CN113004283A - Tetracyclic compounds as plasma kallikrein inhibitors and uses thereof - Google Patents

Tetracyclic compounds as plasma kallikrein inhibitors and uses thereof Download PDF

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CN113004283A
CN113004283A CN201911333008.9A CN201911333008A CN113004283A CN 113004283 A CN113004283 A CN 113004283A CN 201911333008 A CN201911333008 A CN 201911333008A CN 113004283 A CN113004283 A CN 113004283A
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pharmaceutically acceptable
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CN113004283B (en
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吴红丽
柯潇
强晓明
万剑飞
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Chengdu Kanghong Pharmaceutical Group Co ltd
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    • C07D471/12—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains three hetero rings
    • C07D471/14—Ortho-condensed systems

Abstract

The invention provides a tetracyclic plasma kallikrein inhibitor compound with novel structure, good activity and high selectivity, which can be widely used for preventing or treating diseases related to the activity of plasma kallikrein.

Description

Tetracyclic compounds as plasma kallikrein inhibitors and uses thereof
Technical Field
The invention relates to tetracyclic compounds with selective inhibitory activity on plasma kallikrein and uses thereof.
Background
Plasma Kallikrein (PK) is a member of the serine protease family and was first found in mammalian plasma. It is encoded by a single gene located on chromosome 4q35 (KLKB1), synthesized primarily in the liver and present in large amounts in the blood circulation in the form of plasma kallikrein (PPK), which is further activated to PK by factor XIIa cleaving its intrinsic Arg-IIe bond. PK is a key enzyme of kallikrein-kinin system (KKS), and can act on high molecular weight Kininogen (KH) to activate and release small molecular weight Bradykinin (BK), so that it can participate in biological processes such as blood coagulation, fibrinolysis, complement activation and inflammation generation by acting on bradykinin receptor.
In recent years, as the research on the genetics, the molecular science and the pharmacology of plasma kallikrein is more intensive, the physiological and pathological roles of the kallikrein are deeply understood. Research shows that the plasma kallikrein is closely related to various diseases such as inflammatory diseases, tumors, cardiovascular diseases, nephropathy, central nervous system diseases, retinopathy, diabetic retinopathy and the like. For example, Hereditary Angioedema (HAE), which is an autosomal dominant inheritance, is characterized by a decrease in the inhibitory effect of C1-INH in patients, uncontrolled activation of the KKS system, release of vasoactive substances, and increased vascular permeability leading to the typical swelling. At present, macromolecular plasma kallikrein inhibitors such as icaritin, Lanadelimumab and the like are available on the market for clinically treating hereditary angioedema, and the curative effect is remarkable. For another example, in the vitreous of the eye of diabetic macular edema patients, it is found that the KKS system is over-activated, resulting in increased retinal vascular permeability and retinal thickening. Several data have recently been published showing that plasma kallikrein inhibitors can decrease retinal vascular permeability for the treatment of diabetic retinal diseases and diabetic macular edema. At present, small molecule and polypeptide plasma kallikrein inhibitors are used for treating diabetic macular edema and enter clinical research.
However, there are many limitations to the polypeptide and small molecule plasma kallikrein inhibitors reported in the prior art. As icaritin is reported to be at risk of causing allergic reactions. And most of the small molecule plasma kallikrein inhibitors reported so far have a high polarity and ionizable guanidino or amidino functional group, which is considered to be difficult to permeate the biological membrane, resulting in very poor Oral bioavailability (Tamie j.et al, ASP-634: An Oral Drug peptide for diabetes mellitus apparatus. arvo Annual Meeting extract, March 2012, Volume 53, Issue 14). Biocryst developed the Oral plasma Kallikrein Inhibitor BCX4161(dr. philicollis et al, BCX4161, An Oral Kallikrein Inhibitor: Safety and pharmacological Results Of a Phase 1Study In health volnterers. journal Of Allergy and Clinical immunology. volume 133, Issue 2, Supplement,2014, AB39), the pharmacophore benzamidine group In its structure, which may lead to poor physicochemical properties Of the compound and thus to An impact on the bioavailability Of the drug, and therefore, it was necessary to administer larger doses up to 400mg per Clinical dose. Furthermore, the existing plasma kallikrein inhibitors also have the problem of poor selectivity for related enzymes such as KLK1, thrombin and other serine proteases. To date, no small molecule inhibitors of plasma kallikrein have been approved for marketing. Therefore, there is still a need to develop novel selective plasma kallikrein inhibitors with stronger action and less side effects.
Disclosure of Invention
The present invention relates to plasma kallikrein inhibitor compounds, pharmaceutical compositions of said compounds, pharmaceutical uses of said compounds and methods of treatment of the compounds.
In a certain aspect, the present invention provides a compound of formula (I), a pharmaceutically acceptable salt, solvate, stereoisomer, or prodrug thereof:
Figure BDA0002329350050000021
wherein the content of the first and second substances,
a is selected from an aromatic ring or a heteroaromatic ring containing 1 to 3 heteroatoms selected from N, O and S, said aromatic ring or heteroaromatic ring being optionally substituted with the following substituents: halogen, alkyl, alkoxy, haloalkyl, OH, CN, COOR1、CONR1R2、NR1R2、NR1COR2、(CH2)1-3NR1R2、(CH2)1-3OR1and-C (R)1)(R2)NH2；
Or a is selected from a fused 6, 5-or 6, 6-heteroaromatic bicyclic ring containing N and optionally another 1-2 heteroatoms independently selected from N, O and S, said heteroaromatic ring being optionally substituted with the following substituents: halogen, alkyl, alkoxy, haloalkyl, OH, CN, COOR1、CONR1R2、NR1R2、NR1COR2、(CH2)1-3NR1R2、(CH2)1-3OR1and-C (R)1)(R2)NH2；
X1Is CR5Or N; wherein R is5Selected from H, OH, halogen, alkyl, alkoxy, haloalkyl, cycloalkyl, CN, COOR1、CONR1R2、NR1R2、NR1COR2、(CH2)1-3NR1R2、(CH2)1-3OR1and-C (R)1)(R2)NH2；
L1Selected from (CR)3R4)mWherein m is 0, 1, 2;
-C-D-is selected from-NH-CH2-、-N＝CH-、-NCH3-CH2-, -NHCO-, -CH ═ CH-or-CH2-CH2-；
X2Is CH or N;
b is independently selected from H, halogen, alkyl, alkoxy, haloalkyl, OH, CN, COOR1、CONR1R2、NR1R2、NR1COR2、(CH2)1-3NR1R2、(CH2)1-3OR1and-C (R)1)(R2)NH2；
R1And R2Independently selected from H and alkyl, or R1And R2Together with the carbon to which they are attached form a cycloalkyl group;
R3and R4Independently selected from H and alkyl, or R3And R4Together with the carbon to which they are attached form a cycloalkyl group.
In another embodiment, in the compounds of formula (I), A is selected from
Figure BDA0002329350050000031
Wherein X2Is C or N, and when X2When is N, R9Is absent; r6、R7、R8、R9、R10Independently selected from H, OH, halogen, alkyl, alkoxy, haloalkyl, cycloalkyl, CN, COOR1、CONR1R2、NR1R2、NR1COR2、(CH2)1-3NR1R2、(CH2)1-3OR1and-C (R)1)(R2)NH2。
In another embodiment, in the compounds of formula (I), R8Is NH2Or C (R)1)(R2)NH2Wherein R is1And R2Independently selected from H and C1-3Alkyl of R1And R2Independently selected from H and alkyl, or R1And R2Together with the carbon to which they are attached form a cycloalkyl group.
In another embodiment, in the compounds of formula (I), R8Is NH2。
In another embodiment, in the compounds of formula (I), R8Is CH2NH2。
In another embodiment, in the compounds of formula (I), R6、R7、R9、R10Independently selected from H, halogen, alkyl, alkoxy, haloalkyl.
In another embodiment, in the compounds of formula (I), R6、R7、R9、R10Independently selected from H, halogen or CH3。
In another embodiment, in the compounds of formula (I), a is selected from:
Figure BDA0002329350050000032
in another embodiment, in the compounds of formula (I), a is selected from isoquinoline, wherein isoquinoline is optionally substituted with halogen, alkyl, alkoxy, haloalkyl, COOR1、CONR1R2、NR1R2、NR1COR2、(CH2)1-3NR1R2、(CH2)1-3OR1and-C (R)1)(R2)NH2Substitution;
R1and R2Independently selected from H and alkyl, or R1And R2Together with the carbon to which they are attached form a cycloalkyl group.
In another embodiment, in the compounds of formula (I), a is selected from isoquinolines, wherein the isoquinolines are optionally substituted with halo, alkyl, alkoxy, haloalkyl and amino.
In another embodiment, in the compounds of formula (I), a is selected from:
Figure BDA0002329350050000033
in another embodiment, in the compounds of formula (I), L1Selected from the group consisting of a bond, CH2、(CH2)2O。
In another embodiment, in the compounds of formula (I), L1Is selected from CH2。
In another embodiment, in the compounds of formula (I), X1Is CR10Wherein R is10Selected from the group consisting of H, alkyl, haloalkyl, alkoxy and (CH)2)1-3OR1。
In another embodiment, X in the compounds of formula (I)1Is CR10Wherein R is10Selected from H, CH3、CF3、CH2OCH3。
In another embodiment, in the compounds of formula (I) -C-D-is selected from the group consisting of-NH-CH2-、-N＝CH-、-NHCO-。
In another embodiment, X in the compounds of formula (I)2Is CH.
In another embodiment, the compound of formula (I) wherein B is selected from alkyl or alkoxy.
In another embodiment, the compound of formula (I) wherein B is selected from CH3Or OCH3。
In another embodiment, the compound of formula (I) is selected from:
Figure BDA0002329350050000041
a second object of the present invention is to provide a pharmaceutical composition comprising a compound according to the first object of the present invention, a pharmaceutically acceptable salt, solvate, stereoisomer or prodrug thereof, and a pharmaceutically acceptable excipient.
A third object of the present invention is to provide the use of a compound of the first object of the present invention, a pharmaceutically acceptable salt, solvate, stereoisomer or prodrug thereof, in the manufacture of a medicament for the treatment or prevention of a disease or condition in which plasma kallikrein activity is involved.
In another embodiment, the disease in which plasma kallikrein activity is implicated is inflammation.
In another embodiment, the disease in which plasma kallikrein activity is implicated is selected from the group consisting of impaired vision, diabetic retinopathy, diabetic macular edema, hereditary angioedema, diabetes, pancreatitis, cerebral hemorrhage, nephropathy, cardiomyopathy, neuropathy, inflammatory bowel disease, arthritis, septic shock, hypotension, cancer, adult respiratory distress syndrome, disseminated intravascular coagulation, cardiopulmonary bypass surgery and post-surgical hemorrhage.
In another embodiment, the disease in which plasma kallikrein activity is implicated is a retinal vascular permeability disease associated with diabetic retinopathy and diabetic macular edema.
In another embodiment, the disease in which plasma kallikrein activity is implicated is diabetic macular edema.
In another embodiment, the disease in which plasma kallikrein activity is implicated is hereditary angioedema.
The compounds of the present invention may be administered in combination with other therapeutic agents. The co-administration therapy comprises a compound of formula (I) and one or more additional therapeutic agents selected from the group consisting of: therapeutic agents that inhibit platelet derived factor (PDGF), Vascular Endothelial Growth Factor (VEGF), integrin α 5 β 1, steroids, other therapeutic agents that inhibit plasma kallikrein, and other inflammation inhibitors.
When a combination therapy is employed, the compound of the invention and the therapeutic agent of the combination may be present in the same or different pharmaceutical compositions and may be administered separately, sequentially or simultaneously.
In another aspect, the compounds of the invention may be administered in combination with laser therapy of the retina. Laser photocoagulation in combination with anti-VEGF drugs (such as ranibizumab) to treat diabetic macular edema is well known in the art and has been shown to be effective.
