2-substituted piperidine derivative as well as preparation method and medical application thereof

Abstract

2-substituted piperidine derivatives of formula (I), processes for their preparation, pharmaceutical compositions comprising these compounds, and pharmaceutical uses for the treatment of diseases or conditions. # imgabs0 #

Description

Technical Field

[0001] The invention belongs to the field of medicine and relates to 2-substituted piperidine derivatives, a preparation method thereof, a pharmaceutical composition containing the compound, and medical use thereof. Background Art

[0002] The complement system is part of innate immune surveillance and plays a key role in eliminating pathogens and maintaining tissue homeostasis. The complement cascade can be activated through three different pathways, including the classical pathway (CP), the lectin pathway (LP), and the alternative pathway (AP). The CP and LP are initiated on the target surface by the binding of immune complexes and mannan-binding lectins or ficolins to specific patterns of microbial sugar moieties, respectively. However, the AP does not require specific initiation. The AP cascade is initiated by spontaneous hydrolysis of C3 (tick-over) and subsequent deposition of C3b on the activated surface. The three complement activation pathways converge on two major events: C3 cleavage and C5 cleavage. The C3 convertase splits C3 into C3a and C3b. C3b forms additional AP C3 convertase (amplification) and C5 convertase. The C5 convertase cleaves C5 into C5a and C5b. The generated C5b triggers the formation of C5b-9 membrane attack complex (MAC) with C6-C9, thereby lysing bacteria and cells by inserting into the membrane. The cleavage products C3a and C5a act as anaphylatoxins, promoting proinflammatory reactions through the activation and chemotaxis of leukocytes. C3b also promotes phagocytosis through opsonization, playing a key role in clearing bacteria and cell waste (such as immune complexes and apoptotic cells). (Front Immunol. 2015Jun2; 6: 262. doi: 10.3389 / fimmu.2015.00262. eCollection 2015. Complement System Part I-Molecular Mechanisms of Activation and Regulation. Nicolas S Merle, Sarah Elizabeth Church, Veronique Fremeaux-Bacchi, Lubka T Roumenina). AP maintains basal complement activity through the "idling" process. Furthermore, even when triggered by other CPs or LPs, the AP contributes more than 80% of the activation of the terminal cleavage pathway (MAC formation) through the amplification loop. (Harboe, M., Garred, P., E., Lindstad, JK, Stahl, GL, Mollnes, TE, 2009. The down-stream effects of mannan-induced lectin complement pathway activation depend quantitatively on alternative pathway amplification. Mol. Immunol. 47, 373–380. https: / / doi.org / 10.1016 / j.molimm.2009.09.005). Spontaneously activated C3 forms C3 convertase by binding to factor B (FB). After factor D cleaves FB into Bb, C3b and Bb generate AP C3 convertase (C3bBb). The newly formed C3bBb cleaves more C3 to produce more AP C3 convertase, leading to complement cascade amplification. Since AP can exert full complement activity within seconds, it may cause normal tissue damage if not properly controlled. (J Clin Invest. 2020 May 1; 130(5): 2152-2163. doi: 10.1172 / JCI136094. Complementopathies and precision medicine. Eleni Gavriilaki, Robert A Brodsky). Dysregulation of complement activation has been shown to be associated with diseases of multiple organs, including paroxysmal nocturnal hemoglobinuria, age-related macular degeneration, rheumatoid arthritis, hemolytic uremic syndrome, myasthenia gravis, and C3 glomerulonephritis. (J Clin Invest. 2020 May 1; 130(5): 2152-2163. doi: 10.1172 / JCI136094.). Therefore, controlling AP by inhibiting FB may be an effective strategy to limit excessive activation of the complement pathway.

[0003] Currently, there are no approved small molecules for modulating the complement pathway. Examples of factor B inhibitors are described in the following publications: Advanced Vision Therapies Inc. patent publication WO2008 / 106644, entitled "Treatment of diseases characterized by inflammation"; Wellstate Immunotherapeutics patent publication WO2012 / 151468, entitled "Complement Factor B analogs and their uses"; William Marsh Rice University patent publication WO2014 / 035876, entitled "Heat-inactivated Complement Factor B compositions and methods"; Muse. Foundation for Research Development patent publication US1999 / 023485, entitled "Blocking factor b to treat complement-mediated immune disease"; and Novartis patent publications WO2013 / 192345 and US2015 / 126592, entitled "Complement pathway modulators and uses Novartis' patent publications WO2015 / 066241, US2016 / 311779, WO2015 / 009616, US2016 / 152605, WO2014 / 143638, and US2016 / 024079 describe additional factor B inhibitors. Another example of a factor B inhibitor is IONIS Pharmaceuticals Inc.'s patent publication WO2015 / 038939, entitled "Modulators of Complement Factor B". Examples of granted patents involving factor B inhibitors include US 9,452,990, US 9,676,728, US 9,682,968, and US 9,475,806.

[0004] Given the large number of diseases caused by an overactive complement pathway, there are many unmet needs for patients with complement diseases. The present invention is directed to providing compounds that modulate factor B and treat diseases associated with complement pathway dysregulation. Summary of the invention

[0005] In one aspect, the present invention provides a compound of formula (I), or a tautomer, cis or trans isomer, meso, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt, solvate, or prodrug thereof,

[0006]

[0007] in,

[0008] is a saturated or unsaturated ring;

[0009] A is cycloalkyl, heterocyclyl, aryl or heteroaryl;

[0010] L is a key, (CR a R b ) p ;

[0011] R a and R b independently selected from hydrogen, deuterium, halogen, amino, cyano, hydroxy, alkyl, alkoxy, alkylthio, haloalkyl, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl;

[0012] R1 and R2 are independently selected from hydrogen, deuterium, halogen, amino, cyano, hydroxy, alkyl, alkoxy, alkylthio, haloalkyl and hydroxyalkyl;

[0013] R3 and R4 are independently selected from hydrogen, deuterium, halogen, amino, cyano, hydroxyl, alkyl, alkoxy, alkylthio, haloalkyl, haloalkenyl, hydroxyalkyl, deuterated alkoxy, haloalkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl, cycloalkyloxy, heterocyclyloxy, aryloxy and heteroaryloxy, optionally substituted with one or more substituents selected from deuterium, halogen, amino, cyano, hydroxyl, alkyl, alkoxy, alkylthio, haloalkyl, hydroxyalkyl, deuterated alkoxy, haloalkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl, cycloalkyloxy, heterocyclyloxy, aryloxy and heteroaryloxy;

[0014] R5 is independently selected from hydrogen, deuterium, halogen, amino, cyano, hydroxy, alkyl, alkenyl, alkynyl, alkoxy, alkylthio, haloalkyl, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl, optionally substituted with one or more substituents selected from deuterium, halogen, amino, cyano, hydroxy, alkyl, alkoxy, alkylthio, haloalkyl, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl;

[0015] Alternatively, two R5 together with the C atom to which they are attached form a cycloalkyl or heterocyclyl, optionally substituted with one or more substituents selected from hydrogen, deuterium, halogen, amino, cyano, hydroxy, alkyl, alkoxy, alkylalkoxy, alkoxyalkyl, alkylthio, haloalkyl and hydroxyalkyl;

[0016] Alternatively, two R5 together with the C atom to which they are attached form a cycloalkyl or heterocyclyl, optionally substituted with one or more substituents selected from hydrogen, deuterium, halogen, amino, cyano, hydroxy, alkyl, alkoxy, alkylalkoxy, alkoxyalkyl, alkylthio, haloalkyl and hydroxyalkyl;

[0017] Alternatively, two R5 together with the C atom to which they are attached form a carbon-carbon double bond;

[0018] R6 is selected from hydrogen, deuterium, halogen, amino, cyano, hydroxy, alkyl, alkoxy, alkylthio, haloalkyl, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, -(CH2) r OR8, –(CH2) r C(O)R8, -S(O)NHalkyl, -SO2alkyl, -C(O)NHSO2alkyl, and -SO2NHC(O)alkyl;

[0019] R7 is selected from the group consisting of hydrogen, deuterium, halogen, amino, cyano, hydroxy, alkyl, alkoxy, alkylthio, haloalkyl and hydroxyalkyl;

[0020] R9 is selected from the group consisting of deuterium, halogen, amino, cyano, hydroxy, alkyl, alkoxy, alkylthio, haloalkyl, hydroxyalkyl, cycloalkyl and heterocyclyl;

[0021] Alternatively, R9 and one of R6 together form a saturated or unsaturated cycloalkyl or a saturated or unsaturated heterocyclic group, optionally substituted with one or more substituents selected from hydrogen, deuterium, halogen, amino, cyano, hydroxy, alkyl, alkoxy, alkylalkoxy, alkoxyalkyl, alkylthio, haloalkyl and hydroxyalkyl, and the other R6 is selected from hydrogen, deuterium, halogen, amino, cyano, hydroxy, alkyl, alkoxy, alkylthio, haloalkyl, hydroxyalkyl, cycloalkyl, heterocyclic group, aryl, heteroaryl, -(CH2) r OR8, –(CH2) r C(O)R8, -S(O)NHalkyl, -SO2alkyl, -C(O)NHSO2-alkyl and -SO2NHC(O)alkyl;

[0022] R8 is selected from the group consisting of deuterium, halogen, amino, cyano, hydroxy, alkyl, alkoxy, alkylthio, haloalkyl and hydroxyalkyl;

[0023] p is 1, 2, or 3;

[0024] t is 1, 2, or 3;

[0025] m is 1, 2 or 3; and

[0026] n is 0, 1, 2 or 3;

[0027] Provided that R3 and R4 are not methyl at the same time.

[0028] In some embodiments, A is C 6-10 Aryl or 5-10 membered heteroaryl.

[0029] In a preferred embodiment, A is phenyl, benzocycloalkyl or a 5-8 membered heteroaryl containing 1, 2 or 3 N heteroatoms.

[0030] In a more preferred embodiment, A is

[0031] In some embodiments, L is a bond, CH2.

[0032] In some embodiments, wherein R1 and R2 are independently selected from hydrogen.

