Caffeic acid derivatives for the treatment of hyperproliferative diseases

文档序号：1327405 发布日期：2020-07-14 浏览：21次中文

阅读说明：本技术 用于治疗过度增生性疾病的咖啡酸衍生物 (Caffeic acid derivatives for the treatment of hyperproliferative diseases ) 是由 W·普里贝 S·斯科拉 I·福克特 R·齐林斯基 A·贾古玛 R·维努戈帕尔于 2018-11-09 设计创作，主要内容包括：一方面,本发明提供了下式的咖啡酸衍生物：<Image he="137" wi="700" file="DDA0002518686630000011.GIF" imgContent="drawing" imgFormat="GIF" orientation="portrait" inline="no"></Image>其中变量如本文所定义。在另一方面,本公开提供了使用本文公开的化合物的药物组合物和方法,包括用于治疗癌症。(In one aspect, the present invention provides caffeic acid derivatives of the formula:)

1. A compound of the formula:

wherein:

A₁and A₂Each independently is-CH or-N, with the proviso that A is₁And A₂Not all are-N ═ N;

m is 0 to 6;

n is 0, 1 or 2;

x is O, S or NR₄；

Wherein R is₄Is hydrogen, alkyl (_C1-6) Or substituted alkyl_(C1-6)；

R₁And R₁' each is independently alkyl: (_C1-8) Cycloalkyl group (a)_C3-8) -alkanediyl (C)_C1-C8) -cycloalkyl group (_C3-8) Alkenyl group (a)_C2-8) Alkynyl, alkynyl (c)_C2-8) Aryl group (a)_C6-12) Aralkyl group (a)_C7-12) Or a substituted form of any of these groups, or

R₁And R₁' taken together and are alkanediyl(s) ((s))_C2-8) Or substituted alkanediyl (a)_C2-8)；

R₂Is heterocycloalkyl (_C2-12) Dialkylamino group (b), (c) and (d)_C2-8) Heteroaryl group (a)_C1-8) Alkylamino group(s) (ii)_C1-8) Arylamino group (a)_C6-8) Alkoxy group (a)_C1-8) Aryloxy group (a)_C6-12) Or substituted versions of any of these groups; and

R₃is halogen, hydrogen, hydroxy, amino, cyano or mercapto;

or a pharmaceutically acceptable salt thereof.

2. The compound of claim 1, further defined as:

wherein:

m' is 1 to 4;

n is 0 or 1;

R₁and R₁' each is independently alkyl: (_C1-8) Cycloalkyl group (a)_C3-8) -alkanediyl (C)_C1-C8) -cycloalkyl group (_C3-8) Alkenyl group (a)_C2-8) Alkynyl, alkynyl (c)_C2-8) Aryl group (a)_C6-12) Aralkyl group (a)_C7-12) Or substituted versions of any of these groups;

R₂is heterocycloalkyl (_C2-12) Dialkylamino group (b), (c) and (d)_C2-8) Heteroaryl group (a)_C1-8) Alkylamino group(s) (ii)_C1-8) Arylamino group (a)_C6-8) Alkoxy group (a)_C1-8) Aryloxy group (a)_C6-12) Or substituted versions of any of these groups; and

R₃is halogen, hydrogen, hydroxy, amino, cyano or mercapto;

or a pharmaceutically acceptable salt thereof.

3. The compound of claim 1, further defined as:

wherein:

m is 1 to 4;

n is 0 or 1;

R₃is halogen, hydrogen, hydroxy, amino, cyano or mercapto;

or a pharmaceutically acceptable salt thereof.

4. The compound of claim 1, wherein m is 0-2.

5. The compound of claim 4, wherein m is 0 or 1.

6. The compound of claim 5, wherein m is 0.

7. The compound of claim 5, wherein m is 1.

8. The compound of claim 4, wherein m is 2.

9. A compound according to claim 2 or claim 3, wherein m' is 1-3.

10. The compound of claim 9, wherein m' is 1 or 2.

11. The compound of claim 10, wherein m' is 1.

12. The compound of claim 10, wherein m' is 2.

13. The compound of claim 9, wherein m' is 3.

14. A compound according to any one of claims 1 to 13, wherein n is 0.

15. A compound according to any one of claims 1 to 13, wherein n is 1.

16. The compound according to any one of claims 1-15, wherein R₁Is an alkyl group_(C1-8)。

17. The compound of claim 16, wherein R₁Is ethyl.

18. The compound of claim 16, wherein R₁Is propyl.

19. The compound according to any one of claims 1-18, wherein R₁Is' an alkyl group_(C1-8)。

20. The compound of claim 19, wherein R₁' is ethyl.

21. The compound of claim 19, wherein R₁' is propyl.

22. The compound according to any one of claims 1-21, wherein R₂Is heterocycloalkyl_(C2-12)。

23. The compound according to any one of claims 1-21, wherein R₂Is heterocycloalkyl_(C2-8)。

24. The compound of claim 22, wherein R₂Is N-heterocycloalkyl_(C2-8)。

25. The compound of claim 24, wherein R₂Is morpholinyl or 4-methylpiperazin-1-yl.

26. The compound according to any one of claims 1-21, wherein R₂Is a dialkylamino group_(C2-8)。

27. The compound of claim 26, wherein R₂Is a diethylamino group.

28. The compound according to any one of claims 1-27, wherein R₃Is a halogen.

29. The compound of claim 28, wherein R₃Is chlorine.

30. The compound of claim 28, wherein R₃Is bromine.

31. The compound according to any one of claims 1-27, wherein R₃Is hydrogen.

32. The compound according to any one of claims 1-31, wherein the compound is in the form of a pharmaceutically acceptable salt.

