HK1136819B - Novel dithiolopyrrolones and their therapeutic applications - Google Patents
Novel dithiolopyrrolones and their therapeutic applications Download PDFInfo
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Description
Technical Field
The present invention provides novel dithiolopyrrolone compounds and salts thereof which promote the production of leukocytes and are useful for the prevention and treatment of microbial infections (e.g., HIV infections), hematological disorders (e.g., neutropenia), and other related disorders. The invention also provides therapeutic compositions containing particularly useful dithiolopyrrolone compounds and salts thereof, as well as methods and uses in the manufacture of medicaments for treating diseases.
Background
The human blood forming (hematopoietic) system is composed of a variety of leukocytes (including neutrophils, macrophages, basophils, mast cells, eosinophils, T cells and B cells), erythrocytes and thrombocytes (megakaryocytes, platelets).
It is understood that certain hematopoietic growth factors (e.g., chemicals and proteins) naturally present in animals are responsible for differentiating a small number of "stem cells" into a variety of blood cell progenitors for the massive proliferation of these cells and the terminal differentiation of these cell lines into mature blood cells. The hematopoietic regeneration system functions well under normal conditions. However, when affected by chemotherapy, radiation therapy or myelodysplasia itself, it can lead to severe leukopenia, anemia or thrombocytopenia in patients. Neutropenia (neutropenia) refers to an abnormally low level of neutrophils in the blood. Neutrophils are White Blood Cells (WBCs) produced in the bone marrow and account for approximately 60% of blood cells. These cells are particularly important for immune responses and migrate from the blood to the tissues during infection. They ingest or destroy particles and pathogens (germ). Pathogens are microorganisms that cause the production of diseases, such as bacteria, protozoa, viruses and fungi (fungus). Neutropenia is a particularly serious condition for cancer patients with reduced immune function, as it makes the body very susceptible to viral, bacterial and fungal infections. Leukocytes are particularly sensitive to chemotherapy. The number of cells killed during radiation and chemotherapy is related to the dose and frequency of treatment.
Neutropenia is a hematological disorder in which the number of neutrophils in the blood, as measured by Absolute Neutrophil Count (ANC), is abnormally low. A deficiency of neutrophils means an increased risk of microbial infection. Per mm3Healthy adults contain about 2500-. The number of neutrophils is low in the blood of children under 6 years of age. Has already been used forMultiple tissues set the diagnostic threshold for neutropenia at an ANC of about 2000 neutrophils/mm3To about 1500 neutrophils/mm3Different neutrophil measurement levels within the range. See Merck Manual 18thEd.2006, Section11, which is incorporated herein by reference in its entirety. When ANC decreased to 500 neutrophils/mm3Severe neutropenia was diagnosed as follows. The symptoms of increased risk of infection depend on the severity of neutropenia and the duration of the disease.
Neutropenia that can be treated with the compounds and methods of the invention can be a chronic disease. Neutropenia as a chronic disease can be further classified into congenital, periodic and idiopathic neutropenia. A small number of individuals have chronic congenital neutropenia due to inheritance. The most severe congenital neutropenia is Kostmann's syndrome, with other milder variants. Symptoms include frequent infections and fever.
Periodic neutropenia results from a deficiency in regulation of hematopoietic stem cell levels, causing fluctuations in the production of neutrophils and other types of blood cells. Individuals with such diseases have a number of neutrophils of about 100 neutrophils/mm 3-6 days per cycle3. The number of neutrophils varies in a range between the level of severe neutropenia and the level of mild neutropenia for the majority of each cycle.
Chronic idiopathic neutropenia refers to severe chronic neutropenia that does not fall significantly into any of the above categories. Individuals with chronic idiopathic neutropenia often have normal numbers of neutrophils in the early years, and later develop the disease. It is speculated that neutropenia, as a congenital or idiopathic disease, has an estimated incidence in the population of 200,000 in one-out.
Neutropenia can also occur following another disease, such as cancer or acquired immunodeficiency syndrome (AIDS). Neutropenia can also occur after an event (e.g., drug treatment). Therefore, neutropenia may be caused by physiological diseases that directly affect the immune system. For example, when a leukemia, myeloma, lymphoma or metastatic solid tumor (e.g., breast or prostate cancer) infiltrates and replaces bone marrow, it will cause a decrease in the amount of neutrophil production. Transient neutropenia is often associated with viral infections. Chronic neutropenia is often associated with immunodeficiency diseases caused by viral infections (e.g., AIDS caused by HIV infection of the human immunodeficiency virus). Autoimmune neutropenia may be associated with antibodies against neutrophils in the circulation.
Neutropenia, which occurs as a side effect of drug therapy (especially cancer chemotherapy, radiation therapy for cancer therapy and bone marrow transplantation associated with cancer therapy), is more common. Neutropenia occurring after drug treatment can thus be subdivided into two groups. The first group includes immune-mediated neutropenia, which can be caused by drugs that act as haptens to stimulate antibody production. Acute hypersensitivity reactions (such as that caused by phenytoin and phenobarbital) can last for days. However, chronic hypersensitivity reactions can last for months or years. See, The Merck Manual, 18th Ed。
The second group of drug-induced neutropenia includes severe neutropenia, which may occur following massive administration of cytotoxic anticancer drugs, and may also occur with ionizing radiation therapy. These cytotoxic treatments can induce neutropenia due to the proliferative nature of neutrophil precursor cells and the normal rapid turnover rate of circulating neutrophils. See, The Merck Manual, 18thAnd Ed. Risk of neutropenia following cancer chemotherapy or radiotherapy and the type and stage of cancer, as well as the type, dose and time of cancer treatmentThe table is related. More than 1,500,000 cancer patients receive chemotherapy each year in the united states. About half of the chemotherapy patients suffer from neutropenia. Currently, less than 10% of chemotherapy patients receive prophylactic treatment to prevent neutropenia.
Existing hematopoietic disease therapies include the use of proteinogenic hematopoietic factors (proteinogenic hematopoietic factors), such as EPO, G-CSF, GM-CSF, CSF-1, IL-2, IL-3, IL-4, IL-5, IL-6, IL-7, IL-8, IL-9, IL-10, IL-11, IGF-I or LIF (leukemia inhibitory factor) and other chemicals. Therapeutic agents for increasing neutrophil levels consist primarily of filgrastimAnd the latest long-acting derivative of filgrastim (Neulasta)TM) And (4) forming. Filgrastim is a recombinant protein of the human protein G-CSF (granulocyte colony stimulating factor), which selectively stimulates the production of leukocytes. G-CSF is currently the drug of choice for neutropenia. Since both drugs are recombinant proteins, they are not active when administered orally and must be administered by injection. In addition, protein drugs are often metabolized rapidly.
There is a need for new agents, especially non-proteinaceous drugs, that can be used to treat neutropenia. In particular, there is a need for agents that are still biologically active when administered by non-injectable routes. Agents that are active when administered orally are particularly desirable because they can enhance patient compliance.
Dithiolopyrrolones are a group of compounds having a 1, 2-dithiolopenta [4, 3-b ] pyrrol-5 (4H) -one ring. Compounds having this basic structural feature are known in the art to possess a variety of activities, including antibacterial, chemopreventive (Sharma et al, 1994) and anticancer (WO 99/12543, WO2003/080624, all Webster et al). However, it has not been known to date to have an unexpected new activity of increasing leukocytes in animals. Certain synthetic dithiolopyrrolones and their antibacterial activity have been disclosed (D.S. Bhate & Y.M. Sambray, 1963.Hindustan, antibacterial Bulletin 6 (1): 17-18; Katsuaki Hagio et al Bull. chem. Soc. Jpn 1974, 47, 1484-1489; Broom et al WO 9505384 and Godfrey & Dell, GB2170498, Webster et al WO 99/12543, WO2o 03/080624).
The present invention relates to novel dithiolopyrrolones, their activity in increasing leukocytes, and their use in promoting leukocyte production, preventing and treating microbial infections and hematological disorders (e.g., neutropenia).
Disclosure of Invention
In one aspect, the invention provides methods and compositions for treating a hematological disorder (e.g., neutropenia) comprising administering to an individual in need of such treatment an effective amount of a compound of the invention. In another aspect, the invention relates to a pharmaceutical composition comprising a compound of the structure shown below. In yet another aspect, the invention includes novel compounds having the structure shown in formula I below.
Formula I
In the context of the present invention, compounds within the scope of formula I are intended to mean "all types of dithiolopyrrolones" or similar expressions of the invention, the individual compounds disclosed in the present invention being represented by "specific dithiolopyrrolones", "specific compounds" or "compounds of the invention" or similar expressions.
The term "effective amount" when used to describe treatment of a subject means the amount of a compound of formula I that results in an increase in the number of leukocytes, particularly in the subject as by the subjectAbsolute neutrophil counts of blood measure the increase in the number of neutrophil production. An effective amount of a compound of formula I for the prevention and treatment of microbial infections and neutropenia refers to an amount of a compound of formula I that increases the absolute neutrophil count in a subject. An effective amount of a compound of formula I for use in the prevention of neutropenia is one that maintains the absolute neutrophil count of an individual at about 500 neutrophils/mm during a time interval of increased risk of neutropenia3Amount of compound I above the level. Conditions associated with an increased risk of neutropenia include, for example, current or future emergence of cancer chemotherapy regimens.
The term "individual" or "subject" includes both humans and non-human animals. In referring to the disclosed methods of increasing leukocyte (neutrophil) production, unless otherwise indicated, these two terms refer to: (a) organisms with diseases characterized by low WBCs (including neutropenia); or (b) an organism at increased risk of neutropenia due to, for example, future appearance of cancer chemotherapy. The presence of known risk factors may be taken into account when selecting individuals at increased risk for neutropenia. These factors include, for example, cancer requiring chemotherapy or therapeutic ionizing radiation therapy, diseases that directly affect the immune system (e.g., AIDS), or the presence of viruses (e.g., HIV known to cause AIDS).
Detailed Description
According to the present invention, the dithiolopyrrolones of formula I and pharmaceutically acceptable salts thereof are useful for increasing WBC levels, particularly neutrophil levels, in an individual as measured by blood counts.
The dithiolopyrrolones used in the present invention (formula I) can be prepared by one of several methods. These methods generally emulate the synthetic strategies and procedures used in the synthetic methods disclosed in Webster et al (WO2003/080624) and references cited therein, which are incorporated herein by reference in their entirety.
The synthesis of the various types of dithiolopyrrolones of the invention and of the specific dithiolopyrrolone compounds is described below, together with the structure of all the dithiolopyrrolones for which structural information has been given and which has been confirmed by nuclear magnetic resonance spectroscopy NMR or mass spectrometry MS.
The various types of dithiolopyrrolones and specific dithiolopyrrolones mentioned in this invention can be prepared by the disclosed methods and other methods of the present invention using commercially available starting materials by skilled chemists. During such operations, one skilled in the art may utilize any suitable filtration, chromatography, and other purification techniques. A more complete understanding of the present invention may be derived by referring to the preferred embodiments thereof, which are illustrated in the accompanying examples and methods. The examples relate to the use of materials and reagents which are commercially available from chemical companies to the person skilled in the art and are therefore not described in detail.
The compounds used in the methods of the invention may be in the form of pharmaceutically acceptable salts. The term "salt" includes salts commonly used to form alkali metal salts and to form addition salts of the free acid or free base. The term "pharmaceutically acceptable salt" means a salt having a toxicity spectrum limited to a certain range so as to be usable in the field of pharmaceuticals. Suitable acid addition salts may be prepared using inorganic or organic acids. Examples of such inorganic acids are hydrochloric acid, hydrobromic acid, hydroiodic acid, nitric acid, carbonic acid, sulfuric acid, and phosphoric acid. Suitable organic acids may be selected from aliphatic, alicyclic, aromatic, araliphatic, heterocyclic, carboxylic and sulphonic organic acids, examples of such organic acids being formic, acetic, propionic, succinic, glycolic, gluconic, lactic, malic, tartaric, citric, ascorbic, glucuronic, maleic, fumaric, pyruvic, aspartic, glutamic acid, benzoic acid, anthranilic acid, methanesulfonic acid, salicylic acid, 4-hydroxybenzoic acid, phenylacetic acid, mandelic acid, pamoic acid (pamoic acid), methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, pantothenic acid, 2-hydroxyethanesulfonic acid, toluenesulfonic acid, sulfanilic acid, cyclohexylsulfamic acid, stearic acid, alginic acid, beta-hydroxybutyric acid, salicylic acid, galactaric acid, and galacturonic acid.
Suitable base addition salts of the compounds (formula I) used in the process of the invention include, for example, metal salts prepared from calcium, magnesium, potassium, sodium and zinc, or organic salts prepared from chloroupucaine, choline, diethanolamine, ethylenediamine, meglumine (N-methylglucamine) and procaine. All of these salts can be prepared from the corresponding compounds of formula I by conventional methods, for example by reacting the appropriate acid or base with a compound of formula I.
The use of compounds of formula I to increase WBC levels may be associated with one or more therapeutic objectives. Treatment to increase WBC levels may treat diseases associated with WBC, such as neutropenia as a primary disease stage. Alternatively, treatment according to the use and method of the present invention may treat a disease secondary to another factor (event). Such factors (events) include, for example, microbial infection, cancer or drug therapy causing the secondary disease. Microbial infections include infections caused by viruses, bacteria and fungi.
Treatment to increase WBC levels using the methods of the invention may also prevent neutropenia in situations where an individual is at risk of developing neutropenia. Such situations include, for example, an individual preparing to begin treatment with a drug known to cause or suspected to cause neutropenia.
Various drugs are known to have side effects causing neutropenia. Such side effects have been observed in various types of drugs including, for example, thyroid inhibitors, antibiotics, psychotropic drugs (neuroleptics), cardiovascular drugs, analgesics, antimalarials, non-steroidal anti-inflammatory drugs, antihistamines, and combinations thereof. See, Lee, Wintrobe's Hematology, Lippincott, p.1862-1869, and van der Klauw, M.M et al, arch. Neutropenia induced by any of the above drugs may be treated or prevented according to the present invention.
One common drug-induced neutropenia includes severe neutropenia that occurs following massive administration of cytoreductive anticancer drugs, also with ionizing radiation therapy. The predictability of neutropenia in individuals receiving cancer chemotherapy provides the basis for prophylactic administration in the methods of the invention. See, The Merck Manual, 18thEd, 2006, Section11 "Hematology and Oncology", the disclosure of which is incorporated herein by reference in its entirety.
The compounds used in the methods of the invention can be administered to individuals (mammals, including animals and humans) for the treatment or prevention of leukopenia and related conditions, such as neutropenia.
