CN112300069A - Selective sodium channel regulator and preparation and application thereof - Google Patents

Selective sodium channel regulator and preparation and application thereof Download PDF

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CN112300069A
CN112300069A CN202010753365.7A CN202010753365A CN112300069A CN 112300069 A CN112300069 A CN 112300069A CN 202010753365 A CN202010753365 A CN 202010753365A CN 112300069 A CN112300069 A CN 112300069A
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姚元山
李傲
P·K·贾达夫
曹国庆
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Minghui Pharmaceutical Hangzhou Co ltd
Minghui Pharmaceutical Shanghai Co ltd
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Minghui Pharmaceutical Shanghai Co ltd
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    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
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    • C07D413/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
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    • C07C2602/04—One of the condensed rings being a six-membered aromatic ring
    • C07C2602/08—One of the condensed rings being a six-membered aromatic ring the other ring being five-membered, e.g. indane

Abstract

The invention provides a compound as a selective sodium channel regulator and a synthesis and use method thereof, and particularly provides a compound as shown in a formula (I), a preparation method thereof and application thereof as the selective sodium channel regulator. The compounds exhibit excellent activity as sodium channel modulators.

Description

Selective sodium channel regulator and preparation and application thereof
Technical Field
The invention relates to a compound as a selective sodium channel regulator, an isomer, a solvate, a salt of the compound, a medicament taking the compound or the salt as an active ingredient, and application thereof in medicaments for treating and/or preventing target diseases related to sodium channel regulation, such as pain.
Background
Pain is a protective mechanism that protects healthy animals from tissue damage and prevents further damage to the damaged tissue. Nevertheless, there are many cases where pain persists beyond its usefulness, or where patients would benefit from pain suppression.
Neuropathic pain is a form of chronic pain caused by injury to sensory nerves, and can be divided into two categories, pain caused by injury to nerve metabolism and pain caused by injury to nerve continuity. Metabolic injury pain indications include post-herpetic neuropathy, diabetic neuropathy and drug-induced neuropathy. The pain indications caused by the continuous damage of the nerve comprise nerve entrapment injuries such as amputation pain, postoperative nerve injury pain and neuropathic back pain.
Voltage-gated sodium channels (Nav's) are involved in pain signaling. Nav are biological mediators of electrical signal transduction because they mediate the rapid ascending of action potentials of many excitable cell types (e.g., neurons, skeletal muscle cells, cardiac muscle cells). The role of these channels in normal physiology, pathological states caused by mutations in the sodium channel genes, preclinical work in animal models, and evidence of the clinical pharmacology of known sodium channel modulators suggest a central role for Nav's in pain perception. Nav's mediate the rapid upward movement of action potentials of many excitable cell types (e.g., neurons, skeletal muscle cells, cardiac muscle cells) and are therefore involved in the initiation of signaling in these cells. Antagonists that reduce Nav's current may prevent or reduce neural signals due to the role of Nav's in the initiation and propagation of neuronal signals, and Nav's are considered a possible target for pain relief where hyperexcitability is observed. Several clinically useful analgesics have been identified as inhibitors of Nav's. Local anesthetics such as lidocaine block pain by inhibiting Nav channels, and other compounds such as carbamazepine, lamotrigine and tricyclic antidepressants have been shown to be effective in relieving pain by sodium channel inhibition.
Nav's form voltage-gated ion channel superfamily subfamily, and contain 9 isoforms, named Nav1.1-Nav1.9. The tissue localization of the nine isoforms varied. Nav1.4 is skeletal muscle of the main sodium channel, Nav1.5 is myocardial cells of the main sodium channel. Nav 1.7, 1.8 and 1.9 mainly located in the peripheral nervous system, while Nay 1.1, 1.2, 1.3 and 1.6 is central and peripheral nervous system found in the neural channel. The functional behavior of the nine isoforms is similar, but differs in specific aspects of voltage-dependent and kinetic behavior.
The Nav1.8 channel is determined as a possible target for analgesia, and is proved to be a carrier of sodium current, maintains action potential emission of neurons in small dorsal root ganglia, and also participates in spontaneous signal emission of damaged neurons, such as driving neuropathic pain and the like. A major drawback of some known Nav's inhibitors is their poor therapeutic window, which may be the result of their lack of isoform selectivity. Since Navl.8 is primarily restricted to pain-sensing neurons, selective Nav1.8 blockers are unlikely to induce the adverse effects common to non-selective Nav's blockers. Therefore, the field still needs to develop new Nav1.8 selective inhibitors.
Disclosure of Invention
The invention aims to provide a Nav1.8 selective inhibitor.
In a first aspect of the present invention, there is provided a compound represented by the following formula (I), and isomers, solvates or pharmaceutically acceptable salts thereof:
Figure BDA0002610707420000021
L1selected from the group consisting of: CONR4、CONR4Or SO2NR4；
L2Selected from the group consisting of: s (O)p，O，NR4CO or C (R)6)2；
Cyc1 and Cyc2 are each independently selected from: 6-10 membered aryl, 5-10 membered heteroaryl, the heteroatoms of said heteroaryl being independently selected from O, N or S (O)p；
R1Selected from: hydrogen, deuterium, ═ O, halogen, CHF2，CF3，CD3，OCF3，OCH3，OCD3Cyano, nitro, hydroxy, amino, SO2N(R4)2，CON(R4)2，COOR4，SOR7，SO2R7Substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C2-C6 alkynyl, substituted or unsubstituted- (W)m-H, substituted or unsubstituted C3-C8 cycloalkyl, substituted or unsubstituted C4-C8 heterocyclyl, substituted or unsubstituted 6-10 membered aryl, substituted or unsubstituted 5-10 membered heteroaryl, said heteroatoms independently selected from O, N or S (O)p(ii) a Or two adjacent R1And the atoms to which they are attached form a 5-6 membered carbocyclic or heterocyclic ring;
R2selected from: 0 to 4R1Substituted C3-C8 cycloalkyl, 0-4R1Substituted C4-C8 heterocyclyl, 0-4R1Substituted 6-10 membered aryl, 0-4R1Substituted 5-10 membered heteroaryl; or two adjacent R1And the atoms to which they are attached form a 5-6 membered carbocyclic or heterocyclic ring;
R3selected from: hydrogen, deuterium, ═ O, halogen, CF3，CD3，OCF3，OCH3，OCD3Cyano, nitro, hydroxy, amino, COOR4，CON(R4)2，SO2N(R4)2，SOR7，SO2R7Substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C2-C6 alkynyl, substituted or unsubstituted- (W)m-H, substituted or unsubstituted C3-C8 cycloalkyl, substituted or unsubstituted C4-C8 heterocyclyl, substituted or unsubstituted 6-10 membered aryl, substituted or unsubstituted 5-10 membered heteroaryl, said heteroatoms independently selected from O, N or S (O)p(ii) a Or R3Form N with the N atom on Cyc2+-O-；
R4Selected from: hydrogen, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C2-C6 alkynyl, substituted or unsubstituted- (W)m-H, substituted or unsubstituted C3-C8 cycloalkyl, substituted or unsubstituted C4-C8 heterocyclyl, said heteroatoms being independently selected from O, N or S (O)p(ii) a Or two R4And the N atom to which it is attached form a C4-C8 membered heterocyclic ring;
x is selected from: (CH)2)rO(CH2)r，(CH2)rS(CH2)r，(CH2)rNR4(CH2)r，(CH2)rCR4R6(CH2)rSubstituted or unsubstituted C3-C8 cycloalkyl, substituted or unsubstituted C4-C8 heterocyclyl;
n, r are each independently selected from: 0, 1,2,3 or 4;
p is selected from: 0, 1 or 2;
y is selected from: bond, CO, SO2，CR4R6，CS；
R5Selected from: hydrogen, deuterium, halogen, CF3，CD3，OCF3，OCH3，OCD3Cyano, nitro, hydroxy, amino, SO2N(R4)2，CON(R4)2，COOR4，SOR7，SO2R7Substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C2-C6 alkynyl, substituted or unsubstituted- (W)m-H, substituted or unsubstituted C3-C8 cycloalkyl, substituted or unsubstituted C4-C8 heterocyclyl, substituted or unsubstituted 6-10 membered aryl, substituted or unsubstituted 5-10 membered heteroaryl, said heteroatoms independently selected fromFrom O, N or S (O)p；
R6Selected from: hydrogen, halogen, amido, cyano, hydroxy, amino, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C2-C6 alkynyl, substituted or unsubstituted- (W)m-H, substituted or unsubstituted C3-C8 cycloalkyl, substituted or unsubstituted C4-C8 heterocyclyl; or two R6And the atoms to which they are attached form a carbocyclic ring of C3-C8 or a heterocyclic ring of C4-C8;
or R4And R6And the atoms to which they are attached form a carbocyclic ring of C3-C8 or a heterocyclic ring of C4-C8;
R7selected from: hydroxy, amino, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C2-C6 alkynyl, substituted or unsubstituted- (W)m-H, substituted or unsubstituted C3-C8 cycloalkyl, substituted or unsubstituted C4-C8 heterocyclyl;
w is selected from the group consisting of: CH (CH)2，NR4，O，S(O)pAnd at the same time only a maximum of 2W are selected from the group: n, O, S (O)p；
m is selected from: 0, 1,2,3, 4,5 or 6;
or
Figure BDA0002610707420000031
Forming a substituted or unsubstituted C4-C8 heterocyclic ring, a substituted or unsubstituted 5-10 membered heteroaromatic ring;
in each of the above formulae, the heterocyclyl or heteroaryl groups each independently include 1,2, or 3 heteroatoms independently selected from O, N, or S (O)p；
Unless otherwise specified, "substituted" means substituted with one or more (e.g., 2,3, 4, etc.) substituents selected from the group consisting of: halogen, C1-C6 alkyl, halogenated C1-C6 alkyl, C1-C6 alkoxy, halogenated C1-C6 alkoxy, C3-C8 cycloalkyl, halogenated C3-C8 cycloalkyl, oxo, -CN, hydroxy, amino, carboxy, amide, sulfonamide, sulfone; a group selected from the group consisting of unsubstituted or substituted with one or more substituents: a C6-C10 aryl group, a halogenated C6-C10 aryl group, a 5-10 membered heteroaryl group having 1-3 heteroatoms selected from N, S and O, a halogenated 5-10 membered heterocyclyl group having 1-3 heteroatoms selected from N, S and O, and said substituents are selected from the group consisting of: halogen, C1-C6 alkyl, C1-C6 alkoxy, ═ O.
In another preferred embodiment, X is O, NR4Or CR4R6(ii) a And/or said Y is C ═ O.
In another preferred embodiment, the compound of formula (I) has the structure shown in formula (II) below:
Figure BDA0002610707420000032
wherein G is CH or N, and when G is CH, the CH can be replaced by R1Substituted (i.e., R)1Located on G).
In another preferred embodiment, L is1Is CONH, and/or said L2Is O.
In another preferred embodiment, the compound has the structure shown in the following formula (III):
Figure BDA0002610707420000041
wherein Ra, Rb, Rc and Rd are independently selected from the following groups: hydrogen, deuterium, ═ O, halogen, CF3，CD3，OCF3，OCH3，OCD3Cyano, nitro, hydroxy, amino, SO2N(R4)2，CON(R4)2，COOR4，SOR7，SO2R7Substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted- (L)m-H, substituted or unsubstituted C3-C8 cycloalkyl, substituted or unsubstituted C4-C8 heterocyclyl, substituted or unsubstituted 6-10 membered aryl, substituted or unsubstituted 5-10 membered heteroaryl.
In another preferred embodiment, Ra, Rb, Rc and Rd are each independently selected from the group consisting of: hydrogen, deuterium, halogen, CF3，CD3，OCF3，OCH3，OCD3，CN。
In another preferred embodiment, the Cyc2 ring is a benzene ring or pyridine ring.
In another preferred embodiment, the compound of formula (I) has the structure shown in formula (IV) below:
Figure BDA0002610707420000042
wherein A is N or CR8And said R is8Selected from the group consisting of: H. f, and said CR8Can be covered with
Figure BDA0002610707420000043
Substituted (i.e., the substituent is on a);
and when A is N, R3Can form N with A+-O-。
In another preferred embodiment, the compound of formula (I) has a structure as shown in formula (V):
Figure BDA0002610707420000051
in another preferred embodiment, the compound of formula (I) has the structure shown in formula (VI):
Figure BDA0002610707420000052
in another preferred embodiment, the compound of formula (I) has the structure shown below:
Figure BDA0002610707420000053
wherein Ar is a substituted or unsubstituted 5-10 membered heteroaromatic ring.
In another preferred embodiment, the compound is selected from the group consisting of:
Figure BDA0002610707420000061
Figure BDA0002610707420000071
in a second aspect of the invention, there is provided a pharmaceutical composition comprising a pharmaceutically acceptable carrier and a compound, isomer, solvate or pharmaceutically acceptable salt or hydrate thereof according to the first aspect of the invention.
In another preferred embodiment, the pharmaceutical composition is used in a method of treating, ameliorating or preventing a disease or disorder associated with sodium channel modulation; preferably, the disease or condition is pain.
In another preferred embodiment, the pain or disease is selected from the group consisting of: chronic pain, intestinal pain, neuropathic pain, musculoskeletal pain, acute pain, inflammatory pain, cancer pain, idiopathic pain, post-operative pain, visceral pain, multiple sclerosis, peroneal muscular atrophy (Charcot-Marie-Tooth syndrome), incontinence, pathological cough, or cardiac arrhythmia.
In another preferred embodiment, the treatment comprises reducing the severity of pain in the patient.
In another preferred embodiment, the neuropathic pain comprises post-herpetic neuralgia.
In another preferred embodiment, the neuropathic pain comprises idiopathic small-fiber neuropathy.
In another preferred embodiment, the musculoskeletal pain comprises osteoarthritis pain.
In another preferred embodiment, the acute pain comprises acute post-operative pain.
In another preferred embodiment, the post-operative pain comprises a bunion removal pain or an abdominoplasty pain.
In a third aspect of the invention, there is provided a use of a compound of the first aspect of the invention, or a pharmaceutically acceptable salt or hydrate thereof, for the manufacture of a pharmaceutical composition for the treatment, alleviation or prevention of a disease associated with sodium channel modulation; preferably, the disease or condition is pain.
In another preferred embodiment, the pain or disease is selected from the group consisting of: chronic pain, intestinal pain, neuropathic pain, musculoskeletal pain, acute pain, inflammatory pain, cancer pain, idiopathic pain, post-operative pain, visceral pain, multiple sclerosis, peroneal muscular atrophy (Charcot-Marie-Tooth syndrome), incontinence, pathological cough, or cardiac arrhythmia.
It is to be understood that within the scope of the present invention, the above-described features of the present invention and those specifically described below (e.g., in the examples) may be combined with each other to form new or preferred embodiments. Not to be reiterated herein, but to the extent of space.
Detailed Description
The present inventors have conducted extensive and intensive studies for a long time and have unexpectedly found a compound represented by the formula (I). The compounds have unexpected activity in modulating cytokines and/or interferons and are useful in the treatment of diseases mediated by cytokines and/or interferons. The compounds have unexpected activity on Nav1.8 and excellent selectivity on other Navs subtypes, and can be used for treating, relieving or preventing Nav 1.8-related diseases. Based on the above findings, the inventors have completed the present invention.
Definition of
As used herein, the term "alkyl" includes straight or branched chain alkyl groups. E.g. C1-C4Alkyl represents a straight or branched chain alkyl group having 1 to 4 carbon atoms, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, and the like.
As used herein, the term "C3-C8Cycloalkyl "refers to cycloalkyl groups having 3 to 8 carbon atoms. It may be a single ring, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, or the like. Also bicyclic, e.g., bridged, fused or spiro forms.
As used herein, the term“C6-C10Aryl "means an aryl group having 6 to 10 carbon atoms, for example, phenyl or naphthyl and the like.
As used herein, the term "5-10 membered heteroaryl having 1-3 heteroatoms selected from the group consisting of N, S and O" refers to a cyclic aromatic group having 5-10 atoms and wherein 1-3 atoms are heteroatoms selected from the group consisting of N, S and O. It may be a single ring or a condensed ring form. Specific examples may be pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, pyrrolyl, pyrazolyl, imidazolyl, (1,2,3) -triazolyl and (1,2,4) -triazolyl, tetrazolyl, furyl, thienyl, isoxazolyl, thiazolyl, oxazolyl and the like.
Unless specifically stated to be "substituted or unsubstituted", the groups of the present invention may be substituted with a substituent selected from the group consisting of: halogen, nitrile group, nitro group, hydroxyl group, amino group, C1-C6Alkyl-amino, C1-C6Alkyl radical, C2-C6Alkenyl radical, C2-C6Alkynyl, C1-C6Alkoxy, halo C1-C6Alkyl, halo C2-C6Alkenyl, halo C2-C6Alkynyl, halo C1-C6Alkoxy, allyl, benzyl, C6-C12Aryl radical, C1-C6alkoxy-C1-C6Alkyl radical, C1-C6Alkoxy-carbonyl, phenoxycarbonyl, C2-C6Alkynyl-carbonyl, C2-C6Alkenyl-carbonyl, C3-C6Cycloalkyl-carbonyl, C1-C6Alkyl-sulfonyl, and the like.
As used herein, "halogen" or "halogen atom" refers to F, Cl, Br, and I. More preferably, the halogen or halogen atom is selected from F, Cl and Br. "halogenated" means substituted with an atom selected from F, Cl, Br, and I.
Unless otherwise specified, the structural formulae depicted herein are intended to include all isomeric forms (e.g., enantiomers, diastereomers and geometric isomers (or conformational isomers)): for example, R, S configuration containing an asymmetric center, (Z), (E) isomers of double bonds, and the like. Thus, individual stereochemical isomers of the compounds of the present invention or mixtures of enantiomers, diastereomers or geometric isomers (or conformers) thereof are within the scope of the present invention.
As used herein, the term "hydrate" refers to a complex formed by the coordination of a compound of the present invention with water.
The compounds of the present application may be prepared by a variety of synthetic methods well known to those skilled in the art, including the specific embodiments listed below, embodiments formed by combinations of the specific embodiments with other chemical synthetic methods, and equivalents known to those skilled in the art, with preferred embodiments including, but not limited to, the examples of the present application.
The solvent used in the present application can be commercially available. Abbreviations used in this application are as follows: aq represents an aqueous solution; HATU represents O- (7-azabenzotriazol-1-yl) -N, N' -tetramethyluronium hexafluorophosphate; EDC stands for N- (3-dimethylaminopropyl) -N' -ethylcarbodiimide hydrochloride; m-CPBA represents 3-chloroperoxybenzoic acid; eq represents equivalent, equivalent; CDI represents carbonyldiimidazole; DCM represents dichloromethane; PE represents petroleum ether; DIAD represents diisopropyl azodicarboxylate; DMF represents N, N-dimethylformamide; DMSO represents dimethyl sulfoxide; EtOAc for ethyl acetate; EtOH stands for ethanol; MeOH represents methanol; cbz represents benzyloxycarbonyl, an amino protecting group; boc represents tert-butyloxycarbonyl, an amino protecting group; HOAc represents acetic acid; NaCNBH3Represents sodium cyanoborohydride; r.t. represents room temperature; THF represents tetrahydrofuran; TFA represents trifluoroacetic acid; DIPEA stands for diisopropylethylamine; boc2O represents di-tert-butyl dicarbonate; LDA stands for lithium diisopropylamide.
The compound is artificially synthesized or
Figure BDA0002610707420000081
The software names, and the commercial compounds are under the supplier catalog name.
Pharmaceutical compositions and methods of administration
Since the compound of the present invention has excellent activity as a sodium channel modulator, the compound of the present invention and various crystalline forms, pharmaceutically acceptable inorganic or organic salts, hydrates or solvates thereof, and a pharmaceutical composition containing the compound of the present invention as a main active ingredient can be used for the prevention and/or treatment (stabilization, alleviation or cure) of a disease or disorder associated with a sodium channel, such as pain and the like.
The pharmaceutical compositions of the present invention comprise a safe and effective amount of a compound of the present invention in combination with a pharmaceutically acceptable excipient or carrier. Wherein "safe and effective amount" means: the amount of the compound is sufficient to significantly improve the condition without causing serious side effects. Typically, the pharmaceutical composition contains 1-2000mg of a compound of the invention per dose, more preferably, 1-200mg of a compound of the invention per dose. Preferably, said "dose" is a capsule or tablet.
"pharmaceutically acceptable carrier" refers to: one or more compatible solid or liquid fillers or gel substances which are suitable for human use and must be of sufficient purity and sufficiently low toxicity. By "compatible" is meant herein that the components of the composition are capable of intermixing with and with the compounds of the present invention without significantly diminishing the efficacy of the compounds. Examples of pharmaceutically acceptable carrier moieties are cellulose and its derivatives (e.g., sodium carboxymethylcellulose, sodium ethylcellulose, cellulose acetate, etc.), gelatin, talc, solid lubricants (e.g., stearic acid, magnesium stearate), calcium sulfate, vegetable oils (e.g., soybean oil, sesame oil, peanut oil, olive oil, etc.), polyols (e.g., propylene glycol, glycerin, mannitol, sorbitol, etc.), emulsifiers (e.g., propylene glycol, glycerin, mannitol, sorbitol, etc.), and the like
Figure BDA0002610707420000091
) Wetting agents (e.g., sodium lauryl sulfate), coloring agents, flavoring agents, stabilizers, antioxidants, preservatives, pyrogen-free water, and the like.
The mode of administration of the compounds or pharmaceutical compositions of the present invention is not particularly limited, and representative modes of administration include (but are not limited to): oral, parenteral (intravenous, intramuscular, subcutaneous or topical).
Solid dosage forms for oral administration include capsules, tablets, pills, powders and granules. In these solid dosage forms, the active compound is mixed with at least one conventional inert excipient (or carrier), such as sodium citrate or dicalcium phosphate, or with the following ingredients: (a) fillers or extenders, for example, starch, lactose, sucrose, glucose, mannitol and silicic acid; (b) binders, for example, hydroxymethylcellulose, alginates, gelatin, polyvinylpyrrolidone, sucrose and acacia; (c) humectants, for example, glycerol; (d) disintegrating agents, for example, agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain complex silicates, and sodium carbonate; (e) slow solvents, such as paraffin; (f) absorption accelerators, e.g., quaternary ammonium compounds; (g) wetting agents, such as cetyl alcohol and glycerol monostearate; (h) adsorbents, for example, kaolin; and (i) lubricants, for example, talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, or mixtures thereof. In capsules, tablets and pills, the dosage forms may also comprise buffering agents.
Solid dosage forms such as tablets, dragees, capsules, pills, and granules can be prepared using coatings and shells such as enteric coatings and other materials well known in the art. They may contain opacifying agents and the release of the active compound or compounds in such compositions may be delayed in release in a certain part of the digestive tract. Examples of embedding components which can be used are polymeric substances and wax-like substances. If desired, the active compound may also be in microencapsulated form with one or more of the above-mentioned excipients.
Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups or tinctures. In addition to the active compounds, the liquid dosage forms may contain inert diluents commonly employed in the art such as, for example, water or other solvents, solubilizing agents and emulsifiers such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, propylene glycol, 1, 3-butylene glycol, dimethylformamide and oils, in particular, cottonseed, groundnut, corn germ, olive, castor and sesame oils or mixtures of such materials and the like.
