Cyclic peptide compound as well as preparation method and application thereof

Abstract

The invention relates to a compound shown in a formula (I) or an isomer, a solvate, a hydrate, a prodrug, an isotope label and pharmaceutically acceptable salt thereof, and a preparation method and application thereof. The compound has a good inhibitory activity effect on complement, four-arm polyethylene glycol is used as a connecting bond, and the drug loading capacity of bicyclic peptide is increased. # imgabs0 #

Description

Technical Field

[0001] The present invention relates to the field of medicine, and particularly to a cyclic peptide compound, a preparation method thereof and an application thereof. Background Art

[0002] Complement is a system composed of more than 30 plasma proteins and cell-bound proteins, which plays an important role in innate immunity and adaptive immunity. Complement system proteins act in a series of enzymatic cascades through multiple protein interactions and cleavage events. Complement activation occurs through three main pathways: the antibody-dependent classical pathway, the alternative pathway, and the mannan-binding lectin (MBL) pathway. The classical pathway is mainly triggered by immune complexes containing antigens and IgG or IgM, but can also be triggered by other agents such as C-reactive protein. The alternative pathway is mainly triggered by repeating polysaccharides and other polymeric structures (such as those found on bacteria). The lectin pathway is triggered by the binding of mannan-binding lectin (MBL) or ficolin to carbohydrate structures (such as mannan) on heterogeneous surfaces. It has been shown that complement activation is a factor in the pathogenesis of several diseases associated with local or systemic inflammation. Summary of the Invention

[0003] Problems to be Solved by the Invention

[0004] Inappropriate or excessive complement activation is the root cause or contributing factor of many serious diseases and disorders. In the past few decades, a great deal of effort has been made to explore different complement inhibitors as therapeutic agents. However, there is still a need for innovative solutions for inhibiting complement activation for a variety of therapeutic purposes.

[0005] Solutions for Solving the Problems

[0006] In a first aspect, the present invention provides a compound represented by formula (I) or an isomer, solvate, hydrate, prodrug, isotope-labeled compound and pharmaceutically acceptable salt thereof,

[0007]

[0008] Wherein:

[0009] A is selected from R is an organic center;

[0010] L is The symbol "*" represents the connection site of L and A; m is selected from 1, 2, 3, 4, 5, 6, 7 and 8;

[0011] 0 ≤ n 1 ≤ 100;

[0012] 1 ≤ n2 ≤500;

[0013] n 3 is a positive integer, preferably selected from 1, 2, 3, 4, 5, 6, 7, and 8;

[0014] R is preferably selected from

[0015] Preferably, the compound of formula (I) is selected from the following structures:

[0016]

[0017] wherein: 1 ≤ n 1 ≤ 100; 1 ≤ n 2 ≤ 500.

[0018] Preferably, 1 ≤ n 1 ≤ 50.

[0019] Preferably, n 1 = 2, 4, 10, 30, 48.

[0020] Preferably, 50 ≤ n 2 ≤ 400.

[0021] Preferably, n 2 = 68, 92, 113, 158, 196, 227, 283, 296, 327, 352.

[0022] Preferably, n 1 = 2, n 2 = 113, n 3 = 1.

[0023] Preferably, n 1 = 2, n 2 = 227, n 3 = 1.

[0024] Preferably, n 1 = 4, n 2 = 113, n 3 = 1.

[0025] Preferably, n 1 = 4, n 2 = 227, n 3 = 1.

[0026] Preferably, n 1 = 2, n 2 = 113, n 3 = 2.

[0027] Preferably, n 1 = 2, n2 = 227, n 3 = 2.

[0028] Preferably, n 1 = 4, n 2 = 113, n 3 = 2.

[0029] Preferably, n 1 = 4, n 2 = 227, n 3 = 2.

[0030] In a second aspect, the present invention provides a pharmaceutical composition comprising the above compound or its isomers, solvates, hydrates, prodrugs, isotopically labeled compounds, and pharmaceutically acceptable salts and a pharmaceutically acceptable carrier.

[0031] Preferably, the above pharmaceutical composition further comprises an additional therapeutic agent.

[0032] In a third aspect, the present invention provides the use of the above compound or its isomers, solvates, hydrates, prodrugs, isotopically labeled compounds, and pharmaceutically acceptable salts, or the above pharmaceutical composition in the preparation of a complement inhibitor drug.

[0033] Preferably, the complement inhibitor drug is used for the treatment and / or prevention of diseases or disorders selected from hemolytic anemia, PNH, myasthenia gravis, NMO, polyneuropathy, nephropathy, and vasculitis.

[0034] In a fourth aspect, the present invention provides a method for inhibiting complement activation in a subject, comprising administering to the subject the above compound or its isomers, solvates, hydrates, prodrugs, isotopically labeled compounds, and pharmaceutically acceptable salts, or the above pharmaceutical composition.

[0035] Preferably, the subject suffers from a complement-mediated disease selected from hemolytic anemia, PNH, myasthenia gravis, NMO, polyneuropathy, nephropathy, and vasculitis.