Conditions that may prevent neutropenia include administration to individuals undergoing or prepared for subsequent cancer chemotherapy. The methods of the invention also include administering to an individual who has been shown to be associated with or is prepared for an event that increases the risk of the individual subsequently developing neutropenia. Such events include, but are not limited to: therapeutic radiotherapy; a drug treatment other than cancer chemotherapy, wherein the individual is known or suspected to be sensitive to a treatment that increases the risk of neutropenia; a drug treatment other than cancer chemotherapy, wherein the drug is associated with a high incidence of neutropenia; immunodeficiency disorders such as AIDS; or viruses known to cause immunodeficiency, such as HIV.
The use of the invention can be administered to individuals (mammals, including animals and humans)For use in the treatment of a reduction in leukocytes to thereby prevent or treat a microbial infection. It is known that one of the main functions of leukocytes is to combat microbial infections, such as viral, bacterial and fungal infections. Such an activity of increasing leukocytes can be applied to the prevention and treatment of microbial infections. The skilled operator is able to use the methods used by the skilled person. See, The Merck Manual, 18thEd, 2006, the disclosure of which is incorporated herein by reference in its entirety.
The invention also relates to a pharmaceutical composition which contains the compounds or pharmaceutically acceptable salts thereof or a compound selected from the dithiolopyrrolone compounds or pharmaceutically acceptable salts thereof as an active ingredient; and methods of making such pharmaceutical compositions.
Examples of pharmaceutical compositions include any solid (tablets, pills, capsules, granules, powders, etc.) or liquid (solutions, suspensions or emulsions) of suitable compositions for oral, topical administration (or parenteral administration). These formulations may comprise the compound or a salt thereof in pure form or in combination with a carrier or other pharmaceutically active compound. When administered parenterally, these compositions must be sterile.
For the treatment or prevention of infections and neutropenia, it is necessary to determine the specific dose of the compound of the present invention which will achieve a therapeutic effect, according to the individual patient's specific conditions, including the size, weight, age and sex of the patient. Also contemplated are the nature and stage of the disease and the route of administration. For example, daily dosages of about 100 mg/day to 1500 mg/day may be used. Preferably, a daily dosage of about 100 mg/day to 1000 mg/day is used. More preferably, a daily dosage of about 100 mg/day to 500 mg/day is used. Higher or lower dosages are also contemplated. Neutrophil levels in the patient can be monitored and the treatment regimen maintained until neutrophil levels reach a normal range.
For prophylactic administration, the compounds used in the practice of the methods of the invention should be administered sufficiently early in the course of an event that increases the risk of neutropenia so that the compounds are able to reach the site of action in sufficient concentration to exert a therapeutic effect. The pharmacokinetics of a particular compound can be determined by methods known in the art, and the level of the compound in a particular individual's tissue can be determined by routine analysis.
One or more of the compounds used in the practice of the present invention may be administered concurrently, or different dithiolopyrrolones used in the practice of the present invention may be administered at different times during the course of therapeutic or prophylactic treatment.
The methods of the invention may comprise administering a compound of the invention in the form of a pharmaceutical composition in combination with a pharmaceutically acceptable carrier. Such formulations may contain from 0.1 to 99.99 wt% of the active ingredient. By "pharmaceutically acceptable carrier" is meant any carrier, diluent or excipient that is compatible with the other ingredients of the formulation and deleterious to the recipient thereof.
The compounds used in the methods of the invention may be administered to achieve a therapeutic effect by any route, such as enteral (e.g., oral, rectal, intranasal, topical, etc.) and parenteral. Parenteral administration includes, for example, intravenous, intramuscular, intraarterial, intraperitoneal, intravaginal, intravesical (e.g., intravesical), intradermal, topical (topical), or subcutaneous administration. It is also contemplated within the scope of the invention to instill the drug in the patient in a controlled release formulation and to release the drug systemically or locally at a later time. For applications that elevate WBC levels, such as neutrophil levels, a drug may be positioned in a reservoir for controlled release of the drug into the circulatory system.
Preferably, a pharmaceutically acceptable carrier selected according to the chosen route of administration and standard pharmaceutical practice is administered with the active agent. The active agents may be formulated into different dosage forms according to standard procedures in the pharmaceutical manufacturing art. See, Alphonso Gennaro, ed., Remington's pharmaceutical sciences, 18th Ed., (1990) Mack Publishing Co., Easton, Pa. Suitable dosage forms may include, for example, tablets, capsules, solutions, injections, lozenges, suppositories, or suspensions.
For parenteral administration, the active agent may be mixed with a suitable carrier or diluent, for example, water, oils (especially vegetable oils), ethanol, saline solution, aqueous dextrose (glucose) and related sugar solutions, glycerol or glycols, for example propylene glycol or polyethylene glycol. Solutions for parenteral administration preferably contain a pharmaceutically acceptable water-soluble salt of the active agent. Stabilizers, antioxidants and preservatives may also be added. Suitable antioxidants include sulfites, ascorbic acid, citric acid and salts thereof, and sodium EDTA. Suitable preservatives include benzalkonium chloride, methyl or propyl paraben and chlorobutanol. Compositions for parenteral administration may be in the form of aqueous or non-aqueous solutions, dispersions, suspensions or emulsions.
For oral administration, the active agent may be combined with one or more solid inactive ingredients for the preparation of tablets, capsules, pills, powders, granules or other suitable oral dosage forms. For example, the active agent may be combined with at least one excipient, such as fillers, binders, humectants, disintegrants, dissolution retardants, absorption enhancers, humectant absorbents, or lubricants. According to one tablet embodiment, the active agent can be combined with the calcium carboxymethylcellulose, magnesium stearate, mannitol, and starch, and then tableted by conventional tableting methods.
The compositions of the present invention may also be formulated so as to provide sustained or controlled release of the active ingredients described herein. In general, controlled release formulations are compositions that release an active ingredient at a desired rate to maintain constant pharmaceutical activity over a desired period of time. Such dosage forms can provide a drug supply to the body for a predetermined period of time and thereby maintain drug levels within a therapeutic range for a longer period of time than other non-controlled release formulations.
Controlled release of the active ingredient can be stimulated by various inducing factors, such as pH, temperature, enzymes, water or other physiological conditions or compounds. There are a number of drug release mechanisms. For example, in one embodiment, after administration to a patient, the controlled release component can swell and form a porous opening sufficient to release the active component. In the present invention, the term "controlled release component" is used to define one or more compounds that facilitate the controlled release of an active ingredient or a pharmaceutically acceptable salt thereof in a pharmaceutical composition, such as polymers, polymer matrices, gels, permeable membranes, liposomes and/or microspheres. In another embodiment, the controlled release component is biodegradable and is induced upon contact with an aqueous environment, pH, temperature, or enzyme in the body. In another embodiment, a sol-gel may be used, wherein the active ingredient is incorporated into a sol-gel matrix that is solid at room temperature. The matrix is implanted into a patient, preferably a mammal having a body temperature high enough to induce the sol-gel matrix to form a gel, thereby releasing the active ingredient into the patient.
The practice of the invention is illustrated by the following non-limiting examples.
Example 1: activity to increase the number of White Blood Cells (WBCs) in mice
The activity was measured using CDF1 male mice (18g-20 g). Mice were divided into solvent group, 30mg/kg Cyclophosphamide (CTX) group, 15mg/kg test compound group. Mice were treated by IP injection: the test compound group was administered three times on days 1, 3 and 5, and the solvent group and CTX group were administered daily for 6 days. On day 7, peripheral blood samples were collected and blood cells were counted.
As a result: the test compounds significantly increased peripheral blood leukocytes (table 1).
Table 1: effect on mouse peripheral blood leukocytes
| Group of | N | WBC(×109/L) |
| Solvent(s) | 14 | 4.1±0.9 |
| 0058 | 13 | 23.9±8.9 |
| 0227 | 13 | 13.7±3.1 |
| 0230 | 13 | 11.3±2.6 |
| 0249 | 13 | 18.2±1.8 |
| 0253 | 13 | 10.5±2.3 |
| CTX | 11 | 1.41±0.50 |
Example 2: activity to increase WBC number in dogs
The effect of test compounds was determined by administering different doses of test compounds daily to beagle dogs by IV injection for a total of 4 days. On day 5, blood cells were counted.
As a result: 0058 the number of leukocytes in dogs was significantly increased with a clear dose effect (tables 2 and 3).
Table 2: 0058 Effect on leukocytes in Canine
| Dosage (mg/kg) | WBC(×109/L) | Percent (%) increase |
| 1 | 13.0±2.0 | 15.9 |
| 2 | 16.8±1.0 | 48.2 |
| 4 | 21.5±4.1 | 90.3 |
| 8 | 28.8±7.0 | 154.9 |
Comparison with control data
Example 3: therapeutic effect on mouse leukocytes
This activity was determined using CDF1 male mice. Mice were grouped and treated for 6 days by daily IP injection of 30mg/kg CTX. At day 7, when the white blood cell count decreased significantly, therapeutic treatment was initiated and 15mg/kg of test compound was used daily for 3 days. The positive control group was treated with daily subcutaneous injections of 20. mu.g/kg G-CSF. On day 10, peripheral blood samples were collected and blood cells were counted.
As a result: the test compounds had significant therapeutic activity on leukocytes in mice (table 4).
Table 4: the therapeutic effect on leukocytes is expressed by the number of leukocytes (× 10)9/L)。
| Group of | Day 6 | Day 10 |
| Solvent(s) | 5.1±1.0 | 5.0±0.9 |
| CTX | 1.5±0.2 | 4.8±0.8 |
| G-CSF | 1.8±0.7 | 14.7±1.8 |
| 0058 | 2.1±0.8 | 16.2±2.1 |
| 0227 | 1.6±0.4 | 17.3±1.2 |
| 0230 | 1.7±0.5 | 13.1±1.5 |
Example 4: synthesis of Compounds of the invention
Example 4: synthesis of Compounds of the invention
The compounds of the present invention were prepared according to the following synthetic scheme (scheme 1).
Scheme 1
The following table lists the intermediates prepared according to the procedure of the above synthesis scheme (scheme 1), which are used in the subsequent synthesis.
In addition, a 4e compound is synthesized, wherein R1Is 2, 4-dimethoxyphenyl, R2Is H, A is S, B is O, R3Is methyl.
The detailed synthesis steps are as follows:
synthesis of Compounds 1 a-j: under the protection of nitrogen atmosphere at 0-5 ℃, the fully stirred mixture containing 1, 3-di (tert-butylthio) -acetone (10mmol) and R1NH2(10mmol) and Triethylamine (20mmol) in dry THF (100ml) were added dropwise with TiCl-containing solution4(5.5mmol) of a solution of 15ml of dry hexane, added dropwise over 30 minutes. After the addition was complete, the reaction mixture was refluxed for 2 hours. The obtained imine compound 1 was used in the next reaction without purification.
Synthesis of Compounds 2 a-j: oxalyl chloride (0.84ml, 10mmol) was added to the solution obtained in the above step at-10 ℃. Then, Et-containing solution was added dropwise at the same temperature with stirring3N (20mmol) in 100ml THF was added over 30 minutes. Subsequently, the solution was stirred at room temperature for 10 hours. After the precipitate was filtered off, it was washed with diethyl ether (250 ml). The organic solution was washed three times with water and the solvent was evaporated to give a dark brown powder. The powder was recrystallized from ethyl acetate and hexane to give pale yellow crystals (compound 2). All compounds 2a-j can be prepared in the same way in both steps described. The overall yield of the two steps for each compound is about 60-70%.
Synthesis of Compounds 3 a-k: 50g of ammonium acetate in a 250ml three-necked flask were heated to NH in an oil bath under nitrogen atmosphere4 +OAc-And (4) melting. Then, compound 2(5mmol) was added to the flask, and the resulting solution was stirred for 1 hour. The reaction temperature was controlled between 140 ℃ and 165 ℃ depending on the nature of compound 2. After 1 hour the heating was stopped and the reaction mixture was cooled to room temperature. Then, the reaction mixture was dissolved in 100ml of water and extracted three times with 100ml of diethyl ether. Mixing the extracts with Na2SO4Dried and evaporated under reduced pressure. The residue was purified by silica gel column chromatography to give compound 3. The yield of compounds 3a-i was between about 50-60%. Compound 3k is a by-product of the preparation of compounds 3a-j in a yield that depends on the reaction temperature and reaction time.
Synthesis of Compounds 3l and 3 m: a mixture of 30g of benzylamine acetate and 2mmol of compound 2g in a 150ml flask was heated to 170 ℃ under nitrogen. The mixture was stirred at this temperature for about 1 hour. After cooling, 50ml of water were added and extracted twice with 50ml of diethyl ether. Na for organic solvent2SO4Dried and evaporated under reduced pressure. The residue was purified on silica gel. Compounds 3l and 3m were obtained in 25% and 15% yields, respectively.
Synthesis of compound 3 n: a100 ml flask containing 20g of methylamine acetate and 1mmol of compound 2a was heated to 170 ℃ under nitrogen. The mixture was stirred at this temperature for about 1 hour. After cooling, 50ml of water were added and extracted twice with 50ml of diethyl ether. Na for organic solvent phase2SO4Dried and evaporated under reduced pressure. The residue was purified on silica gel. Compound 3n was obtained in 40% yield.
Synthesis of compound 4 a: to a well stirred solution of 200mg (0.474mmol) of compound 3a in 10ml acetic anhydride was added 20mg of concentrated H2SO4. Half an hour later, the solution was transferred to a silica gel column, first with 200ml CH2Cl2Eluting, and adding 500ml of CH containing 20% diethyl ether2Cl2Elution gave 190mg (0.41mmol, 86%) of Compound 4 a.
Synthesis of compound 4 b: 10ml of a solution containing 100mg (0.24mmol) of the compound 3a, 200mg (1.12mmol) of nicotinoyl chloride hydrochloride and 250mg (2.47mmol) of triethylamineThe THF solution was stirred at room temperature for 24 hours. 50ml of diethyl ether are then added and the solution is washed three times with water. With Na2SO4After drying, the solvent was distilled off, and the residue was purified by silica gel column chromatography to give 90mg of compound 4b (0.171mmol, 72%).
Synthesis of compound 4 c: to a solution of 100mg (0.24mmol) of compound 3a in 5ml of dichloromethane was added 300mg of trifluoroacetic anhydride. The resulting solution was stirred for half an hour, and then the solvent was distilled off under reduced pressure to obtain 122mg of compound 4c (0.237mmol, 100%).
Synthesis of compound 4 d: in 5ml of acetonitrile 211mg (0.5mmol) of compound 3a, 1ml of formaldehyde solution and 100mg of NaCNBH3And (4) mixing. While stirring, 0.1ml of glacial acetic acid was added dropwise over 30 minutes. The reaction mixture was stirred for 4 hours, and another 0.1ml of glacial acetic acid was added during the reaction. Diluted with 50ml of ether and extracted with 1N NaOH and water. After drying and evaporation in vacuo, the residue was purified by silica gel column chromatography to give 150mg (0.33mmol) of compound 4d in 67% yield.
