Compounds as complement factor D inhibitors, pharmaceutical compositions thereof and uses thereof

Abstract

Disclosed are compounds, pharmaceutical compositions and uses thereof as complement factor D inhibitors, specifically a compound represented by formula (I), its tautomers, its stereoisomers, its prodrugs, or any one of the foregoing pharmaceutically acceptable salts, or any one of the foregoing solvates, wherein the compound has excellent inhibitory activity against complement factor D and has excellent pharmacokinetic and pharmacodynamic activity. JPEG2024533782000131.jpg47170

Description

[Technical Field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims priority to Chinese Patent Application No. 2021111658382, filed on September 30, 2021, and Chinese Patent Application No. 2022111607012, filed on September 22, 2022. This application cites the above Chinese patent applications in their entirety.

[0002] The present invention relates to the field of medicine, and specifically to compounds capable of inhibiting the activity of complement factor D, their pharmaceutical compositions and uses. [Background technology]

[0003] Complement is a protein found widely in serum, tissue fluids, and cell membrane surfaces in humans and vertebrates. It mediates immune and inflammatory responses. It is mostly a glycoprotein and is produced by various cells, including hepatocytes, macrophages, and intestinal mucosal epithelial cells. Complement is named for its role as a necessary complement for antibodies to achieve cytolytic activity, but it actually mediates both specific and nonspecific immunity. The three activation pathways of the complement system include the classical pathway, the mannan-binding lectin pathway (MBL), and the alternative (bypass) pathway. Complement factor D plays an initial and central role in the cascade activation of the complement bypass pathway. Activation of the bypass pathway is induced by spontaneous hydrolysis of the thioester bond in C3 to generate C3(H2O), which then binds to factor B to form the C3(H2O)B complex. The function of complement factor D is to cleave factor B within the C3(H2O)B complex to form Ba and Bb. In addition to combining with C3b to form C3 convertase, Bb is also involved in the proliferation of preactivated B lymphocytes, whereas Ba inhibits their proliferation. Factor D is highly expressed in adipose tissue and can stimulate glucose transport, promote triglyceride accumulation in adipocytes, and inhibit lipolysis.

[0004] Dysregulation of the complement system plays an important role in the pathogenesis of IgA nephropathy (IgAN), lupus nephritis (LN), and paroxysmal nocturnal hemoglobinuria (PNH). Deposition of complement components and immune-adaptive substances is a common renal pathological finding in IgAN and LN. Complement is the direct cause of PNH hemolysis, C5aR is involved in amplifying complement system damage, and CFB and CFD are key components of the complement bypass pathway and directly involved in regulating 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-induced hemolysis, thrombus formation, and bone marrow dysfunction, resulting in anemia, fatigue, and other debilitating symptoms that severely impact patients' quality of life. Currently, the monoclonal antibody drugs Soliris and Ultomiris are the primary treatments for PNH. Soliris was first approved for the treatment of various ultra-rare diseases, including PNH, atypical hemolytic uremic syndrome (aHUS), generalized myasthenia gravis (gMG), and neuromyelitis optica spectrum disorder (NMOSD). Ultomiris, an upgraded version of Soliris, is a second-generation, long-acting C5 complement inhibitor that was first approved for the treatment of PNH and aHUS in late 2018. Despite treatment with current standard C5 anti-PNH therapies, many PNH patients remain anemic and transfusion-dependent.

[0006] Currently, there are no commercially available small molecule inhibitors of complement factor D, and since the target is the alternative complement pathway, which is a major cause of complement-mediated renal disease (CDRD), developing small molecule inhibitors with good biological activity for the treatment of this disease is of positive significance. Summary of the Invention

[0007] The present invention aims to solve the technical problem of the limited number of existing small molecule inhibitors of complement factor D, and provides compounds as inhibitors of complement factor D, pharmaceutical compositions thereof, and uses thereof. The compounds have excellent inhibitory activity against complement factor D and excellent pharmacokinetic and pharmacodynamic activity.

[0008] The present invention provides a compound represented by formula (I), a tautomer thereof, a stereoisomer thereof, a prodrug thereof, or any one of the pharmaceutically acceptable salts thereof (referring to the compound represented by formula (I), a tautomer thereof, a stereoisomer thereof, or a prodrug thereof), or a solvate of any one of the compounds represented by formula (I), a tautomer thereof, a stereoisomer thereof, a prodrug thereof, or any one of the pharmaceutically acceptable salts thereof). JPEG0007770556000001.jpg47170

[0009] however, R 1 H, D, C 1-6 alkyl or 1, 2 or 3 R 1-1 C replaced by 1-6 alkyl, and each R 1-1 are independently halogen, -CN, -OH, C 1-6 alkoxy or -NH2, R 2 and R 3 are independently H, D, halogen, C 1-6 alkyl or 1, 2 or 3 R 2-1 C replaced by 1-6 alkyl, and each R 2-1 are independently halogen, -CN, -OH, C 1-6 alkoxy or -NH2, R 4 is H or halogen, and m is 0, 1, 2, or 3; R 5 and R 7 are each independently H, halogen, -CN, or C 1-6 Alkyl or C 1-6 is an alkoxy, R6 is C 7-12 cycloalkyl, 1, 2 or 3 R 6-1 C replaced by 7-12 cycloalkyl, "7-12 membered heterocycloalkyl in which the heteroatom is 1, 2 or 3 selected from N, O and S" or 1, 2 or 3 R 6-2 "7-12 membered heterocycloalkyl having 1, 2 or 3 heteroatoms selected from N, O and S" substituted by R 6-1 and R 6-2 are each independently hydroxyl, oxo (=O), halogen, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Haloalkoxy, C 3-6 Cycloalkyl or -(CH2) p -C 3-6 cycloalkyl, and p is 1, 2, 3, or 4; R 6 , R 6-1 and R 6-2 wherein the cycloalkyl is independently a monocyclic, bridged, or spirocyclic ring; R 6 wherein the heterocycloalkyl is a monocyclic, bridged, or spirocyclic ring; R 8 is H, halogen or C 1-6 is alkyl, R 9 H, halogen, C 1-6 alkyl or 1, 2 or 3 R 9-1 C replaced by 1-6 is alkyl, Each R 9-1 are independently halogen, —CN, —OH, or —NH2, and n is 0, 1, 2, 3, or 4; L is -(CR a R b ) q and q is 0, 1, 2 or 3; R aand R b are each independently H, D or halogen, or R a and R b are concatenated together to form C 3-6 forming a cycloalkylene, the formed cycloalkylene being a monocyclic, bridged or spirocyclic ring; R 10 is -COOH or -C(=O)OR c and R c is C 1-6 alkyl or 1, 2 or 3 R c-1 C replaced by 1-6 alkyl, and each R c-1 are independently halogen, —OH, or —C(═O)OC(CH), X is CR d or N and R d is H, halogen or C 1-6 It is alkyl.

[0010] In one embodiment of the present invention, the compound represented by formula (I) has a structure represented by formula (I-1). JPEG0007770556000002.jpg47170

[0011] However, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R d , L, m and n are as defined in any one of the claims of the present invention.

[0012] In one embodiment of the present invention, the compound represented by formula (I) has a structure represented by formula (I-2). JPEG0007770556000003.jpg47170

[0013] However, R 1 , R2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , L, m and n are as defined in any one of the claims of the present invention.

[0014] In one embodiment of the present invention, the compound represented by formula (I) has a structure represented by formula (I-3). JPEG0007770556000004.jpg47170

[0015] However, X, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , L and n are as defined in any one of the claims of the present invention.

[0016] In one embodiment of the present invention, the compound represented by formula (I) has a structure represented by formula (I-4). JPEG0007770556000005.jpg47170

[0017] JPEG0007770556000006.jpg16170

[0018] In some preferred embodiments of the present invention, specific groups in the compound represented by formula (I), a tautomer thereof, a stereoisomer thereof, a prodrug thereof, or any one of the pharmaceutically acceptable salts thereof (referring to the compound represented by formula (I), a tautomer thereof, a stereoisomer thereof, or a prodrug thereof), or any one of the solvates thereof (the compound represented by formula (I), a tautomer thereof, a stereoisomer thereof, a prodrug thereof, or any one of the pharmaceutically acceptable salts described above), are as defined below, and groups not mentioned are as described in one embodiment of the present invention (abbreviated as "in one embodiment of the present invention").

[0019] In one embodiment of the present invention, R 1 is H.

[0020] In one embodiment of the present invention, R 2 and R 3 are independently H, C 1-6 alkyl or 1, 2 or 3 R 2-1 C replaced by 1-6 alkyl, and each R 2-1 are independently halogen or —OH, and the halogen is preferably F.

[0021] In one embodiment of the present invention, R 2 and R 3 are independently H, C 1-3 alkyl or 1, 2 or 3 R 2-1 C replaced by 1-3 alkyl, and each R 2-1 are independently halogen or —OH, and the halogen is preferably F.

[0022] In one embodiment of the present invention, m is 0 or 1.

[0023] In one embodiment of the present invention, R 6means "an 8- to 11-membered heterocycloalkyl having one, two or three heteroatoms selected from N, O and S, and the number of heteroatoms is one, two or three" or one, two or three R 6-2 and "8- to 11-membered heterocycloalkyl wherein the heteroatom is one, two, or three selected from N, O, and S, and the number of heteroatoms is one, two, or three," substituted by, wherein the 8- to 11-membered heterocycloalkyl 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.

[0024] In one embodiment of the present invention, R 6 means "an 8- to 11-membered heterocycloalkyl having one, two or three heteroatoms selected from N, O and S, and the number of heteroatoms is one, two or three" or one, two or three R 6-2and "8- to 11-membered heterocycloalkyl having 1, 2, or 3 heteroatoms selected from N, O, and S, and the number of heteroatoms is 1, 2, or 3," substituted with 2, wherein the 8- to 11-membered heterocycloalkyl 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[4.4]nonyl, 2-azaspiro[4.4]oct ... 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 or 1-oxa-6-azaspiro[3,4]octyl.

[0025] In one embodiment of the present invention, R 5 and R 7 are each independently H or halogen, and the halogen is preferably F.

[0026] In one embodiment of the present invention, each R 6-2 are independently hydroxyl or C 1-6 alkyl, 1-6 Alkyl is preferably methyl.

[0027] In one embodiment of the present invention, each R 6-2 are independently hydroxyl or C 1-3 alkyl, and preferably each R 6-2 are independently hydroxyl, methyl, ethyl, n-propyl, or isopropyl.

[0028] In one embodiment of the present invention, R 8 is H.

[0029] In one embodiment of the present invention, R 9 is H or halogen, said halogen being preferably F.

[0030] In one embodiment of the present invention, n is 0 or 1.

[0031] In one embodiment of the present invention, q is 1.

[0032] In one embodiment of the present invention, R a and R b are each independently H.

[0033] In one embodiment of the present invention, R 10 is -COOH.

[0034] In one embodiment of the present invention, R d is H.

[0035] In one embodiment of the present invention, R 6 means "an 8- to 10-membered heterocycloalkyl having one, two or three heteroatoms selected from N, O and S, and the number of heteroatoms is one, two or three" or one, two or three R 6-2 and "8- to 10-membered heterocycloalkyl having 1, 2 or 3 heteroatoms selected from N, O and S" substituted with, wherein the heterocycloalkyl is a bridged ring or a spiro ring.

[0036] In one embodiment of the present invention, R 6 means "an 8- to 11-membered heterocycloalkyl having one, two or three heteroatoms selected from N, O and S, and the number of heteroatoms is one, two or three" or one, two or three R 6-2and "8- to 11-membered heterocycloalkyl having 1, 2 or 3 heteroatoms selected from N, O and S" substituted with, wherein the heterocycloalkyl is a bridged ring or a spiro ring.

[0037] In one embodiment of the present invention, R 1 is H, R 2 and R 3 are independently H, C 1-3 alkyl or 1, 2 or 3 R 2-1 C replaced by 1-3 alkyl, and each R 2-1 are independently halogen or —OH, R 4 is H or halogen, m is 0 or 1, R 5 and R 7 are each independently H or halogen; R 6 means "an 8- to 11-membered heterocycloalkyl having one, two or three heteroatoms selected from N, O and S, and the number of heteroatoms is one, two or three" or one, two or three R 6-2 "8-11 membered heterocycloalkyl having 1, 2 or 3 heteroatoms selected from N, O and S" substituted with, wherein the heterocycloalkyl is a bridged ring or a spiro ring; Each R 6-2 are independently hydroxyl or C 1-3 is alkyl, R 8 is H, R 9 is H or halogen, n is 0 or 1, L is -(CR a R b ) q -, q is 1, and R a and R b are each independently H, R 10 is -COOH, X is CR d or N and R d is H.

[0038] In one embodiment of the present invention, R 1 , R 2 , R 3 , R 5 , R 7 , R 6-1 , R 6-2 , R 8 , R 9 , R c and R d In the formula, each alkyl is independently methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, or tert-butyl, and is preferably methyl or ethyl.

[0039] In one embodiment of the present invention, R 1-1 , R 2-1 , R 5 , R 7 , R 6-1 and R 6-2 wherein each alkoxy is independently methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, or tert-butoxy.

[0040] In one embodiment of the present invention, R 1-1 , R 2 , R 3 , R 2-1 , R 4 , R 5 , R 7 , R 6-1 , R 6-2 , R 8 , R 9 , R 9-1 , R a , R b , R c-1 and R d wherein each halogen is independently F, Cl, Br or I, and is preferably F.

[0041] In one embodiment of the present invention, R 6wherein each heterocycloalkyl is independently "an 8- to 11-membered heterocycloalkyl having one, two, or three heteroatoms selected from N, O, and S, and having one or two heteroatoms", and the heterocycloalkyl is a bridged ring or a spiro ring, preferably the heterocycloalkyl is linked to the parent ring via an N atom, and the heterocycloalkyl is preferably JPEG0007770556000007.jpg82170

[0042] JPEG0007770556000008.jpg95170

[0043] In one embodiment of the present invention, R 2 is H and R 3 is H, —CH3, —CH2OH, —CH2CH2OH, —CH2F or —CF2H.

[0044] In one embodiment of the present invention, R 1 is H, R 2 is H and R 3 is H, -CH3 or -CH2F, R 4 is H or halogen, m is 0 or 1, R 5 and R 7 are each independently H or F, R 6 means "8-11 membered heterocycloalkyl having 1, 2 or 3 heteroatoms selected from N, O and S" or 1, 2 or 3 R 6-2 wherein the heteroatom is one, two or three selected from N, O and S, and the number of heteroatoms is one, two or three, and is substituted by Each R 6-2 are independently hydroxyl or C 1-3 is alkyl, R 8 is H, R 9is H or F, n is 0 or 1, L is -(CR a R b ) q -, q is 1, and R a and R b are each independently H, R 10 is -COOH, X is CR d or N and R d is H.

[0045] In one embodiment of the present invention, R 1 is H, R 2 is H and R 3 is H, -CH3 or -CH2F, R 4 is H or halogen, m is 0 or 1, R 5 and R 7 are each independently H, R 6 means "8-10 membered heterocycloalkyl having 1, 2 or 3 heteroatoms selected from N, O and S" or 1, 2 or 3 R 6-2 wherein the heteroatom is one, two or three selected from N, O and S, and the number of heteroatoms is one, two or three, and is substituted by R 6-2 is hydroxyl, R 8 is H, R 9 is H or F, n is 0 or 1, L is -(CR a R b ) q -, q is 1, and R a and R b are each independently H, R 10 is -COOH, X is CR dand R d is H.

[0046] In one embodiment of the present invention, R 1 is H, R 2 is H and R 3 is H, -CH3 or -CH2F, R 4 is H or halogen, m is 0 or 1, R 5 and R 7 are each independently H or F, R 6 means "8-10 membered heterocycloalkyl having 1, 2 or 3 heteroatoms selected from N, O and S" or 1, 2 or 3 R 6-2 wherein the heteroatom is one, two or three selected from N, O and S, and the number of heteroatoms is one, two or three, and is substituted by Each R 6-2 independently C 1-3 is alkyl, R 8 is H, R 9 is H or F, n is 0 or 1, L is -(CR a R b ) q -, q is 1, and R a and R b are each independently H, R 10 is -COOH, X is CR d or N and R d is H.

[0047] In one embodiment of the present invention, R 1 is H, R 2 is H and R 3 is H, -CH3 or -CH2F, R4 is H or halogen, m is 0 or 1, R 5 and R 7 are each independently H or F, R 6 means "8-10 membered heterocycloalkyl having 1, 2 or 3 heteroatoms selected from N, O and S" or 1, 2 or 3 R 6-2 wherein the heteroatom is one, two or three selected from N, O and S, and the number of heteroatoms is one, two or three, and is substituted by Each R 6-2 are independently hydroxyl or C 1-3 is alkyl, R 8 is H, R 9 is H or F, n is 0 or 1, L is -(CR a R b ) q -, q is 1, and R a and R b are each independently H, R 10 is -COOH, X is CR d or N and R d is H.

[0048] In one embodiment of the present invention, R 1 is H, R 2 is H and R 3 is H, -CH3 or -CH2F, R 4 is H or halogen, m is 0 or 1, R 5 and R 7 are each independently H, JPEG0007770556000009.jpg117170JPEG0007770556000010.jpg39170R 6-2is hydroxyl, R 8 is H, R 9 is H or F, n is 0 or 1, L is -(CR a R b ) q -, q is 1, and R a and R b are each independently H, R 10 is -COOH, X is CR d and R d is H.

[0049] In one embodiment of the present invention, R 1 is H, R 2 is H and R 3 is H, -CH3 or -CH2F, R 4 is H or halogen, m is 0 or 1, R 5 and R 7 are each independently H or F, JPEG0007770556000011.jpg138170JPEG0007770556000012.jpg19170R 6-2 is methyl, R 8 is H, R 9 is H or F, n is 0 or 1, L is -(CR a R b ) q -, q is 1, and R a and R b are each independently H, R 10 is -COOH, X is CR d or N and R d is H.

[0050] In one embodiment of the present invention, R 1 is H, R 2 is H and R 3 is H, -CH3 or -CH2F, R 4 is H or halogen, m is 0 or 1, R 5 and R 7 are each independently H or F, JPEG0007770556000013.jpg159170R 6-2 is hydroxyl or methyl, R 8 is H, R 9 is H or F, n is 0 or 1, L is -(CR a R b ) q -, q is 1, and R a and R b are each independently H, R 10 is -COOH, X is CR d or N and R d is H.

[0051] In one embodiment of the present invention, R 1 is H, R 2 is H and R 3 is H, -CH3 or -CH2F, R 4 is H or F, m is 0 or 1, R 5 and R 7 are each independently H or F, JPEG0007770556000014.jpg79170R 8 is H, R 9 is H or F, n is 0 or 1, L is -(CR a R b) q -, q is 1, and R a and R b are each independently H, R 10 is -COOH, X is CR d or N and R d is H.

[0052] In one embodiment of the present invention, the compound represented by formula (I) is selected from any one of the following compounds: JPEG0007770556000015.jpg82170JPEG0007770556000016.jpg231170JPEG00077705560 00017.jpg231170JPEG0007770556000018.jpg238170JPEG0007770556000019.jpg95170

[0053] In one embodiment of the present invention, the compound represented by formula (I) is selected from any one of the following compounds: JPEG0007770556000020.jpg90170JPEG0007770556000021.jpg239170JPEG0007770556000022.jpg239170JPEG0007770556000023.jpg235170

[0054] The present invention also provides a method for preparing a compound of formula (I), which comprises the following steps: (1) deprotecting the compound represented by formula II-3 to obtain a compound represented by formula II-4; (2) hydrolyzing the compound represented by formula II-4 to obtain the compound represented by formula (I); JPEG0007770556000025.jpg50170

[0055] However, R 10 is -COOH, and R 1 , R2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R c , X, L, m and n are as defined in any one embodiment of the present invention, and the conditions and operations of the above deprotection reaction and hydrolysis reaction may be the usual conditions and operations for the reaction in the art, preferably R 1 is H.

[0056] In one embodiment of the present invention, the method for preparing the compound of formula (I) comprises the following steps: JPEG0007770556000026.jpg93170

[0057] However, R 10 is -COOH, and R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R c , X, L, m and n are as defined in any one embodiment of the present invention, and the conditions and operations of the above reaction may be the usual conditions and operations of the reaction in the art, preferably R 1 is H.

[0058] The present invention also provides a compound represented by formula II-3 or II-4. JPEG0007770556000027.jpg56170

[0059] However, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , X, L, Rc , m and n are as defined in any one embodiment of the present invention.

[0060] In one embodiment of the present invention, in the compound represented by formula II-3 or II-4, R 1 is H.

[0061] The present invention also provides any one of the following compounds: JPEG0007770556000028.jpg103170JPEG0007770556000029.jpg241170JPEG0007770556000030.jpg241170JPEG0007770556 000031.jpg211170JPEG0007770556000032.jpg39170JPEG0007770556000033.jpg253170JPEG0007770556000034.jpg250170

[0062] The present invention also provides (1) A compound represented by formula (I) according to any one of the above, a tautomer thereof, a stereoisomer thereof, a prodrug thereof, or any one of the above pharmaceutically acceptable salts thereof (referring to the compound represented by formula (I), a tautomer thereof, a stereoisomer thereof, or a prodrug thereof), or any one of the above solvates thereof (referring to the compound represented by formula (I), a tautomer thereof, a stereoisomer thereof, a prodrug thereof, or any one of the above pharmaceutically acceptable salts), and (2) a pharmaceutically acceptable carrier; The present invention provides a pharmaceutical composition comprising:

[0063] The present invention also provides use of a compound represented by formula (I) described in any one of the above, a tautomer thereof, a stereoisomer thereof, a prodrug thereof, or a pharmaceutically acceptable salt of any one of the above (referring to the compound represented by formula (I), a tautomer thereof, a stereoisomer thereof, or a prodrug thereof), or a solvate of any one of the above (referring to the compound represented by formula (I), a tautomer thereof, a stereoisomer thereof, a prodrug thereof, or a pharmaceutically acceptable salt of any one of the above), or a pharmaceutical composition described in any one of the above, in the manufacture of a medicament for treating and / or preventing a disease mediated by complement factor D.