[0036] In a fifth aspect, the present invention provides a method for preparing the compound of formula (I) as claimed in claim 1, comprising the following steps:

[0037] The compound of formula i reacts with the compound of formula ii by a condensation reaction to obtain the compound of formula (I-1);

[0038]

[0039] wherein n 1 and n 2 are as defined above.

[0040] In a sixth aspect, the present invention provides a compound of formula (i) or an isomer, solvate, hydrate, prodrug, isotopically labeled compound, and pharmaceutically acceptable salt thereof,

[0041]

[0042] where 1 ≤ n 1 ≤ 100;

[0043] Preferably, 1 ≤ n 1 ≤ 50;

[0044] More preferably, n 1 = 2, 4, 10, 30, 48.

[0045] Effects of the Invention

[0046] 1. The compounds of the present invention have good inhibitory activity against complement.

[0047] 2. The compounds of the present invention use tetra-arm polyethylene glycol as a linker, increasing the drug loading capacity of the bicyclic peptide.

[0048] 3. The compounds of the present invention have good safety and pharmacokinetic properties and can be used for the development of complement inhibitory drugs. BRIEF DESCRIPTION OF THE DRAWINGS

[0049] Figure 1 Shows the mass spectrum of the compound targeting polypeptide a.

[0050] Figure 2 Shows the 1H NMR spectrum of the compound targeting polypeptide a.

[0051] Figure 3 Shows the HPLC analysis chart of the compound targeting polypeptide a.

[0052] Figure 4 Shows the mass spectrum of the compound targeting polypeptide b.

[0053] Figure 5 Shows the 1H NMR spectrum of the compound targeting polypeptide b.

[0054] Figure 6 Shows the HPLC analysis chart of the compound targeting polypeptide b.

[0055] Figure 7 Shows the HPLC analysis chart of compound 102.

[0056] Figure 8 Shows the HPLC analysis chart of compound 103.

[0057] Figure 9 Shows the HPLC analysis chart of compound 104. Detailed implementation mode

[0058] To make the technical solutions and beneficial effects of the present invention more obvious and understandable, the following will be described in detail by listing specific embodiments. Among them, the drawings are not necessarily drawn to scale, and local features can be enlarged or reduced to more clearly show the details of the local features; unless otherwise defined, the technical and scientific terms used herein have the same meanings as those in the technical field to which this application belongs.

[0059] In a first aspect, the present invention provides a compound represented by formula (I) or its isomers, solvates, hydrates, prodrugs, isotope-labeled compounds, and pharmaceutically acceptable salts,

[0060]

[0061] wherein:

[0062] A is selected from

[0063] R is an organic center;

[0064] L is The symbol "*" represents the connection site of L and A;

[0065] m is selected from 3, 4, 5, 6, 7, and 8;

[0066] 0 ≤ n 1 ≤ 100;

[0067] 1 ≤ n 2 ≤ 500;

[0068] n 3 is a positive integer.

[0069] In some embodiments, n 3 is selected from 1, 2, 3, 4, 5, 6, 7, and 8.

[0070] In some embodiments, R is an organic core group of 1 to 100 atoms. Preferably, R contains 3 to 50 atoms, more preferably, R contains about 3 to 30 atoms. R can be a core composed entirely of carbon atoms, or can optionally contain one or more heteroatoms, such as O, S, N, P, etc., depending on the specific central molecule used. R can be linear, branched, or cyclic, and emits at least 3 independent polymer branches. In structural formula (I), "m" corresponds to the number of polymer branches emitted from "R".

[0071] In some embodiments, R is selected from

[0072] In some embodiments, R is selected from

[0073] In some embodiments, R is selected from

[0074] In some embodiments, R is selected from

[0075] In some embodiments, the compound of formula (I) is selected from the following structures:

[0076]

[0077] wherein: 1 ≤ n 1 ≤ 100; 1 ≤ n 2 ≤ 500.

[0078] In some embodiments, n 1 ranges from about 1 to about 100, n 2 ranges from about 1 to about 500,

[0079] In some embodiments, 1 ≤ n 1 ≤ 50.

[0080] In some embodiments, n 1 ranges from about 1 to about 50.

[0081] In some embodiments, n 1 = 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50.

[0082] In some embodiments, n 1 is about 1, about 2, about 3, about 4, about 5, about 6, about 7, about 8, about 9, about 10, about 11, about 12, about 13, about 14, about 15, about 16, about 17, about 18, about 19, about 20, about 21, about 22, about 23, about 24, about 25, about 26, about 27, about 28, about 29, about 30, about 31, about 32, about 33, about 34, about 35, about 36, about 37, about 38, about 39, about 40, about 41, about 42, about 43, about 44, about 45, about 46, about 47, about 48, about 49, about 50.

[0083] In some embodiments, n 1 = 2, 4, 10, 30, 48.

[0084] In some embodiments, n 1 is about 2, about 4, about 10, about 30, about 48.

[0085] In some embodiments, 50 ≤ n 2 ≤ 400.

[0086] In some embodiments, n 2 ranges from about 50 to about 400.

