M+H]+ = 414.90.

[0093] 1.4 Synthesis of Compound 001-4 Compound 001-3 (2.00 g, 4.8 mmol), 001-2 (1.30 g, 3.9 mmol), potassium carbonate (1.30 g, 9.6 mmol), and [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride (0.35 g, 0.48 mmol) were added sequentially to a 1,4-dioxane / water mixture (30 mL / 3 mL). After purging with nitrogen three times, the reaction mixture was reacted at 80 °C for 2 hours. The mixture was then filtered, and the filtrate was diluted with water (30 mL) and extracted with ethyl acetate (30 mL × 2). The combined organic phases were washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 10 / 1~5 / 1 (v / v)) to obtain compound 001-4. LC / MS (ESI+) m / z: [M+H-Boc]+ = 439.95.

[0094] 1.5 Synthesis of Compound 001-5 Compound 001-4 (4.3 g, 7.96 mmol), 6-aza-spiro[2.5]octane hydrochloride (compound 001-d, 1.4 g, 9.55 mmol), potassium carbonate (3.3 g, 23.87 mmol), tris(dibenzylacetone)dipalladium (400 mg, 10 wt%), and 2-dicyclohexylphosphine-2',4',6'-triisopropylbiphenyl (400 mg, 10 wt%) were added sequentially to 1,4-dioxane (50 mL). The mixture was purged with nitrogen three times, and the reaction was carried out at 90 °C for 4 hours. The reaction mixture was filtered, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography to obtain compound 001-5. LC / MS (ESI+) m / z: [M+H]+ = 571.15.

[0095] 1.6 Synthesis of Compound 001-6 Compound 001-5 (3.5 g, 6.1 mmol) was dissolved in dichloromethane (27 mL), and trifluoroacetic acid (9 mL) was added. The reaction mixture was reacted at room temperature for 1 hour. The pH was adjusted to 8 by adding saturated sodium bicarbonate solution, followed by extraction with ethyl acetate (30 mL × 3). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain compound 001-6 (3.2 g, crude product), which could be used directly in the next step. LC / MS (ESI+) m / z: [M+H]+ = 471.10.

[0096] 1.7 Synthesis of Compound 001 Compound 001-6 (3.1 g, 6.5 mmol) and sodium hydroxide (1.05 g, 26.3 mmol) were added to tetrahydrofuran (10 mL), methanol (5 mL), and water (5 mL). The reaction mixture was reacted at 60 °C for 4 hours. The reaction mixture was purified by preparative high-performance liquid chromatography and then lyophilized to obtain the target compound 001. 1H NMR (400 MHz, DMSO- d 6 ): δ 8.27 (s, 0.59H), 8.10 (s, 1H), 7.67 (d, J= 7.6 Hz, 1H), 7.37-7.40 (m, 2H), 7.28 (d, J= 7.2 Hz, 1H), 7.08-7.14 (m, 3H), 7.00 (s, 1H), 6.92 (d, J= 8.0 Hz, 1H), 6.81 (t, J= 7.6 Hz, 1H), 5.13 (s, 2H), 3.97 (s, 2H), 3.43 (s, 2H), 3.30 (t, J= 5.2 Hz, 4H), 1.48 (t, J= 5.2 Hz, 4H), 0.35 (s, 4H); LC / MS(ESI+) m / z: [M+H] +=457.10.

[0097] Example 2: Synthesis of 2-(2-((3'-(aminomethyl)-5-(7-azaspiro[3.5]nonane-7-yl)-[1,1'-biphenyl]-3-yl)methoxy)phenyl)acetic acid (compound 002)

[0098] The synthesis of compound 002 is based on the same method as that of compound 001, except that the starting material is replaced by the hydrochloride salt of 7-azaspiro[3.5]nonane (002-a). 1H NMR (400 MHz, DMSO- d 6 ): δ 8.27 (br.s, 0.6H), 7.82-7.92 (m, 1H), 7.5 (dd, J= 7.6, 20.0 Hz, 1H), 7. 40 (br.s, 0.6H), 7.33 (t, J= 7.6 Hz, 1H), 7.22-7.27 (m, 1H), 6.99-7.12 (m, 4H), 6.87-6.92 (m, 1H), 6.72-6.79 (m, 1H), 5.11 (d, J= 5.2 Hz, 2H), 4.21 (s, 1H), 3.83 (s, 1H), 3.36 (s, 1H), 3.31 (s, 1H), 3.15 (t, J= 5.2 Hz, 4H), 1.83-1.88 (m, 2H), 1.76-1.78 (m, 4H), 1.64-1.66 (m, 4H); LC / MS(ESI+) m / z: [M+H] +=471.10.

[0099] Example 3: Synthesis of 2-(2-((3'-(aminomethyl)-5-(6-azaspiro[3.4]octane-6-yl)-[1,1'-biphenyl]-3-yl)methoxy)phenyl)acetic acid (compound 003)

[0100] The synthesis of compound 003 is based on the same method as that of compound 001, except that the starting material is replaced by the hydrochloride salt of 6-azaspiro[3.4]octane (003-a). 1H NMR (400 MHz, DMSO- d 6 ): δ 9.51 (s, 1H), 7.98 (d, J= 114.8 Hz, 1H), 7.59 (dd, J= 48.4, 7.6 Hz, 1H), 7.36 (t, J= 7.6 Hz, 1H), 7.31 – 7.22 (m, 2H), 7.11 – 7.01 (m, 2H), 6.91 – 6.67 (m, 3H), 6.51 (d, J= 10.4 Hz, 1H), 5.15 (d, J= 23.2 Hz, 2H), 4.23 (s, 1H), 3.92 (s, 1H), 3.39 (s, 2H), 3.34 – 3.31 (m, 4H), 2.06 – 2.00 (m, 4H), 1.99 – 1.85 (m, 4H); LC / MS(ESI+) m / z: [M+H] +=457.05.

[0101] Example 4: Synthesis of 2-(2-((3'-(aminomethyl)-5-(5-azaspiro[2.5]octane-5-yl)-[1,1'-biphenyl]-3-yl)methoxy)phenyl)acetic acid (compound 004)

[0102] The synthesis of compound 004 is based on the same method as that of compound 001, except that the starting material is replaced by the hydrochloride salt of 5-azaspiro[2.5]octane (004-a). 1H NMR (400 MHz, DMSO- d 6 ): δ 8.33 (s, 1H), 8.04 (s, 1H), 7.67 (d, J= 8.0 Hz, 1H), 7.39 (t, J= 7.6 Hz, 1H), 7.35 – 7.27 (m, 2H), 7.12 (t, J= 7.6 Hz, 2H), 7.08 (s, 1H), 6.98 – 6.90 (m, 2H), 6.82 (t, J= 7.6 Hz, 1H), 5.12 (s, 2H), 3.98 (s, 2H), 3.45 (s, 2H), 3.30 – 3.23 (m, 2H), 3.00 (s, 2H), 1.80 – 1.74 (m, 2H), 1.45 – 1.36 (m, 2H), 0.48 (t, J= 5.6 Hz, 2H), 0.33 (t, J= 4.8 Hz, 2H); LC / MS(ESI+) m / z:[M+H] +=457.10.

[0103] Example 5: Synthesis of 2-(2-((3'-(aminomethyl)-5-(2-azaspiro[3.5]nonane-2-yl)-[1,1'-biphenyl]-3-yl)methoxy)phenyl)acetic acid (compound 005)

[0104] The synthesis of compound 005 is based on the same method as that of compound 001, except that the starting material is replaced by the hydrochloride salt of 2-azaspiro[3.5]nonane (005-a). 1H NMR (400 MHz, DMSO- d 6 ): δ 9.54 (s, 0.25H), 7.98 (d, J= 104.4 Hz, 1H), 7.55 (dd, J= 44.8, 8.0 Hz, 1H), 7.39 – 7.22 (m, 3H), 7.14 – 7.00 (m, 2H), 6.90 – 6.74 (m, 2H), 6.60 (s, 1H), 6.42 (d, J= 13.2 Hz, 1H), 5.13 (d, J= 25.2 Hz, 2H), 4.07 (d, J= 134 Hz, 2H), 3.58 (d, J= 3.2 Hz, 4H), 3.38 (d, J= 4.4 Hz, 2H), 1.67 (s, 4H), 1.42 (d, J= 26.4 Hz, 6H); LC / MS(ESI+) m / z: [M+H] +=471.10.

[0105] Example 6: Synthesis of 2-(2-((3'-(aminomethyl)-5-(3-azabicyclo[3.2.1]octane-3-yl)-[1,1'-biphenyl]-3-yl)methoxy)phenyl)acetic acid (compound 006)

[0106] The synthesis of compound 006 is based on the same method as that of compound 001, except that the starting material is replaced by the hydrochloride salt of 3-azabicyclo[3.2.1]octane (006-a). 1H NMR (400 MHz, DMSO- d 6 ): δ 7.76 (d, J= 54.4 Hz, 1H), 7.50 (dd, J= 14.4, 7.6 Hz, 1H), 7.39 – 7.32 (m, 1H), 7.27 (t, J= 7.2 Hz, 1H), 7.20 – 6.89 (m, 5H), 6.84 – 6.73 (m, 2H), 5.11 (d, J= 54.4 Hz, 2H), 4.00 (d, J= 184.4 Hz, 2H), 3.60 (d, J= 10.0 Hz, 2H), 3.38 (s, 2H), 3.27 (s, 2H), 2.85 – 2.75 (m, 2H), 2.37 (s, 2H), 1.59 (s, 2H), 1.55 (s, 2H); LC / MS(ESI+) m / z: [M+H] +=457.05.

[0107] Example 7: Synthesis of 2-(2-((3'-(aminomethyl)-2'-fluoro-5-(6-azaspiro[2.5]octane-6-yl)-[1,1'-biphenyl]-3-yl)methoxy)phenyl)acetic acid (compound 007)

[0108] 7.1 Synthesis of Compound 007-1 007-a (1.0 g, 5 mmol) was dissolved in tetrahydrofuran (5 mL), and a 1M borane tetrahydrofuran solution (20 mL, 20 mmol) was slowly added dropwise under nitrogen protection. After the addition was complete, the reaction mixture was heated to 60 °C and reacted for 5 hours. The mixture was cooled to room temperature, and the reaction was quenched by slowly adding methanol (20 mL). Then, 1M dilute hydrochloric acid (10 mL) was added, and the mixture was extracted with ethyl acetate (20 mL × 3). The aqueous phase was adjusted to pH 8 to 10 with saturated sodium bicarbonate solution, and then extracted again with ethyl acetate (20 mL × 3). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain compound 007-1 (crude product). LC / MS (ESI+) m / z: [M+H]+ = 204.00.

[0109] 7.2 Synthesis of Compound 007-2 Compound 007-1 (600 mg, crude), dibutyl dicarbonate (704 mg, 3.23 mmol), and triethylamine (594 mg, 5.88 mmol) were dissolved sequentially in dichloromethane (5 mL), and the reaction mixture was reacted overnight at room temperature. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 8 / 1 (v / v)) to give compound 007-2. LC / MS (ESI+) m / z: [M+H]+ = 236.00.

[0110] 7.3 Synthesis of Compound 007-3 Compound 007-2 (600 mg, 1.97 mmol), pinacol diborate (601 mg, 2.37 mmol), potassium acetate (387 mg, 3.95 mmol), and [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride (144 mg, 0.2 mmol) were added sequentially to 1,4-dioxane (5 mL). The mixture was purged with nitrogen three times, and the reaction solution was reacted at 100 °C for 2 hours. After cooling to room temperature, the reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 12 / 1 (v / v)) to give compound 007-3. LC / MS (ESI+) m / z: [M+Ht-Bu]+ = 296.05.

[0111] 7.4 Synthesis of Compound 007-4 007-3 (510 mg, 1.45 mmol), 001-3 (721 mg, 1.74 mmol), potassium carbonate (401 mg, 2.90 mmol), and [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride (106 mg, 0.145 mmol) were added sequentially to 1,4-dioxane (5 mL) and water (1 mL). The reaction mixture was reacted at 100 °C for 2 hours. The reaction mixture was cooled to room temperature, and water (10 mL) was added. The mixture was extracted with ethyl acetate (15 mL × 3). The combined organic phases were washed with saturated brine, 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 = 10 / 1 (v / v)) to obtain compound 007-4.

[0112] 7.5 Synthesis of Compound 007 The synthesis of compound 007 is based on the same method as that of compound 001, except that the intermediate is replaced with 007-4 instead of 001-4. 1H NMR (400 MHz, DMSO- d 6 ): δ 7.49 – 7.32 (m, 2H), 7.32 – 7.15 (m, 2H), 7.15 – 7.04 (m, 2H), 7.04 – 6.96 (m, 2H), 6.93 (d, J= 7.6 Hz, 1H), 6.83 – 6.74 (m, 1H), 5.10 (d, J= 49.6 Hz, 2H), 4.16 (s, 1H), 3.79 (s, 1H), 3.29 (d, J= 4.4 Hz, 4H), 3.26 (s, 2H), 1.46 (dd, J= 13.2, 8 Hz, 4H), 0.33 (d, J= 4.8 Hz, 4H); LC / MS(ESI+) m / z: [M+H] +=475.05.

[0113] Example 8: Synthesis of 2-(2-((3'-(aminomethyl)-5'-fluoro-5-(6-azaspiro[2.5]octane-6-yl)-[1,1'-biphenyl]-3-yl)methoxy)phenyl)acetic acid (compound 008)

[0114] The synthesis of compound 008 is based on the same method as that of compound 007, except that the intermediate 007-1 is replaced with 3-fluoro-5-bromobenzylamine (008-a). 1H NMR (400 MHz, DMSO- d 6 ): δ 9.46 (s, 1H), 7.74 (d, J= 29.6 Hz, 1H), 7.37 (d, J= 40.4 Hz, 2H), 7.28 – 6.94 (m, 5H), 6.94 – 6.67 (m, 2H), 5.14 (d, J= 36.8 Hz, 2H), 4.24 (s, 1H), 3.86 (s, 1H), 3.40 (s, 1H), 3.35 (s, 1H), 3.31 (d, J= 4.8 Hz, 4H), 1.48 (s, 4H), 0.34 (s, 4H);LC / MS(ESI+) m / z:[M+H] +=475.10.

[0115] Example 9: Synthesis of 2-(2-((3'-(aminomethyl)-5-(6-azaspiro[2.5]octane-6-yl)-[1,1'-biphenyl]-3-yl)methoxy)-4-fluorophenyl)acetic acid (compound 009)

[0116] 9.1 Synthesis of Compound 009-1 009-a (1.0 g, 5.42 mmol) was dissolved in N,N-dimethylformamide (15 mL), and cesium carbonate (2.6 g, 8.1 mmol) and methyl iodide (1.16 g, 8.1 mmol) were added. The reaction mixture was reacted at 25 °C for 1 hour. Water (10 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (10 mL × 3). The combined organic phases were washed with saturated brine, 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 = 3 / 1 ~ 1 / 1 (v / v)) to give compound 009-1. LC / MS (ESI+) m / z: [M+H]+ = 199.10.

[0117] 9.2 Synthesis of Compound 009-2 Under nitrogen protection, 009-1 (1.0 g, 5.04 mmol) was dissolved in dichloromethane (20 mL). The reaction system was cooled to -20 °C, and boron tribromide (20 mmol, 15.12 mmol) was slowly added dropwise. After the addition was complete, the reaction was maintained at this temperature for 2 hours. The reaction was quenched by adding methanol (6 mL) dropwise at -20 °C. Water was added, and the mixture was extracted with dichloromethane (10 mL × 3). The combined organic phases were washed with saturated brine, 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 = 3 / 1~1 / 1 (v / v)) to obtain compound 009-2.

[0118] 9.3 Synthesis of Compound 009-3 009-b (1.45 g, 4.42 mmol) and 009-2 (740 mg, 4.02 mmol) were dissolved in N,N-dimethylformamide (20 mL), and potassium carbonate (1.12 g, 8.04 mmol) was added. The mixture was reacted at room temperature for 2 hours. Water was added, and the mixture was extracted with ethyl acetate (10 mL × 3). The combined organic phases were washed with saturated brine, 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 = 3 / 1 to 1 / 1 (v / v)) to give compound 009-3.

[0119] 9.4 Synthesis of Compound 009-4 Compound 009-3 (750 mg, 1.74 mmol) and 001-2 (578 mg, 1.74 mmol), potassium carbonate (480 mg, 3.48 mmol), and [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride (127 mg, 0.174 mmol) were added sequentially to 1,4-dioxane (20 mL) and water (2 mL). The reaction mixture was reacted at 100 °C for 2 hours. The reaction mixture was cooled to room temperature, water was added, and the mixture was extracted with ethyl acetate (10 mL × 3). The combined organic phases were washed with saturated brine, 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 = 3 / 1 to 1 / 1 (v / v)) to obtain compound 009-4.

[0120] 9.5 Synthesis of Compound 009 The synthesis of compound 009 is based on the same method as that of compound 001, except that the raw material is replaced with 009-4 instead of 001-4. 1H NMR (400 MHz, DMSO- d 6 ): δ 9.49 (s, 1H), 7.88 (d, J= 24.0 Hz, 1H), 7.56 (t, J= 8.0 Hz, 1H), 7.39-7.34 (m, 1H), 7.32 – 7.07 (m, 4H), 7.06-6.99 (m, 1H), 6.82-6.79 (m, 1H), 6.68 – 6.56 (m, 1H), 5.17 (d, J= 44.0 Hz, 2H), 4.24 (s, 1H), 3.85 (s, 1H), 3.36 (s, 1H), 3.31 (s, 4H), 3.28 (s, 1H), 1.49 (d, J= 4.0 Hz, 4H), 0.35 (s, 4H); LC / MS(ESI+) m / z: [M+H] +=475.05.

[0121] Example 10: Synthesis of 2-(2-((3'-(aminomethyl)-5-(6-azaspiro[2.5]octane-6-yl)-[1,1'-biphenyl]-3-yl)methoxy)-5-fluorophenyl)acetic acid (compound 010)

[0122] The synthesis of compound 010 is based on the same method as that of compound 009, except that the starting material is changed from 2-methoxy-4-fluorophenylacetic acid (009-a) to 5-fluoro-2-methoxyphenylacetic acid (010-a). 1H NMR (400 MHz, DMSO- d 6 ): δ 8.13 (s, 1H), 7.82 (s, 1H), 7.66 (d, J= 8.0 Hz, 1H), 7.54 (d, J= 8.0 Hz, 1H), 7.47 – 7.30 (m, 2H), 7.30-7.25 (m, 1H), 7.14 (s, 1H), 6.98-6.92 (m, 2H), 6.89 – 6.72 (m, 2H), 5.15 (d, J= 20.0 Hz, 2H), 4.24 (s, 1H), 3.95 (s, 1H), 3.38 (s, 2H), 3.29 (d, J= 8.0 Hz, 4H), 1.49-1.48 (m, 4H), 0.35 (s, 4H); LC / MS(ESI+) m / z: [M+H] +=475.05.

[0123] Example 11: Synthesis of 2-(2-((3'-(aminomethyl)-5-(2-oxa-7-azaspiro[3.5]nonane-7-yl)-[1,1'-biphenyl]-3-yl)methoxy)phenyl)acetic acid (compound 011)

[0124] The synthesis of compound 011 is based on the same method as compound 001, except that the starting material 001-d is replaced with the hydrochloride salt of 2-oxa-7-azaspiro[3.5]nonane (011-a). 1H NMR (400 MHz, DMSO- d 6 ): δ 7.71 (s, 1H), 7.50 (d, J= 7.6 Hz, 1H), 7.35 (t, J= 7.6 Hz, 1H), 7.27 (d, J= 7.6 Hz, 1H), 7.18 (d, J= 8.8 Hz, 2H), 7.04-7.08 (m, 3H), 6.92 (d, J= 8.0 Hz, 1H), 6.80 (t, J= 7.6 Hz, 1H), 5.05 (s, 2H), 4.36 (d, J= 4.0 Hz, 4H)), 3.77 (s, 2H), 3.39 (s, 2H), 3.18 (t, J= 5.6 Hz, 4H), 1.90 (t, J= 5.6 Hz, 4H); LC / MS(ESI+) m / z: [M+H] +=473.05.

[0125] Example 12: Synthesis of 2-(2-((3'-(aminomethyl)-5-(1-oxa-7-azaspiro[3.5]nonane-7-yl)-[1,1'-biphenyl]-3-yl)methoxy)phenyl)acetic acid (compound 012)

[0126] The synthesis of compound 012 is based on the same method as that of compound 001, except that the starting material is replaced by the hydrochloride salt of 1-oxa-7-azaspiro[3.5]nonane (012-a). 1H NMR (400 MHz, DMSO- d 6 ): δ 9.53 (s, 1H), 7.85-8.01 (m, 1H), 7.62-7.53 (m, 1H), 7.43 (s, 1H), 7.39 – 7.32 (m, 1H), 7.30 – 7.23 (m, 1H), 7.14 – 6.96 (m, 4H), 6.91-6.74 (m, 2H), 5.15 (d, J= 32.0 Hz, 2H), 4.43 (t, J=8.0 Hz, 2H), 4.23 (s, 1H), 3.87 (s, 1H), 3.37 (d, J= 16.0 Hz, 4H), 3.20-3.14 (m, 2H), 2.39 (t, J= 8.0 Hz, 2H), 1.98 – 1.79 (m, 4H); LC / MS(ESI+) m / z: [M+H] +=473.05.