[0064] The present invention also provides a method for treating and / or preventing a disease mediated by complement factor D, comprising administering to an individual in need thereof a therapeutically effective amount of a substance X or the pharmaceutical composition described in any one of the above, wherein the substance X is a compound represented by formula (I) described in any one of the above, a tautomer thereof, a stereoisomer thereof, a prodrug thereof, or any one of the pharmaceutically acceptable salts thereof (referring to the compound represented by formula (I), a tautomer thereof, a stereoisomer thereof, or a prodrug thereof), or a solvate thereof (referring to the compound represented by formula (I), a tautomer thereof, a stereoisomer thereof, a prodrug thereof, or any one of the pharmaceutically acceptable salts). Preferably, the individual is a patient according to the present invention.

[0065] In one embodiment of the present invention, the disease mediated by complement factor D includes a blood disease, a kidney disease, a cardiovascular disease, an immune disease, a central nervous system disease, a respiratory system disease, a urogenital system disease, or an eye disease. Preferably, the disease mediated by complement factor D is a blood disease, a kidney disease, a cardiovascular disease, an immune disease, a central nervous system disease, an eye disease, etc.

[0066] In one embodiment of the present invention, the disease mediated by complement factor D is cold agglutinin disease, catastrophic antiphospholipid syndrome, hemolytic anemia, antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV), warm antibody autoimmune hemolytic anemia, paroxysmal nocturnal hemoglobinuria, IgA nephropathy, lupus nephritis, atypical hemolytic uremic syndrome, membranoproliferative glomerulonephritis (MPGN), dense deposition 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, or respiratory distress. syndrome, asthma, chronic obstructive pulmonary disease, emphysema, coronavirus infection (e.g., 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, Behçet's uveitis, proliferative diabetic retinopathy, non-proliferative diabetic retinopathy, glaucoma, hypertensive retinopathy, corneal neovascularization, corneal transplant rejection, corneal dystrophy, autoimmune dry eye disease, Stevens-Johnson syndrome, Sjögren's syndrome, environmental dry eye disease, Fuchs endothelial corneal dystrophy, retinal vein occlusion, or postoperative inflammation.

[0067] In other embodiments of the invention, the immune disease is lupus, allograft rejection, autoimmune thyroid disease (e.g., Graves' disease and Hashimoto's disease), autoimmune uveoretinitis, giant cell arteritis, inflammatory bowel disease (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.

[0068] Furthermore, diseases mediated by complement factor D include, but are not limited to, paroxysmal nocturnal erythrochromia, IgA nephropathy, lupus nephritis, atypical hemolytic uremic syndrome, organ transplant rejection, myasthenia gravis, neuromyelitis optica, membranoproliferative glomerulonephritis, dense deposition 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.

[0069] The present invention also provides use of a compound represented by formula (I) described in any one of the above, a tautomer thereof, a stereoisomer thereof, a prodrug thereof, or any one of the above pharmaceutically acceptable salts thereof (referring to the compound represented by formula (I), a tautomer thereof, a stereoisomer thereof, or a prodrug thereof), or any one of the above solvates thereof (referring to the compound represented by formula (I), a tautomer thereof, a stereoisomer thereof, a prodrug thereof, or any one of the above pharmaceutically acceptable salts), or a pharmaceutical composition described in any one of the above, in the manufacture of a complement factor D inhibitor drug.

[0070] In the above-mentioned use, the complement factor D inhibitor drug can be used in a mammalian organism, and can also be used outside the organism, mainly in experiments, for example, to provide a comparison as a standard sample or control sample, or to prepare a kit according to conventional methods in the art to rapidly detect the effect of inhibiting complement factor D.

[0071] Unless otherwise specified, the terms used in this invention have the following meanings: JPEG0007770556000035.jpg20170

[0072] As used herein, a single dash "-" precedes a substituent to indicate that the specified substituent is attached to the parent moiety by a single bond. When the direction of attachment of a linking group recited in this invention is not specified, the attachment direction is the same as the left-to-right reading order.

[0073] The term "pharmaceutically acceptable" refers to salts, solvents, auxiliary agents, etc. that are generally non-toxic, safe, and suitable for use by a patient. The "patient" is preferably a mammal, more preferably a human. The term "mammal" includes any mammal. Examples of mammals include, but are not limited to, cows, horses, sheep, pigs, cats, dogs, mice, rats, rabbits, guinea pigs, monkeys, humans, etc.

[0074] The term "pharmaceutically acceptable salt" refers to a salt prepared from a relatively non-toxic, pharmaceutically acceptable acid or base with a compound of the present invention. When a compound of the present invention contains a relatively acidic functional group, a base addition salt can be obtained by contacting the neutral form of the compound with a sufficient amount of a pharmaceutically acceptable base in a solution or in 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, diethanolamine salts, and the like. When a compound of the present invention contains a relatively basic functional group, an acid addition salt can be obtained by contacting the neutral form of the compound with a sufficient amount of a pharmaceutically acceptable acid in a solution or in a suitable inert solvent. The pharmaceutically acceptable acid includes inorganic acids, including, but not limited to, hydrochloric acid, hydrobromic acid, hydroiodic acid, nitric acid, carbonic acid, phosphoric acid, phosphorous acid, sulfuric acid, and the like. The pharmaceutically acceptable acid includes organic acids, including, but not limited to, acetic acid, propionic acid, oxalic acid, isobutyric acid, maleic acid, malonic acid, benzoic acid, succinic acid, suberic 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, bitartrate, ascorbic acid, gentisic acid, fumaric acid, gluconic acid, saccharic acid, formic acid, ethanesulfonic acid, pamoic acid (i.e., 4,4'-methylenebis(3-hydroxy-2-naphthoic acid)), amino acids (such as glutamic acid and arginine), and the like. 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.Specifically, reference can be made to 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).

[0075] The term "solvate" refers to a substance formed by combining a compound of the present invention with a stoichiometric or non-stoichiometric amount of a solvent. The solvent molecules in a solvate can be in an ordered or non-ordered arrangement. Such solvents include, but are not limited to, water, methanol, ethanol, etc.

[0076] The term "solvate of a pharmaceutically acceptable salt," as used herein, refers to a substance formed by combining a compound of the present invention with a relatively non-toxic, pharmaceutically acceptable acid or base, or a stoichiometric or non-stoichiometric amount of a solvent. The term "solvate of a pharmaceutically acceptable salt" is defined above and refers to a substance formed by combining a compound of the present invention with a relatively non-toxic, pharmaceutically acceptable acid or base, or a stoichiometric or non-stoichiometric amount of a solvent. The term "solvate of a pharmaceutically acceptable salt" includes, but is not limited to, the hydrochloride monohydrate of a compound of the present invention.

[0077] In the definition of a compound, any variable (e.g., R 1-1 When R occurs more than once, the definition of that variable at each occurrence is independent of its definition at any other occurrence, and such definitions are independent of and do not influence one another. Thus, a particular group may occur with one, two, or three R 1-1 When substituted by a group, i.e., the group is substituted by up to three R 1-1 If R at that position may be substituted by 1-1 The definition of R is the remaining position 1-1 Further, combinations of substituents and / or variables are permissible only if such combinations result in stable compounds.

[0078] In the term "A-membered", A is an integer and generally refers to the number of atoms forming the ring. For example, piperidinyl is an example of a 6-membered heterocycloalkyl, cyclopropyl is an example of a 3-membered cycloalkyl, phenyl is an example of a 6-membered aryl, etc.

[0079] In the term "A- to B-membered", A and B are integers, and the number of atoms forming the ring is in the range of A to B.

[0080] The term "halogen" refers to fluorine, chlorine, bromine or iodine.

[0081] The term "alkyl" refers to a straight or branched chain saturated hydrocarbon group containing the specified number of carbon atoms. In some embodiments, the alkyl is C 1-6 alkyl, e.g., C 1-5 Alkyl, C 1-4 Alkyl, C 1-3 Alkyl, C 1-2 In another embodiment, the alkyl is C 1-3 Examples of alkyl include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, isobutyl, sec-butyl, n-pentyl, n-hexyl, and similar alkyls.

[0082] The term "alkoxy" refers to an -OR X refers to the group, where R X is alkyl as defined above.

[0083] The term "cycloalkyl" refers to a group having a specified number of ring carbon atoms (e.g., C 3-6 , C 7-12 Monocycloalkyl refers to saturated, monocyclic, bridged, or spirocyclic groups consisting of only carbon atoms, having the following structure: Monocycloalkyl includes, but is not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and the like.

[0084] The term "cycloalkylene" refers to a group having a specified number of ring carbon atoms (e.g., C 3-6 , C 7-12 The term "cycloalkylene" refers to a group formed by removing two hydrogen atoms from a saturated, monocyclic, bridged, or spirocyclic alkane having only carbon atoms in the ring, and the two removed hydrogen atoms may be on the same atom or different atoms. Monocycloalkylene includes cyclopropylene (e.g., JPEG0007770556000036.jpg59170

[0085] The term "heterocycloalkyl" refers to a saturated cyclic group having a specified number of ring atoms (e.g., 7 to 12 ring atoms), the ring atoms of which contain at least one heteroatom independently selected from nitrogen, oxygen, and sulfur, and which may be a monocyclic, bridged, or spirocyclic system. Preferably, the number of heteroatoms in a heterocycloalkyl is one, two, or three. The carbon atoms and heteroatoms of a heterocycloalkyl may be optionally oxidized to form oxo or sulfide or other oxidized bonds (e.g., C(=O), S(=O), S(=O)2, or N-oxide), or the nitrogen atom may be quaternized. A heterocycloalkyl can be linked to other fragments or groups within a compound through a ring carbon atom or ring heteroatom. In some embodiments, the heterocycloalkyl is an 8- to 11-membered heterocycloalkyl having 1, 2, or 3 heteroatoms selected from N, O, and S, and the number of heteroatoms is 1 or 2; in other embodiments, the heterocycloalkyl is an 8- to 10-membered heterocycloalkyl having 1, 2, or 3 heteroatoms selected from N, O, and S, and the number of heteroatoms is 1 or 2.Heterocycloalkyl includes azetidinyl, 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, 2-oxa-7-azaspiro[3.5]nonyl, and 2-oxa-7-azaspiro[3.5]nonyl. Examples of cyclohexyl ethers include, but are not limited to, 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, and the like.

[0086] The term "pharmaceutically acceptable carrier" refers to excipients and additives used in the preparation and formulation of pharmaceuticals, and refers to all substances contained in drug formulations except for active ingredients. For details, please refer to the Pharmacopoeia of the People's Republic of China 2015 I-IV or the Handbook of Pharmaceutical Excipients (Raymond C Rowe, 2009 Sixth Edition).

[0087] The term "treatment" refers to therapeutic therapy. With respect to a particular disease, treatment refers to (1) alleviating one or more biological manifestations of the disease or condition, (2) interfering with (a) one or more points in the biological cascade leading to or causing the disease or (b) one or more biological manifestations of the disease, (3) ameliorating one or more symptoms, effects, or side effects associated with the disease or one or more symptoms, effects, or side effects associated with the disease or its treatment, or (4) reducing the disease or one or more biological manifestations of the disease.

[0088] The term "prevention" refers to reducing the risk of acquiring or developing a disease or disorder.

[0089] The term "therapeutically effective amount" refers to the amount of a compound sufficient to effectively treat a disease or condition described herein when administered to a patient. The "therapeutically effective amount" will vary depending on the compound, the disease and its severity, and the age of the patient being treated, but can be adjusted as needed by one skilled in the art.

[0090] The above preferred conditions can be combined in any way to obtain each preferred embodiment of the present invention, without violating the ordinary skill in the art.

[0091] The reagents and raw materials used in the present invention are commercially available.

[0092] The positive effect of the present invention: the compounds of the present invention have excellent inhibitory activity against complement factor D (IC of the example compound against C3b). 50 It has an excellent inhibitory effect on rabbit erythrocyte hemolysis (rabbit erythrocyte hemolysis IC 50 The pharmacokinetic and pharmacodynamic activity of the compound is excellent. DETAILED DESCRIPTION OF THE INVENTION

[0093] The present invention will be further described below by way of examples, but the present invention is not limited to the scope of the examples. In the following examples, experimental methods for which specific conditions are not described are selected according to conventional methods and conditions or product instructions.

[0094] Nouns used in the specific experimental descriptions below (unless otherwise stated) refer to the respective reagents or procedures described below. (Boc)2O: di-tert-butyl dicarbonate; B2Pin2: bis(pinacolato)diboron; DIAD: diisopropyl azodicarboxylate; 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(dibenzylideneacetone)dipalladium; Pd(dppf)Cl2: [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II); Pd(PPh3)4: tetrakis(triphenylphosphine)palladium; PO: oral administration; TEA: triethylamine; TFA: trifluoroacetic acid; THF: tetrahydrofuran; X-Phos: 2-dicyclohexylphospino-2',4',6'-triisopropylbiphenyl;

[0095] <Manufacturing Example> Example 1: Synthesis of 2-(2-((3'-(aminomethyl)-5-(6-azaspiro[2.5]octan-6-yl)-[1,1'-biphenyl]-3-yl)methoxy)phenyl)acetic acid (Compound 001) JPEG0007770556000037.jpg104170

[0096] 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. Di-tert-butyl dicarbonate (15.71 g, 72 mmol) was added to the reaction mixture under ice bath conditions. The reaction mixture was allowed to react at 0 °C for 1 hour. The mixture was then concentrated under reduced pressure and transferred to a 500 mL separatory funnel. 150 mL of ethyl acetate and 200 mL of water were added, followed by extraction and separation. The organic phase was separated. The aqueous phase was further extracted with ethyl acetate (50 mL × 2). The combined organic phase was 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.

[0097] 1.2 Synthesis of compound 001-2 Compound 001-1 (18.02 g, 60 mmol) obtained in step 1.1, bis(pinacolato)diboron (18.28 g, 72 mmol), potassium acetate (11.78 g, 120 mmol), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (4.40 g, 6 mmol), and 1,4-dioxane (120 mL) were sequentially added to a 500 mL reaction flask. After purging with nitrogen gas three times, the resulting reaction solution was heated in an 80 °C oil bath 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, followed by extraction and separation. The organic phase was separated. The aqueous phase was further extracted with ethyl acetate (50 mL x 2), and the combined organic phase was 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 give compound 001-2, which was used directly in the next step. LC / MS (ESI+) m / z: [M+Ht-Bu] + =278.15.

[0098] 1.3 Synthesis of compound 001-3 001-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 in dichloromethane (70 mL) in succession. A solution of bis(4-chlorobenzyl)azodicarboxylate (13.7 g, 37.6 mmol) in dichloromethane (70 mL) was added dropwise to the reaction mixture in an ice bath. 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 to 10 / 1 (v / v)) to obtain compound 001-3. LC / MS (ESI+) m / z: [M+H] + =414.90.

[0099] 1.4 Synthesis of Compound 001-4 001-3 (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(diphenylphosphino)ferrocene]dichloropalladium(II) (0.35 g, 0.48 mmol) were sequentially added to 1,4-dioxane / water (30 mL / 3 mL). After purging with nitrogen gas three times, the reaction solution was reacted at 80 °C for 2 h. Then, it was filtered, and the filtrate was diluted with water (30 mL) and extracted with ethyl acetate (30 mL × 2). The combined organic phase was 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 to 5 / 1 (v / v)) to give compound 001-4. LC / MS(ESI+)m / z:[M+H-Boc] + =439.95.

[0100] 1.5 Synthesis of Compound 001-5 001-4 (4.3 g, 7.96 mmol), 6-azaspiro[2.5]octane hydrochloride (compound 001-d, 1.4 g, 9.55 mmol), potassium carbonate (3.3 g, 23.87 mmol), tris(dibenzylideneacetone)dipalladium (400 mg, 10 wt%), and 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl (400 mg, 10 wt%) were added to 1,4-dioxane (50 mL) in succession. The atmosphere was purged with nitrogen gas three times, and the reaction solution was reacted at 90 °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 to give compound 001-5. LC / MS (ESI+) m / z: [M+H] + =571.15.

[0101] 1.6 Synthesis of Compound 001-6 001-5 (3.5 g, 6.1 mmol) was dissolved in dichloromethane (27 mL), trifluoroacetic acid (9 mL) was added, and the mixture was allowed to react at room temperature for 1 hour. The reaction solution was adjusted to pH 8 by adding saturated aqueous sodium bicarbonate solution, and then extracted with ethyl acetate (30 mL x 3). The combined organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give compound 001-6 (3.2 g, crude product), which was used directly in the next step. LC / MS (ESI+) m / z: [M+H] + =471.10.

[0102] 1.7 Synthesis of Compound 001 001-6 (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), and the reaction solution was reacted at 60° C. for 4 hours. The reaction solution was purified by preparative high-performance liquid chromatography and then lyophilized to obtain the target compound 001.

[0103] 1H NMR(400MHz,DMSO-d6):δ8.27(s,0.59H),8.10(s, 1H),7.67(d,J=7.6Hz,1H),7.37-7.40(m,2H),7.28(d,J=7.2Hz,1H),7.08-7.14(m,3H),7.00(s,1H),6.92(d,J=8.0Hz,1H),6.81(t,J LC / MS(ESI+)m / z:[M+H] + =457.10.

[0104] Example 2: Synthesis of 2-(2-((3'-(aminomethyl)-5-(7-azaspiro[3.5]nonan-7-yl)-[1,1'-biphenyl]-3-yl)methoxy)phenyl)acetic acid (Compound 002) JPEG0007770556000038.jpg35170

[0105] The synthesis of compound 002 can be carried out by referring to the synthesis method of compound 001, and by replacing the raw material 001-d with 7-azaspiro[3.5]nonane hydrochloride (002-a).

[0106] 1 H NMR(400MHz,DMSO-d6):δ8.27(br.s,0.6H),7.82-7.92(m,1H),7.5(dd,J=7.6,20.0Hz,1H),7.40 (br.s,0.6H),7.33(t,J=7.6Hz,1H),7.22-7.27(m,1H),6.99-7.12(m,4H),6.87-6.92(m,1H),6.7 2-6.79(m,1H),5.11(d,J=5.2Hz,2H),4.21(s,1H),3.83(s,1H),3.36(s,1H),3.31(s,1H),3.15( t,J=5.2Hz,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.

[0107] Example 3 Synthesis of 2-(2-((3'-(aminomethyl)-5-(6-azaspiro[3.4]octan-6-yl)-[1,1'-biphenyl]-3-yl)methoxy)phenyl)acetic acid (Compound 003) JPEG0007770556000039.jpg30170

[0108] Compound 003 can be synthesized by referring to the synthesis method for compound 001, except that the raw material 001-d is replaced with 6-azaspiro[3.4]octane hydrochloride (003-a).

[0109] 1 H NMR(400MHz,DMSO-d6):δ9.51(s,1H),7.98(d,J= 114.8Hz,1H),7.59(dd,J=48.4,7.6Hz,1H),7.36(t,J =7.6Hz,1H),7.31-7.22(m,2H),7.11-7.01(m,2H),6.91-6.67(m,3H),6.51(d,J=10.4Hz,1H),5.15(d,J=23.2Hz,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.

[0110] Example 4 Synthesis of 2-(2-((3'-(aminomethyl)-5-(5-azaspiro[2.5]octan-5-yl)-[1,1'-biphenyl]-3-yl)methoxy)phenyl)acetic acid (Compound 004) JPEG0007770556000040.jpg32170

[0111] Compound 004 can be synthesized by referring to the synthesis method of compound 001, except that the raw material 001-d is replaced with 5-azaspiro[2.5]octane hydrochloride (004-a).

[0112] 1H NMR(400MHz,DMSO-d6):δ8.33(s,1H),8.04(s,1H), 7.67(d,J=8.0Hz,1H),7.39(t,J=7.6Hz,1H),7.35-7.27(m,2H),7.12(t,J=7.6Hz ,2H),7.08(s,1H),6.98-6.90(m,2H),6.82(t,J=7.6Hz,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=5.6Hz,2H), 0.33(t,J=4.8Hz,2H); LC / MS(ESI+)m / z:[M+H] + =457.10.

[0113] Example 5 Synthesis of 2-(2-((3'-(aminomethyl)-5-(2-azaspiro[3.5]nonan-2-yl)-[1,1'-biphenyl]-3-yl)methoxy)phenyl)acetic acid (Compound 005) JPEG0007770556000041.jpg30170

[0114] Compound 005 can be synthesized by referring to the synthesis method for compound 001, except that the raw material 001-d is replaced with 2-azaspiro[3.5]nonane hydrochloride (005-a).

[0115] 1 H NMR(400MHz,DMSO-d6):δ9.54(s,0.25H),7.98(d, J=104.4Hz,1H),7.55(dd,J=44.8,8.0Hz,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=13.2Hz,1H),5.13( d,J=25.2Hz,2H),4.07(d,J=134Hz,2H),3.58(d,J=3.2Hz,4H),3.38(d,J=4.4Hz,2H),1.67(s,4H),1.42(d,J=26.4Hz,6H);LC / MS(ESI+)m / z:[M+H] +=471.10.

