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

Abstract

The present invention discloses a compound as a complement factor D inhibitor, a pharmaceutical composition and application thereof, and specifically discloses a compound represented by formula (I), its tautomers, its stereoisomers, its prodrugs, or a pharmaceutically acceptable salt of any of the foregoing, or a solvate of any of the foregoing. The compound has good inhibitory activity against complement factor D and has excellent pharmacokinetic and pharmacodynamic activity.

Description

Technical Field

[0001] The present invention relates to the field of medicine, and in particular to a compound capable of inhibiting the activity of complement factor D, a pharmaceutical composition and application thereof. Background Art

[0002] Complement is a protein found widely in the serum, tissue fluid, and cell membranes of humans and vertebrates, mediating immune and inflammatory responses. Most of these proteins are glycoproteins and are produced by a variety of cells, including hepatocytes, macrophages, and intestinal epithelial cells. Complement is named complement because it is a necessary condition for antibodies to achieve their cytolytic effects, 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 (MBL) pathway, and the alternative (alternative) pathway. Complement factor D plays an early and central role in the activation of the alternative complement pathway. Activation of the alternative complement pathway is initiated by the spontaneous hydrolysis of the thioester bond within C3 to produce C3(H2O), which then associates with factor B to form the C3(H2O)B complex. Complement factor D cleaves factor B within the C3(H2O)B complex to form Ba and Bb. In addition to binding to C3b to form the C3 convertase, Bb also participates in the proliferation of preactivated B lymphocytes, while Ba inhibits their proliferation. Factor D is expressed at high levels in fat, which can stimulate glucose transport, promote the accumulation of triglycerides in fat cells, and inhibit fat decomposition.

[0003] Complement system dysregulation plays a crucial role in the pathogenesis of IgA nephropathy (IgAN), lupus nephritis (LN), and paroxysmal nocturnal hemoglobinuria (PNH). Deposition of complement components and immune complexes is often seen in renal pathology of IgAN and LN. Complement is the direct cause of hemolysis in PNH, while C5aR participates in amplifying complement system damage. CFB and CFD are key components of the alternative complement pathway, directly involved in regulating complement activation. Therefore, C5aR, CFB, and CFD are closely related to the pathogenesis of IgAN, LN, and PNH.

[0004] Paroxysmal nocturnal hemoglobinuria (PNH) is a rare, life-threatening blood disorder characterized by complement-driven hemolysis, thrombosis, and impaired bone marrow function, leading to anemia, fatigue, and other debilitating symptoms that can severely impact patients' quality of life. Currently marketed treatments for PNH primarily include the monoclonal antibody drugs Soliris and Ultomiris. Soliris was first approved for marketing in 2007 and is currently approved for a variety of ultra-rare diseases, including paroxysmal nocturnal hemoglobinuria (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. It was first approved for marketing in late 2018 for indications including PNH and aHUS. Despite treatment with current standard-of-care anti-C5 therapies, a significant proportion of PNH patients remain anemic and transfusion-dependent.

[0005] Currently, there are no drugs on the market for small molecule inhibitors of complement factor D. The target is the alternative complement pathway, which is a key driver of complement-driven renal disease (CDRD). Therefore, the development of small molecule inhibitors with good biological activity has positive significance for the treatment of the above diseases. Summary of the Invention

[0006] The present invention addresses the technical problem of the limited availability of small molecule inhibitors of complement factor D. To this end, the present invention provides a compound, pharmaceutical composition, and application thereof as a complement factor D inhibitor. The compound exhibits excellent inhibitory activity against complement factor D and possesses excellent pharmacokinetic and pharmacodynamic activity.

[0007] The present invention provides a compound represented by formula (I), a tautomer, a stereoisomer, a prodrug thereof, or a pharmaceutically acceptable salt of any of the foregoing (referring to the aforementioned compound represented by formula (I), its tautomer, its stereoisomer, or a prodrug thereof), or a solvate of any of the foregoing (referring to the aforementioned compound represented by formula (I), its tautomer, its stereoisomer, a prodrug thereof, or a pharmaceutically acceptable salt of any of the foregoing):

[0008]

[0009] in:

[0010] R 1 H, D, C 1-6 Alkyl or 1, 2 or 3 R 1-1 Substituted C 1-6 Alkyl; each R 1-1 are independently halogen, -CN, -OH, C 1-6Alkoxy or -NH2;

[0011] R 2 and R 3 are independently H, D, halogen, C 1-6 Alkyl or 1, 2 or 3 R 2-1 Substituted C 1-6 Alkyl; each R 2-1 are independently halogen, -CN, -OH, C 1-6 Alkoxy or -NH2;

[0012] R 4 is H or halogen; m is 0, 1, 2 or 3;

[0013] R 5 and R 7 are independently H, halogen, -CN, C 1-6 Alkyl or C 1-6 alkoxy;

[0014] R 6 C 7-12 Cycloalkyl, 1, 2 or 3 R 6-1 Substituted C 7-12 Cycloalkyl, "a 7-12 membered heterocycloalkyl group having 1, 2 or 3 heteroatoms selected from N, O and S" or "a 7-12 membered heterocycloalkyl group having 1, 2 or 3 heteroatoms ... selected from N, O and S" or "a 7-12 membered heterocycloalkyl group having 1, 2 or 3 heteroatoms" 6-2 Substituted "7-12 membered heterocycloalkyl group having 1, 2 or 3 heteroatoms selected from N, O and S";

[0015] R 6-1 and R 6-2 are independently hydroxy, oxo (=O), halogen, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkyl, C 1-6 Halogenated alkoxy, C 3-6 Cycloalkyl or -(CH2) p -C 3-6 Cycloalkyl; p is 1, 2, 3 or 4;

[0016] R 6 、R 6-1 and R 6-2 In the cycloalkyl group, the cycloalkyl group is independently a monocyclic ring, a bridged ring or a spirocyclic ring;

[0017] R 6 wherein the heterocycloalkyl group is a monocyclic ring, a bridged ring or a spirocyclic ring;

[0018] R 8 is H, halogen or C 1-6 alkyl;

[0019] R 9 H, halogen, C 1-6 Alkyl or 1, 2 or 3 R 9-1 Substituted C 1-6 alkyl;

[0020] Each R 9-1 are independently halogen, -CN, -OH or -NH2; n is 0, 1, 2, 3 or 4;

[0021] L is -(CR a R b ) q -; q is 0, 1, 2 or 3;

[0022] R a and R b are each independently H, D or halogen, or R a and R b Connect together to form C 3-6 Cycloalkylene, the cycloalkylene formed is a monocyclic, bridged or spirocyclic ring;

[0023] R 10 -COOH or -C(=O)OR c ;

[0024] R c C 1-6 Alkyl or 1, 2 or 3 R c-1 Substituted C 1-6 Alkyl; each R c-1 are independently halogen, -OH or -C(=O)OC(CH3)3;

[0025] X is CR d or N; R d is H, halogen or C 1-6 alkyl.

[0026] In one embodiment of the present invention, the compound represented by formula (I) has the structure represented by formula (I-1):

[0027]

[0028] Among them, 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 present invention.

[0029] In one embodiment of the present invention, the compound represented by formula (I) has the structure represented by formula (I-2):

[0030]

[0031] Among them, 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 any one of the present invention.

[0032] In one embodiment of the present invention, the compound represented by formula (I) has the structure represented by formula (I-3):

[0033]

[0034] Among them, 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 present invention.

[0035] In one embodiment of the present invention, the compound represented by formula (I) has a structure represented by formula (I-4):

[0036]

[0037] Among them, 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 defined as described in any one of the present invention; when the carbon atom marked with "*" is a chiral carbon atom, it represents R configuration, S configuration or a mixture thereof.

[0038] In certain preferred embodiments of the present invention, certain groups in the compound as represented by formula (I), its tautomers, its stereoisomers, its prodrugs, or any of the foregoing (referring to the aforementioned compound as represented by formula (I)), its tautomers, its stereoisomers or its prodrugs), or any of the foregoing (referring to the aforementioned compound as represented by formula (I)), its tautomers, its stereoisomers, its prodrugs or any of the foregoing pharmaceutically acceptable salts) are defined as follows. The groups not mentioned are the same as those described in any embodiment of the present invention (referred to as "in a certain embodiment of the present invention").

[0039] In one embodiment of the present invention, R 1 For H.

[0040] In one embodiment of the present invention, R 2 and R 3 Each independently is H, C 1-6 Alkyl or 1, 2 or 3 R 2-1 Substituted C 1-6 Alkyl; each R 2-1 are independently halogen or -OH, wherein the halogen is preferably F.

[0041] In one embodiment of the present invention, R 2 and R 3 Each independently is H, C 1-3 Alkyl or 1, 2 or 3 R 2-1 Substituted C 1-3 Alkyl; each R 2-1 are independently halogen or -OH, wherein the halogen is preferably F.

[0042] In one embodiment of the present invention, m is 0 or 1.

[0043] In one embodiment of the present invention, R 6 "8-11 membered heterocycloalkyl group having 1, 2 or 3 heteroatoms selected from N, O and S" or "8-11 membered heterocycloalkyl group having 1, 2 or 3 heteroatoms" 6-2The substituted "heteroatoms are selected from 1, 2 or 3 of N, O and S, and the number of heteroatoms is 1, 2 or 3 8-11 membered heterocycloalkyl", wherein the 8-11 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.

[0044] In one embodiment of the present invention, R 6 "8-11 membered heterocycloalkyl group having 1, 2 or 3 heteroatoms selected from N, O and S" or "8-11 membered heterocycloalkyl group having 1, 2 or 3 heteroatoms" 6-2 The substituted "heteroatoms are selected from 1, 2 or 3 of N, O and S, and the number of heteroatoms is 1, 2 or 3 8-11 membered heterocycloalkyl", wherein the 8-11 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 [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.

[0045] In one embodiment of the present invention, R 5 and R 7 are each independently H or halogen, preferably F.

[0046] In one embodiment of the present invention, each R 6-2are independently hydroxy or C 1-6 Alkyl, the C 1-6 The alkyl group is preferably a methyl group.

[0047] In one embodiment of the present invention, each R 6-2 are independently hydroxy or C 1-3 Alkyl, preferably, each R 6-2 is independently hydroxy, methyl, ethyl, n-propyl or isopropyl.

[0048] In one embodiment of the present invention, R 8 For H.

[0049] In one embodiment of the present invention, R 9 is H or halogen, and the halogen is preferably F.

[0050] In one embodiment of the present invention, n is 0 or 1.

[0051] In one embodiment of the present invention, q is 1.

[0052] In one embodiment of the present invention, R a and R b Each is independently H.

[0053] In one embodiment of the present invention, R 10 is -COOH.

[0054] In one embodiment of the present invention, R d For H.

[0055] In one embodiment of the present invention, R 6 "8-10 membered heterocycloalkyl group having 1, 2 or 3 heteroatoms selected from N, O and S" or 1, 2 or 3 R 6-2 The substituted "8-10 membered heterocycloalkyl group having 1, 2 or 3 heteroatoms selected from N, O and S", wherein the heterocycloalkyl group is a bridged ring or a spiro ring.

[0056] In one embodiment of the present invention, R 6 "8-11 membered heterocycloalkyl group having 1, 2 or 3 heteroatoms selected from N, O and S" or "8-11 membered heterocycloalkyl group having 1, 2 or 3 heteroatoms" 6-2 The substituted "8-11-membered heterocycloalkyl group having 1, 2 or 3 heteroatoms selected from the group consisting of N, O and S", wherein the heterocycloalkyl group is a bridged ring or a spiro ring.

[0057] In one embodiment of the present invention, R 1 is H;

[0058] R 2and R 3 Each independently is H, C 1-3 Alkyl or 1, 2 or 3 R 2-1 Substituted C 1-3 Alkyl; each R 2-1 are independently halogen or -OH;

[0059] R 4 is H or halogen; m is 0 or 1;

[0060] R 5 and R 7 are each independently H or halogen;

[0061] R 6 "8-11 membered heterocycloalkyl group having 1, 2 or 3 heteroatoms selected from N, O and S" or "8-11 membered heterocycloalkyl group having 1, 2 or 3 heteroatoms" 6-2 Substituted "8-11-membered heterocycloalkyl group having 1, 2 or 3 heteroatoms selected from N, O and S", wherein the heterocycloalkyl group is a bridged ring or a spiro ring;

[0062] Each R 6-2 are independently hydroxy or C 1-3 alkyl;

[0063] R 8 is H;

[0064] R 9 is H or halogen; n is 0 or 1;

[0065] L is -(CR a R b ) q -, q is 1; R a and R b Each independently is H;

[0066] R 10 is -COOH;

[0067] X is CR d or N; R d For H.

[0068] 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 dIn the above, each alkyl group is independently methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl or tert-butyl, preferably methyl or ethyl.

[0069] 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 of the alkoxy groups is independently methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy or tert-butoxy.

[0070] 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, preferably F.

[0071] In one embodiment of the present invention, R 6 In the above, each heterocycloalkyl group is independently "an 8-11-membered heterocycloalkyl group having 1, 2 or 3 heteroatoms selected from N, O and S, and having 1 or 2 heteroatoms", and the heterocycloalkyl group is a bridged ring or a spiro ring; preferably, the heterocycloalkyl group is connected to the parent group through an N atom; the heterocycloalkyl group is preferably

[0072]

[0073] In one embodiment of the present invention, R 6 for

[0074] In one embodiment of the present invention, R 2 H, R 3 is H, -CH3, -CH2OH, -CH2CH2OH, -CH2F or -CF2H.

[0075] In one embodiment of the present invention, R 1is H;

[0076] R 2 H, R 3 is H, -CH3 or -CH2F;

[0077] R 4 is H or halogen, m is 0 or 1;

[0078] R 5 and R 7 are each independently H or F;

[0079] R 6 "8-11 membered heterocycloalkyl group having 1, 2 or 3 heteroatoms selected from N, O and S" or "8-11 membered heterocycloalkyl group having 1, 2 or 3 heteroatoms" 6-2 Substituted "8-11-membered heterocycloalkyl group having 1, 2 or 3 heteroatoms selected from N, O and S";

[0080] Each R 6-2 are independently hydroxy or C 1-3 alkyl;

[0081] R 8 is H;

[0082] R 9 is H or F; n is 0 or 1;

[0083] L is -(CR a R b ) q -;q is 1;R a and R b Each independently is H;

[0084] R 10 is -COOH;

[0085] X is CR d or N; R d For H.

[0086] In one embodiment of the present invention, R 1 is H;

[0087] R 2 H, R 3 is H, -CH3 or -CH2F;

[0088] R 4 is H or halogen, m is 0 or 1;

[0089] R 5 and R 7 Each independently is H;

[0090] R6 "8-10 membered heterocycloalkyl group having 1, 2 or 3 heteroatoms selected from N, O and S" or 1, 2 or 3 R 6-2 Substituted "8-10 membered heterocycloalkyl group having 1, 2 or 3 heteroatoms selected from N, O and S";

[0091] R 6-2 is hydroxyl group;

[0092] R 8 is H;

[0093] R 9 is H or F; n is 0 or 1;

[0094] L is -(CR a R b ) q -;q is 1;R a and R b Each independently is H;

[0095] R 10 is -COOH;

[0096] X is CR d ; R d For H.

[0097] In one embodiment of the present invention, R 1 is H;

[0098] R 2 H, R 3 is H, -CH3 or -CH2F;

[0099] R 4 is H or halogen, m is 0 or 1;

[0100] R 5 and R 7 are each independently H or F;

[0101] R 6 "8-10 membered heterocycloalkyl group having 1, 2 or 3 heteroatoms selected from N, O and S" or 1, 2 or 3 R 6-2 Substituted "8-10 membered heterocycloalkyl group having 1, 2 or 3 heteroatoms selected from N, O and S";

[0102] Each R 6-2 Independently C 1-3 alkyl;

[0103] R 8 is H;

[0104] R 9 is H or F; n is 0 or 1;

[0105] L is -(CR a R b ) q -;q is 1;R a and R b Each independently is H;

[0106] R 10 is -COOH;

[0107] X is CR d or N; R d For H.

[0108] In one embodiment of the present invention, R 1 is H;

[0109] R 2 H, R 3 is H, -CH3 or -CH2F;

[0110] R 4 is H or halogen, m is 0 or 1;

[0111] R 5 and R 7 are each independently H or F;

[0112] R 6 "8-10 membered heterocycloalkyl group having 1, 2 or 3 heteroatoms selected from N, O and S" or 1, 2 or 3 R 6-2 Substituted "8-10 membered heterocycloalkyl group having 1, 2 or 3 heteroatoms selected from N, O and S";

[0113] Each R 6-2 are independently hydroxy or C 1-3 alkyl;

[0114] R 8 is H;

[0115] R 9 is H or F; n is 0 or 1;

[0116] L is -(CR a R b ) q -;q is 1;R a and R b Each independently is H;

[0117] R 10 is -COOH;

[0118] X is CR d or N; R d For H.