Definition of
As used herein, the term "alkyl" by itself or as part of another substituent means (unless otherwise specified) a saturated straight or branched chain hydrocarbon group having the specified number of carbon atoms. The method comprises the following steps: up to 10 carbon atoms (C)1-C10) Or up to 6 carbon atoms (C)1-C6) Or up to 4 carbon atoms (C)1-C4) A linear group of (a); or 3 to 10 carbon atoms (C)3-C10) Or up to 7 carbon atoms (C)3-C7) Or up to 4 carbon atoms (C)3-C4) A branched group of (2). Examples of alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, isobutyl, sec-butyl, n-pentyl, n-hexyl, n-heptyl, n-octyl.
As used herein, "alkoxy" represents the above alkyl group having the specified number of carbon atoms connected by an oxygen bridge. The method comprises the following steps: 1 to 6 carbon atoms (C)1-C6) Or1 to 4 carbon atoms (C)1-C4) A linear group of (a); -3 to 6 carbon atoms (C)3-C6) Or 3 to 4 carbon atoms (C)3-C4) A branched group of (2). Examples of alkoxy groups include, but are not limited to: methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, sec-butoxy, tert-butoxy, n-pentoxy and S-pentoxy.
As used herein, "cycloalkyl" is a monocyclic saturated hydrocarbon group of 3 to 7 carbon atoms. The cycloalkyl group may contain 3 to 7 carbon atoms or 3 to 6 carbon atoms or 3 to 5 carbon atoms or 3 to 4 carbon atoms. Examples of monocyclic cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cycloheptyl.
As used herein, "haloalkyl" is a group formed by partial or complete substitution of hydrogen atoms on an alkyl group as described above with halogen atoms; unless otherwise indicated, halogen is selected from Cl, F, Br and I.
As used herein, the term "aromatic ring" refers to a monocyclic, bicyclic, or polycyclic aromatic hydrocarbon group, e.g., benzene, naphthalene. The term "aryl" also includes rings having two or more ring systems in which two or more carbons are common to two adjoining rings (the rings are "fused rings"), wherein at least one of the rings is an aromatic hydrocarbon and the other rings can be, for example, cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heteroaryl, and/or heterocyclyl. In certain embodiments, the term "aryl" refers to a phenyl group. In certain embodiments, "aryl" has 6 to 10 carbon atoms.
As used herein, the term "heteroaromatic" refers to monocyclic, bicyclic, and polycyclic aromatic groups having from 3 to 12 total atoms in the ring structure, including one or more heteroatoms such as nitrogen, oxygen, or sulfur. Exemplary heteroaromatic groups include azaindolyl, benzo (b) thienyl, benzimidazolyl, benzofuranyl, benzoxazolyl, benzothiazolyl, benzothiadiazolyl, benzotriazolyl, benzoxazolyl, furanyl, imidazolyl, imidazopyridinyl, indolyl, indolinyl, indazolyl, isoindolinyl, isoxazolyl, isothiazolyl, isoquinolyl, oxazolyl, purinyl, pyranyl, pyrazinyl, pyrazolyl, pyridyl, pyrimidinyl, pyrrolyl, pyrrolo [2,3-d ] pyrimidinyl, pyrazolo [3,4-d ] pyrimidinyl, quinolinyl, quinazolinyl, triazolyl, thiazolyl, thienyl, tetrahydroindolyl, tetrazolyl, thiadiazolyl, thienyl, thiomorpholinyl, triazolyl, or tropanyl and the like. The term "aromatic heterocycle" also includes polycyclic ring systems having two or more rings in which two or more carbons are common to two adjoining rings (the rings are "fused rings") in which at least one of the rings is an aromatic group having one or more heteroatoms in the ring structure, e.g., the other rings can be cycloalkyls, cycloalkenyls, cycloalkynyls, aryls, heteroaryls, and/or heterocyclyls.
As used herein, "aroheterobicyclic" refers to a bicyclic aromatic group having from 3 to 12 total atoms in the ring structure, including one or more heteroatoms such as nitrogen, oxygen, or sulfur. Exemplary heteroaromatic bicyclic groups include azaindolyl, benzo (b) thienyl, benzimidazolyl, benzofuranyl, benzoxazolyl, benzothiazolyl, benzothiadiazolyl, benzotriazolyl, benzoxazolyl, imidazopyridinyl, indolyl, indolinyl, indazolyl, isoindolinyl, isoxazolyl, isothiazolyl, isoquinolyl, pyrrolo [2,3-d ] pyrimidinyl, pyrrolo [2,3-b ] pyridine, pyrazolo [3,4-d ] pyrimidinyl, quinolinyl, quinazoline, and the like. The term "aromatic heterocycle" also includes polycyclic ring systems having two or more rings in which two or more carbons are common to two adjoining rings (the rings are "fused rings") in which at least one of the rings is an aromatic group having one or more heteroatoms in the ring structure, e.g., the other rings can be cycloalkyls, cycloalkenyls, cycloalkynyls, aryls, heteroaryls, and/or heterocyclyls.
As used herein, the term "substituted" means that any one or more hydrogen atoms on a particular atom is replaced with a substituent, and may include variations of deuterium and hydrogen, so long as the valency of the particular atom is normal and the substituted compound is stable. When the substituent is a carbonyl group (i.e., ═ O), it means that two hydrogen atoms are substituted. Carbonyl substitution does not occur on aromatic groups. The term "optionally substituted with the following substituents" means that it may or may not be substituted, and unless otherwise specified, the kind and number of the substituents may be arbitrary on the basis of chemical realizability.
As used herein, a wavy line intersecting a bond in a chemical structure indicates the point of attachment of the bond, which wavy bond in the chemical structure intersects the rest of the molecule.
As used herein, the dashed line in the chemical structure represents an optional double bond.
As used herein, "pharmaceutically acceptable salts" include salts derived from inorganic or organic acids including, but not limited to, hydrochloric, hydrobromic, sulfuric, nitric, perchloric, phosphoric, formic, acetic, lactic, maleic, fumaric, succinic, tartaric, glycolic, salicylic, citric, methanesulfonic, benzenesulfonic, benzoic, malonic, trifluoroacetic, trichloroacetic, naphthalene-2-sulfonic and other acids. Pharmaceutically acceptable salts include those in which the compound base to salt molar ratio is other than 1: 1. As an example, the salt may comprise two molecules of organic or inorganic acid per molecule of base. As another example, the salt may comprise 1/2 molecules of organic or inorganic acid per molecule of base.
As used herein, "solvate" refers to a physical association of a compound of the present application with one or more solvent molecules; this physical association involves various degrees of ionic and covalent bonding, including hydrogen bonding; in certain cases, such as when one or more solvent molecules are introduced into the crystal lattice of a crystalline solid, the solvate will be able to be isolated; "solvate" encompasses both solution phase and isolatable solvates; non-limiting examples of suitable solvents include, but are not limited to, isopropanol, ethanol, methanol, DMSO, ethyl acetate, acetic acid, and ethanolamine, and the like; "hydrate" is where the solvent molecule is H2A solvate of O.
Unless otherwise specified, structures depicted herein are also meant to include all isomeric (e.g., enantiomeric, diastereomeric, and geometric (or conformational) forms of the structure; for example, the R and S configurations of each asymmetric center, (Z) and (E) double bond isomers, and (Z) and (E) conformational isomers. Thus, single stereochemical isomers as well as enantiomeric, diastereomeric, and geometric (or conformational) mixtures of these compounds are within the scope of the invention. Unless otherwise specified, all tautomeric forms of the compounds of the invention are within the scope of the invention.
The present invention includes all pharmaceutically acceptable isotopically-labelled compounds, i.e. compounds of formula (I) wherein one or more atoms are replaced by an atom having the same atomic number, but typically a different atomic mass or mass number than that naturally occurring. Examples of suitable isotopes in the compounds of the invention include, but are not limited to: isotopes of hydrogen, e.g.2H and3h; isotopes of carbon, e.g.11C、13C and14c; isotopes of chlorine, e.g.36Cl; isotopes of fluorine, e.g.18F; isotopes of iodine, e.g.123I and125i; isotopes of nitrogen, e.g.13N and15n; isotopes of oxygen, e.g.15O、17O and18o; isotopes of phosphorus, e.g.32P; and isotopes of sulfur, e.g.35S。
As used herein, "prodrug" refers to a compound that is convertible in vivo by metabolic means (e.g., by hydrolysis, reduction, or oxidation) to a compound of the invention.
The term "pharmaceutically acceptable carrier" refers to any formulation or carrier medium capable of delivering an effective amount of an active compound of the present invention without interfering with the biological activity of the active compound and without toxic side effects to the host or patient, including any solvent, dispersion medium, coating material, surfactant, antioxidant, preservative (e.g., antibacterial, antifungal), isotonic agent, absorption delaying agent, salt, preservative, drug stabilizer, binder, excipient, disintegrant, lubricant, sweetener, flavoring agent, dye, and the like, and combinations thereof, known to one of ordinary skill in the art
The term "excipient" is used herein to describe any ingredient other than a compound of the invention which may impart functionality (e.g., drug release rate control) and/or non-functionality (e.g., processing aids or diluents) to the formulation. The choice of excipient will depend largely on factors such as the particular mode of administration, the effect of the excipient on solubility and stability, and the nature of the dosage form. Exemplary excipients may include, but are not limited to, one or more of buffering agents, stabilizing agents, surfactants, wetting agents, lubricants, emulsifiers, suspending agents, preservatives, antioxidants, opacifiers, glidants, processing aids, colorants, sweeteners, fragrances, flavoring agents, diluents, and other known additives.
The compounds of the present invention may be administered in any convenient form of use, such as tablets, powders, capsules, solutions, dispersions, suspensions, syrups, sprays, suppositories, gels, emulsions, patches and the like. Such compositions may contain ingredients conventional in pharmaceutical formulations, such as diluents, carriers, pH adjusting agents, sweeteners, fillers and additional active agents. The active compounds of the present invention may also be formulated in sustained release dosage forms.
The compounds of the invention may be administered by any suitable means, including oral, topical (including buccal and sublingual), rectal, vaginal, transdermal, parenteral, subcutaneous, intraperitoneal, intrapulmonary, intradermal, intrathecal and epidural and intranasal, and, if desired for topical treatment, intralesional administration. Parenteral infusion includes intramuscular, intravenous, intraarterial, intraperitoneal, intracerebral, intraocular, intralesional or subcutaneous administration.
For the treatment of conditions such as retinal vascular permeability diseases associated with diabetic retinopathy and diabetic macular edema, the compounds of the present invention may be administered in a form suitable for injection into the interior region of the eye of a patient, particularly, for intravitreal injection.
The term "therapeutically effective amount" of a compound of the present invention refers to an amount of a compound of the present invention that elicits a biological or medical response in a patient, such as reducing or inhibiting enzyme or protein activity or ameliorating a symptom, alleviating a condition, slowing or delaying disease progression or preventing a disease, and the like. In one non-limiting embodiment, the term "therapeutically effective amount" means an amount of a compound of the invention that is capable of at least partially reducing or inhibiting plasma kallikrein activity when administered to a cell or tissue or to a non-cellular biological substance or medium; or at least partially reducing or inhibiting plasma kallikrein expression. The therapeutically effective dose of the compound, pharmaceutical composition or combination will depend on the species, weight, age and individual condition of the patient, the disease or disorder, or the severity of the condition requiring treatment. It is understood that the total daily amount of the compounds and compositions of the present invention will be determined by the attending physician within the scope of sound medical judgment.
The compounds were named manually or by Chemdraw software and the commercially available compounds were given the supplier catalog name.
Compared with the prior art, the invention has the main advantages that:
provides a series of tetracyclic plasma kallikrein inhibitor compounds with novel structure, good activity and high selectivity, and can be widely used for preventing or treating diseases related to the activity of plasma kallikrein.