Synthesis of compound 4 e: 300mg of triethylamine are added dropwise at room temperature over the course of 1 minute to a solution of 100mg (0.24mmol) of compound 3a and 300mg of methanesulfonyl chloride in 5ml of dry THF. The solution was stirred for 30 minutes, 50ml of diethyl ether were added and the solution was washed three times with water. With Na2SO4After drying, the solvent was distilled off, and the residue was purified by silica gel column chromatography to give 110mg of compound 4e (0.19mmol, 80%).
Synthesis of compound 4 f: a solution of 100mg (0.24mmol) of compound 3a, 200mg (1.37mmol) of 2-thiophenecarbonyl chloride and 200mg (1.98mmol) of trimethylamine in 10ml of THF is refluxed for 10 hours. Then, 50ml of diethyl ether was added, and the solution was washed three times with water. Through Na2SO4After drying, the solvent was distilled off, and the residue was purified by silica gel column chromatography to give 120mg of compound 4f (0.187mmol, 79%).
Synthesis of Compound 4 g: a solution of 100mg (0.24mmol) of compound 3a, 118mg (1.0mmol) of acetoxyacetyl chloride and 120mg (1.19mmol) of triethylamine in 10ml of THF is stirred at room temperature for 24 hours. Then, 50ml of diethyl ether were added and the solution was washed three times with water. After the solvent was distilled off, the residue was dissolved in 10ml of a methanol solution containing 1ml of 0.1N sodium hydroxide. The solution was stirred for 1 hour. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography to give 105mg of compound 4g (0.22mmol, 91%).
Synthesis of compound 4 h: a solution of 100mg (0.35mmol) of compound 3j, 250mg (1.40mmol) of nicotinoyl chloride hydrochloride and 350mg (3.46mmol) of triethylamine in 10ml of THF is stirred at ordinary temperature for 24 hours. Thereafter, 50ml of diethyl ether was added and the solution was washed three times with water. Through Na2SO4After drying, the solvent was distilled off, and the residue was purified by silica gel column chromatography to give 100mg of the compound 4h (0.256mmol, 73%).
Synthesis of compound 4 i: a solution of 100mg (0.255mmol) of the compound 3g, 100mg (1.28mmol) of acetyl chloride and 260mg (2.56mmol) of triethylamine in 10ml of THF is stirred at 50 ℃ for 12 hours. Then 50ml of diethyl ether were added and the solution was washed three times with water. Through Na2SO4After drying, the solvent was distilled off, and the residue was purified by silica gel column chromatography to give 110mg of compound 4i (0.231mmol, 90%).
Synthesis of compound 4 j: to a solution of 100mg (0.255mmol) of the compound in 3g of 5ml of dichloromethane was added 300mg of trifluoroacetic anhydride. The solution was stirred for 30 minutes, and then the solvent was distilled off under reduced pressure to give 125mg of Compound 4j (0.255mmol, 100%).
Synthesis of compound 4 k: to a solution of 50mg (0.104mmol) of compound 3l in 5ml of dichloromethane was added 150mg of trifluoroacetic anhydride. The solution was stirred for 30 minutes, then the solvent was distilled off under reduced pressure to give 60mg of compound 4k (0.104mmol, 100%).
Synthesis of Compound 4 l: to a solution of 50mg (0.107mmol) of compound 3m in 5ml dichloromethane was added 200mg trifluoroacetic anhydride. The solution was stirred for 30 minutes, and then the solvent was distilled off under reduced pressure to give 60mg of compound 4l (0.107mmol, 100%).
Synthesis of compound 4 m: containing 100mg (0.22mmol) of the compound 3c, 70mg (0.9mmol) of acetyl chloride and 100mg (0.99 m)mol) of triethylamine in 10ml of THF are stirred at room temperature for 24 hours. After this 50ml of ether were added and the solution was washed three times with water. Through Na2SO4After drying, the solvent was distilled off, and the residue was purified by silica gel column chromatography to give 80mg of compound 4m (0.162mmol, 73%).
Synthesis of compound 4 n: a solution of 100mg (0.266mmol) of compound 3f, 70mg (0.9mmol) of acetyl chloride and 100mg (0.99mmol) of triethylamine in 10ml of THF is stirred at room temperature for 24 hours. Thereafter, 50ml of diethyl ether was added, and the solution was washed three times with water. Through Na2SO4After drying, the solvent was distilled off, and the residue was purified by silica gel column chromatography to give 90mg of compound 4n (0.215mmol, 81%).
Synthesis of compound 4 o: to a solution of 80mg (0.210mmol) of compound 3b in 5ml of dichloromethane was added 300mg of trifluoroacetic anhydride. The solution was stirred for 30 minutes, then the solvent was distilled off under reduced pressure to give 100mg of Compound 4o (0.210mmol, 100%).
Synthesis of compound 4 p: a solution of 100mg (0.255mmol) of the compound 3g, 50mg (0.64mmol) of acetyl chloride and 1300mg (1.28mmol) of triethylamine in 10ml of THF is stirred at 25 ℃ for 24 hours. After this 50ml of ether were added and the solution was washed three times with water. Through Na2SO4After drying, the solvent was distilled off, and the residue was purified by silica gel column chromatography to give 90mg of compound 4p (0.19mmol, 70%).
Synthesis of compound 4 q: to a solution of 100mg (0.24mmol) of the compound in 5ml of dichloromethane for 3h was added 300mg of trifluoroacetic anhydride. The solution was stirred for 30 minutes, and then the solvent was distilled off under reduced pressure to give 120mg of Compound 4q (0.24mmol, 100%).
Preparation of compound 4 r: to a solution of 50mg (0.124mmol) of compound 3i in 5ml of dichloromethane was added 200mg of trifluoroacetic anhydride. The solution was stirred for 30 minutes, then the solvent was distilled off under reduced pressure to give 57mg of Compound 4r (0.124mmol, 100%).
Synthesis of compound 4 s: to a solution of 50mg of compound 3j in 5ml of dichloromethane was added 200mg of trifluoroacetic anhydride. The solution was stirred for 30 minutes, and then the solvent was distilled off under reduced pressure to give 66mg of compound 4s in 100% yield.
Synthesis of compound 4 t: to a solution of 50mg of compound 3d in 5ml of dichloromethane was added 200mg of trifluoroacetic anhydride. The solution was stirred for 30 minutes, and then the solvent was distilled off under reduced pressure to give 65mg of compound 4s in 100% yield.
Synthesis of compound 4 u: to a solution of 50mg of compound 3n in 5ml of dichloromethane was added 200mg of trifluoroacetic anhydride. The solution was stirred for 30 minutes, and then the solvent was distilled off under reduced pressure to give 62mg of compound 4s in 100% yield.
The dithiolopyrrolone derivatives synthesized using the above intermediates are shown in Table 5.
Table 5: dithiolopyrrolone derivatives of formula I, wherein a ═ C, B ═ O, and n ═ 1.
| Numbering | R1 | R2 | R3 |
| 0003 | 4-methoxyphenyl radical | H | Methyl radical |
| 0004 | 4-methoxyphenyl radical | Acetyl group | Methyl radical |
| 0005 | 4-methoxyphenyl radical | H | Trifluoromethyl radical |
| 0007 | 2, 4-dimethoxy-phenyl | H | CH2CH2COOH |
| 0008 | 4-methylphenyl radical | H | Methyl radical |
| 0012 | 4-methoxyphenyl radical | Benzyl radical | Trifluoromethyl radical |
| 0013 | 4-hydroxyphenyl group | Benzyl radical | Trifluoromethyl radical |
| 0014 | 2, 4-dimethoxy-phenyl | H | Methyl radical |
| 0017 | 3, 4, 5-trimethoxy-phenyl | H | Methyl radical |
| 0018 | 2, 4-dimethoxy-phenyl | H | 3-pyridyl group |
| 0019 | 2, 4-dimethoxy-phenyl | H | N-methyl-3-pyridinium chloride |
| 0020 | 2, 4-dimethoxy-phenyl | H | Trifluoromethyl radical |
| 0022 | 1-ethylpyrazol-5-yl | H | Trifluoromethyl radical |
| 0030 | 2, 4-dimethoxy-phenyl | H | Hydroxymethyl group |
| 0039 | 2, 4-dihydroxyphenyl | H | Methyl radical |
| CSL-25 | Phenyl radical | H | Methyl radical |
| CSL-26 | Benzyl radical | H | Phenyl radical |
| CSL-28 | H | H | 3-pyridoyl |
Synthesis of compound 0003: a solution containing 90mg (0.19mmol) of compound 4p and 6.8mg (0.19mmol) of Hg (OAc)2Is stirred at room temperature for 1 hour. After distilling off TFA under reduced pressure, the residue was dissolved in 100ml CH3In CN. H is to be2And S is introduced into the solution. After 1 hour, N was passed through the solution2Thereby remaining H2S is driven off, and then 0.2mmol of I is added to the solution210ml of CH2Cl2And (3) solution. After half an hour later, the solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography to give 43mg of compound 0003 in 67% yield.1H NMR(100MHz，CDCl3)δ2.2(s，3H)，3.9(s，3H)，6.7(s，1H)，7.0-7.4(dd，4H)，7.8(s，1H)。
Synthesis of compound 0004: compound 0004 was synthesized from compound 4i using the same synthesis method as compound 0003. The yield was 60%.1H NMR(100MHz，CDCl3)δ2.5(s，6H)，3.9(s，3H)，6.95(s，1H)，7.0-7.5(dd，4H)，MS(CI)：363(M+1)。
Synthesis of compound 0005: compound 0005 was synthesized from compound 4j using the same synthesis method as compound 0003. The yield was 75%.1H NMR(100MHz，CDCl3)δ3.9(s，3H)，6.82(s，1H)，7.0-7.4(dd，4H)，8.3(s，1H)。
Synthesis of compound 0008: compound 0008 was synthesized from compound 4n by the same synthesis method as compound 0003. The yield was 70%.1H NMR(100MHz，CDCl3)δ2.1(s，3H)，2.4(s，3H)，6.7(s，1H)，7.3(s，4H)，8.0(s，1H)。
Synthesis of compound 0012: compound 0012 was synthesized from compound 4k using the same synthesis method as compound 0003. The yield was 72%.1H NMR(100MHz，CDCl3)δ3.9(s，3H)，4.2-5.8(dd，2H)，6.9(s，1H)，7.0-7.4(dd，4H)，7.4(s，5H).MS(CI)：465(M+1)。
Synthesis of compound 0013: compound 0013 was synthesized from compound 4l using the same synthesis method as compound 0003. The yield was 65%.1H NMR(100MHz，CDCl3) δ 4.2-5.8(dd, 2H), 6.6(s, 1H), 7.1-7.5 (broad, 9H), 7.4(s, 5H).
Synthesis of compound 0014: compound 0014 was synthesized from compound 4 using the same synthesis method as compound 0003. The yield was 77%.1H NMR(100MHz，CDCl3) δ 2.73(s, 3H), 3.77(s, 3H), 3.82(s, 3H), 6.6(s, 1H), 6.4-7.3 (multiplet, 3H), 8.0 (broadpeak, 1H). 350 (M).
Synthesis of compound 0017: the same synthesis method as that of compound 0003 is adoptedMethod, compound 0017 was synthesized using compound 4 m. The yield was 55%.1H NMR(100MHz，CDCl3) δ 3.8(s, 6H), 3.9(s, 3H), 6.7(s, 1H), 7.4(s, 2H), 7.9 (broad peak, 1H). MS: 380 (M).
Synthesis of compound 0018: compound 0018 was synthesized from compound 4b using the same synthesis method as compound 0003. The yield was 45%.1H NMR(100MHz，CD3OD) delta 3.8(s, 3H), 3.9(s, 3H), 6.7(s, 1H), 6.6-9.2 (multiplet, 7H).
Synthesis of compound 0019: 10mg (0.024mmol) of compound 0018 are dissolved in 1ml CH3In I, the solution was left at room temperature for 10 hours. A red crystal precipitated in the solution, and after filtration, 9mg (0.016mmol) of compound 0019 was obtained in 67% yield.1H NMR(100MHz，CD3OD) delta 3.7(s, 3H), 3.8(s, 3H), 4.4(s, 3H), 6.9(s, 1H), 6.5-9.4 (multiplet, 7H).
Synthesis of compound 0020: compound 0020 was synthesized from compound 4c using the same synthesis method as compound 0003. The yield was 83%.1H NMR(100MHz，CDCl3) δ 3.8(s, 3H), 3.9(s, 3H), 6.6 (multiplet, 3H), 7.2(d, 1H), 8.4(s, 1H). CI 405(M + 1).
Synthesis of compound 0022: compound 0022 was synthesized from compound 4o using the same synthesis method as compound 0003. The yield was 6.6%.1H NMR(100MHz，CDCl3)δ1.5(t，3H)，4.0(q，2H)，6.3(d，1H)，6.9(s，1H)，7.7(d，1H)，8.4(s，1H).MS：CI 363(M+1)。
Synthesis of compound 0024: compound 0024 was synthesized from compound 4d by the same synthesis method as compound 0003. The yield was 19%.1H NMR(100MHz，CDCl3) δ 2.6(s, 6H), 3.8(s, 3H), 3.9(s, 3H), 6.4(s, 1H), 6.5 (multiplet, 2H), 7.2(d, 1H). MS: 337(M + 1).
Synthesis of compound 0028: synthesized by the same synthetic method as the compound 0003 and by using the compound 4fCompound 0028. The yield was 43%.1H NMR(100MHz，CDCl3) δ 3.8(s, 3H), 3.9(s, 3H), 6.5(s, 1H), 6.65 (multiplet, 4H), 7.2 (multiplet, 2H), 7.7 (multiplet, 3H). 529(M + 1).
Synthesis of compound 0030: compound 0030 was synthesized from compound 4g using the same synthesis method as compound 0003. The yield was 41%.1H NMR(100MHz，CDCl3) δ 3.8(s, 3H), 3.9(s, 3H), 4.3(s, 2H), 6.5(s, 1H), 6.65 (multiplet, 2H), 7.2(d, 1H), 8.35(s, 1H). 367(M + 1).
Synthesis of Compound CSL-25: CSL-25 was synthesized using the method of scheme 1. CSL-25 has the following characteristics:1H NMR(100MHz，CDCl3) δ 2.2(s, 3H), 6.8(s, 1H), 7.4-7.6 (multiplet, 5H), 7.8(s, 1H).
Synthesis of Compound CSL-26: CSL-26 was synthesized using the method of scheme 1. CSL-26 has the following characteristics:1H NMR(100MHz，CDCl3) δ 5.1(s, 2H), 6.5(s, 1H), 7.2-8.0 (multiplet, 10H), 8.3(s, 1H).
Synthesis of Compound CSL-28: compound CSL-28 was synthesized from compound 4h using the same synthetic method as compound 0003. The yield was 43%.1H NMR(100MHz，CDCl3) δ 6.8(s, 1H), 7.9(s, 1H), 8.1-9.2 (multiplet 4H), MS: CI, 278(M + 1).