[0127] Example 13: Synthesis of 2-(2-((3'-(aminomethyl)-5-(2-hydroxy-7-azaspiro[3.5]nonane-7-yl)-[1,1'-biphenyl]-3-yl)methoxy)phenyl)acetic acid (compound 013)

[0128] 13.1 Synthesis of Compound 013-1 Weigh 001-4 (400 mg, 0.881 mmol) into a reaction flask, and add 013-a (174 mg, 0.940 mmol), cesium carbonate (1 g, 3.4 mmol), tris(dibenzylacetone)palladium (140 mg, 0.088 mmol), 2-dicyclohexylphosphine-2',4',6'-triisopropylbiphenyl (90 mg, 0.088 mmol), and 1,4-dioxane (5 mL) sequentially. The mixture is purged with nitrogen three times, and the reaction solution is incubated at 100 °C for 4 hours. The reaction solution is filtered, the filtrate is concentrated under reduced pressure, and the residue is purified by silica gel column chromatography (petroleum ether / ethyl acetate = 3 / 1 (v / v)) to obtain compound 013-1. LC / MS (ESI+) m / z: [M+H]+ = 599.15.

[0129] 13.2 Synthesis of Compound 013-2

[0130] 013-1 (200 mg, 340 μmol) was dissolved in methanol (3 mL) and tetrahydrofuran (3 mL). Sodium borohydride (68 mg, 680 μmol) was added in portions at 0 °C, and the reaction mixture was continued to react at 0 °C for 0.5 hours. The reaction mixture was quenched with ammonium chloride aqueous solution (5 mL), extracted with ethyl acetate (10 mL × 2), and the combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain 013-2 (crude product), which could be used directly in the next step. LC / MS (ESI+) m / z: [M+H]+ = 601.10.

[0131] 13.3 Synthesis of Compound 013 The synthesis of compound 013 is based on the same method as that of compound 001, except that the intermediate is replaced with 013-2 instead of 001-5. 1H NMR (400 MHz, DMSO- d 6 ): δ 7.77 (d, J= 20.0 Hz, 1H), 7.48 (d, J= 8.0 Hz, 1H), 7.33(m, 1H), 7.24(m, 1H), 7.18,s, 1H), 7.13(m, 1H) , 7.05(m, 2H) , 7.00(m, 1H) ,6.88 (d, J= 8.0 Hz, 1H), 6.74 (m, 1H), 5.14 (m, 2H), 4.20 (s, 1H), 4.12 (t, J= 16.0 Hz, 1H), 3.76 (s, 2H), 3.28 (s, 2H), 3.12(m, 4H), 2.45 (m,2H), 2.12 (m, 2H), 1.57 (d, J= 4.5 Hz,4H); LC / MS(ESI+) m / z:[M+H] +=487.10.

[0132] Example 14: Synthesis of 2-(2-((3'-(aminomethyl)-5-(2-oxa-8-azaspiro[4.5]decane-8-yl)-[1,1'-biphenyl]-3-yl)methoxy)phenyl)acetic acid (compound 014)

[0133] The synthesis of compound 014 is based on the same method as that of compound 001, except that the intermediate 001-d is replaced with the hydrochloride salt of 2-oxa-8-azaspiro[4.5]decane (014-a). 1H NMR (400 MHz, DMSO- d 6 ): δ 7.86 (s, 1H), 7.55 (d, J= 8.0 Hz, 1H), 7.35 (t, J= 16.0 Hz, 1H), 7.26 (m, 2H), 7.15(m, 1H), 7.08(m, 3H), 6.91 (d, J= 8.0 Hz, 1H), 6.79 (t, J= 12.0Hz, 1H), 5.08 (s, 2H), 3.89 (m, 2H), 3.76(m, 4H), 3.49 (m, 2H), 3.26 (m, 4H), 1.74 (t, J=12.0Hz, 2H), 1.64 (t, J= 12.0 Hz, 4H); LC / MS(ESI+) m / z: [M+H] +=487.15.

[0134] Example 15: Synthesis of 2-(2-((3'-(aminomethyl)-5-(2-oxa-6-azaspiro[3.4]octane-6-yl)-[1,1'-biphenyl]-3-yl)methoxy)phenyl)acetic acid (compound 015) trifluoroacetate

[0135] 15.1 Synthesis of Compound 015-1 015-a (86 mg, 0.4 mmol) was dissolved in dichloromethane (1 mL), and trifluoroacetic acid (2 mL) was added to the system at room temperature. The reaction solution was heated at 60 °C for 2 hours. After cooling to room temperature, the reaction solution was concentrated under reduced pressure to obtain compound 015-1 (crude product), which can be used directly in the next step.

[0136] 15.2 Synthesis of Compound 015 Trifluoroacetate Referring to the synthesis method of compound 001, it is only necessary to replace the intermediate 001-d with 015-1. The preparation method is trifluoroacetic acid conditions, and the trifluoroacetate of compound 015 is obtained by freeze drying. 1H NMR (600 MHz, DMSO- d 6 ): δ 12.20 (s, 1H), 8.17 (s, 2H), 7.78 (s, 1H), 7.69 (d, J= 7.8 Hz, 1H), 7.50 (t, J= 7.8 Hz, 1H), 7.43 (d, J= 7.8 Hz, 1H), 7.22 (t, J= 7.8 Hz, 2H), 7.03 (d, J= 7.8 Hz, 1H), 6.99 (s, 1H), 6.90 (t, J= 7.8 Hz, 1H), 6.72 (s, 1H), 6.68 (s, 1H), 5.11 (s, 2H), 4.61 (d, J= 6.0 Hz, 2H), 4.56 (d, J= 6.0 Hz, 2H), 4.12 (d, J= 4.8 Hz, 2H), 3.60 (d, J= 5.4 Hz, 2H), 3.38 (s, 2H), 2.29 (t, J= 6.6 Hz, 2H ), 2.02-1.96 (m, 2H); LC / MS(ESI+) m / z: [M+H] +=459.05.

[0137] Example 16: Synthesis of 2-(2-((3'-(aminomethyl)-5-(4-oxa-7-azaspiro[2.5]octane-7-yl)-[1,1'-biphenyl]-3-yl)methoxy)phenyl)acetic acid (compound 016) trifluoroacetate

[0138] The synthesis of compound 016 is based on the synthesis method of compound 001, except that the intermediate 001-d is replaced with the hydrochloride of 4-oxa-7-azaspiro[2.5]octane (016-a). 1H NMR (600 MHz, DMSO- d 6 ): δ 9.54 (s, 1H), 7.86 (s, 1H), 7.56 (d, J= 7.9 Hz, 1H), 7.48 (s, 1H), 7.28 (t, J= 7.6 Hz, 1H), 7.13 (m, 2H), 7.05 (m, 3H), 6.94 (s, 1H), 6.76 (t, J= 16.0Hz, 2H), 5.20 (s, 2H), 4.24 (s, 2H), 3.83(m, 2H), 3.39 (s, 2H), 3.29 (m, 2H), 3.21 (s, 2H), 0.77 (m, 2H), 0.69 (m, 2H); LC / MS(ESI+) m / z: [M+H] +=459.05.

[0139] Example 17: Synthesis of 2-(2-((3'-(aminomethyl)-5-(2-azaspiro[3.4]octane-2-yl)-[1,1'-biphenyl]-3-yl)methoxy)phenyl)acetic acid (compound 017)

[0140] The synthesis of compound 017 is based on the same method as that of compound 001, except that the intermediate 001-d is replaced with the hydrochloride salt of 2-azaspiro[3.4]octane (017-a). 1H NMR (600 MHz, DMSO- d 6 ): δ 8.15 (s, 1H), 7.60 (d, J= 8.0 Hz, 1H), 7.39-7.31 (m, 2H), 7.23 (d, J= 8.0 Hz, 1H), 7.03-7.08 (m, 2H), 6.86 (d, J= 8.0 Hz, 1H), 6.77 (t, J= 7.2 Hz, 1H), 6.59 (s, 1H), 6.41 (s, 1H), 5.10 (s, 2H), 3.91 (s, 2H), 3.72 (s, 4H), 3.37 (s, 2H), 1.80 (t, J= 6.8 Hz, 4H), 1.57-1.60 (m, 4H); LC / MS(ESI+) m / z: [M+H] +=457.05.

[0141] Example 18: Synthesis of (S)-2-(2-((3'-(1-amino-2-hydroxyethyl)-5-(6-azaspiro[2.5]octane-6-yl)-[1,1'-biphenyl]-3-yl)methoxy)phenyl)acetic acid (compound 018)

[0142] 18.1 Synthesis of Compound 018-1 018-a (3.5 g, 10.6 mmol) was dissolved in tetrahydrofuran (35 mL), and a 1M borane tetrahydrofuran solution (52.5 mL, 53.1 mmol) was added dropwise at room temperature. After the addition was complete, the reaction mixture was reacted at 80 °C for 1 hour. The reaction mixture was cooled to room temperature, quenched with methanol, and concentrated under reduced pressure. 1N dilute hydrochloric acid (10 mL) was added to the residue, and the mixture was stirred at room temperature for 10 minutes. Then, it was extracted with ethyl acetate (20 mL × 2). The pH of the aqueous layer was adjusted to alkaline with saturated sodium bicarbonate solution, and then extracted with ethyl acetate (20 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 obtain compound 018-1 (crude product), which can be used directly in the next step.

[0143] 18.2 Synthesis of Compound 018-2 018-1 (1.7 g, 5.4 mmol), pinacol diborate (2.0 g, 6.5 mmol), potassium acetate (1.5 g, 9.2 mmol), and [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride (500 mg, 460 μmol) were added sequentially to 1,4-dioxane (10 mL). After purging with nitrogen three times, the reaction mixture was reacted at 80 °C for 3 hours. The reaction mixture was diluted with water (30 mL) and extracted with ethyl acetate (20 mL × 3). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 10 / 1 (v / v)) to obtain compound 018-2.

[0144] 18.3 Synthesis of Compound 018 The synthesis of compound 018 is based on the same method as that of compound 001, except that the intermediate is replaced with 018-2. 1H NMR (400 MHz, DMSO- d 6 ): δ 9.48 (s, 1H), 7.89 (d, J= 8.0 Hz, 1H), 7.54 (s, 1H), 7.43 (s, 1H), 7.29 (t, J= 4.0Hz, 2H), 7.15 (m, 3H), 7.04 (m, 2H), 6.90 (d, J=4.0 Hz, 1H), 6.79 (d, J= 4.0 Hz, 1H), 5.13 (m, 2H), 4.75 – 3.84 (m, 1H), 3.53 (m, 2H), 3.96(m, 2H), 3.29 (s, 4H), 1.49 (s, 4H), 0.35 (s, 4H); LC / MS(ESI+) m / z: [M+H] +=487.05.

[0145] Example 19: Synthesis of (S)-2-(2-((3'-(1-amino-2-hydroxyethyl)-5'-fluoro-5-(6-azaspiro[2.5]octane-6-yl)-[1,1'-biphenyl]-3-yl)methoxy)phenyl)acetic acid (compound 019)

[0146] 19.1 Synthesis of Compound 019-1 019-a (3.0 g, 14.8 mmol) was dissolved in dichloromethane (25 mL), and 019-b (1.8 g, 14.8 mmol) and cesium carbonate (4.8 g, 14.8 mmol) were added. The reaction mixture was reacted at 25 °C for 12 hours. Water (30 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (15 mL × 3). The combined organic phases were washed with saturated brine, 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 = 3 / 1 to 1 / 1 (v / v)) to give compound 019-1. LC / MS (ESI+) m / z: [M+H]+ = 305.90.

[0147] 19.2 Synthesis of Compound 019-2 Vinyl magnesium bromide (16.7 mL, 16.7 mmol) and dimethyl zinc reagent (16.7 mL, 16.7 mmol) were mixed under nitrogen protection and reacted at room temperature for 0.5 h. The system was then cooled to -78 °C, and 019-1 (3.0 g, 9.81 mmol) was slowly added dropwise. After the addition was complete, the reaction was maintained at this temperature for 2 h. The reaction was quenched by adding saturated ammonium chloride aqueous solution (26 mL) dropwise at -78 °C. The mixture was then extracted with ethyl acetate (30 mL × 3). The combined organic phases were washed with saturated brine, 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 = 3 / 1 to 1 / 1 (v / v)) to give compound 019-2. LC / MS (ESI+) m / z: [M+H]+ = 333.90.

[0148] 19.3 Synthesis of Compound 019-3 019-2 (2.5 g, 7.5 mmol) was dissolved in methanol (20 mL), and 4N hydrochloric acid (5 mL, 7.5 mmol) was added. The reaction mixture was reacted at room temperature for 1 hour. The reaction solution was concentrated under reduced pressure, and dichloromethane (20 mL) was added, followed by di-tert-butyl dicarbonate (3.07 g, 14.08 mmol). The reaction mixture was reacted at room temperature for 2 hours. The reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 3 / 1 to 1 / 1 (v / v)) to give compound 019-3. LC / MS (ESI+) m / z: [M+Ht-Bu]+ = 273.90.

[0149] 19.4 Synthesis of Compound 019-4 Under nitrogen protection, 019-3 (2.5 g, 7.58 mmol) was dissolved in a mixture of carbon tetrachloride (20 mL), acetonitrile (20 mL), and water (30 mL). Sodium periodate (3.4 g, 15.9 mmol) and ruthenium trichloride (158 mg, 0.758 mmol) were then added. The reaction mixture was reacted at room temperature for 2 hours. The reaction mixture was extracted with ethyl acetate (30 mL × 3). The combined organic phases were washed with saturated brine, 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 = 10 / 1~2 / 1 (v / v)) to give compound 019-4.

[0150] 19.5 Synthesis of Compound 019-5 019-4 (130 mg, 0.432 mmol) was weighed into a reaction flask, and 1 M borane tetrahydrofuran solution (1.5 mL, 0.864 mmol) was added under nitrogen protection. The reaction solution was reacted at 25 °C for 12 hours. The reaction was quenched with methanol (5 mL), and the insoluble matter was removed by filtration. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 3 / 1~1 / 1 (v / v)) to obtain compound 019-5. LC / MS (ESI+) m / z: [M+Ht-Bu]+ = 277.95.

[0151] 19.6 Synthesis of Compound 019-6 Compound 001-3 (1.0 g, 2.42 mmol), 001-d (320 mg, 2.16 mmol), tris(dibenzylacetone)palladium (240 mg, 0.24 mmol), 2-dicyclohexylphosphine-2',4',6'-triisopropylbiphenyl (120 mg, 0.24 mmol), and cesium carbonate (1.6 g, 4.84 mmol) were added sequentially to 1,4-dioxane (10 mL). The mixture was purged with nitrogen three times, and the reaction was carried out at 100 °C for 4 hours. The reaction solution was filtered, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 3 / 1~1 / 1 (v / v)) to give compound 019-6. LC / MS (ESI+) m / z: [M+H]+ = 443.95.

[0152] 19.7 Synthesis of Compound 019-7 019-6 (170 mg, 2.7 mmol), pinacol diborate (822 mg, 3.24 mmol), potassium acetate (540 mg, 5.4 mmol), and [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride (240 mg, 300 μmol) were added sequentially to 1,4-dioxane (10 mL). The mixture was purged with nitrogen three times, and the reaction solution was reacted at 100 °C for 4 hours. The reaction solution was diluted with water (10 mL) and then extracted with ethyl acetate (10 mL × 3). The combined organic phases were washed with saturated brine, 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 = 10 / 1 (v / v)) to give compound 019-7. LC / MS (ESI+) m / z: [M+H]+ = 492.10.

[0153] 19.8 Synthesis of Compound 019-8 Compound 019-7 (50 mg, 0.045 mmol), 019-5 (38 mg, 0.054 mmol), potassium carbonate (30 mg, 0.09 mmol), and [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride (8.5 mg, 0.05 mmol) were added sequentially to 1,4-dioxane (4 mL) and water (1 mL). The mixture was purged with nitrogen three times, and the reaction solution was reacted at 100 °C for 2 hours. The reaction solution was then diluted with water and extracted with ethyl acetate (10 mL × 3). The combined organic phases were washed with saturated brine, 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 = 3 / 1~1 / 1 (v / v)) to give compound 019-8. LC / MS (ESI+) m / z: [M+H]+ = 619.10.

[0154] 19.9 Synthesis of Compound 019-9 019-8 (35 mg, 0.057 mmol) was dissolved in dichloromethane (5 mL) and trifluoroacetic acid (1 mL) and reacted at room temperature for 0.5 hours. The pH was adjusted to 7-8 by adding saturated sodium bicarbonate aqueous solution (6 mL), and the mixture was extracted with dichloromethane (10 mL × 3). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain compound 019-9 (crude product), which could be used directly in the next step. LC / MS (ESI+) m / z: [M+H]+ = 519.10.

[0155] 19.10 Synthesis of Compound 019 019-9 (22 mg, 0.067 mmol) and sodium hydroxide (11 mg, 0.27 mmol) were dissolved in a mixed solution of tetrahydrofuran (1 mL), methanol (0.5 mL), and water (1 mL), and reacted at 60 °C for 2 hours. The reaction solution was purified by preparative high-performance liquid chromatography and lyophilized to obtain the target compound 019. 1H NMR (400 MHz, DMSO- d 6 ): δ 7.97 (s, 1H), 7.55 (d, J= 12.0 Hz, 1H), 7.38 (s, 1H), 7.18 – 7.09 (m, 4H), 7.05 (s, 1H), 6.94 (d, J= 8.0 Hz, 1H), 6.81 (t, J= 8.0 Hz, 1H), 5.13 (s, 2H), 4.13 (s, 1H), 3.73 – 3.61 (m, 2H), 3.48 (d, J= 16.0 Hz, 1H), 3.39 (s, 1H), 3.34 – 3.30 (m, 4H), 1.50 – 1.46 (m, 4H), 0.35 (s, 4H); LC / MS(ESI+) m / z: [M+H] +=505.05.

[0156] Example 20: Synthesis of (R)-2-(2-((3'-(1-aminoethyl)-2'-fluoro-5-(6-azaspiro[2.5]octyl-6-yl)-[1,1'-biphenyl]-3-yl)methoxy)phenyl)acetic acid (compound 020-A or 020-B) and (S)-2-(2-((3'-(1-aminoethyl)-2'-fluoro-5-(6-azaspiro[2.5]octyl-6-yl)-[1,1'-biphenyl]-3-yl)methoxy)phenyl)acetic acid (compound 020-B or 020-A)

[0157] 20.1 Synthesis of Compound 020-1 020-a (2 g, 5.6 mmol) and hydroxylamine hydrochloride (4.5 g, 37.6 mmol) were dissolved in pyridine (10 mL), and the reaction mixture was reacted at 45 °C for 1 hour. The pH of the reaction mixture was adjusted to 2 with 1 N hydrochloric acid, and the mixture was extracted with ethyl acetate (20 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 obtain compound 020-1 (crude product), which can be directly used for the next step. LC / MS (ESI+) m / z: [M+H]+ = 234.10.

[0158] 20.2 Synthesis of Compound 020-2 020-1 (1.16 g, 0.22 mmol) and zinc powder (2 g, 2.2 mmol) were added to methanol (10 mL), and 6N hydrochloric acid (10 mL) was added dropwise. The reaction solution was reacted at 70 °C for 1 hour. The pH of the reaction solution was adjusted to 8 with sodium bicarbonate aqueous solution (20 mL). The reaction solution was filtered, and the filter cake was washed with water (10 mL). The filtrate was then extracted with ethyl acetate (30 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 obtain compound 020-2 (crude product). LC / MS (ESI+) m / z: [M+H]+ = 220.00.

[0159] 20.3 Synthesis of Compound 020-3 The synthesis method of compound 020-3 is the same as that of compound 001-1 in Example 1.

[0160] 20.4 Synthesis of Compound 020-4 The synthesis method of compound 020-4 is the same as that of compound 001-2 in Example 1.

[0161] 20.5 Synthesis of compounds 020-5 to 020-7 The synthesis methods for compounds 020-5 to 020-7 are the same as those for compounds 001-4 to 001-6 in Example 1.

[0162] 20.6 Synthesis of compounds 020-A and 020-B 020-7 (75 mg, 150 μmol) and sodium hydroxide (300 mg, 3.1 mmol) were dissolved in a mixed solution of tetrahydrofuran (3 mL), methanol (0.5 mL), and water (1 mL). The reaction solution was reacted at 60 °C for 2 hours. The reaction solution was purified by preparative high performance liquid chromatography and lyophilized to obtain compound 020. Compound 020 was chirally resolved (AD-H column, isocratic elution of n-hexane:[(ethanol:methanol = 3:1)] = 6:4 (v / v)) to obtain target compounds 020-A (retention time Rt = 7.640 min) and 020-B (retention time Rt = 13.087 min). Compound 020-A: 1H NMR (400 MHz, DMSO- d 6 ): δ 7.53(m, 1H), 7.35(t, J= 4.0 Hz, 1H), 7.24(m, 3H), 7.06 (m, 2H), 6.99 (d, J= 4.0 Hz, 2H), 6.89 (m, 1H), 5.11 (s, 2H), 4.36 (s, 1H), 3.57 (s, 2H), 3.29 (m 4H), 1.47 (m, 4H), 1.35 (s, 3H), 0.34 (s, 4H); LC / MS(ESI+) m / z:[M+H] +=489.10. Compound 020-B: 1H NMR (400 MHz, DMSO- d 6 ): δ 7.53(m, 1H), 7.35(t, J= 4.0 Hz, 1H), 7.24(m, 3H), 7.06 (m, 2H), 6.99 (d, J= 4.0 Hz, 2H), 6.89 (m, 1H), 5.11 (s, 2H), 4.36 (s, 1H), 3.57 (s, 2H), 3.29 (m 4H), 1.47 (m, 4H), 1.35 (s, 3H), 0.34 (s, 4H); LC / MS(ESI+) m / z:[M+H] +=489.10.