[0033] In some embodiments, wherein R3 and R4 are independently selected from hydrogen, deuterium, halogen, amino, cyano, hydroxyl, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, C 1-6 Haloalkyl, C 1-6 Halogenated alkenyl, C 1-6 Hydroxyalkyl, deuterated C 1-6 Alkoxy, C 1-6 Haloalkoxy, C 3-6 Cycloalkyl, 4-10 membered heterocyclic group, C 6-10 Aryl, 5-10 membered heteroaryl, C 3-6 Cycloalkyloxy, 4-10 membered heterocyclyloxy, C 6-10 Aryloxy and 5-10 membered heteroaryloxy, optionally the C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, deuterated C 1-6 Alkoxy, C 1-6 The haloalkoxy group is selected from deuterium, halogen, amino, cyano, hydroxyl, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 3-6Cycloalkyl, 4-10 membered heterocyclic group, C 6-10 The aryl group and the 5- to 10-membered heteroaryl group are substituted with one or more substituents.

[0034] In a preferred embodiment, R3 and R4 are independently selected from deuterium, halogen, C 1-3 Alkyl, C 1-3 Alkoxy, deuterated C 1-3 Alkoxy, C 1-3 Halogenated alkoxy, C 3-6 Cycloalkyl and C 3-6 Cycloalkyloxy, optionally the C 1-3 Alkyl, C 1-3 Alkoxy, deuterated C 1-3 Alkoxy, C 1-3 The haloalkoxy group is selected from C 3-6 Cycloalkyl, 4-6 membered heterocyclic group, C 6-10 The aryl and 5- to 10-membered heteroaryl groups are substituted with one or more substituents.

[0035] In some embodiments, R5 is independently selected from hydrogen, deuterium, halogen, amino, cyano, hydroxyl, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Alkoxy, C 1-6 Alkylthio, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 3-8 Cycloalkyl, 4-10 membered heterocyclic group, C 5-10 Aryl and 5-10 membered heteroaryl, optionally the C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 3-8 Cycloalkyl, 4-10 membered heterocyclic group, C 5-10 Aryl and 5-10 membered heteroaryl are selected from deuterium, halogen, amino, cyano, hydroxyl, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, C 1-6 Haloalkyl and C 1-6 The hydroxyalkyl group is substituted with one or more substituents.

[0036] In some embodiments, two R5 together with the C atom to which they are attached form a C 3-6 Cycloalkyl or a 4-6 membered heterocyclic group containing 1, 2 or 3 heteroatoms selected from N, O and S, which is optionally selected from hydrogen, deuterium, halogen, amino, cyano, hydroxyl, C 1-6 Alkyl, C1-6 Alkoxy, C 1-6 Alkyl C 1-6 Alkoxy, C 1-6 Alkoxy C 1-6 Alkyl, C 1-6 Alkylthio, C 1-6 Haloalkyl and C 1-6 The hydroxyalkyl group is substituted with one or more substituents.

[0037] In some embodiments, two R5 together with the C atom to which they are attached form a carbon-carbon double bond.

[0038] In some embodiments, R6 is selected from hydrogen, deuterium, halogen, amino, cyano, hydroxyl, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 3-8 Cycloalkyl, 4-10 membered heterocyclic group, C 5-10 Aryl, 5-10 membered heteroaryl, –(CH2) r C 1-6 Alkoxy, –(CH2) r C(O)OH、-S(O)NHC 1-6 Alkyl, -SO2C 1-6 Alkyl, -C(O)NHSO2C 1-6 Alkyl and -SO2NHC(O)C 1-6 alkyl.

[0039] In some embodiments, R6 is -F, -OMe, -CH2OH, -CH2OCH3, -CH2F, -CF2H, -CF3, -COOH, -C(O)NHSO2CH3, -S(O)NHCH3, a 5-6 membered heterocyclyl containing 1 to 3 heteroatoms selected from N, O and S, or a 5-6 membered heteroaryl containing 1 to 3 heteroatoms selected from N, O and S.

[0040] In some embodiments, R7 is hydrogen or C 1-3 alkyl.

[0041] In some embodiments, R9 is selected from deuterium, halogen, amino, cyano, hydroxyl, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 3-8 Cycloalkyl and 4-10 membered heterocyclyl containing 1, 2 or 3 heteroatoms selected from N, O and S.

[0042] In a preferred embodiment, R9 is selected from deuterium, halogen, amino, cyano, hydroxyl, C 1-3 Alkyl, C 1-6 Alkoxy, C 1-3 Alkylthio, C 1-3 Haloalkyl, C 1-3 Hydroxyalkyl, C 3-6 Cycloalkyl and 4-6 membered heterocyclyl containing 1, 2 or 3 heteroatoms selected from N, O and S.

[0043] In a more preferred embodiment, R9 is selected from deuterium, halogen, amino, cyano, hydroxy, methyl, ethyl, cyclopropyl, cyclobutyl.

[0044] In some embodiments, R9 and one of R6 are taken together to form a saturated or unsaturated C 3-7 Cycloalkyl or saturated or unsaturated 3-7 membered heterocyclic group containing 1, 2 or 3 heteroatoms selected from N, O and S, wherein the C 3-7 Cycloalkyl or 3-7 membered heterocyclic group is optionally selected from hydrogen, deuterium, halogen, amino, cyano, hydroxyl, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkyl alkoxy, C 1-6 Alkoxyalkyl, C 1-6 Alkylthio, C 1-6 Haloalkyl and C 1-6 1 or 2 substituents of hydroxyalkyl, the other R6 is selected from hydrogen, deuterium, halogen, amino, cyano, hydroxyl, C 1-3 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 3-8 Cycloalkyl, 4-10 membered heterocyclic group, C 5-10 Aryl, 5-10 membered heteroaryl, –(CH2) r C 1-6 Alkoxy, –(CH2) r C(O)OH、-S(O)NHC 1-6 Alkyl, -SO2C 1-6 Alkyl, -C(O)NHSO2C 1-6 Alkyl and -SO2NHC(O)C 1-6 alkyl.

[0045] In a more preferred embodiment, R9 and one of R6 together form a saturated or unsaturated C 4-6 Cycloalkyl or saturated or unsaturated 4-7 membered heterocyclic group containing 1, 2 or 3 heteroatoms selected from N, O and S, the saturated or unsaturated C 4-6Cycloalkyl or saturated or unsaturated 4-7 membered heterocyclic group is optionally selected from hydrogen, deuterium, halogen, amino, cyano, hydroxyl, C 1-3 Alkyl, C 1-3 Alkoxy, C 1-3 Alkyl alkoxy, C 1-3 Alkoxyalkyl, C 1-3 Alkylthio, C 1-3 Haloalkyl and C 1-3 The hydroxyalkyl group is substituted with one or two substituents, and the other R6 is selected from F, -OMe, -CH2OH, -CH2OCH3, -CH2F, -CF2H, -CF3, -COOH, -C(O)NHSO2CH3, -S(O)NHCH3.

[0046] In a preferred embodiment, the compound of formula (I) may be a compound of formula (II), or a tautomer, cis or trans isomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt, solvate, or prodrug thereof,

[0047]

[0048] In a preferred embodiment, the compound of formula (I) may be a compound of formula (III-a)-(III-b), or a tautomer, cis or trans isomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt, solvate, or prodrug thereof,

[0049]

[0050] in,

[0051] X is CR c R d NR e , O or S;

[0052] is a single bond or a double bond;

[0053] R c , R d and R e are independently selected from hydrogen, deuterium, halogen, amino, cyano, hydroxyl, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 3-8 Cycloalkyl, C 3-8 Heterocyclic group, C 6-10 Aryl and C 6-10 heteroaryl;

[0054] Preferably, R c , R d and R e are independently selected from hydrogen, deuterium, halogen, amino, cyano, hydroxyl, C 1-3 Alkyl, C 1-3 Alkoxy, C 1-3 Alkylthio, C 1-3 Haloalkyl, C 1-3 Hydroxyalkyl, C 3-6 Cycloalkyl, C 4-6 Heterocyclic group, C 6-10 Aryl and C 6-10 heteroaryl;

[0055] Preferably, R c , R d and R e independently selected from hydrogen, deuterium, halogen, amino, cyano, hydroxyl, methyl, ethyl;

[0056] v is 0, 1, 2, or 3.

[0057] In a preferred embodiment, the compound of formula (I) can be a compound of formula (IV-a)-(IV-f), or a tautomer, cis or trans isomer, meso, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt, solvate, or prodrug thereof,

[0058]

[0059] in,

[0060] E is

[0061] R 10 Selected from deuterium, halogen, amino, cyano, hydroxyl, C 1-3 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 1-3 Alkoxy, C 1-3 Alkyl C 1-3 Alkoxy, C 1-3 Alkoxy C 1-3 Alkyl, C 1-3 Alkylthio, C 1-3 Haloalkyl and C 1-3 Hydroxyalkyl;

[0062] n is 1; and,

[0063] z is 0, 1, 2 or 3.

[0064] In a preferred embodiment, for

[0065] In a preferred embodiment, the compound of formula (I) may be a compound of formula (Va)-(Vb), or a tautomer, cis or trans isomer, meso, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt, solvate, or prodrug thereof,

[0066]

[0067] in,

[0068] M is O or CR f R g ;

[0069] R f and R g are independently selected from hydrogen, halogen and C 1-3 alkyl;

[0070] Preferably, R f and R g independently selected from hydrogen, fluorine;

[0071] q is 1, 2, or 3; and,

[0072] s is 0, 1, or 2.

[0073] In a preferred embodiment, the compound of formula (I) can be a compound of formula (VI-a)-(VI-1), or a tautomer, cis or trans isomer, meso, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt, solvate, or prodrug thereof,

[0074]

[0075] In a preferred embodiment, for in,

[0076] for

[0077] The present invention also provides a pharmaceutical composition comprising a therapeutically effective amount of any compound of formula (I)-(VII-f), or a tautomer or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers, diluents or excipients.

[0078] In some embodiments, in the above-mentioned pharmaceutical composition, the amount of the compound, its tautomer, cis or trans isomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof is about 0.1 to 95% by weight of the free base; preferably, about 5 to 70%, for example 70%, 65%, 60%, 55%, 50%, 45%, 40%, 35%, 30%, 25%, 20%, 15%, 10%, 5%.

