2-Substituted piperidine derivatives, their preparation method and medicinal use

Abstract

The present invention provides compounds having a structure represented by formula (I), which are 2-substituted piperidine derivatives, methods for preparing the same, pharmaceutical compositions containing these compounds, and pharmaceutical uses for treating diseases or disorders. [Formula 1] TIFF2025530222000095.tif45170

Description

[Technical Field]

[0001] The present invention belongs to the pharmaceutical field and relates to 2-substituted piperidine derivatives, methods for preparing the same, pharmaceutical compositions containing the compounds, and medical uses thereof. [Background technology]

[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 by three distinct pathways: the classical pathway (CP), the lectin pathway (LP), and the alternative pathway (AP). CP and LP are initiated on target surfaces by the binding of immune complexes and mannan-binding lectins or ficolins, respectively, to specific microbial glycomoiety patterns. However, AP does not require specific initiation. The AP cascade is initiated by spontaneous hydrolysis of C3 (tick-over) and subsequent deposition of C3b on activated surfaces. The three complement activation pathways converge on two major events: C3 cleavage and C5 cleavage. C3 convertase cleaves C3 into C3a and C3b. C3b forms another AP, C3 convertase (amplifier) ​​and C5 convertase. C5 convertase cleaves C5 into C5a and C5b. The resulting C5b disrupts bacteria and cells by inserting membranes, initiating the formation of the C5b-9 membrane attack complex (MAC) with C6-C9. The cleavage products C3a and C5a act as allergenic toxins and promote pro-inflammatory responses by activating and chemotactic leukocytes. C3b also promotes phagocytosis through conditioning and plays an important role in the removal of bacteria and cellular waste (e.g., immune complexes and apoptotic cells) (Non-Patent Document 1). The AP maintains basal complement activity through a "tickover" process. Even when initiated by other CPs or LPs, the AP contributes to over 80% of terminal cleavage pathway activation (MAC formation) through an amplification loop (Non-Patent Document 2). Spontaneously activated C3 forms C3 convertase by binding to factor B (FB). After factor D cleaves FB to Bb, C3b and Bb generate AP C3 convertase (C3bBb). The newly formed C3bBb cleaves more C3, generating more AP C3 convertase, leading to amplification of the complement cascade. AP can exert full complement activity within seconds, potentially damaging normal tissues if not properly controlled (Non-Patent Document 3).Imbalances in complement activation have been shown to be associated with various organ diseases, including paroxysmal nocturnal hemoglobinuria, age-related macular degeneration, rheumatoid arthritis, hemolytic uremic syndrome, myasthenia gravis, and C3 glomerulonephritis (Non-Patent Document 3). Therefore, controlling AP by FB inhibition may be a promising strategy to limit excessive activation of the complement pathway.

[0003] Currently, no small molecules have been approved to modulate the complement pathway. The following disclosures describe examples of factor B inhibitors: U.S. Patent No. 1 to Advanced Vision Therapies Inc., entitled "Treatment of diseases characterized by inflammation," U.S. Patent No. 2,023,499 to Wellstate Immunotherapeutics, entitled "Complement Factor B analogs and their uses," U.S. Patent No. 3,023,499 to William Marsh Rice University, entitled "Heat-inactivated Complement Factor B compositions and methods," U.S. Patent No. 4,023,499 to Muse. Foundation for Research Development, entitled "Blocking factor b to treat complement-mediated immune disease," and U.S. Patent Nos. 5,023,499 and 5,023,499 to Novartis, entitled "Complement pathway modulators and uses thereof." Additional factor B inhibitors are described in Novartis patents U.S. Pat. Nos. 5,629,997, 5,629,997, 5,629,997, 5,629,997, 5,629,997, and 5,629,997. Another example of a factor B inhibitor is U.S. Pat. No. 5,629,997 to IONIS Pharmaceuticals Inc., entitled "Modulators of Complement Factor B." Examples of allowed patents relating to factor B inhibitors include U.S. Pat. Nos. 5,629,997, ... and 5,629,997. [Prior art documents] [Patent documents]

[0004] [Patent Document 1] International Publication No. 2008 / 106644 [Patent Document 2] International Publication No. 2012 / 151468 [Patent Document 3] International Publication No. 2014 / 035876 [Patent Document 4] U.S. Patent Application Publication No. 1999 / 0023485 [Patent Document 5] International Publication No. 2013 / 192345 [Patent Document 6] US Patent Application Publication No. 2015 / 126592 [Patent Document 7] International Publication No. 2015 / 066241 [Patent Document 8] US Patent Application Publication No. 2016 / 0311779 [Patent Document 9] International Publication No. 2015 / 009616 [Patent Document 10] US Patent Application Publication No. 2016 / 0152605 [Patent Document 11] International Publication No. 2014 / 143638 [Patent Document 12] US Patent Application Publication No. 2016 / 0024079 [Patent Document 13] International Publication No. 2015 / 038939 [Patent Document 14] U.S. Patent No. 9,452,990 [Patent Document 15] U.S. Patent No. 9,676,728 [Patent Document 16] U.S. Patent No. 9,682,968 [Patent Document 17] U.S. Patent No. 9,475,806 [Non-patent literature]

[0005] [Non-Patent Document 1] Nicolas S Merle, Sarah Elizabeth Church, Veronique Fremeaux-Bacchi, Lubka T Roumenina, Complement System Part I - Molecular Mechanisms of Activation and Regulation., Front Immunol. June 2, 2015;6:262. doi: 10.3389 / fimmu.2015.00262. eCollection 2015. [Non-patent document 2] Harboe, M., Garred, P., Karlstrom, 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 [Non-patent document 3] Eleni Gavriilaki, Robert A Brodsky, Complementopathies and precision medicine. J Clin Invest. 2020 May 1;130(5):2152-2163. doi: 10.1172 / JCI136094. Summary of the Invention [Problem to be solved by the invention]

[0006] Because many diseases are caused by excessive complement pathway activity, there is a high unmet need for patients with complement disorders. It is an object of the present invention to provide compounds that regulate factor B and treat disorders associated with complement pathway imbalance. [Means for solving the problem]

[0007] In one aspect, the present invention provides a compound having a structure represented by 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: [ka] where: [ka] is a saturated or unsaturated ring, A is a cycloalkyl group, a heterocyclyl group, an aryl group, or a heteroaryl group; L is a bond, (CR a R b ) p and R a and R b are independently selected from the group consisting of hydrogen, deuterium, halogen, amino, cyano, hydroxy, alkyl, alkoxy, alkylthio, haloalkyl, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl groups; R1 and R2 are independently selected from the group consisting of hydrogen, deuterium, halogen, amino, cyano, hydroxy, alkyl, alkoxy, alkylthio, haloalkyl, and hydroxyalkyl groups; R3 and R4 are independently selected from the group consisting of hydrogen, deuterium, halogen, amino, cyano, hydroxy, alkyl, alkoxy, alkylthio, haloalkyl, haloalkenyl, hydroxyalkyl, deuterated alkoxy, haloalkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl, cycloalkyloxy, heterocyclyloxy, aryloxy, and heteroaryloxy groups, optionally substituted with one or more substituents selected from deuterium, halogen, amino, cyano, hydroxy, alkyl, alkoxy, alkylthio, haloalkyl, hydroxyalkyl, deuterated alkoxy, haloalkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl, cycloalkyloxy, heterocyclyloxy, aryloxy, and heteroaryloxy groups; R5 is independently selected from the group consisting of hydrogen, deuterium, halogen, amino, cyano, hydroxy, alkyl, alkenyl, alkynyl, alkoxy, alkylthio, haloalkyl, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl groups, optionally substituted with one or more substituents selected from deuterium, halogen, amino, cyano, hydroxy, alkyl, alkynyl, alkoxy, alkylthio, haloalkyl, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl groups; or two R5 together with the C atom to which they are attached form a cycloalkyl or heterocyclyl group, optionally substituted with one or more substituents selected from hydrogen, deuterium, halogen, amino, cyano, hydroxy, alkyl, alkoxy, alkylalkoxy, alkoxyalkyl, alkylthio, haloalkyl and hydroxyalkyl groups; or two R5 together with the C atom to which they are attached form a cycloalkyl or heterocyclyl group, optionally substituted with one or more substituents selected from hydrogen, deuterium, halogen, amino, cyano, hydroxy, alkyl, alkoxy, alkylalkoxy, alkoxyalkyl, alkylthio, haloalkyl and hydroxyalkyl groups; or two R5 together with the C atoms to which they are attached form a carbon-carbon double bond, R6 is hydrogen, deuterium, halogen, amino group, cyano group, hydroxy group, alkyl group, alkoxy group, alkylthio group, haloalkyl group, hydroxyalkyl group, cycloalkyl group, heterocyclyl group, aryl group, heteroaryl group, -(CH2) r OR8, -(CH2) r selected from the group consisting of C(O)R, —S(O)NH alkyl group, —SO alkyl group, —C(O)NHSO alkyl group and —SONHC(O) alkyl group; R7 is selected from the group consisting of hydrogen, deuterium, halogen, amino, cyano, hydroxy, alkyl, alkoxy, alkylthio, haloalkyl, and hydroxyalkyl groups; R9 is selected from the group consisting of deuterium, halogen, amino, cyano, hydroxy, alkyl, alkoxy, alkylthio, haloalkyl, hydroxyalkyl, cycloalkyl, and heterocyclyl groups; or R9 together with one of R6 form a saturated or unsaturated cycloalkyl group or a saturated or unsaturated heterocyclyl group, optionally the cycloalkyl or heterocyclyl group being substituted with one or more substituents selected from hydrogen, deuterium, halogen, amino, cyano, hydroxy, alkyl, alkoxy, alkylalkoxy, alkoxyalkyl, alkylthio, haloalkyl, and hydroxyalkyl groups, and another R6 is hydrogen, deuterium, halogen, amino, cyano, hydroxy, alkyl, alkoxy, alkylthio, haloalkyl, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, -(CH2) r OR8, -(CH2) r selected from the group consisting of C(O)R, —S(O)NH alkyl group, —SO alkyl group, —C(O)NHSO- alkyl group and —SONHC(O) alkyl group; R8 is selected from the group consisting of deuterium, halogen, amino, cyano, hydroxy, alkyl, alkoxy, alkylthio, haloalkyl, and hydroxyalkyl groups; p is 1, 2 or 3; t is 1, 2 or 3; m is 1, 2, or 3, and n is 0, 1, 2 or 3; The condition is that R3 and R4 are not simultaneously methyl groups.