[0119] In one embodiment of the present invention, R 1 is H;

[0120] R 2 H, R 3 is H, -CH3 or -CH2F;

[0121] R 4 is H or halogen, m is 0 or 1;

[0122] R 5 and R 7 Each independently is H;

[0123] R 6 for Or by 1 R 6-2 Substituted groups:

[0124] R 6-2 is hydroxyl group;

[0125] R 8 is H;

[0126] R 9 is H or F; n is 0 or 1;

[0127] L is -(CR a R b ) q -;q is 1;R a and R b Each independently is H;

[0128] R 10 is -COOH;

[0129] X is CR d ; R d For H.

[0130] In one embodiment of the present invention, R 1 is H;

[0131] R 2 H, R 3 is H, -CH3 or -CH2F;

[0132] R 4 is H or halogen, m is 0 or 1;

[0133] R 5 and R 7 are each independently H or F;

[0134] R 6 for Or by 1 R 6-2 Substituted groups:

[0135] R 6-2 is methyl;

[0136] R 8 is H;

[0137] R 9 is H or F; n is 0 or 1;

[0138] L is -(CR a R b ) q -;q is 1;R a and R b Each independently is H;

[0139] R 10 is -COOH;

[0140] X is CR d or N; R d For H.

[0141] In one embodiment of the present invention, R 1 is H;

[0142] R 2 H, R 3 is H, -CH3 or -CH2F;

[0143] R 4 is H or halogen, m is 0 or 1;

[0144] R 5 and R 7 are each independently H or F;

[0145] R 6 for

[0146] Or by 1 R 6-2Substituted groups:

[0147] R 6-2 is hydroxyl or methyl;

[0148] R 8 is H;

[0149] R 9 is H or F; n is 0 or 1;

[0150] L is -(CR a R b ) q -;q is 1;R a and R b Each independently is H;

[0151] R 10 is -COOH;

[0152] X is CR d or N; R d For H.

[0153] In one embodiment of the present invention, R 1 is H;

[0154] R 2 H, R 3 is H, -CH3 or -CH2F;

[0155] R 4 is H or F, m is 0 or 1;

[0156] R 5 and R 7 are each independently H or F;

[0157] R 6 for

[0158]

[0159] R 8 is H;

[0160] R 9 is H or F; n is 0 or 1;

[0161] L is -(CR a R b ) q -;q is 1;R a and R b Each independently is H;

[0162] R 10 is -COOH;

[0163] X is CR d or N; R d For H.

[0164] In one embodiment of the present invention, the compound represented by formula (I) is selected from any one of the following compounds:

[0165]

[0166]

[0167]

[0168]

[0169] In one embodiment of the present invention, the compound represented by formula (I) is selected from any one of the following compounds:

[0170]

[0171]

[0172]

[0173]

[0174] The present invention also provides a method for preparing the compound represented by formula (I), which comprises the following steps:

[0175] (1) The compound represented by formula II-3 is subjected to a deprotection reaction to obtain the compound represented by formula II-4;

[0176]

[0177] (2) The compound represented by formula II-4 is subjected to hydrolysis reaction to obtain the compound represented by formula (I);

[0178]

[0179] Among them, R 10 is -COOH, R 1 、R 2 、R 3 、R 4 、R 5 、R 6 、R 7 、R 8 、R 9 、R cThe definitions of X, L, m and n are as described in any embodiment of the present invention. The conditions and operations of the above-mentioned deprotection reaction and hydrolysis reaction can be the common conditions and operations of such reactions in the art. Preferably, R 1 For H.

[0180] In one embodiment of the present invention, the preparation method of the compound represented by formula (I) comprises the following steps:

[0181]

[0182] Among them, R 10 is -COOH, 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 embodiment of the present invention, and the reaction conditions and operations can be the common conditions and operations for such reactions in the art; preferably, R 1 For H.

[0183] The present invention also provides a compound as shown in Formula II-3 or Formula II-4:

[0184]

[0185] Among them, 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 defined as described in any embodiment of the present invention.

[0186] In one embodiment of the present invention, in the compound shown in Formula II-3 or Formula II-4, R 1 For H.

[0187] The present invention also provides any of the following compounds:

[0188]

[0189]

[0190]

[0191]

[0192]

[0193]

[0194]

[0195] The present invention also provides a pharmaceutical composition, comprising:

[0196] (1) a compound represented by formula (I) as described in any of the preceding items, its tautomer, its stereoisomer, its prodrug, or a pharmaceutically acceptable salt of any of the foregoing (referring to the aforementioned compound represented by formula (I), its tautomer, its stereoisomer, or its prodrug), or a solvate of any of the foregoing (referring to the aforementioned compound represented by formula (I), its tautomer, its stereoisomer, its prodrug, or a pharmaceutically acceptable salt of any of the foregoing); and

[0197] (2) Pharmaceutically acceptable carrier.

[0198] The present invention also provides the use of a compound represented by formula (I) as described in any of the preceding items, its tautomers, its stereoisomers, its prodrugs, or a pharmaceutically acceptable salt of any of the foregoing (referring to the aforementioned compound represented by formula (I) as described in any of the preceding items, its tautomers, its stereoisomers, its prodrugs, or a pharmaceutically acceptable salt thereof), or a solvate of any of the foregoing (referring to the aforementioned compound represented by formula (I) as described in any of the preceding items, its tautomers, its stereoisomers, its prodrugs, or a pharmaceutically acceptable salt thereof), or a pharmaceutical composition as described in any of the preceding items in the preparation of a drug for treating and / or preventing diseases mediated by complement factor D.

[0199] The present invention also provides a method for treating and / or preventing a disease mediated by complement factor D, comprising administering a therapeutically effective amount of a substance X or the pharmaceutical composition described in any of the preceding items to an individual in need thereof, wherein the substance X is a compound represented by formula (I) as described in any of the preceding items, a tautomer, a stereoisomer, a prodrug thereof, or a pharmaceutically acceptable salt of any of the foregoing (referring to the aforementioned compound represented by formula (I), a tautomer, a stereoisomer, or a prodrug thereof), or a solvate of any of the foregoing (referring to the aforementioned compound represented by formula (I), a tautomer, a stereoisomer, a prodrug thereof, or a pharmaceutically acceptable salt of any of the foregoing). Preferably, the individual is a patient described in the present invention.

[0200] In one embodiment of the present invention, the diseases mediated by complement factor D include blood diseases, kidney diseases, cardiovascular diseases, immune disorders, central nervous system diseases, respiratory diseases, genitourinary system diseases, or eye diseases. Preferably, the diseases mediated by complement factor D are blood diseases, kidney diseases, cardiovascular diseases, immune disorders, central nervous system diseases, eye diseases, etc.

[0201] In a certain 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, membranous proliferative glomerulonephritis (MPGN), dense deposit disease, C3 glomerulonephritis, focal segmental glomerulosclerosis, diabetic nephropathy, systemic lupus or lupus erythematosus, rheumatoid arthritis, inflammatory bowel disease, psoriasis, multiple sclerosis, organ transplant rejection, myasthenia gravis, Alzheimer's disease, respiratory distress syndrome, asthma. , chronic obstructive pulmonary disease, emphysema, coronavirus infection (such as SARS-CoV, MERS-CoV, or SARS-CoV-2 infection), macular degeneration, age-related macular degeneration (AMD), macular edema, diabetic macular edema, choroidal neovascularization (CNV), uveitis, Behçet's uveitis, proliferative diabetic retinopathy, non-proliferative diabetic retinopathy, glaucoma, hypertensive retinopathy, corneal neovascularization, corneal transplant rejection, corneal dystrophies, autoimmune dry eye disease, Stevens-Johnson syndrome, Sjögren's syndrome, environmental dry eye, Fisher's endothelial corneal dystrophy, retinal vein occlusion, or postoperative inflammation.

[0202] In other embodiments of the present invention, the immune disorder is: lupus, allogeneic transplant rejection, autoimmune thyroid disease (such as Graves' disease and Hashimoto's thyroiditis), autoimmune uveoretinitis, giant cell arteritis, inflammatory bowel disease (including Crohn's disease, ulcerative colitis, Crohn's disease, granulomatous enterocolitis, terminal ileitis, Crohn's disease and terminal ileitis), diabetes, multiple sclerosis, pernicious anemia, psoriasis, rheumatoid arthritis, sarcoidosis and scleroderma, etc.

[0203] Furthermore, the complement factor D-mediated diseases include but are not limited to paroxysmal nocturnal hemoglobinuria, IgA nephropathy, lupus nephritis, atypical hemolytic uremic syndrome, organ transplant rejection, myasthenia gravis, neuromyelitis optica, membranous proliferative glomerulonephritis, dense deposit disease, cold agglutinin disease and catastrophic antiphospholipid syndrome, C3 glomerulonephritis and focal segmental glomerulosclerosis, macular degeneration, age-related macular degeneration (AMD), macular edema, diabetic macular edema, etc.

[0204] The present invention also provides the use of a compound represented by formula (I) as described in any of the preceding items, its tautomers, its stereoisomers, its prodrugs, or a pharmaceutically acceptable salt of any of the foregoing (referring to the aforementioned compound represented by formula (I) as described in any of the preceding items, its tautomers, its stereoisomers, its prodrugs or its prodrugs), or a solvate of any of the foregoing (referring to the aforementioned compound represented by formula (I) as described in any of the preceding items, its tautomers, its stereoisomers, its prodrugs or its pharmaceutically acceptable salts), or a pharmaceutical composition as described in any of the preceding items in the preparation of complement factor D inhibitor drugs.

[0205] In the application, the complement factor D inhibitor drug can be used in mammalian organisms; it can also be used in vitro, mainly for experimental purposes, for example: as a standard sample or control sample for comparison, or prepared into a kit according to conventional methods in the art to provide rapid detection of complement factor D inhibitory effects.

[0206] Unless otherwise specified, the terms used in this invention have the following meanings:

[0207] It will be understood by those skilled in the art that the structural formulas used in the present invention to describe groups are based on the conventions used in the art. It means that the corresponding group is connected to other fragments and groups in the compound through this site.

[0208] As used herein, a substituent may be preceded by a single dash "-" to indicate that the named substituent is attached to the parent moiety by a single bond. When a linking group is listed herein without specifying the direction of attachment, the direction of attachment is assumed to be the same as when reading from left to right.

[0209] The term "pharmaceutically acceptable" means that salts, solvents, excipients, etc. are generally non-toxic, safe, and suitable for use with 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, cattle, horses, sheep, pigs, cats, dogs, mice, rats, rabbits, guinea pigs, monkeys, and humans.

[0210] The term "pharmaceutically acceptable salt" refers to a salt prepared from a compound of the present invention with a relatively nontoxic, pharmaceutically acceptable acid or base. When the compound of the present invention contains a relatively acidic functional group, a base addition salt can be obtained by contacting the neutral form of such compound with a sufficient amount of a pharmaceutically acceptable base in a pure solution or a suitable inert solvent. Pharmaceutically acceptable base addition salts include, but are not limited to, lithium salts, sodium salts, potassium salts, calcium salts, aluminum salts, magnesium salts, zinc salts, bismuth salts, ammonium salts, and diethanolamine salts. When the compound of the present invention contains a relatively basic functional group, an acid addition salt can be obtained by contacting the neutral form of such compound with a sufficient amount of a pharmaceutically acceptable acid in a pure solution or 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, acid citric acid, oleic acid, tannic acid, pantothenic acid, bitartrate, ascorbic acid, gentisic acid, fumaric acid, gluconic acid, sugar acid, formic acid, ethanesulfonic acid, pamoic acid (i.e., 4,4'-methylene-bis(3-hydroxy-2-naphthoic acid)), amino acids (e.g., glutamic acid, arginine), etc. When the compounds of the present invention contain relatively acidic and relatively basic functional groups, they can be converted into base addition salts or acid addition salts. For details, see Berge et al., "Pharmaceutical Salts", Journal of Pharmaceutical Science 66: 1-19 (1977), or Handbook of Pharmaceutical Salts: Properties, Selection, and Use (P. Heinrich Stahl and Camille G. Wermuth, ed., Wiley-VCH, 2002).

[0211] The term "solvate" refers to a compound of the present invention combined with a stoichiometric or non-stoichiometric amount of a solvent. The solvent molecules in the solvate may be present in an ordered or non-ordered arrangement. Such solvents include, but are not limited to, water, methanol, and ethanol.

[0212] As described above, the terms "pharmaceutically acceptable salt" and "solvate" in the "pharmaceutically acceptable salt solvate" refer to compounds of the present invention formed by combining 1) with a relatively nontoxic, pharmaceutically acceptable acid or base, and 2) with a stoichiometric or non-stoichiometric amount of a solvent. Such "pharmaceutically acceptable salt solvate" includes, but is not limited to, the hydrochloride monohydrate of the compound of the present invention.

[0213] When any variable (such as R 1-1 ) appears multiple times in the definition of a compound, the definition of each position of the variable is independent of the definition of the other positions, and their meanings are independent of each other and do not affect each other. Therefore, if a group is replaced by 1, 2 or 3 R 1-1 group substituted, that is, the group may be replaced by up to 3 R 1-1 Replace, the position R 1-1 Definition and other positions R 1-1 In addition, combinations of substituents and / or variables are permissible only if such combinations result in stable compounds.

[0214] The term "A-membered," where A is an integer, generally describes a group in which the number of ring atoms is A. 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, and the like.

[0215] The term "AB member," where A and B are integers, describes a range where the number of ring-forming atoms is from A to B.

[0216] The term "halogen" refers to fluorine, chlorine, bromine or iodine.

[0217] The term "alkyl" refers to a straight or branched chain saturated hydrocarbon group having a specified number of carbon atoms. 1-6 Alkyl groups, such as C 1-5 Alkyl, C 1-4 Alkyl, C 1-3 Alkyl, C 1-2 In other embodiments, the alkyl group is C 1-3 Alkyl. Examples of alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, isobutyl, sec-butyl, n-pentyl, n-hexyl, and the like.

[0218] The term "alkoxy" refers to the group -OR X , where R X is an alkyl group as defined above.

[0219] The term "cycloalkyl" refers to a group having the specified number of ring carbon atoms (e.g., C 3-6 、C 7-12), saturated, monocyclic, bridged, or spirocyclic groups whose ring atoms consist only of carbon atoms. Monocyclic alkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and the like.

[0220] The term "cycloalkylene" refers to a group having a specified number of ring carbon atoms (e.g., C 3-6 、C 7-12 ), a saturated, monocyclic, bridged, or spirocyclic alkane whose ring atoms consist only of carbon atoms, and whose two hydrogen atoms are eliminated, and the two hydrogen atoms eliminated may be on the same atom or on different atoms. Monocycloalkylene includes, but is not limited to, cyclopropylene (e.g. ), cyclobutylene (e.g. ), cyclopentylene (e.g. ), cyclohexylene (e.g. )wait.

[0221] The term "heterocycloalkyl" refers to a saturated cyclic group having a specified number of ring atoms (e.g., 7-12 ring atoms) and containing at least one heteroatom independently selected from nitrogen, oxygen, and sulfur, and is a monocyclic, bridged, or spirocyclic ring system. Preferably, the number of heteroatoms in the heterocycloalkyl is 1, 2, or 3. The carbon atoms and heteroatoms of the heterocycloalkyl may be optionally oxidized to form an oxo group or a sulfide group or other oxidized bond (e.g., C(=O), S(=O), S(=O)2, or N-oxide, etc.), or the nitrogen atom may be quaternized. The heterocycloalkyl group may be connected to other fragments or groups in the compound through ring-forming carbon atoms or ring-forming heteroatoms. In some embodiments, the heterocycloalkyl group is an 8-11 membered heterocycloalkyl group having 1, 2 or 3 heteroatoms selected from N, O and S, and having 1 or 2 heteroatoms; in other embodiments, the heterocycloalkyl group is an 8-10 membered heterocycloalkyl group having 1, 2 or 3 heteroatoms selected from N, O and S, and having 1 or 2 heteroatoms. Heterocycloalkyl includes, but is not limited to, 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 , 1-oxa-7-azaspiro[3.5]nonyl, 7-azaspiro[3.5]nonyl, 2,7-diazaspiro[3.5]nonyl, 2-oxa-8-azaspiro[4.5]decyl, 3-oxa-9-azaspiro[5.5]undecyl, 2-oxa-9-azaspiro[5.5]undecyl, 3,9-diazaspiro[5.5]undecyl, 3-azabicyclo[3.2.1]octyl, 3-azaspiro[5,5]undecyl, 8-azaspiro[4.5]decyl, 1-oxa-6-azaspiro[3,4]octyl, etc.

[0222] The term "pharmaceutically acceptable carrier" refers to excipients and additives used in the production of pharmaceuticals and the preparation of prescriptions. These are all substances contained in pharmaceutical preparations, in addition to the active ingredient. For more information, see the Pharmacopoeia of the People's Republic of China (2015 Edition), Part IV, or the Handbook of Pharmaceutical Excipients (Raymond C. Rowe, 2009, Sixth Edition).

[0223] The term "treat" refers to therapeutic treatment. When referring to a specific condition, treatment means: (1) alleviating the disease or one or more biological manifestations of the condition, (2) interfering with (a) one or more points in the biological cascade that leads to or causes the condition or (b) one or more biological manifestations of the condition, (3) ameliorating one or more symptoms, effects, or side effects associated with the condition or one or more symptoms, effects, or side effects associated with the condition or its treatment, or (4) slowing the progression of the condition or one or more biological manifestations of the condition.