[0116] Example 6 Synthesis of 2-(2-((3'-(aminomethyl)-5-(3-azabicyclo[3.2.1]octan-3-yl)-[1,1'-biphenyl]-3-yl)methoxy)phenyl)acetic acid (Compound 006) JPEG0007770556000042.jpg32170

[0117] Compound 006 can be synthesized by referring to the synthesis method for compound 001, except that the raw material 001-d is replaced with 3-azabicyclo[3.2.1]octane hydrochloride (006-a).

[0118] 1 H NMR(400MHz,DMSO-d6):δ7.76(d,J=54.4Hz,1H), 7.50(dd,J=14.4,7.6Hz,1H),7.39-7.32(m,1H),7.27 (t,J=7.2Hz,1H),7.20-6.89(m,5H),6.84-6.73(m,2H),5.11(d,J=54.4Hz,2H),4.00(d,J=184.4Hz,2H),3.60(d,J=10 .0Hz,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.

[0119] Example 7 Synthesis of 2-(2-((3'-(aminomethyl)-2'-fluoro-5-(6-azaspiro[2.5]octan-6-yl)-[1,1'-biphenyl]-3-yl)methoxy)phenyl)acetic acid (Compound 007) JPEG0007770556000043.jpg65170

[0120] 7.1 Synthesis of Compound 007-1 007-a (1.0 g, 5 mmol) was dissolved in tetrahydrofuran (5 mL) and 1 M borane in tetrahydrofuran (20 mL, 20 mmol) was slowly added dropwise under nitrogen gas protection. After the addition was complete, the reaction mixture was heated to 60 °C and reacted for 5 h. After cooling to room temperature, the reaction mixture was quenched by the slow dropwise addition of methanol (20 mL). 1 M dilute hydrochloric acid (10 mL) was added and the mixture was extracted with ethyl acetate (20 mL x 3). The aqueous phase was adjusted to pH 8-10 with saturated aqueous sodium bicarbonate solution. The aqueous phase was further extracted with ethyl acetate (20 mL x 3). The combined organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give compound 007-1 (crude product). LC / MS (ESI+) m / z: [M+H] + =204.00.

[0121] 7.2 Synthesis of Compound 007-2 007-1 (600 mg, crude product), di-tert-butyl dicarbonate (704 mg, 3.23 mmol), and triethylamine (594 mg, 5.88 mmol) were dissolved in dichloromethane (5 mL) and the reaction mixture was allowed to react 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) to obtain compound 007-2. LC / MS (ESI+) m / z: [M+H] + =236.00.

[0122] 7.3 Synthesis of compound 007-3 007-2 (600 mg, 1.97 mmol), bis(pinacolato)diboron (601 mg, 2.37 mmol), potassium acetate (387 mg, 3.95 mmol), and [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (144 mg, 0.2 mmol) were added sequentially to 1,4-dioxane (5 mL). The atmosphere was purged with nitrogen gas 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) to obtain compound 007-3. LC / MS (ESI+) m / z: [M+Ht-Bu]+ =296.05.

[0123] 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(diphenylphosphino)ferrocene]dichloropalladium(II) (106 mg, 0.145 mmol) were added sequentially to 1,4-dioxane (5 mL) and water (1 mL), and the reaction solution was reacted at 100 °C for 2 hours. The reaction solution was cooled to room temperature, water (10 mL) was added, and extracted with ethyl acetate (15 mL × 3). The combined organic phase was 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) to give compound 007-4.

[0124] 7.5 Synthesis of Compound 007 Compound 007 can be synthesized by referring to the synthesis method for compound 001, and replacing intermediate 001-4 with 007-4. 1 H NMR (400MHz, DMSO-d6): δ7.49-7.32(m,2H),7.32-7.15(m,2H),7.15-7.04(m,2H),7.04-6.96(m,2H),6.93(d,J=7.6Hz,1H),6.83-6. 74(m,1H),5.10(d,J=49.6Hz,2H),4.16(s,1H),3.79(s,1H),3.29(d,J=4.4Hz,4H),3.26(s,2H),1.46(dd,J=13.2,8Hz,4H),0.33(d, J=4.8Hz,4H);LC / MS(ESI+)m / z:[M+H] + =475.05.

[0125] Example 8 Synthesis of 2-(2-((3'-(aminomethyl)-5'-fluoro-5-(6-azaspiro[2.5]octan-6-yl)-[1,1'-biphenyl]-3-yl)methoxy)phenyl)acetic acid (Compound 008) JPEG0007770556000044.jpg67170

[0126] Compound 008 can be synthesized by referring to the synthesis method of compound 007, and by replacing the intermediate 007-1 with 3-fluoro-5-bromobenzylamine (008-a).

[0127] 1 H NMR(400MHz,DMSO-d6):δ9.46(s,1H),7.74(d,J= 29.6Hz,1H),7.37(d,J=40.4Hz,2H),7.28-6.94(m,5H), 6.94-6.67(m,2H),5.14(d,J=36.8Hz,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.

[0128] Example 9 Synthesis of 2-(2-((3'-(aminomethyl)-5-(6-azaspiro[2.5]octan-6-yl)-[1,1'-biphenyl]-3-yl)methoxy)-4-fluorophenyl)acetic acid (Compound 009) JPEG0007770556000045.jpg78170

[0129] 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 mixture was allowed to react 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 x 3). The combined organic phase was 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) to give compound 009-1. LC / MS (ESI+) m / z: [M+H] + =199.10.

[0130] 9.2 Synthesis of Compound 009-2 Under nitrogen gas protection, 009-1 (1.0 g, 5.04 mmol) was dissolved in dichloromethane (20 mL). The reaction mixture was cooled to -20 °C, and boron tribromide (20 mmol, 15.12 mmol) was slowly added dropwise. After the addition was complete, the reaction mixture was allowed to react at the same temperature for 2 hours. At -20 °C, methanol (6 mL) was added dropwise to quench the reaction mixture. Water was added, and the mixture was extracted with dichloromethane (10 mL × 3). The combined organic phase was 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) to obtain compound 009-2.

[0131] 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), potassium carbonate (1.12 g, 8.04 mmol) was added, and the mixture was allowed to react at room temperature for 2 hours. Water was added, and the mixture was extracted with ethyl acetate (10 mL × 3). The combined organic phase was 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) to obtain compound 009-3.

[0132] 9.4 Synthesis of Compound 009-4 009-3 (750 mg, 1.74 mmol) and 001-2 (578 mg, 1.74 mmol), potassium carbonate (480 mg, 3.48 mmol), and [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (127 mg, 0.174 mmol) were sequentially added to 1,4-dioxane (20 mL) and water (2 mL), and the reaction solution was reacted at 100 °C for 2 h. The reaction solution was cooled to room temperature, water was added, and extracted with ethyl acetate (10 mL × 3). The combined organic phase was 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) to give compound 009-4.

[0133] 9.5 Synthesis of Compound 009 Compound 009 can be synthesized by referring to the synthesis method for compound 001, and replacing the raw material 001-4 with 009-4. 1 H NMR(400MHz,DMSO-d6):δ9.49(s,1H),7.88(d,J= 24.0Hz,1H),7.56(t,J=8.0Hz,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=44.0Hz,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=4.0Hz,4H),0.35(s,4H);LC / MS(ESI+)m / z:[M+H] + =475.05.

[0134] Example 10 Synthesis of 2-(2-((3'-(aminomethyl)-5-(6-azaspiro[2.5]octan-6-yl)-[1,1'-biphenyl]-3-yl)methoxy)-5-fluorophenyl)acetic acid (Compound 010) JPEG0007770556000046.jpg69170

[0135] Compound 010 can be synthesized by referring to the synthesis method of compound 009, simply by replacing the starting material 2-methoxy-4-fluorophenylacetic acid (009-a) with 5-fluoro-2-methoxyphenylacetic acid (010-a).

[0136] 1 H NMR(400MHz,DMSO-d6):δ8.13(s,1H),7.82(s,1H), 7.66(d,J=8.0Hz,1H),7.54(d,J=8.0Hz,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=20.0Hz,2H),4.24(s,1H),3.95(s,1H),3.38(s,2H),3.29(d,J=8.0Hz, 4H),1.49-1.48(m,4H),0.35(s,4H);LC / MS(ESI+)m / z:[M+H] + =475.05.

[0137] Example 11, Synthesis of 2-(2-((3'-(aminomethyl)-5-(2-oxa-7-azaspiro[3.5]nonan-7-yl)-[1,1'-biphenyl]-3-yl)methoxy)phenyl)acetic acid (Compound 011) JPEG0007770556000047.jpg30170

[0138] Compound 011 can be synthesized by referring to the synthesis method for compound 001, except that the raw material 001-d is replaced with 2-oxa-7-azaspiro[3.5]nonane hydrochloride (011-a).

[0139] 1H NMR(400MHz,DMSO-d6):δ7.71(s,1H),7.50(d,J=7.6Hz,1H),7.35(t,J=7.6Hz,1H ),7.27(d,J=7.6Hz,1H),7.18(d,J=8.8Hz,2H),7.04-7.08(m,3H),6.92(d,J=8.0 Hz,1H),6.80(t,J=7.6Hz,1H),5.05(s,2H),4.36(d,J=4.0Hz,4H)),3.77(s,2H), 3.39(s,2H),3.18(t,J=5.6Hz,4H),1.90(t,J=5.6Hz,4H);LC / MS(ESI+)m / z:[M+H] + =473.05.

[0140] Example 12 Synthesis of 2-(2-((3'-(aminomethyl)-5-(1-oxa-7-azaspiro[3.5]nonan-7-yl)-[1,1'-biphenyl]-3-yl)methoxy)phenyl)acetic acid (Compound 012) JPEG0007770556000048.jpg32170

[0141] The synthesis of compound 012 can be carried out by referring to the synthesis method of compound 001, except that the raw material 001-d is replaced with 1-oxa-7-azaspiro[3.5]nonane hydrochloride (012-a).

[0142] 1 H NMR(400MHz,DMSO-d6):δ9.53(s,1H),7.85-8.01(m,1H),7.62-7.53(m,1H),7.43(s,1 H),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=32.0Hz,2H),4.43(t,J=8.0Hz,2H),4.23(s,1H),3.87(s,1H),3.37(d,J=16.0Hz,4H ),3.20-3.14(m,2H),2.39(t,J=8.0Hz,2H),1.98-1.79(m,4H);LC / MS(ESI+)m / z:[M+H] + =473.05.

[0143] Example 13 Synthesis of 2-(2-((3'-(aminomethyl)-5-(2-hydroxy-7-azaspiro[3.5]nonan-7-yl)-[1,1'-biphenyl]-3-yl)methoxy)phenyl)acetic acid (Compound 013) JPEG0007770556000049.jpg73170

[0144] 13.1 Synthesis of Compound 013-1 001-4 (400 mg, 0.881 mmol) was weighed and placed in a reaction flask. 013-a (174 mg, 0.940 mmol), cesium carbonate (1 g, 3.4 mmol), tris(dibenzylideneacetone)dipalladium (140 mg, 0.088 mmol), 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl (90 mg, 0.088 mmol), and 1,4-dioxane (5 mL) were added sequentially. The atmosphere was purged with nitrogen gas three times, and the reaction solution was incubated 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) to obtain compound 013-1. LC / MS (ESI+) m / z: [M+H] + =599.15.

[0145] 13.2 Synthesis of Compound 013-2 013-1 (200 mg, 340 μmol) was dissolved in methanol (3 mL) and tetrahydrofuran (3 mL). Sodium borohydride (68 mg, 680 μmol) was added in batches at 0° C. The reaction mixture was allowed to react for 0.5 hours at 0° C. The reaction mixture was quenched by adding aqueous ammonium chloride solution (5 mL) and extracted with ethyl acetate (10 mL × 2). The combined organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give 013-2 (crude product), which was used directly in the next step. LC / MS (ESI+) m / z: [M+H] + =601.10.

[0146] 13.3 Synthesis of Compound 013 Compound 013 can be synthesized by referring to the synthesis method for compound 001, and replacing intermediates 001-5 with 013-2. 1 H NMR (400MHz, DMSO-d6): δ7.77(d,J=20.0Hz,1H),7.48(d,J=8.0Hz,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=8.0Hz,1H),6 .74(m,1H),5.14(m,2H),4.20(s,1H),4.12(t,J=16.0Hz,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=4.5Hz,4H);LC / MS(ESI+)m / z:[M+H] + =487.10.

[0147] Example 14, Synthesis of 2-(2-((3'-(aminomethyl)-5-(2-oxa-8-azaspiro[4.5]decan-8-yl)-[1,1'-biphenyl]-3-yl)methoxy)phenyl)acetic acid (Compound 014) JPEG0007770556000050.jpg32170

[0148] Compound 014 can be synthesized by referring to the synthesis method of compound 001, with the intermediate 001-d being replaced with 2-oxa-8-azaspiro[4.5]decane hydrochloride (014-a).

[0149] 1H NMR(400MHz,DMSO-d6):δ7.86(s,1H),7.55(d,J=8.0Hz,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=8.0Hz,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=12.0Hz,4H);LC / MS(ESI+)m / z:[M+H] + =487.15.

[0150] Example 15, Synthesis of Trifluoroacetic Acid of 2-(2-((3'-(aminomethyl)-5-(2-oxa-6-azaspiro[3.4]octan-6-yl)-[1,1'-biphenyl]-3-yl)methoxy)phenyl)acetic acid (Compound 015) JPEG0007770556000051.jpg40170

[0151] 15.1 Synthesis of Compound 015-1 015-a (86 mg, 0.4 mmol) was dissolved in dichloromethane (1 mL), trifluoroacetic acid (2 mL) was added to the reaction system at room temperature, and the reaction solution was heated at 60° C. for 2 hours. The reaction solution was cooled to room temperature and concentrated under reduced pressure to obtain compound 015-1 (crude product), which was used directly in the next step. 15.2 Synthesis of Compound 015 Trifluoroacetic Acid

[0152] The synthesis method of compound 001 can be referred to by replacing the intermediate 001-d with 015-1. The production method is to freeze-dry under trifluoroacetic acid conditions to obtain the trifluoroacetate salt of compound 015.

[0153] 1H NMR(600MHz,DMSO-d6):δ12.20(s,1H),8.17(s,2H),7.78(s,1H),7.69(d,J=7.8Hz,1H),7.50(t,J=7.8Hz ,1H),7.43(d,J=7.8Hz,1H),7.22(t,J=7.8Hz,2H),7.03(d,J=7.8Hz,1H),6.99(s,1H),6.90(t,J=7.8Hz,1 H),6.72(s,1H),6.68(s,1H),5.11(s,2H),4.61(d,J=6.0Hz,2H),4.56(d,J=6.0Hz,2H),4.12(d,J=4.8Hz, 2H),3.60(d,J=5.4Hz,2H),3.38(s,2H),2.29(t,J=6.6Hz,2H),2.02-1.96(m,2H);LC / MS(ESI+)m / z:[M+H] + =459.05.

[0154] Example 16, Synthesis of Trifluoroacetic Acid of 2-(2-((3'-(aminomethyl)-5-(4-oxa-7-azaspiro[2.5]octan-7-yl)-[1,1'-biphenyl]-3-yl)methoxy)phenyl)acetic acid (Compound 016) JPEG0007770556000052.jpg35170

[0155] Compound 016 can be synthesized by referring to the synthesis method of compound 001, with the intermediate 001-d being replaced with 4-oxa-7-azaspiro[2.5]octane hydrochloride (016-a).

[0156] 1 H NMR (600MHz, DMSO-d6): δ9.54(s,1H),7.86(s,1H),7.56(d,J=7.9Hz,1H),7.48(s,1H),7.28(t,J=7.6Hz,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.

[0157] Example 17 Synthesis of 2-(2-((3'-(aminomethyl)-5-(2-azaspiro[3.4]octan-2-yl)-[1,1'-biphenyl]-3-yl)methoxy)phenyl)acetic acid (Compound 017) JPEG0007770556000053.jpg29170

[0158] Compound 017 can be synthesized by referring to the synthesis method for compound 001, with the intermediate 001-d being replaced with 2-azaspiro[3.4]octane hydrochloride (017-a).

[0159] 1 H NMR(600MHz,DMSO-d6):δ8.15(s,1H),7.60(d,J=8.0Hz,1H),7.39-7.31(m,2H),7.23(d,J=8.0Hz,1H),7.03-7.08(m,2H),6.86(d,J=8.0Hz,1H) ,6.77(t,J=7.2Hz,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=6.8Hz,4H),1.57-1.60(m,4H); LC / MS(ESI+)m / z:[M+H] + =457.05.

[0160] Example 18, Synthesis of (S)-2-(2-((3'-(1-amino-2-hydroxyethyl)-5-(6-azaspiro[2.5]octan-6-yl)-[1,1'-biphenyl]-3-yl)methoxy)phenyl)acetic acid (Compound 018) JPEG0007770556000054.jpg72170

[0161] 18.1 Synthesis of Compound 018-1 018-a (3.5 g, 10.6 mmol) was dissolved in tetrahydrofuran (35 mL) and a 1 M solution of borane in tetrahydrofuran (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 and quenched with methanol. The reaction mixture was concentrated under reduced pressure. 1 N dilute hydrochloric acid (10 mL) was added to the residue and stirred at room temperature for 10 minutes. The mixture was then extracted with ethyl acetate (20 mL × 2). The pH of the aqueous phase was adjusted to alkaline with saturated aqueous sodium bicarbonate and extracted with ethyl acetate (20 mL × 2). The combined organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give compound 018-1 (crude product), which was used directly in the next step.

[0162] 18.2 Synthesis of Compound 018-2 018-1 (1.7 g, 5.4 mmol), bis(pinacolato)diboron (2.0 g, 6.5 mmol), potassium acetate (1.5 g, 9.2 mmol), and [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (500 mg, 460 μmol) were sequentially added to 1,4-dioxane (10 mL). The atmosphere was purged with nitrogen gas three times, and the reaction solution was reacted at 80 °C for 3 hours. The reaction solution was diluted with water (30 mL) and extracted with ethyl acetate (20 mL × 3). The combined organic phase was 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) to obtain compound 018-2.

[0163] 18.3 Synthesis of Compound 018 Compound 018 can be synthesized by referring to the synthesis method for compound 001, and replacing intermediate 001-2 with 018-2. 1H NMR(400MHz,DMSO-d6):δ9.48(s,1H),7.89(d,J=8.0Hz,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=4.0H z,1H),6.79(d,J=4.0Hz,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.

[0164] Example 19 Synthesis of (S)-2-(2-((3'-(1-amino-2-hydroxyethyl)-5'-fluoro-5-(6-azaspiro[2.5]octan-6-yl)-[1,1'-biphenyl]-3-yl)methoxy)phenyl)acetic acid (Compound 019) JPEG0007770556000055.jpg86170

[0165] 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 mixture was allowed to react at 25°C for 12 hours. Water (30 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (15 mL x 3). The combined organic phase was 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) to give compound 019-1. LC / MS (ESI+) m / z: [M+H] + =305.90.

[0166] 19.2 Synthesis of Compound 019-2 Vinylmagnesium bromide (16.7 mL, 16.7 mmol) and dimethylzinc reagent (16.7 mL, 16.7 mmol) were mixed under nitrogen gas protection and reacted at room temperature for 0.5 hours. The reaction mixture 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 mixture was allowed to react at this temperature for 2 hours. The reaction mixture was quenched by the dropwise addition of saturated aqueous ammonium chloride (26 mL) at -78 °C, followed by extraction with ethyl acetate (30 mL x 3). The combined organic phase was 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) to give compound 019-2. LC / MS (ESI+) m / z: [M+H] + =333.90.

[0167] 19.3 Synthesis of Compound 019-3 019-2 (2.5 g, 7.5 mmol) was dissolved in methanol (20 mL), 4N hydrochloric acid (5 mL, 7.5 mmol) was added, and the mixture was allowed to react at room temperature for 1 hour. The reaction solution was concentrated under reduced pressure, and dichloromethane (20 mL) was added thereto. Di-tert-butyl dicarbonate (3.07 g, 14.08 mmol) was then added, and the mixture was allowed to react 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) to obtain compound 019-3. LC / MS (ESI+) m / z: [M+Ht-Bu] + =273.90.

[0168] 19.4 Synthesis of Compound 019-4 Under nitrogen gas 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(III) chloride (158 mg, 0.758 mmol) were added and the reaction mixture was allowed to react at room temperature for 2 hours. The reaction mixture was extracted with ethyl acetate (30 mL x 3). The combined organic phase was 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 to 2 / 1) to give compound 019-4.

[0169] 19.5 Synthesis of Compound 019-5 019-4 (130 mg, 0.432 mmol) was weighed and placed in a reaction flask. Under nitrogen gas protection, a 1 M solution of borane in tetrahydrofuran (1.5 mL, 0.864 mmol) was added, and the reaction solution was reacted at 25 °C for 12 hours. Methanol (5 mL) was added to quench the reaction, and the mixture was filtered to remove insoluble materials. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 3 / 1 to 1 / 1) to obtain compound 019-5. LC / MS (ESI+) m / z: [M+Ht-Bu] + =277.95.

[0170] 19.6 Synthesis of Compound 019-6 001-3 (1.0 g, 2.42 mmol), 001-d (320 mg, 2.16 mmol), tris(dibenzylideneacetone)dipalladium (240 mg, 0.24 mmol), 2-dicyclohexylphosphino-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 atmosphere was purged with nitrogen gas three times, and the reaction solution was reacted at 100 °C for 4 h. 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 to 1 / 1) to obtain compound 019-6. LC / MS (ESI+) m / z: [M+H]+ =443.95.