[0008] In some embodiments, A is C 6-10 It is an aryl group or a 5- to 10-membered heteroaryl group.

[0009] In a preferred embodiment, A is a phenyl group, a benzocycloalkyl group, or a 5-8 membered heteroaryl group containing 1, 2 or 3 N heteroatoms; In a more preferred embodiment, A is [ka] is.

[0010] In some embodiments, L is a bond, CH2.

[0011] In some embodiments, R1 and R2 are independently selected from hydrogen.

[0012] In some embodiments, R3 and R4 are independently selected from hydrogen, deuterium, halogen, amino, cyano, hydroxy, C 1-6 Alkyl group, C 1-6 Alkoxy group, C 1-6 Alkylthio group, C 1-6 Haloalkyl group, C 1-6 Haloalkenyl group, C 1-6 Hydroxyalkyl groups, deuterated C 1-6 Alkoxy group, C 1-6 Haloalkoxy group, C 3-6 Cycloalkyl groups, 4- to 10-membered heterocyclyl groups, C 6-10 Aryl group, 5- to 10-membered heteroaryl group, C 3-6 Cycloalkyloxy group, 4- to 10-membered heterocyclyloxy group, C 6-10 aryloxy groups and 5- to 10-membered heteroaryloxy groups, and optionally, 1-6 Alkyl group, C 1-6 Alkoxy group, C 1-6 Alkylthio group, C 1-6 Haloalkyl group, C 1-6 Hydroxyalkyl groups, deuterated C 1-6 Alkoxy group, C 1-6 Haloalkoxy groups are substituted with deuterium, halogen, amino, cyano, hydroxy, and C 1-6 Alkyl group, C 1-6 Alkoxy group, C 1-6 Alkylthio group, C 1-6 Haloalkyl group, C 1-6 Hydroxyalkyl group, C 3-6 Cycloalkyl groups, 4- to 10-membered heterocyclyl groups, C 6-10 It is substituted with one or more substituents selected from an aryl group and a 5- to 10-membered heteroaryl group.

[0013] In a preferred embodiment, R3 and R4 are independently deuterium, halogen, C 1-3 Alkyl group, C 1-3 Alkoxy group, deuterated C 1-3 Alkoxy group, C 1-3 Haloalkoxy group, C 3-6 Cycloalkyl groups and C 3-6 cycloalkyloxy groups, and optionally, the C 1-3 Alkyl group, C 1-3 Alkoxy group, deuterated C 1-3 Alkoxy group, C 1-3 Haloalkoxy groups are C 3-6 Cycloalkyl groups, 4- to 6-membered heterocyclyl groups, C 6-10 It is substituted with one or more substituents selected from an aryl group and a 5- to 10-membered heteroaryl group.

[0014] In some embodiments, R5 is independently hydrogen, deuterium, halogen, amino group, cyano group, hydroxy group, C 1-6 Alkyl group, C 2-6 Alkenyl group, C 2-6 Alkynyl group, C 1-6 Alkoxy group, C 1-6 Alkylthio group, C 1-6 Haloalkyl group, C 1-6 Hydroxyalkyl group, C 3-8 Cycloalkyl groups, 4- to 10-membered heterocyclyl groups, C 5-10 aryl groups and 5- to 10-membered heteroaryl groups, and optionally, 1-6 Alkyl group, C 1-6 Alkoxy group, C 1-6 Alkylthio group, C 1-6 Haloalkyl group, C 1-6 Hydroxyalkyl group, C 3-8 Cycloalkyl groups, 4- to 10-membered heterocyclyl groups, C 5-10 The aryl group and the 5- to 10-membered heteroaryl group may be substituted with deuterium, halogen, amino group, cyano group, hydroxy group, C 1-6 Alkyl group, C 1-6 Alkoxy group, C 1-6 Alkylthio group, C 1-6Haloalkyl groups and C 1-6 It is substituted with one or more substituents selected from hydroxyalkyl groups.

[0015] In some embodiments, two R5, together with the C atom to which they are attached, form a C 3-6 A cycloalkyl group or a 4- to 6-membered heterocyclyl group containing 1, 2, or 3 heteroatoms selected from N, O, or S, 3-6 The cycloalkyl group or the 4- to 6-membered heterocyclyl group may optionally be substituted with hydrogen, deuterium, halogen, amino, cyano, hydroxy, C 1-6 Alkyl group, C 1-6 Alkoxy group, C 1-6 Alkyl C 1-6 Alkoxy group, C 1-6 Alkoxy C 1-6 Alkyl group, C 1-6 Alkylthio group, C 1-6 Haloalkyl groups and C 1-6 It is substituted with one or more substituents selected from hydroxyalkyl groups.

[0016] In some embodiments, two R5 together with the C atom to which they are attached form a carbon-carbon double bond.

[0017] In some embodiments, R6 is hydrogen, deuterium, halogen, amino group, cyano group, hydroxy group, C 1-6 Alkyl group, C 1-6 Alkoxy group, C 1-6 Alkylthio group, C 1-6 Haloalkyl group, C 1-6 Hydroxyalkyl group, C 3-8 Cycloalkyl groups, 4- to 10-membered heterocyclyl groups, C 5-10 Aryl groups and 5- to 10-membered heteroaryl groups, -(CH2) r C 1-6 Alkoxy group, -(CH2) r C(O)OH, -S(O)NHC 1-6 Alkyl group, -SO2C 1-6 Alkyl group, -C(O)NHSO2C 1-6Alkyl group and -SO2NHC(O)C 1-6 The alkyl group is selected from the group consisting of:

[0018] In some embodiments, R6 is -F, -OMe, -CH2OH, -CHOCH3, -CH2F, -CF2H, -CF3, -COOH, -C(O)NHSO2CH3, -S(O)NHCH3, or a 5- to 6-membered heterocyclyl group containing 1-3 heteroatoms selected from N, O, and S, or a 5- to 6-membered heteroaryl group containing 1-3 heteroatoms selected from N, O, and S.

[0019] In some embodiments, R7 is hydrogen or C 1-3 It is an alkyl group.

[0020] In some embodiments, R9 is deuterium, halogen, amino, cyano, hydroxy, C 1-6 Alkyl group, C 1-6 Alkoxy group, C 1-6 Alkylthio group, C 1-6 Haloalkyl group, C 1-6 Hydroxyalkyl group, C 3-8 It is selected from the group consisting of cycloalkyl groups and 4-10 membered heterocyclyl groups containing 1, 2 or 3 heteroatoms selected from N, O or S.

[0021] In a preferred embodiment, R9 is selected from the group consisting of deuterium, halogen, amino, cyano, hydroxy, C 1-3 Alkyl group, C 1-6 Alkoxy group, C 1-3 Alkylthio group, C 1-3 Haloalkyl group, C 1-3 Hydroxyalkyl group, C 3-6 It is selected from the group consisting of cycloalkyl groups and 4-6 membered heterocyclyl groups containing 1, 2 or 3 heteroatoms selected from N, O or S.

[0022] In a more preferred embodiment, R9 is selected from the group consisting of deuterium, halogen, amino, cyano, hydroxy, methyl, ethyl, cyclopropyl, and cyclobutyl.

[0023] In some embodiments, R9, together with one of R6, is a saturated or unsaturated C 3-7 A cycloalkyl group or a saturated or unsaturated 3- to 7-membered heterocyclyl group containing 1, 2 or 3 heteroatoms selected from N, O or S, optionally comprising the C 3-7 The cycloalkyl group or the 3- to 7-membered heterocyclyl group may be selected from the group consisting of hydrogen, deuterium, halogen, amino group, cyano group, hydroxy group, C 1-6 Alkyl group, C 1-6 Alkoxy group, C 1-6 Alkylalkoxy group, C 1-6 Alkoxyalkyl group, C 1-6 Alkylthio group, C 1-6 Haloalkyl groups and C 1-6 hydroxyalkyl groups, and another R6 is hydrogen, deuterium, halogen, amino group, cyano group, hydroxy group, C 1-3 Alkyl group, C 1-6 Alkoxy group, C 1-6 Alkylthio group, C 1-6 Haloalkyl group, C 1-6 Hydroxyalkyl group, C 3-8 Cycloalkyl groups, 4- to 10-membered heterocyclyl groups, C 5-10 Aryl groups and 5- to 10-membered heteroaryl groups, -(CH2) r C 1-6 Alkoxy group, -(CH2) r C(O)OH, -S(O)NHC 1-6 Alkyl group, -SO2C 1-6 Alkyl group, -C(O)NHSO2C 1-6 Alkyl group and -SO2NHC(O)C 1-6 alkyl groups,

[0024] In a more preferred embodiment, R9 together with one of R6 is a saturated or unsaturated C 4-6A cycloalkyl group or a saturated or unsaturated 4- to 7-membered heterocyclyl group containing 1, 2 or 3 heteroatoms selected from N, O or S, optionally forming the saturated or unsaturated C 4-6 The cycloalkyl group or saturated or unsaturated 4- to 7-membered heterocyclyl group may be selected from the group consisting of hydrogen, deuterium, halogen, amino group, cyano group, hydroxy group, C 1-3 Alkyl group, C 1-3 Alkoxy group, C 1-3 Alkylalkoxy group, C 1-3 Alkoxyalkyl group, C 1-3 Alkylthio group, C 1-3 Haloalkyl groups and C 1-3 hydroxyalkyl groups, and another R6 is selected from the group consisting of F, -OMe, -CH2OH, -CH2OCH3, -CH2F, -CF2H, -CF3, -COOH, -C(O)NHSO2CH3, and -S(O)NHCH3.

