Compound as complement factor d inhibitor, pharmaceutical composition thereof and use thereof

Abstract

Disclosed in the present invention are a compound as a complement factor D inhibitor, a pharmaceutical composition thereof and the use thereof. Specifically disclosed are a compound as represented by formula (I), a tautomer thereof, a stereoisomer thereof, a prodrug thereof, or a pharmaceutically acceptable salt of any of the foregoing, or a solvate of any of the foregoing. The compound has a good inhibitory activity on complement factor D, and exhibits good pharmacokinetic and pharmacodynamic activities.

Description

Compounds, pharmaceutical compositions and applications of complement factor D inhibitors

[0001] This application claims priority to Chinese patent application 2024118524236, filed on 2024 / 12 / 16. The entire contents of the aforementioned Chinese patent application are incorporated herein by reference. Technical Field

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

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

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

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

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

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

[0008] This invention provides a pharmaceutically acceptable salt of the compound of formula (I), its tautomers, its stereoisomers, its prodrugs, or any of the foregoing (referring to the compound of formula (I), its tautomers, its stereoisomers, or its prodrugs), or a solvate of any of the foregoing (referring to the compound of formula (I), its tautomers, its stereoisomers, its prodrugs, or any of the foregoing pharmaceutically acceptable salts):

[0009] in:

[0010] R 1 For H, D, C 1-6 Alkyl groups or those with 1, 2, or 3 R groups 1-1 Replacement C 1-6 Alkyl groups; each R 1-1 Independently halogen, -CN, -OH, C 1-6 alkoxy or -NH2;

[0011] R 2 and R 3 Each is independently H, D, halogen, C 1-6 Alkyl groups or those with 1, 2, or 3 R groups 2-1 Replacement C 1-6 Alkyl groups; each R 2-1 Independently halogen, -CN, -OH, C 1-6 alkoxy or -NH2;

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

[0013] R 5 and R 7 Each is independently H, halogen, -CN, C 1-6 Alkyl or C 1-6 Alkoxy;

[0014] R 6H "8-12-membered fused heterocyclic alkyl group selected from 1, 2, or 3 of N, O, and S, with 1, 2, or 3 heteroatoms", or "8-12-membered bridged heterocyclic alkyl group selected from 1, 2, or 3 of N, O, and S, with 2 or 3 heteroatoms", surrounded by 1, 2, or more R... 6-1 The substituted "an 8-12 membered fused heterocyclic alkyl group selected from one, two, or three of N, O, and S, with one, two, or three heteroatoms" is replaced by one, two, or more R... 6-1 The substituted "heteroatom is selected from one, two, or three of N, O, and S, and is an 8-12 membered bridged heterocyclic alkyl group with two or three heteroatoms"

[0015] R 6-1 Each is independently a hydroxyl group, an oxygen group (=O), a halogen, or a carbon group. 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Halogenated alkoxy groups, C 3-6 Cycloalkyl or -(CH2) p -C 3-6 Cycloalkyl; p is 1, 2, 3 or 4;

[0016] R 6-2 and R 6-3 Each is independently a hydroxyl group, an oxygen group (=O), a halogen, or a carbon group. 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Halogenated alkoxy groups, C 3-6 Cycloalkyl or -(CH2) p -C3-6 cycloalkyl;

[0017] x1 and x2 are independently 0, 1, 2, 3 or 4;

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

[0019] R 9 H, halogen, C 1-6 Alkyl groups or those with 1, 2, or 3 R groups 9-1 Replacement C 1-6 alkyl;

[0020] Each R 9-1 It can be halogen, -CN, -OH or -NH2 independently; 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 Each is independently H, D, or halogen, or R. a and R b Connect together to form C 3-6 Cycloalkylene;

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

[0024] R c C 1-6 Alkyl groups or those with 1, 2, or 3 R groups c-1 Replacement C 1-6 Alkyl groups; each R c-1 It can be independently a halogen, -OH, or -C(=O)OC(CH3)3;

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

[0026] In one aspect of the present invention, R 6H It is defined as "an 8-9 membered fused heterocyclic alkyl group whose heteroatoms are selected from 1, 2 or 3 of N, O and S, and whose heteroatoms number 1, 2 or 3" or "an 8 membered bridged heterocyclic alkyl group whose heteroatoms are selected from 1, 2 or 3 of N, O and S, and whose heteroatoms number 2".

[0027] In one aspect of the present invention, R 6H for Or “the heteroatoms are selected from N and O, and the number of heteroatoms is 2 in an 8-membered bridged heterocyclic alkyl group”;

[0028] Ring A is C 3-6 Cycloalkyl or “a 4-6 membered heterocycloalkyl group whose heteroatoms are selected from one or two of N, O and S, and whose heteroatoms number one or two”.

[0029] Ring B is "a 4-6 membered heterocyclic alkyl group selected from one or two of N, O and S heteroatoms, with one or two heteroatoms".

[0030] In one embodiment of the present invention, ring A is C. 5-6 Cycloalkyl or "a 4-6 membered heterocyclic alkyl with one heteroatom selected from N, O and S"; preferably "a 4-6 membered heterocyclic alkyl with one heteroatom selected from N, O and S"; even more preferably "a 4-6 membered heterocyclic alkyl with one heteroatom of O"; and even more preferably "a 5 membered heterocyclic alkyl with one heteroatom of O".

[0031] In one embodiment of the present invention, ring B is "a 5-6 membered heterocyclic alkyl group whose heteroatoms are selected from one or two of N, O and S, and whose heteroatoms number one or two"; more preferably, it is "a 5-6 membered heterocyclic alkyl group whose heteroatoms are one or two of N or O, and whose heteroatoms number one or two"; and even more preferably, it is "a 6 membered heterocyclic alkyl group whose heteroatoms are N and whose heteroatoms number one".

[0032] In one aspect of the present invention, the compound represented by formula (I) has the structure shown in formula (IA):

[0033] Among them, R 1 R 2 R 3 R 4 R 5 R 6H R 7 R 8 R 9 R 10 X, L, m, and n each have the definition described in any of the schemes in this application; when the carbon atom marked with "*" is a chiral carbon atom, it represents the R configuration, S configuration, or a mixture thereof.

[0034] In one aspect of the present invention, the compound represented by formula (I) has the structure represented by formula (II):

[0035] Among them, R 1 R 2 R 3 R 4 R5 R 6H R 7 R 8 R 9 R 10 R d L, m, and n each have their own independent definitions as described in any of the schemes in this application.

[0036] In one aspect of the present invention, the compound represented by formula (I) has the structure shown in formula (II-A):

[0037] Among them, R 1 R 2 R 3 R 4 R 5 R 6H R 7 R 8 R 9 R 10 R d L, m, and n each have the definition described in any of the schemes in this application; when the carbon atom marked with "*" is a chiral carbon atom, it represents the R configuration, S configuration, or a mixture thereof.

[0038] In one aspect of the present invention, the compound represented by formula (I) has the structure represented by formula (III):

[0039] Among them, X and R 2 R 3 R 4 R 5 R 6H R 7 R 8 R 9 L, m, and n each have their own independent definitions as described in any of the schemes in this application.

[0040] In one aspect of the present invention, the compound represented by formula (I) has the structure shown in formula (III-A):

[0041] Among them, X and R 2 R 3 R 4 R 5 R 6H R 7 R 8 R 9 L, m, and n each have the definition described in any of the schemes in this application; when the carbon atom marked with "*" is a chiral carbon atom, it represents the R configuration, S configuration, or a mixture thereof.

[0042] In one aspect of the present invention, the compound represented by formula (I) has the structure shown in formula (IV):

[0043] Among them, R 2 R 3 R 4 R 5 R 6H R 7 R 8 R 9 m and n each independently have the definitions described in any of the embodiments of this application. In one embodiment of the invention, the compound represented by formula (I) has the structure shown in formula (IV-A):

[0044] Among them, R 2 R 3 R 4 R 5 R 6H R 7 R 8 R 9 m and n each have the definition described in any of the schemes in this application; when the carbon atom marked with "*" is a chiral carbon atom, it represents the R configuration, S configuration or a mixture thereof.

[0045] In certain preferred embodiments of the present invention, certain groups in the compound of formula (I), its tautomers, its stereoisomers, its prodrugs, or pharmaceutically acceptable salts of any of the foregoing (referring to the compound of formula (I), its tautomers, its stereoisomers, or its prodrugs), or solvates of any of the foregoing (referring to the compound of formula (I), its tautomers, its stereoisomers, its prodrugs, or pharmaceutically acceptable salts of any of the foregoing) are defined as follows, and groups not mentioned are as described in any embodiment of the present invention (hereinafter referred to as "in a certain embodiment of the present invention").

[0046] In one aspect of the present invention, R 6-1 In this context, the cycloalkyl group is independently a monocyclic, bridged, or spirocyclic ring.

[0047] In one aspect of the present invention, R a and R b Connect together to form C 3-6 Cycloalkylene compounds, which can be monocyclic, bridged, or spirocyclic.

[0048] In one aspect of the present invention, R 1 For H.

[0049] In one aspect of the present invention, R2 For H.

[0050] In one aspect of the present invention, R 3 For H.

[0051] In one aspect of the present invention, R 2 and R 3 Each independently represents H and C. 1-6 Alkyl groups or those with 1, 2, or 3 R groups 2-1 Replacement C 1-6 Alkyl groups; each R 2-1 It is independently a halogen or -OH, wherein the halogen is preferably F.

[0052] In one aspect of the present invention, R 2 and R 3 Each independently represents H and C. 1-3 Alkyl groups or those with 1, 2, or 3 R groups 2-1 Replacement C 1-3 Alkyl groups; each R 2-1 It is independently a halogen or -OH, wherein the halogen is preferably F.

[0053] In one aspect of the present invention, R 4 For H.

[0054] In one embodiment of the present invention, m is 0 or 1; preferably 0.

[0055] In one aspect of the present invention, R 5 For H.

[0056] In one aspect of the present invention, R 7 For H.

[0057] In one aspect of the present invention, R 5 and R 7 Each is independently H or a halogen, preferably F.

[0058] In one aspect of the present invention, R 6H "An 8-10 fused heterocyclic alkyl group selected from one, two, or three of N, O, and S, with one, two, or three heteroatoms", or "An 8-10 bridged heterocyclic alkyl group selected from one, two, or three of N, O, and S, with one, two, or three heteroatoms", surrounded by one, two, or more R... 6-1 The substituted "heteroatom is selected from one, two or three of N, O and S, and the number of heteroatoms is one, two or three, of an 8-10 member fused heterocyclic alkyl group" or is replaced by one, two or more R 6-1 The substituted "heteroatom is selected from one, two, or three of N, O, and S, and is an 8-10 membered bridged heterocyclic alkyl group having one, two, or three heteroatoms"; preferably, the R 6HIt is connected to the benzene ring through a nitrogen atom.

[0059] In one aspect of the present invention, R 6-1 Independently hydroxyl, oxo (=O), halogen, C 1-3 Alkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkyl or C 1-3 Halogenated alkoxy groups.

[0060] In one aspect of the present invention, R 6-2 and R 6-3 Each is independently a hydroxyl, halogen, or C 1-3 alkyl.

[0061] In one embodiment of the present invention, x1 is 0 or 1; preferably 0.

[0062] In one embodiment of the present invention, x2 is 0 or 1; preferably 0.

[0063] In one aspect of the present invention, R 8 For H.

[0064] In one aspect of the present invention, R 9 It is H or a halogen; the halogen is preferably F; R 9 H is preferred.

[0065] In one embodiment of the present invention, n is 0 or 1; preferably 0.

[0066] In one embodiment of the present invention, q is 1.

[0067] In one aspect of the present invention, R a and R b Each is independently represented by H.

[0068] In one aspect of the present invention, R 10 It is -COOH.

[0069] In one aspect of the present invention, R d It is H or halogen.

[0070] In one embodiment of the present invention, X is CR d Or N; R d For H.

[0071] In one aspect of the present invention, R 2 For H and R 3 For H, C 1-3 Alkyl groups or those with 1, 2, or 3 R groups 2-1 Replacement C 1-3 Alkyl groups; each R 2- 1 It can be a halogen or -OH on its own.

[0072] In one aspect of the present invention, R 2 For H and R 3 It can be H, -CH3, -CH2OH, -CH2CH2OH, -CH2F, or -CF2H.

[0073] In one aspect of the present invention, R 6H In this context, each of the fused heterocyclic alkyl groups is independently 8-oxa-3-azabicyclo[4.2.0]octyl, 7-oxa-3-azabicyclo[4.2.0]octyl, 3,8-diazabicyclo[4.2.0]octyl, 3,7-diazabicyclo[4.2.0]octyl, octahydrofurano[2,3-c]pyridyl, octahydrofurano[3,4-c]pyridyl, octahydrofurano[3,2-c]pyridyl, octahydro-1H-pyrrolo[2,3-c]pyridyl, octahydro-1H-pyrrolo[3,2-c]pyridyl, octahydro-1H-pyrrolo[3,4 ... Hydrogen-1H-cyclopentano[c]pyridyl, hexahydro-2H-furano[2,3-c]pyrrole, hexahydro-1H-furano[3,4-c]pyrrole, octahydrocyclopentano[c]pyrrole, octahydropyrrolo[3,4-b]pyrrole, octahydropyrrolo[3,4-c]pyrrole, octahydro-1H-pyrrolo[3,4-b]pyridyl, octahydropyrano[2,3-c]pyrrole, octahydropyrano[3,4-c]pyrrole, octahydro-1H-isoindolyl, octahydropyrrolo[3,4-b][1,4]oxazinyl or hexahydro-5H-[1,4]dioxa[2,3-c]pyrrole.

[0074] In one aspect of the present invention, R 6H In this context, each of the bridged heterocyclic alkyl groups is independently 2-oxa-5-azabicyclo[2.2.2]octyl, 2,5-diazabicyclo[2.2.2]octyl, 3,8-diazabicyclo[3.2.1]octyl, 8-oxa-3-azabicyclo[3.2.1]octyl or 3-oxa-8-azabicyclo[3.2.1]octyl.

