Classifications

• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
  • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
  • A61K31/445—Non condensed piperidines, e.g. piperocaine
  • A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
  • A61K31/454—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. pimozide, domperidone
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P13/00—Drugs for disorders of the urinary system
  • A61P13/12—Drugs for disorders of the urinary system of the kidneys
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
  • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings

Definitions

• the present application relates to a novel complement factor B inhibitor and a pharmaceutical composition and application thereof.
• the complement system is composed of more than 40 proteins, including complement intrinsic components C1 to C9, multiple regulatory factors and complement receptors, and is an important component of the innate immune system.
• the complement system has three activation pathways: the classical pathway (CP) involving intrinsic components C1, C2, and C4; the lectin pathway (LP) involving mannose-binding lectin complex (MBL) and serine protease; and the alternative pathway (AP) involving complement factor B (FB) and complement factor D (FD).
• CP classical pathway
• LP lectin pathway
• MBL mannose-binding lectin complex
• AP alternative pathway
• FB complement factor B
• FD complement factor D
• FB is a trypsin-like serine protease that exists in the blood circulation in the form of zymogen.
• FB is the main component of activating the AP pathway. After being activated, it binds to C3b and is subsequently cleaved by FD to produce a C3 convertase complex (C3bBb) containing the FB catalytic subunit (Bb).
• C3bBb continues to cut C3 to produce more C3b, thereby amplifying the activation of the entire complement system.
• Inhibiting FB activity can prevent the activation of the AP pathway without interfering with the CP and LP pathways, and can avoid the increased risk of infection due to complement system inhibition.
• C5 inhibitors Culizumab and Ravulizumab have been approved for marketing, such as C5 inhibitors Culizumab and Ravulizumab, and C3 inhibitor Pegcetacoplan, with indications for atypical hemolytic uremic syndrome (aHUS), myasthenia gravis, and paroxysmal nocturnal hemoglobinuria (PNH), etc.
• aHUS atypical hemolytic uremic syndrome
• PNH paroxysmal nocturnal hemoglobinuria
• clinical findings show that most PNH patients using C5 or C3 inhibitors fail to completely block AP activation and still have mild to moderate extravascular hemolysis, and there are still a large number of unmet clinical needs for complement-related diseases.
• LNP023 (WO2015009616A1 and WO2019043609A1) is the first small molecule FB inhibitor developed by Novartis. It is currently in Phase III clinical research for the treatment of PNH, immunoglobulin A nephropathy (IgAN), C3 glomerular disease (C3G) and other diseases:
• the present invention provides compounds that modulate, and preferably inhibit, activation of the complement alternative pathway.
• the present invention provides compounds that modulate, and preferably inhibit, complement factor B (FB) activity and/or FB-mediated activation of the complement pathway.
• FB complement factor B
• the novel FB small molecule inhibitor of the present invention has high affinity for FB, can inhibit the catalytic activity of FB, and has a significant inhibitory effect on the activation of the complement alternative pathway, so it has the potential to inhibit the complement system expansion caused by C3 activation, prevent and treat diseases, disorders or conditions mediated by complement activation, especially diseases, disorders or conditions mediated by the activation of the complement alternative pathway.
• the compounds of the present invention have improved pharmacokinetic properties (such as improved bioavailability, improved metabolic stability, suitable half-life and duration of action), improved safety (lower toxicity (such as reduced cardiac toxicity) and/or fewer side effects), less likely to produce drug resistance and other more excellent properties.
• the present invention provides a method for preventing or treating a disease, disorder or condition mediated by complement activation in an individual, particularly a disease, disorder or condition 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 present invention, or a stereoisomer, tautomer, diastereomer, racemate, cis-trans isomer, isotopically labeled compound (preferably deuterated), N-oxide, metabolite, ester, prodrug, crystalline form, hydrate, solvate or pharmaceutically acceptable salt thereof; or administering to the individual a therapeutically effective amount of a pharmaceutical composition according to the present invention; or administering to the individual a therapeutically effective amount of a pharmaceutical combination according to the present invention.
• a compound of formula (I) according to the present invention, or a stereoisomer, tautomer, diastereomer, racemate, cis-trans isomer, iso
• the present invention provides a compound of formula (I) according to the present invention, or a stereoisomer, tautomer, diastereomer, racemate, cis-trans isomer, isotopically labeled compound (preferably deuterated), N-oxide, metabolite, ester, prodrug, crystal form, hydrate, solvate or pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to the present invention, or a pharmaceutical combination according to the present invention, for use as a drug.
• a compound of formula (I) according to the present invention or a stereoisomer, tautomer, diastereomer, racemate, cis-trans isomer, isotopically labeled compound (preferably deuterated), N-oxide, metabolite, ester, prodrug, crystal form, hydrate, solvate or pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to the present invention, or a pharmaceutical combination according to the present invention, for use as a drug.
• the present invention provides a compound of formula (I) according to the present invention, or its stereoisomers, tautomers, diastereomers, racemates, cis-trans isomers, isotopically labeled compounds (preferably deuterated), N-oxides, metabolites, esters, prodrugs, crystalline forms, hydrates, solvates or pharmaceutically acceptable salts, or a pharmaceutical composition according to the present invention, or a pharmaceutical combination according to the present invention for the preparation of a medicament for treating a disease, disorder or condition mediated by complement activation in an individual, in particular a disease, disorder or condition mediated by activation of the complement alternative pathway.
• the disease, disorder or condition is selected from age-related macular degeneration (AMD), geographic atrophy of the macula, diabetic retinopathy, uveitis, retinitis pigmentosa, macular edema, Behcet's uveitis, multifocal choroiditis, Vogt-Koyangi-Harada syndrome, intermediate uveitis, bird-eye retinochoroiditis, sympathetic eye inflammation, ocular cicatricial pemphigoid, ocular pemphigus, non-arteritic ischemic optic neuropathy, postoperative inflammation, retinal vein occlusion, nervous system diseases, multiple sclerosis, stroke, Guillain-Barré syndrome, traumatic brain injury, Parkinson's disease, conditions caused by inappropriate or undesirable complement activation, complications of hemodialysis, hyperacute allograft rejection, xenograft rejection, interleukin-2 (IL-2) induced toxicity during IL-2 therapy,
• AMD age-
• alkylene refers to a linear or branched divalent saturated aliphatic hydrocarbon.
• the alkylene group has 1 to 12 carbon atoms, preferably 1, 2, 3, 4, 5 or 6 carbon atoms, such as methylene, ethylene, propylene or butylene.
• a heteroalkylene group can 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 ).
• a heteroalkylene group can be connected to the rest of the molecule via a heteroatom or a carbon atom in the backbone chain.
• alkynyl means a linear 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 with one or more (such as 1 to 3) identical or different substituents.
• alkynylene is a corresponding divalent group, including, for example, “C 2-6 alkynylene", “C 2-4 alkynylene", etc. Its examples include, but are not limited to The alkynylene group is optionally substituted with one or more (such as 1 to 3) identical or different substituents.
• fused means that two or more ring structures share two adjacent atoms with each other.
• cycloalkyl and cycloalkylene groups are optionally substituted with 1 or more (such as 1 to 3) suitable substituents (e.g. methyl or halogen), for example methyl-substituted cyclopropyl.
• suitable substituents e.g. methyl or halogen
• bicyclo[1.1.1]pentyl such as Bicyclo[2.1.1]hexyl, for example Bicyclo[2.2.1]heptyl, for example Bicyclo[3.2.1]octyl; Bicyclo[5.2.0]nonyl;
• the term "monospirocycloalkyl” refers to a cyclic structure formed by two cycloalkyl groups as defined above sharing one ring carbon atom, which may be saturated (i.e., “monospirocycloalkyl") or partially unsaturated (i.e., having one or more double bonds (i.e., "monospirocycloalkenyl”) and/or triple bonds within the ring).
• heterocyclyl encompasses fused ring structures, and the connection point of the fused ring structure to the other groups can be on any ring in the fused ring structure. Therefore, the heterocyclyl of the present invention also includes, but is not limited to, heterocyclyl and heterocyclyl, heterocyclyl and cycloalkyl, monoheterocyclyl and monoheterocyclyl, monoheterocyclyl and monocycloalkyl, such as 3-7 membered (mono) heterocyclyl and 3-7 membered (mono) heterocyclyl, 3-7 membered (mono) heterocyclyl and (mono) cycloalkyl, 3-7 membered (mono) heterocyclyl and C 4-6 (mono) cycloalkyl, examples of which include, but are not limited to, pyrrolidinyl and cyclopropyl, cyclopentyl and aziridine, pyrrolidinyl and
• the monospiro heterocyclyl group includes, but is not limited to, a 5-11-membered monospiro heterocycloalkyl group, a 6-10-membered monospiro heterocycloalkyl group, a 7-10-membered monospiro heterocycloalkyl group, a 6-10-membered nitrogen-containing monospiro heterocycloalkyl group, a 6-10-membered oxygen-containing monospiro heterocycloalkyl group, a 6-10-membered sulfur-containing monospiro heterocycloalkyl group; and a 5-11-membered monospiro heterocycloalkenyl group, a 6-10-membered monospiro heterocycloalkenyl group, a 7-10-membered monospiro heterocycloalkenyl group, a 6-10-membered nitrogen-containing monospiro heterocycloalkenyl group, a 6-10-membered oxygen-containing monospiro heterocycloal
• the monospiro heterocyclic group may include, for example, a 3-membered/5-membered ring system, a 4-membered/4-membered ring system, a 4-membered/5-membered ring system, a 4-membered/6-membered ring system, a 5-membered/5-membered ring system, a 5-membered/6-membered ring system, and a 6-membered/6-membered ring system, wherein the count of each ring includes the spiro atom.