[0163] Example 21: Synthesis of 2-(2-((3'-(aminomethyl)-2'-fluoro-5-(6-azaspiro[2.5]octane-6-yl)-[1,1'-biphenyl]-3-yl)methoxy)-4-fluorophenyl)acetic acid (compound 021)

[0164] The synthesis of compound 021 is based on the same method as that of compound 007, except that the intermediate is replaced with 009-3 instead of 001-3. 1H NMR (600 MHz, DMSO- d 6 ): δ 8.30 (s, 1H), 7.45 (q, J= 8.0 Hz, 2H), 7.25 (t, J= 8.0 Hz, 1H), 7.20 (t, J= 8.0 Hz, 1H), 7.06 (s, 1H), 7.02 (s, 1H), 6.99 (s, 1H), 6.91 (dd, J 1 = 11.6 Hz, J 2 = 2.4 Hz, 1H), 6.70 (td, J 1 = 8.4 Hz, J 2 = 2.4 Hz, 1H), 5.14 (s, 2H), 3.91 (s, 2H), 3.50 (s, 2H), 3.28 (t, J= 5.2Hz, 4H), 1.46 (t, J= 5.2Hz, 4H), 0.34 (s, 4H); LC / MS(ESI+) m / z: [M+H] +=493.05.

[0165] Example 22: Synthesis of 2-(2-((5'-(aminomethyl)-2'-fluoro-5-(6-azaspiro[2.5]octane-6-yl)-[1,1'-biphenyl]-3-yl)methoxy)phenyl)acetic acid (compound 022)

[0166] The synthesis of compound 022 is based on the same method as that of compound 007, except that the starting material is replaced with 3-bromo-4-fluorobenzonitrile (022-a). 1H NMR (400 MHz, DMSO- d 6 ): δ 7.69 (d, J= 8.0 Hz, 1H), 7.27 (m, 1H), 7.09 (m, 6H), 6.83 (m, 2H), 5.20 (s, 2H), 5.08 (s, 2H), 4.19 (s, 1H), 3.79 (s, 1H), 3.37 (s, 2H), 3.28 (s, 4H), 1.48 (d, J= 4.0 Hz, 4H), 0.35 (s, 4H); LC / MS(ESI+) m / z:[M+H] +=475.05.

[0167] Example 23: Synthesis of 2-(2-((3-(2-(aminomethyl)-3-fluoropyridin-4-yl)-5-(6-azaspirocyclic[2.5]octane-6-yl)benzyl)oxy)phenyl)acetic acid (compound 023)

[0168] 23.1 Synthesis of Compound 023-1 Weigh 12.9 g (91.2 mmol) of tetramethylpiperidone into a reaction flask, add 50 mL of dry tetrahydrofuran, under nitrogen protection, slowly add n-butyllithium (57 mL, 91.2 mmol) at 0 °C, and react at 0 °C for 1 hour. The temperature was then lowered to -78°C, and 023-a (10 g, 76 mmol) was slowly added dropwise while maintaining the temperature below -65°C for 10 minutes. Then, N,N-dimethylformamide (16.7 g, 228.1 mmol) was added dropwise while maintaining the temperature below -65°C for 10 minutes. Next, glacial acetic acid (6.85 g, 114 mmol) and acetic anhydride (11.6 g, 114 mmol) were added dropwise. The temperature was then raised to 0°C, water (100 mL) was added, and the pH was adjusted to 8. The mixture was extracted with ethyl acetate (100 mL × 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 2 / 1~1 / 1 (v / v)) to obtain compound 023-1.

[0169] 23.2 Synthesis of Compound 023-2 8.4 g (52.7 mmol) of 023-1 and 7.66 g (63.2 mmol) of 023-b were weighed into a reaction flask, and dichloromethane (50 mL) and cesium carbonate (34.3 g, 105.3 mmol) were added. The mixture was reacted at room temperature for 2 hours. Water (100 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (50 mL × 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 2 / 1 to 1 / 1 (v / v)) to give compound 023-2. LC / MS (ESI+) m / z: [M+H]+ = 262.95.

[0170] 23.3 Synthesis of Compound 023-3 8.0 g (30.45 mmol) of 023-2 was weighed into a reaction flask, and methanol (60 mL) was added. Under nitrogen protection, sodium borohydride (4.61 g, 121.80 mmol) was slowly added to the system, and the reaction was carried out at room temperature for 2 hours. After the reaction solution was concentrated under reduced pressure, ethyl acetate (50 mL) and saturated sodium bicarbonate aqueous solution (50 mL) were added. The organic phase was separated, and the aqueous phase was extracted with ethyl acetate (50 mL × 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 2 / 1~1 / 1 (v / v)) to obtain compound 023-3. LC / MS (ESI+) m / z: [M+H]+ = 265.05.

[0171] 23.4 Synthesis of Compound 023-4 Weigh 10 g (46.1 mmol) of 023-c into a reaction flask, add N,N-dimethylformamide (50 mL), cesium carbonate (45 g, 138.2 mmol), and methyl iodoforme (16.4 g, 115.2 mmol), and react overnight at room temperature. Add water to the reaction mixture, extract with ethyl acetate (50 mL × 3), combine the organic phases, dry with anhydrous sodium sulfate, filter, concentrate the filtrate under reduced pressure, and purify the residue by silica gel column chromatography (petroleum ether / ethyl acetate = 3 / 1 to 1 / 1 (v / v)) to obtain compound 023-4.

[0172] 23.5 Synthesis of Compound 023-5 023-4 (5 g, 20.4 mmol) was weighed into a reaction flask, and 001-d (3.68 g, 23 mmol), cesium carbonate (20 g, 61.21 mmol), 1,4-dioxane (30 mL), tris(dibenzylacetone)dipalladium (200 mg, 2.04 mmol), and 2-dicyclohexylphosphine-2',4',6'-triisopropylbiphenyl (100 mg, 2.04 mmol) were added. The reaction mixture was reacted at 100 °C for 12 hours. The reaction solution was filtered and concentrated, and the residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 3 / 1~1 / 1 (v / v)) to give compound 023-5. LC / MS (ESI+) m / z: [M+H]+ = 276.05.

[0173] 23.6 Synthesis of Compound 023-6 6.0 g (14.5 mmol) of 023-5 was weighed into a reaction flask, and 30 mL of dichloromethane was added. Boron tribromide (7.28 g, 29.1 mmol) was slowly added dropwise at 0 °C. After the addition was complete, the reaction mixture was brought to room temperature and reacted for 2 hours. The reaction was slowly quenched by adding 30 mL of methanol, followed by adding 30 mL of water. The mixture was extracted with dichloromethane (50 mL × 3), and the organic phases were combined. The mixture was 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 = 3 / 1 to 1 / 1 (v / v)) to obtain compound 023-6. LC / MS (ESI+) m / z: [M+H]+ = 262.05.

[0174] 23.7 Synthesis of Compound 023-7 Weigh 2.4 g (10 mmol) of 023-6 into a reaction flask, add 30 mL of dichloromethane and pyridine (870 mg, 6.26 mmol), and add trifluoromethanesulfonic anhydride (3.4 g, 12 mmol) dropwise at 0 °C. After the addition is complete, the reaction mixture is brought to room temperature and reacted for 2 hours. Water (30 mL) is added to the reaction mixture, and the mixture is extracted with dichloromethane (50 mL × 3). The organic phases are combined, dried over anhydrous sodium sulfate, filtered, and the filtrate is concentrated under reduced pressure. The residue is purified by silica gel column chromatography (petroleum ether / ethyl acetate = 5 / 1 to 1 / 1 (v / v)) to obtain compound 023-7.

[0175] 23.8 Synthesis of Compound 023-8 1.7 g (4.32 mmol) of 023-7 was weighed into a reaction flask, and 50 mL of 1,4-dioxane, 1.7 g (6.5 mmol) of pinacol diborate, 1.3 g (13 mmol) of potassium acetate, and 323 mg (0.44 mmol) of [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride were added. Under nitrogen protection, the reaction mixture was refluxed at 80 °C for 12 hours. The reaction mixture was concentrated, and the residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 5 / 1 to 1 / 1 (v / v)) to give compound 023-8. LC / MS (ESI+) m / z: [M+H]+ = 372.00.

[0176] 23.9 Synthesis of Compound 023-9 Weigh 023-8 (1.5 g, 4.05 mmol) into a reaction flask, add 023-3 (962 mg, 5.3 mmol), 1,4-dioxane (30 mL), and water (5 mL), then add [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride (356 mg, 0.405 mmol) and potassium carbonate (1.68 g, 12.12 mmol). Under nitrogen protection, reflux the reaction solution at 100 °C for 2 hours. Concentrate the reaction solution, and purify the residue by silica gel column chromatography (petroleum ether / ethyl acetate = 5 / 1~1 / 1 (v / v)) to obtain compound 023-9. LC / MS (ESI+) m / z: [M+H]+ = 474.00.

[0177] 23.10 Synthesis of Compound 023-10 Weigh 1.7 g (3.59 mmol) of 023-9 into a reaction flask, add 15 mL of tetrahydrofuran, cool to 0 °C, and slowly add 408 mg (10.77 mmol) of lithium aluminum hydride. React at 0 °C for 1 hour. Add 20 mL of water to the reaction mixture, extract with ethyl acetate (50 mL × 3), combine the organic phases, dry with anhydrous sodium sulfate, filter, concentrate the filtrate under reduced pressure, and purify the residue by silica gel column chromatography (petroleum ether / ethyl acetate = 3 / 1 to 1 / 1 (v / v)) to obtain compound 023-10. LC / MS (ESI+) m / z: [M+H]+ = 446.00.

[0178] 23.11 Synthesis of Compound 023-11 700 mg (1.57 mmol) of 023-10 was weighed into a reaction flask, and 313 mg (1.89 mmol) of 001-c, 824 mg (3.14 mmol) of triphenylphosphine, and 10 mL of dichloromethane were added. Under nitrogen protection, diisopropyl azodicarbonate (635 mg, 3.14 mmol) was slowly added dropwise at 0 °C. After the addition was complete, the reaction mixture was brought to room temperature and reacted for 2 hours. The reaction mixture was concentrated, and the residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 3 / 1 to 1 / 1 (v / v)) to give compound 023-11. LC / MS (ESI+) m / z: [M+H]+ = 594.00.

[0179] 23.12 Synthesis of Compound 023-12 Weigh 400 mg (1.674 mmol) of 023-11 into a reaction flask, add 2 mL of dichloromethane and 2 mL of 1,4-dioxane solution of hydrogen chloride (4N), and react at room temperature for 2 hours. Concentrate the reaction solution to obtain compound 023-12 (crude product), which can be used directly in the next step.

[0180] 23.13 Synthesis of Compound 023 O23-12 (300 mg, 0.613 mmol) and sodium hydroxide (246 mg, 1.84 mmol) were added sequentially to methanol (2 mL) and water (2 mL), and reacted at 60 °C for 2 hours. The reaction solution was purified by preparative high-performance liquid chromatography and lyophilized to obtain the target compound O23. 1H NMR (400 MHz, DMSO- d 6 ): δ 8.52 (d, J= 8.0 Hz, 1H), 8.43 (s, 2H), 7.69 (t, J= 4.0 Hz, 1H), 7.26 – 7.20 (m, 3H), 7.14 (d, J= 12.0 Hz, 2H), 7.04 (d, J= 8.0 Hz, 1H), 6.91 (t, J= 4.0 Hz, 1H), 5.15 (s, 2H), 4.34 (d, J= 4.0 Hz, 2H), 3.59 (s, 2H), 3.37 – 3.30 (m, 4H), 1.51 – 1.44 (m, 4H), 0.35 (s, 4H); LC / MS(ESI+) m / z: [M+H] +=476.00.

[0181] Example 24: Synthesis of 2-(2-((3'-(aminomethyl)-2'-fluoro-5-(2-oxa-7-azaspiro[3.5]nonane-7-yl)-[1,1'-biphenyl]-3-yl)methoxy)phenyl)acetic acid (compound 024 trifluoroacetate)

[0182] 24.1 Synthesis of Compound 024-1 021-1 (407 mg, 1.51 mmol), potassium carbonate (626 mg, 4.53 mmol), 001-3 (1.13 g, 2.72 mmol), [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride (110 mg, 0.15 mmol), 1,4-dioxane (9 mL), and water (1 mL) were added to a 50 mL reaction flask. After purging with nitrogen three times, the reaction mixture was refluxed at 110 °C for 2 hours. The reaction mixture was cooled to room temperature, filtered, and the filtrate was diluted with water (60 mL) and extracted with ethyl acetate (20 mL × 3). The combined organic phases were washed with saturated sodium chloride solution, 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 = 4 / 1 (v / v)) to give compound 024-1. LC / MS(ESI+)m / z:[M+H-Boc] +=457.90.

[0183] 24.2 Synthesis of Compound 024-2 024-1 (303 mg, 0.54 mmol), sodium tributoxide (156 mg, 1.63 mmol), 011-a (121 mg, 0.705 mmol), tris(dibenzylacetone)dipalladium (50 mg, 54.3 μmol), 2-dicyclohexylphosphine-2',6'-dimethoxybiphenyl (45 mg, 108.5 μmol), and toluene (10 mL) were added to a 50 mL reaction flask. After purging with nitrogen three times, the reaction mixture was refluxed at 110 °C for 2 hours. The reaction mixture was cooled to room temperature, the pH was adjusted to 2 with 0.5 M dilute hydrochloric acid, filtered, and the filtrate was diluted with water (60 mL). The filtrate was extracted with ethyl acetate (20 mL × 3). The combined organic phases were washed with saturated sodium chloride aqueous solution, 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 compound 024-2. LC / MS(ESI+)m / z:[M+H] +=591.05.

[0184] 24.3 Synthesis of the trifluoroacetate of compound 024 024-2 (59 mg, 0.1 mmol) and dichloromethane (2 mL) were placed in a flask, and trifluoroacetic acid (0.4 mL) was added to the system at room temperature. The mixture was stirred at room temperature for 2 hours. The reaction solution was concentrated under reduced pressure, and the residue was purified by high performance liquid chromatography. After lyophilization, the trifluoroacetic acid salt of compound 024 was obtained. 1H NMR (600 MHz, DMSO- d 6 ): δ 8.25 (s, 2H), 7.57 (dt, J1= 7.6 Hz, J2= 1.6 Hz, 1H), 7.51 (t, J= 7.6 Hz, 1H), 7.34 (t, J= 7.6 Hz, 1H), 7.22 (d, J= 7.2 Hz, 2H), 7.12 (s, 1H), 7.04-7.0 (m, 3H), 6.90 (t, J= 7.6 Hz, 1H), 5.11 (s, 2H), 4.35 (s, 4H), 4.15 (d, J= 6.0 Hz, 2H), 3.58 (s, 2H), 3.17 (t, J= 5.6 Hz, 3H), 1.89 (t, J= 5.6 Hz, 3H), 1.23 (s, 2H); LC / MS(ESI+) m / z: [M+H] +=491.05.

[0185] Example 25: Synthesis of 2-(2-((3'-(aminomethyl)-2'-fluoro-5-(2-oxa-7-azaspiro[3.5]nonane-7-yl)-[1,1'-biphenyl]-3-yl)methoxy)-5-fluorophenyl)acetic acid (compound 025)

[0186] 25.1 Synthesis of Compound 025-1 Compounds 010-3 (300 mg, 0.69 mmol) and 021-1 (244 mg, 0.69 mmol), potassium carbonate (192 mg, 1.39 mmol), and [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride (52 mg, 0.07 mmol) were dissolved in 1,4-dioxane (10 mL) and water (1 mL) under nitrogen protection. The resulting mixture was reacted at 100 °C for 2 h. The reaction mixture was cooled to room temperature, water was added, and the mixture was extracted with ethyl acetate (10 mL × 3). The combined organic phases were 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 = 3 / 1 to 1 / 1 (v / v)) to give compound 025-1. LC / MS (ESI+) m / z: [M+H-Boc]+ = 475.85.

[0187] 25.2 Synthesis of Compound 025-2 025-1 (300 mg, 0.52 mmol) was weighed into a reaction flask, and 011-a (110 mg, 0.52 mmol), cesium carbonate (680 mg, 2.08 mmol), 1,4-dioxane (10 mL), tris(dibenzylacetone)dipalladium (80 mg, 0.06 mmol), and 2-dicyclohexylphosphine-2',4',6'-triisopropylbiphenyl (150 mg, 0.06 mmol) were added. The reaction mixture was reacted at 100 °C for 4 hours. The reaction solution was filtered, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 3 / 1~1 / 1 (v / v)) to obtain compound 025-2. LC / MS (ESI+) m / z: [M+H]+ = 623.00.

[0188] 25.3 Synthesis of Compound 025 The synthesis of compound 025 is performed according to steps 1.6 and 1.7 of Example 1. 1H NMR (600 MHz, DMSO- d 6 ): δ 7.43 (t, J= 8.0 Hz, 1H), 7.41 – 7.36 (m, 1H), 7.21 (t, J = 8.0 Hz, 1H), 7.08 – 7.04 (m, 2H), 7.02 (s, 1H), 7.00 – 6.94 (m, 3H), 5.10 (s, 2H), 4.34 (s, 4H), 3.83 (s, 2H), 3.51 (s, 2H), 3.18 – 3.12 (m, 4H), 1.90 – 1.87 (m, 4H); LC / MS(ESI+) m / z:[M+H] +=509.05.

[0189] Example 26: Synthesis of 2-(2-((3'-(aminomethyl)-4-fluoro-5-(2-oxa-7-azaspiro[3.5]nonane-7-yl)-[1,1'-biphenyl]-3-yl)methoxy)phenyl)acetic acid (compound 026)

[0190] 26.1 Synthesis of Compound 026-1 Weigh 3.0 g (13.7 mmol) of 026-a into a reaction flask, add 10 mL of sulfuric acid, and slowly add 2.5 g (14.4 mmol) of N-iodosuccinimide at 0°C. Then, raise the temperature to room temperature and react overnight. Pour the reaction solution into ice water, and a solid will precipitate. Filter and dry the solid to obtain compound 026-1.

[0191] 26.2 Synthesis of Compound 026-2 3.6 g (10.44 mmol) of 026-1 was weighed into a reaction flask, and 20 mL of tetrahydrofuran was added. Under nitrogen protection, a tetrahydrofuran solution of borane (31.3 mL, 31.30 mmol, 1M) was slowly added dropwise at 0 °C. After reacting for 10 minutes, the temperature was raised to 60 °C and reacted for 2 hours. The reaction solution was cooled to room temperature, and the reaction was quenched by slowly adding 20 mL of methanol. After quenching, the reaction solution was concentrated, and the residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 10 / 1~1 / 1 (v / v)) to obtain compound 026-2.

[0192] 26.3 Synthesis of Compound 026-3 Weigh 026-2 (1 g, 3.02 mmol) into a reaction flask, add 001-c (551 mg, 3.02 mmol), dichloromethane (20 mL), and triphenylphosphine (1.6 g, 6.04 mmol), purge three times with nitrogen, and slowly add diisopropyl azodicarbonate (2.2 g, 6.04 mmol) at 0 °C. The reaction mixture was then reacted at room temperature for 2 hours. The reaction solution was concentrated, and the residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 10 / 1~1 / 1 (v / v)) to give compound 026-3. LC / MS (ESI+) m / z: [M+H]+ = 480.75.

[0193] 26.4 Synthesis of Compound 026-4 Under nitrogen protection, 026-3 (540 mg, 1.13 mmol) and 001-2 (376 mg, 1.13 mmol), potassium carbonate (312 mg, 2.25 mmol), and [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride (83 mg, 0.113 mmol) were dissolved in 1,4-dioxane (10 mL) and water (1 mL), and reacted at 100 °C for 2 h. The reaction mixture was cooled to room temperature, water was added, and the mixture was extracted with ethyl acetate (10 mL × 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 3 / 1 to 1 / 1 (v / v)) to give compound 026-4. LC / MS (ESI+) m / z: [M+H]+ = 459.90.

[0194] 26.5 Synthesis of Compound 026-5 Weigh 026-4 (400 mg, 0.72 mmol) into a reaction flask, add 011-a (110 mg, 0.72 mmol), cesium carbonate (480 mg, 1.4 mmol), 1,4-dioxane (10 mL), tris(dibenzylacetone)palladium (66 mg, 0.07 mmol), and 2-dicyclohexylphosphine-2',4',6'-triisopropylbiphenyl (32 mg, 0.07 mmol), and react at 100 °C for 4 hours. Cool to room temperature, dilute the reaction solution with water (20 mL), and extract with ethyl acetate (20 mL × 3). Concentrate the organic phase, and purify the residue by silica gel column chromatography (petroleum ether / ethyl acetate = 3 / 1 ~ 1 / 1 (v / v)) to give compound 026-5. LC / MS (ESI+) m / z: [M+H]+ = 605.10.