[0075] In one aspect of the present invention, R 6HThe compounds are 8-oxa-3-azabicyclo[4.2.0]octyl, 7-oxa-3-azabicyclo[4.2.0]octyl, 3,8-diazabicyclo[4.2.0]octyl, 3,7-diazabicyclo[4.2.0]octyl, octahydrofurano[2,3-c]pyridyl, octahydrofurano[3,4-c]pyridyl, octahydrofurano[3,2-c]pyridyl, and octahydro-1 H-pyrrolo[2,3-c]pyridyl, octahydro-1H-pyrrolo[3,2-c]pyridyl, octahydro-1H-pyrrolo[3,4-c]pyridyl, octahydro-1H-cyclopentano[c]pyridyl, hexahydro-2H-furano[2,3-c]pyrryl, hexahydro-1H-furano[3,4-c]pyrryl, octahydrocyclopentano[c]pyrryl, octahydropyrrolo[3,4-b]pyrryl Pyrroloyl, octahydropyrrolo[3,4-c]pyrroloyl, octahydro-1H-pyrrolo[3,4-b]pyridyl, octahydropyrano[2,3-c]pyrroloyl, octahydropyrano[3,4-c]pyrroloyl, octahydro-1H-isoindolyl, octahydropyrrolo[3,4-b][1,4]oxazinyl, hexahydro-5H-[1,4]dioxa[2,3-c]pyrroloyl, 2-oxa-5-aza Bicyclo[2.2.2]octyl, 2,5-diazabicyclo[2.2.2]octyl, 3,8-diazabicyclo[3.2.1]octyl, 8-azabicyclo[3.2.1]octyl, 8-oxa-3-azabicyclo[3.2.1]octyl, 3-oxa-8-azabicyclo[3.2.1]octyl or 3-azabicyclo[3.2.1]octyl, or with 1 or 2 R 6-1The following groups are substituted: 8-oxa-3-azabicyclo[4.2.0]octyl, 7-oxa-3-azabicyclo[4.2.0]octyl, 3,8-diazabicyclo[4.2.0]octyl, 3,7-diazabicyclo[4.2.0]octyl, octahydrofuran[2,3-c]pyridyl, octahydrofuran[3,4-c]pyridyl, octahydrofuran [3,2-c]pyridyl, octahydro-1H-pyrrolo[2,3-c]pyridyl, octahydro-1H-pyrrolo[3,2-c]pyridyl, octahydro-1H-pyrrolo[3,4-c]pyridyl, octahydro-1H-cyclopentano[c]pyridyl, hexahydro-2H-furano[2,3-c]pyrryl, hexahydro-1H-furano[3,4-c]pyrryl, octa ... Hydrocyclopentano[c]pyrrolithyl, octahydropyrrolo[3,4-b]pyrrolithyl, octahydropyrrolo[3,4-c]pyrrolithyl, octahydro-1H-pyrrolo[3,4-b]pyridyl, octahydropyrano[2,3-c]pyrrolithyl, octahydropyrano[3,4-c]pyrrolithyl, octahydro-1H-isoindolyl, octahydropyrrolo[3,4-b][1,4]oxazinyl, hexahydro -5H-[1,4]dioxa[2,3-c]pyrrole, 2-oxa-5-azabicyclo[2.2.2]octyl, 2,5-diazabicyclo[2.2.2]octyl, 3,8-diazabicyclo[3.2.1]octyl, 8-oxa-3-azabicyclo[3.2.1]octyl or 3-oxa-8-azabicyclo[3.2.1]octyl.

[0076] In one embodiment of the present invention, each R 6-1 Independently hydroxyl, oxo (=O), halogen or C 1-3 Alkyl; the C 1-3 The alkyl group is preferably methyl; the halogen is preferably F; each R 6-1 Hydroxyl groups are preferred independently.

[0077] In one embodiment of the present invention, X is CR d .

[0078] In one aspect of the present invention, R d For H.

[0079] In one aspect of the present invention, R 1 R 2 R 3 R 5 R 7 R 6-1 R 6-2 R 6-3 R 8 R 9 R c and R dIn this embodiment, each of the alkyl groups is independently methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl or tert-butyl, preferably methyl or ethyl.

[0080] In one aspect of the present invention, R 1-1 R 2-1 R 5 R 7 R 6-1 R 6-2 and R 6-3 In this context, each of the alkoxy groups is independently methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, or tert-butoxy.

[0081] In one aspect 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 6-3 R 8 R 9 R 9-1 R a R b R c-1 and R d In this embodiment, each of the halogens is independently F, Cl, Br or I, preferably F.

[0082] In one aspect of the present invention, R 6H In this context, each of the fused heterocycloalkyl groups is independently...

[0083] In one aspect of the present invention, R 6H In this context, each of the bridged heterocyclic alkyl groups is independently...

[0084] In one aspect of the present invention, R 6H for Or by one, two or more R 6-1 The following groups are substituted:

[0085] In one aspect of the present invention, R 6H for Or by 1 or 2 R 6-1The following groups are substituted:

[0086] In one aspect of the present invention, R 2 For H, R 3 For H.

[0087] In one aspect of the present invention, R 4 H or halogen, m is 0 or 1

[0088] In one aspect of the present invention, R 4 H is a variable, and m is either 0 or 1.

[0089] In one aspect of the present invention, R 5 and R 7 Each can be H or F independently.

[0090] In one aspect of the present invention, R 5 and R 7 For H.

[0091] In one aspect of the present invention, R 9 It can be H or F.

[0092] In one aspect of the present invention, R 9 Let H be the integer part of the set, and n be 0 or 1.

[0093] In one embodiment of the present invention, each R 6-1 It can be hydroxyl, oxo (=O), F, Cl, methyl, ethyl, n-propyl or isopropyl independently.

[0094] In one embodiment of the present invention, each R 6-1 It can be hydroxyl, oxo (=O), F or methyl independently.

[0095] In one aspect of the present invention, R 6H for

[0096] In one aspect of the present invention, R 6H for

[0097] In one aspect of the present invention, R 1 For H;

[0098] R 2 For H, R 3 The possible values ​​are H, -CH3, -CH2OH, -CH2CH2OH, -CH2F, or -CHF2;

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

[0100] R5 and R 7 Each can be H or F independently;

[0101] R 6H "An 8-9 membered fused heterocyclic alkyl group selected from one, two, or three of N, O, and S, with one, two, or three heteroatoms"; "An 8-9 membered bridged heterocyclic alkyl group selected from one, two, or three of N, O, and S, with two heteroatoms"; bounded by one, two, or three R... 6-1 The substituted "an 8-9 member fused heterocyclic alkyl group selected from one, two, or three of N, O, and S, with one, two, or three heteroatoms" is replaced by one, two, or three R atoms. 6-1 The substituted "heteroatom is selected from one, two or three of N, O and S, and is an 8-9 membered bridged heterocyclic alkyl group with two heteroatoms" Preferably, the R 6H The nitrogen atom is connected to the benzene ring;

[0102] Each R 6-1 Independently hydroxyl, oxo (=O), halogen or C 1-3 alkyl;

[0103] x1 is either 0 or 1;

[0104] x2 is either 0 or 1;

[0105] R 8 For H;

[0106] R 9 For H or F; n is 0 or 1;

[0107] L is -(CR) a R b ) q -; q is 1; R a and R b Each is independently represented by H;

[0108] R 10 -COOH; and

[0109] X is CR d Or N; R d For H.

[0110] In one aspect of the present invention, R 1 For H;

[0111] R 2 For H, R 3 For H;

[0112] R 4 H is a variable, and m is either 0 or 1.

[0113] R5 and R 7 For H;

[0114] R 6H The compounds are 8-oxa-3-azabicyclo[4.2.0]octyl, 7-oxa-3-azabicyclo[4.2.0]octyl, 3,8-diazabicyclo[4.2.0]octyl, 3,7-diazabicyclo[4.2.0]octyl, octahydrofurano[2,3-c]pyridyl, octahydrofurano[3,4-c]pyridyl, octahydrofurano[3,2-c]pyridyl, and octahydro-1 H-pyrrolo[2,3-c]pyridyl, octahydro-1H-pyrrolo[3,2-c]pyridyl, octahydro-1H-pyrrolo[3,4-c]pyridyl, octahydro-1H-cyclopentano[c]pyridyl, hexahydro-2H-furano[2,3-c]pyrryl, hexahydro-1H-furano[3,4-c]pyrryl, octahydrocyclopentano[c]pyrryl, octahydropyrrolo[3,4-b]pyrryl Pyrroloyl, octahydropyrrolo[3,4-c]pyrroloyl, octahydro-1H-pyrrolo[3,4-b]pyridyl, octahydropyrano[2,3-c]pyrroloyl, octahydropyrano[3,4-c]pyrroloyl, octahydro-1H-isoindolyl, octahydropyrrolo[3,4-b][1,4]oxazinyl, hexahydro-5H-[1,4]dioxa[2,3-c]pyrroloyl, 2-oxa-5-aza Bicyclo[2.2.2]octyl, 2,5-diazabicyclo[2.2.2]octyl, 3,8-diazabicyclo[3.2.1]octyl, 8-azabicyclo[3.2.1]octyl, 8-oxa-3-azabicyclo[3.2.1]octyl, 3-oxa-8-azabicyclo[3.2.1]octyl or 3-azabicyclo[3.2.1]octyl, or with 1 or 2 R 6-1The following groups are substituted: 8-oxa-3-azabicyclo[4.2.0]octyl, 7-oxa-3-azabicyclo[4.2.0]octyl, 3,8-diazabicyclo[4.2.0]octyl, 3,7-diazabicyclo[4.2.0]octyl, octahydrofuran[2,3-c]pyridyl, octahydrofuran[3,4-c]pyridyl, octahydrofuran [3,2-c]pyridyl, octahydro-1H-pyrrolo[2,3-c]pyridyl, octahydro-1H-pyrrolo[3,2-c]pyridyl, octahydro-1H-pyrrolo[3,4-c]pyridyl, octahydro-1H-cyclopentano[c]pyridyl, hexahydro-2H-furano[2,3-c]pyrryl, hexahydro-1H-furano[3,4-c]pyrryl, octa ... Hydrocyclopentano[c]pyrrolithyl, octahydropyrrolo[3,4-b]pyrrolithyl, octahydropyrrolo[3,4-c]pyrrolithyl, octahydro-1H-pyrrolo[3,4-b]pyridyl, octahydropyrano[2,3-c]pyrrolithyl, octahydropyrano[3,4-c]pyrrolithyl, octahydro-1H-isoindolyl, octahydropyrrolo[3,4-b][1,4]oxazinyl, hexahydro -5H-[1,4]dioxa[2,3-c]pyrrole, 2-oxa-5-azabicyclo[2.2.2]octyl, 2,5-diazabicyclo[2.2.2]octyl, 3,8-diazabicyclo[3.2.1]octyl, 8-oxa-3-azabicyclo[3.2.1]octyl or 3-oxa-8-azabicyclo[3.2.1]octyl;

[0115] Each R 6-1 Independently hydroxyl, oxo (=O), halogen or C 1-3 alkyl;

[0116] R 8 For H;

[0117] R 9 H is a variable; n is 0 or 1.

[0118] L is -(CR) a R b ) q -; q is 1; R a and R b Each is independently represented by H;

[0119] R 10 -COOH; and

[0120] X is CR d Or N; R d For H.

[0121] In one aspect of the present invention, R 1 For H;

[0122] R 2For H, R 3 For H;

[0123] R 4 H is a variable, and m is either 0 or 1.

[0124] R 5 and R 7 For H;

[0125] R 6H for Or by 1 or 2 R 6-1 The following groups are substituted:

[0126] R 6-1 It can be hydroxyl, oxo (=O), F or methyl;

[0127] R 8 For H;

[0128] R 9 H is a variable; n is 0 or 1.

[0129] L stands for -CH2-;

[0130] R 10 -COOH; and

[0131] X is CH.

[0132] In one aspect of the present invention, R 1 For H;

[0133] R 2 For H, R 3 For H;

[0134] R 4 H is a variable, and m is either 0 or 1.

[0135] R 5 and R 7 For H;

[0136] R 6H for Or by 1 or 2 R 6-1 The following groups are substituted:

[0137] R 6-1 It can be hydroxyl, oxo (=O), F or methyl;

[0138] R 8 For H;

[0139] R 9 H is a variable; n is 0 or 1.

[0140] L stands for -CH2-;

[0141] R 10 -COOH; and

[0142] X is CH.

[0143] In one aspect of the present invention, R 1 For H;

[0144] R 2 For H, R 3 For H;

[0145] R 4 H is a variable, and m is either 0 or 1.

[0146] R 5 and R 7 For H;

[0147] R 6H for Or R 6H for

[0148] R 8 For H;

[0149] R 9 H is a variable; n is 0 or 1.

[0150] L stands for -CH2-;

[0151] R 10 -COOH; and

[0152] X is CH.

[0153] In one aspect of the present invention, the compound represented by formula (I) is selected from any of the following compounds:

[0154] In one aspect of the present invention, the compound represented by formula (I) is selected from the following compounds:

[0155] The present invention also provides a method for preparing the compound represented by formula (I), which includes the following steps:

[0156] (1) The compound shown in formula I-3 undergoes a deprotection reaction to obtain the compound shown in formula I-4;

[0157] (2) The compound shown in formula I-4 is hydrolyzed to obtain the compound shown in formula (I);

[0158] Among them, R 10 For -COOH, R 1 R 2 R 3 R 4 R 5 R 6H R 7 R 8 R 9 R c The definitions of X, L, m, and n are as described in any embodiment of the present invention. The conditions and operations for the above-mentioned deprotection and hydrolysis reactions can be as common as those for such reactions in the art. Preferably, R 1 For H.

[0159] In one aspect of the present invention, the method for preparing the compound represented by formula (I) includes the following steps:

[0160] Among them, R 10 For -COOH, R 1 R 2 R 3 R 4 R 5 R 6H R 7 R 8 R 9 R c The definitions of X, L, m, and n are as described in any embodiment of the present invention, and the conditions and operations of the above reaction can be those commonly used for such reactions in the art; preferably, R 1 For H.

[0161] The present invention also provides compounds as shown in Formula I-3 or Formula I-4:

[0162] Among them, R 1 R 2 R 3 R 4 R 5 R 6H R 7 R 8 R 9 X, L, R c The definitions of m and n are as described in any embodiment of the present invention.