[0171] 19.7 Synthesis of Compound 019-7 019-6 (170 mg, 2.7 mmol), bis(pinacolato)diboron (822 mg, 3.24 mmol), potassium acetate (540 mg, 5.4 mmol), and [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (240 mg, 300 μmol) were added sequentially to 1,4-dioxane (10 mL). The atmosphere was purged with nitrogen gas three times, and the reaction solution was reacted at 100 °C for 4 hours. The reaction solution was diluted with water (10 mL) and further extracted with ethyl acetate (10 mL x 3). The combined organic phase was 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) to give compound 019-7. LC / MS (ESI+) m / z: [M+H] + =492.10. 19.8 Synthesis of Compound 019-8

[0172] 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(diphenylphosphino)ferrocene]dichloropalladium(II) (8.5 mg, 0.05 mmol) were sequentially added to 1,4-dioxane (4 mL) and water (1 mL). The mixture was purged with nitrogen gas three times and reacted at 100°C for 2 hours. Water was added to the reaction solution, followed by extraction with ethyl acetate (10 mL x 3). The combined organic phase was 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) to give compound 019-8. LC / MS (ESI+) m / z: [M+H] + =619.10.

[0173] 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 reaction solution was adjusted to pH 7-8 by adding saturated aqueous sodium bicarbonate (6 mL) and extracted with dichloromethane (10 mL x 3). The combined organic phase was 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 was used directly in the next step. LC / MS (ESI+) m / z: [M+H] + =519.10.

[0174] 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 mixture of tetrahydrofuran (1 mL), methanol (0.5 mL), and water (1 mL), and the mixture was 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.

[0175] 1 H NMR (400MHz, DMSO-d6): δ7.97(s,1H),7.55(d,J=12.0Hz,1H),7.38(s,1H),7. 18-7.09(m,4H),7.05(s,1H),6.94(d,J=8.0Hz,1H),6.81(t,J=8.0Hz,1H),5. 13(s,2H),4.13(s,1H),3.73-3.61(m,2H),3.48(d,J=16.0Hz,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.

[0176] Example 20 Synthesis of (R)-2-(2-((3'-(1-aminoethyl)-2'-fluoro-5-(6-azaspiro[2.5]octan-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]octan-6-yl)-[1,1'-biphenyl]-3-yl)methoxy)phenyl)acetic acid (Compound 020-B or 020-A) JPEG0007770556000056.jpg112170

[0177] 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 solution was reacted at 45 °C for 1 hour. The reaction solution was adjusted to pH 2 with 1N hydrochloric acid and extracted with ethyl acetate (20 mL × 2). The combined organic phase was 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 was directly used in the next step. LC / MS (ESI+) m / z: [M+H] + =234.10.

[0178] 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), 6N hydrochloric acid (10 mL) was added dropwise, and the reaction solution was reacted at 70 °C for 1 hour. The reaction solution was adjusted to pH = 8 with aqueous sodium bicarbonate solution (20 mL), filtered, the cake was rinsed with water (10 mL), and the filtrate was further extracted with ethyl acetate (30 mL × 2). The combined organic phase was 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.

[0179] 20.3 Synthesis of Compound 020-3 The synthesis method of compound 020-3 was the same as that of compound 001-1 in Example 1.

[0180] 20.4 Synthesis of Compound 020-4 The synthesis method of compound 020-4 was the same as that of compound 001-2 in Example 1.

[0181] 20.5 Synthesis of Compounds 020-5 to 020-7 The synthesis method of compounds 020-5 to 020-7 was carried out in accordance with the synthesis method of compounds 001-4 to 001-6 in Example 1. 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 mixture of tetrahydrofuran (3 mL), methanol (0.5 mL), and water (1 mL), and 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 then subjected to chiral separation (AD-H column, n-hexane:[(ethanol:methanol=3:1)]=6:4 isocratic elution) to obtain target compounds 020-A (retention time = 7.640 min) and 020-B (retention time = 13.087 min).

[0182] Compound 020-A: 1 H NMR(400MHz,DMSO-d6):δ7.53(m,1H),7.35(t,J=4.0Hz,1H),7.24(m,3H),7.06(m,2H) ),6.99(d,J=4.0Hz,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.

[0183] Compound 020-B: 1H NMR(400MHz,DMSO-d6):δ7.53(m,1H),7.35(t,J=4.0Hz,1H),7.24(m,3H),7.06(m,2H) ),6.99(d,J=4.0Hz,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.

[0184] Example 21 Synthesis of 2-(2-((3'-(aminomethyl)-2'-fluoro-5-(6-azaspiro[2.5]octan-6-yl)-[1,1'-biphenyl]-3-yl)methoxy)-4-fluorophenyl)acetic acid (Compound 021) JPEG0007770556000057.jpg74170 Compound 021 can be synthesized by referring to the synthesis method for compound 007, and replacing the intermediates 001-3 to 009-3.

[0185] 1 H NMR(600MHz,DMSO-d6):δ8.30(s,1H),7.45(q,J=8.0Hz,2H),7.25(t,J=8.0Hz,1H),7 .20(t,J=8.0Hz,1H),7.06(s,1H),7.02(s,1H),6.99(s,1H),6.91(dd,J1=11.6Hz,J2 =2.4Hz,1H),6.70(td,J1=8.4Hz,J2=2.4Hz,1H),5.14(s,2H),3.91(s,2H),3.50(s,2 H),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.

[0186] Example 22 Synthesis of 2-(2-((5'-(aminomethyl)-2'-fluoro-5-(6-azaspiro[2.5]octan-6-yl)-[1,1'-biphenyl]-3-yl)methoxy)phenyl)acetic acid (Compound 022) JPEG0007770556000058.jpg64170

[0187] Compound 022 can be synthesized by referring to the synthesis method of compound 007, except that the starting material 007-a is replaced with 3-bromo-4-fluorobenzonitrile (022-a).

[0188] 1 H NMR (400MHz, DMSO-d6): δ7.69(d,J=8.0Hz,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=4.0Hz,4H),0.35(s,4H);LC / MS(ESI+)m / z:[M+H] + =475.05.

[0189] Example 23 Synthesis of 2-(2-((3-(2-(aminomethyl)-3-fluoropyridin-4-yl)-5-(6-azaspiro[2.5]octan-6-yl)benzyl)oxy)phenyl)acetic acid (Compound 023) JPEG0007770556000059.jpg123170

[0190] 23.1 Synthesis of Compound 023-1 Triacetoneamine (12.9 g, 91.2 mmol) was weighed and placed in a reaction flask, 50 mL of dry tetrahydrofuran was added, and n-butyllithium (57 mL, 91.2 mmol) was slowly added dropwise at 0°C under nitrogen gas protection, and the reaction was carried out at 0°C for 1 hour. Then cooled to -78 ° C, 023-a (10 g, 76 mmol) was slowly added dropwise, the temperature was maintained below -65 ° C, and the reaction was continued for 10 minutes, N,N-dimethylformamide (16.7 g, 228.1 mmol) was added dropwise, the temperature was maintained below -65 ° C, and the reaction was continued for 10 minutes, glacial acetic acid (6.85 g, 114 mmol) and acetic anhydride (11.6 g, 114 mmol) were added dropwise, and the temperature was raised to 0 ° C, water (100 mL) was added to adjust the pH to 8, and the mixture was extracted with ethyl acetate (100 mL × 3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 2 / 1 to 1 / 1) to obtain compound 023-1.

[0191] 23.2 Synthesis of Compound 023-2 023-1 (8.4 g, 52.7 mmol) and 023-b (7.66 g, 63.2 mmol) were weighed and placed in a reaction flask. Dichloromethane (50 mL) and cesium carbonate (34.3 g, 105.3 mmol) were added and the mixture was allowed to react 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 x 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) to obtain compound 023-2. LC / MS (ESI+) m / z: [M+H] + =262.95.

[0192] 23.3 Synthesis of Compound 023-3 023-2 (8.0 g, 30.45 mmol) was weighed and placed in a reaction flask. Methanol (60 mL) was added. Under nitrogen gas protection, sodium borohydride (4.61 g, 121.80 mmol) was slowly added to the reaction system and allowed to react at room temperature for 2 hours. The reaction solution was concentrated under reduced pressure, followed by the addition of ethyl acetate (50 mL) and saturated aqueous sodium bicarbonate (50 mL). The organic phase was separated, and the aqueous phase was extracted with ethyl acetate (50 mL x 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 = 2 / 1 to 1 / 1) to obtain compound 023-3. LC / MS (ESI+) m / z: [M+H] + =265.05.

[0193] 23.4 Synthesis of Compound 023-4 023-c (10 g, 46.1 mmol) was weighed and placed in a reaction flask, and N,N-dimethylformamide (50 mL), cesium carbonate (45 g, 138.2 mmol), and methyl iodide (16.4 g, 115.2 mmol) were added. The mixture was allowed to react overnight at room temperature. Water 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 = 3 / 1 to 1 / 1) to obtain compound 023-4.

[0194] 23.5 Synthesis of Compound 023-5 023-4 (5 g, 20.4 mmol) was weighed and placed in a reaction flask. 001-d (3.68 g, 23 mmol), cesium carbonate (20 g, 61.21 mmol), 1,4-dioxane (30 mL), tris(dibenzylideneacetone)dipalladium (200 mg, 2.04 mmol), and 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl (100 mg, 2.04 mmol) were added and 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 to 1 / 1) to obtain compound 023-5. LC / MS (ESI+) m / z: [M+H] + =276.05.

[0195] 23.6 Synthesis of Compound 023-6 023-5 (6.0 g, 14.5 mmol) was weighed into a reaction flask, dichloromethane (30 mL) was added, and boron tribromide (7.28 g, 29.1 mmol) was slowly added dropwise at 0 °C. After the addition was complete, the reaction solution was warmed to room temperature and reacted for 2 hours. Methanol (30 mL) was added to slowly quench the reaction. Then, water (30 mL) was added and extracted with dichloromethane (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 = 3 / 1 to 1 / 1) to give compound 023-6. LC / MS (ESI+) m / z: [M+H] + =262.05.

[0196] 23.7 Synthesis of Compound 023-7 023-6 (2.4 g, 10 mmol) was weighed and placed in a reaction flask, dichloromethane (30 mL) was added, pyridine (870 mg, 6.26 mmol) was added, and trifluoromethanesulfonic anhydride (3.4 g, 12 mmol) was added dropwise at 0 °C. After the addition was completed, the reaction solution was warmed to room temperature and reacted for 2 hours. Water (30 mL) was added to the reaction solution, and the mixture was extracted with dichloromethane (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 = 5 / 1 to 1 / 1) to obtain compound 023-7.

[0197] 23.8 Synthesis of Compound 023-8 023-7 (1.7 g, 4.32 mmol) was weighed into a reaction flask, and 1,4-dioxane (50 mL), bis(pinacolato)diboron (1.7 g, 6.5 mmol), potassium acetate (1.3 g, 13 mmol), and [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (323 mg, 0.44 mmol) were added. The reaction solution was refluxed at 80 °C for 12 h under nitrogen gas protection. The reaction solution was concentrated, and the residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 5 / 1 to 1 / 1) to obtain compound 023-8. LC / MS (ESI+) m / z: [M+H] + =372.00.

[0198] 23.9 Synthesis of Compound 023-9 023-8 (1.5 g, 4.05 mmol) was weighed and placed in a reaction flask. 023-3 (962 mg, 5.3 mmol), 1,4-dioxane (30 mL), and water (5 mL) were added. Further, [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (356 mg, 0.405 mmol) and potassium carbonate (1.68 g, 12.12 mmol) were added. The reaction solution was refluxed at 100 °C for 2 hours under nitrogen gas protection. The reaction solution was concentrated, and the residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 5 / 1 to 1 / 1) to obtain compound 023-9. LC / MS (ESI+) m / z: [M+H]+ =474.00.

[0199] 23.10 Synthesis of compound 023-10 023-9 (1.7 g, 3.59 mmol) was weighed and placed in a reaction flask, tetrahydrofuran (15 mL) was added, and the mixture was cooled to 0°C. Lithium aluminum hydride (408 mg, 10.77 mmol) was slowly added and the mixture was allowed to react at 0°C for 1 hour. Water (20 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (50 mL x 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) to obtain compound 023-10. LC / MS (ESI+) m / z: [M+H] + =446.00.

[0200] 23.11 Synthesis of Compound 023-11 023-10 (700 mg, 1.57 mmol) was weighed into a reaction flask, and 001-c (313 mg, 1.89 mmol), triphenylphosphine (824 mg, 3.14 mmol), and dichloromethane (10 mL) were added. Protected with nitrogen gas, diisopropyl azodicarboxylate (635 mg, 3.14 mmol) was slowly added dropwise at 0 °C. After the addition was complete, the reaction solution was warmed to room temperature and reacted for 2 hours. The reaction solution was concentrated, and the residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 3 / 1 to 1 / 1) to obtain compound 023-11. LC / MS (ESI+) m / z: [M+H] + =594.00.

[0201] 23.12 Synthesis of Compound 023-12 023-11 (400 mg, 1.674 mmol) was weighed into a reaction flask, and dichloromethane (2 mL) and a 1,4-dioxane solution of hydrogen chloride (4N, 2 mL) were added, followed by reaction at room temperature for 2 hours. The reaction solution was concentrated to give compound 023-12 (crude product), which was used directly in the next step.

[0202] 23.13 Synthesis of Compound 023 023-12 (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 the mixture was 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 023.

[0203] 1 H NMR(400MHz,DMSO-d6):δ8.52(d,J=8.0Hz,1H),8.43(s,2H),7.69(t,J=4.0Hz,1H),7.26-7.20(m,3H),7.14(d,J=12.0Hz,2H),7.04(d,J=8.0Hz,1H) ,6.91(t,J=4.0Hz,1H),5.15(s,2H),4.34(d,J=4.0Hz,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.

[0204] Example 24, Synthesis of trifluoroacetic acid of 2-(2-((3'-(aminomethyl)-2'-fluoro-5-(2-oxa-7-azaspiro[3.5]nonan-7-yl)-[1,1'-biphenyl]-3-yl)methoxy)phenyl)acetic acid (Compound 024) JPEG0007770556000060.jpg35170

[0205] 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(diphenylphosphino)ferrocene]dichloropalladium(II) (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 gas three times, the reaction solution was refluxed at 110 °C for 2 hours. The reaction solution 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 phase was 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) to obtain compound 024-1. LC / MS(ESI+)m / z:[M+H-Boc] + =457.90.

[0206] 24.2 Synthesis of compound 024-2 024-1 (303 mg, 0.54 mmol), sodium tert-butoxide (156 mg, 1.63 mmol), 011-a (121 mg, 0.705 mmol), tris(dibenzylideneacetone)dipalladium (50 mg, 54.3 μmol), 2-dicyclohexylphosphino-2',6'-dimethoxybiphenyl (45 mg, 108.5 μmol), and toluene (10 mL) were added to a 50 mL reaction flask. After purging with nitrogen gas three times, the reaction solution was refluxed at 110 °C for 2 h. The reaction solution was cooled to room temperature, adjusted to pH 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 phase was washed with saturated aqueous sodium chloride, 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.

[0207] 24.3 Synthesis of trifluoroacetic acid 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 reaction system at room temperature, followed by stirring at room temperature for 2 hours. The reaction solution was concentrated under reduced pressure, and the residue was purified by preparative high-performance liquid chromatography and lyophilized to obtain the trifluoroacetic acid of compound 024.

[0208] 1 H NMR(600MHz,DMSO-d6):δ8.25(s,2H),7.57(dt,J1=7.6Hz,J2=1.6Hz,1H),7.51(t,J= 7.6Hz,1H),7.34(t,J=7.6Hz,1H),7.22(d,J=7.2Hz,2H),7.12(s,1H),7.04-7.0(m,3 H),6.90(t,J=7.6Hz,1H),5.11(s,2H),4.35(s,4H),4.15(d,J=6.0Hz,2H),3.58(s,2 H),3.17(t,J=5.6Hz,3H),1.89(t,J=5.6Hz,3H),1.23(s,2H);LC / MS(ESI+)m / z:[M+H] + =491.05.

[0209] Example 25 Synthesis of 2-(2-((3'-(aminomethyl)-2'-fluoro-5-(2-oxa-7-azaspiro[3.5]nonan-7-yl)-[1,1'-biphenyl]-3-yl)methoxy)-5-fluorophenyl)acetic acid (Compound 025) JPEG0007770556000061.jpg83170

[0210] 25.1 Synthesis of Compound 025-1 Under nitrogen gas protection, 010-3 (300 mg, 0.69 mmol), 021-1 (244 mg, 0.69 mmol), potassium carbonate (192 mg, 1.39 mmol), and [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (52 mg, 0.07 mmol) were dissolved in 1,4-dioxane (10 mL) and water (1 mL). The resulting mixture was reacted at 100 °C for 2 h. The reaction solution was cooled to room temperature, water was added, and the mixture was extracted with ethyl acetate (10 mL × 3). The combined 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) to give compound 025-1. LC / MS (ESI+) m / z: [M+H-Boc] + =475.85.

[0211] 25.2 Synthesis of Compound 025-2 025-1 (300 mg, 0.52 mmol) was weighed and placed in a reaction flask. 011-a (110 mg, 0.52 mmol), cesium carbonate (680 mg, 2.08 mmol), 1,4-dioxane (10 mL), tris(dibenzylideneacetone)dipalladium (80 mg, 0.06 mmol), and 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl (150 mg, 0.06 mmol) were added and 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 to 1 / 1) to obtain compound 025-2. LC / MS (ESI+) m / z: [M+H] + =623.00.

[0212] 25.3 Synthesis of Compound 025 Compound 025 was synthesized according to the synthesis method in steps 1.6 and 1.7 of Example 1.

[0213] 1H NMR(600MHz,DMSO-d6):δ7.43(t,J=8.0Hz,1H),7.41-7.36(m,1H),7.21(t,J=8.0Hz,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.

[0214] Example 26, Synthesis of 2-(2-((3'-(aminomethyl)-4-fluoro-5-(2-oxa-7-azaspiro[3.5]nonan-7-yl)-[1,1'-biphenyl]-3-yl)methoxy)phenyl)acetic acid (Compound 026) JPEG0007770556000062.jpg62170

[0215] 26.1 Synthesis of Compound 026-1 026-a (3.0 g, 13.7 mmol) was weighed and placed in a reaction flask, sulfuric acid (10 mL) was added, and N-iodosuccinimide (2.5 g, 14.4 mmol) was slowly added at 0 ° C., and then the mixture was allowed to warm to room temperature and react overnight. The reaction solution was poured into ice water, and a solid precipitated. The solid was filtered and dried to obtain compound 026-1.

[0216] 26.2 Synthesis of Compound 026-2 026-1 (3.6 g, 10.44 mmol) was weighed and placed in a reaction flask. Tetrahydrofuran (20 mL) was added, and the mixture was protected with nitrogen gas. Borane in tetrahydrofuran (31.3 mL, 31.30 mmol, 1 M) was slowly added dropwise at 0°C. After reacting for 10 minutes, the temperature was raised to 60°C and the reaction was continued for 2 hours. The reaction solution was cooled to room temperature, and methanol (20 mL) was slowly added dropwise to quench the reaction. After quenching, the reaction solution was concentrated, and the residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 10 / 1 to 1 / 1) to obtain compound 026-2.

[0217] 26.3 Synthesis of Compound 026-3 026-2 (1 g, 3.02 mmol) was weighed into a reaction flask, and 001-c (551 mg, 3.02 mmol), dichloromethane (20 mL), and triphenylphosphine (1.6 g, 6.04 mmol) were added. The mixture was purged with nitrogen gas three times. At 0°C, diisopropyl azodicarboxylate (2.2 g, 6.04 mmol) was slowly added dropwise, and the mixture was allowed to react 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 to 1 / 1) to obtain compound 026-3. LC / MS (ESI+) m / z: [M+H] + =480.75.

[0218] 26.4 Synthesis of Compound 026-4 Under nitrogen gas protection, 026-3 (540 mg, 1.13 mmol), 001-2 (376 mg, 1.13 mmol), potassium carbonate (312 mg, 2.25 mmol), and [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (83 mg, 0.113 mmol) were dissolved in 1,4-dioxane (10 mL) and water (1 mL) and reacted at 100°C for 2 hours. The reaction solution was cooled to room temperature, water was added, and the mixture was extracted with ethyl acetate (10 mL x 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) to give compound 026-4. LC / MS (ESI+) m / z: [M+H] + =459.90.

[0219] 26.5 Synthesis of Compound 026-5 026-4 (400 mg, 0.72 mmol) was weighed and placed in a reaction flask. 011-a (110 mg, 0.72 mmol), cesium carbonate (480 mg, 1.4 mmol), 1,4-dioxane (10 mL), tris(dibenzylideneacetone)dipalladium (66 mg, 0.07 mmol), and 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl (32 mg, 0.07 mmol) were added and reacted at 100 °C for 4 h. After cooling to room temperature, the reaction solution was diluted with water (20 mL) and extracted with ethyl acetate (20 mL x 3). The organic phase was concentrated, and the residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 3 / 1 to 1 / 1) to obtain compound 026-5. LC / MS (ESI+) m / z: [M+H] + =605.10.

[0220] 26.6 Synthesis of Compound 026 Compound 026 was synthesized according to the synthesis method in steps 1.6 and 1.7 of Example 1.

[0221] 1 H NMR (400MHz, DMSO-d6): δ8.14(s,1H),7.66(d,J=4.0Hz,2H),7.37(t,J=8.0Hz,1H),7.27-7.22(m,2H),7.12-7.07(m,2H),6.89(d,J=8.0H) z,1H),6.81(t,J=8.0Hz,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.

