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WO2026002007A1 - Inhibiteur du facteur b du complément, composition pharmaceutique à base de celui-ci et utilisation associée - Google Patents

Inhibiteur du facteur b du complément, composition pharmaceutique à base de celui-ci et utilisation associée

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Publication number
WO2026002007A1
WO2026002007A1 PCT/CN2025/103317 CN2025103317W WO2026002007A1 WO 2026002007 A1 WO2026002007 A1 WO 2026002007A1 CN 2025103317 W CN2025103317 W CN 2025103317W WO 2026002007 A1 WO2026002007 A1 WO 2026002007A1
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WIPO (PCT)
Prior art keywords
alkyl
haloalkyl
cycloalkyl
alkylene
alkoxy
Prior art date
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Pending
Application number
PCT/CN2025/103317
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English (en)
Chinese (zh)
Inventor
谷正松
陈照强
秦丽
张晓金
赵岭
邵顺杰
周媛
曹斌
田野
陈斌
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Zhuhai United Laboratories Co Ltd
Original Assignee
Zhuhai United Laboratories Co Ltd
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Filing date
Publication date
Application filed by Zhuhai United Laboratories Co Ltd filed Critical Zhuhai United Laboratories Co Ltd
Publication of WO2026002007A1 publication Critical patent/WO2026002007A1/fr
Pending legal-status Critical Current
Anticipated expiration legal-status Critical

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Definitions

  • This invention belongs to the field of drug synthesis, specifically relating to a novel complement factor B inhibitor, its pharmaceutical composition, and its applications.
  • the complement system is an important component of the body's innate immunity, playing a crucial role in pathogen immune surveillance and maintaining tissue homeostasis.
  • the complement system is involved in the occurrence and development of various diseases, such as neurological disorders like Alzheimer's (AD), neuromyelitis optica (NMO), and myasthenia gravis (gMG); eye diseases like age-related macular degeneration (AMD), uveitis, and glaucoma; kidney diseases such as atypical hemolytic uremic syndrome (aHUS), C3 glomerulonephropathy (C3G), and IgA nephropathy; and hematological diseases such as cold agglutinin disorders, paroxysmal nocturnal hemoglobinuria (PNH), and thrombotic microangiopathy (TMAs).
  • AD Alzheimer's
  • NMO neuromyelitis optica
  • gMG myasthenia gravis
  • AMD age-related macular degeneration
  • uveitis uveitis
  • CFB complement factor B
  • AP alternative pathway
  • LP lectin pathway
  • CFB is a key factor in the alternative pathway (AP), primarily synthesized by hepatocytes and macrophages, and is a crucial component in its activation.
  • AP alternative pathway
  • CFB participates in the body's defense mechanisms, playing a vital role in cell damage and inflammation.
  • CFB is a trypsin-like serine protease, existing in the bloodstream as a zymogen.
  • FB is a major component in activating the AP pathway; upon activation, it binds to C3b, which is subsequently cleaved by FD to produce a C3 convertase complex (C3bBb) containing the FB catalytic subunit (Bb). C3bBb further cleaves C3 to generate more C3b, thus amplifying the activation of the entire complement system.
  • Uncontrolled circulation of C3 leads to the deposition of large amounts of active C3b and terminal complement factors in the glomeruli, causing changes in glomerular structure and function, and further triggering complement system-related nephropathy.
  • LNP023 (WO2015009616A1 and WO2019043609A1) is Novartis' first small molecule FB-targeting inhibitor for the treatment of kidney diseases related to complement system involvement, including paroxysmal nocturnal hemoglobinuria (PNH), immunoglobulin A nephropathy (IgAN), C3 glomerular disease (C3G), and atypical hemolytic uremic syndrome (aHUS).
  • PNH paroxysmal nocturnal hemoglobinuria
  • IgAN immunoglobulin A nephropathy
  • C3G C3 glomerular disease
  • aHUS atypical hemolytic uremic syndrome
  • This invention provides compounds that regulate and preferably inhibit activation of the complement bypass pathway.
  • this invention provides compounds that regulate and preferably inhibit complement factor B (FB) activity and/or FB-mediated complement pathway activation.
  • FB complement factor B
  • novel small molecule inhibitors of FB of the present invention have a high affinity for FB, inhibit its catalytic activity, and exhibit significant inhibitory effects on complement bypass pathway activation. Therefore, they have the potential to inhibit complement system amplification caused by C3 activation, and to prevent and treat diseases, disorders, or conditions mediated by complement activation, particularly those mediated by complement bypass pathway activation.
  • the compounds of the present invention possess superior properties such as improved pharmacokinetic properties (e.g., improved bioavailability, improved metabolic stability, suitable half-life and duration of action), improved safety (lower toxicity (e.g., reduced cardiotoxicity) and/or fewer side effects), and less likelihood of developing drug resistance.
  • the present invention provides compounds of formula (I) as defined below:
  • the present invention provides pharmaceutical compositions comprising a compound of formula (I) according to the invention, or a stereoisomer, tautomer, diastereomer, racemic compound, cis-trans isomer, isotopically labeled compound (preferably deuterated), N-oxide, metabolite, ester, prodrug, crystal form, hydrate, solvate or pharmaceutically acceptable salt, and a pharmaceutically acceptable carrier.
  • the present invention provides a pharmaceutical combination comprising a compound of formula (I) according to the invention, or a stereoisomer, tautomer, diastereomer, racemic compound, cis-trans isomer, isotopically labeled compound (preferably deuterated), N-oxide, metabolite, ester, prodrug, crystal form, hydrate, solvate or pharmaceutically acceptable salt, and another therapeutically active agent.
  • a pharmaceutical combination comprising a compound of formula (I) according to the invention, or a stereoisomer, tautomer, diastereomer, racemic compound, cis-trans isomer, isotopically labeled compound (preferably deuterated), N-oxide, metabolite, ester, prodrug, crystal form, hydrate, solvate or pharmaceutically acceptable salt, and another therapeutically active agent.
  • the present invention provides a method for modulating the activity of the complement bypass pathway in an individual, wherein the method comprises: administering to the individual a therapeutically effective amount of a compound of formula (I) according to the invention, or a stereoisomer, tautomer, diastereomer, racemic compound, cis-trans isomer, isotopically labeled compound (preferably deuterated), N-oxide, metabolite, ester, prodrug, crystal form, hydrate, solvate, or pharmaceutically acceptable salt thereof; or administering to the individual a therapeutically effective amount of a pharmaceutical composition according to the invention; or administering to the individual a therapeutically effective amount of a pharmaceutical combination according to the invention.
  • a compound of formula (I) according to the invention
  • a stereoisomer, tautomer, diastereomer, racemic compound, cis-trans isomer isotopically labeled compound (preferably deuterated), N-oxide, metabolite, ester, prodrug, crystal
  • the present invention provides a method for preventing or treating diseases, disorders, or conditions mediated by complement activation in an individual, particularly diseases, disorders, or conditions mediated by activation of the complement alternative pathway, wherein the method comprises: administering to the individual a therapeutically effective amount of a compound of formula (I) according to the invention, or a stereoisomer, tautomer, diastereomer, racemic compound, cis-trans isomer, isotopically labeled compound (preferably deuterated), N-oxide, metabolite, ester, prodrug, crystal form, hydrate, solvate, or pharmaceutically acceptable salt thereof; or administering to the individual a therapeutically effective amount of a pharmaceutical composition according to the invention; or administering to the individual a therapeutically effective amount of a pharmaceutical combination according to the invention.
  • a compound of formula (I) according to the invention, or a stereoisomer, tautomer, diastereomer, racemic compound, cis-trans isomer, isotopically labele
  • the present invention provides a compound of formula (I) according to the invention, or a stereoisomer, tautomer, diastereomer, racemic compound, cis-trans isomer, isotopically labeled compound (preferably deuterated), N-oxide, metabolite, ester, prodrug, crystal form, hydrate, solvate or pharmaceutically acceptable salt, or a pharmaceutical composition according to the invention, or a pharmaceutical combination according to the invention, which are used as pharmaceuticals.
  • a compound of formula (I) according to the invention or a stereoisomer, tautomer, diastereomer, racemic compound, cis-trans isomer, isotopically labeled compound (preferably deuterated), N-oxide, metabolite, ester, prodrug, crystal form, hydrate, solvate or pharmaceutically acceptable salt, or a pharmaceutical composition according to the invention, or a pharmaceutical combination according to the invention, which are used as pharmaceuticals.
  • the present invention provides the use of a compound of formula (I) according to the invention, or its stereoisomers, tautomers, diastereomers, racemic derivatives, cis-trans isomers, isotopically labeled compounds (preferably deuterated), N-oxides, metabolites, esters, prodrugs, crystal forms, hydrates, solvates or pharmaceutically acceptable salts, or pharmaceutical compositions according to the invention, or pharmaceutical combinations according to the invention, in the preparation of medicaments for treating diseases, disorders or conditions mediated by complement activation in an individual, particularly diseases, disorders or conditions mediated by activation of the complement alternative pathway.
  • a compound of formula (I) according to the invention or its stereoisomers, tautomers, diastereomers, racemic derivatives, cis-trans isomers, isotopically labeled compounds (preferably deuterated), N-oxides, metabolites, esters, prodrugs, crystal forms, hydrates, solvates or pharmaceutically acceptable salts, or pharmaceutical composition
  • the diseases, disorders, or conditions described are selected from age-related macular degeneration (AMD), geographic macular atrophy, diabetic retinopathy, uveitis, retinitis pigmentosa, macular edema, Behcet's uveitis, multifocal choroiditis, Vogt-Koyangi-Harada syndrome, intermediate uveitis, skeletal retinochoroiditis, sympathetic ophthalmia, ocular cicatricial pemphigoid, ocular pemphigoid, non-arterial ischemic optic neuropathy, postoperative inflammation, retinal vein occlusion, neurological disorders, multiple sclerosis, etc.
  • AMD age-related macular degeneration
  • AMD age-related macular degeneration
  • diabetic retinopathy diabetic retinopathy
  • uveitis retinitis pigmentosa
  • macular edema macular edema
  • Behcet's uveitis
  • alkane refers to a straight-chain or branched saturated aliphatic hydrocarbon.
  • alkyl refers to a straight-chain or branched monovalent saturated aliphatic hydrocarbon, which can be considered as a group obtained by losing one hydrogen atom from an alkane.
  • the alkyl group has 1 to 12, for example 1 to 6 (e.g., 1, 2, 3, 4, 5, or 6) carbon atoms.
  • C1-6 alkyl refers to a straight-chain or branched group with 1 to 6 carbon atoms, including " C2-6 alkyl", “ C2-5 alkyl", and " C1-4 alkyl".
  • C1-6 alkyl examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, and n-hexyl.
  • the alkyl group is optionally substituted with one or more (such as one to three) suitable substituents such as halogens (in which case the group is called a "haloalkyl", for example CF3 , C2F5 , CHF2 , CH2F , CH2CF3 , CH2Cl , or -CH2CH2CF3 , etc. ).
  • C1-4 alkyl refers to an alkyl group having one to four carbon atoms (i.e., methyl, ethyl, n-propyl , isopropyl, n-butyl, isobutyl, sec-butyl, or tert-butyl).
  • alkylene refers to a straight-chain or branched divalent saturated aliphatic hydrocarbon.
  • the alkylene has 1 to 12 carbon atoms, preferably 1, 2, 3, 4, 5 or 6 carbon atoms, such as methylene, ethylene, propylene or butylene.
  • heteroalkyl means an alkyl group as defined herein, in which one or more CH2 atoms in the skeleton are replaced by heteroatoms, each independently selected from O, S, S(O), S(O) 2 , NR', and combinations thereof, wherein R' is a hydrogen atom or a C1-6 alkyl or a halo- C1-6 alkyl.
  • R' is a hydrogen atom or a C1-6 alkyl or a halo- C1-6 alkyl.
  • the heteroalkylene group may be, for example, a 2- to 6-membered heteroalkylene group, a 2- to 5-membered heteroalkylene group, or a 2- to 4-membered heteroalkylene group (e.g., -CH2OCH2CH3 , -CH2N ( CH3 ) CH2CH3 ) .
  • the heteroalkyl group may be attached to the remainder of the molecule via heteroatoms or carbon atoms in the skeleton chain.
  • alkenyl refers to a straight-chain or branched monovalent aliphatic hydrocarbon group containing one or more double bonds.
  • the alkenyl group has 2-6 carbon atoms (" C2-6 alkenyl").
  • alkynyl refers to a straight-chain or branched monovalent aliphatic hydrocarbon group containing one or more triple bonds.
  • the alkynyl group has 2, 3, 4, 5, or 6 carbon atoms ("C 2-6 alkynyl"), such as ethynyl, 2-propynyl, 2-butynyl, 1,3-butadiynyl, etc.
  • the alkynyl group is optionally substituted by one or more (such as 1 to 3) identical or different substituents.
  • ynynyl refers to a corresponding divalent group, including, for example, “C 2-6 ynynyl,””C 2-4 ynynyl,” etc. Examples include, but are not limited to, [examples not included in the text].
  • the alynyl group may optionally be substituted by one or more (such as 1 to 3) identical or different substituents.
  • cycloalkyl refers to a monocyclic or polycyclic hydrocarbon ring having, for example, 3 to 10 (suitably 3 to 8, more preferably 3 to 7, 3 to 6, 4 to 6, or 5 to 6) cyclic carbon atoms, either saturated (i.e., “cycloalkyl” and “cycloalkylene-subcycloalkyl”) or partially unsaturated (i.e., having one or more double bonds (i.e., “cycloalkenyl” and “cycloalkenylene”) and/or triple bonds within the ring.
  • fusion means that two or more ring structures share two adjacent atoms with each other.
  • bridge or “bridging” or “bridge connection” means that two or more ring structures share two non-adjacent atoms.
  • screw or “screwed connection” refers to two or more ring structures sharing one atom with each other.
  • cycloalkyl refers to a saturated monocyclic or polycyclic (such as bicyclic) hydrocarbon ring (e.g., monocyclic, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, or bicyclic, including spirocyclic, fused, or bridged systems (such as bicyclic [1.1.1]pentyl, bicyclic [2.2.1]heptyl, bicyclic [3.2.1]octyl, or bicyclic [5.2.0]nonyl, decahydronaphthyl, etc.), optionally substituted with one or more (such as one to three) suitable substituents.
  • monocyclic such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl
  • the cycloalkyl group has 3 to 15 carbon atoms, suitably 3 to 10 carbon atoms.
  • C "3-6 cycloalkyl” refers to a saturated non-aromatic monocyclic or polycyclic (such as bicyclic) hydrocarbon ring (e.g., cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl) with 3 to 6 cyclic carbon atoms.
  • the cycloalkyl group is optionally substituted with one or more (such as 1 to 3) suitable substituents, such as methyl-substituted cyclopropyl.
  • the heterocyclic group may be attached to the remainder of the molecule by any one of the carbon atoms or a nitrogen atom (if present).
  • the “heterocyclic group” can be a monocyclic or polycyclic system (polycyclic systems include, but are not limited to, bicyclic, tricyclic, tetracyclic, or pentacyclic groups).
  • a 3-12 membered heterocyclic group is a group having 3-12 (e.g., 3-7, 4-6, or 5-6) carbon atoms and heteroatoms in a ring, such as, but not limited to, ethylene oxide, aziridinyl, azetidinyl, oxetanyl, thioheterocyclic butane, tetrahydrofuranyl, dioxolinyl, pyrrolyl, pyrrolidone, imidazoalkyl, pyrazolyl, pyrrolinyl, tetrahydropyranyl, piperidinyl, morpholinyl, dithianyl, thiomorpholinyl, piperazinyl, or trithianyl.
  • 3-12 e.g., 3-7, 4-6, or 5-6 carbon atoms and heteroatoms in a ring
  • 3-12 e.g., 3-7, 4-6, or 5-6 carbon atoms and heteroatoms in a
  • aryl refers to a monocyclic or fused-ring aromatic group having a conjugated ⁇ -electron system.
  • C6-10 aryl means an aromatic group containing 6 to 10 carbon atoms, such as phenyl or naphthyl.
  • the aryl group may optionally be substituted with one or more (such as 1 to 3) suitable substituents (e.g., halogen, -OH, -CN, -NO2, C1-6 alkyl , etc.).
  • heteroaryl refers to a monocyclic, bicyclic, or tricyclic aromatic ring system having 5, 6, 8, 9, 10, 11, 12, 13, or 14 ring atoms, particularly 1, 2, 3, 4, 5, 6, 9, or 10 carbon atoms, and containing at least one heteroatom (which may be the same or different, for example, oxygen, nitrogen, or sulfur), and additionally, in each case, may be benzofused.
  • the heteroaryl group is selected from thienyl, furanyl, pyrroleyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl (including 1,2,3-triazolyl, 1,2,4-triazolyl), thiazolyl, etc., and their benzo[derivatives]; or pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, etc., and their benzo[derivatives].
  • halogenated or halogenated is defined as including F, Cl, Br or I.
  • substitution refers to the selective replacement of one or more (e.g., one, two, three, or four) hydrogen atoms on a specified atom by a designated group, provided that the substitution does not exceed the normal valence of the specified atom in the present case and that the substitution forms a stable compound. Combinations of substituents and/or variables are permitted only if such combinations form a stable compound.
  • a group is described as “optionally substituted” or “optionally substituted”, then the group may be: (1) unsubstituted or (2) substituted. If the carbon of the group is described as being optionally substituted with one or more of the substituents in the list, then one or more hydrogens on the carbon (to the extent that any hydrogens are present) may be substituted individually and/or together with independently selected optional substituents. If the nitrogen of the group is described as being optionally substituted with one or more of the substituents in the list, then one or more hydrogens on the nitrogen (to the extent that any hydrogens are present) may each be substituted with independently selected optional substituents.
  • Optional substituents may be selected from: deuterium, halogen, OH, SH, CN, NO2 , C1 -6 alkyl, C1 - 6 haloalkyl, C2 - 6 alkenyl, C2-6 ynyl, -OC1 -6 alkyl, -O-haloC1-6 alkyl, -OC2- 6 alkenyl, -OC2- 6 ynyl, -SC1- 6 alkyl, NH2, -NH(C1 -6 alkyl), -N(C1 - 6 alkyl) 2 , -C1-6 alkylene-OH, -C1-6 alkylene-SH, -C1 -6 alkylene-CN, -C1- 6 alkylene-NH2, -C1- 6 alkylene-NH(C1 -6 alkyl), -C1-6 alkylene-N(C1-6 alkyl) 2 , -C1-6 alkyl-OC1 -6 alkyl, -
  • each substituent is selected independently of the others. Therefore, each substituent may be the same as or different from another (other) substituent.
  • one or more means one or more under reasonable conditions, such as two, three, four, five, six, seven, eight, nine, or ten.
  • connection point of a substituent may be derived from any suitable location of the substituent.
  • a substituent When a substituent is shown to be a bond that passes through the ring and connects two atoms (“floating bond”), such a substituent may be bonded to any cyclic atom in the substituted ring, unless otherwise stated.
  • a substituted hydrogen atom In cases where a substituted hydrogen atom is shown to be carried by a substituted ring member, the substituted hydrogen atom is substantially substituted (i.e., not present) when the floating bond is bonded to that substituted ring member.
  • This invention also includes all pharmaceutically acceptable isotopically labeled compounds that are identical to the compounds of this invention, except that one or more atoms are replaced by atoms having the same atomic number but a different atomic mass or mass number than the dominant atomic mass or mass number found in nature.
  • isotopes suitable for inclusion in the compounds of this invention include (but are not limited to) isotopes of hydrogen (e.g., deuterium (D, 2H ), tritium (T, 3H )); isotopes of carbon (e.g., 11C , 13C , and 14C ); isotopes of chlorine (e.g., 36Cl ); isotopes of fluorine (e.g., 18F ); isotopes of iodine (e.g., 123I and 125I ); isotopes of nitrogen (e.g., 13N and 15N ); isotopes of oxygen (e.g., 15O , 17O , and 18O ); isotopes of phosphorus (e.g., 32P ); and isotopes of sulfur (e.g., 35S ).
  • isotopes of hydrogen e.g., deuterium (D, 2H ), tri
  • Radioactive isotopes tritium (i.e., 3H ) and carbon-14 (i.e., 14C ) are particularly suitable for this purpose due to their ease of incorporation and detection.
  • Substitution with positron-emitting isotopes e.g., 11C , 18F , 15O , and 13N ) can be used in positron emission tomography (PET) studies to examine substrate acceptor occupancy.
  • PET positron emission tomography
  • Isotopically labeled compounds of the present invention can be prepared by methods similar to those described in the accompanying routes and/or examples and preparations, by using a suitable isotopically labeled reagent instead of the previously used unlabeled reagent.
  • Pharmaceutically acceptable solvates of the present invention include those in which the crystallization solvent can be isotopically substituted, for example, D2O , acetone- d6 , or DMSO- d6 .