In addition to these inert diluents, the compositions can also contain adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents.
Suspensions, in addition to the active compounds, may contain suspending agents as, for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum methoxide and agar, or mixtures of these substances, and the like.
Compositions for parenteral injection may comprise physiologically acceptable sterile aqueous or anhydrous solutions, dispersions, suspensions or emulsions, and sterile powders for reconstitution into sterile injectable solutions or dispersions. Suitable aqueous and nonaqueous carriers, diluents, solvents or vehicles include water, ethanol, polyols and suitable mixtures thereof.
The compounds of the present invention may be administered alone or in combination with other pharmaceutically acceptable therapeutic agents.
When administered in combination, the pharmaceutical composition further comprises one or more (2, 3, 4, or more) other pharmaceutically acceptable therapeutic agents. One or more (2, 3, 4, or more) of such other pharmaceutically acceptable therapeutic agents may be used simultaneously, separately or sequentially with a compound of the invention for the prevention and/or treatment of cytokine and/or interferon mediated diseases.
When the pharmaceutical composition is used, a safe and effective amount of the compound of the present invention is suitable for mammals (such as human beings) to be treated, wherein the administration dose is a pharmaceutically-considered effective administration dose, and for a human body with a weight of 60kg, the daily administration dose is usually 1 to 2000mg, preferably 1 to 500 mg. Of course, the particular dosage will depend upon such factors as the route of administration, the health of the patient, and the like, and is within the skill of the skilled practitioner.
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 under conventional conditions or conditions recommended by the manufacturers. Unless otherwise indicated, percentages and parts are by weight.
Examples
Example 1
Figure BDA0002610707420000101
First step of
Compound 1a (10.00g, 38.90mmol) and potassium carbonate (16.10g, 116.72mmol) were dissolved in N, N-dimethylformamide (100mL) under nitrogen, methyl iodide (8.30g, 58.35mmol) was added, and the resulting reaction solution was stirred at room temperature for 2 hours. After the reaction was completed, water (50mL) was added to quench the reaction, ethyl acetate (50mL) was added, the mixture was separated, the aqueous phase was extracted with ethyl acetate (30mL × 3), the organic phase was combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give 1b (12.00g) in yield: 99 percent.
1H NMR(400MHz,DMSO-d6)δ7.66(dd,J＝8.7,0.4Hz,1H),7.10(d,J＝2.6Hz,1H),6.91–6.84(m,1H),3.85(s,3H).
Second step of
To a solution of compound 1b (12.00g,44.28mmol) in tetrahydrofuran (100mL) was slowly added n-butyllithium (2.5M, 20mL, 0.50mmol) dropwise under nitrogen at-78 ℃. After the addition was complete, stirring was continued at this temperature for 30 minutes. Triisopropyl borate (11.66g, 62.0mmol) was added dropwise to the above reaction solution at-78 ℃ and reacted at this temperature for 2 hours. After the reaction was completed, the pH was adjusted to 4-5 with 1N hydrochloric acid (60mL), ethyl acetate (50mL) was added, the layers were separated, the aqueous phase was extracted with ethyl acetate (30mL × 3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give crude 1c (6.00g), yield: 42 percent.
1H NMR(400MHz,CDCl3)δ7.85(d,J＝8.2Hz,1H),6.88(d,J＝8.2Hz,1H),6.72(s,1H),5.78(s,2H),3.93(s,3H).
The third step
To a solution of compound 1c (6.00g, 25.53mmol), sodium hydroxide (1.50g, 38.30mmol), sodium bicarbonate (21.40g, 255.32mmol), acetone (100mL) and ethylenediaminetetraacetic acid (745mg,2.60mmol) in water (100mL) at 0 deg.C was added oxone complex salt (18.17g,28.10mmol), which was then warmed to room temperature and stirred for 2 hours. After the reaction was completed, the pH was adjusted to acidity with 2N hydrochloric acid (180mL), ethyl acetate (100mL) was added, liquid separation was performed, the aqueous phase was extracted with ethyl acetate (50mL × 3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a residue, which was purified by column chromatography (ethyl acetate: petroleum ether ═ 0 to 100%) to obtain 1d (2.30 g). Yield: 43 percent
1H NMR(400MHz,CDCl3)δ6.87(d,J＝8.4Hz,1H),6.73(d,J＝10.4Hz,2H),3.88(d,J＝0.6Hz,3H).
The fourth step
To compound 1e (200mg, 1.09mmol) in dry tetrahydrofuran (5mL) was slowly added lithium diisopropylamide (0.55mL, 1.20mmol) dropwise under nitrogen at-78 ℃. After stirring at this temperature for 30 minutes after the completion of the dropwise addition, a solution of ethyl chloroformate (154mg, 1.43mmol) in dry tetrahydrofuran (10mL) was added dropwise. The reaction mixture was stirred at-78 ℃ for 40 minutes, then allowed to warm to room temperature and stirred for 1 hour. After completion of the reaction, the reaction mixture was quenched with a saturated ammonium chloride solution (20mL), extracted with ethyl acetate (50mL × 3), the organic phases were combined, washed with a saturated saline solution (30mL × 1), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give a residue, which was purified by column chromatography (ethyl acetate: petroleum ether ═ 0 to 100%) to give compound 1f (30 mg). Yield: 12 percent.
1H NMR(400MHz,DMSO-d6)δ8.01(dd,J＝14.4,8.5Hz,1H),7.43(t,J＝9.0Hz,1H),4.43–4.30(m,2H),1.34–1.22(m,3H).
The fifth step
Compound 1f (4.00g, 15.74mmol) was dissolved in methanol (40mL), and 1N aqueous sodium hydroxide solution (40mL) was added. The reaction was stirred at room temperature for 2 hours under nitrogen. After completion of the reaction, 6N hydrochloric acid was added to the reaction mixture to adjust the pH to about 1, and the mixture was diluted with water (60mL), extracted with ethyl acetate (100 mL. times. 3), and the organic phases were combined, washed with saturated brine (50 mL. times. 1), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give 1g (1.50g) of the compound. Yield: 38 percent.
1H NMR(400MHz,DMSO-d6)δ7.99(dd,J＝14.4,8.5Hz,1H),7.42(t,J＝8.9Hz,1H).
The sixth step
Sodium methoxide (35mg, 0.64mmol) was added to a solution of 1h (200mg, 1.28mmol) and paraformaldehyde (153mg, 5.12mmol) in methanol (15mL) under nitrogen at 0 deg.C. After the addition was complete, the reaction was allowed to warm to room temperature and stirring was continued for 16 hours. The reaction was cooled to 0 ℃ and sodium borohydride (98mg, 2.56mmol) was added portionwise, then warmed to room temperature and stirring continued for 16 h. After completion of the reaction, concentration under reduced pressure gave a residue, which was diluted with water (20mL), extracted with ethyl acetate (20mL × 3), combined with an organic phase, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give a residue, which was purified by column chromatography (ethyl acetate: petroleum ether ═ 0-100%) to give 1i (96mg) in yield: 44 percent.
MS-ESI calculated value [ M +1 ]]+171, found value 171.
1H NMR(400MHz,CDCl3)δ7.55–7.43(m,2H),7.10–6.93(m,1H),2.94(s,3H).
Seventh step
To a mixed solution of 1i (100mg, 0.59mmol) of acetic acid (4mL) and water (2mL) was added potassium cyanate (95mg, 1.18mmol) under nitrogen, and stirring was continued at room temperature for 48 hours. After completion of the reaction, the reaction mixture was directly concentrated under reduced pressure, diluted with water (20mL), extracted with ethyl acetate (20mL × 3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give a residue, which was purified by column chromatography (methanol: dichloromethane ═ 0 to 100%) to give 1j (41mg) in yield: 32 percent.
MS-ESI calculated value [ M +1 ]]+214, measured value 214.
1H NMR(400MHz,DMSO-d6)δ8.30–8.08(m,2H),7.53(t,J＝9.4Hz,1H),6.24(s,2H),3.12(s,3H).
Eighth step
1j (200mg, 0.93mmol) was dissolved in methanol (10mL) and 10% wet palladium on carbon catalyst (10%, 40mg) was added at room temperature. The reaction was replaced three times with hydrogen (15psi) and placed under a hydrogen atmosphere (15psi) and stirring continued at room temperature for 4 hours. After completion of the reaction, filtration under reduced pressure was carried out, and the filtrate was concentrated under reduced pressure to give a residue, which was purified by column chromatography (methanol: dichloromethane ═ 0 to 100%) to give 1k (150mg) in yield: 88 percent.
1H NMR(400MHz,DMSO-d6)δ6.88(t,J＝9.9Hz,1H),6.44(dd,J＝6.4,2.8Hz,2H),5.68(s,2H),5.10(s,2H),2.97(s,3H).
The ninth step
To a solution of compound 1g (237mg, 1.05mmol) in thionyl chloride (10mL) was added a catalytic amount of N, N-dimethylformamide. The reaction solution was stirred at 90 ℃ for 2 hours. After the reaction solution is finished, directly concentrating the reaction solution and drying. The crude product was dissolved in methylene chloride (10mL), and triethylamine (213mg, 2.11mmol) and 1k (150mg, 0.81mmol) were added in that order. The reaction solution was stirred at room temperature for 4 hours. After completion of the reaction, the reaction mixture was directly concentrated under reduced pressure to give a residue, which was purified by column chromatography (methanol: dichloromethane ═ 0 to 100%) to give 1f (155mg), yield: 48 percent.
MS-ESI calculated value [ M +1 ]]+392, found 392.
The tenth step
To a solution of compound 1l (150mg, 0.38mmol) in N, N-dimethylformamide (10mL) under nitrogen at room temperature were added compound 1g (88mg, 0.42mmol) and cesium carbonate (370mg,1.14mmol) in that order. The reaction was brought to 60 ℃ and stirring was continued for 3 hours. After the reaction was completed, the reaction solution was cooled to room temperature, quenched with water (30mL), extracted with ethyl acetate (20mL × 3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give a residue, which was purified by thin layer chromatography (methanol: dichloromethane ═ 0 to 100%) to give 1(80mg) in yield: 36 percent.
MS-ESI calculated value [ M +1 ]]+580, found 580.
1H NMR(400MHz,DMSO-d6)δ10.94(s,1H),7.74(t,J＝8.5Hz,1H),7.68(dd,J＝7.2,2.3Hz,1H),7.59–7.52(m,1H),7.32(d,J＝8.7Hz,1H),7.24(t,J＝9.5Hz,2H),7.02(d,J＝8.8Hz,1H),6.60(d,J＝9.0Hz,1H),5.97(s,2H),3.76(s,3H),3.04(s,3H).
Example 2
Figure BDA0002610707420000131
First step of
Compound 2a (5.00g, 27.31mmol) was dissolved in dry tetrahydrofuran (50mL) and cooled to-78 ℃ with replacement of nitrogen. Lithium diisopropylamide (15mL, 30.00mmol) was slowly added dropwise and stirred at-78 deg.C for 30 min. Ethyl chloroformate (3.84g, 35.38mmol) was dissolved in dry tetrahydrofuran (10mL) and slowly added to the reaction mixture, followed by stirring at-78 ℃ for 40 minutes, then naturally warmed to room temperature and stirred for 1 hour. After quenching the reaction with saturated ammonium chloride solution (50mL), extraction with ethyl acetate (50mL × 3) was performed, the organic phases were combined, washed with saturated brine (30mL × 1), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give a residue, which was purified by column chromatography (ethyl acetate: petroleum ether ═ 0-100%) to give compound 2b (3.10g), yield: 45 percent.
1H NMR(400MHz,DMSO-d6)δ8.86(s,1H),4.42(d,J＝7.2Hz,2H),1.30(t,J＝7.2Hz,3H).
Second step of
2b (340mg, 1.35mmol) and 1d (280mg, 1.35mmol) were dissolved in N, N-dimethylformamide (10mL), and cesium carbonate (877mg, 2.69mmol) was added under ice bath. After the nitrogen gas was replaced three times, the reaction system was stirred and reacted for 1.5 hours while continuing to cool on ice, the temperature was raised to room temperature, water (20mL) and ethyl acetate (30mL) were added, liquid was separated, the aqueous phase was extracted with ethyl acetate (30mL × 3), the organic phase was combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a residue, which was purified by column chromatography (petroleum ether: ethyl acetate ═ 0 to 100%) to obtain 2c (300mg), yield: 51 percent.
1H NMR(400MHz,CD3OD)δ7.94(s,1H),7.31(d,J＝8.8Hz,1H),7.11(d,J＝2.4Hz,1H),7.00–6.95(m,1H),4.40(qd,J＝7.2,1.6Hz,2H),3.79(s,3H),1.35(td,J＝7.2,1.6Hz,3H).
The third step
2c (300mg, 0.68mmol) was dissolved in a mixed solvent of tetrahydrofuran (15mL) and water (15mL), and sodium hydroxide (135mg, 3.38mmol) was added in portions under ice-bath conditions, and after replacing nitrogen, the reaction system was warmed to room temperature and stirred for 2 hours. The pH was adjusted to about 2 with 1N dilute hydrochloric acid, extracted with dichloromethane (30mL x3), the organic phases combined and washed with saturated brine (20mL x1), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give crude 2d (290 mg).
1H NMR(400MHz,CDCl3)δ7.89(s,1H),7.25(s,1H),7.24–7.20(m,1H),6.89–6.87(m,1H),3.78(s,3H).
The fourth step
Compound 1h (300mg, 1.92mmol) was dissolved in a mixed solution of acetic acid (10mL) and water (5mL), followed by addition of potassium cyanate (312mg, 3.84 mmol). After stirring at room temperature for 16 hours, the reaction solution was concentrated under reduced pressure to give a residue, which was purified by column chromatography (methanol: dichloromethane 0-100%) to give 2e (90mg), a two-step yield: 24 percent.
The fifth step
Compound 2e (80mg, 0.40mmol) was dissolved in methanol (10mL), followed by addition of wet palladium on carbon (5mg, 0.04mmol) and replacement of hydrogen gas, followed by stirring at room temperature for 1 hour. Filtration through celite, and concentration under reduced pressure afforded crude 2f (50mg), yield: 74 percent.
The sixth step
Compound 2d (80mg, 0.20mmol) was dissolved in dichloromethane (5mL), followed by addition of oxalyl chloride (50mg, 0.40mmol) and N, N-dimethylformamide (20uL), stirring at room temperature for 2 hours, addition of compound 2f (42mg, 0.25mmol) and triethylamine (61mg, 0.60mmol), and stirring at room temperature for 2 hours. The reaction solution was concentrated under reduced pressure to give a residue, which was purified by column chromatography (methanol: dichloromethane ═ 0 to 100%) to give 2(55mg), yield: 50 percent.
MS-ESI calculated value [ M +1 ]]+567, found 567.
1H NMR(400MHz,DMSO-d6)δ10.93(s,1H),8.37(s,1H),8.36–8.31(m,1H),8.09(s,1H),7.37–7.33(m,2H),7.20(s,1H),7.17–7.09(m,1H),6.98–6.96(m,1H),6.21(s,2H),3.76(s,3H).
Example 3
Figure BDA0002610707420000141
Figure BDA0002610707420000151
First step of
Compound 3a (1.00g, 5.02mmol) was dissolved in dichloromethane (10mL), and sodium bicarbonate (1.30g, 15.06mmol), aqueous ammonia (10mL) and thionyl chloride (20mL) were added under ice-bath. After nitrogen substitution, stirring at room temperature for 2 hours, filtration, and concentration of the filtrate under reduced pressure gave crude 3b (900mg), yield: 91 percent.
1H NMR(400MHz,DMSO-d6)δ8.28–8.26(m,1H),8.19–8.14(m,1H),7.57(s,1H),7.45–7.40(m,1H),7.04(s,1H),3.58(s,2H).
Second step of
3b (900mg, 4.54mmol) was dissolved in methanol (15mL) and 10% wet palladium on carbon (180mg) was added at room temperature. The hydrogen (15psi) was replaced three times and placed under hydrogen (15psi) for 4 hours at room temperature. After the reaction was completed, filtration was performed under reduced pressure, and the filtrate was concentrated under reduced pressure to give crude product 3c (800mg), yield: 100 percent.
1H NMR(400MHz,DMSO-d6)δ7.34(s,1H),6.85(s,1H),6.73(t,J＝9.2Hz,1H),6.42–6.40(m,1H),6.38–6.35(m,1H),4.82(s,2H),3.23(s,2H).
The third step
Compound 1g (2.00g, 8.85mmol), cesium carbonate (5.77g, 17.70mmol) and iodomethane (2.51g, 17.70mmol) were dissolved in N, N-dimethylformamide (100mL), and the mixture was stirred at room temperature for 2 hours while displacing nitrogen. After dilution with water (60mL), extraction with ethyl acetate (100mL × 3), organic phases were combined, washed with saturated brine (50mL × 1), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give 3d (1.50g), yield: 70 percent. MS-ESI calculated value [ M +1 ]]+241, measured value 241.
The fourth step
3d (1.50g, 6.25mmol) and 1d (1.30g, 6.25mmol) were dissolved in N, N-dimethylformamide (10mL), and cesium carbonate (4.07g, 12.5mmol) was added under ice bath. After the replacement with nitrogen gas three times, the reaction system was further stirred for 1.5 hours under ice bath, warmed to room temperature, added with water (20mL) and ethyl acetate (30mL), separated, the aqueous phase was extracted with ethyl acetate (30mL × 3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give a residue, which was purified by column chromatography (petroleum ether: ethyl acetate ═ 0-100%) to give 3e (1.20g), yield: 45 percent.
MS-ESI calculated value [ M +1 ]]+429, found 429.
The fifth step
3e (1.20g, 2.80mmol) was dissolved in a mixed solvent of tetrahydrofuran (15mL) and water (15mL), and sodium hydroxide (561mg, 14.02mmol) was added in portions under ice-bath conditions, and after replacing nitrogen, the reaction system was warmed to room temperature and stirred for 2 hours. Adjusted to pH about 2 with 1N dilute hydrochloric acid, extracted with dichloromethane (30mL x3), combined organic phases, washed with brine (20mL x1), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give crude 3f (800mg) in yield: and 69 percent.
MS-ESI calculated value [ M +1 ]]+415, found value 415.
The sixth step
3f (50mg, 0.12mmol) was dissolved in N, N-dimethylformamide (5mL), 3c (24mg, 0.14mmol), 2- (7-benzotriazole oxide) -N, N' -tetramethyluronium hexafluorophosphate (69mg, 0.18mmol), N-diisopropylethylamine (47mg, 0.36mmol) were added, then nitrogen substitution was carried out three times, after stirring at room temperature for 2 hours, water (15mL) and ethyl acetate (15mL) were added, liquid separation was carried out, the aqueous phase was extracted with ethyl acetate (20mL × 3), organic phase was combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give a residue, which was purified by methanol: dichloromethane ═ 0 to 100% to give 3(21mg) in yield: 32 percent.
MS-ESI calculated value [ M +1 ]]+565, found 565.
1H NMR(400MHz,CD3OD)δ7.66–7.57(m,3H),7.25(d,J＝8.8Hz,1H),7.11–7.05(m,2H),6.93–6.92(m,1H),6.61(d,J＝8.8Hz,1H),3.77(s,3H),3.57(s,2H).
Example 4
Figure BDA0002610707420000161
First step of
Compound 1h (500mg, 3.20mmol) was dissolved in dichloromethane (10mL) and then 4a (460mg, 3.85mmol) was added slowly under ice bath. After stirring overnight after being replaced with nitrogen three times, water (50mL) was added to dilute the solution and extracted with dichloromethane (50mL × 3), the organic phases were combined, washed with saturated brine (50mL × 1), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give a residue, which was purified by column chromatography (methanol: dichloromethane ═ 0-100%) to give 4b (358mg) in yield: 41 percent.
MS-ESI calculated value [ M +1 ]]+276, found 276.
Second step of
Compound 4b (100mg, 0.36mmol) was dissolved in tetrahydrofuran (2mL) and then 60% sodium hydride (44mg, 1.08mmol) was slowly added while cooling on ice. After stirring for 2 hours after purging with nitrogen three times, water (20mL) was added to dilute the solution and extracted with ethyl acetate (20mL × 3), the organic phases were combined, washed with saturated brine (20mL x1), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a residue, which was purified by column chromatography (methanol: dichloromethane 0-100%) to obtain compound 4c (60mg) in yield: 70 percent.
MS-ESI calculated value [ M +1 ]]+240, measured value 240.
The third step
Compound 4c (60mg, 0.25mmol) was dissolved in methanol (2mL) and 10% wet palladium on carbon (10mg) was added. After hydrogen substitution three times, stirring was carried out for 2 hours, and the reaction mixture was filtered and concentrated under reduced pressure to give 4d (40mg) in yield: 77 percent.
MS-ESI calculated value [ M +1 ]]+210, measured value 210.
The fourth step
Dissolving 2d (80mg, 0.20mmol) in N, N-dimethylformamide (4mL), adding 4d (40mg, 0.20mmol), 2- (7-benzotriazole oxide) -N, N' -tetramethyluronium hexafluorophosphate (115mg, 0.30mmol), N-diisopropylethylamine (78mg, 0.60mmol), then displacing with nitrogen three times, stirring at room temperature for 2 hours, adding water (20mL) and ethyl acetate (20mL), separating, extracting the aqueous phase with ethyl acetate (20mL × 3), combining the organic phases, drying over anhydrous sodium sulfate, filtering, concentrating under reduced pressure to give a residue, and purifying the residue by column chromatography (methanol: dichloromethane ═ 0-100%) to give 4(39mg) in yield: 33 percent.
MS-ESI calculated value [ M +1 ]]+607, found 607.
1H NMR(400MHz,DMSO-d6)δ11.04(s,1H),8.11(s,1H),7.62–7.60(m,1H),7.36–7.34(m,2H),7.23–7.20(m,2H),6.98–6.96(m,1H),6.66(s,1H),3.76(s,3H),3.49–3.47(m,2H),3.21(s,2H),1.93–1.90(m,2H).
Example 5
Figure BDA0002610707420000171
First step of
After 1i (100mg, 0.59mmol) was dissolved in dichloromethane (10mL) and methanesulfonyl chloride (0.14mL, 1.76mmol), triethylamine (0.25mL, 1.76mmol) and nitrogen were added thereto three times, the reaction was stirred at room temperature overnight. Concentration under reduced pressure gave a residue, which was subjected to column chromatography (ethyl acetate: petroleum ether ═ 0 to 100%) to give compound 5a (55mg), yield: 38 percent.
MS-ESI calculated value [ M +1 ]]+249, found 249.
Second step of
Compound 5a (55mg, 0.22mmol) was dissolved in anhydrous methanol (10mL), 10% wet palladium on carbon (11mg) was added three times at room temperature, replaced with hydrogen, and then stirred at room temperature for 2 hours. Filtration through celite, and concentration under reduced pressure afforded crude 5b (39mg), yield: 81 percent.
MS-ESI calculated value [ M +1 ]]+219, found value 219.