[0087] In some embodiments, n 2＝50、51、52、53、54、55、56、57、58、59、60、61、62、63、64、65、66、67、68、69、70、71、72、73、74、75、76、77、78、79、80、81、82、83、84、85、86、87、88、89、90、91、92、93、94、95、96、97、98、99、100、101、102、103、104、105、106、107、108、109、110、111、112、113、114、115、116、117、118、119、120、121、122、123、124、125、126、127、128、129、130、131、132、133、134、135、136、137、138、139、140、141、142、143、144、145、146、147、148、149、150、151、152、153、154、155、156、15、158、159、160、161、162、163、164、165、166、167、168、169、170、171、172、173、174、175、176、177、178、179、180、181、182、183、184、185、186、187、188、189、190、191、192、193、194、195、196、197、198、199、200、201、202、203、204、205、206、207、208、209、210、211、212、213、214、215、216、217、218、219、220、221、222、223、224、225、226、227、228、229、230、231、232、233、234、235、236、237、238、239、240、241、242、243、244、245、246、247、248、249、250、251、252、253、254、255、256、257、258、259、260、261、262、263、264、265、266、267、268、269、270、271、272、273、274、275、276、277、278、279、280、281、282、283、284、285、286、287、288、289、290、291、292、293、294、295、296、297、298、299、300、301、302、303、304、305、306、307、308、309、310、311、312, 313, 314, 315, 316, 317, 318, 319, 320, 321, 322, 323, 324, 325, 326, 327, 328, 329, 330, 331, 332, 333, 334, 335, 336, 337, 338, 339, 340, 341, 342, 343, 344, 345, 346, 347, 348, 349, 350, 351, 352, 353, 354, 355, 356, 357, 358, 359, 360, 361, 362, 363, 364, 365, 366, 367, 368, 369, 370, 371, 372, 373, 374, 375, 376, 377, 378, 379, 380, 381, 382, 383, 384, 385, 386, 387, 388, 389, 390, 391, 392, 393, 394, 395, 396, 397, 398, 399, 400。

[0088] In some embodiments, n 2be approximately 50, approximately 51, approximately 52, approximately 53, approximately 54, approximately 55, approximately 56, approximately 57, approximately 58, approximately 59, approximately 60, approximately 61, approximately 62, approximately 63, approximately 64, approximately 65, approximately 66, approximately 67, approximately 68, approximately 69, approximately 70, approximately 71, approximately 72, approximately 73, approximately 74, approximately 75, approximately 76, approximately 77, approximately 78, approximately 79, approximately 80, approximately 81, approximately 82, approximately 83, approximately 84, approximately 85, approximately 86, approximately 87, approximately 88, approximately 89, approximately 90, approximately 91, approximately 92, approximately 93, approximately 94, approximately 95, approximately 96, approximately 97, approximately 98, approximately 99, approximately 100, approximately 101, approximately 102, approximately 103, approximately 104, approximately 105, approximately 106, approximately 107, approximately 108, approximately 109, approximately 110, approximately 111, approximately 112, approximately 113, approximately 114, approximately 115, approximately 116, approximately 117, approximately 118, approximately 119, approximately 120, approximately 121, approximately 122, approximately 123, approximately 124, approximately 125, approximately 126, approximately 127, approximately 128, approximately 129, approximately 130, approximately 131, approximately 132, approximately 133, approximately 134, approximately 135, approximately 136, approximately 137, approximately 138, approximately 139, approximately 140, approximately 141, approximately 142, approximately 143, approximately 144, approximately 145, approximately 146, approximately 147, approximately 148, approximately 149, approximately 150, approximately 151, approximately 152, approximately 153, approximately 154, approximately 155, approximately 156, approximately 157, approximately 158, approximately 159, approximately 160, approximately 161, approximately 162, approximately 163, approximately 164, approximately 165, approximately 166, approximately 167, approximately 168, approximately 169, approximately 170, approximately 171, approximately 172, approximately 173, approximately 174, approximately 175, approximately 176, approximately 177, approximately 178, approximately 179, approximately 180, approximately 181, approximately 182, approximately 183, approximately 184, approximately 185, approximately 186, approximately 187, approximately 188, approximately 189, approximately 190, approximately 191, approximately 192, approximately 193, approximately 194, approximately 195, approximately 196, approximately 197, approximately 198, approximately 199, approximately 200, approximately 201, approximately 202, approximately 203, approximately 204, approximately 205, approximately 206, approximately 207, approximately 208, approximately 209, approximately 210, approximately 211, approximately 212, approximately 213, approximately 214, approximately 215, approximately 216, approximately 217, approximately 218, approximately 219, approximately 220, approximately 221, approximately 222, approximately 223, approximately 224Approximately 225, approximately 226, approximately 227, approximately 228, approximately 229, approximately 230, approximately 231, approximately 232, approximately 233, approximately 234, approximately 235, approximately 236, approximately 237, approximately 238, approximately 239, approximately 240, approximately 241, approximately 242, approximately 243, approximately 244, approximately 245, approximately 246, approximately 247, approximately 248, approximately 249, approximately 250, approximately 251, approximately 252, approximately 253, approximately 254, approximately 255, approximately 256, approximately 257, approximately 258, approximately 259, approximately 260, approximately 261, approximately 262, approximately 263, approximately 264, approximately 265, approximately 266, approximately 267, approximately 268, approximately 269, approximately 270, approximately 271, approximately 272, approximately 273, approximately 274, approximately 275, approximately 276, approximately 277, approximately 278, approximately 279, approximately 280, approximately 281, approximately 282, approximately 283, approximately 284, approximately 285, approximately 286, approximately 287, approximately 288, approximately 289, approximately 290, approximately 291, approximately 292, approximately 293, approximately 294, approximately 295, approximately 296, approximately 297, approximately 298, approximately 299, approximately 300, approximately 301, approximately 302, approximately 303, approximately 304, approximately 305, approximately 306, approximately 307, approximately 308, approximately 309, approximately 310, approximately 311, approximately 312, approximately 313, approximately 314, approximately 315, approximately 316, approximately 317, approximately 318, approximately 319, approximately 320, approximately 321, approximately 322, approximately 323, approximately 324, approximately 325, approximately 326, approximately 327, approximately 328, approximately 329, approximately 330, approximately 331, approximately 332, approximately 333, approximately 334, approximately 335, approximately 336, approximately 337, approximately 338, approximately 339, approximately 340, approximately 341, approximately 342, approximately 343, approximately 344, approximately 345, approximately 346, approximately 347, approximately 348, approximately 349, approximately 350, approximately 351, approximately 352, approximately 353, approximately 354, approximately 355, approximately 356, approximately 357, approximately 358, approximately 359, approximately 360, approximately 361, approximately 362, approximately 363, approximately 364, approximately 365, approximately 366, approximately 367, approximately 368, approximately 369, approximately 370, approximately 371, approximately 372, approximately 373, approximately 374, approximately 375, approximately 376, approximately 377, approximately 378, approximately 379, approximately 380, approximately 381, approximately 382, approximately 383, approximately 384, approximately 385, approximately 386, approximately 387, approximately 388, approximately 389, approximately 390About 391, about 392, about 393, about 394, about 395, about 396, about 397, about 398, about 399, about 400.