[0224] The term "prevent" refers to the reduction of the risk of acquiring or developing a disease or disorder.

[0225] The term "therapeutically effective amount" refers to an amount of a compound that, when administered to a patient, is sufficient to effectively treat a disease or condition described herein. The "therapeutically effective amount" will vary depending on the compound, the condition and its severity, and the age of the patient to be treated, but can be adjusted as needed by those skilled in the art.

[0226] Without violating the common sense in the art, the above-mentioned preferred conditions can be arbitrarily combined to obtain preferred embodiments of the present invention.

[0227] The reagents and raw materials used in the present invention are commercially available.

[0228] The positive effect of the present invention is that the compounds of the present invention have good inhibitory activity against complement factor D (IC of the example compounds against C3b 50 value is 0.01-100nM), and has a good inhibitory effect on rabbit erythrocyte hemolysis (rabbit erythrocyte hemolysis IC 50 value is 0.1-500nM), and has excellent pharmacokinetic and pharmacodynamic activity. DETAILED DESCRIPTION

[0229] The present invention is further illustrated by way of examples below, but the present invention is not limited to the scope of the examples. Experimental methods in the following examples where specific conditions are not specified were performed according to conventional methods and conditions, or selected according to the product specifications.

[0230] The nouns used in the following experimental descriptions represent (unless otherwise specified) the following reagents or operations:

[0231] (Boc)2O: di-tert-butyl dicarbonate; B2Pin2: diboronic acid pinacol ester; DIAD: diisopropyl azodicarboxylate; DMF: N,N-dimethylformamide; DCM: dichloromethane; DIEA: N,N-diisopropylethylamine; Et3N: triethylamine; EA: ethyl acetate; IV: intravenous; KOAc: potassium acetate; MeOH: methanol; MeCN: acetonitrile; PPh3: triphenylphosphine; Pd2(dba)3: tris(dibenzylideneacetone)dipalladium; Pd(dppf)Cl2: [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium; Pd(PPh3)4: tetrakis(triphenylphosphine)palladium; PO: oral administration; TEA: triethylamine; TFA: trifluoroacetic acid; THF: tetrahydrofuran; X-Phos: 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl;

[0232] <Preparation Example>

[0233] Example 1. Synthesis of 2-(2-((3'-(aminomethyl)-5-(6-azaspiro[2.5]octane-6-yl)-[1,1'-biphenyl]-3-yl)methoxy)phenyl)acetic acid (Compound 001)

[0234]

[0235] 1.1 Synthesis of Compound 001-1

[0236] Compound 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-cooling. The reaction mixture was reacted at 0°C for 1 h, 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, and the organic phase was separated. The aqueous phase was further extracted with ethyl acetate (50 mL × 2). The combined organic phases were washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 10 / 1 (v / v)) to obtain compound 001-1, which was used directly in the next step.

[0237] 1.2 Synthesis of Compound 001-2

[0238] Compound 001-1 (18.02 g, 60 mmol) obtained in step 1.1, pinacol diboron (18.28 g, 72 mmol), potassium acetate (11.78 g, 120 mmol), [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (4.40 g, 6 mmol), and 1,4-dioxane (120 mL) were added sequentially to a 500 mL reaction flask. After nitrogen substitution three times, the resulting reaction solution was heated in an 80°C oil bath for 4 h. The reaction solution was cooled to room temperature and filtered. The filtrate was concentrated under reduced pressure, and 150 mL of ethyl acetate and 200 mL of water were added for extraction and separation. The organic phase was separated. The aqueous phase was extracted with ethyl acetate (50 mL x 2). The combined organic phases were washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 8 / 1 (v / v)) to obtain compound 001-2, which was used directly in the next step. LC / MS (ESI+) m / z: [M+Ht-Bu] + =278.15.

[0239] 1.3 Synthesis of Compound 001-3

[0240] 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 sequence. A solution of bis(4-chlorobenzyl)azodicarboxylate (13.7 g, 37.6 mmol) in dichloromethane (70 mL) was added dropwise to the above system under an ice bath. After the addition was complete, the reaction was continued at 0°C for 2 h. 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.

[0241] 1.4 Synthesis of Compound 001-4

[0242] 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]palladium dichloride (0.35 g, 0.48 mmol) were added sequentially to 1,4-dioxane / water (30 mL / 3 mL). After nitrogen substitution three times, the reaction solution was reacted at 80°C for 2 h and then filtered. The filtrate was diluted with water (30 mL) and extracted with ethyl acetate (30 mL x 2). The combined organic phases were washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 10 / 1 to 5 / 1 (v / v)) to obtain compound 001-4. LC / MS (ESI+) m / z: [M+H-Boc] + =439.95.

[0243] 1.5 Synthesis of Compound 001-5

[0244] 001-4 (4.3 g, 7.96 mmol), 6-aza-spiro[2.5]octane hydrochloride (compound 001-d, 1.4 g, 9.55 mmol), potassium carbonate (3.3 g, 23.87 mmol), tris(dibenzylideneacetone)dipalladium (400 mg, 10 wt%), and 2-dicyclohexylphosphine-2',4',6'-triisopropylbiphenyl (400 mg, 10 wt%) were added to 1,4-dioxane (50 mL) in sequence. The atmosphere was purged with nitrogen three times, and the reaction mixture was reacted at 90°C for 4 h. The reaction mixture was filtered, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography to obtain compound 001-5. LC / MS (ESI+) m / z: [M+H] + =571.15.

[0245] 1.6 Synthesis of Compound 001-6

[0246] 001-5 (3.5 g, 6.1 mmol) was dissolved in dichloromethane (27 mL), and trifluoroacetic acid (9 mL) was added. The reaction mixture was allowed to react at room temperature for 1 hour. Saturated aqueous sodium bicarbonate was added to the reaction solution to adjust the pH to 8, and then extracted with ethyl acetate (30 mL x 3). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain compound 001-6 (3.2 g, crude product), which was used directly in the next step. LC / MS (ESI+) m / z: [M+H] + =471.10.

[0247] 1.7 Synthesis of Compound 001

[0248] 001-6 (3.1 g, 6.5 mmol) and sodium hydroxide (1.05 g, 26.3 mmol) were added to tetrahydrofuran (10 mL), methanol (5 mL), and water (5 mL). The reaction mixture was reacted at 60°C for 4 h. The reaction mixture was purified by preparative HPLC and lyophilized to obtain the target compound 001.

[0249] 1 H 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=7.6Hz,1H),5.13(s,2H),3.97(s,2H),3.43(s,2H),3. 30(t,J=5.2Hz,4H),1.48(t,J=5.2Hz,4H),0.35(s,4H); LC / MS(ESI+)m / z: [M+H] + =457.10.

[0250] 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)

[0251]

[0252] The synthesis of compound 002 was based on the synthesis method of compound 001, except that the raw material 001-d was replaced with the hydrochloride salt of 7-azaspiro[3.5]nonane (002-a).

[0253] 1H 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.

[0254] Example 3. Synthesis of 2-(2-((3'-(aminomethyl)-5-(6-azaspiro[3.4]octane-6-yl)-[1,1'-biphenyl]-3-yl)methoxy)phenyl)acetic acid (Compound 003)

[0255]

[0256] The synthesis of compound 003 was carried out by referring to the synthesis method of compound 001, except that the raw material 001-d was replaced with the hydrochloride salt of 6-azaspiro[3.4]octane (003-a).

[0257] 1 H NMR (400MHz, DMSO-d6): δ9.51(s,1H),7.98(d,J=114.8Hz,1H),7.59(dd,J=48.4,7.6 Hz,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.

[0258] Example 4. Synthesis of 2-(2-((3'-(aminomethyl)-5-(5-azaspiro[2.5]octane-5-yl)-[1,1'-biphenyl]-3-yl)methoxy)phenyl)acetic acid (Compound 004)

[0259]

[0260] The synthesis of compound 004 was carried out by referring to the synthesis method of compound 001, except that the raw material 001-d was replaced with the hydrochloride salt of 5-azaspiro[2.5]octane (004-a).

[0261] 1 H 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,1 H),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=7.6H z,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.

[0262] 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)

[0263]

[0264] The synthesis of compound 005 was based on the synthesis method of compound 001, except that the raw material 001-d was replaced with the hydrochloride salt of 2-azaspiro[3.5]nonane (005-a).

[0265] 1H 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.

[0266] 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)

[0267]

[0268] The synthesis of compound 006 was carried out by referring to the synthesis method of compound 001, except that the raw material 001-d was replaced with the hydrochloride salt of 3-azabicyclo[3.2.1]octane (006-a).

[0269] 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,2 H),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.

[0270] Example 7. Synthesis of 2-(2-((3'-(aminomethyl)-2'-fluoro-5-(6-azaspiro[2.5]octane-6-yl)-[1,1'-biphenyl]-3-yl)methoxy)phenyl)acetic acid (Compound 007)

[0271]

[0272] 7.1 Synthesis of Compound 007-1

[0273] 007-a (1.0 g, 5 mmol) was dissolved in tetrahydrofuran (5 mL). A 1 M borane solution in tetrahydrofuran (20 mL, 20 mmol) was slowly added dropwise under nitrogen. After the addition, the reaction mixture was heated to 60°C and reacted for 5 h. After cooling to room temperature, the reaction mixture was slowly quenched by the addition of methanol (20 mL). 1 M dilute hydrochloric acid (10 mL) was then added and the mixture was extracted with ethyl acetate (20 mL × 3). The aqueous phase was adjusted to pH 8-10 with saturated sodium bicarbonate aqueous solution and extracted with ethyl acetate (20 mL × 3). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain compound 007-1 (crude product). LC / MS (ESI+) m / z: [M+H] + =204.00.

[0274] 7.2 Synthesis of Compound 007-2

[0275] Compound 007-1 (600 mg, crude), di-tert-butyl dicarbonate (704 mg, 3.23 mmol), and triethylamine (594 mg, 5.88 mmol) were dissolved in dichloromethane (5 mL) in that order. 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.

[0276] 7.3 Synthesis of Compound 007-3

[0277] 007-2 (600 mg, 1.97 mmol), pinacol diboronate (601 mg, 2.37 mmol), potassium acetate (387 mg, 3.95 mmol), and [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (144 mg, 0.2 mmol) were added sequentially to 1,4-dioxane (5 mL). The atmosphere was purged with nitrogen three times, and the reaction mixture was reacted at 100°C for 2 h. After cooling to room temperature, the reaction mixture 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.

[0278] 7.4 Synthesis of Compound 007-4

[0279] 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]palladium dichloride (106 mg, 0.145 mmol) were added to 1,4-dioxane (5 mL) and water (1 mL) in sequence, and the reaction solution was reacted at 100°C for 2 h. The reaction solution was cooled to room temperature, water (10 mL) was added, and the mixture was extracted with ethyl acetate (15 mL x 3). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 10 / 1) to obtain compound 007-4.

[0280] 7.5 Synthesis of Compound 007

[0281] The synthesis of compound 007 was based on the synthesis of compound 001, except that the intermediate 001-4 was replaced by 007-4.

[0282] 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.

[0283] Example 8. Synthesis of 2-(2-((3'-(aminomethyl)-5'-fluoro-5-(6-azaspiro[2.5]octane-6-yl)-[1,1'-biphenyl]-3-yl)methoxy)phenyl)acetic acid (Compound 008)

[0284]

[0285] The synthesis of compound 008 was based on the synthesis of compound 007, except that the intermediate 007-1 was replaced with 3-fluoro-5-bromobenzylamine (008-a).

[0286] 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=3 6.8Hz,2H),4.24(s,1H),3.86(s,1H),3.40(s,1H),3.35(s,1H),3.31(d,J=4.8Hz,4H),1.48(s,4H),0.34(s,4H); LC / MS(ESI+)m / z: [M+H] + =475.10.

[0287] Example 9. Synthesis of 2-(2-((3'-(aminomethyl)-5-(6-azaspiro[2.5]octane-6-yl)-[1,1'-biphenyl]-3-yl)methoxy)-4-fluorophenyl)acetic acid (Compound 009)

[0288]

[0289] 9.1 Synthesis of Compound 009-1

[0290] 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 iodomethane (1.16 g, 8.1 mmol) were added. The reaction mixture was allowed to react at 25°C for 1 h. Water (10 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (10 mL x 3). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 3 / 1 to 1 / 1) to obtain compound 009-1. LC / MS (ESI+) m / z: [M+H] + =199.10.

[0291] 9.2 Synthesis of Compound 009-2

[0292] Under nitrogen, 009-1 (1.0 g, 5.04 mmol) was dissolved in dichloromethane (20 mL). The reaction system was cooled to -20°C and boron tribromide (20 mmol, 15.12 mmol) was slowly added dropwise. The reaction temperature was maintained for 2 h. Methanol (6 mL) was added dropwise at -20°C to quench the reaction. Water was added and the mixture was extracted with dichloromethane (10 mL x 3). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 3 / 1 to 1 / 1) to obtain compound 009-2.

[0293] 9.3 Synthesis of Compound 009-3

[0294] Compound 009-b (1.45 g, 4.42 mmol) and compound 009-2 (740 mg, 4.02 mmol) were dissolved in N,N-dimethylformamide (20 mL), and potassium carbonate (1.12 g, 8.04 mmol) was added. The mixture was allowed to react at room temperature for 2 h. Water was added, and the mixture was extracted with ethyl acetate (10 mL x 3). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 3 / 1 to 1 / 1) to obtain compound 009-3.

[0295] 9.4 Synthesis of Compound 009-4

[0296] 009-3 (750 mg, 1.74 mmol), 001-2 (578 mg, 1.74 mmol), potassium carbonate (480 mg, 3.48 mmol), and [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (127 mg, 0.174 mmol) were added to 1,4-dioxane (20 mL) and water (2 mL) in that order. The reaction mixture was reacted at 100°C for 2 h. The reaction mixture was cooled to room temperature, water was added, and extraction was performed with ethyl acetate (10 mL x 3). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 3 / 1 to 1 / 1) to obtain compound 009-4.

[0297] 9.5 Synthesis of Compound 009

[0298] The synthesis of compound 009 was based on the synthesis method of compound 001, except that the raw material 001-4 was replaced by 009-4.

[0299] 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),6.6 8–6.56(m,1H),5.17(d,J=44.0Hz,2H),4.24(s,1H),3.85(s,1H),3.36(s,1H),3.3 1(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.

[0300] Example 10. Synthesis of 2-(2-((3'-(aminomethyl)-5-(6-azaspiro[2.5]octane-6-yl)-[1,1'-biphenyl]-3-yl)methoxy)-5-fluorophenyl)acetic acid (Compound 010)

[0301]

[0302] The synthesis of compound 010 was based on the synthesis method of compound 009, except that the raw material was replaced by 5-fluoro-2-methoxyphenylacetic acid (010-a) instead of 2-methoxy-4-fluorophenylacetic acid (009-a).

[0303] 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,2 H),6.89–6.72(m,2H),5.15(d,J=20.0Hz,2H),4.24(s,1H),3.95(s,1H),3.38(s,2 H),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.

[0304] 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)

[0305]

[0306] The synthesis of compound 011 was based on the synthesis method of compound 001, except that the raw material 001-d was replaced with the hydrochloride salt of 2-oxa-7-azaspiro[3.5]nonane (011-a).

[0307] 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.

[0308] 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)

[0309]

[0310] The synthesis of compound 012 was based on the synthesis method of compound 001, except that the raw material 001-d was replaced with the hydrochloride salt of 1-oxa-7-azaspiro[3.5]nonane (012-a).

[0311] 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.

[0312] 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)

[0313]

[0314] 13.1 Synthesis of Compound 013-1

[0315] Compound 001-4 (400 mg, 0.881 mmol) was weighed into a reaction flask, followed by the addition of compound 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). The atmosphere was purged with nitrogen three times, and the reaction mixture was stirred at 100°C for 4 h. The reaction mixture 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.

[0316] 13.2 Synthesis of Compound 013-2

[0317] 013-1 (200 mg, 340 μmol) was dissolved in methanol (3 mL) and tetrahydrofuran (3 mL). Sodium borohydride (68 mg, 680 μmol) was added portionwise at 0°C. The reaction mixture was allowed to react for 0.5 h at 0°C. The reaction mixture was quenched by the addition of aqueous ammonium chloride (5 mL) and extracted with ethyl acetate (10 mL x 2). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to afford 013-2 (crude product), which was used directly in the next step. LC / MS (ESI+) m / z: [M+H] + =601.10.

[0318] 13.3 Synthesis of Compound 013

[0319] The synthesis of compound 013 was based on the synthesis method of compound 001, except that the intermediate 001-5 was replaced by 013-2.

[0320] 1H 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.

[0321] Example 14. Synthesis of 2-(2-((3'-(aminomethyl)-5-(2-oxa-8-azaspiro[4.5]decane-8-yl)-[1,1'-biphenyl]-3-yl)methoxy)phenyl)acetic acid (Compound 014)

[0322]

[0323] The synthesis of compound 014 was based on the synthesis method of compound 001, except that the intermediate 001-d was replaced by the hydrochloride salt of 2-oxa-8-azaspiro[4.5]decane (014-a).

[0324] 1 H 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.