• the monospiro heterocyclic group is optionally substituted with 1 or more (such as 1 to 3) suitable substituents (such as methyl, ethyl or oxo).
• heteroaryl refers to a monocyclic or polycyclic (e.g., bicyclic or tricyclic) aromatic ring system having 5 to 14 ring atoms, e.g., 5, 6, 7, 8, 9, 10, 11, 12, 13 or 14 ring atoms, particularly having 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12 or 13 carbon atoms and 1, 2, 3, 4 or 5 identical or different heteroatoms independently selected from N, O, S and S(O) 2 .
• One or more ring carbon atoms in the heteroaryl may be replaced by C(O).
• the heteroaryl may be benzo-fused.
• heteroaryl groups include, but are not limited to, pyridyl, pyridonyl, pyrimidinyl, pyrimidonyl, pyrazinyl, pyridazinyl, thiazolyl, thienyl, oxazolyl, furanyl, pyrrolyl, pyrazolyl, triazolyl, tetrazolyl, isoxazolyl, isothiazolyl, imidazolyl, triazinyl, oxadiazolyl, thiadiazolyl, benzothiazolyl, benzisothiazolyl, imidazopyridinyl, quinolyl, indolyl, pyrrolopyridazinyl, benzo
• the heteroaryl group may be optionally substituted with one or more (e.g., 1, 2, 3, or 4) suitable substituents.
• halo or halogen group is defined to include F, Cl, Br, or I.
• substituted means that one or more (e.g., one, two, three, or four) hydrogens on the designated atom are replaced by a selection from the indicated group, provided that the normal valence of the designated atom in the present context is not exceeded and the substitution forms a stable compound. Combinations of substituents and/or variables are permitted only if such combinations form stable compounds.
• a group is described as “optionally substituted with” or “optionally substituted,” the group may be: (1) unsubstituted or (2) substituted. If a carbon of a group is described as optionally substituted with one or more of the listed substituents, one or more hydrogens on that carbon (to the extent of any hydrogens present) may be replaced, individually and/or together, with independently selected optional substituents. If a nitrogen of a group is described as optionally substituted with one or more of the listed substituents, one or more hydrogens on the nitrogen (to the extent of any hydrogens present) may each be replaced with an independently selected optional substituent.
• the optional substituents may be selected from the group consisting of halogen, OH, SH, CN, NO 2 , C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, -OC 1-6 alkyl, -O-haloC 1-6 alkyl, -OC 2-6 alkenyl, -OC 2-6 alkynyl, -SC 1-6 alkyl, NH 2 , -NH(C 1-6 alkyl), -N(C 1-6 alkyl) 2 , -C 1-6 alkylene-OH, -C 1-6 alkylene-SH, -C 1-6 alkylene-CN, -C 1-6 alkylene-NH 2 , -C 1-6 alkylene-NH(C 1-6 alkyl), -C 1-6 alkylene-N(C 1-6 alkyl) 2 , -C 1-6 alkyl-OC 1-6 alkyl, -C 1-6 -
• each substituent is selected independently of the other.
• each substituent may be the same as or different from another (other) substituent.
• one or more means 1 or more than 1, such as 2, 3, 4, 5 or 10, where reasonable.
• the point of attachment of a substituent may be from any suitable position of the substituent.
• the present invention also includes all pharmaceutically acceptable isotopically labeled compounds which are identical to the compounds of the present invention except that one or more atoms are replaced by an atom having the same atomic number but an atomic mass or mass number different from the atomic mass or mass number prevalent in nature.
• isotopes suitable for inclusion in the compounds of the present invention include, but are not limited to, isotopes of hydrogen (e.g., deuterium (D, 2 H), tritium (T, 3 H)); isotopes of carbon (e.g., 11 C, 13 C, and 14 C); isotopes of chlorine (e.g., 36 Cl); isotopes of fluorine (e.g., 18 F); isotopes of iodine (e.g., 123 I and 125 I); isotopes of nitrogen (e.g., 13 N and 15 N); isotopes of oxygen (e.g., 15 O, 17 O, and 18 O); isotopes of phosphorus (e.g., 32 P); and isotopes of sulfur (e.g., 35 S).
• isotopes of hydrogen e.g., deuterium (D, 2 H), tritium (T, 3 H)
• Certain isotopically labeled compounds of the invention can be used in drug and/or substrate tissue distribution studies (e.g., analysis).
• the radioisotopes tritium (i.e., 3 H) and carbon-14 (i.e., 14 C) are particularly useful for this purpose because they are easily incorporated and easily detected.
• Substitution with positron emitting isotopes e.g., 11 C, 18 F, 15 O, and 13 N
• PET positron emission tomography
• Isotopically labeled compounds of the invention can be prepared by methods similar to those described in the accompanying routes and/or examples and preparations by using appropriate isotopically labeled reagents instead of previously employed non-labeled reagents.
• Pharmaceutically acceptable solvates of the invention include those in which the crystallization solvent can be isotopically substituted, for example, D 2 O, acetone-d 6 , or DMSO-d 6.
• the isotopically labeled compounds of the invention are deuterated.
• stereoisomer means an isomer formed due to at least one asymmetric center, which has the same chemical composition but different spatial arrangements of atoms or groups. In compounds with one or more (e.g., 1, 2, 3, or 4) asymmetric centers, it can produce a racemic mixture, a single enantiomer, a diastereomeric mixture, and a single diastereomer. Specific individual molecules can also exist as geometric isomers (cis/trans). Similarly, the compounds of the present invention can exist as mixtures (commonly referred to as tautomers) of two or more structures in rapid equilibrium in different forms.
• tautomers include keto-enol tautomers, phenol-ketone tautomers, nitroso-oxime tautomers, imine-enamine tautomers, etc. It is to be understood that the scope of the present application encompasses 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 stereoisomers that have two or more chiral centers and whose molecules are not mirror images of each other. Diastereomers have different physical properties, such as melting points, boiling points, spectral properties, and reactivity. Mixtures of diastereomers can be separated by high-resolution analytical methods such as electrophoresis and chromatography.
• enantiomers refers to two stereoisomers of a compound that are non-superimposable mirror images of one another.
• chiral refers to molecules that have the property of non-superimposability of mirror image pairs, whereas the term “achiral” refers to molecules that are superimposable on their mirror image pairs.
• the compounds of the present invention can be prepared in racemic form, or can be prepared by enantioselective synthesis or by resolution. Prepared as a single enantiomer.
• racemate refers to an equimolar mixture of two enantiomers devoid of optical activity.
• cis-trans isomers or “geometric isomers” is caused by the inability to rotate freely around double bonds or single bonds of ring-forming carbon atoms.
• the compounds provided herein include all cis, trans, syn, anti,
• Z isomers and their corresponding mixtures.
• the compounds of the invention are intended to exist in the form of stereoisomers, which include cis and trans isomers, optical isomers (e.g., R and S enantiomers), diastereomers, geometric isomers, rotational isomers, conformational isomers, atropisomers, and mixtures thereof.
• the compounds of the invention may exhibit more than one type of isomerism and consist of mixtures thereof (e.g., racemic mixtures and diastereomeric pairs).
• a bold solid line may be used.
• thick dashed line The chemical bonds in the compounds are depicted to show the relative relationship of the two chiral centers but are not intended to imply any absolute stereochemistry. For example, indicates that the bond connecting Ra and the bond connecting Rb on the ring are cis relative to each other, and Covered Two enantiomers.
• compositions of the present invention may exist in free form for treatment, or, where appropriate, in the form of pharmaceutically acceptable derivatives thereof.
• pharmaceutically acceptable derivatives include, but are not limited to, pharmaceutically acceptable salts, esters, solvates, metabolites or prodrugs, which, after being administered to a patient in need, can directly or indirectly provide a compound of the present invention or a metabolite or residue thereof. Therefore, when referring to "compounds of the present invention" herein, the above-mentioned various derivative forms of the compounds are also intended to be covered.
• pharmaceutically acceptable means that the substance or composition must be chemically and/or toxicologically compatible with the other ingredients making up the formulation and/or the mammal to be treated therewith.
• Pharmaceutically acceptable salts of the compounds of the present invention include acid addition salts and base addition salts thereof.
• Suitable acid addition salts are formed from acids that form pharmaceutically acceptable salts. Examples include aspartate, benzoate, bicarbonate/carbonate, bisulfate/sulfate, fumarate, gluceptate, gluconate, glucuronate, hexafluorophosphate, hydrobromide/bromide, hydroiodide/iodide, maleate, malonate, methylsulfate, naphthylate, nicotinate, nitrate, orotate, oxalate, palmitate and other similar salts.
• Suitable base addition salts are formed from bases which form pharmaceutically acceptable salts. Examples include aluminum, arginine, choline, diethylamine, lysine, magnesium, meglumine, potassium and other similar salts.
• esters means an ester derived from the compounds of the general formulae herein, including physiologically hydrolyzable esters (which can be hydrolyzed under physiological conditions to release the compounds of the present invention in free acid or alcohol form).
• physiologically hydrolyzable esters which can be hydrolyzed under physiological conditions to release the compounds of the present invention in free acid or alcohol form.
• the compounds of the present invention themselves may also be esters.
• the present invention encompasses all possible crystalline forms or polymorphs of the compounds of the present invention, which may be a single polymorph or a mixture of more than one polymorph in any ratio.
• the compounds of the present invention may exist in the form of solvates (preferably hydrates), wherein the compounds of the present invention contain polar solvents as structural elements of the crystal lattice of the compounds, in particular water, methanol or ethanol.