[0025] In one preferred embodiment, the compound having the structure represented by Formula (I) may be a compound having the structure represented by Formula (II), or a tautomer, cis or trans isomer, meso isomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt, solvate, or prodrug thereof. [ka]

[0026] In one preferred embodiment, the compound having the structure of Formula (I) may be a compound having the structure of Formula (III-a)-(III-b), or a tautomer, cis or trans isomer, meso isomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, [ka] where: X is CR c R d , N.R.e , O or S; [ka] is a single or double bond, R c , R d and R e are independently hydrogen, deuterium, halogen, amino group, cyano group, hydroxy group, C 1-6 Alkyl group, C 1-6 Alkoxy group, C 1-6 Alkylthio group, C 1-6 Haloalkyl group, C 1-6 Hydroxyalkyl group, C 3-8 Cycloalkyl groups, C 3-8 Heterocyclyl group, C 6-10 Aryl groups and C 6-10 heteroaryl groups; Preferably, R c , R d and R e are independently hydrogen, deuterium, halogen, amino group, cyano group, hydroxy group, C 1-3 Alkyl group, C 1-3 Alkoxy group, C 1-3 Alkylthio group, C 1-3 Haloalkyl group, C 1-3 Hydroxyalkyl group, C 3-6 Cycloalkyl groups, C 4-6 Heterocyclyl group, C 6-10 Aryl groups and C 6-10 heteroaryl groups; Preferably, R c , R d and R e are independently selected from the group consisting of hydrogen, deuterium, halogen, amino group, cyano group, hydroxy group, methyl group, and ethyl group; v is 0, 1, 2 or 3;

[0027] In one preferred embodiment, the compound having the structure of Formula (I) may be a compound having the structure of Formula (IV-a)-(IV-f), or a tautomer, cis or trans isomer, meso isomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, [ka] where: E is [ka] and R 10 is a deuterium, halogen, amino group, cyano group, hydroxy group, C 1-3 Alkyl group, C 2-4 Alkenyl group, C 2-4 Alkynyl group, C 1-3 Alkoxy group, C 1-3 Alkyl C 1-3 Alkoxy group, C 1-3 Alkoxy C 1-3 Alkyl group, C 1-3 Alkylthio group, C 1-3 Haloalkyl groups and C 1-3 hydroxyalkyl groups, n is 1, and z is 0, 1, 2 or 3.

[0028] In one preferred embodiment, [ka] teeth, [ka] is.

[0029] In one preferred embodiment, the compound having the structure of Formula (I) may be a compound having the structure of Formula (Va)-(Vb), or a tautomer, cis or trans isomer, meso isomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, [ka] where: M is O or CR f R g and R f and R g are independently hydrogen, halogen and C 1-3 alkyl groups, Preferably, R f and R g are independently selected from hydrogen and fluorine; q is 1, 2 or 3, and s is 0, 1, or 2.

[0030] In one preferred embodiment, the compound having the structure of Formula (I) may be a compound having the structure of Formula (VI-a)-(VI-l), or a tautomer, cis or trans isomer, meso isomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, [ka]

[0031] In one preferred embodiment, [ka] teeth, [ka] where: [ka] teeth, [ka] is.

[0032] The present invention further provides pharmaceutical compositions, which include a therapeutically effective amount of a compound having a structure represented by any of Formulas (I)-(VII-f), or a tautomer or pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers, diluents, or excipients.

[0033] In some embodiments, in the pharmaceutical composition, the amount of the compound, its tautomer, cis or trans isomer, meso isomer, racemate, enantiomer, diastereomer, or mixture, or a pharmaceutically acceptable salt thereof, is about 0.1% to 95% by weight of the free base, preferably about 5% to 70%, e.g., 70%, 65%, 60%, 55%, 50%, 45%, 40%, 35%, 30%, 25%, 20%, 15%, 10%, or 5%.

[0034] In some embodiments, the pharmaceutical composition is prepared in tablet, capsule, liquid form, or injectable form.

[0035] In some embodiments, in the pharmaceutical composition, the amount of the compound, its tautomer, cis or trans isomer, meso isomer, racemate, enantiomer, diastereomer, or mixture, or a pharmaceutically acceptable salt thereof, is about 1 to 1000 mg, preferably about 1 to 500 mg, and 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.

[0036] In some embodiments, the compound, its tautomer, cis or trans isomer, meso isomer, racemate, enantiomer, diastereomer, or mixture, or a pharmaceutically acceptable salt thereof, can be administered by any suitable route of administration, for example, oral, parenteral, buccal, sublingual, nasal, rectal, intrathecal, or transdermal, and the pharmaceutical composition is adjusted accordingly.

[0037] In some embodiments, the compound, its tautomer, cis or trans isomer, meso isomer, racemate, enantiomer, diastereomer, or mixture, or a pharmaceutically acceptable salt, is prepared in solid or liquid form, for example, a syrup, suspension, emulsion, tablet, capsule, powder, granule, or lozenge.

[0038] In another aspect, the invention relates to a method for modulating alternative complement pathway activity, comprising administering to a subject in need thereof an effective amount of a compound having a structure represented by any of Formulas (I)-(VI-f) or a pharmaceutical composition comprising the same.

[0039] In another aspect, the invention relates to a method of treating a disorder or disease mediated by complement activation, particularly alternative complement pathway activation, in a subject, comprising administering to a subject in need thereof an effective amount of a compound having a structure represented by any of Formulas (I)-(VI-f) or a pharmaceutical composition comprising same.

[0040] In a preferred embodiment, the disease or disorder is age-related macular degeneration, geographic atrophy, diabetic retinopathy, uveitis, retinitis pigmentosa, macular edema, uveitis due to Behcet's disease, multifocal choroiditis, Vogt-Koyanagi-Harada syndrome, intermediate uveitis, shotgun retinochoroiditis, sympathetic ophthalmia, ocular cicatricial pemphigoid, ocular pemphigus, non-arteritic ischemic optic neuropathy, postoperative inflammation, retinal vein occlusion, neuropathy, multiple sclerosis, stroke, Guillain-Barré syndrome, traumatic brain injury, Parkinson's disease, disorders of inappropriate or unwanted complement activation, hemodialysis complications, hyperacute allograft rejection, xenograft rejection, interleukin-2 induced toxicity during IL-2 therapy, inflammatory disorders, inflammation in autoimmune diseases, Crohn's disease, adult respiratory distress syndrome, myocarditis, post-ischemic reperfusion blood flow obstruction, myocardial infarction, balloon angioplasty, post-pump syndrome in cardiopulmonary bypass or renal bypass, atherosclerosis, hemodialysis, renal ischemia, mesenteric artery reperfusion after aortic reconstruction, infection 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, fibrosing dust diseases, pulmonary fibrosis, asthma, allergy, bronchoconstriction, hypersensitivity pneumonitis, parasitic diseases, Goodpasture's syndrome, pulmonary vasculitis, vasculitis microimmunity, immune complex-associated inflammation, antiphospholipid syndrome, glomerulonephritis, and obesity. DETAILED DESCRIPTION OF THE INVENTION

[0041] Various publications, articles, and patents are cited or described throughout the specification; each of these references is incorporated herein by reference in its entirety. Any discussion of documents, acts, materials, devices, products, or the like which has been included in the present specification is for the purpose of providing a context for the present disclosure. Such discussion is not an admission that any or all of those matters form part of the prior art with respect to the present disclosure.

[0042] The following provides definitions of terms used in this application. Any term not defined herein will adopt the ordinary meaning as understood by one of ordinary skill in the art.

[0043] "Alkyl group" means C1-C 20It refers to saturated aliphatic hydrocarbon groups, including straight-chain and branched-chain groups. Preferably, the alkyl group is an alkyl group having 1 to 12, sometimes preferably 1 to 6, sometimes more preferably 1 to 4 carbon atoms. Representative examples include a methyl group, an ethyl group, an n-propyl group, an isopropyl group, an n-butyl group, an isobutyl group, a tert-butyl group, a sec-butyl group, an n-pentyl group, a 1,1-dimethylpropyl group, a 1,2-dimethylpropyl group, a 2,2-dimethylpropyl group, a 1-ethylpropyl group, a 2-methylbutyl group, a 3-methylbutyl group, an n-hexyl group, a 1-ethyl-2-methylpropyl group, a 1,1,2-trimethylpropyl group, a 1,1-dimethylbutyl group, a 1,2-dimethylbutyl group, a 2,2-dimethylbutyl group, a 1,3-dimethylbutyl group, a 2-ethylbutyl group, a 2-methylpentyl group, a 3-methylpentyl group, a 4-methylpentyl group, a 2,3-dimethylbutyl group, an n-heptyl group, a 2-methylhexyl group, a 3-methylhexyl group, a 4-methylhexyl group, a 5-methylhexyl group, a 2 ,3-dimethylpentyl group, 2,4-dimethylpentyl group, 2,2-dimethylpentyl group, 3,3-dimethylpentyl group, 2-ethylpentyl group, 3-ethylpentyl group, n-octyl group, 2,3-dimethylhexyl group, 2,4-dimethylhexyl group, 2,5-dimethylhexyl group, 2,2-dimethylhexyl group, 3,3-dimethylhexyl group, 4,4-dimethylhexyl group, 2-ethylhexyl group

[0033] The alkyl group includes, but is not limited to, 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. Alkyl groups may be substituted or unsubstituted. When substituted, the one or more substituents may be substituted at any available point of attachment, and preferably the one or more substituents are independently one or more substituents selected from the group consisting of alkyl groups, halogens, alkoxy groups, alkenyl groups, alkynyl groups, alkylsulfonic acid groups, alkylamino groups, thiol, hydroxy groups, nitro groups, cyano groups, amino groups, cycloalkyl groups, heterocycloalkyl groups, aryl groups, heteroaryl groups, cycloalkoxy groups, heterocyclyl groups, cycloalkylthio groups, heterocycloalkylthio groups, and oxo groups.

[0044] The term "alkenyl group" refers to an alkyl group having at least two carbon atoms and at least one carbon-carbon double bond as defined above, such as a vinyl group, a 1-propenyl group, a 2-propenyl group, a 1-, 2- or 3-butenyl group, and preferably C 2-20 alkenyl group, more preferably C 2-12 alkenyl groups, most preferably C 2-6It is an alkenyl group. The alkenyl group may be substituted or unsubstituted. When substituted, the one or more substituents are preferably one or more, in some cases preferably 1 to 5, and in some cases more preferably 1 to 3 groups, and these groups are independently selected from the group consisting of alkyl groups, halogens, alkoxy groups, alkenyl groups, alkynyl groups, alkylsulfonic acid groups, alkylamino groups, thiol, hydroxy groups, nitro groups, cyano groups, amino groups, cycloalkyl groups, heterocycloalkyl groups, aryl groups, heteroaryl groups, cycloalkoxy groups, heterocyclyl groups, cycloalkylthio groups, heterocycloalkylthio groups, and oxo groups.

[0045] The term "alkynyl group" refers to an alkyl group having at least two carbon atoms and at least one carbon-carbon triple bond as defined above, such as an ethynyl group, a 1-propynyl group, a 2-propynyl group, a 1-, 2- or 3-butynyl group, and preferably C 2-20 Alkynyl groups, more preferably C 2-12 Alkynyl groups, most preferably C 2-6 It is an alkynyl group. The alkynyl group may be substituted or unsubstituted. When substituted, the one or more substituents are preferably one or more, in some cases preferably 1 to 5, and in some cases more preferably 1 to 3 groups, and the groups are independently selected from the group consisting of alkyl groups, alkenyl groups, alkynyl groups, alkoxy groups, alkylsulfonic acid groups, alkylamino groups, halogens, thiol, hydroxy groups, nitro groups, cyano groups, cycloalkyl groups, heterocycloalkyl groups, aryl groups, heteroaryl groups, cycloalkoxy groups, heterocycloalkoxy groups, cycloalkylthio groups, and heterocycloalkylthio groups.