[0325] Example 15. Synthesis 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) trifluoroacetate

[0326]

[0327] 15.1 Synthesis of Compound 015-1

[0328] Dissolve 015-a (86 mg, 0.4 mmol) in dichloromethane (1 mL), add trifluoroacetic acid (2 mL) at room temperature, and heat the reaction mixture at 60°C for 2 h. Cool the reaction mixture to room temperature and concentrate under reduced pressure to obtain compound 015-1 (crude product), which can be used directly in the next step.

[0329] 15.2 Synthesis of Compound 015 Trifluoroacetate

[0330] Referring to the synthesis method of compound 001, it is only necessary to replace the intermediate 001-d with 015-1. The preparation method is trifluoroacetic acid conditions, and lyophilization is used to obtain the trifluoroacetate salt of compound 015.

[0331] 1 H 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.

[0332] Example 16. Synthesis 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) trifluoroacetate

[0333]

[0334] The synthesis of compound 016 was based on the synthesis method of compound 001, except that the intermediate 001-d was replaced with the hydrochloride salt of 4-oxa-7-azaspiro[2.5]octane (016-a).

[0335] 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.

[0336] 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)

[0337]

[0338] The synthesis of compound 017 was based on the synthesis method of compound 001, except that the intermediate 001-d was replaced by the hydrochloride salt of 2-azaspiro[3.4]octane (017-a).

[0339] 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.

[0340] Example 18. Synthesis of (S)-2-(2-((3'-(1-amino-2-hydroxyethyl)-5-(6-azaspiro[2.5]octane-6-yl)-[1,1'-biphenyl]-3-yl)methoxy)phenyl)acetic acid (Compound 018)

[0341]

[0342] 18.1 Synthesis of Compound 018-1

[0343] 018-a (3.5 g, 10.6 mmol) was dissolved in tetrahydrofuran (35 mL), and a 1M borane solution in tetrahydrofuran (52.5 mL, 53.1 mmol) was added dropwise at room temperature. After the addition, the reaction mixture was reacted at 80°C for 1 h. The reaction mixture was cooled to room temperature, quenched with methanol, and concentrated under reduced pressure. 1N dilute hydrochloric acid (10 mL) was added to the residue, stirred at room temperature for 10 min, and then extracted with ethyl acetate (20 mL × 2). The aqueous layer was adjusted to alkaline pH with saturated sodium bicarbonate aqueous solution, and then extracted with ethyl acetate (20 mL × 2). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain compound 018-1 (crude product), which was used directly in the next step.

[0344] 18.2 Synthesis of Compound 018-2

[0345] 018-1 (1.7 g, 5.4 mmol), diboronic acid pinacol ester (2.0 g, 6.5 mmol), potassium acetate (1.5 g, 9.2 mmol), and 1,1-bis(diphenylphosphino)ferrocenepalladium dichloride (500 mg, 460 μmol) were added to 1,4-dioxane (10 mL) in sequence. After nitrogen substitution three times, the reaction solution was reacted at 80°C for 3 h. The reaction solution was diluted with water (30 mL) and extracted with ethyl acetate (20 mL x 3). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 10 / 1) to obtain compound 018-2.

[0346] 18.3 Synthesis of Compound 018

[0347] The synthesis of compound 018 refers to the synthesis method of compound 001, except that the intermediate 001-2 is replaced by 018-2.

[0348] 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.

[0349] Example 19. Synthesis of (S)-2-(2-((3'-(1-amino-2-hydroxyethyl)-5'-fluoro-5-(6-azaspiro[2.5]octane-6-yl)-[1,1'-biphenyl]-3-yl)methoxy)phenyl)acetic acid (Compound 019)

[0350]

[0351] 19.1 Synthesis of Compound 019-1

[0352] 019-a (3.0 g, 14.8 mmol) was dissolved in dichloromethane (25 mL), and 019-b (1.8 g, 14.8 mmol) and cesium carbonate (4.8 g, 14.8 mmol) were added. The reaction mixture was reacted at 25°C for 12 h. Water (30 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (15 mL × 3). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 3 / 1 to 1 / 1) to obtain compound 019-1. LC / MS (ESI+) m / z: [M+H] + =305.90.

[0353] 19.2 Synthesis of Compound 019-2

[0354] Under nitrogen, vinylmagnesium bromide (16.7 mL, 16.7 mmol) and dimethylzinc reagent (16.7 mL, 16.7 mmol) were mixed and reacted at room temperature for 0.5 h. The system was cooled to -78°C and 019-1 (3.0 g, 9.81 mmol) was slowly added dropwise. After the addition was complete, the temperature was maintained for 2 h. The reaction was quenched by the addition of saturated aqueous ammonium chloride (26 mL) at -78°C and extracted with ethyl acetate (30 mL x 3). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 3 / 1 to 1 / 1) to obtain compound 019-2. LC / MS (ESI+) m / z: [M+H] + =333.90.

[0355] 19.3 Synthesis of Compound 019-3

[0356] 019-2 (2.5 g, 7.5 mmol) was dissolved in methanol (20 mL), and 4N hydrochloric acid (5 mL, 7.5 mmol) was added. The mixture was allowed to react at room temperature for 1 h. The reaction solution was concentrated under reduced pressure, and dichloromethane (20 mL) was added, followed by di-tert-butyl dicarbonate (3.07 g, 14.08 mmol). The mixture was allowed to react at room temperature for 2 h. 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.

[0357] 19.4 Synthesis of Compound 019-4

[0358] Under nitrogen, 019-3 (2.5 g, 7.58 mmol) was dissolved in a mixture of carbon tetrachloride (20 mL), acetonitrile (20 mL), and water (30 mL). Sodium periodate (3.4 g, 15.9 mmol) and ruthenium trichloride (158 mg, 0.758 mmol) were then added. The reaction mixture was allowed to react at room temperature for 2 h. The reaction mixture was extracted with ethyl acetate (30 mL × 3). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 10 / 1 to 2 / 1) to obtain compound 019-4.

[0359] 19.5 Synthesis of Compound 019-5

[0360] 019-4 (130 mg, 0.432 mmol) was weighed into a reaction flask and a 1 M borane solution in tetrahydrofuran (1.5 mL, 0.864 mmol) was added under nitrogen. The reaction mixture was allowed to react at 25°C for 12 h. Methanol (5 mL) was added to quench the reaction, and the insoluble material was removed by filtration. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 3 / 1 to 1 / 1) to obtain compound 019-5. LC / MS (ESI+) m / z: [M+Ht-Bu] + =277.95.

[0361] 19.6 Synthesis of Compound 019-6

[0362] 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 to 1,4-dioxane (10 mL) in sequence. The atmosphere was purged with nitrogen three times, and the reaction mixture was reacted at 100°C for 4 h. The reaction mixture 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.

[0363] 19.7 Synthesis of Compound 019-7

[0364] 019-6 (170 mg, 2.7 mmol), pinacol diboronate (822 mg, 3.24 mmol), potassium acetate (540 mg, 5.4 mmol), and 1,1-bis(diphenylphosphino)ferrocenepalladium dichloride (240 mg, 300 μmol) were added sequentially to 1,4-dioxane (10 mL). The atmosphere was purged with nitrogen three times, and the reaction mixture was reacted at 100°C for 4 h. The reaction mixture was diluted with water (10 mL) and extracted with ethyl acetate (10 mL x 3). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 10 / 1) to obtain compound 019-7. LC / MS (ESI+) m / z: [M+H] + =492.10.

[0365] 19.8 Synthesis of Compound 019-8

[0366] 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]palladium dichloride (8.5 mg, 0.05 mmol) were added sequentially to 1,4-dioxane (4 mL) and water (1 mL). The atmosphere was purged with nitrogen three times, and the reaction mixture was reacted at 100°C for 2 h. The reaction mixture was added with water and extracted with ethyl acetate (10 mL x 3). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 3 / 1 to 1 / 1) to obtain compound 019-8. LC / MS (ESI+) m / z: [M+H] + =619.10.

[0367] 19.9 Synthesis of Compound 019-9

[0368] 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 h. Saturated aqueous sodium bicarbonate solution (6 mL) was added to the reaction solution to adjust the pH to 7-8, 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 to obtain compound 019-9 (crude product), which was used directly in the next step. LC / MS (ESI+) m / z: [M+H] + =519.10.

[0369] 19.10 Synthesis of Compound 019

[0370] 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 reacted at 60°C for 2 h. The reaction solution was purified by preparative HPLC and lyophilized to obtain the target compound 019.

[0371] 1H 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.

[0372] Example 20. Synthesis of (R)-2-(2-((3'-(1-aminoethyl)-2'-fluoro-5-(6-azaspiro[2.5]octyl-6-yl)-[1,1'-biphenyl]-3-yl)methoxy)phenyl)acetic acid (Compound 020-A or 020-B) and (S)-2-(2-((3'-(1-aminoethyl)-2'-fluoro-5-(6-azaspiro[2.5]octane-6-yl)-[1,1'-biphenyl]-3-yl)methoxy)phenyl)acetic acid (Compound 020-B or 020-A)

[0373]

[0374] 20.1 Synthesis of Compound 020-1

[0375] 020-a (2 g, 5.6 mmol) and hydroxylamine hydrochloride (4.5 g, 37.6 mmol) were dissolved in pyridine (10 mL), and the reaction mixture was reacted at 45°C for 1 h. The reaction mixture was adjusted to pH 2 with 1N hydrochloric acid and extracted with ethyl acetate (20 mL x 2). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain compound 020-1 (crude product), which was directly used in the next step. LC / MS (ESI+) m / z: [M+H] + =234.10.

[0376] 20.2 Synthesis of Compound 020-2

[0377] 020-1 (1.16 g, 0.22 mmol) and zinc powder (2 g, 2.2 mmol) were added to methanol (10 mL), and 6N hydrochloric acid (10 mL) was added dropwise. The reaction solution was reacted at 70°C for 1 h. The reaction solution was adjusted to pH = 8 with aqueous sodium bicarbonate solution (20 mL). The reaction solution was filtered, the filter cake was rinsed with water (10 mL), and the filtrate was 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.

[0378] 20.3 Synthesis of Compound 020-3

[0379] The synthesis method of compound 020-3 refers to the synthesis method of compound 001-1 in Example 1.

[0380] 20.4 Synthesis of Compound 020-4

[0381] The synthesis method of compound 020-4 refers to the synthesis method of compound 001-2 in Example 1.

[0382] 20.5 Synthesis of Compounds 020-5 to 020-7

[0383] The synthesis method of compounds 020-5 to 020-7 refers to the synthesis method of compounds 001-4 to 001-6 in Example 1.

[0384] 20.6 Synthesis of Compounds 020-A and 020-B

[0385] 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). The reaction mixture was reacted at 60°C for 2 h. The reaction mixture was purified by preparative HPLC and lyophilized to obtain compound 020. Chiral separation of compound 020 (AD-H column, isocratic elution with n-hexane:[(ethanol:methanol=3:1)]=6:4) afforded the target compounds 020-A (retention time=7.640 min) and 020-B (retention time=13.087 min).

[0386] Compound 020-A:

[0387] 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(m4H),1.47(m,4H),1.35(s,3H),0.34(s,4H); LC / MS(ESI+)m / z: [M+H] + =489.10.

[0388] Compound 020-B:

[0389] 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(m4H),1.47(m,4H),1.35(s,3H),0.34(s,4H); LC / MS(ESI+)m / z: [M+H] + =489.10.

[0390] Example 21. Synthesis of 2-(2-((3'-(aminomethyl)-2'-fluoro-5-(6-azaspiro[2.5]octane-6-yl)-[1,1'-biphenyl]-3-yl)methoxy)-4-fluorophenyl)acetic acid (Compound 021)

[0391]

[0392] The synthesis of compound 021 refers to the synthesis method of compound 007, except that the intermediate 001-3 is replaced by 009-3.

[0393] 1H 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.

[0394] Example 22. Synthesis of 2-(2-((5'-(aminomethyl)-2'-fluoro-5-(6-azaspiro[2.5]octane-6-yl)-[1,1'-biphenyl]-3-yl)methoxy)phenyl)acetic acid (Compound 022)

[0395]

[0396] The synthesis of compound 022 was based on the synthesis method of compound 007, except that the starting material 007-a was replaced with 3-bromo-4-fluorobenzonitrile (022-a).

[0397] 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.

[0398] 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)

[0399]

[0400] 23.1 Synthesis of Compound 023-1

[0401] Weigh tetramethylpiperidone (12.9 g, 91.2 mmol) into a reaction flask, add 50 mL of dry tetrahydrofuran, protect with nitrogen, slowly add n-butyl lithium (57 mL, 91.2 mmol) dropwise at 0°C, and react at 0°C for 1 h. Then the temperature was lowered to -78 ° C, 023-a (10 g, 76 mmol) was slowly added dropwise, the temperature was kept below -65 ° C, the reaction was carried out for 10 min, N, N-dimethylformamide (16.7 g, 228.1 mmol) was added dropwise, the temperature was kept below -65 ° C, the reaction was carried out for 10 min, glacial acetic acid (6.85 g, 114 mmol) and acetic anhydride (11.6 g, 114 mmol) were added dropwise, and then the temperature was raised to 0 ° C, water (100 mL) was added, the pH was adjusted to 8, and the mixture was extracted with ethyl acetate (100 mL × 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 2 / 1 to 1 / 1) to obtain compound 023-1.

[0402] 23.2 Synthesis of Compound 023-2

[0403] Compound 023-1 (8.4 g, 52.7 mmol) and compound 023-b (7.66 g, 63.2 mmol) were weighed into a reaction flask, and dichloromethane (50 mL) and cesium carbonate (34.3 g, 105.3 mmol) were added. The mixture was reacted at room temperature for 2 h. 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.

[0404] 23.3 Synthesis of Compound 023-3

[0405] 023-2 (8.0 g, 30.45 mmol) was weighed into a reaction flask, and methanol (60 mL) was added. Under nitrogen protection, sodium borohydride (4.61 g, 121.80 mmol) was slowly added to the above system and reacted at room temperature for 2 h. The reaction solution was concentrated under reduced pressure, and ethyl acetate (50 mL) and saturated sodium bicarbonate aqueous solution (50 mL) were added. The organic phase was separated, and the aqueous phase was extracted with ethyl acetate (50 mL × 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 2 / 1 to 1 / 1) to obtain compound 023-3. LC / MS (ESI+) m / z: [M+H] + =265.05.

[0406] 23.4 Synthesis of Compound 023-4

[0407] 023-c (10 g, 46.1 mmol) was weighed into a reaction flask, and N,N-dimethylformamide (50 mL), cesium carbonate (45 g, 138.2 mmol), and iodomethane (16.4 g, 115.2 mmol) were added. The reaction mixture was allowed to react at room temperature overnight. Water 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 023-4.

[0408] 23.5 Synthesis of Compound 023-5

[0409] Compound 023-4 (5 g, 20.4 mmol) was weighed into a reaction flask, and compound 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. The mixture was reacted at 100°C for 12 h. 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.

[0410] 23.6 Synthesis of Compound 023-6

[0411] 023-5 (6.0 g, 14.5 mmol) was weighed into a reaction flask, and dichloromethane (30 mL) was added. Boron tribromide (7.28 g, 29.1 mmol) was slowly added dropwise at 0°C. After completion, the reaction solution was warmed to room temperature and reacted for 2 h. Methanol (30 mL) was added to slowly quench the reaction, followed by water (30 mL). Extraction was performed with dichloromethane (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 023-6. LC / MS (ESI+) m / z: [M+H] + =262.05.

[0412] 23.7 Synthesis of Compound 023-7

[0413] 023-6 (2.4 g, 10 mmol) was weighed into a reaction flask, and dichloromethane (30 mL) and pyridine (870 mg, 6.26 mmol) were added. Trifluoromethanesulfonic anhydride (3.4 g, 12 mmol) was added dropwise at 0°C. The reaction mixture was warmed to room temperature and allowed to react for 2 h. Water (30 mL) was added to the reaction mixture, and the mixture was extracted with dichloromethane (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 = 5 / 1 to 1 / 1) to obtain compound 023-7.

[0414] 23.8 Synthesis of Compound 023-8

[0415] Compound 023-7 (1.7 g, 4.32 mmol) was weighed into a reaction flask and added with 1,4-dioxane (50 mL), bis(pinacolato) borate (1.7 g, 6.5 mmol), potassium acetate (1.3 g, 13 mmol), and 1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (323 mg, 0.44 mmol). Under nitrogen, the reaction mixture was refluxed at 80°C for 12 h. The reaction mixture 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.

[0416] 23.9 Synthesis of Compound 023-9

[0417] 023-8 (1.5 g, 4.05 mmol) was weighed into a reaction flask, and 023-3 (962 mg, 5.3 mmol), 1,4-dioxane (30 mL), and water (5 mL) were added. 1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (356 mg, 0.405 mmol) and potassium carbonate (1.68 g, 12.12 mmol) were then added. Under nitrogen, the reaction solution was refluxed at 100°C for 2 h. 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.

[0418] 23.10 Synthesis of Compound 023-10

[0419] 023-9 (1.7 g, 3.59 mmol) was weighed into a reaction flask, tetrahydrofuran (15 mL) was added, the temperature was cooled to 0°C, and lithium aluminum tetrahydride (408 mg, 10.77 mmol) was slowly added. The reaction was allowed to react at 0°C for 1 h. 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.