The third step
After dissolving 5b (39mg, 0.18mmol) in N, N-dimethylformamide (5mL), 2d (62mg, 0.15mmol), 2- (7-benzotriazole oxide) -N, N' -tetramethyluronium hexafluorophosphate (85mg, 0.22mmol), N-diisopropylethylamine (58mg, 0.45mmol) were added and then replaced with nitrogen three times, and after stirring at room temperature for 3 hours, water (30mL) and ethyl acetate (30mL) were added, liquid separation was performed, the aqueous phase was extracted with ethyl acetate (20mLx3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give a residue, which was purified by column chromatography (methanol: dichloromethane ═ 0-100%) to give 5(17mg) yield: 15 percent.
MS-ESI calculated value [ M +1 ]]+616, found 616.
1H NMR(400MHz,DMSO-d6)δ11.15(s,1H),8.13(s,1H),7.74–7.73(m,1H),7.60–7.54(m,1H),7.35–7.32(m,2H),7.21(d,J＝2.4Hz,1H),6.98(d,J＝9.6Hz,1H),3.76(s,3H),3.18(s,3H),3.05(s,3H).
Example 6
Figure BDA0002610707420000181
First step of
After 1h (500mg, 3.21mmol) was dissolved in dichloromethane (10mL), 6a (0.33mL, 3.85mmol) was added and the mixture was replaced with nitrogen three times, the reaction was stirred at room temperature overnight. Concentration under reduced pressure gave a residue, which was subjected to column chromatography (ethyl acetate: petroleum ether ═ 0 to 100%) to give 6b (314mg), yield: 37 percent.
MS-ESI calculated value [ M +1 ]]+262, measured value 262.
Second step of
6b (300mg, 1.15mmol) was dissolved in anhydrous tetrahydrofuran (10mL), 60% sodium hydride (83mg, 3.45mmol) was added under ice-bath, and the mixture was replaced with nitrogen three times and stirred at room temperature for 5 hours. Concentration under reduced pressure gave a residue, which was purified by column chromatography (ethyl acetate: petroleum ether ═ 0 to 100%) to give 6c (229mg), yield: 88 percent.
MS-ESI calculated value [ M +1 ]]+226, found value 226.
The third step
6c (229mg, 1.02mmol) was dissolved in anhydrous methanol (10mL), palladium on carbon (46mg) was added at room temperature, and the mixture was replaced with hydrogen gas three times, followed by stirring at room temperature for 2 hours. Filtration over celite and concentration of the filtrate under reduced pressure gave crude 6d (178mg), yield: 89 percent.
MS-ESI calculated value [ M +1 ]]+196, found 196.
The fourth step
After 6d (50mg, 0.26mmol) was dissolved in N, N-dimethylformamide (5mL), 2d (89mg, 0.21mmol), 2- (7-benzotriazole oxide) -N, N' -tetramethyluronium hexafluorophosphate (122mg, 0.32mmol), N-diisopropylethylamine (83mg, 0.64mmol) were added, then nitrogen substitution was carried out three times, after stirring at room temperature for 4 hours, water (30mL) and ethyl acetate (30mL) were added, liquid separation was carried out, the aqueous phase was extracted with ethyl acetate (20mL × 3), organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give a residue, which was purified by column chromatography (methanol: dichloromethane ═ 0-100%) to give 6(30mg) in yield: 20 percent.
MS-ESI calculated value [ M +1 ]]+593, found 593.
1H NMR(400MHz,DMSO-d6)δ11.04(s,1H),8.11(s,1H),7.78–7.77(m,1H),7.45–7.43(m,1H),7.35–7.34(m,1H),7.21(s,2H),7.00–6.94(m,2H),3.81-3.80(m,2H),3.76(s,3H),3.42–3.36(m,2H).
Example 7
Figure BDA0002610707420000191
First step of
7a (3.00g, 16.38mmol), N, N-dimethylformamide dimethyl acetal (3.90g, 32.76mmol) was dissolved in toluene, then replaced with nitrogen three times, heated to 110 ℃ and stirred for 2 hours, then diluted with water (100mL), extracted with ethyl acetate (100mL x2), washed with saturated brine (100mL x1), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give 7b (2.50g), yield: and 64 percent.
Second step of
After 7b (500mg, 2.08mmol) was dissolved in ethanol (10mL), hydroxylamine hydrochloride (296mg, 4.17mmol) was further added, nitrogen gas was substituted three times, and the mixture was stirred at 90 ℃ for 2 hours, the reaction solution was concentrated under reduced pressure to give a residue, which was purified by column chromatography (ethyl acetate: petroleum ether ═ 0-100%) to give 7c (150mg), yield: 35 percent.
The third step
7c (150mg, 0.72mmol), iron powder (201mg, 3.59mmol), ammonium chloride (384mg, 7.17mmol) were dissolved in a mixed solvent of ethanol (6mL) and water (2mL), then replaced with nitrogen three times, heated to 80 ℃ and stirred for 2 hours, cooled to room temperature, filtered through celite, diluted with water (100mL), extracted with ethyl acetate (100mL x2), washed with saturated brine (100mL x1), dried over anhydrous sodium sulfate, concentrated under reduced pressure to give a residue, which was purified by column chromatography (methanol: dichloromethane ═ 0-100%) to give 7d (18mg), yield: 14 percent.
MS-ESI calculated value [ M +1 ]]+179, found 179.
The fourth step
After 2d (42mg, 0.10mmol), 7d (18mg, 0.10mmol) were dissolved in N, N-dimethylformamide (2mL), and further 2- (7-benzotriazole oxide) -N, N' -tetramethyluronium hexafluorophosphate (57mg, 0.15mmol), N-diisopropylethylamine (32mg, 0.25mmol) was added, followed by nitrogen substitution three times, stirring at room temperature for 2 hours, direct concentration under reduced pressure gave a residue, which was purified by column chromatography (methanol: dichloromethane ═ 0 to 100%) to give 7(4mg) with yield: 7 percent.
MS-ESI calculated value [ M +1 ]]+576, found 576.
1H NMR(400MHz,CD3OD)δ8.49(d,J＝2.0Hz,1H),8.22–8.21(m,1H),8.02(s,1H),7.79–7.76(m,1H),7.32–7.31(m,2H),7.07(d,J＝2.4Hz,1H),6.92(d,J＝8.8Hz,1H),6.81(s,1H),3.80(s,3H).
Example 8
Figure BDA0002610707420000201
First step of
After 7b (1.00g, 4.16mmol) was dissolved in ethanol (20mL), hydrazine hydrate (416mg, 8.33mmol) was added thereto, the mixture was replaced with nitrogen three times, and the mixture was heated to 90 ℃ and stirred for 2 hours, the reaction mixture was concentrated under reduced pressure to give a residue, which was purified by column chromatography (ethyl acetate: petroleum ether ═ 0-100%) to give 8a (300mg), yield: 35 percent.
Second step of
Dissolving 8a (100mg, 0.48mmol), iron powder (135mg, 2.40mmol), ammonium chloride (257mg, 4.80mmol) in a mixed solvent of ethanol (6mL) and water (2mL), then displacing with nitrogen three times, heating to 80 ℃, stirring for 2 hours, cooling to room temperature, filtering with celite, diluting with water (100mL), extracting with ethyl acetate (100mL x2), washing with saturated brine (100mL x1), drying over anhydrous sodium sulfate, concentrating the organic phase under reduced pressure to give a residue, and purifying the residue by column chromatography (methanol: dichloromethane ═ 0-100%) to give 8b (40mg) in yield: and 47 percent.
MS-ESI calculated value [ M +1 ]]+178, found 178.
The third step
2d (100mg, 0.51mmol), 8b (40mg, 0.51mmol) were dissolved in N, N-dimethylformamide (5mL), and 2- (7-benzotriazole oxide) -N, N' -tetramethyluronium hexafluorophosphate (290mg, 0.76mmol), N-diisopropylethylamine (164mg, 1.27mmol) was further added, followed by nitrogen substitution three times, stirring at room temperature for 2 hours, and concentration under reduced pressure gave a residue, which was purified by column chromatography (methanol: dichloromethane ═ 0 to 100%) to give 8(3mg), yield: 1 percent.
MS-ESI calculated value [ M +1 ]]+575, found 575.
1H NMR(400MHz,DMSO-d6)δ11.20(s,1H),8.48(d,J＝2.8Hz,1H),8.37–8.35(m,1H),8.15(s,1H),7.62(s,1H),7.46–7.35(m,2H),7.21(s,1H),7.11(s,1H),6.98(d,J＝8.4Hz,1H),3.76(s,3H).
Example 9
Figure BDA0002610707420000211
First step of
Compound 9a (200mg, 1.28mmol) was dissolved in tetrahydrofuran (10mL), and triethylamine (337mg, 3.33mmol) was added. After purging with nitrogen, methyl chloroformate (315mg, 3.33mmol) was added dropwise under ice bath. Stir at room temperature for 2 hours, filter, and concentrate under reduced pressure to give crude 9b (350mg), yield: 100 percent.
MS-ESI calculated value [ M +1 ]]+273, found 273.
Second step of
Compound 9b (350mg, 1.28mmol) was dissolved in tetrahydrofuran (5mL) and heavy water (5mL), and sodium deuteroborohydride (268.10g, 6.40mmol) was added three times with nitrogen at room temperature, followed by stirring at room temperature for 2 hours. The reaction was quenched with water (20mL) under ice-bath, extracted three times with ethyl acetate (20mL x3), the organic phases combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give a residue which was purified by column chromatography (ethyl acetate: petroleum ether ═ 0-100%) to give 9c (150mg) in yield: 91 percent.
The third step
Compound 9c (150mg, 1.16mmol) was dissolved in N, N-dimethylformamide (10mL), followed by addition of 2b (296mg, 1.16mmol), addition of cesium carbonate (757mg, 2.32mmol) under ice bath, stirring for 2 hours under ice bath, filtration, concentration under reduced pressure to give a residue, which was purified by column chromatography (ethyl acetate: petroleum ether ═ 0-100%) to give 9d (100mg) in yield: 24 percent.
MS-ESI calculated value [ M +1 ]]+365, found 365.
1H NMR(400MHz,CDCl3)δ11.28(s,1H),8.33(s,1H),8.00(s,1H),7.27–7.24(m,1H),7.04–7.01(m,1H),4.52(q,J＝7.2Hz,2H),1.45(t,J＝7.2Hz,3H).
The fourth step
Compound 9d (200mg, 0.55mmol) was dissolved in a mixed solvent of tetrahydrofuran (10mL) and water (10mL), and sodium hydroxide (268.10g, 6.40mmol) was added thereto at room temperature, and the mixture was stirred at room temperature overnight after being replaced with nitrogen three times. PH was adjusted to about 2 with 2N hydrochloric acid, extracted with ethyl acetate (20mL × 3), the organic phases were combined, washed with saturated brine (30mL × 1), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give a residue, which was purified by column chromatography (methanol: dichloromethane ═ 0-100%) to give 9e (90mg), yield: 49 percent.
MS-ESI calculated value [ M +1 ]]+337, found 337.
The fifth step
After 9e (30mg, 0.09mmol) was dissolved in N, N-dimethylformamide (4mL), 1k (18mg, 0.10mmol), 2- (7-benzotriazole oxide) -N, N' -tetramethyluronium hexafluorophosphate (51mg, 0.13mmol), N-diisopropylethylamine (35mg, 0.27mmol) were added, then nitrogen substitution was carried out three times, stirring was carried out at room temperature for 2 hours, water (30mL) and ethyl acetate (30mL) were added, liquid separation was carried out, the aqueous phase was extracted with ethyl acetate (20mLx3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give a residue, which was purified by column chromatography (methanol: dichloromethane ═ 0 to 100%) to give 9(8mg) in yield: 18 percent.
MS-ESI calculated value [ M +1 ]]+502, measured value 502.
1H NMR(400MHz,DMSO-d6)δ11.15(s,1H),8.06(s,1H),7.59(s,1H),7.48(s,1H),7.28–7.23(m,3H),7.10(s,1H),5.99(s,2H),3.04(s,3H).
Example 10
Figure BDA0002610707420000221
First step of
Compound 10a (300mg, 1.28mmol) was dissolved in anhydrous ethanol (10mL), after three nitrogen replacements, cooled to-15 ℃, 15% sodium thiomethoxide solution (0.5mL) was added dropwise, stirred for 2 hours in ice bath, water (20mL) and ethyl acetate (20mL) were added, liquid separation was performed, the aqueous phase was extracted with ethyl acetate (20mL × 3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give a residue, which was purified by column chromatography (ethyl acetate: petroleum ether ═ 0-100%) to give 10b (220mg) in yield: 85 percent.
1H NMR(400MHz,CDCl3)δ8.28–8.26(m,1H),8.16–8.12(m,1H),7.24–7.17(m,1H),3.74(s,2H),2.06(s,3H).
Second step of
Compound 10b (220mg, 1.09mmol) was dissolved in methylene chloride (10mL), and m-chloroperoxybenzoic acid (823mg, 4.38mmol) was added thereto at room temperature, followed by stirring at room temperature for 2 hours. Filtration and concentration under reduced pressure gave a residue which was purified by column chromatography (ethyl acetate: petroleum ether 0-100%) to give 10c (240mg) in yield: 94 percent.
1H NMR(400MHz,CDCl3)δ8.43–8.41(m,1H),8.32–8.30(m,1H),7.35–7.30(m,1H),4.38(s,2H),2.91(s,3H).
The third step
Compound 10c (240mg, 1.03mmol) was dissolved in absolute ethanol (10mL) and water (10mL), ammonium chloride (550mg, 10.30mmol) and iron powder (288mg, 5.15mmol) were added at room temperature, and the mixture was replaced with nitrogen gas three times, heated to 80 ℃ and stirred for 3 hours. Filtration and concentration under reduced pressure gave a residue which was purified by column chromatography (methanol: dichloromethane ═ 0 to 100%) to give 10d (200mg), yield: 96 percent.
MS-ESI calculated value [ M +1 ]]+204, measured value 204.
1H NMR(400MHz,CD3OD)δ6.95–6.82(m,1H),6.81–6.74(m,2H),4.34(s,2H),2.88(s,3H).
The fourth step
After 10d (29mg, 0.14mmol) was dissolved in N, N-dimethylformamide (5mL), 2d (50mg, 0.12mmol), 2- (7-benzotriazole oxide) -N, N' -tetramethyluronium hexafluorophosphate (69mg, 0.18mmol), N-diisopropylethylamine (47mg, 0.36mmol) were added, then replaced with nitrogen three times, and after stirring at room temperature for 2 hours, water (30mL) and ethyl acetate (30mL) were added, liquid separation was performed, the aqueous phase was extracted with ethyl acetate (20mL × 3), organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give a residue, which was purified by column chromatography (methanol: dichloromethane ═ 0-100%) to give 10(37mg) yield: 51 percent.
MS-ESI calculated value [ M +1 ]]+601, measured value 601.
1H NMR(400MHz,DMSO-d6)δ11.16(s,1H),8.16(s,1H),7.79–7.78(m,1H),7.71–7.66(m,1H),7.40(d,J＝8.8Hz,1H),7.34–7.32(m,1H),7.25(s,1H),7.02(d,J＝8.8Hz,1H),4.59(s,2H),3.80(s,3H),3.04(s,3H).
Example 11
Figure BDA0002610707420000231
First step of
Compound 3a (100mg, 0.50mmol) was dissolved in methanol (5mL) under nitrogen protection in an ice bath, and then thionyl chloride (1mL) was added slowly, and the resulting reaction was stirred at room temperature for 2 hours. After the reaction was completed, concentration was performed under reduced pressure to obtain 11a (100mg), yield: 93 percent.
1H NMR(400MHz,CDCl3)δ8.22–8.17(m,2H),7.20(t,J＝8.8Hz,1H),3.75–3.73(m,5H).
Second step of
11a (100mg, 0.47mmol) was dissolved in methanol (5mL) and 10% wet palladium on carbon (20mg) was added at room temperature. The hydrogen (15psi) was replaced three times and placed under a hydrogen atmosphere (15psi) and stirring continued at room temperature for 4 hours. Filtration through celite and concentration of the filtrate under reduced pressure gave crude 11b (95mg) in yield: 100 percent.
The third step
After 11b (88mg, 0.53mmol) was dissolved in N, N-dimethylformamide (5mL), 2d (200mg, 0.48mmol), 2- (7-benzotriazole oxide) -N, N' -tetramethyluronium hexafluorophosphate (274mg, 0.72mmol), N-diisopropylethylamine (187mg, 1.45mmol) were added and then replaced with nitrogen three times, and after stirring at room temperature for 2 hours, water (15mL) and ethyl acetate (15mL) were added, liquid separation was performed, the aqueous phase was extracted with ethyl acetate (20mL × 3), organic phase was combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give a residue, which was purified by column chromatography (methanol: dichloromethane ═ 0-100%) to give 11c (80mg) in yield: 29 percent.
The fourth step
Compound 11c (20mg, 0.03mmol) was dissolved in dichloroethane (10mL), and trimethyltin hydroxide (25mg, 0.14mmol) was added at room temperature, replaced three times with nitrogen, and then stirred at 90 ℃ overnight. Extraction with ethyl acetate (10mL × 3), organic phases were combined, washed with saturated brine (20mL × 1), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give a residue, which was purified by column chromatography (methanol: dichloromethane ═ 0 to 100%) to give 11(16mg) in yield: 81 percent.
MS-ESI calculated value [ M +1 ]]+567, found 567.
1H NMR(400MHz,DMSO-d6)δ11.00(s,1H),8.11(s,1H),7.56–7.48(m,2H),7.36(d,J＝8.8Hz,1H),7.20(s,1H),7.15–7.13(m,1H),6.98(d,J＝8.4Hz,1H),3.76(s,5H).
Example 12
Figure BDA0002610707420000241
Figure BDA0002610707420000251
First step of
After 12a (1.00g, 5.92mmol) was dissolved in triethylamine (0.8mL) and acetic acid (0.8mL), glyoxal (344mg, 5.92mmol), ammonium acetate (3.19g, 41.44mmol) was added and nitrogen was replaced three times, the reaction was stirred at 120 ℃ overnight. Concentration under reduced pressure gave a residue, which was purified by column chromatography (ethyl acetate: petroleum ether 0-100%) to give 12b (320mg) in yield: 26 percent.
MS-ESI calculated value [ M +1 ]]+208, found 208.
Second step of
Compound 12b (320mg, 1.55mmol) was dissolved in anhydrous methanol (10mL), 10% wet palladium on carbon (64mg) was added three times at room temperature, replaced with hydrogen, and then stirred at room temperature for 2 hours. Filtration through celite and concentration under reduced pressure afforded crude 12c (269mg), yield: 98 percent.
MS-ESI calculated value [ M +1 ]]+178, found 178.
The third step
2b (3.00g, 11.76mmol) and 12d (2.00g, 10.41mmol) were dissolved in N, N-dimethylformamide (10mL), and cesium carbonate (7.70g, 23.63mmol) was added under ice bath. After the replacement with nitrogen gas three times, the reaction system was further stirred for 1.5 hours under ice bath, warmed to room temperature, added with water (20mL) and ethyl acetate (30mL), separated, the aqueous phase was extracted with ethyl acetate (50mL × 3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give a residue, which was purified by column chromatography (ethyl acetate: petroleum ether ═ 0-100%) to give 12e (4.40g), yield: 99 percent.
The fourth step
12e (4.40g, 10.30mmol) was dissolved in a mixed solvent of tetrahydrofuran (20mL) and water (20mL), and sodium hydroxide (2.00g, 50.00mmol) was added in portions under ice-bath conditions, and after replacing nitrogen, the reaction system was warmed to room temperature and stirred for 2 hours. The pH was adjusted to about 2 with 1N dilute hydrochloric acid, extracted with dichloromethane (30mL x3), the organic phases were combined and washed with saturated brine (20mL x1), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give crude 12f (4.00g) in yield: 97 percent.
MS-ESI calculated value [ M +1 ]]+400, found value 400.
The fifth step
12c (50mg, 0.28mmol) was dissolved in N, N-dimethylformamide (5mL), 12f (93mg, 0.23mmol), 2- (7-benzotriazole oxide) -N, N' -tetramethyluronium hexafluorophosphate (131mg, 0.35mmol), N-diisopropylethylamine (89mg, 0.69mmol) were added, then nitrogen substitution was carried out three times, after stirring at room temperature for 3 hours, water (30mL) and ethyl acetate (30mL) were added, liquid separation was carried out, the aqueous phase was extracted with ethyl acetate (20mL × 3), organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give a residue, which was purified by column chromatography (methanol: dichloromethane ═ 0-100%) to give 12(19mg) in yield: 15 percent.
MS-ESI calculated value [ M +1 ]]+559, found 559.
1H NMR(400MHz,CD3OD)δ8.06–8.05(m,2H),7.80–7.74(m,1H),7.28–7.23(m,2H),7.21–7.18(m,4H),2.26(s,3H)
Example 13
Figure BDA0002610707420000261
First step of
13a (696mg, 4.00mmol), 13b (1.11g,6mmol), [1,1' -bis (diphenylphosphino) ferrocene ] dichloropalladium (326mg,0.40mmol), sodium carbonate (848mg,8.00mmol) were dissolved in a mixed solvent of dioxane (8mL) and water (4mL), followed by replacement of nitrogen gas, stirring at 100 ℃ for 16 hours, filtration through celite, dilution with water (50mL) and extraction with ethyl acetate (50mL × 3), concentration under reduced pressure to give a residue, which was purified by column chromatography (methanol: dichloromethane ═ 0-100%) to give 13c (235mg), yield: 25 percent.
MS-ESI calculated value [ M +1 ]]+235, found 235.
Second step of
13c (235mg, 1.00mol), iron powder (280mg, 5.00mmol), ammonium chloride (535mg, 10.00mmol) were dissolved in ethanol (8mL) and water (2mL), then replaced with nitrogen three times, after stirring for 2 hours at 80 ℃, filtered over celite, diluted with water (50mL) and extracted with ethyl acetate (50mL × 3), concentrated under reduced pressure to give a residue, which was purified by column chromatography (methanol: dichloromethane ═ 0-100%) to give 13d (40mg) in yield: 20 percent.
MS-ESI calculated value [ M +1 ]]+205, found value 205.
The third step
After 2d (83mg, 0.20mmol), 13d (40mg, 0.22mmol) were dissolved in N, N-dimethylformamide (5mL), and further 2- (7-benzotriazole oxide) -N, N' -tetramethyluronium hexafluorophosphate (114mg, 0.30mmol), N-diisopropylethylamine (65mg, 0.50mmol) was added, followed by nitrogen substitution three times, stirring at room temperature for 2 hours, concentration under reduced pressure gave a residue, which was purified by column chromatography (methanol: dichloromethane ═ 0 to 100%) to give 13(23mg), yield: 20 percent.
MS-ESI calculated value [ M +1 ]]+602, measured value 602.
1H NMR(400MHz,DMSO-d6)δ11.61(s,1H),11.07(s,1H),8.11(s,1H),7.73–7.70(m,1H),7.58–7.56(m,1H),7.53–7.52(m,1H),7.42–7.38(m,1H),7.37–7.33(m,1H),7.24–7.18(m,2H),6.99–6.97(m,1H),6.27–6.24(m,1H),3.76(s,3H).
Example 14
Figure BDA0002610707420000271
First step of
Compound 1i (100mg, 0.59mmol), acetic anhydride (2mL) were dissolved in acetic acid (10mL), stirred at room temperature for 2 hours, the reaction was diluted with water (30mL) and extracted with ethyl acetate (50mL x3), the organic phases were combined, washed with saturated brine (20mL x1), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give a residue, which was purified by column chromatography (ethyl acetate: petroleum ether ═ 0-100%) to give 14a (108mg) in yield: 86 percent.