  • the isotopically labeled compounds of the present invention are deuterated.
  • stereoisomer refers to isomers formed due to at least one asymmetric center, having the same chemical composition but different spatial arrangements of atoms or groups. In compounds having one or more (e.g., 1, 2, 3, or 4) asymmetric centers, racemic mixtures, single enantiomers, diastereomer mixtures, and individual diastereomers can occur. Specific individual molecules can also exist as geometric isomers (cis/trans). Similarly, the compounds of the present invention can exist as mixtures of two or more structurally different forms in rapid equilibrium (commonly referred to as tautomers).
  • tautomers include keto-enol tautomers, phenol-keto tautomers, nitroso-oxime tautomers, imine-enamine tautomers, etc. It should be understood that the scope of this application covers all such isomers or mixtures thereof in any proportion (e.g., 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%).
  • diastereomer refers to a stereoisomer that has two or more chiral centers and whose molecules are not mirror images of each other. Diastereomers possess different physical properties, such as melting point, boiling point, spectral properties, and reactivity. Mixtures of diastereomers can be separated using high-resolution analytical methods such as electrophoresis and chromatography.
  • enantiomer refers to two stereoisomers of a compound that are non-overlapping mirror images of each other.
  • chirality refers to molecules that have mirror pairs that are not overlapping, while the term “chirality” refers to molecules that can overlap on their mirror pairs.
  • the compounds of the present invention can be prepared in racemic form, or a single enantiomer can be prepared by enantioselective synthesis or by resolution.
  • racemate refers to an equimolar mixture of two enantiomers that lack optical activity.
  • cis-trans isomers or “geometric isomers” arise from the fact that the single bonds of double or cyclic carbon atoms cannot rotate freely.
  • the compounds presented herein include all cis, trans, syn, anti, enumble (E), and sixteen (Z) isomers and their corresponding mixtures.
  • Solid lines may be used in this article. solid wedge Or virtual wedge The chemical bonds of the compounds of the present invention are depicted. Solid lines are used to depict bonds to asymmetric carbon atoms to indicate that all possible stereoisomers (e.g., specific enantiomers, racemic mixtures, etc.) are included at that carbon atom. Solid or dashed wedges are used to depict bonds to asymmetric carbon atoms to indicate the presence of the indicated stereoisomers. When present in racemic mixtures, solid and dashed wedges are used to define relative stereochemistry, not absolute stereochemistry.
  • the compounds of the present invention are intended to exist as stereoisomers (including cis and trans isomers, optical isomers (e.g., R and S enantiomers), diastereomers, geometric isomers, rotational isomers, conformational isomers, trans-blocking isomers, and mixtures thereof).
  • the compounds of the present invention may exhibit more than one type of isomerism and may consist of mixtures thereof (e.g., racemic mixtures and diastereomer pairs).
  • Thick solid lines may be used when the compound contains two chiral centers. and thick dashed lines The chemical bonds in the compound are depicted to show the relative relationship between the two chiral centers, but do not imply any absolute stereochemistry. For example, This indicates that the key connecting Ra on the ring and the key connecting Rb are in sequence with each other, and Coverage and Two corresponding isomers.
  • compositions of the present invention may exist in their free form for therapeutic purposes, or, where appropriate, in their pharmaceutically acceptable derivative forms.
  • pharmaceutically acceptable derivatives include, but are not limited to, pharmaceutically acceptable salts, esters, solvates, metabolites, or prodrugs, which, upon administration to a patient in need, can directly or indirectly provide the compounds of the present invention or their metabolites or residues. Therefore, when referring to "compounds of the present invention” herein, it is also intended to cover the various derivative forms of the compounds described above.
  • pharmaceutically acceptable means that a substance or composition must be chemically and/or toxicologically compatible with other components constituting the formulation and/or the mammals treated with it.
  • Pharmaceutically acceptable salts of the compounds of the present invention include their acid addition salts and base addition salts.
  • Suitable acid addition salts are formed from acids that form pharmaceutically acceptable salts. Examples include aspartate, benzoate, bicarbonate/carbonate, bisulfate/sulfate, fumarate, glucohepanoate, glucuronate, hexafluorophosphate, hydrobromide/bromide, hydroiodate/iodide, maleate, malonate, methyl sulfate, naphthylcarbamate, nicotinate, nitrate, orotate, oxalate, palmitate, and other similar salts.
  • esters means an ester derived from the various general formula compounds of this application, including physiologically hydrolyzable esters (the compounds of the present invention that can be hydrolyzed under physiological conditions to release free acids or alcohols).
  • the compounds of the present invention may themselves also be esters.
  • This invention covers all possible crystalline forms or polymorphs of the compounds of this invention, which may be a single polymorph or a mixture of more than one polymorph in any proportion.
  • the compounds of the present invention can exist as solvates (preferably hydrates), wherein the compounds of the present invention contain a polar solvent, particularly, for example, water, methanol, or ethanol, as a structural element of the lattice of the compound.
  • a polar solvent particularly, for example, water, methanol, or ethanol
  • the amount of the polar solvent, particularly water, can be stoichiometric or non-stoichiometric.
  • nitrogen-containing heterocycles can form N-oxides because nitrogen requires available lone pairs of electrons to be oxidized into oxides; those skilled in the art will identify nitrogen-containing heterocycles that can form N-oxides. Those skilled in the art will also recognize that tertiary amines can form N-oxides.
  • N-oxides of heterocycles and tertiary amines are well known to those skilled in the art, including the oxidation of heterocycles and tertiary amines with peroxy acids such as peracetic acid and m-chloroperoxybenzoic acid (MCPBA), hydrogen peroxide, alkyl peroxides such as tert-butyl peroxide, sodium perborate, and dioxiranes such as dimethyldioxirane.
  • MCPBA m-chloroperoxybenzoic acid
  • hydrogen peroxide alkyl peroxides such as tert-butyl peroxide, sodium perborate
  • dioxiranes such as dimethyldioxirane.
  • the scope of this invention also includes metabolites of the compounds of this invention, i.e., substances formed in the body when the compounds of this invention are administered. Such products can be generated, for example, by oxidation, reduction, hydrolysis, amidation, deamidation, esterification, defatting, enzymatic hydrolysis, etc., of the administered compound. Therefore, this invention includes metabolites of the compounds of this invention, including compounds obtained by methods that expose the compounds of this invention to mammals for a time sufficient to produce their metabolites.
  • This invention further includes, within its scope, prodrugs of the compounds of the invention, which are certain derivatives of the compounds of the invention that may themselves have little or no pharmacological activity, and which, when administered to or onto the body, can be converted, for example, by hydrolysis and cleavage into the compounds of the invention having the desired activity.
  • prodrugs are functional group derivatives of the compounds that are readily converted in vivo into the desired therapeutically active compounds. Further information regarding the use of prodrugs can be found in “Pro-drugs as Novel Delivery Systems,” Vol. 14, ACS Symposium Series (T. Higuchi and V. Stella) and “Bioreversible Carriers in Drug Design,” Pergamon Press, 1987 (edited by E.B. Roche, American Pharmaceutical Association).
  • the prodrug of the present invention can be prepared, for example, by replacing appropriate functional groups present in the compounds of the present invention with certain portions known to those skilled in the art as “pro-moiety” (e.g., “Design of Prodrugs”, as described in H. Bundgaard (Elsevier, 1985)).
  • This invention also covers compounds of the invention containing protecting groups.
  • protection of sensitive or reactive groups on any relevant molecule may be necessary and/or desired, thereby forming a form of chemical protection for the compounds of the invention.
  • This can be achieved by conventional protecting groups, for example, those described in *Protective Groups in Organic Chemistry*, ed. J.F.W. McOmie, Plenum Press, 1973; and T.W. Greene & P.G.M. Wuts, *Protective Groups in Organic Synthesis*, John Wiley & Sons, 1991, which are incorporated herein by reference.
  • Protecting groups can be removed at appropriate subsequent stages using methods known in the art.
  • the term “about” means within ⁇ 10% of the stated value, preferably within ⁇ 5%, and more preferably within ⁇ 2%.
  • R1 is independently selected from deuterium, halogen, OH, SH, CN, NH2 , -NH ( C1-6 alkyl), -N ( C1-6 alkyl) 2 , C1-6 alkyl, C1-6 alkoxy, -NH ( C1-6 haloalkyl), -N (C1-6 haloalkyl ) 2 , C1-6 haloalkyl, C1-6 haloalkoxy, -NH ( C1-6 deuterated alkyl), -N ( C1-6 deuterated alkyl) 2 , C1-6 deuterated alkyl, C1-6 deuterated alkoxy, C3-6 cycloalkyl, or 4-7 membered heterocyclic groups;
  • R2 is selected from hydrogen, deuterium, halogen, OH, SH, CN, NH2 , -NH ( C1-6 alkyl), -N ( C1-6 alkyl) 2 , C1-6 alkyl, C1-6 alkoxy, -NH ( C1-6 haloalkyl), -N ( C1-6 haloalkyl) 2 , C1-6 haloalkyl, C1-6 haloalkoxy, -NH ( C1-6 deuterated alkyl), -N ( C1-6 deuterated alkyl) 2 , C1-6 deuterated alkyl, C1-6 deuterated alkoxy, C3-6 cycloalkyl, or 4-7 membered heterocyclic groups;
  • R3 is selected from hydrogen, deuterium, halogen, OH, SH, CN, -NR3a R3b , C1-6 alkyl, C1-6 haloalkyl, C1-6 deuteralkyl, C1-6 alkoxy, C1-6 haloalkoxy, C1-6 deuteralkyl, -S ( C1-6 alkyl), C3-6 cycloalkyl, 4-7 membered heterocyclic, C6-10 aryl, 5-10 membered heteroaryl, -C1-6 alkylene- OC1-6 alkyl, -OC1-6 alkylene- OC1-6 alkyl, -C1-6 alkylene-OH, -C1-6 alkylene-CN or -C1-6 alkylene- NR3a R3b ;
  • R3a and R3b are each independently selected from H, C1-6 alkyl, C1-6 haloalkyl, or C1-6 deuteralkyl when they appear;
  • R4 is selected from hydrogen, deuterium, halogen, OH, CN, SH, NH2, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 alkoxy, -S ( C1-6 alkyl), -NH ( C1-6 haloalkyl), -N ( C1-6 haloalkyl) 2 , C3-10 cycloalkyl, 3-12 membered heterocyclic, -C1-6 alkylene- C3-10 cycloalkyl, or -C1-6 alkylene-3-12 membered heterocyclic; wherein the C1-6 alkyl, C2-6 alkenyl, C2-6 alkoxy, -S ( C1-6 alkyl), -NH ( C1-6 haloalkyl), -N ( C1-6 haloalkyl)2, C3-10 cycloalkyl, 3-12 membered heterocyclic, -C1-6 alkylene- C3-10 cycloalkyl, -N ( C1-6 hal
  • Rg and Rh are each independently selected from hydrogen or deuterium
  • n is selected from 0, 1, 2, 3 or 4;
  • R1 is independently selected from deuterium, C1-6 alkyl, C1-6 alkoxy, -NH ( C1-6 haloalkyl), -N ( C1-6 haloalkyl) 2 , C1-6 haloalkyl, C1-6 haloalkoxy, -NH ( C1-6 deuterium alkyl), -N ( C1-6 deuterium alkyl) 2 , C1-6 deuterium alkyl, C1-6 deuterium alkoxy, C3-6 cycloalkyl or 4-7 membered heterocyclic group;
  • R2 is selected from hydrogen, deuterium, halogen, OH, SH, CN, NH2 , -NH ( C1-6 alkyl), -N ( C1-6 alkyl) 2 , C1-6 alkyl, C1-6 alkoxy, -NH ( C1-6 haloalkyl), -N ( C1-6 haloalkyl) 2 , C1-6 haloalkyl, C1-6 haloalkoxy, -NH ( C1-6 deuterated alkyl), -N ( C1-6 deuterated alkyl) 2 , C1-6 deuterated alkyl, C1-6 deuterated alkoxy, C3-6 cycloalkyl, or 4-7 membered heterocyclic groups;
  • R3 is selected from hydrogen, deuterium, halogen, OH, SH, CN, -NR3a R3b , C1-6 alkyl, C1-6 haloalkyl, C1-6 deuteralkyl, C1-6 alkoxy, C1-6 haloalkoxy, C1-6 deuteralkyl, -S ( C1-6 alkyl), C3-6 cycloalkyl, 4-7 membered heterocyclic, C6-10 aryl, 5-10 membered heteroaryl, -C1-6 alkylene- OC1-6 alkyl, -OC1-6 alkylene- OC1-6 alkyl, -C1-6 alkylene-OH, -C1-6 alkylene-CN or -C1-6 alkylene- NR3a R3b ;
  • R3a and R3b are independently selected from H, C1-6 alkyl, C1-6 haloalkyl, or C1-6 deuteralkyl each time they appear;
  • R4 is selected from hydrogen, deuterium, halogen, OH, CN, SH, NH2, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 alkoxy, -S ( C1-6 alkyl), -NH ( C1-6 haloalkyl), -N ( C1-6 haloalkyl) 2 , C3-10 cycloalkyl, 3-12 membered heterocyclic, -C1-6 alkylene- C3-10 cycloalkyl, or -C1-6 alkylene-3-12 membered heterocyclic; wherein the C1-6 alkyl, C2-6 alkenyl, C2-6 alkoxy, -S ( C1-6 alkyl), -NH ( C1-6 haloalkyl), -N ( C1-6 haloalkyl)2, C3-10 cycloalkyl, 3-12 membered heterocyclic, -C1-6 alkylene- C3-10 cycloalkyl, -N ( C1-6 hal
  • Rg and Rh are each independently selected from hydrogen or deuterium
  • n is selected from 0, 1, 2, 3 or 4;
  • R1 is independently selected from deuterium, halogen, OH, SH, CN, NH2 , -NH ( C1-6 alkyl), -N ( C1-6 alkyl) 2 , C1-6 alkyl, C1-6 alkoxy, -NH ( C1-6 haloalkyl), -N (C1-6 haloalkyl ) 2 , C1-6 haloalkyl, C1-6 haloalkoxy, -NH ( C1-6 deuterated alkyl), -N ( C1-6 deuterated alkyl) 2 , C1-6 deuterated alkyl, C1-6 deuterated alkoxy, C3-6 cycloalkyl, or 4-7 membered heterocyclic groups;
  • R2 is selected from deuterium, C1-6 alkoxy, -NH ( C1-6 haloalkyl), -N ( C1-6 haloalkyl) 2 , C1-6 haloalkyl, C1-6 haloalkoxy, -NH (C1-6 deuterium alkyl), -N (C1-6 deuterium alkyl ) 2 , C1-6 deuterium alkyl, C1-6 deuterium alkoxy, or 4-7 membered heterocyclic groups;
  • R3 is selected from hydrogen, deuterium, halogen, OH, SH, CN, -NR3a R3b , C1-6 alkyl, C1-6 haloalkyl, C1-6 deuteralkyl, C1-6 alkoxy, C1-6 haloalkoxy, C1-6 deuteralkyl, -S ( C1-6 alkyl), C3-6 cycloalkyl, 4-7 membered heterocyclic, C6-10 aryl, 5-10 membered heteroaryl, -C1-6 alkylene- OC1-6 alkyl, -OC1-6 alkylene- OC1-6 alkyl, -C1-6 alkylene-OH, -C1-6 alkylene-CN or -C1-6 alkylene- NR3a R3b ;
  • R3a and R3b are each independently selected from H, C1-6 alkyl, C1-6 haloalkyl, or C1-6 deuteralkyl when they appear;
  • R4 is selected from hydrogen, deuterium, halogen, OH, CN, SH, NH2, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 alkoxy, -S ( C1-6 alkyl), -NH ( C1-6 haloalkyl), -N ( C1-6 haloalkyl) 2 , C3-10 cycloalkyl, 3-12 membered heterocyclic, -C1-6 alkylene- C3-10 cycloalkyl, or -C1-6 alkylene-3-12 membered heterocyclic; wherein the C1-6 alkyl, C2-6 alkenyl, C2-6 alkoxy, -S ( C1-6 alkyl), -NH ( C1-6 haloalkyl), -N ( C1-6 haloalkyl)2, C3-10 cycloalkyl, 3-12 membered heterocyclic, -C1-6 alkylene- C3-10 cycloalkyl, -N ( C1-6 hal
  • Rg and Rh are each independently selected from hydrogen or deuterium
  • n is selected from 0, 1, 2, 3 or 4;
  • R1 is independently selected from deuterium, halogen, OH, SH, CN, NH2 , -NH ( C1-6 alkyl), -N ( C1-6 alkyl) 2 , C1-6 alkyl, C1-6 alkoxy, -NH ( C1-6 haloalkyl), -N (C1-6 haloalkyl ) 2 , C1-6 haloalkyl, C1-6 haloalkoxy, -NH ( C1-6 deuterated alkyl), -N ( C1-6 deuterated alkyl) 2 , C1-6 deuterated alkyl, C1-6 deuterated alkoxy, C3-6 cycloalkyl, or 4-7 membered heterocyclic groups;
  • R2 is selected from hydrogen, deuterium, halogen, OH, SH, CN, NH2 , -NH ( C1-6 alkyl), -N ( C1-6 alkyl) 2 , C1-6 alkyl, C1-6 alkoxy, -NH ( C1-6 haloalkyl), -N ( C1-6 haloalkyl) 2 , C1-6 haloalkyl, C1-6 haloalkoxy, -NH ( C1-6 deuterated alkyl), -N ( C1-6 deuterated alkyl) 2 , C1-6 deuterated alkyl, C1-6 deuterated alkoxy, C3-6 cycloalkyl, or 4-7 membered heterocyclic groups;
  • R3 is selected from hydrogen, deuterium, halogen, OH, SH, CN, -NR3a R3b , C1-6 alkyl, C1-6 haloalkyl, C1-6 deuteralkyl, C1-6 alkoxy, C1-6 haloalkoxy, C1-6 deuteralkyl, -S ( C1-6 alkyl), C3-6 cycloalkyl, 4-7 membered heterocyclic, C6-10 aryl, 5-10 membered heteroaryl, -C1-6 alkylene- OC1-6 alkyl, -OC1-6 alkylene- OC1-6 alkyl, -C1-6 alkylene-OH, -C1-6 alkylene-CN or -C1-6 alkylene- NR3a R3b ;
  • R3a and R3b are each independently selected from H, C1-6 alkyl, C1-6 haloalkyl, or C1-6 deuteralkyl when they appear;
  • Rg and Rh are each independently selected from hydrogen or deuterium
  • n is selected from 0, 1, 2, 3 or 4;
  • R1 is independently selected from deuterium, C1-6 alkyl, C1-6 alkoxy, -NH ( C1-6 haloalkyl), -N ( C1-6 haloalkyl) 2 , C1-6 haloalkyl, C1-6 haloalkoxy, -NH ( C1-6 deuterium alkyl), -N ( C1-6 deuterium alkyl) 2 , C1-6 deuterium alkyl, C1-6 deuterium alkoxy, C3-6 cycloalkyl or 4-7 membered heterocyclic group;
  • R2 is selected from deuterium, C1-6 alkoxy, -NH ( C1-6 haloalkyl), -N ( C1-6 haloalkyl) 2 , C1-6 haloalkyl, C1-6 haloalkoxy, -NH (C1-6 deuterium alkyl), -N (C1-6 deuterium alkyl ) 2 , C1-6 deuterium alkyl, C1-6 deuterium alkoxy, or 4-7 membered heterocyclic groups;
  • R 3 is selected from deuterium, 4-7 membered heterocyclic groups, C 6-10 aryl groups, 5-10 membered heteroaryl groups, or -C 1-6 alkylene-CN groups;
  • R3a and R3b are each independently selected from C1-6 haloalkyl or C1-6 deuteralkyl when they appear;
  • Rg and Rh are each independently selected from hydrogen or deuterium
  • n is selected from 0, 1, 2, 3 or 4;
  • R1 is independently selected from halogen, OH, SH, CN, NH2 , -NH ( C1-6 alkyl) or -N ( C1-6 alkyl) 2 ;
  • R2 is selected from hydrogen, halogen, OH, SH, CN, NH2 , -NH ( C1-6 alkyl), -N ( C1-6 alkyl), C1-6 alkyl, or C3-6 cycloalkyl;
  • R3 is selected from hydrogen, halogen, OH, SH, CN, -NR3a R3b , C1-6 alkyl, C1-6 haloalkyl, C1-6 deuterated alkyl, C1-6 alkoxy, C1-6 haloalkoxy, C1-6 deuterated alkoxy, -S ( C1-6 alkyl), C3-6 cycloalkyl, -C1-6 alkylene - OC1-6 alkyl, -OC1-6 alkylene -OC1-6 alkyl , -C1-6 alkylene-OH, or -C1-6 alkylene- NR3a R3b ;
  • R3a and R3b are independently selected from H or C1-6 alkyl groups each time they appear;
  • R4 is selected from hydrogen, halogen, OH, CN, SH, NH2, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 alkoxy, -NH ( C1-6 haloalkyl), -N ( C1-6 haloalkyl) 2 , C3-10 cycloalkyl , 3-12 membered heterocyclic, -C1-6 alkylene- C3-10 cycloalkyl, or -C1-6 alkylene- 3-12 membered heterocyclic; wherein the C1-6 alkyl , C2-6 alkenyl, C2-6 alkoxy, -NH ( C1-6 haloalkyl), -N ( C1-6 haloalkyl) 2 , C3-10 cycloalkyl, 3-12 membered heterocyclic, -C1-6 alkylene - C3-10 cycloalkyl , or -C
  • the 1-6 alkylene-3-12-membered heterocyclic group is optionally
  • Rg and Rh are each independently selected from hydrogen or deuterium
  • n is selected from 0, 1, 2, 3 or 4;
  • both Rg and Rh are hydrogen.