[0079] In some embodiments, the above-mentioned pharmaceutical composition is formulated into a tablet, capsule, liquid form or injection form.

[0080] In some embodiments, in the above-mentioned pharmaceutical composition, the amount of the compound, its tautomer, cis or trans isomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof is about 1 to 1000 mg; preferably, about 1 to 500 mg, more preferably, about 1 mg, 2 mg, 3 mg, 5 mg, 10 mg, 20 mg, 40 mg, 50 mg, 60 mg, 80 mg, 100 mg, 200 mg, 300 mg, 400 mg or 500 mg.

[0081] In some embodiments, the compound, its tautomer, cis or trans isomer, meso racemate, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof can be administered by any suitable route of administration, such as oral, parenteral, buccal, sublingual, intranasal, rectal, intrathecal, or transdermal administration, and the pharmaceutical composition is adjusted accordingly.

[0082] In some embodiments, the compound, its tautomer, cis or trans isomer, meso racemate, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt is formulated in a solid or liquid form, such as a syrup, suspension, emulsion, tablet, capsule, powder, granule or lozenge.

[0083] In another aspect, the present invention relates to a method for modulating complement alternative pathway activity, comprising administering to a subject in need thereof an effective amount of any compound of Formula (I)-(VI-f) or a pharmaceutical composition comprising the same.

[0084] In another aspect, the present invention relates to a method for treating a condition or disease mediated by complement activation, particularly by activation of the complement alternative pathway, in a subject, comprising administering to a subject in need thereof an effective amount of any compound of formula (I)-(VI-f) or a pharmaceutical composition comprising the same.

[0085] In a preferred embodiment, the disease or condition is selected from age-related macular degeneration, geographic atrophy, diabetic retinopathy, uveitis, retinitis pigmentosa, macular edema, Behcet's uveitis, multifocal choroiditis, Vogt-Koyangi-Harada syndrome, intermediate uveitis, birdshot retinochoroiditis, sympathetic eye inflammation, ocular bicornuate pemphigoid, ocular pemphigus, non-arteritic ischemic optic neuropathy, postoperative inflammation, retinal vein occlusion, nervous system diseases, multiple sclerosis, stroke, Guillain-Barré syndrome, traumatic brain injury, Parkinson's disease, inappropriate or adverse complement activation disorders, hemodialysis complications, hyperacute allograft rejection, xenograft rejection, interleukin-2-induced toxicity during IL-2 therapy, inflammatory diseases, inflammation of autoimmune diseases, Crohn's disease, adult respiratory Distress syndrome, myocarditis, post-ischemia-reperfusion condition, myocardial infarction, balloon angioplasty, post-extracorporeal circulation or renal bypass pump syndrome, atherosclerosis, hemodialysis, renal ischemia, mesenteric artery reperfusion after aortic reconstruction, infectious diseases or sepsis, immune complex disorders and autoimmune diseases, rheumatoid arthritis, systemic lupus erythematosus (SLE), SLE nephritis, proliferative nephritis, liver fibrosis, hemolytic anemia, myasthenia gravis, tissue regeneration, nerve regeneration, dyspnea, hemoptysis, ARDS, asthma, chronic obstructive pulmonary disease (COPD), emphysema, pulmonary embolism and infarction, pneumonia, fibrosis, pulmonary fibrosis, asthma, allergy, bronchoconstriction, hypersensitivity pneumonitis, parasitic diseases, Goodpasture's syndrome, pulmonary vasculitis, micro-immune vasculitis, immune complex-related inflammation, antiphospholipid syndrome, glomerulonephritis and obesity. DETAILED DESCRIPTION OF THE INVENTION

[0087] Various publications, articles and patents are cited or described in the specification; each of these references is incorporated herein by reference in its entirety. Discussions of documents, acts, materials, devices, articles, etc., which have been included in this specification are intended to provide context for the disclosure. Such discussion is not an admission that any or all of these matters constitute part of the prior art related to the present disclosure.

[0088] Given below are definitions of terms used in this application. Any term not defined herein is taken to have the ordinary meaning as understood by those skilled in the art.

[0089] "Alkyl" refers to a C1-C 20Saturated aliphatic hydrocarbon groups of straight and branched chain groups. Preferably, the alkyl group is an alkyl group having 1 to 12, sometimes preferably 1 to 6, and sometimes more preferably 1 to 4 carbon atoms. Representative examples include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2-methylpropyl, 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1,3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2,3-dimethylbutyl, n-heptyl, 2-methylhexyl, 3-methylhexyl, 4-methylhexyl, 5-methylhexyl , 2,3-dimethylpentyl, 2,4-dimethylpentyl, 2,2-dimethylpentyl, 3,3-dimethylpentyl, 2-ethylpentyl, 3-ethylpentyl, n-octyl, 2,3-dimethylhexyl, 2,4-dimethylhexyl, 2,5-dimethylhexyl, 2,2-dimethylhexyl, 3,3-dimethylhexyl, 4,4-dimethylhexyl, 2-ethylhexyl, 3-ethylhexyl, 4-ethylhexyl, 2-methyl-2-ethylpentyl, 2-methyl-3-ethylpentyl, n-nonyl, 2-methyl-2-ethylhexyl, 2-methyl-3-ethylhexyl, 2,2-diethylpentyl, n-decyl, 3,3-diethylhexyl, 2,2-diethylhexyl, and branched chain isomers thereof. More preferably, the alkyl group is a lower alkyl group having 1 to 6 carbon atoms. Representative examples include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2-methylpropyl, 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1,3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2,3-dimethylbutyl, etc. The alkyl group can be substituted or unsubstituted. When substituted, the substituent may be substituted at any available point of attachment, preferably the substituent is one or more substituents independently selected from alkyl, halogen, alkoxy, alkenyl, alkynyl, alkylthio, alkylamino, mercapto, hydroxy, nitro, cyano, amino, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkyloxy, heterocyclyl, cycloalkylthio, heterocycloalkylthio and oxo.

[0090] "Alkenyl" refers to an alkyl group as defined above having at least two carbon atoms and at least one carbon-carbon double bond, such as ethenyl, 1-propenyl, 2-propenyl, 1-, 2- or 3-butenyl, etc., preferably C 2-20Alkenyl, more preferably C 2-12 Alkenyl, most preferably C 2-6 Alkenyl. Alkenyl may be substituted or unsubstituted. When substituted, the substituents are preferably one or more, sometimes preferably one to five, sometimes more preferably one to three groups independently selected from alkyl, halogen, alkoxy, alkenyl, alkynyl, alkylthio, alkylamino, sulfhydryl, hydroxyl, nitro, cyano, amino, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkyloxy, heterocyclyl, cycloalkylthio, heterocycloalkylthio and oxo.

[0091] "Alkynyl" refers to an alkyl group as defined above having at least two carbon atoms and at least one carbon-carbon triple bond, such as ethynyl, 1-propynyl, 2-propynyl, 1-, 2- or 3-butynyl, etc., preferably C 2-20 Alkynyl, more preferably C 2-12 Alkynyl, most preferably C 2-6 Alkynyl. Alkynyl may be substituted or unsubstituted. When substituted, the substituents are preferably one or more, sometimes preferably one to five, sometimes more preferably one to three groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkyloxy, heterocycloalkyloxy, cycloalkylthio and heterocycloalkylthio.

[0092] "Alkylene" refers to a saturated straight or branched aliphatic hydrocarbon group having two residues derived by removing two hydrogen atoms from the same carbon atom or two different carbon atoms of a parent alkane. A straight or branched group containing 1 to 20 carbon atoms preferably has 1 to 12 carbon atoms, more preferably 1 to 6 carbon atoms. Non-limiting examples of alkylene include, but are not limited to, methylene (-CH2-), 1,1-ethylene (-CH(CH3)-), 1,2-ethylene (-CH2CH2-), 1,1-propylene (-CH(CH2CH3)-), 1,2-propylene (-CH2CH(CH3)-), 1,3-propylene (-CH2CH2CH2-), 1,4-butylene (-CH2CH2CH2CH2-), etc. Alkylene can be substituted or unsubstituted. When substituted, the substituents are preferably one or more, sometimes preferably one to five, sometimes more preferably one to three groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkyloxy, heterocycloalkyloxy, cycloalkylthio and heterocycloalkylthio.

[0093] "Alkenylene" refers to an alkylene group as defined above having at least two carbon atoms and at least one carbon-carbon double bond, preferably C 2-20 Alkenylene, more preferably C2-12 Alkenylene, most preferably C 2-6 Alkenylene. Non-limiting examples of alkenylene include, but are not limited to, -CH=CH-, -CH=CHCH2-, -CH=CHCH2CH2-, -CH2CH=CHCH2-, etc. Alkenylene can be substituted or unsubstituted. When substituted, the substituents are preferably one or more, sometimes preferably one to five, sometimes more preferably one to three groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, sulfhydryl, hydroxyl, nitro, cyano, cycloalkyl, heterocyclyl, aryl, heteroaryl, cycloalkyloxy, heterocycloalkyloxy, cycloalkylthio, and heterocycloalkylthio.

[0094] "Alkyne" refers to an alkynyl group as defined above having at least two carbon atoms and at least one carbon-carbon triple bond, preferably C 2-20 Alkyne, more preferably C 2-12 Alkyne, most preferably C 2-6 Alkynylidene. Non-limiting examples of alkynyllidene include, but are not limited to, -CH≡CH-, -CH≡CHCH2-, -CH≡CHCH2CH2-, -CH2CH≡CHCH2-, etc. Alkynylidene can be substituted or unsubstituted. When substituted, the substituent is preferably one or more, sometimes preferably one to five, sometimes more preferably one to three groups, the groups being independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, sulfhydryl, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkyloxy, heterocycloalkyloxy, cycloalkylthio, and heterocycloalkylthio.