[0163] In one aspect of the present invention, in the compound represented by formula I-3 or formula I-4, R 1 For H.

[0164] The present invention also provides a pharmaceutical composition comprising:

[0165] (1) A pharmaceutically acceptable salt of the compound represented by formula (I) of any embodiment of the present invention, its tautomers, its stereoisomers, its prodrugs, or any of the foregoing (referring to the compound represented by formula (I) of any embodiment of the present invention, its tautomers, its stereoisomers, or its prodrugs), or a solvate of any of the foregoing (referring to the compound represented by formula (I) of any embodiment of the present invention, its tautomers, its stereoisomers, its prodrugs, or any of the foregoing pharmaceutically acceptable salts); and

[0166] (2) Pharmaceutically acceptable carrier.

[0167] The present invention also provides the use of compounds of formula (I) as described in any embodiment of the present invention, their tautomers, their stereoisomers, their prodrugs, or pharmaceutically acceptable salts of any of the foregoing (referring to compounds of formula (I) as described in any embodiment of the present invention, their tautomers, their stereoisomers, or their prodrugs), or solvates of any of the foregoing (referring to compounds of formula (I) as described in any embodiment of the present invention, their tautomers, their stereoisomers, their prodrugs, or pharmaceutically acceptable salts of any of the foregoing), or pharmaceutical compositions of any embodiment of the present invention in the preparation of medicaments for treating and / or preventing complement factor D-mediated diseases.

[0168] The present invention also provides a method for treating and / or preventing complement factor D-mediated diseases, comprising: administering to an individual in need a therapeutically effective amount of substance X or a pharmaceutical composition according to any embodiment of the present invention, wherein substance X is a compound of formula (I) according to any embodiment of the present invention, its tautomer, its stereoisomer, its prodrug, or a pharmaceutically acceptable salt of any of the foregoing (referring to a compound of formula (I) according to any embodiment of the present invention, its tautomer, its stereoisomer, or its prodrug), or a solvate of any of the foregoing (referring to a compound of formula (I) according to any embodiment of the present invention, its tautomer, its stereoisomer, its prodrug, or a pharmaceutically acceptable salt of any of the foregoing). Preferably, the individual is a patient according to the present invention.

[0169] In one embodiment of the present invention, the diseases mediated by complement factor D include blood diseases, kidney diseases, cardiovascular diseases, immune disorders, central nervous system diseases, respiratory diseases, genitourinary system diseases, or eye diseases. Preferably, the diseases mediated by complement factor D are, for example, blood diseases, kidney diseases, cardiovascular diseases, immune disorders, central nervous system diseases, or eye diseases.

[0170] In one embodiment of the present invention, the complement factor D-mediated diseases include cold agglutinin disease, catastrophic antiphospholipid syndrome, hemolytic anemia, antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV), warm antibody-type 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 erythematosus, rheumatoid arthritis, inflammatory bowel disease, psoriasis, multiple sclerosis, organ transplant rejection, myasthenia gravis, Alzheimer's disease, acute respiratory distress syndrome, and asthma. Chronic obstructive pulmonary disease, emphysema, coronavirus infection (such as SARS-CoV, MERS-CoV, or SARS-CoV-2 infection), macular degeneration, age-related macular degeneration (AMD), macular edema, diabetic macular edema, choroidal neovascularization (CNV), uveitis, Behcet's uveitis, proliferative diabetic retinopathy, non-proliferative diabetic retinopathy, glaucoma, hypertensive retinopathy, corneal neovascularization, corneal transplant rejection, corneal dystrophy, autoimmune dry eye disease, Stevens-Johnson syndrome, Sjögren's syndrome, environmental dry eye disease, Fehling's endothelial dystrophy, retinal vein occlusion, or postoperative inflammation.

[0171] In other embodiments of the present invention, the immune diseases include: lupus, allogeneic transplant rejection, autoimmune thyroid diseases (such as Graves' disease and Hashimoto's thyroiditis), autoimmune uveitis, giant cell arteritis, inflammatory bowel diseases (including Crohn's disease, ulcerative colitis, regional enteritis, granulomatous enteritis, terminal ileitis, regional ileitis and terminal ileitis), diabetes, multiple sclerosis, pernicious anemia, psoriasis, rheumatoid arthritis, sarcoidosis and scleroderma, etc.

[0172] Furthermore, the diseases mediated by complement factor D 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.

[0173] The present invention also provides the use of the compound of formula (I) of any embodiment of the present invention, its tautomer, its stereoisomer, its prodrug, or a pharmaceutically acceptable salt of any of the foregoing (referring to the compound of formula (I) of any embodiment of the present invention, its tautomer, its stereoisomer, or its prodrug), or a solvate of any of the foregoing (referring to the compound of formula (I) of any embodiment of the present invention, its tautomer, its stereoisomer, its prodrug, or a pharmaceutically acceptable salt of any of the foregoing), or the pharmaceutical composition of any embodiment of the present invention in the preparation of a complement factor D inhibitor drug.

[0174] In the aforementioned applications, the complement factor D inhibitor drug can be used in mammalian organisms; it can also be used in vitro, primarily for experimental purposes, such as providing a standard or control sample for comparison, or preparing a kit according to conventional methods in the art to provide rapid detection of the complement factor D inhibition effect.

[0175] The compounds of the present invention can be used in combination with other therapeutic agents.

[0176] Terminology Definitions and Explanations

[0177] Unless otherwise stated, the definitions of groups and terms recorded in this application specification and claims, including definitions as examples, exemplary definitions, preferred definitions, definitions recorded in tables, and definitions of specific compounds in the examples, can be arbitrarily combined and combined with each other. Such combinations and combinations of group definitions and compound structures should be understood as being within the scope of this application specification and / or claims.

[0178] The term "optional" (or "optionally", "optionally") means that the object is substituted by 0, 1 or more substituents. For example, "optionally substituted by 1, 2 or more R" means that the object may not be substituted by R (no substitution) or may be substituted by 1, 2 or more R.

[0179] "Substitution" refers to the replacement of hydrogen atoms in a molecule by other different atoms or groups. Alternatively, it can mean the replacement of the lone pair of electrons on an atom by another atom or group; for example, the lone pair of electrons on a sulfur atom can be replaced by an oxygen atom to form a hydrogen atom.

[0180] In this application Or "-" indicates the connection site between the group and other parts of the molecule.

[0181] When a functional group has one or more connectable sites, any one or more of these sites can be linked to other functional groups via chemical bonds. When the chemical bond connection is non-directional and a hydrogen atom is present at the connectable site, the number of hydrogen atoms at that site decreases accordingly with the number of bonds being formed, resulting in a functional group with a corresponding valence. For example... This indicates that any connectable site on the piperidinyl group can be linked to other groups via a single chemical bond, including at least... These three connection methods, even if an H atom is drawn on -N-, This also includes

[0182] When any variable (e.g., R) appears multiple times in the definition of a compound, the definition of that variable at each position is independent of its definitions at other positions; their meanings are mutually independent and do not affect each other. Therefore, if a group is substituted by one, two, or three R groups—that is, if the group may be substituted by up to three R groups—the definition of R at that position is independent of the definitions of R at other positions. Furthermore, combinations of substituents and / or variables are only permitted if the combination produces a stable compound.

[0183] Term "C" n-m "and "C n -C m ", where n and m are integers, representing a group containing n to m carbon atoms. Examples include C 1-6 C 1-3 The term is intended to explicitly disclose each member within that scope, namely C. n C n+1 C n+2 ......C m-2 C m-1 C m For example, C 1-6 The intention is to disclose C1, C2, C3, C4, C5, and C6. "C" n-m The meaning of "C" is the same as "C". n -C m "same.

[0184] The term "n-ary", where n is an integer, usually describes the number of ring atoms in which n are formed.

[0185] The term "nm-aryl" refers to a cyclic atom in which n and m are integers, describing the number of cyclic atoms in a range from n to m. For example, piperidinyl is an example of a 6-membered heterocyclic alkyl ring, pyrazolyl is an example of a 5-membered heteroaryl ring, and pyridinyl is an example of a 6-membered heteroaryl ring.

[0186] Unless otherwise stated, the numerical ranges described in this specification and claims are equivalent to describing at least each specific integer value therein. For example, the numerical range "1-10" is equivalent to describing each integer value in the numerical range "1-10", namely 1, 2, 3, 4, 5, 6, 7, 8, 9, 10.

[0187] Unless otherwise stated, "multiple" means two or more, such as 2, 3, 4, 5, 6, 7, 8 or 9.

[0188] Unless otherwise stated, "more than" means three or more, such as 3, 4, 5, 6, 7, 8 or 9.

[0189] Term "C" 1-6 "alkyl" refers to a straight-chain or branched saturated hydrocarbon group having 1-6 carbon atoms. The C 1-6 Alkyl groups include C 1-3 Alkyl, C 1-4 Alkyl, C 3-4 Alkyl, C 4-6 Alkyl groups, etc. Examples of such alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, n-butyl, n-pentyl, n-hexyl, isopropyl, isobutyl, sec-butyl, tert-butyl, isopentyl, 2-methylbutyl, 1-methylbutyl, 1-ethylpropyl, 1,2-dimethylpropyl, neopentyl, 1,1-dimethylpropyl, 4-methylpentyl, 3-methylpentyl, 2-methylpentyl, 1-methylpentyl, 2-ethylbutyl, 1-ethylbutyl, 3,3-dimethylbutyl, 2,2-dimethylbutyl, 1,1-dimethylbutyl, 2,3-dimethylbutyl, 1,3-dimethylbutyl, or 1,2-dimethylbutyl, etc., or their isomers.

[0190] The term "halogen" refers to fluorine, chlorine, bromine, and iodine.

[0191] The term "halogenation" refers to the substitution of one or more halogens.

[0192] Term "C" 1-6 "Halogenated alkyl" refers to an alkyl group as defined in this invention, which is substituted with one or more halogens as defined above. The halogenated alkyl group includes, but is not limited to, monofluoromethyl, difluoromethyl, trifluoromethyl, trichloromethyl, 2,2,2-trifluoroethyl, 2,2-difluoroethyl, 1-fluoromethyl-2-fluoroethyl, 3-bromo-2-fluoropropyl, 1-bromomethyl-2-bromoethyl, etc.

[0193] The term "alkoxy group" refers to an alkyl group as defined in this invention, which is attached to a benzene ring molecule via an oxygen atom. The alkoxy group includes C... 1- 6-alkoxy, C 1-3 Alkoxy groups, etc. The alkoxy groups include, but are not limited to, methoxy, ethoxy, propoxy, 2-propoxy, butoxy, tert-butoxy, pentoxy, and hexoxy groups.

[0194] Term "C" 1-6 "Haloalkoxy group" refers to an alkoxy group as defined in this invention, which is substituted with one or more halogens as defined above. Preferably, C10 is used. 1-3 Halogenated alkoxy groups.

[0195] The term "heterocyclic alkyl" refers to a saturated ring or ring system having a specified number of ring atoms and containing 1 to 5 heteroatoms selected from O, S, and N, wherein N and S may optionally be oxidized to various oxidation states to form nitrogen oxides, -S(=O)-, or -S(=O)2- states. The heterocyclic alkyl includes monocyclic heterocyclic alkyl, fused heterocyclic alkyl, spirocyclic alkyl, or bridged heterocyclic alkyl. The heterocyclic alkyl can be a 3-, 4-, 5-, 6-, or 7-membered monocyclic, a 5-, 6-, 7-, 8-, 9-, 10-, 11-, or 12-membered bicyclic, or a 10-, 11-, 12-, 13-, or 14-membered tricyclic ring system. The heterocyclic alkyl group includes 3-14-membered heterocyclic alkyl, 5-14-membered heterocyclic alkyl, 4-12-membered heterocyclic alkyl, 7-12-membered heterocyclic alkyl, 8-12-membered heterocyclic alkyl, 8-11-membered heterocyclic alkyl, 8-10-membered heterocyclic alkyl, 8-9-membered heterocyclic alkyl, 5-8-membered heterocyclic alkyl, 4-6-membered heterocyclic alkyl, 4-5-membered heterocyclic alkyl, 5-6-membered heterocyclic alkyl, etc., wherein the 8-12-membered heterocyclic alkyl contains 1, 2 or 3 N and 0, 1 or 2 O or S, wherein N and S can also be optionally oxidized to various oxidation states to form nitrogen oxides, -S(=O)- or -S(=O)2- states.