[0420] 23.11 Synthesis of Compound 023-11

[0421] 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. Under nitrogen, diisopropyl azodicarboxylate (635 mg, 3.14 mmol) was slowly added dropwise at 0°C. After addition, the reaction mixture was warmed to room temperature and reacted for 2 h. 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.

[0422] 23.12 Synthesis of Compound 023-12

[0423] Weigh 023-11 (400 mg, 1.674 mmol) into a reaction flask, add dichloromethane (2 mL) and a 4N solution of hydrogen chloride in 1,4-dioxane (2 mL). React at room temperature for 2 h. Concentrate the reaction mixture to obtain compound 023-12 (crude product), which can be used directly in the next step.

[0424] 23.13 Synthesis of Compound 023

[0425] 023-12 (300 mg, 0.613 mmol) and sodium hydroxide (246 mg, 1.84 mmol) were added to methanol (2 mL) and water (2 mL) in sequence and reacted at 60°C for 2 h. The reaction solution was purified by preparative HPLC and lyophilized to obtain the target compound 023.

[0426] 1H 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.

[0427] Example 24. Synthesis 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 trifluoroacetate)

[0428]

[0429] 24.1 Synthesis of Compound 024-1

[0430] 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)ferrocenepalladium dichloride (110 mg, 0.15 mmol), 1,4-dioxane (9 mL), and water (1 mL) were added to a 50 mL reaction flask. After nitrogen was replaced three times, the reaction solution was refluxed at 110°C for 2 hours. The reaction solution was cooled to room temperature and filtered. The filtrate was diluted with water (60 mL) and extracted with ethyl acetate (20 mL x 3). The combined organic phases were washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 4 / 1) to obtain compound 024-1. LC / MS (ESI+) m / z: [M+H-Boc] + =457.90.

[0431] 24.2 Synthesis of Compound 024-2

[0432] 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 nitrogen was replaced three times, the reaction solution was refluxed at 110°C for 2 hours. 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 x 3). The combined organic phases were washed with saturated sodium chloride aqueous solution, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to obtain compound 024-2. LC / MS (ESI+) m / z: [M+H] + =591.05.

[0433] 24.3 Synthesis of Trifluoroacetate Salt of Compound 024

[0434] 024-2 (59 mg, 0.1 mmol) and dichloromethane (2 mL) were placed in a flask. Trifluoroacetic acid (0.4 mL) was added to the mixture at room temperature and stirred for 2 hours. The reaction mixture was concentrated under reduced pressure, and the residue was purified by preparative HPLC and lyophilized to obtain the trifluoroacetic acid salt of compound 024.

[0435] 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.

[0436] 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)

[0437]

[0438] 25.1 Synthesis of Compound 025-1

[0439] Under nitrogen, 010-3 (300 mg, 0.69 mmol) and 021-1 (244 mg, 0.69 mmol), potassium carbonate (192 mg, 1.39 mmol), and [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (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 hours. The reaction solution was cooled to room temperature, water was added, and extraction was performed with ethyl acetate (10 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 = 3 / 1 to 1 / 1) to obtain compound 025-1. LC / MS (ESI+) m / z: [M+H-Boc] + =475.85.

[0440] 25.2 Synthesis of Compound 025-2

[0441] Compound 025-1 (300 mg, 0.52 mmol) was weighed into a reaction flask, and compound 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. The mixture was reacted at 100°C for 4 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 = 3 / 1 to 1 / 1) to obtain compound 025-2. LC / MS (ESI+) m / z: [M+H] + =623.00.

[0442] 25.3 Synthesis of Compound 025

[0443] The synthesis of compound 025 was carried out according to the synthesis method of steps 1.6 and 1.7 in reference example 1.

[0444] 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.

[0445] 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)

[0446]

[0447] 26.1 Synthesis of Compound 026-1

[0448] Weigh 026-a (3.0 g, 13.7 mmol) into a reaction flask, add sulfuric acid (10 mL), and slowly add N-iodosuccinimide (2.5 g, 14.4 mmol) at 0°C. Then warm the temperature to room temperature and react overnight. Pour the reaction solution into ice water, and a solid precipitates. Filter and dry the solid to obtain compound 026-1.

[0449] 26.2 Synthesis of Compound 026-2

[0450] 026-1 (3.6 g, 10.44 mmol) was weighed into a reaction flask, and tetrahydrofuran (20 mL) was added. Under nitrogen, borane 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 quenched by the slow addition of methanol (20 mL). 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.

[0451] 26.3 Synthesis of Compound 026-3

[0452] 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 atmosphere was purged with nitrogen three times, and diisopropyl azodicarboxylate (2.2 g, 6.04 mmol) was slowly added dropwise at 0°C. The mixture was then 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.

[0453] 26.4 Synthesis of Compound 026-4

[0454] Under nitrogen, 026-3 (540 mg, 1.13 mmol) and 001-2 (376 mg, 1.13 mmol), potassium carbonate (312 mg, 2.25 mmol), and [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (83 mg, 0.113 mmol) were dissolved in 1,4-dioxane (10 mL) and water (1 mL) and reacted at 100°C for 2 hours. The reaction solution was cooled to room temperature, water was added, and extracted with ethyl acetate (10 mL × 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 3 / 1 to 1 / 1) to obtain compound 026-4. LC / MS (ESI+) m / z: [M+H] + =459.90.

[0455] 26.5 Synthesis of Compound 026-5

[0456] Compound 026-4 (400 mg, 0.72 mmol) was weighed into a reaction flask, and compound 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. The mixture was reacted at 100°C for 4 hours. 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.

[0457] 26.6 Synthesis of Compound 026

[0458] The synthesis of compound 026 was carried out according to the synthesis method of steps 1.6 and 1.7 in reference example 1.

[0459] 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.

[0460] 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)

[0461]

[0462] 27.1 Synthesis of Compound 027-1

[0463] 027-a (2.0 g, 7.4 mmol) was dissolved in acetonitrile (20 mL), and N-bromosuccinimide (1.31 g, 7.4 mmol) and azobisisobutyronitrile (120 mg, 0.74 mmol) were added. The mixture was reacted at 80°C for 2 hours. The reaction solution was concentrated, and the residue was purified by silica gel column chromatography to obtain compound 027-1.

[0464] 27.2 Synthesis of Compound 027-2

[0465] Compound 027-1 (1.8 g, 5.19 mmol) was dissolved in acetonitrile (20 mL). Potassium carbonate (1.43 g, 10.38 mmol) and methyl o-hydroxyphenylacetate (905.5 mg, 5.45 mmol) were added and reacted at 25°C for 2 hours. The reaction mixture 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.

[0466] 27.3 Synthesis of Compound 027-3

[0467] 027-2 (1.0 g, 2.3 mmol) was weighed into a reaction flask and potassium carbonate (640 mg, 4.6 mmol), 001-2 (0.77 g, 2.3 mmol), 1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (100 mg, 10 wt%), 1,4-dioxane (10 mL), and water (1 mL) were added. The reaction was allowed to proceed at 90°C under nitrogen for 2 hours. The reaction solution was cooled to room temperature, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to obtain compound 027-3. LC / MS (ESI+) m / z: [M+H] + =558.1.

[0468] 27.4 Synthesis of Compound 027-4

[0469] 027-3 (120 mg, 0.21 mmol) was 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-dicyclohexylphosphine-2',4',6'-triisopropylbiphenyl (12 mg, 10 wt%) were added. The mixture was reacted at 100°C under nitrogen for 2 hours. After cooling to room temperature, the reaction mixture was filtered, the filtrate was concentrated, and the residue was purified by silica gel column chromatography to obtain compound 027-4. LC / MS (ESI+) m / z: [M+H] + =605.1.

[0470] 27.5 Synthesis of Compound 027

[0471] The synthesis of compound 027 was carried out according to the synthesis method of steps 1.6 and 1.7 in reference example 1.

[0472] 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.

[0473] 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)

[0474]

[0475] 28.1 Synthesis of Compound 028-1

[0476] Zinc powder (4.7 g, 71.86 mmol) was weighed into a reaction flask, and tetrahydrofuran (10 mL) was added. Trimethylsilyl chloride (390 mg, 3.59 mmol) was added under nitrogen. The mixture was reacted at 50°C for 0.5 h, and then 028-a (6.0 g, 35.93 mmol) was slowly added dropwise. The mixture was reacted at 70°C for 2 h to obtain a solution of compound 028-1, which was used directly in the next step.

[0477] 28.2 Synthesis of Compound 028-2

[0478] 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-dicyclohexylphosphine-2',4',6'-triisopropylbiphenyl (500 mg, 0.95 mmol) were added. Under nitrogen, a solution of compound 028-1 (12 mL) obtained in step 28.1 was slowly added dropwise. The mixture was reacted at 70°C for 2 hours. The reaction solution was quenched with saturated aqueous ammonium chloride (10 mL) and extracted with ethyl acetate (30 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 = 10 / 1 to 1 / 1) to obtain compound 028-2. LC / MS (ESI+) m / z: [M+H] + =213.10

[0479] 28.3 Synthesis of Compound 028-3

[0480] 028-2 (1.8 g, 8.5 mmol) was weighed into a reaction flask, dichloromethane (20 mL) was added, and under nitrogen protection, boron tribromide (18 mL, 17.0 mmol) was slowly added dropwise at 0°C. After reacting for 10 minutes, the mixture was transferred to room temperature and the reaction was continued for 10 minutes. Ethanol (10 mL) was slowly added dropwise to quench the reaction, and water (10 mL) was added to dilute it. The mixture was extracted with dichloromethane (30 mL × 3). The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 10 / 1 to 1 / 1) to obtain compound 028-3. LC / MS (ESI+) m / z: [M+H] +=199.10.

[0481] 28.4 Synthesis of Compound 028-4

[0482] Weigh 028-3 (0.75 g, 3.65 mmol) into a reaction flask, add 009-b (1.2 g, 3.65 mmol), potassium carbonate (1.1 g, 7.3 mmol) and N,N-dimethylformamide (20 mL), and react at room temperature for 2 hours. The reaction solution was diluted with water (20 mL) and extracted with ethyl acetate (30 mL × 3). The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 10 / 1 to 1 / 1) to obtain compound 028-4. LC / MS (ESI+) m / z: [M+H] + =446.75.

[0483] 28.5 Synthesis of Compound 028

[0484] The synthesis of compound 028 refers to the synthesis method of compound 027, except that 027-2 in the synthesis step is replaced by 028-4.

[0485] 1 H 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),7.09-7.0 3(m,1H),7.00–6.93(m,3H),5.09(s,2H),4.35(s,4H),3.97(s,2H),3.4 3(s,2H),3.21–3.16(m,4H),1.93–1.88(m,4H); LC / MS(ESI+)m / z: [M+H] + =491.05.

[0486] Example 29. Synthesis of 2-(2-((3'-(aminomethyl)-5-(3-oxa-9-azaspiro[5.5]undec-9-yl)-[1,1'-biphenyl]-3-yl)methoxy)phenyl)acetic acid (Compound 029)

[0487]

[0488] The synthesis of compound 029 refers to the synthesis method of compound 001, except that the raw material in the step 001-d is replaced by 3-oxa-9-azaspiro[5.5]undecane (029-a).

[0489] 1H 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.

[0490] Example 30. Synthesis of 2-(2-((3'-(aminomethyl)-5-(2-oxa-9-azaspiro[5.5]undec-9-yl)-[1,1'-biphenyl]-3-yl)methoxy)phenyl)acetic acid (Compound 030)

[0491]

[0492] The synthesis of compound 030 refers to the synthesis method of compound 001, except that the raw material in the step 001-d is replaced by 2-oxa-9-azaspiro[5.5]undecane (030-a).

[0493] 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= 8.0Hz,1H),6.80(t,J=7.2Hz,1H),5.14(s,2H),3.94(s,2H),3.55(s,2H),3.40(d ,J=2.4Hz,4H),3.23(t,J=5.6Hz,4H),1.62–1.51(m,8H); LC / MS(ESI+)m / z: [M+H] + =501.15.

[0494] 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)

[0495]

[0496] The synthesis of compound 031 was carried out by referring to the synthesis method of compound 001, except that the raw material 001-d was replaced with 6-oxa-2-azaspiro[3.4]octane (031-a).

[0497] 1 H NMR (400MHz, DMSO-d6): δ9.47(s,1H),7.92(d,J=59.6Hz,1H),7.53(dd,J=30.0,8Hz,1H),7.3 9–7.33(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) ,6.48(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),3.74(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.

[0498] 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)

[0499]

[0500] The synthesis of compound 032 was based on the synthesis method of compound 001, except that the raw material 001-d was replaced with 2-methyl-2,7-diazaspiro[3.5]nonane (032-a).

[0501] 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=7.6H z,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,1H),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.

[0502] Example 33. Synthesis of 2-(2-((3'-(aminomethyl)-5-(3,9-diazaspiro[5.5]undec-3-yl)-[1,1'-biphenyl]-3-yl)methoxy)phenyl)acetic acid (Compound 033) trifluoroacetate

[0503]

[0504] 33.1 Synthesis of Compound 033-1

[0505] 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-dicyclohexylphosphine-2',6'-dimethoxybiphenyl (33 mg, 80 μmol), and toluene (4 mL) were added to a 50 mL reaction flask. After nitrogen was replaced three times, the reaction solution was refluxed at 110°C for 2 hours. 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 phases were washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to obtain compound 033-1. LC / MS (ESI+) m / z: [M+H] + =700.10.

[0506] 33.2 Synthesis of Compound 033 Trifluoroacetate

[0507] 033-1 (78 mg, 0.11 mmol) and dichloromethane (2 mL) were placed in a flask. 4-Fluorophenylboronic acid (31 mg, 0.22 mmol) was added to the mixture at room temperature. The mixture was stirred for 2 hours to remove nitrogen oxides. Trifluoroacetic acid (0.2 mL) was then added to the mixture and allowed to react at room temperature for 1 hour. The reaction solution was concentrated under reduced pressure, and the residue was purified by preparative HPLC to obtain the trifluoroacetate salt of compound 033.

[0508] 1 H 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),3.6 0(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.

[0509] 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)

[0510]

[0511] The synthesis of compound 034 was carried out by referring to the synthesis method of compound 001, except that the raw material 001-d was replaced with 2-azaspiro[4.4]nonane (034-a).

[0512] 1H NMR (400MHz, DMSO-d6): δ8.11(s,1H),7.66(d,J=6.0Hz,1H),7.37(t,J=6.0Hz,1H),7.3 0–7.22(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,2 H),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.

[0513] Example 35. Synthesis of (S)-2-(2-((3'-(1-aminoethyl)-5-(4-oxa-7-azaspiro[2.5]octane-7-yl)-[1,1'-biphenyl]-3-yl)methoxy)phenyl)acetic acid (Compound 035-A or 035-B) and (R)-2-(2-((3'-(1-aminoethyl)-5-(4-oxa-7-azaspiro[2.5]octane-7-yl)-[1,1'-biphenyl]-3-yl)methoxy)phenyl)acetic acid (Compound 035-B or 035-A)

[0514]

[0515] 35.1 Synthesis of Compound 035-1

[0516] 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. The reaction solution was concentrated, and 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.

[0517] 35.2 Synthesis of Compound 035-2

[0518] 035-1 (7.50 g, 24.98 mmol), bis(diphenylphosphino)ferrocenepalladium(II) chloride (7.61 g, 29.98 mmol), potassium acetate (4.90 g, 49.97 mmol), and 1,1'-bis(diphenylphosphino)ferrocenepalladium(II) chloride (0.75 g, 2.50 mmol) were dissolved in 1,4-dioxane (80 mL). The atmosphere was purged with nitrogen three times and the mixture was 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 phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 10 / 1 to 3 / 1) to obtain compound 035-2. LC / MS (ESI+) m / z: [M+H-tBu] + =292.05.

[0519] 35.3 Synthesis of Compound 035-3

[0520] 001-3 (3.2 g, 7.74 mmol), 035-2 (1.42 g, 6.45 mmol), potassium carbonate (1.78 g, 12.89 mmol) and tetrakis(triphenylphosphine)palladium (0.7 g, 0.64 mmol) were dissolved in a mixed solution of 1,4-dioxane and water (40 mL, 1,4-dioxane / water = 4 / 1). The atmosphere was purged with nitrogen three times and the mixture was 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 phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 8 / 1 to 3 / 1) to give compound 035-3. LC / MS (ESI+) m / z: [M+H-Boc] + =453.95.

[0521] 35.4 Synthesis of Compound 035-4

[0522] 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 atmosphere was purged with nitrogen three times and the mixture was reacted at 100°C for 16 hours. After cooling to room temperature, the reaction solution was diluted with water (15 mL) and extracted with ethyl acetate (10 mL x 3). The combined organic phases were washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 10 / 1 to 1 / 1) to obtain compound 035-4. LC / MS (ESI+) m / z: [M+H] + =587.15.

[0523] 35.5 Synthesis of Compounds 035-A and 035-B

[0524] The synthesis of compound 035 was carried out according to the synthesis method of steps 1.6 and 1.7 in Example 1. 035 was further subjected to chiral separation by supercritical fluid chromatography (method: AD-3-IPA + CAN(DEA)-40-3mL-35T) to give 035-A (retention time Rt = 1.097 min) and 035-B (retention time Rt = 1.773 min).

