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WO2024051849A1 - Dérivés de pipéridine substitués en position 2, leurs procédés de préparation et leurs utilisations médicinales - Google Patents

Dérivés de pipéridine substitués en position 2, leurs procédés de préparation et leurs utilisations médicinales Download PDF

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Publication number
WO2024051849A1
WO2024051849A1 PCT/CN2023/117941 CN2023117941W WO2024051849A1 WO 2024051849 A1 WO2024051849 A1 WO 2024051849A1 CN 2023117941 W CN2023117941 W CN 2023117941W WO 2024051849 A1 WO2024051849 A1 WO 2024051849A1
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Prior art keywords
alkyl
alkoxy
cycloalkyl
halogen
group
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PCT/CN2023/117941
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English (en)
Inventor
Avinash KHANNA
Matthew KIER
Hugh Y. Zhu
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Jiangsu Hansoh Pharmaceutical Group Co Ltd
Shanghai Hansoh Biomedical Co Ltd
Hansoh Bio LLC
Original Assignee
Jiangsu Hansoh Pharmaceutical Group Co Ltd
Shanghai Hansoh Biomedical Co Ltd
Hansoh Bio LLC
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Application filed by Jiangsu Hansoh Pharmaceutical Group Co Ltd, Shanghai Hansoh Biomedical Co Ltd, Hansoh Bio LLC filed Critical Jiangsu Hansoh Pharmaceutical Group Co Ltd
Priority to CN202380064279.7A priority Critical patent/CN119923389A/zh
Priority to AU2023339335A priority patent/AU2023339335A1/en
Priority to JP2025514347A priority patent/JP2025530222A/ja
Priority to EP23862542.0A priority patent/EP4584255A1/fr
Priority to CA3266935A priority patent/CA3266935A1/fr
Priority to KR1020257009417A priority patent/KR20250065621A/ko
Publication of WO2024051849A1 publication Critical patent/WO2024051849A1/fr
Priority to MX2025002790A priority patent/MX2025002790A/es
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00—Drugs for disorders of the senses
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/438—The ring being spiro-condensed with carbocyclic or heterocyclic ring systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/10—Spiro-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
    • C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
    • C07D491/10—Spiro-condensed systems
    • C07D491/107—Spiro-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring

Definitions

  • the present invention belongs to the field of medicine, and relates to 2-substituted piperidine derivatives, preparation methods thereof, pharmaceutical compositions comprising the compounds, and medical uses thereof.
  • the complement system is a part of the innate immunosurveillance, playing a critical role in eliminating pathogens and in the tissue homeostasis.
  • the complement cascade can be activated by three different pathways including classical (CP) , lectin (LP) , and alternative pathway (AP) .
  • the CP and LP are initiated on target surfaces by immune complexes and binding of mannan-binding lectin or ficolin to a particular of microbial sugar moiety pattern, respectively.
  • the AP does not require specific initiation.
  • the AP cascade is initiated by spontaneous hydrolysis of C3 (tick-over) and subsequent deposition of C3b on an activating surface.
  • the three complement activation pathways converge on two major events, C3 cleavage and C5 cleavage.
  • C3 convertases split C3 into C3a and C3b.
  • C3b forms additional AP C3 convertases (amplification) as well as C5 convertases.
  • C5 convertases cleave C5 into C5a and C5b.
  • the produced C5b initiates the formation of the C5b-9 membrane attack complex (MAC) with C6-C9, leading to lysis of bacteria and cells by insertion into a membrane.
  • the split products C3a and C5a function as anaphylatoxins to promote pro-inflammatory responses through activation and chemotaxis of leukocytes.
  • C3b also plays a key role in removing bacteria and cellular waste such as immune complexes and apoptotic cells through promoting phagocytosis by opsonization.
  • 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 ) .
  • the spontaneous activated C3 forms C3 convertase by binding with factor B (FB) .
  • C3b and Bb After cleavage of FB into Bb by factor D, C3b and Bb generate the AP C3 convertase (C3bBb) .
  • the newly formed C3bBb cleaves more C3 to generate more AP C3 convertases, leading to the amplification of complement cascade.
  • This invention aims to provide compounds which modulate Factor B and treat disorders associated with the dysregulation of the Complement pathway.