[0089] In some embodiments, n 2 = 68, 92, 113, 158, 196, 227, 283, 296, 327, 352.

[0090] In some embodiments, n 2 is about 68, about 92, about 113, about 158, about 196, about 227, about 283, about 296, about 327, about 352.

[0091] In some embodiments, n 1 = 2, n 2 = 113, n 3 = 1.

[0092] In some embodiments, n 1 is about 2, n 2 is about 113.

[0093] In some embodiments, n 1 = 2, n 2 = 227, n 3 = 1.

[0094] In some embodiments, n 1 is about 2, n 2 is about 227.

[0095] In some embodiments, n 1 = 4, n 2 = 113, n 3 = 1.

[0096] In some embodiments, n 1 is about 4, n 2 is about 113.

[0097] In some embodiments, n 1 = 4, n 2 = 227, n 3 = 1.

[0098] In some embodiments, n 1 is about 4, n 2 is about 227.

[0099] In some embodiments, n 1 = 2, n 2 = 113, n 3 = 2.

[0100] In some embodiments, n 1 is about 2, and n 2 is about 113.

[0101] In some embodiments, n 1 = 2, n 2 = 227, n 3 = 2.

[0102] In some embodiments, n 1 is about 2, and n 2 is about 227.

[0103] In some embodiments, n 1 = 4, n 2 = 113, n 3 = 2.

[0104] In some embodiments, n 1 is about 4, and n 2 is about 113.

[0105] In some embodiments, n 1 = 4, n 2 = 227, n 3 = 2.

[0106] In some embodiments, n 1 is about 4, and n 2 is about 227.

[0107] In a second aspect, the present invention provides a pharmaceutical composition comprising the above compound or its isomers, solvates, hydrates, prodrugs, isotopically labeled compounds, and pharmaceutically acceptable salts and pharmaceutically acceptable carriers.

[0108] In some embodiments, the above pharmaceutical composition further comprises an additional therapeutic agent.

[0109] In a third aspect, the present invention provides the use of the above compound or its isomers, solvates, hydrates, prodrugs, isotopically labeled compounds, and pharmaceutically acceptable salts, or the above pharmaceutical composition in the preparation of a complement inhibitor drug.

[0110] In some embodiments, the complement inhibitor drug is used for treating and / or preventing diseases or disorders selected from hemolytic anemia, PNH, myasthenia gravis, NMO, polyneuropathy, nephropathy, and vasculitis.

[0111] Fourth aspect, the present invention provides a method for inhibiting complement activation in a subject, comprising administering to the subject the above-mentioned compound or its isomers, solvates, hydrates, prodrugs, isotopically labeled compounds and pharmaceutically acceptable salts, or the above-mentioned pharmaceutical composition.