Detailed Description
The invention will be further illustrated with reference to the following specific examples. It should be understood that these examples are for illustrative purposes only and are not intended to limit the scope of the present invention. The experimental procedures, in which specific conditions are not noted in the following examples, are generally carried out according to conventional conditions or according to conditions recommended by the manufacturers. The chemical reactions described in the examples (preparations) can be readily modified to prepare a number of other compounds of the invention, and alternative methods for preparing the compounds of the invention are considered to be within the scope of the invention. Unless otherwise defined, terms used herein have the same meaning as those familiar to those skilled in the art. In addition, any methods and materials similar or equivalent to those described herein can be used in the present invention.
Example 1
N- ((6-amino-2, 4-dimethylpyridin-3-yl) methyl) -9-methoxy-12, 13-dihydro-5H-imidazo [1,2-a]Naphthalene [2,3-e][1,4]Diaza derivatives
Figure BDA0002329350050000091
-2-carboxamides
Figure BDA0002329350050000092
Step a): preparation of ethyl 2-amino-2- (hydroxyimino) acetate
Slowly adding water (110mL) into a mixed solution of ethyl cyanoformate (30.0g, 0.303mol), hydroxylamine hydrochloride (31.6g, 0.455mol) and sodium carbonate (80.3g, 0.758mol) in ethanol (200mL), stirring the reaction solution at 20 ℃ to react for 10h, evaporating the solvent under reduced pressure after the reaction is finished, extracting the residue with ethyl acetate (200mL multiplied by 3), combining organic layers, drying with anhydrous sodium sulfate, filtering, evaporating the filtrate under reduced pressure to dryness to obtain ethyl 2-amino-2- (hydroxyimino) acetate with the yield of 65.0%,1HNMR(400MHz,DMSO-d6)δ10.66-9.12(m,1H),5.79-5.31(m,2H),4.07-3.97(m,2H),1.18-1.13(m,3H)，ESI-MS(m/z)：133.2[M+H]+。
step b): preparation of tert-butyl 3- (((1-amino-2-ethoxy-2-oxyethylene) amino) oxy) acrylate
Ethyl 2-amino-2- (hydroxyimino) acetate (9.0g,68.120mmol), tert-butyl propiolate (8.59g, 68.120mmol), triethylamine (10.4mL, 74.932mmol) and ethanol (90mL) were added to a reaction flask, stirred at 35 ℃ for reaction for 10h, after the reaction was completed, the solvent was evaporated under reduced pressure, the residue was diluted with water (150mL), extracted with ethyl acetate (150 mL. times.3), the organic layers were combined, washed with saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, filtered, the filtrate was evaporated to dryness under reduced pressure, and the crude product was purified by silica gel column chromatography (eluent: petroleum ether/ethyl acetate 3/1) to give tert-butyl 3- (((1-amino-2-ethoxy-2-oxyethylene) amino) oxy) acrylate in 62.5% yield,1H NMR(400MHz,CDCl3)δ7.85(d,J＝12.4Hz,1H),5.56(d,J＝12.4Hz,1H),5.37(br s,2H),4.39(q,J＝7.2Hz,2H),1.47(s,9H),1.42-1.37(m,3H)，ESI-MS(m/z)：297.2[M+K]+。
step c): preparation of 1H-imidazole-2-carboxylic acid ethyl ester-4-carboxylic acid tert-butyl ester
Adding tert-butyl 3- (((1-amino-2-ethoxy-2-oxyethylene) amino) oxy) acrylate (2.0g, 7.744mmol) and xylene (15mL) into a reaction flask, microwave reacting at 155 ℃ for 3h, after the reaction is finished, evaporating the solvent under reduced pressure, purifying the residue by silica gel column chromatography (eluent: petroleum ether/ethyl acetate 3/1) to obtain yellow solid with the yield of 89.2%,1H NMR(400MHz,CDCl3) δ 7.85-7.57(m,1H),4.41-4.32(m,2H),1.51(d, J ═ 2.4Hz,9H),1.38-1.32(m, 3H). Step d): preparation of 6-methoxy-3-nitro-2-naphthoic acid
Adding ethyl 3-nitropropionate (7.2g, 48.733mmol) and absolute ethanol (25mL) into a reaction bottle, slowly dropwise adding 20% sodium ethoxide ethanol solution (20.7mL, 60.916mmol) at 0 ℃, maintaining the reaction solution at 0-5 ℃, adding ethanol suspension of 4-methoxy-phthalaldehyde (5.0g, 30.458mmol), naturally heating to room temperature for reaction for 16h, pouring into ice water after the reaction is finished, stirring for reaction for 1h, regulating the pH value to be 4 with acetic acid, filtering, washing filter cakes with appropriate amount of water and ethanol respectively, and drying under reduced pressure and vacuum, purifying the obtained solid by preparative HPLC to obtain 6-methoxy-3-nitro-2-naphthoic acid with the yield of 40.3%; ESI-MS (m/z): 248.1[ M + H]+。
Step e): preparation of (6-methoxy-3-nitronaphthalen-2-yl) methanol
At 0 ℃ adding BH3THF (16.18mL, 16.180mmol) was added dropwise to a tetrahydrofuran (20mL) solution of 6-methoxy-3-nitro-2-naphthoic acid (2.0g, 8.090mmol) and reacted at room temperature for 5h, quenched with methanol (200mL) and concentrated under reduced pressure to give (6-methoxy-3-nitronaphthalen-2-yl) methanol, which was used in the next step without purification; ESI-MS (m/z): 234.1[ M + H]+. Step f): (6-methoxy-3-nitronaphthalen-2-yl) methanol methanesulfonate
Methanesulfonyl chloride (0.5mL, 6.432mmol) was added dropwise to a solution of (6-methoxy-3-nitronaphthalen-2-yl) methanol (1.0g, 4.288mmol) and triethylamine (1.2mL, 8.576mmol) in dichloromethane (20mL) to react at 40 ℃ for 8h, after the reaction was completed, the reaction solution was poured into ice water (50mL), extracted with dichloromethane (50 mL. times.3), the organic layers were combined, washed with a saturated aqueous sodium chloride solution (80 mL. times.2), dried over anhydrous sodium sulfate, filtered, and the filtrate was evaporated to dryness under reduced pressure to give (6-methoxy-3-nitronaphthalen-2-yl) methanol methanesulfonate, which was used in the next reaction without purification.
Step g): preparation of 4- (tert-butyl) 2-ethyl 1- ((6-methoxy-3-nitronaphthalen-2-yl) methyl) -1H-imidazole-2, 4-dicarboxylic acid
Adding (6-methoxy-3-nitronaphthalen-2-yl) methanol methanesulfonate (1.0g, 3.212mmol), ethyl 1H-imidazole-2-carboxylate-4-carboxylic acid tert-butyl ester (735mg, 3.059mmol), potassium carbonate (676mg, 4.894mmol) and acetonitrile (20mL) into a reaction flask, stirring at 50 ℃ for reaction for 5H, evaporating the solvent under reduced pressure after the reaction is finished, adding water (10mL) into the residue, diluting the residue, extracting with ethyl acetate (20mL multiplied by 3), combining organic layers, washing with saturated aqueous sodium chloride (20mL), drying with anhydrous sodium sulfate, filtering, evaporating the filtrate under reduced pressure, purifying the obtained crude product by silica gel column chromatography (eluent: petroleum ether/ethyl acetate ═ 2/1) to obtain 4- (tert-butyl) 2-ethyl 1- ((6-methoxy-3-nitronaphthalen-2-yl) methyl) -1H-imidazole- 2, 4-dicarboxylic acid, yield 45.9%, ESI-MS (m/z): 456.2[ M + H]+。
Step h): preparation of 4- (tert-butyl) 2-ethyl 1- ((3-amino-6-methoxy-2-yl) methyl) -1H-imidazole-2, 4-dicarboxylic acid
Zinc powder (862mg, 13.173mmol) was added to 4- (tert-butyl) 2-ethyl 1- ((6-methoxy-3-nitronaphthalen-2-yl) methyl) -1H-imidazole-2, 4-dicarboxylic acid (g-l) at 25 ℃ ((600mg, 1.317mmol) and ammonium chloride (705mg, 13.173mmol) in ethanol (20mL) at 25 ℃ for 4h, after completion of the reaction, filtration, concentration of the filtrate under reduced pressure, and purification of the resulting crude product by silica gel column chromatography (eluent: petroleum ether/ethyl acetate 1/1) to give 4- (tert-butyl) 2-ethyl 1- ((3-amino-6-methoxy-2-yl) methyl) -1H-imidazole-2, 4-dicarboxylic acid in 56.1% yield; ESI-MS (m/z): 426.3[ M + H]+。
Step i): 9-methoxy-13-oxo-12, 13-dihydro-5H-imidazo [1,2-a ]]Naphthalene [2,3-e][1,4]Diaza derivatives
Figure BDA0002329350050000111
Preparation of tert-butyl (2-carboxylate)
Adding 4- (tert-butyl) 2-ethyl 1- ((3-amino-6-methoxy-2-yl) methyl) -1H-imidazole-2, 4-dicarboxylic acid (250mg, 0.588mmol), potassium tert-butoxide (82mg, 0.735mmol) and DMF (5mL) into a reaction flask, stirring at 25 ℃ for reaction for 8H, after the reaction is finished, adding water (20mL) for quenching, extracting with ethyl acetate (20mL multiplied by 4), combining organic layers, washing with saturated sodium chloride aqueous solution (10mL), drying with anhydrous sodium sulfate, filtering, evaporating the filtrate under reduced pressure to dryness to obtain a white solid, obtaining the crude product yield of 67.2%, and directly using the crude product in the next reaction without purification; ESI-MS (m/z): 380.2[ M + H]+。
Step j): 9-methoxy-12, 13-dihydro-5H-imidazo [1,2-a ]]Naphthalene [2,3-e][1,4]Diaza derivatives
Figure BDA0002329350050000112
Preparation of tert-butyl (2-carboxylate)
At 0 ℃ adding BH3THF (1.58mL, 1.581mmol) is added dropwise to 9-methoxy-13-oxo-12, 13-dihydro-5H-imidazo [1,2-a ]]Naphthalene [2,3-e][1,4]Diaza derivatives
Figure BDA0002329350050000113
-tert-butyl 2-carboxylate (120mg, 0.316mmol) in tetrahydrofuran (2mL) at 50 ℃ for 2h, quenched with methanol (5mL), and concentrated under reduced pressure to give a tan solid which is used in the next step without purification; ESI-MS (m/z): 366.2[ M + H]+。
Step k): 9-methoxy-12, 13-diHydrogen-5H-imidazole [1,2-a ]]Naphthalene [2,3-e][1,4]Diaza derivatives
Figure BDA0002329350050000114
Preparation of (E) -2-carboxylic acid
Mixing 9-methoxy-12, 13-dihydro-5H-imidazole [1,2-a ]]Naphthalene [2,3-e][1,4]Diaza derivatives
Figure BDA0002329350050000115
Adding tert-butyl-2-formate (80mg, 0.219mmol) and 8N hydrochloric acid (1mL) into a reaction flask, heating to 45 ℃ for reaction for 2H, evaporating the solvent under reduced pressure after the reaction is finished, and purifying by preparative HPLC to obtain 9-methoxy-12, 13-dihydro-5H-imidazole [1,2-a ]]Naphthalene [2,3-e][1,4]Diaza derivatives
Figure BDA0002329350050000116
-2-carboxylic acid, yield 75.1%; ESI-MS (m/z): 310.2[ M + H]+。
Step l): n- ((6-amino-2, 4-dimethylpyridin-3-yl) methyl) -9-methoxy-12, 13-dihydro-5H-imidazo [1,2-a]Naphthalene [2,3-e][1,4]Diaza derivatives