• polar solvents as structural elements of the crystal lattice of the compounds, in particular water, methanol or ethanol.
• the amount of polar solvents, in particular water may exist in a stoichiometric or non-stoichiometric ratio.
• nitrogen-containing heterocycles are capable of forming N-oxides, as nitrogen requires an available lone pair of electrons to oxidize to an oxide; those skilled in the art will recognize nitrogen-containing heterocycles that are capable of forming N-oxides. Those skilled in the art will also recognize that tertiary amines are capable of forming N-oxides.
• Synthetic methods for preparing N-oxides of heterocycles and tertiary amines are well known to those skilled in the art and include the use of peroxyacids such as peracetic acid and meta-chloroperbenzoic acid (MCPBA), hydrogen peroxide, alkyl hydroperoxides such as tert-butyl hydroperoxide, and N-oxides of tertiary amines. Hydrogen peroxide, sodium perborate and dioxirane such as dimethyldioxirane are used to oxidize heterocycles and tertiary amines. These methods for preparing N-oxides have been widely described and reviewed in the literature, see for example: TL Gilchrist, Comprehensive Organic Synthesis, vol.
• N-oxide also known as amine oxide
• C 1-6 alkylene or C 2-6 alkenylene is optionally substituted by 1, 2, 3 or more substituents independently selected from the group consisting of halogen, OH, SH, CN, C 1-4 haloalkyl, -OC 1-4 alkyl, -NR 1a R 1b , C 3-10 cycloalkyl, 3-10 membered heterocyclyl, C 6-10 aryl and 5-10 membered heteroaryl; and
• R 7a is each independently selected from: H, C 1-6 alkyl, -(CH 2 ) q -C 3-10 cycloalkyl, -(CH 2 ) q -3-10 membered heterocycloalkyl, q is selected from an integer from 0 to 6, and the C 1-6 alkyl, -(CH 2 ) q -C 3-10 cycloalkyl, -(CH 2 ) q -3-10 membered heterocycloalkyl are each independently optionally substituted with 1, 2 or more substituents independently selected from deuterium, halogen, OH, SH, NH 2 , CN, oxo, C 1-6 alkyl, C 2-6 alkenyl , C 2-6 alkynyl, C 1-6 alkoxy, C 1-6 haloalkyl and C 1-6 haloalkoxy; and
• R 4c is selected from H, C 1-6 alkyl and C 1-6 haloalkyl
• R 4a and R 4b are each independently selected from H, halogen, OH, SH, CN, C 1-6 alkyl, C 1-6 haloalkyl, NR 5a R 5b , -C(O)OR 5a and -C(O)-NR 5a R 5b ; and
• R is selected from: C3-10 cycloalkyl, C3-10 cycloalkenyl, 3-10 membered heterocycloalkyl, 3-10 membered heterocycloalkenyl, C5-10 bridged cycloalkyl, C5-10 bridged cycloalkenyl, 5-10 membered bridged heterocycloalkyl, 5-10 membered bridged heterocycloalkenyl, C5-11 monospirocycloalkyl, C5-11 monospirocycloalkenyl, phenyl and 5 or 6 membered heteroaryl, each of which is optionally substituted by 1, 2 or more substituents independently selected from the following groups:
• R is selected from the group consisting of cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, cycloheptenyl, cyclooctenyl, azetidinyl, oxetanyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydrothiophenyl, oxazolidine, thiazolidinyl, pyrazolidinyl, imidazolidinyl, piperidinyl, piperazinyl, hexahydropyrimidinyl, triazinyl, morpholinyl, thiomorpholinyl, azocanyl, dihydropyrrolyl, dihydroimidazolyl, azooctenyl, azet
• R is selected from C3-10 cycloalkyl, 3-10 membered heterocyclyl, C5-10 bridged cycloalkyl, 5-10 membered bridged heterocyclyl, C5-11 monospirocycloalkyl, 5-11 membered monospiro heterocyclyl, C6-10 aryl and 5-10 membered heteroaryl, each of which is optionally substituted with 1, 2 or more substituents independently selected from the following groups:
• R 1a , R 1b , R 1c and R 1d are independently selected at each occurrence from H, C 1-4 alkyl, C 1-4 haloalkyl, -C 1-4 alkylene-OH, -C 1-4 alkylene-SH, -C 1-4 alkylene-NH 2 and -C 1-4 alkylene-CN, wherein R 1c , R 1d together with the carbon atom to which they are both attached optionally form an optionally substituted C 3-6 cycloalkyl or an optionally substituted 3-6 membered heterocycloalkyl.
• R 9 is selected from: cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl; cyclobutenyl, cyclopentenyl, cyclohexenyl, cycloheptenyl, cyclooctenyl; azetidinyl, oxetanyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydrothiophenyl, oxazolidine, thiazolidinyl, pyrazolidinyl, imidazolidinyl, piperidinyl, piperazinyl, hexahydropyrimidinyl, triazinyl, morpholinyl, thiomorpholinyl, azocanyl; dihydropyrrolyl, dihydroimidazolyl; azooctenyl; C 5
• R1 is -L2 - RL ;
• L2 is the linear or branched C1-6 alkylene group, or the linear or branched C2-6 alkenylene group,
• one available C atom in the C 1-6 alkylene or C 2-6 alkenylene is substituted with two substituents, so that the two substituents together with the C atom form an optionally substituted C 3-6 cycloalkylene or an optionally substituted 3 to 6-membered heterocycloalkylene; or optionally, two adjacent carbon atoms in the C 1-6 alkylene or C 2-6 alkenylene are connected by a straight-chain C 1-4 alkylene to form an optionally substituted C 3-6 cycloalkylene, or by -S-, -O-, -NH-, or a straight-chain 2 to 4-membered heteroalkylene to form an optionally substituted 3 to 6-membered heterocycloalkylene; and
• C 1-6 alkylene or C 2-6 alkenylene is optionally substituted by 1, 2, 3 or more substituents independently selected from the group consisting of halogen, OH, SH, CN, C 1-4 haloalkyl, -OC 1-4 alkyl, -NR 1a R 1b , C 3-10 cycloalkyl, 3-10 membered heterocyclyl, C 6-10 aryl and 5-10 membered heteroaryl; and
• CH 2 (if present) of the L 2 -RL moiety attached to the carbon atom indicated by the symbol "#" is optionally replaced by O, S or NR 1e ;
• RL is selected from the group consisting of: R10 , -OR10 , -SR10 and -NR1e - R10 .
• the C 3-6 cycloalkylene group is cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl.
• the 3- to 6-membered heterocycloalkylene is a 4- to 6-membered heterocycloalkylene, preferably an azetidinyl, oxetanyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydrothiophenyl, piperidinyl, tetrahydropyranyl, tetrahydrothiopyranyl, morpholinyl or Thiomorpholinyl.
• R 1 is: -CR al R bl -(CR cl R dl ) m -R 10 , -CR al R bl -(CR cl R dl ) m -OR 10 , -CR al R bl -(CR cl R dl ) m -SR 10 , -CR al R bl -(CR cl R dl ) m -NR 1e -R 10 , -O-(CR cl R dl ) m -R 10 , -S-(CR cl R dl ) m -R 10 , or -NR 1e -(CR cl R dl ) m -R 10 ;
• the C 3-6 cycloalkylene is cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl.
• n 0, 1 or 2.
• the present invention provides compounds of formula (I) according to the present invention, including compounds of formula (I-1) to formula (I-7), wherein R 10 is selected from: H, R 11 , F, Cl, OH, SH, CN, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, -OC 1-4 alkyl, -OC 2-4 alkenyl, -OC 2-4 alkynyl, guanidinyl and -C 1-4 alkylene-guanidinyl, wherein the C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, -OC 1-6 alkyl, -OC 2-4 alkenyl and -OC 2-4 alkynyl are optionally substituted by 1, 2 or more substituents independently selected from halogen, OH, SH and NH 2 .
• R 10 is selected from the group consisting of: H, R 11 , F, Cl, OH, SH, CN, methyl, ethyl, allyl, propargyl, -OCH 3 , -OCH 2 CH 3 , guanidinyl, and -CH 2 CH 2 guanidinyl.
• R 10 is selected from the group consisting of: H, R 11 , F, Cl, OH, SH, CN, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, -OC 1-4 alkyl, -OC 2-4 alkenyl, -OC 2-4 alkynyl, and guanidinyl, wherein the C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, -OC 1-6 alkyl, -OC 2-4 alkenyl, and -OC 2-4 alkynyl are optionally substituted with 1, 2 or more substituents independently selected from halogen, OH, SH, and NH 2.