[0112] In some embodiments, the subject has a complement-mediated disease, and the complement-mediated disease is selected from hemolytic anemia, PNH, myasthenia gravis, NMO, polyneuropathy, nephropathy and vasculitis.

[0113] Fifth aspect, the present invention provides a method for preparing the compound of formula (I) as claimed in claim 1, comprising the following steps:

[0114] The compound of formula i reacts with the compound of formula ii by a condensation reaction to obtain the compound of formula (I-1);

[0115]

[0116] where n 1 and n 2 are as defined above.

[0117] Sixth aspect, the present invention provides a compound of formula (i) or its isomers, solvates, hydrates, prodrugs, isotopically labeled compounds and pharmaceutically acceptable salts,

[0118]

[0119] where 1 ≤ n 1 ≤ 100.

[0120] In some embodiments, n 1 is from about 1 to about 100.

[0121] In some embodiments, 1 ≤ n 1 ≤ 50.

[0122] In some embodiments, n 1 is from about 1 to about 50

[0123] In some embodiments, n 1 = 2, 4, 10, 30, 48.

[0124] In some embodiments, n 1 is about 2, about 4, about 10, about 30, about 48.

[0125] In some embodiments, the condensation reaction occurs in the presence of a condensing agent.

[0126] In some embodiments, the condensing agent includes but is not limited to 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride, N,N'-dicyclohexylcarbodiimide, N,N'-diisopropylcarbodiimide, O-benzotriazol-1-yl-N,N,N',N'-tetramethyluronium tetrafluoroborate, 1-hydroxybenzotriazole, 1-hydroxy-7-azabenzotriazole, O-benzotriazol-1-yl-N,N,N',N'-tetramethyluronium hexafluorophosphate, 2-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (HATU), 2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate, benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate or benzotriazol-1-yl-oxytripyrrolidinophosphonium hexafluorophosphate, N,N'-diisopropylethylamine (DIEA).

[0127] In some embodiments, the condensing agent is selected from N,N'-diisopropylethylamine (DIEA).

[0128] Glossary of terms:

[0129] Unless otherwise stated, the terms used in the specification and claims have the following meanings.

[0130] In the chemical structure of the compounds of the present invention, the bond does not specify the configuration, that is, the bond can be or or contain both and two configurations. In the chemical structure of the compounds of the present invention, the bond does not specify the configuration, that is, it can be the Z configuration or the E configuration, or contain both configurations at the same time.

[0131] The term "isomer" includes all isomeric forms including enantiomers, diastereomers and geometric isomers including cis-trans isomers. Therefore, the individual stereochemical isomers of the compounds designed in the present invention or mixtures of their enantiomers, diastereomers, or geometric isomers (or cis-trans isomers) are all within the scope of the present invention.

[0132] The term "isotope label" can introduce isotopes into any compound involved in the present invention, and the introduced isotopes can be 2 H, 3 H, 13 C, 14 C, 15 N, 17 O, 18 O, 31 P, 32 P, 35S, 18 F, 36 Cl, and specific isotopic derivatives can be prepared by conventional techniques.

[0133] The term "pharmaceutically acceptable salts" means that the compounds of the present invention exist in the form of their medicinal salts, including acid addition salts and base addition salts. Pharmaceutically acceptable salts are described in pharmaceutically salts described by S.M. Berge in J. Pharmaceutical Sciences (Volume 66: pages 1-19, 1977). In the present invention, pharmaceutically acceptable non-toxic acid addition salts mean salts formed by the compounds in the present invention with organic or inorganic acids, and organic or inorganic acids include but are not limited to hydrochloric acid, sulfuric acid, hydrobromic acid, hydroiodic acid, phosphoric acid, nitric acid, perchloric acid, acetic acid, oxalic acid, maleic acid, fumaric acid, tartaric acid, benzenesulfonic acid, methanesulfonic acid, salicylic acid, succinic acid, citric acid, lactic acid, propionic acid, benzoic acid, p-toluenesulfonic acid, malic acid, etc. Pharmaceutically acceptable non-toxic base addition salts mean salts formed by the compounds in the present invention with organic or inorganic bases, including but not limited to alkali metal salts, such as lithium, sodium or potassium salts; alkaline earth metal salts, such as calcium or magnesium salts; organic base salts, such as ammonium salts formed by reacting with organic bases containing N groups or N + (C 1-6 alkyl) 4 salts.

[0134] The term "pharmaceutical composition" means a mixture containing one or more compounds described herein or their physiologically / pharmaceutically acceptable salts or prodrugs and other chemical components, as well as other components such as physiologically / pharmaceutically acceptable carriers and excipients. The purpose of the pharmaceutical composition is to facilitate the administration to an organism, promote the absorption of the active ingredient and thus exert its biological activity.

[0135] The term "therapeutically effective amount" refers to a sufficient amount of a drug or agent that is non-toxic but can achieve the desired effect. The determination of the effective amount varies from person to person, depending on the age and general condition of the recipient, and also depends on the specific active substance. The appropriate effective amount in a particular case can be determined by those skilled in the art according to conventional tests.