[0195] 26.6 Synthesis of Compound 026 The synthesis of compound 026 is performed according to steps 1.6 and 1.7 of Example 1. 1H NMR (400 MHz, DMSO- d 6 ): δ 8.14 (s, 1H), 7.66 (d, J= 4.0 Hz, 2H), 7.37 (t, J= 8.0 Hz, 1H), 7.27-7.22 (m, 2H), 7.12-7.07 (m, 2H), 6.89 (d, J= 8.0 Hz, 1H), 6.81 (t, J= 8.0 Hz, 1H), 5.25 (s, 2H), 4.37 (s, 4H), 3.93 (s, 2H), 3.39 (s, 2H), 3.00 (s, 4H), 2.07-1.86 (m, 4H);LC / MS(ESI+) m / z:[M+H] +=491.05.

[0196] Example 27: Synthesis of 2-(2-((3'-(aminomethyl)-6-fluoro-5-(2-oxa-7-azaspiro[3.5]nonane-7-yl)-[1,1'-biphenyl]-3-yl)methoxy)phenyl)acetic acid (compound 027)

[0197] 27.1 Synthesis of Compound 027-1 2.0 g (7.4 mmol) of 027-a was weighed and dissolved in acetonitrile (20 mL). N-bromobutyldiamide (1.31 g, 7.4 mmol) and azobisisobutyronitrile (120 mg, 0.74 mmol) were added, and the mixture was reacted at 80 °C for 2 hours. The reaction solution was concentrated, and the residue was purified by silica gel column chromatography to obtain compound 027-1.

[0198] 27.2 Synthesis of Compound 027-2 1.8 g (5.19 mmol) of 027-1 was weighed and dissolved in acetonitrile (20 mL). Potassium carbonate (1.43 g, 10.38 mmol) and methyl o-hydroxyphenylacetate (905.5 mg, 5.45 mmol) were added, and the mixture was reacted at 25 °C for 2 hours. The reaction solution was filtered, the filtrate was concentrated, and the residue was purified by silica gel column chromatography to obtain compound 027-2. LC / MS (ESI+) m / z: [M+H]+ = 432.8.

[0199] 27.3 Synthesis of Compound 027-3 Weigh 027-2 (1.0 g, 2.3 mmol) into a reaction flask, add potassium carbonate (640 mg, 4.6 mmol), 001-2 (0.77 g, 2.3 mmol), [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride (100 mg, 10 wt%), 1,4-dioxane (10 mL), and water (1 mL). React at 90 °C for 2 hours under nitrogen protection. Cool the reaction solution to room temperature, filter, concentrate the filtrate under reduced pressure, and purify the residue by silica gel column chromatography to obtain compound 027-3. LC / MS (ESI+) m / z: [M+H]+ = 558.1.

[0200] 27.4 Synthesis of Compound 027-4 027-3 (120 mg, 0.21 mmol) was weighed and dissolved in 1,4-dioxane (5 mL). 011-a (48.7 mg, 0.25 mmol), cesium carbonate (210 mg, 0.64 mmol), tris(dibenzylacetone)palladium (12 mg, 10 wt%), and 2-dicyclohexylphosphine-2',4',6'-triisopropylbiphenyl (12 mg, 10 wt%) were added. The reaction mixture was reacted at 100 °C for 2 hours under nitrogen protection. After cooling to room temperature, the reaction mixture was filtered, the filtrate was concentrated, and the residue was purified by silica gel column chromatography to obtain compound 027-4. LC / MS (ESI+) m / z: [M+H]+ = 605.1.

[0201] 27.5 Synthesis of Compound 027 The synthesis of compound 027 follows the synthesis method described in steps 1.6 and 1.7 of Example 1. 1H NMR (400 MHz, DMSO- d 6 ): δ 7.98 (s, 1H), 7.61 (d, J= 7.2 Hz, 1H), 7. 43 (d, J= 5.6 Hz, 1H), 7.38 (t, J= 8.0 Hz, 1H), 7.30 (d, J= 7.6 Hz, 1H), 7.10-7.08 (m, 3H), 6.90 (d, J= 8.4 Hz, 1H), 6.80 (t, J= 7.6 Hz, 1H), 5.10 (s, 2H), 4.37 (s, 4H), 3.94 (s, 2H), 3.36 (s, 2H), 2.95 (t, J= 5.2 Hz, 4H), 1.95 (t, J= 5.6 Hz, 4H); LC / MS(ESI+) m / z: [M+H] +=491.0.

[0202] Example 28: Synthesis of 2-(2-((3'-(aminomethyl)-5-(2-oxa-7-azaspiro[3.5]nonane-7-yl)-[1,1'-biphenyl]-3-yl)methoxy)-3-fluorophenyl)acetic acid (compound 028)

[0203] 28.1 Synthesis of Compound 028-1 Zinc powder (4.7 g, 71.86 mmol) was weighed into a reaction flask, tetrahydrofuran (10 mL) was added, and trimethylchlorosilane (390 mg, 3.59 mmol) was added under nitrogen protection. The reaction was carried out at 50 °C for 0.5 h, and then 028-a (6.0 g, 35.93 mmol) was slowly added dropwise. The reaction was carried out at 70 °C for 2 h to obtain a solution of compound 028-1, which was used directly in the next step.

[0204] 28.2 Synthesis of Compound 028-2 Weigh 2.0 g (9.75 mmol) of 028-b into a reaction flask, add tetrahydrofuran (10 mL), tris(dibenzylacetone)dipalladium (1.0 g, 0.98 mmol), and 2-dicyclohexylphosphine-2',4',6'-triisopropylbiphenyl (500 mg, 0.95 mmol), and slowly add a solution (12 mL) of compound 028-1 obtained in step 28.1 under nitrogen protection. React at 70 °C for 2 hours. Quench the reaction solution with saturated ammonium chloride aqueous solution (10 mL), and extract with ethyl acetate (30 mL × 3). Dry the combined organic phases with anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure. Purify the residue by silica gel column chromatography (petroleum ether / ethyl acetate = 10 / 1~1 / 1 (v / v)) to give compound 028-2. LC / MS (ESI+) m / z: [M+H]+ = 213.10.

[0205] 28.3 Synthesis of Compound 028-3 Weigh 1.8 g (8.5 mmol) of 028-2 into a reaction flask, add 20 mL of dichloromethane, and under nitrogen protection, slowly add 18 mL (17.0 mmol) of boron tribromide dropwise at 0 °C. After reacting for 10 minutes, transfer to room temperature and continue reacting for another 10 minutes. Quench the reaction by slowly adding 10 mL of ethanol, dilute with 10 mL of water, extract with dichloromethane (30 mL × 3), dry the organic phase with anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure. Purify the residue by silica gel column chromatography (petroleum ether / ethyl acetate = 10 / 1~1 / 1 (v / v)) to give compound 028-3. LC / MS (ESI+) m / z: [M+H]+ = 199.10.

[0206] 28.4 Synthesis of Compound 028-4 Weigh 028-3 (0.75 g, 3.65 mmol) into a reaction flask, add 009-b (1.2 g, 3.65 mmol), potassium carbonate (1.1 g, 7.3 mmol), and N,N-dimethylformamide (20 mL), and react at room temperature for 2 hours. Dilute the reaction solution with water (20 mL) and extract with ethyl acetate (30 mL × 3). Dry the organic phase with anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure. Purify the residue by silica gel column chromatography (petroleum ether / ethyl acetate = 10 / 1~1 / 1 (v / v)) to give compound 028-4. LC / MS (ESI+) m / z: [M+H]+ = 446.75.

[0207] 28.5 Synthesis of Compound 028 The synthesis of compound 028 is based on the same method as that of compound 027, except that 027-2 in the synthesis step is replaced with 028-4. 1H NMR (400 MHz, DMSO- d 6 ): δ 8.18 (s, 1H), 7.68 (d, J= 8.0 Hz, 1H), 7.53 (s, 1H), 7.39 (t, J= 8.0 Hz, 1H), 7.28 (d, J= 8.0 Hz, 1H), 7.18 (s, 1H), 7.09-7.03 (m, 1H), 7.00 – 6.93 (m, 3H), 5.09 (s, 2H), 4.35 (s, 4H), 3.97 (s, 2H), 3.43 (s, 2H), 3.21 – 3.16 (m, 4H), 1.93 – 1.88 (m, 4H); LC / MS(ESI+) m / z: [M+H] +=491.05.

[0208] Example 29: Synthesis of 2-(2-((3'-(aminomethyl)-5-(3-oxa-9-azaspiro[5.5]undecane-9-yl)-[1,1'-biphenyl]-3-yl)methoxy)phenyl)acetic acid (compound 029)

[0209] The synthesis of compound 029 is based on the synthesis method of compound 001, except that the starting material in the step 001-d is replaced with 3-oxa-9-azaspiro[5.5]undecane (029-a). 1H NMR (600 MHz, DMSO- d 6 ): δ 8.25 (s, 2H), 7.79 (s, 1H), 7.70 (d, J= 5.6 Hz, 1H), 7.50 (t, J= 5.2 Hz, 1H), 7.43 (d, J= 5.2 Hz, 1H), 7.25 – 7.18 (m, 4H), 7.15 (d, J= 2.0 Hz, 1H), 7.03 (d, J= 5.2 Hz, 1H), 6.93 – 6.87 (m, 1H), 5.13 (s, 2H), 4.12 (dd, J= 4.0 Hz, J= 7.6 Hz, 2H), 3.60 (s, 2H), 3.60 – 3.57 (m, 4H), 3.32 – 3.25 (m, 4H), 1.69 – 1.62 (m, 4H), 1.51 – 1.46 (m, 4H); LC / MS(ESI+) m / z:[M+H] +=501.10.

[0210] Example 30: Synthesis of 2-(2-((3'-(aminomethyl)-5-(2-oxa-9-azaspiro[5.5]undecane-9-yl)-[1,1'-biphenyl]-3-yl)methoxy)phenyl)acetic acid (compound 030)

[0211] The synthesis of compound 030 is based on the synthesis method of compound 001, except that the starting material in the step 001-d is replaced with 2-oxa-9-azaspiro[5.5]undecane (030-a). 1H NMR (400 MHz, DMSO- d 6 ): δ 8.17 (s, 1H), 7.67 (d, J= 8.0 Hz, 1H), 7.41 (s, 1H), 7.37 (t, J= 7.6 Hz, 1H), 7.26 (d, J= 7.6 Hz, 1H), 7.14 – 7.05 (m, 3H), 6.97 (s, 1H), 6.90 (d, J= 8.0 Hz, 1H), 6.80 (t, J= 7.2 Hz, 1H), 5.14 (s, 2H), 3.94 (s, 2H), 3.55 (s, 2H), 3.40 (d, J= 2.4 Hz, 4H), 3.23 (t, J= 5.6 Hz, 4H), 1.62 – 1.51 (m, 8H); LC / MS(ESI+) m / z:[M+H] +=501.15.

[0212] Example 31: Synthesis of 2-(2-((3'-(aminomethyl)-5-(6-oxa-2-azaspiro[3.4]octane-2-yl)-[1,1'-biphenyl]-3-yl)methoxy)phenyl)acetic acid (compound 031)

[0213] The synthesis of compound 031 is based on the same method as that of compound 001, except that the raw material 001-d is replaced with 6-oxa-2-azaspiro[3.4]octane (031-a). 1H NMR (400 MHz, DMSO- d 6 ): δ 9.47 (s, 1H), 7.92 (d, J= 59.6 Hz, 1H), 7.53 (dd, J= 30.0, 8 Hz, 1H), 7.39 – 7.33 (m, 1H), 7.30 – 7.24 (m, 2H), 7.17 – 7.00 (m, 2H), 6.92 – 6.74 (m, 2H), 6.64 (d, J= 5.6 Hz, 1H), 6.48 (d, J= 23.2 Hz, 1H), 5.14 (d, J= 32.0 Hz, 2H), 4.24 (s, 1H), 3.86 (s, 4H), 3.83 (d, J= 3.2 Hz, 2H), 3.74 (t, J= 7.2 Hz, 3H), 3.38 (d, J= 13.2 Hz, 2H), 2.18 – 2.13 (m, 2H); LC / MS(ESI+) m / z:[M+H] +=459.05.

[0214] Example 32: Synthesis of 2-(2-((3'-(aminomethyl)-5-(2-methyl-2,7-diazaspiro[3.5]nonane-7-yl)-[1,1'-biphenyl]-3-yl)methoxy)phenyl)acetic acid (compound 032)

[0215] The synthesis of compound 032 is based on the synthesis method of compound 001, except that the starting material is replaced by 2-methyl-2,7-diazaspiro[3.5]nonane (032-a). 1H NMR (400 MHz, DMSO- d 6 ): δ 11.67 – 11.47 (m, 1H), 10.08 (s, 1H), 8.23 ​​(s, 2H), 7.78 (s, 1H), 7.69 (d, J= 7.6 Hz, 1H), 7.50 (t, J= 7.6 Hz, 1H), 7.43 (d, J= 7.6 Hz, 1H), 7.23 (t, J= 7.6 Hz, 2H), 7.14 (d, J= 5.8 Hz, 2H), 7.07 (s, 1H), 7.03 (d, J= 8.2 Hz, 1H), 6.90 (t, J= 7.4 Hz, 1H), 5.12 (s, 2H), 4.11 (d, J= 5.4 Hz, 4H), 3.88 – 3.75 (m, 2H), 3.60 (s, 2H), 3.23 (d, J= 36.8 Hz, 4H), 2.87 (d, J= 4.2 Hz, 3H), 1.90 (s, 4H); LC / MS(ESI+) m / z: [M+H] +=486.05.

[0216] Example 33: Synthesis of 2-(2-((3'-(aminomethyl)-5-(3,9-diazaspiro[5.5]undecane-3-yl)-[1,1'-biphenyl]-3-yl)methoxy)phenyl)acetic acid (compound 033)trifluoroacetate

[0217] 33.1 Synthesis of Compound 033-1 001-4 (216 mg, 0.4 mmol), sodium terbutoxide (77 mg, 0.8 mmol), 033-a (122 mg, 0.48 mmol), tris(dibenzylacetone)palladium (37 mg, 40 μmol), 2-dicyclohexylphosphine-2',6'-dimethoxybiphenyl (33 mg, 80 μmol), and toluene (4 mL) were added to a 50 mL reaction flask. After purging with nitrogen three times, the reaction mixture was refluxed at 110 °C for 2 hours. The reaction mixture was cooled to room temperature, the pH was adjusted to 2 with 0.5 M dilute hydrochloric acid, filtered, and the filtrate was diluted with water (60 mL) and extracted with ethyl acetate (20 mL × 3). The combined organic phases were washed with saturated sodium chloride solution, 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 compound 033-1. LC / MS(ESI+) m / z: [M+H] +=700.10.

[0218] 33.2 Synthesis of compound 033 trifluoroacetate 033-1 (78 mg, 0.11 mmol) and dichloromethane (2 mL) were placed in a flask. 4-fluorophenylboronic acid (31 mg, 0.22 mmol) was added to the system at room temperature, and the mixture was stirred for 2 hours at room temperature to remove nitrogen oxides. Then, trifluoroacetic acid (0.2 mL) was added to the system, and the reaction was carried out for 1 hour at room temperature. The reaction solution was concentrated under reduced pressure, and the residue was purified by preparative high-performance liquid chromatography to obtain the trifluoroacetate salt of compound 033. 1H NMR (400 MHz, DMSO- d 6 ): δ 8.49 (s, 2H), 8.26 (s, 3H), 7.78 (s, 1H), 7.69 (d, J= 7.6 Hz, 1H), 7.50 (t, J= 7.6 Hz, 1H), 7.43 (d, J= 7.6 Hz, 1H), 7.22 (d, J= 7.2 Hz, 2H), 7.15 (d, J= 5.6 Hz, 2H), 7.10 (s, 1H), 7.04 (d, J= 8.0 Hz, 1H), 6.91 (t, J= 7.6 Hz, 1H), 5.13 (s, 2H), 4.12 (q, J= 5.6 Hz, 2H), 3.60 (s, 2H), 3.27 (t, J= 6.0 Hz, 4H), 3.09 (s, 4H), 1.64 (d, J= 5.6 Hz, 8H); LC / MS(ESI+) m / z:[M+H] +=500.10.

[0219] Example 34: Synthesis of 2-(2-((3'-(aminomethyl)-5-(2-azaspiro[4.4]nonane-2-yl)-[1,1'-biphenyl]-3-yl)methoxy)phenyl)acetic acid (compound 034)

[0220] The synthesis of compound 034 is based on the synthesis method of compound 001, except that the starting material is replaced by 2-azaspiro[4.4]nonane (034-a). 1H NMR (400 MHz, DMSO- d 6 ): δ 8.11 (s, 1H), 7.66 (d, J= 6.0 Hz, 1H), 7.37 (t, J= 6.0 Hz, 1H), 7.30 – 7.22 (m, 2H), 7.15 – 7.05 (m, 2H), 6.90 (d, J= 12.0 Hz, 1H), 6.80 (t, J= 6.0 Hz, 1H), 6.68 (s, 1H), 6.53 (s, 1H), 5.13 (s, 2H), 3.94 (s, 2H), 3.42 (s, 2H), 3.39-3.37 (m, 2H), 3.21 (s, 2H), 1.88 (t, J= 6.0 Hz, 2H), 1.70 – 1.65 (m, 4H), 1.64 – 1.56 (m, 4H); LC / MS(ESI+) m / z: [M+H] +=471.10.

[0221] Example 35: Synthesis of (S)-2-(2-((3'-(1-aminoethyl)-5-(4-oxa-7-azaspiro[2.5]octane-7-yl)-[1,1'-biphenyl]-3-yl)methoxy)phenyl)acetic acid (compound 035-A or 035-B) and (R)-2-(2-((3'-(1-aminoethyl)-5-(4-oxa-7-azaspiro[2.5]octane-7-yl)-[1,1'-biphenyl]-3-yl)methoxy)phenyl)acetic acid (compound 035-B or 035-A))

[0222] 35.1 Synthesis of Compound 035-1 Weigh 500 mg (2.5 mmol) of 035-a into a reaction flask, add 599.95 mg (2.75 mmol) of dibutyl dicarbonate, triethylamine (505.77 mg, 5 mmol), and dichloromethane (5 mL), and react at room temperature for 2 hours. After concentrating the reaction solution, the residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 20 / 1~15 / 1 (v / v)) to obtain compound 035-1, which was directly used in the next step. LC / MS (ESI+) m / z: [M+H-tBu]+ = 244.0.

[0223] 35.2 Synthesis of Compound 035-2 035-1 (7.50 g, 24.98 mmol), pinacol diborate (7.61 g, 29.98 mmol), potassium acetate (4.90 g, 49.97 mmol), and [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride (0.75 g, 2.50 mmol) were dissolved in 1,4-dioxane (80 mL), purged with nitrogen three times, and reacted at 85 °C for 10 h. After cooling to room temperature, the reaction mixture was diluted with water (80 mL) and extracted with ethyl acetate (100 mL × 3). The combined organic phases were washed with saturated brine, 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 = 10 / 1~3 / 1 (v / v)) to give compound 035-2. LC / MS(ESI+) m / z:[M+H-tBu] +=292.05.

[0224] 35.3 Synthesis of Compound 035-3 Compound 001-3 (3.2 g, 7.74 mmol), 035-2 (1.42 g, 6.45 mmol), potassium carbonate (1.78 g, 12.89 mmol), and tetrakis(triphenylphosphine)palladium (0.7 g, 0.64 mmol) were dissolved in a mixed solution of 1,4-dioxane and water (40 mL, 1,4-dioxane / water = 4 / 1 (v / v)), purged with nitrogen three times, and reacted at 80 °C for 16 h. After cooling to room temperature, the reaction mixture was extracted with ethyl acetate (50 mL × 3). The combined organic phases were washed with saturated brine, 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 = 8 / 1~3 / 1 (v / v)) to give compound 035-3. LC / MS (ESI+) m / z: [M+H-Boc]+ = 453.95.

[0225] 35.4 Synthesis of Compound 035-4 035-3 (0.2 g, 0.36 mmol), 016-a (65 mg, 0.43 mmol), tris(dibenzylacetone)palladium (20 mg, 0.04 mmol), 2-dicyclohexylphosphine-2',4',6'-triisopropylbiphenyl (20 mg, 0.04 mmol), and cesium carbonate (0.5 g, 1.44 mmol) were dissolved in 1,4-dioxane (3 mL), and the mixture was purged with nitrogen three times. The reaction mixture was then reacted at 100 °C for 16 hours. After cooling to room temperature, the reaction mixture was diluted with water (15 mL) and extracted with ethyl acetate (10 mL × 3). The combined organic phases were washed with saturated brine (10 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 = 10 / 1~1 / 1 (v / v)) to give compound 035-4. LC / MS(ESI+) m / z: [M+H] +=587.15.