• R 11 is selected from -(CH 2 ) 0-6 -C 3-10 cycloalkyl, -(CH 2 ) 0-6 -3-10 membered heterocyclyl, -(CH 2 ) 0-6 -C 5-10 bridged cycloalkyl, -(CH 2 ) 0-6 -5-10 membered bridged heterocyclyl, -(CH 2 ) 0-6 -C 5-11 monospirocycloalkyl, -(CH 2 ) 0-6 -5-11 membered monospiroheterocyclyl, -(CH 2 ) 0-6 -C 6-10 aryl and -(CH 2 ) 0-6 -5-10 membered heteroaryl, each of which is optionally substituted with 1, 2 or more substituents independently selected from the groups listed in Group A1:
• R 11 is selected from: -(CH 2 ) 0-3 -C 3-10 cycloalkyl, -(CH 2 ) 0-3 -C 3-10 cycloalkenyl, -(CH 2 ) 0-3 -3-10 membered heterocycloalkyl, -(CH 2 ) 0-3 -3-10 membered heterocycloalkenyl, -(CH 2 ) 0-3 -C 5-10 bridged cycloalkyl, -(CH 2 ) 0-3 -C 5-10 bridged cycloalkenyl, -(CH 2 ) 0-3 -5-10 membered bridged heterocycloalkyl, -(CH 2 ) 0-3 -5-10 membered bridged heterocycloalkenyl, -(CH 2 ) 0-3 -C 5-11 monospirocycloalkyl, -(CH 2 ) 0-3 -C 5-11 monospirocycloalkyl, -(CH 2
• R 11 is selected from: C 3-10 cycloalkyl, C 3-10 cycloalkenyl, 3-10 membered heterocycloalkyl, 3-10 membered heterocycloalkenyl, C 5-11 monospirocycloalkyl, 5-11 membered monospiroheterocycloalkyl, -(CH 2 ) 0-3 -phenyl, and -(CH 2 ) 0-3 -5 or 6 membered heteroaryl, each of which is optionally substituted with 1, 2 or more substituents independently selected from the groups listed in Group A3:
• Group A3 deuterium, halogen, -OR 1a , -SR 1a , CN, ⁇ O, ⁇ NH, C 1-4 alkyl, C 1-4 haloalkyl, C 2-4 alkenyl, C 2-4 alkynyl, -C 1-4 alkylene-OR 1a , -C 1-4 alkylene-SR 1a , -C 1-4 alkylene-NR 1a R 1b , -NR 1a R 1b , -NR 1a -C(O)R 1b , C 3-6 cycloalkyl, 3-6 membered heterocycloalkyl, 5 or 6 membered heteroaryl, -NR 1a -(optionally substituted C 3-6 cycloalkyl) and -CR 1c R 1d -C(O)-NR 1a R 1b ; and R 1a , R 1b , R 1c and R 1d are independently selected at each occurrence from H and C In some embodiments, Group
• R 11 is selected from the groups listed in Group B:
• Group B cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, oxetanyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydrothiophenyl, oxazolidine, thiazolidinyl, pyrazolidinyl, imidazolidinyl, piperidinyl, piperazinyl, hexahydropyrimidinyl, triazinyl, morpholinyl, thiomorpholinyl, dihydropyrrolyl, dihydroimidazolyl, azacyclooctenyl, 5-11 membered monospiro heterocycloalkyl, phenyl, -CH2 -phenyl, pyrrolyl, -CH2 -pyrrolyl, furanyl, thienyl, pyrazolyl, pyridinyl, -
• the group B further comprises an imidazole group and/or
• R 11 is selected from: C 3-10 cycloalkyl, C 3-10 cycloalkenyl, 3-10 membered heterocycloalkyl, 3-10 membered heterocycloalkenyl, C 5-10 bridged cycloalkyl, C 5-10 bridged cycloalkenyl, 5-10 membered bridged heterocycloalkyl, 5-10 membered bridged heterocycloalkenyl, C 5-11 monospirocycloalkyl, C 5-11 monospirocycloalkenyl, 5-11 membered monospiroheterocycloalkyl, 5-11 membered monospiroheterocycloalkenyl, phenyl and 5 or 6 membered heteroaryl, each of which is optionally substituted with 1, 2 or more substituents independently selected from the following groups:
• R 11 is selected from cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl; azetidinyl, oxetanyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydrothiophenyl, oxazolidine, thiazolidinyl, pyrazolidinyl, imidazolidinyl, piperidinyl, piperazinyl, hexahydropyrimidinyl, triazinyl, morpholinyl, thiomorpholinyl, dihydropyrrolyl, dihydroimidazolyl, azacyclooctenyl; 5-11 membered monospiro heterocycloalkyl; phenyl; pyrrolyl, furanyl, thienyl, pyrazolyl, pyridinyl, pyridonyl, oxazolyl, iso
• R2 is H, halogen, OH , SH, CN, C1-4 alkyl, -C1-4 alkylene-OH, -C1-4 alkylene-SH, -NR2aR2b , -NR2a- C(O)R2b, -NR2a-C(O)OR2b, -NR2a-C(O)NR2aR2b and -NR2a - S ( O ) 2 - R2b ; and
• R2 is H, F, Cl, OH, SH, methyl, ethyl, -CH2 -OH, -CH2-SH, -NH2 , -NH-C(O) CH3 , -NH-C(O) OCH3 , -NH-C(O) NH2 , and -NH- S (O) 2CH3 .
• the present invention provides a compound of formula (I) having a structure of formula (I-8):
• Ring D is C 3-8 cycloalkyl, 3-8 membered heterocycloalkyl, C 5-8 bridged cycloalkyl, or 5-8 membered bridged heterocycloalkyl.
• R6 is selected from:
• R 7a are each independently selected from the group consisting of H, C 1-6 alkyl, -(CH 2 ) q -C 3-6 cycloalkyl, and -(CH 2 ) q -4-7 membered heterocycloalkyl, q is selected from an integer from 0 to 4, and the C 1-6 alkyl, the C 3-6 cycloalkyl in the -(CH 2 ) q -C 3-6 cycloalkyl, and the 4-7 membered heterocycloalkyl in the -(CH 2 ) q -4-7 membered heterocycloalkyl are each independently optionally substituted by 1, 2 or more substituents independently selected from the group consisting of deuterium, halogen, OH, SH, NH 2 , CN, oxo, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 alkoxy, C 1-6 haloalkyl, and C 1-6 haloal
• R6 is selected from:
• -NH(C 1-4 alkyl), -NH(C 3-6 partially unsaturated cycloalkyl) and -NH(4-6 membered heterocycloalkyl) are each independently optionally substituted with 1, 2 or more substituents independently selected from deuterium, halogen, OH, oxo, SH, NH 2 , CN, C 1-4 alkyl and C 1-4 haloalkyl,
• R6 is selected from the group consisting of: H, halogen, OH, SH, CN, N( R7a ) 2 , C1-6 alkyl, -OC1-6 alkyl, -OC1-6 alkyl- C3-6 cycloalkyl, and C3-6 cycloalkyl optionally substituted with 1, 2 or more substituents independently selected from deuterium, halogen, OH, SH, NH2 , CN, oxo, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 alkoxy, C1-6 haloalkyl and C1-6 haloalkoxy substituents, and C3-6 cycloalkyl optionally substituted with 1, 2 or more substituents independently selected from deuterium, halogen, OH, SH, NH2 , CN, oxo, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl , C1-6 alkoxy, C1-6 hal
• R6 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-halogenated C1-6 alkyl, -OC1-6 alkyl- C3-10 cycloalkyl, and C1-6 alkyl optionally substituted with 1, 2 or more substituents independently selected from deuterium, halogen, OH, SH, NH2 , CN, oxo, C1-6 alkyl, C2-6 alkenyl , C2-6 alkynyl, C1-6 alkoxy, C1-6 haloalkyl and C1-6 haloalkoxy.
• 3-10 cycloalkyl optionally 1, 2 or more independently selected from 3-10 membered heterocycloalkyl substituted with deuterium, halogen, OH, SH, NH2 , CN, oxo, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 alkoxy, C1-6 haloalkyl and C1-6 haloalkoxy substituents; the C1-6 alkyl in said -NH( C1-6 alkyl), -N( C1-6 alkyl) 2 , and the C3-10 cycloalkyl in said -NH( C3-10 cycloalkyl) are each independently optionally substituted with 1, 2 or more substituents independently selected from deuterium, halogen, OH, SH, NH2 , CN, oxo, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 alkoxy, C1-6 haloalkyl and C1-6 haloalk
• R6 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 C3-6 cycloalkyl optionally substituted with 1 , 2 or more substituents independently selected from halogen, OH, SH, NH2 , CN, C1-4 alkyl and C1-4 haloalkyl.
• ring D is C 4-6 cycloalkyl or 5-8 membered bridged heterocycloalkyl.
• ring D is cyclohexane or Among them, $ A is the connection point with ring A, and $ L1 is the connection point with L1 .
• R 6 is selected from:
• R6 is selected from: C1-4 alkyl, C1-4 haloalkyl, and C3-6 cycloalkyl optionally substituted by 1, 2 or more substituents independently selected from deuterium, halogen, OH, SH, NH2 , CN, C1-4 alkyl and C1-4 haloalkyl, and 4-7 membered heterocycloalkyl optionally substituted by 1, 2 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, and C1-4 haloalkoxy.
• CH 2 (if present) of the L 2 -RL moiety connected to the carbon atom indicated by the symbol "#" is optionally replaced by O, S or NR 1e ;
• R 3a and R 3b at each occurrence are independently selected from H and C 1-4 alkyl.
• the present invention provides compounds of formula (I) according to the present invention, including compounds of formula (I-1) to formula (I-8), wherein Z is O. In other embodiments, Z is S. In other embodiments, Z is NH.
• the present invention provides compounds of formula (I) according to the present invention, including compounds of formula (I-1) to formula (I-8), wherein X is CR 7 , Y is N, and Z is NH.
• the present invention provides compounds of formula (I) according to the present invention, including compounds of formula (I-1) to formula (I-8), wherein X is N, Y is CR 8 , and Z is NH.
• the present invention provides compounds of formula (I) according to the present invention, including compounds of formula (I-1) to formula (I-8), wherein X is C(R 7 ) 2 , Y is C(R 8 ) 2 , and Z is NH.
• the present invention provides compounds of formula (I) according to the present invention, including compounds of formula (I-1) to formula The compound of (I-8), wherein R is:
• the present invention provides compounds of formula (I) according to the present invention, including compounds of formula (I-1) to formula (I-8), wherein the compound has a structure of formula (I-9):
• R 1 , R 2 , R 4 , R 5 , R 7 , R 8 and L 1 are each as defined in the embodiments described above.