[0525] 035-A (retention time Rt = 1.097 min):

[0526] 1 H NMR (400MHz, DMSO-d6): δ8.27(s,1H),7.69(d,J=7.8Hz,1H),7.54(s,1H),7.38(t,J=7.6H z,1H),7.26(d,J=7.4Hz,1H),7.13(s,1H),7.09(d,J=4.8Hz,2H),6.96(s,1H),6.89(d,J=8 .6Hz,1H),6.80(t,J=7.4Hz,1H),5.11(s,2H),4.25(d,J=6.2Hz,1H),3.83(s,2H),3.43–3 .26(m,4H),3.20(s,2H),1.50(d,J=6.4Hz,3H),0.80–0.61(m,4H); LC / MS(ESI+)m / z: [M+H] + =473.05.

[0527] 035-B (retention time Rt = 1.773 min):

[0528] 1 H NMR (400MHz, DMSO-d6): δ8.25(s,1H),7.69(d,J=7.8Hz,1H),7.53(s,1H),7.39(t,J=7.6Hz,1H),7.2 7(d,J=7.6Hz,1H),7.13(s,1H),7.10(dt,J=4.0,3.6Hz,2H),6.97(s,1H),6.90(d,J=8.4Hz,1H),6.81 (t,J=7.4Hz,1H),5.12(s,2H),4.26(d,J=6.6Hz,1H),3.87–3.80(m,2H),3.40(dd,J=17.8,12.0Hz,2 H),3.31–3.26(m,2H),3.20(s,2H),1.50(d,J=6.8Hz,3H),0.77–0.65(m,4H); LC / MS(ESI+)m / z: [M+H] + =473.05.

[0529] Example 36, (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) and Synthesis

[0530]

[0531] 36.1 Synthesis of Compound 036-1

[0532] 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 atmosphere was purged with nitrogen three times and the mixture was 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 and 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.

[0533] 36.2 Synthesis of Compounds 036-A and 036-B

[0534] The synthesis of compound 036 was carried out according to the synthesis method of steps 1.6 and 1.7 in Example 1. Compound 036 was further subjected to chiral separation by supercritical fluid chromatography (method: OD-MeOH(DEA)-40-3mL-35T) to give 036-A (retention time Rt = 0.912 min) and 036-B (retention time Rt = 1.354 min).

[0535] 036-A (retention time Rt = 0.912 min):

[0536] 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),5.1 1(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.

[0537] 036-B (retention time Rt = 1.354 min):

[0538] 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,1 H),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.

[0539] Example 37. Synthesis of 2-(2-((3'-(1-aminoethyl)-5-(6-azaspiro[2.5]octane-6-yl)-[1,1'-biphenyl]-3-yl)methoxy)phenyl)acetic acid (Compound 037)

[0540]

[0541] 37.1 Synthesis of Compound 037-1

[0542] 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 atmosphere was purged with nitrogen three times and the mixture was reacted at 100°C for 16 hours. After cooling to room temperature, the reaction solution was diluted with water (15 mL) and extracted with ethyl acetate (10 mL x 3). The combined organic phases were washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 10 / 1 to 1 / 1) to obtain compound 037-1. LC / MS (ESI+) m / z: [M+H] + =585.15.

[0543] 37.2 Synthesis of Compound 037

[0544] The synthesis of compound 037 was carried out according to the synthesis method of steps 1.6 and 1.7 in reference example 1.

[0545] 1 H 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.

[0546] Example 38. Synthesis of (S)-2-(2-((3'-(1-aminoethyl)-5-(3-oxa-9-azaspiro[5.5]undec-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]undec-9-yl)-[1,1'-biphenyl]-3-yl)methoxy)phenyl)acetic acid (Compound 038-B or 038-A)

[0547]

[0548] 38.1 Synthesis of Compound 038-1

[0549] 035-3 (300 mg, 0.54 mmol) was weighed into a reaction flask, and 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) were added. After nitrogen displacement, the reaction was carried out 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 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 obtain compound 038-1. LC / MS (ESI+) m / z: [M+H] + =629.15.

[0550] 38.2 Synthesis of Compounds 038-A and 038-B

[0551] The synthesis of compound 038 was carried out according to the synthesis method of steps 1.6 and 1.7 in Example 1. Compound 038 was further subjected to chiral separation 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).

[0552] 038-A (retention time Rt = 1.079 min):

[0553] 1 H 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=8.8 Hz,1H),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.

[0554] 038-B (retention time Rt = 1.627 min):

[0555] 1H NMR (400MHz, DMSO-d6): δ8.32(s,2H),7.79(s,1H),7.67(d,J=7.6Hz,1H),7.50(t,J=7.6 Hz,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,4 H),1.73–1.58(m,4H),1.55(d,J=6.8Hz,3H),1.51–1.44(m,4H); LC / MS(ESI+)m / z: [M+H] + =515.05.

[0556] Example 39. Synthesis of (S)-2-(2-((3'-(1-aminoethyl)-5-(2-oxa-9-azaspiro[5.5]undec-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]undec-9-yl)-[1,1'-biphenyl]-3-yl)methoxy)phenyl)acetic acid (Compound 039-B or 039-A)

[0557]

[0558] 39.1 Synthesis of Compound 039-1

[0559] 035-3 (300 mg, 0.54 mmol) was weighed into a reaction flask, followed by the addition of 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). After nitrogen displacement, the reaction solution was reacted at 100°C for 5 hours, then diluted with water (10 mL) and extracted with ethyl acetate (20 mL x 3). The combined organic phases were washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to obtain compound 039-1. LC / MS (ESI+) m / z: [M+H] + =629.15.

[0560] 39.2 Synthesis of Compounds 039-A and 039-B

[0561] The synthesis of compound 039 followed the synthesis method of steps 1.6 and 1.7 in Example 1. Compound 039 was further subjected to chiral separation 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).

[0562] 039-A (retention time Rt = 0.935 min):

[0563] 1 H NMR (400MHz, DMSO-d6): δ8.28(s,2H),7.79(s,1H),7.68(d,J=7.6Hz,1H),7.51(t,J=7 .6Hz,1H),7.45(d,J=8.0Hz,1H),7.21(d,J=7.6Hz,2H),7.16(s,2H),7.10(s,1H),7.0 3(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.

[0564] 039-B (retention time Rt = 1.302 min):

[0565] 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=15.0H z,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.

[0566] Example 40. Synthesis of (S)-2-(2-((3'-(1-aminoethyl)-5-(6-oxa-2-azaspiro[3.4]octane-2-yl)-[1,1'-biphenyl]-3-yl)methoxy)phenyl)acetic acid (Compound 040-A or 040-B) and (R)-2-(2-((3'-(1-aminoethyl)-5-(6-oxa-2-azaspiro[3.4]octane-2-yl)-[1,1'-biphenyl]-3-yl)methoxy)phenyl)acetic acid (Compound 040-B or 040-A)

[0567]

[0568] 40.1 Synthesis of Compound 040-1

[0569] 035-3 (300 mg, 0.54 mmol) was weighed and dissolved in 1,4-dioxane (5 mL), and 031-a (67 mg, 0.60 mmol), cesium carbonate (706 mg, 2.16 mmol), tris(dibenzylideneacetone)dipalladium (30 mg, 10 wt%) and 2-dicyclohexylphosphine-2',4',6'-triisopropylbiphenyl (30 mg, 10 wt%) were added. The reaction solution was reacted at 100 ° C. under nitrogen protection for 2 hours, filtered, and the filtrate was concentrated. The residue was purified by silica gel column chromatography to obtain compound 040-1.

[0570] 40.2 Synthesis of Compounds 040-A and 040-B

[0571] The synthesis of compound 040 followed the method described in steps 1.6 and 1.7 of Example 1. Compound 040 was further subjected to chiral separation by supercritical fluid chromatography (Method: Cellulose-2-3-MeOH + CAN(DEA)-50-3mL-35T) to afford 040-A (retention time Rt = 1.272 min) and 040-B (retention time Rt = 1.982 min).

[0572] 040-A (retention time Rt = 1.272 min):

[0573] 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),7.2 6(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,1 H),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),3.3 7(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.

[0574] 040-B (retention time Rt = 1.982 min):

[0575] 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,1 H),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),3.3 7(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.

[0576] Example 41. Synthesis of 2-(2-((3'-(1-aminoethyl)-5-(1-oxa-6-azaspiro[3.4]octane-6-yl)-[1,1'-biphenyl]-3-yl)methoxy)phenyl)acetic acid (Compound 041)

[0577]

[0578] 41.1 Synthesis of Compound 041-1

[0579] 035-3 (0.5 g, 0.90 mmol), 041-a (175 mg, 0.58 mmol), tris(dibenzylideneacetone)dipalladium (50 mg, 0.09 mmol), 2-dicyclohexylphosphine-2',4',6'-triisopropylbiphenyl (25 mg, 0.09 mmol) and cesium carbonate (1.2 g, 3.6 mmol) were dissolved in 1,4-dioxane (5 mL), the nitrogen atmosphere was replaced three times, and the reaction was carried out at 100°C for 16 hours. 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.

[0580] 41.2 Synthesis of Compound 041

[0581] The synthesis of compound 041 followed the synthesis method of steps 1.6 and 1.7 in reference example 1.

[0582] 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),3.3 9–3.28(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.

[0583] 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 Synthesis of (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)

[0584]

[0585] 42.1 Synthesis of Compound 042-1

[0586] Compound 035-3 (500 mg, 0.9 mmol) was weighed into a reaction flask, and compound 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-dicyclohexylphosphine-2',4',6'-triisopropylbiphenyl (60 mg, 0.056 mmol) were added. The reaction solution was reacted at 100°C for 24 hours, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 1 / 1) to obtain compound 042-1. LC / MS (ESI+) m / z: [M+H] + =601.05.

[0587] 42.2 Synthesis of Compounds 042-A and 042-B

[0588] The synthesis of compound 042 was carried out according to the synthesis method of steps 1.6 and 1.7 in Example 1. 042 was further subjected to chiral separation by supercritical fluid chromatography (method: OD-MeOH(DEA)-40-3mL-35T) to give 042-A (retention time Rt = 0.913 min) and 042-B (retention time Rt = 1.444 min).

[0589] 042-A (retention time Rt = 0.913 min):

[0590] 1H NMR (400MHz, DMSO-d6): δ8.26(s,1H),7.67(dd,J=8.0,8.0Hz,1H),7.50(s,1H),7.37( t,J=16.0Hz,1H),7.27(t,J=16.0Hz,1H),7.11(m,2H),7.09(s,1H),7.00(s,1H),6.90 (d,J=8.0Hz,1H),6.80(m,1H),5.11(m,2H),4.36(s,4H),4.23(d,J=12.0Hz,1H),3.43 –3.31(m,2H),3.19(m,4H),1.91(m,4H),1.49(d,J=4.0Hz,3H); LC / MS(ESI+)m / z: [M+H] + =487.10.

[0591] 042-B (retention time Rt = 1.444 min):

[0592] 1 H NMR (400MHz, DMSO-d6): δ8.26(s,1H),7.67(dd,J=8.0,8.0Hz,1H),7.50(s,1H),7.37(t,J=16.0Hz,1H),7 .27(8.10(m,1H),7.61(dd,J=8.0,8.0Hz,1H),7.45(s,1H),7.37(t,J=16.0Hz,1H),7.27(t,J=16.0Hz,1H ),7.09m,3H),7.00(s,1H),6.90(d,J=8.0Hz,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=8.0Hz,3H); LC / MS(ESI+)m / z: [M+H] + =487.10.

[0593] 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 Synthesis of (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)

[0594]

[0595] 43.1 Synthesis of Compound 043-1

[0596] Compound 035-3 (600 mg, 1.08 mmol) was weighed into a reaction flask, and compound 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-dicyclohexylphosphine-2',4',6'-triisopropylbiphenyl (50 mg, 0.11 mmol) were added. Under nitrogen, the reaction mixture was reacted at 100°C for 5 hours. After cooling to room temperature, the reaction mixture was diluted with water (10 mL) and extracted with ethyl acetate (20 mL x 3). The combined organic phases were washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to obtain compound 043-1. LC / MS (ESI+) m / z: [M+H] + =601.10.

[0597] 43.2 Synthesis of Compounds 043-A and 043-B

[0598] The synthesis of compound 043 was carried out according to the synthesis method of steps 1.6 and 1.7 in 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).

[0599] 043-A (retention time Rt = 1.54 min):

[0600] 1H 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=4.0H z,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.

[0601] 043-B (retention time Rt = 2.386 min):

[0602] 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.

[0603] 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)

[0604]

[0605] 44.1 Synthesis of Compound 044-1

[0606] 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 mixture was reacted at 0°C for 0.5 h. Saturated aqueous sodium sulfite solution was added to quench the reaction, filtered, and the solid was dried to obtain compound 044-1.

[0607] 44.2 Synthesis of Compound 044-2

[0608] 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) in sequence. The reaction solution was refluxed at 80°C for 1 h. 044-1 (3.0 g, 10.8 mol) was then dissolved in 5 mL of acetonitrile and slowly added dropwise to the above system. The reaction was allowed to react at 80°C for 12 h. The reaction was quenched by adding saturated aqueous ammonium chloride solution and extracted with ethyl acetate (30 mL x 3). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to obtain compound 044-2.

[0609] 44.3 Synthesis of Compound 044-3

[0610] Under nitrogen protection, tetraisopropoxytitanium (2.6 g, 9.22 mol) was added dropwise to a 1N, 20 mL ammonia methanol solution of 044-2 (2.4 g, 4.61 mol) and the reaction was allowed to proceed at 25°C for 2 h. Sodium borohydride (262.3 mg, 6.91 mol) was then added and the reaction was allowed to proceed at room temperature for 2 h. 6N hydrochloric acid was added to the reaction solution to adjust its pH to 2, and the solution was extracted with ethyl acetate. 6N sodium hydroxide solution was added to the aqueous phase to adjust its pH to 10, and the solution was extracted with ethyl acetate. The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the crude product of compound 044-3, which was used directly in the next step. LC / MS (ESI+) m / z: [M+H] + =218.00.

[0611] 44.4 Synthesis of Compound 044

[0612] The synthesis of compound 044 refers to the synthesis method of compound 001, except that 001-a in the synthesis steps is replaced by 044-3 and 001-d is replaced by 011-a.

[0613] 1H 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.

[0614] 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)

[0615]

[0616] 45.1 Synthesis of Compound 045-1

[0617] Compound 027-3 (100 mg, 0.17 mmol) was dissolved in 1,4-dioxane (5 mL). Compound 001-d (31.7 mg, 0.21 mmol), cesium carbonate (166 mg, 0.51 mmol), tris(dibenzylideneacetone)dipalladium (10 mg, 10 wt%), and 2-dicyclohexylphosphine-2',4',6'-triisopropylbiphenyl (10 mg, 10 wt%) were added. The reaction mixture was reacted at 100°C under nitrogen for 2 hours, 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.

[0618] 45.2 Synthesis of Compound 045

[0619] The synthesis of compound 045 was carried out according to the synthetic method of steps 1.6 and 1.7 in reference example 1.

[0620] 1H 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,1 H), 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.

[0621] Example 46. Synthesis of (S)-2-(2-((3'-(1-amino-2-hydroxyethyl)-5-(8-azaspiro[4.5]decane-8-yl)-[1,1'-biphenyl]-3-yl)methoxy)phenyl)acetic acid (Compound 046)

[0622]

[0623] The synthesis of compound 046 was carried out by referring to the synthesis method of compound 018, except that the raw material 001-d was replaced with the hydrochloride salt of 8-azaspiro[4.5]decane (046-a).

[0624] 1 H NMR (400MHz, DMSO-d6): δ8.05(d,J=63.0Hz,1H),7.60(dd,J=46.0,7.6Hz,1H),7.38 (dd,J=16.8,9.6Hz,2H),7.23(dd,J=20.4,7.4Hz,1H),7.19–6.89(m,5H),6.88–6.7 0(m,1H),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.

[0625] Example 47. Synthesis of (R)-2-(2-((3'-(1-amino-2-hydroxyethyl)-5-(3-azaspiro[5.5]undec-3-yl)-[1,1'-biphenyl]-3-yl)methoxy)phenyl)acetic acid (Compound 047-A) trifluoroacetate and (S)-2-(2-((3'-(1-amino-2-hydroxyethyl)-5-(3-azaspiro[5.5]undec-3-yl)-[1,1'-biphenyl]-3-yl)methoxy)phenyl)acetic acid (Compound 047-B) trifluoroacetate

[0626] 47.1 Synthesis of Compound 047-1

[0627] 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 in tetrahydrofuran (1 M, 9.1 mL, 9.1 mmol) was slowly added. The reaction was maintained at 0°C for 3 hours. Methanol (10 mL) was slowly added dropwise to quench the reaction. After 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.