[0136] The term "solvate" refers to the physical association of a compound of the present invention with one or more, preferably 1-3, solvent molecules, whether organic or inorganic. This physical association includes hydrogen bonds. In some cases, for example, when one or more, preferably 1-3, solvent molecules are incorporated into the crystal lattice of a crystalline solid, the solvate will be separated. Exemplary solvates include but are not limited to hydrates, ethanolates, methanolates, and isopropanolates. Solvation methods are well known in the art.

[0137] The term "prodrug" refers to a compound that can be converted in vivo under physiological conditions, for example, by hydrolysis in the blood, to produce the active parent drug compound.

[0138] The term "pharmaceutically acceptable" means that these compounds, materials, compositions, and / or dosage forms are, within the scope of reasonable medical judgment, suitable for contact with the tissues of a patient without excessive toxicity, irritation, allergic response, or other problems or complications, have a reasonable benefit / risk ratio, and are effective for their intended use.

[0139] As used herein, the terms "about", "approximately equal to", "≈" encompass range values within a ±25% margin of the given numerical value. In other embodiments, the term "about" encompasses range values within a ±20%, ±15%, ±10%, or ±5% margin of the given numerical value. For example, in one embodiment, "about 100" represents values such as 90 - 110 (i.e., 100 ± 10%).

[0140] The above terms related to the present invention have been defined, and those skilled in the art can also understand the above terms in combination with the prior art. The following further describes based on the content of the present invention and the definitions of the terms.

[0141] The following further describes the preparation of the compounds and pharmaceutically acceptable salts of the present invention with reference to examples, but these examples do not limit the scope of the present invention.

[0142] For the experimental methods not specified with specific conditions in the examples of the present invention, they are generally carried out under conventional conditions or according to the conditions recommended by the raw material or commercial manufacturer. The reagents not specified with specific sources are conventional reagents purchased from the market.

[0143] Example 1 Synthesis of Targeting Polypeptide a

[0144] The chemical structure of targeting polypeptide a is:

[0145]

[0146] The target peptide was synthesized by solid-phase synthesis using the Fmoc method. 2-CTC Resin was used, and 20% piperidine / DMF was used to remove Fmoc. The coupling reagent was HOBT / DIC, and DMF was used as the reaction solvent. The reaction was monitored by the ninhydrin detection method. The following protected amino acids were sequentially linked to the resin: Fmoc-1-amino-3,6-dioxaoctane hydrochloride → Fmoc-Thr(tBu)-OH, Fmoc-Cys(Acm)-OH, Fmoc-Arg(pbf)-OH, Fmoc-His(trt)-OH, Fmoc-Ala-OH, Fmoc-Gly-OH, Fmoc-Trp(Boc)-OH, Fmoc-Asp(OtBu)-OH, Fmoc-Gln(trt)-OH, Fmoc-Trp(1-Me)-OH, Fmoc-Val-OH, Fmoc-Cys(Acm)-OH, Fmoc-Ile-OH. It was acetylated with acetic anhydride and pyridine, and then 2 oxidized, washed with 20% piperidine / DMF, DMF, DCM, and methanol, and then dried. The resin was cleaved with 95% TFA / 2.5% Tis / 2.5% H 2 O, and then precipitated and washed with ice-cold methyl tert-butyl ether (MTBE). The crude product was purified by preparative reverse-phase HPLC and then freeze-dried to obtain the pure target polypeptide a. MS of target polypeptide a: [M+2] 2+ was 879.90, [M+3] 3+ was 586.65.

[0147] For the detailed process, reference can be made to: CN105582523B: Complement inhibitor analogs have been synthesized that have higher complement inhibitory activity than complementin. Some of them are described in the following documents: WO2004 / 026328 (PCT / US2003 / 029653); Morikis, D. et al., Biochem Soc Trans, 32 (Pt 1): 28-32, 2004; Mallik, B. et al., J. Med. Chem., 274-286, 2005; and / or Katragadda, M. et al., J. Med. Chem., 49: 4616-4622, 2006, all of which are incorporated herein by reference. Any of the complement inhibitory peptides and peptidomimetics described therein can be used in the present invention. For example, SEQ ID NOs: 4-13 described in WO2004 / 026328 can be used in the present invention.

[0148] Example 2 Synthesis of Target Polypeptide b

[0149] The chemical structure of target polypeptide b is:

[0150]

[0151] The target peptide was synthesized by solid-phase synthesis using the Fmoc method. Rinke Amide Resin was used. 20% piperidine / DMF was used to remove Fmoc. The coupling reagent was HOBT / DIC. DMF was used as the reaction solvent. The reaction was monitored by the ninhydrin detection method. The following protected amino acids were sequentially linked to the resin: Fmoc-Lys(Boc)-OH, Fmoc-AEEA-OH, Fmoc-Thr(tBu)-OH, Fmoc-Cys(Acm)-OH, Fmoc-Arg(pbf)-OH, Fmoc-His(trt)-OH, Fmoc-Ala-OH, Fmoc-Gly-OH, Fmoc-Trp(Boc)-OH, Fmoc-Asp(OtBu)-OH, Fmoc-Gln(trt)-OH, Fmoc-Trp(1-Me)-OH, Fmoc-Val-OH, Fmoc-Cys(Acm)-OH, Fmoc-Ile-OH. It was acetylated with acetic anhydride and pyridine, and then 2 oxidized, washed with 20% piperidine / DMF, DMF, DCM, and methanol, and then dried. The resin was cleaved with 95% TFA / 2.5% Tis / 2.5% H 2 O, and then precipitated and washed with ice-cold methyl tert-butyl ether (MTBE). The crude product was purified by preparative HPLC and then lyophilized to obtain the pure target polypeptide b. MS of target polypeptide b: [M+2] 2+ was 951.15, [M+3] 3+ was 634.40.