[0222] Example 27 Synthesis of 2-(2-((3'-(aminomethyl)-6-fluoro-5-(2-oxa-7-azaspiro[3.5]nonan-7-yl)-[1,1'-biphenyl]-3-yl)methoxy)phenyl)acetic acid (Compound 027) JPEG0007770556000063.jpg70170

[0223] 27.1 Synthesis of Compound 027-1 027-a (2.0 g, 7.4 mmol) was weighed and dissolved in acetonitrile (20 mL), and N-bromosuccinimide (1.31 g, 7.4 mmol) and azobisisobutyronitrile (120 mg, 0.74 mmol) were added, followed by reaction 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.

[0224] 27.2 Synthesis of Compound 027-2 027-1 (1.8 g, 5.19 mmol) was weighed and dissolved in acetonitrile (20 mL), and potassium carbonate (1.43 g, 10.38 mmol) and methyl o-hydroxyphenylacetate (905.5 mg, 5.45 mmol) were added. 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.

[0225] 27.3 Synthesis of Compound 027-3 027-2 (1.0 g, 2.3 mmol) was weighed and placed in a reaction flask, followed by potassium carbonate (640 mg, 4.6 mmol), 001-2 (0.77 g, 2.3 mmol), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (100 mg, 10 wt%), 1,4-dioxane (10 mL), and water (1 mL). The reaction was carried out at 90 °C for 2 hours under nitrogen gas protection. The reaction solution was cooled to room temperature and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography to obtain compound 027-3. LC / MS (ESI+) m / z: [M+H] + =558.1.

[0226] 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(dibenzylideneacetone)dipalladium (12 mg, 10 wt%), and 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl (12 mg, 10 wt%) were added and reacted at 100 °C for 2 hours under nitrogen gas protection. After cooling to room temperature, the reaction solution 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.

[0227] 27.5 Synthesis of Compound 027 Compound 027 was synthesized according to the synthesis method in steps 1.6 and 1.7 of Example 1.

[0228] 1 H NMR(400MHz,DMSO-d6):δ7.98(s,1H),7.61(d,J=7.2Hz,1H),7.43(d,J=5.6Hz, 1H),7.38(t,J=8.0Hz,1H),7.30(d,J=7.6Hz,1H),7.10-7.08(m,3H),6.90(d,J =8.4Hz,1H),6.80(t,J=7.6Hz,1H),5.10(s,2H),4.37(s,4H),3.94(s,2H),3.3 6(s,2H),2.95(t,J=5.2Hz,4H),1.95(t,J=5.6Hz,4H);LC / MS(ESI+)m / z:[M+H] + =491.0.

[0229] Example 28, Synthesis of 2-(2-((3'-(aminomethyl)-5-(2-oxa-7-azaspiro[3.5]nonan-7-yl)-[1,1'-biphenyl]-3-yl)methoxy)-3-fluorophenyl)acetic acid (Compound 028) JPEG0007770556000064.jpg62170

[0230] 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 gas protection. The mixture was reacted at 50 °C for 0.5 hours, and then 028-a (6.0 g, 35.93 mmol) was slowly added dropwise. The mixture was reacted at 70 °C for 2 hours to obtain a solution of compound 028-1, which was directly used in the next step.

[0231] 28.2 Synthesis of Compound 028-2 028-b (2.0 g, 9.75 mmol) was weighed into a reaction flask, and tetrahydrofuran (10 mL), tris(dibenzylideneacetone)dipalladium (1.0 g, 0.98 mmol), and 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl (500 mg, 0.95 mmol) were added. Under nitrogen gas protection, a solution of compound 028-1 (12 mL) obtained in step 28.1 was slowly added dropwise and reacted at 70 °C for 2 h. The reaction solution was quenched by adding saturated aqueous ammonium chloride (10 mL) and extracted with ethyl acetate (30 mL × 3). The combined 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 = 10 / 1 to 1 / 1) to give compound 028-2. LC / MS(ESI+)m / z:[M+H] + =213.10.

[0232] 28.3 Synthesis of Compound 028-3 028-2 (1.8 g, 8.5 mmol) was weighed into a reaction flask, dichloromethane (20 mL) was added, and the mixture was protected with nitrogen gas. At 0 °C, boron tribromide (18 mL, 17.0 mmol) was slowly added dropwise. The reaction was allowed to proceed for 10 minutes, then the mixture was cooled to room temperature and the reaction was continued for 10 minutes. Ethanol (10 mL) was slowly added dropwise to quench the reaction, and the mixture was diluted with water (10 mL). The mixture was extracted with dichloromethane (30 mL x 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 = 10 / 1 to 1 / 1) to give compound 028-3. LC / MS (ESI+) m / z: [M+H] + =199.10.

[0233] 28.4 Synthesis of Compound 028-4 028-3 (0.75 g, 3.65 mmol) was weighed and placed in a reaction flask. 009-b (1.2 g, 3.65 mmol), potassium carbonate (1.1 g, 7.3 mmol), and N,N-dimethylformamide (20 mL) were added and reacted at room temperature for 2 hours. The reaction solution was diluted with water (20 mL) and extracted with ethyl acetate (30 mL x 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 = 10 / 1 to 1 / 1) to obtain compound 028-4. LC / MS (ESI+) m / z: [M+H] + =446.75.

[0234] 28.5 Synthesis of Compound 028 Compound 028 can be synthesized by referring to the synthesis method for compound 027, and replacing 027-2 in the synthesis step with 028-4.

[0235] 1H NMR(400MHz,DMSO-d6):δ8.18(s,1H),7.68(d,J=8.0Hz,1H),7.53(s,1H),7.39(t,J=8.0Hz,1H),7.28(d,J= 8.0Hz,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.

[0236] Example 29, Synthesis of 2-(2-((3'-(aminomethyl)-5-(3-oxa-9-azaspiro[5.5]undecan-9-yl)-[1,1'-biphenyl]-3-yl)methoxy)phenyl)acetic acid (Compound 029) JPEG0007770556000065.jpg30170

[0237] Compound 029 can be synthesized by referring to the synthesis method for compound 001, and replacing the raw material in that step from 001-d with 3-oxa-9-azaspiro[5.5]undecane (029-a).

[0238] 1 H NMR(600MHz,DMSO-d6):δ8.25(s,2H),7.79(s,1H),7.70(d,J=5.6Hz,1H),7.50(t,J=5.2Hz ,1H),7.43(d,J=5.2Hz,1H),7.25-7.18(m,4H),7.15(d,J=2.0Hz,1H),7.03(d,J=5.2Hz,1H ),6.93-6.87(m,1H),5.13(s,2H),4.12(dd,J=4.0Hz,J=7.6Hz,2H),3.60(s,2H),3.60-3.5 7(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.

[0239] Example 30 Synthesis of 2-(2-((3'-(aminomethyl)-5-(2-oxa-9-azaspiro[5.5]undecan-9-yl)-[1,1'-biphenyl]-3-yl)methoxy)phenyl)acetic acid (Compound 030) JPEG0007770556000066.jpg32170

[0240] Compound 030 can be synthesized by referring to the synthesis method for compound 001, except that the raw material in that step is replaced by 2-oxa-9-azaspiro[5.5]undecane (030-a) instead of 001-d.

[0241] 1 H NMR(400MHz,DMSO-d6):δ8.17(s,1H),7.67(d,J=8.0Hz,1H),7.41(s,1H),7.37(t,J =7.6Hz,1H),7.26(d,J=7.6Hz,1H),7.14-7.05(m,3H),6.97(s,1H),6.90(d,J=8.0H z,1H),6.80(t,J=7.2Hz,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=5.6Hz,4H),1.62-1.51(m,8H);LC / MS(ESI+)m / z:[M+H]+=501.15.

[0242] Example 31 Synthesis of 2-(2-((3'-(aminomethyl)-5-(6-oxa-2-azaspiro[3.4]octan-2-yl)-[1,1'-biphenyl]-3-yl)methoxy)phenyl)acetic acid (Compound 031) JPEG0007770556000067.jpg32170

[0243] Compound 031 can be synthesized by referring to the synthesis method for compound 001, except that the raw material 001-d is replaced with 6-oxa-2-azaspiro[3.4]octane (031-a).

[0244] 1H NMR(400MHz,DMSO-d6):δ9.47(s,1H),7.92(d,J=59.6Hz,1H),7.53(dd,J=30.0,8Hz,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=5.6Hz,1H),6.4 8(d,J=23.2Hz,1H),5.14(d,J=32.0Hz,2H),4.24(s,1H),3.86(s,4H),3.83(d,J=3.2Hz,2H),3.7 4(t,J=7.2Hz,3H),3.38(d,J=13.2Hz,2H),2.18-2.13(m,2H);LC / MS(ESI+)m / z:[M+H]+=459.05.

[0245] Example 32 Synthesis of 2-(2-((3'-(aminomethyl)-5-(2-methyl-2,7-diazaspiro[3.5]nonan-7-yl)-[1,1'-biphenyl]-3-yl)methoxy)phenyl)acetic acid (Compound 032) JPEG0007770556000068.jpg30170

[0246] Compound 032 can be synthesized by referring to the synthesis method for compound 001, except that the raw material 001-d is replaced with 2-methyl-2,7-diazaspiro[3.5]nonane (032-a).

[0247] 1H NMR(400MHz,DMSO-d6):δ11.67-11.47(m,1H),10.08(s,1H),8.23(s,2H),7.78(s,1H),7.69(d,J=7.6Hz, 1H),7.50(t,J=7.6Hz,1H),7.43(d,J=7.6Hz,1H),7.23(t,J=7.6Hz,2H),7.14(d,J=5.8Hz,2H),7.07(s,1 H),7.03(d,J=8.2Hz,1H),6.90(t,J=7.4Hz,1H),5.12(s,2H),4.11(d,J=5.4Hz,4H),3.88-3.75(m,2H),3 .60(s,2H),3.23(d,J=36.8Hz,4H),2.87(d,J=4.2Hz,3H),1.90(s,4H);LC / MS(ESI+)m / z:[M+H]+=486.05.

[0248] Example 33, Synthesis of trifluoroacetic acid of 2-(2-((3'-(aminomethyl)-5-(3,9-diazaspiro[5.5]undecan-3-yl)-[1,1'-biphenyl]-3-yl)methoxy)phenyl)acetic acid (Compound 033) JPEG0007770556000069.jpg35170

[0249] 33.1 Synthesis of compound 033-1 001-4 (216 mg, 0.4 mmol), sodium tert-butoxide (77 mg, 0.8 mmol), 033-a (122 mg, 0.48 mmol), tris(dibenzylideneacetone)dipalladium (37 mg, 40 μmol), 2-dicyclohexylphosphino-2',6'-dimethoxybiphenyl (33 mg, 80 μmol), and toluene (4 mL) were added to a 50 mL reaction flask. After purging with nitrogen gas three times, the reaction solution was refluxed at 110 °C for 2 h. The reaction solution was cooled to room temperature, adjusted to pH 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 phase was 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.

[0250] 33.2 Synthesis of trifluoroacetic acid of compound 033 033-1 (78 mg, 0.11 mmol) and dichloromethane (2 mL) were placed in a flask, and 4-fluorophenylboronic acid (31 mg, 0.22 mmol) was added to the reaction system at room temperature. The mixture was stirred at room temperature for 2 hours to remove nitrogen oxides, and then trifluoroacetic acid (0.2 mL) was added to the reaction system and reacted at room temperature for 1 hour. The reaction solution was concentrated under reduced pressure, and the residue was purified by preparative high-performance liquid chromatography to obtain the trifluoroacetic acid of compound 033.

[0251] 1H NMR (400MHz, DMSO-d6): δ8.49(s,2H),8.26(s,3H),7.78(s,1H),7.69(d,J=7.6Hz,1H),7.50(t ,J=7.6Hz,1H),7.43(d,J=7.6Hz,1H),7.22(d,J=7.2Hz,2H),7.15(d,J=5.6Hz,2H),7.10(s,1H) ),7.04(d,J=8.0Hz,1H),6.91(t,J=7.6Hz,1H),5.13(s,2H),4.12(q,J=5.6Hz,2H),3.60(s,2H) ),3.27(t,J=6.0Hz,4H),3.09(s,4H),1.64(d,J=5.6Hz,8H);LC / MS(ESI+)m / z:[M+H]+=500.10.

[0252] Example 34, Synthesis of 2-(2-((3'-(aminomethyl)-5-(2-azaspiro[4.4]nonan-2-yl)-[1,1'-biphenyl]-3-yl)methoxy)phenyl)acetic acid (Compound 034) JPEG0007770556000070.jpg34170

[0253] The synthesis of compound 034 can be performed by referring to the synthesis method of compound 001, except that the raw material 001-d is replaced with 2-azaspiro[4.4]nonane (034-a).

[0254] 1 H NMR(400MHz,DMSO-d6):δ8.11(s,1H),7.66(d,J=6.0Hz,1H),7.37(t,J=6.0Hz,1H),7.30- 7.22(m,2H),7.15-7.05(m,2H),6.90(d,J=12.0Hz,1H),6.80(t,J=6.0Hz,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=6.0Hz,2H),1.70-1.65(m,4H),1.64-1.56(m,4H);LC / MS(ESI+)m / z:[M+H]+=471.10.

[0255] Example 35 Synthesis of (S)-2-(2-((3'-(1-aminoethyl)-5-(4-oxa-7-azaspiro[2.5]octan-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]octan-7-yl)-[1,1'-biphenyl]-3-yl)methoxy)phenyl)acetic acid (Compound 035-B or 035-A) JPEG0007770556000071.jpg70170

[0256] 35.1 Synthesis of Compound 035-1 035-a (500 mg, 2.5 mmol) was weighed into a reaction flask, and di-tert-butyl dicarbonate (599.95 mg, 2.75 mmol), triethylamine (505.77 mg, 5 mmol), and dichloromethane (5 mL) were added. The mixture was allowed to 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 to 15 / 1) to obtain compound 035-1, which was used directly in the next step. LC / MS (ESI+) m / z: [M+H-tBu] + =244.0.

[0257] 35.2 Synthesis of Compound 035-2 035-1 (7.50 g, 24.98 mmol), bis(pinacolato)diboron (7.61 g, 29.98 mmol), potassium acetate (4.90 g, 49.97 mmol), and [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (0.75 g, 2.50 mmol) were dissolved in 1,4-dioxane (80 mL). The mixture was purged with nitrogen gas three times and reacted at 85 °C for 10 hours. After cooling to room temperature, the reaction solution was diluted with water (80 mL) and extracted with ethyl acetate (100 mL x 3). The combined organic phase was 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 to 3 / 1) to obtain compound 035-2. LC / MS(ESI+) m / z:[M+H-tBu] + =292.05.

[0258] 35.3 Synthesis of Compound 035-3 001-3 (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 mixture of 1,4-dioxane and water (40 mL, 1,4-dioxane / water = 4 / 1). The mixture was purged with nitrogen gas three times and reacted at 80 °C for 16 hours. After cooling to room temperature, the reaction solution was extracted with ethyl acetate (50 mL × 3). The combined organic phase was 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 to 3 / 1) to give compound 035-3. LC / MS (ESI+) m / z: [M+H-Boc] + =453.95.

[0259] 35.4 Synthesis of Compound 035-4 035-3 (0.2 g, 0.36 mmol), 016-a (65 mg, 0.43 mmol), tris(dibenzylideneacetone)dipalladium (20 mg, 0.04 mmol), 2-dicyclohexylphosphino-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). The mixture was purged with nitrogen gas three times and reacted at 100 °C for 16 h. After cooling to room temperature, the reaction solution was diluted with water (15 mL) and extracted with ethyl acetate (10 mL × 3). The combined 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 to 1 / 1) to give compound 035-4. LC / MS(ESI+)m / z:[M+H] + =587.15.

[0260] 35.5 Synthesis of Compounds 035-A and 035-B The synthesis of compound 035 was carried out in accordance with the synthesis methods of steps 1.6 and 1.7 of Example 1. 035 was further subjected to chiral separation by supercritical fluid chromatography (Method: AD-3-IPA+CAN(DEA)-40-3mL-35T) to obtain 035-A (retention time Rt = 1.097 min) and 035-B (retention time Rt = 1.773 min).

[0261] 035-A (retention time Rt=1.097min): 11H 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, 1H), 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。

[0262] 035 - B (Retention time Rt = 1.773 min): 1 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 = 6.6 Hz, 1H), 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。

[0263] Example 36, Synthesis of (S)-2-(2-((3'-(1-aminoethyl)-5-(2-oxa-8-azaspiro[4.5]decan-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]decan-8-yl)-[1,1'-biphenyl]-3-yl)methoxy)phenyl)acetic acid (Compound 036-B or 036-A) JPEG0007770556000072.jpg90170

[0264] 36.1 Synthesis of compound 036-1 035-3 (0.1 g, 0.18 mmol), 014-a (36 mg, 0.19 mmol), tris(dibenzylideneacetone)dipalladium (10 mg, 0.02 mmol), 2-dicyclohexylphosphino-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). The mixture was purged with nitrogen gas three times and reacted at 100 °C for 16 hours. After cooling to room temperature, the reaction solution was diluted with water (10 mL) and extracted with ethyl acetate (10 mL x 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 to 1 / 1) to obtain compound 036-1. LC / MS (ESI+) m / z: [M+H] + =615.10.

[0265] 36.2 Synthesis of Compounds 036-A and 036-B The synthesis of compound 036 was carried out in accordance with the synthesis methods in steps 1.6 and 1.7 of Example 1. Compound 036 was further chiral separated by supercritical fluid chromatography (Method: OD-MeOH(DEA)-40-3 mL-35 T) to give 036-A (retention time Rt = 0.912 min) and 036-B (retention time Rt = 1.354 min).

[0266] 036-A (Holding time Rt=0.912min): 1 H NMR (400MHz, DMSO-d6): δ8.24(s,1H),7.67(d,J=7.8Hz,1H),7.47(s,1H),7.39(t,J=7.8Hz,1H),7.27(d,J= 7.6Hz,1H),7.11(dd,J=12.8,7.0Hz,3H),7.00(s,1H),6.92(d,J=8.4Hz,1H),6.81(t,J=7.4Hz,1H),5.11(s, 2H),4.27(q,J=6.4Hz,1H),3.77(t,J=7.2Hz,2H),3.40(dd,J=18.2,10.8Hz,2H),3.26(ddt,J=18.2,12.0,6. 0Hz,4H),1.76(t,J=7.2Hz,2H),1.71-1.59(m,4H),1.50(d,J=6.8Hz,3H);LC / MS(ESI+)m / z:[M+H]+=501.10.

[0267] 036-B (Holding time Rt=1.354min): 1 H NMR (400MHz, DMSO-d6): δ8.26(s,1H),7.67(d,J=7.8Hz,1H),7.49(s,1H),7.38(t,J=7.6Hz,1H),7.26(d, J=7.6Hz,1H),7.11(dd,J=14.8,8.4Hz,3H),6.99(s,1H),6.91(d,J=8.6Hz,1H),6.81(d,J=7.4Hz,1H),5. 11(s,2H),4.25(d,J=6.8Hz,1H),3.77(t,J=7.0Hz,2H),3.50(s,2H),3.45-3.33(m,2H),3.33-3.18(m,4H ),1.76(t,J=7.2Hz,2H),1.65(d,J=5.0Hz,4H),1.50(d,J=6.8Hz,3H);LC / MS(ESI+)m / z:[M+H]+=501.10.

[0268] Example 37, 2-(2-((3'-(1-アミノエチル))-5-(6-アザスピロ[2.5]オクタン- Synthesis of 6-イル)-[1,1'-ビフェニル]-3-イル)メトキシ)フェニル)phthalic acid (compound 037) JPEG0007770556000073.jpg35170

[0269] 37.1 Synthesis of Compound 037-1 035-3 (0.5 g, 0.90 mmol), 001-d (160 mg, 1.08 mmol), tris(dibenzylideneacetone)dipalladium (50 mg, 0.09 mmol), 2-dicyclohexylphosphino-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). The mixture was purged with nitrogen gas three times and reacted at 100 °C for 16 h. After cooling to room temperature, the reaction solution was diluted with water (15 mL) and extracted with ethyl acetate (10 mL × 3). The combined 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 to 1 / 1) to obtain compound 037-1. LC / MS (ESI+) m / z: [M+H] + =585.15.

[0270] 37.2 Synthesis of Compound 037 Compound 037 was synthesized according to the synthesis method in steps 1.6 and 1.7 of Example 1.

[0271] 1H NMR(400MHz,DMSO-d6):δ8.32(s,2H),7.78(s,1H),7.69(d,J=7.8Hz,1H),7.52(t,J=7.8Hz,1H),7 .45(d,J=7.8Hz,1H),7.26(d,J=10.0Hz,2H),7.22(dd,J=7.6,1.3Hz,2H),7.19(s,1H),7.04(d,J=8 .0Hz,1H),6.90(dd,J=11.6,4.1Hz,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=6.8Hz,3H),1.52(d,J=5.4Hz,4H),0.37(s,4H);LC / MS(ESI+)m / z:[M+H]+=471.05.