  • the present invention in one aspect, provides a compound of formula (I) , or a tautomer, cis-or trans-isomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt, solvate, or prodrug thereof,
  • A is cycloalkyl, heterocyclyl, aryl or heteroaryl
  • L is bond, (CR a R b ) p ;
  • 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;
  • 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;
  • R 3 and R 4 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, cycloalkylxoy, heterocyclylxoy, arylxoy and heteroarylxoy, optionally the hydroxy, alkyl, alkoxy, alkylthio, haloalkyl, hydroxyalkyl, deuterated alkoxy, haloalkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl, cycloalkylxoy, heterocyclylxoy, arylxoy and heteroarylxoy substituted with one or more substituents selected from deuterium, halogen, amino,
  • R 5 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, optionally the amino, alkyl, alkoxy, alkylthio, haloalkyl, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl substituted with one or more substituents selected from deuterium, halogen, amino, cyano, hydroxy, alkyl, alkoxy, alkylthio, haloalkyl and hydroxyalkyl;
  • R 5 together with the C atom to which they are attached form a cycloalkyl or heterocyclyl, optionally the cycloalkyl or heterocyclyl substituted with one or more substituents selected from hydrogen, deuterium, halogen, amino, cyano, hydroxy, alkyl, alkoxy, alkylalkoxy, alkoxyalkyl, alkylthio, haloalkyl and hydroxyalkyl;
  • R 5 together with the C atom to which they are attached form a cycloalkyl or heterocyclyl, optionally the cycloalkyl or heterocyclyl substituted with one or more substituents selected from hydrogen, deuterium, halogen, amino, cyano, hydroxy, alkyl, alkoxy, alkylalkoxy, alkoxyalkyl, alkylthio, haloalkyl and hydroxyalkyl;
  • R 6 is selected from the group consisting of hydrogen, deuterium, halogen, amino, cyano, hydroxy, alkyl, alkoxy, alkylthio, haloalkyl, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, – (CH 2 ) r OR 8 , – (CH 2 ) r C (O) R 8 , -S (O) NHalkyl, -SO 2 alkyl, -C (O) NHSO 2 alkyl and -SO 2 NHC (O) alkyl;
  • R 7 is selected from the group consisting of hydrogen, deuterium, halogen, amino, cyano, hydroxy, alkyl, alkoxy, alkylthio, haloalkyl and hydroxyalkyl;
  • R 9 is selected from the group consisting of deuterium, halogen, amino, cyano, hydroxy, alkyl, alkoxy, alkylthio, haloalkyl, hydroxyalkyl, cycloalkyl and heterocyclyl;
  • R 9 taken together with one of R 6 form a saturated or unsaturated cycloalkyl or a saturated or unsaturated heterocyclyl, optionally the cycloalkyl or heterocyclyl is substituted with one or more substituents selected from hydrogen, deuterium, halogen, amino, cyano, hydroxy, alkyl, alkoxy, alkylalkoxy, alkoxyalkyl, alkylthio, haloalkyl and hydroxyalkyl, and another R 6 is selected from the group consisting of hydrogen, deuterium, halogen, amino, cyano, hydroxy, alkyl, alkoxy, alkylthio, haloalkyl, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, — (CH 2 ) r OR 8 , – (CH 2 ) r C (O) R 8 , -S (O) NHalkyl, -SO 2 alkyl, -C
  • R 8 is selected from the group consisting of deuterium, halogen, amino, cyano, hydroxy, alkyl, alkoxy, alkylthio, haloalkyl and hydroxyalkyl;
  • p 1, 2 or 3;
  • t 1, 2 or 3;
  • n 1, 2 or 3;
  • n 0, 1, 2 or 3;
  • R 3 and R 4 are not simultaneously methyl.
  • A is C 6-10 aryl or 5-10 membered heteroaryl.
  • A is phenyl, benzocycloalkyl, or 5-8 membered heteroaryl containing 1, 2 or 3 of N heteroatoms;
  • A is N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-phenyl
  • L is bond, CH 2 .
  • R 1 and R 2 are independently selected from hydrogen.
  • R 3 and R 4 are independently selected from the group consisting of hydrogen, deuterium, halogen, amino, cyano, hydroxy, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkylthio, C 1-6 haloalkyl, C 1-6 haloalkenyl C 1-6 hydroxyalkyl, deuterated C 1-6 alkoxy, C 1-6 haloalkoxy, C 3-6 cycloalkyl, 4-10 membered heterocyclyl, C 6-10 aryl, 5-10 membered heteroaryl, C 3-6 cycloalkyloxy, 4-10 membered heterocyclyloxy, C 6-10 aryloxy and 5-10 membered heteroaryloxy, optionally the C 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkylthio, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, deuterated C 1-6 alkoxy, C 1-6 haloalkoxy substituted with
  • R 3 and R 4 are independently selected from the group consisting of deuterium, halogen, C 1-3 alkyl, C 1-3 alkoxy, deuterated C 1-3 alkoxy, C 1-3 haloalkoxy, C 3-6 cycloalkyl and C 3-6 cycloalkyloxy, optionally the C 1-3 alkyl, C 1-3 alkoxy, deuterated C 1-3 alkoxy, C 1-3 haloalkoxy substituted with one or more substituents selected from C 3-6 cycloalkyl, 4-6 membered heterocyclyl, C 6-10 aryl and 5-10 membered heteroaryl.
  • R 5 is independently selected from the group consisting of hydrogen, deuterium, halogen, amino, cyano, hydroxy, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 alkoxy, C 1- 6 alkylthio, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, C 3-8 cycloalkyl, 4-10 membered heterocyclyl, C 5-10 aryl and 5-10 membered heteroaryl, optionally the C 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkylthio, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, C 3-8 cycloalkyl, 4-10 membered heterocyclyl, C 5-10 aryl and 5-10 membered heteroaryl substituted with one or more substituents selected from deuterium, halogen, amino, cyano, hydroxy, C 1-6 alkyl, C 1-6 alkoxy, C 1-6
  • two of R 5 together with the C atom to which they are attached form C 3-6 cycloalkyl or 4-6 membered heterocyclyl containing 1, 2 or 3 heteroatoms selected from N, O or S, optionally substituted with one or more substituents selected from hydrogen, deuterium, halogen, amino, cyano, hydroxy, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkylC 1-6 alkoxy, C 1-6 alkoxyC 1-6 alkyl, C 1-6 alkylthio, C 1-6 haloalkyl and C 1-6 hydroxyalkyl.
  • two of R 5 together with the C atom to which they are attached form a carbon-carbon double bond.
  • R 6 is selected from the group consisting of hydrogen, deuterium, halogen, amino, cyano, hydroxy, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkylthio, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, C 3-8 cycloalkyl, 4-10 membered heterocyclyl, C 5-10 aryl and 5-10 membered heteroaryl, – (CH 2 ) r C 1-6 alkoxy, – (CH 2 ) r C (O) OH, -S (O) NHC 1-6 alkyl, -SO 2 C 1-6 alkyl, -C (O) NHSO 2 C 1-6 alkyl and -SO 2 NHC (O) C 1-6 alkyl.
  • 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 5-6 membered heterocyclyl containing 1-3 of heteroatom selected from N, O and S, or 5-6 membered heteroaryl containing 1-3 of heteroatom selected from N, O and S.
  • R 7 is hydrogen or C 1-3 alkyl.