Figure BDA0002329350050000117
Preparation of (E) -2-carboxamides
Mixing 9-methoxy-12, 13-dihydro-5H-imidazole [1,2-a ]]Naphthalene [2,3-e][1,4]Diaza derivatives
Figure BDA0002329350050000123
-2-carboxylic acid (50mg, 0.162mmol), 5- (aminomethyl) -4, 6-dimethylpyridine-2-diamine dihydrochloride (40mg, 0.178mmol), HBTU (92mg, 0.243mmol), triethylamine (0.07mL, 0.486mmol) and DMF (1mL) were added to a reaction flask, stirred at room temperature for 5H, after the reaction was completed, concentrated under reduced pressure, and the residue was purified by preparative HPLC to give N- ((6-amino-2, 4-dimethylpyridin-3-yl) methyl) -9-methoxy-12, 13-dihydro-5H-imidazo [1,2-a ] -N]Naphthalene [2,3-e][1,4]Diaza derivatives
Figure BDA0002329350050000124
-2-formamide, yield 52.3%; ESI-MS (m/z): 443.3[ M + H]+。
Example 2
N- ((1-aminoisoquinolin-6-yl) methyl) -9-methoxy-12, 13-dihydro-5H-imidazo [1,2-a [ ]]Naphthalene [2,3-e][1,4]Diaza derivatives
Figure BDA0002329350050000125
Preparation of (E) -2-carboxamides
Figure BDA0002329350050000121
The procedure is as in example 1, except that 5- (aminomethyl) -4, 6-dimethylpyridine-2-diamine dihydrochloride is replaced in step l by 6- (aminomethyl) isoquinolin-1-amine to give N- ((1-aminoisoquinolin-6-yl) methyl) -9-methoxy-12, 13-dihydro-5H-imidazo [1,2-a ] amine]Naphthalene [2,3-e][1,4]Diaza derivatives
Figure BDA0002329350050000126
-2-carboxamide; ESI-MS (m/z): 465.3[ M + H]+。
Example 3
N- ((1-amino-7-methoxyisoquinolin-6-yl) methyl) -9-methoxy-12, 13-dihydro-5H-imidazo [1, 2-a)]Naphthalene [2,3-e][1,4]Diaza derivatives
Figure BDA0002329350050000127
Preparation of (E) -2-carboxamides
Figure BDA0002329350050000122
The procedure is as in example 1, except that 5- (aminomethyl) -4, 6-dimethylpyridine-2-diamine dihydrochloride is replaced in step l by 6- (aminomethyl) -methoxyisoquinolin-1-amine to give N- ((1-amino-7-methoxyisoquinolin-6-yl) methyl) -9-methoxy-12, 13-dihydro-5H-imidazo [1, 2-a)]Naphthalene [2,3-e][1,4]Diaza derivatives
Figure BDA0002329350050000128
-2-carboxamide; ESI-MS (m/z): 495.2[ M + H]+。
Example 4
N- (4- (Ammonia)Methyl) benzyl) -9-methoxy-12, 13-dihydro-5H-imidazo [1,2-a]Naphthalene [2,3-e][1,4]Diaza derivatives
Figure BDA0002329350050000129
Preparation of (E) -2-carboxamides
Figure BDA0002329350050000131
Step a): (4- ((9-methoxy-12, 13-dihydro-5H-imidazo [1, 2-a)]Naphthalene [2,3-e][1,4]Diaza derivatives
Figure BDA0002329350050000133
Preparation of tert-butyl (2-carboxamide) methyl) benzyl) carbamate
Mixing 9-methoxy-12, 13-dihydro-5H-imidazole [1,2-a ]]Naphthalene [2,3-e][1,4]Diaza derivatives
Figure BDA0002329350050000134
Adding 100mg, 0.323mmol of-2-formic acid, 115mg, 0.485mmol of tert-butyl (4- (aminomethyl) benzyl) carbamate, 184mg, 0.485mmol of HBTU and 3mL of DMF (dimethyl formamide) into a reaction flask, stirring at room temperature for reaction for 5 hours, after the reaction is finished, adding water (20mL) into the reaction solution for dilution, extracting with ethyl acetate (20mL multiplied by 2), combining organic layers, washing with a saturated sodium chloride aqueous solution (10mL multiplied by 2), drying with anhydrous sodium sulfate, filtering, and concentrating the filtrate under reduced pressure to obtain a white solid which is directly used for the next reaction without purification; ESI-MS (m/z): 528.3[ M + H]+。
Step b): n- (4- (aminomethyl) benzyl) -9-methoxy-12, 13-dihydro-5H-imidazo [1,2-a]Naphthalene [2,3-e][1,4]Diaza derivatives
Figure BDA0002329350050000135
Preparation of (E) -2-carboxamides
Mixing (4- ((9-methoxy-12, 13-dihydro-5H-imidazo [1, 2-a))]Naphthalene [2,3-e][1,4]Diaza derivatives
Figure BDA0002329350050000136
-2-carboxamide) methyl) benzyl) carbamic acid tert-butyl ester (100mg, 0.190mmol) and hydrochloric acid (5mL,6N) were addedStirring at room temperature in a reaction bottle for reaction for 1H, concentrating under reduced pressure after the reaction is finished, and purifying the obtained crude product by preparative HPLC to obtain N- (4- (aminomethyl) benzyl) -9-methoxy-12, 13-dihydro-5H-imidazole [1,2-a]Naphthalene [2,3-e][1,4]Diaza derivatives
Figure BDA0002329350050000137
-2-formamide, yield 31.9%; ESI-MS (m/z): 428.3[ M + H]+。
Example 5
N- ((6-amino-2, 4-dimethylpyridin-3-yl) methyl) -9-methoxy-5H-imidazo [1,2-a]Naphthalene [2,3-e][1,4]Diaza derivatives
Figure BDA0002329350050000138
Preparation of (E) -2-carboxamides
Figure BDA0002329350050000132
Step a): 9-methoxy-5H-imidazo [1,2-a ]]Naphthalene [2,3-e][1,4]Diaza derivatives
Figure BDA0002329350050000139
Preparation of (E) -2-carboxylic acid
Mixing 9-methoxy-12, 13-dihydro-5H-imidazole [1,2-a ]]Naphthalene [2,3-e][1,4]Diaza derivatives
Figure BDA00023293500500001310
-2-carboxylic acid (200mg, 0.647mmol), MnO2(562mg, 6.466mmol) and dichloroethane (2mL) are added into a reaction flask, the temperature is raised to 65 ℃ for reaction for 5H, after the reaction is finished, filtration and reduced pressure concentration are carried out, the obtained crude product is purified by preparative HPLC, and 9-methoxy-5H-imidazole [1,2-a ] is obtained]Naphthalene [2,3-e][1,4]Diaza derivatives
Figure BDA0002329350050000142
-2-carboxylic acid, yield 51.9%; ESI-MS (m/z): 308.2[ M + H]+。
Step b): n- ((6-amino-2, 4-dimethylpyridin-3-yl) methyl) -9-methoxy-5H-imidazo [1,2-a]Naphthalene [2,3-e][1,4]Diaza derivatives
Figure BDA0002329350050000143
Preparation of (E) -2-carboxamides
With 9-methoxy-5H-imidazole [1,2-a ]]Naphthalene [2,3-e][1,4]Diaza derivatives
Figure BDA0002329350050000144
The operation procedure of using-2-carboxylic acid as a raw material and using step l in example 1 was the same as that of N- ((6-amino-2, 4-dimethylpyridin-3-yl) methyl) -9-methoxy-5H-imidazo [1, 2-a-]Naphthalene [2,3-e][1,4]Diaza derivatives
Figure BDA0002329350050000145
-2-carboxamide, yield 38.4%; ESI-MS (m/z): 441.2[ M + H]+。
Example 6
N- ((6-amino-2, 4-dimethylpyridin-3-yl) methyl) -9-methoxy-13-oxo-12, 13-dihydro-5H-imidazo [1,2-a]Naphthalene [2,3-e][1,4]Diaza derivatives
Figure BDA0002329350050000146
Preparation of (E) -2-carboxamides
Figure BDA0002329350050000141
Step a): 9-methoxy-13-oxo-12, 13-dihydro-5H-imidazo [1,2-a ]]Naphthalene [2,3-e][1,4]Diaza derivatives
Figure BDA0002329350050000147
Preparation of (E) -2-carboxylic acid
Mixing 9-methoxy-13-oxo-12, 13-dihydro-5H-imidazole [1,2-a ]]Naphthalene [2,3-e][1,4]Diaza derivatives
Figure BDA0002329350050000148
Adding tert-butyl-2-formate (300mg, 0.790mmol) and 5N hydrochloric acid (0.6mL) into a reaction bottle, heating to 50 ℃ for reaction for 5 hours, and after the reaction is finished, evaporating under reduced pressure to remove the solvent, wherein the obtained crude product is directly used for the next reaction, and the yield is 85.0%; ESI-MS (m/z): 324.1[ M + H]+. Step b): n- ((6-amino-2, 4-dimethyl)Pyridin-3-yl) methyl) -9-methoxy-13-oxo-12, 13-dihydro-5H-imidazo [1,2-a]Naphthalene [2,3-e][1,4]Diaza derivatives
Figure BDA0002329350050000149
Preparation of (E) -2-carboxamides
Mixing 9-methoxy-13-oxo-12, 13-dihydro-5H-imidazole [1,2-a ]]Naphthalene [2,3-e][1,4]Diaza derivatives
Figure BDA00023293500500001410
-2-carboxylic acid (200mg, 0.619mmol), 5- (aminomethyl) -4, 6-dimethylpyridine-2-diamine (103mg, 0.681mmol), HATU (306mg, 0.805mmol), triethylamine (0.13mL, 0.928mmol) and DMF (4mL) were added to a reaction flask, stirred at room temperature for reaction for 6H, after the reaction was complete, concentrated under reduced pressure and the residue was purified by preparative HPLC to give N- ((6-amino-2, 4-dimethylpyridin-3-yl) methyl) -9-methoxy-13-oxo-12, 13-dihydro-5H-imidazo [1,2-a ] N- ((6-amino-2, 4-dimethylpyridin-3-yl) methyl) -9-methoxy-13-oxo-12, 13-dihydro-5H]Naphthalene [2,3-e][1,4]Diaza derivatives
Figure BDA00023293500500001411
-2-formamide, yield 36.8%; ESI-MS (m/z): 457.2[ M + H]+。
Example 7
N- ((6-amino-2, 4-dimethylpyridin-3-yl) methyl) -9-methoxy-12, 13-dihydro-5H-naphthalene [2,3-e]Pyrrole [1,2-a ]][1,4]Diaza derivatives
Figure BDA00023293500500001412
Preparation of (E) -2-carboxamides
Figure BDA0002329350050000151
Step a-d): 9-methoxy-12, 13-dihydro-5H-naphthalene [2,3-e ]]Pyrrole [1,2-a ]][1,4]Diaza derivatives
Figure BDA0002329350050000152
Preparation of ethyl (E) -2-carboxylate
Starting from (6-methoxy-3-nitronaphthalen-2-yl) methanol methanesulfonate and ethyl 1H-pyrrole-2, 4-dicarboxylate, the other operations have been carried outThe procedure is as in example 1, step g-j, to give 9-methoxy-12, 13-dihydro-5H-naphthalene [2,3-e ]]Pyrrole [1,2-a ]][1,4]Diaza derivatives
Figure BDA0002329350050000153
-2-carboxylic acid tert-ethyl ester; ESI-MS (m/z): 337.2[ M + H]+。
Step e): 9-methoxy-12, 13-dihydro-5H-naphthalene [2,3-e ]]Pyrrole [1,2-a ]][1,4]Diaza derivatives
Figure BDA0002329350050000154
Preparation of (E) -2-carboxylic acid
Reacting LiOH2O (25mg, 0.594mmol) in water (1mL) was added 9-methoxy-12, 13-dihydro-5H-naphthalene [2,3-e ]]Pyrrole [1,2-a ]][1,4]Diaza derivatives
Figure BDA0002329350050000155
Reacting ethyl-2-carboxylate (100mg, 0.297mmol) in methanol (1 mL)/tetrahydrofuran (1mL) at 25 ℃ for 8H, freeze-drying the reaction solution after the reaction is finished, dissolving the obtained solid in dichloromethane/methanol mixed solution (10mL, 1:1), filtering to remove insoluble substances, and concentrating the filtrate under reduced pressure to obtain 9-methoxy-12, 13-dihydro-5H-naphthalene [2,3-e ]]Pyrrole [1,2-a ]][1,4]Diaza derivatives
Figure BDA0002329350050000156
-2-carboxylic acid; ESI-MS (m/z): 309.2[ M + H]+。
Step f): n- ((6-amino-2, 4-dimethylpyridin-3-yl) methyl) -9-methoxy-12, 13-dihydro-5H-naphthalene [2,3-e]Pyrrole [1,2-a ]][1,4]Diaza derivatives
Figure BDA0002329350050000157
Preparation of (E) -2-carboxamides
With 9-methoxy-12, 13-dihydro-5H-naphthalene [2,3-e ]]Pyrrole [1,2-a ]][1,4]Diaza derivatives
Figure BDA0002329350050000158