[0196] The term "fused heterocyclic alkyl" refers to a saturated polycyclic heterocyclic group having a specified number of ring atoms, in which each ring in the system shares an adjacent pair of atoms with other rings in the system. Its ring atoms consist of a carbon atom and one, two, or more heteroatoms independently selected from O, S, and N, wherein N and S may optionally be oxidized to various oxidation states to form nitrogen oxides, -S(=O)-, or -S(=O)2- states. The fused heterocyclic alkyl includes 5-14-membered fused heterocyclic alkyl, 7-12-membered fused heterocyclic alkyl, 8-12-membered fused heterocyclic alkyl, 8-10-membered fused heterocyclic alkyl, 8-9-membered fused heterocyclic alkyl, etc., preferably 8-10-membered fused heterocyclic alkyl, more preferably 8-9-membered fused heterocyclic alkyl. Depending on the number of constituent rings, it can be classified as bicyclic, tricyclic, tetracyclic, or polycyclic fused heterocyclic alkyl, preferably bicyclic or tricyclic, more preferably 4-membered / 6-membered, 5-membered / 6-membered, or 5-membered / 5-membered bicyclic fused heterocyclic alkyl. Non-limiting examples of fused heterocyclic alkyl groups include: 8-oxa-3-azabicyclo[4.2.0]octyl, 7-oxa-3-azabicyclo[4.2.0]octyl, 3,8-diazabicyclo[4.2.0]octyl, 3,7-diazabicyclo[4.2.0]octyl, octahydrofurano[2,3-c]pyridyl, octahydrofurano[3,4-c]pyridyl, octahydrofurano[3,2-c]pyridyl, octahydro-1H-pyrrolo[2,3-c]pyridyl, octahydro-1H-pyrrolo[3,2-c]pyridyl, octahydro-1H-pyrrolo[3,4-c]pyridyl, octahydro- 1H-cyclopentano[c]pyridyl, hexahydro-2H-furano[2,3-c]pyrryl, hexahydro-1H-furano[3,4-c]pyrryl, octahydrocyclopentano[c]pyrryl, octahydropyrrolo[3,4-b]pyrryl, octahydropyrrolo[3,4-c]pyrryl, octahydro-1H-pyrrolo[3,4-b]pyridyl, octahydropyrano[2,3-c]pyrryl, octahydropyrano[3,4-c]pyrryl, octahydro-1H-isoindolyl, octahydropyrrolo[3,4-b][1,4]oxazinyl and hexahydro-5H-[1,4]dioxa[2,3-c]pyrryl, etc.; more preferably:

[0197] The term "bridged heterocyclic alkyl" refers to a saturated cyclic group having a specified number of ring atoms, comprising any two or more cyclic structures sharing two non-directly connected atoms. Its ring atoms consist of a carbon atom and one, two, or more heteroatoms independently selected from O, S, and N, wherein N and S can optionally be oxidized to various oxidation states to form nitrogen oxides, -S(=O)-, or -S(=O)2- states. The bridged heterocyclic alkyl includes 5-14-membered bridged heterocyclic alkyl, 8-12-membered bridged heterocyclic alkyl, 8-10-membered bridged heterocyclic alkyl, 8-9-membered bridged heterocyclic alkyl, 8-membered bridged heterocyclic alkyl, etc., preferably 8-9-membered bridged heterocyclic alkyl, more preferably 8-membered bridged heterocyclic alkyl. Depending on the number of constituent rings, it can be classified as bicyclic, tricyclic, tetracyclic, or polycyclic bridged heterocyclic alkyl, preferably bicyclic, tricyclic, or tetracyclic, more preferably bicyclic or tricyclic. Non-limiting examples of bridged heterocyclic alkyl groups include: 2-oxa-5-azabicyclo[2.2.2]octyl, 2,5-diazabicyclo[2.2.2]octyl, 3,8-diazabicyclo[3.2.1]octyl, 8-azabicyclo[3.2.1]octyl, 8-oxa-3-azabicyclo[3.2.1]octyl, 3-oxa-8-azabicyclo[3.2.1]octyl, and 3-azabicyclo[3.2.1]octyl, etc.; more preferably:

[0198] Term "C" 3-6 "Cycloalkyl" refers to a monovalent or polyvalent cyclic alkane having 3-6 carbon atoms, including monocyclic, bicyclic, or tricyclic alkanes, wherein the bicyclic and tricyclic alkanes include fused rings, bridged rings, or spirocyclic rings. The C 3-6 Examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, spiro[2.2]pentyl, spiro[2.3]hexyl, bicyclo[1.1.1]pentyl, bicyclo[3.1.0]hexyl, bicyclo[2.1.1]hexyl, etc.

[0199] Term "C" 3-6 "Cycloalkylene" refers to a divalent cyclic alkane having 3-6 carbon atoms, including monocyclic, bicyclic, or tricyclic alkanes. The bicyclic and tricyclic alkanes include fused rings, bridged rings, or spirocyclic rings. The divalent cyclic alkane refers to a group formed by eliminating two hydrogen atoms from a cyclic alkane; the two eliminated hydrogen atoms can be on the same atom or on different atoms. The C... 3-6 Examples of cycloalkylene groups include, but are not limited to, cyclopropylene groups (e.g., cycloalkylene). ), cyclobutylene (e.g.) ), cyclopentylene (e.g.) ), cyclohexylene (e.g.) )wait.

[0200] Those skilled in the art will understand that the compounds shown in formula (I) can exist in the form of various pharmaceutically acceptable salts. If these compounds have a basic center, they can form acid addition salts; if these compounds have an acidic center, they can form base addition salts; if these compounds contain both an acidic center (e.g., a carboxyl group) and a basic center (e.g., an amino group), they can also form internal salts.

[0201] The compounds of the present invention may exist as solvates (such as hydrates), wherein the compounds of the present invention contain a polar solvent, particularly, for example, water, methanol, or ethanol, as a structural element of the lattice of the compound. The amount of the polar solvent, particularly water, may be stoichiometric or non-stoichiometric.

[0202] The term "pharmaceutically acceptable salt" refers to a salt prepared from the compounds of the present invention with a relatively non-toxic, pharmaceutically acceptable acid or base. When the compounds of the present invention contain relatively acidic functional groups, base addition salts can be obtained by contacting the prototype of such compounds 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, or salts containing ammonia or organic amines (such as ethylamine, ethanolamine, triethanolamine, etc.), amino acids, or other bases known to those skilled in the art. When the compounds of the present invention contain relatively basic functional groups, acid addition salts can be obtained by contacting the prototype of such compounds with a sufficient amount of a pharmaceutically acceptable acid in a pure solution or a suitable inert solvent. The pharmaceutically acceptable acids include inorganic acids, including but not limited to: hydrochloric acid, hydrobromic acid, hydroiodic acid, nitric acid, carbonic acid, phosphoric acid, phosphorous acid, sulfuric acid, etc. The pharmaceutically acceptable acids include organic acids, including but not limited to: acetic acid, propionic acid, oxalic acid, isobutyric acid, maleic acid, malonic acid, benzoic acid, succinic acid, octanoic acid, fumaric acid, lactic acid, mandelic acid, phthalic acid, benzenesulfonic acid, p-toluenesulfonic acid, citric acid, salicylic acid, tartaric acid, methanesulfonic acid, isonicotinic acid, oleic acid, tannic acid, pantothenic acid, ascorbic acid, gentian acid, fumaric acid, gluconic acid, succinic acid, formic acid, ethanesulfonic acid, dihydroxynaphthyl acid (i.e., 4,4'-methylene-bis(3-hydroxy-2-naphthylcarboxylic acid)), amino acids (e.g., glutamic acid, arginine), etc. When the compounds of the present invention contain both relatively acidic and relatively basic functional groups, they can be converted into base addition salts or acid addition salts.

[0203] Pharmaceutically acceptable salt forms may include those in which the ratio of the molecules constituting the salt is not 1:1. For example, a salt may contain more than one inorganic or organic acid molecule per molecule of base, such as two hydrochloric acid molecules per molecule of the compound represented by formula (I). As another example, a salt may contain less than one inorganic or organic acid molecule per molecule of base, such as two molecules of the compound represented by formula (I) per molecule of tartaric acid.

[0204] The term "solvate" refers to a substance formed by the combination of the compound of this invention with a stoichiometric or non-stoichiometric solvent. Solvent molecules in a solvate can exist in an ordered or disordered arrangement. The solvents include, but are not limited to, water, methanol, and ethanol.

[0205] As described above, the terms "pharmaceutical-acceptable salt" and "solvent" in the term "pharmaceutical-acceptable salt solvate" refer to substances formed by the following: 1) compounds of the present invention prepared with a relatively non-toxic, pharmaceutically acceptable acid or base; and 2) substances formed by combining with a stoichiometric or non-stoichiometric solvent. The term "pharmaceutical-acceptable salt solvate" includes, but is not limited to, hydrochloric acid monohydrates of the compounds of the present invention.

[0206] As used herein, the term "prodrug" refers to a compound that can be metabolized in vivo to provide a compound of formula (I). Therefore, a prodrug includes compounds that can be prepared by modifying one or more functional groups in a compound of formula (I) to provide a corresponding compound that can be metabolized in vivo to provide a compound of formula I or II. Such modifications are known in the art. For example, one or more hydroxyl or amino groups in a compound of formula (I) can be acylated with an alkyl-C(=O)- group or with residues from an amino acid to provide a prodrug.

[0207] The compounds described herein may include all stereoisomers of the compound. The term "stereoisomer" refers to isomers resulting from different spatial arrangements of atoms in a molecule, including enantiomers, diastereomers, cis-trans isomers, and conformational isomers.

[0208] Unless otherwise specified, use wedge-shaped solid line keys. and wedge-shaped dashed key Represents the absolute configuration of the center of a solid. Uses straight solid lines as keys. and straight dashed key It indicates the relative configuration of a stereocenter, such as the cis-trans configuration of alicyclic compounds.

[0209] Depending on their molecular structure, the compounds of the present invention can be chiral (having one or more stereocenters), and therefore may exist in various enantiomeric forms. Thus, these compounds can exist in racemic or optically active forms. The compounds of the present invention encompass isomers of each chiral carbon in the R or S configuration, or mixtures thereof, or racemates. The compounds of the present invention or intermediates thereof can be isolated as enantiomeric compounds by chemical or physical methods known to those skilled in the art, or used in this form for synthesis. Racemic mixtures are reacted with optically active resolving agents to yield diastereomers. Examples of suitable resolving agents are optically active acids, such as tartaric acid in R and S forms, diacetyltartaric acid, dibenzoyltartaric acid, mandelic acid, malic acid, lactic acid, suitable N-protected amino acids (e.g., N-benzoylproline or N-benzenesulfonylproline), or various optically active camphorsulfonic acids. Chromatographic enantiomeric separation can also be advantageously performed using optically active resolving agents (e.g., dinitrobenzoylphenylglycine immobilized on silica gel, cellulose triacetate or other carbohydrate derivatives, or chiral derivatized isobutylene ester polymers). Suitable eluents for this purpose are aqueous or alcoholic solvent mixtures, such as hexane / isopropanol / acetonitrile.

[0210] In some embodiments, the compounds of the present invention have an (R)-configuration. In other embodiments, the compounds have an (S)-configuration. In compounds having more than one chiral center, each chiral center in the compound may be independently (R) or (S), unless otherwise stated.

[0211] The compounds described in this invention may also include tautomeric forms. Tautomeric forms arise from the exchange of single bonds with adjacent double bonds and the accompanying proton migration. Tautomeric forms include proton-shift tautomers, which are isomeric protonated states having the same empirical formula and total charge. Examples of proton-shift tautomers include keto-enol pairs, amide-imino pairs, lactam-lactamimide pairs, enamine-imide pairs, and cyclic forms in which protons can occupy two or more positions in the heterocyclic system, such as 1H- and 3H-imidazolium, 1H-, 2H- and 4H-1,2,4-triazole, 1H- and 2H-isoindole, and 1H- and 2H-pyrazole. Tautomeric forms may be in equilibrium or spatially locked into one form through appropriate substitution. This disclosure is intended to include all such tautomers of the said compounds.

[0212] The compounds described in this invention may also include all isotopes of the atoms present in the intermediates or the final compound. Isotopes include those atoms having the same atomic number but different mass numbers. Examples of isotopes that can be incorporated into the compounds of this invention include, but are not limited to, isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine, and chlorine, for example, 2 H (deuterium, D)3 H (tritium, T), 11 C 13 C 14 C 15 N、 18 F, 31 P, 32 P, 35 S, 36 Cl and 125I The isotope-labeled compounds of this invention can be prepared by replacing non-isotope-labeled reagents with readily available isotope-labeled reagents.

[0213] The terms "carrier" and "pharmaceutically acceptable carrier" refer to a diluent, adjuvant, excipient, or medium that is administered or formulated with a compound for administration. Non-limiting examples of such pharmaceutically acceptable carriers include liquids such as water, saline, and oils; and solids such as gum arabic, gelatin, starch paste, talc, keratin, colloidal silica, urea, etc. Additionally, auxiliaries, stabilizers, thickeners, lubricants, flavoring agents, and coloring agents may be used. The corresponding stable isomers can be separated by known methods, such as extraction, filtration, or column chromatography.

[0214] The term "patient" or "subject" refers to a living organism that suffers from or is susceptible to a disease or symptom that can be treated by application of the drug or drug composition provided by the present invention, preferably a mouse, rat, other rodent, rabbit, dog, cat, pig, cattle, sheep, horse or primate, and most preferably a human.

[0215] "Disease" or "symptom" refers to a state or health condition in which a patient or subject can be treated with the medicine, pharmaceutical composition or method provided by this invention.

[0216] The term "treatment" refers to preventing, halting, or slowing the progression of a subject's disease or ailment, or eliminating a subject's disease or ailment. In some embodiments, "treatment" means halting or slowing the progression of a subject's disease or ailment, or eliminating a subject's disease or ailment. In one embodiment, "treatment" means reducing at least one objective manifestation of a subject's disease or ailment.

[0217] The term "effective amount" refers to an amount sufficient to produce the desired biological effect.

[0218] The term “therapeutic effective amount” refers to an amount sufficient to produce the desired therapeutic effect, which includes one or more of the following: (1) prevention of disease: for example, prevention of disease, disorder or condition in an individual who is susceptible to disease, disorder or condition but has not yet experienced or developed the pathology or symptoms of the disease. (2) suppression of disease: for example, suppression of disease, disorder or condition in an individual who is experiencing or developing the pathology or symptoms of the disease (i.e., preventing the further development of the pathology and / or symptoms). (3) relief of disease: for example, relief of disease, disorder or condition in an individual who is experiencing or developing the pathology or symptoms of the disease (i.e., reversal of the pathology and / or symptoms). Detailed Implementation

[0219] The following detailed description, in conjunction with specific embodiments, illustrates the general formula compounds of the present invention, their preparation methods, and applications in further detail. The following embodiments are merely illustrative and explanatory of the present invention and should not be construed as limiting the scope of protection of the present invention. All technologies implemented based on the above content of the present invention are covered within the scope of protection intended by the present invention.

[0220] Unless otherwise stated, the raw materials and reagents used in the following examples are commercially available products or can be prepared by known methods.