  • R 9 is selected from the group consisting of deuterium, halogen, amino, cyano, hydroxy, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkylthio, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, C 3-8 cycloalkyl and 4-10 membered heterocyclyl containing 1, 2 or 3 heteroatoms selected from N, O or S.
  • R 9 is selected from the group consisting of deuterium, halogen, amino, cyano, hydroxy, C 1-3 alkyl, C 1-6 alkoxy, C 1-3 alkylthio, C 1-3 haloalkyl, C 1-3 hydroxyalkyl, C 3-6 cycloalkyl and 4-6 membered heterocyclyl containing 1, 2 or 3 heteroatoms selected from N, O or S.
  • R 9 is selected from the group consisting of deuterium, halogen, amino, cyano, hydroxy, methyl, ethyl, cyclopropyl, cyclobutyl.
  • R 9 taken together with one of R 6 form a saturated or unsaturated C 3-7 cycloalkyl or a saturated or unsaturated 3-7 membered heterocyclyl containing 1, 2 or 3 heteroatoms selected from N, O or S, optionally the C 3-7 cycloalkyl or 3-7 membered heterocyclyl is substituted with 1 or 2 substituents selected from hydrogen, deuterium, halogen, amino, cyano, hydroxy, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkylalkoxy, C 1-6 alkoxyalkyl, C 1-6 alkylthio, C 1-6 haloalkyl and C 1-6 hydroxyalkyl, and another R 6 is selected from the group consisting of hydrogen, deuterium, halogen, amino, cyano, hydroxy, C 1-3 alkyl, C 1-6 alkoxy, C 1-6 alkylthio, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, C 3
  • R 9 taken together with one of R 6 form a saturated or unsaturated C 4-6 cycloalkyl or a saturated or unsaturated 4-7 membered heterocyclyl containing 1, 2 or 3 heteroatoms selected from N, O or S, optionally the saturated or unsaturated C 4-6 cycloalkyl or saturated or unsaturated 4-7 membered heterocyclyl is substituted with 1 or 2 substituents selected from hydrogen, deuterium, halogen, amino, cyano, hydroxy, C 1-3 alkyl, C 1-3 alkoxy, C 1-3 alkylalkoxy, C 1-3 alkoxyalkyl, C 1-3 alkylthio, C 1-3 haloalkyl and C 1-3 hydroxyalkyl, and another R 6 is selected from the group consisting of F, -OMe, -CH 2 OH, -CH 2 OCH 3 , -CH 2 F, -CF 2 H, -CF 3 , –COOH, -C (O)
  • the compound of formula (I) may be compounds of formula (II) , or a tautomer, cis-or trans-isomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt, solvate, or prodrug thereof,
  • the compound of formula (I) may be compounds of formula (III-a) - (III-b) , or a tautomer, cis-or trans-isomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt, solvate, or prodrug thereof,
  • X is CR c R d , NR e , O or S;
  • R c, R d and R e are independently selected from the group consisting of hydrogen, deuterium, halogen, amino, cyano, hydroxy, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkylthio, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, C 3-8 cycloalkyl, C 3-8 heterocyclyl, C 6-10 aryl and C 6-10 heteroaryl;
  • R c, R d and R e are independently selected from the group consisting of hydrogen, deuterium, halogen, amino, cyano, hydroxy, C 1-3 alkyl, C 1-3 alkoxy, C 1-3 alkylthio, C 1-3 haloalkyl, C 1-3 hydroxyalkyl, C 3-6 cycloalkyl, C 4-6 heterocyclyl, C 6-10 aryl and C 6-10 heteroaryl;
  • R c, R d and R e are independently selected from the group consisting of hydrogen, deuterium, halogen, amino, cyano, hydroxy, methyl, ethyl;
  • v 0, 1, 2 or 3.
  • the compound of formula (I) may be compounds of formula (IV-a) -(IV-f) , or a tautomer, cis-or trans-isomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt, solvate, or prodrug thereof,
  • R 10 is selected from deuterium, halogen, amino, cyano, hydroxy, C 1-3 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 1-3 alkoxy, C 1-3 alkylC 1-3 alkoxy, C 1-3 alkoxyC 1-3 alkyl, C 1-3 alkylthio, C 1-3 haloalkyl and C 1-3 hydroxyalkyl;
  • n 1;
  • z 0, 1, 2 or 3.
  • the compound of formula (I) may be compounds of formula (V-a) -(V-b) , or a tautomer, cis-or trans-isomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt, solvate, or prodrug thereof,
  • M is O or CR f R g ;
  • R f and R g are independently selected from hydrogen, halogen and C 1-3 alkyl
  • R f and R g are independently selected from hydrogen, fluorine;
  • q 1, 2 or 3;
  • s 0, 1 or 2.
  • the compound of formula (I) may be compounds of formula (VI-a) -(VI-l) , or a tautomer, cis-or trans-isomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt, solvate, or prodrug thereof,
  • the present invention also provides a pharmaceutical composition, comprising a therapeutically effective amount of a compound of any formula (I) - (VII-f) , or tautomer, or pharmaceutically acceptable salt thereof, together with one or more pharmaceutically acceptable carriers, diluents or excipients.
  • the amount of the compound, tautomer, cis-or trans-isomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or pharmaceutically acceptable salts thereof is about 0.1-95%by weight of free base; preferably, is about 5-70%, e.g. 70%, 65%, 60%, 55%, 50%, 45%, 40%, 35%, 30%, 25%, 20%, 15%, 10%, 5%.
  • above stated pharmaceutical composition is formulated as a tablet, capsule, liquid form or injection form.
  • the amount of the compound, tautomer, cis-or trans-isomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or pharmaceutically acceptable salts thereof is about 1-1000mg; preferably, is about 1-500mg, more preferably, is about 1mg, 2mg, 3mg, 5mg, 10mg, 20mg, 40mg, 50mg, 60mg, 80mg, 100mg, 200mg, 300mg, 400m or 500mg.