• R 5 is independently selected at each occurrence from the group consisting of: 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, -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 alkyleneC(O)OR 6a , -OC 1-4 alkyleneC(O)NR 6a R 6b , C 1-4
• R 5 at each occurrence is independently selected from the group consisting of: 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 and C 3-6 cycloalkyl.
• R 6a and R 6b at each occurrence are independently selected from H and C 1-4 alkyl.
• R 4 is -OC 1-4 alkyl, -O-deuterated C 1-4 alkyl, or cyclopropyl
• R 5 is H or C 1-4 alkyl.
• R 4 is -O-CH 3 , -O-CD 3 , or cyclopropyl
• R 5 is methyl.
• R4 and R5 are independently selected at each occurrence from the group consisting of: H, F, Cl, OH, SH, CN, -NH2 , -NHCH3 , -NH( CH3 ) 2 , methyl, ethyl, CF3 , vinyl, ethynyl, -O- CH3 , -S- CH3 , and cyclopropane.
• R 4 is -OC 1-4 alkyl
• R 5 is hydrogen or C 1-4 alkyl.
• R 4 is -O-CH 3
• R 5 is methyl.
• R7 and R8 are each independently selected at each occurrence from: H, F, Cl, OH, SH, CN, NH2 , -NH( CH3 ), -N( CH3 ) 2 , methyl, ethyl and cyclopropyl, preferably H, F, Cl, methyl, ethyl and cyclopropyl.
• L 1 is selected from the group consisting of: *-CR 4a R 4b -NR 4c -, *-C(O)-NR 4c -, *-C(S)-NR 4c -, *-S(O) 2 -NR 4c -, *-NR 4c -C(O)-, *-NR 4c -S(O) 2 -, *-NR 4c -CR 4a R 4b -, and *-NR 4c -C(S)-, wherein the bond indicated by * is connected to the phenyl ring B; and
• R 4a and R 4b are each independently selected from H, deuterium, F, Cl, OH, SH, CN, C 1-4 alkyl, C 1-4 haloalkyl, NR 5a R 5b , -C(O)OR 5a and -C(O)-NR 5a R 5b ; or R 4a and R 4b together with the carbon atom to which they are both attached form a C 3-4 cycloalkyl or 4-5 membered heterocycloalkyl.
• L 1 is selected from the group consisting of: *-CR 4a R 4b -NR 4c -, *-C(O)-NR 4c -, *-C(S)-NR 4c -, *-S(O) 2 -NR 4c -, *-NR 4c -C(O)-, *-NR 4c -S(O) 2 -, *-NR 4c -CR 4a R 4b -, and *-NR 4c -C(S)-, wherein the bond marked with * is attached to the phenyl ring B; and R 4a and R 4b are each independently selected from the group consisting of: H, F, Cl, OH, SH, CN, C 1-4 alkyl, C 1-4 haloalkyl, NR 5a R 5b , -C(O)OR 5a , and -C(O)-NR 5a R 5b , preferably H, F, Cl, OH, SH, CN, CH 3
• R 5a and R 5b at each occurrence are independently selected from H and C 1-4 alkyl.
• R 4a and R 4b are each independently selected from H, F, Cl, OH, SH, CN, -NH 2 , -C(O)OH, -C(O)OCH 3 , -C(O)-NH 2 , and -C(O)-NCH 3 .
• R 4c is selected from H, C 1-4 alkyl and C 1-4 haloalkyl.
• R 4c is selected from H, methyl, ethyl, -CH 2 F, -CHF 2 and -CF 3 .
• L1 is selected from the group consisting of: * -CH2- NH-, * -CF2- NH-, * -CD2 -NH-, *-CH( CF3 )-NH-, *-C( CH3 ) 2 -NH-, * -CH2 -N( CH3 )-, * -CH2- N(CH2CH3)-, * -CH2 -N( CH2F ) -, *-C(O)-NH-, *-C(S)-NH- , *-S(O) 2- NH-, *-NH-CH2-, *-NH- CF2- , *-NH- C (O)-, *-NH-C(S)-, *-NH-S(O) 2 ...
• the bond marked with * is connected to the phenyl ring B.
• L1 is selected from the group consisting of: * -CH2- NH-, * -CF2- NH-, *-CH( CF3 ) -NH- , * -CH2- N(CH3) - , *-CH2-N( CH2CH3 )-, * -CH2 - N( CH2F )-, *-C(O)-NH-, * -C (S)-NH-, *-S(O) 2 -NH-, *-NH- CH2- , *-NH-CF2-, *-NH-C(O)-, *-NH-C(S)-, *-NH-S(O) 2 ... *-CH 2 -NH- and *-C(O)-NH-, wherein the bond indicated by * is connected to the phenyl ring B, are more preferred.
• the present invention provides a compound of formula (I) according to the present invention, which has a structure of formula (I-19):
• L 1 is selected from *-CR 4a R 4b -NR 4c - and *-C(O)-NR 4c -, wherein the bond marked with * is connected to the phenyl ring B;
• R 4c is H
• R 4 is selected from -OC 1-6 alkyl and C 3-6 cycloalkyl, wherein said -OC 1-6 alkyl and C 3-6 cycloalkyl are each optionally substituted with 1, 2, 3 or more D;
• R5 is selected from C1-6 alkyl
• Ring D is C 4-6 cycloalkyl or 5-8 membered bridged heterocycloalkyl
• R6 is selected from:
• ring D is preferably cyclohexane or wherein $ A is the connection point to ring A, and $ L1 is the connection point to L1 . More preferably, Part of Among them, $ A is the connection point with ring A, and $ L1 is the connection point with L1 .
• L 1 is selected from *-CH 2 -NH-, *-CD 2 -NH-, and *-C(O)-NH-, wherein the bond indicated by * is attached to the phenyl ring B.
• R6 is selected from:
• 4-6 membered heterocycloalkyl and -C 1-4 alkylene-4-6 membered heterocycloalkyl wherein the 4-6 membered heterocycloalkyl is optionally substituted at each occurrence with 1, 2 or more substituents independently selected from deuterium, halogen, CN and C 1-4 alkyl, and
• C 1-4 alkyl C 1-6 haloalkyl, -C 1-4 haloalkyl-OH, -C 1-4 alkylene-CN, C 2-4 alkynyl, -C 1-4 alkylene-O-halogenated C 1-4 alkyl, -NH(4-6 membered heterocycloalkyl),
• 4-6 membered heterocycloalkyl and -C 1-4 alkylene-4-6 membered heterocycloalkyl wherein the 4-6 membered heterocycloalkyl is optionally substituted at each occurrence with 1, 2 or more substituents independently selected from deuterium, halogen, CN and C 1-4 alkyl, and
• halo or halogen is independently selected from F and Cl at each occurrence.
• R 6 is selected from:
• 4-6 membered heterocycloalkyl and -C 1-4 alkylene-4-6 membered heterocycloalkyl wherein the 4-6 membered heterocycloalkyl at each occurrence is independently 4-6 membered heterocycloalkyl with 1 N heteroatom and is optionally substituted with 1, 2 or more substituents independently selected from deuterium, F, CN and C 1-4 alkyl.
• the compound of formula (I-19) has a structure having one of formulas (I-28)-(I-31):
• R is selected from -NH(4-6 membered heterocycloalkyl), and 4-6 membered heterocycloalkyl with 1 N heteroatom, wherein the 4-6 membered heterocycloalkyl with 1 N heteroatom is attached to the rest of the molecule through the N heteroatom and is optionally substituted with 1, 2, 3 or more substituents independently selected from deuterium, F, Cl, CN, and C 1-4 alkyl.
• the disease, disorder or condition is selected from age-related macular degeneration, geographic macular atrophy, diabetic retinopathy, uveitis, retinitis pigmentosa, macular edema, Behcet's uveitis, multifocal choroiditis, Vogt-Koyangi-Harada syndrome, intermediate uveitis, avian eye retinochoroiditis, sympathetic eye inflammation, ocular cicatricial pemphigoid, ocular pemphigus, non-arteritic ischemic optic neuropathy, postoperative inflammation, retinal vein occlusion, nervous system disease, multiple sclerosis, stroke, Guillain-Barré syndrome, traumatic brain injury, Parkinson's disease, conditions resulting from inappropriate or undesired complement activation, complications of hemodialysis, hyperacute allograft rejection, xenograft rejection, interleukin-2 (IL-2)-induced toxicity during IL-2 therapy, inflammatory diseases
• the disease, disorder or condition is selected from age-related macular degeneration (AMD), geographic atrophy of the macula, diabetic retinopathy, uveitis, retinitis pigmentosa, macular edema, Behcet's uveitis, multifocal choroiditis, Vogt-Koyangi-Harada syndrome, intermediate uveitis, avian eye retinochoroiditis, sympathetic eye inflammation, ocular cicatricial pemphigoid, ocular pemphigus, non-arteritic ischemic optic neuropathy, postoperative inflammation, retinal vein occlusion, nervous system disease, multiple multiple sclerosis, stroke, Guillain-Barré syndrome, traumatic brain injury, Parkinson's disease, conditions resulting from inappropriate or undesired complement activation, complications of hemodialysis, hyperacute allograft rejection, xenograft rejection, IL-2-induced toxicity during interleukin-2 (AMD), geographic
• Step 6 Dissolve 2-6 (1.6 g, 5.04 mmol) and N,N-diisopropylethylamine (1.95 g, 15.12 mmol) in dichloromethane (30 mL) at room temperature, add N-phenylbistrifluoromethylsulfonimide (2.34 g, 6.55 mmol) at 0°C, and stir at room temperature for 3 hours.