Synthesis of compound 0050: compound 0050 was synthesized from compound 4q by the same synthesis method as compound 0003. The yield was 80%.1H NMR(100MHz，CDCl3) δ 0.9(t, 3H), 1.3(d, 3H), 1.65 (multiplet, 2H), 2.7 (multiplet, 1H), 6.9(s, 1H), 7.3(s, 4H), 8.4(s, 1H).
Synthesis of compound 0061: using the same synthetic method as that for compound 0003, compound 0061 was synthesized using compound 4 s. The yield was 82%.1H NMR(100MHz，CDCl3)，2.8(s，3H)，6.6(s，1H)，8.4(s，1H)。
Synthesis of compound 0092: compound 0092 was synthesized using compound 4r in the same manner as compound 0003. The yield was 77%.1H NMR(100MHz，CDCl3) δ 1.26(d, 6H), 3.0 (multiplet, 1H), 6.7(s, 1H), 7.35(s, 4H), 8.6(s, 1H).
Synthesis of compound 0103: compound 4t was synthesized to obtain 0103 by the same synthesis method as compound 0003. The yield was 85%.1H NMR(100MHz，CDCl3)，4.3(s，2H)，6.6(s，1H)，7.3(s，5H)，8.4(s，1H)。
Synthesis of compound 0119: compound 0119 was synthesized from compound 4u using the same synthesis method as compound 0003. The yield was 85%.1H NMR(100MHz，CDCl3) δ 2.7(s, 3H), 3.8(s, 3H), 3.85(s, 3H), 6.55(s, 1H), 6.6 (multiplet, 2H), 7.2(d, 1H), 8.4(s, 1H).
When R is3is-NR4R5、-OR6and-NHSO2R6Aryl, heterocyclic or some groups that are unstable under the final reaction conditions of scheme 1, the following synthetic route (scheme 2) is an efficient route to synthesize the analogs.
The following compounds were prepared according to the following synthetic scheme (scheme 2).
Scheme 2
Some of the intermediates listed in table 6 were synthesized by the method set forth in scheme 2.
Table 6: intermediate product in synthesis of dithiolopyrrolone derivatives
| Numbering | R1 | R2 |
| 0021 | 2, 4-Dimethoxyphenyl | H |
| 0051 | 4-isobutylphenyl | H |
| 0079 | Methyl radical | H |
| 0093 | 4-isopropylphenyl group | H |
| 0104 | Benzyl radical | H |
| 0120 | 2, 4-Dimethoxyphenyl | Methyl radical |
Synthesis of compound 0021: 1g of compound 0020 is dissolved in 150ml of methanol solution containing 5ml of hydrochloric acid. The solution was refluxed for 2 hours. The solvent was distilled off in vacuo to give 0.76g of compound 0021 as a dark green powder.
Intermediates 0051, 0079, 0093, 0104 and 0120 were synthesized using 0050, 0061, 0092, 0103 and 0119, respectively, in the same synthesis method as 0021.
Table 7 lists the dithiolopyrrolone derivatives prepared by the method described in scheme 2.
Table 7: dithiolopyrrolone derivatives of formula I, wherein a ═ C, B ═ O, and n ═ 1.
| Numbering | R1 | R2 | R3 |
| 0023 | 2, 4-dimethoxy-phenyl | H | 2-furyl radical |
| 0025 | 2, 4-dimethoxy-phenyl | H | 2, 4-Dimethoxyphenyl |
| 0026 | 2, 4-dimethoxyPhenyl radical | H | 4-trifluoromethylphenyl group |
| 0029 | 2, 4-dimethoxy-phenyl | H | 2-thienyl radical |
| 0032 | 2, 4-dimethoxy-phenyl | H | 3, 5-difluorophenyl |
| 0033 | 2, 4-dimethoxy-phenyl | H | 2, 3, 4-trifluorophenyl |
| 0036 | 2, 4-dimethoxy-phenyl | H | 4-fluoro-phenyl |
| 0037 | 2, 4-dimethoxy-phenyl | H | Thiophene-2-methyl |
| 0038 | 2, 4-Bomethoxy-phenyl | H | 4-Nitrophenyl radical |
| 0040 | 2, 4-dimethoxy-phenyl | H | 4-N, N-dimethylamino-phenyl |
| 0041 | 2, 4-dimethoxy-phenyl | H | 4-aminophenyl |
| 0042 | 2, 4-dimethoxy-phenyl | H | 2, 2, 5, 5-tetramethyl-tetrahydro-1, 3, 4, 6, 8-pentaoxa-cyclopenta [ a ]]Inden-8 a-yl (2, 2, 5, 5-tetramethylhydro-1, 3, 4, 6, 8-pentaoxa-cyclopenta [ a ]]inden-8a-yl |
| 0043 | 2, 4-Didimethoxy-phenyl | H | 6-hydroxy-5-hydroxymethyl-2, 2-dimethyl-dihydro-furo [2, 3-d][1，3]Dioxol-3 a-yl (6-hydroxy-5-hydroxymethy-2, 2-dimethyl-furo [2, 3-d)][1，3]dioxol-3a-yl |
| 0044 | 2, 4-dimethoxy-phenyl | H | 2, 3, 4-Trihydroxyl-5-hydroxymethyl-tetrahydrofuran-2-yl |
| 0047 | 2, 4-dimethoxy-phenyl | H | 3-trifluoromethylphenyl group |
| 0052 | 2, 4-dimethoxy-phenyl | H | 4-morpholin-4-ylmethyl |
| 0046 | 2, 4-dimethoxy-phenyl | H | 1, 2, 3, 4, 5-pentahydroxy-pentyl |
| 0054 | 4-isobutylphenyl | H | 4-trifluoromethylphenyl group |
| 0055 | 4-isobutylphenyl | H | 2-furyl radical |
| 0056 | 4-isobutylphenyl | H | 2-thienyl radical |
| 0057 | 4-isobutylphenyl | H | 3-trifluoromethylphenyl group |
| 0058 | 2, 4-dimethoxy-phenyl | H | 3, 5-bis (trifluoromethyl) phenyl |
| 0059 | 4-isobutylphenyl | H | 3, 5-bis (trifluoromethyl) phenyl |
| 0062 | 2, 4-dimethoxy-phenyl | H | 4-piperazin-1-ylmethyl |
| 0066 | 2, 4-dimethoxy-phenyl | H | 4-morpholin-4-ylmethyl-phenyl |
| 0068 | 2, 4-dimethoxy-phenyl | H | 4- (4-methyl-piperazin-1-ylmethyl) -phenyl |
| 0069 | 2, 4-dimethoxy-phenyl | H | 4-piperazin-1-ylmethyl-phenyl |
| 0185 | 4-isopropylphenyl group | H | 4- (4-methyl-piperazin-1-ylmethyl) -phenyl |
| 0187 | 4-isobutylphenyl | H | 4- (4-methyl-piperazin-1-ylmethyl) -phenyl |
| 0189 | Methyl radical | H | 4- (4-methyl-piperazin-1-ylmethyl) -phenyl |
| 0096 | 4-isopropylphenyl group | H | 3, 5-dihydroxy-4-isopropyl-phenyl |
| 0102 | 2, 4-dimethoxy-phenyl | H | 3, 5-dihydroxy-4-isopropyl-phenyl |
| 0107 | Benzyl radical | H | 3, 5-dihydroxy-4-isopropyl-phenyl |
| 0110 | Methyl radical | H | 3, 5-dihydroxy-4-isopropyl-phenyl |
| 0113 | Benzyl radical | H | 2-thienyl radical |
| 0116 | Benzyl radical | H | 4-morpholin-4-ylmethyl-phenyl |
| 0122 | 2, 4-dimethoxy-phenyl | Methyl radical | 4-morpholin-4-ylmethyl-phenyl |
| 0125 | 4-isopropylphenyl group | H | 3-morpholin-4-ylmethyl-phenyl |
| 0126 | 2, 4-dimethoxy-phenyl | H | 3-morpholin-4-ylmethyl-phenyl |
| 0128 | 4-isopropylphenyl group | H | Pyridin-3-yl |
| 0135 | Benzyl radical | H | Pyridin-3-yl |
| 0136 | Benzyl radical | H | 3- (4-methyl-piperazin-1-ylmethyl) -phenyl |
| 0137 | Benzyl radical | H | 3-morpholin-4-ylmethyl-phenyl |
| 0211 | 2, 4-dimethoxy-phenyl | H | 3, 5-bis (trifluoromethyl) -phenylamino |
| 0212 | 2, 4-dimethoxy-phenyl | H | Toluene-4-sulfonylamino |
| 0213 | 2, 4-dimethoxy-phenyl | H | 2, 4-difluoro-phenylamino |
| 0227 | 2, 4-dimethoxy-phenyl | H | Phenoxy radical |
| 0228 | 2, 4-dimethoxy-phenyl | H | 2-Methylpropoxy group |
| 0229 | 2, 4-dimethoxy-phenyl | H | Benzyloxy radical |
| 0230 | 2, 4-dimethoxy-phenyl | H | Ethoxy radical |
| 0231 | 2, 4-dimethoxy-phenyl | H | Methoxy radical |
| 0232 | 2, 4-dimethoxy-phenyl | H | H |
| 0233 | 2, 4-dimethoxy-phenyl | H | Isopropoxy group |
| 0234 | 2, 4-methoxy-phenyl | H | Propargyloxy group |
| 0235 | 2, 4-dimethoxy-phenyl | H | Propoxy group |
| 0236 | 2, 4-dimethoxy-phenyl | H | 4-methoxyphenoxy radical |
| 0237 | 2, 4-dimethoxy-phenyl | H | N-pentyloxy radical |
| 0238 | 2, 4-dimethoxy-phenyl | H | Pyranyl methoxy |
| 0239 | 2, 4-dimethoxy-phenyl | H | N-butoxy radical |
| 0240 | 2, 4-dimethoxy-phenyl | H | Cyclopentyloxy radical |
| 0241 | 2, 4-dimethoxy-phenyl | H | N-heptyloxy radical |
| 0242 | 2, 4-dimethoxy-phenyl | H | 2-chloro-phenoxy |
| 0243 | 2, 4-dimethoxy-phenyl | H | 4-chloro-phenoxy |
| 0244 | 2, 4-dimethoxy-phenyl | H | 4-p-tolyloxy |
| 0245 | 2, 4-dimethoxy-phenyl | H | 2-FuranylmethylOxy radical |
| 0246 | 2, 4-dimethoxy-phenyl | H | 1-Phenylethoxy |
| 0247 | 2, 4-dimethoxy-phenyl | H | 2-thienyl methoxy |
| 0248 | 2, 4-dimethoxy-phenyl | H | Pyridin-3-yloxy |
| 0249 | 2, 4-dimethoxy-phenyl | H | Bis (2-hydroxy-ethyl) -amino |
| 0250 | 2, 4-dimethoxy-phenyl | H | Benzylamino group |
| 0251 | 2, 4-dimethoxy-phenyl | H | Butylamino group |
| 0252 | 2, 4-dimethoxy-phenyl | H | Phenylamino group |
| 0253 | 2, 4-dimethoxy-phenyl | H | Ethyl thio radical |
| 0254 | 2, 4-dimethoxy-phenyl | H | Ethoxy radical |
| 0255 | 2, 4-dimethoxy-phenyl | H | Phenoxy radical |
| 0256 | 2, 4-dimethoxy-phenyl | H | Propargyloxy group |
| 0257 | 2, 4-dimethoxy-phenyl | H | N, N-dimethylaminoethoxy |
| 0258 | 2, 4-dimethoxy-phenyl | H | N-methylaminoethoxy |
| 0259 | 2, 4-dimethoxy-phenyl | H | N, N-dimethylaminoethoxy |
Table 8: dithiolopyrrolone derivatives of formula I, when a ═ C, B ═ S, n ═ 1, are 0214. When a is S, B O, n is 2, the compound is 0215.
| Numbering | R1 | R2 | R3 |
| 0214 | 2, 4-dimethoxy-phenyl | H | 3, 5-difluoro-phenylamino |
| 0215 | 2, 4-dimethoxy-phenyl | H | Methyl radical |
Compound (I)0023 synthesis: 50mg (0.16mmol) of compound 0021 are dissolved in 20ml of dry THF. While stirring well, 43mg (0.32mmol) of 2-furoyl chloride was added, followed by dropwise addition of 50mg of triethylamine over 2 minutes. The reaction was complete in 30 min and the product was purified by column chromatography to give 51mg (0.12mmol, 80%) of compound 0023.1H NMR(100MHz，CDCl3) δ 3.8(s, 3H), 3.9(s, 3H), 6.5(s, 1H), 6.6 (multiplet, 3H), 7.2 (multiplet, 2H), 7.6(d, 1H), 8.4(s, 1H). 403(M + 1).
Synthesis of compound 0025: compound 0025 was obtained by reacting compound 0021 with 2, 4-dimethoxybenzoyl chloride using the same synthetic method as compound 0023. The yield was 89%.1H NMR(100MHz，CDCl3) δ 3.8(s, 3H), 3.9(s, 3H), 3.93(s, 3H), 4.07(s, 3H), 6.4(s, 1H), 6.6 (multiplet, 4H), 7.2(d, 1H), 8.2(d, 1H), 10.2(s, 1H). 473(M + 1).
Synthesis of compound 0026: compound 0026 was obtained by reaction of compound 0021 with 4-trifluoromethylbenzoyl chloride using the same synthetic method as compound 0023. The yield was 90%.1H NMR(100MHz，CDCl3) δ 3.8(s, 3H), 3.9(s, 3H), 6.5(s, 1H), 6.6 (multiplet, 2H), 7.25(d, 1H), 7.8(d, 2H), 8.1(d, 2H), 8.4(s, 1H). MS: 480 (M).
Synthesis of compound 0029: compound 0029 was obtained by reacting compound 0021 with 2-thiophenecarbonyl chloride using the same synthesis method as compound 0023. The yield was 88%.1H NMR(100MHz，CDCl3) δ 3.8(s, 3H), 3.9(s, 3H), 6.55(s, 1H), 6.63 (multiplet, 2H), 7.2 (multiplet, 2H), 7.7 (multiplet, 2H). 418 (M).
Synthesis of compound 0031: compound 0031 was obtained by reacting compound 0021 with heptanoyl chloride using the same synthesis method as compound 0023. The yield was 74%.1H NMR(100MHz，CDCl3) δ 0.9(t, 3H), 1.4 (multiplet, 8H), 2.4(t, 2H), 3.8(s, 3H), 3.9(s, 3H), 4.3(s, 2H), 6.6(s, 1H), 6.65 (multiplet)Heavy peak, 2H), 7.2(d, 1H), 8.4(s, 1H) MS: 420 (M).