Second step of
14a (108mg, 0.51mmol) was dissolved in methanol (5mL) and 10% wet palladium on carbon (20mg) was added. After hydrogen substitution, the reaction was stirred at room temperature for 1 hour. The reaction mixture was filtered through celite, and concentrated under reduced pressure to give 14b (96mg) in yield: 100 percent.
MS-ESI calculated value [ M +1 ]]+183, found value 183.
The third step
After 2d (80mg, 0.19mmol) was dissolved in N, N-dimethylformamide (5mL), 14b (35mg, 0.19mmol), 2- (7-benzotriazole oxide) -N, N' -tetramethyluronium hexafluorophosphate (108mg, 0.28mmol), N-diisopropylethylamine (74mg, 0.57mmol) were added, then nitrogen substitution was carried out three times, stirring was carried out at room temperature for 2 hours, water (20mL) and ethyl acetate (20mL) were added, liquid separation was carried out, the aqueous phase was extracted with ethyl acetate (20mL × 3), organic phase was combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give a residue, which was purified by column chromatography (methanol: dichloromethane ═ 0 to 100%) to give 14(25mg) in yield: 23 percent.
MS-ESI calculated value [ M +1 ]]+580, found 580.
1H NMR(400MHz,DMSO-d6)δ11.17(s,1H),8.15(s,1H),7.71–7.70(m,1H),7.54–7.41(m,1H),7.40–7.33(m,2H),7.21(s,1H),6.99–6.97(m,1H),3.76(s,3H),3.07(s,3H),1.75(s,3H).
Example 15
Figure BDA0002610707420000281
First step of
Compound 1i (2.00g, 11.76mmol) was dissolved in toluene (50mL) and the nitrogen gas was replaced. To the reaction solution were added methylcarbamoyl chloride (2.20g, 23.52mmol), triethylamine (3.56g, 35.29mmol), and 4-dimethylaminopyridine (144mg,1.17mmol), followed by stirring at 110 ℃ overnight. The reaction was quenched with water (50mL) and extracted with ethyl acetate (50mL x3), the organic phases combined and washed with saturated brine (30mL x1), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give a residue which was purified by column chromatography (methanol: dichloromethane ═ 0-100%) to give 15a (190mg) in yield: 7 percent.
Second step of
15a (190mg, 0.83mmol) was dissolved in methanol (10mL), 10% wet palladium on carbon (20mg) was added, hydrogen was replaced and the mixture was stirred at room temperature for 2 hours, filtered through celite, and concentrated under reduced pressure to give 15b (160mg), yield: 98 percent.
The third step
2d (70mg, 0.16mmol) was dissolved in N, N-dimethylformamide (5mL), 15b (50mg, 0.25mmol), 2- (7-benzotriazole oxide) -N, N' -tetramethyluronium hexafluorophosphate (96mg, 0.25mmol), N-diisopropylethylamine (65mg, 0.50mmol) were added, then nitrogen substitution was carried out three times, after stirring overnight at room temperature, water (15mL) and ethyl acetate (15mL) were added, liquid separation was carried out, the aqueous phase was extracted with ethyl acetate (20mL × 3), organic phase was combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give a residue, which was purified by column chromatography (methanol: dichloromethane ═ 0 to 100%) to give 15(49mg) with a yield of 49%. .
MS-ESI calculated value [ M +1 ]]+594, found 594.
1H NMR(400MHz,DMSO-d6)δ10.93(s,1H),7.74(t,J＝8.4Hz,1H),7.66–7.64(m,1H),7.58–7.52(m,1H),7.31(d,J＝8.8Hz,1H),7.26–7.20(m,2H),7.02(d,J＝8.4Hz,1H),6.60(d,J＝8.8Hz,1H),6.13(d,J＝4.4Hz,1H),3.76(s,3H),3.04(s,3H),2.47(s,3H).
Example 16
Figure BDA0002610707420000282
Figure BDA0002610707420000291
First step of
Compound 2f (74mg, 0.44mmol), 1g (100mg, 0.44mmol) and 2- (7-benzotriazol oxide) -N, N' -tetramethyluronium hexafluorophosphate (217mg, 0.57mmol) were dissolved in N, N-dimethylformamide (10mL), triethylamine (89mg, 0.88mmol) was added thereto, and stirred at room temperature for 2 hours, the reaction solution was separated by adding water (50mL) and ethyl acetate (50mL), the aqueous phase was extracted three times with ethyl acetate (30mL × 3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give crude 16a (150mg), yield: 90 percent of
Second step of
16a (140mg, 0.37mmol), 1d (100mg, 0.37mmol) and cesium carbonate (241mg, 0.74mmol) were dissolved in N, N-dimethylformamide (10mL), stirred at room temperature for 6 hours, the reaction mixture was added with water (50mL) and ethyl acetate (50mL), separated, the aqueous phase was extracted with ethyl acetate (30mL × 3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure and purified by column chromatography (methanol: dichloromethane ═ 0-100%) to give 16(7mg) in yield: 3 percent of
1H NMR(400MHz,DMSO-d6)δ10.87(s,1H),9.73(s,1H),8.22–8.19(m,1H),7.73(t,J＝8.8,1H),7.48–7.47(m,1H),7.31(d,J＝8.8,1H),7.20–7.17(m,4H),7.11–7.01(m,1H),6.60(d,J＝8.8,1H),3.76(s,3H).
Example 17
Figure BDA0002610707420000292
First step of
17a (300mg, 1.97mmol) was dissolved in tetrahydrofuran (4mL) and glacial acetic acid (4mL) and potassium cyanate (2.10g, 32.30mmol) were added. After replacement with nitrogen three times, the mixture was stirred at room temperature for 2 hours, water (50mL) and ethyl acetate (50mL) were added for liquid separation, the aqueous phase was extracted with ethyl acetate (30mL × 3) three times, the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give a residue, which was purified by column chromatography (ethyl acetate: petroleum ether ═ 0 to 100%) to give 17b (150mg) in yield: 39 percent.
1H NMR(400MHz,DMSO-d6)δ8.13(d,J＝9.2Hz,2H),7.52(d,J＝9.2Hz,2H),6.51(s,2H),3.23(s,3H).
Second step of
17b (150mg, 0.76mmol) was dissolved in a solution of methanol (3mL) and water (3mL), followed by the addition of reduced iron powder (186mg, 3.32mmol) and ammonium chloride (107mg, 2.00 mmol). After the reaction solution was stirred at room temperature for 2 hours after being substituted with nitrogen three times, the reaction solution was filtered through celite, the filtrate was concentrated under reduced pressure to obtain a residue, which was diluted with water (20mL), extracted with ethyl acetate (20mL × 3), and the organic phases were combined, washed with saturated brine (50mL × 1), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a residue, which was purified by column chromatography (methanol: dichloromethane ═ 0 to 100%) to obtain 17c (50mg) with yield: 39 percent.
MS-ESI calculated value [ M +1 ]]+166, found 166.
The third step
After 2d (50mg, 0.12mmol) was dissolved in N, N-dimethylformamide (10mL), 17c (50mg, 0.30mmol), 2- (7-benzotriazole oxide) -N, N' -tetramethyluronium hexafluorophosphate (55mg, 0.14mmol), N-diisopropylethylamine (46mg, 0.36mmol) were added, then replaced with nitrogen three times, stirred at room temperature for 2 hours, water (60mL) and ethyl acetate (60mL) were added, liquid separation was performed, the aqueous phase was extracted with ethyl acetate (20mL × 3), organic phase was combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give a residue, which was purified by preparative HPLC to give 17(2mg), yield: 3 percent.
MS-ESI calculated value [ M +1 ]]+563, found 563.
1H NMR(400MHz,DMSO-d6)δ11.00(s,1H),8.11(s,1H),7.59(d,J＝8.8Hz,2H),7.36–7.36(m,1H),7.23(d,J＝8.8Hz,4H),5.73(s,2H),3.77(s,3H),3.08(s,3H).
Example 18
Figure BDA0002610707420000301
First step of
Compound 11a (500mg, 2.30mmol) was dissolved in anhydrous tetrahydrofuran (5mL) under nitrogen protection at-78 deg.C, lithium diisopropylamide (3.5mL) was slowly added to maintain at-78 deg.C for 30 minutes, bromoacetonitrile (423mg, 3.50mmol) was then slowly added, and the resulting reaction was stirred at room temperature for 2 hours. After completion of the reaction, water (15mL) and ethyl acetate (15mL) were added, the mixture was separated, the aqueous phase was extracted with ethyl acetate (20mL × 3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give 18a (200mg), yield: 34 percent.
Second step of
18a (50mg, 0.2mmol) was dissolved in a mixed solvent of tetrahydrofuran (10mL) and water (2mL), a borane-tetrahydrofuran solution (0.06mL) was added under ice-bath conditions, and the reaction mixture was stirred at 70 ℃ for 4 hours. After completion of the reaction, water (15mL) and ethyl acetate (15mL) were added, the mixture was separated, the aqueous phase was extracted with ethyl acetate (20mL × 3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give 18b (30mg) in yield: 79 percent.
The third step
18b (50mg, 0.25mmol) was dissolved in N, N-dimethylformamide (5mL), and 2d (97mg, 0.23mmol), 2- (7-benzotriazole oxide) -N, N, N ', N' -tetramethyluronium hexafluorophosphate (134mg, 0.35mmol), N, N-diisopropylethylamine (90mg, 0.70mmol) were further added, followed by nitrogen substitution three times, stirring was performed at room temperature for 2 hours, then water (15mL) and ethyl acetate (15mL) were added, liquid separation was performed, the aqueous phase was extracted with ethyl acetate (20mL × 3), organic phase was combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give a residue, which was purified by column chromatography (methanol: dichloromethane ═ 0-100%) to give 18(80mg) with a yield of 29%.
MS-ESI calculated value [ M +1 ]]+592, measured value 592.
1H NMR(400MHz,DMSO-d6)δ11.01(s,1H),8.11(s,1H),7.89(s,1H),7.54–7.52(m,2H),7.35(d,J＝8.8Hz,1H),7.19–7.13(m,2H),6.99–6.97(m,1H),3.77–3.70(m,6H),3.28–3.26(m,2H).
Example 19
Figure BDA0002610707420000311
First step of
After 2b (200mg, 0.81mmol) was dissolved in N, N-dimethylformamide (10mL), 19a (206mg, 0.97mmol) and cesium carbonate (790mg, 2.43mmol) were added under ice bath and replaced with nitrogen three times, the reaction system was stirred under ice bath for 3 hours. Water (30mL) and ethyl acetate (30mL) were added, the layers were separated, the aqueous layer was extracted with ethyl acetate (20mL × 3), the organic layers were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give a residue, which was purified by column chromatography (methanol: dichloromethane ═ 0-100%) to give 19b (263 mg). Yield: 73 percent.
MS-ESI calculated value [ M +1 ]]+448, found 448.
Second step of
19b (263mg, 0.59mmol) was dissolved in anhydrous tetrahydrofuran (5mL) and water (5mL), and after sodium hydroxide (118mg, 2.94mmol) was added at room temperature and replaced with nitrogen three times, the mixture was stirred at room temperature for 16 hours. Water (30mL) and ethyl acetate (30mL) were added, the layers were separated, the aqueous phase was extracted with ethyl acetate (20mL × 3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give a residue, which was purified by column chromatography (methanol: dichloromethane ═ 0-100%) to give 19c (166mg), yield: 67%.
MS-ESI calculated value [ M +1 ]]+420, found value 420.
The third step
After dissolving 19c (80mg, 0.19mmol) in N, N-dimethylformamide (5mL), 1k (42mg, 0.23mmol), 2- (7-benzotriazole oxide) -N, N' -tetramethyluronium hexafluorophosphate (109mg, 0.29mmol), N-diisopropylethylamine (74mg, 0.57mmol) were added and then replaced with nitrogen three times, and after stirring at room temperature for 3 hours, water (30mL) and ethyl acetate (30mL) were added, liquid separation was performed, the aqueous phase was extracted with ethyl acetate (20mL × 3), organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give a residue, which was purified by column chromatography (methanol: dichloromethane ═ 0 to 100%) to give 19(38mg) in yield: 34 percent.
MS-ESI calculated value [ M +1 ]]+585, found 585.
1H NMR(400MHz,DMSO-d6)δ11.11(s,1H),8.36(s,1H),7.78(s,1H),7.55–7.53(m,1H),7.50–7.46(m,1H),7.27–7.22(m,2H),5.99(s,2H),3.04(s,3H).
Example 20
Figure BDA0002610707420000321
First step of
1i (50mg, 0.29mmol) was dissolved in anhydrous methanol (10mL), 10% wet palladium on carbon (10mg) was added at room temperature, hydrogen was replaced three times, and the mixture was stirred at room temperature for 2 hours. Filtration through celite, and concentration under reduced pressure afforded crude 20a (39mg), yield: 95 percent.
MS-ESI calculated value [ M +1 ]]+141, found value 141.
Second step of
After dissolving 20a (39mg, 0.28mmol) in N, N-dimethylformamide (5mL), 2d (96mg, 0.23mmol), 2- (7-benzotriazole oxide) -N, N' -tetramethyluronium hexafluorophosphate (131mg, 0.35mmol), N-diisopropylethylamine (89mg, 0.69mmol) were added and then replaced with nitrogen three times, and after stirring at room temperature for 4 hours, water (30mL) and ethyl acetate (30mL) were added, liquid separation was performed, the aqueous phase was extracted with ethyl acetate (20mL × 3), organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give a residue, which was purified by column chromatography (methanol: dichloromethane ═ 0-100%) to give 20b (70mg) in yield: 46 percent.
MS-ESI calculated value [ M +1 ]]+538, measured value 538.
The third step
20b (70mg, 0.13mmol) was dissolved in pyridine (2mL), and then acetoxyacetic acid (18mg, 0.16mmol), phosphorus oxychloride (60mg, 0.39mmol) were added under ice bath, and after three times replacement with nitrogen, stirring was carried out at 0 ℃ for 1 hour. Concentration under reduced pressure gave a residue, which was purified by column chromatography (ethyl acetate: petroleum ether 0-100%) to give 20c (44mg), yield: 54 percent.
MS-ESI calculated value [ M +1 ]]+638, found 638.
The fourth step
20c (40mg, 0.06mmol) was dissolved in a mixed solvent of tetrahydrofuran (2mL) and water (2mL), and sodium hydroxide (5mg, 0.13mmol) was further added, followed by replacement with nitrogen three times, stirring at room temperature for 4 hours, then addition of a saturated solution of ammonium chloride (5mL), addition of water (30mL) and ethyl acetate (30mL), liquid separation, extraction of the aqueous phase with ethyl acetate (20mL × 3), organic phase combination, drying over anhydrous sodium sulfate, filtration, concentration under reduced pressure to give a residue, and purification of the residue by column chromatography (methanol: dichloromethane ═ 0 to 100%) gave 20(16mg) in yield: and 43 percent.
MS-ESI calculated value [ M +1 ]]+596, found 596.
1H NMR(400MHz,CD3OD)δ8.00(s,1H),7.77–7.76(m,1H),7.60–7.59(m,1H),
7.31–7.28(m,2H),7.08(s,1H),6.93(d,J＝9.2Hz,1H),4.00–3.96(m,1H),3.80(s,1H),
3.79(s,3H),3.24(s,3H).
Example 21
Figure BDA0002610707420000331
First step of
After dissolving 2d (70mg, 0.17mmol) in N, N-dimethylformamide (4mL), 20a (25mg, 0.17mmol), 2- (7-benzotriazole oxide) -N, N' -tetramethyluronium hexafluorophosphate (97mg, 0.25mmol), N-diisopropylethylamine (66mg, 0.51mmol) were added and then replaced with nitrogen three times, stirring was performed at room temperature for 2 hours, water (20mL) and ethyl acetate (20mL) were added, liquid separation was performed, the aqueous phase was extracted with ethyl acetate (20mL × 3), organic phase was combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give a residue, which was purified by column chromatography (methanol: dichloromethane ═ 0 to 100%) to give 21a (80mg) with yield: 88 percent.
MS-ESI calculated value [ M +1 ]]+538, measured value 538.
Second step of
21a (120mg, 0.22mmol) and 21b (58mg, 0.33mmol) were dissolved in pyridine (5mL), and phosphorus oxychloride (1mL) was slowly added under ice-bath conditions, and the mixture was stirred at room temperature for 2 hours while displacing nitrogen. Pyridine was removed by concentration under reduced pressure, and then diluted with water (30mL), extracted with ethyl acetate (30mL x3), the organic phases were combined, washed with saturated brine (20mL x1), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give a residue, which was purified by column chromatography (methanol: dichloromethane ═ 0-100%) to give 21(20mg) in yield: 15 percent.
MS-ESI calculated value [ M +1 ]]+595, found 595.
1H NMR(400MHz,DMSO-d6)δ8.15–8.11(s,2H),8.01(s,2H),7.89–7.83(m,1H),7.57(s,1H),7.46–7.38(m,2H),7.22(s,1H),6.99(d,J＝7.6Hz,1H),3.76(s,5H),3.18(s,3H).
Example 22
Figure BDA0002610707420000341
First step of
22a (3.04g, 20.00mmol), paraformaldehyde (2.40g, 80.00mmol), and sodium methoxide (540mg, 10.00mmol) were dissolved in methanol (100mL), and then replaced with nitrogen three times, and after stirring at room temperature for 12 hours, sodium borohydride (1.52g, 40.00mmol) was added, replaced with nitrogen three times, and after stirring at room temperature for 12 hours, the residue was directly concentrated under reduced pressure to give a residue, which was purified by column chromatography (ethyl acetate: petroleum ether ═ 0 to 100%) to give 22b (2.00g), yield: 60 percent.
MS-ESI calculated value [ M +1 ]]+167, found 167.
Second step of
22b (332mg, 2.00mol), sodium cyanate (520mg, 4.00mmol) were dissolved in a mixed solvent of acetic acid (10mL) and water (2mL), and the mixture was replaced with nitrogen gas three times, stirred at room temperature for 12 hours, then diluted with water (50mL), extracted with ethyl acetate (50mL x2), washed with saturated brine (50mL x1), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give a residue, which was purified by column chromatography (ethyl acetate: petroleum ether ═ 0 to 100%) to give 22c (200mg), yield: 48 percent.
MS-ESI calculated value [ M +1 ]]+210, measured value 210.
The third step
22c (200mg, 1.00mmol), iron powder (280mg, 5.00mmol), ammonium chloride (535mg, 10.00mmol) were dissolved in a mixed solvent of ethanol (6mL) and water (2mL), then replaced with nitrogen three times, heated to 80 ℃ and stirred for 2 hours, cooled to room temperature, filtered through celite, diluted with water (50mL), extracted with ethyl acetate (100mL x2), the organic phases were combined, washed with saturated brine (50mL x1), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give a residue, which was purified by column chromatography (methanol: dichloromethane 0-100%) to give 22d (50mg), yield: 28 percent.
The fourth step
2d (100mg, 0.51mmol), 22d (50mg, 0.51mmol) were dissolved in N, N-dimethylformamide (5mL), and 2- (7-benzotriazole oxide) -N, N' -tetramethyluronium hexafluorophosphate (290mg, 0.76mmol), N-diisopropylethylamine (164mg, 1.27mmol) was further added, followed by nitrogen substitution three times, stirring at room temperature for 2 hours, and concentration under reduced pressure to give a residue, which was purified by column chromatography (methanol: dichloromethane ═ 10%) to give 22(64mg), yield: 22 percent.
MS-ESI calculated value [ M +1 ]]+577, found 577.
1H NMR(400MHz,DMSO-d6)δ10.98(s,1H),8.11–8.10(m,1H),7.46–7.40(m,2H),7.36(d,J＝8.8Hz,1H),7.24–7.21(m,2H),7.00–6.98(m,1H),5.57(s,2H),3.77(s,3H),2.99(s,3H),2.10(s,3H).
Example 23
Figure BDA0002610707420000351
First step of
23a (400mg, 2.87mmol) was dissolved in anhydrous methanol (10mL), and paraformaldehyde (345mg, 11.50mmol) and sodium methoxide (78mg, 1.44mmol) were added under ice-cooling, and the mixture was replaced with nitrogen three times, followed by stirring at room temperature for 16 hours. Sodium borohydride (326mg, 8.63mmol) was added thereto while cooling on ice, and the mixture was replaced with nitrogen three times and stirred at room temperature for 16 hours. Water (30mL) and ethyl acetate (30mL) were added, the layers were separated, the aqueous phase was extracted with ethyl acetate (20mL × 3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give a residue, which was purified by column chromatography (ethyl acetate: petroleum ether ═ 0-100%) to give 23b (224mg), yield: 51 percent.
MS-ESI calculated value [ M +1 ]]+154, found 154.
Second step of
23b (200mg, 1.31mmol) was dissolved in dichloromethane (10mL), acetyl chloride (123mg, 1.57mmol), triethylamine (397mg, 3.93mmol) were further added, and then, after three times of nitrogen substitution, stirring at room temperature for 4 hours, concentration under reduced pressure was carried out to obtain a residue, which was purified by column chromatography (methanol: dichloromethane 0-100%) to obtain 23c (214mg), yield: 84 percent.
MS-ESI calculated value [ M +1 ]]+196, found 196.
The third step
23c (200mg, 1.02mmol) was dissolved in anhydrous methanol (10mL), and wet palladium on carbon (40mg) was added thereto at room temperature, and the mixture was stirred at room temperature for 4 hours after replacing hydrogen gas three times. Filtration through celite, and concentration under reduced pressure afforded crude 23d (136mg), yield: 81 percent.
MS-ESI calculated value [ M +1 ]]+166, found 166.
The fourth step
23d (48mg, 0.29mmol) was dissolved in pyridine (2mL), and then 2d (100mg, 0.24mmol) and phosphorus oxychloride (110mg, 0.72mmol) were added thereto under ice bath, and the mixture was stirred at 0 ℃ for 1 hour after replacing nitrogen three times. Concentration under reduced pressure gave a residue, which was purified by column chromatography (ethyl acetate: petroleum ether ═ 0 to 100%) to give 23(5mg), yield: 3 percent.
MS-ESI calculated value [ M +1 ]]+593, found 593.
1H NMR(400MHz,CD3OD)δ8.41(d,J＝6.0Hz,1H),8.03(s,1H),7.75(s,1H),7.58(d,J＝6.0Hz,1H),7.33(d,J＝8.8Hz,1H),7.08(s,1H),6.93(d,J＝8.8Hz,1H),3.80(s,3H),3.33(s,3H),2.06(s,3H).
Example 24
Figure BDA0002610707420000361
First step of
After dissolving 1h (500mg, 3.20mmol) in N, N-dimethylformamide (10mL), 21b (561mg, 3.20mmol), 2- (7-benzotriazole oxide) -N, N' -tetramethyluronium hexafluorophosphate (1.83g, 4.80mmol), N-diisopropylethylamine (1.24g, 9.60mmol) were added, followed by three times replacement with nitrogen, stirring at room temperature for 2 hours, water (50mL) and ethyl acetate (50mL) were added, liquid separation was performed, the aqueous phase was extracted with ethyl acetate (50mL × 3), organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give a residue, which was purified by column chromatography (methanol: dichloromethane ═ 0-100%) to give 24a (686mg) in yield: and 69 percent.