Using (E) -2-carboxylic acid and 5- (aminomethyl) -4, 6-lutidine-2-diamine as starting materials, the procedure was as in step b of example 6 to give N- ((6-amino-2, 4-lutidin-3-yl) methyl) -9-methoxy-12, 13-dihydro-5H-naphthalene [2,3-e]Pyrrole [1,2-a ]][1,4]Diaza derivatives
Figure BDA0002329350050000159
-2-carboxamide; ESI-MS (m/z): 442.3[ M + H]+。
Example 8
N- ((6-amino-2, 4-dimethylpyridin-3-yl) methyl) -9-methyl-12, 13-dihydro-5H-imidazo [1',2':1, 2)][1,4]Diaza derivatives
Figure BDA00023293500500001510
[6,5-g]Preparation of quinoline-2-carboxamides
Figure BDA0002329350050000161
Step a): preparation of methyl 2- ((((9H-fluoren-9-yl) methoxy) carbonyl) amino) -4-nitrobenzoate
Adding 2-amino-4-nitrobenzoic acid methyl ester (10.0g, 50.979mmol) and dioxane (150mL) into a reaction bottle, uniformly stirring, adding an aqueous solution (35mL) of sodium bicarbonate (21.4g, 254.895mmol), adding chloroformic acid-9-fluorenylmethyl ester (Fmoc-Cl, 14.5g, 56.077mmol), stirring at room temperature for 24 hours after the addition is finished, concentrating under reduced pressure after the reaction is finished, and purifying the obtained crude product by silica gel column chromatography (eluent: petroleum ether/ethyl acetate ═ 6/1) to obtain 2- ((((9H-fluoren-9-yl) methoxy) carbonyl) amino) -4-nitrobenzoic acid methyl ester with the yield of 78.0%; ESI-MS (m/z): 419.2[ M + H]+。
Step b): preparation of methyl 2- ((((9H-fluoren-9-yl) methoxy) carbonyl) amino) -4-aminobenzoate
Adding zinc powder (23.4g, 358.500mmol) into a mixed solution of 2- ((((9H-fluorene-9-yl) methoxy) carbonyl) amino) -4-nitrobenzoic acid methyl ester (15.0g, 35.850mmol) and ammonium chloride (19.2g, 358.500mmol) in ethanol (150mL) at 25 ℃, continuing stirring and reacting for 10H at 25 ℃, filtering after the reaction is finished, concentrating the filtrate under reduced pressure, purifying the obtained crude product by silica gel column chromatography (eluent: dichloromethane/methanol ═ 10/1) to obtain 2- (((9H-fluorene-9-yl) methoxy) carbonyl) amino) -4-aminobenzoic acid methyl ester, and collecting the methyl 2- (((9H-fluorene-9-yl) methoxy) carbonyl) amino) -4-aminobenzoateThe rate is 58.2%; ESI-MS (m/z): 389.2[ M + H]+。
Step c): preparation of 7- ((((9H-fluoren-9-yl) methoxy) carbonyl) amino) -2-methylquinoline-6-carboxylic acid
Slowly adding 2-butenal (1.62g, 23.171mmol) into a hydrochloric acid solution (40mL) of methyl 2- ((((9H-fluorene-9-yl) methoxy) carbonyl) amino) -4-nitrobenzoate (7.5g, 19.309mmol) under a reflux condition, heating to reflux for 2H after the addition is finished, cooling to room temperature after the reaction is finished, concentrating under reduced pressure, washing residual solids with a proper amount of diethyl ether, and drying under reduced pressure and vacuum to obtain 7- (((9H-fluorene-9-yl) methoxy) carbonyl) amino) -2-methylquinoline-6-formic acid which can be directly used for the next reaction without purification; ESI-MS (m/z): 425.2[ M + H]+。
Step d): preparation of (9H-fluoren-9-yl) methyl (6- (hydroxymethyl) -2-methylquinolin-7-yl) carbamate
At 0 ℃ adding BH3THF (28.3mL, 28.272mmol) was added dropwise to a solution of 7- ((((9H-fluoren-9-yl) methoxy) carbonyl) amino) -2-methylquinoline-6-carboxylic acid (4.0g, 9.424mmol) in tetrahydrofuran (40mL) and reacted at room temperature for 5H, methanol (300mL) was added and quenched, concentrated under reduced pressure, and the resulting crude product was purified by silica gel column chromatography (eluent: petroleum ether/ethyl acetate ═ 3/1) to give (9H-fluoren-9-yl) methyl (6- (hydroxymethyl) -2-methylquinolin-7-yl) carbamate in 81.6% yield; ESI-MS (m/z): 411.2[ M + H]+。
Step e): preparation of methyl (7- ((((9H-fluoren-9-yl) methoxy) carbonyl) amino) -2-methylquinolin-6-yl) methyl methanesulfonate
Methanesulfonyl chloride (0.85mL, 10.964mmol) was added dropwise to a solution of (9H-fluoren-9-yl) methyl (6- (hydroxymethyl) -2-methylquinolin-7-yl) carbamate (3.0g, 7.309mmol) and N, N-diisopropylethylamine (1.9mL, 10.904mmol) in dichloromethane (60mL), after the reaction is finished, the reaction solution is diluted by ice water (200mL), extracted by dichloromethane (150mL multiplied by 3), combined with organic layers, washed by saturated sodium chloride aqueous solution (100mL multiplied by 3), dried by anhydrous sodium sulfate, filtered, and evaporated to dryness under reduced pressure to obtain (7- ((((9H-fluoren-9-yl) methoxy) carbonyl) amino) -2-methylquinolin-6-yl) methyl methanesulfonate, which is directly used for the next reaction without purification.
Step f): preparation of 4- (tert-butyl) 2-ethyl 1- ((7- ((((9H-fluoren-9-yl) methoxy) carbonyl) amino) -2-methylquinolin-6-yl) methyl) -1H-imidazole-2, 4-dicarboxylic acid
Adding (7- (((9H-fluoren-9-yl) methoxy) carbonyl) amino) -2-methylquinolin-6-yl) methyl methanesulfonate (3.5g, 7.164mmol), potassium carbonate (2.48g, 17.910mmol) and dry acetonitrile (70mL) into a reaction flask, stirring at 50 ℃ for reaction for 6H, evaporating the solvent under reduced pressure after the reaction is finished, adding water (150mL) into the residue for dilution, extracting with ethyl acetate (200 mL. times.3), combining organic layers, washing with saturated aqueous sodium chloride (100 mL. times.3), drying with anhydrous sodium sulfate, filtering, evaporating the filtrate under reduced pressure, and purifying the obtained crude product by silica gel column chromatography (eluent: petroleum ether/ethyl acetate. times. 3/1) to obtain 4- (tert-butyl) 2-ethyl 1- ((7- ((((9H-fluoren-9-yl) methoxy) carbonyl) amino) -2-methylquinoline-6-yl) methyl-6-quinoline -yl) methyl) -1H-imidazole-2, 4-dicarboxylic acid, yield 52.8%; ESI-MS (m/z): 633.3[ M + H]+。
Step g): preparation of 4- (tert-butyl) 2-ethyl 1- ((7-amino-2-methylquinolin-6-yl) methyl) -1H-imidazole-2, 4-dicarboxylic acid
Adding a dichloromethane solution (30mL) of 4- (tert-butyl) 2-ethyl 1- ((7- ((((9H-fluoren-9-yl) methoxy) carbonyl) amino) -2-methylquinolin-6-yl) methyl) -1H-imidazole-2, 4-dicarboxylic acid (2.0g, 3.161mmol) and 20% (v/v) piperidine into a reaction bottle, stirring at room temperature for reaction for 40min, concentrating under reduced pressure after the reaction is finished, and purifying the obtained crude product by silica gel column chromatography (eluent: dichloromethane/methanol-15/1), wherein the yield is 85.1%; ESI-MS (m/z): 411.3[ M + H]+。
Step h): 9-methyl-13-oxo-12, 13-dihydro-5H-imidazo [1',2':1,2][1,4]Diaza derivatives
Figure BDA0002329350050000171
[6,5-g]Preparation of quinoline-2-carboxylic acid tert-butyl ester
Adding 4- (tert-butyl) 2-ethyl 1- (4- ((1H-pyrazol-1-yl) methyl) -2-aminobenzyl) -1H-imidazole-2, 4-dicarboxylic acid (1.0g, 2.436mmol), potassium tert-butoxide (355mg, 3.167mmol) and DMF (10mL) into a reaction bottle, stirring at 25 ℃ for reaction for 12H, adding water (50mL) for quenching after the reaction is finished, and using dichloromethane (50mL)3) Extracting, mixing organic layers, washing with saturated sodium chloride aqueous solution (10mL), drying with anhydrous sodium sulfate, filtering, and evaporating the filtrate under reduced pressure to obtain 9-methyl-13-oxo-12, 13-dihydro-5H-imidazole [1',2':1,2][1,4]Diaza derivatives
Figure BDA0002329350050000182
[6,5-g]Quinoline-2-carboxylic acid tert-butyl ester, which is directly used for the next reaction without purification; ESI-MS (m/z): 365.2[ M + H]+。
Step i): 9-methyl-12, 13-dihydro-5H-imidazo [1',2':1,2][1,4]Diaza derivatives
Figure BDA0002329350050000183
[6,5-g]Preparation of quinoline-2-carboxylic acid tert-butyl ester
At 25 ℃ adding BH3THF (4.1mL, 4.116mmol) was added dropwise to 9-methyl-13-oxo-12, 13-dihydro-5H-imidazo [1',2':1,2][1,4]Diaza derivatives
Figure BDA0002329350050000184
[6,5-g]Quinoline-2-carboxylic acid tert-butyl ester (500mg, 1.372mmol) in tetrahydrofuran (5mL) was reacted at 50 ℃ for 2.5H, quenched with methanol (15mL), concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography (eluent: petroleum ether/ethyl acetate 1/1) to give 9-methyl-12, 13-dihydro-5H-imidazo [1',2':1, 2:, 2)][1,4]Diaza derivatives
Figure BDA0002329350050000185
[6,5-g]Quinoline-2-carboxylic acid tert-butyl ester, yield 77.0%; ESI-MS (m/z): 351.2[ M + H]+。
Step h): 9-methyl-12, 13-dihydro-5H-imidazo [1',2':1,2][1,4]Diaza derivatives
Figure BDA0002329350050000186
[6,5-g]Preparation of quinoline-2-carboxylic acid
9-methyl-12, 13-dihydro-5H-imidazole [1',2':1, 2' ]][1,4]Diaza derivatives
Figure BDA0002329350050000187
[6,5-g]Quinoline-2-carboxylic acid tert-butyl ester (350mg, 0.999mmol) and 8N saltAdding acid (5mL) into a reaction bottle, heating to 60 ℃ for reaction for 2H, after the reaction is finished, evaporating the solvent under reduced pressure, and purifying by preparative HPLC to obtain 9-methyl-12, 13-dihydro-5H-imidazole [1',2':1, 2)][1,4]Diaza derivatives
Figure BDA0002329350050000188
[6,5-g]Quinoline-2-carboxylic acid, yield 83.1%; ESI-MS (m/z): 295.2[ M + H]+。
Step i): n- ((6-amino-2, 4-dimethylpyridin-3-yl) methyl) -9-methyl-12, 13-dihydro-5H-imidazo [1',2':1, 2)][1,4]Diaza derivatives
Figure BDA0002329350050000189
[6,5-g]Preparation of quinoline-2-carboxamides
9-methyl-12, 13-dihydro-5H-imidazole [1',2':1, 2' ]][1,4]Diaza derivatives
Figure BDA00023293500500001810
[6,5-g]Quinoline-2-carboxylic acid (100mg, 0.340mmol), 5- (aminomethyl) -4, 6-dimethylpyridine-2-diamine dihydrochloride (80mg, 0.357mmol), HBTU (168mg, 0.442mmol), triethylamine (0.24mL, 1.700mmol) and DMF (3mL) were added to a reaction flask, the mixture was stirred at room temperature for 5 hours, after the reaction was completed, ethyl acetate was added to dilute the mixture (30mL), the mixture was washed with water and saturated sodium chloride in this order, dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the residue was purified by preparative HPLC to give N- ((6-amino-2, 4-dimethylpyridin-3-yl) methyl) -9-methyl-12, 13-dihydro-5H-imidazole [1',2':1,2][1,4]Diaza derivatives
Figure BDA00023293500500001811
[6,5-g]Quinoline-2-carboxamide, yield 37.8%; ESI-MS (m/z): 428.3.