[0628] 47.2 Synthesis of Compound 047-2

[0629] Compound 047-1 (700 mg, 2.21 mmol) was weighed into a reaction flask, and 2,2-dimethoxypropane (461 mg, 4.43 mmol), p-toluenesulfonic acid monohydrate (21 mg, 0.11 mmol), and toluene (5 mL) were added. The temperature was raised to 50°C and the reaction was allowed to react for 15 hours. The reaction system was adjusted to pH 8 with saturated aqueous sodium bicarbonate solution and extracted with ethyl acetate (10 mL x 3). The combined organic phases were washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography to obtain compound 047-2.

[0630] 47.3 Synthesis of Compound 047-3

[0631] 047-2 (400 mg, 1.12 mmol) was weighed into a reaction flask, followed by the addition of pinacol diboron (314 mg, 1.24 mmol), potassium acetate (221 mg, 2.25 mmol), [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (80 mg, 0.11 mmol), and 1,4-dioxane (5 mL). After nitrogen substitution three times, the reaction mixture was incubated at 100°C for 2 hours and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography to yield compound 047-3.

[0632] 47.4 Synthesis of Compound 047-4

[0633] Compound 001-3 (400 mg, 0.96 mmol) was weighed into a reaction flask, followed by the addition of compound 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). The atmosphere was purged with nitrogen three times and the temperature was raised to 100°C for 2 hours. The reaction mixture was diluted with water (10 mL) and extracted with ethyl acetate (10 mL x 3). The combined organic phases were washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate concentrated under reduced pressure. The residue was purified by silica gel column chromatography to yield compound 047-4.

[0634] 47.5 Synthesis of Compound 047-5

[0635] 047-4 (150 mg, 0.25 mmol) was weighed into a reaction flask, followed by 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). The atmosphere was purged with nitrogen three times, and the reaction mixture was reacted at 100°C for 2 hours. After cooling to room temperature, the reaction mixture 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 concentrated under reduced pressure. The residue was purified by silica gel column chromatography to obtain compound 047-5.

[0636] 47.6 Synthesis of Compound 047-A Trifluoroacetate

[0637] The synthesis of compound 047-A was carried out according to the synthesis method of steps 1.6 and 1.7 in Example 1. Trifluoroacetic acid was used in the preparation process to obtain the trifluoroacetate salt of compound 047-A.

[0638] 1H NMR (400MHz, DMSO-d6): δ8.39(s,2H),7.78(s,1H),7.68(d,J=7.6Hz,1H),7.49(t,J=7 .6Hz,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,2H),3.24(s,4H),1.55(s,4H),1.40(d,J=14.4Hz,10H); LC / MS(ESI+)m / z: [M+H] + =529.10.

[0639] 47.7 Synthesis of Compound 047-B Trifluoroacetate

[0640]

[0641] The synthesis of compound 047-B refers to the synthesis method of compound 047-A, except that the raw material 047-a (R configuration) is replaced with (S)-2-(3-bromophenyl)-2-((tert-butoxycarbonyl)amino)acetic acid (S configuration).

[0642] 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 .6Hz,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,2H),3.26(s,4H),1.56(s,4H),1.41(d,J=13.8Hz,10H); LC / MS(ESI+)m / z: [M+H] + =529.10.

[0643] Example 48. Synthesis of (R)-2-(2-((3'-(1-amino-2-hydroxyethyl)-5-(2-azaspiro[3.4]octane-2-yl)-[1,1'-biphenyl]-3-yl)methoxy)phenyl)acetic acid (Compound 048-A) and Synthesis of (S)-2-(2-((3'-(1-amino-2-hydroxyethyl)-5-(2-azaspiro[3.4]octane-2-yl)-[1,1'-biphenyl]-3-yl)methoxy)phenyl)acetic acid (Compound 048-B)

[0644]

[0645] 48.1 Synthesis of Compound 048-A

[0646] The synthesis of compound 048-A was carried out according to the synthesis method of compound 047-A in Example 47, except that the raw material 047-c was replaced with 2-azaspiro[3.4]octane (048-a).

[0647] 1 H 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 ),6.45(s,1H),5.22–5.01(m,2H),4.69–4.56(m,1H),3.80–3.69(m,4H),3.48–3.41(m,1H),3 .38(s,2H),2.04–1.93(m,1H),1.87–1.76(m,4H),1.68–1.56(m,4H); LC / MS(ESI+)m / z: [M+H] + =487.10.

[0648] 48.2 Synthesis of Compound 048-B

[0649]

[0650] The synthesis of compound 048-B refers to the synthesis method of 048-A, except that the raw material 047-4 (R configuration) is replaced with S configuration.

[0651] 1H 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),3.5 3–3.42(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.

[0652] 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 Synthesis of (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)

[0653]

[0654] 49.1 Synthesis of Compound 049-A

[0655] The synthesis of compound 049-A was carried out according to the synthesis method of compound 047-A in Example 47, except that the raw material 047-c was replaced with 2-azaspiro[4.4]nonane (049-a).

[0656] 1H 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=6.8 Hz,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.

[0657] 49.2 Synthesis of Compound 049-B

[0658]

[0659] The synthesis of compound 049-B refers to the synthesis method of 049-A, except that the raw material 047-4 (R configuration) is replaced with S configuration.

[0660] 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), 7.36(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,2 H),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.

[0661] 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)

[0662]

[0663] 50.1 Synthesis of Compound 050-1

[0664] 020-a (2.0 g, 9.2 mmol) was weighed and dissolved in tetrahydrofuran (20 mL). Lithium bis(trimethylsilyl)amide (1 M, 10.1 mL, 10.1 mmol) was added at -78°C under nitrogen. After 1 hour of reaction, trimethylsilyl chloride (1.08 g, 10.1 mmol) was added at -78°C and the temperature was slowly warmed to room temperature for 1 hour. The reaction solution was concentrated, and acetonitrile (20 mL) and 1-chloromethyl-4-fluoro-1,4-diazabicyclo[2.2.2]octane bis(tetrafluoroborate) salt (4.7 g, 11.4 mmol) were added. The reaction 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 phases were 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.

[0665] 50.2 Synthesis of Compound 050-2

[0666] Weigh 050-1 (600 mg, 5.19 mmol) and dissolve it in an ethanolic solution of ammonia (2M, 3.8 mL). Add tetraisopropyl titanate (1.08 g, 3.8 mmol) and react at 25°C for 2 hours. Then add sodium borohydride (116 mg, 3.06 mmol) and react for 2 hours. The reaction solution is slowly quenched with saturated aqueous ammonium chloride (5 mL) and extracted with ethyl acetate (10 mL × 3). The combined organic phase is washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate is concentrated under reduced pressure. The residue is purified by silica gel column chromatography to obtain compound 050-2. LC / MS (ESI+) m / z: [M+H] + =236.1.

[0667] 50.3 Synthesis of Compound 050

[0668] The synthesis of compound 050 refers to the synthesis method of compound 001, except that 001-a in the synthesis steps is replaced by 050-2 and 001-d is replaced by 041-a.

[0669] 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.

[0670] 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)

[0671]

[0672] 51.1 Synthesis of Compound 051-1

[0673] 051-a (5 g, 2.7 mmol), 051-b (2.8 g, 2.7 mmol), and ammonium acetate (4.2 g, 5.4 mmol) were dissolved in ethanol (100 mL) in sequence. The reaction mixture was reacted at 80°C for 24 hours. The reaction mixture was filtered, rinsed with ethanol, and the filter cake was dried under reduced pressure to obtain compound 051-1. LC / MS (ESI+) m / z: [M+H] + =246.00.

[0674] 51.2 Synthesis of Compound 051-2

[0675] 051-1 (3.7 g, 15.2 mmol) was dissolved in tetrahydrofuran (70 mL), the nitrogen atmosphere was replaced, and borane 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. The reaction solution was concentrated under reduced pressure, water (50 mL) was added, and then extracted with ethyl acetate (30 mL×2). 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 (dichloromethane / methanol = 5 / 1) to obtain compound 051-2. LC / MS (ESI+) m / z: [M+H] + =230.00.

[0676] 51.3 Synthesis of Compound 051

[0677] The synthesis of compound 050 refers to the synthesis method of compound 001, except that 001-a in the synthesis steps is replaced by 051-2.

[0678] 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=16.0H z,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),3.3 2–3.27(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.

[0679] 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)

[0680]

[0681] 52.1 Synthesis of Compound 052-1

[0682] 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 × 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.

[0683] 52.2 Synthesis of Compound 052-2

[0684] 052-1 (4.5 g, 25 mmol) was 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 mixture was allowed to react at 50°C overnight under nitrogen. The mixture 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.

[0685] 52.3 Synthesis of Compound 052-3

[0686] 052-2 (4.2 g, 20 mmol) was dissolved in toluene (20 mL), and sodium perborate tetrahydrate (11.2 g, 40 mmol) was added. The reaction mixture was allowed to react at room temperature for 2 hours, then diluted with water (50 mL) and extracted with ethyl acetate (10 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 = 3 / 1 to 1 / 1) to obtain compound 052-3.

[0687] 52.4 Synthesis of Compound 052-4

[0688] Under nitrogen protection, 052-3 (2.0 g, 6.8 mmol), bis-pinacol boronate (2.6 g, 10.2 mmol), potassium acetate (1.36 g, 13.6 mmol), and [1,1'-bis(diphenylphosphino)ferrocene] palladium dichloride (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 phases were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to obtain compound 052-4. LC / MS (ESI+) m / z: [M+H] + =386.05.

[0689] 52.5 Synthesis of Compound 052

[0690] The synthesis of compound 052 refers to the synthesis method of compound 001, except that 001-2 is replaced by 052-4.

[0691] 1 H 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),5.1 3(s,2H),4.58(d,J=8.0Hz,1H),3.83-3.79(m,1H),3.76-3.71(m,1H),3.58(s, 2H),3.40–3.22(m,4H),1.56–1.39(m,4H),0.35(s,4H); LC / MS(ESI+)m / z: [M+H] + =505.10.

[0692] 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)

[0693]

[0694] 53.1 Synthesis of Compound 053-1

[0695] Compound 020-5 (300 mg, 0.52 mmol) was weighed into a reaction flask, followed by the addition of compound 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). After nitrogen displacement, the reaction mixture was reacted at 100°C for 2 hours, then diluted with water (10 mL) and extracted with ethyl acetate (20 mL x 3). The organic phases were combined, washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate concentrated under reduced pressure. The residue was purified by silica gel column chromatography to yield compound 053-1. LC / MS (ESI+) m / z: [M+H] + =619.05.

[0696] 53.2 Synthesis of Compound 053

[0697] The synthesis of compound 053 was carried out according to the synthesis method of steps 1.6 and 1.7 in reference example 1.

[0698] 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.

[0699] 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)

[0700]

[0701] The synthesis of compound 054 was carried out by referring to the synthesis method of compound 053, except that the raw material 011-a was replaced by 012-a.

[0702] 1H 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,2H),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.

[0703] Example 55. Synthesis of 2-(2-((3'-(1-aminoethyl)-2'-fluoro-5-(3-oxa-9-azaspiro[5.5]undec-9-yl)-[1,1'-biphenyl]-3-yl)methoxy)phenyl)acetic acid (Compound 055)

[0704]

[0705] The synthesis of compound 055 was carried out by referring to the synthesis method of compound 053, except that the raw material 011-a was replaced by 029-a.

[0706] 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.

[0707] Example 56. Synthesis of 2-(2-((3'-(1-aminoethyl)-2'-fluoro-5-(2-oxa-9-azaspiro[5.5]undec-9-yl)-[1,1'-biphenyl]-3-yl)methoxy)phenyl)acetic acid (Compound 056)

[0708]

[0709] The synthesis of compound 056 was carried out by referring to the synthesis method of compound 053, except that the raw material 011-a was replaced by 030-a.

[0710] 1 H NMR (400MHz, DMSO-d6): δ8.38(d,J=4.0Hz,2H),7.56(t,J=16.0Hz,2H),7.38(t,J=12. 0Hz,1H),7.23(t,J=16.0Hz,2H),7.15(s,1H),7.03(d,J=8.0Hz,3H),6.90(t,J=16.0H z,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.

[0711] <Biological Activity Test>

[0712] 1. In vitro screening of complement factor D inhibitory activity (C3b method)

[0713] 1.1 Experimental materials and instruments

[0714] V-bottom plate (AXYGEN), DMSO (Sigma), MicroVue Bb Plus ELISA kit (Quidel), complement factor C3b (abbreviated as factor C3b, Complementtech), complement factor B (abbreviated as factor B, Complement tech), complement factor D (abbreviated as factor D, Complement tech), EDTA (McLean), GVB o (Complement tech), EGTA (Aladdin), MgCl2 (Aladdin), NaOH (Sinopharm), microplate reader (Molecular Devices, SpectraMax i3x), microplate constant temperature oscillator (Thermo, MB100-2A), pipette (Gilson)

[0715] 1.2 Preparation before the experiment

[0716] 1.2.1 Preparation of Mg-EGTA

[0717] 0.1M Mg-EGTA: Weigh 3.8 g EGTA, 0.9521 g MgCl2, and 0.7 g NaOH. Adjust the pH to 7.5 with NaOH. Make up to 100 mL with distilled water. Filter through a 0.2 μm sterile filter. Aliquot and store at 4°C.

[0718] 1.2.2 Preparation of working fluid

[0719] Buffer: 0.1M Mg-EGTA solution with GVB o Buffer was diluted 10-fold to 10 mM;

[0720] Factor B working solution: 1 mg / mL Factor B solution (10.75 μM) was diluted 6.7-fold with buffer to 1.6 μM;

[0721] Factor C3b working solution: 1 mg / mL factor C3b solution (5.68 μM) was diluted 5-fold with buffer to 1.12 μM;

[0722] Factor D working solution: 0.1 mg / mL Factor D solution (4.17 μM) was diluted 1303-fold with buffer to 3.2 nM.

[0723] Note: a. The above dilution ratios are for reference only and should be adjusted according to the actual concentration marked on the reagent;

[0724] b. Factor B: 93KDa, Factor D: 24KDa, Factor C3b: 176KDa.

[0725] 1.2.3 Preparation of stop solution

[0726] Stop solution: weigh an appropriate amount of EDTA powder and use a certain amount of GVB o The buffer was dissolved, the pH was adjusted to 7.5 with NaOH, and the mixture was stirred until clear to prepare a 10 mM solution.

[0727] 1.2.4 Compound preparation

[0728] Compound stock solution: 40 mM compound solution was diluted with DMSO to 1 mM stock solution, and the 1 mM stock solution was diluted 3-fold with DMSO to prepare 8 points of compound stock solution at each concentration;

[0729] Compound working solution: Dilute 250 times with buffer to obtain compound solutions of various concentrations.

[0730] 1.3 Experimental steps

[0731] In a V-bottomed 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 positive control group; 20 μL of 0.2% DMSO buffer was added to the blank control group; the cells were incubated at 37°C for 15 min; factor B working solution and factor C3b working solution were mixed in a 1:1 ratio, 20 μL of the mixture was added to each well, and the cells were incubated at 37°C for 30 min; 40 μL of stop solution was added to terminate the reaction; and the amount of product Bb produced was detected using a MicroVue Bb Plus ELISA kit.

[0732] 1.4 ELISA

[0733] 1.4.1 Remove the required ELISA plate wells and return them to room temperature. Rewrap the remaining wells and store at 4°C.

[0734] 1.4.2 Wash twice with 300 μL 1× Wash Buffer, incubating the first wash at 25°C for 1 min.

[0735] 1.4.3 Dilute the sample 8-fold with Complement Specimen Diluent, add 100 μL of sample to each well, and incubate at 25°C for 30 min.

[0736] 1.4.4 Discard the liquid in the wells and wash five times with 300 μL 1× Wash Buffer. Incubate the first wash at room temperature for 1 min.

[0737] 1.4.5 Add 50 μL of Bb Plus Conjugate to each well and incubate at 25°C for 30 min.

[0738] 1.4.6 Discard the liquid in the wells and wash five times with 300 μL 1× Wash Buffer. Incubate the first wash at room temperature for 1 min.

[0739] 1.4.7 Add 100 μL of the compound working solution (Substrate Solution) to each well and incubate at 25°C for 15 min.

[0740] 1.4.8 Add 100 μL of Stop Solution to each well and measure the absorbance at 450 nm within 30 min.

[0741] 1.5 Data Analysis

[0742] 1.5.1 Inhibition rate of each drug concentration:

[0743]

[0744] The PC group represents 0% inhibition rate, and the NC group represents 100% inhibition rate.

[0745] 1.5.2 Calculate the signal-to-background ratio (S / B):

[0746] The average OD value of the PC group / the average OD value of the NC group represents the size of the signal window.

[0747] 1.5.3 Z' factor:

[0748] Calculation formula:

[0749]

[0750] The Z' factor should be greater than 0.4.

[0751] 1.5.4 Compound IC 50 :

[0752] IC 50 : half-inhibitory concentration, representing the concentration of the compound that inhibits the enzyme activity of complement factor D by 50%;

[0753] Collect data to calculate the inhibition rate and the log value of compound concentration, and use GraphPad Prism software to calculate IC 50 The inhibitory activities of the compounds of the present invention on complement factor D are shown in Table 1.

[0754] Table 1: Inhibitory activity of the compounds of the present invention on complement factor D

[0755]

[0756]

[0757] Experimental conclusion: The compound of the present invention has a good inhibitory effect on complement factor D.