Second step of
24a (200mg, 0.64mmol) was dissolved in methanol (2mL) and then wet palladium on carbon (20mg) was added. After replacing hydrogen three times and stirring for 2 hours, the reaction solution was filtered through celite, and concentrated under reduced pressure to give crude 24b (170mg), yield: 94 percent.
The third step
After dissolving 2d (250mg, 0.60mmol) in N, N-dimethylformamide (10mL), 24b (170mg, 0.60mmol), 2- (7-benzotriazole oxide) -N, N' -tetramethyluronium hexafluorophosphate (343mg, 0.90mmol), N-diisopropylethylamine (233mg, 1.80mmol) were added and then replaced with nitrogen three times, stirring was performed at room temperature for 2 hours, water (20mL) and ethyl acetate (20mL) were added, liquid separation was performed, the aqueous phase was extracted with ethyl acetate (20mL × 3), organic phase was combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give a residue, which was purified by column chromatography (methanol: dichloromethane ═ 0 to 100%) to give 24c (300mg) with yield: 73 percent.
The fourth step
Compound 24c (300mg, 0.44mmol) was dissolved in 2N ethyl acetate hydrochloride solution (5mL), stirred for 2 hours, and the reaction solution was concentrated under reduced pressure to give crude 24(180mg), yield: 67%.
MS-ESI calculated value [ M +1 ]]+581, found 581
1H NMR(400MHz,DMSO-d6)δ11.22(s,1H),10.34(s,1H),8.36–8.34(m,1H),8.17(s,2H),8.10(s,1H),7.40(d,J＝8.8Hz,2H),7.30–7.28(m,1H),7.22(s,1H),6.99(d,J＝9.2Hz,1H),3.83(s,2H),3.77(s,3H).
Example 25
Figure BDA0002610707420000371
First step of
Compound 25a (50mg, 0.32mmol) was dissolved in acetone (10mL) and then 25b (73mg, 0.48mmol) and potassium carbonate (132mg, 0.95mmol) were added, after three nitrogen replacements, heated to 70 ℃ and stirred overnight, water and ethyl acetate were added, extracted three times with ethyl acetate (20mL x3), the organic phases combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give crude 25c (80 mg).
MS-ESI calculated value [ M +1 ]]+229, found 229.
Second step of
Compound 25c (80mg, 0.35mmol) was dissolved in anhydrous methanol (10mL), and wet palladium on carbon (15mg) was added at room temperature, and after replacing hydrogen gas three times, stirring was performed at room temperature for 2 hours. Filtration through celite and concentration under reduced pressure gave crude 25d (60mg) in two steps: 87 percent.
MS-ESI calculated value [ M +1 ]]+199, found 199.
The third step
After 25d (60mg, 0.30mmol) was dissolved in N, N-dimethylformamide (5mL), 2d (126mg, 0.30mmol), 2- (7-benzotriazole oxide) -N, N' -tetramethyluronium hexafluorophosphate (173mg, 0.45mmol), N-diisopropylethylamine (117mg, 0.91mmol) were added and then replaced with nitrogen three times, and after stirring at room temperature for 2 hours, water (30mL) and ethyl acetate (30mL) were added, liquid separation was performed, the aqueous phase was extracted with ethyl acetate (20mL × 3), organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give a residue, which was purified by column chromatography (methanol: dichloromethane ═ 0-100%) to give 25(100mg) yield: and 55 percent.
MS-ESI calculated value [ M +1 ]]+596, found 596.
1H NMR(400MHz,DMSO-d6)δ11.00(s,1H),8.10(s,1H),7.52(s,1H),7.52–7.21(m,6H),6.99–6.98(m,1H),4.53(s,1H),3.76(s,3H),1.44(d,J＝6.0Hz,3H).
Example 26
Figure BDA0002610707420000381
First step of
After 25a (50mg, 0.32mmol) was dissolved in acetone (10mL), 26a (66mg, 0.48mmol) and potassium carbonate (132mg, 0.95mmol) were added, nitrogen was replaced three times, the mixture was heated to 70 ℃ and stirred overnight, water (20mL) and ethyl acetate (20mL) were added, the mixture was separated, the aqueous phase was extracted with ethyl acetate (20mL × 3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give crude 26b (70 mg).
MS-ESI calculated value [ M +1 ]]+215, measured value 215.
Second step of
Compound 26b (70mg, 0.33mmol) was dissolved in anhydrous methanol (10mL), 10% wet palladium on carbon (15mg) was added at room temperature, hydrogen was replaced three times, and the mixture was stirred at room temperature for 2 hours. Filtration through celite, and concentration under reduced pressure afforded crude 26c (40mg), two-step yield: 67%.
MS-ESI calculated value [ M +1 ]]+185, found value 185.
The third step
26c (40mg, 0.22mmol) was dissolved in N, N-dimethylformamide (5mL), and 2d (90mg, 0.22mmol), 2- (7-benzotriazole oxide) -N, N' -tetramethyluronium hexafluorophosphate (124mg, 0.33mmol), N-diisopropylethylamine (84mg, 0.65mmol) were added, followed by nitrogen substitution three times, after stirring at room temperature for 2 hours, water (30mL) and ethyl acetate (30mL) were added, liquid separation was performed, the aqueous phase was extracted with ethyl acetate (20mL × 3), organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give a residue, which was purified by column chromatography (methanol: dichloromethane ═ 0-100%) to give 26(84mg) yield: 66 percent.
MS-ESI calculated value [ M +1 ]]+582, found 582.
1H NMR(400MHz,DMSO-d6)δ11.01(s,1H),8.11(s,1H),7.49(s,1H),7.36–7.31(m,3H),7.21(s,3H),6.98(d,J＝8.4Hz,1H),4.49(s,2H),3.76(s,3H).
Example 27
Figure BDA0002610707420000391
First step of
27a (2.00g, 13.40mmol) was dissolved in tetrahydrofuran (50mL), benzyl alcohol (1.50g, 13.40mmol) and potassium hydroxide (3.70g, 26.80mmol) were added to this solution in this order, and the reaction mixture was heated to 40 ℃ for 16 hours. The reaction was cooled to room temperature, concentrated under reduced pressure to give a residue, to which were added water (50mL) and ethyl acetate (30mL), separated, the aqueous phase was extracted with ethyl acetate (30mL × 1), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give crude product 27b (2.70g), yield: 91 percent.
MS-ESI calculated value [ M +1 ]]+221, found 221.
1H NMR(400MHz,DMSO-d6)δ8.18(s,1H),8.03(s,1H),7.43–7.42(m,2H),7.36–7.25(m,3H),5.41(s,2H).
Second step of
Compound 27b (200mg, 0.91mmol) was dissolved in dioxane (4mL) and 13a (168mg, 0.91mmol), tetrakis (triphenylphosphine) palladium (104mg, 0.09mmol) and sodium carbonate (193mg, 1.82mmol) were added, respectively. Introducing nitrogen into the reaction system, bubbling for 5 minutes, putting the microwave tube into a microwave instrument, heating to 115 ℃, and reacting for 40 minutes. After the reaction was completed, the reaction solution was filtered, and the filtrate was concentrated under reduced pressure and purified by column chromatography (ethyl acetate: petroleum ether ═ 0 to 100%) to give 27c (70mg) in yield: 24 percent.
MS-ESI calculated value [ M +1 ]]+326, found 326.
The third step
27c (30mg, 0.09mmol) was dissolved in a mixed solvent of ethanol (2mL) and water (0.5mL), iron powder (26mg, 0.46mmol) and ammonium chloride (49mg, 0.92mmol) were added in this order, and the reaction mixture was heated to 80 ℃ and reacted for 3 hours. After completion of the reaction, the reaction solution was filtered, the filtrate was separated by adding water (20mL) and ethyl acetate (20mL), the aqueous phase was extracted with ethyl acetate (10mL), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give a residue, which was purified by column chromatography (ethyl acetate: petroleum ether ═ 0 to 100%) to give 27d (26mg) with yield: 96 percent
MS-ESI calculated value [ M +1 ]]+296, found 296.
The fourth step
Compound 2d (37mg, 0.09mmol) was dissolved in N, N-dimethylformamide (2mL), and 27d (26mg, 0.09mmol), 2- (7-benzotriazole oxide) -N, N, N ', N' -tetramethyluronium hexafluorophosphate (40mg, 0.11mmol) and triethylamine (27mg, 0.26mmol) were added to the reaction mixture, followed by stirring at room temperature for 2 hours. Water (20mL) and ethyl acetate (20mL) were added, the layers were separated, the aqueous phase was extracted with ethyl acetate (20mL × 2), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give a residue, which was purified by column chromatography (ethyl acetate: petroleum ether ═ 0-100%) to give 27e (40mg), yield: 67 percent
MS-ESI calculated value [ M +1 ]]+693, found 693.
The fifth step
Compound 27e (40mg, 0.06mmol) was dissolved in tetrahydrofuran (2mL), palladium on carbon (10mg) was added to the reaction solution, the reaction solution was purged with hydrogen balloon three times, and stirred at room temperature under hydrogen for 1 hour. After completion of the reaction, the reaction mixture was filtered through celite, the filter cake was washed twice with methanol, the filtrate was concentrated under reduced pressure to give a residue, and the residue was purified by column chromatography (methanol: dichloromethane ═ 0 to 100%) to give 27(9mg) in yield: 25 percent of
MS-ESI calculated value [ M +1 ]]+603, found 603.
1H NMR(400MHz,DMSO-d6)δ12.52(s,1H),11.14(s,1H),8.12(s,1H),7.82(s,1H),7.65–7.64(m,1H),7.47–7.44(m,2H),7.37–7.36(m,1H),7.26–7.20(m,2H),6.98(d,J＝7.6Hz,1H),5.72(s,1H),3.76(s,3H).
Example 28
Figure BDA0002610707420000401
First step of
Compound 1i (200mg, 1.17mmol) was dissolved in anhydrous dichloromethane (10mL), oxalyl chloride (195mg,1.54mmol) was added to the mixed solution under nitrogen blanket and then N, N-diisopropylethylenediamine (496mg, 3.84mmol) was added. Stirring at-78 deg.C for 1 hr, adding ammonia (2mL) to spot plate to detect the disappearance of raw material and new spot. The reaction solution was quenched with water and separated by ethyl acetate (50mL), the aqueous phase was extracted three times with ethyl acetate (30mL × 3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure and purified by column chromatography (methanol: dichloromethane ═ 0-100%) to give product 28a (150mg) in yield: 53 percent.
Second step of
Compound 28a (150mg, 0.62mmol) was dissolved in methanol (10mL), and then wet palladium on carbon (5mg, 0.04mmol) was added, and the reaction system was replaced with hydrogen balloon three times and stirred at room temperature for 1 hour. Concentration of the organic phase under reduced pressure after the appearance of a new spot gave crude 28b (100mg), yield: 76 percent.
MS-ESI calculated value [ M +1 ]]+212, measured value 212.
The third step
Compound 28b (100mg, 0.47mmol), 2d (195mg, 0.47mmol) and 2- (7-benzotriazole oxide) -N, N' -tetramethyluronium hexafluorophosphate (217mg, 0.57mmol) were dissolved in N, N-dimethylformamide (10mL), N-diisopropylethylenediamine (182mg, 1.42mmol) was added thereto, the mixture was stirred at room temperature for 2 hours, the reaction mixture was added with water (50mL) and ethyl acetate (50mL) to separate the liquid, the aqueous phase was extracted three times with ethyl acetate (30mL × 3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated by column chromatography (methanol: dichloromethane 0 to 100%) to obtain product 28(30mg) with yield: 10 percent.
1H NMR(400MHz,DMSO-d6)δ11.14(s,1H),8.27–8.08(m,2H),7.84–7.21(m,6H),6.99(s,1H),3.76(s,3H),3.15(s,3H).
MS-ESI calculated value [ M +1 ]]+609, found 609.
Example 29
Figure BDA0002610707420000411
First step of
Compound 1h (200mg, 1.28mmol) was dissolved in anhydrous dichloromethane (10mL), oxalyl chloride (195mg,1.54mmol) was added to the reaction system under nitrogen blanket, followed by N, N-diisopropylethylenediamine (496mg, 3.84 mmol). After stirring at-78 ℃ for 1 hour, aqueous ammonia (2mL) was added. The reaction was quenched with water (50mL), extracted three times with ethyl acetate (30mL × 3), the organic phases combined, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure and purified by column chromatography (methanol: dichloromethane ═ 0-100%) to give product 29a (210mg) in yield: 46 percent.
Second step of
Compound 29a (100mg, 0.44mmol) was dissolved in methanol (10mL), and then 10% wet palladium on carbon (5mg, 0.04mmol) was added, and the reaction system was replaced with hydrogen balloon three times and stirred at room temperature for 1 hour. The organic phase was concentrated under reduced pressure to give crude 29b (80mg), yield: 92 percent.
MS-ESI calculated value [ M +1 ]]+198, found 198.
The third step
Compound 29b (48mg, 0.24mmol), 2d (100mg, 0.24mmol) and 2- (7-benzotriazole oxide) -N, N' -tetramethyluronium hexafluorophosphate (182mg, 0.48mmol) were dissolved in N, N-dimethylformamide (10mL), N-diisopropylethylenediamine (92mg, 0.72mmol) was added thereto, the mixture was stirred at room temperature for 2 hours, the reaction mixture was added with water (50mL) and ethyl acetate (50mL) to separate the liquid, the aqueous phase was extracted with ethyl acetate (30mL × 3), the organic phase was combined, dried over anhydrous sodium sulfate, filtered, and concentrated by column chromatography (methanol: dichloromethane 0 to 100%) to obtain product 29(13mg) with yield: 9 percent of
1H NMR(400MHz,DMSO-d6)δ11.09(s,1H),10.14(s,1H),8.34(s,1H),8.12–8.05(m,3H),7.46(s,1H),7.36–7.35(m,1H),7.29–7.27(m,1H),7.21(s,1H),6.98(d,J＝9.2Hz,1H),3.76(s,3H).
MS-ESI calculated value [ M +1 ]]+595, found 595.15.
Example 30
Figure BDA0002610707420000421
First step of
Compound 1i (100mg, 0.59mmol) and compound 30a (50mg, 0.59mmol) were dissolved in pyridine (3mL), followed by addition of phosphorus oxychloride (1mL) while cooling on ice. After the mixture was replaced with nitrogen three times, the mixture was stirred at room temperature for 2 hours. Water (10mL) and ethyl acetate (10mL) were added to separate the solution, the aqueous phase was extracted with ethyl acetate (10mL × 3), the organic phases were combined, dried over anhydrous sodium sulfate, the organic layer was filtered and dried, and purified by column chromatography (ethyl acetate: petroleum ether ═ 0-100%) to give 30b (50mg) in yield: 36 percent.
MS-ESI calculated value [ M +1 ]]+238, found value 238.
Second step of
After compound 30b (60mg, 0.34mmol) was dissolved in methanol (2mL) and 10% wet palladium on carbon (6mg) was added to replace hydrogen, the reaction was stirred at room temperature for 2 hours. The reaction solution was filtered, and concentrated under reduced pressure to give a residue, which was purified by column chromatography (methanol: dichloromethane ═ 0 to 100%) to give compound 30c (40mg) in yield: 76 percent.
MS-ESI calculated value [ M +1 ]]+208, found 208.
The third step
Compound 30c (40mg, 0.19mmol) was dissolved in N, N-dimethylformamide (4mL), and 2d (84mg, 0.19mmol), 2- (7-benzotriazole oxide) -N, N' -tetramethyluronium hexafluorophosphate (110mg, 0.29mmol), N-diisopropylethylamine (75mg, 0.58mmol) were added, followed by nitrogen substitution three times, after stirring at room temperature for 2 hours, water (6mL) and ethyl acetate (6mL) were added, liquid separation was performed, the aqueous phase was extracted with ethyl acetate (6mL × 3), organic phase was combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give a residue, which was purified by column chromatography (methanol: dichloromethane ═ 0-100%) to give 30(8mg) yield: 7 percent.
MS-ESI calculated value [ M +1 ]]+605, found value 605.
1H NMR(400MHz,DMSO-d6)δ11.26(s,1H),8.13(s,1H),7.78–7.64(m,2H),7.39(s,2H),7.23(s,1H),7.00(s,1H),3.78–3.60(m,5H),3.14(s,3H).
Example 31
Figure BDA0002610707420000431
First step of
Dissolving 31a (100mg, 0.55mmol) in a mixed solvent of acetic acid (4mL) and water (1mL), adding sodium cyanate (142mg, 2.20mmol), then displacing with nitrogen three times, stirring at room temperature overnight, adding water (50mL) and ethyl acetate (50mL), separating, extracting the aqueous phase with ethyl acetate (50mL × 3), combining the organic phases, drying over anhydrous sodium sulfate, filtering, concentrating under reduced pressure to give a residue, and purifying the residue by column chromatography (methanol: dichloromethane ═ 0-100%) to give 31b (60mg), yield: 48 percent.
MS-ESI calculated value [ M +1 ]]+228, found 228.
Second step of
Compound 31b (60mg, 0.26mmol) was dissolved in methanol (2mL) and 10% wet palladium on carbon (10mg) was added. After replacement with hydrogen gas three times and stirring for 2 hours, the reaction mixture was filtered through celite, and the filtrate was concentrated under reduced pressure to give compound 31c (50mg) in yield: 99 percent.
MS-ESI calculated value [ M +1 ]]+198, measured value 198
The third step
After dissolving 2d (106mg, 0.26mmol) in N, N-dimethylformamide (4mL), 31c (53mg, 0.26mmol), 2- (7-benzotriazole oxide) -N, N' -tetramethyluronium hexafluorophosphate (149mg, 0.39mmol), N-diisopropylethylamine (101mg, 0.78mmol) were added and then replaced with nitrogen three times, and after stirring at room temperature for 2 hours, water (20mL) and ethyl acetate (20mL) were added, liquid separation was performed, the aqueous phase was extracted with ethyl acetate (20mL × 3), organic phase was combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give a residue, which was purified by methanol: dichloromethane ═ 0-100% to give 31(49mg) with yield: 33 percent.
MS-ESI calculated value [ M +1 ]]+595 found value595。
1H NMR(400MHz,DMSO-d6)δ11.09(s,1H),8.12(s,1H),7.58–7.56(m,2H),7.36–7.35(m,1H),7.27–7.25(m,1H),7.21(s,1H),6.99(d,J＝7.6Hz,1H),5.85(s,2H),3.76(s,3H),3.48(q,J＝7.2Hz,2H),0.96(t,J＝7.2Hz,3H).
Example 32
Figure BDA0002610707420000441
First step of
1i (200mg, 1.17mmol) and 32a (252mg, 1.17mmol) were dissolved in pyridine (5mL), phosphorus oxychloride (0.5mL) was slowly added dropwise under ice bath, followed by three nitrogen replacements, stirring at room temperature for 1 hour, pyridine was removed by concentration under reduced pressure to obtain a residue, water (50mL) and ethyl acetate (50mL) were added, liquid was separated, the aqueous phase was extracted with ethyl acetate (50mL × 3), the organic phases were combined and then dried over anhydrous sodium sulfate, filtration and concentration under reduced pressure to obtain a residue, and the residue was purified by column chromatography (methanol: dichloromethane ═ 0 to 100%) to obtain 32b (90mg), yield: 21 percent.
MS-ESI calculated value [ M +1 ]]+368, measured value 368.
Second step of
Compound 32b (90mg, 0.24mmol) was dissolved in methanol (2mL) and 10% wet palladium on carbon (10mg) was added. After replacement with hydrogen gas three times, stirring was carried out for 2 hours, and the reaction mixture was filtered and concentrated under reduced pressure to give compound 32c (70mg) in yield: 87 percent.
MS-ESI calculated value [ M +1 ]]+338, measured value 338
The third step
After dissolving 2d (123mg, 0.30mmol) in N, N-dimethylformamide (4mL), 32c (70mg, 0.30mmol), 2- (7-benzotriazole oxide) -N, N' -tetramethyluronium hexafluorophosphate (172mg, 0.45mmol), N-diisopropylethylamine (117mg, 0.90mmol) were added and then replaced with nitrogen three times, and after stirring at room temperature for 2 hours, water (20mL) and ethyl acetate (20mL) were added, liquid separation was performed, the aqueous phase was extracted with ethyl acetate (20mL × 3), organic phase was combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give a residue, which was purified by column chromatography (methanol: dichloromethane ═ 0 to 100%) to give 32d (70mg) with yield: 32 percent.
MS-ESI calculated value [ M +1 ]]+735, found value 735.
The fourth step
32d (70mg, 0.10mmol) was dissolved in ethyl acetate hydrochloride solution (5mL), and the reaction was stirred at room temperature for 2 hours. Then, concentration under reduced pressure gave 32(30mg), yield: 50 percent.
MS-ESI calculated value [ M +1 ]]+635, found value 635.
1H NMR(400MHz,DMSO-d6)δ11.63–11.43(m,1H),8.10–7.80(m,1H),7.67(s,1H),7.46(s,2H),7.22(s,1H),7.00–6.98(m,1H),4.02–3.87(m,1H),3.77(s,3H),3.17(s,2H),3.02(s,1H),2.47(s,3H),1.90–1.76(m,4H).
Example 33
Figure BDA0002610707420000451
First step of
After compound (1 h) (1.00g, 6.41mmol), sodium carbonate (8.20g, 76.86mmol) and 2, 2' -bipyridine (5.00g, 32.03mmol) were dissolved in 1, 2-dichloroethane (10mL) and the mixture was stirred at 60 ℃ for 30 minutes three times with replacement of oxygen, the reaction system was stirred at 80 ℃ for 30 minutes while returning to room temperature, cyclopropylboronic acid (1.10g, 12.81mmol) and copper acetate (5.20g, 28.82mmol) were added to the reaction mixture twice and stirred at 80 ℃ for 30 minutes, and the reaction system was stirred at room temperature overnight. After the reaction solution was diluted with dichloromethane (8mL) and filtered, the filtrate was separated with water (10mL), the aqueous phase was extracted with dichloromethane (10mL × 3), the organic phases were combined and filtered, the filtrate was concentrated under reduced pressure to give a residue, and the residue was purified by column chromatography (ethyl acetate: petroleum ether ═ 0-100%) to give 33a (430mg) in yield: 34 percent.
MS-ESI calculated value [ M +1 ]]+197, found value 197.
1H NMR(400MHz,DMSO-d6)δ7.69–7.66(m,1H),7.50–7.42(m,1H),7.24–7.22(m,1H),6.68(s,1H),2.42(s,1H),0.75–0.72(m,2H),0.46(s,2H).
Second step of
Compound 33a (380mg, 1.94mmol) was dissolved in a mixed solvent (5mL) of glacial acetic acid (5mL) and water (1mL), followed by addition of sodium cyanate (650mg, 7.75mmol) and stirring at 80 ℃ for 8 hours. Water (10mL) and ethyl acetate (10mL) were added for separation, the aqueous phase was extracted with ethyl acetate (10mL × 3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give a residue, which was purified by column chromatography (ethyl acetate: petroleum ether ═ 0-100%) to give 33b (30mg) in yield: 7 percent.
MS-ESI calculated value [ M +1 ]]+240, measured value 240.