[0226] 35.5 Synthesis of compounds 035-A and 035-B The synthesis of compound 035 followed steps 1.6 and 1.7 of Example 1. 035 was further chirally resolved by supercritical fluid chromatography (Method: AD-3-IPA+CAN(DEA)-40-3 mL-35 T) to obtain 035-A (retention time Rt = 1.097 min) and 035-B (retention time Rt = 1.773 min). 035-A (Retention time Rt = 1.097 min): 1H NMR (400 MHz, DMSO-d6): δ 8.27 (s, 1H), 7.69 (d, J = 7.8 Hz, 1H), 7.54 (s, 1H), 7.38 (t, J = 7.6 Hz, 1H), 7.26 (d, J = 7.4 Hz, 1H), 7.13 (s, 1H), 7.09 (d, J = 4.8 Hz, 2H), 6.96 (s, 1H), 6.89 (d, J = 8.6 Hz, 1H), 6.80 (t, J = 7.4 Hz, 1H), 5.11 (s, 2H), 4.25 (d, J = 6.2 Hz, H), 3.83 (s, 2H), 3.43 – 3.26 (m, 4H), 3.20 (s, 2H), 1.50 (d, J = 6.4 Hz, 3H), 0.80 – 0.61 (m, 4H); LC / MS(ESI+) m / z: [M+H]+ = 473.05. 035-B (Retention time Rt = 1.773 min): 1H NMR (400 MHz, DMSO-d6): δ 8.25 (s, 1H), 7.69 (d, J = 7.8 Hz, 1H), 7.53 (s, 1H), 7.39 (t, J = 7.6 Hz, 1H), 7.27 (d, J = 7.6 Hz, 1H), 7.13 (s, 1H), 7.10 (dt, J = 4.0, 3.6 Hz, 2H), 6.97 (s, 1H), 6.90 (d, J = 8.4 Hz, 1H), 6.81 (t, J = 7.4 Hz, 1H), 5.12 (s, 2H), 4.26 (d, J =H, 6.6 Hz), 3.87 – 3.80 (m, 2H), 3.40 (dd, J = 17.8, 12.0 Hz, 2H), 3.31 – 3.26 (m, 2H), 3.20 (s, 2H), 1.50 (d, J = 6.8 Hz, 3H), 0.77 – 0.65 (m, 4H); LC / MS(ESI+) m / z: [M+H]+ = 473.05.

[0227] It should be noted that there seems to be a small error in the "4.25 (d, J = 6.2 Hz, H)" in the original text which is likely a typo and is marked as such in the translation. Also, the "4.26 (d, J =H, 6.6 Hz)" in the translation is adjusted to a more standard format based on the context.Example 36, (S)-2-(2-((3'-(1-aminoethyl)-5-(2-oxa-8-azaspiro[4.5]decane-8-yl)-[1,1'-biphenyl]-3-yl)methoxy)phenyl)acetic acid (compound 036-A or 036-B) and (R)-2-(2-((3'-(1-aminoethyl)-5-(2-oxa-8-azaspiro[4.5]decane-8-yl)-[1,1'-biphenyl]-3-yl)methoxy)phenyl)acetic acid (compound 036-B or 036-A) and synthesis

[0228] 36.1 Synthesis of Compound 036-1 035-3 (0.1 g, 0.18 mmol), 014-a (36 mg, 0.19 mmol), tris(dibenzylacetone)palladium (10 mg, 0.02 mmol), 2-dicyclohexylphosphine-2',4',6'-triisopropylbiphenyl (10 mg, 0.02 mmol), and cesium carbonate (0.3 g, 0.91 mmol) were dissolved in 1,4-dioxane (3 mL), and the mixture was purged with nitrogen three times. The reaction mixture was then reacted at 100 °C for 16 hours. After cooling to room temperature, the reaction mixture was diluted with water (10 mL) and extracted with ethyl acetate (10 mL × 3). The organic phases were combined. The organic phase was washed with saturated brine (10 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 = 10 / 1~1 / 1 (v / v)) to give compound 036-1. LC / MS(ESI+) m / z:[M+H] +=615.10.

[0229] 36.2 Synthesis of compounds 036-A and 036-B The synthesis of compound 036 was performed according to steps 1.6 and 1.7 of Example 1. Compound 036 was further chirally resolved by supercritical fluid chromatography (Method: OD-MeOH(DEA)-40-3 mL-35 T) to obtain 036-A (retention time Rt = 0.912 min) and 036-B (retention time Rt = 1.354 min).

[0230] 036-A (Retention time Rt = 0.912 min): 1H NMR (400 MHz, DMSO-d6): δ 8.24 (s, 1H), 7.67 (d, J = 7.8 Hz, 1H), 7.47 (s, 1H), 7.39 (t, J = 7.8 Hz, 1H), 7.27 (d, J = 7.6 Hz, 1H), 7.11 (dd, J = 12.8, 7.0 Hz, 3H), 7.00 (s, 1H), 6.92 (d, J = 8.4 Hz, 1H), 6.81 (t, J = 7.4 Hz, 1H), 5.11 (s, 2H), 4.27 (q, J = 6.4 Hz, 1H), 3.77 (t, J = 7.2 Hz, 2H), 3.40 (dd, J = 18.2, 10.8 Hz, 2H), 3.26 (ddt, J = 18.2, 12.0, 6.0 Hz, 4H), 1.76 (t, J = 7.2 Hz, 2H), 1.71 – 1.59 (m, 4H), 1.50 (d, J = 6.8 Hz, 3H); LC / MS(ESI+) m / z: [M+H]+ = 501.10。 036-B (Retention time Rt = 1.354 min): 1H NMR (400 MHz, DMSO-d6): δ 8.26 (s, 1H), 7.67 (d, J = 7.8 Hz, 1H), 7.49 (s, 1H), 7.38 (t, J = 7.6 Hz, 1H), 7.26 (d, J = 7.6 Hz, 1H), 7.11 (dd, J = 14.8, 8.4 Hz, 3H), 6.99 (s, 1H), 6.91 (d, J = 8.6 Hz, 1H), 6.81 (d, J = 7.4 Hz, 1H), 5.11 (s, 2H), 4.25 (d, J = 6.8 Hz, 1H), 3.77 (t, J = 7.0 Hz, 2H), 3.50 (s, 2H), 3.45 – 3.33 (m, 2H), 3.33 – 3.18 (m, 4H), 1.76 (t, J = 7.2 Hz, 2H), 1.65 (d, J = 5.0 Hz, 4H), 1.50 (d, J = 6.8 Hz, 3H); LC / MS(ESI+) m / z: [M+H]+ = 501.10。

[0231] Example 37: Synthesis of 2-(2-((3'-(1-aminoethyl)-5-(6-azaspiro[2.5]octane-6-yl)-[1,1'-biphenyl]-3-yl)methoxy)phenyl)acetic acid (compound 037)

[0232] 37.1 Synthesis of Compound 037-1 035-3 (0.5 g, 0.90 mmol), 001-d (160 mg, 1.08 mmol), tris(dibenzylacetone)palladium (50 mg, 0.09 mmol), 2-dicyclohexylphosphine-2',4',6'-triisopropylbiphenyl (25 mg, 0.09 mmol), and cesium carbonate (0.6 g, 3.61 mmol) were dissolved in 1,4-dioxane (5 mL), and the mixture was purged with nitrogen three times. The reaction mixture was then reacted at 100 °C for 16 hours. After cooling to room temperature, the reaction mixture was diluted with water (15 mL) and extracted with ethyl acetate (10 mL × 3). The combined organic phases were washed with saturated brine (10 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 = 10 / 1~1 / 1 (v / v)) to give compound 037-1. LC / MS(ESI+) m / z:[M+H] +=585.15.

[0233] 37.2 Synthesis of Compound 037 The synthesis of compound 037 follows the synthesis method described in steps 1.6 and 1.7 of Example 1. 1H NMR (400 MHz, DMSO- d 6 ): δ 8.32 (s, 2H), 7.78 (s, 1H), 7.69 (d, J= 7.8 Hz, 1H), 7.52 (t, J= 7.8 Hz, 1H), 7.45 (d, J= 7.8 Hz, 1H), 7.26 (d, J= 10.0 Hz, 2H), 7.22 (dd, J= 7.6, 1.3 Hz, 2H), 7.19 (s, 1H), 7.04 (d, J= 8.0 Hz, 1H), 6.90 (dd, J= 11.6, 4.1 Hz, 1H), 5.14 (s, 2H), 4.51 – 4.45 (m, 1H), 3.60 (s, 2H), 3.40 – 3.33 (m, 4H), 1.55 (d, J= 6.8 Hz, 3H), 1.52 (d, J= 5.4 Hz, 4H), 0.37 (s, 4H); LC / MS(ESI+) m / z:[M+H] +=471.05.

[0234] Example 38. Synthesis of (S)-2-(2-((3'-(1-aminoethyl)-5-(3-oxa-9-azaspiro[5.5]undecane-9-yl)-[1,1'-biphenyl]-3-yl)methoxy)phenyl)acetic acid (compound 038-A or 038-B) and (R)-2-(2-((3'-(1-aminoethyl)-5-(3-oxa-9-azaspiro[5.5]undecane-9-yl)-[1,1'-biphenyl]-3-yl)methoxy)phenyl)acetic acid (compound 038-B or 038-A))

[0235] 38.1 Synthesis of Compound 038-1 Weigh 035-3 (300 mg, 0.54 mmol) into a reaction flask, add 029-a (93 mg, 0.60 mmol), cesium carbonate (705 mg, 2.16 mmol), 1,4-dioxane (3 mL), tris(dibenzylacetone)dipalladium (49 mg, 0.05 mmol), and 2-dicyclohexylphosphine-2',4',6'-triisopropylbiphenyl (25 mg, 0.05 mmol). After purging with nitrogen, react at 100 °C for 5 hours. Cool to room temperature, dilute the reaction solution with water (10 mL), and extract with ethyl acetate (20 mL × 3). Combine the organic phases and wash with saturated brine (10 mL), dry to anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure. Purify the residue by silica gel column chromatography to obtain compound 038-1. LC / MS(ESI+) m / z: [M+H] +=629.15.

[0236] 38.2 Synthesis of compounds 038-A and 038-B The synthesis of compound 038 was performed according to steps 1.6 and 1.7 of Example 1. Compound 038 was further chirally resolved by supercritical fluid chromatography (Method: OD-EtOH(DEA)-40-3 mL-35 T) to obtain 038-A (retention time Rt = 1.079 min) and 038-B (retention time Rt = 1.627 min). 038-A (Retention time Rt = 1.079 min): 1H NMR (400 MHz, DMSO- d 6 ): δ 8.25 (s, 1H), 7.66 (d, J= 7.4 Hz, 1H), 7.47 (s, 1H), 7.37 (t, J= 7.4 Hz, 1H), 7.26 (d, J= 7.2 Hz, 1H), 7.16 – 7.03 (m, 3H), 6.98 (s, 1H), 6.90 (d, J= 8.8 Hz, 1H), 6.79 (d, J= 7.2 Hz, 1H), 5.10 (s, 2H), 4.24 (s, 1H), 3.59 (s, 4H), 3.35 (s, 2H), 3.25 (s, 4H), 1.64 (s, 4H), 1.49 (s, 3H), 1.49 – 1.41 (m, 4H); LC / MS(ESI+) m / z: [M+H] +=515.05. 038-B (Retention time Rt = 1.627 min): 1H NMR (400 MHz, DMSO- d 6 ): δ 8.32 (s, 2H), 7.79 (s, 1H), 7.67 (d, J= 7.6 Hz, 1H), 7.50 (t, J= 7.6 Hz, 1H), 7.44 (d, J= 7.8 Hz, 1H), 7.22 (d, J= 7.6 Hz, 2H), 7.08 (s, 1H), 7.07 – 6.96 (m, 3H), 6.90 (t, J= 7.4 Hz, 1H), 5.12 (s, 2H), 4.50 (s, 1H), 3.60 (s, 4H), 3.57 (s, 2H), 3.28 – 3.23 (m, 4H), 1.73 – 1.58 (m, 4H), 1.55 (d, J = 6.8 Hz, 3H), 1.51 – 1.44 (m, 4H); LC / MS(ESI+) m / z: [M+H] +=515.05.

[0237] Example 39. Synthesis of (S)-2-(2-((3'-(1-aminoethyl)-5-(2-oxa-9-azaspiro[5.5]undecane-9-yl)-[1,1'-biphenyl]-3-yl)methoxy)phenyl)acetic acid (compound 039-A or 039-B) and (R)-2-(2-((3'-(1-aminoethyl)-5-(2-oxa-9-azaspiro[5.5]undecane-9-yl)-[1,1'-biphenyl]-3-yl)methoxy)phenyl)acetic acid (compound 039-B or 039-A))

[0238] 39.1 Synthesis of Compound 039-1 Weigh 035-3 (300 mg, 0.54 mmol) into a reaction flask, then add 030-a (93 mg, 0.60 mmol), cesium carbonate (705 mg, 2.16 mmol), 1,4-dioxane (3 mL), tris(dibenzylacetone)palladium (49 mg, 0.05 mmol), and 2-dicyclohexylphosphine-2',4',6'-triisopropylbiphenyl (25 mg, 0.05 mmol) sequentially. After purging with nitrogen, the reaction mixture was reacted at 100 °C for 5 hours, then diluted with water (10 mL) and extracted with ethyl acetate (20 mL × 3). The combined organic phases were washed with saturated brine (10 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 obtain compound 039-1. LC / MS(ESI+) m / z: [M+H] +=629.15.

[0239] 39.2 Synthesis of compounds 039-A and 039-B The synthesis of compound 039 followed steps 1.6 and 1.7 of Example 1. Compound 039 was further chirally resolved by supercritical fluid chromatography (Method: OD-MeOH(DEA)-40-3 mL-35 T) to obtain 039-A (retention time Rt = 0.935 min) and 039-B (retention time Rt = 1.302 min). 039-A (Retention time Rt = 0.935 min): 1H NMR (400 MHz, DMSO- d 6 ): δ 8.28 (s, 2H), 7.79 (s, 1H), 7.68 (d, J= 7.6 Hz, 1H), 7.51 (t, J= 7.6 Hz, 1H), 7.45 (d, J= 8.0 Hz, 1H), 7.21 (d, J= 7.6 Hz, 2H), 7.16 (s, 2H), 7.10 (s, 1H), 7.03 (d, J= 8.0 Hz, 1H), 6.92 – 6.88 (m, 1H), 5.13 (s, 2H), 4.51 – 4.48 (m, 1H), 3.60 (s, 2H), 3.58 (s, 2H), 3.40 (s, 2H), 3.27 – 3.25 (m, 4H), 1.58 – 1.54 (m, 11H); LC / MS(ESI+) m / z: [M+H] +=515.05. 039-B (Retention time Rt = 1.302 min): 1H NMR (400 MHz, DMSO- d 6 ): δ 8.27 (s, 1H), 7.66 (d, J= 7.8 Hz, 1H), 7.48 (s, 1H), 7.37 (t, J= 7.6 Hz, 1H), 7.26 (d, J= 7.6 Hz, 1H), 7.16 – 7.04 (m, 3H), 6.97 (s, 1H), 6.90 (d, J= 8.4 Hz, 1H), 6.80 (t, J= 7.2 Hz, 1H), 5.10 (s, 2H), 4.24 (d, J= 6.6 Hz, 1H), 3.55 (s, 2H), 3.41 (d, J= 13.0 Hz, 2H), 3.33 (d, J= 15.0 Hz, 2H), 3.24 (t, J= 5.6 Hz, 4H), 1.65 – 1.52 (m, 8H), 1.50 (d, J= 6.6 Hz, 3H); LC / MS(ESI+) m / z: [M+H] +=515.05.

[0240] Example 40: Synthesis of (S)-2-(2-((3'-(1-aminoethyl)-5-(6-oxa-2-azaspiro[3.4]octane-2-yl)-[1,1'-biphenyl]-3-yl)methoxy)phenyl)acetic acid (compound 040-A or 040-B) and (R)-2-(2-((3'-(1-aminoethyl)-5-(6-oxa-2-azaspiro[3.4]octane-2-yl)-[1,1'-biphenyl]-3-yl)methoxy)phenyl)acetic acid (compound 040-B or 040-A)

[0241] 40.1 Synthesis of Compound 040-1 Weigh out 035-3 (300 mg, 0.54 mmol) and dissolve it in 1,4-dioxane (5 mL). Add 031-a (67 mg, 0.60 mmol), cesium carbonate (706 mg, 2.16 mmol), tris(dibenzylacetone)palladium (30 mg, 10 wt%) and 2-dicyclohexylphosphine-2',4',6'-triisopropylbiphenyl (30 mg, 10 wt%). The reaction solution was reacted at 100 °C for 2 hours under nitrogen protection. After filtration, the filtrate was concentrated, and the residue was purified by silica gel column chromatography to obtain compound 040-1.

[0242] 40.2 Synthesis of compounds 040-A and 040-B The synthesis of compound 040 followed steps 1.6 and 1.7 of Example 1. Compound 040 was further chirally resolved by supercritical fluid chromatography (Method: Cellulose-2-3-MeOH+CAN(DEA)-50-3 mL-35 T) to obtain 040-A (retention time Rt = 1.272 min) and 040-B (retention time Rt = 1.982 min). 040-A (Retention time Rt = 1.272 min): 1H NMR (400 MHz, DMSO- d 6 ): δ 8.24 (s, 1H), 7.62 (d, J= 7.8 Hz, 1H), 7.39 (dd, J= 18.0, 10.4 Hz, 2H), 7.26 (d, J= 7.4 Hz, 1H), 7.09 (t, J= 6.4 Hz, 2H), 6.90 (d, J= 8.6 Hz, 1H), 6.80 (t, J= 7.4 Hz, 1H), 6.64 (s, 1H), 6.48 (s, 1H), 5.09 (s, 2H), 4.24 (d, J= 6.6 Hz, 1H), 3.87 (s, 2H), 3.83 (s, 2H), 3.75 (s, 2H), 3.37 (dd, J= 28.2, 15.0 Hz, 4H), 2.16 (t, J= 6.8 Hz, 2H), 1.49 (d, J= 6.4 Hz, 3H); LC / MS(ESI+) m / z: [M+H] +=473.10. 040-B (Retention time Rt = 1.982 min): 1H NMR (400 MHz, DMSO- d 6 ): δ 8.21 (s, 1H), 7.60 (d, J= 7.4 Hz, 1H), 7.38 (dd, J= 16.8, 9.2 Hz, 2H), 7.25 (d, J= 6.8 Hz, 1H), 7.08 (d, J= 6.8 Hz, 2H), 6.90 (d, J= 8.2 Hz, 1H), 6.80 (t, J= 7.2 Hz, 1H), 6.64 (s, 1H), 6.48 (s, 1H), 5.09 (s, 2H), 4.22 (d, J= 5.4 Hz, 1H), 3.87 (s, 2H), 3.83 (s, 2H), 3.75 (s, 2H), 3.37 (dt, J= 24.8, 12.3 Hz, 4H), 2.16 (t, J= 6.8 Hz, 2H), 1.48 (d, J= 4.8 Hz, 3H); LC / MS(ESI+) m / z:[M+H] +=473.10.

[0243] Example 41: Synthesis of 2-(2-((3'-(1-aminoethyl)-5-(1-oxa-6-azaspiro[3.4]octane-6-yl)-[1,1'-biphenyl]-3-yl)methoxy)phenyl)acetic acid (compound 041)

[0244] 41.1 Synthesis of Compound 041-1 035-3 (0.5 g, 0.90 mmol), 041-a (175 mg, 0.58 mmol), tris(dibenzylacetone)palladium (50 mg, 0.09 mmol), 2-dicyclohexylphosphine-2',4',6'-triisopropylbiphenyl (25 mg, 0.09 mmol), and cesium carbonate (1.2 g, 3.6 mmol) were dissolved in 1,4-dioxane (5 mL), and the mixture was purged with nitrogen three times. The reaction mixture was then reacted at 100 °C for 16 hours. The reaction mixture was diluted with water (15 mL) and extracted with ethyl acetate (10 mL × 3). The combined organic phases were washed with saturated brine (10 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 = 10 / 1~1 / 1 (v / v)) to give compound 041-1. LC / MS(ESI+) m / z:[M+H] +=587.10.

[0245] 41.2 Synthesis of Compound 041 The synthesis of compound 041 is performed according to steps 1.6 and 1.7 of Example 1. 1H NMR (400 MHz, DMSO- d 6 ): δ 7.95 (d, J= 42.0 Hz, 1H), 7.54 (d, J= 7.4 Hz, 1H), 7.33 (dt, J= 16.0, 7.7 Hz, 2H), 7.14 (d, J= 6.6 Hz, 2H), 7.06 (t, J= 7.2 Hz, 1H), 6.91 (d, J= 8.0 Hz, 1H), 6.79 (t, J= 7.4 Hz, 1H), 6.72 – 6.54 (m, 2H), 5.07 (s, 2H), 4.43 (t, J= 6.6 Hz, 2H), 4.11 (q, J= 6.6 Hz, 1H), 3.57 (d, J= 40.0 Hz, 2H), 3.39 – 3.28 (m, 4H), 2.80 – 2.61 (m, 2H), 2.41 – 2.12 (m, 3H), 1.37 (d, J= 6.6 Hz, 3H); LC / MS(ESI+) m / z:[M+H] +=473.10.

[0246] Example 42: Synthesis of (S)-2-(2-((3'-(1-aminoethyl)-5-(2-oxa-7-azaspiro[3.5]nonane-7-yl)-[1,1'-biphenyl]-3-yl)methoxy)phenyl)acetic acid (compound 042-A or 042-B) and (R)-2-(2-((3'-(1-aminoethyl)-5-(2-oxa-7-azaspiro[3.5]nonane-7-yl)-[1,1'-biphenyl]-3-yl)methoxy)phenyl)acetic acid (compound 042-B or 042-A)

[0247] 42.1 Synthesis of Compound 042-1 035-3 (500 mg, 0.9 mmol) was weighed into a reaction flask, and 011-a (130 mg, 0.99 mmol), cesium carbonate (1.2 g, 3.6 mmol), 1,4-dioxane (5 mL), tris(dibenzylacetone)palladium (100 mg, 0.056 mmol) and 2-dicyclohexylphosphine-2',4',6'-triisopropylbiphenyl (60 mg, 0.056 mmol) were added. The reaction solution was reacted at 100 °C for 24 hours, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 1 / 1 (v / v)) to give compound 042-1. LC / MS (ESI+) m / z: [M+H]+ = 601.05.