[0221] The terms used in the following specific experimental descriptions represent (unless otherwise stated) the following reagents or procedures:

[0222] Pd / C: Palladium on carbon; BnCl: Benzyl chloride; (Boc)₂O: NaBH₄: Sodium borohydride; Pd₂(dba)₃: Tris(dibenzylacetone)dipalladium; X-phos: 2-Dicyclohexylphospho-2',4',6'-triisopropylbiphenyl; LiOH.H₂O: Lithium hydroxide monohydrate; LiOH: Lithium hydroxide; TFA: Trifluoroacetic acid; NaOH: Sodium hydroxide; NBS: N-bromosuccinimide; TosCl: p-Toluenesulfonyl chloride; BnHN₂: Benzylamine; MeOH: Methanol; DCM: Dichloromethane; IV: Intravenous injection; PO: Oral administration;

[0223] <Preparation Examples>

[0224] Example 1: Synthesis of 2-(2-((3'-(aminomethyl)-5-(hexahydrofurano[3,2-c]pyridin-5(4H)-yl)-[1,1'-biphenyl]-3-yl)methoxy)phenyl)acetic acid (compound 001)

[0225] 1.1 Synthesis of Compound 001-1

[0226] Add 001-a (1900 mg, 12.37 mmol), 10% wet palladium on carbon (400 mg), and methanol (30 mL) to a reaction flask. React overnight at room temperature. Add 2 g of potassium carbonate solid to the reaction solution, stir for 30 minutes, and filter. Concentrate the filtrate under reduced pressure to obtain compound 001-1 (crude product), which can be used directly in the next step. LC-MS: [M+H] + =122.10.

[0227] 1.2 Synthesis of Compound 001-2

[0228] Add 001-1 (1200 mg, 9.91 mmol), benzyl chloride (1254.41 mg, 9.91 mmol), and acetonitrile (20 mL) to a reaction flask. React overnight at 60 °C. Concentrate under reduced pressure to remove acetonitrile. Add methyl tert-butyl ether (20 mL), stir for 1 h, discard the supernatant, and concentrate the solid under reduced pressure to obtain compound 001-2, which can be used directly in the next step. LC-MS: [M+H] + =212.05.

[0229] 1.3 Synthesis of Compound 001-3

[0230] 001-2 (3000 mg, 12.11 mmol) and methanol (30 mL) were added to a reaction flask. Sodium borohydride (900 mg, 23.79 mmol) was added in portions under ice bath conditions, and the reaction was carried out at room temperature for 2 h. The reaction was quenched by adding water (50 mL), and the organic solvent was removed under reduced pressure. The aqueous phase was extracted with ethyl acetate (50 mL × 2). The combined organic phases were washed with saturated sodium chloride aqueous solution (50 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 10 / 1-3 / 1) to give compound 001-3. LC-MS: [M+H] + =216.05.

[0231] 1.4 Synthesis of Compound 001-4

[0232] Add 001-3 (900 mg, 4.18 mmol), methanol (3 mL), and 10% wet palladium on carbon (250 mg, 0.23 mmol) to a reaction flask. React overnight at room temperature under a hydrogen atmosphere. Filter the reaction mixture, and concentrate the filtrate under reduced pressure to obtain compound 001-4, which can be used directly in the next step. LC-MS: [M+H] + =128.10.

[0233] 1.5 Synthesis of Compound 001-5

[0234] IN-01 (1000 mg, 1.85 mmol), 001-4 (282.34 mg, 2.22 mmol), X-Phos (88.19 mg, 0.19 mmol), tris(dibenzylacetone)palladium (106.38 mg, 0.19 mmol), cesium carbonate (1205.53 mg, 3.7 mmol), and 1,4-dioxane (20 mL) were added to a reaction flask, and the mixture was reacted overnight at 90 °C. The reaction solution was concentrated under reduced pressure, and ethyl acetate (100 mL) and water (100 mL) were added. The organic phase was separated, washed with saturated sodium chloride aqueous solution (100 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 (petroleum ether / ethyl acetate = 10 / 1-4 / 1) to give compound 001-5. LC-MS: [M+H] + =587.25.

[0235] 1.6 Synthesis of Compound 001-6

[0236] Add 001-5 (600 mg, 1.02 mmol), dichloromethane (15 mL), and a 1,4-dioxane solution of HCl (1.8 mL, 4 M) to a reaction flask. React at room temperature for 3 h. The reaction solution is then concentrated under reduced pressure to obtain compound 001-6 (crude product), which can be used directly in the next step. LC-MS: [M+H] + =487.20.

[0237] 1.7 Synthesis of Compound 001

[0238] Compound 001-6 (496 mg, 1.02 mmol), monohydrate, lithium hydroxide (256.8 mg, 6.12 mmol), methanol (6 mL), water (6 mL), and tetrahydrofuran (6 mL) were added to a reaction flask and reacted overnight at room temperature. Water (20 mL) was added to the reaction solution, and the reaction system was adjusted to a weakly alkaline state using HCl in a 1,4-dioxane solution. The reaction solution was concentrated under reduced pressure and purified by preparative high-performance liquid chromatography (under alkaline conditions). The purified solution was then freeze-dried to obtain compound 001. LC-MS: [M+H] + =473.20.

[0239] 1HNMR (600MHz, DMSO-d6) δ8.22(s,3H),7.77(s,1H),7.68(d,J=7.7Hz,1H),7.48(t,J=7.7Hz,1H),7.42(d ,J=7.6Hz,1H),7.21(t,J=8.4Hz,2H),7.16(s,2H),7.10(s,1H),7.02(d,J=8.1Hz,1H),6.88(t,J=7.3Hz ,1H),5.12(s,2H),4.10(q,J=5.4Hz,2H),3.97–3.83(m,2H),3.67(m,1H),3.59(s,2H),3.56(m,1H),3.4 5(m,1H),3.13(t,J=10.3Hz,1H),2.93-2.80(m,1H),2.41(s,1H),1.98(m,2H),1.88(m,1H),1.60(m,1H).

[0240] Example 2: Synthesis of 2-(2-((3'-(aminomethyl)-5-(tetrahydro-1H-furano[3,4-c]pyrrole-5(3H)-yl)-[1,1'-biphenyl]-3-yl)methoxy)phenyl)acetic acid (compound 002)

[0241] 2.1 Synthesis of Compound 002-1

[0242] IN-01 (1 g, 1.85 mmol), 002-a (0.30 g, 2.04 mmol), cesium carbonate (2411.07 mg, 7.4 mmol), tris(dibenzylacetone)dipalladium (10.93 mg, 0.019 mmol), 2-dicyclohexylphosphine-2',4',6'-triisopropylbiphenyl (88.19 mg, 0.19 mmol), and 1,4-dioxane (20 mL) were added to a reaction flask, purged with nitrogen, and reacted overnight at 90 °C. 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 = 4 / 1-1 / 1) to give compound 002-1. LC-MS: [M+H] + =573.30.

[0243] 2.2 Synthesis of Compound 002-2

[0244] 0.5 g (0.87 mmol) of compound 002-1 was dissolved in 6 mL of dichloromethane. Trifluoroacetic acid (2 mL) was added under stirring, and the reaction mixture was allowed to react at room temperature for 1 h. The reaction mixture was concentrated under reduced pressure, and the residue was diluted with water (20 mL). The pH was adjusted to 9-10 with saturated sodium carbonate solution, and the mixture was extracted with ethyl acetate (20 mL × 3). The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain compound 001-2 (crude product), which could be used directly in the next step. LC-MS: [M+H] + =473.20.

[0245] 2.3 Synthesis of Compound 002

[0246] Compound 001-2 (0.4 g, 0.85 mmol) was weighed and dissolved in methanol (2 mL), tetrahydrofuran (2 mL), and water (1 mL). Sodium hydroxide (0.14 g, 3.4 mmol) was added, and the reaction solution was reacted at 60 °C for 2 h. After cooling, the reaction solution was purified by preparative high-performance liquid chromatography (under alkaline conditions) and freeze-dried to obtain compound 002. LC-MS: [M+H] + =459.20.

[0247] 1 H NMR (600MHz, DMSO-d6) δ8.21(s,2H),7.78(s,1H),7.68(d,J=7.7Hz,1H),7.50(t,J=7.7Hz,1 H),7.42(d,J=7.6Hz,1H),7.22(t,J=8.0Hz,2H),7.09–7.02(m,2H),6.90(t,J=7.4Hz,1H),6. 81(s,1H),6.76(s,1H),5.12(s,2H),4.11(q,J=5.6Hz,2H),3.87(dd,J=8.4,6.7Hz,2H),3.6 0(s,2H),3.57(dd,J=8.8,3.1Hz,2H),3.47–3.40(m,2H),3.27(d,J=7.7Hz,2H),3.03(s,2H).

[0248] Example 3: Synthesis of 2-(2-((3'-(aminomethyl)-5-(5-hydroxyhexahydrocyclopentadien[c]pyrrole-2(1H)-yl)-[1,1'-biphenyl]-3-yl)methoxy)phenyl)acetic acid (compound 003)

[0249] 3.1 Synthesis of Compound 003-1

[0250] At room temperature, 003-a (1 g, 4.44 mmol) was dissolved in dichloromethane (5 mL), and a solution of 1,4-dioxane in HCl (4.4 mL, 17.76 mmol, 4.0 M) was added. The reaction mixture was reacted at room temperature for 2 hours. The reaction mixture was then concentrated under reduced pressure to give compound 003-1 (crude product), which could be used directly in the next step. LC-MS: [M+H] + =140.10.

[0251] 3.2 Synthesis of Compound 003-2

[0252] At room temperature, IN-01 (500.0 mg, 0.93 mmol) was dissolved in 1,4-dioxane (10 mL), and 003-1 (230 mg, 1.86 mmol), tris(dibenzylacetone)dipalladium (85.1 mg, 0.093 mmol), 2-dicyclohexylphosphine-2',4',6'-triisopropylbiphenyl (44.3 mg, 0.093 mmol) and cesium carbonate (1.36 g, 4.19 mmol) were added. Under nitrogen protection, the mixture was heated to 90 °C and reacted for 16 hours. The reaction solution was cooled to room temperature, and water (30 mL) was added. The mixture was extracted with ethyl acetate (20 mL × 2). The combined organic phases were washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 5 / 1 to 3 / 1) to give compound 003-2. LC-MS:[M+H] + =585.30.

[0253] 3.3 Synthesis of Compound 003-3

[0254] At room temperature, 003-2 (130 mg, 0.22 mmol) was dissolved in methanol (1.5 mL) and tetrahydrofuran (1.5 mL), cooled to 0 °C, and sodium borohydride (16.6 mg, 0.44 mmol) was added. The reaction mixture was then allowed to react at room temperature for 0.5 hours. The reaction mixture was quenched with saturated ammonium chloride aqueous solution (3 mL), water (5 mL) was added, and the mixture was extracted with ethyl acetate (5 mL × 2). The combined organic phases were washed with saturated brine (5 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain compound 003-3 (crude product), which could be used directly in the next step.

[0255] 3.4 Synthesis of Compound 003-4

[0256] At room temperature, 003-3 (130 mg, 0.22 mmol) was dissolved in dichloromethane (1.5 mL), and trifluoroacetic acid (767.5 mg, 6.73 mmol) was added. The reaction mixture was reacted at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure, and the residue was treated with water (8 mL) and ethyl acetate (6 mL). The aqueous phase was separated, and the pH of the aqueous phase was adjusted to 9–10 with saturated sodium carbonate solution. Extraction was performed with ethyl acetate (6 mL × 3). The combined organic phases were washed with saturated brine (8 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain 003-4 (crude product), which could be used directly in the next step. LC-MS: [M+H] + =487.20.

[0257] 3.5 Synthesis of Compound 003

[0258] At room temperature, 003-4 (60 mg, 0.12 mmol) was dissolved in methanol (1 mL) and water (0.5 mL), and lithium hydroxide (28.7 mg, 1.2 mmol) was added. The reaction solution was heated to 40 °C and reacted for 1 hour. Trifluoroacetic acid was added to adjust the pH of the reaction solution to 7–8. The residue was purified by preparative high-performance liquid chromatography (HPLC) and freeze-dried to obtain compound 003. LC-MS: [M+H] + =473.20.

[0259] 1 H NMR(600MHz,DMSO-d6)δ9.54(s,1H),7.82(s,1H),7.51(d,J=6.9Hz,1H),7.31(s,1H) ,7.25(t,J=7.7Hz,1H),7.07(d,J=7.3Hz,1H),7.05–6.99(m,2H),6.79(s,1H),6.77– 6.72(m,2H),6.61(s,1H),5.17(s,2H),4.62(s,1H),4.21(s,2H),4.07(s,1H),2.97( s,4H),2.67(s,2H),2.59(s,1H),2.52(s,1H),2.11–2.05(m,2H),1.43–1.37(m,2H).

[0260] Example 4: Synthesis of 2-(2-((3'-(aminomethyl)-5-(octahydro-2H-pyrrolo[3,4-c]pyridin-2-yl)-[1,1'-biphenyl]-3-yl)methoxy)phenyl)acetic acid (compound 004)

[0261] 4.1 Synthesis of Compound 004-1

[0262] At room temperature, 004-a (69.7 mg, 0.31 mmol) was dissolved in 1,4-dioxane (3 mL), and IN-01 (150.0 mg, 0.28 mmol), tris(dibenzylacetone)dipalladium (25.6 mg, 0.028 mmol), 2-dicyclohexylphosphine-2',4',6'-triisopropylbiphenyl (13.3 mg, 0.028 mmol) and cesium carbonate (228.0 mg, 0.7 mmol) were added. Under nitrogen protection, the mixture was heated to 100 °C and reacted for 4 hours. The reaction mixture was then diluted with water (20 mL) and extracted with ethyl acetate (15 mL × 2). The combined organic phases were washed with saturated brine (20 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 = 5 / 1 to 3 / 1) to give compound 004-1. LC-MS:[M+H] + =686.35.

[0263] 4.2 Synthesis of Compound 004-2

[0264] At room temperature, 004-1 (150 mg, 0.22 mmol) was dissolved in dichloromethane (2 mL), and trifluoroacetic acid (921 mg, 8.08 mmol) was added. The reaction mixture was reacted at room temperature for 2 hours. The reaction mixture was concentrated under reduced pressure, and the residue was treated with water (10 mL) and ethyl acetate (6 mL). The aqueous phase was separated, and the pH of the aqueous phase was adjusted to 9–10 with saturated sodium carbonate solution. Extraction was performed with ethyl acetate (6 mL × 3). The combined organic phases were washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain compound 004-2 (crude product), which could be used directly in the next step. LC-MS: [M+H] + =486.20.

[0265] 4.3 Synthesis of Compound 004

[0266] At room temperature, 004-2 (120 mg, 0.22 mmol) was dissolved in methanol (2 mL) and water (1 mL), and lithium hydroxide (35.9 mg, 1.5 mmol) was added. The reaction solution was heated to 40 °C and reacted for 1 hour. Trifluoroacetic acid was added to adjust the pH of the reaction solution to 7–8. The residue was purified by preparative high-performance liquid chromatography (HPLC) and freeze-dried to obtain compound 004. LC-MS: [M+H] + =472.20.