  • the compound, tautomer, cis-or trans-isomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or pharmaceutically acceptable salts thereof is can be administered by any suitable route of administration, e.g. oral, parenteral, buccal, sublingual, nasal, rectal, intrathecal or transdermal administration, and the pharmaceutical compositions adapted accordingly.
  • the compound, tautomer, cis-or trans-isomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or pharmaceutically acceptable salts is formulated as a soild or liquid form, e.g. syrups, suspension, emulsion, tablets, capsules, powders, granules or lozenges.
  • the present invention relates to a method of modulating complement alternative pathway activity, comprising administering to a subject in need thereof an effective amount of a compound any formula (I) - (VI-f) , or a pharmaceutical composition comprising the same.
  • the present invention relates to a method of treating a disorder or a disease in a subject mediated by complement activation, in particular mediated by activation of the complement alternative pathway, comprising administering to a subject in need thereof an effective amount of a compound any formula (I) - (VI-f) , or a pharmaceutical composition comprising the same.
  • the disease or disorder is selected from the group consisting of age-related macular degeneration, geographic atrophy, diabetic retinopathy, uveitis, retinitis pigmentosa, macular edema, Behcet's uveitis, multifocal choroiditis, Vogt-Koyangi-Harada syndrome, imtermediate uveitis, birdshot retino-chorioditis, sympathetic ophthalmia, ocular dicatricial pemphigoid, ocular pemphigus, nonartertic ischemic optic neuropathy, post-operative inflammation, retinal vein occlusion, neurological disorders, multiple sclerosis, stroke, Guillain Barre Syndrome, traumatic brain injury, Parkinson's disease, disorders of inappropriate or undesirable complement activation, hemodialysis complications, hyperacute allograft rejection, xenograft rejection, interleukin-2 induced toxicity during IL-2 therapy, inflammatory disorders, inflammation
  • Alkyl refers to a saturated aliphatic hydrocarbon group including C 1 -C 20 straight chain and branched chain groups.
  • an alkyl group is an alkyl having 1 to 12, sometimes preferably 1 to 6, sometimes more preferably 1 to 4, carbon atoms.
  • Representative examples include, but are not limited to methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1, 1-dimethyl propyl, 1, 2-dimethyl propyl, 2, 2-dimethyl propyl, 1-ethyl propyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2-methylpropyl, 1, 1, 2-trimethylpropyl, 1, 1-dimethylbutyl, 1, 2-dimethylbutyl, 2, 2-dimethylbutyl, 1, 3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2, 3-dimethylbutyl, n-heptyl, 2-methylhexyl, 3-methylhexyl, 4-methylhexyl, 5-methylhexyl,
  • an alkyl group is a lower alkyl having 1 to 6 carbon atoms.
  • Representative examples include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1, 1-dimethylpropyl, 1, 2-dimethylpropyl, 2, 2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2-methylpropyl, 1, 1, 2-trimethylpropyl, 1, 1-dimethylbutyl, 1, 2-dimethylbutyl, 2, 2-dimethylbutyl, 1, 3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2, 3-dimethylbutyl, etc.
  • the alkyl group can be substituted or unsubstituted.
  • the substituent group (s) can be substituted at any available connection point, preferably the substituent group (s) is one or more substituents independently selected from the group consisting of alkyl, halogen, alkoxy, alkenyl, alkynyl, alkylsulfo, alkylamino, thiol, hydroxy, nitro, cyano, amino, cycloalkyl, heterocyclic alkyl, aryl, heteroaryl, cycloalkoxyl, heterocylic, cycloalkylthio, heterocylic alkylthio and oxo group.
  • Alkenyl refers to an alkyl defined as above that has at least two carbon atoms and at least one carbon-carbon double bond, for example, vinyl, 1-propenyl, 2-propenyl, 1-, 2-, or 3-butenyl, etc., preferably C 2-20 alkenyl, more preferably C 2-12 alkenyl, and most preferably C 2-6 alkenyl.
  • the alkenyl group can be substituted or unsubstituted.
  • the substituent group (s) is preferably one or more, sometimes preferably one to five, sometimes more preferably one to three, group (s) independently selected from the group consisting of alkyl, halogen, alkoxy, alkenyl, alkynyl, alkylsulfo, alkylamino, thiol, hydroxy, nitro, cyano, amino, cycloalkyl, heterocyclic alkyl, aryl, heteroaryl, cycloalkoxyl, heterocylic, cycloalkylthio, heterocylic alkylthio and oxo group.
  • Alkynyl refers to an alkyl defined as above that has at least two carbon atoms and at least one carbon-carbon triple bond, for example, ethynyl, 1-propynyl, 2-propynyl, 1-, 2-, or 3-butynyl etc., preferably C 2-20 alkynyl, more preferably C 2-12 alkynyl, and most preferably C 2-6 alkynyl.
  • the alkynyl group can be substituted or unsubstituted.
  • the substituent group (s) is preferably one or more, sometimes preferably one to five, sometimes more preferably one to three, group (s) independently selected from the group consisting of alkyl, alkenyl, alkynyl, alkoxy, alkylsulfo, alkylamino, halogen, thiol, hydroxy, nitro, cyano, cycloalkyl, heterocyclic alkyl, aryl, heteroaryl, cycloalkoxyl, heterocylic alkoxyl, cycloalkylthio and heterocylic alkylthio.
  • Alkylene refers to a saturated linear or branched aliphatic hydrocarbon group, wherein having 2 residues derived by removing two hydrogen atoms from the same carbon atom of the parent alkane or two different carbon atoms.
  • the straight or branched chain group containing 1 to 20 carbon atoms preferably has 1 to 12 carbon atoms, more preferably 1 to 6 carbon atoms.