[0095] "Cycloalkyl" refers to a saturated and / or partially unsaturated monocyclic or polycyclic hydrocarbon radical having 3 to 20 carbon atoms, preferably 3 to 12 carbon atoms, more preferably 3 to 10 carbon atoms, most preferably 3 to 8 carbon atoms or 3 to 6 carbon atoms. Representative examples of monocyclic cycloalkyls include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cycloheptatrienyl, cyclooctyl, etc. Polycyclic cycloalkyls include cycloalkyls having spirocyclic, condensed or bridged rings.

[0096] "Spirocycloalkyl" refers to a 5 to 20-membered polycyclic group, the rings being connected by a common carbon atom (called a spiro atom), wherein one or more rings may contain one or more double bonds, but none of the rings has a completely conjugated π electron system. Preferably, the spirocycloalkyl is 6 to 14 yuan, more preferably 7 to 10 yuan, and most preferably 7 to 8 yuan. According to the common number of spiro atoms, the spirocycloalkyl is divided into a monospirocycloalkyl, a dispirocycloalkyl or a polyspirocycloalkyl, preferably a monospirocycloalkyl or a dispirocycloalkyl, more preferably a 4 yuan / 4 yuan, 4 yuan / 5 yuan, 4 yuan / 6 yuan, 5 yuan / 5 yuan or a 5 yuan / 6 yuan monospirocycloalkyl. Representative examples of spirocycloalkyl include, but are not limited to, the following substituents:

[0097]

[0098] "Fused cycloalkyl" refers to a 5-20 membered polycyclic hydrocarbon group, wherein each ring in the system shares a pair of adjacent carbon atoms with another ring, wherein one or more rings may contain one or more double bonds, but no ring has a completely conjugated π electron system. Preferably, the fused cycloalkyl is 6 to 14 members, more preferably 7 to 10 members, and most preferably 7 to 8 members. Depending on the number of rings, the fused cycloalkyl is divided into a bicyclic, tricyclic, tetracyclic or polycyclic fused cycloalkyl, preferably a bicyclic or tricyclic fused cycloalkyl, more preferably a 5-membered / 5-membered or 5-membered / 6-membered bicyclic fused cycloalkyl. Representative examples of fused cycloalkyls include, but are not limited to, the following substituents:

[0099]

[0100] "Bridged cycloalkyl" refers to a 5-20 membered polycyclic hydrocarbon group in which every two rings in the system share two unconnected carbon atoms. These rings may have one or more double bonds, but do not have a completely conjugated π electron system. Preferably, the bridged cycloalkyl is 6 to 14 members, more preferably 7 to 10 members, and most preferably 7 to 8 members. Depending on the number of rings, the bridged cycloalkyl is divided into a bicyclic, tricyclic, tetracyclic or polycyclic bridged cycloalkyl, preferably a bicyclic, tricyclic or tetracyclic bridged cycloalkyl, more preferably a bicyclic or tricyclic bridged cycloalkyl. Representative examples of bridged cycloalkyls include, but are not limited to, the following substituents:

[0101]

[0102] Cycloalkyl can be fused with the ring of aryl, heteroaryl or heterocycloalkyl, wherein the ring bonded to the parent structure is cycloalkyl. Representative examples include but are not limited to indanyl acetic acid, tetralin, benzocycloheptyl, etc. Cycloalkyl is optionally substituted or unsubstituted. When substituted, the substituent is preferably one or more, sometimes preferably one to five, sometimes more preferably one to three substituents, the substituents being independently selected from alkyl, halogen, alkoxy, alkenyl, alkynyl, alkylthio, alkylamino, sulfhydryl, hydroxyl, nitro, cyano, amino, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkyloxy, heterocyclyl, cycloalkylthio, heterocycloalkylthio and oxo. Representative examples include but are not limited to the following substituents:

[0103]

[0104] "Heterocyclyl" refers to a 3- to 20-membered saturated and / or partially unsaturated monocyclic or polycyclic hydrocarbon group having one or more, sometimes preferably one to five, sometimes more preferably one to three, selected from N, O and S(O) m (wherein m is 0, 1 or 2) heteroatoms as ring atoms, but the ring does not contain -OO-, -OS- or -SS-, and the remaining ring atoms are C. Preferably, the heterocyclic group is a 3 to 12-membered heterocyclic group with 1 to 4 heteroatoms, more preferably a 3 to 10-membered heterocyclic group with 1 to 3 heteroatoms, and most preferably a 5 to 6-membered heterocyclic group with 1 to 2 heteroatoms. Representative examples of monocyclic heterocyclic groups include, but are not limited to, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, homopiperazinyl, etc. Polycyclic heterocyclic groups include heterocyclic groups with spirocyclic, condensed or bridged rings.

[0105] "Spiro heterocyclyl" refers to a 5- to 20-membered polycyclic heterocyclyl, the rings being linked via a common carbon atom (called a spiro atom), wherein the rings have one or more, sometimes preferably one to five, sometimes more preferably one to three, selected from N, O and S(O) m (wherein m is 0, 1 or 2) heteroatoms as ring atoms, the remaining ring atoms are C, wherein one or more rings may contain one or more double bonds, but no ring has a completely conjugated π electron system. Preferably, the spiro heterocyclic group is 6 to 14 members, more preferably 7 to 10 members, and most preferably 7 to 8 members. According to the common number of spiro atoms, the spiro heterocyclic group is divided into a monospiro heterocyclic group, a dispiro heterocyclic group or a polyspiro heterocyclic group, preferably a monospiro heterocyclic group or a dispiro heterocyclic group, more preferably a 4-membered / 4-membered, 4-membered / 5-membered, 4-membered / 6-membered, 5-membered / 5-membered or 5-membered / 6-membered monospiro heterocyclic group. Representative examples of spiro heterocyclic groups include, but are not limited to, the following substituents:

[0106]

[0107] "Fused heterocyclyl" refers to a 5- to 20-membered polycyclic heterocyclyl, wherein each ring in the system shares a pair of adjacent carbon atoms with another ring, wherein one or more rings may contain one or more double bonds, but no ring has a completely conjugated π electron system, wherein the rings have one or more, sometimes preferably one to five, sometimes more preferably one to three selected from N, O and S(O) p (wherein p is 0, 1 or 2) as the heteroatom of the ring, and the remaining ring atoms are C. Preferably, the fused heterocyclic group is 6 to 14 members, more preferably 7 to 10 members, and most preferably 7 to 8 members. According to the number of rings, the fused heterocyclic group is divided into a bicyclic, tricyclic, tetracyclic or polycyclic fused heterocyclic group, preferably a bicyclic or tricyclic fused heterocyclic group, more preferably a 5-membered / 5-membered or 5-membered / 6-membered bicyclic fused heterocyclic group. Representative examples of fused heterocyclic groups include, but are not limited to, the following substituents:

[0108]

[0109] "Bridged heterocyclyl" refers to a 5- to 14-membered polycyclic heterocycloalkyl group, wherein each two rings in the system share two non-connected atoms, the rings may have one or more double bonds, but do not have a completely conjugated π-electron system, and the rings have one or more selected from N, O and S(O) m (wherein m is 0, 1 or 2) heteroatoms as ring atoms, and the remaining ring atoms are C. Preferably, the bridged heterocyclic group is 6 to 14 members, more preferably 7 to 10 members, and most preferably 7 to 8 members. According to the number of rings, the bridged heterocyclic group is divided into a bicyclic, tricyclic, tetracyclic or polycyclic bridged heterocyclic group, preferably a bicyclic, tricyclic or tetracyclic bridged heterocyclic group, more preferably a bicyclic or tricyclic bridged heterocyclic group. Representative examples of bridged heterocyclic groups include, but are not limited to, the following substituents:

[0110]

[0111] The heterocyclic ring may be fused to an aryl, heteroaryl or cycloalkyl ring, wherein the ring bonded to the parent structure is the heterocyclic ring. Representative examples include, but are not limited to, the following substituents:

[0112] wait.

[0113] Heterocyclyl is optionally substituted or unsubstituted. When substituted, the substituent is preferably one or more, sometimes preferably one to five, sometimes more preferably one to three groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, sulfhydryl, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkyloxy, heterocycloalkyloxy, cycloalkylthio and heterocycloalkylthio.

[0114] "Aryl" refers to a 6- to 14-membered all-carbon monocyclic or polycyclic fused ring (a "fused" ring system means that each ring in the system shares a pair of adjacent carbon atoms with another ring in the system) group, and has a completely conjugated π electron system. Preferably, the aryl group is 6 to 10 members, such as phenyl and naphthyl, and most preferably phenyl. The aryl group can be fused with a heteroaryl, heterocyclyl or cycloalkyl ring, wherein the ring bonded to the parent structure is the aryl group. Representative examples include, but are not limited to, the following substituents:

[0115]

[0116] Aryl can be substituted or unsubstituted. When substituted, the substituent is preferably one or more, sometimes preferably one to five, sometimes more preferably one to three substituents, the substituents being independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkyloxy, heterocycloalkyloxy, cycloalkylthio and heterocycloalkylthio.

[0117] "Heteroaryl" refers to an aryl system having 1 to 4 heteroatoms selected from O, S and N as ring atoms and having 5 to 14 ring atoms. Preferably, the heteroaryl is 5 to 10-membered, more preferably 5 or 6-membered, such as thiadiazolyl, pyrazolyl, oxazolyl, oxadiazolyl, imidazolyl, triazolyl, thiazolyl, furanyl, thienyl, pyridyl, pyrrolyl, N-alkylpyrrolyl, pyrimidyl, pyrazinyl, imidazolyl, tetrazolyl, isoxazolyl, etc. The heteroaryl group can be fused to the ring of an aryl, heterocyclyl or cycloalkyl group, wherein the ring bonded to the parent structure is a heteroaryl group. Representative examples include, but are not limited to, the following substituents:

[0118]

[0119] Heteroaryl can be substituted or unsubstituted. When substituted, the substituents are preferably one or more, sometimes preferably one to five, sometimes more preferably one to three substituents, independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, sulfhydryl, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkyloxy, heterocycloalkyloxy, cycloalkylthio and heterocycloalkylthio.