  • the compound described in this invention is not:
  • the compounds of formula (I) of the present invention have the structures shown in formula (I-1) or (I-2):
  • the compounds of formula (I) of the present invention have the structures shown in formula (I-3) or (I-4):
  • n is selected from 0, 1, or 2; preferably, n is selected from 0 or 1; preferably, n is 0.
  • the compound of formula (I) of the present invention has a structure shown in one of formulas (II-1)-(II-6):
  • the compound of formula (I) of the present invention has the structure shown in formula (II-1):
  • the compounds of formula (I) of the present invention have the structure shown in one of formulas (II-7)-(II-18):
  • the compounds of formula (I) of the present invention have the structures shown in formulas (II-7):
  • the compounds of formula (I) of the present invention have the structure shown in one of formulas (II-19)-(II-30):
  • the compounds of formula (I) of the present invention have the structure shown in formula (II-19):
  • R1 is selected from deuterium, halogen, OH, SH, CN, NH2 , -NH ( C1-4 alkyl), -N ( C1-4 alkyl) 2 , C1-4 alkyl, C1-4 alkoxy, -NH ( C1-4 haloalkyl), -N ( C1-4 haloalkyl) 2 , C1-4 haloalkyl, C1-4 haloalkoxy, -NH ( C1-4 deuterated alkyl), -N ( C1-4 deuterated alkyl) 2 , C1-4 deuterated alkyl, C1-4 deuterated alkoxy, C3-6 cycloalkyl, or 4-7 membered heterocyclic groups.
  • R1 is selected from halogens or C1-4 alkyl groups.
  • R1 is selected from F, Cl, or methyl.
  • R2 is selected from hydrogen, deuterium, halogen, OH, SH, CN, NH2 , -NH ( C1-4 alkyl), -N ( C1-4 alkyl) 2 , C1-4 alkyl, C1-4 alkoxy, -NH ( C1-4 haloalkyl), -N ( C1-4 haloalkyl) 2 , C1-4 haloalkyl, C1-4 haloalkoxy, -NH ( C1-4 deuterated alkyl), -N ( C1-4 deuterated alkyl) 2 , C1-4 deuterated alkyl, C1-4 deuterated alkoxy, C3-6 cycloalkyl, or 4-7 membered heterocyclic groups.
  • R2 is selected from hydrogen, halogen, or C1-4 alkyl.
  • R2 is selected from hydrogen or halogen.
  • R2 is selected from hydrogen, F, or Cl.
  • R2 is hydrogen
  • R3 is selected from hydrogen, deuterium, halogen, OH, SH, CN, -NR3a R3b , C1-4 alkyl, C1-4 haloalkyl, C1-4 deuteralkyl, C1-4 alkoxy, C1-4 haloalkoxy, C1-4 deuteralkyl, -S ( C1-4 alkyl), C3-6 cycloalkyl, 4-7 heterocyclic, C6-10 aryl, 5-6 heteroaryl, -C1-4 alkylene- OC1-4 alkyl, -OC1-4 alkylene - OC1-4 alkyl, -C1-4 alkylene-OH, -C1-4 alkylene-CN, or -C1-4 alkylene- NR3a R3b .
  • R3a and R3b are independently selected from H, C1-4 alkyl, C1-4 haloalkyl, or C1-4 deuteralkyl each time they appear.
  • R3 is selected from halogens, CN, C1-4 alkyl, -S ( C1-4 alkyl), -NR3a R3b , C1-4 alkoxy, C3-6 cycloalkyl, 4-7 heterocyclic, or -C1-4 alkylene- OC1-4 alkyl.
  • R3a and R3b are independently selected from H or C1-4 alkyl groups each time they appear.
  • R3 is selected from F, Cl, CN, C1-4 alkyl, -S ( C1-4 alkyl), -NR3a R3b , C1-4 alkoxy, C3-6 cycloalkyl, 4-7 heterocyclic, or -C1-4 alkylene- OC1-4 alkyl.
  • R3a and R3b are independently selected from H or C1-4 alkyl groups each time they appear; preferably, one of R3a and R3b is H and the other is C1-4 alkyl.
  • R3 is selected from CN, C1-4 alkyl, C1-4 alkoxy, and C3-6 cycloalkyl.
  • R3 is a C1-4 alkyl group.
  • R3 is selected from CN, C1-4 alkyl, -S ( C1-4 alkyl), C1-4 alkoxy, C3-6 cycloalkyl, or 4-7 membered heterocyclic groups.
  • R3 is selected from F, Cl, -CN, -CH3 , -CH2CH3 , -CH ( CH3 ) 2 , -SCH3 , -NHCH3, -OCH3 , -OCH2CH3 , -OCH(CH3 ) 2 , -CH2OCH3 , cyclopropyl, cyclobutyl , oxacyclobutyl ( e.g. ) ), thioheterobutyl (e.g.) ) or nitrogen-containing heterocyclic butyl (e.g. ).
  • R3 is selected from CN, -CH3 , -CH2CH3 , -CH ( CH3 ) 2 , -SCH3 , cyclobutyl , oxacyclobutyl, -OCH3 , cyclopropyl or -OCH2CH3 .
  • R3 is selected from CN, -CH3 , -CH2CH3 , -CH( CH3 ) 2 , -SCH3 , cyclobutyl or oxacyclobutyl.
  • R4 is selected from C1-4 alkyl, C2-4 alkenyl, C2-4 alkynyl, C1-4 alkoxy, -S ( C1-4 alkyl), -NH ( C1-4 haloalkyl), -N ( C1-4 haloalkyl), C3-6 cycloalkyl, 4-7 membered heterocyclic, -C1-4 alkylene- C3-6 cycloalkyl, or -C1-4 alkylene- 4-7 membered heterocyclic; wherein the C1-4 alkyl , C2-4 alkenyl , C2-4 alkoxy, -S ( C1-4 alkyl), -NH ( C1-4 haloalkyl), -N ( C1-4 haloalkyl), C3-6 cycloalkyl, 4-7 membered heterocyclic, -C1-4 alkylene- C3-6 cycloalkyl , or -C
  • the 1-4 alkylene-4-7-membered heterocyclic group is optionally substituted with 1, 2, 3, 4, 5 or 6
  • R4 is selected from C1-6 alkyl, C3-10 cycloalkyl, -C1-6 alkylene- C3-10 cycloalkyl; the C1-6 alkyl is optionally substituted with 1, 2, 3, 4, 5 or 6 substituents selected from halogen, C1-6 alkoxy, C1-6 haloalkoxy, -S( C1-6 haloalkyl), -S(O)( C1-6 haloalkyl), -S(O) 2 ( C1-6 haloalkyl), -O( C3-6 halocycloalkyl); the C3-10 cycloalkyl in the C3-10 cycloalkyl and -C1-6 alkylene- C3-10 cycloalkyl is optionally substituted with 1, 2, 3 , 4, 5 or 6 substituents selected from halogen, C1-6 haloalkyl or C1-6 haloalkoxy.
  • R4 is selected from C1-4 alkyl; the C1-4 alkyl is optionally substituted by 1, 2, 3, 4, 5 or 6 substituents selected from halogen, C1-4 alkoxy, C1-4 haloalkoxy, -S ( C1-4 haloalkyl) or -O ( C3-6 halocycloalkyl).
  • R4 is selected from C1-4 alkyl groups; the C1-4 alkyl group is optionally substituted by 1, 2, 3, 4, 5 or 6 substituents selected from halogens, C1-4 alkoxy groups or C1-4 haloalkoxy groups.
  • R4 is selected from (Preferred) ), (Preferred) ), (Preferred) ), (Preferred) ), (Preferred) ), (Preferred) ), (Preferred) ),
  • R4 is selected from (Preferred) ), (Preferred) ), (Preferred) ), (Preferred) ).
  • R4 is selected from (Preferred) )or (Preferred) ).
  • the compounds of the present invention have the structure shown in formula (III-1):
  • n is selected from 0 or 1;
  • p is selected from 0, 1, 2, or 3;
  • Ra and Rb are each independently selected from H, deuterium, halogen, C1-6 alkyl, C1-6 haloalkyl, C1-6 alkoxy or C1-6 haloalkoxy;
  • L is selected from -CR L1 R L2 -, -C 3-6 cycloalkyl-, -C 3-6 halocycloalkyl-, -OC 3-6 cycloalkyl-*, -OC 3-6 halocycloalkyl-*, -SC 3-6 cycloalkyl-* or -SC 3-6 halocycloalkyl-*, wherein the bond marked with "*" is connected to Q;
  • RL1 and RL2 are each independently selected from H, deuterium, halogen, CN, OH, NH2 , C1-6 alkyl, C1-6 haloalkyl, C1-6 alkoxy or C1-6 haloalkoxy; or RL1 , RL2 and the carbon atoms they are attached to form C3-6 cycloalkyl or 4-7 heterocyclic groups;
  • R1 , R2 , R3 , Rg , and Rh are as defined in any of the aforementioned schemes.
  • the compounds of the present invention have the structure shown in formula (III-2) or (III-3):
  • the compounds of the present invention have a structure shown in any of formulas (III-4)-(III-7):
  • the compounds of the present invention have the structures shown in any of formulas (III-8)-(III-11):
  • n is selected from 0.
  • p is selected from 0, 1, or 2.
  • p is 1.
  • Q is selected from C1-3 haloalkyl (e.g., C1-3 fluoroalkyl) and C1-3 haloalkoxy (e.g., C1-3 fluoroalkoxy).
  • Q is selected from C1-3 haloalkyl (e.g., C1-3 fluoroalkyl).
  • Q is selected from -OCF 3 or -CF 3 .
  • Ra and Rb are each independently selected from H, deuterium, halogen, C1-6 alkyl, or C1-6 haloalkyl.
  • Ra and Rb are each independently selected from H or C1-6 alkyl groups.
  • Ra and Rb are both H, or one of Ra and Rb is H and the other is a C1-3 alkyl group; more preferably, Ra and Rb are both H.
  • RL1 and RL2 are each independently selected from H, C1-6 alkyl, or C1-6 alkoxy; or RL1 , RL2 , and the carbon atoms to which they are attached together form a C3-6 cycloalkyl group.
  • RL1 and RL2 are both H, or one of RL1 and RL2 is H and the other is a C1-3 alkyl or C1-3 alkoxy group.
  • one of RL1 and RL2 is H and the other is a C1-3 alkoxy group.
  • L is selected from -CR L1 R L2 -,
  • L is selected from -CH2- , -CH( CH3 )-, -CH( OCH3 )-,
  • L is selected from -CH2- , -CH( CH3 )-, or -CH( OCH3 )-.
  • L is -CH(OCH 3 )-.
  • the compound of the present invention has the structure shown in formula (IV-1):
  • R1 , R2 , R3 , Rg , Rh , n, Ra , Rb , RL1 , and RL2 are defined as in any of the aforementioned schemes.
  • the compounds of the present invention have the structure shown in formula (IV-3):
  • the compounds of this invention are selected from:
  • the compounds of the present invention have the structure shown in formula (I-18):
  • ring D is a 5-10 member bridged heterocyclic alkyl group
  • R 4 is selected from:
  • C3-10 cyclic hydrocarbon group -C1-6 alkylene- C3-10 cyclic hydrocarbon group, -OC1-6 alkylene- C3-10 cyclic hydrocarbon group, or -C(O) -C3-10 cyclic hydrocarbon group
  • the C3-10 cyclic hydrocarbon group is independently and optionally substituted with one, two, or more substituents independently selected from deuterium, halogen, OH, SH, NH2 , CN, oxo, C1-6 alkyl, C2-6 alkenyl, C2-6 alkoxy, C1-6 haloalkyl, or C1-6 haloalkoxy groups in each occurrence, and
  • R 7a are each independently selected from: H, C1-6 alkyl, -( CH2 ) q - C3-10 cycloalkyl or -( CH2 ) q -3-10 heterocyclic alkyl, where q is an integer selected from 0 to 6, and each of the C1-6 alkyl, -( CH2 ) q - C3-10 cycloalkyl or -( CH2 ) q - 3-10 heterocyclic alkyl is optionally substituted by one, two or more substituents independently selected from deuterium, halogen, OH, SH, NH2 , CN, oxo, C1-6 alkyl, C2-6 alkenyl, C2-6 alkoxy, C1-6 haloalkyl or C1-6 haloalkoxy; and
  • R 4c is selected from H, C1-6 alkyl, or C1-6 haloalkyl
  • R5 is selected from: H, halogen, OH, SH, CN, -NR 6a R 6b , C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 ynyl, -OC 1-6 alkyl, -SC 1-6 alkyl, -C1-6 alkylene-OH, -C1-6 alkylene-SH, or C3-10 cyclic hydrocarbon; and
  • R5a , R5b , R6a , or R6b are each independently selected from H or C1-6 alkyl groups when they appear.
  • R2 or R8 is independently selected from: H, halogen, OH, SH, CN, NH2 , -NH ( C1-6 alkyl), -N ( C1-6 alkyl) 2 , C1-6 alkyl or C3-10 cyclic hydrocarbon group each time it appears;
  • R4 is selected from: H, halogen, OH, SH, CN, NH2 , -NH ( C1-6 alkyl), -N ( C1-6 alkyl) 2 , C1-6 alkyl, C1-6 haloalkyl, -C1-6 alkylene -OH, -C1-6 alkylene-SH, -C1-6 alkylene-CN, -OC1-6 alkyl, -O- haloC1-6 alkyl, -OC1-6 alkyl- C3-10 cyclic hydrocarbon, and C3-10 cyclic hydrocarbons optionally substituted with one, two or more substituents independently selected from halogen, OH, SH, NH2 , CN, C1-6 alkyl or C1-6 haloalkyl; and
  • Rg or Rh are each independently selected from H, halogen, OH, SH, CN, C1-6 alkyl, C1-6 haloalkyl , NR5aR5b , -C(O) OR5a or -C(O) -NR5aR5b ; and
  • R5 is selected from: halogen, OH, SH, CN, -NR 6a R 6b , C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, -OC 1-6 alkyl, -SC 1-6 alkyl, -C 1-6 alkylene-OH, -C 1-6 alkylene-SH or C 3-10 cyclic hydrocarbon.
  • ring D is a 5-8 membered bridged heterocyclic alkyl group.
  • ring D is Where $ A is the connection point with ring A, and $ L1 is the connection point with L1 ;
  • R4 is selected from:
  • Each of the following is optionally substituted with one, two, three, four, five, six or more C1-6 alkyl, C2-6 alkenyl or C2-6 ynyl groups independently selected from halogen, OH, SH, NH2 or CN .
  • R 7a are each independently selected from: H, C1-6 alkyl, -( CH2 ) q - C3-6 cycloalkyl or -( CH2 ) q -4-7 heterocyclic alkyl, where q is an integer selected from 0 to 4, and each of the C1-6 alkyl, the C3-6 cycloalkyl in the -( CH2 ) q - C3-6 cycloalkyl, and the 4-7 heterocyclic alkyl in the -( CH2 ) q -4-7 heterocyclic alkyl is optionally substituted by one, two or more substituents independently selected from deuterium, halogen, OH, SH, NH2, CN, oxo, C1-6 alkyl , C2-6 alkenyl, C2-6 alkoxy, C1-6 haloalkyl or C1-6 haloalkoxy.
  • R4 is selected from:
  • R4 is selected from: H, halogen, OH, SH, CN, N( R7a ) 2 , C1-6 alkyl, -OC1-6 alkyl or -OC1-6 alkyl- C3-6 cycloalkyl, and optionally substituted with one, two or more substituents independently selected from deuterium, halogen, OH, SH, NH2 , CN, oxo, C1-6 alkyl, C2-6 alkenyl, C2-6 alkoxy, C1-6 haloalkyl and C1-6 haloalkoxy, optionally substituted with one, two or more substituents independently selected from deuterium, halogen, OH, SH, NH2 , CN, oxo, C1-6 alkyl, C2-6 alkenyl, C2-6 alkoxy, C1-6 haloalkyl or C3-6 cycloalkyl. 4-7 membered heterocyclic alkyl groups substituted with 1-6 haloalkoxy groups.
  • R4 is selected from: H, halogen, OH, SH, CN, NH2 , -NH ( C1-6 alkyl), -N ( C1-6 alkyl) 2 , -NH ( C3-10 cycloalkyl), C1-6 alkyl, C1-6 haloalkyl, -C1-6 alkylene-OH, -C1-6 alkylene-SH, -C1-6 alkylene-CN, -OC1-6 alkyl, -O- haloC1-6 alkyl, -OC1-6 alkyl- C3-10 cycloalkyl, and optionally substituted with one, two or more substituents independently selected from deuterium, halogen, OH, SH , NH2 , CN, oxo, C1-6 alkyl, C2-6 alkenyl, C2-6 alkoxy, C1-6 haloalkyl or C1-6 haloalkoxy.
  • the 3-10 cyclic hydrocarbon group is optionally substituted with one, two, or more substituents independently selected from deuterium, halogen, OH, SH, NH2 , CN, oxo, C1-6 alkyl, C2-6 alkenyl, C2-6 alkoxy, C1-6 haloalkyl, or C1-6 haloalkoxy.
  • the C1-6 alkyl group of -NH( C1-6 alkyl), -N( C1-6 alkyl) 2 , and the C3-10 cyclic hydrocarbon group of -NH ( C3-10 cyclic hydrocarbon) are each optionally substituted with one, two, or more substituents independently selected from deuterium, halogen, OH, SH, NH2 , CN, oxo, C1-6 alkyl, C2-6 alkenyl, C2-6 alkoxy, C1-6 haloalkyl, or C1-6 haloalkyl. Substituents of 1-6 haloalkoxy groups.
  • R4 is selected from: H, F, Cl, OH, SH, CN , NH2, -NH ( C1-4 alkyl), -N ( C1-4 alkyl) 2 , -NH ( C3-6 cycloalkyl), -NH (C1-4 alkylene)-( C3-6 cycloalkyl), -NH (C1-4 alkylene)-CN, C1-4 alkyl , C1-4 haloalkyl, -C1-4 alkylene-OH, -C1-4 alkylene-SH, -C1-4 alkylene-CN, -OC1-4 alkyl, -O - haloC1-4 alkyl, -OC1-4 alkyl- C3-6 cycloalkyl, and optionally substituted with one, two or more substituents independently selected from deuterium, halogen, OH, SH, NH2, CN, C1-4 alkyl or C1-4 haloalkyl.
  • 3-6 cycloalkyl optionally substituted with one, two or more substituents independently selected from deuterium, halogen, OH, SH, NH2 , CN, oxo, C1-4 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-4 alkoxy, C1-4 haloalkyl or C1-4 haloalkoxy; the C1-4 alkyl in -NH( C1-4 alkyl) 2 and the C3-6 cycloalkyl in -NH( C3-6 cycloalkyl) 2 are each optionally substituted with one, two or more substituents independently selected from deuterium, halogen, OH, oxo, SH, NH2 , CN, C1-6 alkyl or C1-6 haloalkyl.
  • R4 is selected from: H, OH, SH, -NH ( C1-4 alkyl), -NH ( C3-6 partially unsaturated cycloalkyl), -NH ( C1-4 alkylene)-( C3-6 cycloalkyl), -NH ( C1-4 alkylene)-CN, C1-4 alkyl, C1-4 haloalkyl, -OC1-4 alkyl, -O- haloC1-4 alkyl, -OC1-4 alkyl- C3-6 cycloalkyl, and C3-6 cycloalkyl optionally substituted with one, two or more substituents independently selected from deuterium, halogen, OH, SH, NH2 , CN, C1-4 alkyl or C1-4 haloalkyl, optionally substituted with one, two or more substituents independently selected from deuterium, halogen, OH, SH, NH2 , CN, C1-4 alkyl or C3-6 haloalkyl.