33. The compound of claim 32, wherein the pharmaceutically acceptable salt is an HCl salt.

34. The compound of claim 32, wherein the pharmaceutically acceptable salt is a maleate salt.

35. The compound according to any one of claims 1-31, wherein the compound is not in the form of a salt.

36. A compound according to claim 1, further defined as:

or a pharmaceutically acceptable salt of any of the above formulas.

37. The compound of claim 36, wherein the pharmaceutically acceptable salt comprises HCl or maleic acid.

38. The compound of claim 37, further defined as:

39. a pharmaceutical composition comprising:

a. a compound according to any one of claims 1-38; and

b. and (3) an excipient.

40. A method of treating and/or preventing a disease or condition in a patient in need thereof, comprising administering to the patient a compound or pharmaceutical composition according to any one of claims 1-39 in an amount sufficient to treat and/or prevent the disease or condition.

41. The method according to claim 40, wherein the disease or condition is a hyperproliferative disease.

42. The method according to claim 41, wherein said hyperproliferative disease is a skin disease.

43. The method according to claim 42, wherein the skin disease or disorder is psoriasis.

44. The method according to claim 41, wherein said hyperproliferative disease is cancer.

45. The method according to claim 44, wherein the cancer is a carcinoma, sarcoma, lymphoma, leukemia, melanoma, mesothelioma, multiple myeloma, or seminoma.

46. The method according to claim 45, wherein said cancer is cutaneous T cell lymphoma (CTC L).

47. The method of claim 44, wherein the cancer is bladder cancer, hematologic cancer, bone cancer, brain cancer, breast cancer, central nervous system cancer, cervical cancer, colon cancer, endometrial cancer, esophageal cancer, gallbladder cancer, genital cancer, genitourinary tract cancer, head cancer, kidney cancer, larynx cancer, liver cancer, lung cancer, muscle tissue cancer, neck cancer, oral or nasal mucosa cancer, ovarian cancer, pancreatic cancer, prostate cancer, skin cancer, spleen cancer, small intestine cancer, large intestine cancer, stomach cancer, testicular cancer, or thyroid cancer.

48. The method according to any one of claims 40-47, wherein said compound or pharmaceutical composition is administered orally, intra-arterially, intravenously, or topically.

49. The method of claim 48, wherein the compound or pharmaceutical composition is administered topically.

1. Field of the invention

The present invention relates generally to the treatment of cell proliferative diseases such as cancer. More particularly, the invention relates to caffeic acid derivatives useful in the treatment of cellular proliferative diseases such as cancer, pharmaceutical compositions comprising these compounds and methods of treatment using these compounds or compositions.

Background

Disclosure of Invention

In some aspects, the present disclosure provides caffeic acid derivatives useful for treating or preventing a disease or disorder. In some embodiments, the compound is further defined by the formula:

in certain aspects, the present disclosure provides compounds of the formula:

wherein:

A₁and A₂Each independently is-CH or-N, with the proviso that A is₁And A₂Not all are-N ═ N;

m is 0 to 6;

n is 0, 1 or 2;

x is O, S or NR₄；

Wherein R is₄Is hydrogen, alkyl (C1-6) or substituted alkyl (C1-6);

R₁and R₁' each independently is alkyl (C1-8), cycloalkyl (C3-8), -alkanediyl (C1-C8) -cycloalkyl (C3-8), alkenyl (C2-8), alkynyl (C2-8), aryl (C6-12), aralkyl (C7-12), or a substituted version of any of these, or

R₁And R₁' together and is an alkanediyl group (C2-8) or a substituted alkanediyl group (C2-8);

R₂is heterocycloalkyl (C2-12), dialkylamino (C2-8), heteroaryl (C1-8), alkylamino (C1-8), arylamino (C6-8), alkoxy (C1-8), aryloxy (C6-12), or substituted versions of any of these groups; and

R₃is halogen, hydrogen, hydroxy, amino, cyano or mercapto;

or a pharmaceutically acceptable salt thereof.

In some embodiments, the compound is further defined as:

wherein:

m' is 1 to 4;

n is 0 or 1;

R₂is heterocycloalkyl (C2-12), dialkylamino (C2-8), heteroaryl (C1-8), alkylamino (C1-8), arylamino (C6-8), alkoxy (C1-8), aryloxy (C6-12), or substituted versions of any of these groups; and

R₃is halogen, hydrogen, hydroxy, amino, cyano or mercapto;

or a pharmaceutically acceptable salt thereof.

In some embodiments, the compound is further defined as:

wherein:

m' is 1 to 4;

n is 0 or 1;

R₂is heterocycloalkyl (C2-12), dialkylamino (C2-8), heteroaryl (C1-8), alkylamino (C1-8), arylamino (C6-8), alkoxy (C1-8), aryloxy (C6-12), or substituted versions of any of these groups; and

R₃is halogen, hydrogen, hydroxy, amino, cyano or mercapto;

or a pharmaceutically acceptable salt thereof.