• Step 5 Compound 3-6 (1.15 g, 3.97 mmol) was dissolved in 1,2-dichloroethane (10 mL) solution, and compound 3-5 (800 mg, 3.32 mmol) was added. The reaction was stirred at 25 ° C for 30 min, and then sodium triacetoxyborohydride (1.40 g, 6.62 mmol) was added. The reaction was stirred at 25 ° C for 18 hours under a nitrogen atmosphere, and the reaction was monitored by LCMS. Water (30 mL) was added to the reaction mixture and extracted with ethyl acetate (2x30 mL).
• Step 1 Add 2-(7-azobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (410.96 mg, 1.08 mmol), compound 1-6 (173.86 mg, 0.72 mmol) and triethylamine (145.82 mg, 1.44 mmol) to a solution of compound 3-5 (220 mg, 0.72 mmol) in N,N-dimethylformamide (10 mL), and stir the reaction at 30 ° C for 18 hours. Monitor the reaction by LCMS. Add water (30 mL) to the reaction mixture and extract with ethyl acetate (2x30 mL).
• Step 2 Dissolve compound 4-1 (370 mg, 0.70 mmol) in methanol (5 mL) and water (1 mL), and add lithium hydroxide (40.80 mg, 0.97 mmol). Stir the reaction at 50 ° C for 18 hours under a nitrogen atmosphere, and monitor the reaction by LCMS. Add dilute hydrochloric acid (1N) to the reaction, adjust the pH of the reaction solution to 5-6, and filter out the solid to obtain a crude product. The crude product is purified by a reverse phase column with a flow rate of 25 mL/min and a gradient of 38%-68% acetonitrile/buffer (0.1 mol/L formic acid aqueous solution) to obtain compound 4.
• Step 3 Compound 4 (200 mg, 0.48 mmol) was further subjected to chiral separation (chromatographic column: DAICEL CHIRALPAK AD 250 mm ⁇ 30 mm, 10 ⁇ m; mobile phase: ⁇ : carbon dioxide, B: [0.1% ammonia-ethanol]; gradient: B%: 15%) to obtain compound 4-P1 and compound 4-P2.
• Step 1 Compound 5-1 (2 g, 7.24 mmol) was dissolved in tetrahydrofuran (20 mL), and a tetrahydrofuran solution of isopropylmagnesium chloride-lithium chloride (6.44 mL, 1.3 M) was added at -40 ° C. After stirring for 50 minutes, cuprous iodide (0.41 g, 2.17 mmol) was added, and then stirred at 0 ° C for 10 minutes. Cyclobutyric acid chloride (1.29 g, 10.87 mmol) dissolved in THF (20 mL) was added at -40 ° C. After 5 minutes, the mixture was heated to 0 ° C and stirred for 2 hours.
• Step 3 Compound 5-3 (255 mg, 0.84 mmol) was dissolved in N, N-dimethylformamide (1 mL), 2-(7-azobenzotriazole)-N, N, N', N'-tetramethyluronium hexafluorophosphate (476.34 mg, 1.25 mmol) was added under ice bath, and N, N-diisopropylethylamine (0.42 mL, 2.51 mmol) in N, N-dimethylformamide (1 mL) solution was dropped into the reaction solution, the reaction solution was moved to room temperature, stirred for 15 minutes, and 1-6 (220 mg, 1.00 mmol) in N, N-dimethylformamide (2 mL) solution was dropped into the reaction solution, and reacted at room temperature for 2 hours.
• Step 5 Compound 5 (70 mg, 0.18 mmol) was further subjected to chiral separation (chromatographic column: ChiralPak AS, 150 ⁇ 4.6 mm I.D., 3 ⁇ m; mobile phase: ⁇ : carbon dioxide, B: [0.05% DEA-ethanol]; gradient: B%: 5%-40%) to obtain compound 5-P1 and compound 5-P2.
• Step 4 Compound 6-1-P1 (115 mg, 0.23 mmol) was dissolved in tetrahydrofuran (1.5 mL), methanol (1.5 mL) and water (1.5 mL), lithium hydroxide (27 mg, 0.97 mmol) was added, and the mixture was heated to 50° C. and stirred for 16 hours. The reaction was monitored by LCMS. After the reaction, the pH value of the reaction solution was adjusted to neutral, filtered, and the filtrate was concentrated. The crude product was purified by reverse phase chromatography: 15%-100% acetonitrile/buffer (0.01 mol/L ammonium bicarbonate aqueous solution) gradient to obtain compound 6-P1.
• Step 3 Compound 7-4 (70 mg, 0.27 mmol) and compound 1-6 (82.42 mg, 0.27 mmol) were dissolved in N, N-dimethylformamide (5 ml), 2-(7-azobenzotriazole)-N, N, N', N'-tetramethyluronium hexafluorophosphate (112.91 mg, 0.30 mmol) and N, N-diisopropylethylamine (0.11 mL, 0.68 mmol) were added, and the reaction was stirred at room temperature for 12 hours. The reaction was monitored by LCMS. The reaction solution was poured into water (150 ml) and extracted with ethyl acetate (2 ⁇ 150 ml).
• Step 3 Dissolve compound 8-3 (856 mg, 3.92 mmol) in dichloromethane (100 mL) solution, add Dess-Martin reagent (1.8 g, 4.28 mmol), and stir at room temperature for 2 hours. Monitor the reaction by LCMS. Add saturated sodium carbonate solution (20 mL) and saturated sodium thiosulfate solution (20 mL) to the reaction solution, stir the reaction solution at room temperature for 30 minutes, and extract with dichloromethane (3 ⁇ 50 mL). The combined organic phase is washed with saturated brine (20 ml), dried over anhydrous sodium sulfate and concentrated. The crude product is purified by silica gel chromatography: 3%-10% dichloromethane/methanol gradient to obtain compound 8-4.
• Step 5 Compound 8-5 (407 mg, 1.33 mmol) was dissolved in N, N-dimethylformamide (3 mL), 2-(7-azobenzotriazole)-N, N, N', N'-tetramethyluronium hexafluorophosphate (759 mg, 2.00 mmol) and N, N-diisopropylethylamine (516 mg, 4.00 mmol) were added, stirred for 5 minutes, and compound 1-6 (345 mg, 1.33 mmol) was added, and the mixture was reacted at room temperature for 2 hours. The reaction was monitored by LCMS. The reaction solution was poured into water (30 ml) and extracted with dichloromethane (3 ⁇ 50 ml).
• Step 7 Compound 8 (40 mg, 0.092 mmol) was further subjected to chiral separation (chromatographic column: ChiralPak IG, 250 mm ⁇ 30 mm I.D., 10 ⁇ m; mobile phase: A: carbon dioxide, B: [0.1% ammonia water-ethanol]; gradient: B%: 40%) to obtain compound 8-P1 and compound 8-P2.
• Chromatographic column ChiralPak IG, 100mm ⁇ 4.6mm I.D., 3 ⁇ m
• mobile phase A: carbon dioxide
• B ethanol (0.05% diethylamine)
• gradient B%: 40%, gradient flow for 5 minutes, 40% for 5 minutes, 5% for 2.5 minutes, flow rate: 2.5mL/min, separation wavelength 220nm.
• Step 5 Compound 9-4 (160 mg, 0.50 mmol) was dissolved in N, N-dimethylformamide (5 mL) solution, compound 1-6 (151.53 mg, 0.50 mmol), N, N-diisopropylethylamine (0.25 mL, 1.49 mmol) and 2-(7-azobenzotriazole)-N, N, N', N'-tetramethyluronium hexafluorophosphate (283.06 mg, 0.74 mmol) were added, and the reaction solution was stirred at 20 ° C for 18 hours. Monitored by LCMS.
• the reaction solution was diluted with water (30 mL) and ethyl acetate (30 mL), the aqueous phase was extracted with ethyl acetate (2x30 ml), the organic phases were combined, washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated.
• Step 8 Compound 9 (100 mg, 0.25 mmol) was subjected to chiral separation (chromatographic column: ChiralPak IG, 250 mm ⁇ 30 mm I.D., 10 ⁇ m; mobile phase: ⁇ : carbon dioxide, B: [0.1% ammonia water-methanol]; gradient: B%: 30%) to obtain compound 9-P1 and compound 9-P2.
• Chromatographic column ChiralPak IG, 100mm ⁇ 4.6mm I.D., 3 ⁇ m
• mobile phase A: carbon dioxide
• B methanol (0.05% diethylamine)
• gradient B%: 5%-40% gradient flow for 5 minutes, 40% for 5 minutes, 5% for 2.5 minutes
• flow rate 2.5mL/min
• separation wavelength 220nm separation wavelength 220nm.
• Step 1 Dissolve triphenylphosphine (22.4 g, 85.60 mmol) in toluene (400 mL), stir evenly, then add compound 10-1 (20.0 g, 77.82 mmol), stir at 80°C under nitrogen protection for 16 hours, and monitor the reaction by LCMS and TLC. After the reaction, precipitate is filtered, and the filter cake is washed with toluene, and the filter cake is collected to obtain compound 10-2.
• MS m/z (ESI): 440.0 [M-Br+H] + .
• Step 3 Dissolve compound 10-3 (1.9 g, 4.42 mmol) in dichloromethane (10 mL), add 4,4,4-trifluorobutyraldehyde (558 mg, 4.42 mmol), and stir at room temperature for 16 hours. Monitor the reaction by LCMS and TLC. Add water (20 mL) to the reaction solution and extract with dichloromethane (3 ⁇ 50 mL). The combined organic phase is washed with saturated brine (100 ml), dried over anhydrous sodium sulfate and concentrated. The concentrated crude product is purified by silica gel chromatography: 0%-25% ethyl acetate/petroleum ether gradient to obtain compound 10-4.