  • R4 is selected from the groups listed in group C:
  • group C further includes the following groups:
  • R4 is selected from H, OH, SH, methyl, ethyl, isopropyl, -CF3 , -CH2CF3 , -CH2CHF2 , etc. -CH 2 CN ⁇ -OCH 3 , -OCH 2 CH 3 , -OCF 3 , -OCH 2 CF 3 , Cyclopropyl, difluorocyclopropyl, Amino, -NHCH3 , -N( CH3 ) 2 , -NHCH2CH3 , -NHCH2CN , -NHCH2CF3 , -NH - cyclopropyl, -NHCH2 -cyclopropyl -NH-cyclobutane, -O-CH 2 -cyclopropyl or
  • R4 is selected from: H, OH, SH, methyl, ethyl, isopropyl, -CF3 , -CH2CF3 , -CH2CHF2 , etc. -CH 2 CN ⁇ -OCH 3 , -OCH 2 CH 3 , -OCF 3 , -OCH 2 CF 3 , Cyclopropyl, difluorocyclopropyl, Amino, -NHCH3 , -N( CH3 ) 2, -NHCH2CH3 , -NHCH2CN , -NHCH2CF3 , -NH - cyclopropyl, -NHCH2 -cyclopropyl -NH-cyclobutane, -O-CH 2 -cyclopropyl or
  • R4 is selected from: H, F, Cl, OH, SH, CN, NH2 , -NH ( C1-4 alkyl), -N ( C1-4 alkyl) 2 , C1-4 alkyl, C1-4 haloalkyl, -C1-4 alkylene-OH, -C1-4 alkylene-SH, -C1-4 alkylene-CN, -OC1-4 alkyl, -O- haloC1-4 alkyl, -OC1-4 alkyl- C3-6 cycloalkyl, and optionally C3-6 cycloalkyl substituted with one, two or more substituents independently selected from halogen, OH, SH, NH2 , CN, C1-4 alkyl or C1-4 haloalkyl.
  • R4 is selected from: H, OH, SH, C1-4 alkyl, C1-4 haloalkyl, -OC1-4 alkyl, -O- haloC1-4 alkyl, -OC1-4 alkyl- C3-6 cycloalkyl, and optionally C3-6 cycloalkyl substituted with one, two or more substituents independently selected from halogen, OH, SH, NH2 , CN, C1-4 alkyl or C1-4 haloalkyl.
  • R4 is selected from: H, OH, SH, methyl, ethyl , isopropyl, -CF3 , -CH2CF3, -OCH3 , -OCH2CH3, -OCF3 , -OCH2CF3 , difluorocyclopropyl or -O- CH2 - cyclopropyl .
  • m is 1.
  • ring D is Where $ A is the connection point with ring A, and $ L1 is the connection point with L1 ;
  • R4 is selected from:
  • R4 is selected from:
  • C1-4 alkyl C1-6 haloalkyl, -C1-4 haloalkyl-OH, -C1-4 alkylene-CN, or C2-4 ynyl.
  • C3-6 cycloalkyl or -C1-4 alkylene- C3-6 cycloalkyl wherein the C3-6 cycloalkyl group is independently and optionally substituted with one, two or more substituents independently selected from deuterium, halogen, OH, SH, NH2 , CN, C1-4 alkyl, C1-4 haloalkyl or C1-4 haloalkoxy groups in each occurrence.
  • each of the 4-7 membered heterocyclic alkyl groups is optionally substituted by one, two or more substituents selected independently from deuterium, halogen, OH, oxo, SH, NH2 , CN, C1-6 alkyl or C1-6 haloalkyl.
  • R4 is selected from:
  • C1-4 alkyl C1-6 haloalkyl, -C1-4 haloalkyl-OH, -C1-4 alkylene-CN, C2-4 ynyl or -NH (4-6 membered heterocyclic alkyl),
  • R4 is selected from: H, F, Cl, OH, SH, CN, NH2 , -NH ( C1-4 alkyl), -N ( C1-4 alkyl) 2 , -NH (C3-6 cycloalkyl), -NH ( C1-4 alkylene)-( C3-6 cycloalkyl), -NH ( C1-4 alkylene)-CN, C1-4 alkyl , C1-4 haloalkyl, -C1-4 alkylene-OH, -C1-4 alkylene-SH, -C1-4 alkylene-CN, -OC1-4 alkyl, -O -haloC1-4 alkyl , -OC1-4 alkyl- C3-6 cycloalkyl, and optionally substituted with one, two or more substituents independently selected from deuterium, halogen, OH, SH, NH2, CN, C1-4 alkyl or C1-4 haloalkyl.
  • 3-6 cycloalkyl optionally substituted with one, two or more substituents independently selected from deuterium, halogen, OH, SH, NH2 , CN, oxo, C1-4 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-4 alkoxy, C1-4 haloalkyl or C1-4 haloalkoxy; the C1-4 alkyl in -NH( C1-4 alkyl) 2 and the C3-6 cycloalkyl in -NH( C3-6 cycloalkyl) 2 are each optionally substituted with one, two or more substituents independently selected from deuterium, halogen, OH, oxo, SH, NH2 , CN, C1-6 alkyl or C1-6 haloalkyl.
  • R4 is selected from: C1-4 alkyl, C1-4 haloalkyl, and C3-6 cycloalkyl optionally substituted with one, two or more substituents independently selected from deuterium, halogen, OH, SH, NH2 , CN, C1-4 alkyl and C1-4 haloalkyl, and optionally substituted with one, two or more substituents independently selected from deuterium, halogen, OH, SH, NH2 , CN, oxo, C1-4 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-4 alkoxy, C1-4 haloalkyl or C1-4 haloalkoxy alkyl.
  • ring D is a 5-8 membered bridged heterocyclic alkyl group
  • R4 is selected from C1-4 alkyl groups, C1-4 haloalkyl groups, and optionally C3-6 cycloalkyl groups substituted with one, two or more substituents independently selected from deuterium, halogen, OH, SH, NH2, CN, C1-4 alkyl groups or C1-4 haloalkyl groups; and optionally 4-7 membered heterocyclic alkyl groups substituted with one, two or more substituents independently selected from deuterium, halogen, OH, SH, NH2, CN, C1-4 alkyl groups or C1-4 haloalkyl groups; more preferably, Part of Where $ A is the connection point with ring A, and $ L1 is the connection point with L1 .
  • R3 is independently selected each time it appears from: H, halogen, OH, SH, CN, -NR 6a R 6b , C1-4 alkyl, C1-4 haloalkyl, C2-4 alkenyl, C2-4 alkynyl, -OC 1-4 alkyl, -OC 1-4 haloalkyl, -SC 1-4 alkyl, -S(O) 2 -C 1-4 alkyl, -C 1-4 alkylene-OC 1-6 alkyl, -OC 1-4 alkylene-OC 1-4 alkyl, -C 1-4 alkylene -OH, -C 1-4 alkylene-SH, -C 1-4 alkylene-NR 6a R 6b , -C 1-4 alkylene-NR 6a -C(O)R 6b , -OC 1-4 alkylene C(O)OR 6a , -OC 1-4 alkylene C(O)NR 6a R 6b C3-6 cycloalkyl
  • R5 is independently selected each time it appears from: H, halogen, OH, SH, CN, -NR 6a R 6b , C 1-4 alkyl, C 1-4 haloalkyl, C 2-4 alkenyl, C 2-4 ynyl, -OC 1-4 alkyl, -OC 1-4 haloalkyl, -SC 1-4 alkyl, -S(O) 2 -C 1-4 alkyl, -C 1-4 alkylene-OC 1-6 alkyl, -OC 1-4 alkylene-OC 1-4 alkyl, -C 1-4 alkylene-OH, -C 1-4 alkylene-SH, -C 1-4 alkylene-NR 6a R 6b , -C 1-4 alkylene-NR 6a -C(O)R 6b , -OC 1-4 alkylene C(O)OR 6a , -OC 1-4 alkylene C(O)NR 6a R 6b , C 3-6 cycloalky
  • R3 is independently selected each time it appears from: H, halogen, OH, SH, CN, -NR6a R6b , C1-4 alkyl, C1-4 haloalkyl, C2-4 alkenyl, C2-4 ynyl, -OC1-4 alkyl, -SC1-4 alkyl, or C3-6 cycloalkyl , wherein the C1-4 alkyl, C1-4 haloalkyl, C2-4 alkenyl, C2-4 ynyl, -OC1-4 alkyl, -SC1-4 alkyl, or C3-6 cycloalkyl are each optionally substituted with one or more D atoms, and
  • R5 is selected independently each time it appears from: H, halogen, OH, SH, CN, -NR 6a R 6b , C 1-4 alkyl, C 1-4 haloalkyl, C 2-4 alkenyl, C 2-4 alkynyl, -OC 1-4 alkyl, -SC 1-4 alkyl or C 3-6 cycloalkyl.
  • R3 or R5 is independently selected each time it appears from: halogen, OH, SH, CN, -NR 6a R 6b , C1-4 alkyl, C1-4 haloalkyl, C2-4 alkenyl, C2-4 ynyl, -OC 1-4 alkyl, -OC 1-4 haloalkyl, -SC 1-4 alkyl, -S(O) 2 -C1-4 alkyl, -C1-4 alkylene-OC 1-6 alkyl, -OC 1-4 alkylene-OC 1-4 alkyl, -C 1-4 alkylene-OH, -C 1-4 alkylene-SH, -C 1-4 alkylene-NR 6a R 6b , -C 1-4 alkylene-NR 6a -C(O)R 6b , -OC 1-4 alkylene C(O)OR 6a , -OC 1-4 alkylene C(O)NR 6a R 6b , C3-6 cycloalkyl or
  • R3 is independently selected each time it appears from: H, F, Cl, OH, SH, CN, -NH2 , -NHCH3 , -NH( CH3 ) 2 , methyl, ethyl, CF3 , vinyl, ethynyl, -O- CH3 , -O- CD3 , -S- CH3 , -S- CD3 , and cyclopropyl
  • R5 is independently selected each time it appears from: H, F, Cl, OH, SH, CN , -NH2, -NHCH3 , -NH( CH3 ) 2 , methyl, ethyl, CF3 , vinyl, ethynyl, -O- CH3 , -S- CH3 , or cyclopropyl.
  • R3 is -O- CH3 .
  • R5 is H or methyl. In some preferred embodiments, R5 is methyl.
  • Step 1 Compound 3-1 (500 g, 2992.22 mmol) was dissolved in DMF (6 L), followed by the sequential addition of potassium carbonate (496.3 g, 3590.66 mmol) and benzyl bromide (511.7 g, 2992.22 mmol). The reaction was carried out at room temperature for 4 hours, and the reaction was monitored by TLC until completion. After the reaction was complete, the reaction solution was poured into water, and a large amount of solid precipitated. The solid was filtered to obtain a filter cake, which was then dried under vacuum to obtain compound 3-2. MS m/z (ESI): 258.2 [M+H] + .
  • Step 10 Compound 3-11 (4 g, 18.00 mmol) was dissolved in tetrahydrofuran (50 mL), and lithium aluminum hydride (1.02 g, 27.00 mmol) was added in portions at 0 °C. The reaction mixture was stirred at 0 °C for half an hour, then allowed to rise to room temperature and reacted overnight. The reaction was confirmed to be complete by TLC. The reaction mixture was quenched with 1.0 M dilute HCl, extracted three times with dichloromethane (3 ⁇ 50 mL), the organic phases were combined and washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure at room temperature to obtain compound 3-12.
  • Step 12 Compound 3-13 (1.5 g, 4.90 mmol) was dissolved in N,N-dimethylformamide (20 mL), and compound 1-7 (1.48 g, 4.90 mmol) and N,N-diisopropylethylamine (1.90 g, 14.69 mmol) were added. The reaction was carried out overnight at 85 °C, and the reaction was monitored to be complete by LCMS. Water (50 mL) was added to the reaction solution, and the mixture was extracted three times with ethyl acetate (3 ⁇ 50 mL). The combined organic phases were washed with saturated brine and then concentrated under reduced pressure.
  • Step 13 Compound 3-14 (1.30 g, 2.98 mmol) dissolved in a mixture of acetonitrile (30 mL) and water (15 mL) was added to a 100 mL single-necked flask at 0 °C. Then, [bis(trifluoroacetoxy)iodide]benzene (2.57 g, 5.96 mmol) was slowly added. The reaction was allowed to proceed at room temperature for 16 hours, and the reaction was monitored for completeness by LC-MS. The reaction solution was quenched by slow addition of saturated sodium bicarbonate aqueous solution at room temperature. The precipitated solid was filtered off, and the mother liquor was extracted three times with dichloromethane (3 ⁇ 40 mL).
  • Step 14 Compound 3-15 (300 mg, 0.73 mmol) was dissolved in acetonitrile (5 mL), compound 3-9 (201 mg, 0.73 mmol) and 5 drops of acetic acid were added, and the reaction mixture was stirred at room temperature for 16 hours. Then sodium borohydride (83 mg, 2.19 mmol) and methanol (3 mL) were added, and the reaction mixture was stirred at room temperature for another hour. The reaction was monitored for completion by LCMS. The reaction mixture was quenched with saturated sodium bicarbonate solution, extracted three times with ethyl acetate (3 ⁇ 40 mL), the combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure.
  • Step 15 Compound 3-16 (250 mg, 0.38 mmol) was dissolved in a mixed solvent of tetrahydrofuran (3 mL), methanol (3 mL), and water (3 mL). Lithium hydroxide (630.20 mg, 15.02 mmol) was added, and the mixture was heated to 60 °C for 1 hour. The reaction was monitored by LCMS to ensure completion. The reaction solution was cooled to room temperature, and dilute HCl solution (2.0 M) was slowly added dropwise to adjust the pH to approximately 5-7. A large amount of solid precipitated.
  • Step 1 Compounds 1-3 (10.5 g, 40.96 mmol) and 4-1 (8.95 g, 53.25 mmol) were dissolved in tetrahydrofuran (200 mL). A solution of bis(trimethylsilylamino)lithium (1.0 N, 81.92 mL, 81.92 mmol) was slowly added dropwise at 0 °C. The reaction was carried out at room temperature for 16 hours, and the reaction was monitored for completeness by LC-MS. The reaction solution was quenched with ice water and extracted three times with ethyl acetate (3 ⁇ 100 mL). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure.
  • Step 2 Compound 4-2 (9.7 g, 23.98 mmol) and saturated sodium hydroxide solution (70 mL, 1420 mmol) were dissolved in ethanol (200 mL) and reacted at 100 °C for 3 days. The reaction was monitored for completeness by LCMS. The pH of the reaction solution was adjusted to approximately 3 by adding 6 N hydrochloric acid dropwise at 0 °C, resulting in the precipitation of a large amount of solid. The solid was filtered off and dried under vacuum to obtain compound 4-3. MS m/z (ESI): 409.2 [M+H] + .
  • Step 3 Compound 4-3 (1.5 g, 3.67 mmol) was dissolved in N,N-dimethylformamide (200 mL). Potassium carbonate (1.52 g, 11.02 mmol) and iodoethane (0.88 mL, 11.02 mmol) were slowly added at 0 °C. The reaction mixture was stirred at room temperature for 16 hours, and the reaction was monitored for completeness by LC-MS. The reaction solution was quenched with ice water and extracted with ethyl acetate (3 ⁇ 50 mL). The combined organic phases were washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure.
  • Step 4 Compound 4-4 (200 mg, 0.46 mmol) was dissolved in dioxane (5 mL). Under nitrogen protection, 10% palladium on carbon (50 mg) and ammonium formate (433.35 mg, 6.87 mmol) were added. The reaction was carried out at 100 °C for 32 hours, and the reaction was monitored for completeness by LCMS. After cooling the reaction solution to room temperature, it was filtered, and the filtrate was evaporated to dryness to obtain compound 4-5. MS m/z (ESI): 317.2 [M+H] + .
  • Step 5 Compound 4-6 (50 g, 384.41 mmol) was dissolved in dichloromethane (500 mL). Triethylamine (106.6 mL, 768.82 mmol) and p-toluenesulfonyl chloride (87.94 g, 461.29 mmol) were added sequentially at 0 °C. After the addition was complete, the reaction mixture was stirred at room temperature for 16 hours, and the reaction was monitored for completeness by LC-MS. Water (500 mL) was added to the reaction mixture, and the mixture was extracted three times with dichloromethane (3 ⁇ 400 mL).
  • Step 6 Compounds 4-5 (1.89 g, 5.98 mmol) and 4-7 (1.7 g, 5.98 mmol) were dissolved in N,N-dimethylformamide (30 mL). N,N-diisopropylethylamine (5.21 mL, 29.90 mmol) was slowly added at 0 °C. The reaction was allowed to proceed for 32 hours at room temperature, and the reaction was monitored for completeness by LC-MS. The reaction solution was quenched with water (50 mL) and extracted three times with ethyl acetate (3 ⁇ 50 mL). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure.
  • Step 7 Compounds 4-8 (1.4 g, 3.03 mmol, crude) were dissolved in acetonitrile (10 mL) and water (5 mL), and [bis(trifluoroacetoxy)iodo]benzene (2.62 g, 6.07 mmol) was added. The reaction was carried out at room temperature for 3 hours, and the reaction was monitored to be complete by LCMS. Saturated sodium bicarbonate solution was added to the reaction solution to adjust the pH to >7, and the mixture was extracted three times with ethyl acetate (3 ⁇ 40 mL). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure.
  • Step 8 Compound 4-9 (180 mg, 0.45 mmol) was dissolved in acetonitrile (5 mL), and compound 1-14 (156.07 mg, 0.54 mmol) was added. The mixture was heated to 60 °C and reacted overnight. Sodium cyanoborohydride (56.56 mg, 0.90 mmol) was added at room temperature, and the reaction was continued at room temperature for 2 hours. The reaction was monitored for completeness by LCMS. The reaction solution was added to ice water (40 mL), and extracted three times with ethyl acetate (3 ⁇ 40 mL). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure.
  • Step 9 Compound 4-10 (260 mg, 0.39 mmol) was dissolved in a mixed solvent of tetrahydrofuran (3 mL), methanol (3 mL), and water (3 mL). Lithium hydroxide (654.58 mg, 15.60 mmol) was added, and the mixture was reacted at 60 °C for 1 hour. The reaction was monitored for completeness by LCMS. The reaction solution was cooled to room temperature, and dilute HCl (2.0 M) was slowly added dropwise to adjust the pH to approximately 5-7. A large amount of solid precipitated.
  • the crude solid obtained by filtration was purified by reversed-phase chromatography using a Waters-Xbridge-C18-10 ⁇ m-19 ⁇ 250 mm column; mobile phase: (A: 10 mM NH4HCO3 / H2O ; B: ACN; gradient: B%: 0%-95%).
  • the purified product was obtained.
  • Step 1 Compound 4-7 (66 g, 232.19 mmol) and compound 1-7 (14.04 g, 46.44 mmol) dissolved in N,N-dimethylformamide (300 mL) were added to a 1000 mL single-necked flask. Then, N,N-diisopropylethylamine (38.48 mL, 232.19 mmol) was slowly added, and the reaction was carried out at room temperature for 40 hours. The reaction was monitored for completeness by LCMS. The reaction solution was quenched by slowly adding ice water (400 mL) at room temperature. The mixture was extracted three times with ethyl acetate (3 ⁇ 300 mL).
  • Step 2 Compound 5-1 (9 g, 21.72 mmol) dissolved in a mixture of acetonitrile (60 mL) and water (30 mL) was added to a 250 mL single-necked flask. Then, [bis(trifluoroacetoxy)iodo]benzene (18.77 g, 43.43 mmol) was slowly added. The reaction was carried out at room temperature for 16 hours, and the reaction was monitored by LCMS. The reaction solution was quenched by slow addition of saturated sodium bicarbonate solution at room temperature. The mixture was extracted three times with dichloromethane (3 ⁇ 50 mL).
  • Step 3 Compound 3-9 (3.4 g, 12.07 mmol) was dissolved in a mixed solution of tetrahydrofuran (10 mL), methanol (10 mL), and water (10 mL). Lithium hydroxide (5.07 g, 120.73 mmol) was added, and the reaction mixture was heated to 60 °C and stirred for 3 hours. The reaction was monitored by LCMS to indicate completion. The reaction mixture was cooled to room temperature, quenched with ice water, and extracted three times with ethyl acetate (3 ⁇ 30 mL). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure.
  • Step 4 Compound 5-2 (4.5 g, 11.65 mmol) was dissolved in acetonitrile (5 mL), and compound 5-3 (2.02 g, 11.65 mmol) and acetic acid (1 mL) were added. The mixture was stirred overnight at room temperature. Then, sodium borohydride (1.3 g, 34.95 mmol) and methanol (2 mL) were added, and the mixture was stirred for another 0.5 hours at room temperature. The reaction was monitored for completeness by LCMS.
  • reaction solution was quenched slowly with ice water, extracted three times with ethyl acetate (3 ⁇ 50 mL), and the combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure.