In some embodiments, m is 0 to 2. In some embodiments, m is 0 or 1. In some embodiments, m is 0. In other embodiments, m is 1. In other embodiments, m is 2. In some embodiments, m' is 1 to 3. In some embodiments, m' is 1 or 2. In some embodiments, m' is 1. In other embodiments, m' is 2. In other embodiments, m' is 3. In some embodiments, n is 0. In other embodiments, n is 1. In some embodiments, R₁Is alkyl (C)1-8), for example ethyl or propyl. In some embodiments, R₁' is an alkyl group (C1-8), such as ethyl or propyl. In some embodiments, R₂Is heterocycloalkyl (C2-12). In some embodiments, R₂Is heterocycloalkyl (C2-8). In some embodiments, R₂Is N-heterocycloalkyl (C2-8), for example morpholinyl or 4-methylpiperazin-1-yl. In other embodiments, R₂Is a dialkylamino group (C2-8), such as diethylamino. In some embodiments, R₃Is halogen, for example chlorine or bromine. In other embodiments, R₃Is hydrogen. In some embodiments, the compound is in the form of a pharmaceutically acceptable salt, such as a hydrochloride or maleate salt. In other embodiments, the compound is not in the form of a salt.

In some embodiments, the compound is further defined as:

or a pharmaceutically acceptable salt of any of these formulae. In some embodiments, the pharmaceutically acceptable salt comprises hydrochloric acid or maleic acid.

In some embodiments, the compound is further defined as:

in some aspects, the present disclosure provides a pharmaceutical composition comprising:

a) a compound disclosed herein; and

b) and (3) an excipient.

In some aspects, the disclosure provides methods of treating and/or preventing a disease or condition in a patient in need thereof, comprising administering to the patient an amount of a compound or pharmaceutical composition disclosed herein sufficient to treat and/or prevent the disease or condition, in some embodiments, the disease or condition is a hyperproliferative disease, in some embodiments, the hyperproliferative disease is a skin disease, such as psoriasis, in other embodiments, the hyperproliferative disease is a cancer, in some embodiments, the cancer is a carcinoma, sarcoma, lymphoma, leukemia, melanoma, mesothelioma, multiple myeloma, or seminoma, in some embodiments, the cancer is a cutaneous T-cell lymphoma (CTC L), in other embodiments, the cancer is bladder cancer, hematological cancer, bone cancer, brain cancer, breast cancer, central nervous system cancer, cervical cancer, colon cancer, endometrial cancer, esophageal cancer, gallbladder cancer, genital cancer, urogenital cancer, head cancer, kidney cancer, lung cancer, liver cancer, oral cancer, cervical tissue cancer, oral mucosal cancer, oral cancer, thyroid cancer, and other embodiments, the pharmaceutical composition is administered in an oral, the oral, a method, or oral composition, and the method.

Other objects, features and advantages of the present disclosure will become apparent from the following detailed description. It should be understood, however, that the detailed description and the specific examples, while indicating specific embodiments of the invention, are given by way of illustration only, since various changes and modifications within the spirit and scope of the invention will become apparent to those skilled in the art from this detailed description. Note that the inability to assign a particular compound to a particular general formula means that it also does not belong to another general formula.

Detailed Description

The present disclosure provides caffeic acid derivatives. In addition, pharmaceutical compositions thereof and methods of using these compounds and their pharmaceutical compositions are provided herein.

I. Compound and synthesis method thereof

The compounds of the present invention (also referred to as "compounds of the present disclosure") are set forth, for example, in the summary of the invention section above and in the claims below. They can be prepared using the synthetic methods outlined in the examples section. These methods can be further modified and optimized using the principles and techniques of organic chemistry applied by those skilled in the art. For example, in March's Advanced Organic Chemistry by Smith: these principles and techniques are taught in Reactions, mechanics, and Structure, (2013), which is incorporated herein by reference. In addition, the synthesis method can be further modified and optimized for preparative pilot plant or large scale production (batch or continuous) using the principles and techniques of process chemistry applied by those skilled in the art. Such principles and techniques are taught, for example, in the Practical Process Research & Development-A Guide for Organic Chemists (2012) of Anderson, which is incorporated herein by reference.

All compounds of the invention are useful in the prevention and treatment of one or more diseases or conditions discussed herein or elsewhere. However, in some embodiments, one or more compounds characterized or exemplified herein as intermediates, metabolites, and/or prodrugs may also be useful in the prevention and treatment of one or more diseases or conditions. Thus, unless expressly stated to the contrary, all compounds of the present invention are considered to be "active compounds" and "therapeutic compounds" which are contemplated for use as Active Pharmaceutical Ingredients (APIs). The actual suitability for human or veterinary use is typically determined using a combination of clinical trial procedures and regulatory procedures, such as those performed by the Food and Drug Administration (FDA). In the united states, the FDA is responsible for protecting public health by ensuring the safety, effectiveness, quality, and safety of human and veterinary drugs, vaccines and other biological products, and medical equipment.

In some embodiments, the compounds of the present invention have the advantage of: they may be more potent, less toxic, longer acting, more potent, produce fewer side effects, be more readily absorbed and/or have better pharmacokinetic properties (e.g., higher oral bioavailability and/or lower clearance rates), and/or have other useful pharmacological, physical or chemical properties, whether for the indications described herein or for other indications, relative to compounds known in the art.

The compounds of the invention may contain one or more asymmetrically substituted carbon or nitrogen atoms, and may be isolated in optically active or racemic forms. Thus, unless a particular stereochemistry or isomeric form is specifically indicated, all chiral, diastereomeric, racemic form, epimeric form and all geometric isomeric forms of the formula are intended. The compounds may exist as racemates and racemic mixtures, single enantiomers, diastereomeric mixtures and individual diastereomers. In some embodiments, a single diastereomer is obtained. The chiral center of the compounds of the present invention may have the S or R configuration.

The chemical formulae used to represent the compounds of the invention generally show only one of the possible different tautomers. For example, many types of keto groups are known to exist in equilibrium with corresponding enol groups. Similarly, many types of imine groups exist in equilibrium with enamine groups. Regardless of which tautomer is depicted for a given compound, and whichever is most prevalent, all tautomers of a given formula are meant.