[0046] An "alkylene group" is a saturated, straight- or branched-chain 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. Straight- or branched-chain groups containing 1 to 20 carbon atoms preferably have 1 to 12 carbon atoms, more preferably 1 to 6 carbon atoms. Non-limiting examples of alkylene groups include, but are not limited to, methylene (-CH-), 1,1-ethylene (-CH(CH)-), 1,2-ethylene (-CHCH-), 1,1-propylene (-CH(CHCH)-), 1,2-propylene (-CHCH(CH)-), 1,3-propylene (-CHCHCH-), 1,4-butylene (-CHCHCHCHCH-), and the like. Alkylene groups may be substituted or unsubstituted. When substituted, the one or more substituents are preferably one or more, in some cases preferably 1 to 5, and in some cases more preferably 1 to 3 groups, which are independently selected from the group consisting of alkyl groups, alkenyl groups, alkynyl groups, alkoxy groups, alkylsulfonic acid groups, alkylamino groups, halogens, thiol, hydroxy groups, nitro groups, cyano groups, cycloalkyl groups, heterocycloalkyl groups, aryl groups, heteroaryl groups, cycloalkoxy groups, heterocycloalkoxy groups, cycloalkylthio groups, and heterocycloalkylthio groups.

[0047] An "alkenylene group" is an alkylene group having at least two carbon atoms and at least one carbon-carbon double bond as defined above, and preferably C 2-20 alkenylene group, more preferably C 2-12 alkenylene group, most preferably C 2-6It is an alkenylene group. Non-limiting examples of alkenylene groups include, but are not limited to, -CH=CH-, -CH=CHCH2-, -CH=CHCH2CH2-, -CH2CH=CHCH2-, and the like. The alkenylene group may be substituted or unsubstituted. When substituted, the one or more substituents are preferably one or more, sometimes preferably 1 to 5, sometimes more preferably 1 to 3 groups, and the groups are independently selected from the group consisting of alkyl groups, alkenyl groups, alkynyl groups, alkoxy groups, alkylsulfonic acid groups, alkylamino groups, halogens, thiol, hydroxy groups, nitro groups, cyano groups, cycloalkyl groups, heterocycloalkyl groups, aryl groups, heteroaryl groups, cycloalkoxy groups, heterocycloalkoxy groups, cycloalkylthio groups, and heterocycloalkylthio groups.

[0048] An "alkynylene group" is an alkynyl group having at least two carbon atoms and at least one carbon-carbon triple bond as defined above, preferably C 2-20 Alkynylene group, more preferably C 2-12 Alkynylene groups, most preferably C 2-6 It is an alkynylene group. Non-limiting examples of alkenylene groups include, but are not limited to, -CH≡CH-, -CH≡CHCH2-, -CH≡CHCH2CH2-, -CH2CH≡CHCH2-, and the like. The alkynylene group may be substituted or unsubstituted. When substituted, the one or more substituents are preferably one or more, sometimes preferably 1 to 5, sometimes more preferably 1 to 3 groups, and the groups are independently selected from the group consisting of alkyl groups, alkenyl groups, alkynyl groups, alkoxy groups, alkylsulfonic acid groups, alkylamino groups, halogens, thiol, hydroxy groups, nitro groups, cyano groups, cycloalkyl groups, heterocycloalkyl groups, aryl groups, heteroaryl groups, cycloalkoxy groups, heterocycloalkoxy groups, cycloalkylthio groups, and heterocycloalkylthio groups.

[0049] A "cycloalkyl group" is a saturated and / or partially unsaturated monocyclic or polycyclic hydrocarbon group having 3 to 20 carbon atoms, preferably 3 to 12 carbon atoms, more preferably 3 to 10 carbon atoms, and most preferably 3 to 8 carbon atoms or 3 to 6 carbon atoms. Representative examples of monocyclic cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cycloheptatrienyl, cyclooctyl, and the like. Polycyclic cycloalkyl groups include cycloalkyl groups having spiro rings, fused rings, or bridged rings.

[0050] A "spirocycloalkyl group" is a 5- to 20-membered polycyclic group in which the rings are connected by one common carbon atom (called a spiro atom), and one or more rings may contain one or more double bonds, but no ring has a completely conjugated π-electron system. Preferably, the spirocycloalkyl group has 6 to 14 members, more preferably 7 to 10 members, and most preferably 7 to 8 members. Depending on the number of common spiro atoms, the spirocycloalkyl group is divided into a monospirocycloalkyl group, a bisspirocycloalkyl group, or a polyspirocycloalkyl group, and is preferably a monospirocycloalkyl group or a bisspirocycloalkyl group, and more preferably a 4-membered / 4-membered, 4-membered / 5-membered, 4-membered / 6-membered, 5-membered / 5-membered, or 5-membered / 6-membered monospirocycloalkyl group. Representative examples of spirocycloalkyl groups include: [ka] The substituents include, but are not limited to:

[0051] A "fused cycloalkyl group" is a 5- to 20-membered polycyclic hydrocarbon group, in which each ring in the system shares an adjacent pair of carbon atoms with another ring, and in which 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 group has 6 to 14 members, more preferably 7 to 10 members, and most preferably 7 to 8 members. Depending on the number of ring members, the fused cycloalkyl group is divided into bicyclic, tricyclic, tetracyclic, or polycyclic fused cycloalkyl groups, and is preferably a bicyclic or tricyclic fused cycloalkyl group, more preferably a 5-membered / 5-membered or 5-membered / 6-membered bicyclic fused cycloalkyl group. Representative examples of fused cycloalkyl groups include: [ka] The substituents include, but are not limited to:

[0052] A "bridged cycloalkyl group" is a 5- to 20-membered polycyclic hydrocarbon group in which every two rings in the system share two unlinked 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 group has 6 to 14 members, more preferably 7 to 10 members, and most preferably 7 to 8 members. Depending on the number of ring members, the bridged cycloalkyl group is divided into bicyclic, tricyclic, tetracyclic, or polycyclic bridged cycloalkyl groups, and is preferably a bicyclic, tricyclic, or tetracyclic bridged cycloalkyl group, more preferably a bicyclic or tricyclic bridged cycloalkyl group. Representative examples of bridged cycloalkyl groups include: [ka] The substituents include, but are not limited to:

[0053] A cycloalkyl group may be fused to the ring of an aryl group, heteroaryl group, or heterocycloalkyl group, where the ring attached to the parent structure is the cycloalkyl group. Representative examples are indane, cycloalkyl groups, and cycloalkyl groups. Examples of cycloalkyl groups include, but are not limited to, cyclohexane, tetrahydronaphthalene, benzocycloheptyl, and the like. The cycloalkyl group is optionally substituted or unsubstituted. When substituted, the one or more substituents are preferably one or more, and in some cases preferably 1 to 5, and in some cases more preferably 1 to 3, and these substituents are independently selected from the group consisting of alkyl groups, halogens, alkoxy groups, alkenyl groups, alkynyl groups, alkylsulfonic acid groups, alkylamino groups, thiol, hydroxy groups, nitro groups, cyano groups, amino groups, cycloalkyl groups, heterocycloalkyl groups, aryl groups, heteroaryl groups, cycloalkoxy groups, heterocyclyl groups, cycloalkylthio groups, heterocycloalkylthio groups, and oxo groups. Representative examples are: [ka] The substituents include, but are not limited to:

[0054] A "heterocyclyl group" is a 3- to 20-membered saturated and / or partially unsaturated monocyclic or polycyclic hydrocarbon group, which may have one or more, optionally preferably 1 to 5, and optionally more preferably N, O, and S(O) m (where m is 0, 1, or 2), the ring atoms are 1 to 3 heteroatoms selected from the group consisting of -OO-, -OS-, or -SS-, and the remaining ring atoms are C. Preferably, the heterocyclyl group is a 3- to 12-membered heterocyclyl group having 1 to 4 heteroatoms, more preferably a 3- to 10-membered heterocyclyl group having 1 to 3 heteroatoms, and most preferably a 5- or 6-membered heterocyclyl group having 1 to 2 heteroatoms. Representative examples of monocyclic heterocyclyl groups include, but are not limited to, a pyrrolidinyl group, a piperidine group, a piperazinyl group, a morpholinyl group, a sulfonate-morpholinyl group, a homopiperazinyl group, and the like. Polycyclic heterocyclyl groups include heterocyclyl groups having a spiro ring, a fused ring, or a bridged ring.

[0055] A "spiroheterocyclyl group" is a 5- to 20-membered polycyclic heterocyclyl group, in which the rings are joined by one common carbon atom (called a spiroatom), and wherein the rings may be one or more, optionally preferably 1 to 5, and optionally more preferably N, O, and S(O). m (where m is 0, 1, or 2), and the remaining ring atoms are C, where 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 spiroheterocyclyl group has 6 to 14 members, more preferably 7 to 10 members, and most preferably 7 to 8 members. Depending on the number of common spiro atoms, the spiroheterocyclyl group is divided into a monospiroheterocyclyl group, a bisspiroheterocyclyl group, or a polyspiroheterocyclyl group, and is preferably a monospiroheterocyclyl group or a bisspiroheterocyclyl 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 monospiroheterocyclyl group. Representative examples of spiroheterocyclyl groups include: [ka] The substituents include, but are not limited to:

[0056] A "fused heterocyclyl group" is a 5- to 20-membered polycyclic heterocyclyl group, in which each ring in the system shares an adjacent pair of carbon atoms with another ring, in which one or more rings may contain one or more double bonds, but in which no ring has a completely conjugated pi-electron system, and in which the rings are one or more, optionally preferably 1 to 5, and optionally more preferably N, O, and S(O) p(wherein p is 0, 1 or 2), and the remaining ring atoms are C. Preferably, the fused heterocyclyl group has 6 to 14 ring members, more preferably 7 to 10 ring members, and most preferably 7 to 8 ring members. Depending on the number of ring members, the fused heterocyclyl group is divided into bicyclic, tricyclic, tetracyclic or polycyclic fused heterocyclyl groups, preferably bicyclic or tricyclic fused heterocyclyl groups, more preferably 5-membered / 5-membered or 5-membered / 6-membered bicyclic fused heterocyclyl groups. Representative examples of fused heterocyclyl groups are: [ka] The substituents include, but are not limited to:

[0057] A "bridged heterocyclyl group" is a 5- to 14-membered polycyclic heterocycloalkyl group, in which every two rings in the system share two non-linking atoms, the rings may have one or more double bonds but do not have a completely conjugated pi-electron system, and the rings are not heterocyclic, and ... m (where m is 0, 1 or 2), and the remaining ring atoms are C. Preferably, the bridged heterocyclyl group has 6 to 14 ring members, more preferably 7 to 10 ring members, and most preferably 7 to 8 ring members. Depending on the number of ring members, the bridged heterocyclyl group is divided into bicyclic, tricyclic, tetracyclic or polycyclic bridged heterocyclyl groups, and is preferably a bicyclic, tricyclic or tetracyclic bridged heterocyclyl group, more preferably a bicyclic or tricyclic bridged heterocyclyl group. Representative examples of bridged heterocyclyl groups include: [ka] The substituents include, but are not limited to:

[0058] The ring of the heterocyclyl group may be fused to the ring of an aryl group, heteroaryl group, or cycloalkyl group, where the ring attached to the parent structure is the heterocyclyl group. Representative examples are: [ka] The substituents include, but are not limited to, the following:

[0059] The heterocyclyl group is optionally substituted or unsubstituted. When substituted, the one or more substituents are preferably one or more, optionally preferably 1 to 5, optionally more preferably 1 to 3 groups, independently selected from the group consisting of alkyl groups, alkenyl groups, alkynyl groups, alkoxy groups, alkylsulfonic acid groups, alkylamino groups, halogens, thiol, hydroxy groups, nitro groups, cyano groups, cycloalkyl groups, heterocycloalkyl groups, aryl groups, heteroaryl groups, cycloalkoxy groups, heterocycloalkoxy groups, cycloalkylthio groups, heterocyclyl groups, and alkylthio groups.

[0060] An "aryl group" is a 6- to 14-membered all-carbon monocyclic or polycyclic fused ring (a "fused" ring system means that each ring in the system shares an adjacent pair of 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-membered, such as phenyl and naphthyl groups, and most preferably phenyl groups. An aryl group may be fused to a ring of a heteroaryl group, heterocyclyl group, or cycloalkyl group, where the ring attached to the parent structure is an aryl group. Representative examples are: [ka] The substituents include, but are not limited to:

[0061] The aryl group may be substituted or unsubstituted. When substituted, the number of substituents is preferably one or more, in some cases preferably 1 to 5, and in some cases more preferably 1 to 3, and these substituents are independently selected from the group consisting of alkyl groups, alkenyl groups, alkynyl groups, alkoxy groups, alkylsulfonic acid groups, alkylamino groups, halogens, thiol, hydroxy groups, nitro groups, cyano groups, cycloalkyl groups, heterocycloalkyl groups, aryl groups, heteroaryl groups, cycloalkoxy groups, heterocycloalkoxy groups, cycloalkylthio groups, heterocyclyl groups, and alkylthio groups.

[0062] A "heteroaryl group" is an aryl system having 1 to 4 heteroatoms selected from the group consisting of O, S, and N as ring atoms, and having 5 to 14 ring atoms. Preferably, the heteroaryl group is 5 to 10-membered, more preferably 5 or 6-membered, such as thiadiazolyl, pyrazolyl, oxazolyl, oxadiazolyl, imidazolyl, triazolyl, thiazolyl, furyl, thienyl, pyridyl, pyrrolyl, N-alkylpyrrolyl, pyrimidinyl, pyrazinyl, imidazolyl, tetrazolyl, isoxazolyl, and the like. Heteroaryl groups may be fused with a ring of an aryl, heterocyclyl, or cycloalkyl group, where the ring attached to the parent structure is the heteroaryl group. Representative examples include: [ka] The substituents include, but are not limited to:

[0063] The heteroaryl group may be substituted or unsubstituted. When substituted, the number of substituents is preferably one or more, in some cases preferably 1 to 5, and in some cases more preferably 1 to 3, and these substituents are independently selected from the group consisting of alkyl groups, alkenyl groups, alkynyl groups, alkoxy groups, alkylsulfonic acid groups, alkylamino groups, halogens, thiol, hydroxy groups, nitro groups, cyano groups, cycloalkyl groups, heterocycloalkyl groups, aryl groups, heteroaryl groups, cycloalkoxy groups, heterocycloalkoxy groups, cycloalkylthio groups, and heterocycloalkylthio groups.

[0064] The term "alkoxy group" refers to an -O-(alkylyl) or -O-(unsubstituted cycloalkylyl) group, where the alkyl group is as defined above. Representative examples include, but are not limited to, a methoxy group, an ethoxy group, a propoxy group, a butoxy group, a cyclopropoxy group, a cyclobutoxy group, a cyclopentyloxy group, a cyclohexyloxy group, and the like. The alkoxy group may be substituted or unsubstituted. When substituted, the substituents are preferably one or more, in some cases preferably 1 to 5, and in some cases more preferably 1 to 3, and these substituents are independently selected from the group consisting of alkyl groups, alkenyl groups, alkynyl groups, alkoxy groups, alkylsulfonic acid groups, alkylamino groups, halogens, thiol, hydroxy groups, nitro groups, cyano groups, cycloalkyl groups, heterocycloalkyl groups, aryl groups, heteroaryl groups, cycloalkoxy groups, heterocycloalkoxy groups, cycloalkylthio groups, and heterocycloalkylthio groups.

[0065] A "haloalkoxy group" is an alkoxy group substituted with one or more halogens, where alkoxy is as defined above.

[0066] The hydrogen atoms of the present invention may be substituted with their isotopes, deuterium. Any hydrogen atom in the example compounds of the present invention may be substituted with a deuterium atom.

[0067] A "bond" is a covalent bond and is represented by the symbol "-".

[0068] A "hydroxyalkyl group" is an alkyl group substituted with a hydroxy group, where alkyl is as defined above.

[0069] A "hydroxyl" or "hydroxy" is an --OH group.

[0070] "Halogen" or "halogenated" refers to a fluorine, chlorine, bromine, or iodine atom.

[0071] An "amino group" is an -NH2 group.

[0072] A "cyano group" is a -CN group.

[0073] A "nitro group" is a -NO2 group.

[0074] An "oxo group" is a =O group.

[0075] A "carboxyl group" is a -C(O)OH group.

[0076] An "alkoxycarbonyl group" is a -C(O)O (alkylyl) or (cycloalkylyl) group, where the alkyl and cycloalkyl groups are as defined above.

[0077] When groups or substituents are stated to be "independently selected from" a list of choices (and variations thereof), 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 terms "A and B are independently selected from a and b" or "A and B are each independently selected from a and b" are intended to cover the choices 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.

[0078] "Optionally" or "optionally" means that the subsequently described event or circumstance may, but does not necessarily, occur, and the statement includes both cases where the event or circumstance may occur and cases where it does not occur. For example, "a heterocyclyl group optionally substituted with an alkyl group" means that the alkyl group may, but does not necessarily, be present, and the statement includes cases where the heterocyclyl group is substituted with an alkyl group and cases where the heterocyclyl group is not substituted with an alkyl group.

[0079] "Substituted" means that one or more hydrogen members of a group are independently replaced with a corresponding number of substituents. In some embodiments, the number of such hydrogen members is up to 5. In other embodiments, it is 1 to 3. Needless to say, substituents are present only in their possible chemical positions. Those skilled in the art can determine whether substitution is possible without undue effort by experiment or theory. For example, the combination of an amino group or hydroxy group having free hydrogen with a carbon atom having an unsaturated bond (e.g., an olefin) may be unstable.

[0080] A "pharmaceutical composition" is a mixture of one or more compounds according to the present invention or physiologically / pharmaceutically acceptable salts or prodrugs thereof with other chemical components, such as physiologically / pharmaceutically acceptable carriers and excipients. The purpose of a pharmaceutical composition is to facilitate administration of the compound to an organism and favor absorption of the active ingredient, thereby exerting its biological activity.

[0081] A "pharmaceutically acceptable salt" is a salt of a compound of the present invention, which salt is safe and effective when used in mammals and possesses the relevant biological activity. [Example]

[0082] The following examples are intended to illustrate the present invention, but should not be construed as limiting the scope of the present invention. Unless specific conditions are specified for experimental methods in the examples of the present invention, conventional conditions or those recommended by the manufacturers of raw materials and products are generally followed. Any reagents for which a specific source is not specified are commonly available commercially.

[0083] The structure of each compound is identified by nuclear magnetic resonance (NMR) and / or mass spectrometry (MS). The NMR chemical displacements (δ) are within the range of 10 -6 The NMR spectra are given in ppm. NMR was measured on a Varian Mercury 300 MHz and a Bruker Avance III 400 MHz instrument. The solvents used were deuterated dimethyl sulfoxide (DMSO-d6), deuterated chloroform (CDCl3), and deuterated methanol (CD3OD).

[0084] High-performance liquid chromatography (HPLC) was performed on an Agilent 1200DAD high-pressure liquid chromatograph (Sunfire C18 150 × 4.6 mm chromatographic column) and a Waters 2695-2996 high-pressure liquid chromatograph (Gimini C18 150 × 4.6 mm chromatographic column). Liquid chromatography-mass spectrometry (LCMS) was performed on an Agilent 1200 high-pressure liquid chromatograph-mass spectrometer (Sunfire C18 4.6 × 50 mm 3.5 μm chromatographic column) and an Agilent 19091S-433 HP-5 high-pressure liquid chromatograph-mass spectrometer (XBridge C18 4.6 × 50 mm 3.5 μm chromatographic column).

[0085] Chiral high performance liquid chromatography (HPLC) was performed on an SFC Thar 80&150&200 (Waters).

[0086] Mean rate of ATPase inhibition and IC 50 Values ​​are measured with a Victor Nivo multimodal reader (PerkinElmer, USA).

[0087] The thin-layer silica gel plates used in thin-layer chromatography are Yantai Xinnuo silica gel plates. The size of the plates used in TLC is 0.15mm to 0.2mm, and the size of the plates used in thin-layer chromatography for product purification is 0.4mm to 0.5mm.

[0088] Column chromatography generally uses 200-300 mesh silica gel from Qingdao Haiyang as the carrier.

[0089] The known starting materials of the present invention can be prepared by common synthetic methods in the prior art or may be purchased from sources such as ABCR GmbH & Co. KG, Acros Organics, Aldrich Chemical Company, Accela ChemBio Inc. or Dari Chemical Company.