[0272] Example 38 Synthesis of (S)-2-(2-((3'-(1-aminoethyl)-5-(3-oxa-9-azaspiro[5.5]undecan-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]undecan-9-yl)-[1,1'-biphenyl]-3-yl)methoxy)phenyl)acetic acid (Compound 038-B or 038-A) JPEG0007770556000074.jpg77170

[0273] 38.1 Synthesis of Compound 038-1 035-3 (300 mg, 0.54 mmol) was weighed and placed in a reaction flask, followed by 029-a (93 mg, 0.60 mmol), cesium carbonate (705 mg, 2.16 mmol), 1,4-dioxane (3 mL), tris(dibenzylideneacetone)dipalladium (49 mg, 0.05 mmol), and 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl (25 mg, 0.05 mmol). After purging with nitrogen gas, the mixture 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 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 to obtain compound 038-1. LC / MS(ESI+)m / z:[M+H] + =629.15.

[0274] 38.2 Synthesis of Compounds 038-A and 038-B The synthesis of compound 038 was carried out in accordance with the synthesis methods in steps 1.6 and 1.7 of Example 1. Compound 038 was further chiral separated by supercritical fluid chromatography (Method: OD-EtOH(DEA)-40-3mL-35T) to give 038-A (retention time Rt = 1.079 min) and 038-B (retention time Rt = 1.627 min).

[0275] 038-A (retention time Rt=1.079min): 1H NMR(400MHz,DMSO-d6):δ8.25(s,1H),7.66(d,J=7.4Hz,1H),7.47(s,1H),7.37(t,J= 7.4Hz,1H),7.26(d,J=7.2Hz,1H),7.16-7.03(m,3H),6.98(s,1H),6.90(d,J=8.8Hz,1 H),6.79(d,J=7.2Hz,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.

[0276] 038-B (holding time Rt=1.627min): 1 H NMR(400MHz,DMSO-d6):δ8.32(s,2H),7.79(s,1H),7.67(d,J=7.6Hz,1H),7.50(t,J=7.6Hz ,1H),7.44(d,J=7.8Hz,1H),7.22(d,J=7.6Hz,2H),7.08(s,1H),7.07-6.96(m,3H),6.90(t ,J=7.4Hz,1H),5.12(s,2H),4.50(s,1H),3.60(s,4H),3.57(s,2H),3.28-3.23(m,4H),1.7 3-1.58(m,4H),1.55(d,J=6.8Hz,3H),1.51-1.44(m,4H);LC / MS(ESI+)m / z:[M+H]+=515.05.

[0277] Example 39 Synthesis of (S)-2-(2-((3'-(1-aminoethyl)-5-(2-oxa-9-azaspiro[5.5]undecan-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]undecan-9-yl)-[1,1'-biphenyl]-3-yl)methoxy)phenyl)acetic acid (Compound 039-B or 039-A) JPEG0007770556000075.jpg80170

[0278] 39.1 Synthesis of Compound 039-1 035-3 (300 mg, 0.54 mmol) was weighed and placed in a reaction flask. Then, 030-a (93 mg, 0.60 mmol), cesium carbonate (705 mg, 2.16 mmol), 1,4-dioxane (3 mL), tris(dibenzylideneacetone)dipalladium (49 mg, 0.05 mmol), and 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl (25 mg, 0.05 mmol) were sequentially added. After purging with nitrogen gas, the reaction solution was reacted at 100 °C for 5 hours, diluted with water (10 mL), and extracted with ethyl acetate (20 mL × 3). The combined 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 to obtain compound 039-1. LC / MS(ESI+)m / z:[M+H] + =629.15.

[0279] 39.2 Synthesis of Compounds 039-A and 039-B The synthesis of compound 039 was carried out in accordance with the synthesis methods in steps 1.6 and 1.7 of Example 1. Compound 039 was further chiral separated by supercritical fluid chromatography (Method: OD-MeOH(DEA)-40-3mL-35T) to give 039-A (retention time Rt = 0.935 min) and 039-B (retention time Rt = 1.302 min).

[0280] 039-A (holding time Rt=0.935min): 1H NMR (400MHz, DMSO-d6): δ8.28(s,2H),7.79(s,1H),7.68(d,J=7.6Hz,1H),7.51(t,J=7.6 Hz,1H),7.45(d,J=8.0Hz,1H),7.21(d,J=7.6Hz,2H),7.16(s,2H),7.10(s,1H),7.03(d,J =8.0Hz,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.

[0281] 039-B (holding time Rt=1.302min): 1 H NMR(400MHz,DMSO-d6):δ8.27(s,1H),7.66(d,J=7.8Hz,1H),7.48(s,1H),7.37(t,J=7.6Hz,1H),7 .26(d,J=7.6Hz,1H),7.16-7.04(m,3H),6.97(s,1H),6.90(d,J=8.4Hz,1H),6.80(t,J=7.2Hz,1H) ,5.10(s,2H),4.24(d,J=6.6Hz,1H),3.55(s,2H),3.41(d,J=13.0Hz,2H),3.33(d,J=15.0Hz,2H), 3.24(t,J=5.6Hz,4H),1.65-1.52(m,8H),1.50(d,J=6.6Hz,3H);LC / MS(ESI+)m / z:[M+H]+=515.05.

[0282] Example 40 Synthesis of (S)-2-(2-((3'-(1-aminoethyl)-5-(6-oxa-2-azaspiro[3.4]octan-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]octan-2-yl)-[1,1'-biphenyl]-3-yl)methoxy)phenyl)acetic acid (Compound 040-B or 040-A) JPEG0007770556000076.jpg82170

[0283] 40.1 Synthesis of compound 040-1 035-3 (300 mg, 0.54 mmol) was dissolved in 1,4-dioxane (5 mL), 031-a (67 mg, 0.60 mmol), cesium carbonate (706 mg, 2.16 mmol), tris(dibenzylideneacetone)dipalladium (30 mg, 10 wt%) and 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl (30 mg, 10 wt%) were added, and the reaction solution was reacted at 100°C under nitrogen gas protection for 2 hours, filtered, the filtrate was concentrated, and the residue was purified by silica gel column chromatography to obtain compound 040-1.

[0284] 40.2 Synthesis of Compounds 040-A and 040-B The synthesis of compound 040 was carried out in accordance with the synthesis methods of steps 1.6 and 1.7 of Example 1. Compound 040 was further chiral separated by supercritical fluid chromatography (Method: Cellulose-2-3-MeOH+CAN(DEA)-50-3mL-35T) to give 040-A (retention time Rt=1.272 min) and 040-B (retention time Rt=1.982 min).

[0285] 040-A (holding time Rt=1.272min): 1H NMR (400MHz, DMSO-d6): δ8.24(s,1H),7.62(d,J=7.8Hz,1H),7.39(dd,J=18.0,10.4Hz,2H),7.26( d,J=7.4Hz,1H),7.09(t,J=6.4Hz,2H),6.90(d,J=8.6Hz,1H),6.80(t,J=7.4Hz,1H),6.64(s,1H),6 .48(s,1H),5.09(s,2H),4.24(d,J=6.6Hz,1H),3.87(s,2H),3.83(s,2H),3.75(s,2H),3.37(dd,J= 28.2,15.0Hz,4H),2.16(t,J=6.8Hz,2H),1.49(d,J=6.4Hz,3H);LC / MS(ESI+)m / z:[M+H]+=473.10.

[0286] 040-B (Holding time Rt = 1.982 min): 1 H NMR (400MHz, DMSO-d6): δ8.21(s,1H),7.60(d,J=7.4Hz,1H),7.38(dd,J=16.8,9.2Hz,2H),7.25(d ,J=6.8Hz,1H),7.08(d,J=6.8Hz,2H),6.90(d,J=8.2Hz,1H),6.80(t,J=7.2Hz,1H),6.64(s,1H),6. 48(s,1H),5.09(s,2H),4.22(d,J=5.4Hz,1H),3.87(s,2H),3.83(s,2H),3.75(s,2H),3.37(dt,J= 24.8,12.3Hz,4H),2.16(t,J=6.8Hz,2H),1.48(d,J=4.8Hz,3H);LC / MS(ESI+)m / z:[M+H]+=473.10.

[0287] Example 41, 2-(2-((3'-(1-アミノエチル)-5-(1-オキサ-6-ア ザスピロ[3.4]オクタン-6-イル)-[1,1'-ビフェニル]-3-イル)メト Synthesis of キシ) フェニル) anhydrous acid (compound 041) JPEG0007770556000077.jpg38170

[0288] 41.1 Synthesis of Compound 041-1 035-3 (0.5 g, 0.90 mmol), 041-a (175 mg, 0.58 mmol), tris(dibenzylideneacetone)dipalladium (50 mg, 0.09 mmol), 2-dicyclohexylphosphino-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). The mixture was purged with nitrogen gas three times and reacted at 100 °C for 16 h. The reaction solution was diluted with water (15 mL) and extracted with ethyl acetate (10 mL × 3). The combined 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 to 1 / 1) to obtain compound 041-1. LC / MS(ESI+)m / z:[M+H] + =587.10.

[0289] 41.2 Synthesis of Compound 041 Compound 041 was synthesized according to the synthesis method in steps 1.6 and 1.7 of Example 1.

[0290] 1 H NMR(400MHz,DMSO-d6):δ7.95(d,J=42.0Hz,1H),7.54(d,J=7.4Hz,1H),7.33(dt,J=16.0,7.7Hz,2H), 7.14(d,J=6.6Hz,2H),7.06(t,J=7.2Hz,1H),6.91(d,J=8.0Hz,1H),6.79(t,J=7.4Hz,1H),6.72-6.54( m,2H),5.07(s,2H),4.43(t,J=6.6Hz,2H),4.11(q,J=6.6Hz,1H),3.57(d,J=40.0Hz,2H),3.39-3.28( m,4H),2.80-2.61(m,2H),2.41-2.12(m,3H),1.37(d,J=6.6Hz,3H);LC / MS(ESI+)m / z:[M+H]+=473.10.

[0291] Example 42: Synthesis of (S)-2-(2-((3'-(1-aminoethyl)-5-(2-oxa-7-azaspiro[3.5]nonan-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]nonan-7-yl)-[1,1'-biphenyl]-3-yl)methoxy)phenyl)acetic acid (Compound 042-B or 042-A) JPEG0007770556000078.jpg80170

[0292] 42.1 Synthesis of Compound 042-1 035-3 (500 mg, 0.9 mmol) was weighed and placed in 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(dibenzylideneacetone)dipalladium (100 mg, 0.056 mmol), and 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl (60 mg, 0.056 mmol) were added. The reaction solution was reacted at 100 °C for 24 hours, then filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 1 / 1) to obtain compound 042-1. LC / MS (ESI+) m / z: [M+H] + =601.05.

[0293] 42.2 Synthesis of Compounds 042-A and 042-B The synthesis of compound 042 was carried out in accordance with the synthesis methods in steps 1.6 and 1.7 of Example 1. 042 was further subjected to chiral separation by supercritical fluid chromatography (Method: OD-MeOH(DEA)-40-3mL-35T) to obtain 042-A (retention time Rt = 0.913 min) and 042-B (retention time Rt = 1.444 min).

[0294] 042-A (retention time Rt=0.913min): 11H NMR (400 MHz, DMSO-d6): 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。

[0295] 042 - B (Retention time Rt = 1.444 min): 1 1H NMR (400 MHz, DMSO-d6): 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。

[0296] Example 43: Synthesis of (S)-2-(2-((3'-(1-aminoethyl)-5-(1-oxa-7-azaspiro[3.5]nonan-7-yl)-[1,1'-biphenyl]-3-yl)methoxy)phenyl)acetic acid (Compound 043-A or 043-B) and (R)-2-(2-((3'-(1-aminoethyl)-5-(1-oxa-7-azaspiro[3.5]nonan-7-yl)-[1,1'-biphenyl]-3-yl)methoxy)phenyl)acetic acid (Compound 043-B or 043-A) JPEG0007770556000079.jpg96170

[0297] 43.1 Synthesis of Compound 043-1 035-3 (600 mg, 1.08 mmol) was weighed into a reaction flask, and 012-a (160 mg, 1.2 mmol), cesium carbonate (1.4 g, 4.32 mmol), 1,4-dioxane (3 mL), tris(dibenzylideneacetone)dipalladium (100 mg, 0.11 mmol), and 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl (50 mg, 0.11 mmol) were added. The reaction solution was reacted at 100 °C for 5 hours under nitrogen gas protection. 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 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 to obtain compound 043-1. LC / MS(ESI+)m / z:[M+H] + =601.10.

[0298] 43.2 Synthesis of Compounds 043-A and 043-B The synthesis of compound 043 was carried out in accordance with the synthesis methods of steps 1.6 and 1.7 of Example 1. 043 was further subjected to chiral separation by supercritical fluid chromatography to obtain 043-A (retention time Rt = 1.54 min) and 043-B (retention time Rt = 2.386 min).

[0299] 043-A (holding time Rt=1.54min): 1 H NMR(400MHz,DMSO-d6):δ8.25(s,1H),7.67(d,J=8.0Hz,1H),7.49(s,1H),7.37(t,J=8.0Hz,1H),7.25 (d,J=8.0Hz,1H),7.13(s,1H),7.08(d,J=4.0Hz,2H),6.99(s,1H),6.90(d,J=8.0Hz,1H),6.80(t,J=8 .0Hz,1H),5.10(s,2H),4.42(s,1H),4.23(d,J=8.0Hz,1H),3.38-3.35(m,4H),3.18(d,J=4.0Hz,2H), 2.39(t,J=8.0Hz,2H),1.90(d,J=4.0Hz,4H),1.49(d,J=8.0Hz,3H);LC / MS(ESI+)m / z:[M+H]+=487.10.

[0300] 043-B (holding time Rt=2.386min): 1 H NMR(400MHz,DMSO-d6):δ8.00-7.93(d,J=8.0Hz,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=8.0Hz, 1H),3.38-3.35(m,4H),3.18(d,J=4.0Hz,2H),2.39(t,J=8.0Hz,2H),1.90 (d,J=4.0Hz,4H),1.49(d,J=8.0Hz,3H);LC / MS(ESI+)m / z:[M+H]+=487.10.

[0301] Example 44, Synthesis of 2-(2-((3'-(1-amino-2-fluoroethyl)-5-(2-oxa-7-azaspiro[3.5]nonan-7-yl)-[1,1'-biphenyl]-3-yl)methoxy)phenyl)acetic acid (Compound 044) JPEG0007770556000080.jpg72170

[0302] 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 for 0.5 hours at 0° C. The reaction system was quenched by adding saturated aqueous sodium sulfite solution, filtered, and dried as a solid to obtain compound 044-1.

[0303] 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 in acetonitrile (20 mL) and refluxed at 80 °C for 1 hour. 044-1 (3.0 g, 10.8 mol) was then dissolved in 5 mL of acetonitrile and slowly added dropwise to the reaction mixture. The mixture was then reacted at 80 °C for 12 hours. The reaction mixture was quenched with saturated aqueous ammonium chloride and extracted with ethyl acetate (30 mL × 3). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, and then filtered. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to obtain compound 044-2.

[0304] 44.3 Synthesis of Compound 044-3 Under nitrogen gas protection, titanium tetraisopropoxide (2.6 g, 9.22 mol) was added dropwise to a solution of 044-2 (2.4 g, 4.61 mol) in 1N ammonia methanol (20 mL) and reacted at 25 °C for 2 hours. Sodium borohydride (262.3 mg, 6.91 mol) was then added and reacted at room temperature for 2 hours. The reaction solution was adjusted to pH 2 with 6N hydrochloric acid and extracted with ethyl acetate. The aqueous phase was adjusted to pH 10 with 6N sodium hydroxide solution and 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 was used directly in the next step. LC / MS (ESI+) m / z: [M+H] + =218.00.

[0305] 44.4 Synthesis of Compound 044 Compound 044 can be synthesized by referring to the synthesis method for compound 001, by replacing 001-a with 044-3 and 001-d with 011-a in the synthesis steps.

[0306] 1 H NMR (400MHz, DMSO-d6): δ8.75(s,2H),7.83(s,1H),7.74(d,J=8.0Hz,1H),7.54(t,J=8. 0Hz,1H),7.48(d,J=8.0Hz,1H),7.25-7.21(m,2H),7.16(d,J=8.0Hz,2H),7.10(s,1H),7 .03(d,J=8.0Hz,1H),6.90(t,J=8.0Hz,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.

[0307] Example 45 Synthesis of 2-(2-((3'-(aminomethyl)-6-fluoro-5-(6-azaspiro[2.5]octan-6-yl)-[1,1'-biphenyl]-3-yl)methoxy)phenyl)acetic acid (Compound 045) JPEG0007770556000081.jpg31170

[0308] 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(dibenzylideneacetone)dipalladium (10 mg, 10 wt%), and 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl (10 mg, 10 wt%) were added. The reaction solution was reacted at 100 °C for 2 hours under nitrogen gas protection, 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.

[0309] 45.2 Synthesis of Compound 045 Compound 045 was synthesized according to the synthesis method in steps 1.6 and 1.7 of Example 1.

[0310] 1 H NMR (400MHz, DMSO-d6): δ7.79(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=7.6Hz,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.

[0311] Example 46, Synthesis of (S)-2-(2-((3'-(1-amino-2-hydroxyethyl)-5-(8-azaspiro[4.5]decan-8-yl)-[1,1'-biphenyl]-3-yl)methoxy)phenyl)acetic acid (Compound 046) JPEG0007770556000082.jpg35170

[0312] Compound 046 can be synthesized by referring to the synthesis method of compound 018, with the raw material 001-d being replaced with 8-azaspiro[4.5]decane hydrochloride (046-a).

[0313] 1 H NMR(400MHz,DMSO-d6):δ8.05(d,J=63.0Hz,1H),7.60(dd,J=46.0,7.6Hz,1H),7.38(d d,J=16.8,9.6Hz,2H),7.23(dd,J=20.4,7.4Hz,1H),7.19-6.89(m,5H),6.88-6.70(m,1 H),5.11(s,2H),4.12(s,1H),3.67(s,2H),3.37(d,J=6.8Hz,2H),3.22(dd,J=16.8,11 .3Hz,4H),1.71-1.48(m,8H),1.46(d,J=6.6Hz,4H);LC / MS(ESI+)m / z:[M+H]+=515.15.

[0314] Example 47: Synthesis of trifluoroacetic acid salts of (R)-2-(2-((3'-(1-amino-2-hydroxyethyl)-5-(3-azaspiro[5.5]undecan-3-yl)-[1,1'-biphenyl]-3-yl)methoxy)phenyl)acetic acid (Compound 047-A) and (S)-2-(2-((3'-(1-amino-2-hydroxyethyl)-5-(3-azaspiro[5.5]undecan-3-yl)-[1,1'-biphenyl]-3-yl)methoxy)phenyl)acetic acid (Compound 047-B) JPEG0007770556000083.jpg69170

[0315] 47.1 Synthesis of Compound 047-1 047-a (1 g, 3.03 mmol) was weighed into a reaction flask, tetrahydrofuran (5 mL) was added, and the mixture was cooled to 0 °C in an ice-water bath. Borane tetrahydrofuran complex (1 M, 9.1 mL, 9.1 mmol) was slowly added. After the addition was complete, the mixture was allowed to react for 3 hours at 0 °C. Methanol (10 mL) was slowly added dropwise to quench the reaction. After the quenching was complete, the reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography to obtain compound 047-1. LC / MS (ESI+) m / z: [M+H-tBu] + =260.00.

[0316] 47.2 Synthesis of Compound 047-2 047-1 (700 mg, 2.21 mmol) was weighed and placed in a reaction flask. 2,2-Dimethoxypropane (461 mg, 4.43 mmol), p-toluenesulfonic acid monohydrate (21 mg, 0.11 mmol), and toluene (5 mL) were added, and the mixture was heated to 50 °C and reacted for 15 hours. The reaction mixture was adjusted to pH 8 with saturated aqueous sodium bicarbonate and extracted with ethyl acetate (10 mL × 3). The combined organic phase was washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, and then filtered. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to obtain compound 047-2.

[0317] 47.3 Synthesis of Compound 047-3 047-2 (400 mg, 1.12 mmol) was weighed into a reaction flask, and bis(pinacolato)diboron (314 mg, 1.24 mmol), potassium acetate (221 mg, 2.25 mmol), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (80 mg, 0.11 mmol), and 1,4-dioxane (5 mL) were added. After purging with nitrogen gas three times, the reaction solution was reacted at 100 °C for 2 hours, then directly concentrated under reduced pressure. The residue was purified by silica gel column chromatography to obtain compound 047-3.

[0318] 47.4 Synthesis of Compound 047-4 001-3 (400 mg, 0.96 mmol) was weighed and placed in a reaction flask. 047-3 (389 mg, 0.96 mmol), potassium carbonate (267 mg, 1.93 mmol), 1,4-dioxane (5 mL), and tetrakis(triphenylphosphine)palladium (111 mg, 0.09 mmol) were added. The mixture was purged with nitrogen gas three times, then heated to 100 °C and reacted for 2 hours. The reaction solution was diluted with water (10 mL) and extracted with ethyl acetate (10 mL × 3). The combined 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 to obtain compound 047-4.

[0319] 47.5 Synthesis of Compound 047-5 047-4 (150 mg, 0.25 mmol) was weighed and placed in a reaction flask. 047-c (51 mg, 0.27 mmol), cesium carbonate (320 mg, 0.98 mmol), 1,4-dioxane (2 mL), tris(dibenzylideneacetone)dipalladium (22 mg, 0.02 mmol), and 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl (12 mg, 0.02 mmol) were added. The atmosphere was purged with nitrogen gas three times, and the reaction solution was reacted at 100 °C for 2 hours. After cooling to room temperature, the reaction solution was diluted with water (10 mL) and extracted with ethyl acetate (10 mL x 3). The organic phases were combined, 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 047-5.