In addition, the atoms comprising the compounds of the present invention are intended to include all isotopic forms of these atoms. Isotopes used herein include those atoms having the same atomic number but different mass numbers. By way of general example, and not limitation, isotopes of hydrogen include tritium and deuterium, while isotopes of carbon include¹³C and¹⁴C。

the compounds of the invention may also exist in prodrug form. Since prodrugs are known to enhance many desirable pharmaceutical qualities (e.g., solubility, bioavailability, manufacturing, etc.), the compounds used in certain methods of the invention may be delivered in prodrug form, if desired. Thus, the present invention encompasses prodrugs of the compounds of the present invention and methods of delivering the prodrugs. Prodrugs of the compounds used in the present invention may be prepared by modifying functional groups present in the compound in such a way that the modifications are cleaved, either in routine manipulation or in vivo, to the parent compound. Thus, prodrugs include, for example, compounds described herein wherein a hydroxy, amino, or carboxy group is bonded to any group that, when the prodrug is administered to a subject, cleaves to form a hydroxy, amino, or carboxylic acid, respectively.

Other examples of pharmaceutically acceptable Salts and methods of making and using the same are described in Handbook of pharmaceutical Salts: properties, and Use (2002), which is incorporated herein by reference.

It will be appreciated that many organic compounds may form complexes with the solvents in which they react or from which they precipitate or crystallize. These complexes are referred to as "solvates". If the solvent is water, the complex is referred to as a "hydrate". It should also be understood that many organic compounds may exist in more than one solid form, including crystalline and amorphous forms. All solid forms of the compounds provided herein, including any solvates thereof, are within the scope of the invention.

Pharmaceutical formulations and routes of administration

For administration to a patient in need of such treatment, a pharmaceutical formulation (also referred to as a pharmaceutical formulation), pharmaceutical composition, pharmaceutical product, drug (medical product), pharmaceutical product (medical product), drug (medical) or drug (medical)) comprises a therapeutically effective amount of a compound of the present invention formulated with one or more excipients and/or pharmaceutical carriers suitable for the indicated route of administration. In some embodiments, the compounds of the present invention are formulated in a manner suitable for treating human and/or veterinary patients. In some embodiments, formulation comprises mixing or combining one or more compounds of the invention with one or more of the following excipients: lactose, sucrose, starch powder, cellulose esters of alkanoic acids, cellulose alkyl esters, talc, stearic acid, magnesium stearate, magnesium oxide, sodium and calcium salts of phosphoric and sulfuric acids, gelatin, gum arabic, sodium alginate, polyvinylpyrrolidone and/or polyvinyl alcohol. In some embodiments, for example for oral administration, the pharmaceutical formulation may be formulated as a tablet or capsule. In some embodiments, the compound may be dissolved or slurried in water, polyethylene glycol, propylene glycol, ethanol, corn oil, cottonseed oil, peanut oil, sesame oil, benzyl alcohol, sodium chloride, and/or various buffers. The pharmaceutical formulations may be subjected to conventional pharmaceutical operations such as sterilization and/or may comprise pharmaceutical carriers and/or excipients, for example preservatives, stabilizers, wetting agents, emulsifiers, encapsulating agents such as lipids, dendrimers, polymers, proteins such as albumin, or nucleic acids, and buffers, and the like.

The pharmaceutical preparation can be administered by a variety of methods, such as orally or by injection (e.g., subcutaneously, intravenously, intraperitoneally, etc.). Depending on the route of administration, the compounds of the present invention may be coated in a material that protects the compound from the action of acids and other natural conditions that may inactivate the compound. In order to administer the active compounds by means other than parenteral administration, it is necessary to coat the compound with or co-administer the compound with a material that prevents its inactivation. For example, the active compound can be administered to the patient in a suitable carrier such as a liposome or diluent. Pharmaceutically acceptable diluents include saline and buffered aqueous solutions. Liposomes include water-in-oil-in-water CGF emulsions as well as conventional liposomes.

The compounds of the invention may also be administered parenterally, intraperitoneally, intraspinally, or intracerebrally. Dispersions can be prepared in glycerol, liquid polyethylene glycols, and mixtures thereof, and oils. Under normal conditions of storage and use, these preparations may contain a preservative to prevent the growth of microorganisms.

Pharmaceutical compositions suitable for injectable use include sterile aqueous solutions (where water soluble) or dispersions and sterile powders for the extemporaneous preparation of sterile injectable solutions or dispersions. The carrier can be a solvent or dispersion medium containing, for example, water, ethanol, polyol (including, but not limited to, glycerol, propylene glycol, and liquid polyethylene glycol), suitable mixtures thereof, and vegetable oils. Proper fluidity can be maintained, for example, by the use of a coating such as lecithin, by the maintenance of the required particle size in the case of dispersions and by the use of surfactants. The action of microorganisms can be prevented by various antibacterial and antifungal agents including, but not limited to, parabens, chlorobutanol, phenol, ascorbic acid, and thimerosal. In many cases, it will be preferable to include isotonic agents, for example, sugars, sodium chloride, or polyalcohols such as mannitol and sorbitol in the composition. Prolonged absorption of the injectable compositions can be brought about by including in the composition an agent which delays absorption, for example, aluminum monostearate or gelatin.