[0090] Unless otherwise stated in the examples, all of the following reactions are carried out under an argon or nitrogen gas atmosphere.

[0091] The term "argon atmosphere" or "nitrogen gas atmosphere" refers to a reaction flask equipped with a balloon containing 1 L of argon or nitrogen gas.

[0092] The term "hydrogen gas atmosphere" refers to a reaction flask equipped with a balloon containing 1 L of hydrogen gas.

[0093] MS is mass spectrometry, where (+) is the positive pattern, usually giving M+1 (or M+H) absorption, where M=molecular mass.

[0094] Synthesis Procedure: Procedure for the synthesis of tert-butyl 4-(chloromethyl)-5-methoxy-7-methyl-1H-indole-1-carboxylate (Int A) [ka]

[0095] At room temperature under nitrogen gas, (chloromethylene)dimethylimiclolide (711 mg, 5.56 mmol) was added in one portion to a solution of tert-butyl 4-(hydroxymethyl)-5-methoxy-7-methyl-1H-indole-1-carboxylate (CAS: 1644667-10-6 - 950 mg, 3.45 mmol) in CHCl (10 mL), and the mixture was stirred at this temperature for 2 h. The reaction mixture was cooled to 0 °C and quenched with 5% aqueous NaHCO. The mixture was extracted with CHCl (3 × 20 mL). The combined organic layers were washed with brine (20 mL), dried over anhydrous NaSO, filtered, and concentrated. The crude product, tert-butyl 4-(chloromethyl)-5-methoxy-7-methyl-1H-indole-1-carboxylate (Int A, 900 mg), was obtained as a yellow oil. LCMS (m / z): [M-Cl] + C 16 H 20 Calculated value for NO3: 274.1; measured value: 274.1.

[0096] Synthetic procedure for 3,3-difluoro-1'-((5-methoxy-7-methyl-1H-indol-4-yl)methyl)-2'',3''-dihydrodispiro[cyclobutane-1,4'-piperidine-2',1''-indene]-5''-carboxylic acid [ka]

[0097] Step 1 A solution of methyl 1-oxo-2,3-dihydro-1H-indene-5-carboxylate (750 mg, 3.94 mmol), 3-((trimethylsilyl)-methyl)butan-3-en-1-amine (1.12 g, 7.10 mmol), and AcOH (355 mg, 5.91 mmol) in MeOH was stirred at 50 °C for 40 h. The reaction mixture was neutralized with saturated NaHCO solution and extracted with DCM (50 mL × 3). The combined organic layer was washed with brine (50 mL), dried over anhydrous NaSO, 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+).

[0098] Step 2 Cbz-Cl (815 mg, 4.78 mmol) was added dropwise to a stirred solution of methyl 4'-methylene-2,3-dihydrospiro[indene-1,2'-piperidine]-5-carboxylate (820 mg, 3.19 mmol) and K2CO3 (1.32 g, 9.56 mmol) in THF (10 mL) at 0 °C under nitrogen gas. The reaction mixture was stirred at 25 °C for 16 h. The reaction mixture was quenched with NaHCO3 solution (30 mL) and extracted with EtOAc (30 mL x 3). 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+).

[0099] Step 3 Trichloroacetyl chloride (4.4 g, 24 mmol, 10 equiv.) was added to a suspension of Cu-Zn (3.5 g, 3% Cu) and methyl 4'-methylene-2,3-dihydrospiro[indene-1,2'-piperidine]-1',5-dicarboxylate (b, 1.0 g, 2.4 mmol, 1.0 equiv.) in dioxane (20 mL, 20 V) at 20 °C under a nitrogen atmosphere within 30 min. The mixture was heated to 35 °C and maintained for 3 h. The reaction mixture was quenched with NH4Cl solution. The solid was filtered, and the filtrate was extracted with ethyl acetate (30 mL x 3, 30 V) and washed with brine (40 mL, 40 V). The combined filtrate was dried over Na2SO4 and concentrated in vacuo to give the oily crude product 2,2-dichloro-3-oxo-2',3''-dihydrodispiro[cyclobutane-1,4'-piperidine-2',1''-indene]-1',5''-dicarboxylate 1'-benzyl 5''-methyl c (1.2 g crude), which could be used in the next step without purification. LCMS (m / z): [M+H] + C 26 H 26 Calculated for Cl2NO5, 502.1; Found, 502.3.

[0100] Step 4 To a solution of 1'-benzyl 5''-methyl 2,2-dichloro-3-oxo-2'',3''-dihydrodispiro[cyclobutane-1,4'-piperidine-2',1''-indene]-1',5''-dicarboxylate (c, 1.2 g, crude) in MeOH (50 mL) was added NHCl (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 h and then filtered. The filtrate was concentrated in vacuo, and the residue was purified by silica gel flash column chromatography (ethyl acetate:petroleum ether = 2:1) to give the product 1'-benzyl 5''-methyl 3-oxo-2'',3''-dihydrodispiro[cyclobutane-1,4'-piperidine-2',1''-indene]-1',5''-dicarboxylate d (500 mg, 50% yield over two steps) as an oil. LCMS (m / z): [M+H] + C 26 H 28Calculated value for NO5: 434.2; measured value: 434.0.

[0101] Step 5 At 0°C, 1'-benzyl 5''-methyl 3-oxo-2'',3''-dihydrodispiro[cyclobutane-1,4'-piperidine-2',1''-indene]-1',5''-dicarboxylate (d, 500 mg, 1.15 mmol) was dissolved in BAST (1.5 mL). The reaction mixture was stirred at 50°C for 12 h. 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 extracted with dichloromethane (30 mL x 3), 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'-piperidine-2',1''-indene]-1',5''-dicarboxylate 1'-benzyl 5''-methyl e (300 mg, 57% yield) as an oil. LCMS (m / z): [M+H] + C 26 H 28 Calculated value for F2NO4: 456.2; Found: 456.0.

[0102] Step 6 To a stirred solution of 1'-benzyl 5''-methyl 3,3-difluoro-2'',3''-dihydrodispiro[cyclobutane-1,4'-piperidine-2',1''-indene]-1',5''-dicarboxylate (e, 240 mg, 0.527 mmol) in MeOH (5 mL) at 25 °C, Pd(OH)2 / C (100 mg) was added. The reaction mixture was stirred under H2 at 25 °C for 2 h. After filtration, the solution was concentrated in vacuo to give methyl 3,3-difluoro-2'',3''-dihydrodispiro[cyclobutane-1,4'-piperidine-2',1''-indene]-5''-carboxylate f (155 mg, 92% yield) as an oil. LCMS (m / z): [M+H] + C 18 H 22Calculated value for F2NO2: 322.1; Measured value: 322.1.

[0103] Step 7 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), CsCO (471 mg, 1.45 mmol), and NaI (109 mg, 0.72 mmol) in acetonitrile (3 mL) was stirred at 80 °C for 2 h. 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 a white solid, methyl 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''-carboxylate g (180 mg, 63%). LCMS (m / z): [M+H] + C 34 H 41 Calculated for F2N2O5, 595.1; Found, 595.1.

[0104] Step 8 A solution of methyl 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''-carboxylate (180 mg, 0.30 mmol) and NaOH (60 mg, 1.51 mmol) in MeOH / THF / HO (1 / 1 / 0.2 mL) was stirred at 60 °C for 1 h. The reaction mixture was neutralized with saturated citric acid solution and extracted with DCM / MeOH (10 / 1, 20 mL x 3). 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 give Example 1 Isomer 1 (36.27 mg, 25%), which 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). NHOH], flow rate: 12.5 mL / min, column temperature: 38 °C, retention time = 4.75 min) to give Example 1 Isomer 2 (42.33 mg, 29%, white solid) as the formate salt. MS: m / z = 481.0 (M+1, ESI+).

[0105] Example 1 Isomer 1: 1 HNMR (400MHz,CD3OD) δ 8.08(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).

[0106] Example 1 Isomer 2: 1 HNMR (400MHz, CD3OD) δ 8.44(s,1H),8.14-8.08(m,1H),8.01(s,1H),7.63(d,J=8.1Hz,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),4.06-3.9 5(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).

[0107] The following examples were synthesized using the above ester hydrolysis procedure using the appropriate starting materials:

[0108] [Table 1-1] [Table 1-2] [Table 1-3] [Table 1-4] [Table 1-5] [Table 1-6] [Table 1-7] [Table 1-8] [Table 1-9] [Table 1-10]

Table 1-11

Table 1-12

Table 1-13

Table 1-14

Table 1-15

Table 1-16

Table 1-17

Table 1-18

Table 1-19

Table 1-20

Table 1-21

Table 1-22

Table 1-23

Table 1-24

Table 1-25

Table 1-26

Table 1-27

[0109] Biological Example 1: Factor B Binding Assay by TR-FRET Materials and reagents 1. Recombinant human factor B catalytic domain (aa 470-764, C-terminal his-tag, in-house produced) 2. 5X Kinase Buffer A (Thermo Fisher, Catalog No. PV3189) 3. LANCE Eu-W1024 anti-6xHis antibody (PerkinElmer, catalog number AD0401) 4. Probe (TRFRET_tool 2, reported in WO 2015 / 009616) [ka] 5. DMSO (Thermo Fisher Scientific) 6. Compounds - 10 mM pre-solution in DMSO 7. Victor Nivo Multimodal Reader (PerkinElmer) 8. OptiPlate-384, white, opaque 384-well microplate (PerkinElmer, catalog number 6007290)

[0110] Experimental procedure The factor B binding affinity of each test compound was measured using time-resolved fluorescence resonance energy transfer (TR-FRET) technology. 10 nM recombinant his-tagged factor B catalytic domain, different concentrations of inhibitor, 4 nM LANCE Eu-W1024 anti-6xHis antibody, and 100 nM TRFRET_tool2 tracer were incubated in 1X kinase buffer A for 1 h. Measurements were performed in a 15 μL reaction volume by adding 5 μL of test compound, 5 μL of factor B / antibody mixture, 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 nm and 665 nm. The TR-FRET signals of different concentrations of compound were measured, and the relative fluorescence emission ratio (665 nm / 615 nm) versus inhibitor concentration was plotted using a four-parameter dose-response inhibition curve with a variable slope model in GraphPad Prism. The IC values ​​for the emission ratio were calculated from [compound]. 50 The binding affinity of each compound was determined by estimating

[0111] The above assay measures the binding affinity of the compounds of the present invention to the recombinant factor B catalytic domain, and the IC 50 The values ​​(nM) are shown in the table below.