Synthesis of compound 0032: compound 0032 was obtained by reacting compound 0021 with 3, 4-difluorobenzoyl chloride using the same synthesis method as compound 0023. The yield was 81%.1H NMR(100MHz，CDCl3) δ 3.8(s, 3H), 3.9(s, 3H), 6.5(s, 1H), 6.6 (multiplet, 2H), 7.1 (multiplet, 2H), 7.5 (multiplet, 2H), 8.4(s, 1H). 448 (M).
Synthesis of compound 0033: compound 0033 was obtained by reacting compound 0021 with 2, 3, 4-trifluorobenzoyl chloride using the same synthesis method as compound 0023. The yield was 84%.1H NMR(100MHz，CDCl3) δ 3.8(s, 3H), 3.9(s, 3H), 6.5(s, 1H), 6.6 (multiplet, 2H), 7.2 (multiplet, 2H), 7.9 (multiplet, 1H), 8.6(s, 1H). 466 (M).
Synthesis of compound 0036: compound 0036 was obtained by the reaction of compound 0021 with 4-fluorobenzoyl chloride using the same synthesis method as compound 0023. The yield was 85%.1H NMR(100MHz，CDCl3) δ 3.8(s, 3H), 3.9(s, 3H), 6.5(s, 1H), 6.65 (multiplet, 3H), 7.1 (multiplet, 2H), 7.5 (multiplet, 2H), 8.4(s, 1H). 430 (M).
Synthesis of compound 0037: compound 0037 was obtained by the reaction of compound 0021 with thiopheneacetyl chloride using the same synthetic method as compound 0023. The yield was 81%.1H NMR(100MHz，CDCl3) δ 3.75(s, 3H), 3.85(s, 3H), 3.9(s, 2H), 6.42(s, 1H), 6.55 (multiplet, 2H), 7.1-7.3 (multiplet, 4H), 8.2(s, 1H). MS: 433(M + 1).
Synthesis of compound 0038: compound 0038 was obtained by the same synthetic method as compound 0023, by the reaction of compound 0021 with 4-nitrobenzoyl chloride. The yield was 81%.1H NMR(100MHz，CDCl3) δ 3.8(s, 3H), 3.85(s, 3H), 6.55 (multiplet, 3H), 7.1-7.3(dd, 1H), 8.2(dd, 4H), 8.9(s, 1H). 458 (M)+1)。
Synthesis of compound 0040: 100mg (0.32mmol) of compound 0021, 55mg (0.32mmol) of 4-dimethylaminobenzoic acid and 75mg (0.34mmol) of DCC are dissolved in 20ml of dry CH2Cl2In (1). The solution was stirred for 2 hours. After the solvent was distilled off, the residue was purified by a silica gel column to obtain 65mg (60%) of compound 0040.1H NMR(100MHz，CDCl3) δ 3.1(s, 6H), 3.8(s, 3H), 3.85(s, 3H), 6.4(s, 1H), 6.5 (multiplet, 2H), 6.8(d, 2H), 7.25(d, 1H), 7.85(d, 2H), 8.1(s, 1H) MS: 456(M + 1).
Synthesis of compound 0041: 100mg (0.32mmol) of compound 0021, 80mg (0.32mmol) of 4-trifluoroacetylaminobenzoic acid and 75mg (0.34mmol) of DCC are dissolved in 20ml of dry CH2Cl2In (1). The solution was stirred for 2 hours. After the solvent was distilled off, the residue was dissolved in 40ml of methanol. After 2ml of concentrated HCl was added to the solution, the resulting solution was refluxed for 1 hour. The product was extracted with ethyl acetate and washed with water and dried over sodium sulfate. After the solvent was distilled off, the residue was purified by silica gel column chromatography to obtain 50mg (40%) of compound 0041.1H NMR(100MHz，DMSO-d6) δ 3.7(s, 3H), 3.8(s, 3H), 5.9(s, 2H), 6.6(d, 2H), 6.7 (multiplet, 2H), 6.8(s, 1H), 7.2(d, 1H), 7.75(d, 2H), 9.55(s, 1H). 428(M + 1).
Synthesis of compound 0042: 100mg (0.32mmol) of compound 0021, 100mg (0.33mmol) of 2, 3: 4, 6-bis-O-isopropylidene-2-keto-L-gulonic acid monohydrate and 80mg (0.35mmol) of DCC were dissolved in 20ml of dry CH2Cl2In (1). The solution was stirred for 2 hours, the solvent was distilled off, and the residue was purified by silica gel column chromatography to give 110mg (60%) of compound 0042.1HNMR(100MHz，CDCl3) δ 1.4(s, 3H), 1.42(s, 3H), 1.6(s, 6H), 3.75(s, 3H), 3.85(s, 3H), 4.1-4.7 (multiplet, 5H), 6.4(s, 1H), 6.5-6.6 (multiplet, 2H), 7.2(d, 1H), 9.0(s, 1H). 565(M + 1).
Synthesis of compound 0043: 20ml of a 1N HCl and THF (1: 5) mixed solution containing 50mg of compound 0042 were added at room temperatureStirred for 3 hours. The product was extracted with ethyl acetate and washed with water. After the solvent was distilled off, the residue was purified by silica gel column chromatography to give 42mg (85%) of compound 0043.1H NMR(100MHz，CDCl3) δ 1.4(s, 3H), 1.42(s, 3H), 3.8(s, 3H), 3.9(s, 3H), 4.1-4.7 (multiplet, 5H), 6.5(s, 1H), 6.5-6.6 (multiplet, 2H), 7.2(d, 1H), 9.0(s, 1H). MS: 525(M + 1).
Synthesis of compound 0044: a mixed solution of 20ml of acetic acid and water (7: 3) containing 50mg of compound 0042 was refluxed for 4 hours. The solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography to give 36mg (85%) of compound 0044.1H NMR(100MHz，CDCl3) δ 2.6-4.5(broad, 10H), 3.8(s, 3H), 3.9(s, 3H), 6.5-6.6 (multiplet, 3H), 7.2(d, 1H), 9.0(s, 1H). 485(M + 1).
Synthesis of compound 0047: compound 0047 was obtained by reaction of compound 0021 with 3-trifluoromethylbenzoyl chloride using the same synthesis method as compound 0023. The yield was 85%.1H NMR(100MHz，CDCl3) δ 3.8(s, 3H), 3.85(s, 3H), 6.55(s, 1H), 6.6 (multiplet, 2H), 7.2(d, 1H), 7.8(s, 1H), 7.7-8.4 (multiplet, 4H). MS: 487(M + 1).
Synthesis of compound 0052: 100mg of compound 0021 are dissolved in 40ml of dry THF. 100mg of chloroacetyl chloride was added while stirring well, and then 50mg of triethylamine was added dropwise over 2 minutes. The reaction was completed in 30 minutes. The product was extracted with ethyl acetate and washed with water. After the solvent was distilled off, the residue was dissolved in 10ml of acetonitrile. To the solution was added 0.5ml of morpholine, followed by stirring at 60 ℃ for 4 hours. The product was extracted with ethyl acetate and washed with water. After the solvent was distilled off, the residue was purified by silica gel column chromatography to obtain 65mg of compound 0052. The yield was 50%.1H NMR(100MHz，CDCl3) δ 2.8 (multiplet, 4H), 3.8 (multiplet, 4H), 3.81(s, 3H), 3.85(s < 3H), 6.45(s, 1H), 6.6 (multiplet, 2H), 7.25(d, 1H), 9.45(s, 1H) MS: 436(M + 1).
Synthesis of compound 0054: by mixingCompound 0054 was obtained by a similar method to that of compound 0023, by reacting compound 0051 with 4-trifluoromethylbenzoyl chloride. The yield was 85%.1H NMR(100MHz，CDCl3) δ 0.9(t, 3H), 1.3(d, 3H), 1.65 (multiplet, 2H), 2.7 (multiplet, 1H), 6.9(s, 1H), 7.3(s, 4H), 7.8(d, 2H), 8.1(d, 2H), 8.4(s, 1H) MS: 477(M + 1).
Synthesis of compound 0055: compound 0055 was obtained by reaction of compound 0051 with 2-furoyl chloride using the same synthetic method as compound 0023. The yield was 90%.1H NMR(100MHz，CDCl3) δ 0.9(t, 3H), 1.3(d, 3H), 1.65 (multiplet, 2H), 2.7 (multiplet, 1H), 6.6(dd, 1H), 6.9(s, 1H), 7.3(s, 4H), 7.4(d, 1H), 7.6(d, 1H), 8.4(s, 1H) MS: 413(M + 1).
Synthesis of compound 0056: compound 0056 was obtained by reaction of compound 0051 with 2-thiophenecarbonyl chloride using the same synthesis method as compound 0023. The yield was 90%.1H NMR(100MHz，CDCl3) δ 0.9(t, 3H), 1.3(d, 3H), 1.65 (multiplet, 2H), 2.7 (multiplet, 1H), 6.85(s, 1H), 7.2(dd, 1H), 7.3(s, 4H), 7.6(d, 2H), 7.8(d, 2H), 8.2(s, 1H) MS: 429(M + 1).
Synthesis of compound 0057: compound 0057 was obtained by the reaction of compound 0051 with 3-trifluoromethylbenzoyl chloride using the same synthesis method as compound 0023. The yield was 88%.1H NMR(100MHz，CDCl3) δ 0.9(t, 3H), 1.3(d, 3H), 1.65 (multiplet, 2H), 2.7 (multiplet, 1H), 6.9(s, 1H), 7.35(s, 4H), 7.6-8.3 (multiplet, 4H), 8.4(s, 1H). 477(M + 1).
Compound 0058(N- [4- (2, 4-dimethoxy-phenyl) -5-oxo-4, 5-dihydro- [1, 2)]Dithiolopeno [4, 3-b ] s]Pyrrol-6-yl]-synthesis of 3, 5-bis (trifluoromethyl) -benzamide): compound 0058 was obtained by reacting compound 0021 with 3, 5-bis (trifluoromethyl) benzoyl chloride using the same synthesis method as compound 0023. The yield was 88%.1H NMR(100MHz，CDCl3) δ 3.8(s, 3H), 3.85(s, 3H), 6.55(s, 1H), 6.6 (multiplet, 2H), 7.2(d, 1H), 8.1(s, 1H), 8.4(s, 2H), 8.6(s, 1H). MS: 545(M + 1).
Synthesis of compound 0059: compound 0059 was obtained by reacting compound 0051 with 3, 5-bis (trifluoromethyl) benzoyl chloride using the same synthetic method as compound 0023. The yield was 80%.1HNMR(100MHz，CDCl3) δ 0.9(t, 3H), 1.3(d, 3H), 1.65 (multiplet, 2H), 2.7 (multiplet, 1H), 6.95(s, 1H), 7.3(s, 4H), 8.1(s, 1H), 8.4(s, 2H), 8.6(s, 1H) MS: 549(M + 1).
Synthesis of compound 0062: 100mg of compound 0021 are dissolved in 40ml of dry THF. 100mg of chloroacetyl chloride was added while stirring well, and then 100mg of triethylamine was added dropwise over 2 minutes. The reaction was completed in 30 minutes. The product was extracted with ethyl acetate and washed with water. After the solvent was distilled off, the residue was dissolved in 10ml of DMF. To the solution was added 200mg of piperazine, followed by stirring at 60 ℃ for 4 hours. The product was extracted with ethyl acetate and washed with water. After the solvent was distilled off, the residue was purified by silica gel column chromatography to obtain 70mg of a compound 0062. The yield was 53%.1H NMR(100MHz，CDCl3) δ 2.7 (multiplet, 4H), 3.1 (multiplet, 4H), 3.2(s, 2H), 3.4(s, 1H), 3.8(s, 3H), 3.9(s, 3H), 6.4(s, 1H), 6.6 (multiplet, 2H), 7.2(d, 1H), 9.2(s, 1H) MS: 435(M + 1).
Synthesis of compound 0066: 100mg of compound 0021 are dissolved in 40ml of dry THF. While stirring well, 120mg of 4-chloromethylbenzoyl chloride was added, followed by dropwise addition of 100mg of triethylamine over 2 minutes. The reaction was completed in 30 minutes. The product was extracted with ethyl acetate and washed with water. After the solvent was distilled off, the residue was dissolved in 2ml of morpholine. The solution was stirred at 60 ℃ for 2 hours and water was added. The product was extracted with ethyl acetate and washed with water. After the solvent was distilled off, the residue was purified by silica gel column chromatography to give 110mg of compound 0066. The yield was 68%.1H NMR(100MHz，CDCl3) δ 2.5 (multiplet, 4H), 3.8 (multiplet, 4H), 3.6(s, 2H), 3.85(s, 3H), 3.9(s, 3H), 6.5(s, 1H), 6.6 (multiplet, 2H), 7.2(d, 1H), 7.7(dd, 4H), 8.3(s, 1H). MS: 512(M + 1).
Synthesis of compound 0068: 100mg of compound 0021 are dissolved in 40ml of dry THF. While stirring well, 120mg of 4-chloromethylbenzoyl chloride was added, followed by dropwise addition of 100mg of triethylamine over 2 minutes. The reaction was completed in 30 minutes. The product was extracted with ethyl acetate and washed with water. After the solvent was distilled off, the residue was dissolved in 2ml of N-methylpiperazine. The solution was stirred at 60 ℃ for 2 hours and water was added. The product was extracted with ethyl acetate and washed with water. After the solvent was distilled off, the residue was purified by silica gel column chromatography to give 120mg of compound 0068. The yield was 70%.1H NMR(100MHz，CDCl3) δ 2.4(s, 3H), 2.6(s, 8H), 3.6(s, 2H), 3.85(s, 3H), 3.9(s, 3H), 6.45(s, 1H), 6.6 (multiplet, 2H), 7.2(d, 1H), 7.7(dd, 4H), 8.3(s, 1H). MS: 525(M + 1).
Synthesis of compound 0069: 100mg of compound 0021 are dissolved in 40ml of dry THF. While stirring well, 120mg of 4-chloromethylbenzoyl chloride was added, followed by dropwise addition of 100mg of triethylamine over 2 minutes. The reaction was completed in 30 minutes. The product was extracted with ethyl acetate and washed with water. After the solvent was distilled off, the residue was dissolved in 10ml of DMF. To the solution was added 200mg of piperazine and stirred at 60 ℃ for 4 hours. The product was extracted with ethyl acetate and washed with water. After evaporation of the solvent, the product was purified by silica gel column chromatography to give 125mg of compound 0069 in 70% yield.1H NMR(100MHz，CDCl3) δ 2.6(s, 4H), 3.1 (multiplet, 4H), 3.6(s, 2H), 3.85(s, 3H), 3.9(s, 3H), 6.5(s, 1H), 6.6 (multiplet, 2H), 7.25(d, 1H), 7.7(dd, 4H), 8.4(s, 1H) MS: 511(M + 1).