  • the crude product was purified by silica gel column chromatography (mobile phase gradient: 0%-20% ethyl acetate/petroleum ether) to obtain compound 5-4. MS m/z (ESI): 544.2 [M+H] + .
  • Step 5 Compound 5-4 (2.7 g, 4.97 mmol) was dissolved in a mixed solvent of tetrahydrofuran (15 mL), methanol (15 mL), and water (15 mL). Lithium hydroxide (4.17 g, 99.33 mmol) was added, and the reaction was carried out at room temperature for 3 hours. The reaction was monitored for completeness by LCMS. Dilute HCl (1.0 M) was slowly added dropwise to the reaction solution to adjust the pH to approximately 5-7. A large amount of solid precipitated out. The obtained solid was filtered, slurried with pure water, and then vacuum dried to obtain the purified product. MS m/z (ESI): 516.2 [M+H] + .
  • Step 1 Compound 3-9 (800 mg, 2.93 mmol) was dissolved in methanol (10 mL), and sodium borohydride (221 mg, 5.85 mmol) was added at 0 °C. The reaction mixture was stirred at room temperature for 1 hour, and the reaction was monitored for completeness by LCMS. The reaction mixture was quenched with ice water, extracted three times with ethyl acetate (3 ⁇ 50 mL), and the combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (mobile phase gradient: 0%–20% ethyl acetate/petroleum ether) to obtain compound 6-1.
  • Step 2 Compound 6-1 (690 mg, 2.51 mmol) was dissolved in N,N-dimethylformamide (5 mL), and N-chlorosuccinimide (1 g, 7.52 mmol) was added. The reaction mixture was stirred at 40 °C for 16 hours, and the reaction was monitored to be complete by LCMS. The reaction mixture was quenched with saturated sodium bicarbonate solution, extracted three times with ethyl acetate (3 ⁇ 50 mL), and the combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the crude product.
  • Step 3 Compound 6-2 (490 mg, 1.58 mmol) was dissolved in 1,2-dichloroethane (30 mL), and active MnO2 (3.44 g, 39.50 mmol) was added. The reaction solution was stirred at 50 °C for 16 hours, and the reaction was monitored to be complete by LCMS. The reaction solution was filtered, and the filtrate was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (mobile phase gradient: 0%–10% ethyl acetate/petroleum ether) to obtain compound 6-3. MS m/z (ESI): 308.2 [M+H] + .
  • Step 4 Compound 6-3 (260 mg, 0.84 mmol) and compound 5-2 (415 mg, 1.10 mmol) were dissolved in acetonitrile (5 mL), and 4 drops of acetic acid were added. The reaction mixture was stirred at room temperature for 16 hours. LCMS monitoring showed the formation of a large amount of imine. Then, sodium borohydride (95 mg, 2.52 mmol) and methanol (3 mL) were added, and the reaction mixture was stirred at room temperature for another hour. LCMS monitoring showed the reaction was complete.
  • Step 5 Compound 6-4 (200 mg, 0.29 mmol) was dissolved in tetrahydrofuran (4 mL), methanol (4 mL), and water (4 mL). Lithium hydroxide monohydrate (495 mg, 11.80 mmol) was added. The reaction mixture was stirred at 60 °C for 2 hours, and the reaction was monitored for completeness by LCMS. After the reaction mixture cooled to room temperature, the pH was adjusted to between 5 and 7 using 2 M dilute hydrochloric acid. A large amount of solid precipitated.
  • the crude solid obtained by filtration was purified by reversed-phase chromatography [model: Waters-Xbridge-C18-10 ⁇ m-19 ⁇ 250 mm; mobile phase: (A: 10 mM NH4HCO3 / H2O ; B: ACN; gradient: B%: 0%-95%)] to obtain the purified product.
  • Step 1 Compound 3-8 (2 g, 4.91 mmol) dissolved in 1,4-dioxane (10 mL) and water (2 mL) was added to a 100 mL single-necked flask. Under nitrogen protection, potassium trifluoroborate (1.97 g, 14.73 mmol), 1,1-bis(diphenylphosphine)diberberine palladium dichloride (0.37 g, 0.49 mmol), and potassium carbonate (1.36 g, 9.82 mmol) were added sequentially. The reaction was carried out at 90 °C for 16 hours, and the reaction was detected by LCMS.
  • Step 2 Add a solution of compound 7-1 (1 g, 3.50 mmol) dissolved in tetrahydrofuran (10 mL) and methanol (10 mL) to a 100 mL single-necked flask, then add PtO2 (0.80 g, 3.50 mmol), displace the solution with hydrogen gas, and react at room temperature for 1 hour. The reaction was monitored for completeness by LCMS. Filter the reaction solution, and concentrate the filtrate under reduced pressure to obtain compound 7-2. MS m/z (ESI): 288.2 [M+H] + .
  • Step 3 Compound 7-2 (100 mg, 0.35 mmol) was dissolved in acetonitrile (5 mL), and compound 5-2 (134.47 mg, 0.35 mmol) and 3 drops of acetic acid were added. The reaction mixture was stirred for 1 h, and then sodium triacetoxyborohydride (221.26 mg, 1.04 mmol) was added. The mixture was stirred overnight at room temperature, and the reaction was monitored for completeness by LCMS. The reaction mixture was quenched slowly with ice water at room temperature, and extracted three times with ethyl acetate (3 ⁇ 50 mL). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure.
  • Step 4 Compound 7-3 (50 mg, 0.08 mmol) was dissolved in a mixed solvent of tetrahydrofuran (2 mL), methanol (2 mL), and water (2 mL). Lithium hydroxide (127.58 mg, 3.04 mmol) was added, and the mixture was heated to 60 °C for 1 hour. The reaction was monitored for completeness by LCMS. The reaction solution was cooled to room temperature, and dilute HCl (2.0 M) was slowly added dropwise to adjust the pH to approximately 5-7. A large amount of solid precipitated.
  • the crude solid obtained by filtration was purified by reversed-phase chromatography using a Waters-Xbridge-C18-10 ⁇ m-19 ⁇ 250 mm column; mobile phase: (A: 10 mM NH4HCO3 / H2O ; B: ACN ; gradient: B%: 0%-95%).
  • the purified product was obtained.
  • Step 1 Add a solution of compound 3-8 (1.0 g, 2.45 mmol) dissolved in 1,4-dioxane (10 mL) and water (2 mL) to a 20 mL microwave tube. Under nitrogen protection, add isopropenylboronic acid pinacol ester (1.24 g, 7.36 mmol), 1,1-bis(diphenylphosphine)dimerferropalladium dichloride (0.18 g, 0.25 mmol), and potassium carbonate (1.02 g, 7.36 mmol) sequentially. Microwave the mixture at 100 °C for 2 hours, and monitor the reaction until complete by LCMS.
  • Step 2 Add a solution of compound 8-1 (650 mg, 2.17 mmol) dissolved in tetrahydrofuran (10 mL) and methanol (10 mL) to a 100 mL single-necked flask, then add platinum dioxide (100 mg), displace the solution with hydrogen for protection, and react at room temperature for 1 hour. The reaction was monitored by LCMS to confirm completion. Filter the reaction solution, concentrate the filtrate under reduced pressure, and purify the crude product by silica gel column chromatography (mobile phase gradient: 0%-30% ethyl acetate/petroleum ether) to obtain compound 8-2. MS m/z (ESI): 302.2 [M+H] + .
  • Step 3 Compound 8-2 (120 mg, 0.40 mmol) was dissolved in acetonitrile (5 mL), and compound 5-2 (185 mg, 0.48 mmol) and 5 drops of acetic acid were added. The mixture was stirred overnight at room temperature. LCMS monitoring showed the formation of a large amount of imine. Then, sodium borohydride (38 mg, 1.00 mmol) and methanol (3 mL) were added at 0 °C, and the reaction was continued for 1 hour at room temperature. LCMS monitoring showed the reaction was complete.
  • reaction solution was quenched with saturated sodium bicarbonate solution, extracted three times with ethyl acetate (3 ⁇ 40 mL), and the combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure.
  • the crude product was purified by silica gel column chromatography (mobile phase gradient: 0%-40% ethyl acetate/petroleum ether) to obtain compound 8-3.
  • Step 4 Compound 8-3 (110 mg, 0.16 mmol) was dissolved in a mixed solvent of methanol (4 mL), water (4 mL), and tetrahydrofuran (4 mL). Lithium hydroxide monohydrate (275 mg, 6.55 mmol) was added, and the reaction was carried out at 60 °C for 2 hours. The reaction was monitored for completeness by LCMS. The reaction solution was cooled to room temperature, and dilute HCl (2.0 M) was slowly added dropwise to adjust the pH to approximately 5–7. A large amount of solid precipitated.
  • Step 1 A solution of compound 3-8 (500 mg, 1.2 mmol) dissolved in toluene (30 mL) and water (6 mL) was added to a 10 mL single-necked flask. Cyclobutylboronic acid (1.17 g, 4656 mmol), [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride (89.0 mg, 0.1 mmol), and cesium carbonate (1.170 mg, 3.6 mmol) were added sequentially. Nitrogen gas was then introduced, and the mixture was reacted at 100 °C for 16 hours. The reaction was monitored for completeness by LC-MS.
  • Step 2 Compound 5-2 (200 mg, 0.52 mmol) and compound 9-1 (162.21 mg, 0.52 mmol) were dissolved in acetonitrile (5 mL), and 4 drops of acetic acid were added. The reaction mixture was stirred at room temperature for 16 hours. Then, sodium borohydride (59 mg, 1.56 mmol) and methanol (3 mL) were added, and the reaction mixture was stirred at room temperature for another hour. The reaction was monitored for completeness by LCMS.
  • Step 3 Compound 9-2 (200 mg, 0.33 mmol) was dissolved in a mixed solvent of tetrahydrofuran (4 mL), methanol (4 mL), and water (4 mL). Lithium hydroxide monohydrate (490.90 mg, 11.70 mmol) was added. The reaction solution was stirred at 60 °C for 1 hour, and the reaction was monitored for completeness by LCMS. After the reaction solution cooled to room temperature, the pH was adjusted to between 5 and 7 with 2N dilute hydrochloric acid. A large amount of solid precipitated.
  • the crude solid obtained by filtration was purified by reversed-phase chromatography [model: Waters-Xbridge-C18-10 ⁇ m-19 ⁇ 250mm; mobile phase: (A: 10 mM NH4HCO3 / H2O ; B: ACN; gradient: B%: 0%-95%)] to obtain the purified product.
  • Step 1 Compound 3-8 (27 g, 66.28 mmol) was added to a mixed solvent of toluene (810 mL) and water (135 mL), followed by the sequential addition of cyclopropylboronic acid (17.08 g, 198.84 mmol), [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride (9.70 g, 13.26 mmol), and potassium carbonate (18.32 g, 132.56 mmol). After purging with nitrogen, the reaction was carried out overnight at 110 °C, and the reaction was monitored by LCMS.
  • reaction solution was quenched with water, extracted three times with ethyl acetate (3 ⁇ 300 mL), and the combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure.
  • the crude product was purified by silica gel column chromatography (mobile phase gradient: 0%–10% ethyl acetate/petroleum ether) to obtain compound 10-1.
  • Step 2 Compound 5-2 (200 mg, 0.52 mmol) and compound 10-1 (155 mg, 0.52 mmol) were dissolved in acetonitrile (5 mL), and 4 drops of acetic acid were added. The reaction mixture was stirred at room temperature for 16 hours. Then, sodium borohydride (59 mg, 1.56 mmol) and methanol (3 mL) were added, and the reaction mixture was stirred at room temperature for another hour. The reaction was monitored for completeness by LCMS.
  • Step 3 Compound 10-2 (220 mg, 0.33 mmol) was dissolved in a mixed solvent of tetrahydrofuran (4 mL), methanol (4 mL), and water (4 mL). Lithium hydroxide monohydrate (551 mg, 13.14 mmol) was added. The reaction solution was stirred at 60 °C for 2 hours, and the reaction was monitored for completeness by LCMS. After the reaction solution cooled to room temperature, the pH was adjusted to between 5 and 7 with 2 M hydrochloric acid. A large amount of solid precipitated.
  • the crude solid obtained by filtration was purified by reversed-phase chromatography [model: Waters-Xbridge-C18-10 ⁇ m-19 ⁇ 250mm; mobile phase: (A: 10 mM NH4HCO3 / H2O ; B: ACN; gradient: B%: 0%-95%)] to obtain the purified product.
  • Step 1 Add a 10 mL DMF (10 mL) solution of compound 3-7 (600 mg, 1.2 mmol) to a 10 mL single-necked flask, followed by the addition of potassium carbonate (602.4 mg, 4.36 mmol) and iodoethane (679.85 mg, 4.36 mmol). Incubate at room temperature for 16 hours. Detect the reaction as complete by LC-MS. Quench the reaction solution with water, extract three times with ethyl acetate (3 ⁇ 40 mL), wash the combined organic phases with saturated brine, dry with anhydrous sodium sulfate, and concentrate under reduced pressure.
  • Step 2 Compound 5-2 (200 mg, 0.52 mmol) and compound 11-1 (157.01 mg, 0.52 mmol) were dissolved in acetonitrile (5 mL), and 4 drops of acetic acid were added. The reaction mixture was stirred at room temperature for 16 hours. LCMS monitoring showed the formation of a large amount of imine. Then, sodium borohydride (59 mg, 1.56 mmol) and methanol (3 mL) were added, and the reaction mixture was stirred at room temperature for another hour. LCMS monitoring showed the reaction was complete.
  • Step 3 Compound 11-2 (220 mg, 0.33 mmol) was dissolved in a mixed solvent of tetrahydrofuran (4 mL), methanol (4 mL), and water (4 mL). Lithium hydroxide monohydrate (548 mg, 13.06 mmol) was added. The reaction solution was stirred at 60 °C for 1 hour, and the reaction was monitored for completeness by LCMS. After the reaction solution cooled to room temperature, the pH was adjusted to between 5 and 7 using 2 M dilute hydrochloric acid. A large amount of solid precipitated.
  • Step 1 Compound 3-8 (1.0 g, 2.45 mmol) was dissolved in N,N-dimethylformamide (20 mL), and tetrakis(triphenylphosphine)palladium (1.42 g, 1.23 mmol) and zinc cyanide (865 mg, 7.36 mmol) were added. After purging with nitrogen, the reaction mixture was stirred at 100 °C for 2 hours, and the reaction was monitored to be complete by LCMS.
  • Step 2 Compound 12-1 (120 mg, 0.65 mmol) and compound 5-2 (250 mg, 0.65 mmol) were dissolved in acetonitrile (5 mL), and 4 drops of acetic acid were added. The reaction mixture was stirred at room temperature for 16 hours. LCMS monitoring showed the formation of a large amount of imine. Then, sodium borohydride (246 mg, 6.50 mmol) and methanol (3 mL) were added, and the reaction mixture was stirred at room temperature for another 3 hours. LCMS monitoring showed the reaction was complete.
  • Step 3 Compound 12-2 (100 mg, 0.18 mmol) was dissolved in a mixed solvent of tetrahydrofuran (2 mL), methanol (2 mL), and water (2 mL). Lithium hydroxide (37.83 mg, 0.90 mmol) was added, and the reaction was carried out at room temperature for 2 hours. The reaction was monitored by LCMS to indicate completion. Dilute HCl (2.0 M) was slowly added dropwise to the reaction solution to adjust the pH to approximately 5-7. A large amount of solid precipitated out.
  • the crude solid obtained by filtration was purified by reversed-phase chromatography using a Waters-Xbridge-C18-10 ⁇ m-19 ⁇ 250 mm mobile phase (A: 10 mM NH4HCO3 / H2O ; B: ACN ; gradient: B%: 0%-95%).
  • the purified product was obtained.
  • Step 1 Add a 40 mL solution of acetonitrile (4 g, 18.5 mmol) of compound 4-6 to a 500 mL single-necked flask. Then, sequentially add CuI (0.7 g, 3.70 mmol), 2-fluorosulfonyl difluoroacetic acid (6.59 g, 36.99 mmol), and anhydrous sodium sulfate (1 g, 33.00 mmol) at 70 °C. Maintain the mixture at 70 °C and stir for 1.5 hours. Detect the reaction as complete by LC-MS. After the reaction mixture cools to room temperature, quench it slowly with ice water. Extract three times with ethyl acetate (3 ⁇ 40 mL).
  • Step 2 Compound 13-1 (1690.71 mg, 6.35 mmol) and compound 1-7 (1600 mg, 5.29 mmol) dissolved in N,N-dimethylformamide (20 mL) were added to a 100 mL single-necked flask at 0 °C. Then, N,N-diisopropylethylamine (4.62 mL, 26.46 mmol) was slowly added, and the mixture was stirred at 60 °C for 10 hours. The reaction was monitored by LC-MS to confirm completion.
  • Step 3 Compound 13-2 (400 mg, 1.01 mmol) dissolved in a mixture of acetonitrile (10 mL) and water (10 mL) was added to a 100 mL single-necked flask at 0 °C. Then, [bis(trifluoroacetoxy)iodo]benzene (871.90 mg, 2.02 mmol) was slowly added. The reaction was carried out at room temperature for 16 hours, and the reaction was monitored by LC-MS to confirm completion. The reaction solution was quenched by slow addition of saturated sodium bicarbonate solution at room temperature. The precipitated solid was filtered off, and the mother liquor was extracted three times with dichloromethane (3 ⁇ 50 mL).
  • Step 4 Compound 13-3 (170 mg, 0.46 mmol) was dissolved in methanol (5 mL), followed by the addition of compound 1-14 (200 mg, 0.69 mmol) and 3 drops of acetic acid. After stirring for 0.5 h, sodium cyanoborohydride (86.99 mg, 1.38 mmol) was added, and the mixture was stirred overnight at room temperature. The reaction was monitored for completeness by LCMS. The reaction solution was quenched slowly with ice water, and extracted three times with ethyl acetate (3 ⁇ 50 mL). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure.
  • Step 5 Compound 13-4 (200 mg, 0.31 mmol) was dissolved in a mixed solvent of methanol (7 mL) and water (2 mL). Lithium hydroxide (523.06 mg, 12.47 mmol) was added, and the mixture was heated to 60 °C for 1 hour. The reaction was monitored for completeness by LCMS. The reaction solution was cooled to room temperature, and then dilute HCl ( 1.0 M) was slowly added dropwise to adjust the pH to approximately 5-7. A large amount of solid precipitated.
  • the crude solid obtained by filtration was purified by reversed-phase chromatography using a Waters-Xbridge-C18-10 ⁇ m-19 ⁇ 250 mm column; mobile phase: (A: 10 mM NH4HCO3 / H2O ; B: ACN; gradient: B%: 0%-95%).
  • the purified product was obtained.
  • Step 1 Compound 13-3 (170 mg, 0.46 mmol) was dissolved in methanol (5 mL), followed by the addition of compound 3-9 (189.18 mg, 0.69 mmol) and 3 drops of acetic acid. After stirring for 0.5 h, sodium cyanoborohydride (86.99 mg, 1.38 mmol) was added, and the mixture was stirred overnight at room temperature. The reaction was monitored for completeness by LCMS. The reaction solution was quenched slowly with ice water, and extracted three times with ethyl acetate (3 ⁇ 50 mL). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure.
  • Step 2 Compound 14-1 (180 mg, 0.29 mmol) was dissolved in a mixed solvent of tetrahydrofuran (3 mL), methanol (3 mL), and water (3 mL). Lithium hydroxide (482.79 mg, 11.51 mmol) was added, and the mixture was heated to 60 °C for 1 hour. The reaction was monitored for completeness by LCMS. The reaction solution was cooled to room temperature, and dilute HCl (2.0 M) was slowly added dropwise to adjust the pH to approximately 5-7. A large amount of solid precipitated.
  • the crude solid obtained by filtration was purified by reversed-phase chromatography using a Waters-Xbridge-C18-10 ⁇ m-19 ⁇ 250 mm column; mobile phase: (A: 10 mM NH4HCO3 / H2O ; B: ACN; gradient: B%: 0%-95%).
  • the purified product was obtained.
  • Step 1 Add a 200 mL solution of DCM containing 8.5 g (111.71 mmol) of compound 15-1 to a 500 mL single-necked flask. Then, add p-toluenesulfonyl chloride (21.30 g, 111.71 mmol) and triethylamine (30.97 mL, 223.42 mmol) sequentially at 0 °C. React at room temperature for 16 hours, and the reaction is monitored by LCMS to confirm completion. Quench the reaction mixture with saturated sodium bicarbonate solution. Extract three times with DCM (3 ⁇ 200 mL). Wash the combined organic phases with saturated brine, dry with anhydrous sodium sulfate, and concentrate under reduced pressure.