[0267] 1H NMR (400MHz, DMSO-d6) δ8.00(s,1H),7.63(d,J=7.4Hz,1H),7.40(t,J=7.5Hz,1H),7.30(d,J= 7.2Hz,1H),7.20-7.10(m,4H),6.96(d,J=8.0Hz,1H),6.83(t,J=7.3Hz,1H),6.69(s,1H),6.57 (s,1H),5.13(s,2H),3.98(s,2H),3.48(s,2H),3.43(d,J=9.3Hz,2H),3.37(d,J=5.6Hz,2H),3 .32-3.27(m,2H),3.09(d,J=10.2Hz,1H),2.99(s,1H),2.87(s,2H),1.80(s,1H),1.59(s,1H).

[0268] Example 5: Synthesis of 2-(2-((3'-(aminomethyl)-5-(hexahydropyrrolo[3,4-b][1,4]oxazine-6(2H)-yl)-[1,1'-biphenyl]-3-yl)methoxy)phenyl)acetic acid (compound 005)

[0269] 5.1 Synthesis of Compound 005-1

[0270] Add 005-a (5 g, 29.55 mmol) and ethylene glycol (1.83 g, 29.55 mmol) to a reaction flask, followed by the addition of N-bromosuccinimide (5.79 g, 32.51 mmol) in portions. React overnight at room temperature. Add water (150 mL) to the reaction mixture and extract with ethyl acetate (100 mL). Wash the organic phase with water (150 mL × 2) and saturated sodium chloride solution (150 mL), respectively. Dry the phase on anhydrous sodium sulfate, filter, and depressurize the filtrate to obtain compound 005-1 (crude product), which can be used directly in the next step. LC-MS: [M+H-Boc] + =255.95.

[0271] 5.2 Synthesis of Compound 005-2

[0272] In a reaction flask, 005-1 (6.6 g, 21.28 mmol), N,N-diisopropylethylamine (5.50 g, 42.56 mmol), dichloromethane (100 mL), and p-toluenesulfonyl chloride (4.87 g, 25.54 mmol) were added, and the mixture was reacted overnight at room temperature. The reaction system was washed successively with water (100 mL), 10% potassium carbonate aqueous solution (100 mL), 10% citric acid (100 mL), and saturated sodium chloride aqueous solution (100 mL). The organic phase was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 20 / 1-10 / 1) to give compound 005-2. LC-MS: [M+H-Boc] + =409.95.

[0273] 5.3 Synthesis of Compound 005-3

[0274] Add 005-2 (3.8 g, 8.18 mmol), N,N-diisopropylethylamine (3.17 g, 24.54 mmol), N,N-dimethylformamide (150 mL), and benzylamine (0.88 g, 8.18 mmol) to a reaction flask, and react overnight at 75 °C. Cool the reaction solution to room temperature, add water (200 mL) and ethyl acetate (100 mL), separate the organic phase, wash successively with water (150 mL) and saturated sodium chloride aqueous solution (150 mL), dry to anhydrous sodium sulfate, filter, concentrate the filtrate under reduced pressure, and purify the residue by silica gel column chromatography (petroleum ether / ethyl acetate = 20 / 1-10 / 1) to give compound 005-3. LC-MS: [M+H] + =319.10.

[0275] 5.4 Synthesis of Compound 005-4

[0276] Add 005-3 (1200 mg, 3.77 mmol), dichloromethane (10 mL), and a 1,4-dioxane solution of HCl (8 mL, 4 M) to a reaction flask. React at room temperature for 2 h. Concentrate the reaction solution under reduced pressure to obtain compound 005-4 (crude product), which can be used directly in the next step. LC-MS: [M+H] + =219.10.

[0277] Synthesis of compound 005-5 (5.5)

[0278] IN-01 (1000 mg, 1.85 mmol), 005-4 (592.57 mg, 2.04 mmol), cesium carbonate (3013.84 mg, 9.25 mmol), X-Phos (88.19 mg, 0.19 mmol), tris(dibenzylacetone)dipalladium (106.38 mg, 0.19 mmol), and 1,4-dioxane (30 mL) were added to a reaction flask. The mixture was reacted overnight at 100 °C under nitrogen protection. Water (100 mL) and ethyl acetate (100 mL) were added to the reaction solution. The organic phase was separated, washed with saturated sodium chloride aqueous solution (50 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 10 / 1-3 / 1) to give compound 005-5. LC-MS: [M+H] + =678.30.

[0279] 5.6 Synthesis of Compound 005-6

[0280] Add 005-5 (300 mg, 0.44 mmol), 150 mg (0.14 mmol), and 10 mL of methanol to a reaction flask. React at 40 °C for 5 h. Filter the reaction solution and concentrate the filtrate under reduced pressure to obtain compound 005-6 (crude product), which can be used directly in the next step. LC-MS: [M+H] + =588.30.

[0281] 5.7 Synthesis of Compound 005-7

[0282] Add 005-6 (230 mg, 0.39 mmol), dichloromethane (10 mL), and a 1,4-dioxane solution of HCl (1 mL, 4 M) to a reaction flask, and react at room temperature for 2 h. After allowing the reaction mixture to stand, a solid precipitates; discard the supernatant, and concentrate the solid under reduced pressure to obtain compound 005-7, which can be used directly in the next step. LC-MS: [M+H] + =488.20.

[0283] 5.8 Synthesis of Compound 005

[0284] In a reaction flask, 005-7 (190 mg, 0.39 mmol), monohydrate, lithium hydroxide (98.19 mg, 2.34 mmol), methanol (4 mL), water (4 mL), and tetrahydrofuran (4 mL) were added, and the mixture was reacted overnight at room temperature. Water (20 mL) was added to the reaction solution, and the reaction mixture was adjusted to a weakly alkaline state using 1,4-dioxane HCl. Dichloromethane (5 mL) was added, and the aqueous phase was separated. The aqueous phase was purified by preparative high-performance liquid chromatography (under alkaline conditions) and freeze-dried to obtain compound 005. LC-MS: [M+H] + =474.20.

[0285] 1 H NMR(600MHz,DMSO-d6)δ9.69(s,1H),9.44(s,1H),8.22(s,3H),7.75(s,1H),7.67(d,J=8.0Hz,1H ),7.49(t,J=7.6Hz,1H),7.42(d,J=7.6Hz,1H),7.21(m,2H),7.09-6.98(m,2H),6.88(t,J=7.3Hz, 1H),6.65(d,J=16.9Hz,2H),5.12(s,2H),4.40(t,J=3.6Hz,1H),4.12-4.03(m,3H),3.97-3.91(m, 1H), 3.70 (m, 2H), 3.62-3.53 (m, 4H), 3.42 (d, J = 11.2Hz, 1H), 3.29 (m, 1H), 3.15 (d, J = 12.5Hz, 1H).

[0286] Example 6: Synthesis of 2-(2-((3'-(aminomethyl)-5-(2-oxa-5-azabicyclo[2.2.2]octane-5-yl)-[1,1'-biphenyl]-3-yl)methoxy)phenyl)acetic acid (compound 006)

[0287] 6.1 Synthesis of Compound 006-1

[0288] At room temperature, IN-01 (1.0 g, 1.85 mmol) was dissolved in 1,4-dioxane (15 mL), and 006-a (210 mg, 1.85 mmol), tris(dibenzylacetone)dipalladium (169 mg, 0.19 mmol), 2-dicyclohexylphosphine-2',4',6'-triisopropylbiphenyl (88 mg, 0.19 mmol), and cesium carbonate (2.4 g, 7.4 mmol) were added. Under nitrogen protection, the mixture was heated to 90 °C and reacted for 2 hours. The reaction mixture was then extracted with ethyl acetate (15 mL × 2) after adding water (20 mL). The combined organic phases were washed with saturated brine (20 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 = 5 / 1 to 3 / 1) to give compound 006-1. LC-MS: [M+H] + =573.25.

[0289] 6.2 Synthesis of Compound 006-2

[0290] At room temperature, 006-1 (800 mg, 1.40 mmol) was dissolved in dichloromethane (6 mL), and trifluoroacetic acid (2 mL) was added. The reaction mixture was reacted at room temperature for 2 hours. The reaction mixture was concentrated under reduced pressure, and the residue was adjusted to pH 9–10 with saturated sodium carbonate aqueous solution and extracted with ethyl acetate (6 mL × 3). The combined organic phases were washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give compound 006-2 (crude product), which could be used directly in the next step. LC-MS: [M+H] + =473.20.

[0291] 6.3 Synthesis of Compound 006

[0292] Compound 006-2 (700 mg) was dissolved in methanol (4 mL), tetrahydrofuran (2 mL), and water (2 mL) at room temperature. Lithium hydroxide (177 mg, 7.4 mmol) was added, and the reaction mixture was heated to 40 °C and reacted for 2 hours. The reaction solution was purified by preparative high-performance liquid chromatography (0.1% formic acid) and lyophilized to obtain compound 006. LC-MS: [M+H] + =459.15.

[0293] 1 H NMR (600MHz, DMSO-d6) δ8.09(s,1H),7.68(d,J=7.8Hz,1H),7.39(t,J=7.6Hz,1H),7.29(d,J=7.6 Hz,1H),7.24(s,1H),7.15–7.08(m,2H),6.92(d,J=8.0Hz,1H),6.84(s,1H),6.81(t,J=7.2Hz,1H) The 6.71 (s, 1H), 5.13 (s, 2H), 4.10 (s, 1H), 4.01 (t, J = 13.8 Hz, 3H), 3.97 (s, 2H), 3.75 (d, J = 10.4 Hz, 1H), 3.44 (s, 2H), 3.41 (d, J = 10.4 Hz, 1H), 2.07–1.96 (m, 2H), 1.95–1.86 (m, 1H), and 1.74–1.67 (m, 1H) compounds of the present invention can be prepared by methods well known to those skilled in the art and / or by modifications of the methods described in WO2023 / 051793A1 or CN115894367A.

[0294] The compounds of the present invention can be prepared according to the following synthetic schemes:

[0295] Among them, R 2 R 3 R 4 R5 R 6H R 7 R 8 R 9 R c The definitions of X, m, and n are as described in any embodiment of the present invention, and the conditions and operations of the above-mentioned deprotection reaction and hydrolysis reaction are as common to such reactions in the art.

[0296] Furthermore, the compounds of the present invention can be prepared according to the following synthetic scheme:

[0297] Among them, R c C 1-6 Alkyl groups or those with 1, 2, or 3 R groups c-1 Replacement C 1-6 Alkyl groups; each R c-1 It can be halogen, -OH or -C(=O)OC(CH3)3 independently.

[0298] Exemplary compounds of the present invention are described in Table 1 provided below. The structural information of the compounds is illustrated in this table.

[0299] Table 1 Compounds of the present invention

[0300] Biological activity test

[0301] 1. In vitro screening experiment for complement factor D inhibitory activity (C3b method)

[0302] 1.1 Experimental Materials and Instruments

[0303] V-type substrate (AXYGEN), DMSO (Sigma), MicroVue Bb Plus ELISA kit (Quidel), complement factor C3b (Complement Tech), complement factor B (Complement Tech), complement factor D (Complement Tech), EDTA (Maclean), GVB o Complement Tech, EGTA (Aladdin), MgCl2 (Aladdin), NaOH (Sinopharm), Microplate reader (Molecular Devices, SpectraMax i3x), Microplate shaker (Thermo, MB100-2A), Pipettes (Gilson).

[0304] 1.2 Preparations before the experiment

[0305] 1.2.1 Preparation of Mg-EGTA

[0306] 0.1M Mg-EGTA: Weigh 3.8g EGTA, 0.9521g MgCl2, and 0.7g NaOH. Adjust the pH to 7.5 with NaOH, add distilled water to a final volume of 100mL, filter through a 0.2μm sterile filter, dispense, and store at 4℃.

[0307] 1.2.2 Preparation of working solution

[0308] Buffer: 0.1M Mg-EGTA solution using GVB o Dilute the buffer solution 10-fold to 10mM;

[0309] Factor B working solution: Dilute 1 mg / mL factor B solution (10.75 μM) 6.7 times with buffer to 1.6 μM;

[0310] Factor C3b working solution: 1 mg / mL factor C3b solution (5.68 μM) was diluted 5-fold with buffer to 1.12 μM;

[0311] Factor D working solution: 0.1 mg / mL factor D solution (4.17 μM) was diluted 1303 times with buffer to 3.2 nM.

[0312] Note: a. The dilution ratios above are for reference only and should be adjusted according to the actual concentration indicated on the reagent.

[0313] b. Factor B: 93 kDa, Factor D: 24 kDa, Factor C3b: 176 kDa.

[0314] 1.2.3 Preparation of Termination Solution

[0315] Termination solution: Weigh an appropriate amount of EDTA powder and add a certain amount of GVB. o Dissolve in buffer solution, adjust pH to 7.5 with NaOH, stir until clear, and prepare a 10 mM solution.

[0316] 1.2.4 Compound Preparation

[0317] Compound stock solution: Dilute 40mM compound solution with DMSO to prepare 1mM stock solution, then dilute 1mM stock solution with DMSO 3 times, and prepare stock solutions of various concentrations at 8 points;

[0318] Compound working solutions: Dilute with buffer solution 250 times to obtain compound solutions of various concentrations.

[0319] 1.3 Experimental Procedure

[0320] In the V-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 buffer containing 0.4% DMSO were added to the positive control group; and 20 μL of buffer containing 0.2% DMSO was added to the blank control group. The mixture was incubated at 37°C for 15 min. Factor B working solution and factor C3b working solution were mixed 1:1 and 20 μL of the mixture was added to each well. The mixture was incubated at 37°C for 30 min. The reaction was terminated by adding 40 μL of stop solution. The amount of Bb product generated was detected using the MicroVue Bb Plus ELISA kit.

[0321] 1.4 ELISA detection

[0322] 1.4.1 Remove the required wells of the ELISA plate and allow them to return to room temperature. Repackage the remaining plates and store them at 4°C.