[0120] "Alkoxy" refers to -O-(alkyl) and -O-(unsubstituted cycloalkyl) groups, wherein alkyl is as defined above. Representative examples include, but are not limited to, methoxy, ethoxy, propoxy, butoxy, cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, cyclohexyloxy, etc. Alkoxy can be substituted or unsubstituted. When substituted, the substituent is preferably one or more, sometimes preferably one to five, sometimes more preferably one to three substituents, the substituents being independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, sulfhydryl, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkyloxy, heterocycloalkyloxy, cycloalkylthio, and heterocycloalkylthio.

[0121] "Haloalkoxy" refers to an alkoxy group substituted with one or more halogens, wherein alkoxy is as defined above.

[0122] The hydrogen atoms of the present invention may be replaced by their isotope deuterium. Any hydrogen atoms in the compounds of the embodiments of the present invention may also be replaced by deuterium atoms.

[0123] "Bond" refers to a covalent bond, with the symbol "—".

[0124] "Hydroxyalkyl" refers to an alkyl group substituted with a hydroxy group, wherein alkyl is as defined above.

[0125] "Hydroxyl" or "hydroxy" refers to an -OH group.

[0126] "Halogen" or "halo" refers to a fluorine, chlorine, bromine or iodine atom.

[0127] "Amino" refers to the -NH2 group.

[0128] "Cyano" refers to a -CN group.

[0129] "Nitro" refers to a -NO2 group.

[0130] "Oxo" refers to a =0 group.

[0131] "Carboxy" refers to a -C(O)OH group.

[0132] "Alkoxycarbonyl" means a -C(O)O(alkyl) or -C(O)O(cycloalkyl) group where alkyl and cycloalkyl are as defined above.

[0133] When it is stated that a group or substituent is "independently selected from" (and variations thereof) a selection list, this means that the selection of any one such group or substituent does not determine the selection of any other such group or substituent. By way of illustration, but not limitation, the term "A and B are independently selected from a and b" or "A and B are each independently selected from a and b" is intended to encompass the selections wherein A is a and B is a, A is b and B is b, A is a and B is b, and A is b and B is a.

[0134] "Optional" or "optionally" means that the subsequently described event or circumstance can but need not occur, and that the description includes instances where the event or circumstance occurs and instances where it does not occur. For example, "heterocyclyl optionally substituted with alkyl" means that alkyl can but need not be present, and that the description includes instances where heterocyclyl is substituted with alkyl and instances where heterocyclyl is not substituted with alkyl.

[0135] "Substituted" refers to that one or more hydrogens in a group are independently replaced by a corresponding number of substituents. In some embodiments, the number of such hydrogens is up to 5. In other embodiments, it is 1 to 3. It goes without saying that substituents are only present in their possible chemical positions. Those skilled in the art can determine whether substitution is possible by experiment or theory without having to pay too much effort. For example, the combination of an amino or hydroxyl group with free hydrogen and a carbon atom (such as olefinic) with an unsaturated bond may be unstable.

[0136] "Pharmaceutical composition" refers to a mixture of one or more compounds described in the present invention or their physiologically / pharmaceutically acceptable salts or prodrugs and other chemical components such as physiologically / pharmaceutically acceptable carriers and excipients. The purpose of a pharmaceutical composition is to facilitate the administration of the compound to an organism, facilitate the absorption of the active ingredient, and thus exert biological activity.

[0137] "Pharmaceutically acceptable salt" refers to a salt of the compound of the present invention, which is safe and effective when used in mammals and has the corresponding biological activity. DETAILED DESCRIPTION

[0138] The following examples are used to illustrate the present invention, but they should not be considered to limit the scope of the present invention. Unless otherwise specified, the specific conditions of the experimental methods in the examples of the present invention are generally based on conventional conditions or the recommended conditions of the raw material and product manufacturers. Reagents without specific sources are all commercially available conventional reagents.

[0139] The structure of each compound was identified by nuclear magnetic resonance (NMR) and / or mass spectrometry (MS). NMR chemical shifts (δ) were expressed in 10 -6(ppm) are given. NMR was measured on a Varian Mercury 300MHz Bruker Avance III 400MHz instrument. The solvents used were deuterated dimethyl sulfoxide (DMSO-d6), deuterated chloroform (CDCl3) and deuterated methanol (CD3OD).

[0140] High performance liquid chromatography (HPLC) was measured on an Agilent 1200DAD high pressure liquid chromatograph (Sunfire C18 150×4.6 mm column) and a Waters 2695-2996 high pressure liquid chromatograph (Gimini C18 150×4.6 mm column). Liquid chromatography mass spectrometry (LCMS) was measured on an Agilent 1200 high pressure liquid chromatograph mass spectrometer (Sunfire C18 4.6*50 mm 3.5 um column) and an Agilent 19091S-433HP-5 high pressure liquid chromatograph mass spectrometer (XBridge C18 4.6*50 mm 3.5 um column).

[0141] Chiral high performance liquid chromatography (HPLC) was performed on SFC Thar 80 & 150 & 200 (Waters).

[0142] Average rate and IC of ATPase inhibition 50 The values ​​were determined by Victor Nivo multi-mode plate reader (PerkinElmer, USA).

[0143] The thin layer silica gel plate used in thin layer chromatography is Yantai Xinnuo silica gel plate. The size of the plate used in TLC is 0.15 to 0.2 mm, and the size of the plate used in thin layer chromatography for product purification is 0.4 to 0.5 mm.

[0144] Column chromatography generally uses Qingdao Ocean 200 to 300 mesh silica gel as the carrier.

[0145] The raw materials known in the present invention can be prepared by conventional synthesis methods in the prior art, or can be purchased from ABCR GmbH & Co. KG, Acros Organics, Aldrich Chemical Company, Accela ChemBio Inc or Darui Chemical Co., Ltd., etc.

[0146] Unless otherwise specified in the examples, the following reactions were carried out under an argon or nitrogen atmosphere.

[0147] The term "argon atmosphere" or "nitrogen atmosphere" means that the reaction flask is equipped with a balloon with 1 L of argon or nitrogen.

[0148] The term "hydrogen atmosphere" means that the reaction flask was equipped with a balloon with 1 L of hydrogen.

[0149] MS is mass spectrometry, where (+) refers to the positive mode, usually giving the M+1 (or M+H) absorption, where M = molecular mass.

[0150] Synthesis process:

[0151] Synthesis of tert-butyl 4-(chloromethyl)-5-methoxy-7-methyl-1H-indole-1-carboxylate Int A

[0152]

[0153] At room temperature, under nitrogen, to a solution of tert-butyl 4-(hydroxymethyl)-5-methoxy-7-methyl-1H-indole-1-carboxylate (CAS: 1644667-10-6-950mg, 3.45mmol) in CH2Cl2 (10mL) was added (chloromethylene) dimethyl imine chloride (711mg, 5.56mmol) at one time, and the mixture was stirred at this temperature for 2 hours. The reaction mixture was cooled to 0°C and then quenched with 5% NaHCO3 aqueous solution. The mixture was extracted with CH2Cl2 (3x 20mL). The combined organic layers were washed with brine (20mL), dried over anhydrous Na2SO4, filtered and concentrated. The crude product tert-butyl 4-(chloromethyl)-5-methoxy-7-methyl-1H-indole-1-carboxylate Int A (900mg) was obtained as a yellow oil. LCMS (m / z): [M-Cl] + C 16 H 20 NO3 calculated, 274.1; measured, 274.1.

[0154] Synthesis of 3,3-difluoro-1'-((5-methoxy-7-methyl-1H-indol-4-yl)methyl)-2",3"-dihydrodispiro[cyclobutane-1,4'-piperidin-2',1"-indene]-5"-carboxylic acid

[0155]

[0156] Step 1

[0157] A MeOH solution of 1-oxo-2,3-dihydro-1H-indene-5-carboxylic acid methyl ester (750 mg, 3.94 mmol), 3-((trimethylsilyl)-methyl)but-3-ene-1-amine (1.12 g, 7.10 mmol) and AcOH (355 mg, 5.91 mmol) was stirred at 50 ° C for 40 hours. The reaction mixture was neutralized with saturated NaHCO3 solution and then extracted with DCM (50 mLx3). The combined organic layer was washed with brine (50 mL), dried over anhydrous Na2SO4, filtered and concentrated. The residue was purified by silica gel flash column chromatography (PE / EtOAc=1 / 1) to give compound a (860 mg, 85%) as a black oil. MS: m / z=258.1 (M+1, ESI+).

[0158] Step 2

[0159] At 0 ° C, under nitrogen, Cbz-Cl (815 mg, 4.78 mmol) was added dropwise to a stirred solution of 4'-methylene-2,3-dihydrospiro[indene-1,2'-piperidine]-5-carboxylic acid methyl ester (820 mg, 3.19 mmol) and K2CO3 (1.32 g, 9.56 mmol) in THF (10 mL). The reaction mixture was stirred at 25 ° C for 16 hours. The reaction mixture was quenched with NaHCO3 solution (30 mL) and then extracted with EtOAc (30 mLx3). The combined organic layer was washed with brine (30 mL), dried over anhydrous Na2SO4, filtered and concentrated. The residue was purified by silica gel flash column chromatography (PE / EtOAc=5 / 1) to give 1'-benzyl 5-methyl 4'-methylene-2,3-dihydrospiro[indene-1,2'-piperidine]-1',5-dicarboxylate b (1.05 g, 84%) as a colorless oil. MS: m / z=391.9 (M+1, ESI+).

[0160] Step 3

[0161] At 20 ° C, under a nitrogen atmosphere, trichloroacetyl chloride (4.4 g, 24 mmol, 10 equivalents) was added to a suspension of Cu-Zn (3.5 g, 3% Cu) and 4'-methylene-2,3-dihydrospiro[indene-1,2'-piperidine]-1',5-dicarboxylic acid methyl ester b (1.0 g, 2.4 mmol, 1.0 equivalents) in dioxane (20 mL, 20 V) within 30 minutes. The mixture was heated to 35 ° C for 3 hours. The reaction mixture was quenched with NH4Cl solution. The solid was filtered out and the filtrate was extracted with ethyl acetate (30 mL x 3, 30 V) and washed with brine (40 mL, 40 V). The combined filtrates were dried over Na2SO4 and concentrated in vacuo to give an oily crude product, 2,2-dichloro-3-oxo-2",3"-dihydrodispiro[cyclobutane-1,4'-piperidin-2',1"-indene]-1',5"-dicarboxylic acid 1'-benzyl 5"-methyl ester c (1.2 g crude), which was used in the next step without further purification. LCMS (m / z): [M+H] + C 26 H 26 Calculated Cl2NO5, 502.1; measured, 502.3.