[0152] Synthesis of Compound 102 in Example 3

[0153] The chemical structure of Compound 102 is:

[0154]

[0155] 0.997 g (n is approximately 227, 1.0 eq), 123 mg of target polypeptide b (2.2 eq), 23 ul of DIEA (5.5 eq), 15 ml of DMF, and 5 ml of DCM were added to a 50 ml single-neck flask. The reaction was stirred at room temperature and monitored by HPLC until completion. It was diluted with 20 ml of DMF and added to 200 ml of ice-cold methyl tert-butyl ether. It was filtered, washed twice with MTBE, and dried under reduced pressure to obtain the crude product. The crude product was purified by preparative reverse-phase HPLC and then lyophilized to obtain 0.76 g of pure Compound 102.

[0156] Synthesis of Compound 103 in Example 4

[0157] The chemical structure of Compound 103 is as follows:

[0158]

[0159] Add 0.602 g (1.0 eq), 276 mg of targeting polypeptide a (4.4 eq), 55 μl of DIEA (11.0 eq), 12 ml of DMF, stir the reaction at room temperature, and monitor the reaction completion by HPLC. Add 10 ml of DMF for dilution, and add it to 160 ml of ice-cold methyl tert-butyl ether. Discard the supernatant, wash it twice with MTBE, and dry it under reduced pressure to obtain the crude product. After purification by preparative reverse-phase HPLC and lyophilization, 0.64 g of pure Compound 103 is obtained.

[0160] Synthesis of Compound 104 in Example 5

[0161] The chemical structure of Compound 104 is as follows:

[0162]

[0163] Add 0.994 g (1.0 eq), 222 mg of targeting polypeptide a (4.4 eq), 45 μl of DIEA (11.0 eq), 15 ml of DMF, 5 ml of DCM, stir the reaction at room temperature, and monitor the reaction completion by HPLC. Add 20 ml of DMF for dilution, and add it to 200 ml of ice-cold methyl tert-butyl ether. Discard the supernatant, wash it twice with MTBE, and dry it under reduced pressure to obtain the crude product. After purification by preparative reverse-phase HPLC and lyophilization, 0.51 g of pure Compound 104 is obtained.

[0164] It should be noted that the selection of n 2 can be changed according to actual needs. When different PEG molecules are selected, the corresponding n 2 will also be different. Therefore, referring to the above experiments, those skilled in the art have also prepared other drug molecules as follows:

[0165] Compound <![CDATA[n 1 > <![CDATA[n 2 > <![CDATA[n 3 > Example 6 105 Approximately 2 Approximately 327 1 Example 7 106 Approximately 4 Approximately 113 1 Example 8 107 Approximately 4 Approximately 227 1 Example 9 118 Approximately 4 Approximately 327 1 Example 10 109 Approximately 30 Approximately 113 1 Example 11 110 Approximately 30 Approximately 227 1 Example 12 111 Approximately 30 Approximately 327 1 Example 13 112 Approximately 48 Approximately 113 1 Example 14 113 Approximately 48 Approximately 227 1 Example 15 114 Approximately 48 Approximately 327 1 Example 16 115 Approximately 2 Approximately 327 2 Example 17 116 Approximately 4 Approximately 113 2 Example 18 117 Approximately 4 Approximately 227 2 Example 19 118 Approximately 4 Approximately 327 2 Example 20 119 Approximately 30 Approximately 113 2 Example 21 120 Approximately 30 Approximately 227 2 Example 22 121 Approximately 30 Approximately 327 2 Example 23 122 Approximately 48 Approximately 113 2 Example 24 123 Approximately 48 Approximately 227 2 Example 25 124 Approximately 48 Approximately 327 2 Example 26 125 0 Approximately 113 1 Example 27 126 0 Approximately 227 1 Example 28 127 0 Approximately 113 2 Example 29 128 0 Approximately 227 2

[0166] Example 30 Pharmacokinetic Test

[0167] Dissolve the drug in a solvent, divide the rats aged 6 - 9 weeks into 3 groups on average, and inject various drugs such as Compound 102, Compound 103, and Compound 104 into each group at a dose of 20 mg / mL per kilogram respectively. Collect 150 μl of mouse blood intravenously at different time points. The results are shown in Table 1 - 5.