The third step
After compound 33b (30mg, 0.13mmol) was dissolved in methanol (2mL), 10% wet palladium on carbon (3mg) was added and hydrogen was replaced, the reaction system was stirred at room temperature for 2 hours. The reaction solution was filtered through celite, and the filtrate was concentrated under reduced pressure to give a residue, which was purified by column chromatography (methanol: dichloromethane 0-100%) to give compound 33c (15mg) in yield: 58 percent.
MS-ESI calculated value [ M +1 ]]+210, measured value 210.
The fourth step
After dissolving 2d (30mg, 0.07mmol) in N, N-dimethylformamide (2mL), 33c (15mg, 0.07mmol), 2- (7-benzotriazole oxide) -N, N' -tetramethyluronium hexafluorophosphate (40mg, 0.10mmol), N-diisopropylethylamine (27mg, 0.21mmol) were added and then replaced with nitrogen three times, stirring was performed at room temperature for 2 hours, water (6mL) and ethyl acetate (6mL) were added for liquid separation, the aqueous phase was extracted with ethyl acetate (10mL × 3), the organic phase was combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give a residue, which was purified by methanol: dichloromethane ═ 0-100% to give 33(3mg) in yield: 4 percent.
MS-ESI calculated value [ M +1 ]]+607, found 607.
1H NMR(400MHz,DMSO-d6)δ11.06(s,1H),8.11(s,1H),7.50–7.48(m,2H),7.37(d,J＝8.8Hz,1H),7.21–7.18(m,2H),6.99(d,J＝8.4Hz,1H),6.30(s,2H),3.76(s,3H),2.87(d,J＝8.4Hz,1H),0.81–0.77(m,2H),0.45–0.42(m,2H).
Example 34
Figure BDA0002610707420000461
First step of
Isoiodopropane (1.60g, 9.41mmol) was dissolved in N, N-dimethylformamide (30mL), followed by addition of 60% sodium hydride (307mg) under ice-bath conditions. After the replacement with nitrogen gas three times, the mixture was stirred at 0 ℃ for 1 hour, and then 1 hour (1.00g, 6.40mmol) of the compound was added to the above mixed solution, and after the replacement with nitrogen gas three times, the mixture was stirred at room temperature for 2 hours. Water (50mL) and ethyl acetate (50mL) were added for separation, the aqueous phase was extracted with ethyl acetate (30mL × 3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give a residue, which was purified by column chromatography (ethyl acetate: petroleum ether ═ 0-100%) to give 34a (200mg), yield: 15 percent of
MS-ESI calculated value [ M +1 ]]+199, found 199.
Second step of
Compound 34a (200mg, 1.00mmol) was dissolved in a solution of water (4mL) and then glacial acetic acid (4mL) and potassium cyanate (810mg, 10.00mmol) were added. After replacement with nitrogen three times, the mixture was stirred at room temperature for 2 hours, water (50mL) and ethyl acetate (50mL) were added to separate the mixture, the aqueous phase was extracted with ethyl acetate (30mL × 3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give a residue, which was purified by column chromatography (ethyl acetate: petroleum ether ═ 0 to 100%) to give 34b (103mg) in yield: 42 percent.
MS-ESI calculated value [ M +1 ]]+242, found value 242.
The third step
34b (103mg, 0.42mmol) was dissolved in methanol (4mL), 10% wet palladium on carbon (20mg) was added, hydrogen was replaced, and the reaction was stirred at room temperature for 2 hours. The reaction solution was filtered, dried and purified by column chromatography (methanol: dichloromethane ═ 0 to 100%) to give compound 34c (40mg) in yield: 44 percent.
MS-ESI calculated value [ M +1 ]]+212, measured value 212
The fourth step
Dissolving 2d (25mg, 0.12mmol) in N, N-dimethylformamide (5mL), adding 34c (25mg, 0.11mmol), 2- (7-benzotriazole oxide) -N, N' -tetramethyluronium hexafluorophosphate (61mg, 0.16mmol), N-diisopropylethylamine (57mg, 0.44mmol), then displacing with nitrogen three times, stirring at room temperature for 2 hours, adding water (60mL) and ethyl acetate (60mL), separating, extracting the aqueous phase with ethyl acetate (20mL × 3), combining the organic phases, drying over anhydrous sodium sulfate, filtering, concentrating under reduced pressure column chromatography to give a residue, and purifying the residue (ethyl acetate: petroleum ether ═ 0-100%) to give 34(3mg), yield: 8 percent.
MS-ESI calculated value [ M +1 ]]+609, found 609.
1H NMR(400MHz,DMSO-d6)δ7.98(s,1H),7.54–7.46(m,2H),7.37(s,1H),7.28–7.05(m,2H),7.03–7.01(m,1H),5.73(s,2H),4.40–4.39(m,1H),3.70(s,3H),0.58(s,6H).
Example 35
Figure BDA0002610707420000471
First step of
Compound 1h (1.25g, 8.00mmol) and compound 35a (2.00g, 8.00mmol) were dissolved in N, N-dimethylformamide (20mL), followed by the addition of N, N-diisopropylethylenediamine (1.95g, 16.00 mmol). After stirring at room temperature for 20 hours, the reaction mixture was quenched with water, separated with ethyl acetate (50mL), the aqueous phase was extracted with ethyl acetate (30mL × 3), the organic phases were combined and washed with saturated brine (100mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure and purified by column chromatography (methanol: dichloromethane ═ 0 to 100%) to give product 35b (800mg) in yield: 26 percent.
Second step of
Compound 35b (800mg, 1.55mmol) and iodomethane were dissolved in acetonitrile (20mL), the reaction was purged with nitrogen, then silver tetrafluoroborate (603mg, 3.10mmol) was added, and the mixture was heated to 60 ℃ and stirred for 18 hours. The reaction was filtered and the organic phase was concentrated under reduced pressure to give crude 35c (60mg), yield: and 55 percent.
The third step
Compound 35c (600mg, 1.13mmol) and cesium carbonate (972mg, 2.27mmol) were dissolved in acetonitrile (10mL), stirred at room temperature for 6 hours, TLC detected new spots, the reaction mixture was concentrated to remove acetonitrile, water (50mL) and ethyl acetate (50mL) were added for separation, the aqueous phase was extracted with ethyl acetate (30 mL. times. 3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give product 35d (400 mg).
The fourth step
Compound 35d (400mg, 0.62mmol) was dissolved in methanol (10mL), and then wet palladium on carbon (7mg, 0.06mmol) was added, and the reaction system was replaced with hydrogen balloon three times and stirred at room temperature for 1 hour. Concentration of the organic phase under reduced pressure after the appearance of a new spot gave crude 35e (260mg), two-step yield: 71 percent.
1H NMR(400MHz,CDCl3)δ6.93–6.88(m,1H),6.72–6.71(m,1H),6.53–6.46(m,1H),5.19(s,1H),4.31(s,1H),3.79–3.75(m,1H),3.69–3.64(m,2H),3.47(s,1H),2.74(s,1H),2.08–2.00(m,1H),1.45(s,9H).
The fifth step
After compound 35e (260mg, 0.84mmol), 2d (350mg, 0.84mmol) and 2- (7-benzotriazole oxide) -N, N' -tetramethyluronium hexafluorophosphate (414mg, 1.09mmol) were dissolved in N, N-dimethylformamide (20mL), N-diisopropylethylenediamine (205mg, 1.68mmol) was added thereto, the mixture was stirred at room temperature for 2 hours, a new spot was detected by TLC, the reaction mixture was added with water (50mL) and ethyl acetate (50mL) and separated, the aqueous phase was extracted three times with ethyl acetate (30mL × 3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and purified by column chromatography under reduced pressure (methanol: dichloromethane ═ 0 to 100%) to give product 35f (350mg) in yield: 59 percent.
The sixth step
Compound 35f (100mg, 0.14mmol) was dissolved in a solution of hydrochloric acid in methanol (10mL) and stirred at room temperature for 1 hour. The organic phase was concentrated under reduced pressure to give the product 35(260mg), yield: 71 percent.
MS-ESI calculated value [ M +1 ]]+607, found 607.
1H NMR(400MHz,CD3OD)δ8.02–8.00(m,1H),7.97(s,1H),7.54–7.49(m,1H),7.34–7.33(m,1H),7.30–7.24(m,1H),7.09–7.08(m,1H),6.94(d,J＝8.8Hz,1H),4.30(t,J＝8.8Hz,1H),4.03–3.93(m,1H),3.87–3.85(m,1H),3.80(s,3H),2.75–2.65(m,1H),2.31–2.20(m,1H).
Example 36
Figure BDA0002610707420000491
First step of
Compound 36a (30mg, 0.09mmol) was dissolved in ultra-dry 1, 4-dioxane (5mL), and compound 36b (31mg, 0.13mmol), cuprous iodide (7mg, 0.04mmol), tripotassium phosphate (38mg, 0.18mmol), and ethylenediamine (0.05mL) were added to the reaction system, and the reaction was allowed to warm to 110 ℃ for overnight reaction with tube sealing. After the system was cooled to room temperature, water (50mL) and ethyl acetate (50mL × 3) were added to the reaction system to extract, and after the organic phases were combined, the mixture was washed with saturated brine (50mL × 1), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a residue, which was purified by column chromatography (ethyl acetate: petroleum ether ═ 0 to 100%) to obtain compound 36c (11mg) in yield: 28 percent.
MS-ESI calculated value [ M +1 ]]+444, found value 444.
Second step of
After 36c (10mg, 0.02mmol) was dissolved in ethyl acetate hydrochloride gas (5mL), the nitrogen gas was replaced three times, the reaction was carried out at normal temperature for 4 hours, and the reaction solution was concentrated under reduced pressure to obtain compound 36d (7mg) in yield: 87 percent.
MS-ESI calculated value [ M +1 ]]+344, found 344.
The third step
After 36d (7mg, 0.02mmol) was dissolved in N, N-dimethylformamide (3mL), 2d (7mg, 0.02mmol), 2- (7-benzotriazole oxide) -N, N' -tetramethyluronium hexafluorophosphate (10mg, 0.03mmol), N-diisopropylethylamine (7mg, 0.05mmol) were added and then replaced with nitrogen three times, and after reaction at room temperature for 2 hours, water (30mL) and ethyl acetate (30mL) were added to the reaction system, liquid separation was performed, the aqueous phase was extracted with ethyl acetate (10mL × 3), organic phase was combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a residue, which was purified by thin layer chromatography (methanol: dichloromethane ═ 0 to 100%) to obtain 36e (11mg) with yield: 87 percent.
MS-ESI calculated value [ M +1 ]]+741, found value 741.
The fourth step
36e (11mg, 0.02mmol) was dissolved in anhydrous methanol (5mL), palladium on carbon (3mg) was added at room temperature and replaced with hydrogen three times, followed by stirring at room temperature for 3 hours. Filtration and concentration of the organic phase under reduced pressure gave a residue which was purified by column chromatography (methanol: dichloromethane ═ 0 to 100%) to give 36(2mg), yield: 22 percent.
MS-ESI calculated value [ M +1 ]]+607, found 607.
1H NMR(400MHz,CD3OD)δ7.99(s,1H),7.78–7.77(m,1H),7.53–7.51(m,1H),7.31(d,J＝8.8Hz,1H),7.26–7.24(m,1H),7.08(s,1H),6.95–6.93(m,1H),3.78(s,3H),3.69(t,J＝5.6Hz,2H),3.60(s,2H),3.20(t,J＝5.6Hz,2H).
Example 37
Figure BDA0002610707420000501
First step of
Compound 37a (500mg, 3.80mmol) was dissolved in a tetrahydrofuran (10mL) solution, to which benzyl bromide (655mg, 3.80mmol) and potassium hydroxide (426mg, 7.60mmol) were added in this order, and the reaction mixture was heated to 40 ℃ and reacted for 16 hours. After completion of the reaction, the reaction mixture was concentrated under reduced pressure to obtain a residue, which was separated by adding water (30mL) and ethyl acetate (20mL), the aqueous phase was extracted with ethyl acetate (20mL), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain crude product 37b (524mg), yield: and 63 percent.
MS-ESI calculated value [ M +1 ]]+221, found 221.
Second step of
In a 7mL microwave tube, compound 37b (200mg, 0.91mmol) was dissolved in 1, 4-dioxane (4mL) and 13a (168mg, 0.91mmol), tetrakis (triphenylphosphine) palladium (104mg, 0.09mmol) and sodium carbonate (193mg, 1.82mmol) were added, respectively. Introducing nitrogen into the reaction system, bubbling for 5 minutes, putting the microwave tube into a microwave instrument, heating to 115 ℃, and reacting for 40 minutes. After the reaction was completed, the reaction solution was filtered, and the filtrate was concentrated under reduced pressure and purified by column chromatography (ethyl acetate: petroleum ether ═ 0 to 100%) to give 37c (67mg) in yield: 23 percent.
MS-ESI calculated value [ M +1 ]]+326, found 326.
The third step
Compound 37c (67mg, 0.21mmol) was dissolved in ethanol: water-4: 1(2mL), iron powder (58mg, 1.03mmol) and ammonium chloride (110mg, 2.06mmol) were added to the solution, respectively, and the reaction was heated to 80 ℃ for 3 hours. After completion of the reaction, the reaction solution was filtered, the filtrate was separated by adding water (20mL) and ethyl acetate (20mL), the aqueous phase was extracted with ethyl acetate (10mL), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give a residue, which was purified by column chromatography (ethyl acetate: petroleum ether ═ 0 to 100%) to give 37d (51mg) with yield: 82 percent.
MS-ESI calculated value [ M +1 ]]+296, found 296.
The fourth step
Compound 37d (50mg, 0.17mmol) was dissolved in methylene chloride (5mL), and then boron tribromide (128mg, 0.51mmol) was added at-78 ℃ to react the reaction mixture at-78 ℃ for 3 hours. After completion of the reaction, methanol (2mL) was slowly added at-78 ℃, and concentrated under reduced pressure to give a residue, which was purified by column chromatography (ethyl acetate: petroleum ether ═ 0-100%) to give 37e (25mg) in yield: 72 percent.
MS-ESI calculated value [ M +1 ]]+206, measured value 206.
The fifth step
Compound 2d (56mg, 0.13mmol) was dissolved in N, N-dimethylformamide (2mL), 37e (25mg, 0.12mmol), 2- (7-benzotriazole oxide) -N, N, N ', N' -tetramethyluronium hexafluorophosphate (70mg, 0.18mmol) and N, N-diisopropylethylamine (50mg, 0.39mmol) were added to the reaction mixture, respectively, and the mixture was stirred at room temperature for 2 hours. After completion of the reaction, water (20mL) and ethyl acetate (20mL) were added, liquid separation was performed, the aqueous phase was extracted with ethyl acetate (20mL × 2), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a residue, which was purified by column chromatography (ethyl acetate: petroleum ether ═ 0-100%) to obtain 37(3mg) in yield: 4 percent.
MS-ESI calculated value [ M +1 ]]+603, found 603.
1H NMR(400MHz,CD3OD)δ7.99(s,2H),7.84–7.83(m,1H),7.74–7.73(m,1H),7.53(s,1H),7.32(d,J＝8.4Hz,1H),7.23(t,J＝9.6Hz,1H),7.08(s,1H),6.94–6.93(m,1H),3.78(s,3H).
Example 38
Figure BDA0002610707420000511
First step of
13a (200mg, 1.08mmol) and 38a (252mg, 1.19mmol) were dissolved in 1.4-dioxane (5mL), followed by addition of sodium carbonate (230mg, 2.16mmol) and palladium tetratriphenylphosphine (126mg, 0.11mmol), followed by three nitrogen replacements, stirring at 115 ℃ for 2 hours, the reaction solution was filtered and concentrated to give a residue, water (50mL) and ethyl acetate (50mL) were added, liquid separation was performed, the aqueous phase was extracted with ethyl acetate (50mL × 3), the organic phase was combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give a residue, which was purified by column chromatography (methanol: dichloromethane ═ 0-100%) to give 38b (90 mg). Yield: 30 percent.
MS-ESI calculated value [ M +1 ]]+236, found value 236.
Second step of
Compound 38b (60mg, 0.26mmol) was dissolved in a mixed solvent of ethanol (2.5mL) and water (2.5mL), followed by addition of iron powder (72mg, 1.30mmol) and ammonium chloride (136mg, 2.60 mmol). After the reaction mixture was stirred at 80 ℃ for 2 hours after being substituted three times with nitrogen, the reaction mixture was filtered, and the organic solvent was removed by concentration under reduced pressure to obtain a residue, which was purified by column chromatography (methanol: dichloromethane 0-100%) to obtain 38c (50 mg). Yield: 94 percent.
MS-ESI calculated value [ M +1 ]]+338, measured value 338.
The third step
After dissolving 2d (111mg, 0.27mmol) in N, N-dimethylformamide (4mL), 38c (55mg, 0.27mmol), 2- (7-benzotriazole oxide) -N, N' -tetramethyluronium hexafluorophosphate (154mg, 0.40mmol), N-diisopropylethylamine (105mg, 0.81mmol) were added and then replaced with nitrogen three times, stirring was performed at room temperature for 2 hours, water (20mL) and ethyl acetate (20mL) were added, liquid separation was performed, the aqueous phase was extracted with ethyl acetate (20mL × 3), organic phase was combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give a residue, which was purified by column chromatography (methanol: dichloromethane ═ 0 to 100%) to give 38(10mg) in yield: 8 percent.
MS-ESI calculated value [ M +1 ]]+604, measured value 604.
1H NMR(400MHz,DMSO-d6)δ11.23(s,1H),11.17(s,1H),8.27(s,1H),8.14(s,1H),7.84–7.83(m,1H),7.38–7.35(m,2H),7.21(s,1H),6.99–6.98(m,2H),3.76(s,3H).
Example 39
Figure BDA0002610707420000521
Example 39(19mg) was obtained from 1h and 39a through a multi-step reaction by referring to the procedure for synthesizing example 35 from 1h and 35a in example 35.
MS-ESI calculated value [ M +1 ]]+607, found 607.
1H NMR(400MHz,DMSO-d6)δ11.74(s,1H),8.81(s,2H),8.06(s,1H),7.94(s,1H),7.63–7.49(m,2H),7.37–7.36(m,1H),7.21(s,1H),6.99–6.98(m,1H),4.19(s,1H),3.77(s,3H),1.29–1.23(m,4H).
Example 40
Figure BDA0002610707420000522
Figure BDA0002610707420000531
First step of
After dissolving 2d (470mg, 1.14mmol) in N, N-dimethylformamide (4mL), 20a (160mg, 1.14mmol), 2- (7-benzotriazole oxide) -N, N' -tetramethyluronium hexafluorophosphate (652mg, 1.71mmol), N-diisopropylethylamine (442mg, 3.42mmol) were added and then replaced with nitrogen three times, stirring was performed at room temperature for 2 hours, water (20mL) and ethyl acetate (20mL) were added, liquid separation was performed, the aqueous phase was extracted with ethyl acetate (20mL × 3), organic phase was combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give a residue, which was purified by column chromatography (methanol: dichloromethane ═ 0-100%) to give 40a (400mg) with yield: 65 percent.
MS-ESI calculated value [ M +1 ]]+538, measured value 538.
Second step of
After 40a (410mg, 0.76mmol) was dissolved in N, N-dimethylformamide (5mL), bromoacetyl bromide (233mg, 1.15mmol) and potassium carbonate (315mg, 2.28mmol) were added, followed by three nitrogen replacements, stirring at room temperature for 2 hours, water (20mL) and ethyl acetate (20mL) were added, liquid separation was performed, the aqueous phase was extracted with ethyl acetate (20mL × 3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give 40b (620mg), yield: 90 percent.
MS-ESI calculated value [ M +1 ]]+658, found 658.
The third step
40b (100mg, 0.15mmol) was dissolved in methanol (3mL), triethylamine (0.1mL, 0.46mmol) and dimethylamine solution (2mL) were added, followed by nitrogen substitution three times, stirring at room temperature for 2 hours, then water (20mL) and ethyl acetate (20mL) were added, liquid separation was performed, the aqueous phase was extracted with ethyl acetate (20mL × 3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give a residue, which was purified by column chromatography (methanol: dichloromethane ═ 0 to 100%) to give 40(40mg) with yield: and 43 percent.
MS-ESI calculated value [ M +1 ]]+623, found value 623.
1H NMR(400MHz,DMSO-d6)δ11.39–11.27(m,1H),8.12(s,1H),7.82–7.80(m,1H),7.61(s,1H),7.42–7.40(m,2H),7.23(s,1H),7.00(d,J＝8.8Hz,1H),3.77(s,3H),3.13(s,3H),2.51(s,2H),2.38(s,6H).
EXAMPLE 41
Figure BDA0002610707420000532
First step of
41a (1.90g, 10.00mmol),41b (1.54g, 10.00mmol),1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (2.50g, 13.00mmol), 4-dimethylaminopyridine (3.10g, 25.00mmol) were dissolved in N, N-dimethylformamide (50mL), then replaced with nitrogen three times, stirred at room temperature for 16 hours, added with water (30mL), then ethyl acetate (30 mL. times. 2) was used, washed with saturated brine and dried with anhydrous sodium sulfate, the organic phase was concentrated under reduced pressure to give a residue, which was purified by column chromatography (ethyl acetate: petroleum ether ═ 0-100%) to give 41c (1.10g), yield: 34 percent.
MS-ESI calculated value [ M +1 ]]+326, found 326.
Second step of
41c (500mg, 1.50mmol), tert-butyl carbamate (410mg, 3.00mmol), tris (dibenzylideneacetone) dipalladium (27mg, 0.03mmol),4, 5-bis (diphenylphosphino) -9, 9-dimethylxanthene (26mg, 0.05mmol), cesium carbonate (980mg, 2mmol) were dissolved in toluene (20mL), then replaced with nitrogen three times, stirred at room temperature for 16 hours, the reaction solution was filtered through celite, extracted with water and ethyl acetate (50mLx2), and the organic phase was concentrated under reduced pressure to give a residue, which was purified by column chromatography (ethyl acetate: petroleum ether ═ 0-100%) to give 41d (200 mg). Yield: 37 percent.
MS-ESI calculated value [ M +1 ]]+363, measured value 363.
The third step
41d (200mg, 0.55mmol) was dissolved in ethyl acetate hydrochloride gas (10mL, 3mol/L), then replaced with nitrogen three times, stirred at room temperature for 2 hours, and directly concentrated under reduced pressure to give a residue, which was purified by column chromatography (methanol: dichloromethane ═ 0-100%) to give 41e (110mg), yield: 76 percent.
MS-ESI calculated value [ M +1 ]]+263, found 263.
The fourth step
41e (110mg, 0.42mmol), 2d (210mg, 0.50mmol) were dissolved in N, N-dimethylformamide (5mL), and 2- (7-benzotriazole oxide) -N, N, N ', N' -tetramethyluronium hexafluorophosphate (240mg, 0.62mmol), N, N-diisopropylethylamine (136mg, 1.05mmol) was added thereto, followed by nitrogen substitution three times, stirring at room temperature for 2 hours, and then directly concentrated under reduced pressure to give a residue, which was purified by column chromatography (methanol: dichloromethane 0-100%) to give 41f (180mg), yield: 65 percent.
MS-ESI calculated value [ M +1 ]]+660, found 660.