  • Step 2 Add a 140 mL solution of acetonitrile (14 g, 60.80 mmol) of compound 15-2 to a 500 mL single-necked flask. Then, sequentially add CuI (2.32 g, 12.16 mmol), 2-fluorosulfonyl difluoroacetic acid (21.65 g, 121.59 mmol), and anhydrous sodium sulfate (1 g, 33.00 mmol) at 70 °C. Continue stirring at 70 °C for 1.5 hours. Detect the reaction as complete by LCMS. After the reaction solution cools to room temperature, quench with ice water. Extract three times with ethyl acetate (3 ⁇ 200 mL).
  • Step 3 At room temperature, add a solution of compound 1-7 (5.24 g, 17.34 mmol) and compound 15-3 (4.63 g, 16.52 mmol) dissolved in N,N-dimethylformamide (200 mL) to a 500 mL single-necked flask. Then, slowly add N,N-diisopropylethylamine (14.43 mL, 82.59 mmol) and react at 80 °C for 16 hours. The reaction was monitored by LCMS to confirm completion. After the reaction solution cooled to room temperature, it was quenched slowly with water. The mixture was extracted three times with ethyl acetate (3 ⁇ 200 mL).
  • Step 4 At room temperature, a mixture of compound 15-4 (3 g, 7.31 mmol) dissolved in acetonitrile (80 mL) and water (40 mL) was added to a 100 mL single-necked flask. Then, [bis(trifluoroacetoxy)iodo]benzene (6.32 g, 14.62 mmol) was slowly added, and the reaction was carried out at room temperature for 2 hours. The reaction was detected by LCMS. The reaction solution was quenched with saturated sodium bicarbonate solution, and the precipitated solid was filtered off. The mother liquor was extracted three times with dichloromethane (3 ⁇ 200 mL).
  • Step 5 Compound 15-5 (300 mg, 0.75 mmol) was dissolved in acetonitrile (5 mL), compound 3-9 (204 mg, 0.75 mmol) and 5 drops of acetic acid were added, and the mixture was stirred overnight at room temperature. Then, sodium borohydride (85 mg, 2.24 mmol) and methanol (3 mL) were added at 0 °C, and the reaction was continued at room temperature for 1 hour. The reaction was monitored for completion by LCMS. The reaction solution was quenched slowly with water at room temperature, extracted three times with ethyl acetate (3 ⁇ 50 mL), and the combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure.
  • Step 6 Compound 15-6 (300 mg, 0.47 mmol) was dissolved in a mixed solvent of tetrahydrofuran (4 mL), methanol (4 mL), and water (4 mL). Lithium hydroxide monohydrate (787 mg, 18.76 mmol) was added, and the mixture was heated to 60 °C and reacted for 2 hours. The reaction was monitored by LCMS to ensure completion. After the reaction solution cooled to room temperature, the pH was adjusted to between 5 and 7 using 2 M dilute hydrochloric acid. A large amount of solid precipitated.
  • the crude solid obtained by filtration was purified by reversed-phase chromatography [model: Waters-Xbridge-C18-10 ⁇ m-19 ⁇ 250 mm; mobile phase: (A: 10 mM NH4HCO3 / H2O ; B: ACN ; gradient: B%: 0%-95%)] to obtain the purified product.
  • Step 1 Add a solution of compound 16-1 (8.5 g, 111.71 mmol) in dichloromethane (200 mL) to a 500 mL single-necked flask. Then, add p-toluenesulfonyl chloride (21.30 g, 111.71 mmol) and triethylamine (15.48 mL, 111.71 mmol) sequentially at 0 °C. The reaction was allowed to proceed for 16 hours at room temperature, and the reaction was monitored by LC-MS. The reaction mixture was quenched with saturated sodium bicarbonate solution and extracted three times with DCM (3 ⁇ 200 mL).
  • Step 2 Add a 200 mL solution of acetonitrile (10 g, 33.00 mmol) of compound 16-2 to a 25 mL single-necked flask. At 70 °C, add cuprous iodide (1.26 g, 6.60 mmol), 2-fluorosulfonyl difluoroacetic acid (11.75 g, 66.01 mmol), and anhydrous sodium sulfate (1 g, 33.00 mmol) sequentially. Stir at 70 °C for 1.5 hours. Detect the reaction as complete by LCMS. After the reaction solution cools to room temperature, quench with ice water slowly. Extract three times with ethyl acetate (3 ⁇ 100 mL).
  • Step 3 Compound 1-7 (6.47 g, 21.41 mmol) and compound 16-3 (6 g, 21.41 mmol) dissolved in N,N-dimethylformamide (140 mL) were added to a 250 mL single-necked flask at 0 °C. Then, N,N-diisopropylethylamine (18.69 mL, 107.03 mmol) was slowly added, and the reaction was carried out at 100 °C for 3 hours. The reaction was monitored by LC-MS to confirm completion. After the reaction solution cooled to room temperature, it was quenched slowly with water. The mixture was extracted three times with ethyl acetate (3 ⁇ 200 mL).
  • Step 4 Compound 16-4 (2.7 g, 6.58 mmol) dissolved in a mixture of acetonitrile (30 mL) and water (15 mL) was added to a 250 mL single-necked flask at 0 °C. Then, [bis(trifluoroacetoxy)iodo]benzene (5.68 g, 13.16 mmol) was slowly added. The reaction was carried out at room temperature for 1.5 hours, and the reaction was monitored by LCMS to confirm completion. The reaction solution was quenched with saturated sodium bicarbonate solution, and the precipitated solid was filtered off. The mother liquor was extracted three times with dichloromethane (3 ⁇ 200 mL).
  • Step 5 Compound 16-5 (300 mg, 0.78 mmol) was dissolved in acetonitrile (10 mL), compound 3-9 (214.40 mg, 0.78 mmol) and 5 drops of acetic acid were added, and the mixture was stirred overnight at room temperature.
  • Sodium borohydride (89.02 mg, 2.35 mmol) was added at 0 °C, and the reaction was continued at room temperature for 1 hour. The reaction was monitored for completeness by LCMS.
  • the reaction solution was quenched by slow addition of water at room temperature, and extracted three times with ethyl acetate (3 ⁇ 50 mL). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure.
  • Step 6 Compound 16-6 (220 mg, 0.34 mmol) was dissolved in a mixed solvent of tetrahydrofuran (3 mL), methanol (3 mL), and water (3 mL). Lithium hydroxide (577.15 mg, 13.75 mmol) was added, and the mixture was heated to 60 °C for 2 hours. The reaction was monitored by LCMS to ensure completion. The reaction solution was cooled to room temperature, and dilute HCl (2.0 M) was slowly added dropwise to adjust the pH to approximately 5-7. A large amount of solid precipitated out. The solid was filtered to obtain a white solid.
  • the crude product was purified by reversed-phase chromatography using a Waters-Xbridge-C18-10 ⁇ m-19 ⁇ 250 mm column; mobile phase: (A: 10 mM NH4HCO3 / H2O ; B: ACN; gradient: B%: 0%-95%).
  • the purified product was obtained.
  • Step 1 A solution of compound 17-1 (30.7 g, 259.88 mmol) in dichloromethane (300 mL) was added to a 500 mL single-necked flask. 2,2,2-Trichloroacetamide benzyl ester (72.19 g, 285.87 mmol) and trifluoromethanesulfonic acid (2.3 mL, 25.99 mmol) were added sequentially at 0 °C. The reaction was carried out at room temperature for 2 hours, and the reaction was monitored for completeness by LC-MS. The reaction solution was quenched by slow addition of sodium bicarbonate solution at room temperature. The mixture was extracted three times with dichloromethane (3 ⁇ 200 mL).
  • Step 2 A tetrahydrofuran (300 mL) solution of compound 17-2 (30 g, 144.05 mmol) was added to a 500 mL three-necked flask. Lithium aluminum hydride (6.56 g, 172.86 mmol) was slowly added at 0 °C, and the reaction was maintained at 0 °C for 1 hour. The reaction was detected as complete by LCMS. The reaction solution was quenched by slow addition of dilute hydrochloric acid (1 M) in an ice-water bath. The mixture was extracted three times with ethyl acetate (3 ⁇ 200 mL).
  • Step 3 Add a 250 mL solution of dichloromethane containing 21.3 g (100.44 mmol) of compound 17-3 to a 500 mL single-necked flask. Slowly add Dys-Martin oxidant (55.38 g, 130.58 mmol) at 0 °C, and allow the mixture to return to room temperature for 2 hours. Monitor the reaction for completeness by TLC. Quench the reaction mixture slowly with saturated sodium bicarbonate solution. Extract three times with ethyl acetate (3 ⁇ 100 mL). Wash the combined organic phases with saturated brine, dry with anhydrous sodium sulfate, and concentrate under reduced pressure.
  • Dys-Martin oxidant 55.38 g, 130.58 mmol
  • Step 4 Add a solution of compound 17-4 (15 g, 84.16 mmol) in dichloromethane (150 mL) to a 500 mL single-necked flask. Slowly add diethylaminosulfur trifluoride (27.13 g, 168.32 mmol) at 0 °C, and allow the mixture to return to room temperature for 2 hours. Monitor the reaction for completeness by TLC. Quench the reaction mixture with sodium bicarbonate solution slowly in an ice-water bath. Extract three times with dichloromethane (3 ⁇ 100 mL). Wash the combined organic phases with saturated sodium bicarbonate solution, dry with anhydrous sodium sulfate, and concentrate under reduced pressure.
  • Step 5 Add a tetrahydrofuran (80 mL) solution of compound 17-5 (4.5 g, 22.47 mmol) to a 500 mL single-necked flask, add 10% palladium on carbon (1 g), displace the hydrogen atmosphere, and react at room temperature for 16 hours. Monitor the reaction for completeness by TLC. Filter the reaction solution directly and dry it. The filtrate containing compound 17-6 is used directly for the next step of the reaction.
  • Step 6 Add the tetrahydrofuran solution containing compound 17-6 from the previous step to a 500 mL single-necked flask. Slowly add p-toluenesulfonyl chloride (5.19 g, 27.25 mmol) and triethylamine (4.60 g, 45.41 mmol) at 0 °C. Allow the mixture to return to room temperature and react for 16 hours. Monitor the reaction for completeness using LC-MS. Quench the reaction mixture with ice water, extract three times with dichloromethane (3 ⁇ 50 mL), wash the combined organic phases with saturated brine, dry with anhydrous sodium sulfate, and concentrate under reduced pressure.
  • p-toluenesulfonyl chloride 5.19 g, 27.25 mmol
  • triethylamine 4.60 g, 45.41 mmol
  • Step 7 Compound 17-7 (1.3 g, 4.92 mmol) and compound 1-7 (1.49 g, 4.92 mmol) dissolved in N,N-dimethylformamide (50 mL) were added to a 250 mL single-necked flask at 0 °C. Then, N,N-diisopropylethylamine (0.64 g, 4.92 mmol) was slowly added. The reaction was allowed to proceed for 32 hours at room temperature, and the reaction was confirmed by LC-MS.
  • reaction solution was quenched slowly with ice water at room temperature, extracted three times with ethyl acetate (3 ⁇ 50 mL), and the combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure.
  • the crude product was purified by silica gel column chromatography [mobile phase gradient: 0%-50% ethyl acetate/petroleum ether] to obtain compound 17-8.
  • Step 8 Compound 17-8 (1.4 g, 3.55 mmol) dissolved in a mixture of acetonitrile (30 mL) and water (15 mL) was added to a 250 mL single-necked flask at 0 °C. Then, [bis(trifluoroacetoxy)iodide]benzene (3.07 g, 7.10 mmol) was slowly added. The reaction was carried out at room temperature for 16 hours, and the reaction was monitored by LC-MS to confirm completion. The reaction solution was quenched by slow addition of saturated sodium bicarbonate solution at room temperature. The precipitated solid was filtered off, and the mother liquor was extracted three times with dichloromethane (3 ⁇ 50 mL).
  • Step 9 Compound 17-9 (250 mg, 0.68 mmol) was dissolved in acetonitrile (8 mL), compound 3-9 (187 mg, 0.68 mmol) and 5 drops of acetic acid were added, and the mixture was stirred overnight at room temperature.
  • the reaction solution was quenched slowly with ice water at room temperature, extracted three times with ethyl acetate (3 ⁇ 50 mL), the combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure.
  • Step 10 Compound 17-10 (200 mg, 0.32 mmol) was dissolved in a mixed solvent of methanol (4 mL), water (4 mL), and tetrahydrofuran (4 mL). Lithium hydroxide monohydrate (538 mg, 12.82 mmol) was added, and the mixture was heated to 60 °C for 2 hours. The reaction was monitored by LCMS to ensure completion. The reaction solution was cooled to room temperature, and dilute HCl (2.0 M) was slowly added dropwise to adjust the pH to approximately 5-7. A large amount of solid precipitated.
  • the crude solid obtained by filtration was purified by reversed-phase chromatography using a Waters-Xbridge-C18-10 ⁇ m-19 ⁇ 250 mm mobile phase gradient: (A: 10 mM NH4HCO3 / H2O B: ACN ; gradient: B%: 0%-95%).
  • the purified product was obtained.
  • Step 1 Add a 100 mL solution of compound 18-1 (5 g, 42.33 mmol) in dichloromethane (100 mL) to a 100 mL single-necked flask. Add 2,2,2-trichloroacetamide benzyl ester (11.76 g, 46.56 mmol) and trifluoromethanesulfonic acid (0.37 mL, 4.23 mmol) sequentially at 0 °C. Allow the mixture to return to room temperature for 2 hours, monitoring the reaction until complete via LC-MS. Quench the reaction solution slowly with sodium bicarbonate solution at room temperature. Extract three times with dichloromethane (3 ⁇ 100 mL).
  • Step 3 Add a 200 mL solution of dichloromethane containing 10 g (55.48 mmol) of compound 18-3 to a 500 mL single-necked flask. Slowly add Dys-Martin oxidant (30.59 g, 72.12 mmol) at 0 °C, and allow the mixture to return to room temperature for 2 hours. Monitor the reaction for completeness by TLC. Quench the reaction mixture slowly with saturated sodium bicarbonate solution. Extract three times with ethyl acetate (3 ⁇ 100 mL). Wash the combined organic phases with saturated brine, dry with anhydrous sodium sulfate, and concentrate under reduced pressure.
  • Step 4 Add a 150 mL solution of dichloromethane containing 6.9 g (38.71 mmol) of compound 18-4 to a 500 mL single-necked flask. Slowly add 12.48 g (77.43 mmol) of diethylaminotrifluoride at 0 °C, and allow the mixture to return to room temperature for 2 hours. Monitor the reaction for completeness by TLC. Quench the reaction mixture with sodium bicarbonate solution slowly in an ice-water bath. Extract three times with dichloromethane (3 ⁇ 100 mL). Wash the combined organic phases with saturated sodium bicarbonate solution, dry with anhydrous sodium sulfate, and concentrate under reduced pressure.
  • Step 6 Add the tetrahydrofuran solution containing compound 18-6 from the previous step to a 500 mL single-necked flask. Slowly add p-toluenesulfonyl chloride (6.23 g, 32.70 mmol) and triethylamine (7.55 mL, 54.50 mmol) at 0 °C. React at room temperature for 16 hours, and monitor the reaction for completeness by LCMS. Quench the reaction solution with ice water, extract three times with dichloromethane (3 ⁇ 50 mL), wash the combined organic phases with saturated brine, dry with anhydrous sodium sulfate, and concentrate under reduced pressure.
  • Step 7 Compound 18-7 (1.75 g, 6.61 mmol) and compound 1-7 (2 g, 6.61 mmol) dissolved in N,N-dimethylformamide (50 mL) were added to a 250 mL single-necked flask at 0 °C. Then, N,N-diisopropylethylamine (5.76 mL, 33.07 mmol) was slowly added dropwise. The reaction was allowed to proceed for 32 hours at room temperature, and the reaction was confirmed by LC-MS.
  • reaction solution was quenched slowly with ice water at room temperature, extracted three times with ethyl acetate (3 ⁇ 50 mL), and the combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure.
  • the crude product was purified by silica gel column chromatography (mobile phase gradient: 0%-50% ethyl acetate/petroleum ether) to obtain compound 18-8.
  • Step 8 Compound 18-8 (3.4 g, 8.62 mmol) dissolved in a mixture of acetonitrile (30 mL) and water (15 mL) was added to a 250 mL single-necked flask at 0 °C. Then, [bis(trifluoroacetoxy)iodo]benzene (7.45 g, 17.24 mmol) was slowly added. The reaction was carried out at room temperature for 16 hours, and the reaction was monitored by LCMS to confirm completion. The reaction solution was quenched by slow addition of saturated sodium bicarbonate solution at room temperature. The precipitated solid was filtered off, and the mother liquor was extracted three times with dichloromethane (3 ⁇ 50 mL).
  • Step 9 Compound 18-9 (300 mg, 0.82 mmol) was dissolved in acetonitrile (8 mL), compound 3-9 (223.77 mg, 0.82 mmol) and 5 drops of acetic acid were added, and the mixture was stirred overnight at room temperature.
  • Sodium borohydride (77 mg, 2.05 mmol) and methanol (4 mL) were added at 0 °C, and the reaction was continued at room temperature for 1 hour. The reaction was monitored for completion by LCMS.
  • the reaction solution was quenched slowly with ice water at room temperature, extracted three times with ethyl acetate (3 ⁇ 50 mL), the combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure.
  • Step 10 Compound 18-10 (220 mg, 0.35 mmol) was dissolved in a mixed solvent of methanol (4 mL), water (4 mL), and tetrahydrofuran (4 mL). Lithium hydroxide (591.94 mg, 14.11 mmol) was added, and the mixture was heated to 60 °C for 2 hours. The reaction was monitored by LCMS to ensure completion. The reaction solution was cooled to room temperature, and dilute HCl (2.0 M) was slowly added dropwise to adjust the pH to approximately 5-7. A large amount of solid precipitated.
  • the crude solid obtained by filtration was purified by reversed-phase chromatography using a Waters-Xbridge-C18-10 ⁇ m-19 ⁇ 250 mm mobile phase gradient: (A: 10 mM NH4HCO3 / H2O B: ACN; gradient: B%: 0%-95%).
  • the purified product was obtained.
  • Step 1 Compound 18-9 (200 mg, 0.55 mmol) was dissolved in acetonitrile (8 mL), and compound 7-2 (156.83 mg, 0.55 mmol) was added. The mixture was stirred overnight at room temperature. Sodium borohydride (62.42 mg, 1.65 mmol) and methanol (4 mL) were added at 0 °C, and the reaction was continued for 2 hours at room temperature. The reaction was monitored by LCMS to indicate completion. The reaction solution was quenched slowly with ice water at room temperature. The mixture was extracted three times with ethyl acetate (3 ⁇ 50 mL). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure.
  • Step 2 Compound 19-1 (156 mg, 0.24 mmol) was dissolved in a mixed solvent of tetrahydrofuran (3 mL), methanol (3 mL), and water (3 mL). Lithium hydroxide (410.51 mg, 9.78 mmol) was added, and the mixture was heated to 60 °C and reacted for 1 hour. The reaction was monitored by LCMS to ensure completion. The reaction solution was cooled to room temperature, and dilute HCl (2.0 M) was slowly added dropwise to adjust the pH to approximately 5-7. A large amount of solid precipitated.
  • the crude solid obtained by filtration was purified by reversed-phase chromatography using a Waters-Xbridge-C18-10 ⁇ m-19 ⁇ 250 mm mobile phase gradient: (A: 10 mM NH4HCO3 / H2O B: ACN ; gradient: B%: 0%-95%).
  • the purified product was obtained.
  • Step 1 Compound 1-7 (2 g, 6.61 mmol) and (S)-(-)-3,3,3-trifluoro-1,2-epoxypropane (2.22 g, 19.84 mmol) dissolved in N,N-dimethylformamide (30 mL) were added to a 100 mL single-necked flask at room temperature. Then, N,N-diisopropylethylamine (4.27 g, 33.07 mmol) was slowly added, and the reaction was carried out at room temperature for 16 hours. The reaction was detected by LCMS. The reaction solution was quenched with ice water at room temperature and extracted three times with dichloromethane (3 ⁇ 50 mL).
  • Step 2 Compound 20-1 (1.3 g, 3.14 mmol) was dissolved in N,N-dimethylformamide (20 mL), and Cs2CO3 (2.04 g, 6.27 mmol) was added. The reaction mixture was stirred at room temperature for 1 hour, and then iodomethane (0.33 mL, 4.08 mmol) was added. The mixture was stirred at room temperature for another 16 hours, and the reaction was monitored by LCMS to indicate completion. The reaction mixture was quenched by slow addition of saturated ammonium chloride solution at room temperature. The mixture was extracted three times with ethyl acetate (3 ⁇ 50 mL).