  • Non-limiting examples of alkylene groups include, but are not limited to, methylene (-CH 2 -) , 1, 1-ethylene (-CH (CH 3 ) -) , 1, 2-ethylene (-CH 2 CH 2 ) -, 1, 1-propylene (-CH (CH 2 CH 3 ) -) , 1, 2-propylene (-CH 2 CH (CH 3 ) -) , 1, 3-propylene (-CH 2 CH 2 CH 2 -) , 1, 4-butylidene (-CH 2 CH 2 CH 2 CH 2 -) etc.
  • the alkylene group can be substituted or unsubstituted.
  • the substituent group (s) is preferably one or more, sometimes preferably one to five, sometimes more preferably one to three, group (s) independently selected from the group consisting of selected from alkyl, alkenyl, alkynyl, alkoxy, alkylsulfo, alkylamino, halogen, thiol, hydroxy, nitro, cyano, cycloalkyl, heterocyclic alkyl, aryl, heteroaryl, cycloalkoxyl, heterocylic alkoxyl, cycloalkylthio and heterocylic alkylthio.
  • Alkenylene refers to an alkylene defined as above that has at least two carbon atoms and at least one carbon-carbon double bond, preferably C 2-20 alkenylene, more preferably C 2-12 alkenylene, and most preferably C 2-6 alkenylene.
  • the alkenylene group can be substituted or unsubstituted.
  • the substituent group (s) is preferably one or more, sometimes preferably one to five, sometimes more preferably one to three, group (s) independently selected from the group consisting of selected from alkyl, alkenyl, alkynyl, alkoxy, alkylsulfo, alkylamino, halogen, thiol, hydroxy, nitro, cyano, cycloalkyl, heterocyclic alkyl, aryl, heteroaryl, cycloalkoxyl, heterocylic alkoxyl, cycloalkylthio and heterocylic alkylthio.
  • Alkynylene refers to an alkynyl defined as above that has at least two carbon atoms and at least one carbon-carbon triple bond, preferably C 2-20 alkynylene, more preferably C 2-12 alkynylene, and most preferably C 2-6 alkynylene.
  • alkenylene groups include, but are not limited to, -CH ⁇ CH-, -CH ⁇ CHCH 2 -, -CH ⁇ CHCH 2 CH 2 -, -CH 2 CH ⁇ CHCH 2 -etc.
  • the alkynylene group can be substituted or unsubstituted.
  • the substituent group (s) is preferably one or more, sometimes preferably one to five, sometimes more preferably one to three, group (s) independently selected from the group consisting of selected from alkyl, alkenyl, alkynyl, alkoxy, alkylsulfo, alkylamino, halogen, thiol, hydroxy, nitro, cyano, cycloalkyl, heterocyclic alkyl, aryl, heteroaryl, cycloalkoxyl, heterocylic alkoxyl, cycloalkylthio and heterocylic alkylthio.
  • Cycloalkyl refers to 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 cycloalkyls include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cycloheptatrienyl, cyclooctyl, etc.
  • Polycyclic cycloalkyl includes a cycloalkyl having a spiro ring, fused ring or bridged ring.
  • “Spiro Cycloalkyl” refers to a 5 to 20 membered polycyclic group with rings connected through one common carbon atom (called a spiro atom) , wherein one or more rings can contain one or more double bonds, but none of the rings has a completely conjugated pi-electron system.
  • a spiro cycloalkyl is 6 to 14 membered, more preferably 7 to 10 membered, and most preferably . 7 to 8 membered.
  • a spiro cycloalkyl is divided into mono-spiro cycloalkyl, di-spiro cycloalkyl, or poly-spiro cycloalkyl, and preferably refers to a mono-spiro cycloalkyl or di-spiro cycloalkyl, more preferably 4-membered/4-membered, 4-membered/5-membered, 4-membered/6-membered, 5-membered/5-membered, or 5-membered/6-membered mono-spiro cycloalkyl.
  • Representative examples of spiro cycloalkyl include, but are not limited to the following substituents:
  • “Fused Cycloalkyl” refers to a 5 to 20 membered polycyclic hydrocarbon group, wherein each ring in the system shares an adjacent pair of carbon atoms with another ring, wherein one or more rings can contain one or more double bonds, but none of the rings has a completely conjugated pi-electron system.
  • a fused cycloalkyl group is 6 to 14 membered, more preferably 7 to 10 membered, and most preferably . 7 to 8 membered.
  • fused cycloalkyl is divided into bicyclic, tricyclic, tetracyclic or polycyclic fused cycloalkyl, and preferably refers to a bicyclic or tricyclic fused cycloalkyl, more preferably 5-membered/5-membered, or 5-membered/6-membered bicyclic fused cycloalkyl.
  • fused cycloalkyls include, but are not limited to, the following substituents:
  • Bridged Cycloalkyl refers to a 5 to 20 membered polycyclic hydrocarbon group, wherein every two rings in the system share two disconnected carbon atoms. The rings can have one or more double bonds, but have no completely conjugated pi-electron system.
  • a bridged cycloalkyl is 6 to 14 membered, more preferably 7 to 10 membered, and most preferably 7 to 8 membered.
  • bridged cycloalkyl is divided into bicyclic, tricyclic, tetracyclic or polycyclic bridged cycloalkyl, and preferably refers to a bicyclic, tricyclic or tetracyclic bridged cycloalkyl, more preferably a bicyclic or tricyclic bridged cycloalkyl.
  • Representative examples of bridged cycloalkyls include, but are not limited to, the following substituents:
  • the cycloalkyl can be fused to the ring of an aryl, heteroaryl or heterocyclic alkyl, wherein the ring bound to the parent structure is cycloalkyl.
  • Representative examples include, but are not limited to indanylacetic, tetrahydronaphthalene, benzocycloheptyl and so on.
  • the cycloalkyl is optionally substituted or unsubstituted.