The compounds of the invention may be administered orally, for example, with an inert diluent or an ingestible edible carrier. The compound and other ingredients may also be enclosed in hard or soft shell gelatin capsules, compressed into tablets, or incorporated directly into the diet of a subject. For oral therapeutic administration, the compounds of the present invention may be incorporated with excipients and used in the form of ingestible tablets, troches, lozenges, capsules, elixirs, suspensions, syrups, wafers, and similar oral preparations. Of course, the percentage of therapeutic compound in the composition and formulation may vary. The amount of therapeutic compound in such pharmaceutical formulations is such that a suitable dosage will be obtained.

In some embodiments, the therapeutic compound may also be topically applied to the skin, eye, or mucosa. Alternatively, if local delivery to the lung is desired, the therapeutic compound may be administered by inhalation in a dry powder or aerosol formulation.

In some embodiments, it may be advantageous to formulate parenteral compositions in dosage unit form for ease of administration and uniformity of dosage. Dosage unit form as used herein refers to physically discrete units suitable as unitary dosages for the subject to be treated; each unit containing a predetermined quantity of a therapeutic compound calculated to produce the desired therapeutic effect in association with the desired pharmaceutical carrier. In some embodiments, the specification for the dosage unit form of the invention is determined by, and directly depends on: (a) unique characteristics of therapeutic compounds and the particular therapeutic effect to be achieved, and (b) limitations inherent in the art of compounding such therapeutic compounds for treating a selected condition in a patient. In some embodiments, the active compound is administered at a therapeutically effective dose sufficient to treat a condition associated with the condition of the patient. For example, the efficacy of a compound can be assessed in an animal model system that can predict the efficacy of treatment of a disease in a human or other animal.

In some embodiments, an effective dose range of a therapeutic compound can be extrapolated from effective doses determined in animal studies for a variety of different animals. Generally, the Human Equivalent Dose (HED) (in mg/kg) can be calculated according to the following formula (see, e.g., Reagan-Shaw et al, FASEB J., 22 (3): 659-661, 2008, incorporated herein by reference):

HED (mg/kg) ═ animal dose (mg/kg) × (animal K)_mHuman K_m)

Using K in the conversion_mThe factors may result in more accurate HED values that are based on Body Surface Area (BSA) rather than just body weight. K in humans and various animals_mThe values are well known. For example, an average of 60 kg of K for a human (with 1.6 square meters of BSA)_m37, and a K of a 20 kg child (with a BSA of 0.8 m square)_mIs 25. K in certain related animal models_mAre also well known and include: mouse K_m3 (assuming body weight of 0.02kg, BSA of 0.007); hamster K_m5 (assuming body weight of 0.08kg, BSA of 0.02); rat K_m6 (assuming a body weight of 0.15 kg, BSA of 0.025), monkey K_mWas 12 (assuming a weight of 3 kg, BSA 0.24).

The precise amount of the therapeutic composition depends on the judgment of the practitioner and is specific to each individual. Nevertheless, the calculated dose of HED may still provide general guidance. Other factors that affect dosage include the physical and clinical state of the patient, the route of administration, the intended therapeutic purpose and efficacy, the stability and toxicity of the particular therapeutic formulation.

The actual dose of a compound of the present disclosure or a composition comprising a compound of the present disclosure administered to a subject can be determined by physical and physiological factors such as the type of animal treated, age, sex, weight, severity of the condition, the type of disease treated, previous or current therapeutic intervention, the subject's idiopathic disease, and the route of administration. These factors can be determined by the skilled person. The physician responsible for administration will typically determine the concentration of the active ingredient in the composition and the appropriate dosage for the individual subject. In the event of any complication, the dosage may be adjusted by the individual physician.

In some embodiments, a therapeutically effective amount will generally vary from about 0.001mg/kg to about 1000mg/kg, from about 0.01mg/kg to about 750mg/kg, from about 100mg/kg to about 500mg/kg, from about 1mg/kg to about 250mg/kg, from about 10mg/kg to about 150mg/kg, administered in one or more doses per day for one or more days (depending on the course of the mode of administration and the factors discussed above). Other suitable dosage ranges include 1mg to 10,000mg per day, 100mg to 10,000mg per day, 500mg to 10,000mg per day, and 500mg to 1,000mg per day. In some specific embodiments, the amount is less than 10,000mg per day, which ranges from 750mg to 9,000mg per day.

In some embodiments, the amount of active compound in the pharmaceutical formulation is from about 2% to about 75% by weight. In some of these embodiments, the amount is from about 25% to about 60% by weight.

Single or multiple doses are contemplated. The desired time interval for delivery of multiple doses can be determined by one of ordinary skill in the art using no more than routine experimentation. For example, two doses may be administered to a subject at approximately 12 hour intervals per day. In some embodiments, the dose is administered once daily.

The agent may be administered on a conventional schedule. As used herein, a conventional schedule refers to a predetermined specified time period. The regular schedule may include time periods of the same or different duration, so long as the schedule is predetermined. For example, a conventional schedule may include twice daily dosing, once every two days dosing, once every three days dosing, once every four days dosing, once every five days dosing, once every six days dosing, once weekly dosing, once monthly dosing, or any set number of days or weeks between dosing. Alternatively, the predetermined regular schedule may include twice daily dosing for the first week, once daily dosing for the subsequent months, and so forth. In other embodiments, the invention provides one or more agents that can be administered orally, with or without the timing of oral administration being dependent on food intake. Thus, for example, the dose may be taken every morning and/or every evening, whenever the subject has eaten or will eat.