[0162] Step 4

[0163] To a solution of 2,2-dichloro-3-oxo-2",3"-dihydrodispiro[cyclobutane-1,4'-piperidine-2',1"-indene]-1',5"-dicarboxylic acid 1'-benzyl 5"-methyl ester c (1.2 g, crude) in MeOH (50 mL) were added NH4Cl (2.6 g, 48 mmol) and zinc (1.6 g, 24 mmol) at room temperature. The reaction mixture was stirred at 60°C for 2 hours and then filtered. The filtrate was concentrated in vacuo and the residue was purified by flash column chromatography on silica gel (ethyl acetate: petroleum ether = 2 / 1) to give the product 3-oxo-2",3"-dihydrodispiro[cyclobutane-1,4'-piperidine-2',1"-indene]-1',5"-dicarboxylic acid 1'-benzyl 5"-methyl ester d as an oil (500 mg, 50% yield for two steps). LCMS (m / z): [M+H] + C 26 H 28 NO5 calculated, 434.2; measured, 434.0.

[0164] Step 5

[0165] 3-Oxo-2",3"-dihydrodispiro[cyclobutane-1,4'-piperidin-2',1"-indene]-1',5"-dicarboxylic acid 1'-benzyl 5"-methyl ester d (500 mg, 1.15 mmol) was dissolved in BAST (1.5 mL) at 0°C. The reaction mixture was stirred at 50°C for 12 hours. The reaction was cooled to room temperature and 15 mL of ethyl acetate was added. The reaction mixture was poured very carefully into ice (20 mL). The residue was washed with dichloromethane (30 mL x 5% ethanol). 3) extraction, washed with brine (30 mL), and dried over Na2SO4. The filtrate was concentrated in vacuo and purified by silica gel flash column chromatography (ethyl acetate: petroleum ether = 1 / 5) to give the product 3,3-difluoro-2",3"-dihydrodispiro[cyclobutane-1,4'-piperidin-2',1"-indene]-1',5"-dicarboxylic acid 1'-benzyl 5"-methyl ester e as an oil (300 mg, yield 57%). LCMS (m / z): [M+H] + C 26 H 28 F2NO4 calculated, 456.2; measured, 456.0.

[0166] Step 6

[0167] To a stirred solution of 3,3-difluoro-2",3"-dihydrodispiro[cyclobutane-1,4'-piperidin-2',1"-indene]-1',5"-dicarboxylic acid 1'-benzyl 5"-methyl ester e (240 mg, 0.527 mmol) in MeOH (5 mL) at 25°C was added Pd(OH)2 / C (100 mg). The reaction mixture was stirred at 25°C under H2 for 2 h. After filtration, the solution was concentrated in vacuo to give 3,3-difluoro-2",3"-dihydrodispiro[cyclobutane-1,4'-piperidin-2',1"-indene]-5"-carboxylic acid methyl ester f as an oil (155 mg, 92% yield). LCMS (m / z): [M+H] + C 18 H 22 F2NO2 calculated, 322.1; measured, 322.1.

[0168] Step 7

[0169] A solution of methyl 3,3-difluoro-2",3"-dihydrodispiro[cyclobutane-1,4'-piperidine-2',1"-indene]-5"-carboxylate f (155 mg, 0.48 mmol), tert-butyl 4-(chloromethyl)-5-methoxy-7-methyl-1H-indole-1-carboxylate (180 mg, 0.58 mmol), Cs2CO3 (471 mg, 1.45 mmol) and NaI (109 mg, 0.72 mmol) in acetonitrile (3 mL) was stirred at 80°C for 2 hours. After filtration, the solution was concentrated in vacuo, and the residue was purified by silica gel flash column chromatography (PE / EtOAc=10 / 1) to give 1'-((1-(tert-butoxycarbonyl)-5-methoxy-7-methyl-1H-indol-4-yl)methyl)-3,3-difluoro-2",3"-dihydrodispiro[cyclobutane-1,4'-piperidin-2',1"-indene]-5"-carboxylic acid methyl ester (180 mg, 63%) as a white solid. LCMS (m / z): [M+H] + C 34 H 41 F2N2O5 calculated, 595.1; measured, 595.1.

[0170] Step 8

[0171] A solution of 1'-((1-(tert-butoxycarbonyl)-5-methoxy-7-methyl-1H-indol-4-yl)methyl)-3,3-difluoro-2",3"-dihydrodispiro[cyclobutane-1,4'-piperidine-2',1"-indene]-5"-carboxylic acid methyl ester (180 mg, 0.30 mmol) and NaOH (60 mg, 1.51 mmol) in MeOH / THF / H2O (1 / 1 / 0.2 mL) was stirred at 60°C for 1 hour. The reaction mixture was neutralized with saturated citric acid solution and then extracted with DCM / MeOH (10 / 1, 20 mLx3). The combined organic layers were concentrated in vacuo and the residue was purified by preparative HPLC (acetonitrile-H2O, 0.1% FA) and SFC (column: CHIRALPAK AD-H 250 mm x 20 mm, 5 μm; mobile phase: 40% EtOH [0.2% NH4OH] in CO2; flow rate: 12.5 mL / min; column temperature: 38°C, retention time = 3.54 min) to obtain Example 1 Isomer 1 (36.27 mg, 25%), which was prepared by preparative HPLC (acetonitrile-H2O, 0.1% FA) and SFC (column: CHIRALPAK AD-H 250 mm x 20 mm, 5 μm; mobile phase: 40% EtOH [0.2% NH4OH] in CO2; flow rate: 12.5 mL / min; column temperature: 38°C, retention time = 3.54 min). NH4OH] in CO2; flow rate: 12.5 mL / min; column temperature: 38°C, retention time = 4.75 min) to obtain Example 1 Isomer 2 (42.33 mg, 29%, white solid) as formate salt. MS: m / z = 481.0 (M+1, ESI+).

[0172] Example 1 Isomer 1: 1 HNMR(400MHz,CD3OD)δ8.08(m,1H),7.98(s,1H),7.60(d,J=8.1Hz,1H),7.28(d ,J=3.1Hz,1H),6.70(s,1H),6.23(d,J=3.0Hz,1H),4.15-4.04(m,1H),4.02-3. 89(m,1H),3.65(s,3H),3.52-3.41(m,2H),3.27-3.11(m,2H),2.95-2.75(m,2H ),2.73-2.60(m,1H),2.56-2.42(m,6H),2.40-2.29(m,1H),2.11-1.94(m,3H).

[0173] Example 1 Isomer 2: 1HNMR(400MHz,CD3OD)δ8.44(s,1H),8.14-8.08(m,1H),8.01(s,1H),7.63(d,J=8.1H z,1H),7.29(d,J=3.2Hz,1H),6.71(s,1H),6.24(d,J=3.1Hz,1H),4.17-4.08(m,1H) ,4.06-3.95(m,1H),3.64(s,3H),3.56-3.47(m,2H),3.28-3.14(m,2H),2.98-2.77( m,2H),2.75-2.64(m,1H),2.58-2.44(m,6H),2.43-2.29(m,1H),2.14-1.96(m,3H).

[0174] The following examples were synthesized using the above ester hydrolysis procedure and appropriate starting materials:

[0175] Table A

[0176]

[0177]

[0178]

[0179]

[0180]

[0181]

[0182]

[0183]

[0184]

[0185]

[0186]

[0187]

[0188]

[0189]

[0190]

[0191]

[0192]

[0193]

[0194]

[0195]

[0196]

[0197]

[0198]

[0199]

[0200] Biological Example 1. Factor B Binding Assay by TR-FRET

[0201] Materials and reagents

[0202] 1. Recombinant human factor B catalytic domain (aa470-764, C-terminal histidine tag, produced in-house)

[0203] 2.5X Kinase Buffer A (Thermo Fisher, CAT# PV3189)

[0204] 3. LANCE Eu-W1024 anti-6xHis antibody (PerkinElmer, CAT#AD0401)

[0205] 4. Probe (TRFRET_tool 2, reported in WO 2015 / 009616)

[0206]

[0207] 5.DMSO(Thermo Fisher Scientific)

[0208] 6. Compounds - 10 mM stock solution in DMSO

[0209] 7.Victor Nivo Multimode Microplate Reader (PerkinElmer)

[0210] 8.OptiPlate-384, white opaque 384-well microplate (PerkinElmer, CAT#6007290)

[0211] Experimental procedures

[0212] The Factor B binding affinity of each test compound was determined using the time-resolved fluorescence resonance energy transfer (TR-FRET) technique. 10 nM recombinant histidine-tagged Factor B catalytic domain, varying concentrations of inhibitor, 4 nM LANCEEu-W1024 anti-6xHis antibody, and 100 nM TRFRET_tool2 tracer were incubated in 1X Kinase Buffer A for 1 hour. Measurements were performed in a 15 μL reaction volume by adding 5 μL of test compound, 5 μL of Factor B / antibody mix, and 5 μL of tracer to a white opaque 384-well assay plate. TR-FRET signals were read on a plate reader with an excitation wavelength of 340 nm and detection wavelengths of 615 and 665 nm. IC was estimated by measuring TR-FRET signals for varying concentrations of compound and plotting relative fluorescence emission ratios (665 nm / 615 nm) versus inhibitor concentration using a four-parameter dose-response inhibition curve with a variable slope model in GraphPad Prism. 50 , to determine the binding affinity of each compound.

[0213] The binding affinity of the compounds of the invention to the catalytic domain of recombinant factor B was determined by the above assay, IC 50 Values ​​(nM) are shown in the table below.

[0214] Table 1. IC values ​​of the compounds of the present invention for human factor B 50 Value (nM)

[0215] Example# Isomers <![CDATA[Factor B TR-FRET IC 50 (nM)]]> 1 1 1.05 2 1 2.01 3 1 1.14

[0216] The example compounds of the present invention were tested in the above assay and showed an IC of 50 (nM) is 0.5 to 250 nM.