[0112] [Table 2]

[0113] In the above assay, example compounds of the present invention were tested and showed IC 50 (nM) was shown to be 0.5 to 250 nM.

[0114] Biological Example 2. Target Retention Times for Factor B Inhibitors Measured by Surface Plasmon Resonance (SPR) Materials and reagents 1. Recombinant human factor B catalytic domain (aa 470-764, C-terminal his-tag, in-house produced) 2. PBS-P+ Buffer 10X (Cytiva, Cat. No. 28995084) 3. S series sensor chip NTA (Cytiva, catalog number BR100532) 4. Amine Coupling Kit (Cytiva, Catalog No. BR100050) 5. DMSO (Millipore Sigma, Cat. No. 34869-1L) 6. Greiner 96-well plate, polypropylene (Sigma-Aldrich, catalog number M7310-100EA) 7. Microplate foil, 96 wells (Cytiva, Cat. No. 28975816) 8. Biacore 8k (Cytiva)

[0115] Experimental procedure 1X PBS-P+ buffer was filled into a Biacore 8k instrument and docked onto a Cytiva NTA chip. Recombinant human factor B catalytic domain was immobilized onto the NTA chip using 1X PBS-P+ buffer (containing 20 mM phosphate buffer, 2.7 mM KCl, 137 mM NaCl, and 0.05% (v / v) Tween-20) to achieve a level of approximately 5,000 resonance units (RU). Protein ligands were further crosslinked to the sensor chip surface using an amine coupling kit. Immobilization and binding experiments were performed at room temperature.

[0116] After buffer exchange with 1X PBS-P+ buffer containing 2% (v / v) DMSO, a pre-run was performed for at least 30 min at a flow rate of 30 μl / min to obtain a stable surface. The kinetic constants of the compounds were measured by single-cycle kinetics of six consecutive injections (or multi-cycle kinetics of eight consecutive injections), where the compound concentrations were increased (depending on potency) within the ranges of 0.8–200 nM, 12.5–400 nM, 4.1–1,000 nM, or 41–10,000 nM. For each concentration, single-cycle kinetic experiments were performed with an association time of 60 s and a dissociation time of 300 s (or a dissociation time of 120 s for multi-cycle kinetic experiments). A flow rate of 30 μl / min was used. A blank run was performed under the same conditions before compound injection.

[0117] SPR sensorgrams were analyzed using the Biacore Insight evaluation software with the double-referencing method. The resulting curves were fitted using a 1:1 binding model. The kinetic constants (ka, kd, KD) of the replicates were averaged. Based on the dissociation constant kd, the retention time (tR) was calculated using the formula tR = 1 / kd. Based on the dissociation constant kd, the binding half-life (t1 / 2) was calculated using the formula t1 / 2 = ln2 / kd.

[0118] [Table 3]

[0119] In the above assay, exemplary compounds of the present invention were tested and found to have a K D (nM) was shown to be 0.5 to 250 nM.

[0120] Biological Example 3: Inhibition of human MAC deposition An AP deposition assay was used to quantify the inhibitory effect of compounds on complement protein deposition after LPS activation of the alternative complement pathway. Compound test concentrations started at 11.1 μM or 3.70 μM and were diluted 3-fold in DMSO to obtain eight concentration points, with each concentration tested in technical triplicate. Human serum and test compounds were combined in GVB buffer containing 5 mM MgCl2 and 10 mM EGTA and added to black Maxisorp plates coated with LPS. After a period of incubation, the plates were inverted and ELISA detection of complement proteins bound to LPS was performed. A primary antibody detecting human C5b-9 and a compatible secondary antibody conjugated to HRP were used. Peroxidase activity was detected using a Quantablu Fluorescent Peroxidase Substrate Kit, and the amount of alternative pathway complement protein deposition was determined by measuring fluorescence at 340 nm / 435 nm using an i3x plate reader.

[0121] [Table 4]

[0122] In the above assay, example compounds of the present invention were tested and showed IC 50 (nM) was shown to be 125-5000nM.

[0123] Biological Example 4: Inhibition of AP-dependent hemolysis 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 at concentrations starting at 100 μM and diluted 3-fold in DMSO, yielding 8–11 concentration points. Each concentration was tested in technical triplicate. Human serum was added to rabbit reticulocytes in GVB buffer containing MgCl2 and EGTA. After incubation at 37°C for a period of time, spontaneous division of rabbit red blood cells due to serum AP complement activity was quantified using OD405 absorbance (measured on an i3x plate reader).

[0124] [Table 5]

[0125] In the above assay, example compounds of the present invention were tested and showed IC 50 (nM) was shown to be 125-5000nM.

[0126] Biological Example 5: Pharmacokinetic Study in Rats Three-month-old Norway Brown rats were administered an example compound intravenously (0.5 mg / kg dose, formulation: 10% 1,2-propylene glycol + 25% (20% solutol HS 15 in water) + 65% phosphate buffered saline, 0.1 mg / mL) and an example compound as a clear solution (0.5% MC + 0.5% Tween 80 in water, 1 mg / mL) at a dose of 2 mg / kg via oral perfusion. Plasma was collected from the rats at 0.25, 0.5, 1, 6, and 24 hours post-dose. The concentration of the test article in the plasma was measured by HPLC-MS / MS, with two separate plasma samples at each time point. Chromatography was performed on a Waters BEH C18 Column (2.1 × 50 mm, 1.7 μm) (MAC-MOD Analytical, Chadds Ford, PA) using a gradient elution method of water and acetonitrile, both containing 0.025% carboxylic acid - 1 mM NHOAc. Mass spectrometry measurements under positive electrospray ionization were performed on an API 6500 triple quadrupole mass spectrometer (Sciex, Framingham, MA) using [M+H] as the precursor ion. + The aim was to quantify mass transition. Relevant pharmacokinetic parameters were estimated using non-atrial methods using WinNonlin (company version, version 8.2).

[0127] [Table 6]

[0128] Conclusion: The present invention describes compounds as effective factor B inhibitors, which have desirable physicochemical properties. The described compounds can be used as the therapeutic agents claimed above.

Claims

1. Formula (I): 【Chemical 1】 or a tautomer, cis or trans isomer, meso isomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, having the structure 【Chemistry 2】 is a saturated or unsaturated ring, A is C ６－１０ an aryl group or a 5- to 10-membered heteroaryl group; L is a bond or CH ２ and R ａ and R ｂ are independently selected from the group consisting of hydrogen, deuterium, halogen, amino, cyano, hydroxy, alkyl, alkoxy, alkylthio, haloalkyl, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl groups; R １ and R ２ are independently selected from the group consisting of hydrogen, deuterium, halogen, amino, cyano, hydroxy, alkyl, alkoxy, alkylthio, haloalkyl, and hydroxyalkyl groups; R ３ and R ４ are independently hydrogen, deuterium, halogen, amino group, cyano group, hydroxy group, C １－６ Alkyl group, C １－６ Alkoxy group, C １－６ Alkylthio group, C １－６ Haloalkyl group, C １－６ Haloalkenyl group, C １－６ Hydroxyalkyl group, deuterated C １－６ Alkoxy group, C １－６ Haloalkoxy group, C ３－６ Cycloalkyl group, 4- to 10-membered heterocyclyl group, C ６－１０ aryl group, 5- to 10-membered heteroaryl group, C ３－６ cycloalkyloxy group, 4- to 10-membered heterocyclyloxy group, C ６－１０ aryloxy groups and 5- to 10-membered heteroaryloxy groups, and optionally, １－６ Alkyl group, C １－６ Alkoxy group, C １－６ Alkylthio group, C １－６ Haloalkyl group, C １－６ Hydroxyalkyl group, deuterated C １－６ Alkoxy group, C １－６ The haloalkoxy group is a group selected from the group consisting of deuterium, halogen, amino, cyano, hydroxy, C １－６ Alkyl group, C １－６ Alkoxy group, C １－６ Alkylthio group, C １－６ Haloalkyl group, C １－６ Hydroxyalkyl group, C ３－６ Cycloalkyl group, 4- to 10-membered heterocyclyl group, C ６－１０ substituted with one or more substituents selected from aryl groups and 5- to 10-membered heteroaryl groups; R ５ is, independently, Hydrogen, deuterium, halogen, amino group, cyano group, hydroxy group, C １－６ Alkyl group, C ２－６ Alkenyl group, C ２－６ Alkynyl group, C １－６ Alkoxy group, C １－６ Alkylthio group, C １－６ Haloalkyl group, C １－６ Hydroxyalkyl group, C ３－８ Cycloalkyl group, 4- to 10-membered heterocyclyl group, C ５－１０ aryl groups and 5- to 10-membered heteroaryl groups, and optionally, １－６ Alkyl group, C １－６ Alkoxy group, C １－６ Alkylthio group, C １－６ Haloalkyl group, C １－６ Hydroxyalkyl group, C ３－８ Cycloalkyl group, 4- to 10-membered heterocyclyl group, C ５－１０ The aryl group and the 5- to 10-membered heteroaryl group may be substituted with deuterium, halogen, amino group, cyano group, hydroxy group, C １－６ Alkyl group, C １－６ Alkoxy group, C １－６ Alkylthio group, C １－６ Haloalkyl groups and C １－６ substituted with one or more substituents selected from hydroxyalkyl groups; or two R's ５ together with the C atoms to which they are attached, ３－６ forming a cycloalkyl group or a 4- to 6-membered heterocyclyl group containing 1, 2 or 3 heteroatoms selected from N, O or S, ３－６ The cycloalkyl group or 4- to 6-membered heterocyclyl group may optionally be selected from the group consisting of hydrogen, deuterium, halogen, amino, cyano, hydroxy, C １－６ Alkyl group, C １－６ Alkoxy group, C １－６ Alkyl C １－６ Alkoxy group, C １－６ Alkoxy C １－６ Alkyl group, C １－６ Alkylthio group, C １－６ Haloalkyl groups and C １－６ substituted with one or more substituents selected from hydroxyalkyl groups; or two R's ５ form a carbon-carbon double bond together with the C atom to which they are attached, R ６ represents hydrogen, deuterium, halogen, amino group, cyano group, hydroxy group, C １－６ Alkyl group, C １－６ Alkoxy group, C １－６ Alkylthio group, C １－６ Haloalkyl group, C １－６ Hydroxyalkyl group, C ３－８ Cycloalkyl group, 4- to 10-membered heterocyclyl group, C ５－１０ aryl groups and 5- to 10-membered heteroaryl groups, -(CH ２ ) ｒ C １－６ Alkoxy group, -(CH ２ ) ｒ C(O)OH, -S(O)NHC １－６ Alkyl group, —SO ２ C １－６ Alkyl group, —C(O)NHSO ２ C １－６ Alkyl group and -SO ２ NHC(O)C １－６ alkyl groups, R ７ is hydrogen or C １－３ is an alkyl group, R ９ represents deuterium, halogen, amino group, cyano group, hydroxy group, C １－６ Alkyl group, C １－６ Alkoxy group, C １－６ Alkylthio group, C １－６ Haloalkyl group, C １－６ Hydroxyalkyl group, C ３－８ selected from the group consisting of cycloalkyl groups and 4-10 membered heterocyclyl groups containing 1, 2 or 3 heteroatoms selected from N, O or S; or R ９ is R ６ and one of the following: saturated or unsaturated C ３－７ A cycloalkyl group or a saturated or unsaturated 3- to 7-membered heterocyclyl group containing 1, 2 or 3 heteroatoms selected from N, O or S, optionally ３－７ The cycloalkyl group or the 3- to 7-membered heterocyclyl group may be selected from the group consisting of hydrogen, deuterium, halogen, amino, cyano, hydroxy, C １－６ Alkyl group, C １－６ Alkoxy group, C １－６ Alkylalkoxy group, C １－６ Alkoxyalkyl group, C １－６ Alkylthio group, C １－６ Haloalkyl groups and C １－６ hydroxyalkyl groups, and another R ６ represents hydrogen, deuterium, halogen, amino group, cyano group, hydroxy group, C １－３ Alkyl group, C １－６ Alkoxy group, C １－６ Alkylthio group, C １－６ Haloalkyl group, C １－６ Hydroxyalkyl group, C ３－８ Cycloalkyl group, 4- to 10-membered heterocyclyl group, C ５－１０ aryl groups and 5- to 10-membered heteroaryl groups, -(CH ２ ) ｒ C １－６ Alkoxy group, -(CH ２ ) ｒ C(O)OH, -S(O)NHC １－６ Alkyl group, —SO ２ C １－６ Alkyl group, —C(O)NHSO ２ C １－６ Alkyl group and -SO ２ NHC(O)C １－６ alkyl groups, R ８ is selected from the group consisting of deuterium, halogen, amino, cyano, hydroxy, alkyl, alkoxy, alkylthio, haloalkyl, and hydroxyalkyl groups; 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; As a condition, R ３ and R ４ is not simultaneously a methyl group, or a tautomer, cis or trans isomer, meso isomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt, solvate, or prodrug thereof.