  • Step 3 At room temperature, a mixture of compound 20-2 (850 mg, 1.98 mmol) dissolved in acetonitrile (16 mL) and water (8 mL) was added to a 100 mL single-necked flask. Then, [bis(trifluoroacetoxy)iodo]benzene (1.71 g, 3.97 mmol) was slowly added, and the reaction was carried out at room temperature for 2 hours. The reaction was detected as complete by LCMS. The reaction solution was quenched by slowly adding saturated sodium bicarbonate solution at room temperature. The precipitated solid was filtered off, and the mother liquor was extracted three times with dichloromethane (3 ⁇ 50 mL).
  • Step 4 Compound 20-3 (300 mg, 0.60 mmol) and compound 3-9 (164 mg, 0.60 mmol) were dissolved in acetonitrile (5 mL), and 4 drops of acetic acid were added. The reaction mixture was stirred at room temperature for 16 hours. Then, sodium borohydride (68 mg, 1.80 mmol) and methanol (3 mL) were added, and the reaction mixture was stirred at room temperature for another hour. The reaction was monitored for completion by LCMS. The reaction mixture was quenched by slowly adding saturated sodium bicarbonate solution at room temperature.
  • Step 5 Compound 20-4 (200 mg, 0.30 mmol) was dissolved in tetrahydrofuran (4 mL), methanol (4 mL), and water (4 mL). Lithium hydroxide monohydrate (510 mg, 12.16 mmol) was added. The reaction mixture was stirred at 60 °C for 2 hours, and the reaction was monitored for completion by LCMS. After the reaction mixture cooled to room temperature, the pH was adjusted to between 5 and 7 with 2 M hydrochloric acid. A large amount of solid precipitated.
  • the crude solid obtained by filtration was purified by reversed-phase chromatography [model: Waters-Xbridge-C18-10 ⁇ m-19 ⁇ 250 mm; mobile phase gradient: (A: 10 mM NH4HCO3 / H2O B: ACN; gradient: B%: 0%-95%)] to obtain the purified product.
  • the purified product (115 mg, 0.22 mmol) was dissolved in methanol (5 mL), and 0.15 mL of 4 N hydrochloric acid-methanol solution was slowly added dropwise with stirring. After stirring for 10 min, the methanol was evaporated to dryness at room temperature. Then, 5 mL of deionized water was added, and the mixture was sonicated and lyophilized to obtain compound 20.
  • Step 1 At room temperature, compound 1-7 (1.00 g, 3.31 mmol) was dissolved in ethanol (20 mL), and R-(+)-2-trifluoromethyl ethylene oxide (1.11 g, 9.92 mmol) and N,N-diisopropylethylamine (2.14 g, 16.54 mmol) were added. The reaction was carried out at room temperature for 16 hours, and the reaction was detected by LCMS. The reaction solution was quenched slowly with ice water at room temperature, extracted three times with dichloromethane (3 ⁇ 50 mL), and the combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure.
  • Step 2 At room temperature, compound 21-1 (1000 mg, 2.41 mmol) was dissolved in DMF (20 mL). Cesium carbonate (1179.28 mg, 3.62 mmol) and methyl iodide (0.39 mL, 4.83 mmol) were added sequentially with stirring, and the mixture was stirred overnight. The reaction was monitored by LCMS to ensure completion. The reaction solution was quenched by slow addition of saturated ammonium chloride solution at room temperature. The mixture was extracted three times with ethyl acetate (3 ⁇ 50 mL). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure.
  • Step 3 At room temperature, compound 21-2 (500 mg, 1.16 mmol) was dissolved in a mixed solvent of acetonitrile (5 mL) and water (5 mL), and then [bis(trifluoroacetoxy)iodo]benzene (1.0 g, 5.79 mmol) was added. The reaction was carried out at room temperature for 18 hours, and the reaction was detected by LCMS. The reaction solution was quenched by slowly adding saturated sodium bicarbonate solution at room temperature. The precipitated solid was filtered off, and the mother liquor was extracted three times with dichloromethane (3 ⁇ 50 mL). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure.
  • Step 4 At room temperature, compound 21-3 (300 mg, 0.75 mmol) was dissolved in acetonitrile (3 mL), followed by the addition of compound 3-9 (204.77 mg, 0.75 mmol) and 3 drops of acetic acid. The reaction mixture was stirred overnight. Then, sodium borohydride (85.12 mg, 2.25 mmol) and methanol (3 mL) were added, and the reaction mixture was stirred for another hour at room temperature. The reaction was monitored for completion by LCMS. The reaction mixture was quenched by slow addition of saturated sodium bicarbonate solution at room temperature. Extraction was performed three times with ethyl acetate (3 ⁇ 50 mL).
  • Step 5 Compound 21-4 (250 mg, 0.38 mmol) was dissolved in a mixed solvent of tetrahydrofuran (3 mL), methanol (3 mL), and water (3 mL). Lithium hydroxide (638 mg, 15.2 mmol) was added, and the mixture was heated to 60 °C for 1 hour. The reaction was monitored by LCMS to ensure completion. After the reaction solution cooled to room temperature, the pH was adjusted to between 5 and 7 using 2 M hydrochloric acid. A large amount of solid precipitated.
  • the crude solid obtained by filtration was purified by reversed-phase chromatography using a Waters-Xbridge-C18-10 ⁇ m-19 ⁇ 250 mm mobile phase gradient: (A: 10 mM NH4HCO3 / H2O ; B: ACN ; gradient: B%: 0%-95%).
  • the purified product was obtained.
  • Step 1 Compound 20-3 (200 mg, 0.50 mmol) and compound 1-14 (145 mg, 0.50 mmol) were dissolved in acetonitrile (5 mL), and 4 drops of acetic acid were added. The reaction mixture was stirred at room temperature for 16 hours. Then, sodium borohydride (57 mg, 1.50 mmol) and methanol (3 mL) were added, and the reaction mixture was stirred at room temperature for another hour. The reaction was monitored for completion by LCMS. The reaction mixture was quenched by slowly adding saturated sodium bicarbonate solution at room temperature. The mixture was extracted three times with ethyl acetate (3 ⁇ 50 mL).
  • Step 2 Compound 22-1 (180 mg, 0.27 mmol) was dissolved in tetrahydrofuran (4 mL), methanol (4 mL), and water (4 mL). Lithium hydroxide (256 mg, 10.69 mmol) was added. The reaction mixture was stirred at 60 °C for 3 hours, and the reaction was monitored for completion by LCMS. After the reaction mixture cooled to room temperature, the pH was adjusted to between 5 and 7 with 2 M hydrochloric acid. A large amount of solid precipitated.
  • the crude solid obtained by filtration was purified by reversed-phase chromatography [model: Waters-Xbridge-C18-10 ⁇ m-19 ⁇ 250 mm; mobile phase gradient: (A: 10 mM NH4HCO3 / H2O ; B: ACN ; gradient: B%: 0%-95%)] to obtain the purified product.
  • Step 1 Compound 20-3 (130 mg, 0.32 mmol) and compound 10-1 (98 mg, 0.32 mmol) were dissolved in acetonitrile (5 mL), and 4 drops of acetic acid were added. The reaction mixture was stirred at room temperature for 16 hours. Then, sodium borohydride (37 mg, 0.97 mmol) and methanol (3 mL) were added, and the reaction mixture was stirred at room temperature for another hour. The reaction was monitored for completion by LCMS. The reaction mixture was quenched by slowly adding saturated sodium bicarbonate solution at room temperature. The mixture was extracted three times with ethyl acetate (3 ⁇ 50 mL).
  • Step 2 Compound 23-1 (130 mg, 0.19 mmol) was dissolved in tetrahydrofuran (3 mL), methanol (3 mL), and water (3 mL). Lithium hydroxide (182 mg, 7.60 mmol) was added. The reaction mixture was stirred at 60 °C for 2 hours, and the reaction was monitored by LCMS to ensure completion. After the reaction mixture cooled to room temperature, the pH was adjusted to between 5 and 7 with 2 M hydrochloric acid. A large amount of solid precipitated.
  • the crude solid obtained by filtration was purified by reversed-phase chromatography [model: Waters-Xbridge-C18-10 ⁇ m-19 ⁇ 250 mm; mobile phase gradient: ( A: 10 mM NH4HCO3 /H2O; B: ACN; gradient: B%: 0%-95%)] to obtain the purified product.
  • Step 1 Silver trifluoromethanesulfonate (106.94 g, 416.20 mmol), potassium fluoride (32.24 g, 554.94 mmol), and 1-chloromethyl-4-fluoro-1,4-diazidobicyclo[2.2.2]octanebistetrafluoroborate (73.72 g, 208.10 mmol) were dissolved in ethyl acetate (400 mL). Compound 24-1 (25 g, 138.73 mmol) was added under nitrogen protection.
  • Step 2 Compound 24-2 (9.0 g, 36.26 mmol) was dissolved in tetrahydrofuran (150 mL). Lithium aluminum hydride (2.06 g, 54.39 mmol) was added in portions at 0 °C. The reaction mixture was stirred at 0 °C for 0.5 hours, then allowed to return to room temperature overnight. The reaction was monitored by TLC to confirm its completion. The reaction mixture was quenched by slow addition of dilute HCl (1 M) in an ice-water bath. The mixture was extracted three times with dichloromethane (3 ⁇ 100 mL). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain compound 24-3.
  • Step 3 Compound 24-3 (5 g) was dissolved in dichloromethane (60 mL), triethylamine (7.02 g, 69.40 mmol) was added, and trifluoromethanesulfonic anhydride (9.79 g, 34.70 mmol) was added at 0 °C. The reaction was allowed to proceed overnight at room temperature. The reaction was monitored by TLC until it was complete. The reaction solution was quenched with ice water, extracted three times with dichloromethane (3 ⁇ 100 mL), and the combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain compound 24-4.
  • Step 4 Compound 24-4 (9 g) was dissolved in N,N-dimethylformamide (30 mL), and compound 1-7 (990 mg, 3.26 mmol) and N,N-diisopropylethylamine (2.93 mL, 16.30 mmol) were added. The reaction mixture was stirred overnight at room temperature, and the reaction was monitored by LCMS. The reaction mixture was quenched with water at room temperature and extracted three times with dichloromethane (3 ⁇ 100 mL). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure.
  • Step 5 Compound 24-5 (130 mg, 0.30 mmol) was dissolved in a mixed solvent of acetonitrile (2 mL) and water (1 mL). Compound [bis(trifluoroacetoxy)iodide]benzene (262.19 mg, 0.61 mmol) was added, and the mixture was stirred at room temperature for 2 hours. The reaction was monitored by LCMS to indicate completion. The reaction solution was quenched by slow addition of saturated sodium bicarbonate solution at room temperature. The precipitated solid was filtered off, and the mother liquor was extracted three times with dichloromethane (3 ⁇ 50 mL). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure.
  • Step 6 Compound 24-6 (200 mg, 0.50 mmol) was dissolved in acetonitrile (5 mL), compound 5-3 (86.51 mg, 0.50 mmol) and 5 drops of acetic acid were added, and the mixture was stirred overnight at room temperature. Then sodium borohydride (15.13 mg, 0.40 mmol) and methanol (1 mL) were added, and the mixture was stirred for another hour at room temperature. The reaction was monitored for completion by LCMS. The reaction solution was quenched by slow addition of saturated sodium bicarbonate solution at room temperature, and extracted three times with dichloromethane (3 ⁇ 50 mL).
  • Step 7 Compound 24-7 (190 mg, 0.34 mmol) was dissolved in a mixed solution of tetrahydrofuran (2 mL), methanol (2 mL), and water (2 mL). Lithium hydroxide (71.5 mg, 1.7 mmol) was added, and the reaction mixture was stirred overnight at room temperature. The reaction was monitored by LCMS to indicate completion. The reaction solution was directly purified by reversed-phase chromatography [Model: Waters-Xbridge-C18-10 ⁇ m-19 ⁇ 250 mm; mobile phase gradient: (A: 10 mM NH4HCO3 / H2O ; B: ACN; gradient: B%: 0%-95%)] to obtain the purified product.
  • the purified product (70 mg, 0.132 mmol) was dissolved in methanol (5 mL), and 99.1 ⁇ L of 4N hydrochloric acid in methanol solution was added. After stirring for 10 min, the methanol was evaporated to dryness at room temperature. Then, 5 mL of deionized water was added, and the mixture was sonicated and lyophilized to obtain compound 24.
  • Step 1 Silver trifluoromethanesulfonate (106.94 g, 416.20 mmol), potassium fluoride (32.24 g, 554.94 mmol), and 1-chloromethyl-4-fluoro-1,4-diazidobicyclo[2.2.2]octanebistetrafluoroborate (73.72 g, 208.10 mmol) were dissolved in ethyl acetate (400 mL). Compound 25-1 (25 g, 138.73 mmol) was added under nitrogen protection.
  • Step 3 Compound 25-3 (9 g) was dissolved in dichloromethane (100 mL), triethylamine (12.64 g, 124.92 mmol) was added, and trifluoromethanesulfonic anhydride (17.62 g, 62.46 mmol) was added at 0 °C. The reaction was allowed to proceed overnight at room temperature, and the reaction was monitored by TLC until completion. The reaction solution was quenched with ice water, extracted three times with dichloromethane (3 ⁇ 100 mL), and the combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain compound 25-4.
  • Step 4 Compound 25-4 (17 g) was dissolved in N,N-dimethylformamide (40 mL), followed by the sequential addition of compound 1-7 (1.24 g, 4.10 mmol) and N,N-diisopropylethylamine (2.65 g, 20.52 mmol). The reaction was stirred overnight at room temperature, and the reaction was monitored by LCMS. The reaction solution was quenched with ice water at room temperature and extracted three times with dichloromethane (3 ⁇ 50 mL). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure.
  • Step 5 Compound 25-5 (550 mg, 1.28 mmol) was dissolved in a mixed solvent of acetonitrile (10 mL) and water (5 mL), and then compound [bis(trifluoroacetoxy)iodo]benzene (1109.27 mg, 2.57 mmol) was added. The reaction was carried out at room temperature for 2 hours, and the reaction was monitored by LCMS. The reaction solution was quenched by slowly adding saturated sodium bicarbonate solution at room temperature. The precipitated solid was filtered off, and the mother liquor was extracted three times with dichloromethane (3 ⁇ 50 mL). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure.
  • Step 6 Compound 25-6 (120 mg, 0.30 mmol) was dissolved in acetonitrile (3 mL), compound 5-3 (51.91 mg, 0.30 mmol) and 2 drops of acetic acid were added, and the mixture was stirred overnight at room temperature. Then, sodium borohydride (34.05 mg, 0.90 mmol) and methanol (1 mL) were added, and the reaction was continued for 2 hours. The reaction was monitored for completion by LCMS. The reaction solution was quenched by slow addition of saturated sodium bicarbonate solution at room temperature, and extracted three times with dichloromethane (3 ⁇ 50 mL). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure.
  • Step 1 Compound 1-14 (5 g, 17.28 mmol) was dissolved in a mixed solvent of tetrahydrofuran (10 mL), methanol (10 mL), and water (10 mL). Lithium hydroxide (14.5 g, 345.6 mmol) was added, and the reaction mixture was heated to 60 °C and stirred for 3 hours. The reaction was monitored by LCMS to indicate completion. The reaction mixture was quenched in water and extracted three times with ethyl acetate (3 ⁇ 40 mL). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure.
  • Step 2 Compound 24-6 (80 mg, 0.20 mmol) was dissolved in acetonitrile (3 mL), compound 50-2 (115.42 mg, 0.61 mmol) and 2 drops of acetic acid were added, and the mixture was stirred overnight at room temperature. Then, sodium borohydride (15.13 mg, 0.40 mmol) and methanol (1 mL) were added, and the reaction was stirred for another 2 hours. The reaction was monitored by LCMS to indicate completion. The reaction solution was quenched with saturated sodium bicarbonate solution, extracted three times with dichloromethane (3 ⁇ 40 mL), and the combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure.
  • Step 1 Compound 1-14 (10 g, 34.56 mmol) and sodium dihydrogen phosphate (20.04 g, 167.02 mmol) were added to a mixed solvent of acetonitrile (50 mL) and water (50 mL). Hydrogen peroxide (16.76 mL, 167.02 mmol, 30%) was slowly added at 0 °C and stirred for 15 minutes. Then, sodium chlorite (9.67 g, 106.89 mmol) was added while maintaining 0 °C. After the addition was complete, the mixture was allowed to rise to room temperature and reacted for 3 hours. The reaction was monitored by LCMS to indicate completion.
  • reaction liquid was quenched with water and extracted three times with ethyl acetate (3 ⁇ 100 mL). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure.
  • the crude product was purified by silica gel column chromatography (mobile phase gradient: 0%–20% ethyl acetate) to give a white solid compound 51-1 (6 g, 19.65 mmol, 56.86%).
  • Step 2 At room temperature, compound 51-1 (5.00 g, 16.38 mmol) and potassium carbonate (6.79 g, 49.13 mmol) were dissolved in N,N-dimethylformamide (80 mL), and iodomethane (4.65 g, 32.75 mmol) was added dropwise. The mixture was stirred for 3 hours, and the reaction was monitored by LCMS and TLC. The reaction was quenched with ice water (100 mL), and extracted three times with ethyl acetate (3 ⁇ 100 mL). The combined organic phases were washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure.
  • Step 3 Compound 51-2 (5.20 g, 16.28 mmol) was dissolved in methanol (120 mL). Sodium borodeuteride (1.37 g, 32.57 mmol) was slowly added at 0 °C, and the mixture was stirred at 20 °C for 4 hours. The reaction was monitored by LC-MS and TLC. Sodium sulfate decahydrate was added at 0 °C, and the mixture was stirred for 2 hours. The mixture was filtered, dried, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (mobile phase gradient: 0%-50% ethyl acetate/petroleum ether) to give compound 51-3. MS m/z (ESI): 194.2 [M+H] + .
  • Step 4 At room temperature, compound 51-3 (3.00 g, 15.52 mmol) was dissolved in dichloromethane (120 mL), and manganese dioxide (1.48 g, 17.08 mmol) was added. The mixture was heated to 50 °C and stirred for 24 hours. The reaction was monitored by LCMS and TLC. The product was filtered, dried, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (mobile phase gradient: 0%-50% ethyl acetate/petroleum ether) to obtain compound 51-4. MS m/z (ESI): 191.2 [M+H] + .
  • Step 5 Compound 129-6 (224 mg, 0.60 mmol), compound 51-4 (115 mg, 0.60 mmol), and acetic acid (40 mg, 0.60 mmol) were dissolved in methanol (8 mL). After stirring at 25 °C for 16 hours, sodium deuterated borohydride (127 mg, 3.02 mmol) was slowly added at 0 °C, and stirring was continued at 25 °C for 2 hours. The reaction was monitored by LCMS to indicate completion. The reaction solution was poured into a saturated ammonium chloride solution and extracted three times with ethyl acetate (3 ⁇ 50 mL). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure.
  • Step 6 Compound 51-5 (270 mg, 0.49 mmol) was dissolved in methanol (15 mL) and water (3 mL), and lithium hydroxide (104 mg, 2.47 mmol) was added. The mixture was heated to 60 °C and stirred for 18 hours. The reaction was monitored by LCMS to indicate completion. The pH of the reaction solution was adjusted to neutral with dilute HCl (2N), and then concentrated under reduced pressure.
  • Step 1 Compounds 1-7 (500 mg, 1.65 mmol) and 2,2-difluoropropyltoluenesulfonic acid (477 mg, 4.96 mmol) were dissolved in dimethyl sulfoxide (5 mL). N,N-diisopropylethylamine (641 mg, 4.96 mmol) and sodium iodide (25 mg, 0.17 mmol) were added separately. The mixture was stirred at 130 °C under a nitrogen atmosphere for 18 hours, and the reaction was monitored by LCMS. Ice water (50 mL) was added to the reaction solution, and the mixture was extracted three times with ethyl acetate (3 ⁇ 100 mL).
  • Step 2 Compound 52-1 (230 mg, 0.60 mmol) was dissolved in acetonitrile (5 mL) and water (5 mL). (bis(trifluoroacetyloxy)iodide)benzene (260 mg, 0.60 mmol) was added at 0 °C. The mixture was stirred for 18 hours at room temperature under a nitrogen atmosphere, and the reaction was monitored by LCMS. The reaction solution was quenched by slowly adding saturated sodium bicarbonate solution at room temperature. The precipitated solid was filtered off, and the mother liquor was extracted three times with dichloromethane (3 ⁇ 50 mL). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure.
  • Step 3 Compound 52-2 (130 mg, 0.37 mmol) and compound 1-14 (75 mg, 0.26 mmol) were dissolved in N,N-dimethylformamide (2 mL), sodium cyanoborohydride (70 mg, 1.11 mmol) and 1 drop of acetic acid were added, and the mixture was stirred at 60 °C under a nitrogen atmosphere for 18 hours. The reaction was monitored by LCMS. Ice water was added to the reaction solution, and the mixture was extracted three times with ethyl acetate (3 ⁇ 100 mL). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure.