example 9
N- ((1-aminoisoquinolin-6-yl) methyl) -9-methyl-12, 13-dihydro-5H-imidazo [1',2':1,2][1,4]Diaza derivatives
Figure BDA00023293500500001812
[6,5-g]Preparation of quinoline-2-carboxamides
Figure BDA0002329350050000181
The procedure is as in example 8, except that in step k the 5- (aminomethyl) -4, 6-dimethylpyridine-2-diamine is replaced by 6- (aminomethyl) isoquinolin-1-amine to give N- ((1-aminoisoquinolin-6-yl) methyl) -9-methyl-12, 13-dihydro-5H-imidazo [1',2':1,2][1,4]Diaza derivatives
Figure BDA0002329350050000194
[6,5-g]Quinoline-2-carboxamide; ESI-MS (m/z): 450.3[ M + H]+。
Example 10
N- ((1-amino-7-methoxyisoquinolin-6-yl) methyl) -9-methyl-12, 13-dihydro-5H-imidazo [1',2':1, 2)][1,4]Diaza derivatives
Figure BDA0002329350050000195
[6,5-g]Preparation of quinoline-2-carboxamides
Figure BDA0002329350050000191
The procedure is as in example 8, except that in step k the 5- (aminomethyl) -4, 6-dimethylpyridine-2-diamine is replaced by 6- (aminomethyl) -methoxyisoquinolin-1-amine to give N- ((1-amino-7-methoxyisoquinolin-6-yl) methyl) -9-methyl-12, 13-dihydro-5H-imidazo [1',2':1,2][1,4]Diaza derivatives
Figure BDA0002329350050000196
[6,5-g]Quinoline-2-carboxamide; ESI-MS (m/z): 480.3[ M + H]+。
Example 11
N- (4- (aminomethyl) benzyl) -9-methyl-12, 13-dihydro-5H-imidazo [1',2':1,2][1,4]Diaza derivatives
Figure BDA0002329350050000197
[6,5-g]Preparation of quinoline-2-carboxamides
Figure BDA0002329350050000192
Using 9-methyl-12, 13-dihydro-5H-imidazole [1',2':1,2][1,4]Diaza derivatives
Figure BDA0002329350050000198
[6,5-g]Quinoline-2-carboxylic acid was used as the starting material and the other operations were performed as in example 4 to give N- (4- (aminomethyl) benzyl) -9-methyl-12, 13-dihydro-5H-imidazo [1',2':1,2][1,4]Diaza derivatives
Figure BDA0002329350050000199
[6,5-g]Quinoline-2-carboxamide; ESI-MS (m/z): 413.3[ M + H]+。
Example 12
N- ((6-amino-2, 4-dimethylpyridin-3-yl) methyl) -9-methyl-5H-imidazo [1',2':1,2][1,4]Diaza derivatives
Figure BDA00023293500500001910
[6,5-g]Preparation of quinoline-2-carboxamides
Figure BDA0002329350050000193
Using 9-methyl-12, 13-dihydro-5H-imidazole [1',2':1,2][1,4]Diaza derivatives
Figure BDA00023293500500001911
[6,5-g]Quinoline-2-carboxylic acid as starting material and the other operations are as in example 5 to give N- ((6-amino-2, 4-dimethylpyridin-3-yl) methyl) -9-methyl-5H-imidazo [1',2':1,2][1,4]Diaza derivatives
Figure BDA0002329350050000203
[6,5-g]Quinoline-2-carboxamide; ESI-MS (m/z): 426.3[ M + H]+。
Example 13
N- ((6-amino-2, 4-dimethylpyridin-3-yl) methyl) -9-methyl-13-oxo-12, 13-dihydro-5H-imidazo [1',2':1,2][1,4]Diaza derivatives
Figure BDA0002329350050000204
[6,5-g]Preparation of quinoline-2-carboxamides
Figure BDA0002329350050000201
By using 9-methyl-13-oxo-12, 13-dihydro-5H-imidazole [1',2':1,2][1,4]Diaza derivatives
Figure BDA0002329350050000205
[6,5-g]Quinoline-2-carboxylic acid tert-butyl ester was used as the starting material, and the other procedures were carried out as in example 6 to give N- ((6-amino-2, 4-dimethylpyridin-3-yl) methyl) -9-methyl-13-oxo-12, 13-dihydro-5H-imidazo [1',2':1,2][1,4]Diaza derivatives
Figure BDA0002329350050000206
[6,5-g]Quinoline-2-carboxamide; ESI-MS (m/z): 442.2[ M + H]+。
Example 14
N- ((6-amino-2, 4-dimethylpyridin-3-yl) methyl) -2-methyl-11, 12-dihydro-6H-pyrrolo [1',2':1,2][1,4]Diaza derivatives
Figure BDA0002329350050000207
[6,5-g]Preparation of quinoline-2-carboxamides
Figure BDA0002329350050000202
Step a-d): 2-methyl-11, 12-dihydro-6H-pyrrole [1',2':1,2][1,4]Diaza derivatives
Figure BDA0002329350050000208
[6,5-g]Preparation of quinoline-9-carboxylic acid ethyl ester
Starting with methyl (7- (((9H-fluoren-9-yl) methoxy) carbonyl) amino) -2-methylquinolin-6-yl) methyl methanesulfonate and ethyl 1H-pyrrole-2, 4-dicarboxylate, the other procedures were as in example 8, to give 2-methyl-11, 12-dihydro-6H-pyrrole [1',2':1,2][1,4]Diaza derivatives
Figure BDA0002329350050000209
[6,5-g]Quinoline-9-carboxylic acid ethyl ester; ESI-MS (m/z): 322.2[ M + H]+。
Step e): 2-methyl-11, 12-dihydro-6H-pyrrole [1',2':1,2][1,4]Diaza derivatives
Figure BDA00023293500500002010
[6,5-g]Preparation of quinoline-9-carboxylic acid
With 2-methyl-11, 12-dihydro-6H-pyrrole [1',2':1,2][1,4]Diaza derivatives
Figure BDA00023293500500002011
[6,5-g]Quinoline-9-carboxylic acid Ethyl ester, the other procedures were the same as in example 7, to give 2-methyl-11, 12-dihydro-6H-pyrrolo [1',2':1,2 ')][1,4]Diaza derivatives
Figure BDA0002329350050000212
[6,5-g]Quinoline-9-carboxylic acid; ESI-MS (m/z): 294.2[ M + H]+。
Step f): n- ((6-amino-2, 4-dimethylpyridin-3-yl) methyl) -2-methyl-11, 12-dihydro-6H-pyrrolo [1',2':1,2][1,4]Diaza derivatives
Figure BDA0002329350050000213
[6,5-g]Preparation of quinoline-2-carboxamides
With 2-methyl-11, 12-dihydro-6H-pyrrole [1',2':1,2][1,4]Diaza derivatives
Figure BDA0002329350050000214
[6,5-g]Quinoline-9-carboxylic acid and 5- (aminomethyl) -4, 6-lutidine-2-diamine as starting materials, the other procedures were as in step k of example 8 to give N- ((6-amino-2, 4-lutidin-3-yl) methyl) -2-methyl-11, 12-dihydro-6H-pyrrole [1',2':1,2][1,4]Diaza derivatives
Figure BDA0002329350050000215
[6,5-g]Quinoline-2-carboxamide; ESI-MS (m/z): 427.3[ M + H]+。
Example 15
Preparation of N- ((R) -1- (((S) -1- ((4- (aminomethyl) benzyl) amino) -1-oxo-3-phenylprop-2-yl) amino) -3- (4-ethoxyphenyl) -1-oxopropyl-2-yl) benzamide
Figure BDA0002329350050000211
Step a): preparation of (R) -2-amino-3- (4-ethoxyphenyl) propionic acid hydrochloride
(R) -2- ((tert-butoxycarbonyl) amino) -3- (4-ethoxyphenyl) propionic acid (2.0g, 6.465mmol) was placed in a reaction flask, a self-made dioxane hydrochloride solution (5.3M, 50mL) was added, the reaction was carried out at room temperature for 3 hours, the resulting white solid was collected by filtration, and the filter cake was washed with dioxane (20mL), petroleum ether (50mL), diethyl ether (10mL) and dried in vacuo to give a white solid product with 98.0% yield, ESI-MS (M/z): 210.1[ M + H]+。
Step b): preparation of ((benzyloxy) carbonyl) -D-phenylalanine
Adding (R) -2-amino-3- (4-ethoxyphenyl) propionic acid hydrochloride (500mg, 2.035mmol) and sodium hydroxide (179mg, 4.478mmol) into a reaction flask, adding water (15mL) and stirring to dissolve, cooling to 0 deg.C, slowly adding a dioxane solution (15mL) of benzyl chloroformate (382mg, 2.239mmol) dropwise, stirring at room temperature overnight, after the reaction is completed, evaporating the solvent, adding water to dilute (30mL), adding diethyl ether (30mL) to extract, discarding the organic phase, adjusting the pH of the aqueous layer to 3-4 with 1N hydrochloric acid aqueous solution, extracting with ethyl acetate (50 mL. times.2), combining the organic layers, washing with saturated sodium chloride aqueous solution (30mL), drying over anhydrous sodium sulfate, filtering, concentrating the filtrate to obtain ((benzyloxy) carbonyl) -D-phenylalanine with a yield of 99.0%, ESI-MS (m/z): 300.1[ M + H]+。
Step c): preparation of benzyl (S) - (1- ((4- (((tert-butoxycarbonyl) amino) methyl) benzyl) amino) -1-oxo-3-phenylpropyl-2-yl) carbamate
((benzyloxy) carbonyl) -L-phenylalanine (1.39g, 4.655mmol), (4- (aminomethyl) benzyl) carbamic acid tert-butyl ester (1.0g, 4.232mmol), HATU (3.22g, 8.464mmol), triethylamine (1.77mL, 12.696mmol) and dry dichloromethane (30mL) were added to a reaction flask under nitrogen protectionStirring and reacting for 4 hours at room temperature, after the reaction is finished, adding dichloromethane (50mL) and saturated ammonium chloride aqueous solution (100mL) into the reaction liquid for extraction, extracting an aqueous layer with dichloromethane (50mL), combining organic layers, washing with saturated potassium carbonate aqueous solution (100mL) and saturated sodium chloride aqueous solution (100mL) in sequence, drying with anhydrous sodium sulfate, filtering, concentrating the filtrate under reduced pressure, dispersing the obtained crude product into a mixed solution of petroleum ether and ethyl acetate (v/v ═ 8:1, 25mL), stirring for 25min, performing suction filtration, washing a filter cake with corresponding mixed solution, and performing vacuum drying at 40 ℃ under reduced pressure to obtain an off-white solid with the yield of 97.0 percent; ESI-MS (m/z): 518.3[ M + H]+。
Step d): preparation of tert-butyl (S) - (4- ((2-amino-3-phenylpropylamino) methyl) benzyl) carbamate
Adding (S) - (1- ((4- (((tert-butoxycarbonyl) amino) methyl) benzyl) amino) -1-oxo-3-phenylpropyl-2-yl) carbamic acid benzyl ester (2.0g, 3.864mmol) and methanol (150mL) into a reaction bottle, uniformly stirring, adding Pd/C (400mg), introducing a hydrogen gas chamber, stirring for 24h, filtering after the reaction is finished, washing a filter cake with methanol (100mL), combining the filtrate, and concentrating under reduced pressure to obtain a white-like solid, wherein the yield is 92.0%, ESI-MS (m/z): 384.3[ M + H]+。
Step e): preparation of tert-butyl (4- ((5R,8S) -8-benzyl-5- (4-ethoxybenzyl) -3,6, 9-trioxo-1-phenyl-2-oxo-4, 7, 10-triazaundecan-11-yl) benzyl) carbamate