2. A is a phenyl group, a benzocycloalkyl group, or a 5-8 membered heteroaryl group containing 1, 2 or 3 N heteroatoms; Preferably, A is 【Chemistry 3】 2. The compound of claim 1, wherein:

3. R １ and R ２ are independently selected from hydrogen, or a tautomer, cis or trans isomer, meso isomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt, solvate, or prodrug thereof.

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

5. R ６ is -F, -OMe, -CH ２ OH, -CH ２ OCH ３ , -CH ２ F, -CF ２ H, -CF ３ , -COOH, -C(O)NHSO ２ CH ３ , -S(O)NHCH ３ or a 5- to 6-membered heterocyclyl group containing 1 to 3 heteroatoms selected from N, O and S, or a 5- to 6-membered heteroaryl group containing 1 to 3 heteroatoms selected from N, O and S, or a tautomer, cis or trans isomer, meso isomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt, solvate, or prodrug thereof.

6. R ９ represents deuterium, halogen, amino group, cyano group, hydroxy group, C １－３ Alkyl group, C １－６ Alkoxy group, C １－３ Alkylthio group, C １－３ Haloalkyl group, C １－３ Hydroxyalkyl group, C ３－６ is selected from the group consisting of a cycloalkyl group and a 4-6 membered heterocyclyl group containing 1, 2 or 3 heteroatoms selected from N, O or S; Preferably, R ９ is selected from the group consisting of deuterium, halogen, amino, cyano, hydroxy, methyl, ethyl, cyclopropyl, and cyclobutyl groups; or R ９ is R ６ and one of the following: saturated or unsaturated C ４－６ A cycloalkyl group or a saturated or unsaturated 4- to 7-membered heterocyclyl group containing 1, 2 or 3 heteroatoms selected from N, O or S, optionally forming said saturated or unsaturated C ４－６ The cycloalkyl group or saturated or unsaturated 4- to 7-membered heterocyclyl group may be selected from the group consisting of hydrogen, deuterium, halogen, amino group, cyano group, hydroxy group, C １－３ Alkyl group, C １－３ Alkoxy group, C １－３ Alkylalkoxy group, C １－３ Alkoxyalkyl group, C １－３ Alkylthio group, C １－３ Haloalkyl groups and C １－３ hydroxyalkyl groups, and another R ６ is F, -OMe, -CH ２ OH, -CH ２ OCH ３ , -CH ２ F, -CF ２ H, -CF ３ , -COOH, -C(O)NHSO ２ CH ３ , -S(O)NHCH ３ The compound according to any one of claims 1 to 5, or a tautomer or a pharmaceutically acceptable salt thereof, selected from the group consisting of:

7. The compound has the formula (II): 【Chemistry 4】 or a tautomer, cis or trans isomer, meso isomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt, solvate, or prodrug thereof.

8. The compound has a structure represented by formula (III-a)-(III-b): 【Chemistry 5】 where: X is CR ｃ R ｄ , N.R. ｅ or O, 【Chemistry 6】 is a single or double bond, R ｃ , R ｄ and R ｅ are independently hydrogen, deuterium, halogen, amino group, cyano group, hydroxy group, C １－６ Alkyl group, C １－６ Alkoxy group, C １－６ Alkylthio group, C １－６ Haloalkyl group, C １－６ Hydroxyalkyl group, C ３－８ Cycloalkyl group, C ３－８ Heterocyclyl group, C ６－１０ Aryl groups and C ６－１０ heteroaryl groups; Preferably, R ｃ , R ｄ and R ｅ are independently hydrogen, deuterium, halogen, amino group, cyano group, hydroxy group, C １－３ Alkyl group, C １－３ Alkoxy group, C １－３ Alkylthio group, C １－３ Haloalkyl group, C １－３ Hydroxyalkyl group, C ３－６ Cycloalkyl group, C ４－６ Heterocyclyl group, C ６－１０ Aryl groups and C ６－１０ heteroaryl groups; Preferably, R ｃ , R ｄ and R ｅ are independently selected from the group consisting of hydrogen, deuterium, halogen, amino, cyano, hydroxy, methyl, ethyl, cyclopropyl, and cyclobutyl; 8. The compound of any one of claims 1 to 7, wherein v is 0, 1, 2 or 3, or a tautomer, cis or trans isomer, meso isomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt, solvate, or prodrug thereof.

9. The compound has a structure represented by formula (II-a)-(II-b): 【Chemistry 7】 where: E is 【Chemistry 8】 and R １０ represents hydrogen, deuterium, halogen, amino group, cyano group, hydroxy group, C １－３ Alkyl group, C ２－４ Alkenyl group, C ２－４ Alkynyl group, C １－３ Alkoxy group, C １－３ Alkylthio group, C １－３ Haloalkyl groups and C １－３ hydroxyalkyl groups, n is 2, and 9. The compound of any one of claims 1 to 8, wherein z is 0, 1, 2 or 3, or a tautomer, cis or trans isomer, meso isomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt, solvate, or prodrug thereof.

10. 【Chemical 9】 teeth, 【Chemistry 10】 10. The compound of claim 8 or 9, wherein:

11. The compound has a structure represented by formula (V-a)-(V-b), 【Chemistry 11】 where: M is CR ｆ R ｇ and R ｆ and R ｇ are independently hydrogen, halogen and C １－３ alkyl groups, Preferably, R ｆ and R ｇ are independently selected from hydrogen and fluorine; q is 1, 2 or 3, and 11. The compound of any one of claims 1 to 10, wherein s is 0, 1 or 2, or a tautomer, cis or trans isomer, meso isomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt, solvate, or prodrug thereof.

12. The compounds have the formulas (VI-a)-(VI-l): 【Chemistry 12】 or a tautomer, cis or trans isomer, meso isomer, racemic form, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt, solvate, or prodrug thereof.

13.

13. teeth, 【Chemistry 14】 where: 【Chemistry 15】 teeth, 【Chemistry 16】 13. The compound of claim 12, wherein:

14.

17. 【Chemistry 18】 【Chemistry 19】 【Chemistry 20】 【Chemical 21】 【Chemical 22】 【Chemical 23】 【Chemistry 24】 【Chemistry 25】 【Chemical 26】 【Chemical 27】 【Chemical Formula 28】 【Chemical 29】 【Chemistry 30】 or a tautomer, cis or trans isomer, meso isomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, selected from the group consisting of:

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

16. 16. A method for modulating alternative complement pathway activity in a subject, comprising 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. 16. A method for treating a disorder or disease in a subject that is mediated by complement activation, in particular by alternative complement pathway activation, comprising 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 diseases or disorders include age-related macular degeneration, geographic atrophy, diabetic retinopathy, uveitis, retinitis pigmentosa, macular edema, uveitis due to Behcet's disease, multifocal choroiditis, Vogt-Koyanagi-Harada syndrome, intermediate uveitis, shotgun retinochoroiditis, sympathetic ophthalmia, ocular cicatricial pemphigoid, ocular pemphigus, non-arteritic ischemic optic neuropathy, postoperative inflammation, retinal vein occlusion, neuropathy, multiple sclerosis, stroke, Guillain-Barre syndrome, traumatic brain injury, Parkinson's disease, disorders of inappropriate or unwanted complement activation, hemodialysis complications, hyperacute allograft rejection, xenograft rejection, interleukin-2 induced toxicity during IL-2 therapy, inflammatory disorders, inflammation in autoimmune diseases, Crohn's disease, adult respiratory distress syndrome, myocarditis, post-ischemic reperfusion injury, and myocardial infarction.

18. The method of claim 17, wherein the patient is selected from the group consisting of: balloon angioplasty, post-pump syndrome in cardiopulmonary bypass or renal bypass, atherosclerosis, hemodialysis, renal ischemia, mesenteric artery reperfusion after aortic reconstruction, infection 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, fibrosing dust diseases, pulmonary fibrosis, asthma, allergies, bronchoconstriction, hypersensitivity pneumonitis, parasitic diseases, Goodpasture's syndrome, pulmonary vasculitis, vasculitis microimmunity, immune complex-associated inflammation, antiphospholipid syndrome, glomerulonephritis, and obesity.

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