  • the substituent group (s) is preferably one or more, sometimes preferably one to five, sometimes more preferably one to three, substituents independently selected from the group consisting of alkyl, halogen, alkoxy, alkenyl, alkynyl, alkylsulfo, alkylamino, thiol, hydroxy, nitro, cyano, amino, cycloalkyl, heterocyclic alkyl, aryl, heteroaryl, cycloalkoxyl, heterocylic, cycloalkylthio, heterocylic alkylthio and oxo group.
  • substituents include, but are not limited to, the following substituents:
  • Heterocyclyl refers to a 3 to 20 membered saturated and/or partially unsaturated monocyclic or polycyclic hydrocarbon group having one or more, sometimes preferably one to five, sometimes more preferably one to three, heteroatoms selected from the group consisting of N, O, and S (O) m (wherein m is 0, 1, or 2) as ring atoms, but excluding -O-O-, -O-S-or -S-S-in the ring, the remaining ring atoms being C.
  • heterocyclyl is a 3 to 12 membered having 1 to 4 heteroatoms; more preferably a 3 to 10 membered having 1 to 3 heteroatoms; most preferably a 5 to 6 membered having 1 to 2 heteroatoms.
  • monocyclic heterocyclyls include, but are not limited to, pyrrolidyl, piperidyl, piperazinyl, morpholinyl, sulfo-morpholinyl, homopiperazinyl, and so on.
  • Polycyclic heterocyclyl includes the heterocyclyl having a spiro ring, fused ring or bridged ring.
  • “Spiro heterocyclyl” refers to a 5 to 20 membered polycyclic heterocyclyl with rings connected through one common carbon atom (called a spiro atom) , wherein said rings have one or more, sometimes preferably one to five, sometimes more preferably one to three, heteroatoms selected from the group consisting of N, O, and S (O) m (wherein m is 0, 1 or 2) as ring atoms, the remaining ring atoms being C, wherein one or more rings can contain one or more double bonds, but none of the rings has a completely conjugated pi-electron system.
  • a spiro heterocyclyl is 6 to 14 membered, more preferably 7 to 10 membered, and most preferably 7 to 8 membered.
  • spiro heterocyclyl is divided into mono-spiro heterocyclyl, di-spiro heterocyclyl, or poly-spiro heterocyclyl, and preferably refers to mono-spiro heterocyclyl or di-spiro heterocyclyl, more preferably 4-membered/4-membered, 4-membered/5-membered, 4-membered/6-membered, 5-membered/5-membered, or 5-membered/6-membered mono-spiro heterocyclyl.
  • Representative examples of spiro heterocyclyl include, but are not limited to the following substituents:
  • “Fused Heterocyclyl” refers to a 5 to 20 membered polycyclic heterocyclyl group, wherein each ring in the system shares an adjacent pair of carbon atoms with the other ring, wherein one or more rings can contain one or more double bonds, but none of the rings has a completely conjugated pi-electron system, and wherein said rings have one or more, sometimes preferably one to five, sometimes more preferably one to three, heteroatoms selected from the group consisting of N, O, and S (O) p (wherein p is 0, 1, or 2) as ring atoms, the remaining ring atoms being C.
  • a fused heterocyclyl is 6 to 14 membered, more preferably 7 to 10 membered, and most preferably 7 to 8 membered.
  • fused heterocyclyl is divided into bicyclic, tricyclic, tetracyclic or polycyclic fused heterocyclyl, preferably refers to bicyclic or tricyclic fused heterocyclyl, more preferably 5-membered/5-membered, or 5-membered/6-membered bicyclic fused heterocyclyl.
  • Representative examples of fused heterocyclyl include, but are not limited to, the following substituents:
  • “Bridged Heterocyclyl” refers to a 5 to 14 membered polycyclic heterocyclic alkyl group, wherein every two rings in the system share two disconnected atoms, the rings can have one or more double bonds, but have no completely conjugated pi-electron system, and the rings have one or more heteroatoms selected from the group consisting of N, O, and S (O) m (wherein m is 0, 1, or 2) as ring atoms, the remaining ring atoms being C.
  • a bridged heterocyclyl is 6 to 14 membered, more preferably 7 to 10 membered, and most preferably 7 to 8 membered.
  • bridged heterocyclyl is divided into bicyclic, tricyclic, tetracyclic or polycyclic bridged heterocyclyl, and preferably refers to bicyclic, tricyclic or tetracyclic bridged heterocyclyl, more preferably bicyclic or tricyclic bridged heterocyclyl.
  • bridged heterocyclyl include, but are not limited to, the following substituents:
  • the ring of said heterocyclyl can be fused to the ring of an aryl, heteroaryl or cycloalkyl, wherein the ring bound to the parent structure is heterocyclyl.
  • Representative examples include, but are not limited to the following substituents:
  • the heterocyclyl is optionally substituted or unsubstituted.
  • the substituent group (s) is preferably one or more, sometimes preferably one to five, sometimes more preferably one to three, group (s) independently selected from the group consisting of alkyl, alkenyl, alkynyl, alkoxy, alkylsulfo, alkylamino, halogen, thiol, hydroxy, nitro, cyano, cycloalkyl, heterocyclic alkyl, aryl, heteroaryl, cycloalkoxyl, heterocylic alkoxyl, cycloalkylthio, heterocylic and alkylthio.
  • Aryl refers to a 6 to 14 membered all-carbon monocyclic ring or a 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 pi-electron system.
  • aryl is 6 to 10 membered, such as phenyl and naphthyl, most preferably phenyl.
  • the aryl can be fused to the ring of heteroaryl, heterocyclyl or cycloalkyl, wherein the ring bound to parent structure is aryl.
  • Representative examples include, but are not limited to, the following substituents:
  • the aryl group can be substituted or unsubstituted.