• Step 10 Compound 10 (48 mg, 0.10 mmol) was further subjected to chiral separation (chromatographic column: Chiralpak AD-3 50 ⁇ 4.6 mm I.D., 3 ⁇ m; mobile phase: A: carbon dioxide, B: [0.05% DEA-ethanol]; gradient: B%: 5%-40%) to obtain compound 10-P1 and compound 10-P2.
• Step 3 Compound 11 (100 mg, 0.22 mmol) was further subjected to chiral separation (chromatographic column: ChiralPak AS, 150 ⁇ 4.6 mm I.D., 3 ⁇ m; mobile phase: ⁇ : carbon dioxide, B: [0.05% DEA-ethanol]; gradient: B%: 5%-40%) to obtain compound 11-P1 and compound 11-P2.
• Chromatographic column ChiralPak AS, 150 ⁇ 4.6mm I.D., 3 ⁇ m
• mobile phase A: carbon dioxide
• B ethanol (0.05% DEA)
• gradient B%: 5%-40% gradient flow for 5 minutes, 40% for 2.5 minutes, 5% for 2.5 minutes, flow rate: 2.5mL/min, separation wavelength 220nm.
• Step 1 Compound 5-1 (5.0 g, 19.08 mmol) was dissolved in tetrahydrofuran (70 mL), and a tetrahydrofuran solution (16.1 mL, 1.3 M) of isopropylmagnesium chloride-lithium chloride was added at -40 ° C. After stirring for 50 minutes, cuprous iodide (1.1 g, 5.72 mmol) was added, and then stirred at 0 ° C for 10 minutes, and then a tetrahydrofuran (20 mL) solution of 12-1 (3.8 g, 28.62 mmol) was added at -40 ° C. After 5 minutes, the mixture was heated to 0 ° C and stirred for 2 hours.
• Step 2 Compound 12-2 (500 mg, 2.15 mmol) was dissolved in methanol (10 mL), and ammonium acetate (1.9 g, 25.83 mmol) and sodium cyanoborohydride (405 mg, 6.46 mmol) were added. The mixture was heated to 60 °C under argon protection for 5 hours. The reaction was monitored by LCMS. The reaction solution was cooled to room temperature, quenched with dilute hydrochloric acid (1 N), and extracted with ethyl acetate (3 ⁇ 30 mL). The combined organic phase was washed with saturated brine (30 mL), dried over anhydrous sodium sulfate and concentrated.
• Step 3 Dissolve compound 12-3 (251 mg, 0.82 mmol) in N,N-dimethylformamide (2 mL), add 2-(7-azobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (586 mg, 1.54 mmol) under ice bath, and drop a solution of N,N-diisopropylethylamine (0.51 mL, 3.09 mmol) in N,N-dimethylformamide (2 mL) into the reaction solution. Move to room temperature and stir for 15 minutes, then drop a solution of compound 1-6 (240 mg, 1.03 mmol) in N,N-dimethylformamide (2 mL) into the reaction solution.
• 2-(7-azobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate 586 mg, 1.54 mmol
• Step 5 Compound 12 (100 mg, 0.24 mmol) was further subjected to chiral separation (chromatographic column: Chiralpak IG-3 100 ⁇ 4.6 mm I.D., 3 ⁇ m; mobile phase: ⁇ : carbon dioxide, B: [0.05% DEA-methanol]; gradient: B%: 40%) to obtain compound 12-P1 and compound 12-P2.
• Step 1 Compound 12-3 (100 mg, 0.43 mmol) was dissolved in methanol (5 mL), 3-6 (99 mg, 0.34 mmol) and sodium cyanoborohydride (67 mg, 1.07 mmol) were added, 2 drops of acetic acid were added, and the reaction was stirred for 16 hours under argon protection. The reaction was monitored by LCMS. The reaction was quenched with dilute hydrochloric acid (1 N) and extracted with ethyl acetate (3 ⁇ 10 mL). The combined organic phase was washed with saturated brine (20 mL), dried over anhydrous sodium sulfate and concentrated.
• Step 3 Compound 13 (98 mg, 0.25 mmol) was further subjected to chiral separation (chromatographic column: Chiralpak AD-3 50*4.6 mm I.D., 3 ⁇ m; mobile phase: ⁇ : carbon dioxide, B: [0.05% DEA-ethanol]; gradient: B%: 5%-40%) to obtain compound 13-P1 and compound 13-P2.
• Step 1 Compound 5-1 (4 g, 15.26 mmol) was dissolved in tetrahydrofuran (8 mL), and a tetrahydrofuran solution of isopropylmagnesium chloride-lithium chloride (12.88 mL, 1.3 M) was added at -40 ° C. After stirring for 50 minutes, cuprous iodide (0.87 g, 4.58 mmol) was added, and then stirred at 0 ° C for 10 minutes, and then a tetrahydrofuran (4 mL) solution of cyclohexanoyl chloride (3.36 g, 22.90 mmol) was added at -40 ° C.
• Step 3 Compound 14-2 (120 mg, 0.39 mmol) was dissolved in N,N-dimethylformamide (4 mL), 2-(7-azobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (224 mg, 0.59 mmol) and N,N-diisopropylethylamine (101 mg, 0.79 mmol) were added, and after stirring at room temperature for 5 minutes, 1-6 (97 mg, 0.39 mmol) was added and continued to stir for 2 hours. The reaction was monitored by LCMS.
• Step 5 Compound 14 (100 mg, 0.24 mmol) was subjected to chiral separation (chromatographic column: ChiralPak AD, 50 ⁇ 4.6 mm I.D., 3 ⁇ m; mobile phase: ⁇ : carbon dioxide, B: [0.05% DEA-ethanol]; gradient: B%: 5%-40%) to obtain compound 14-P1 and compound 14-P2.
• Step 3 Compound 17-3 (500 mg, 2.51 mmol) was dissolved in methanol (10 mL), and ammonium acetate (2.32 g, 30.11 mmol) and sodium cyanoborohydride (630.77 mg, 10.04 mmol) were added. The reaction system was stirred at 60 ° C for 16 hours under nitrogen protection. The reaction was monitored by LCMS and TLC. It was quenched with hydrochloric acid (1N) and extracted with ethyl acetate (3x30 mL). The combined organic phase was washed with saturated brine (30 mL), dried over anhydrous sodium sulfate and concentrated.
• Step 1 Dissolve compound 18-1 (6.8 g, 29.66 mmol) in tetrahydrofuran (30 mL), add borane tetrahydrofuran solution (29.66 mL, 2 M) at 0°C, and stir at 0°C for 4 hours. Monitor the reaction by LCMS and TLC. Directly concentrate to obtain compound 18-2.
• MS m/z (ESI): 160 [M-55] + .
• Step 3 Compound 5-1 (3 g, 14.07 mmol) was dissolved in tetrahydrofuran (50 mL), and a tetrahydrofuran solution of isopropylmagnesium chloride-lithium chloride (14.07 mL, 1.3 M) was slowly added dropwise under nitrogen protection at -40°C. After stirring for 1 hour, a tetrahydrofuran solution (15 mL) of 18-3 (3 g, 14.07 mmol) was added dropwise and continued to stir at -40°C for 3 hours. The reaction was monitored by LCMS and TLC.
• Step 4 Compound 5-1 (732.08 mg, 2.79 mmol) was dissolved in tetrahydrofuran (15 mL), and a tetrahydrofuran solution of isopropylmagnesium chloride-lithium chloride (2.79 mL, 1.3 M) was slowly added dropwise under nitrogen protection at -40°C. After stirring for 1 hour, a tetrahydrofuran solution (5 mL) of compound 20-3 (635 mg, 2.79 mmol) was added and continued to stir for 3 hours. The reaction was monitored by LCMS and TLC.
• Step 7 Compound 1-6 (496.99 mg, 1.63 mmol), 2-(7-azobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (804.09 mg, 2.12 mmol), N,N-diisopropylethylamine (629.93 mg, 4.88 mmol) were dissolved in N,N-dimethylformamide (15 mL), compound 20-6 (590 mg, 1.63 mmol) was added, and stirred at room temperature for 4 hours. The reaction was monitored by LCMS.
• Step 9 Compound 20-8 (482 mg) was dissolved in methanol (5 mL), tetrahydrofuran (5 mL) and water (5 mL), lithium hydroxide (84.01 mg, 3.51 mmol) was added, and the mixture was stirred at 50°C for 3 hours. The reaction was monitored by LCMS. Hydrochloric acid (1 M) was added to adjust the pH of the system to about 4, and the mixture was directly concentrated. The crude product was purified by silica gel chromatography column: 30% methanol/dichloromethane, and then by reverse phase chromatography column: 15%-100% acetonitrile/buffer (0.01 mol/L ammonium bicarbonate aqueous solution) gradient purification to obtain compound 20-P1.
• Step 2 Compound 5-1 (1.08 g, 4.12 mmol) was dissolved in tetrahydrofuran (10 mL), and a tetrahydrofuran solution of isopropylmagnesium chloride-lithium chloride (4.46 mL, 1.3 M) was added at -78 ° C. After stirring for 90 minutes, a tetrahydrofuran solution (10 mL) of compound 21-2 (800 mg, 3.43 mmol) was added at -78 ° C. After 5 minutes, the mixture was heated to 0 ° C and stirred for 1 hour. The reaction was monitored by LCMS and TLC.