[0168] Table 1 Pharmacokinetic Data of Compound 102

[0169]

[0170] Table 2 Pharmacokinetic data of Compound 103

[0171]

[0172]

[0173] Table 3 Pharmacokinetic data of Compound 104

[0174]

[0175]

[0176] Table 4 Summary of pharmacokinetic data of Compound 102, Compound 103, and Compound 104

[0177]

[0178] It can be seen that the data of Compound 104 prepared in the present invention is relatively close to that of the control compound 102 in the pharmacokinetic experiment, and the AUC 0-inf is 30% higher than that of Compound 102, and the MRT 0-last exceeds 14.3%, and the half-life is also extended by 16.3%.

[0179] Meanwhile, in terms of drug loading, those skilled in the art can see from the structure that Compound 102 can only be loaded with drugs at both ends, and the drug loading ratio is 1:2, while the structure of the present application can be loaded with drugs on 4 bonds, and the drug loading ratio is 1:4, and the drug loading is significantly larger than that of Compound 102.

[0180] It should be understood that the above embodiments are all exemplary and do not cover all possible implementation manners included in the claims. Without departing from the scope of the present disclosure, various deformations and changes can also be made on the basis of the above embodiments. Similarly, the various technical features of the above embodiments can also be combined arbitrarily to form other embodiments of the present invention that may not be clearly described. Therefore, the above embodiments only represent several implementation manners of the present invention and do not limit the protection scope of the present invention patent.

Claims

1. A compound of formula (I) or an isomer, solvate, hydrate, prodrug, isotopically labeled compound, or pharmaceutically acceptable salt thereof, wherein: A is selected from R is an organic center; L is The symbol "*" represents the connection site between L and A; m is selected from 1, 2, 3, 4, 5, 6, 7, and 8; 0≤n 1 ≤100； 1≤n 2 ≤500； n 3 is a positive integer, preferably selected from 1, 2, 3, 4, 5, 6, 7, and 8; R is preferably selected from 2. The compound of formula (I) or an isomer, solvate, hydrate, prodrug, isotopically labeled compound, or pharmaceutically acceptable salt thereof according to claim 1, wherein the compound of formula (I) is selected from the following structures: where: 1 ≤ n 1 ≤ 100; 1 ≤ n 2 ≤ 500.

3. The compound or an isomer, solvate, hydrate, prodrug, isotopically labeled compound, or pharmaceutically acceptable salt thereof according to claim 2, wherein 1 ≤ n 1 ≤ 50; preferably, 50 ≤ n 2 ≤ 400.

4. The compound or an isomer, solvate, hydrate, prodrug, isotopically labeled compound, or pharmaceutically acceptable salt thereof according to claim 2, wherein n 1 and n 2 take the following values: where n 1 and n 2 take values as randomly combined from the above table; Preferably, n 1 = 2, n 2 = 113, n 3 = 1; n 1 = 2, n 2 = 227, n 3 = 1; n 1 = 4, n 2 = 113, n 3 = 1; n 1 = 4, n 2 = 227, n 3 = 1; n 1 = 2, n 2 = 113, n 3 = 2; n 1 = 2, n 2 = 227, n 3 = 2; n 1 = 4, n 2 = 113, n 3 = 2; n 1 = 4, n 2 = 227, n 3 = 2.

5. A pharmaceutical composition comprising the compound or an isomer, solvate, hydrate, prodrug, isotopically labeled compound, or pharmaceutically acceptable salt thereof according to any one of claims 1-4 and a pharmaceutically acceptable carrier.

6. The pharmaceutical composition according to claim 5, which further comprises an additional therapeutic agent.

7. Use of the compound or an isomer, solvate, hydrate, prodrug, isotopically labeled compound, or pharmaceutically acceptable salt thereof according to any one of claims 1-4, or the pharmaceutical composition according to any one of claims 5-6, in the preparation of a complement inhibitor drug; Preferably, the complement inhibitor drug is used for treating and / or preventing a disease or disorder selected from hemolytic anemia, PNH, myasthenia gravis, NMO, polyneuropathy, nephropathy, and vasculitis.

8. A method for inhibiting complement activation in a subject, comprising administering to the subject the compound or an isomer, solvate, hydrate, prodrug, isotopically labeled compound, or pharmaceutically acceptable salt thereof according to any one of claims 1-4, or the pharmaceutical composition according to any one of claims 5-6; Preferably, the subject suffers from a complement-mediated disease selected from hemolytic anemia, PNH, myasthenia gravis, NMO, polyneuropathy, nephropathy, and vasculitis.

9. A method for preparing the compound of formula (I-1) according to claim 2, wherein it comprises the following steps: The compound of formula i reacts with the compound of formula ii by a condensation reaction to obtain the compound of formula (I-1); where n 1 and n 2 as defined in claim 2.

10. A compound of formula (i) or an isomer, solvate, hydrate, prodrug, isotopically labeled compound, or pharmaceutically acceptable salt thereof, where 1 ≤ n 1 ≤ 100; Preferably, 1 ≤ n 1 ≤ 50; More preferably, n 1 = 2, 4, 10, 30, 48.

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