[0323] 1.4.2 Wash twice with 300 μL of 1× Wash Buffer. Incubate the first wash at 25°C for 1 min.

[0324] 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;

[0325] 1.4.4 Discard the liquid in the wells and wash 5 times with 300 μL 1× Wash Buffer. Incubate at room temperature for 1 min for the first wash.

[0326] 1.4.5 Add 50 μL of Bb Plus Conjugate to each well and incubate at 25°C for 30 min;

[0327] 1.4.6 Discard the liquid in the well and wash 5 times with 300 μL 1× Wash Buffer. Incubate at room temperature for 1 min for the first wash.

[0328] 1.4.7 Add 100 μL of the compound working solution to each well and incubate at 25 °C for 15 min;

[0329] 1.4.8 Add 100 μL of stop solution to each well and measure the absorbance at 450 nm within 30 min.

[0330] 1.5 Data Analysis

[0331] 1.5.1 Inhibition rate at different drug concentrations:

[0332] The PC group represents 0% inhibition rate, and the NC group represents 100% inhibition rate.

[0333] 1.5.2 Calculate the signal-to-ground ratio (S / B):

[0334] The average OD value of the PC group / the average OD value of the NC group represents the size of the signal window.

[0335] 1.5.3 Z' factor:

[0336] Calculation formula:

[0337] The Z' factor should be greater than 0.4.

[0338] 1.5.4 Compound IC 50 :

[0339] IC 50 Half-inhibition concentration (WIC) represents the concentration at which a compound inhibits the enzyme activity of complement factor D by 50%.

[0340] Data were collected to calculate the logarithm of inhibition rate versus compound concentration, and IC was calculated using GraphPad Prism software. 50 Value. IC50 value of the inhibitory activity of the compound of the present invention against complement factor D. 50 ≤100nM, preferred IC 50 ≤30nM.

[0341] The compounds of this invention exhibit excellent inhibitory activity against complement factor D.

[0342] 2. Rabbit erythrocyte hemolysis method for evaluating the inhibitory activity of compounds on alternative pathways.

[0343] 2.1 Experimental Materials and Instruments

[0344] Normal Human Serum (NHS, collected from healthy individuals), Normal Human Plasma (NHP, Shanghai Yuduo), 96-well ELISA plate (Jet Biofil), Japanese White Rabbit (Wuhan Wanqian Jiaxing), Alsace solution (Pronosai), centrifuge (Thermo, PICO17), constant temperature shaker (Shanghai Fuma), decolorizing shaker (Beijing Liuyi), cell counter (Invitrogen, Counter Countess II) (GVB) o EGTA, MgCl 2、 NaOH, microplate reader, microplate shaker, pipette, etc. (same as in Experiment 1).

[0345] 2.2 Preparation of working solution

[0346] 48% NHP: Dilute 100% NHP to 48% with buffer.

[0347] 26.4% NPS: 100% NHS diluted to 26.4% with buffer.

[0348] Rabbit erythrocyte suspension: Blood was collected from the marginal ear vein of rabbits, anticoagulated with Abercrombie's solution at a 1:1 ratio, aliquoted, and stored at 4°C for up to 4 weeks. Before use, centrifuge at 500g for 5 min to discard the Abercrombie's solution, wash three times with an equal volume of buffer at 500g for 5 min, and finally adjust the density to 6×10⁻⁶ with buffer. 8 per mL.

[0349] 2.3 Experimental Procedure

[0350] In a 96-well microplate, the experimental group was treated with 50 μL of 48% NHP or 26.4% NHS and 50 μL of compound solution; the positive control group was treated with 50 μL of 48% NHP or 26.4% NHS and 50 μL of buffer containing 0.2% DMSO; the blank control group was treated with 50 μL of buffer containing 48% inactivated NHP or 26.4% inactivated NHS and 0.2% DMSO; the H2O group was treated with 100 μL of double-distilled water; the plates were incubated at 37°C for 15 min; 20 μL of rabbit red blood cell suspension was added to each well, and the plates were incubated at 37°C on a shaker for 30 min; the plates were centrifuged at 2000g (3380 rpm) for 5 min, and 100 μL of supernatant was transferred to a new 96-well microplate. The absorbance was measured at 415 nm.

[0351] 2.4 Data Analysis

[0352] 2.4.1 Percentage of hemolysis at each drug concentration:

[0353] The PC group represents 100% hemolysis, and the NC group represents 0% hemolysis.

[0354] 2.4.2 Calculate the signal-to-ground ratio (S / B):

[0355] The average OD value of the PC group / the average OD value of the NC group represents the size of the signal window.

[0356] 2.4.3 Z' factor:

[0357] Calculation formula:

[0358] 2.4.4 Compound IC 50 :

[0359] IC 50Half-inhibitory concentration (IC50). Data were collected to calculate the logarithm of hemolysis percentage versus compound concentration, and IC50 was calculated using GraphPad Prism software. 50 Values. The inhibitory activity of the compounds of this invention against rabbit erythrocyte hemolysis is shown in Table 1.

[0360] Table 1: Inhibitory activity of the compounds of the present invention against rabbit erythrocyte hemolysis

[0361] IC50 of the inhibitory activity of the compounds of this invention against rabbit erythrocyte hemolysis 50 ≤250nM, IC preferred 50 ≤100nM, superior IC 50 ≤50nM.

[0362] The compound of this invention has a good inhibitory effect on rabbit erythrocyte hemolysis.

[0363] 3. In vivo pharmacokinetic studies of the compounds of this invention

[0364] After acclimatization, SPF-grade SD rats were administered the compounds of this invention at doses of 1 mg / kg via single gavage or tail vein bolus. Plasma samples were collected at specific time points after administration, and the concentrations of the compounds in the plasma were determined by LC-MS / MS (AB SCIEX Qtrap4500). The pharmacokinetic parameters of each compound were calculated using software to demonstrate the in vivo pharmacokinetic properties of the compounds of this invention in animals.

[0365] The compounds of this invention can achieve high in vivo exposure and high oral bioavailability at low doses, and have superior overall pharmacokinetic properties.

Claims

1. The compound represented by formula (I), its tautomer, its stereoisomer, its prodrug, or a pharmaceutically acceptable salt of any of the foregoing, or a solvate of any of the foregoing: in: R 1 is H, D, C 1-6 alkyl or C 1-1 alkyl substituted by 1, 2 or 3 R 1-6 alkyl; each R 1-1 independently halogen, -CN, -OH, C 1-6 alkoxy or -NH2; R 2 and R 3 each independently H, D, halogen, C 1-6 alkyl or C 2-1 alkyl substituted with 1, 2, or 3 R 1-6 ; each R 2-1 is independently halogen, -CN, -OH, C 1-6 alkoxy, or -NH2; R 4 R is H or halogen; m is 0, 1, 2 or 3; R 5 and R 7 each independently H, halogen, -CN, C 1-6 alkyl or C 1-6 alkoxy; R 6H "8-12-membered fused heterocyclic alkyl group selected from 1, 2, or 3 of N, O, and S, with 1, 2, or 3 heteroatoms", "8-12-membered bridged heterocyclic alkyl group selected from 1, 2, or 3 of N, O, and S, with 2 or 3 heteroatoms", surrounded by 1, 2, or more R... 6-1 The substituted heteroatom is selected from one, two, or three of N, O, and S, and is an 8-12 membered fused heterocyclic alkyl group having one, two, or three heteroatoms, or is replaced by one, two, or more R atoms. 6-1 The substituted heteroatom is selected from one, two, or three of N, O, and S, and is an 8-12 membered bridged heterocyclic alkyl group with two or three heteroatoms. R 6-1 each independently hydroxyl, oxo (=0), halogen, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkyl, C 1-6 haloalkoxy, C 3-6 cycloalkyl or -(CH2) p -C 3-6 cycloalkyl; p is 1, 2, 3 or 4; R 6-2 and R 6-3 each independently is hydroxyl, oxo (=0), halogen, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkyl, C 1-6 haloalkoxy, C 3-6 cycloalkyl or -(CH2) p -C 3-6 cycloalkyl; x1 and x2 are independently 0, 1, 2, 3 or 4; R 8 R is H, halogen or C 1-6 alkyl; R 9 H, halogen, C 1-6 alkyl or C 9-1 substituted C 1-6 alkyl; Each R 9-1 It can be halogen, -CN, -OH or -NH2 independently; n is 0, 1, 2, 3 or 4; L is -(CR) a R b ) q -; q is 0, 1, 2, or 3; R a and R b Each is independently H, D, or halogen, or R. a and R b Connect together to form C 3-6 Cycloalkylene; R 10 -COOH or -C(=O)OR c ; R c C 1-6 Alkyl groups or those with 1, 2, or 3 R groups c-1 Replacement C 1-6 Alkyl groups; each R c-1 It can be independently a halogen, -OH, or -C(=O)OC(CH3)3; X is CR d Or N; R d H, halogen or C 1-6 alkyl.

2. The compound of formula (I) as claimed in claim 1, its tautomer, its stereoisomer, its prodrug, or a pharmaceutically acceptable salt of any of the foregoing, or a solvate of any of the foregoing, characterized in that, R 6H The heteroatom is selected from 1, 2 or 3 of N, O and S, and the number of heteroatoms is 1, 2 or 3, which is an 8-9 member fused heterocyclic alkyl group or the heteroatom is selected from 1, 2 or 3 of N, O and S, and the number of heteroatoms is 2. Ideally, R 6H for Or "the heteroatoms are selected from N and O, and the number of heteroatoms is 2 in an 8-membered bridged heterocyclic alkyl group"; Ring A is independently C 3-6 Cycloalkyl or "a 4-6 membered heterocycloalkyl group whose heteroatoms are selected from one or two of N, O and S, and whose heteroatoms number one or two"; Ring B is "a 4-6 membered heterocyclic alkyl group selected from one or two of N, O and S, with one or two heteroatoms"; Ring A is preferably C 5-6 The cycloalkyl group is a 4-6 membered heterocyclic alkyl group in which the heteroatom is selected from N, O and S and the heteroatom number is 1; more preferably, it is a 4-6 membered heterocyclic alkyl group in which the heteroatom is selected from N, O and S and the heteroatom number is 1; even more preferably, it is a 4-6 membered heterocyclic alkyl group in which the heteroatom is O and the heteroatom number is 1; more preferably, it is a 5 membered heterocyclic alkyl group in which the heteroatom is O and the heteroatom number is 1. Ring B is preferably "a 5-6 membered heterocyclic alkyl group whose heteroatoms are selected from one or two of N, O and S, and whose heteroatoms number one or two"; it is also preferably "a 5-6 membered heterocyclic alkyl group whose heteroatoms are one or two of N or O, and whose heteroatoms number one or two"; and it is even more preferably "a 6 membered heterocyclic alkyl group whose heteroatoms are N and whose heteroatoms number one".

3. The compound of formula (I) as claimed in claim 1, its tautomer, its stereoisomer, its prodrug, or a pharmaceutically acceptable salt of any of the foregoing, or a solvate of any of the foregoing, characterized in that, The compound represented by formula (I) satisfies one or more of the following conditions: (1)R 1 For H; (2)R 2 and R 3 Each independently represents H and C. 1-3 Alkyl groups or those with 1, 2, or 3 R groups 2-1 Replacement C 1-3 Alkyl groups; each R 2-1 It is independently a halogen or -OH, wherein the halogen is preferably F; (3) m is 0 or 1; (4)R 5 and R 7 Each is independently H or a halogen, preferably F; (5)R 6H "8-10 fused heterocyclic alkyl groups selected from one, two, or three of N, O, and S, with one, two, or three heteroatoms", "8-10 bridged heterocyclic alkyl groups selected from one, two, or three of N, O, and S, with two or three heteroatoms", surrounded by one, two, or more R... 6-1 The substituted heteroatom is selected from one, two, or three of N, O, and S, and is an 8-10 member fused heterocyclic alkyl group having one, two, or three heteroatoms, or is replaced by one, two, or more R atoms. 6-1 The substituted heteroatom is selected from one, two, or three of N, O, and S, and is an 8-10 membered bridged heterocyclic alkyl group having two or three heteroatoms; preferably, the R 6H The nitrogen atom is connected to the benzene ring; (6) Each R 6-1 Independently hydroxyl, oxo (=O), halogen, C 1-3 Alkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkyl or C 1-3 Halogenated alkoxy groups; (7) Each R 6-2 and R 6-3 Each is independently a hydroxyl, halogen, or C 1-3 alkyl; (8) x1 is 0 or 1; (9) x2 is 0 or 1; (10)R 8 For H; (11)R 9 The halogen is H or a halogen, preferably F; (12) n is 0 or 1; (13) q is 1; (14)R a and R b Each is independently represented by H; (15)R 10 -COOH; and (16)R d It is H or halogen.

4. The compound of formula (I) as claimed in claim 1, its tautomer, its stereoisomer, its prodrug, or a pharmaceutically acceptable salt of any of the foregoing, or a solvate 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 For H and R 3 For H, C 1-3 Alkyl groups or those with 1, 2, or 3 R groups 2-1 Replacement C 1-3 Alkyl groups; each R 2-1 Independently halogenated or -OH; preferably, R 2 For H, R 3 The derivatives are H, -CH3, -CH2OH, -CH2CH2OH, -CH2F, or -CF2H; (2)R 6H In this context, each of the fused heterocyclic alkyl groups is independently 8-oxa-3-azabicyclo[4.2.0]octyl, 7-oxa-3-azabicyclo[4.2.0]octyl, 3,8-diazabicyclo[4.2.0]octyl, 3,7-diazabicyclo[4.2.0]octyl, octahydrofurano[2,3-c]pyridyl, octahydrofurano[3,4-c]pyridyl, octahydrofurano[3,2-c]pyridyl, octahydro-1H-pyrrolo[2,3-c]pyridyl, octahydro-1H-pyrrolo[3,2-c]pyridyl, octahydro-1H-pyrrolo[3,4 ... Hydrogen-1H-cyclopentano[c]pyridyl, hexahydro-2H-furano[2,3-c]pyrryl, hexahydro-1H-furano[3,4-c]pyrryl, octahydrocyclopentano[c]pyrryl, octahydropyrrolo[3,4-b]pyrryl, octahydropyrrolo[3,4-c]pyrryl, octahydro-1H-pyrrolo[3,4-b]pyridyl, octahydropyrano[2,3-c]pyrryl, octahydropyrano[3,4-c]pyrryl, octahydro-1H-isoindolyl, octahydropyrrolo[3,4-b][1,4]oxazinyl or hexahydro-5H-[1,4]dioxa[2,3-c]pyrryl; (3)R 6H In this context, each of the bridged heterocyclic alkyl groups is independently 2-oxa-5-azabicyclo[2.2.2]octyl, 2,5-diazabicyclo[2.2.2]octyl, 3,8-diazabicyclo[3.2.1]octyl, 8-oxa-3-azabicyclo[3.2.1]octyl, or 3-oxa-8-azabicyclo[3.2.1]octyl; (4) Each R 6-1 Independently hydroxyl, oxo (=O), halogen or C 1-3 Alkyl; preferably hydroxyl; (5) x1 is 0; (6) x2 is 0; (7) X is CR d ;and (8)R d For H.