[0217] Biological Example 2. Target retention time of factor B inhibitors determined by surface plasmon resonance (SPR)

[0218] Materials and reagents

[0219] 1. Recombinant human factor B catalytic domain (aa470-764, C-terminal histidine tag, produced in-house)

[0220] 2. PBS-P+ buffer 10X (Cytiva, CAT#28995084)

[0221] 3. Series S Sensor Chip NTA (Cytiva, CAT#BR100532)

[0222] 4. Amine coupling kit (Cytiva, CAT#BR100050)

[0223] 5. DMSO (Millipore Sigma, CAT#34869-1L)

[0224] 6. Greiner 96-well plate, polypropylene (Sigma-Aldrich, CAT#M7310-100EA)

[0225] 7. Microplate foil, 96 wells (Cytiva, CAT# 28975816)

[0226] 8. Biacore 8k (Cytiva)

[0227] Experimental procedures

[0228] The Biacore 8k instrument was loaded with 1X PBS-P+ buffer and then docked to the Cytiva NTA chip. The recombinant human factor B catalytic domain was immobilized on the NTA chip using 1XPBS-P+ buffer [20mM phosphate buffer, containing 2.7mM KCl, 137mM NaCl and 0.05% (v / v) Tween-20] to a level of approximately 5000 resonance units (RU). The protein ligand was further cross-linked to the sensor chip surface using an amine coupling kit. Immobilization and binding experiments were performed at room temperature.

[0229] The buffer was replaced with 1X PBS-P+ buffer containing 2% (v / v) DMSO, and then a pre-run of at least 30 minutes was performed at a flow rate of 30 μl / min to obtain a stable surface. The kinetic constants of the compound were determined by single-cycle kinetics (or multi-cycle kinetics of eight continuous injections) of six consecutive injections of the compound at increasing concentrations of 0.8 to 200 nM, 12.5 to 400 nM, 4.1 to 1,000 nM or 41 to 10,000 nM (depending on the efficacy). Single-cycle kinetic experiments were performed with a binding time of 60 seconds per concentration and a dissociation time of 300 seconds (or a dissociation time of 120 seconds for multi-cycle kinetic experiments). A flow rate of 30 μl / min was used. A blank run was performed under the same conditions before injecting the compound.

[0230] The SPR sensorgram was analyzed using Biacore Insight Evaluation Software using a dual reference method. The resulting curve was fitted with a 1:1 binding model. The repeated kinetic constants (ka, kd, KD) were averaged. The retention time (tR) was calculated based on the dissociation constant kd using the formula tR = 1 / kd. The binding half-life (t1 / 2) was calculated based on the dissociation constant kd using the formula t1 / 2 = ln2 / kd.

[0231] Table 2 Kinetic constants and target retention times of the compounds of the present invention for human factor B

[0232] Example# Isomers <![CDATA[K D (nM)]]> Retention time(s) <![CDATA[t 1 / 2 (s)]]> 1 1 0.9 1017 705 2 1 2.2 1175 814 3 1 1.73 1092 757

[0233] The example compounds of the present invention were tested in the above assay and showed K for human factor B. D (nM) is 0.5 to 250 nM.

[0234] Biological Example 3: Inhibition of human MAC deposition

[0235] To quantify the inhibitory effect of compounds on complement protein deposition after LPS activation of the alternative complement pathway, an AP deposition assay was used. Compounds were tested starting at 11.1 μM or 3.70 μM and diluted 3-fold in DMSO to generate 8 concentration points, each of which was tested in technical triplicate. Human serum was mixed with test compounds in GVB buffer containing 5 mM MgCl2 10 mM EGTA and added to LPS-coated black Maxisorp plates. After an incubation period, the plates were inverted and complement proteins bound to LPS were detected by ELISA. A primary antibody detecting human C5b-9 was used, followed by a compatible HRP-conjugated secondary antibody. Peroxidase activity was detected using the Quantablu Fluorescent Peroxidase Substrate Kit and fluorescence was measured at 340 nm / 435 nm using an i3x plate reader to determine the amount of alternative pathway complement protein deposition.

[0236] Table 3. Inhibition of MAC (Membrane Attack Complex) Formation

[0237] Example# Isomers <![CDATA[IC 50 (nM)]]> 1 1 147 2 1 129 3 1 193

[0238] The example compounds of the present invention were tested in the above assay and showed an IC of 50 (nM) is 125 to 5000 nM.

[0239] Biological Example 4: Inhibition of AP-dependent hemolysis

[0240] To quantify the inhibitory effect of compounds on the hemolytic activity of the alternative complement pathway, an AP hemolysis assay was used. Compounds were tested starting at 100 μM and diluted 3-fold in DMSO to generate 8 to 11 concentration points, each of which was tested in technical triplicate. Human serum was added to rabbit reticulocytes in GVB buffer solution containing MgCl2 and EGTA. After a period of incubation at 37°C, spontaneous lysis of rabbit erythrocytes due to serum AP complement activity was quantified using OD405 absorbance (measured using an i3x plate reader).

[0241] Table 4. Inhibition of rabbit reticulocyte hemolysis

[0242] Example# Isomers <![CDATA[IC 50 (nM)]]> 1 1 220 2 1 283 3 1 252

[0243] The example compounds of the present invention were tested in the above assay and showed an IC of 50 (nM) is 125 to 5000 nM.

[0244] Biological Example 5: Pharmacokinetic Study in Rats

[0245] Three-month-old brown Norway rats were intravenously administered with the example compound (0.5 mg / kg dose, formulation: 10% 1,2-propylene glycol + 25% (20% solutol HS15 aqueous solution) + 65% phosphate buffered saline, 0.1 mg / mL), and administered with a 2 mg / kg dose via oral gavage with a clear solution (0.5% MC + 0.5% Tween 80 aqueous solution, 1 mg / mL). Plasma was collected from rats at each time point of 0.25, 0.5, 1, 6, and 24 hours after administration. The concentration of the test substance in plasma was measured by HPLC-MS / MS, with two separate plasma samples for each time point. Chromatographic separation was performed on a Waters BEH C18 Column (2.1×50 mm, 1.7 μm) column (MAC-MOD Analytical, Chadds Ford, PA) using a gradient elution method of water and acetonitrile, both of which contained 0.025% formic acid-1 mM NH4OAc. Mass spectrometry measurements in positive electrospray ionization were aimed at quantifying [M+H] as precursor ions on an API 6500 triple quadrupole mass spectrometer (Sciex, Framingham, MA). + Mass transitions. Relevant pharmacokinetic parameters were estimated using non-compartmental methods using WinNonlin (Enterprise, version 8.2).

[0246] Table 5. PK study results obtained in rats (0.5 mpk IV and 2 mpk PO)

[0247]

[0248] Conclusion: The present invention describes compounds that are potent inhibitors of Factor B, having desirable physicochemical properties. The described compounds can be used as therapeutic agents as claimed above.

Claims

1. A compound of formula (I): or a tautomer, cis or trans isomer, meso-isomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, in, is a saturated or unsaturated ring; A is C 6-10 Aryl or 5-10 membered heteroaryl; L is a bond or CH2; R a and R b independently selected from hydrogen, deuterium, halogen, amino, cyano, hydroxy, alkyl, alkoxy, alkylthio, haloalkyl, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl; R1 and R2 are independently selected from hydrogen, deuterium, halogen, amino, cyano, hydroxy, alkyl, alkoxy, alkylthio, haloalkyl and hydroxyalkyl; R3 and R4 are independently selected from hydrogen, deuterium, halogen, amino, cyano, hydroxyl, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, C 1-6 Haloalkyl, C 1-6 Halogenated alkenyl, C 1-6 Hydroxyalkyl, deuterated C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 3-6 Cycloalkyl, 4-10 membered heterocyclic group, C 6-10 Aryl, 5-10 membered heteroaryl, C 3-6 Cycloalkyloxy, 4-10 membered heterocyclyloxy, C 6-10 Aryloxy and 5-10 membered heteroaryloxy, the C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, deuterated C 1-6 Alkoxy, C 1-6 The haloalkoxy group is optionally selected from deuterium, halogen, amino, cyano, hydroxy, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 3-6 Cycloalkyl, 4-10 membered heterocyclic group, C 6-10 Aryl and 5-10 membered heteroaryl are substituted with one or more substituents; R5 is independently selected from hydrogen, deuterium, halogen, amino, cyano, hydroxyl, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Alkoxy, C 1-6 Alkylthio, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 3-8 Cycloalkyl, 4-10 membered heterocyclic group, C 5-10 Aryl and 5-10 membered heteroaryl, the C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 3-8 Cycloalkyl, 4-10 membered heterocyclic group, C 5-10 Aryl and 5-10 membered heteroaryl are optionally selected from deuterium, halogen, amino, cyano, hydroxyl, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, C 1-6 Haloalkyl and C 1-6 The hydroxyalkyl group is substituted with one or more substituents; Alternatively, the two R5 atoms together with the C atoms to which they are attached form a C 3-6 Cycloalkyl or a 4-6 membered heterocyclic group containing 1, 2 or 3 heteroatoms selected from N, O and S, which is optionally selected from hydrogen, deuterium, halogen, amino, cyano, hydroxyl, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkyl C 1-6 Alkoxy, C 1-6 Alkoxy C 1-6 Alkyl, C 1-6 Alkylthio, C 1-6 Haloalkyl and C 1-6 The hydroxyalkyl group is substituted with one or more substituents; Alternatively, two R5 together with the C atom to which they are attached form a carbon-carbon double bond; R6 is selected from hydrogen, deuterium, halogen, amino, cyano, hydroxyl, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 3-8 Cycloalkyl, 4-10 membered heterocyclic group, C 5-10 Aryl, 5-10 membered heteroaryl, –(CH2) r C 1-6 Alkoxy, –(CH2) r C(O)OH、-S(O)NHC 1-6 Alkyl, -SO2C 1-6 Alkyl, -C(O)NHSO2C 1-6 Alkyl and -SO2NHC(O)C 1-6 alkyl; R7 is hydrogen or C 1-3 alkyl; R9 is selected from deuterium, halogen, amino, cyano, hydroxyl, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 3-8 Cycloalkyl and 4-10 membered heterocyclyl containing 1, 2 or 3 heteroatoms selected from N, O and S; Alternatively, R9 and one of R6 together form a saturated or unsaturated C 3-7 Cycloalkyl or saturated or unsaturated 3-7 membered heterocyclic group containing 1, 2 or 3 heteroatoms selected from N, O and S, wherein the C 3-7 Cycloalkyl or 3-7 membered heterocyclic group is optionally selected from hydrogen, deuterium, halogen, amino, cyano, hydroxyl, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkyl alkoxy, C 1-6 Alkoxyalkyl, C 1-6 Alkylthio, C 1-6 Haloalkyl and C 1-6 1 or 2 substituents of hydroxyalkyl, the other R6 is selected from hydrogen, deuterium, halogen, amino, cyano, hydroxyl, C 1-3 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 3-8 Cycloalkyl, 4-10 membered heterocyclic group, C 5-10 Aryl, 5-10 membered heteroaryl, –(CH2) r C 1-6 Alkoxy, –(CH2) r C(O)OH、-S(O)NHC 1-6 Alkyl, -SO2C 1-6 Alkyl, -C(O)NHSO2C 1-6 Alkyl and -SO2NHC(O)C 1-6 alkyl; R8 is selected from the group consisting of deuterium, halogen, amino, cyano, hydroxy, alkyl, alkoxy, alkylthio, haloalkyl and hydroxyalkyl; p is 1, 2, or 3; t is 1, 2, or 3; m is 1, 2 or 3; n is 0, 1, 2 or 3; and, r is 0, 1, 2, or 3; Provided that R3 and R4 are not methyl at the same time.