[0758] 2. Rabbit erythrocyte hemolysis assay to evaluate the inhibitory activity of compounds on the alternative pathway

[0759] 2.1 Experimental materials and instruments

[0760] Normal Human Serum, NHS (collected from healthy individuals), Normal Human Plasma, NHP (Shanghai Yuduo), 96-well ELISA plate (Jet Biofil), Japanese big-eared white rabbit (Wuhan Wanqian Jiaxing), Aldrich solution (Punosai), centrifuge (Thermo, PICO17), constant temperature shaker (Shanghai Fuma), decolorization shaker (Beijing Liuyi), cell counter (Invitrogen, Counter Countess II) (GVBo, EGTA, MgCl2, NaOH, microplate reader, microplate constant temperature shaker, pipette, etc. are the same as those in Experiment 1).

[0761] 2.2 Preparation of working solution

[0762] 48% NHP: 100% NHP was diluted to 48% with buffer;

[0763] 26.4% NPS: 100% NHS diluted to 26.4% with buffer;

[0764] Rabbit red blood cell suspension: Blood was collected from the rabbit ear vein, anticoagulated with Aldrich solution (1:1), aliquoted and stored at 4°C. It can be stored for 4 weeks. Before use, centrifuge at 500g for 5 minutes and discard the Aldrich solution. Wash three times with an equal volume of buffer (500g) and centrifuge at 500g for 5 minutes. Finally, adjust the density to 6×10 8 pieces / mL.

[0765] 2.3 Experimental steps

[0766] In a 96-well ELISA plate, 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 buffer were added to the blank control group; 100 μL of double-distilled water was added to the H2O group; the plates were incubated at 37°C for 15 min; 20 μL of rabbit erythrocyte suspension was added to each well, and the plates were incubated on a shaker at 37°C for 30 min; the plates were centrifuged at 2000 g (3380 rpm) for 5 min, 100 μL of the supernatant was transferred to a new 96-well ELISA plate, and the absorbance was measured at 415 nm.

[0767] 2.4 Data Analysis

[0768] 2.4.1 Hemolysis percentage at each drug concentration:

[0769]

[0770] The PC group represents 100% hemolysis, and the NC group represents 0% hemolysis.

[0771] 2.4.2 Calculate the signal-to-background ratio (S / B):

[0772] The average OD value of the PC group / the average OD value of the NC group represents the size of the signal window.

[0773] 2.4.3 Z' factor:

[0774] Calculation formula:

[0775]

[0776] 2.4.4 Compound IC 50 :

[0777] IC 50 : Half inhibitory concentration. Data were collected to calculate the log value of hemolysis percentage and compound concentration, and IC was calculated using GraphPadPrism software. 50 The inhibitory activities of the compounds of the present invention on rabbit erythrocyte hemolysis are shown in Table 2.

[0778] Table 2: Inhibitory activity of the compounds of the present invention on rabbit erythrocyte hemolysis

[0779]

[0780]

[0781] Experimental conclusion: The compound of the present invention has a good inhibitory effect on rabbit erythrocyte hemolysis.

[0782] 3. In vivo pharmacokinetic studies of the compounds of the present invention

[0783] After acclimation, SPF-grade SD rats were administered 1 or 3 mg / kg of the compounds of the present invention by single oral gavage or tail vein bolus injection, respectively. Plasma was collected at specific time points after administration, and the compound concentration in plasma was determined by LC-MS / MS (AB SCIEX Qtrap4500). The PK parameters of each compound were calculated using software to reflect the pharmacokinetic properties of the compounds of the present invention in animals. The PK parameters of the compounds of the present invention are shown in Table 3.

[0784] Table 3: PK test of the compounds of the present invention on SD rats

[0785]

[0786]

[0787] Experimental conclusion: The compound of the present invention can achieve higher in vivo exposure and higher oral bioavailability at a lower dose, and has better overall pharmacokinetic properties.

[0788] The above describes exemplary embodiments of the present invention. However, the scope of protection of this application is not limited to the above exemplary embodiments. Any modifications, equivalent substitutions, improvements, etc. made by those skilled in the art within the spirit and principles of the present invention shall be included in the scope of protection defined by the claims of this application.

Claims

1. A compound represented by formula (I), a stereoisomer thereof, or a pharmaceutically acceptable salt of any of the foregoing: in: R 1 is H; R 2 and R 3 Each independently is H, C 1-6 Alkyl or 1, 2 or 3 R 2-1 Substituted C 1-6 Alkyl; each R 2-1 are independently halogen, -OH or C 1-6 alkoxy; R 4 is halogen; m is 0, 1, 2 or 3; R 5 and R 7 are independently H, halogen, C 1-6 Alkyl or C 1-6 alkoxy; R 6 "8-11 membered heterocycloalkyl group having 1, 2 or 3 heteroatoms selected from N, O and S" or 1, 2 or 3 R 6-2 Substituted "8-11-membered heterocycloalkyl group having 1, 2 or 3 heteroatoms selected from N, O and S"; R 6-2 are independently hydroxyl, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl or C 1-6 haloalkoxy; R 6 wherein the heterocycloalkyl group is a bridged ring or a spiro ring; R 8 H or C 1-6 alkyl; R 9 Halogen or C 1-6 Alkyl; n is 0, 1, 2, 3 or 4; L is -(CR a R b ) q -; q is 1, 2 or 3; R a and R b are each independently H or halogen; R 10 -COOH or -C(=O)OR c ; R c C 1-6 alkyl; X is CR d or N; R d is H, halogen or C 1-6 alkyl.

2. The compound of formula (I) according to claim 1, its stereoisomers, or a pharmaceutically acceptable salt of any of the foregoing, characterized in that: The compound represented by formula (I) satisfies one or more of the following conditions: (1)R 2 and R 3 Each independently is H, C 1-3 Alkyl or 1, 2 or 3 R 2-1 Substituted C 1-3 Alkyl; each R 2-1 are independently halogen or -OH; (2) m is 0 or 1; (3)R 5 and R 7 are each independently H or halogen; (4)R 6 wherein the 8-11 membered heterocycloalkyl group is 6-azaspiro[2.5]octyl, 5-azaspiro[2.5]octyl, 6-azaspiro[3.4]octyl, 2-azaspiro[3.4]octyl, 2-oxa-6-azaspiro[3.4]octyl, 6-oxa-2-azaspiro[3.4]octyl, 4-oxa-7-azaspiro[2.5]octyl, 2-azaspiro[4.4]nonyl, 2-azaspiro[3.5]nonyl, 2-oxa-7-azaspiro[3.5]nonyl, 1-oxa-7-azaspiro[2.5]octyl, [3.5]nonyl, 7-azaspiro[3.5]nonyl, 2,7-diazaspiro[3.5]nonyl, 2-oxa-8-azaspiro[4.5]decyl, 3-oxa-9-azaspiro[5.5]undecyl, 2-oxa-9-azaspiro[5.5]undecyl, 3,9-diazaspiro[5.5]undecyl, 3-azabicyclo[3.2.1]octyl, 3-azaspiro[5,5]undecyl, 8-azaspiro[4.5]decyl or 1-oxa-6-azaspiro[3,4]octyl; (5) Each R 6-2 are independently hydroxy or C 1-3 alkyl; (6)R 8 is H; (7)R 9 is a halogen; (8) n is 0 or 1; (9)q is 1; (10)R a and R b is H; (11)R 10 is -COOH; (12)R d For H.

3. The compound represented by formula (I) according to claim 2, its stereoisomer, or a pharmaceutically acceptable salt of any of the foregoing, characterized in that: The compound represented by formula (I) satisfies one or more of the following conditions: (1) Each R 2-1 wherein the halogen is F; (2)R 5 and R 7 wherein the halogen is F; (3) Each R 6-2 are independently hydroxy, methyl, ethyl, n-propyl or isopropyl; (4)R 9 wherein the halogen is F.

4. The compound represented by formula (I) according to claim 1, its stereoisomers, or a pharmaceutically acceptable salt of any of the foregoing, characterized in that: R 6 "8-10 membered heterocycloalkyl group having 1, 2 or 3 heteroatoms selected from N, O and S" or 1, 2 or 3 R 6-2 The substituted "8-10 membered heterocycloalkyl group having 1, 2 or 3 heteroatoms selected from N, O and S".

5. The compound represented by formula (I) according to claim 1, its stereoisomers, or a pharmaceutically acceptable salt of any of the foregoing, characterized in that: R 1 is H; R 2 and R 3 Each independently is H, C 1-3 Alkyl or 1, 2 or 3 R 2-1 Substituted C 1-3 Alkyl; each R 2-1 are independently halogen or -OH; R 4 is halogen; m is 0 or 1; R 5 and R 7 are each independently H or halogen; R 6 "8-11 membered heterocycloalkyl group having 1, 2 or 3 heteroatoms selected from N, O and S" or 1, 2 or 3 R 6-2 Substituted "8-11-membered heterocycloalkyl group having 1, 2 or 3 heteroatoms selected from N, O and S", wherein the heterocycloalkyl group is a bridged ring or a spiro ring; Each R 6-2 are independently hydroxy or C 1-3 alkyl; R 8 is H; R 9 is halogen; n is 0 or 1; L is -(CR a R b ) q -, q is 1; R a and R b Each independently is H; R 10 is -COOH; X is CR d or N; R d For H.

6. The compound represented by formula (I) according to claim 1, its stereoisomers, or a pharmaceutically acceptable salt of any of the foregoing, characterized in that: The compound represented by formula (I) satisfies one or more of the following conditions: (1)R 2 、R 3 、R 5 、R 7 、R 6-2 、R 8 、R 9 、R c and R d wherein each of the alkyl groups is independently methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl or tert-butyl; (2)R 2-1 、R 5 、R 7 and R 6-2 wherein each of the alkoxy groups is independently methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy or tert-butoxy; (3)R 2-1 、R 4 、R 5 、R 7 、R 9 、R a 、R b and R d wherein each halogen is independently F, Cl, Br or I; (4)R 6 In the above, each heterocycloalkyl group is independently "an 8-11 membered heterocycloalkyl group having 1, 2 or 3 heteroatoms selected from N, O and S, with 1 or 2 heteroatoms", and the heterocycloalkyl group is a bridged ring or a spiro ring; the heterocycloalkyl group is connected to the parent group through a nitrogen atom.

7. The compound represented by formula (I) according to claim 6, its stereoisomer, or a pharmaceutically acceptable salt of any of the foregoing, characterized in that: The compound represented by formula (I) satisfies one or more of the following conditions: (1)R 2 、R 3 、R 5 、R 7 、R 6-2 、R 8 、R 9 、R c and R d In which each of the alkyl groups is independently a methyl group or an ethyl group; (2)R 2-1 、R 4 、R 5 、R 7 、R 9 、R a 、R b and R d wherein each halogen is independently F; (3)R 6 wherein the heterocycloalkyl group is 8. The compound represented by formula (I) according to claim 1, its stereoisomers, or a pharmaceutically acceptable salt of any of the foregoing, characterized in that: The compound represented by formula (I) satisfies one or more of the following conditions: (1)R 2 H, R 3 is H, -CH3, -CH2OH, -CH2CH2OH, -CH2F or -CF2H; (2)R 6 for 9. The compound represented by formula (I) according to claim 1, its stereoisomers, or a pharmaceutically acceptable salt of any of the foregoing, characterized in that: The compound represented by formula (I) satisfies any of the following conditions: (1)R 1 is H; R 2 H, R 3 is H, -CH3 or -CH2F; R 4 is halogen, m is 0 or 1; R 5 and R 7 are each independently H or F; R 6 "8-11 membered heterocycloalkyl group with 1, 2 or 3 heteroatoms selected from N, O and S" or "8-11 membered heterocycloalkyl group with 1, 2 or 3 heteroatoms selected from N, O and S" or "8-11 membered heterocycloalkyl group with 1, 2 or 3 heteroatoms selected from N, O and S" 6-2 Substituted "8-11-membered heterocycloalkyl group having 1, 2 or 3 heteroatoms selected from N, O and S"; Each R 6-2 are independently hydroxy or C 1-3 alkyl; R 8 is H; R 9 is F; n is 0 or 1; L is -(CR a R b ) q -;q is 1;R a and R b Each independently is H; R 10 is -COOH; X is CR d or N; R d is H; (2)R 1 is H; R 2 H, R 3 is H, -CH3 or -CH2F; R 4 is halogen, m is 0 or 1; R 5 and R 7 are each independently H or F; R 6 "8-11 membered heterocycloalkyl group with 1, 2 or 3 heteroatoms selected from N, O and S" or "8-11 membered heterocycloalkyl group with 1, 2 or 3 heteroatoms selected from N, O and S" or "8-11 membered heterocycloalkyl group with 1, 2 or 3 heteroatoms selected from N, O and S" 6-2 Substituted "8-11-membered heterocycloalkyl group having 1, 2 or 3 heteroatoms selected from N, O and S"; Each R 6-2 are independently hydroxy or C 1-3 alkyl; R 8 is H; R 9 is F; n is 0 or 1; L is -(CR a R b ) q -;q is 1;R a and R b Each independently is H; R 10 is -COOH; X is CR d or N; R d is H; (3)R 1 is H; R 2 H, R 3 is H, -CH3 or -CH2F; R 4 is halogen, m is 0 or 1; R 5 and R 7 are each independently H or F; R 6 for Or by 1 R 6-2 Substituted groups: R 6-2 is hydroxyl or methyl; R 8 is H; R 9 is F; n is 0 or 1; L is -(CR a R b ) q -;q is 1;R a and R b Each independently is H; R 10 is -COOH; X is CR d or N; R d is H; (4)R 1 is H; R 2 H, R 3 is H, -CH3 or -CH2F; R 4 is F, m is 0 or 1; R 5 and R 7 are each independently H or F; R 6 for R 8 is H; R 9 is F; n is 0 or 1; L is -(CR a R b ) q -;q is 1;R a and R b Each independently is H; R 10 is -COOH; X is CR d or N; R d For H.

10. The compound of formula (I) according to any one of claims 1 to 9, its stereoisomers, or a pharmaceutically acceptable salt of any of the foregoing, characterized in that: The compound represented by formula (I) has the structure represented by formula (I-1): Among them, 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 1-9.

11. The compound of formula (I) according to any one of claims 1 to 9, its stereoisomers, or a pharmaceutically acceptable salt of any of the foregoing, characterized in that: The compound represented by formula (I) has the structure represented by formula (I-2): Among them, 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 any one of claims 1-9.

12. The compound of formula (I) according to any one of claims 1 to 9, its stereoisomers, or a pharmaceutically acceptable salt of any of the foregoing, characterized in that: The compound represented by formula (I) has the structure represented by formula (I-3): Among them, 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 1-9.

13. The compound of formula (I) according to any one of claims 1 to 9, its stereoisomers, or a pharmaceutically acceptable salt of any of the foregoing, characterized in that: The compound represented by formula (I) has the structure represented by formula (I-4): Among them, 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 any one of claims 1 to 9; when the carbon atom marked with "*" is a chiral carbon atom, it represents R configuration, S configuration or a mixture thereof.

14. The compound of formula (I) according to claim 1, its stereoisomers, or a pharmaceutically acceptable salt of any of the foregoing, characterized in that: The compound represented by formula (I) is selected from any one of the following compounds:

15. The compound of formula (I) according to claim 14, its stereoisomers, or a pharmaceutically acceptable salt of any of the foregoing, characterized in that: The compound represented by formula (I) is selected from any one of the following compounds:

16. A method for preparing a compound represented by formula (I), characterized in that: It includes the following steps: (1) The compound represented by formula II-3 is subjected to a deprotection reaction to obtain the compound represented by formula II-4; (2) The compound represented by formula II-4 is subjected to a hydrolysis reaction to obtain the compound represented by formula (I); Among them, R 10 is -COOH, 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 of claims 1-15.

17. A compound as shown in formula II-3 or formula II-4: in, 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 1-15.

18. A compound as shown below:

19. A pharmaceutical composition, characterized in that The pharmaceutical composition comprises: (1) a compound of formula (I) according to any one of claims 1 to 15, a stereoisomer thereof, or a pharmaceutically acceptable salt of any of the foregoing; and (2) Pharmaceutically acceptable carrier.

20. Use of a compound of formula (I) according to any one of claims 1 to 15, a stereoisomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, or a pharmaceutical composition according to claim 19 in the preparation of a medicament for treating and / or preventing diseases mediated by complement factor D, characterized in that: The complement factor D-mediated disease is selected from anti-neutrophil cytoplasmic antibody-associated vasculitis, paroxysmal nocturnal hemoglobinuria, IgA nephropathy, atypical hemolytic uremic syndrome, membranoproliferative glomerulonephritis, C3 glomerulonephritis, rheumatoid arthritis, myasthenia gravis, Alzheimer's disease, coronavirus infection and macular degeneration.

21. The use according to claim 20, characterized in that It meets one or both of the following conditions: (1) The coronavirus infection is SARS-CoV-2 infection; (2) The macular degeneration described is age-related macular degeneration.

22. Use of the compound of formula (I) according to any one of claims 1 to 15, its stereoisomers, or a pharmaceutically acceptable salt of any one of the foregoing, or the pharmaceutical composition according to claim 19 in the preparation of a complement factor D inhibitor.

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