[0248] 42.2 Synthesis of compounds 042-A and 042-B The synthesis of compound 042 was performed according to steps 1.6 and 1.7 of Example 1. 042 was further chirally resolved by supercritical fluid chromatography (Method: OD-MeOH(DEA)-40-3 mL-35 T) to obtain 042-A (retention time Rt = 0.913 min) and 042-B (retention time Rt = 1.444 min). 042-A (Retention time Rt = 0.913 min): 1H NMR (400 MHz, DMSO- d 6 ): δ 8.26 (s, 1H), 7.67 (dd, J= 8.0, 8.0 Hz, 1H), 7.50 (s, 1H), 7.37 (t, J= 16.0 Hz, 1H), 7.27 (t, J= 16.0 Hz, 1H), 7.11(m, 2H), 7.09(s, 1H), 7.00 (s, 1H), 6.90 (d, J= 8.0 Hz, 1H), 6.80 (m, 1H), 5.11 (m, 2H), 4.36 (s, 4H), 4.23 (d, J= 12.0 Hz, 1H), 3.43 – 3.31 (m, 2H), 3.19(m, 4H), 1.91 (m, 4H), 1.49 (d, J= 4.0 Hz, 3H); LC / MS(ESI+) m / z:[M+H] +=487.10. 042-B (Retention time Rt = 1.444 min): 1H NMR (400 MHz, DMSO- d 6 ): δ 8.26 (s, 1H), 7.67 (dd, J= 8.0, 8.0 Hz, 1H), 7.50 (s, 1H), 7.37 (t, J= 16.0 Hz, 1H), 7.27 (8.10 (m, 1H), 7.61 (dd, J= 8.0, 8.0 Hz, 1H), 7.45 (s, 1H), 7.37 (t, J= 16.0 Hz, 1H), 7.27 (t, J= 16.0 Hz, 1H), 7.09 m, 3H), 7.00 (s, 1H), 6.90 (d, J= 8.0 Hz, 1H), 6.80 (m, 1H), 5.09 (m, 2H), 4.35 (s, 4H), 4.16 (d, J= 12.0 Hz, 1H), 3.35 – 3.32 (m, 2H), 3.20 – 3.17 (m, 4H), 1.91 (m, 4H), 1.43 (d, J= 8.0 Hz, 3H); LC / MS(ESI+) m / z: [M+H] +=487.10.

[0249] Example 43: Synthesis of (S)-2-(2-((3'-(1-aminoethyl)-5-(1-oxa-7-azaspiro[3.5]nonane-7-yl)-[1,1'-biphenyl]-3-yl)methoxy)phenyl)acetic acid (compound 043-A or 043-B) and synthesis of (R)-2-(2-((3'-(1-aminoethyl)-5-(1-oxa-7-azaspiro[3.5]nonane-7-yl)-[1,1'-biphenyl]-3-yl)methoxy)phenyl)acetic acid (compound 043-B or 043-A)

[0250] 43.1 Synthesis of Compound 043-1 Weigh 035-3 (600 mg, 1.08 mmol) into a reaction flask, add 012-a (160 mg, 1.2 mmol), cesium carbonate (1.4 g, 4.32 mmol), 1,4-dioxane (3 mL), tris(dibenzylacetone)dipalladium (100 mg, 0.11 mmol), and 2-dicyclohexylphosphine-2',4',6'-triisopropylbiphenyl (50 mg, 0.11 mmol). Under nitrogen protection, the reaction solution was reacted at 100 °C for 5 hours. After cooling to room temperature, the reaction solution was diluted with water (10 mL) and extracted with ethyl acetate (20 mL × 3). The combined organic phases were washed with saturated brine (10 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 compound 043-1. LC / MS(ESI+) m / z:[M+H] +=601.10.

[0251] 43.2 Synthesis of compounds 043-A and 043-B The synthesis of compound 043 was performed according to steps 1.6 and 1.7 of Example 1. 043 was further chirally resolved by supercritical fluid chromatography to obtain 043-A (retention time Rt = 1.54 min) and 043-B (retention time Rt = 2.386 min). 043-A (Retention time Rt = 1.54 min): 1H NMR (400 MHz, DMSO- d 6 ): δ 8.25 (s, 1H), 7.67 (d, J= 8.0 Hz, 1H), 7.49 (s, 1H), 7.37 (t, J= 8.0 Hz, 1H), 7.25 (d, J= 8.0 Hz, 1H), 7.13 (s, 1H), 7.08 (d, J= 4.0 Hz, 2H), 6.99 (s, 1H), 6.90 (d, J= 8.0 Hz, 1H), 6.80 (t, J= 8.0 Hz, 1H), 5.10 (s, 2H), 4.42 (s, 1H), 4.23 (d, J= 8.0 Hz, 1H), 3.38-3.35 (m, 4H), 3.18 (d, J= 4.0 Hz, 2H), 2.39 (t, J= 8.0 Hz, 2H), 1.90 (d, J= 4.0 Hz, 4H), 1.49 (d, J= 8.0 Hz, 3H); LC / MS(ESI+) m / z:[M+H] +=487.10. 043-B (Retention time Rt = 2.386 min): 1H NMR (400 MHz, DMSO- d 6 ): δ 8.00-7.93 (d, J= 8.0 Hz, 1H), 7.55(s, 1H), 7.43-7.29 (m, 3H), 7.16-6.97 (m, 5H), 5.10 (s, 2H), 4.42 (s, 1H), 4.23 (d, J= 8.0 Hz, 1H), 3.38-3.35 (m, 4H), 3.18 (d, J= 4.0 Hz, 2H), 2.39 (t, J= 8.0 Hz, 2H), 1.90 (d, J= 4.0 Hz, 4H), 1.49 (d, J= 8.0 Hz, 3H); LC / MS(ESI+) m / z: [M+H] +=487.10.

[0252] Example 44: Synthesis of 2-(2-((3'-(1-amino-2-fluoroethyl)-5-(2-oxa-7-azaspiro[3.5]nonane-7-yl)-[1,1'-biphenyl]-3-yl)methoxy)phenyl)acetic acid (compound 044)

[0253] 44.1 Synthesis of Compound 044-1 044-a (4 g, 20.1 mmol) was dissolved in dichloromethane (25 mL), and bromine (1.2 mL, 20.1 mmol) was added at 0 °C. The reaction solution was reacted at 0 °C for 0.5 hours. The reaction was quenched by adding saturated sodium sulfite aqueous solution, filtered, and the solid was dried to give compound 044-1.

[0254] 44.2 Synthesis of Compound 044-2 Zinc fluoride (1.12 g, 10.8 mol), potassium fluoride (315 mg, 5.04 mol), and tetrabutylammonium fluoride trihydrate (2.55 g, 7.2 mol) were dissolved sequentially in acetonitrile (20 mL). The reaction mixture was refluxed at 80 °C for 1 hour. Then, 044-1 (3.0 g, 10.8 mol) was dissolved in 5 mL of acetonitrile and slowly added dropwise to the above system. The reaction was carried out at 80 °C for 12 hours. The reaction was quenched by adding saturated ammonium chloride aqueous solution, and extracted with ethyl acetate (30 mL × 3). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to obtain compound 044-2.

[0255] 44.3 Synthesis of Compound 044-3 Under nitrogen protection, tetraisopropoxytitanium (2.6 g, 9.22 mol) was added dropwise to a methanol solution (1N, 20 mL) of ammonia containing 044-2 (2.4 g, 4.61 mol), and the reaction was carried out at 25 °C for 2 hours. Sodium borohydride (262.3 mg, 6.91 mol) was then added, and the reaction was carried out at room temperature for 2 hours. The pH of the reaction solution was adjusted to 2 with 6N hydrochloric acid, and the mixture was extracted with ethyl acetate. The pH of the aqueous phase was adjusted to 10 with 6N sodium hydroxide solution, and the mixture was extracted with ethyl acetate. The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the crude product of compound 044-3, which could be used directly in the next step. LC / MS (ESI+) m / z: [M+H]+ = 218.00.

[0256] 44.4 Synthesis of Compound 044 The synthesis of compound 044 is based on the same method as that of compound 001. Simply replace 001-a with 044-3 and 001-d with 011-a in the synthesis steps. 1H NMR (400 MHz, DMSO- d 6 ): δ 8.75 (s, 2H), 7.83 (s, 1H), 7.74 (d, J = 8.0 Hz, 1H), 7.54 (t, J = 8.0 Hz, 1H), 7.48 (d, J = 8.0 Hz, 1H), 7.25-7.21 (m, 2H), 7.16 (d, J = 8.0 Hz, 2H), 7.10 (s, 1H), 7.03 (d, J = 8.0 Hz, 1H), 6.90 (t, J = 8.0 Hz, 1H), 5.12 (s, 2H), 4.87 – 4.72 (m, 3H), 4.36 (s, 4H), 3.60 (s, 2H), 3.26 – 3.15 (m, 4H), 1.94 – 1.90 (m, 4H); LC / MS(ESI+) m / z: [M+H] +=505.05.

[0257] Example 45: Synthesis of 2-(2-((3'-(aminomethyl)-6-fluoro-5-(6-azaspiro[2.5]octane-6-yl)-[1,1'-biphenyl]-3-yl)methoxy)phenyl)acetic acid (compound 045)

[0258] 45.1 Synthesis of Compound 045-1 027-3 (100 mg, 0.17 mmol) was weighed and dissolved in 1,4-dioxane (5 mL). 001-d (31.7 mg, 0.21 mmol), cesium carbonate (166 mg, 0.51 mmol), tris(dibenzylacetone)palladium (10 mg, 10 wt%), and 2-dicyclohexylphosphine-2',4',6'-triisopropylbiphenyl (10 mg, 10 wt%) were added. The reaction mixture was reacted at 100 °C for 2 hours under nitrogen protection. The mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to obtain compound 045-1. LC / MS (ESI+) m / z: [M+H]+ = 589.10.

[0259] 45.2 Synthesis of Compound 045 The synthesis of compound 045 is performed according to steps 1.6 and 1.7 of Example 1. 1H NMR (400 MHz, DMSO- d 6 ): δ 7.79 (s, 1H), 7.74 (s, 1H), 7.40-7.40(m, 2H), 7.28-7.12(m, 1H), 7.07-7.05(m, 3H), 6.89 (d, J= 7.6 Hz, 1H), 6.78 (t, J= 7.6Hz, 1H), 5.10 (s, 2H), 3.93 (s, 2H), 3.34 (s, 2H), 3.15 (s, 4H), 1.50 (s, 4H), 0.31 (s, 4H); LC / MS(ESI+) m / z:[M+H] +=475.10.

[0260] Example 46: Synthesis of (S)-2-(2-((3'-(1-amino-2-hydroxyethyl)-5-(8-azaspiro[4.5]decane-8-yl)-[1,1'-biphenyl]-3-yl)methoxy)phenyl)acetic acid (compound 046)

[0261] The synthesis of compound 046 is based on the same method as that of compound 018, except that the starting material 001-d is replaced with the hydrochloride salt of 8-azaspiro[4.5]decane (046-a). 1H NMR (400 MHz, DMSO- d 6 ): δ 8.05 (d, J= 63.0 Hz, 1H), 7.60 (dd, J= 46.0, 7.6 Hz, 1H), 7.38 (dd, J= 16.8, 9.6 Hz, 2H), 7.23 (dd, J= 20.4, 7.4 Hz, 1H), 7.19 – 6.89 (m, 5H), 6.88 – 6.70 (m, 1H), 5.11 (s, 2H), 4.12 (s, 1H), 3.67 (s, 2H), 3.37 (d, J= 6.8 Hz, 2H), 3.22 (dd, J= 16.8, 11.3 Hz, 4H), 1.71 – 1.48 (m, 8H), 1.46 (d, J= 6.6 Hz, 4H); LC / MS(ESI+) m / z: [M+H] +=515.15.

[0262] Example 47: Synthesis of trifluoroacetate of (R)-2-(2-((3'-(1-amino-2-hydroxyethyl)-5-(3-azaspiro[5.5]undecane-3-yl)-[1,1'-biphenyl]-3-yl)methoxy)phenyl)acetic acid (compound 047-A) and synthesis of trifluoroacetate of (S)-2-(2-((3'-(1-amino-2-hydroxyethyl)-5-(3-azaspiro[5.5]undecane-3-yl)-[1,1'-biphenyl]-3-yl)methoxy)phenyl)acetic acid (compound 047-B)

[0263] 47.1 Synthesis of Compound 047-1 Weigh 1 g (3.03 mmol) of 047-a into a reaction flask, add 5 mL of tetrahydrofuran, cool to 0°C using an ice-water bath, and slowly add the tetrahydrofuran complex of borane (1 M, 9.1 mL, 9.1 mmol). Maintain the reaction at 0°C for 3 hours after the addition is complete. Quench the reaction by slowly adding 10 mL of methanol. After complete quenching, concentrate the reaction solution under reduced pressure. Purify the residue by silica gel column chromatography to obtain compound 047-1. LC / MS (ESI+) m / z: [M+H-tBu]+ = 260.00.

[0264] 47.2 Synthesis of Compound 047-2 700 mg (2.21 mmol) of 047-1 was weighed into a reaction flask, and 461 mg (4.43 mmol) of 2,2-dimethoxypropane, 21 mg (0.11 mmol) of p-toluenesulfonic acid monohydrate, and 5 mL of toluene were added. The mixture was heated to 50 °C and reacted for 15 hours. The pH of the reaction system was adjusted to 8 with saturated sodium bicarbonate aqueous solution, and the mixture was extracted with ethyl acetate (10 mL × 3). The combined organic phases were washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography to obtain compound 047-2.

[0265] 47.3 Synthesis of Compound 047-3 400 mg (1.12 mmol) of 047-2 was weighed into a reaction flask, and pinacol diboronate (314 mg, 1.24 mmol), potassium acetate (221 mg, 2.25 mmol), [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (80 mg, 0.11 mmol), and 1,4-dioxane (5 mL) were added. After purging with nitrogen three times, the reaction solution was reacted at 100 °C for 2 hours and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography to obtain compound 047-3.

[0266] 47.4 Synthesis of Compound 047-4 Weigh 001-3 (400 mg, 0.96 mmol) into a reaction flask, add 047-3 (389 mg, 0.96 mmol), potassium carbonate (267 mg, 1.93 mmol), 1,4-dioxane (5 mL), and tetra(triphenylphosphine)palladium (111 mg, 0.09 mmol), purge with nitrogen three times, and react at 100 °C for 2 hours. Dilute the reaction solution with water (10 mL) and extract with ethyl acetate (10 mL × 3). Wash the combined organic phases with saturated brine (10 mL), dry with anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure. Purify the residue by silica gel column chromatography to obtain compound 047-4.

[0267] 47.5 Synthesis of Compound 047-5 Weigh 047-4 (150 mg, 0.25 mmol) into a reaction flask, add 047-c (51 mg, 0.27 mmol), cesium carbonate (320 mg, 0.98 mmol), 1,4-dioxane (2 mL), tris(dibenzylacetone)dipalladium (22 mg, 0.02 mmol), and 2-dicyclohexylphosphine-2',4',6'-triisopropylbiphenyl (12 mg, 0.02 mmol), purge with nitrogen three times, and react at 100 °C for 2 hours. Cool to room temperature, dilute the reaction solution with water (10 mL), and extract with ethyl acetate (10 mL × 3). Combine the organic phases and wash with saturated brine (10 mL), dry to anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure. Purify the residue by silica gel column chromatography to obtain compound 047-5.

[0268] 47.6 Synthesis of compound 047-A trifluoroacetate The synthesis of compound 047-A followed steps 1.6 and 1.7 of Example 1. The preparation process used trifluoroacetic acid conditions, ultimately yielding the trifluoroacetate salt of compound 047-A. 1H NMR (400 MHz, DMSO- d 6 ): δ 8.39 (s, 2H), 7.78 (s, 1H), 7.68 (d, J= 7.6 Hz, 1H), 7.49 (t, J= 7.6 Hz, 1H), 7.42 (d, J= 7.6 Hz, 1H), 7.21 (d, J= 7.6 Hz, 2H), 7.14 (s, 2H), 7.09 (s, 1H), 7.02 (d, J= 8.0 Hz, 1H), 6.89 (t, J= 7.6 Hz, 1H), 5.12 (s, 2H), 4.37 (s, 1H), 3.82 – 3.67 (m, 2H), 3.59 (s, 2H), 3.24 (s, 4H), 1.55 (s, 4H), 1.40 (d, J= 14.4 Hz, 10H); LC / MS(ESI+) m / z: [M+H] +=529.10.

[0269] 47.7 Synthesis of compound 047-B trifluoroacetate The synthesis of compound 047-B is based on the same method as that of compound 047-A, except that the starting material is replaced by (S)-2-(3-bromophenyl)-2-((tert-butoxycarbonyl)amino)acetic acid (S-configuration). 1H NMR (400 MHz, DMSO- d 6 ): δ 8.40 (s, 2H), 7.79 (s, 1H), 7.69 (d, J= 7.6 Hz, 1H), 7.50 (t, J= 7.6 Hz, 1H), 7.43 (d, J= 7.6 Hz, 1H), 7.22 (d, J= 7.6 Hz, 2H), 7.16 (s, 2H), 7.11 (s, 1H), 7.03 (d, J= 8.2 Hz, 1H), 6.90 (t, J= 7.4 Hz, 1H), 5.13 (s, 2H), 4.38 (s, 1H), 3.81 – 3.68 (m, 2H), 3.60 (s, 2H), 3.26 (s, 4H), 1.56 (s, 4H), 1.41 (d, J= 13.8 Hz, 10H); LC / MS(ESI+) m / z: [M+H] +=529.10.

[0270] Example 48: Synthesis of (R)-2-(2-((3'-(1-amino-2-hydroxyethyl)-5-(2-azaspiro[3.4]octane-2-yl)-[1,1'-biphenyl]-3-yl)methoxy)phenyl)acetic acid (compound 048-A) and synthesis of (S)-2-(2-((3'-(1-amino-2-hydroxyethyl)-5-(2-azaspiro[3.4]octane-2-yl)-[1,1'-biphenyl]-3-yl)methoxy)phenyl)acetic acid (compound 048-B)

[0271] 48.1 Synthesis of Compound 048-A The synthesis of compound 048-A is based on the synthesis method of compound 047-A in Example 47, except that the starting material is replaced by 2-azaspiro[3.4]octane (048-a) instead of 047-c. 1H NMR (400 MHz, DMSO- d 6 ): δ 9.51 (s, 1H), 7.96 (s, 1H), 7.49 (d, J= 7.6 Hz, 1H), 7.35 (s, 1H), 7.26 (t, J= 7.6 Hz, 1H), 7.16 – 7.02 (m, 3H), 6.83 (d, J= 8.4 Hz, 1H), 6.78 (t, J= 7.2 Hz, 1H), 6.59 (s, 1H), 6.45 (s, 1H), 5.22 – 5.01 (m, 2H), 4.69 – 4.56 (m, 1H), 3.80 – 3.69 (m, 4H), 3.48 – 3.41 (m, 1H), 3.38 (s, 2H), 2.04 – 1.93 (m, 1H), 1.87 – 1.76 (m, 4H), 1.68 – 1.56 (m, 4H); LC / MS(ESI+) m / z: [M+H] +=487.10.

[0272] 48.2 Synthesis of Compound 048-B The synthesis of compound 048-B is similar to that of 048-A, except that the starting material is changed from 047-4 (R configuration) to S configuration. 1H NMR (400 MHz, DMSO- d 6 ): 9.49 (d, J= 8.8 Hz, 1H), 7.93 (d, J= 30.0 Hz, 1H), 7.51 (t, J= 8.4 Hz, 1H), 7.34 (d, J= 11.2 Hz, 1H), 7.31 – 7.03 (m, 4H), 6.95 – 6.73 (m, 2H), 6.58 (d, J= 6.8 Hz, 1H), 6.47 (d, J= 15.6 Hz, 1H), 5.21 – 5.04 (m, 2H), 4.63 (d, J= 8.0 Hz, 1H), 3.80 – 3.69 (m, 5H), 3.58 (s, 1H), 3.53 – 3.42 (m, 2H), 3.34 (d, J= 8.8 Hz, 1H), 1.82 (s, 4H), 1.66 – 1.56 (m, 4H); LC / MS(ESI+) m / z: [M+H] +=487.10.