Treatment of cancer and other hyperproliferative diseases

Although hyperproliferative diseases may be associated with any disease that causes cells to begin to proliferate uncontrollably, a typical example is cancer. Psoriasis is another example. One of the key factors of cancer is that the normal apoptotic cycle of cells is interrupted, and therefore, agents that interrupt cell growth are very important as therapeutic agents for treating these diseases. In some embodiments, caffeic acid derivatives described herein can be used to reduce cell count, and thus can be used to treat a variety of cancers or other malignancies.

In some embodiments, the cancer, cancerous tissue or cancerous cells may be treated by the compounds, methods and compositions disclosed herein, in certain embodiments, the cancer cells or tissues may include, but are not limited to, cells or tissues from the bladder, blood, bone marrow, brain, breast, colon, esophagus, gastrointestinal tract, gingiva, head, kidney, liver, lung, nasopharynx, neck, ovary, prostate, skin, stomach, pancreas, testis, tongue, cervix or uterus, in some embodiments, the cancer may be of the histological type: malignant tumor, carcinoma, undifferentiated carcinoma, giant cell carcinoma and spindle cell carcinoma, small cell carcinoma, papillary carcinoma, squamous cell carcinoma, lymphoepitheliomatoid carcinoma, basal cell carcinoma, hairy cell carcinoma, transitional cell carcinoma, papillary cell carcinoma, adenocarcinoma, malignant gastrinosarcoma, cholangiocarcinoma, mixed adenocarcinoma and cholangiocarcinoma of the gland, adenocarcinomas of the trabecular gland, adenocystic carcinoma of the adenocarcinomas, familial carcinoma, carcinomas of the adenocarcinomas of the carcinomas of the adenocarcinomas of the carcinomas, carcinomas of the adenocarcinomas of the carcinomas of.

In another aspect, the compounds, compositions and methods disclosed herein are useful for treating cancer or other hyperproliferative diseases. Although hyperproliferative diseases may be associated with any disease that causes cells to begin to proliferate uncontrollably, a typical example is cancer. One of the key factors in cancer is that the normal apoptotic cycle of the cell is interrupted. Therefore, agents that interrupt cell growth are important as therapeutic agents for treating these diseases. In the present disclosure, the compounds of the present disclosure may be used to cause a decrease in cell count and may be used to treat various types of cancer.

In certain embodiments, cancer cells that can be treated with a compound or composition of the present disclosure include, but are not limited to, cells of the bladder, blood, bone marrow, brain, breast, colon, esophagus, gastrointestinal tract, gum, head, kidney, liver, lung, nasopharynx, neck, ovary, prostate, skin, stomach, pancreas, testis, tongue, cervix, and uterus.

In some embodiments, tumors that can be used for the treatment methods of the present invention include any malignant cell type, such as those found in solid tumors or hematological tumors. Exemplary solid tumors may include, but are not limited to, tumors of organs selected from the group consisting of: pancreas, colon, caecum, stomach, brain, head, neck, ovary, kidney, larynx, sarcoma, lung, bladder, melanoma, prostate, and breast. Examples of hematological tumors include tumors of myeloma, T or B cell malignancies, leukemias, lymphomas, blastomas, myelomas, and the like. Other examples of cancers that can be treated using the methods provided herein include, but are not limited to, lung cancer (including small cell lung cancer, non-small cell lung cancer, adenocarcinoma of the lung, and squamous carcinoma of the lung), cancer of the peritoneum, gastric cancer (including gastrointestinal and gastrointestinal stromal cancer), pancreatic cancer, cervical cancer, ovarian cancer, liver cancer, bladder cancer, breast cancer, colon cancer, colorectal cancer, endometrial or uterine cancer, salivary gland carcinoma, kidney cancer, prostate cancer, vulval cancer, thyroid cancer, various types of head and neck cancer, and melanoma.

In certain embodiments of the methods for treating cancer in a patient, comprising administering to the patient a pharmaceutically effective amount of a compound of the present disclosure, the pharmaceutically effective amount is 0.1-1000 mg/kg. In certain embodiments, the pharmaceutically effective amount is administered as a single dose per day. In certain embodiments, the pharmaceutically effective amount is administered in two or more doses per day. For example, the compound may be administered by contacting tumor cells during ex vivo clearance. The treatment method may include any one or more of: a) inducing cytotoxicity in tumor cells; b) killing the tumor cells; c) inducing apoptosis of tumor cells; d) inducing differentiation of tumor cells; or e) inhibiting the growth of tumor cells. The tumor cell may be any type of tumor cell, such as a brain cell. Other types of cells include, for example, bladder cancer cells, breast cancer cells, lung cancer cells, colon cancer cells, prostate cancer cells, liver cancer cells, pancreatic cancer cells, stomach cancer cells, testicular cancer cells, brain cancer cells, ovarian cancer cells, lymphatic cancer cells, skin cancer cells, brain cancer cells, bone cancer cells, or soft tissue cancer cells.

In some embodiments, the method of treatment further comprises monitoring the progress of the treatment. In some of these embodiments, the method comprises the step of determining the level of change in a hematological parameter and/or Cancer Stem Cell (CSC) assay in a patient who is experiencing or is susceptible to a condition or symptom thereof associated with cancer, wherein the patient has been administered a therapeutic amount of a compound or composition described herein, as a diagnostic marker or diagnostic measure (e.g., screening, assay). The marker levels determined in this method can be compared to known marker levels in healthy normal controls or other diseased patients to determine the disease condition of the patient. In some embodiments, a second level of the marker in the patient is determined at a time point after the first level is determined, and the two levels are compared to monitor the course of the disease or the efficacy of the treatment. In some embodiments, the level of the pre-treatment marker in the patient is determined prior to initiation of treatment according to the methods described herein. This pre-treatment marker level can then be compared to the marker level in the patient after treatment has begun to determine the efficacy of the treatment.