Adding tert-butyl ((benzyloxy) carbonyl) -D-phenylalanine (257mg, 0.860mmol), (S) - (4- ((2-amino-3-phenylalanyl) methyl) benzyl) carbamate (300mg, 0.782mmol), HATU (595mg, 1.564mmol), triethylamine (237mg, 2.346mmol) and dichloromethane into a reaction bottle (10mL), reacting overnight at room temperature, after the reaction is finished, adding dichloromethane (100mL) into the reaction solution for dilution, washing with 1N hydrochloric acid aqueous solution (100mL) and saturated sodium chloride aqueous solution (100mL), drying with anhydrous sodium sulfate, filtering, concentrating the filtrate under reduced pressure, pulping the obtained crude product with petroleum ether/ethyl acetate mixed solvent (9:1, v/v, 50mL), filtering, drying under reduced pressure to obtain a white solid with the yield of 90.5%; ESI-MS (m/z): 709.4[ M + H]+。
Step f): preparation of tert-butyl (4- (((S) -2- ((R) -2-amino-3- (4-ethoxyphenyl) propylamino) -3-phenylalanyl) methyl) benzyl) carbamate
Adding tert-butyl (4- ((5R,8S) -8-benzyl-5- (4-ethoxybenzyl) -3,6, 9-trioxo-1-phenyl-2-oxo-4, 7, 10-triazaundecanon-11-yl) benzyl) carbamate (500mg, 0.705mmol) and methanol (70mL) into a reaction bottle, stirring for dissolving, adding Pd/C (100mg), introducing a hydrogen gas chamber for reacting for 4 hours, filtering, washing a filter cake with methanol (50mL), combining filtrates, and concentrating under reduced pressure to obtain a white solid with the yield of 89.1%; ESI-MS (m/z): 575.4[ M + H ]]+。
Step g): preparation of tert-butyl (4- (((S) -2- ((R) -2-benzoylamino-3- (4-ethoxyphenyl) propylamino) -3-phenylpropylamino) methyl) benzyl) carbamate
Adding tert-butyl (4- (((S) -2- ((R) -2-amino-3- (4-ethoxyphenyl) propylamino) -3-phenylpropylamino) methyl) benzyl) carbamate (361mg, 0.628mmol), triethylamine (191mg, 1.884mmol) and dichloromethane (20mL) into a reaction bottle, uniformly stirring, slowly dropwise adding a dichloromethane solution (2mL) of benzoyl chloride (106mg, 0.754mmol), reacting at room temperature for 6 hours, adding dichloromethane (80mL), diluting, sequentially washing with saturated ammonium chloride (100mL) and saturated saline (100mL), drying over anhydrous sodium sulfate, filtering, concentrating under reduced pressure to 5mL, cooling, filtering to separate out a solid, washing a filter cake with an appropriate amount of ethyl acetate, and drying under reduced pressure in vacuum to obtain a white solid with the yield of 57.1%; ESI-MS (m/z): 679.4[ M + H]+. Step h): preparation of N- ((R) -1- (((S) -1- ((4- (aminomethyl) benzyl) amino) -1-oxo-3-phenylprop-2-yl) amino) -3- (4-ethoxyphenyl) -1-oxopropyl-2-yl) benzamide
Adding (4- (((S) -2- ((R) -2-benzoylamino-3- (4-ethoxyphenyl) propylamino) -3-phenylpropylamino) methyl) benzyl) carbamic acid tert-butyl ester (100mg, 0.158mmol) and dioxane hydrochloride solution (3mL) into a reaction bottle, stirring at room temperature for reaction for 1.5h, evaporating under reduced pressure after the reaction is finished, adding ethanol (2mL) into the residue, ultrasonically crushing and pulping, filtering, washing the filter cake with a small amount of ethanol, drying under reduced pressure at 40 ℃ to obtain a white solid, wherein the yield is 83.0%,1H NMR(400MHz,DMSO-d6)δ8.64(t,J＝6.0Hz,1H),8.59(d,J＝8.4Hz,1H),8.50(d,J＝8.4Hz,1H),8.29(s,3H),7.81-7.65(m,2H),7.51(t,J＝7.6Hz,1H),7.46-7.33(m,4H),7.30-7.08(m,8H),6.76(d,J＝8.4Hz,2H),4.69-4.53(m,2H),4.40-4.21(m,2H),4.04-3.85(m,4H),3.06(dd,J1＝13.6Hz,J2＝4.8Hz,1H),2.83(dd,J1＝13.6,J2＝10.0Hz,1H),2.69(d,J＝7.6Hz,2H),1.27(t,J＝7.6Hz,3H)；ESI-MS(m/z)：579.3[M+H]+。
biological activity assay
1. Determination of Human plasma kallikrein (Human PK) inhibitory Activity
The procedure reported by Johansen et al (Johansen el al, int.J.Tiss.Reac.1986,8,185) was used with partial modifications, in 10mM PBS,1mM EDTA, 0.1% BSA, pH 7.4. Adding 0.4nM human plasma kallikrein (commercially available from Enzyme Research Laboratories) 10. mu.L to a 384-well microplate in sequence, adding 5. mu.L of a test compound solution, mixing the solution uniformly, incubating the mixture at 37 ℃ for 15min, adding 5. mu.L of a reaction substrate N-Benzoyl-pro-phe-Arg-p-Nitroanilide (commercially available from sigma) (500. mu.M) to each well for color development, measuring the optical density (OD value) of each well at 405nM by a microplate reader kinetic model, and comparing the measured optical density (OD value) with a blank well without the test sample to calculate the inhibition rate of the compound on the Enzyme [ inhibition rate ═ 100% (1-sample set OD value/blank set OD value)%]IC was calculated using a four parameter model in Prism GraphPad50A value; each compound was assayed in 2 replicates each, each experiment was independently repeated three times. And the IC of inhibition of human plasma kallikrein by the compounds of the examples was assessed as follows50：+(100～500nM)、++(50～100nM)、+++(10～50nM)、++++(<10nM), the results are shown in table 1:
TABLE 1
Example numbering IC50(human plasma kallikrein) Example numbering IC50(human plasma kallikrein)
Example 1 + Example 9 +++
Example 2 ++ Example 10 +
Example 3 + Example 11 ++
Example 4 ++ Example 12 +
Example 5 + Example 13 +
Example 6 ++ Example 14 ++
Example 7 +++ Example 15 +
Example 8 +++
2. Determination of human Thrombin inhibitory Activity
The method reported by H.C. Hemker et al (Handbook of Synthetic Substrates) was used with partial modification, the reaction solution being 50mM Tris-HCl, pH 8.3,130mM NaCl, 0.5% BSA. Adding 0.2nM human thrombin (commercially available from Enzyme Research Laboratories) 10. mu.L and 5. mu.L of a test compound solution into a 384 micro-well plate in sequence, mixing the solutions uniformly, incubating the mixture for 15min at 37 ℃, adding 5. mu.L of 75. mu.M reaction substrate BOC-Val-Pro-AFC (commercially available from sigma) into each well, developing the mixture, measuring the fluorescence value of each well at an excitation wavelength of 380nM and an emission wavelength of 500nM in a microplate reader kinetic mode, and calculating the inhibition rate of the compound on the Enzyme [ inhibition rate ═ (1-sample group fluorescence value/blank group fluorescence value) x 100% compared with a blank well without the test sample%]IC was calculated using a four parameter model in Prism GraphPad50A value; each compound was assayed in 2 replicates each, each experiment was independently repeated three times.
3. Trypsin (Trypsin) inhibitory activity assay
The method reported by H.C.Hemker et al (Handbook of Synthetic Substrates) is adopted, and partial improvement is made, the reaction solution is 200mM Tris-HCl,20mM CaCl2And the pH value is 7.8. Adding 10 μ L of 12.5nM trypsin (commercially available from Biovision) and 5 μ L of test compound solution to 384 microwell plate in sequence, mixing, incubating at 37 deg.C for 15min, adding 5 μ L of 200 μ M L-BAPA (commercially available from Sigma) to each well, developing, measuring optical density (OD value) of each well at 405nM with microplate reader kinetic pattern, and comparing with blank wells without test sample, calculating the inhibition rate of compound on enzyme [ inhibition rate ═ 1-sample group OD value/blank group OD value) x 100%]At PrIC computation in ismGraphPad with four-parameter mode50A value; each compound was assayed in 2 replicates each, each experiment was independently repeated three times.
4. Determination of human factor xia (factor xia) inhibitory Activity
The method reported by H.C. Hemker et al (Handbook of Synthetic Substrates) was used with partial modification, with the reaction solution being 0.05M Tris/HCl,0.15M NaCl, BSA (0.1mg/ml) and pH 8.0. Adding 15nM human coagulation factor XIa (commercially available from Enzyme Research Laboratories) 10. mu.L to 384 microwell plate, adding 5. mu.L of test compound solution, mixing, incubating at 37 ℃ for 15min, adding 5. mu.L of 400. mu.M reaction substrate N-Benzoyl-pro-phe-Arg-p-Nitroanilide (commercially available from sigma) to each well, developing, measuring optical density (OD value) of each well at 405nM by microplate reader kinetic mode, comparing with blank wells without test sample, and calculating the inhibition rate of the compound on Enzyme [ inhibition rate [ (1-sample group value/group blank OD value) OD x 100% ] -]IC was calculated using a four parameter model in Prism GraphPad50A value; each compound was assayed in 2 replicates each, each experiment was independently repeated three times.
5. Determination of human coagulation factor Xa (factor Xa) inhibitory Activity
The method reported by H.C. Hemker et al (Handbook of Synthetic Substrates) was used with some modifications, with the reaction solution being 0.05M Tris,0.1M NaCl, pH 7.4. Adding 10 μ L of 3nM human blood coagulation factor Xa (commercially available from Enzyme Research Laboratories) and 5 μ L of a test compound solution to 384 microwell plates in this order, mixing the solutions, incubating the wells at 37 ℃ for 15min, adding 5 μ L of 400 μ M reaction substrate N-Benzoyl-Val-Gly-Arg p-nitroanilide hydrochloride (commercially available from Sigma) to each well, developing the color, measuring the optical density (OD value) of each well at 405nM using microplate reader kinetic pattern, comparing the measured optical density with a blank well without the test sample, and calculating the inhibition rate [ inhibition rate ═ 1-sample group OD value/blank group OD value) x 100%]IC was calculated using a four parameter model in Prism GraphPad50A value; each compound was assayed in 2 replicates each, each experiment was independently repeated three times.