Synthesis of compound 0080: 80mg of Compound 0079 were dissolved in 20ml of dry THF. To this solution 150mg of 3-nicotinoyl carbonyl chloride was added and 100mg of triethylamine was added dropwise. The resulting solution was stirred at room temperature for 30 minutes. The product was extracted with ethyl acetate and washed with water. After the solvent was distilled off, the residue was made into siliconPurification by gel column chromatography gave 90mg of compound 0080. The yield was 80%.1H NMR(100MHz，CD3OD)δ2.8(s，3H)，6.7(s，1H)，7.6(d，1H)，8.4(dd，1H)，8.7(s，1H)，8.9(d，1H)，9.2(s，1H).MS：292(M+1)。
Synthesis of compound 0110: 80mg of Compound 0079 were dissolved in 20ml of dry THF. To the solution was added 180mg of 3, 5-dimethoxy-4-isopropylbenzoyl chloride, and 100mg of triethylamine was added dropwise while stirring. The resulting solution was stirred at room temperature for 30 minutes. The product was extracted with ethyl acetate and washed with water. After evaporation of the solvent, the residue was dissolved in 5ml of dichloromethane and 100mg of BBr were added at-78 ℃3. The solution is stirred at room temperature overnight, then 100ml of water are added and the product is extracted with ethyl acetate and dried over sodium sulfate. After the solvent was distilled off, the residue was purified by silica gel column chromatography to obtain 50mg of compound 0110. The yield was 40%.1H NMR(100MHz，CDCl3) δ 1.24(d, 3H), 1.26(d, 3H), 3.1 (multiplet, 1H), 2.75(s, 3H), 6.6(s, 1H), 6.95(s, 2H), 8.3(s, 1H). 565(M + 1).
Synthesis of compound 0096: 100mg of compound 0093 was dissolved in 20ml of dry THF. To the solution was added 180mg of 3, 5-dimethoxy-4-isopropylbenzoyl chloride, and 100mg of triethylamine was added dropwise while stirring. The resulting solution was stirred at room temperature for 30 minutes. The product was extracted with ethyl acetate and washed with water. After the solvent was distilled off, the residue was dissolved in 5ml of methylene chloride, and 100mg of BBr was added to the solution at-78 ℃3. The solution is stirred at room temperature overnight, then 100ml of water are added and the product is extracted with ethyl acetate and dried over sodium sulfate. After the solvent was distilled off, the residue was purified by silica gel column chromatography to give 60mg of compound 0096. The yield was 43%.1H NMR(100MHz，CDCl3) δ 1.24(d, 6H), 1.26(d, 6H), 3.05 (multiplet, 2H), 6.88(s, 1H), 6.98(s, 2H), 7.3(s, 4H). 469(M + 1).
Synthesis of compound 0102: 100mg of compound 0021, 80mg of 3, 5-diacetoxy-4-isopropylbenzoic acid and 80mg ofDCC was added to 10ml of dry dichloromethane. The solution was stirred at room temperature for 2 hours. After purification by column chromatography, the resulting product was dissolved in 20ml of methanol. To this solution was added 2ml of an aqueous solution containing 50mg of sodium carbonate, and the resulting solution was stirred at 50 ℃ for 4 hours. The product was extracted with ethyl acetate, washed with water and purified by column to give 30mg of compound 0102. The yield was 16%.1H NMR(100MHz，CDCl3) δ 1.24(d, 6H), 1.26(d, 6H), 3.1 (multiplet, 1H), 3.75(s, 3H), 3.85(s, 3H), 6.6(s, 1H), 6.62 (multiplet, 2H), 6.95(s, 2H), 7.2(d, 1H), 8.3(s, 1H). MS: 487(M + 1).
Synthesis of compound 0107: 0107 was synthesized from 0104 by the same method as 0096. The yield was 52%.1H NMR(100MHz，CDCl3) δ 1.25(d, 3H), 1.27(d, 3H), 3.05 (multiplet, 1H), 5.02(s, 2H), 6.6(s, 1H), 6.95(s, 2H), 7.1(s, 5H), 8.4(s, 1H). MS: 441(M + 1).
Synthesis of compound 0113: the compound 0113 can be obtained by the reaction of 0104 and 2-thiophenecarbonyl chloride with the same synthetic method as 0023. The yield was 90%.1H NMR(100MHz，CDCl3)，δ5.05(s，2H)，6.85(s，1H)，7.2(dd，1H)，7.25(s，5H)，7.6(d，1H)，7.8(d，1H)，8.3(s，1H).MS：373(M+1)。
Synthesis of compound 0116: the compound 0116 was synthesized from 0104 by the same synthesis method as 0066. The yield was 50%.1H NMR(100MHz，CDCl3) δ 2.5 (multiplet, 4H), 3.6(s, 2H), 3.8 (multiplet, 4H), 4.9(s, 2H), 6.5(s, 1H), 7.12(s, 5H), 7.6(dd, 4H), 8.3(s, 1H) MS: 466(M + 1).
Synthesis of compound 0122: compound 0122 was synthesized from 0120 using the same synthesis method as 0066. The yield was 55%.1H NMR(100MHz，CDCl3) δ 2.5 (multiplet, 4H), 2.9(s, 3H), 3.6(s, 2H), 3.8 (multiplet, 4H), 3.85(s, 3H), 3.9(s, 3H), 6.6(s, 1H)6.7 (multiplet, 2H), 7.2(d, 1H), 7.7(dd, 4H), 8.4(s, 1H). MS: 526(M + 1).
Synthesis of compound 0125: 100mg of compound 0093 was dissolved in 40ml of dry THF. While stirring well, 120mg of 3-chloromethylbenzoyl chloride was added, followed by dropwise addition of 100mg of triethylamine over 2 minutes. The reaction was completed in 30 minutes. The product was extracted with ethyl acetate and washed with water. After the solvent was distilled off, the residue was dissolved in 2ml of morpholine. The solution was stirred at 60 ℃ for 2 hours and water was added. The product was extracted with ethyl acetate and washed with water. After the solvent was distilled off, the residue was purified by silica gel column chromatography to give 100mg of compound 0125. The yield was 60%.1H NMR(100MHz，CDCl3) δ 1.27(d, 6H), 2.6 (multiplet, 4H), 3 (multiplet, 1H), 3.65(s, 2H), 3.8 (multiplet, 4H), 6.85(s, 1H), 7.4(s, 4H), 7.4-8.0 (multiplet, 4H), 8.35(s, 1H). MS: 494(M + 1).
Synthesis of compound 0126: compound 0126 was synthesized from 0021 using the same synthetic method as compound 0125. The yield was 60%.1H NMR(100MHz，CDCl3) δ 2.55 (multiplet, 4H), 3.6(s, 2H), 3.8 (multiplet, 4H), 3.85(s, 3H), 3.9(s, 3H), 6.45(s, 1H), 6.6 (multiplet, 2H), 7.25(d, 1H), 7.4-8.0 (multiplet, 4H), 8.25(s, 1H). 512(M + 1).
Synthesis of compound 0128: compound 0128 was synthesized from 0093 using the same synthesis method as 0080. The yield was 80%.1H NMR(100MHz，CDCl3) δ 1.26(d, 6H), 3.0 (multiplet, 1H), 7.02(s, 1H), 7.35(s, 4H), 7.8(s, 1H), 8.7(s, 1H), 9.0(s, 1H), 9.2(s, H), 9.4(s, 1H). 396(M + 1).
Synthesis of Compound 0135: compound 0135 was synthesized from 0104 using the same synthesis method as 0080. The yield was 82%.1H NMR(100MHz，CDCl3)δ4.1(s，2H)，6.7(s，1H)，7.25(s，5H)，7.6(d，1H)，8.4(dd，1H)，8.7(s，1H)，8.9(d，1H)，9.2(s，1H).MS：299(M+1)。
Synthesis of compound 0136: 100mg of compound 0104 are dissolved in 40ml of dry THF. While stirring well, 120mg of 3-chloromethylbenzoyl chloride was added, followed by dropwise addition of 100mg of triethylamine over 2 minutes. The reaction was completed in 30 minutes. The product was extracted with ethyl acetate and washed with water. After the solvent was distilled off, the residue was dissolved in 2ml of N-methylpiperazine. The solution was stirred at 60 ℃ for 2 hours and water was added. The product was extracted with ethyl acetate and washed with water. After the solvent was distilled off, the product was purified by silica gel column chromatography to obtain 115mg of compound 0136. The yield was 70%.1H NMR(100MHz，CD3OD)δ4.1(s，2H)，6.7(s，1H)，7.25(s，5H)，7.6(d，1H)，8.4(dd，1H)，8.7(s，1H)，8.9(d，1H)，9.2(s，1H).MS：479(M+1)。
Synthesis of compound 0137: 100mg of compound 0104 are dissolved in 40ml of dry THF. While stirring well, 120mg of 3-chloromethylbenzoyl chloride was added, followed by dropwise addition of 100mg of triethylamine over 2 minutes. The reaction was completed in 30 minutes. The product was extracted with ethyl acetate and washed with water. After the solvent was distilled off, the residue was dissolved in 2ml of morpholine. The solution was stirred at 60 ℃ for 2 hours and water was added. The product was extracted with ethyl acetate and washed with water. After the solvent was distilled off, the residue was purified by silica gel column chromatography to give 130mg of compound 0137. The yield was 75%.1H NMR(100MHz，CD3OD) δ 2.4(s, 3H), 2.6(s, 8H), 3.6(s, 2H), 5.05(s, 2H), 6.5(s, 1H), 7.35(s, 5H), 7.4-8.0 (multiplet, 4H), 8.2(s, 1H). 466(M + 1).
Synthesis of compound 0211: 50mg (0.16mmol) of compound 0021 are dissolved in 20ml of dry THF. 50mg (0.2mmol) of 3, 5-bis (trifluoromethyl) -phenyl isocyanate are added with good stirring. The reaction was completed in 30 min and the product was purified by silica gel column to give 73mg (0.13mmol, 77%) of compound 0211.1H NMR(100MHz，CDCl3) δ 3.67(s, 3H), 3.75(s, 3H),), 6.4(s, 1H), 6.52 (multiplet, 3H),), 7.23(d, 1H), 7.47(s, 1H), 7.52(s, 2H), 8.74(s, 1H), 9.2(s, 1H). MS: 564(M + 1).
Synthesis of compound 0212: 50mg (0.16mmol) of compound 0021 are dissolved in 20ml of dry DMF. While stirring well, 55mg (0.2mmol) of p-toluenesulfonyl isocyanate was added. The reaction was complete in 30 min and the product was purified on a silica gel column to yield 60mg (0.12mmol, 75%) of compound 0212.1H NMR(100MHz，CDCl3)δ2.21(s，3H)，3.68(s，3H)，3.73(s，3H)，6.397(s，1H)，6.45(s，1H)，6.5(d，J＝9.2，1H)，6.97(d，J＝8，2H)，7.73(d，J＝8，2H)，7.95(d，J＝8，1H)，9.8(s，1H)，MS：506(M+1)。
Synthesis of compound 0213: 50mg (0.16mmol) of compound 0021 are dissolved in 20ml of dry DMF. While stirring well, 32mg (0.2mmol) of 3, 5-difluorophenylisocyanate was added. The reaction was complete in 30 min and the product was purified on a silica gel column to yield 45mg (0.10mmol, 60%) of compound 0213.1H NMR(100MHz，CDCl3)δ3.67(s，3H)，3.71(s，3H)，6.38(mult，2H)，6.44(s，1H)，6.66(mult，1H)，6.66(mult，1H)，7.14(d，1H)，7.60(mult，1H)，8.16(s，1H)，9.06(s，1H)，MS：464(M+1)。
Synthesis of compound 0214: 50mg (0.16mmol) of compound 0021 are dissolved in 20ml of dry DMF. While stirring well, 45mg (0.2mmol) of 3, 5-difluorophenylisocyanate isothiocyanate was added. The reaction was complete in 30 min and the product was purified on a silica gel column to yield 40mg (0.08mmol, 50%) of compound 0212.1H MR(100MHz，CDCl3)δ3.72(s，3H)，3.752(s，3H)，6.37(s，1H)，6.42(d，1H)，6.72(mult，2H)，7.02(mult，1H)，7.16(d，1H)，7.53(mult，1H)，7.45(mult，1H)，8.12(s，1H)，9.35(s，1H)，MS：480(M+1)。
Synthesis of compound 0215: 50mg (0.16mmol) of compound 0021 are dissolved in 20ml of dry DMF. While stirring well, 26mg (0.2mmol) of methanesulfonyl chloride was added. The reaction was complete in 30 min and the product was purified on a silica gel column to yield 50mg (0.13mmol, 70%) of compound 0215.1H NMR(100MHz，CDCl3)δ2.86(s，3H)，3.76(s，3H)，3.79(s，3H)，6.6(s，1H)，6.4-7.3 (multiplet, 3H), 9.4(s, 1H).
Synthesis of compound 0227: intermediate 0021(300mg, 0.9mmol) was dissolved in tetrahydrofuran (20 ml). Triethylamine (200mg, 2mmol) was added thereto, and phenyl chloroformate (281mg, 1.8mmol) was added dropwise to the resulting mixture at-20 ℃ and stirred for 2 hours. The solvent was distilled off under vacuum. Dichloromethane (20ml) was added and washed with water (20ml × 3). The organic phase was dried over anhydrous sodium sulfate. The solvent was distilled off under vacuum. Purification by chloroform/methanol column gave 0227(273mg)1H-NMR(DMSO-d6)：3.75(38，s)，3.84(38，s)，6.63-6.83(3H，m)，7.20-7.46(6H，m)，10.10(1H，S).m/z：428.05.m.p 204℃-206℃。
Synthesis of compound 0228: intermediate 0021(300mg, 0.9mmol) was dissolved in tetrahydrofuran (20 ml). Triethylamine (300mg, 3mmol) was added, and isobutyl chloroformate (365mg, 2.7mmol) was added dropwise to the resulting mixture at 0 ℃ and stirred for 1.5 hours. The solvent was distilled off under vacuum. Dichloromethane (20ml) was added and washed with water (20ml × 3). The organic phase was dried over anhydrous sodium sulfate. The solvent was distilled off under vacuum. Purification by chloroform/methanol column afforded product 0228(248 mg). ' H-NMR (DMSO-d 6): 0.92(6H, d), 1.91(1H, m), 3.74(3H, s), 3.82(3H, s), 3.89(2H, d), 6.60-6.75(3H, m), 7.19(1H, d), 9.35(1H, s). m/z: 408.08, respectively; m.p. 226 ℃ -227 ℃.
Synthesis of compound 0229: intermediate 0021(300mg, 0.9mmol) was dissolved in tetrahydrofuran (20 ml). Triethylamine (181mg, 1.8mmol) was added, and benzyl chloroformate (306mg, 1.8mmol) was added dropwise at 20 ℃ and stirred for 1 hour. The solvent was distilled off under vacuum. Dichloromethane (20ml) was added and washed with water (20ml × 3). The organic phase was dried over anhydrous sodium sulfate. The solvent was distilled off under vacuum. Purification by chloroform/methanol column gave product 0229(260 mg). ' H-NMR (DMSO-d 6): 3.74(3H, s), 3.82(3H, s), 3.89(2H, s)6.60-6.75(3H, m), 7.10-7.90(6H, m), 9.35(1H, s). m/z: 442.07, respectively; m.p. 165-166 ℃.