  • Step 4 Compound 52-3 (70 mg, 0.11 mmol) was dissolved in tetrahydrofuran (1 mL), methanol (1 mL), and water (1 mL). Lithium hydroxide (34 mg, 0.56 mmol) was added, and the mixture was heated to 50 °C and stirred for 4 hours. The reaction was monitored by LCMS to ensure completion. The pH of the reaction solution was adjusted to neutral using dilute hydrochloric acid (1 N). The solution was filtered and the filtrate was concentrated.
  • Step 1 Compound 25-6 (150 mg, 0.37 mmol) was dissolved in acetonitrile (5 mL), compound 50-2 (107 mg, 0.57 mmol) and 2 drops of acetic acid were added, and the mixture was stirred overnight at room temperature.
  • the reaction was monitored by LCMS to indicate completion.
  • the reaction solution was quenched in ice water, extracted three times with dichloromethane (3 ⁇ 40 mL), and the combined organic phases were washed three times with saturated brine. The mixture was then dried over anhydrous sodium sulfate and concentrated under reduced pressure.
  • Step 1 Compound 34-0 (10 g, 62.26 mmol) and 4-methoxybenzyl chloride (10.13 mL, 74.71 mmol) were dissolved in N,N-dimethylformamide (100 mL), and potassium carbonate (25.81 g, 186.78 mmol) was added. The mixture was stirred at 25 °C for 18 hours. The reaction was monitored by LCMS. The reaction was quenched with water (50 mL), extracted with dichloromethane (3 ⁇ 60 mL), and the combined organic phases were washed with saturated brine (100 mL), dried, and concentrated.
  • Step 2 Compound 34-1 (14 g), p-toluenesulfonylmethylisocyanate (16.71 g, 85.60 mmol), and tert-butanol (8.13 mL, 85.60 mmol) were dissolved in ethylene glycol dimethyl ether (140 mL) under a nitrogen atmosphere. A tetrahydrofuran solution of potassium tert-butoxide (114.1 mL, 1.0 M, 114.1 mmol) was added dropwise at 0 °C. After 1 hour, the system was brought to room temperature and stirred for another 24 hours. The reaction was monitored by LC-MS.
  • Step 3 Compound 34-2 (4.88 g, 19.04 mmol) and ethyl p-fluorobenzoate (5.12 mL, 38.07 mmol) were dissolved in tetrahydrofuran (50 mL). Under nitrogen protection at 0 °C, a tetrahydrofuran solution of bis(trimethylsilylamino)lithium (28.6 mL, 1.0 M, 28.6 mmol) was added dropwise. The system was then transferred to room temperature and stirred for 2 hours. The reaction was monitored by LCMS and TLC.
  • Step 1 Compound 109-1 (6.84 g, 63.87 mmol) and sodium acetate (28.57 g, 348.47 mmol) were dissolved in water (200 mL). Under a nitrogen atmosphere at 0 °C, 1,3-propanone dicarboxylic acid (8.28 mL, 72.57 mmol) and hydrochloric acid (72.57 mL, 1N) were added sequentially. After stirring for 1 hour, a tetrahydrofuran solution (9.43 mL, 58.08 mmol, 40%) containing succinaldehyde was added, and the mixture was stirred at 40 °C for 18 hours. The reaction was monitored by LC-MS.
  • Step 2 Compound 109-2 (6.30 g, 29.27 mmol), tert-butanol (6.36 mL, 43.90 mmol), and p-toluenesulfonylmethylisocyanate (8.57 g, 43.90 mmol) were dissolved in ethylene glycol dimethyl ether (70 mL). A tetrahydrofuran solution of potassium tert-butoxide (58.54 mL, 58.54 mmol, 1 M) was added dropwise at 0 °C under a nitrogen atmosphere. The mixture was then heated to 25 °C and stirred for 18 hours. The reaction was monitored by LC-MS.
  • reaction mixture was quenched in saturated ammonium chloride solution (200 mL), extracted with ethyl acetate (2 ⁇ 200 mL), and the combined organic phases were washed with saturated brine (300 mL), dried, and concentrated.
  • the crude product was purified by silica gel column chromatography using a gradient of 0%–35% ethyl acetate/petroleum ether to obtain compound 109-3.
  • Step 3 Compound 109-3 (2.85 g, 12.60 mmol) and ethyl p-fluorobenzoate (3.39 g, 20.15 mmol) were dissolved in tetrahydrofuran (60 mL). A tetrahydrofuran solution of bis(trimethylsilylamino)lithium (25.19 mL, 25.19 mmol, 1 M) was added dropwise at 0 °C under a nitrogen atmosphere. The mixture was then heated to 25 °C and stirred for 18 hours. The reaction was monitored by LCMS.
  • Step 5 At 25°C, compound 109-5 (380 mg, 0.97 mmol) was dissolved in acetonitrile (4 mL) and water (4 mL), and [bis(trifluoroacetoxy)iodo]benzene (833 mg, 1.94 mmol) was added. The mixture was stirred for 2 hours. The reaction was monitored by LCMS. The reaction solution was quenched in saturated sodium bicarbonate solution (30 mL), extracted with ethyl acetate (2 ⁇ 40 mL), and the combined organic phases were washed with saturated brine (60 mL), dried, and concentrated.
  • Step 6 At 25°C, compound 109-6 (252 mg, 0.69 mmol), compound 1-14 (200 mg, 0.69 mmol), and acetic acid (42 mg, 0.69 mmol) were dissolved in acetonitrile (4 mL). After stirring for 1 hour, sodium triacetoxyborohydride (293 mg, 1.38 mmol) was added, and stirring was continued for 18 hours. The reaction was monitored by LCMS. The reaction solution was quenched in saturated ammonium chloride solution (50 mL), extracted with ethyl acetate (2 ⁇ 60 mL), and the combined organic phases were washed with saturated brine (60 mL), dried, and concentrated.
  • Step 1 At 25°C, compound 103-1 (450 mg, 1.49 mmol) was dissolved in N,N-dimethylformamide (5 mL), followed by the addition of acetic acid (2 drops) and cyclopropylformaldehyde (156 mg, 2.23 mmol). After stirring for 2 hours, sodium cyanoborocyanate (252 mg, 2.23 mmol) was added, and stirring continued for 18 hours. The reaction was monitored by LCMS. The reaction was quenched with water (30 mL), extracted with ethyl acetate (2 ⁇ 30 mL), and the combined organic phases were washed with saturated brine (20 mL), dried, and concentrated.
  • Step 3 At 25°C, compound 113-2 (200 mg, 0.61 mmol) was dissolved in acetonitrile (5 mL) and acetic acid (0.1 mL), and compound 1-14 (264 mg, 0.91 mmol) was added. After stirring for 1 hour, sodium cyanoborohydride (194 mg, 0.91 mmol) was added, and stirring was continued for 2 hours. The reaction was monitored by LCMS. The reaction was quenched with water (10 mL), extracted with ethyl acetate (2 ⁇ 10 mL), and the combined organic phases were washed with saturated brine (10 mL), dried, and concentrated. The crude product was purified by silica gel column chromatography using a 0%-10% methanol/dichloromethane gradient to give compound 113-3. MS m/z (ESI): 602.7 [M+H] + .
  • Step 1 At 25°C, compound 103-1 (500 mg, 1.65 mmol), cyclopropionic acid (157 mg, 1.82 mmol), and N,N-diisopropylethylamine (0.86 mL, 4.96 mmol) were dissolved in N,N-dimethylformamide (10 mL), and 2-(7-azobenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate (692 mg, 1.82 mmol) was added, and the mixture was stirred for 2 hours. The reaction was monitored by LCMS.
  • Step 3 At 25°C, compounds 1-14 (307 mg, 1.06 mmol), 114-2 (363 mg, 1.06 mmol), and acetic acid (72 mg, 1.20 mmol) were dissolved in acetonitrile (8 mL). After stirring for 24 hours, sodium triacetoxyborohydride (449 mg, 2.12 mmol) was added, and stirring was continued for 4 hours. The reaction was monitored by LCMS. The reaction mixture was poured into a saturated ammonium chloride solution (50 mL), extracted with ethyl acetate (2 ⁇ 60 mL), and the combined organic phases were washed with saturated brine (60 mL), dried, and concentrated.
  • Step 1 Compound 115-1 (400 mg, 4.44 mmol) and triethylamine (1.15 mL, 8.88 mmol) were dissolved in dichloromethane (15 mL). p-Toluenesulfonyl chloride (931 mg, 4.88 mmol) was added at 0 °C under a nitrogen atmosphere, and the mixture was stirred at 25 °C for 18 hours. The reaction was monitored by TLC. The crude product was concentrated and purified by silica gel column chromatography using a gradient of 1%–20% ethyl acetate/petroleum ether to obtain compound 115-2.
  • Step 4 At 25°C, compound 115-4 (460 mg, 1.33 mmol), compound 1-14 (320 mg, 1.11 mmol), and acetic acid (0.21 mL, 2.19 mmol) were dissolved in acetonitrile (10 mL). After stirring for 2 hours, sodium triacetoxyborohydride (469 mg, 2.21 mmol) was added, and stirring was continued for 16 hours. The reaction was monitored by LCMS. The reaction solution was poured into a saturated ammonium chloride solution (50 mL), extracted with ethyl acetate (2 ⁇ 60 mL), and the combined organic phases were washed with saturated brine (60 mL), dried, and concentrated.
  • Step 1 At 25°C, compound 119-1 (50.00 g, 299.11 mmol) and benzyl bromide (51.20 g, 299.11 mmol) were dissolved in N,N-dimethylformamide (500 mL), and cesium carbonate (116.70 g, 358.94 mmol) was added in portions. The mixture was stirred for 4 hours. The reaction was monitored by LCMS and TLC. The reaction was quenched with water (500 mL), extracted with ethyl acetate (3 ⁇ 500 mL), and the combined organic phases were washed with saturated brine (1 L), dried, and concentrated. The crude product was purified by silica gel column chromatography using a gradient of 0%–25% ethyl acetate/petroleum ether to give compound 119-2.
  • Step 2 At room temperature, compound 119-2 (74.50 g, 289.56 mmol) and N,N-dimethylformamide dimethyl acetal (103.50 g, 868.67 mmol) were dissolved in N,N-dimethylformamide (750 mL), and tetrahydropyrrole (61.8 g, 868.67 mmol) was added. The mixture was heated to 90 °C and stirred for 16 hours. The reaction was monitored by LCMS and TLC. The solution was concentrated to obtain compound 119-3.
  • Step 4 At 25°C, compound 119-4 (65.00 g, 273.91 mmol) and di-tert-butyl dicarbonate (119.60 g, 547.83 mmol) were dissolved in acetonitrile (650 mL), and 4-dimethylaminopyridine (33.4 g, 273.91 mmol) was added. The mixture was stirred for 16 hours. The reaction was monitored by LCMS and TLC. The mixture was concentrated, quenched with water (300 mL), extracted with ethyl acetate (3 ⁇ 300 mL), and the combined organic phases were washed with saturated brine (500 mL), dried, and concentrated. The crude product was purified by silica gel column chromatography using a gradient of 0%–25% ethyl acetate/petroleum ether to give compound 119-5.
  • Step 5 Compound 119-5 (46.30 g, 137.22 mmol) and ammonium formate (8.60 g, 137.22 mmol) were dissolved in ethanol (500 mL), and palladium on carbon (5 g, 10%) was added. The mixture was stirred at 50 °C under a nitrogen atmosphere for 2 hours. The reaction was monitored by LCMS and TLC. The mixture was filtered, concentrated, diluted with water (300 mL), extracted with ethyl acetate (3 ⁇ 300 mL), and the combined organic phases were washed with saturated brine (500 mL), dried, and concentrated.
  • Step 6 At 20°C, paraformaldehyde (44.40 g, 493.35 mmol) and triethylamine (39.90 g, 394.68 mmol) were dissolved in tetrahydrofuran (500 mL), and magnesium chloride (35.20 g, 370.01 mmol) was added. After stirring for 30 minutes, compound 119-6 (30.50 g, 123.34 mmol) was added, and the mixture was heated to 70°C and stirred for 3 hours. The reaction was monitored by LCMS. The mixture was filtered, concentrated, quenched with water (500 mL), and extracted with ethyl acetate (3 ⁇ 500 mL).
  • Step 7 At room temperature, compound 119-7 (3.00 g, 10.90 mmol) was dissolved in N,N-dimethylformamide (30 mL), and deuterated iodomethane (1.36 mL, 21.79 mmol) was added. The mixture was stirred for 2 hours. The reaction was monitored by LCMS. The reaction was quenched with water (20 mL), extracted with ethyl acetate (3 ⁇ 20 mL), and the combined organic phases were washed with saturated brine (40 mL), dried, and concentrated. The crude product was purified by silica gel column chromatography using a 10%–20% ethyl acetate/petroleum ether gradient to give compound 119-8.
  • Step 8 Compound 103-1 (1.00 g, 3.31 mmol) and 2,2,2-trifluoroethyltrifluoromethane sulfonate (1.15 g, 4.96 mmol) were dissolved in dichloromethane (200 mL). Triethylamine (0.86 mL, 6.61 mmol) was added at 0 °C, and the mixture was stirred at room temperature for 18 hours. The reaction was monitored by LCMS. The reaction was quenched with water (20 mL), extracted with dichloromethane (3 ⁇ 60 mL), and the combined organic phases were washed with saturated brine (100 mL), dried, and concentrated.
  • Step 9 At 25°C, compound 119-9 (1.00 g, 2.60 mmol) was dissolved in acetonitrile (10 mL) and water (10 mL), and [bis(trifluoroacetoxy)iodo]benzene (1.23 g, 2.86 mmol) was added. The mixture was stirred for 3 hours. The reaction was monitored by LCMS. The reaction mixture was poured into a saturated sodium bicarbonate solution (50 mL), extracted with ethyl acetate (2 ⁇ 60 mL), and the combined organic phases were washed with saturated brine (80 mL), dried, and concentrated.
  • Step 10 Compounds 119-10 (240 mg, 0.67 mmol) and 119-8 (196.9 mg, 0.67 mmol) were dissolved in acetonitrile (5 mL) at 25 °C. After stirring for 1 hour, sodium triacetoxyborohydride (285.5 mg, 1.35 mmol) was added, and stirring was continued for 17 hours. The reaction was monitored by LCMS. The reaction was quenched with saturated ammonium chloride solution (50 mL), extracted with ethyl acetate (2 ⁇ 60 mL), and the combined organic phases were washed with saturated brine (60 mL), dried, and concentrated.
  • Step 2 Compound 122-1 (7.30 g, 11.59 mmol) was dissolved in methanol (100 mL) and water (20 mL), and lithium hydroxide (2.43 g, 57.95 mmol) was added. The mixture was heated to 60 °C and stirred for 12 hours. The reaction was monitored by LCMS. The solution was concentrated, and the pH of the system was adjusted to neutral by adding hydrochloric acid (1 N). The solution was filtered, concentrated, and the crude product was purified by a reversed-phase chromatography column using a gradient of 25%–95% acetonitrile/buffer (0.1 mol/Aqueous bicarbonate solution) to obtain compound 122.
  • Step 1 At 20 °C, compounds 1-6 (5.00 g, 16.38 mmol) and potassium carbonate (6.79 g, 49.13 mmol) were dissolved in N,N-dimethylformamide (80 mL), and iodomethane (4.65 g, 32.75 mmol) was added dropwise, followed by stirring for 3 hours. The reaction was monitored by LCMS and TLC. The reaction was quenched with water (100 mL), extracted with ethyl acetate (3 ⁇ 100 mL), and the combined organic phases were washed with saturated brine (100 mL), dried, and concentrated.
  • Step 4 At 20°C, compound 123-3 (480 mg, 2.52 mmol) and compound 119-10 (1.08 g, 3.03 mmol) were dissolved in methanol (30 mL), and acetic acid (5 drops) was added. After stirring for 1 hour, sodium borodeuteride (211 mg, 5.05 mmol) was slowly added at 0°C, and the mixture was heated to room temperature and stirred for 4 hours. The reaction was monitored by LCMS and TLC. The reaction was quenched with water (100 mL), extracted with ethyl acetate (3 ⁇ 100 mL), and the combined organic phases were washed with saturated brine (100 mL), dried, and concentrated.
  • Step 5 Compound 123-4 (1.00 g, 1.88 mmol) was dissolved in methanol (20 mL), water (20 mL), and tetrahydrofuran (20 mL). Lithium hydroxide (135 mg, 5.64 mmol) was added, and the mixture was stirred at 50 °C for 3 hours. The reaction was monitored by LCMS. The pH was adjusted to 5 with hydrochloric acid (1 N), and water (100 mL) was added. The mixture was extracted with ethyl acetate (3 ⁇ 100 mL). The combined organic phases were washed with saturated brine (100 mL), dried, and concentrated.
  • Step 1 Compound 124-1 (30.3 g, 154.64 mmol) was dissolved in sulfuric acid (120 mL) and nitric acid (8 mL) under ice bath conditions and stirred at 0 °C for 2 hours. The reaction was monitored by LCMS. The reaction was quenched with water (1000 mL), and the pH was adjusted to neutral with sodium carbonate solid. Extraction was performed with ethyl acetate (3 ⁇ 500 mL). The combined organic phases were washed with saturated brine (500 mL), dried over anhydrous sodium sulfate, and concentrated.
  • Step 2 Compound 124-2 (1.5 g, 6.25 mmol) was dissolved in anhydrous tetrahydrofuran (15 mL) under nitrogen protection at -20 °C. A tetrahydrofuran solution of vinyl magnesium bromide (25 mL, 1 M, 25 mmol) was added, and the mixture was stirred at room temperature for 1.5 hours. The reaction was monitored by LCMS. The reaction was quenched with saturated ammonium chloride solution (100 mL), water (100 mL) was added, and the mixture was extracted with ethyl acetate (3 ⁇ 100 mL). The combined organic phases were washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, and concentrated.
  • Step 3 Compound 124-3 (2.0 g, 8.51 mmol) was dissolved in 1,4-dioxane (15 mL) and water (5 mL), and cesium carbonate (5.6 g, 17.19 mmol), [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride (625 mg, 0.86 mmol) and cyclopropylboronic acid (1.1 g, 12.81 mmol) were added. The reaction was stirred at 90 °C for 16 hours. The reaction was monitored by TLC. The reaction was quenched with water (20 mL) and extracted with ethyl acetate (3 ⁇ 15 mL).

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Abstract

La présente invention concerne un inhibiteur du facteur B du complément de formule (I), une composition pharmaceutique à base de celui-ci et une utilisation associée.
PCT/CN2025/103317 2024-06-25 2025-06-25 Inhibiteur du facteur b du complément, composition pharmaceutique à base de celui-ci et utilisation associée Pending WO2026002007A1 (fr)

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Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN105579444A (zh) * 2013-07-15 2016-05-11 诺华股份有限公司 哌啶基吲哚衍生物和它们作为补体因子b抑制剂的用途
CN109414441A (zh) * 2016-06-27 2019-03-01 艾其林医药公司 治疗医学障碍的喹唑啉和吲哚化合物
CN114057758A (zh) * 2020-08-07 2022-02-18 上海美悦生物科技发展有限公司 补体因子b抑制剂及其药物组合物、制备方法和用途
WO2023139534A1 (fr) * 2022-01-24 2023-07-27 Novartis Ag Dérivés de pipéridinyle spirocycliques en tant qu'inhibiteurs du facteur b du complément et leurs utilisations
WO2023187715A1 (fr) * 2022-04-01 2023-10-05 Novartis Ag Inhibiteurs du facteur b du complément et leurs utilisations
WO2024141011A1 (fr) * 2022-12-31 2024-07-04 深圳晶泰科技有限公司 Inhibiteur du facteur b du complément, composition pharmaceutique et utilisation de celui-ci

Patent Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN105579444A (zh) * 2013-07-15 2016-05-11 诺华股份有限公司 哌啶基吲哚衍生物和它们作为补体因子b抑制剂的用途
CN109414441A (zh) * 2016-06-27 2019-03-01 艾其林医药公司 治疗医学障碍的喹唑啉和吲哚化合物
CN114057758A (zh) * 2020-08-07 2022-02-18 上海美悦生物科技发展有限公司 补体因子b抑制剂及其药物组合物、制备方法和用途
WO2023139534A1 (fr) * 2022-01-24 2023-07-27 Novartis Ag Dérivés de pipéridinyle spirocycliques en tant qu'inhibiteurs du facteur b du complément et leurs utilisations
WO2023187715A1 (fr) * 2022-04-01 2023-10-05 Novartis Ag Inhibiteurs du facteur b du complément et leurs utilisations
WO2024141011A1 (fr) * 2022-12-31 2024-07-04 深圳晶泰科技有限公司 Inhibiteur du facteur b du complément, composition pharmaceutique et utilisation de celui-ci

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