The fifth step
41f (180mg, 0.27mmol) was dissolved in tetrahydrofuran and water (2 mL: 2mL), sodium hydroxide (54mg, 1.35mmol) was added, then nitrogen gas was substituted three times, stirring was carried out at room temperature for 16 hours, then 6N hydrochloric acid was added to adjust pH to about 1, extracted water and ethyl acetate (30 mL. times. 2), washing was carried out with saturated brine, dried over anhydrous sodium sulfate, and organic phase was concentrated under reduced pressure to obtain 41g (130mg), yield: 75 percent.
MS-ESI calculated value [ M +1 ]]+646, found 646.
The sixth step
41g (130mg, 0.20mmol), diphenylphosphorylazide (83mg, 0.30mmol), triethylamine (41mg, 0.40mmol), tert-butanol (30mg, 0.40mmol) were dissolved in toluene (10mL), and then replaced with nitrogen three times, after stirring at 105 ℃ for 16 hours, water and ethyl acetate (30mL × 2) were extracted, followed by washing with saturated brine and anhydrous sodium sulfate, and direct concentration under reduced pressure to obtain a residue, which was purified by column chromatography (methanol: dichloromethane ═ 0 to 100%) to obtain 41(12mg), yield: 9 percent.
MS-ESI calculated value [ M +1 ]]+617, found 617.
1H NMR(400MHz,CD3OD)δ7.99(s,1H),7.80–7.78(m,1H),7.73–7.69(m,1H),7.33–7.30(m,2H),7.09(s,1H),6.91–6.87(m,2H),6.75–6.73(m,1H),6.32(t,J＝7.2Hz,1H),3.78(s,3H).
Example 42
Figure BDA0002610707420000551
First step of
After 1i (170mg, 1.00mmol), 2-iodoacetamide (925mg, 5mmol), potassium carbonate (414mg, 3.00mmol) were dissolved in acetonitrile (5mL), stirred at 80 ℃ for 72 hours under a sealed tube condition, water and ethyl acetate (30mL × 2) were extracted, dried with saturated brine and anhydrous sodium sulfate, and the organic phase was concentrated under reduced pressure to give a residue, which was purified by column chromatography (methanol: dichloromethane ═ 0 to 100%) to give 42a (30mg) in yield: 13 percent.
MS-ESI calculated value [ M +1 ]]+228, found 228.
Second step of
42a (30mg, 0.13mmol) was dissolved in tetrahydrofuran (5mL), 10% wet palladium on carbon (10mg) was added, the mixture was replaced three times with hydrogen, and after stirring at room temperature for 1 hour, the reaction mixture was directly filtered and dried to give 42b (20mg) in yield: 78 percent.
MS-ESI calculated value [ M +1 ]]+198, found 198.
The third step
2d (63mg, 0.15mmol), 42b (20mg, 0.10mmol) were dissolved in N, N-dimethylformamide (5mL), and 2- (7-benzotriazole oxide) -N, N' -tetramethyluronium hexafluorophosphate (86mg, 0.23mmol), N-diisopropylethylamine (48mg, 0.38mmol) was further added, followed by nitrogen substitution three times, stirring at room temperature for 2 hours, and direct concentration under reduced pressure to give a residue, which was purified by column chromatography (methanol: dichloromethane ═ 10%) to give 42(6mg) with yield: 10 percent.
MS-ESI calculated value [ M +1 ]]+595, found 595.
1H NMR(400MHz,CD3OD)δ7.97(s,1H),7.37–7.31(m,2H),7.11–7.68(m,4H),3.79–3.75(m,5H),2.91(s,3H).
Example 43
Figure BDA0002610707420000552
Figure BDA0002610707420000561
First step of
40b (100mg, 0.15mmol) was dissolved in methanol (3mL), triethylamine (0.1mL, 0.46mmol) and a methylamine solution (2mL) were added, followed by replacement with nitrogen three times, stirring at room temperature for 2 hours, then water (20mL) and ethyl acetate (20mL) were added, liquid separation was performed, the aqueous phase was extracted with ethyl acetate (20mL × 3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give a residue, which was purified by column chromatography (methanol: dichloromethane ═ 0 to 100%) to give 43(30mg) in yield: 33 percent.
MS-ESI calculated value [ M +1 ]]+609, found 609.
1H NMR(400MHz,DMSO-d6)δ11.52–11.39(m,1H),8.11(s,1H),7.88–7.80(m,1H),7.62–7.61(m,1H),7.44–7.41(m,2H),7.24(s,1H),7.01–6.99(m,1H),4.18(s,1H),3.77(s,3H),3.16(s,3H),2.53(s,2H),2.40(s,3H).
Example 44
Figure BDA0002610707420000562
First step of
After compound 44a (20.00g, 13.32mmol) was dissolved in acetone (100mL), 20% aqueous sodium carbonate solution (250mL) was added and replaced with nitrogen three times, benzyl chloroformate (29.50g, 17.32mmol) was added dropwise in an ice bath, and the mixture was stirred at room temperature overnight to complete the reaction, PH 1 was adjusted with 4N hydrochloric acid to produce a solid, which was then filtered and the crude product was oil-pumped to dryness to give 44b (7.50g), yield: 19 percent.
MS-ESI calculated value [ M +1 ]]+267, found 267.
Second step of
Compound 44b (7.50g, 28.19mmol) was dissolved in acetonitrile (100mL), ethyl acetate (5mL), water (5mL) and (bis (trifluoroacetoxy) iodo) benzene (12.70g, 39mmol) were added at room temperature, the mixture was replaced three times with nitrogen, and the mixture was stirred at room temperature overnight. After stirring for 20 minutes in an ice bath, filtration and oil pump dry gave crude 44c (5.00g), yield: 75 percent.
MS-ESI calculated value [ M +1 ]]+239, found value 239.
The third step
Compound 44c (5.00g, 21.00mmol) was dissolved in acetonitrile (150mL), and sodium bicarbonate (11.50g, 136.55mmol) and methanesulfonyl chloride (2.65g, 23mmol) were added at room temperature after three replacements with nitrogen and stirring at 80 ℃ overnight. Slowly cooled to room temperature, filtered and oil pumped to dryness to give crude 44d (2.00g), yield: 44 percent.
The fourth step
Compound 44d (500mg, 2.27mmol) and 36a (500mg, 1.48mmol) were dissolved in dimethyl sulfoxide (10mL), and cuprous iodide (112.7mg, 0.59mmol), anhydrous potassium phosphate (627mg, 2.96mmol) and dimethylethylenediamine (10 drops) were added at room temperature, bubbled with nitrogen, and the mixture was added to 120 ℃ and the reaction was stirred overnight with a tube sealed. Slowly cooled to room temperature, water (30mL) and ethyl acetate (30mL) were added thereto at room temperature, the mixture was separated, the aqueous phase was extracted with ethyl acetate (20mL × 3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give a residue, which was purified by column chromatography (ethyl acetate: petroleum ether ═ 0-100%) to give 44e (200mg), yield: 31 percent.
The fifth step
Compound 44e (200mg, 0.47mmol) was dissolved in ethyl acetate (5mL), and 3M ethyl acetate hydrochloride gas (10mL) was added at room temperature and stirred at room temperature for 3 hours. Concentration under reduced pressure gave a residue which was oil pumped to dryness to give crude 44f (160mg), yield: 94 percent.
MS-ESI calculated value [ M +1 ]]+330, measured value 330.
The sixth step
44f (65mg, 0.20mmol) was dissolved in N, N-dimethylformamide (5mL), and 2d (100mg, 0.24mmol), 2- (7-benzotriazole oxide) -N, N' -tetramethyluronium hexafluorophosphate (112.7mg, 0.30mmol), N-diisopropylethylamine (76.5mg, 0.59mmol) were further added, followed by three times of nitrogen substitution, stirring at room temperature for 3 hours, then water (30mL) and ethyl acetate (30mL) were added, liquid separation was performed, the aqueous phase was extracted with ethyl acetate (20mL × 3), organic phase was combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give a residue, which was purified by column chromatography (ethyl acetate: petroleum ether ═ 0-100%) to give 44g (60mg) in yield: 42 percent.
Seventh step
44g (60mg, 0.083mmol) of the compound was dissolved in tetrahydrofuran (10mL), and palladium on carbon (10mg) was added at room temperature to replace three times with hydrogen gas, followed by stirring at room temperature for 6 hours. Filtration and concentration under reduced pressure gave a residue, which was purified by column chromatography (methanol: dichloromethane ═ 0 to 100%) to give 44(41mg), yield: 84 percent.
MS-ESI calculated value [ M +1 ]]+593, found 593.
1H NMR(400MHz,CD3OD)δ8.26–8.25(m,1H),7.98(s,1H),7.44–7.43(m,1H),7.32(d,J＝8.8Hz,1H),7.18–7.12(m,1H),7.07(s,1H),6.93(d,J＝8.0Hz,1H),4.34(s,1H),4.19–4.15(m,1H),3.80(s,3H),3.71–3.68(m,1H).
Example 45
Figure BDA0002610707420000581
First step of
After dissolving 2d (50mg, 0.12mmol) in N, N-dimethylformamide (3mL), 3c (20mg, 0.12mmol), 2- (7-benzotriazole oxide) -N, N' -tetramethyluronium hexafluorophosphate (68mg, 0.18mmol), N-diisopropylethylamine (47mg, 0.36mmol) were added and then replaced with nitrogen three times, stirring was performed at room temperature for 2 hours, water (20mL) and ethyl acetate (20mL) were added, liquid separation was performed, the aqueous phase was extracted with ethyl acetate (20mL x3), organic phase was combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give a residue, which was purified by column chromatography (methanol: dichloromethane ═ 0-10%) to give 45(20mg) with yield: 29 percent.
MS-ESI calculated value [ M +1 ]]+566, measured value 566.
1H NMR(400MHz,CD3OD)δ7.97(s,1H),7.59–7.50(m,2H),7.32–7.30(m,1H),7.11–7.08(m,2H),6.95–6.91(m,1H),3.79(s,3H),3.57(s,2H).
Example 46
Figure BDA0002610707420000582
First step of
Compound 1i (1.20g, 7.05mmol), dimethylcarbamoyl chloride (1.51g, 14.0mmol) were dissolved in toluene (100mL), triethylamine (2.14g, 21.15mmol) and a catalytic amount of 4-dimethylaminopyridine (86mg, 0.70mmol) were slowly added dropwise at room temperature, the temperature was raised to 130 ℃ by replacing nitrogen gas and stirred for 2 hours, the reaction system was diluted with water (30mL), and extracted with ethyl acetate (50mL × 3), after organic phase combination, washed with saturated brine (20mL), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure to remove the organic solvent, and purified by column chromatography (ethyl acetate: petroleum ether ═ 0 to 100%) to give compound 2c (120mg) in yield: 7 percent.
Second step of
Compound 2c (50mg, 0.24mmol) was dissolved in methanol (5mL) and palladium on carbon (10%) was added. After hydrogen substitution, the reaction was stirred at room temperature for 1 hour. The reaction mixture was filtered, concentrated under reduced pressure, and the organic solvent was removed under reduced pressure to give compound 2(102 mg). Yield: 97 percent.
MS-ESI calculated value [ M +1 ]]+212, measured value 212.
The third step
3f (80mg, 0.19mmol) was dissolved in N, N-dimethylformamide (5mL), 46b (41mg, 0.19mmol) was added, 2- (7-benzotriazole oxide) -N, N, N ', N' -tetramethyluronium hexafluorophosphate (108mg, 0.28mmol), N, N-diisopropylethylamine (74mg, 0.57mmol) was added, then nitrogen substitution was carried out three times, after stirring at room temperature for 2 hours, water (20mL) and ethyl acetate (20mL) were added, liquid separation was carried out, the aqueous phase was extracted with ethyl acetate (20mL × 3), organic phase was combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give a residue, which was purified by column chromatography (methanol: dichloromethane ═ 0-100%) to give 46(47 mg). Yield: 41 percent.
MS-ESI calculated value [ M +1 ]]+608, measured value 608.
1H NMR(400MHz,DMSO-d6)δ10.90(s,1H),7.77–7.72(m,1H),7.53–7.52(m,1H),7.48–7.46(m,1H),7.31(d,J＝8.8Hz,1H),7.28–7.21(m,1H),7.01(d,J＝8.8Hz,1H),6.61(d,J＝8.4Hz,1H),3.75(s,3H),2.96(s,3H),2.59(s,6H).
Example 47
Figure BDA0002610707420000591
First step of
Compound 1h (1.20g, 7.69mmol) and deuterated paraformaldehyde (0.89g, 9.23mmol) were dissolved in dry deuterated methanol (20mL), and the mixture was allowed to spontaneously warm to room temperature under replacement of nitrogen and stirred for 1 hour. Sodium deuteroborohydride (0.65g, 15.38mmol) was added in portions at 0 ℃, then naturally warmed to room temperature and stirred for 3 hours, extracted with a saturated ammonium chloride solution (50mL) and ethyl acetate (50mL × 3), the organic phases were combined, washed with a saturated saline (30mL), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure to remove the organic solvent, and purified by column chromatography (ethyl acetate: petroleum ether ═ 0-100%) to obtain compound 47a (960mg) in yield: 72 percent.
MS-ESI calculated value [ M +1 ]]+174, measured value 174.
Second step of
Compound 47a (960mg, 5.55mmol) was dissolved in a solution of water (10mL), followed by the addition of glacial acetic acid (10mL) and potassium cyanate (899mg, 11.10 mmol). After replacement with nitrogen three times, the mixture was stirred at room temperature for 2 hours, water (50mL) and ethyl acetate (50mL) were added for liquid separation, the aqueous phase was extracted with ethyl acetate (30mL × 3) three times, the organic phases were combined, dried over anhydrous sodium sulfate, filtered, the organic layer was spin-dried, and purified by column chromatography (ethyl acetate: petroleum ether ═ 0-100%) to obtain 47b (910mg) in yield: 88 percent.
MS-ESI calculated value [ M +1 ]]+217, found value 217.
The third step
47b (910mg, 4.21mmol) was dissolved in methanol (20mL), 10% wet palladium on carbon (91mg) was added, hydrogen was replaced, and the reaction was stirred at room temperature for 2 hours. The reaction solution was filtered, dried and purified by column chromatography (methanol: dichloromethane ═ 0 to 100%) to obtain compound 47c (680mg) in yield: 87 percent.
MS-ESI calculated value [ M +1 ]]+187, found: 187.
the fourth step
After 47c (60mg, 0.14mmol) was dissolved in N, N-dimethylformamide (5mL), 2d (27mg, 0.14mmol), 2- (7-benzotriazole oxide) -N, N' -tetramethyluronium hexafluorophosphate (80mg, 0.21mmol), N-diisopropylethylamine (54mg, 0.42mmol) were added, then nitrogen gas was replaced three times, and after stirring at room temperature for 2 hours, water (60mL) and ethyl acetate (60mL) were added, liquid separation was performed, the aqueous phase was extracted with ethyl acetate (20mL × 3), organic phase was combined, dried over anhydrous sodium sulfate, filtered, and concentrated by column chromatography under reduced pressure to give a residue, which was purified (ethyl acetate: petroleum ether ═ 0-100%) to give 47(32 mg). Yield: 39 percent.
1H NMR(400MHz,DMSO-d6)δ11.08(s,1H),8.11(s,1H),7.60–7.59(m,1H),7.49–7.48(m,1H),7.36(d,J＝8.8Hz,1H),7.27–7.22(m,2H),6.99(d,J＝8.8Hz,1H),5.99(s,2H),3.76(s,3H).
Example 48
Figure BDA0002610707420000601
First step of
3f (120mg, 0.29mmol) was dissolved in N, N-dimethylformamide (5mL), 47c (54mg, 0.29mmol), 2- (7-benzotriazole oxide) -N, N' -tetramethyluronium hexafluorophosphate (165mg, 0.44mmol), N-diisopropylethylamine (84mg, 0.65mmol) were added, then nitrogen substitution was performed three times, after stirring at room temperature for 2 hours, water (20mL) and ethyl acetate (20mL) were added, liquid separation was performed, the aqueous phase was extracted with ethyl acetate (20mL × 3), organic phase was combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give a residue, which was purified (methanol: dichloromethane ═ 0-100%) to give 48(61mg) yield: 36 percent.
MS-ESI calculated value [ M +1 ]]+583, found 583.
1H NMR(400MHz,DMSO-d6)δ10.93(s,1H),7.74(t,J＝8.6Hz,1H),7.70–7.66(m,1H),7.60–7.53(m,1H),7.32–7.30(m,1H),7.26–7.17(m,2H),7.01–7.00(m,1H),6.60(d,J＝8.8Hz,1H),5.97(s,2H),3.76(s,3H).
Example 49
Figure BDA0002610707420000611
First step of
49a (80mg, 0.37mmol) was dissolved in N, N-dimethylformamide (3mL), and 1k (82mg, 0.44mmol), 2- (7-benzotriazole oxide) -N, N' -tetramethyluronium hexafluorophosphate (211mg, 0.56mmol), N-diisopropylethylamine (120mg, 0.93mmol) were further added, followed by nitrogen substitution three times, stirring was performed at room temperature for 2 hours, then water (10mL) and ethyl acetate (10mL) were added, liquid separation was performed, the aqueous phase was extracted with ethyl acetate (10mL × 3), organic phase was combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give a residue, which was purified by column chromatography (ethyl acetate: petroleum ether ═ 0-100%) to give 49b (75 mg). Yield: 53 percent.
MS-ESI calculated value [ M +1 ]]+382, measured value 382.
Second step of
Dissolving 3(75mg, 0.19mmol) in N, N-dimethylformamide (3mL), adding 4(62mg, 0.29mmol) and cesium carbonate (192mg, 0.59mmol), then displacing with nitrogen three times, stirring at 60 ℃ for 2 hours, adding water (10mL) and ethyl acetate (10mL), separating, extracting the aqueous phase with ethyl acetate (10mL × 3), combining the organic phases, drying over anhydrous sodium sulfate, filtering, concentrating under reduced pressure to give a residue, and purifying the residue by column chromatography (methanol: dichloromethane ═ 0 to 100%) to give compound 49(6mg) in yield: 6 percent.
MS-ESI calculated value [ M +1 ]]+570, found 570.
1H NMR(400MHz,DMSO-d6)δ10.16–10.12(m,1H),7.46–7.45(m,1H),7.30–7.00(m,5H),6.83–6.68(m,2H),6.00–5.83(m,1H),3.83–3.72(m,3H),3.05(s,3H),2.92–2.78(m,4H).
Example 50
Figure BDA0002610707420000621
First step of
After dissolving 2d (100mg, 0.24mmol) in N, N-dimethylformamide (10mL), adding 50a (33mg, 0.24mmol), 2- (7-benzotriazole oxide) -N, N' -tetramethyluronium hexafluorophosphate (182mg, 0.48mmol), N-diisopropylethylamine (93mg, 0.72mmol), then displacing with nitrogen three times, stirring overnight at room temperature, adding water (15mL) and ethyl acetate (15mL), separating, extracting the aqueous phase with ethyl acetate (20mL x3), combining the organic phases, drying over anhydrous sodium sulfate, filtering, concentrating under reduced pressure to give a residue, and purifying the residue by column chromatography (methanol: dichloromethane ═ 0-100%) to give 50b (110mg) in yield: 85 percent.
Second step of
50b (110mg, 0.21mmol) was dissolved in a methanol solution (10mL), then replaced with nitrogen three times, cobalt chloride hexahydrate (49mg, 0.21mmol) and sodium borohydride (24mg, 0.42mmol) were added respectively at 0 ℃, warmed to room temperature and stirred for 12 hours, and then concentrated under reduced pressure to give a residue, which was purified by column chromatography (methanol: dichloromethane 0-100%) to give compound 50(41mg), yield: 36 percent.
MS-ESI calculated value [ M +1 ]]+538, measured value 538.
1H NMR(400MHz,CD3OD)δ8.05–8.04(m,1H),7.97(s,1H),7.51–7.49(m,1H),7.32–7.31(m,1H),7.26–7.23(m,1H),7.10(s,1H),6.96–6.93(m,1H),4.15(s,2H),3.80(s,3H).
Example 51
Figure BDA0002610707420000622
Figure BDA0002610707420000631
First step of
Compound 51a (100mg, 0.52mmol) was dissolved in dry N, N-dimethylformamide (10mL), benzyl alcohol (168mg, 1.56mmol) was slowly added dropwise, and the temperature was lowered to 0 ℃ with replacement of nitrogen. Sodium hydride (15mg, 0.62mmol) was added slowly, and the mixture was stirred at 0 ℃ for 30 minutes, then allowed to warm to room temperature naturally and stirred for 1 hour. Extraction was performed with saturated ammonium chloride solution (50mL) and ethyl acetate (50mL × 3), and the organic phases were combined, washed with saturated brine (30mL), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure to remove the organic solvent, and purified by column chromatography (ethyl acetate: petroleum ether ═ 0-100%) to obtain compound 51b (85mg) in yield: 62 percent.
MS-ESI calculated value [ M +1 ]]+266, found 266.
Second step of
Compound 51b (85mg, 0.32mmol), 13a (59mg, 0.32mmol), [1,1' -bis (diphenylphosphino) ferrocene ] dichloropalladium (23mg,0.03mmol) and potassium carbonate (132mg, 0.96mmol) were dissolved in 1, 4-dioxane (10mL), nitrogen was replaced, stirring was performed at 90 ℃ for 2 hours, the reaction system was diluted with water (30mL), and extracted with ethyl acetate (50mL × 3), the organic phases were combined, washed with saturated brine (20mL), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure to remove the organic solvent, and purified by column chromatography (ethyl acetate: petroleum ether ═ 0 to 100%) to give compound 51c (91mg) in yield: 88 percent.
MS-ESI calculated value [ M +1 ]]+326, found 326.
The third step
51c (91mg, 0.28mmol) was dissolved in anhydrous methanol (10ml), followed by addition of wet palladium on carbon (30mg), hydrogen substitution three times, stirring at room temperature for 2 hours, and then concentration under reduced pressure to remove the solvent. Column chromatography purification (methanol: dichloromethane ═ 0 to 100%) afforded compound 51d (21mg), yield: 37 percent of
MS-ESI calculated value [ M +1 ]]+206, measured value 206.
The fourth step
After dissolving 2d (45mg, 0.11mmol) in N, N-dimethylformamide (10mL), 51d (21mg, 0.10mmol), 2- (7-benzotriazole oxide) -N, N' -tetramethyluronium hexafluorophosphate (38mg, 0.11mmol), N-diisopropylethylamine (43mg, 0.33mmol) were added and then replaced with nitrogen three times, and after stirring at room temperature for 2 hours, water (60mL) and ethyl acetate (60mL) were added, liquid separation was performed, the aqueous phase was extracted with ethyl acetate (20mL × 3), organic phase was combined, dried over anhydrous sodium sulfate, filtered, and concentrated by column chromatography under reduced pressure to give a residue, which was purified (methanol: dichloromethane ═ 0 to 100%) to give 51(12mg) with yield: 18 percent.
MS-ESI calculated value [ M +1 ]]+603, found 603.
1H NMR(400MHz,DMSO-d6)δ11.10(s,1H),8.23(s,1H),8.12(s,1H),8.03(s,1H),7.71–7.70(m,1H),7.64–7.62(m,1H),7.36(d,J＝8.8Hz,1H),7.28–7.26(m,1H),7.20(s,1H),6.98(d,J＝7.6Hz,1H),3.76(s,3H).