In some embodiments, the patient is a mammal, e.g., a primate, preferably a higher primate, e.g., a human (e.g., a patient having or at risk of having a condition described herein). In some embodiments, the patient is in need of an enhancement of the immune response of the patient. In certain embodiments, the patient is immunocompromised or at risk of immunocompromising. For example, in some embodiments, the patient is receiving or has received chemotherapy and/or radiation therapy. Alternatively or in combination, the patient is immunocompromised or at risk for immune impairment due to the infection.

Definition of

When used in the context of chemical groups: "Hydrogen" means-H; "hydroxy" means-OH; "oxo" represents ═ O; "carbonyl" refers to-C (═ O) -; "carboxy" means-C (═ O) OH (also written as-COOH or-CO)₂H) (ii) a "halo" independently means-F, -Cl, -Br, or-I; "amino" means-NH₂(ii) a "hydroxyamino" refers to-NHOH; "nitro" means-NO₂(ii) a Imino ═ NH; "cyano" means-CN; "isocyano" means-N ═ C ═ O; "azido" refers to-N₃(ii) a In a monovalent context, "phosphate" refers to-OP (O) (OH)₂Or a deprotonated form thereof; in a divalent context, "phosphate" refers to-OP (O) (OH) O-or its deprotonated form; "mercapto" means-SH; "thio" means ═ S; "Sulfonyl" means-S (O)₂-; "sulfinyl" means-S (O) -.

In the context of chemical formulae, the symbol "-" denotes a single bond, "═ denotes a double bond," ≡ denotes a triple bond. The symbol "- - -" represents an optional bond, if present, a single bond or a double bond. SymbolRepresents a single bond or a double bond. Thus, formulaIncluding, for exampleIt is understood that none of such ring atoms forms part of more than one double bond. Furthermore, it should be noted that the covalent bond symbol "-" does not indicate any preferred stereochemistry when linking one or two stereogenic atoms. Rather, it encompasses all stereoisomers and mixtures thereof. When a vertical cut is made through a bond (e.g., for a methyl,) Time, symbolIndicates the point of attachment of the group. Note that the point of attachment of the larger group is usually only discerned in this way to aid the reader in unambiguously discerning the point of attachment. SymbolRepresents a single bond in which the group attached to the thick end of the wedge is "out of the page". SymbolRepresents a single bond in which the group attached to the thick end of the wedge "goes into the page". SymbolRepresents a single bond in which the geometry (e.g., E or Z) around the double bond is indeterminate. Thus, both options and combinations thereof are contemplated. Any undefined valency on an atom of a structure shown in this application implicitly indicates a hydrogen atom bonded to the atom. Bold dots on a carbon atom indicate that the hydrogen attached to the carbon is oriented out of the plane of the paper.

For example, when a variable is represented as a "floating group" in a ring system, such as the group "R" in the formula:

the variable may replace any hydrogen atom attached to any ring atom, including a hydrogen that is delineated, implied, or explicitly defined, so long as a stable structure is formed. When a variable is represented as a "floating group" on a fused ring system as the group "R" in the formula:

unless otherwise specified, this variable may replace a hydrogen attached to any ring atom of any fused ring. Substitutable hydrogens include the depicted hydrogen (e.g., a hydrogen attached to a nitrogen in the above formula), implied hydrogens (e.g., a hydrogen not shown in the above formula but understood to be present), well defined hydrogens, and optional hydrogens whose presence depends on the nature of the ring atoms (e.g., a hydrogen attached to group X when X is equal to-CH-), so long as a stable structure is formed. In the examples shown, R may be located on the 5-or 6-membered ring of the fused ring system. In the above formula, the subscript letter "y" immediately following R included in parentheses represents a numerical variable. Unless otherwise specified, this variable may be 0, 1, 2, or any integer greater than 2, limited only by the maximum number of substitutable hydrogen atoms of the ring or ring system.

For chemical groups and classes of compounds, the number of carbon atoms in the group or class is as follows: "Cn" or "C ═ n" defines the exact number of carbon atoms (n) in the group/class. "C.ltoreq.n" defines the maximum number of carbon atoms (n) that can be present in the group/class, and the minimum number is as small as possible for the group/class in question. For example, it is understood that the smallest number of carbon atoms in the groups "alkyl (C.ltoreq.8)", "cycloalkanediyl (C.ltoreq.8)", "heteroaryl (C.ltoreq.8)" and "acyl (C.ltoreq.8)" is one (1), that the smallest number of carbon atoms in the groups "alkenyl (C.ltoreq.8)", "alkynyl (C.ltoreq.8)" and "heterocycloalkyl (C.ltoreq.8)" is two (2), that the smallest number of carbon atoms in the groups "cycloalkyl (C.ltoreq.8)" is three (3), and that the smallest number of carbon atoms in the groups "aryl (C.ltoreq.8)" and "aryldiyl (C.ltoreq.8)" is six (6). "Cn-n '" defines the minimum number (n) and the maximum number (n') of carbon atoms in the group. Thus, "alkyl (C2-10)" means those alkyl groups having 2 to 10 carbon atoms. These carbon number indicators may precede or follow the chemical group or class they modify and may or may not be included in parentheses and do not imply any change in meaning. Thus, the terms "C5 olefin", "C5-olefin", "olefin (C5)" and "olefin C5" are synonymous. Each carbon atom is counted to determine if the group or compound falls within the specified number of carbon atoms, except as described below. For example, the group dihexylamino is an example of a dialkylamino (C ═ 12) group; however, it is not an example of a dialkylamino (C ═ 6) group. Likewise, phenethyl is an example of an aralkyl (C ═ 8) group. When any chemical group or class of compounds defined herein is modified by the term "substituted", no carbon atom in the moiety that replaces a hydrogen atom is counted for. Thus, a methoxyhexyl group having a total of seven carbon atoms is an example of a substituted alkyl group (C1-6). Unless otherwise specified, the carbon atoms of any chemical group or class of compounds listed in the claims without carbon atom limitation are limited to less than or equal to twelve (12).