[0273] Example 49: Synthesis of (R)-2-(2-((3'-(1-amino-2-hydroxyethyl)-5-(2-azaspiro[4.4]nonane-2-yl)-[1,1'-biphenyl]-3-yl)methoxy)phenyl)acetic acid (compound 049-A) and synthesis of (S)-2-(2-((3'-(1-amino-2-hydroxyethyl)-5-(2-azaspiro[4.4]nonane-2-yl)-[1,1'-biphenyl]-3-yl)methoxy)phenyl)acetic acid (compound 049-B)

[0274] 49.1 Synthesis of Compound 049-A The synthesis of compound 049-A is based on the synthesis method of compound 047-A in Example 47, except that the starting material is replaced by 2-azaspiro[4.4]nonane (049-a). 1H NMR (400 MHz, DMSO- d 6 ): δ 9.49 (d, J= 9.2 Hz, 1H), 8.02 (d, J= 42.4 Hz, 1H), 7.59 (dd, J= 35.2, 7.6 Hz, 1H), 7.36 (t, J= 7.6 Hz, 1H), 7.28 – 7.24 (m, 1H), 7.20 (s, 1H), 7.13 – 7.04 (m, 2H), 6.97 – 6.73 (m, 2H), 6.67 (s, 1H), 6.62 – 6.51 (m, 1H), 5.23 – 5.03 (m, 2H), 4.70 – 4.51 (m, 1H), 4.12 – 4.07 (m, 1H), 3.68 – 3.61 (m, 2H), 3.49 – 3.41 (m, 2H), 3.37 (d, J= 6.8 Hz, 2H), 3.25 – 3.18 (m, 2H), 1.88 (t, J= 6.8 Hz, 2H), 1.70 – 1.65 (m, 4H), 1.63 – 1.53 (m, 4H); LC / MS(ESI+) m / z: [M+H] +=501.10.

[0275] 49.2 Synthesis of Compound 049-B The synthesis of compound 049-B is based on the same method as that of 049-A, except that the starting material is changed from 047-4 (R configuration) to S configuration. 1H NMR (400 MHz, DMSO- d 6 ): 9.50 (d, J= 9.2 Hz, 1H), 8.04 (d, J= 64.8 Hz, 1H), 7.60 (dd, J= 44.4, 7.8 Hz, 1H), 7.36 (t, J= 7.6 Hz, 1H), 7.28 – 7.21 (m, 2H), 7.14 – 7.06 (m, 2H), 6.94 – 6.76 (m, 2H), 6.68 (s, 1H), 6.59 – 6.53 (m, 1H), 5.11 (s, 2H), 4.15 – 4.09 (m, 1H), 3.69 – 3.66 (m, 2H), 3.47 (d, J= 15.2 Hz, 2H), 3.39 – 3.36 (m, 2H), 3.22 (s, 2H), 1.88 (t, J= 6.8 Hz, 2H), 1.70 – 1.66 (m, 4H), 1.63 – 1.56 (m, 4H); LC / MS(ESI+) m / z: [M+H] +=501.10.

[0276] Example 50: Synthesis of 2-(2-((3'-(1-amino-2-fluoroethyl)-2'-fluoro-5-(1-oxa-6-azaspiro[3.4]octane-6-yl)-[1,1'-biphenyl]-3-yl)methoxy)phenyl)acetic acid (compound 050)

[0277] 50.1 Synthesis of Compound 050-1 Weigh 2.0 g (9.2 mmol) of 020-a and dissolve it in 20 mL of tetrahydrofuran. Under nitrogen protection at -78 °C, add 1 M (10.1 mL, 10.1 mmol) of bis(trimethylsilyl)aminolithium and react for 1 hour. Then, under nitrogen protection at -78 °C, add 1.08 g (10.1 mmol) of trimethylchlorosilane and slowly raise the temperature to room temperature for 1 hour. Concentrate the reaction solution and add 20 mL of acetonitrile and 4.7 g (11.4 mmol) of 1-chloromethyl-4-fluoro-1,4-diazabicyclo[2.2.2]octane di(tetrafluoroborate). React at room temperature for 2 hours. Quench the reaction solution slowly with 15 mL of saturated ammonium chloride solution and extract with ethyl acetate (50 mL × 3). Wash the combined organic phases with 50 mL of saturated brine, dry with anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure. The residue was purified by silica gel column chromatography to give compound 050-1. LC / MS (ESI+) m / z: [M+H]+=234.1.

[0278] 50.2 Synthesis of Compound 050-2 600 mg (5.19 mmol) of compound 050-1 was weighed and dissolved in an ethanol solution of ammonia (2 M, 3.8 mL). Tetraisopropyl titanate (1.08 g, 3.8 mmol) was added, and the reaction was carried out at 25 °C for 2 hours. Sodium borohydride (116 mg, 3.06 mmol) was then added, and the reaction was carried out for another 2 hours. The reaction mixture was slowly quenched with a saturated ammonium chloride aqueous solution (5 mL) and extracted with ethyl acetate (10 mL × 3). The combined organic phases were washed with saturated brine (10 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 compound 050-2. LC / MS (ESI+) m / z: [M+H]+ = 236.1.

[0279] 50.3 Synthesis of Compound 050 The synthesis of compound 050 is based on the same method as that of compound 001. Simply replace 001-a with 050-2 and 001-d with 041-a in the synthesis steps. 1H NMR (400 MHz, DMSO- d 6 ): δ 7.61 (t, J= 7.2 Hz, 1H), 7.41-7.38 (m, 1H), 7.24 (t, J= 8.4 Hz, 1H), 7.17-8.15 (m, 1H), 7.05-7.01 (m, 1H), 6.90 (d, J= 8.4 Hz, 1H), 6.81-6.71 (m, 3H), 6.51 (d, J= 12.8 Hz, 1H), 5.01 (s, 2H), 4.52-4.38 (m, 5H), 3.57 (d, J= 11.2 Hz, 1H), 3.46 (d, J= 10.8 Hz, 1H), 3.3 (s, 2H), 3.2 (s, 2H), 2.76-2.48 (m, 2H), 2.34-2.41 (m, 1H), 2.16-1.97 (m, 1H); LC / MS(ESI+) m / z: [M+H] +=509.10.

[0280] Example 51: Synthesis of 2-(2-((3'-(1-amino-3-hydroxypropyl)-5-(6-azaspiro[2.5]octane-6-yl)-[1,1'-biphenyl]-3-yl)methoxy)phenyl)acetic acid (compound 051)

[0281] 51.1 Synthesis of Compound 051-1 051-a (5 g, 2.7 mmol), 051-b (2.8 g, 2.7 mmol), and ammonium acetate (4.2 g, 5.4 mmol) were dissolved sequentially in ethanol (100 mL), and the reaction mixture was reacted at 80 °C for 24 hours. The reaction mixture was filtered, washed with ethanol, and the filter cake was dried under reduced pressure to obtain compound 051-1. LC / MS (ESI+) m / z: [M+H]+ = 246.00.

[0282] 51.2 Synthesis of Compound 051-2 051-1 (3.7 g, 15.2 mmol) was dissolved in tetrahydrofuran (70 mL), and nitrogen gas was introduced. A tetrahydrofuran solution of borane (10 mL) was added dropwise at 0 °C, and the reaction mixture was reacted at 45 °C for 5 hours. The reaction was quenched by slow dropwise addition of methanol, and the mixture was concentrated under reduced pressure. Water (50 mL) was added, and the mixture was extracted with ethyl acetate (30 mL × 2). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (dichloromethane / methanol = 5 / 1 (v / v)) to give compound 051-2. LC / MS (ESI+) m / z: [M+H]+ = 230.00.

[0283] 51.3 Synthesis of Compound 051 The synthesis of compound 050 is based on the same method as that of compound 001, except that 001-a in the synthesis step is replaced with 051-2. 1H NMR (400 MHz, DMSO- d 6 ): δ 8.26 (s, 1H), 7.68 (d, J= 8.0 Hz, 1H), 7.46 (s, 1H), 7.37 (t, J= 16.0 Hz, 1H), 7.22 (d, J= 8.0 Hz, 1H), 7.15 (s, 1H), 7.09 (m, 2H), 7.01 (s, 1H), 6.91 (d, J= 12.0 Hz, 1H), 6.79 (d, J=8.0Hz, 1H), 5.11 (s, 2H), 4.19 (s, 1H), 3.40 (t, J= 8.0 Hz, 2H), 3.34 (s, 2H), 3.32 – 3.27 (m, 4H), 2.16 – 1.94 (m, 2H), 1.53 – 1.46 (m, 4H), 0.35 (s, 4H); LC / MS(ESI+) m / z: [M+H] +=501.10.

[0284] Example 52: Synthesis of 2-(2-((3'-(1-amino-2-hydroxyethyl)-2'-fluoro-5-(6-azaspiro[2.5]octane-6-yl)-[1,1'-biphenyl]-3-yl)methoxy)phenyl)acetic acid (compound 052)

[0285] 52.1 Synthesis of Compound 052-1 052-a (3.0 g, 18.9 mmol) was dissolved in dichloromethane (50 mL), and cesium carbonate (12.4 g, 37.8 mmol) and 023-b (2.3 g, 18.9 mmol) were added. The reaction mixture was reacted at 25 °C for 2 hours, diluted with water (50 mL), and extracted with dichloromethane (30 mL × 2). The organic phase was 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 = 3 / 1 to 1 / 1 (v / v)) to give compound 052-1. LC / MS (ESI+) m / z: [M+H]+ = 262.00.

[0286] 52.2 Synthesis of Compound 052-2 4.5 g (25 mmol) of 052-1 was weighed and dissolved in 30 mL of toluene. 10 g (37.3 mmol) of bis[(pinacol)boryl]methane, 1.11 g (2.5 mmol) of 1,2-bis(diphenylphosphine)benzene, 360 mg (2.5 mmol) of cuprous bromide, and 6 g (74.5 mmol) of lithium terbutoxide were added. The reaction mixture was reacted overnight at 50 °C under nitrogen protection. The mixture was then diluted with 30 mL of water and extracted with ethyl acetate (30 mL × 3). The organic phase was 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 = 3 / 1 to 1 / 1 (v / v)) to give compound 052-2. LC / MS (ESI+) m / z: [M+H]+ = 404.05.

[0287] 52.3 Synthesis of Compound 052-3 052-2 (4.2 g, 20 mmol) was dissolved in toluene (20 mL), and sodium perborate tetrahydrate (11.2 g, 40 mmol) was added. The reaction mixture was reacted at room temperature for 2 hours, then diluted with water (50 mL), and extracted with ethyl acetate (10 mL × 3). The combined organic phases were 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 = 3 / 1 to 1 / 1 (v / v)) to give compound 052-3.

[0288] 52.4 Synthesis of Compound 052-4 Under nitrogen protection, 052-3 (2.0 g, 6.8 mmol), bis-pinacolborate (2.6 g, 10.2 mmol), potassium acetate (1.36 g, 13.6 mmol), and [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride (460 mg, 0.68 mmol) were dissolved in 1,4-dioxane (20 mL). The reaction mixture was reacted at 100 °C for 2 h, then diluted with water (20 mL) and extracted with ethyl acetate (10 mL × 3). The combined organic phases were 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 compound 052-4. LC / MS (ESI+) m / z: [M+H]+ = 386.05.

[0289] 52.5 Synthesis of Compound 052 The synthesis of compound 052 is based on the same method as compound 001, except that 001-2 is replaced with 052-4. 1H NMR (400 MHz, DMSO- d 6 ): δ 8.48 (s, 2H), 7.61 – 7.51 (m, 2H), 7.37 (t, J= 8.0 Hz, 1H), 7.25 – 7.20 (m, 2H), 7.17 (s, 1H), 7.05- 7.00(m, 3H), 6.90 (t, J=8.0 Hz, 1H), 5.13 (s, 2H), 4.58 (d, J= 8.0 Hz, 1H), 3.83-3.79 (m, 1H), 3.76-3.71 (m, 1H), 3.58 (s, 2H), 3.40 – 3.22 (m, 4H), 1.56 – 1.39 (m, 4H), 0.35 (s, 4H); LC / MS(ESI+) m / z: [M+H] +=505.10.

[0290] Example 53: Synthesis of 2-(2-((3'-(1-aminoethyl)-2'-fluoro-5-(2-oxa-7-azaspiro[3.5]nonane-7-yl)-[1,1'-biphenyl]-3-yl)methoxy)phenyl)acetic acid (compound 053)

[0291] 53.1 Synthesis of Compound 053-1 Weigh 020-5 (300 mg, 0.52 mmol) into a reaction flask, add 011-a (99 mg, 0.58 mmol), cesium carbonate (683 mg, 2.1 mmol), 1,4-dioxane (3 mL), tris(dibenzylacetone)dipalladium (48 mg, 0.05 mmol), and 2-dicyclohexylphosphine-2',4',6'-triisopropylbiphenyl (25 mg, 0.05 mmol). After purging with nitrogen, the reaction mixture was reacted at 100 °C for 2 hours, then diluted with water (10 mL) and extracted with ethyl acetate (20 mL × 3). Combine the organic phases and wash with saturated brine (10 mL), dry to anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure. The residue was purified by silica gel column chromatography to give compound 053-1. LC / MS (ESI+) m / z: [M+H]+ = 619.05.

[0292] 53.2 Synthesis of Compound 053 The synthesis of compound 053 is performed according to steps 1.6 and 1.7 of Example 1. 1H NMR (400 MHz, DMSO- d 6 ): δ 8.07 (d, J= 8.0 Hz, 1H), 7.54 (t, J= 6.8 Hz, 1H), 7.38 – 7.30 (m, 1H), 7.29 – 7.17 (m, 2H), 7.16 – 7.07 (m, 2H), 7.05 – 6.91 (m, 3H), 6.85 (t, J= 7.2 Hz, 1H), 5.11 (d, J= 28.4 Hz, 2H), 4.35 (s, 1H), 4.34 – 4.27 (m, 4H), 3.44 (s, 2H), 3.20 – 3.10 (m, 4H), 1.93 – 1.84 (m, 4H), 1.32 (dd, J= 16.8, 6.8 Hz, 3H); LC / MS(ESI+) m / z: [M+H] +=505.10.

[0293] Example 54: Synthesis of 2-(2-((3'-(1-aminoethyl)-2'-fluoro-5-(1-oxa-7-azaspiro[3.5]nonane-7-yl)-[1,1'-biphenyl]-3-yl)methoxy)phenyl)acetic acid (compound 054)

[0294] The synthesis of compound 054 is based on the same method as that of compound 053, except that the starting material is replaced with 012-a instead of 011-a. 1H NMR (400 MHz, DMSO- d 6 ): δ 8.12 (s, 1H), 7.55 (t, J= 6.8 Hz, 1H), 7.33 (td, J= 7.6, 1.6 Hz, 1H), 7.29 – 7.16 (m, 2H), 7.16 – 7.05 (m, 2H), 7.05 – 6.91 (m, 3H), 6.82 (t, J= 7.6 Hz, 1H), 5.10 (d, J = 40.4 Hz, 2H), 4.46 – 4.37 (m, 2H), 4.31 (q, J= 6.8 Hz, 1H), 3.36 – 3.29 (m, 4H), 3.18 – 3.11 (m, 2H), 2.37 (t, J= 7.6 Hz, 2H), 1.94 – 1.79 (m, 4H), 1.31 (dd, J= 21.4, 6.7 Hz, 3H); LC / MS(ESI+) m / z:[M+H] +=505.10.

[0295] Example 55: Synthesis of 2-(2-((3'-(1-aminoethyl)-2'-fluoro-5-(3-oxa-9-azaspiro[5.5]undecane-9-yl)-[1,1'-biphenyl]-3-yl)methoxy)phenyl)acetic acid (compound 055)

[0296] The synthesis of compound 055 is based on the same method as that of compound 053, except that the starting material is replaced with 029-a instead of 011-a. 1H NMR (400 MHz, DMSO- d 6 ): δ 7.54 (s, 1H), 7.33 (m, 1H), 7.27 – 7.16 (m, 2H), 7.08 (m, 2H), 6.95 (m, 3H), 6.82 (t, J= 16.0 Hz, 1H), 5.05 (s, 2H), 4.31 (d, J= 8.0Hz, 1H), 3.59 – 3.54 (m, 4H), 3.31 (s, 2H), 3.24 – 3.19 (m, 4H), 1.70 – 1.55 (m, 4H), 1.49 – 1.41 (m, 4H), 1.29 (d, J= 4.0 Hz, 3H); LC / MS(ESI+) m / z: [M+H] +=533.10.

[0297] Example 56: Synthesis of 2-(2-((3'-(1-aminoethyl)-2'-fluoro-5-(2-oxa-9-azaspiro[5.5]undecane-9-yl)-[1,1'-biphenyl]-3-yl)methoxy)phenyl)acetic acid (compound 056)

[0298] The synthesis of compound 056 is based on the same method as that of compound 053, except that the starting material is replaced with 030-a instead of 011-a. 1H NMR (400 MHz, DMSO- d 6 ): δ 8.38 (d, J= 4.0 Hz, 2H), 7.56 (t, J= 16.0 Hz, 2H), 7.38 (t, J= 12.0 Hz, 1H), 7.23 (t, J=16.0 Hz, 2H), 7.15 (s, 1H), 7.03 (d, J= 8.0 Hz, 3H), 6.90 (t, J=16.0 Hz, 1H), 5.12 (s, 2H), 4.73 – 4.69 (m, 1H), 3.56 (d, J= 12.0 Hz, 4H), 3.39 (s, 2H), 3.24 (t, J= 12.0 Hz, 4H), 1.58 (d, J= 8.0 Hz, 4H), 1.55 (s, 3H), 1.53 (s, 4H); LC / MS(ESI+) m / z: [M+H] +=533.10.

[0299] [<] [Biological activity testing] [>]

[0300] [1.] [Complement Factor] [D] [Inhibition activity()] [C3b] [French] In vitro screening experiment

[0301] 1.1 Experimental Materials and Instruments V-shaped well trays (AXYGEN), DMSO (Sigma), MicroVue Bb Plus ELISA kit (Quidel), Complement Factor C3b (Complement Tech), Complement Factor B (Complement Tech), Complement Factor D (Complement Tech), EDTA (McClene), GF-β (Complement Tech), EGTA (Aladdin), MgCl2 (Aladdin), NaOH (Sinopharm), Enzyme labeling reader (Molecular Devices, SpectraMax i3x), Microplate thermostatic shaker (Thermo, MB100-2A), Pipettes (Gilson).

[0302] 1.2 Preparations before the experiment

[0303] 1.2.1 Preparation of Mg-EGTA 0.1 M Mg-EGTA: Weigh 3.8 g EGTA, 20.9521 g MgCl, and 0.7 g NaOH. Adjust the pH to 7.5 with NaOH, add distilled water to a final volume of 100 mL, filter through a 0.2 μm sterile filter, aliquot, and store at 4℃.

[0304] 1.2.2 Preparation of working solution Buffer: Dilute 0.1 M Mg-EGTA solution 10-fold with GVB 0 buffer to 10 mM; Factor B working solution: Dilute 1 mg / mL Factor B solution (10.75 μM) 6.7 times with buffer to 1.6 μM; Factor C3b working solution: 1 mg / mL factor C3b solution (5.68 μM) was diluted 5-fold with buffer to 1.12 μM; Factor D working solution: 0.1 mg / mL factor D solution (4.17 μM) was diluted 1303 times with buffer to 3.2 nM. Note: a. The above dilution ratios are for reference only and should be adjusted according to the actual concentration indicated on the reagent; b. Factor B: 93kDa, Factor D: 24kDa, Factor C3b: 176kDa.

[0305] 1.2.3 Preparation of Termination Solution Termination solution: Weigh an appropriate amount of EDTA powder, dissolve it in a certain amount of GVB 0 buffer, adjust the pH to 7.5 with NaOH, stir until clear, and prepare a 10 mM solution.

[0306] 1.2.4 Compound Preparation Stock solutions of compounds: A 40 mM compound solution was diluted with DMSO to prepare a 1 mM stock solution. The 1 mM stock solution was then diluted 3 times with DMSO. Stock solutions of compounds of various concentrations were prepared by taking 8 samples. Compound working solutions: Dilute 250 times with buffer solution to obtain compound solutions of various concentrations.

[0307] 1.3 Experimental Procedure In a V-shaped well tray, 10 μL of factor D solution and 10 μL of compound solution were added to the experimental group; 10 μL of factor D solution and buffer containing 0.4% DMSO were added to the positive control group; and 20 μL of buffer containing 0.2% DMSO was added to the blank control group. The mixture was incubated at 37°C for 15 min. Factor B working solution and factor C3b working solution were mixed 1:1 and 20 μL of the mixture was added to each well. The mixture was incubated at 37°C for 30 min. The reaction was terminated by adding 40 μL of stop solution. The amount of product Bb generated was detected using the MicroVue Bb Plus ELISA kit.

[0308] 1.4 ELISA Detection 1.4.1 Remove the required enzyme-labeled wells and allow them to return to room temperature. Repackage the remaining equipment and store at 4°C. 1.4.2 Wash twice with 300 μL of wash buffer per wash. Incubate at 25°C for 1 min after the first wash. 1.4.3 Dilute the sample 8-fold with complement specimen diluent, add 100 μL of sample to each well, and incubate at 25°C for 30 min; 1.4.4 Discard the liquid in the wells and wash five times with 300 μL of wash buffer per wash. Incubate at room temperature for 1 min after the first wash. 1.4.5 Add 50 μL of Bb Plus Conjugate to each well and incubate at 25°C for 30 min; 1.4.6 Discard the liquid in the wells and wash five times with 300 μL of wash buffer per wash. Incubate at room temperature for 1 min after the first wash. 1.4.7 Add 100 μL of the compound working solution to each well and incubate at 25°C for 15 min; 1.4.8 Add 100 μL of stop solution to each well and measure the absorbance at 450 nm within 30 min.

[0309] 1.5 Data Analysis

[0310] 1.5.1 Inhibition rate at various drug concentrations: The PC group represents 0% inhibition rate, and the NC group represents 100% inhibition rate.