  • the substituent group (s) is preferably one or more, sometimes preferably one to five, sometimes more preferably one to three, substituents independently selected from the group consisting of alkyl, alkenyl, alkynyl, alkoxy, alkylsulfo, alkylamino, halogen, thiol, hydroxy, nitro, cyano, cycloalkyl, heterocyclic alkyl, aryl, heteroaryl, cycloalkoxyl, heterocylic alkoxyl, cycloalkylthio, heterocylic and alkylthio.
  • Heteroaryl refers to 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 annular atoms.
  • a heteroaryl is 5-to 10-membered, more preferably 5-or 6-membered, for example, thiadiazolyl, pyrazolyl, oxazolyl, oxadiazolyl, imidazolyl, triazolyl, thiazolyl, furyl, thienyl, pyridyl, pyrrolyl, N-alkyl pyrrolyl, pyrimidinyl, pyrazinyl, imidazolyl, tetrazolyl, isoxazolyl and the like.
  • the heteroaryl can be fused with the ring of an aryl, heterocyclyl or cycloalkyl, wherein the ring bound to parent structure is heteroaryl. Representative examples include, but are not limited to, the following substituents
  • the heteroaryl group can be substituted or unsubstituted.
  • the substituent group (s) is preferably one or more, sometimes preferably one to five, sometimes more preferably one to three, substituents independently selected from the group consisting of alkyl, alkenyl, alkynyl, alkoxy, alkylsulfo, alkylamino, halogen, thiol, hydroxy, nitro, cyano, cycloalkyl, heterocyclic alkyl, aryl, heteroaryl, cycloalkoxyl, heterocylic alkoxyl, cycloalkylthio, heterocylic alkylthio.
  • Alkoxy refers to both an -O- (alkyl) and an -O- (unsubstituted cycloalkyl) group, wherein the alkyl is defined as above. Representative examples include, but are not limited to, methoxy, ethoxy, propoxy, butoxy, cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, cyclohexyloxy, and the like. The alkoxyl can be substituted or unsubstituted.
  • the substituent is preferably one or more, sometimes preferably one to five, sometimes more preferably one to three, substituents independently selected from the group consisting of alkyl, alkenyl, alkynyl, alkoxy, alkylsulfo, alkylamino, halogen, thiol, hydroxy, nitro, cyano, cycloalkyl, heterocyclic alkyl, aryl, heteroaryl, cycloalkoxyl, heterocylic alkoxyl, cycloalkylthio and heterocylic alkylthio.
  • Haloalkoxy refers to an alkoxy group substituted by one or more halogen (s) , wherein the alkoxy is as defined above.
  • the hydrogen atom of the present invention can be substituted by its isotope deuterium. Any of the hydrogen atoms in the compounds of the examples of the present invention can also be substituted by deuterium atom.
  • “Bond” refers to a covalent bond using a sign of “-” .
  • Hydroalkyl refers to an alkyl group substituted by a hydroxy group, wherein alkyl is as defined above.
  • Haldroxyl or “hydroxy” refers to an -OH group.
  • Halogen or “halo” refers to fluoro, chloro, bromo or iodo atoms.
  • Amino refers to a -NH 2 group.
  • Cyano refers to a -CN group.
  • Niro refers to a -NO 2 group.
  • Carboxyl refers to a -C (O) OH group.
  • Alkoxycarbonyl refers to a -C (O) O (alkyl) or (cycloalkyl) group, wherein the alkyl and cycloalkyl are defined as above.
  • groups or substituents are “independently selected from” (and variants thereof) a list of choices, it is meant that the choice for any one of such groups or substituents does not determine the choice for any other one of such groups or substituents.
  • the term “A and B are independently selected from a and b” or “each of A and B is independently selected from a and b” is meant to encompass selections where 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.
  • heterocyclic group optionally substituted by an alkyl means that an alkyl group can be, but need not be, present, and the description includes the case of the heterocyclic group being substituted with an alkyl and the heterocyclic group being not substituted with an alkyl.
  • “Substituted” refers to one or more hydrogen a members in a group independently substituted with a corresponding number of substituents. In some embodiments, the number of such hydrogen members is up to 5. In other embodiemtns it si between 1 and 3. It goes without saying that the substituents exist in their only possible chemical position. The person skilled in the art is able to determine if the substitution is possible or impossible without paying excessive efforts by experiment or theory. For example, the combination of amino or hydroxyl group having free hydrogen and carbon atoms having unsaturated bonds (such as olefinic) may be unstable.
  • a “pharmaceutical composition” refers to a mixture of one or more of the compounds described in the present invention or physiologically/pharmaceutically acceptable salts or prodrugs thereof and other chemical components such as physiologically/pharmaceutically acceptable carriers and excipients.
  • the purpose of a pharmaceutical composition is to facilitate administration of a compound to an organism, which is conducive to the absorption of the active ingredient and thus displaying biological activity.
  • “Pharmaceutically acceptable salts” refer to salts of the compounds of the invention, such salts being safe and effective when used in a mammal and have corresponding biological activity.
  • each compound is identified by nuclear magnetic resonance (NMR) and/or mass spectrometry (MS) .
  • NMR chemical shifts ( ⁇ ) are given in 10 -6 (ppm) .
  • NMR is determined by Varian Mercury 300 MHz Bruker Avance III 400MHz machine.
  • the solvents used are deuterated-dimethyl sulfoxide (DMSO-d 6 ) , deuterated-chloroform (CDCl 3 ) and deuterated-methanol (CD 3 OD) .
  • HPLC High performance liquid chromatography
  • LCMS Liquid Chromatography Mass Spectrometry
  • the average rates of ATPase inhibition, and the IC 50 values are determined by Victor Nivo multimode plate reader (PerkinElmer, USA) .
  • the thin-layer silica gel plates used in thin-layer chromatography are Yantai Xinnuo silica gel plate.
  • the dimension of the plates used in TLC is 0.15 mm to 0.2 mm, and the dimension of the plates used in thin-layer chromatography for product purification was 0.4 mm to 0.5 mm.