Synthesis of compound 0230: intermediate 0021(300mg, 0.9mmol) was dissolved in tetrahydrofuran (20 ml). Triethylamine (181mg, 1.8mmol) was added, and ethyl chloroformate (97mg, 0.9mmol) was added dropwise at 50 ℃ and stirred for 1 hour. The solvent was distilled off under vacuum. Dichloromethane (20ml) was added and washed with water (20ml × 3). The organic phase was dried over anhydrous sodium sulfate. The solvent was distilled off under vacuum. Purification by chloroform/methanol column gave 0230(228 mg). ' H-NMR (DMSO-d 6): 1.25(3H, m), 3.74(3H, s), 3.84(3H, s), 4.17(2H, m), 6.62-6.76(3H, m), 7.72(1H, d), 9.31(1H, s). m/z: 380.05, respectively; m.p. 208-210 ℃.
Synthesis of compound 0231: intermediate 0021(500mg, 1.5mmol) was dissolved in tetrahydrofuran (20 ml). Triethylamine (272mg, 2.7mmol) was added, and methyl chloroformate (256mg, 2.7mmol) was added dropwise at 30 ℃ and stirred for 30 minutes. The solvent was distilled off under vacuum. Dichloromethane (30ml) was added and washed with water (20ml × 3). The organic phase was dried over anhydrous sodium sulfate. The solvent was distilled off under vacuum. Purification by chloroform/methanol column gave product 0231(380 mg). ' H-NMR (DMSO-d 6): 3.68(3H, s), 3.72(3H, s), 5,82(3H, s), 6.37-6.80(3H, m), 7.23(1H, d), 9.4(1H, s). m/z: 366.03, respectively; m.p. 186 ℃ -188 ℃.
Synthesis of compound 0232: intermediate 0021(400mg, 1.5mmol) was dissolved in tetrahydrofuran (20 ml). Triphosgene (234mg, 0.8mmol) was added and triethylamine (272mg, 2.7mmol) was added dropwise at room temperature and stirred for 1 hour. Distillation under vacuum removed 80% of the solvent. 1ml of hydrochloric acid was added and stirred for 5 minutes. The residual solvent was distilled. Dichloromethane (20ml) was added and washed with water (20ml × 3). The organic phase was dried over anhydrous sodium sulfate. The solvent was distilled off under vacuum. Purification by chloroform/methanol column gave product 0232(240 mg). ' H-NMR (DMSO-d 6): 3.73(3H, s), 3.82(3H, s)6.22-6.73 (tetrahedron, m), 7.18(1H, d), 8.31(1H, s), m/z: 351.03, respectively; m.p245-248 ℃.
Synthesis of compound 0233: isopropanol (36mg, 0.6mmol), triethylamine (61mg, 0.6mmol) were dissolved in 20ml dichloromethane. 5ml of dichloromethane containing triphosgene (180ml, 0.6mmol) were added dropwise at 0 ℃. The reaction was allowed to warm to room temperature and stirred for 30 minutes. Washed with water (20 ml. times.3). The organic phase was dried over anhydrous sodium sulfate. The solvent was distilled off under vacuum. Dichloromethane (20ml) and intermediate 0021(300mg, 0.9mmol) were added. Stirred at room temperature for 2 hours. Washed with water (20 ml. times.3). The organic phase was dried over anhydrous sodium sulfate. The solvent was distilled off under vacuum. Purification by chloroform/methanol column gave product 0233(260 mg). ' H-NMR (DMSO-d 6): 1.24(6H, d), 3.72(3H, s), 3.81(3H, s), 4.87(1H, s), 6.59-7.18(4H, m), 9.14(1H, s). m/z: 394.09, respectively; m.p. 230-232 ℃.
Synthesis of compound 0234: intermediate 0021(300mg, 0.9mmol) was dissolved in chloroform (20 ml). Triethylamine (181mg, 1.8mmol) was added, and allyl chloroformate (216mg, 1.8mmol) was added dropwise at room temperature, followed by stirring for 1.5 hours. Washed with water (20 ml. times.3). The organic phase was dried over anhydrous sodium sulfate. The solvent was distilled off under vacuum. Purification by chloroform/methanol column gave product 0234(290 mg). ' H-NMR (DMSO-d 6): 3.73(3H, s), 3.81(3H, s), 4.61(2H, d), 5.23(1H, dd), 5.39(1H, dd), 5.95(2H, m), 6.60-7.19(4H, m), 9.48(1H, s). m/z: 392.06, respectively; m.p210 ℃ -212 ℃.
Synthesis of compound 0235: n-propanol (36mg, 0.6mmol) and triethylamine (61mg, 0.6mmol) were dissolved in tetrahydrofuran (20 ml). Tetrahydrofuran (5ml) containing triphosgene (180ml, 0.6mmol) was added dropwise at 0 ℃. The reaction was allowed to warm to room temperature and stirred for 30 minutes. Dichloromethane (20ml) and intermediate 0021(300mg, 0.9mmol) were added. Stirred at room temperature for 1.5 hours. Distillation to remove residual solvent. Dichloromethane was added and washed with water (20ml × 3). The organic phase was dried over anhydrous sodium sulfate. The solvent was distilled off under vacuum. Purification by chloroform/methanol column gave product 0235(285 mg). ' H-NMR (DMSO-d 6): 0.96(3H, t), 1.61(2H, m), 3.18(2H, t), 3.78(3H, s), 3.84(3H, s), 6.28-7.50(4H, m), 9.31(1H, s). m/z: 394.06, respectively; m.p. 202-204 ℃.
Synthesis of compound 0236: 3-methoxyphenol (74.4mg, 0.6mmol) and triethylamine (61mg, 0.6mmol) were dissolved in tetrahydrofuran (20 ml). Tetrahydrofuran (5ml) containing triphosgene (180ml, 0.6mmol) was added dropwise at 0 ℃. The mixture was stirred at 40 ℃ for 1.5 hours. Intermediate 0021(300mg, 0.9mmol) was added. Stirred at room temperature for 3.5 hours. Distillation to remove residual solvent. Dichloromethane (20ml) was added and washed with water (20ml × 3). The organic phase was dried over anhydrous sodium sulfate. The solvent was distilled off under vacuum. Purification by chloroform/methanol column gave product 0236(180 mg). ' H-NMR (DMSO-d 6): 3.73(3H, s), 3.74(3H, s), 3.83(3H, s), 6.62-7.23(8H, m), 9.99(1H, s). m/z: 458.06; m.p. 204 ℃ -207 ℃.
Synthesis of compound 0237: n-pentanol (53mg, 0.6mmol) and triethylamine (61mg, 0.6mmol) were dissolved in tetrahydrofuran (20 ml). Tetrahydrofuran (5ml) containing triphosgene (180ml, 0.6mmol) was added dropwise at 0 ℃. The reaction was allowed to warm to room temperature and stirred for 1 hour. Intermediate 0021(300mg, 0.9mmol) was added. Stirred at room temperature for 2.5 hours. Distillation to remove residual solvent. Dichloromethane (20ml) was added and washed with water (20ml × 3). The organic phase was dried over anhydrous sodium sulfate. The solvent was distilled off under vacuum. Purification by chloroform/methanol column gave product 0237(240 mg). ' H-NMR (DMSO-d 6): 0.89(3H, t), 1.34(4H, m), 1.61(2H, t), 3.74(3H, s), 3.83(3H, s), 4.09(2H, t), 6.61-7.21(4H, m), 9.33(1H, s). m/z: 422.10, respectively; m.p. 178 ℃ -179 ℃.
Synthesis of compound 0238: tetrahydrofurfuryl benzoate (61mg, 0.6mmol) and triethylamine (61mg, 0.6mmol) were dissolved in tetrahydrofuran (20 ml). Tetrahydrofuran (5ml) containing triphosgene (180ml, 0.6mmol) was added dropwise at 0 ℃. The reaction was allowed to warm to room temperature and stirred for 30 minutes. Intermediate 0021(300mg, 0.9mmol) was added. Stirred at room temperature for 2 hours. Distillation to remove residual solvent. Dichloromethane (20ml) was added and washed with water (20ml × 3). The organic phase was dried over anhydrous sodium sulfate. The solvent was distilled off under vacuum. Purification by chloroform/methanol column gave 0238(243 mg). ' H-NMR (DMSO-d 6): 1.95(4H, m), 3.77(3H, s), 3.87(3H, s), 3.91(1H, m), 3.93(2H, d), 4.25(2H, t), 6.28-6.58(3H, m), 6.97(1H, s), 7.18(1H, d). m/z: 436.08; m.p. 156-158 ℃.
Synthesis of compound 0239: n-butanol (44mg, 0.6mmol) and triethylamine (61mg, 0.6mmol) were dissolved in tetrahydrofuran (20 ml). Tetrahydrofuran (5ml) containing triphosgene (180ml, 0.6mmol) was added dropwise at 0 ℃. The reaction was allowed to warm to room temperature and stirred for 1 hour. Intermediate 0021(300mg, 0.9mmol) was added. Stirred at room temperature for 2 hours. Distillation to remove residual solvent. Dichloromethane (20ml) was added and washed with water (20ml × 3). The organic phase was dried over anhydrous sodium sulfate. The solvent was distilled off under vacuum. Purification by chloroform/methanol column gave product 0239(280 mg). ' H-NMR (DMSO-d 6): 0.91(3H, t), 1.38(2H, m), 1.59(2H, m), 3.73(3H, s), 3.82(3H, s), 4.11(2H, t), 6.61-7.20(4H, m), 9.31(1H, s). m/z: 408.08, respectively; m.p. 177 ℃ -178 ℃.
Synthesis of compound 0240: cyclopentanol (78mg, 0.9mmol) and triethylamine (61mg, 0.6mmol) were dissolved in tetrahydrofuran (20 ml). Tetrahydrofuran (5ml) containing triphosgene (270ml, 0.9mmol) was added dropwise at 0 ℃. The reaction was allowed to warm to room temperature and stirred for 1.5 hours. Intermediate 0021(500mg, 1.5mmol) was added. Stirred at room temperature for 3 hours. Distillation to remove residual solvent. Dichloromethane (20ml) was added and washed with water (20ml × 3). The organic phase was dried over anhydrous sodium sulfate. The solvent was distilled off under vacuum. Purification by chloroform/methanol column gave the product 0240(300 mg). ' H-NMR (DMSO-d 6): 1.56(2H, s), 1.69(2H, s), 1.85(2H, t), 3.72(3H, s), 3.82(3H, s), 5.07(1H, s), 6.61-7.19(4H, m), 9.16(1H, s). m/z: 420.08, respectively; m.p. 228-230 ℃.
Synthesis of compound 0241: 1-heptanol (70mg, 0.6mmol) and triethylamine (61mg, 0.6mmol) were dissolved in tetrahydrofuran (20 ml). Tetrahydrofuran (5ml) containing triphosgene (180ml, 0.6mmol) was added dropwise at 0 ℃. The reaction was allowed to warm to room temperature and stirred for 1.5 hours. Intermediate 0021(300mg, 0.9mmol) was added. Stirred at room temperature for 2 hours. Distillation to remove residual solvent. Dichloromethane (20ml) was added and washed with water (20ml × 3). The organic phase was dried over anhydrous sodium sulfate. The solvent was distilled off under vacuum. Purification by chloroform/methanol column afforded 0241(220 mg). ' H-NMR (DMSO-d 6): 0.87(3H, t), 1.31(8H, t), 1,59(2H, t), 3.72(3H, s), 3.82(3H, s), 4.09(2H, t), 6.61-7.20(4H, m), 9.31(1H, s). m/z: 450.13, respectively; m.p. 144-146 ℃.
Synthesis of compound 0242: chloroethanol (48mg, 0.6mmol), triethylamine (61mg, 0.6mmol) were dissolved in tetrahydrofuran (20 ml). Tetrahydrofuran (5ml) containing triphosgene (180ml, 0.6mmol) was added dropwise at 0 ℃. The reaction was allowed to warm to room temperature and stirred for 30 minutes. Intermediate 0021(300mg, 0.9mmol) was added. Stirred at room temperature for 1 hour. Distillation to remove residual solvent. Dichloromethane (20ml) was added and washed with water (20ml × 3). The organic phase was dried over anhydrous sodium sulfate. The solvent was distilled off under vacuum. Purification by chloroform/methanol column gave the product 0242(220 mg). ' H-NMR (DMSO-d 6): 3.72(3H, s), 3.82(3H, s), 4.37(2H, t), 6.61-7.21(4H, m), 9.61(1H, s). m/z: 414.01, respectively; m.p. 211 ℃ -214 ℃.
Synthesis of compound 0243: 4-chlorophenol (77mg, 0.6mmol) and triethylamine (61mg, 0.6mmol) were dissolved in tetrahydrofuran (20 ml). Tetrahydrofuran (5ml) containing triphosgene (180ml, 0.6mmol) was added dropwise at 0 ℃. Stirred at 40 ℃ for 30 minutes. Intermediate 0021(300mg, 0.9mmol) was added. Stirred at room temperature for 3.5 hours. Distillation to remove residual solvent. Dichloromethane (20ml) was added and washed with water (20ml × 3). The organic phase was dried over anhydrous sodium sulfate. The solvent was distilled off under vacuum. Purification by chloroform/methanol column gave 0243(200 mg). ' H-NMR (DMSO-d 6): 3.75(3H, s), 3.84(3H, s), 6.48-7.70(8H, m), 9.53(1H, s). m/z: 462.01, respectively; m.p. 233 deg.C-236 deg.C.
Synthesis of compound 0244: 4-Methylphenol (65mg, 0.6mmol) and triethylamine (61mg, 0.6mmol) were dissolved in tetrahydrofuran (20 ml). Tetrahydrofuran (5ml) containing triphosgene (180ml, 0.6mmol) was added dropwise at 0 ℃. Stirred at 40 ℃ for 1 hour. Intermediate 0021(300mg, 0.9mmol) was added. Stirred at room temperature for 2 hours. Distillation to remove residual solvent. Dichloromethane (20ml) was added and washed with water (20ml × 3). The organic phase was dried over anhydrous sodium sulfate. The solvent was distilled off under vacuum. Purification by chloroform/methanol column afforded 0244(210 mg). ' H-NMR (DMSO-d 6): 2.20(3H, s), 3.75(3H, s), 3.84(3H, s), 6.61-7.77(8H, m), 9.43(1H, s). m/z: 442.04, respectively; m.p260-262 ℃.