Example 52
Figure BDA0002610707420000641
First step of
The compound (1 h) (500mg, 3.20mmol) was added to iodoethanol (5mL), the nitrogen gas was replaced, and the mixture was heated to 90 ℃ under sealed conditions and stirred overnight. The organic solvent was removed under reduced pressure by concentration and purification by column chromatography (ethyl acetate: petroleum ether ═ 0 to 100%) to give compound 52a (266mg), yield: 41 percent.
Second step of
Compound 52a (200mg, 1.00mmol) was dissolved in water (5mL) and glacial acetic acid (5mL), sodium cyanate (195mg, 3.00mmol) was added at room temperature, stirred at room temperature for 5 hours, the reaction system was diluted with water (30mL), and extracted with ethyl acetate (50mL × 3), the organic phases were combined, washed with saturated brine (20mL), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure to remove the organic solvent, and purified by column chromatography (ethyl acetate: petroleum ether ═ 0-100%) to give compound 52b (90mg) in yield: 37 percent.
The third step
Compound 52b (70mg, 0.29mmol) was dissolved in dichloromethane (10mL), pyridine (68mg, 0.86mmol) was added, and after nitrogen substitution, tert-butyldimethylsilyl trifluoromethanesulfonate (152mg, 0.57mmol) was added under an ice bath. The organic solvent was removed by concentration under reduced pressure and purified by column chromatography (ethyl acetate: petroleum ether ═ 0 to 100%) to obtain compound 52c (65mg), yield: and 63 percent.
The fourth step
52c (65mg, 0.18mmol) was dissolved in anhydrous methanol (10mL), palladium on carbon (6.5mg, 10%) was added, and the mixture was replaced with hydrogen three times, and stirred at room temperature for 2 hours. After the reaction was completed, filtration and concentration under reduced pressure gave 52d (52mg) in yield: 87 percent.
MS-ESI calculated value [ M +1 ]]+328, found 328.
The fifth step
Dissolving 52d (52mg, 0.16mmol) in N, N-dimethylformamide (10mL), adding 2d (60mg, 0.14mmol), 2- (7-benzotriazole oxide) -N, N' -tetramethyluronium hexafluorophosphate (82mg, 0.22mmol), N-diisopropylethylamine (56mg, 0.43mmol), then displacing with nitrogen three times, stirring at room temperature for 2 hours, adding water (20mL) and ethyl acetate (20mL), separating, extracting the aqueous phase with ethyl acetate (20mL × 3), combining the organic phases, drying over anhydrous sodium sulfate, filtering, concentrating under reduced pressure column chromatography to obtain a residue, and purifying the residue (methanol: dichloromethane ═ 0-100%) to obtain 52e (42mg) with yield: 40 percent.
MS-ESI calculated value [ M +1 ]]+725, found value 725.
The sixth step
52e (42mg, 0.06mmol) was dissolved in anhydrous methanol (5mL), p-toluenesulfonic acid (20mg, 0.12mmol) was added, followed by hydrogen substitution three times, and stirring was performed at room temperature for 2 hours. After the reaction was completed, water (20mL) and ethyl acetate (20mL) were added, liquid separation was performed, the aqueous phase was extracted with ethyl acetate (20mL × 3), the organic phase was combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a residue, which was purified by column chromatography (methanol: dichloromethane ═ 0 to 100%) to obtain 52(23mg), yield: 65 percent.
MS-ESI calculated value [ M +1 ]]+611, found value 611.
1H NMR(400MHz,DMSO-d6)δ11.18(s,1H),8.09(s,1H),7.64–7.63(m,1H),7.57–7.56(m,1H),7.39(d,J＝8.8Hz,1H),7.27–7.22(m,2H),6.99(d,J＝8.8Hz,1H),5.89(s,2H),4.70(t,J＝4.8Hz,1H),3.77(s,3H),3.48–3.31(m,4H).
Example 53
Figure BDA0002610707420000651
First step of
Compound 36a (2.10g, 6.53mmol) was dissolved in ultra-dry 1, 4-dioxane (20mL), and compound 53a (1.35g, 5.45mmol), cuprous iodide (413mg, 2.18mmol), tripotassium phosphate (2.31g, 10.87mmol) and N, N-dimethylethylenediamine (1mL) were added to the reaction system, and the reaction was allowed to proceed overnight while the reaction was allowed to warm to 110 ℃. After the system was cooled to room temperature, water (50mL) and ethyl acetate (50mL × 3) were added to the reaction system to extract, and after the organic phases were combined, the mixture was washed with saturated brine (50mL × 1), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a residue, which was purified by column chromatography (ethyl acetate: petroleum ether ═ 0 to 100%) to obtain compound 53b (490mg) in yield: 16 percent.
MS-ESI calculated value [ M +1 ]]+458, measured value 458.
Second step of
Compound 53b (490mg, 1.07mmol) was dissolved in ethyl acetate hydrochloride gas (5mL), and then the nitrogen gas was replaced three times, followed by reaction at room temperature for 4 hours. Concentration under reduced pressure gave compound 53c (370mg), yield: 97 percent.
MS-ESI calculated value [ M +1 ]]+358, found 358.
The third step
After compound 53c (278mg, 0.67mmol) was dissolved in N, N-dimethylformamide (8mL), 2d (200mg, 0.56mmol), 2- (7-benzotriazole oxide) -N, N' -tetramethylurea hexafluorophosphate (318mg, 0.84mmol), N-diisopropylethylamine (216mg, 1.67mmol) were added and then replaced with nitrogen three times, and reacted at room temperature for 2 hours, water (30mL) and ethyl acetate (30mL) were added to the reaction system, liquid separation was performed, the aqueous phase was extracted with ethyl acetate (10mL × 3), organic phase was combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a residue, which was purified by thin layer chromatography (methanol: dichloromethane ═ 0 to 100%) to obtain 53d (280mg) with yield: and 55 percent.
MS-ESI calculated value [ M +1 ]]+755, measured value 755.
The fourth step
Compound 53d (110mg, 0.14mmol) was dissolved in hydrobromic acid acetic acid solution (10mL), then replaced with nitrogen three times, warmed to 60 ℃ for reaction for 30 minutes, cooled to room temperature, and concentrated under reduced pressure to give a residue, which was purified by thin layer chromatography (methanol: dichloromethane ═ 0-100%) to give 53(82mg), yield: 94 percent.
MS-ESI calculated value [ M +1 ]]+621, measured value 621.
1H NMR(400MHz,DMSO-d6)δ11.30(s,1H),8.12(s,1H),7.85–7.84(m,1H),7.38–7.33(m,3H),7.23(s,1H),7.00(d,J＝8.8Hz,1H),3.94–3.90(m,1H),3.76(s,3H),3.61–3.55(m,2H),2.19–2.17(m,1H),1.99–1.97(m,2H),1.83–1.81(m,1H).
Example 54
Figure BDA0002610707420000661
Referring to the procedure for synthesizing example 53 from 36a and 53a in example 53, example 54 was obtained from 36a and 54a through a multi-step reaction.
MS-ESI calculated value [ M +1 ]]+621 measured value 621
1H NMR(400MHz,DMSO-d6)δ11.39(s,1H),8.35(s,2H),8.11(s,1H),7.88–7.87(m,1H),7.48–7.31(m,3H),7.23(s,1H),7.00(d,J＝8.8Hz,1H),4.12–4.11(m,1H),3.77(s,3H),3.62–3.57(m,2H),2.24–2.22(m,1H),2.01–1.90(m,3H).
Example 55
Figure BDA0002610707420000671
First step of
After compound 3f (45mg, 0.11mmol) was dissolved in N, N-dimethylformamide (8mL), 53c (39mg, 0.11mmol), 2- (7-benzotriazole oxide) -N, N' -tetramethylurea hexafluorophosphate (63mg, 0.16mmol), N-diisopropylethylamine (43mg, 0.33mmol) were added thereto, followed by nitrogen substitution three times, and reaction at room temperature for 2 hours, water (30mL) and ethyl acetate (30mL) were added to the reaction system, liquid separation was performed, the aqueous phase was extracted with ethyl acetate (10mL × 3), organic phase was combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give a residue, which was purified by thin layer chromatography (methanol: dichloromethane ═ 0 to 100%) to give 55a (41mg) with yield: 49 percent.
MS-ESI calculated value [ M +1 ]]+754, measured value 754
Second step of
Compound 55a (41mg, 0.05mmol) was dissolved in hydrobromic acid acetic acid solution (10mL), then replaced with nitrogen three times, warmed to 60 ℃ for reaction for 30 minutes, cooled to room temperature, and concentrated under reduced pressure to give a residue, which was purified by thin layer chromatography (methanol: dichloromethane ═ 0-100%) to give 55(5mg), yield: 15 percent.
MS-ESI calculated value [ M +1 ]]+620, found value 620.
1H NMR(400MHz,CD3OD)δ7.89(d,J＝4.4Hz,1H),7.67–7.62(m,1H),7.51–7.48(m,1H),7.26–7.23(m,2H),7.07(s,1H),6.93(d,J＝8.8Hz,1H),6.61(d,J＝8.8Hz,1H),4.59(s,1H),3.79–3.3.70(m,4H),3.63–3.3.61(m,1H),2.34–2.31(m,1H),2.17–2.02(m,2H),1.92–1.88(m,1H).
Example 56
Figure BDA0002610707420000672
Figure BDA0002610707420000681
First step of
After compound 3f (50mg, 0.12mmol) was dissolved in N, N-dimethylformamide (10mL), 56a (43mg, 0.12mmol), 2- (7-benzotriazole oxide) -N, N' -tetramethylurea hexafluorophosphate (68mg, 0.18mmol), N-diisopropylethylamine (46mg, 0.36mmol) were added thereto, followed by nitrogen substitution three times, and reaction at room temperature for 2 hours, water (30mL) and ethyl acetate (30mL) were added to the reaction system, liquid separation was performed, the aqueous phase was extracted with ethyl acetate (10mL × 3), organic phase was combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a residue, which was purified by thin layer chromatography (methanol: dichloromethane ═ 0 to 100%) to obtain 56b (55mg) with yield: 61 percent.
MS-ESI calculated value [ M +1 ]]+754, measured value 754.
Second step of
Compound 56b (55mg, 0.07mmol) was dissolved in hydrobromic acid acetic acid solution (10mL), then replaced with nitrogen three times, warmed to 60 ℃ for reaction for 30 minutes, cooled to room temperature, and concentrated under reduced pressure to give a residue, which was purified by thin layer chromatography (methanol: dichloromethane ═ 0-100%) to give 56(2mg), yield: 5 percent.
MS-ESI calculated value [ M +1 ]]+620, found value 620.
1H NMR(400MHz,DMSO-d6)δ11.16(s,1H),8.38(s,2H),7.96(d,J＝4.8Hz,1H),7.74–7.72(m,1H),7.50–7.49(m,1H),7.35–7.27(m,2H),7.25(s,1H),7.02(d,J＝8.8Hz,1H),6.60(d,J＝8.8Hz,1H),4.13–4.10(m,1H),3.76(s,3H),3.62–3.50(m,2H),2.26–2.25(m,1H),2.01–1.95(m,3H).
Example 57
Figure BDA0002610707420000682
First step of
44f (155mg, 0.47mmol) was dissolved in N, N-dimethylformamide (10mL), 3f (234mg, 0.57mmol), 2- (7-benzotriazole oxide) -N, N, N ', N' -tetramethyluronium hexafluorophosphate (269mg, 0.71mmol), N, N-diisopropylethylamine (182mg, 1.41mmol) were added, then nitrogen gas was substituted three times, after stirring at room temperature for 3 hours, water (30mL) and ethyl acetate (30mL) were added, liquid separation was performed, the aqueous phase was extracted with ethyl acetate (30 mL. times. 3), the organic phase was combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give a residue, which was purified by column chromatography (ethyl acetate: petroleum ether ═ 0-100%) to give 57a (160 mg). Yield: and 47 percent.
Second step of
Compound 57a (160mg, 0.08mmol) was dissolved in tetrahydrofuran (10mL), palladium on carbon (20mg) was added at room temperature and replaced with hydrogen three times, followed by stirring at room temperature for 6 hours. Filtration and concentration under reduced pressure gave a residue which was purified by column chromatography (methanol: dichloromethane 0-100%) to give 57(55 mg). Yield: 42 percent.
MS-ESI calculated value [ M +1 ]]+592, measured value 592.
1H NMR(400MHz,DMSO-d6)δ10.94(s,1H),8.26–8.25(m,1H),7.73(t,J＝8.8Hz,1H),7.44–7.43(m,1H),7.31(d,J＝8.8Hz,1H),7.25–7.23(m,2H),7.01(d,J＝8.0Hz,1H),6.60(d,J＝9.2Hz,1H),4.23–4.22(m,1H),4.02–4.01(m,1H),3.75(s,3H),3.50(s,1H).
Biological activity assay
The in vitro inhibition effect of the compound on Nav1.8 was tested on HEK293 cells stably expressing human Nav1.8 using a manual patch clamp assay. Test compounds were dissolved in DMSO to prepare 9mM stock solutions, which were dissolved in extracellular fluid at the desired concentration on the day of testing. The extracellular fluid component comprises (mM) NaCl, 137; KCl, 4; CaCl2,1.8；MgCl21, 1; HEPES, 10; glucose 10; pH 7.4(NaOH titration). Cells were clamped at-80 mV and then depolarized to 10mV with a square wave lasting 10 milliseconds to give a NaV1.8 current. This procedure is repeated every 5 seconds. And detecting the maximum current caused by the square wave, perfusing a test compound (dissolved in extracellular fluid according to the required concentration) after the maximum current is stabilized, and calculating the blocking strength of the compound to Nav1.8 according to the current strength before and after the compound is perfused after the reaction is stabilized. Data collection and analysis were performed using pCLAMP 10(Molecular Devices, Union City, Calif.), and current stabilization means that the current varies over time within a limited range. The test results are shown in the following tables-1 and-2.
Inhibitory Activity of the Compounds of Table-1 on Nav1.8
Examples IC50(nM)
Example 1 0.3
Example 3 3.9
Example 4 0.8
Example 13 0.9
Example 14 1.5
Example 15 1.1
Example 16 3.5
EXAMPLE 41 1.0
Example 45 3.9
Example 46 2.7
Example 47 1.9
Example 48 0.6
TABLE-2 The% blockade of Nav1.8 channels at a concentration of 4nM of the compound
Figure BDA0002610707420000691
Figure BDA0002610707420000701
All documents referred to herein are incorporated by reference into this application as if each were individually incorporated by reference. Furthermore, it should be understood that various changes and modifications of the present invention can be made by those skilled in the art after reading the above teachings of the present invention, and these equivalents also fall within the scope of the present invention as defined by the appended claims.

Claims (10)

1. A compound of formula (I), and isomers, solvates or pharmaceutically acceptable salts thereof:
Figure FDA0002610707410000011
L1selected from the group consisting of: CONR4、CONR4Or SO2NR4；
L2Selected from the group consisting of: s (O)p，O，NR4CO or C (R)6)2；
Cyc1 and Cyc2 are each independently selected from: 6-10 membered aryl, 5-10 membered heteroaryl, the heteroatoms of said heteroaryl being independently selected from O, N or S (O)p；
R1Selected from: hydrogen, deuterium, ═ O, halogen, CHF2，CF3，CD3，OCF3，OCH3，OCD3Cyano, nitro, hydroxy, amino, SO2N(R4)2，CON(R4)2，COOR4，SOR7，SO2R7Substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstitutedSubstituted C2-C6 alkynyl, substituted or unsubstituted- (W)m-H, substituted or unsubstituted C3-C8 cycloalkyl, substituted or unsubstituted C4-C8 heterocyclyl, substituted or unsubstituted 6-10 membered aryl, substituted or unsubstituted 5-10 membered heteroaryl, said heteroatoms independently selected from O, N or S (O)p(ii) a Or two adjacent R1And the atoms to which they are attached form a 5-6 membered carbocyclic or heterocyclic ring;
R2selected from: 0 to 4R1Substituted C3-C8 cycloalkyl, 0-4R1Substituted C4-C8 heterocyclyl, 0-4R1Substituted 6-10 membered aryl, 0-4R1Substituted 5-10 membered heteroaryl; or two adjacent R1And the atoms to which they are attached form a 5-6 membered carbocyclic or heterocyclic ring;
R3selected from: hydrogen, deuterium, ═ O, halogen, CF3，CD3，OCF3，OCH3，OCD3Cyano, nitro, hydroxy, amino, COOR4，CON(R4)2，SO2N(R4)2，SOR7，SO2R7Substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C2-C6 alkynyl, substituted or unsubstituted- (W)m-H, substituted or unsubstituted C3-C8 cycloalkyl, substituted or unsubstituted C4-C8 heterocyclyl, substituted or unsubstituted 6-10 membered aryl, substituted or unsubstituted 5-10 membered heteroaryl, said heteroatoms independently selected from O, N or S (O)p(ii) a Or R3Form N with the N atom on Cyc2+-O-；
R4Selected from: hydrogen, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C2-C6 alkynyl, substituted or unsubstituted- (W)m-H, substituted or unsubstituted C3-C8 cycloalkyl, substituted or unsubstituted C4-C8 heterocyclyl, said heteroatoms being independently selected from O, N or S (O)p(ii) a Or two R4And the N atom to which it is attached form a C4-C8 membered heterocyclic ring;
x is selected from: (CH)2)rO(CH2)r，(CH2)rS(CH2)r，(CH2)rNR4(CH2)r，(CH2)rCR4R6(CH2)rSubstituted or unsubstituted C3-C8 cycloalkyl, substituted or unsubstituted C4-C8 heterocyclyl;
n, r are each independently selected from: 0, 1,2,3 or 4;
p is selected from: 0, 1 or 2;
y is selected from: bond, CO, SO2，CR4R6，CS；
R5Selected from: hydrogen, deuterium, halogen, CF3，CD3，OCF3，OCH3，OCD3Cyano, nitro, hydroxy, amino, SO2N(R4)2，CON(R4)2，COOR4，SOR7，SO2R7Substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C2-C6 alkynyl, substituted or unsubstituted- (W)m-H, substituted or unsubstituted C3-C8 cycloalkyl, substituted or unsubstituted C4-C8 heterocyclyl, substituted or unsubstituted 6-10 membered aryl, substituted or unsubstituted 5-10 membered heteroaryl, said heteroatoms independently selected from O, N or S (O)p；
R6Selected from: hydrogen, halogen, amido, cyano, hydroxy, amino, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C2-C6 alkynyl, substituted or unsubstituted- (W)m-H, substituted or unsubstituted C3-C8 cycloalkyl, substituted or unsubstituted C4-C8 heterocyclyl; or two R6And the atoms to which they are attached form a carbocyclic ring of C3-C8 or a heterocyclic ring of C4-C8;
or R4And R6And the atoms to which they are attached form a carbocyclic ring of C3-C8 or a heterocyclic ring of C4-C8;
R7selected from: hydroxy, amino, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C2-C6 alkynyl, substituted or unsubstituted- (W)m-H, substituted or unsubstituted C3-C8 cycloalkyl, substituted or unsubstituted C4-C8 heterocyclyl;
w is selected from the group consisting of: CH (CH)2，NR4，O，S(O)pAnd at the same time only a maximum of 2W are selected from the group: n, O, S (O)p；
m is selected from: 0, 1,2,3, 4,5 or 6;
or
Figure FDA0002610707410000021
Forming a substituted or unsubstituted C4-C8 heterocyclic ring, a substituted or unsubstituted 5-10 membered heteroaromatic ring;
in each of the above formulae, the heterocyclyl or heteroaryl groups each independently include 1,2, or 3 heteroatoms independently selected from O, N, or S (O)p；
Unless otherwise specified, "substituted" means substituted with one or more (e.g., 2,3, 4, etc.) substituents selected from the group consisting of: halogen, C1-C6 alkyl, halogenated C1-C6 alkyl, C1-C6 alkoxy, halogenated C1-C6 alkoxy, C3-C8 cycloalkyl, halogenated C3-C8 cycloalkyl, oxo, -CN, hydroxy, amino, carboxy, amide, sulfonamide, sulfone; a group selected from the group consisting of unsubstituted or substituted with one or more substituents: a C6-C10 aryl group, a halogenated C6-C10 aryl group, a 5-10 membered heteroaryl group having 1-3 heteroatoms selected from N, S and O, a halogenated 5-10 membered heterocyclyl group having 1-3 heteroatoms selected from N, S and O, and said substituents are selected from the group consisting of: halogen, C1-C6 alkyl, C1-C6 alkoxy, ═ O.
2. The compound of claim 1, wherein X is O, NR4Or C R4R6(ii) a And/or said Y is C ═ O.
3. The compound of any one of claims 1 or 2, wherein the compound of formula (I) has a structure as shown in formula (II):
Figure FDA0002610707410000022
wherein G is CH or N, andwhen G is CH, the CH may be R1Substituted (i.e., R)1Located on G).
4. The compound of claims 1-3, wherein L is1Is CONH, and/or said L2Is O.
5. The compound of claim 1, wherein the compound has the structure of formula (III):
Figure FDA0002610707410000031
wherein Ra, Rb, Rc and Rd are independently selected from the following groups: hydrogen, deuterium, ═ O, halogen, CF3，CD3，OCF3，OCH3，OCD3Cyano, nitro, hydroxy, amino, SO2N(R4)2，CON(R4)2，COOR4，SOR7，SO2R7Substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted- (L)m-H, substituted or unsubstituted C3-C8 cycloalkyl, substituted or unsubstituted C4-C8 heterocyclyl, substituted or unsubstituted 6-10 membered aryl, substituted or unsubstituted 5-10 membered heteroaryl.
6. The compound of claim 1, wherein said compound is selected from the group consisting of:
Figure FDA0002610707410000032
Figure FDA0002610707410000041
Figure FDA0002610707410000051
Figure FDA0002610707410000061
Figure FDA0002610707410000071
Figure FDA0002610707410000081
Figure FDA0002610707410000091
Figure FDA0002610707410000101
Figure FDA0002610707410000111
Figure FDA0002610707410000121
7. a pharmaceutical composition comprising a pharmaceutically acceptable carrier and a compound, isomer, solvate or pharmaceutically acceptable salt or hydrate thereof of claim 1.
8. The pharmaceutical composition of claim 7, wherein the pharmaceutical composition is for use in a method of treating, ameliorating or preventing a disease or disorder associated with sodium channel modulation; preferably, the disease or condition is pain.
9. Use of a compound according to any one of claims 1 to 6, or a pharmaceutically acceptable salt or hydrate thereof, for the preparation of a pharmaceutical composition for the treatment, alleviation or prevention of diseases associated with sodium channel modulation; preferably, the disease or condition is pain.
10. The use according to claim 9, wherein the pain or disease is selected from the group consisting of: chronic pain, intestinal pain, neuropathic pain, musculoskeletal pain, acute pain, inflammatory pain, cancer pain, idiopathic pain, post-operative pain, visceral pain, multiple sclerosis, peroneal muscular atrophy (Charcot-Marie-Tooth syndrome), incontinence, pathological cough, or cardiac arrhythmia.
CN202010753365.7A 2019-07-31 2020-07-30 Selective sodium channel regulator and preparation and application thereof Pending CN112300069A (en)

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