[0320] 47.6 Synthesis of trifluoroacetic acid of compound 047-A The synthesis of compound 047-A referred to the synthesis methods in steps 1.6 and 1.7 of Example 1. The preparation process was carried out under trifluoroacetic acid conditions, and the trifluoroacetic acid of compound 047-A was finally obtained.

[0321] 1 H NMR (400MHz, DMSO-d6): δ8.39(s,2H),7.78(s,1H),7.68(d,J=7.6Hz,1H),7.49(t,J=7.6H z,1H),7.42(d,J=7.6Hz,1H),7.21(d,J=7.6Hz,2H),7.14(s,2H),7.09(s,1H),7.02(d,J= 8.0Hz,1H),6.89(t,J=7.6Hz,1H),5.12(s,2H),4.37(s,1H),3.82-3.67(m,2H),3.59(s,2 H),3.24(s,4H),1.55(s,4H),1.40(d,J=14.4Hz,10H);LC / MS(ESI+)m / z:[M+H]+=529.10.

[0322] 47.7 Synthesis of trifluoroacetic acid of compound 047-B JPEG0007770556000084.jpg40170 Compound 047-B can be synthesized by referring to the synthesis method for compound 047-A, and replacing the raw material 047-a (R configuration) with (S)-2-(3-bromophenyl)-2-((tert-butoxycarbonyl)amino)acetic acid (S configuration).

[0323] 1 H NMR(400MHz,DMSO-d6):δ8.40(s,2H),7.79(s,1H),7.69(d,J=7.6Hz,1H),7.50(t,J=7.6H z,1H),7.43(d,J=7.6Hz,1H),7.22(d,J=7.6Hz,2H),7.16(s,2H),7.11(s,1H),7.03(d,J= 8.2Hz,1H),6.90(t,J=7.4Hz,1H),5.13(s,2H),4.38(s,1H),3.81-3.68(m,2H),3.60(s,2 H),3.26(s,4H),1.56(s,4H),1.41(d,J=13.8Hz,10H);LC / MS(ESI+)m / z:[M+H]+=529.10.

[0324] Example 48: Synthesis of (R)-2-(2-((3'-(1-amino-2-hydroxyethyl)-5-(2-azaspiro[3.4]octan-2-yl)-[1,1'-biphenyl]-3-yl)methoxy)phenyl)acetic acid (Compound 048-A) and (S)-2-(2-((3'-(1-amino-2-hydroxyethyl)-5-(2-azaspiro[3.4]octan-2-yl)-[1,1'-biphenyl]-3-yl)methoxy)phenyl)acetic acid (Compound 048-B) JPEG0007770556000085.jpg38170

[0325] 48.1 Synthesis of Compound 048-A Compound 048-A can be synthesized by referring to the synthesis method of compound 047-A in Example 47, with the raw material 047-c being replaced with 2-azaspiro[3.4]octane (048-a).

[0326] 1H NMR (400MHz, DMSO-d6): δ9.51(s,1H),7.96(s,1H),7.49(d,J=7.6Hz,1H),7.35(s,1H),7.26(t, J=7.6Hz,1H),7.16-7.02(m,3H),6.83(d,J=8.4Hz,1H),6.78(t,J=7.2Hz,1H),6.59(s,1H),6.4 5(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,2 H),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. 48.2 Synthesis of Compound 048-B JPEG0007770556000086.jpg40170The synthesis of compound 048-B can be performed by referring to the synthesis method for 048-A, and replacing the raw material 047-4 (R configuration) with an S configuration.

[0327] 1 H NMR(400MHz,DMSO-d6):9.49(d,J=8.8Hz,1H),7.93(d,J=30.0Hz,1H),7.51(t,J=8.4Hz,1H),7. 34(d,J=11.2Hz,1H),7.31-7.03(m,4H),6.95-6.73(m,2H),6.58(d,J=6.8Hz,1H),6.47(d,J=15. 6Hz,1H),5.21-5.04(m,2H),4.63(d,J=8.0Hz,1H),3.80-3.69(m,5H),3.58(s,1H),3.53-3.42( m,2H),3.34(d,J=8.8Hz,1H),1.82(s,4H),1.66-1.56(m,4H);LC / MS(ESI+)m / z:[M+H]+=487.10.

[0328] Example 49: Synthesis of (R)-2-(2-((3'-(1-amino-2-hydroxyethyl)-5-(2-azaspiro[4.4]nonan-2-yl)-[1,1'-biphenyl]-3-yl)methoxy)phenyl)acetic acid (Compound 049-A) and (S)-2-(2-((3'-(1-amino-2-hydroxyethyl)-5-(2-azaspiro[4.4]nonan-2-yl)-[1,1'-biphenyl]-3-yl)methoxy)phenyl)acetic acid (Compound 049-B) JPEG0007770556000087.jpg35170

[0329] 49.1 Synthesis of Compound 049-A Compound 049-A can be synthesized by referring to the synthesis method of compound 047-A in Example 47, with the raw material 047-c being replaced with 2-azaspiro[4.4]nonane (049-a).

[0330] 1 H NMR (400MHz, DMSO-d6): δ9.49(d,J=9.2Hz,1H),8.02(d,J=42.4Hz,1H),7.59(dd,J=35.2,7.6Hz,1H),7.36(t,J=7. 6Hz,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=6.8Hz,2H) ,3.25-3.18(m,2H),1.88(t,J=6.8Hz,2H),1.70-1.65(m,4H),1.63-1.53(m,4H);LC / MS(ESI+)m / z:[M+H]+=501.10.

[0331] 49.2 Synthesis of Compound 049-B JPEG0007770556000088.jpg33170The synthesis of compound 049-B can be performed by referring to the synthesis method for 049-A, and replacing the raw material 047-4 (R configuration) with an S configuration.

[0332] 1 H NMR(400MHz,DMSO-d6):9.50(d,J=9.2Hz,1H),8.04(d,J=64.8Hz,1H),7.60(dd,J=44.4,7.8Hz,1H),7.3 6(t,J=7.6Hz,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=15.2Hz,2H),3.39-3.36(m,2H),3.22 (s,2H),1.88(t,J=6.8Hz,2H),1.70-1.66(m,4H),1.63-1.56(m,4H);LC / MS(ESI+)m / z:[M+H]+=501.10.

[0333] Example 50 Synthesis of 2-(2-((3'-(1-amino-2-fluoroethyl)-2'-fluoro-5-(1-oxa-6-azaspiro[3.4]octan-6-yl)-[1,1'-biphenyl]-3-yl)methoxy)phenyl)acetic acid (Compound 050) JPEG0007770556000089.jpg73170

[0334] 50.1 Synthesis of Compound 050-1 020-a (2.0 g, 9.2 mmol) was weighed and dissolved in tetrahydrofuran (20 mL). Under nitrogen gas protection, lithium bis(trimethylsilyl)amide (1 M, 10.1 mL, 10.1 mmol) was added and the mixture was allowed to react for 1 hour. Then, trimethylchlorosilane (1.08 g, 10.1 mmol) was added at -78 °C and the mixture was slowly warmed to room temperature and allowed to react for 1 hour. The reaction solution was concentrated, and acetonitrile (20 mL) and 1-chloromethyl-4-fluoro-1,4-diazoniabicyclo[2.2.2]octane bis(tetrafluoroborate) salt (4.7 g, 11.4 mmol) were added. The mixture was allowed to react at room temperature for 2 hours. The reaction solution was slowly quenched with saturated aqueous ammonium chloride (15 mL) and extracted with ethyl acetate (50 mL x 3). The combined organic phase was washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to obtain compound 050-1. LC / MS (ESI+) m / z: [M+H] + =234.1.

[0335] 50.2 Synthesis of Compound 050-2 050-1 (600 mg, 5.19 mmol) was weighed and dissolved in ammonia ethanol solution (2 M, 3.8 mL), and tetraisopropyl titanate (1.08 g, 3.8 mmol) was added and reacted at 25 °C for 2 hours. Next, sodium borohydride (116 mg, 3.06 mmol) was added and reacted for 2 hours. The reaction solution was slowly quenched with saturated aqueous ammonium chloride solution (5 mL) and extracted with ethyl acetate (10 mL × 3). The combined 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 to obtain compound 050-2. LC / MS (ESI+) m / z: [M+H] + =236.1.

[0336] 50.3 Synthesis of Compound 050 The synthesis of compound 050 can be performed by referring to the synthesis method of compound 001, and by replacing 001-a with 050-2 and 001-d with 041-a in the synthesis steps.

[0337] 1 H NMR(400MHz,DMSO-d6):δ7.61(t,J=7.2Hz,1H),7.41-7.38(m,1H),7.24(t,J=8.4Hz,1H),7.17-8 .15(m,1H),7.05-7.01(m,1H),6.90(d,J=8.4Hz,1H),6.81-6.71(m,3H),6.51(d,J=12.8Hz,1H),5 .01(s,2H),4.52-4.38(m,5H),3.57(d,J=11.2Hz,1H),3.46(d,J=10.8Hz,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.

[0338] Example 51 Synthesis of 2-(2-((3'-(1-amino-3-hydroxypropyl)-5-(6-azaspiro[2.5]octan-6-yl)-[1,1'-biphenyl]-3-yl)methoxy)phenyl)acetic acid (Compound 051) JPEG0007770556000090.jpg62170

[0339] 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 successively dissolved in ethanol (100 mL), and the reaction solution was reacted at 80°C for 24 hours. The reaction solution was filtered, rinsed with ethanol, and the cake was dried under reduced pressure to obtain compound 051-1. LC / MS (ESI+) m / z: [M+H] + =246.00.

[0340] 51.2 Synthesis of Compound 051-2 051-1 (3.7 g, 15.2 mmol) was dissolved in tetrahydrofuran (70 mL), the mixture was purged with nitrogen gas, and borane in tetrahydrofuran (10 mL) was added dropwise at 0°C. The reaction solution was reacted at 45°C for 5 hours. Methanol was slowly added dropwise to quench the reaction, and the reaction solution was concentrated under reduced pressure. Water (50 mL) was added, and the mixture was extracted with ethyl acetate (30 mL x 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) to obtain compound 051-2. LC / MS (ESI+) m / z: [M+H] + =230.00.

[0341] 51.3 Synthesis of Compound 051 Compound 050 can be synthesized by referring to the synthesis method for compound 001, and replacing 001-a in the synthesis step with 051-2.

[0342] 1 H NMR(400MHz,DMSO-d6):δ8.26(s,1H),7.68(d,J=8.0Hz,1H),7.46(s,1H),7.37(t,J=16.0Hz, 1H),7.22(d,J=8.0Hz,1H),7.15(s,1H),7.09(m,2H),7.01(s,1H),6.91(d,J=12.0Hz,1H),6. 79(d,J=8.0Hz,1H),5.11(s,2H),4.19(s,1H),3.40(t,J=8.0Hz,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.

[0343] Example 52 Synthesis of 2-(2-((3'-(1-amino-2-hydroxyethyl)-2'-fluoro-5-(6-azaspiro[2.5]octan-6-yl)-[1,1'-biphenyl]-3-yl)methoxy)phenyl)acetic acid (Compound 052) JPEG0007770556000091.jpg77170

[0344] 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 solution was reacted at 25 °C for 2 hours, diluted with water (50 mL), and extracted with dichloromethane (30 mL x 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) to obtain compound 052-1. LC / MS (ESI+) m / z: [M+H] + =262.00.

[0345] 52.2 Synthesis of Compound 052-2 052-1 (4.5 g, 25 mmol) was weighed and dissolved in toluene (30 mL). Bis[(pinacolato)boryl]methane (10 g, 37.3 mmol), 1,2-bis(diphenylphosphino)benzene (1.11 g, 2.5 mmol), cuprous bromide (360 mg, 2.5 mmol), and lithium tert-butoxide (6 g, 74.5 mmol) were added. The reaction solution was reacted overnight at 50 °C under nitrogen gas protection. The solution was then diluted with water (30 mL) and extracted with ethyl acetate (30 mL x 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) to obtain compound 052-2. LC / MS (ESI+) m / z: [M+H] + =404.05.

[0346] 52.3 Synthesis of Compound 052-3 052-2 (4.2 g, 20 mmol) was dissolved in toluene (20 mL), sodium perborate tetrahydrate (11.2 g, 40 mmol) was added, and the reaction solution was reacted at room temperature for 2 hours. Then, water (50 mL) was added to dilute the mixture and extracted with ethyl acetate (10 mL × 3). The combined 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) to obtain compound 052-3.

[0347] 52.4 Synthesis of Compound 052-4 Under nitrogen gas protection, 052-3 (2.0 g, 6.8 mmol), bis(pinacolato)diboron (2.6 g, 10.2 mmol), potassium acetate (1.36 g, 13.6 mmol), and [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (460 mg, 0.68 mmol) were dissolved in 1,4-dioxane (20 mL). The reaction solution was reacted at 100 °C for 2 hours, then diluted with water (20 mL), and extracted with ethyl acetate (10 mL × 3). The combined 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 to give compound 052-4. LC / MS (ESI+) m / z: [M+H] + =386.05.

[0348] 52.5 Synthesis of Compound 052 Compound 052 can be synthesized by referring to the synthesis method for compound 001, and replacing 001-2 with 052-4.

[0349] 1H NMR(400MHz,DMSO-d6):δ8.48(s,2H),7.61-7.51(m,2H),7.37(t,J=8.0Hz,1H),7 .25-7.20(m,2H),7.17(s,1H),7.05-7.00(m,3H),6.90(t,J=8.0Hz,1H),5.13(s,2 H),4.58(d,J=8.0Hz,1H),3.83-3.79(m,1H),3.76-3.71(m,1H),3.58(s,2H),3.4 0-3.22(m,4H),1.56-1.39(m,4H),0.35(s,4H);LC / MS(ESI+)m / z:[M+H]+=505.10.

[0350] Example 53 Synthesis of 2-(2-((3'-(1-aminoethyl)-2'-fluoro-5-(2-oxa-7-azaspiro[3.5]nonan-7-yl)-[1,1'-biphenyl]-3-yl)methoxy)phenyl)acetic acid (Compound 053) JPEG0007770556000092.jpg38170

[0351] 53.1 Synthesis of Compound 053-1 020-5 (300 mg, 0.52 mmol) was weighed into a reaction flask, and 011-a (99 mg, 0.58 mmol), cesium carbonate (683 mg, 2.1 mmol), 1,4-dioxane (3 mL), tris(dibenzylideneacetone)dipalladium (48 mg, 0.05 mmol), and 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl (25 mg, 0.05 mmol) were added. After purging with nitrogen gas, the reaction solution was reacted at 100 °C for 2 hours. Then, water (10 mL) was added and the mixture was diluted and extracted with ethyl acetate (20 mL × 3). The organic phases were combined, 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 053-1. LC / MS(ESI+)m / z:[M+H] + =619.05.

[0352] 53.2 Synthesis of Compound 053 Compound 053 was synthesized according to the synthesis method in steps 1.6 and 1.7 of Example 1.

[0353] 1 H NMR(400MHz,DMSO-d6):δ8.07(d,J=8.0Hz,1H),7.54(t,J=6.8Hz,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=7.2Hz,1H),5 .11(d,J=28.4Hz,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=16.8,6.8Hz,3H);LC / MS(ESI+)m / z:[M+H]+=505.10.

[0354] Example 54, Synthesis of 2-(2-((3'-(1-aminoethyl)-2'-fluoro-5-(1-oxa-7-azaspiro[3.5]nonan-7-yl)-[1,1'-biphenyl]-3-yl)methoxy)phenyl)acetic acid (Compound 054) JPEG0007770556000093.jpg38170 Compound 054 can be synthesized by referring to the synthesis method for compound 053, and replacing the raw materials 011-a with 012-a.

[0355] 1 H NMR(400MHz,DMSO-d6):δ8.12(s,1H),7.55(t,J=6.8Hz,1H),7.33(td,J=7.6,1.6Hz,1H),7.29 -7.16(m,2H),7.16-7.05(m,2H),7.05-6.91(m,3H),6.82(t,J=7.6Hz,1H),5.10(d,J=40.4Hz,2 H),4.46-4.37(m,2H),4.31(q,J=6.8Hz,1H),3.36-3.29(m,4H),3.18-3.11(m,2H),2.37(t,J= 7.6Hz,2H),1.94-1.79(m,4H),1.31(dd,J=21.4,6.7Hz,3H);LC / MS(ESI+)m / z:[M+H]+=505.10.

[0356] Example 55, Synthesis of 2-(2-((3'-(1-aminoethyl)-2'-fluoro-5-(3-oxa-9-azaspiro[5.5]undecan-9-yl)-[1,1'-biphenyl]-3-yl)methoxy)phenyl)acetic acid (Compound 055) JPEG0007770556000094.jpg38170 To synthesize compound 055, refer to the synthesis method for compound 053, and replace the raw materials 011-a with 029-a.

[0357] 1 H NMR(400MHz,DMSO-d6):δ7.54(s,1H),7.33(m,1H),7.27-7.16(m,2H),7.08 (m,2H),6.95(m,3H),6.82(t,J=16.0Hz,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=4.0Hz,3H);LC / MS(ESI+)m / z:[M+H]+=533.10.

[0358] Example 56, Synthesis of 2-(2-((3'-(1-aminoethyl)-2'-fluoro-5-(2-oxa-9-azaspiro[5.5]undecan-9-yl)-[1,1'-biphenyl]-3-yl)methoxy)phenyl)acetic acid (Compound 056) JPEG0007770556000095.jpg40170 Compound 056 can be synthesized by referring to the synthesis method for compound 053, and replacing the raw materials 011-a with 030-a.

[0359] 1H NMR(400MHz,DMSO-d6):δ8.38(d,J=4.0Hz,2H),7.56(t,J=16.0Hz,2H),7.38(t,J=12.0H z,1H),7.23(t,J=16.0Hz,2H),7.15(s,1H),7.03(d,J=8.0Hz,3H),6.90(t,J=16.0Hz,1H) ,5.12(s,2H),4.73-4.69(m,1H),3.56(d,J=12.0Hz,4H),3.39(s,2H),3.24(t,J=12.0Hz ,4H),1.58(d,J=8.0Hz,4H),1.55(s,3H),1.53(s,4H);LC / MS(ESI+)m / z:[M+H]+=533.10.

[0360] <Biological activity test analysis> 1. In vitro screening experiment of complement factor D inhibitory activity (C3b method) 1.1 Experimental materials and equipment V-bottom plate (AXYGEN), DMSO (Sigma), MicroVue Bb Plus ELISA kit (Quidel), complement factor C3b (abbreviated as factor C3b, Complement tech), complement factor B (abbreviated as factor B, Complement tech), complement factor D (abbreviated as factor D, Complement tech), EDTA (Macklin), GVB o (Complement tech), EGTA (Aladdin), MgCl2 (Aladdin), NaOH (Sinopharm), microplate reader (Molecular Devices, SpectraMax i3x), microplate thermostatic shaker (Thermo, MB100-2A), pipette gun (Gilson)

[0361] 1.2 Preparation before the experiment 1.2.1 Preparation of Mg-EGTA 0.1M Mg-EGTA: 3.8g EGTA, 0.9521g MgCl2, 0.7g NaOH were weighed out, the pH was adjusted to 7.5 with NaOH, and the solution was made up to 100mL with distilled water, filtered through a 0.2µm sterile filter, individually wrapped, and stored at 4°C.

[0362] 1.2.2 Preparation of working solution Buffer: 0.1M Mg-EGTA solution in GVB o Diluted 10-fold to 10 mM with buffer. Factor B working solution: 1 mg / mL factor B solution (10.75 μM) was diluted 6.7-fold 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-fold with buffer to 3.2 μM. Note: a) The above dilution factors are for reference only and should be adjusted according to the actual concentrations listed in the reagents. b, factor B: 93KDa, factor D: 24KDa, factor C3b: 176KDa.

[0363] 1.2.3 Preparation of stop solution Stop solution: Weigh out an appropriate amount of EDTA powder and add it to a specified amount of GVB o It was dissolved in buffer, the pH was adjusted to 7.5 with NaOH, and stirred until clear, to prepare a 10 mM solution.

[0364] 1.2.4 Preparation of Compounds Compound mother solution: 40 mM compound solution was diluted with DMSO to 1 mM mother solution, and the 1 mM mother solution was diluted 3-fold with DMSO in 8 steps to prepare compound mother solutions of various concentrations. Compound working solution: Compound solutions of various concentrations were obtained by diluting 250-fold with buffer.

[0365] 1.3 Experimental steps In a V-bottom plate, 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 0.4% DMSO buffer were added to the negative control group; and 20 μL of 0.2% DMSO buffer was added to the blank control group. These were then incubated at 37°C for 15 minutes. The factor B working solution and factor C3b working solution were mixed uniformly at a 1:1 ratio, and 20 μL of the mixture was added to each well. These were then incubated at 37°C for 30 minutes. 40 μL of stop solution was added to stop the reaction, and the amount of product Bb produced was detected using the MicroVue Bb Plus ELISA Kit.