5. The compound of formula (I) as claimed in claim 1, its tautomer, its stereoisomer, its prodrug, or a pharmaceutically acceptable salt of any of the foregoing, or a solvate of any of the foregoing, characterized in that, The compound represented by formula (I) satisfies one or more of the following conditions: (1)R 1 R 2 R 3 R 5 R 7 R 6-1 R 6-2 R 6-3 R 8 R 9 R c and R d In this context, each of the alkyl groups is independently methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, or tert-butyl, preferably methyl or ethyl; (2)R 1-1 R 2-1 R 5 R 7 R 6-1 R 6-2 and R 6-3 In this context, each of the alkoxy groups is independently methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, or tert-butoxy; (3)R 1-1 R 2 R 3 R 2-1 R 4 R 5 R 7 R 6-1 R 6-2 R 6-3 R 8 R 9 R 9-1 R a R b R c-1 and R d In this context, each of the halogens is independently F, Cl, Br, or I, preferably F; (4)R 6H In this context, each of the fused heterocycloalkyl groups is independently... (5)R 6H In this context, each of the bridged heterocyclic alkyl groups is independently... (6)R 2 For H; (7)R 3 For H; (8)R 4 For H; (9) m is 0; (10)R 5 For H; (11)R 7 For H; (12)R 9 For H; and (13) n is 0.

6. The compound of formula (I) as claimed in claim 1, its tautomer, its stereoisomer, its prodrug, or a pharmaceutically acceptable salt of any of the foregoing, or a solvate 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 For H and R 3 For H; (2)R 4 H is a variable, and m is either 0 or 1. (3)R 5 and R 7 For H; (4)R 9 H is a variable, and n is either 0 or 1. (5)R 6-1 Independently hydroxyl, oxo (=O), F, Cl, methyl, ethyl, n-propyl or isopropyl; preferably, R 6-1 It can be independently hydroxyl, oxo (=O), F or methyl; (6)R 6H for and (7)R 6H for 7. The compound of formula (I) as claimed in claim 1, its tautomer, its stereoisomer, its prodrug, or a pharmaceutically acceptable salt of any of the foregoing, or a solvate of any of the foregoing, characterized in that, The compound represented by formula (I) satisfies any of the following conditions: (1)R 1 For H; R 2 For H, R 3 The possible values ​​are H, -CH3, -CH2OH, -CH2CH2OH, -CH2F, or -CHF2; R 4 For H or halogen, m is 0 or 1; R 5 and R 7 Each can be H or F independently; R 6H "8-9 membered fused heterocyclic alkyl groups selected from 1, 2, or 3 of N, O, and S, with 1, 2, or 3 heteroatoms"; "8-9 membered bridged heterocyclic alkyl groups selected from 1, 2, or 3 of N, O, and S, with 2 heteroatoms"; bounded by 1, 2, or 3 R... 6-1 The substituted "an 8-9 member fused heterocyclic alkyl group selected from one, two, or three of N, O, and S, with one, two, or three heteroatoms" is replaced by one, two, or three R atoms. 6-1 The substituted heteroatom is selected from one, two, or three of N, O, and S, and is an 8-9 membered bridged heterocyclic alkyl group with two heteroatoms. Preferably, the R 6H The nitrogen atom is connected to the benzene ring; Each R 6-1 Independently hydroxyl, oxo (=O), halogen or C 1-3 alkyl; x1 is either 0 or 1; x2 is 0 or 1; R 8 For H; R 9 For H or F; n is 0 or 1; L is -(CR) a R b ) q -; q is 1; R a and R b Each is independently represented by H; R 10 -COOH; and X is CR d Or N; R d For H; (2)R 1 For H; R 2 For H, R 3 For H; R 4 H is a variable, and m is either 0 or 1. R 5 and R 7 For H; R 6H The compounds are 8-oxa-3-azabicyclo[4.2.0]octyl, 7-oxa-3-azabicyclo[4.2.0]octyl, 3,8-diazabicyclo[4.2.0]octyl, 3,7-diazabicyclo[4.2.0]octyl, octahydrofurano[2,3-c]pyridyl, octahydrofurano[3,4-c]pyridyl, octahydrofurano[3,2-c]pyridyl, and octahydro-1 H-pyrrolo[2,3-c]pyridyl, octahydro-1H-pyrrolo[3,2-c]pyridyl, octahydro-1H-pyrrolo[3,4-c]pyridyl, octahydro-1H-cyclopentano[c]pyridyl, hexahydro-2H-furano[2,3-c]pyrryl, hexahydro-1H-furano[3,4-c]pyrryl, octahydrocyclopentano[c]pyrryl, octahydropyrrolo[3,4-b]pyrryl Pyrroloyl, octahydropyrrolo[3,4-c]pyrroloyl, octahydro-1H-pyrrolo[3,4-b]pyridyl, octahydropyrano[2,3-c]pyrroloyl, octahydropyrano[3,4-c]pyrroloyl, octahydro-1H-isoindolyl, octahydropyrrolo[3,4-b][1,4]oxazinyl, hexahydro-5H-[1,4]dioxa[2,3-c]pyrroloyl, 2-oxa-5-aza Bicyclo[2.2.2]octyl, 2,5-diazabicyclo[2.2.2]octyl, 3,8-diazabicyclo[3.2.1]octyl, 8-azabicyclo[3.2.1]octyl, 8-oxa-3-azabicyclo[3.2.1]octyl, 3-oxa-8-azabicyclo[3.2.1]octyl or 3-azabicyclo[3.2.1]octyl, or with 1 or 2 R 6-1 The following groups are substituted: 8-oxa-3-azabicyclo[4.2.0]octyl, 7-oxa-3-azabicyclo[4.2.0]octyl, 3,8-diazabicyclo[4.2.0]octyl, 3,7-diazabicyclo[4.2.0]octyl, octahydrofurano[2,3-c]pyridyl, octahydrofurano[3,4-c]pyridyl, octahydrofurano[3,2-c]pyridyl, octahydro-1H-pyrrolo[2,3-c]pyridyl, octahydro-1H-pyrrolo[3,2-c]pyridyl, octahydro-1H-cyclopentano[c]pyridyl, hexahydro-2H-furano[2,3-c]pyrryl, hexahydro-1H-furano[3,4-c]pyrryl, octahydrocyclopentano[c]pyrryl Octahydropyrrolo[3,4-b]pyrrol, octahydropyrrolo[3,4-c]pyrrol, octahydro-1H-pyrrolo[3,4-b]pyridyl, octahydropyranolo[2,3-c]pyrrol, octahydropyranolo[3,4-c]pyrrol, octahydro-1H-isoindolyl, octahydropyrrolo[3,4-b][1,4]oxazinyl, hexahydro-5H-[1,4]dioxa[2,3-c]pyrrol, 2-oxa-5-azabicyclo[2.2.2]octyl, 2,5-diazabicyclo[2.2.2]octyl, 3,8-diazabicyclo[3.2.1]octyl, 8-oxa-3-azabicyclo[3.2.1]octyl or 3-oxa-8-azabicyclo[3.2.1]octyl; Each R 6-1 Independently hydroxyl, oxo (=O), halogen or C 1-3 alkyl; R 8 For H; R 9 H is a variable; n is 0 or 1. L is -(CR) a R b ) q -; q is 1; R a and R b Each is independently represented by H; R 10 -COOH; and X is CR d Or N; R d For H; (3)R 1 For H; R 2 For H, R 3 For H; R 4 H is a variable, and m is either 0 or 1. R 5 and R 7 For H; R 6H for Or by 1 or 2 R 6-1 The following groups are substituted: R 6-1 It can be hydroxyl, oxo (=O), F or methyl; R 8 For H; R 9 H is a variable; n is 0 or 1. L stands for -CH2-; R 10 -COOH; and X is CH; (4)R 1 For H; R 2 For H, R 3 For H; R 4 H is a variable, and m is either 0 or 1. R 5 and R 7 For H; R 6H for Or by 1 or 2 R 6-1 The following groups are substituted: R 6-1 It can be hydroxyl, oxo (=O), F or methyl; R 8 For H; R 9 H is a variable; n is 0 or 1. L stands for -CH2-; R 10 -COOH; and X is CH; (5)R 1 For H; R 2 For H, R 3 For H; R 4 H is a variable, and m is either 0 or 1. R 5 and R 7 For H; R 6H for Or R 6H for R 8 For H; R 9 H is a variable; n is 0 or 1. L stands for -CH2-; R 10 -COOH; and X is CH.

8. The compound of formula (I) as claimed in any one of claims 1-7, its tautomer, its stereoisomer, its prodrug, or a pharmaceutically acceptable salt of any of the foregoing, or a solvate of any of the foregoing, characterized in that, The compound represented by formula (I) has the structure shown in formula (IA): When the carbon atom marked with "*" is a chiral carbon atom, it indicates the R configuration, S configuration, or a mixture thereof; The compound represented by formula (I) has the structure shown in formula (II): Preferably, the compound represented by formula (I) has the structure shown in formula (II-A): When the carbon atom marked with "*" is a chiral carbon atom, it indicates the R configuration, S configuration, or a mixture thereof; Preferably, the compound represented by formula (I) has the structure shown in formula (III): Preferably, the compound represented by formula (I) has the structure shown in formula (III-A): When the carbon atom marked with "*" is a chiral carbon atom, it indicates the R configuration, S configuration, or a mixture thereof; Preferably, the compound represented by formula (I) has the structure shown in formula (IV): Preferably, the compound represented by formula (I) has the structure shown in formula (IV-A): When the carbon atom marked with "*" is a chiral carbon atom, it indicates the R configuration, S configuration, or a mixture thereof.

9. The compound of formula (I) as claimed in claim 1, its tautomer, its stereoisomer, its prodrug, or a pharmaceutically acceptable salt of any of the foregoing, or a solvate of any of the foregoing, characterized in that, The compound represented by formula (I) is selected from any of the following compounds:

10. The compound of formula (I) as claimed in claim 1, its tautomer, its stereoisomer, its prodrug, or a pharmaceutically acceptable salt of any of the foregoing, or a solvate of any of the foregoing, characterized in that, The compound represented by formula (I) is selected from the following compounds:

11. A method for preparing the compound shown in formula (I), characterized in that, It includes the following steps: (1) The compound shown in formula I-3 undergoes a deprotection reaction to obtain the compound shown in formula I-4; (2) The compound shown in formula I-4 is hydrolyzed to obtain the compound shown in formula (I); Among them, R 10 For -COOH, R 1 R 2 R 3 R 4 R 5 R 6H R 7 R 8 R 9 R c The definitions of X, L, m, and n are as described in any one of claims 1-8; preferably, R 1 For H.

12. A pharmaceutical composition, characterized in that, The pharmaceutical composition comprises: (1) The compound of formula (I) as claimed in any one of claims 1-10, its tautomer, its stereoisomer, its prodrug, or a pharmaceutically acceptable salt of any of the foregoing, or a solvate of any of the foregoing; and (2) Pharmaceutically acceptable carrier.

13. The use of the compound of formula (I) as claimed in any one of claims 1-10, its tautomer, its stereoisomer, its prodrug, or a pharmaceutically acceptable salt of any of the foregoing, or a solvate of any of the foregoing, or the pharmaceutical composition of claim 12 in the preparation of a medicament for treating and / or preventing complement factor D-mediated diseases, wherein the complement factor D-mediated diseases are blood diseases, kidney diseases, cardiovascular diseases, immune diseases, central nervous system diseases, respiratory diseases, genitourinary diseases, or eye diseases.

14. The application as described in claim 13, characterized in that, The diseases mediated by complement factor D include cold agglutinin disease, catastrophic antiphospholipid syndrome, hemolytic anemia, antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV), warm antibody-type autoimmune hemolytic anemia, paroxysmal nocturnal hemoglobinuria, IgA nephropathy, lupus nephritis, atypical hemolytic uremic syndrome, membranoproliferative glomerulonephritis (MPGN), dense deposit disease, C3 glomerulonephritis, focal segmental glomerulosclerosis, diabetic nephropathy, systemic lupus erythematosus, rheumatoid arthritis, inflammatory bowel disease, psoriasis, multiple sclerosis, organ transplant rejection, myasthenia gravis, Alzheimer's disease, acute respiratory distress syndrome, asthma, and chronic obstructive pulmonary disease. Coronavirus-related lung disease, emphysema, coronavirus infection (such as SARS-CoV, MERS-CoV, or SARS-CoV-2 infection), macular degeneration, age-related macular degeneration (AMD), macular edema, diabetic macular edema, choroidal neovascularization (CNV), uveitis, Behcet's uveitis, proliferative diabetic retinopathy, non-proliferative diabetic retinopathy, glaucoma, hypertensive retinopathy, corneal neovascularization, corneal transplant rejection, corneal dystrophy, autoimmune dry eye disease, Stevens-Johnson syndrome, Sjögren's syndrome, environmental dry eye disease, Fehling's endothelial dystrophy, retinal vein occlusion, or postoperative inflammation.

15. The use of the compound of formula (I) as claimed in any one of claims 1-10, its tautomer, its stereoisomer, its prodrug, or a pharmaceutically acceptable salt of any of the foregoing, or a solvate of any of the foregoing, or the use of the pharmaceutical composition of claim 12 in the preparation of a complement factor D inhibitor medicament.

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