[0311] 1.5.2 Calculate the signal-to-ground ratio (S / B): The average OD value of the PC group / the average OD value of the NC group represents the size of the signal window.

[0312] 1.5.3 Z' factor: Calculation formula: The Z' factor should be greater than 0.4.

[0313] 1.5.4 Compound IC 50: IC50: Half-inhibitory concentration, representing the concentration at which a compound inhibits the enzyme activity of complement factor D by 50%; Data were collected to calculate the logarithmic value of inhibition rate versus compound concentration, and the IC50 value was calculated using GraphPad Prism software. The inhibitory activity of the compounds of this invention against complement factor D is shown in Table 1.

[0314] Table 1: Inhibitory activity of the compounds of this invention against complement factor D Compound numbering C3b IC 50(nM) 001 10 003 3 004 19 006 4 007 12 008 18 011 18 012 6 013 11 014 14 016 26 017 6 021 11 023 15 024 4 025 7 029 6 030 4 031 3 032 10 033 2 034 1

[0315] Experimental conclusion: The compound of this invention has a good inhibitory effect on complement factor D.

[0316] [2.] [Rabbit erythrocyte hemolysis method for evaluating the inhibitory activity of compounds on alternative pathways]

[0317] 2.1 Experimental Materials and Instruments Normal Human Serum (NHS, collected from healthy individuals), Normal Human Plasma (NHP, collected from Shanghai Yuduo), 96-well microplate (Jet Biofil), Japanese white rabbit (Wuhan Wanqian Jiaxing), Alsace solution (Pronosai), centrifuge (Thermo, PICO17), constant temperature shaking incubator (Shanghai Fuma), decolorizing shaking incubator (Beijing Liuyi), cell counter (Invitrogen, Counter Countess II) (GVB o, EGTA, MgCl 2, NaOH, microplate reader, microplate constant temperature shaking incubator, pipette, etc., as in Experiment 1).

[0318] 2.2 Preparation of working solution 48% NHP: Dilute 100% NHP to 48% with buffer. 26.4% NPS: 100% NHS diluted to 26.4% with buffer. Rabbit red blood cell suspension: Blood was collected from the marginal ear vein of rabbits, anticoagulated with Alderman's solution at a 1:1 ratio, aliquoted and stored at 4℃, where it can be stored for 4 weeks. Before use, centrifuge at 500 g for 5 min and discard Alderman's solution. Wash three times with an equal volume of buffer, centrifuge at 500 g for 5 min, and finally adjust the density to 6 × 10⁸ cells / mL with buffer.

[0319] 2.3 Experimental Procedure In a 96-well microplate, the experimental group was added with 50 μL of 48% NHP or 26.4% NHS and 50 μL of compound solution; the positive control group was added with 50 μL of 48% NHP or 26.4% NHS and 50 μL of buffer containing 0.2% DMSO; the blank control group was added with 50 μL of buffer containing 48% deactivated NHP or 26.4% deactivated NHS and 0.2% DMSO; the H2O group was added with 100 μL of double-distilled water; incubated at 37℃ for 15 min; 20 μL of rabbit red blood cell suspension was added to each well, and incubated in a shaking incubator at 37℃ for 30 min; centrifuged at 2000 g (3380 rpm) for 5 min, and 100 μL of supernatant was transferred to a new 96-well microplate, and the absorbance was measured at 415 nm.

[0320] 2.4 Data Analysis

[0321] 2.4.1 Percentage of hemolysis at each drug concentration: The PC group represents 100% hemolysis, and the NC group represents 0% hemolysis.

[0322] 2.4.2 Calculate the signal-to-ground ratio (S / B): The average OD value of the PC group / the average OD value of the NC group represents the size of the signal window.

[0323] 2.4.3 Z' factor: Calculation formula:

[0324] 2.4.4 Compound IC 50: IC50: Half-inhibitory concentration. Data were collected to calculate the logarithmic value of hemolysis percentage versus compound concentration, and the IC50 value was calculated using GraphPad Prism software. The inhibitory activity of the compounds of this invention against rabbit erythrocyte hemolysis is shown in Table 2.

[0325] Table 2: Inhibitory activity of the compounds of the present invention against rabbit erythrocyte hemolysis Compound numbering Rabbit erythrocyte hemolysis IC50 (nM) 001 41 002 98 003 43 004 36 005 73 006 54 007 59 008 196 009 218 010 159 011 13 012 4 013 28 014 10 015 7 016 19 017 65 021 65 023 76 024 27 025 12 026 16 028 58 029 10 030 22 031 6 032 8 033 3 034 11 035 183 036 44 038 206 039 127 040 138 041 151 042 50 043 93 044 133 055 117 056 70

[0326] Experimental conclusion: The compound of this invention has a good inhibitory effect on rabbit erythrocyte hemolysis.

[0327] [3.] [In vivo pharmacokinetic studies of the compounds of this invention]

[0328] After acclimatization, SPF-grade SD rats were administered the compounds of this invention at doses of 1 mg / kg via single gavage or tail vein bolus. Plasma samples were collected at specific time points after administration, and the concentrations of the compounds in the plasma were determined by LC-MS / MS (AB SCIEX Qtrap4500). The pharmacokinetic parameters of each compound were calculated using software to illustrate the in vivo pharmacokinetic properties of the compounds of this invention. The pharmacokinetic parameters of the compounds of this invention are shown in Table 3.

[0329] Table 3: PK experiment of the compounds of the present invention on SD rats compound Dosage mg / kg Administration method C max (ng / mL) T 1 / 2 (hr) AUC last (ng / mL*hr) Oral bioavailability F (%) 001 1 PO (3% DMSO + 4% Tween) 577±12.3 4.13±1.38 3238±115 40.3% IV 1803±227 3.59±0.18 8031±574 / 007 1 PO (3% DMSO + 4% Tween) 936±184 1.46±0.02 2312±385 70.2% IV 3273±680 0.64±0.06 3291±215 / 010 1 PO (3% DMSO + 4% Tween) 349±34.4 3.18±0.24 1751±137 30.9% IV 1840±171 3.31±0.44 5659±394 / 023 3 PO (3% DMSO + 4% Tween) 1017±132 4.10±0.37 7478±974 35.3% 1 IV 3407±344 4.58±0.08 7058±1335 /

[0330] Experimental conclusion: The compounds of this invention can achieve high in vivo exposure and high oral bioavailability at low doses, and have superior overall pharmacokinetic properties.

[0331] The exemplary embodiments of the present invention have been described above. However, the scope of protection of this application is not limited to the exemplary embodiments described above. Any modifications, equivalent substitutions, improvements, etc., made by those skilled in the art within the spirit and principles of the present invention should be included within the scope of protection defined by the patent claims of this application.

Claims

1. A compound of formula (I), its tautomer, its stereoisomer, or a pharmaceutically acceptable salt thereof, (I) wherein: R1 is H; R2 and R3 are each independently H, C1-6 alkyl, or C1-6 alkyl substituted with 1, 2, or 3 R2-1s; each R2-1 is independently halogen, -OH, or C1-6 alkoxy; R4 is H or halogen; m is 0, 1, 2, or 3; R5 and R7 are each independently H, halogen, C1-6 alkyl, or C1-6 alkoxy; R6 is "an 8-11 membered heterocyclic alkyl group selected from 1, 2, or 3 of N, O, and S, with 1, 2, or 3 heteroatoms" or "an 8-11 membered heterocyclic alkyl group selected from 1, 2, or 3 of N, O, and S, with 1, 2, or 3 heteroatoms substituted with 1, 2, or 3 R6-2s", wherein the heterocyclic alkyl group is a bridged ring or a spiro ring; R6-2 are each independently hydroxyl, C1-6 alkyl, C1-6 alkoxy, C1-6 haloalkyl, or C1-6 haloalkoxy; R8 is H or C1-6 alkyl; R9 is H, halogen, or C1-6 alkyl; n is 0, 1, 2, 3, or 4; L is -(CRaRb)q-; q is 0, 1, 2, or 3; Ra and Rb are each independently H or halogen; R10 is -COOH or -C(=O)ORc; Rc is C1-6 alkyl; X is CRd or N; Rd is H, halogen, or C1-6 alkyl.

2. A compound of formula (I) as claimed in claim 1, its tautomers, its stereoisomers, or a pharmaceutically acceptable salt thereof, characterized in that the compound of formula (I) satisfies one or more of the following conditions: (1) R2 and R3 are each independently H, C1-3 alkyl or C1-3 alkyl substituted by 1, 2 or 3 R2-1; each R2-1 is independently halogen or -OH; (2) m is 0 or 1; (3) R5 and R7 are each independently H or halogen; (4) In R6, the 8-11 member heterocyclic alkyl group is 6-azaspiro[2.5]octyl, 5-azaspiro[2.5]octyl, 6-azaspiro[3.4]octyl, 2-azaspiro[3.4]octyl, 2-oxa-6-azaspiro[3.4]octyl, 6-oxa-2-azaspiro[3.4]octyl, 4-oxa-7-azaspiro[2.5]octyl, 2-azaspiro[4.4]nonyl, 2-azaspiro[3.5]nonyl, 2-oxa-7-azaspiro[3.5]nonyl, 1-oxa-7-azaspiro[3.5]nonyl. Spirospiro[3.5]nonyl, 7-azaspiro[3.5]nonyl, 2,7-diazaspiro[3.5]nonyl, 2-oxa-8-azaspiro[4.5]decyl, 3-oxa-9-azaspiro[5.5]undecyl, 2-oxa-9-azaspiro[5.5]undecyl, 3,9-diazaspiro[5.5]undecyl, 3-azabicyclo[3.2.1]octyl, 3-azaspiro[5.5]undecyl, 8-azaspiro[4.5]decyl or 1-oxa-6-azaspiro[3.4]octyl; (5) Each R6-2 is independently hydroxyl or C1-3 alkyl; (6) R8 is H; (7) R9 is H or halogen; (8) n is 0 or 1; (9) q is 1; (10) Ra and Rb are each independently H; (11) R10 is -COOH; (12) Rd is H.

3. The compound represented by formula (I) as claimed in claim 2, its tautomers, its stereoisomers, or a pharmaceutically acceptable salt of any of the foregoing, characterized in that the compound represented by formula (I) satisfies one or more of the following conditions: (1) in each R2-1, the halogen is F; (2) in R5 and R7, the halogen is F; (3) in each R6-2, the halogen is independently hydroxyl, methyl, ethyl, n-propyl, or isopropyl; (4) in R9, the halogen is F.

4. The compound represented by formula (I) as claimed in claim 1, its tautomers, its stereoisomers, or a pharmaceutically acceptable salt of any of the foregoing, characterized in that R6 is "an 8-10 membered heterocyclic alkyl group selected from one, two, or three of N, O, and S, having one, two, or three heteroatoms" or "an 8-10 membered heterocyclic alkyl group selected from one, two, or three of N, O, and S, having one, two, or three heteroatoms" substituted by one, two, or three R6-2.

5. A compound of formula (I) as claimed in claim 1, its tautomers, its stereoisomers, or a pharmaceutically acceptable salt of any of the foregoing, characterized in that: R1 is H; R2 and R3 are each independently H, a C1-3 alkyl group, or a C1-3 alkyl group substituted with 1, 2, or 3 R2-1 groups; each R2-1 is independently a halogen or -OH; R4 is H or a halogen; m is 0 or 1; R5 and R7 are each independently H or a halogen; R6 is "an 8-11 membered heterocyclic alkyl group selected from 1, 2, or 3 of N, O, and S, with 1, 2, or 3 heteroatoms" or an 8-11 membered heterocyclic alkyl group substituted with 1, 2, or 3 R6-2 groups, wherein... The heterocyclic alkyl group is a bridged ring or a spiro ring; each R6-2 is independently a hydroxyl group or a C1-3 alkyl group; R8 is H; R9 is H or a halogen; n is 0 or 1; L is -(CRaRb)q-, q is 1; Ra and Rb are each independently H; R10 is -COOH; X is CRd or N; Rd is H.

6. A compound of formula (I) as claimed in claim 1, its tautomers, its stereoisomers, or a pharmaceutically acceptable salt of any of the foregoing, characterized in that the compound of formula (I) satisfies one or more of the following conditions: (1) in R2, R3, R5, R7, R6-2, R8, R9, Rc, and Rd, each of the alkyl groups is independently methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, or tert-butyl; (2) in R2-1, R5, R7, and R6-2, each of the alkoxy groups is independently methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, or tert-butoxy; (3) in R2-1, R4, R5, R7, R9, Ra, Rb, and Rd, each of the halogens is independently F, Cl, Br, or I; (4) In R6, each of the heterocyclic alkyl groups is independently "an 8-11 member heterocyclic alkyl group whose heteroatoms are selected from 1, 2 or 3 of N, O and S, and whose heteroatoms number 1 or 2", and the heterocyclic alkyl group is a bridged ring or a spiro ring.

7. The compound represented by formula (I) as claimed in claim 6, its tautomers, its stereoisomers, or a pharmaceutically acceptable salt of any of the foregoing, characterized in that the compound represented by formula (I) satisfies one or more of the following conditions: (1) in R2, R3, R5, R7, R6-2, R8, R9, Rc and Rd, each of the alkyl groups is independently methyl or ethyl; (2) in R2-1, R4, R5, R7, R9, Ra, Rb and Rd, each of the halogens is independently F; (3) in R6, each of the heterocyclic alkyl groups is connected to the parent compound via an N atom.

8. A compound represented by formula (I) as claimed in claim 6, its tautomers, its stereoisomers, or a pharmaceutically acceptable salt of any of the foregoing, characterized in that, in R6, the heterocyclic alkyl group is , ...

9. A compound represented by formula (I) as claimed in claim 1, its tautomers, its stereoisomers, or a pharmaceutically acceptable salt of any of the foregoing, characterized in that the compound represented by formula (I) satisfies one or more of the following conditions: (1) R2 is H, R3 is H, -CH3, -CH2OH, -CH2CH2OH, -CH2F or -CF2H; (2) R6 is , ...

10. A compound of formula (I) as claimed in claim 1, its tautomers, its stereoisomers, or a pharmaceutically acceptable salt of any of the foregoing, characterized in that the compound of formula (I) satisfies any of the following conditions: (1) R1 is H; R2 is H, R3 is H, -CH3 or -CH2F; R4 is H or a halogen, m is 0 or 1; R5 and R7 are each independently H or F; R6 is "an 8-11 membered heterocyclic alkyl group selected from one, two or three of N, O and S, with one, two or three heteroatoms" or "an 8-11 membered heterocyclic alkyl group selected from one, two or three of N, O and S, with one, two or three heteroatoms" substituted by one, two or three R6-2 atoms; wherein, The heterocyclic alkyl group is a bridged ring or a spiro ring; each R6-2 is independently hydroxyl or C1-3 alkyl; R8 is H; R9 is H or F; n is 0 or 1; L is -(CRaRb)q-; q is 1; Ra and Rb are each independently H; R10 is -COOH; X is CRd or N; Rd is H; (2) R1 is H; R2 is H, R3 is H, -CH3 or -CH2F; R4 is H or halogen, m is 0 or 1; R5 and R7 are each independently H or F; R6 is "an 8-10 membered heterocyclic alkyl group selected from one, two or three types of N, O and S, with one, two or three heteroatoms" or "an 8-10 membered heterocyclic alkyl group selected from one, two or three types of N, O and S, with one, two or three heteroatoms" substituted by one, two or three R6-2 groups; wherein the heterocyclic alkyl group is a bridged ring or a spiro ring; each R6-2 is independently hydroxyl or C1-3 alkyl; R8 is H; R9 is H or F; n is 0 or 1; L is -(CRaRb)q-; q is 1; Ra and Rb are each independently H; R10 is -COOH; X is CRd or N; Rd is H; (3) R1 is H; R2 is H, R3 is H, -CH3 or -CH2F; R4 is H or halogen, m is 0 or 1; R5 and R7 are each independently H or F; R6 is, or is replaced by one of the following groups: , or; R6-2 is hydroxyl or methyl; R8 is H; R9 is H or F; n is 0 or 1; L is -(CRaRb)q-; q is 1; Ra and Rb are each independently H; R10 is -COOH; X is CRd or N; Rd is H; (4) R1 is H; R2 is H, R3 is H, -CH3 or -CH2F; R4 is H or F, m is 0 or 1; R5 and R7 are each independently H or F; R6 is, or; R8 is H; R9 is H or F; n is 0 or 1; L is -(CRaRb)q-; q is 1; Ra and Rb are each independently H; R10 is -COOH; X is CRd or N; Rd is H.

11. A compound represented by formula (I) as claimed in any one of claims 1 to 10, its tautomers, its stereoisomers, or a pharmaceutically acceptable salt of any of the foregoing, characterized in that the compound represented by formula (I) has the structure shown in formula (I-1): (I-1) wherein R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, Rd, L, m, and n are defined as described in any one of claims 1 to 10.

12. A compound represented by formula (I) as claimed in any one of claims 1 to 10, its tautomers, its stereoisomers, or a pharmaceutically acceptable salt of any of the foregoing, characterized in that the compound represented by formula (I) has the structure shown in formula (I-2): (I-2) wherein R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, L, m, and n are defined as described in any one of claims 1 to 10.

13. A compound represented by formula (I) as claimed in any one of claims 1 to 10, its tautomers, its stereoisomers, or a pharmaceutically acceptable salt of any of the foregoing, characterized in that the compound represented by formula (I) has the structure shown in formula (I-3): (I-3) wherein, X, R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, L and n are defined as described in any of the requests 1 to 10.

14. A compound represented by formula (I) as claimed in any one of claims 1 to 10, its tautomers, its stereoisomers, or a pharmaceutically acceptable salt of any of the foregoing, characterized in that the compound represented by formula (I) has the structure shown in formula (I-4): (I-4) wherein, The definitions of X, R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, L, m, and n are as described in any of claims 1 to 10; when the carbon atom marked with "" is a chiral carbon atom, it indicates the R configuration, the S configuration, or a mixture thereof.

15. A compound represented by formula (I) as claimed in claim 1, its tautomers, its stereoisomers, or a pharmaceutically acceptable salt of any of the foregoing, characterized in that the compound represented by formula (I) is selected from any of the following compounds: , ...

16. A compound represented by formula (I) as claimed in claim 15, its tautomers, its stereoisomers, or a pharmaceutically acceptable salt of any of the foregoing, characterized in that the compound represented by formula (I) is selected from any of the following compounds: , ...

17. A method for preparing a compound as shown in formula (I), characterized in that it comprises the following steps: (1) The compound shown in formula II-3 is deprotected to obtain the compound shown in formula II-4; (2) The compound shown in formula II-4 is hydrolyzed to obtain the compound shown in formula (I); wherein R10 is -COOH, and R1, R2, R3, R4, R5, R6, R7, R8, R9, Rc, X, L, m and n are defined as described in any one of claims 1 to 16.

18. A compound as shown in Formula II-3 or Formula II-4: or wherein R1, R2, R3, R4, R5, R6, R7, R8, R9, X, L, Rc, m and n are defined as described in any one of claims 1 to 16.

19. A compound represented by any of the following: , ...

20. A pharmaceutical composition, characterized in that the pharmaceutical composition comprises: (1) A compound of formula (I) as claimed in any one of claims 1 to 16, its tautomer, its stereoisomer, or a pharmaceutically acceptable salt thereof; and (2) a pharmaceutically acceptable carrier.

21. The use of a compound of formula (I) as claimed in any one of claims 1 to 16, its tautomer, its stereoisomer, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as claimed in claim 20, in the preparation of a medicament for treating complement factor D-mediated diseases, said complement factor D-mediated diseases being blood disorders, kidney diseases, cardiovascular diseases, immune disorders, central nervous system diseases, respiratory diseases, genitourinary diseases, or eye diseases.

22. The application as claimed in claim 21, characterized in that the complement factor D-mediated diseases are cold agglutinin diseases, catastrophic antiphospholipid syndrome, hemolytic anemia, anti-neutrophil cytoplasmic antibody-associated vasculitis, warm antibody-type autoimmune hemolytic anemia, paroxysmal nocturnal hemoglobinuria, IgA nephropathy, lupus nephritis, atypical uremic hemolytic syndrome, membranous proliferative glomerulonephritis, dense deposit disease, C3 glomerulonephritis, focal segmental glomerulosclerosis, diabetic nephropathy, systemic lupus erythematosus or lupus erythematosus, rheumatoid arthritis, inflammatory bowel disease, psoriasis, multiple sclerosis, organ transplantation... Transplant rejection, myasthenia gravis, Alzheimer's disease, respiratory distress syndrome, asthma, chronic obstructive pulmonary disease, emphysema, coronavirus infection, macular degeneration, macular edema, choroidal neovascularization, uveitis, Behcet's uveitis, proliferative diabetic retinopathy, non-proliferative diabetic retinopathy, glaucoma, hypertensive retinopathy, corneal neovascularization, post-transplant rejection, corneal dystrophy, autoimmune dry eye disease, Stephens-Johnson syndrome, Sjögren's syndrome, environmental dry eye disease, Fehling's endothelial dystrophy, retinal vein occlusion or postoperative inflammation.

23. The application as described in claim 22, characterized in that the complement factor D-mediated disease is SARS-CoV, MERS-CoV, SARS-CoV-2 infection, age-related macular degeneration, or diabetic macular edema.

24. The use of a compound of formula (I) as claimed in any one of claims 1 to 16, its tautomer, its stereoisomer, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as claimed in claim 20, in the preparation of a complement factor D inhibitor medicament.