Synthesis of compound 0245: 2-Furanylmethanol (59mg, 0.6mmol) and pyridine (56mg, 0.7mmol) were dissolved in tetrahydrofuran (20 ml). Tetrahydrofuran (5ml) containing triphosgene (180ml, 0.6mmol) was added dropwise at 0 ℃. The reaction was allowed to warm to room temperature and stirred for 30 minutes. Intermediate 0021(300mg, 0.9mmol) was added. Stirred at room temperature for 1 hour. Distillation to remove residual solvent. Dichloromethane (20ml) was added and washed with water (20ml × 3). The organic phase was dried over anhydrous sodium sulfate. The solvent was distilled off under vacuum. Purification through a chloroform/methanol column afforded the product 0245(235 mg).
Synthesis of compound 0246: alpha-phenylethyl alcohol (73mg, 0.6mmol) and triethylamine (61mg, 0.6mmol) were dissolved in 20ml of tetrahydrofuran. Tetrahydrofuran (5ml) containing triphosgene (180ml, 0.6mmol) was added dropwise at 0 ℃. The reaction was allowed to warm to room temperature and stirred for 1.5 hours. Intermediate 0021(300mg, 0.9mmol) was added. Stirred at 50 ℃ for 1 hour. Distillation to remove residual solvent. Dichloromethane (20ml) was added and washed with water (20ml × 3). The organic phase was dried over anhydrous sodium sulfate. The solvent was distilled off under vacuum. Purification by chloroform/methanol column afforded 0246(200 mg). ' H-NMR (DMSO-d 6): 2.94(2H, t), 3.73(3H, s), 3.83(3H, s), 4.30(2H, t), 6.61-7.31(9H, m), 9.41(1H, s). m/z: 456.08, respectively; m.p. 200-203 ℃.
Synthesis of compound 0247: 2-Thienylmethanol (68mg, 0.6mmol) and triethylamine (61mg, 0.6mmol) were dissolved in tetrahydrofuran (20 ml). Tetrahydrofuran (5ml) containing triphosgene (180ml, 0.6mmol) was added dropwise at-20 ℃. The reaction was allowed to warm to room temperature and stirred for 1 hour. Intermediate 0021(300mg, 0.9mmol) was added. Stirred at room temperature for 1 hour. Distillation to remove residual solvent. Dichloromethane (20ml) was added and washed with water (20ml × 3). The organic phase was dried over anhydrous sodium sulfate. The solvent was distilled off under vacuum. Purification through a chloroform/methanol column afforded 0247(225 mg). ' H-NMR (DMSO-d 6): 3.73(3H, s), 3.82(3H, s), 5.34(2H, s), 6.61-7.57(7H, m), 9.56(1H, s). m/z: 448.01, respectively; m.p. 225-226 deg.C.
Synthesis of compound 0248: 3-hydroxypyridine (114mg, 1.2mmol) and triethylamine (120mg, 1.2mmol) were dissolved in tetrahydrofuran (30 ml). Tetrahydrofuran (5ml) containing triphosgene (360ml, 1.2mmol) was added dropwise at-15 ℃. Stirred at 40 ℃ for 1.5 hours. Intermediate 0021(600mg, 1.8mmol) was added. Stirred at 50 ℃ for 3 hours. Distillation to remove residual solvent. Dichloromethane (40ml) was added and washed with water (20 ml. times.3). The organic phase was dried over anhydrous sodium sulfate. The solvent was distilled off under vacuum. Purification by chloroform/methanol column afforded 0248(300 mg). ' H-NMR (DMSO-d 6): 3.73(3H, s), 3.82(3H, s), 6.23-7.42(8H, m), 10.23(1H, s). m/z: 429.05, respectively; m.p. 176-178 ℃.
Synthesis of compound 0249: morpholine (52mg, 0.6mmol) and triethylamine (61mg, 0.6mmol) were dissolved in tetrahydrofuran (20 ml). Tetrahydrofuran (5ml) containing triphosgene (180ml, 0.6mmol) was added dropwise at 0 ℃. The reaction was allowed to warm to room temperature and stirred for 1 hour. Intermediate 0021(300mg, 0.9mmol) was added. Stirred at room temperature for 1 hour. Distillation to remove residual solvent. Dichloromethane (20ml) was added and washed with water (20ml × 3). The organic phase was dried over anhydrous sodium sulfate. The solvent was distilled off under vacuum. Purification by chloroform/methanol column afforded 0249(238 mg). ' H-NMR (DMSO-d 6): 3.43(4H, t), 3.58(4H, t), 3.72(3H, s), 3.82(3H, s), 6.60-7.20(4.H, m), 8.23(1H, s). m/z: 421.08, respectively; m.p. 226 ℃ -227 ℃.
Synthesis of compound 0250: triphosgene (180mg, 0.6mmol) was dissolved in tetrahydrofuran (10 ml). Cooled to 0 ℃. A solution of intermediate 0021(300mg, 0.9mmol) and triethylamine (200mg, 2mmol) in tetrahydrofuran (20ml) was added dropwise. Stirred at 20 ℃ for 1 hour. Benzylamine (147mg, 1.4mmol) was added and stirred at 20 ℃ for 1 hour. Distillation to remove residual solvent. Dichloromethane (20ml) was added and washed with water (20ml × 3). The organic phase was dried over anhydrous sodium sulfate. The solvent was distilled off under vacuum. Purification by chloroform/methanol column afforded the product 0250(320 mg). ' H-NMR (DMSO-d 6): 3.72(3H, s), 3.82(3H, s), 4.31(2H, s), 6.61-7.37(9H, m), 8.39(1H, s). m/z: 441.08, respectively; m.p. 249-250 ℃.
Synthesis of compound 0251: triphosgene (180mg, 0.6mmol) was dissolved in tetrahydrofuran (10 ml). Cooled to 0 ℃. A solution of intermediate 0021(300mg, 0.9mmol) and triethylamine (200mg, 2mmol) in tetrahydrofuran (20ml) was added dropwise. The reaction was allowed to warm to room temperature and stirred for 1 hour. Butylamine (88mg, 1.4mmol) was added and stirred at room temperature for 1 hour. Distillation to remove residual solvent. Dichloromethane (20ml) was added and washed with water (20ml × 3). The organic phase was dried over anhydrous sodium sulfate. The solvent was distilled off under vacuum. Purification by chloroform/methanol column afforded product 0251(270 mg). ' H-NMR (DMSO-d 6): 0.91(3H, t), 1.38(4H, m), 3.08(2H, t), 3.74(3H, s), 3.83(3H, s), 6.61-7.21(4H, m), 8.22(1H, s). m/z: 407.10, respectively; m.p. 247 deg.C-249 deg.C.
Synthesis of compound 0252: triphosgene (180mg, 0.6mmol) was dissolved in tetrahydrofuran (10 ml). Cooled to 0 ℃. A solution of intermediate 0021(300mg, 0.9mmol) and triethylamine (200mg, 2mmol) in tetrahydrofuran (20ml) was added dropwise. The reaction was allowed to warm to 50 ℃ and stirred for 1 hour. Aniline (130mg, 1.4mmol) was added and stirred at 50 ℃ for 1 hour. Distillation to remove residual solvent. Dichloromethane (20ml) was added and washed with water (20ml × 3). The organic phase was dried over anhydrous sodium sulfate. The solvent was distilled off under vacuum. Purification by chloroform/methanol column afforded product 0252(300 mg). ' H-NMR (DMSO-d 6): 3.74(3H, s), 3.83(3H, s), 6.70-7.50(9H, m), 8.58(1H, s), 9.18(1H, s). m/z: 427.10, respectively; m.p. 220-222 ℃.
Synthesis of compound 0253: in tetrahydrofuran (30ml) were dissolved ethanethiol (37mg, 0.6mmol) and triethylamine (61mg, 0.6 mmol). A solution of triphosgene (180mg, 0.6mmol) in tetrahydrofuran (5ml) was added dropwise at-15 ℃. The reaction was allowed to warm to room temperature and stirred for 30 minutes. Intermediate 0021(300mg, 0.9mmol) was added. Stirred at 50 ℃ for 1 hour. Distillation to remove residual solvent. Dichloromethane (20ml) was added and washed with water (20ml × 3). The organic phase was dried over anhydrous sodium sulfate. The solvent was distilled off under vacuum. Purification by chloroform/methanol column afforded product 0253(220 mg). ' H-NMR (DMSO-d 6): 1.23(3H, t), 2.87(2H, m), 3.74(3H, s), 3.84(3H, s), 6.62-7.72(4H, m), 10.39(1H, s). m/z: 396.01, respectively; m.p. 200-202 deg.C.
Synthesis of compound 0254: intermediate 0021(300mg, 0.9mmol) was dissolved in tetrahydrofuran (20 ml). Triethylamine (181mg, 1.8mmol) was added. Ethyl chloroformate (194mg, 1.8mmol) was added dropwise. Stirred at room temperature for 1 hour. Distillation to remove residual solvent. Dichloromethane (20ml) was added and washed with water (20ml × 3). The organic phase was dried over anhydrous sodium sulfate. The solvent was distilled off under vacuum. Purification by chloroform/methanol column afforded product 0254(228 mg).
Synthesis of compound 0255: intermediate 0021(300mg, 0.9mmol) was dissolved in tetrahydrofuran (20 ml). Triethylamine (181mg, 1.8mmol) was added. Phenyl chloroformate (281mg, 1.8mmol) was added dropwise. Stirred at room temperature for 1 hour. Distillation to remove residual solvent. Dichloromethane (20ml) was added and washed with water (20ml × 3). The organic phase was dried over anhydrous sodium sulfate. The solvent was distilled off under vacuum. Purification by chloroform/methanol column afforded the product 0255(273 mg).
Synthesis of compound 0256: intermediate 0021(300mg, 0.9mmol) was dissolved in chloroform (20 ml). Triethylamine (181mg, 1.8mmol) was added. Propiolic chloroformate (216mg, 1.8mmol) was added dropwise. Stirred at room temperature for 1.5 hours. Washed with water (20 ml. times.3). The organic phase was dried over anhydrous sodium sulfate. The solvent was distilled off under vacuum. Purification by chloroform/methanol column gave the product 0256(290 mg).
Synthesis of compound 0257: triphosgene (180mg, 0.6mmol) was dissolved in tetrahydrofuran (10 ml). Cooled to 0 ℃. A solution of intermediate 0021(300mg, 0.9mmol) and triethylamine (200mg, 2mmol) in tetrahydrofuran (20ml) was added dropwise. The reaction was allowed to warm to room temperature and stirred for 1 hour. N, N-dimethylaminoethanol (88mg, 1.4mmol) was added and stirred at room temperature for 1 hour. Distillation to remove residual solvent. Dichloromethane (20ml) was added and washed with water (20ml × 3). The organic phase was dried over anhydrous sodium sulfate. The solvent was distilled off under vacuum. Purification by chloroform/methanol column afforded product 0257(270 mg).
Conclusion
Although various embodiments of the present invention are disclosed herein, some adaptations and modifications in accordance with the common general knowledge of those skilled in the art are also included within the scope of the present invention. Such modifications include the substitution of known equivalents for any aspect of the invention to achieve the same result in substantially the same way. Numerical ranges also include the endpoints of the defined ranges.
Claims (9)
1. A compound selected from the group consisting of:
a)1- (3, 5-bis (trifluoromethyl) -phenyl) -3- [4- (2, 4-dimethoxy-phenyl) -5-oxo-4, 5-dihydro- [1, 2] dithioleno [4, 3-b ] pyrrol-6-yl ] -urea,
b)1- (toluene-4-sulfonyl) -3- [4- (2, 4-dimethoxy-phenyl) -5-oxo-4, 5-dihydro- [1, 2] dithioleno [4, 3-b ] pyrrol-6-yl ] -urea,
c)1- (2, 4-difluoro-phenyl) -3- [4- (2, 4-dimethoxy-phenyl) -5-oxo-4, 5-dihydro- [1, 2] dithio-cyclopenta [4, 3-b ] pyrrol-6-yl ] -urea,
s) [4- (2, 4-dimethoxy-phenyl) -5-oxo-4, 5-dihydro- [1, 2] dithio-cyclopenta [4, 3-b ] pyrrol-6-yl ] -carbamic acid 2-chloro-phenyl ester,
z)3- [4- (2, 4-dimethoxy-phenyl) -5-oxo-4, 5-dihydro- [1, 2] dithio-cyclopenta [4, 3-b ] pyrrol-6-yl ] -1, 1-bis (2-hydroxy-ethyl) -urea,
ee)1- (3, 5-difluoro-phenyl) -3- [4- (2, 4-dimethoxy-phenyl) -5-oxo-4, 5-dihydro- [1, 2] dithio-cyclopenta [4, 3-b ] pyrrol-6-yl ] -thiourea,
ff) N- [4- (2, 4-dimethoxy-phenyl) -5-oxo-4, 5-dihydro- [1, 2] dithio-cyclopenta [4, 3-b ] pyrrol-6-yl ] -methanesulfonamide.
2. A pharmaceutical composition comprising a compound of claim 1 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier or diluent.
3. Use of a compound according to claim 1 in the manufacture of a medicament.
4. The use according to claim 3, wherein the medicament is for increasing leukocytes for the prophylaxis or treatment of viral, bacterial and/or fungal infections or hematological diseases.
5. The use according to claim 4, wherein the medicament is for increasing leukocytes for the prevention or treatment of viral, bacterial and/or fungal infections.
6. The use according to claim 4, wherein the medicament is for increasing leukocytes for preventing or treating neutropenia in a hematological disorder.
7. The use of a compound of formula I in the manufacture of a medicament for increasing leukocytes,
wherein:
(a) a is carbon (C), B is oxygen (O) and n is 1, R1、R2And R3Independently selected from the group consisting of: hydrogen, alkyl (C1-C18), aralkyl (C7-C18), cycloalkyl (C3-C18), aryl (C6-C18), and heterocycle (C3-C18).
8. The use according to claim 7, wherein the medicament is for increasing leukocytes for the prevention or treatment of neutropenia.
9. The use of claim 8, wherein the compound is selected from the group consisting of:
a) n- [4- (2, 4-dimethoxy-phenyl) -5-oxo-4, 5-dihydro- [1, 2] dithioleno [4, 3-b ] pyrrol-6-yl ] -3, 5-bis (trifluoromethyl) -benzamide;
b) n- [4- (4-isopropyl-phenyl) -5-oxo-4, 5-dihydro- [1, 2] dithioleno [4, 3-b ] pyrrol-6-yl ] -3, 5-bis (trifluoromethyl) -benzamide.
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US84791906P | 2006-09-29 | 2006-09-29 | |
| US60/847,919 | 2006-09-29 | ||
| PCT/IB2007/053641 WO2008038175A2 (en) | 2006-09-29 | 2007-09-10 | Dithiolopyrrolones compounds and their therapeutic applications |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| HK1136819A1 HK1136819A1 (en) | 2010-07-09 |
| HK1136819B true HK1136819B (en) | 2012-08-31 |
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