  • the known starting material of the invention can be prepared by the conventional synthesis method in the prior art, or can be purchased from ABCR GmbH &Co. KG, Acros Organics, Aldrich Chemical Company, Accela ChemBio Inc or Dari chemical Company, etc.
  • argon atmosphere or “nitrogen atmosphere” means that a reaction flask is equipped with a balloon having 1 L of argon or nitrogen.
  • hydrogen atmosphere means that a reaction flask was equipped with a balloon having 1 L of hydrogen.
  • Factor B binding affinity of each compound tested was determined using a time-resolved fluorescence resonance energy transfer (TR-FRET) techonology. 10 nM recombinant his-tagged Factor B catalytic domain, varying concentrations of inhibitors, 4 nM LANCE Eu-W1024 Anti-6xHis Antibody and 100 nM TRFRET_tool2 tracer was incubated in 1X Kinase Buffer A for 1 h. Measurement was performed in a reaction volume of 15 ⁇ L by adding 5 ⁇ L of the test compound, 5 ⁇ L of Factor B/antibody mixture and 5 ⁇ L of tracer into white opaque 384-well assay plates.
  • TR-FRET time-resolved fluorescence resonance energy transfer
  • the TR-FRET signal was read on a plate reader with an excitation wavelength of 340 nm and detection wavelengths of 615 and 665 nm. Binding affinity was determined for each compound by measuring TR-FRET signal at various concentrations of compound and plotting the relative fluorescence Emission Ratio (665 nm/615 nm) against the inhibitor concentration to estimate the IC 50 from [Compound] vs Emission Ratio using the four parameters dose-response inhibition curve with a variable slope model in GraphPad Prism.
  • Example compounds in present invention were tested in above assay and show IC 50 (nM) 0.5-250 nM against human Factor B.
  • Recombinant human Factor B catalytic domain (a. a. 470-764, C-terminal his-tagged, produced in-house)
  • Biacore 8k instrument was primed using 1X PBS-P+ buffer before docking a Cytiva NTA chip.
  • Recombinant human Factor B catalytic domain were immobilized on a NTA chip to a level of about 5000 resonance units (RU) using 1X PBS-P+ buffer [20 mM phosphate buffer with 2.7 mM KCl, 137 mM NaCl, and 0.05% (v/v) Tween-20] .
  • the protein ligand was further crosslinked to sensorchip surface by amine coupling kit. Immobilization and binding experiment were performed at room temperature.
  • a pre-run was performed for a period of at least 30 min at a flow rate of 30 ⁇ l/min to obtain a stable surface.
  • the kinetic constants of the compounds were determined by single-cycle kinetics with six consecutive injections (or multi-cycle kinetics with eight consecutive injections) with an increasing compound concentration in ranges of 0.8–200 nM, 12.5–400 nM, 4.1–1,000 nM or 41–10,000 nM depending on the potency.
  • Example compounds in present invention were tested in above assay and show K D (nM) 0.5-250 nM against human Factor B.
  • the AP deposition assay was employed. Test concentration of the compounds started at 11.1 ⁇ M or 3.70 ⁇ M and were diluted 3-fold in DMSO to produce 8 concentration points, with each concentration tested in technical triplicates. Human serum was combined with test compounds in GVB buffer containing 5mM MgCl2 10mM EGTA, and was added to LPS coated black Maxisorp plates. After a period of incubation, the plate was inverted, and ELISA detection of complement proteins bound to LPS was performed. A primary antibody that detected human C5b-9 was used, followed by a compatible HRP conjugated secondary antibody. Peroxidase activity was detected using the Quantablu Fluorogenic Peroxidase substrate kit and fluorescence was measured at 340nm/435nm using the i3x plate reader to determine the quantity of alternative pathway complement protein deposition.
  • Example compounds in present invention were tested in above assay and show IC 50 (nM) 125-5000 nM against human Factor B.
  • the AP hemolytic assay was employed. Test concentration of the compounds started at 100 ⁇ M and were diluted 3-fold in DMSO to produce 8-11 concentration points, with each concentration tested in technical triplicates. Human serum was added to rabbit reticulocytes in a solution of GVB buffer with MgCl2 and EGTA. After a period of incubation at 37°C, spontaneous lysis of rabbit erythrocytes due to serum AP complement activity was quantified using OD405 absorbance, measured using the i3x plate reader.
  • Example compounds in present invention were tested in above assay and show IC 50 (nM) 125-5000 nM against human Factor B.
  • Example compound intravenously (0.5 mg/kg dose, formulation: 10%1, 2-Propanediol+25% (20%solutol HS 15 in water) +65%phosphate buffered saline at 0.1 mg/mL) and via oral gavage at 2 mg/kg dose as a clear solution (0.5%MC + 0.5%Tween 80 in water at 1 mg/mL) .
  • Plasma was collected from rats per time point at 0.25, 0.5, 1, 6, and 24 h after administration. The concentrations of the test article were measured in plasma by HPLC–MS/MS, two individual plasma samples at each time point.
  • the present invention describes compounds that are potent factor B inhibitors with desirable physiochemical properties.
  • the described compounds may serve as useful as therapeutic agents for claims made above.

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Abstract

La présente invention concerne des composés de formule (I) utilisés en tant que dérivés de pipéridine substitués en position 2, leur procédé de préparation, des compositions pharmaceutiques comprenant les composés, et des utilisations pharmaceutiques pour le traitement d'une maladie ou d'un trouble.
PCT/CN2023/117941 2022-09-10 2023-09-11 Dérivés de pipéridine substitués en position 2, leurs procédés de préparation et leurs utilisations médicinales Ceased WO2024051849A1 (fr)

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EP23862542.0A EP4584255A1 (fr) 2022-09-10 2023-09-11 Dérivés de pipéridine substitués en position 2, leurs procédés de préparation et leurs utilisations médicinales
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