6. Determination of human plasmin (plasmin) inhibitory Activity
H.C.Hemker et al (Handbook _ o) were usedf Synthetic _ sub) with partial modification, reaction solution 0.05M Tris/HC1,0.13M NaCl, BSA (5mg/ml), pH 8.3. Adding 10 μ L of 2nM human plasmin (commercially available from Enzyme Research Laboratories) to a 384-well plate in sequence, adding 5 μ L of a test compound solution, mixing the solution uniformly, incubating the mixture at 37 ℃ for 15min, adding 5 μ L of a 1.2mM reaction substrate Tosyl-Gly-Pro-Lys-4-nitanilide (commercially available from Sigma) to each well, developing the color, measuring the optical density (OD value) of each well at 405nM by a microplate reader kinetic mode, comparing the optical density (OD value) with a blank well without the test sample, and calculating the inhibition rate of the compound on the Enzyme [ inhibition rate ═ 100%]IC was calculated using a four parameter model in Prism GraphPad50A value; each compound was assayed in 2 replicates each, each experiment was independently repeated three times.
The data of the above test for the inhibitory activity of human thrombin, trypsin, human factor XIa, human factor Xa, and human plasmin are shown in table 2:
TABLE 2
Example numbering Human thrombin Trypsin Factor XIa Blood coagulation factor Xa Plasmin and method of use
Example 1 >10μM >10μM >10μM >10μM >10μM
Example 2 >10μM >10μM >10μM >10μM >10μM
Example 3 >10μM >10μM >10μM >10μM >10μM
Example 4 >10μM >10μM >10μM >10μM >10μM
Example 5 >10μM >10μM >10μM >10μM >10μM
Example 6 >10μM >10μM >10μM >10μM >10μM
Example 7 >10μM >10μM >10μM >10μM >10μM
Example 8 >10μM >10μM >10μM >10μM >10μM
Example 9 >10μM >10μM >10μM >10μM >10μM
Example 10 >10μM >10μM >10μM >10μM >10μM
Example 11 >10μM >10μM >10μM >10μM >10μM
Example 12 >10μM >10μM >10μM >10μM >10μM
Example 13 >10μM >10μM >10μM >10μM >10μM
Example 14 >10μM >10μM >10μM >10μM >10μM

Claims (27)

1. A compound of formula (I), a pharmaceutically acceptable salt, solvate, stereoisomer or prodrug thereof:
Figure FDA0002329350040000011
wherein A is selected from aromatic ring or aromatic heterocycle, and the aromatic heterocycleThe ring contains 1 to 3 heteroatoms selected from N, O and S, the aromatic or heteroaromatic ring being optionally substituted with the following substituents: halogen, alkyl, alkoxy, haloalkyl, OH, CN, COOR1、CONR1R2、NR1R2、NR1COR2、(CH2)1-3NR1R2、(CH2)1-3OR1and-C (R)1)(R2)NH2；
Or a is selected from a fused 6, 5-or 6, 6-heteroaromatic bicyclic ring containing N and optionally another 1-2 heteroatoms independently selected from N, O and S, said heteroaromatic ring being optionally substituted with the following substituents: halogen, alkyl, alkoxy, haloalkyl, OH, CN, COOR1、CONR1R2、NR1R2、NR1COR2、(CH2)1-3NR1R2、(CH2)1-3OR1 and-C (R)1)(R2)NH2；
L1Selected from (CR)3R4)mWherein m is 0, 1, 2;
X1is CR5Or N; wherein R is5Selected from H, OH, halogen, alkyl, alkoxy, haloalkyl, cycloalkyl, CN, COOR1、CONR1R2、NR1R2、NR1COR2、(CH2)1-3NR1R2、(CH2)1-3OR1and-C (R)1)(R2)NH2；
-C-D-is selected from-NH-CH2-、-N＝CH-、-NCH3-CH2-, -NHCO-, -CH ═ CH-or-CH2-CH2-；
X2Is CH or N;
b is independently selected from H, halogen, alkyl, alkoxy, haloalkyl, OH, CN, COOR1、CONR1R2、NR1R2、NR1COR2、(CH2)1-3NR1R2、(CH2)1-3OR1and-C (R)1)(R2)NH2；
R1And R2Independently selected from H and alkyl, or R1And R2Together with the carbon to which they are attached form a cycloalkyl group;
R3and R4Independently selected from H and alkyl, or R3And R4Together with the carbon to which they are attached form a cycloalkyl group.
2. The compound, pharmaceutically acceptable salt, solvate, stereoisomer or prodrug thereof of claim 1 wherein a is selected from
Figure FDA0002329350040000012
Wherein X3Is C or N, and when X3When is N, R9Is absent;
R6、R7、R8、R9、R10independently selected from H, OH, halogen, alkyl, alkoxy, haloalkyl, cycloalkyl, CN, COOR1、CONR1R2、NR1R2、NR1COR2、(CH2)1-3NR1R2、(CH2)1-3OR1and-C (R)1)(R2)NH2，R1And R2Independently selected from H and alkyl, or R1And R2Together with the carbon to which they are attached form a cycloalkyl group.
3. The compound, pharmaceutically acceptable salt, solvate, stereoisomer, or prodrug thereof of claim 1, wherein R is8Is NH2Or C (R)1)(R2)NH2Wherein R is1And R2Independently selected from H and C1-3Alkyl group of (1).
4. The compound of claim 1, pharmaceutically acceptable salt, solvate, stereoisomer thereofA structure or prodrug, wherein R is8Is NH2。
5. The compound, pharmaceutically acceptable salt, solvate, stereoisomer, or prodrug thereof of claim 1, wherein R is8Is CH2NH2。
6. The compound, pharmaceutically acceptable salt, solvate, stereoisomer, or prodrug thereof of claim 1, wherein R is6、R7、R9、R10Independently selected from H, halogen, alkyl, alkoxy, haloalkyl.
7. The compound, pharmaceutically acceptable salt, solvate, stereoisomer, or prodrug thereof of claim 1, wherein R is6、R7、R9、R10Independently selected from H, halogen or CH3。
8. The compound, pharmaceutically acceptable salt, solvate, stereoisomer, or prodrug thereof of claim 1, wherein a is selected from:
Figure FDA0002329350040000021
9. the compound, pharmaceutically acceptable salt, solvate, stereoisomer or prodrug thereof according to claim 1 wherein a is selected from isoquinoline, wherein isoquinoline is optionally substituted with halogen, alkyl, alkoxy, haloalkyl, COOR1、CONR1R2、NR1R2、NR1COR2、(CH2)1-3NR1R2、(CH2)1-3OR1and-C (R)1)(R2)NH2Substitution; r1And R2Independently of each otherSelected from H and alkyl, or R1And R2Together with the carbon to which they are attached form a cycloalkyl group.
10. The compound, pharmaceutically acceptable salt, solvate, stereoisomer, or prodrug thereof of claim 1, wherein a is selected from the group consisting of isoquinoline, wherein isoquinoline is optionally substituted with halo, alkyl, alkoxy, haloalkyl, and amino.
11. The compound, pharmaceutically acceptable salt, solvate, stereoisomer, or prodrug thereof of claim 1, wherein a is selected from:
Figure FDA0002329350040000022
12. the compound, pharmaceutically acceptable salt, solvate, stereoisomer, or prodrug thereof of claim 1, wherein L is1Selected from the group consisting of a bond, CH2、(CH2)2O。
13. The compound, pharmaceutically acceptable salt, solvate, stereoisomer, or prodrug thereof of claim 1, wherein L is1Is selected from CH2。
14. The compound, pharmaceutically acceptable salt, solvate, stereoisomer or prodrug thereof of claim 1 wherein X is1Is CR5Wherein R is5Selected from the group consisting of H, alkyl, haloalkyl, alkoxy and (CH)2)1-3OR1。
15. The compound, pharmaceutically acceptable salt, solvate, stereoisomer or prodrug thereof of claim 1 wherein X is1Is CR5Wherein R is5Selected from H, CH3、CF3、CH2OCH3。
16. The compound, pharmaceutically acceptable salt, solvate, stereoisomer or prodrug thereof of claim 1, wherein-C-D-is selected from-NH-CH2-、-N＝CH-、-NHCO-。
17. The compound, pharmaceutically acceptable salt, solvate, stereoisomer or prodrug thereof of claim 1 wherein X is2Is CH.
18. The compound, pharmaceutically acceptable salt, solvate, stereoisomer or prodrug thereof of claim 1 wherein B is selected from alkyl or alkoxy.
19. The compound, pharmaceutically acceptable salt, solvate, stereoisomer or prodrug thereof of claim 1 wherein B is selected from CH3Or OCH3。
20. The compound, pharmaceutically acceptable salt, solvate, stereoisomer or prodrug thereof according to claim 1, wherein the compound is selected from the group consisting of:
Figure FDA0002329350040000031
21. a pharmaceutical composition characterized by comprising a compound of any one of claims 1-20, a pharmaceutically acceptable salt, solvate, stereoisomer, or prodrug thereof, and a pharmaceutically acceptable excipient.
22. Use of a compound of any one of claims 1-20, a pharmaceutically acceptable salt, solvate, stereoisomer, or prodrug thereof in the manufacture of a medicament for the prevention or treatment of a disease associated with plasma kallikrein activity.
23. Use according to claim 22, characterized in that the disease involving plasma kallikrein activity is inflammation.
24. Use according to claim 22, characterized in that the diseases involving plasma kallikrein activity are selected from the group consisting of impaired vision, diabetic retinopathy, diabetic macular edema, hereditary angioedema, diabetes, pancreatitis, cerebral hemorrhage, nephropathy, cardiomyopathy, neuropathy, inflammatory bowel disease, arthritis, septic shock, hypotension, cancer, adult respiratory distress syndrome, disseminated intravascular coagulation, cardiopulmonary bypass surgery and post-surgical bleeding.
25. Use according to claim 22, characterized in that the disease involving plasma kallikrein activity is a retinal vascular permeability disease associated with diabetic retinopathy and diabetic macular edema.
26. The use according to claim 22, characterized in that the disease involving plasma kallikrein activity is diabetic macular edema.
27. The use according to claim 22, characterized in that the disease involving plasma kallikrein activity is hereditary angioedema.
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Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5880122A (en) * 1996-11-01 1999-03-09 American Home Products Corporation 3-Carboxamide derivatives of 5H-pyrrolo 2,1-c! 1,4!-benzodiazepines
WO2001023357A2 (en) * 1999-09-27 2001-04-05 Amgen Inc. Fused cycloheptane and fused azacycloheptane compounds and their use as integrin receptor antagonists
CN102834397A (en) * 2010-02-11 2012-12-19 百时美施贵宝公司 Macrocycles as factor xia inhibitors
US20180319771A1 (en) * 2015-10-27 2018-11-08 Boehringer Ingelheim International Gmbh Heteroarylcarboxamide derivatives as plasma kallikrein inhibitors

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5880122A (en) * 1996-11-01 1999-03-09 American Home Products Corporation 3-Carboxamide derivatives of 5H-pyrrolo 2,1-c! 1,4!-benzodiazepines
WO2001023357A2 (en) * 1999-09-27 2001-04-05 Amgen Inc. Fused cycloheptane and fused azacycloheptane compounds and their use as integrin receptor antagonists
CN102834397A (en) * 2010-02-11 2012-12-19 百时美施贵宝公司 Macrocycles as factor xia inhibitors
US20180319771A1 (en) * 2015-10-27 2018-11-08 Boehringer Ingelheim International Gmbh Heteroarylcarboxamide derivatives as plasma kallikrein inhibitors

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
孟江平，等: "苯并咪唑类药物研究进展", 《中国新药杂志》 *

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