• Step 2 Under nitrogen atmosphere, compound 22-2 (9.4 g, 45.37 mmol), p-toluenesulfonylmethyl isocyanide (13.29 g, 68.05 mmol) and tert-butanol (6.47 mL, 2.17 mmol) were dissolved in ethylene glycol dimethyl ether (80 mL), and a tetrahydrofuran solution of potassium tert-butoxide (90.73 mL, 1 M) was added dropwise at 0°C. After 1 hour, the system was warmed to room temperature and stirred for 24 hours. The reaction was monitored by LCMS.
• Step 3 Compound 22-3 (5.69 g, 26.07 mmol) and methyl p-fluorobenzoate (8.04 g, 52.15 mmol) were dissolved in tetrahydrofuran (40 mL), and a tetrahydrofuran solution of lithium bis(trimethylsilyl)amide (52.15 mL, 1 M) was added dropwise at 0°C under nitrogen protection, and then the system was moved to room temperature and stirred for 2 hours. The reaction was monitored by LCMS and TLC. Saturated ammonium chloride solution (50 mL) was added to quench, and the mixture was extracted with ethyl acetate (3 ⁇ 100 mL).
• Step 5 Compound 23-5-P1 (230 mg, 0.65 mmol) was dissolved in 1,4-dioxane (5 mL), thiourea (247 mg, 3.25 mmol) and acetic acid (1 mL) were added, and the system was heated to 85 ° C and stirred for 6 hours. The reaction was monitored by LCMS. The reaction solution was concentrated under reduced pressure, dichloromethane was added to the crude product, and the pH was adjusted to neutral with saturated sodium bicarbonate solution, extracted with dichloromethane (3 ⁇ 100 mL), and the combined organic phase was washed with saturated brine (80 mL), then dried over anhydrous sodium sulfate and concentrated.
• Step 6 Compound 23-6-P1 (100 mg, 0.36 mmol) was dissolved in N, N-dimethylformamide (3 mL), and 1-6 (132.1 mg, 0.43 mmol), 2-(7-azobenzotriazole)-N, N, N', N'-tetramethyluronium hexafluorophosphate (205.6 mg, 0.54 mmol) and N, N-diisopropylethylamine (116.5 mg, 0.9 mmol) were added in sequence. Stir at room temperature for 1 hour. The reaction was monitored by LCMS. Water (20 mL) was added to quench and extracted with ethyl acetate (3 ⁇ 20 mL).
• Step 5 Compound 25-5 (917 mg, 4.60 mmol) was dissolved in dichloromethane (10 mL), triethylamine (1.92 mL, 13.81 mmol), 4-dimethylaminopyridine (112 mg, 0.92 mmol) and di-tert-butyl dicarbonate (1.5 g, 6.90 mmol) were added, and stirred at room temperature for 30 minutes. The reaction was monitored by LCMS. Water (10 mL) was added to quench the mixture, and the mixture was extracted with ethyl acetate (3 ⁇ 50 mL). The combined organic phase was washed with saturated sodium bicarbonate and 1% sodium bicarbonate. The mixture was washed with brine (100 mL), dried and concentrated.
• Step 2 Compound 28-1 (192 mg, 0.33 mmol) was dissolved in tetrahydrofuran (2 mL), methanol (2 mL) and water (2 mL), lithium hydroxide (120 mg, 2.86 mmol) was added, and the mixture was heated to 50°C and stirred for 16 hours. The reaction was monitored by LCMS. Hydrochloric acid (1 N) was added to adjust the pH to neutral, filtered, the filter cake was washed with methanol, and the filtrate was concentrated. The crude product was purified by reverse phase chromatography: 0%-95% acetonitrile/buffer (0.01 mol/L formic acid aqueous solution) gradient to obtain compound 28-P1.
• Step 1 Compound 16-6 (288 mg, 0.83 mmol) was dissolved in N, N-dimethylformamide (10 mL) solution, and compound 25-7 (130 mg, 0.41 mmol), 2-(7-azobenzotriazole)-N, N, N', N'-tetramethyluronium hexafluorophosphate (156.74 mg, 0.41 mmol) and N, N-diisopropylethylamine (0.14 mL, 0.82 mmol) were added, and stirred at 25 ° C for 18 hours. The reaction was monitored by LCMS. Water (30 mL) was added to the system to quench, and extracted with ethyl acetate (2 ⁇ 30 mL).
• compound 30-P2 was obtained from compound 30-2-P2.
• Step 1 Compound 31-1 (3.40 g, 14.58 mmol) and triethylamine (2.43 mL, 17.50 mmol) were dissolved in tetrahydrofuran (40 mL), and isobutyl chloroformate (2.09 mL, 16.04 mmol) was added at 0°C, and stirred for 1 hour under ice bath. Filter and concentrate, and acetonitrile (40 mL) and a hexane solution of trimethylsilylated diazomethane (36.45 mL, 72.90 mmol, 2 M) were added to the crude product in sequence, and stirred at room temperature for 17 hours. The reaction was monitored by LCMS and TLC.
• Step 2 Compound 31-2 (1.6 g, 6.22 mmol), silver benzoate (286 mg, 1.24 mmol) and triethylamine (63 mg, 0.62 mmol) were dissolved in methanol (30 mL), heated to 60 ° C and stirred for 2 hours. The reaction solution was concentrated, and the crude product was purified by silica gel chromatography: 2%-33% ethyl acetate/petroleum ether gradient to obtain compound 31-3.
• Step 3 Compound 31-3 (570 mg, 2.18 mmol) was dissolved in tetrahydrofuran (10 mL), and a hexane solution of diisobutylaluminum hydride (6.54 mL, 6.54 mmol, 1 M) was slowly added dropwise at -78 °C, and the system was moved to an ice bath and stirred for 2 hours. The reaction was monitored by LCMS and TLC. The reaction solution was quenched with water (1 mL), stirred for 0.5 hours under an ice bath, filtered, and the filtrate was concentrated to obtain compound 31-4.
• Step 4 Compound 31-4 (450 mg, 1.93 mmol) was dissolved in dichloromethane (10 mL), Dess-Martin periodinane (982 mg, 2.32 mmol) was added, stirred at room temperature for 2 hours, and the reaction was monitored by TLC. The reaction solution was filtered, the filtrate was concentrated, and the crude product was purified by silica gel chromatography: 2%-33% ethyl acetate/petroleum ether gradient to obtain compound 31-5.
• Step 8 Compound 1-6 (121 mg, 0.40 mmol) and 31-8 (145 mg, 0.40 mmol) were dissolved in N, N-dimethylformamide (3 mL), and then 2-(7-azobenzotriazole)-N, N, N', N'-tetramethyluronium hexafluorophosphate (150 mg, 0.39 mmol) and N, N-diisopropylethylamine (0.20 mL, 1.18 mmol) were added. The reaction was stirred at room temperature for 18 hours. The reaction was monitored by LCMS.
• Step 2 Compound 32-2 (1.2 g, 4.66 mmol) was dissolved in methanol (10 mL), N, N-diisopropylethylamine (1.41 g, 14 mmol) and silver benzoate (107 mg, 0.46 mmol) were added, and stirred at room temperature for 3 hours. The reaction was monitored by LCMS. Water (50 mL) was added to quench, and extracted with ethyl acetate (2x100 mL). The combined organic phase was washed with saturated brine (50 mL), dried over anhydrous sodium sulfate and concentrated.
• Step 1 Dissolve dimethylhydroxylamine hydrochloride (296 mg, 3.03 mmol) in N, N-dimethylformamide (15 mL), add 2-(7-azobenzotriazole)-N, N, N', N'-tetramethyluronium hexafluorophosphate (2.4 g, 5.48 mmol) and diisopropylethylamine (2.1 mL, 12.14 mmol) at room temperature, stir for 30 minutes, then add compound 33-1 (700 mg, 2.88 mmol), stir at room temperature for 2 hours. Monitor the reaction by LCMS and TLC.
• Step 4 Compound 33-4 (150 mg, 0.41 mmol) was dissolved in N, N-dimethylformamide (5 mL), and compound 1-6 (126 mg, 0.41 mmol), 2-(7-azobenzotriazole)-N, N, N', N'-tetramethyluronium hexafluorophosphate (236 mg, 0.62 mmol) and N, N-diisopropylethylamine (133.6 mg, 1.03 mmol) were added in sequence, and stirred at room temperature for 1 hour. The reaction was monitored by LCMS. Water (20 mL) was added to quench, and extracted with ethyl acetate (3 ⁇ 20 mL).
• Step 4 At 25°C, compound 52-4 (334 mg, 1.51 mmol) was dissolved in methanol (4 mL), compound 3-6 (350 mg, 1.21 mmol) and acetic acid (0.01 mL, 0.15 mmol) were added, and after stirring for 0.5 hours, sodium cyanoborohydride (143 mg, 2.27 mmol) was added, and stirring was continued for 2 hours. The reaction was monitored by LCMS. Concentrated, quenched by adding water (5 mL), extracted with ethyl acetate (3 ⁇ 10 mL), and the combined organic phases were washed with saturated brine (5 mL), dried and concentrated.
• Step 1 Compound 5-1 (500 mg, 1.91 mmol) was dissolved in tetrahydrofuran (10 mL), and a tetrahydrofuran solution of isopropylmagnesium chloride-lithium chloride (1.6 mL, 2.01 mmol, 1.3 M) was added dropwise at -40 °C. After stirring for 1 hour, cyclohexanone (281 mg, 2.86 mmol) was added, and the mixture was heated to 0 °C after 5 minutes and continued to stir for 2 hours. The reaction was monitored by LCMS and TLC. Water (30 mL) was added to quench the mixture, and the mixture was extracted with ethyl acetate (3 ⁇ 30 mL).

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