[0366] 1.4 ELISA detection 1.4.1 The required microplate wells were removed and allowed to warm to room temperature, and the remainder were repackaged and stored at 4°C. 1.4.2 Wash twice with 300 μL of 1× Wash Buffer, incubating the first wash at 25°C for 1 minute. 1.4.3 The samples were diluted 8-fold with Complement Specimen Diluent, and 100 μL of sample was added to each well and incubated at 25°C for 30 minutes. 1.4.4 Discard the liquid in the wells and wash five times with 300 μL of 1× Wash Buffer, incubating the first wash for 1 minute at room temperature. 1.4.5 50 μL of Bb Plus Conjugate was added to each well and incubated at 25°C for 30 minutes. 1.4.6 Discard the liquid in the wells and wash five times with 300 μL of 1× Wash Buffer, incubating the first wash for 1 minute at room temperature. 1.4.7 100 μL of compound working solution (Substrate Solution) was added to each well and incubated at 25°C for 15 minutes. 1.4.8 100 μL of Stop Solution was added to each well, and the absorbance at 450 nm was detected within 30 minutes. 1.5 Data Analysis 1.5.1 Inhibition rate for each drug concentration: JPEG0007770556000096.jpg12170PC group represents 0% inhibition rate, and NC group represents 100% inhibition rate. 1.5.2 Calculation of signal-to-background ratio (S / B): The mean value of OD in the PC group / mean value of OD in the NC group represents the size of the signal window. 1.5.3 Z' factor: Calculation formula: JPEG0007770556000097.jpg13170Z' factor must be 0.4 or greater. 1.5.4 Compound IC 50 : I C 50 : Half-inhibitory concentration, which represents the concentration at which a compound inhibits 50% of the enzymatic activity of complement factor D.

[0367] Data were collected and the log values ​​of inhibition rate and compound concentration were calculated, and IC values ​​were calculated using GraphPad Prism software. 50 The inhibitory activity of the compounds of the present invention against complement factor D is shown in Table 1. JPEG0007770556000098.jpg138170 Experimental conclusion: The compounds of the present invention have excellent inhibitory effect on complement factor D.

[0368] 2. Inhibitory activity of compounds against bypass pathways using rabbit erythrocyte hemolysis assay 2.1 Experimental materials and equipment Normal human serum, NHS (collected from healthy individuals), normal human plasma, NHP (Shanghai Yuduo), 96-well enzyme plate (Jet Biofil), Japanese large-ear white rabbit (Wuhan WQJX), Alsever's solution (Procell), centrifuge (Thermo, PICO17), thermostatic shaker (Shanghai Fuma), decolorizing shaker (Beijing Liuyi), cell counter (Invitrogen, Counter Countess II) (GVB o , EGTA, MgCl2、 NaOH, microplate reader, microplate thermostatic shaker, pipette gun, etc. were the same as in Experiment 1).

[0369] 2.2 Preparation of working solution 48% NHP: 100% NHP was diluted to 48% with buffer. 26.4% NPS: 100% NHS was diluted to 26.4% with buffer. Rabbit red blood cell suspension: Blood was collected from the ear vein of a rabbit and anticoagulated with Alsever solution in a 1:1 ratio. The blood was individually packaged and stored at 4°C for up to 4 weeks. Before use, the blood was centrifuged at 500g for 5 minutes, discarding the Alsever solution. The blood was then washed three times with the same volume of buffer, centrifuged three times at 500g for 5 minutes, and finally diluted to a density of 6 x 10 with buffer. 8 The concentration was adjusted to 1 / mL.

[0370] 2.3 Experimental steps In a 96-well microplate, 50 μL of 48% NHP or 26.4% NHS and 50 μL of compound solution were added to the experimental group; 50 μL of 48% NHP or 26.4% NHS and 50 μL of buffer containing 0.2% DMSO were added to the positive control group; 50 μL of 48% inactivated NHP or 26.4% inactivated NHS and 0.2% DMSO were added to the blank control group; and 100 μL of double-distilled water was added to the HO group and incubated at 37°C for 15 minutes. 20 μL of rabbit red blood cell suspension was added to each well and incubated in a shaker at 37°C for 30 minutes, followed by centrifugation at 2000 g (3380 rpm) for 5 minutes. 100 μL of the supernatant was transferred to a new 96-well microplate and the absorbance at 415 nm was detected.

[0371] 2.4 Data analysis 2.4.1 Hemolysis rate for each drug concentration: JPEG0007770556000099.jpg12170The PC group represents 100% hemolysis, and the NC group represents 0% hemolysis. 2.4.2 Calculation of signal-to-background ratio (S / B): The mean value of OD in the PC group / mean value of OD in the NC group represents the size of the signal window. 2.4.3 Z' factor: Calculation formula: JPEG0007770556000100.jpg131702.4.4 Compound IC 50 : I C 50 The data were collected and the log values ​​of the hemolysis rate and compound concentration were calculated, and the IC was calculated using GraphPad Prism software. 50 The inhibitory activity of the compounds of the present invention against rabbit erythrocyte hemolysis is shown in Table 2. JPEG0007770556000101.jpg245170 Experimental conclusion: The compound of the present invention has excellent inhibitory effect on rabbit erythrocyte hemolysis.

[0372] 3. In vivo pharmacokinetic studies of the compounds of the present invention After acclimatization, SPF SD rats were administered 1 or 3 mg / kg of the compound of the present invention via intragastric administration or tail vein injection. After administration, plasma was collected at specific time points, and the compound concentration in plasma was detected via LC-MS / MS (AB SCIEX Qtrap4500). PK parameters of each compound were calculated using software to demonstrate the pharmacokinetic properties of the compound of the present invention in the animal body. The PK parameters of the compound of the present invention are shown in Table 3. JPEG0007770556000102.jpg100170 Experimental conclusion: The compounds of the present invention can achieve higher exposure in the body and higher oral bioavailability at lower doses, and have better overall pharmacokinetic properties.

[0373] The above describes exemplary embodiments of the present invention. However, the scope of protection of the present application is not limited to the above exemplary embodiments. Any modifications, equivalent replacements, improvements, etc. made by those skilled in the art within the spirit and principle of the present invention should be included in the scope of protection defined by the claims of the present application.

Claims

1. A compound represented by formula (I), a tautomer thereof, a stereoisomer thereof, a pharmaceutically acceptable salt of any one of them, or a solvate of any one of them. (however, R １ H, D, C １－６ alkyl or one, two or three R １－１ C substituted by １－６ alkyl, and each R １－１ are independently halogen, —CN, —OH, C １－６ Alkoxy or -NH ２ and R ２ and R ３ are each independently H, D, halogen, or C １－６ alkyl or one, two or three R ２－１ C substituted by １－６ alkyl, and each R ２－１ are independently halogen, —CN, —OH, C １－６ Alkoxy or -NH ２ and R ４ is H or halogen, m is 0, 1, 2 or 3, R ５ and R ７ are each independently H, halogen, —CN, or C １－６ Alkyl or C １－６ is an alkoxy, R ６ means "an 8- to 11-membered heterocycloalkyl having one, two or three heteroatoms selected from N, O and S, and the number of heteroatoms is one, two or three" or one, two or three R ６－２ "8- to 11-membered heterocycloalkyl having 1, 2, or 3 heteroatoms selected from N, O, and S" substituted with, wherein the heterocycloalkyl is a bridged ring or a spiro ring; R ６－２ are each independently hydroxyl, oxo (=O), halogen, C １－６ Alkyl, C １－６ Alkoxy, C １－６ Haloalkyl, C １－６ Haloalkoxy, C ３－６ Cycloalkyl or -(CH ２ ) ｐ -C ３－６ cycloalkyl, and p is 1, 2, 3, or 4; R ６－２ wherein the cycloalkyl is independently a monocyclic, bridged, or spirocyclic ring; R ８ is H, halogen or C １－６ is alkyl, R ９ is H, halogen, C １－６ alkyl or one, two or three R ９－１ C substituted by １－６ is alkyl, Each R ９－１ are independently halogen, —CN, —OH or —NH ２ and n is 0, 1, 2, 3 or 4; L is -(CR ａ R ｂ ) ｑ - and q is 0, 1, 2 or 3; R ａ and R ｂ are each independently H, D or halogen, or R ａ and R ｂ are linked together to form C ３－６ forming a cycloalkylene, the formed cycloalkylene being a monocyclic, bridged or spirocyclic ring; R １０ is —COOH or —C(═O)OR ｃ and R ｃ is C １－６ alkyl or one, two or three R ｃ－１ C substituted by １－６ alkyl, and each R ｃ－１ are independently halogen, —OH, or —C(═O)OC(CH ３ ) ３ and X is CR ｄ or N, and R ｄ is H, halogen or C １－６ It is alkyl.)

2. The compound represented by formula (I) according to claim 1, its tautomer, its stereoisomer, or a pharmaceutically acceptable salt of any one of them, or a solvate of any one of them, characterized in that the compound represented by formula (I) satisfies one or more of the following conditions: ((1) R １ is H, (2) R ２ and R ３ are each independently H, C １－３ alkyl or one, two or three R ２－１ C substituted by １－３ alkyl, and each R ２－１ are independently halogen or —OH, (3) m is 0 or 1; (4) R ５ and R ７ are each independently H or halogen; (5) R ６ are 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, 3-azabicyclo[3.2.1]octyl, 3-azaspiro[5,5]undecyl, 8-azaspiro[4.5]decyl or 1-oxa-6-azaspiro[3,4]octyl; (6) Each R ６－２ are independently hydroxyl, methyl, ethyl, n-propyl, or isopropyl; (7) R ８ is H, (8) R ９ is H or a halogen, (9) n is 0 or 1; (10) q is 1; (11) R ａ and R ｂ are each independently H; (12) R １０ is —COOH, (13) R ｄ is H.)

3. R ６ means "8- to 10-membered heterocycloalkyl having 1, 2 or 3 heteroatoms selected from N, O and S" or 1, 2 or 3 R ６－２ a tautomer thereof, a stereoisomer thereof, or a pharmaceutically acceptable salt of any one of them, or a solvate of any one of them.

4. R １ is H, R ２ and R ３ are each independently H, C １－３ alkyl or one, two or three R ２－１ C substituted by １－３ alkyl, and each R ２－１ are independently halogen or —OH, R ４ is H or halogen, m is 0 or 1, R ５ and R ７ are each independently H or halogen; R ６ means "an 8- to 11-membered heterocycloalkyl having one, two or three heteroatoms selected from N, O and S, and the number of heteroatoms is one, two or three" or one, two or three R ６－２ "8-11 membered heterocycloalkyl having 1, 2 or 3 heteroatoms selected from N, O and S" substituted with, wherein the heterocycloalkyl is a bridged ring or a spiro ring; Each R ６－２ are independently hydroxyl or C １－３ is alkyl, R ８ is H, R ９ is H or halogen, n is 0 or 1, L is -(CR ａ R ｂ ) ｑ -, q is 1, and R ａ and R ｂ are each independently H; R １０ is —COOH, X is CR ｄ or N, and R ｄ is H, a tautomer thereof, a stereoisomer thereof, a pharmaceutically acceptable salt of any one of them, or a solvate of any one of them.

5. The compound represented by formula (I) according to claim 1, its tautomer, its stereoisomer, or a pharmaceutically acceptable salt of any one of them, or a solvate of any one of them, characterized in that the compound represented by formula (I) satisfies one or more of the following conditions: ((1) R １ , R ２ , R ３ , R ５ , R ７ , R ６－２ , R ８ , R ９ , R ｃ and R ｄ wherein each alkyl is independently methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, or tert-butyl; (2) R １－１ , R ２－１ , R ５ , R ７ , and R ６－２ wherein each alkoxy is independently methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, or tert-butoxy; (3) R １－１ , R ２ , R ３ , R ２－１ , R ４ , R ５ , R ７ , R ６－２ , R ８ , R ９ , R ９－１ , R ａ , R ｂ , R ｃ－１ and R ｄ wherein each halogen is independently F, Cl, Br, or I; (4) R ６ wherein the heterocycloalkyl is linked to the parent molecule via the N atom.

6. A compound represented by formula (I) according to claim 1, its tautomer, its stereoisomer, or a pharmaceutically acceptable salt of any one of these, or a solvate of any one of these, characterized in that the compound represented by formula (I) satisfies one or more of the following conditions: ((1) R １ , R ２ , R ３ , R ５ , R ７ , R ６－２ , R ８ , R ９ , R ｃ and R ｄ wherein each alkyl is independently methyl or ethyl; (2) R １－１ , R ２ , R ３ , R ２－１ , R ４ , R ５ , R ７ , R ６－２ , R ８ , R ９ , R ９－１ , R ａ , R ｂ , R ｃ－１ and R ｄ wherein each halogen is F; (3) R ６ wherein the heterocycloalkyl is

7. The compound represented by formula (I) according to claim 1, its tautomer, its stereoisomer, or a pharmaceutically acceptable salt of any one of them, or a solvate of any one of them, characterized in that the compound represented by formula (I) satisfies one or more of the following conditions: ((1) R ２ is H and R ３ is H, -CH ３ , -CH ２ OH, -CH ２ CH ２ OH, -CH ２ F or -CF ２ H,

8. The compound represented by formula (I) according to claim 1, its tautomer, its stereoisomer, or a pharmaceutically acceptable salt of any one of them, or a solvate of any one of them, characterized in that the compound represented by formula (I) satisfies any one of the following conditions: ((1) R １ is H, R ２ is H and R ３ is H, -CH ３ or -CH ２ F, R ４ is H or halogen, m is 0 or 1, R ５ and R ７ are each independently H or F; R ６ means "8-11 membered heterocycloalkyl in which the number of heteroatoms is 1, 2 or 3, and the heteroatom is 1, 2 or 3, selected from N, O and S" or 1, 2 or 3 R ６－２ wherein the heteroatoms are 1, 2 or 3 selected from N, O and S, and the number of heteroatoms is 1, 2 or 3, and is substituted by Each R ６－２ are independently hydroxyl or C １－３ is alkyl, R ８ is H, R ９ is H or F, n is 0 or 1, L is -(CR ａ R ｂ ) ｑ -, q is 1, and R ａ and R ｂ are each independently H; R １０ is —COOH, X is CR ｄ or N, and R ｄ is H, (2) R １ is H, R ２ is H and R ３ is H, -CH ３ or -CH ２ F, R ４ is H or halogen, m is 0 or 1, R ５ and R ７ are each independently H or F; R ６ means "8-10 membered heterocycloalkyl in which the number of heteroatoms is 1, 2 or 3, and the heteroatom is 1, 2 or 3, selected from N, O and S" or 1, 2 or 3 R ６－２ wherein the heteroatoms are 1, 2 or 3 selected from N, O and S, and the number of heteroatoms is 1, 2 or 3, and is 8 to 10 membered heterocycloalkyl substituted with Each R ６－２ are independently hydroxyl or C １－３ is alkyl, R ８ is H, R ９ is H or F, n is 0 or 1, L is -(CR ａ R ｂ ) ｑ -, q is 1, and R ａ and R ｂ are each independently H; R １０ is —COOH, X is CR ｄ or N, and R ｄ is H, (3) R １ is H, R ２ is H and R ３ is H, -CH ３ or -CH ２ F, R ４ is H or halogen, m is 0 or 1, R ５ and R ７ are each independently H or F; R ６－２ is hydroxyl or methyl, R ８ is H, R ９ is H or F, n is 0 or 1, L is -(CR ａ R ｂ ) ｑ -, q is 1, and R ａ and R ｂ are each independently H; R １０ is —COOH, X is CR ｄ or N, and R ｄ is H, (4) R １ is H, R ２ is H and R ３ is H, -CH ３ or -CH ２ F, R ４ is H or F, m is 0 or 1, R ５ and R ７ are each independently H or F; R ８ is H, R ９ is H or F, n is 0 or 1, L is -(CR ａ R ｂ ) ｑ -, q is 1, and R ａ and R ｂ are each independently H; R １０ is —COOH, X is CR ｄ or N, and R ｄ is H.)

9. The compound represented by formula (I) according to any one of claims 1 to 8, characterized in that the compound represented by formula (I) has a structure represented by formula (I-1) or a structure represented by formula (I-2), a tautomer thereof, a stereoisomer thereof, a pharmaceutically acceptable salt of any one of them, or a solvate of any one of them. (However, R １ , R ２ , R ３ , R ４ , R ５ , R ６ , R ７ , R ８ , R ９ , R １０ , R ｄ , L, m and n are as defined in any one of claims 1 to 8.

10. The compound represented by formula (I) according to any one of claims 1 to 8, characterized in that it has a structure represented by formula (I-3), a tautomer thereof, a stereoisomer thereof, a pharmaceutically acceptable salt of any one of them, or a solvate of any one of them. (However, X, R １ , R ２ , R ３ , R ４ , R ５ , R ６ , R ７ , R ８ , R ９ , R １０ , L and n are as defined in any one of claims 1 to 8.

11. The compound represented by formula (I) according to any one of claims 1 to 8, characterized in that it has a structure represented by formula (I-4), a tautomer thereof, a stereoisomer thereof, a pharmaceutically acceptable salt of any one of them, or a solvate of any one of them. (However, X, R １ , R ２ , R ３ , R ４ , R ５ , R ６ , R ７ , R ８ , R ９ , R １０ , L, m, and n are as defined in at least one of claims 1 to 8, and when the carbon atom marked with " " is a chiral carbon atom, it represents the R configuration, the S configuration, or a mixture thereof.)

12. The compound represented by formula (I) according to claim 1, characterized in that the compound represented by formula (I) is selected from any one of the following compounds: a compound represented by formula (I), a tautomer thereof, a stereoisomer thereof, a pharmaceutically acceptable salt of any one of these, or a solvate of any one of these:

13. The compound represented by formula (I) according to claim 12, characterized in that the compound represented by formula (I) is selected from any one of the following compounds: a tautomer thereof, a stereoisomer thereof, a pharmaceutically acceptable salt of any one of them, or a solvate of any one of them.

14. (1) deprotecting a compound of formula II-3 to obtain a compound of formula II-4; (2) hydrolyzing the compound of formula II-4 to obtain the compound of formula (I); Including, Here, R １０ is —COOH, and R １ , R ２ , R ３ , R ４ , R ５ , R ６ , R ７ , R ８ , R ９ , R ｃ 10. A method for preparing a compound of formula (I), characterized in that X, L, m and n are as defined in at least one of claims 1 to 8.

15. A compound represented by formula II-3 or II-4. (where R １ , R ２ , R ３ , R ４ , R ５ , R ６ , R ７ , R ８ , R ９ , X, L, R ｃ , m and n are as defined in any one of claims 1 to 8.

16. A compound represented by any one of the following formulas:

17. (1) A compound represented by formula (I) according to any one of claims 1 to 8, a tautomer thereof, a stereoisomer thereof, a pharmaceutically acceptable salt of any one of these, or a solvate of any one of these; and (2) a pharmaceutically acceptable carrier; A pharmaceutical composition comprising:

18. 10. Use of a pharmaceutical composition of a compound of formula (I) according to any one of claims 1 to 8, a tautomer thereof, a stereoisomer thereof, a pharmaceutically acceptable salt of any one of them, or a solvate of any one of them, in the manufacture of a medicament for treating and / or preventing a disease mediated by complement factor D, which is a blood disease, a kidney disease, a cardiovascular disease, an immune disease, a central nervous system disease, a respiratory system disease, a genitourinary system disease, or an eye disease.

19. The diseases mediated by complement factor D include cold agglutinin disease, catastrophic antiphospholipid syndrome, hemolytic anemia, antineutrophil cytoplasmic antibody-associated vasculitis, warm antibody autoimmune hemolytic anemia, paroxysmal nocturnal hemoglobinuria, IgA nephropathy, lupus nephritis, atypical hemolytic uremic syndrome, membranoproliferative glomerulonephritis, dense deposition disease, C3 glomerulonephritis, focal segmental glomerulosclerosis, diabetic nephropathy, systemic lupus erythematosus, rheumatoid arthritis, inflammatory bowel disease, psoriasis, multiple sclerosis, organ transplant rejection, myasthenia gravis, Alzheimer's disease, respiratory distress syndrome, asthma, and the like.

19. The use according to claim 18, characterized in that the condition is selected from the group consisting of glaucoma, chronic obstructive pulmonary disease, emphysema, coronavirus infection, macular degeneration, age-related macular degeneration, macular edema, diabetic macular edema, choroidal neovascularization, 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, Stevens-Johnson syndrome, Sjogren's syndrome, environmental dry eye disease, Fuchs endothelial corneal dystrophy, retinal vein occlusion, and postoperative inflammation.

20. Use of a pharmaceutical composition of a compound represented by formula (I) according to any one of claims 1 to 8, a tautomer thereof, a stereoisomer thereof, a pharmaceutically acceptable salt of any one of these, or a solvate of any one of these, in the manufacture of a complement factor D inhibitor medicament.

21. 18. Use of the pharmaceutical composition of claim 17 in the manufacture of a medicament for treating and / or preventing a disease mediated by complement factor D, which is a blood disease, a kidney disease, a cardiovascular disease, an immune disease, a central nervous system disease, a respiratory system disease, a genitourinary system disease or an eye disease.

22. The diseases mediated by complement factor D include cold agglutinin disease, catastrophic antiphospholipid syndrome, hemolytic anemia, antineutrophil cytoplasmic anti-associated vasculitis, warm antibody autoimmune hemolytic anemia, paroxysmal nocturnal hemoglobinuria, IgA nephropathy, lupus nephritis, atypical hemolytic uremic syndrome, membranoproliferative glomerulonephritis, dense deposition disease, C3 glomerulonephritis, focal segmental glomerulosclerosis, diabetic nephropathy, systemic lupus erythematosus, rheumatoid arthritis, inflammatory bowel disease, psoriasis, multiple sclerosis, organ transplant rejection, myasthenia gravis, Alzheimer's disease, respiratory distress syndrome, and asthma. , chronic obstructive pulmonary disease, emphysema, coronavirus infection, macular degeneration, age-related macular degeneration, macular edema, diabetic macular edema, choroidal neovascularization, 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, Stevens-Johnson syndrome, Sjogren's syndrome, environmental dry eye disease, Fuchs endothelial corneal dystrophy, retinal vein occlusion or postoperative inflammation.

23. 20. Use of the pharmaceutical composition of claim 17 in the manufacture of a complement factor D inhibitor medicament.

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