2. The compound according to claim 1, or its tautomer, cis or trans isomer, meso-isomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, wherein A is phenyl, benzocycloalkyl, or a 5-8 membered heteroaryl group containing 1, 2 or 3 N heteroatoms; Preferably, A is 3. A compound according to any one of claims 1 to 2, or a tautomer, cis or trans isomer, meso, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, wherein R1 and R2 are independently selected from hydrogen.

4. A compound according to any one of claims 1 to 3, or a tautomer, cis or trans isomer, meso, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, wherein R3 and R4 are independently selected from deuterium, halogen, C 1-3 Alkyl, C 1-3 Alkoxy, deuterated C 1-3 Alkoxy, C 1-3 Halogenated alkoxy, C 3-6 Cycloalkyl and C 3-6 Cycloalkyloxy, the C 1-3 Alkyl, C 1-3 Alkoxy, deuterated C 1-3 Alkoxy, C 1-3 The haloalkoxy group is optionally selected from C 3-6 Cycloalkyl, 4-6 membered heterocyclic group, C 6-10 The aryl and 5- to 10-membered heteroaryl groups are substituted with one or more substituents.

5. A compound according to any one of claims 1 to 4, or a tautomer, cis or trans isomer, meso, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, wherein R6 is -F, -OMe, -CH2OH, -CH2OCH3, -CH2F, -CF2H, -CF3, -COOH, -C(O)NHSO2CH3, -S(O)NHCH3, a 5-6 membered heterocyclyl containing 1 to 3 heteroatoms selected from N, O and S, or a 5-6 membered heteroaryl containing 1 to 3 heteroatoms selected from N, O and S.

6. A compound according to any one of claims 1 to 5 or a tautomer thereof, or a pharmaceutically acceptable salt thereof, wherein R9 is selected from deuterium, halogen, amino, cyano, hydroxyl, C 1-3 Alkyl, C 1-6 Alkoxy, C 1-3 Alkylthio, C 1-3 Haloalkyl, C 1-3 Hydroxyalkyl, C 3-6 Cycloalkyl and 4-6 membered heterocyclyl containing 1, 2 or 3 heteroatoms selected from N, O and S; Preferably, R9 is selected from deuterium, halogen, amino, cyano, hydroxyl, methyl, ethyl, cyclopropyl, cyclobutyl; Alternatively, R9 and one of R6 together form a saturated or unsaturated C 4-6 Cycloalkyl or saturated or unsaturated 4-7 membered heterocyclic group containing 1, 2 or 3 heteroatoms selected from N, O and S, the saturated or unsaturated C 4-6 Cycloalkyl or saturated or unsaturated 4-7 membered heterocyclic group is optionally selected from hydrogen, deuterium, halogen, amino, cyano, hydroxyl, C 1-3 Alkyl, C 1-3 Alkoxy, C 1-3 Alkyl alkoxy, C 1-3 Alkoxyalkyl, C 1-3 Alkylthio, C 1-3 Haloalkyl and C 1-3 The hydroxyalkyl group is substituted with one or two substituents, and the other R6 is selected from F, -OMe, -CH2OH, -CH2OCH3, -CH2F, -CF2H, -CF3, -COOH, -C(O)NHSO2CH3, -S(O)NHCH3.

7. A compound according to any one of claims 1 to 6, or a tautomer, cis or trans isomer, meso, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, wherein the compound is of formula (II):

8. A compound according to any one of claims 1 to 7 or its tautomer, cis or trans isomer, meso-isomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, wherein the compound is of formula (III-a)-(III-b): in, X is CR c R d NR e or O; is a single bond or a double bond; R c , R d and R e are independently selected from hydrogen, deuterium, halogen, amino, cyano, hydroxyl, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 3-8 Cycloalkyl, C 3-8 Heterocyclic group, C 6-10 Aryl and C 6-10 heteroaryl; Preferably, R c , R d and R e are independently selected from hydrogen, deuterium, halogen, amino, cyano, hydroxyl, C 1-3 Alkyl, C 1-3 Alkoxy, C 1-3 Alkylthio, C 1-3 Haloalkyl, C 1-3 Hydroxyalkyl, C 3-6 Cycloalkyl, C 4-6 Heterocyclic group, C 6-10 Aryl and C 6-10 heteroaryl; Preferably, R c , R d and R e independently selected from hydrogen, deuterium, halogen, amino, cyano, hydroxy, methyl, ethyl, cyclopropyl, cyclobutyl; v is 0, 1, 2, or 3.

9. A compound according to any one of claims 1 to 8, or a tautomer, cis or trans isomer, meso, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, wherein the compound is of formula (II-a)-(II-b): in, E is R 10 Selected from hydrogen, deuterium, halogen, amino, cyano, hydroxyl, C 1-3 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 1-3 Alkoxy, C 1-3 Alkylthio, C 1-3 Haloalkyl and C 1-3 Hydroxyalkyl; n is 2; and, z is 0, 1, 2 or 3.

10. A compound according to any one of claims 8 or 9 or its tautomer, cis or trans isomer, meso, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, wherein for 11. A compound according to any one of claims 1 to 10 or a tautomer, cis or trans isomer, meso, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, wherein the compound is of formula (Va)-(Vb): in, M is CR f R g ; R f and R g are independently selected from hydrogen, halogen and C 1-3 alkyl; Preferably, R f and R g independently selected from hydrogen and fluorine; q is 1, 2, or 3; and, s is 0, 1, or 2.

12. A compound according to any one of claims 1 to 11 or its tautomer, cis or trans isomer, meso-isomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, wherein the compound is of formula (VI-a)-(VI-1):

13. A compound according to any one of claims 12 or its tautomer, cis or trans isomer, meso, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, wherein for in, for 14. A compound selected from: or a tautomer, cis or trans isomer, meso racemate, racemate, enantiomer, diastereomer, or a mixture thereof, or a pharmaceutically acceptable salt, solvate, or prodrug thereof.

15. A pharmaceutical composition comprising a therapeutically effective amount of a compound according to any one of claims 1 to 14 or a tautomer or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier or excipient.

16. A method for modulating complement alternative pathway activity in a subject, wherein the method comprises administering to the subject a therapeutically effective amount of a compound according to any one of claims 1 to 14 or a pharmaceutical composition according to claim 15.

17. A method for treating a condition or disease mediated by complement activation, particularly by activation of the complement alternative pathway, in a subject, wherein the method comprises administering to the subject a therapeutically effective amount of a compound according to any one of claims 1 to 14 or a pharmaceutical composition according to claim 15.

18. The method of claim 17, wherein the disease or condition is selected from the group consisting of age-related macular degeneration, geographic atrophy, diabetic retinopathy, uveitis, retinitis pigmentosa, macular edema, Behcet's uveitis, multifocal choroiditis, Vogt-Koyangi-Harada syndrome, intermediate uveitis, birdshot retinochoroiditis, sympathetic ophthalmia, ocular pemphigoid, ocular pemphigus, non-arteritic ischemic optic neuropathy, postoperative inflammation, retinal vein occlusion, neurological disease, multiple sclerosis, stroke, Guillain-Barré syndrome, traumatic brain injury, Parkinson's disease, inappropriate or adverse complement activation disorders, complications of hemodialysis, hyperacute allograft rejection, xenograft rejection, interleukin-2-induced toxicity during IL-2 therapy, inflammatory diseases, inflammation of autoimmune diseases, Crohn's disease, adult respiratory distress syndrome, myocarditis, post-ischemia-reperfusion syndrome, myocardial infarction, balloon angioplasty, post-extracorporeal circulation or renal bypass pump syndrome, atherosclerosis, hemodialysis, renal ischemia, mesenteric artery reperfusion after aortic reconstruction, infectious diseases or sepsis, immune complex disorders and autoimmune diseases, rheumatoid arthritis, systemic lupus erythematosus, SLE nephritis, proliferative nephritis, liver fibrosis, hemolytic anemia, myasthenia gravis, tissue regeneration, nerve regeneration, dyspnea, hemoptysis, ARDS, asthma, chronic obstructive pulmonary disease, emphysema, pulmonary embolism and infarction, pneumonia, fibrosis, pulmonary fibrosis, asthma, allergy, bronchoconstriction, hypersensitivity pneumonitis, parasitic diseases, Goodpasture's syndrome, pulmonary vasculitis, micro-immune vasculitis, immune complex-related inflammation, antiphospholipid syndrome, glomerulonephritis, and obesity.

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