The term "saturated" when used to modify a compound or chemical group means that the compound or chemical group does not have carbon-carbon double and triple bonds, unless described below. When the term is used to modify an atom, it means that the atom is not part of any double or triple bond. In the case of substituted forms of saturated groups, one or more carbon-oxygen double bonds or carbon-nitrogen double bonds may be present. And carbon-carbon double bonds that may occur as part of keto-enol tautomerism or imine/enamine tautomerism are not excluded when such bonds are present. When the term "saturated" is used to modify a solution of a substance, it means that no more of the substance can dissolve in the solution.

The term "aliphatic" means that the compound or chemical group so modified is an acyclic or cyclic (but not aromatic) compound or group. In aliphatic compounds/groups, the carbon atoms may be linked together in a straight chain, branched chain or non-aromatic ring (alicyclic). Aliphatic compounds/groups may be saturated, i.e. linked together by single carbon-carbon bonds (alkanes/alkyls), or may be unsaturated, having one or more double carbon-carbon bonds (alkenes/alkenyls) or having one or more triple carbon-carbon bonds (alkynes/alkynes).

The term "aromatic" means that the compound or chemical group so modified has a planar ring of unsaturated atoms in which there are 4n +2 electrons in a fully conjugated cyclic pi-system. Aromatic compounds or chemical groups can be described as a single resonant structure; however, the description of one resonant structure also refers to any other resonant structure. For example:

also refers to

The depiction of aromatic compounds may also be circled to represent the delocalization of electrons in a fully conjugated cyclic pi-system, two non-limiting examples of which are shown below:

the term "alkyl", when used without the "substituted" modifier, refers to a monovalent saturated aliphatic group having a carbon atom as the point of attachment, being a straight or branched chain acyclic structure, and having no atoms other than carbon and hydrogen. group-CH₃(Me)、-CH₂CH₃(Et)、-CH₂CH₂CH₃(n-Pr or propyl), -CH (CH)₃)₂(i-Pr、ⁱPr or isopropyl), -CH₂CH₂CH₂CH₃(n-Bu)、-CH(CH₃)CH₂CH₃(sec-butyl), -CH₂CH(CH₃)₂(isopropyl), -C (CH)₃)₃(tert-butyl, t-Bu or^tBu) and-CH₂C(CH₃)₃(neopentyl) is a non-limiting example of an alkyl group. The term "alkanediyl", when used without the "substituted" modifier, refers to a divalent saturated aliphatic group having one or two saturated carbon atoms as the point of attachment, being a straight or branched chain acyclic structure, having no carbon-carbon double or triple bonds, and having no atoms other than carbon and hydrogen. group-CH₂- (methylene), -CH₂CH₂-、-CH₂C(CH₃)₂CH₂-and-CH₂CH₂CH₂-is a non-limiting example of an alkanediyl group. The term "alkylene" when used without the "substituted" modifier means a diThe valency group is CRR ', wherein R and R' are independently hydrogen or alkyl. Non-limiting examples of alkylene groups include: CH (CH)₂、＝CH(CH₂CH₃) And ═ C (CH)₃)₂. "alkane" refers to a class of compounds having the formula H-R, wherein R is alkyl, as that term is defined above. When any of these terms is used with the "substituted" modifier, one or more hydrogen atoms have been independently replaced with-OH, -F, -Cl, -Br, -I, -NH₂、-NO₂、-CO₂H、-CO₂CH₃、-CN、-SH、-OCH₃、-OCH₂CH₃、-C(O)CH₃、-NHCH₃、-NHCH₂CH₃、-N(CH₃)₂、-C(O)NH₂、-C(O)NHCH₃、-C(O)N(CH₃)₂、-OC(O)CH₃、-NHC(O)CH₃、-S(O)₂OH or-S (O)₂NH₂And (4) substitution. The following groups are non-limiting examples of substituted alkyls: -CH₂OH、-CH₂Cl、-CF₃、-CH₂CN、-CH₂C(O)OH、-CH₂C(O)OCH₃、-CH₂C(O)NH₂、-CH₂C(O)CH₃、-CH₂OCH₃、-CH₂OC(O)CH₃、-CH₂NH₂、-CH₂N(CH₃)₂and-CH₂CH₂And (4) Cl. The term "haloalkyl" is a subset of substituted alkyl wherein hydrogen atom substitution is limited to halo (i.e., -F, -Cl, -Br, or-I) such that no other atoms besides carbon, hydrogen, and halogen are present. group-CH₂Cl is a non-limiting example of a haloalkyl group. The term "fluoroalkyl" is a subset of substituted alkyls in which hydrogen atom substitution is limited to fluorine, such that no other atoms than carbon, hydrogen, and fluorine are present. group-CH₂F、-CF₃and-CH₂CF₃Are non-limiting examples of fluoroalkyl groups.

The term "cycloalkyl", when used without the "substituted" modifier, refers to a monovalent saturated aliphatic radical having as its point of attachment a carbon atom that forms one or more non-aromatic substituentsPart of the ring structure, no carbon-carbon double or triple bonds, and no atoms other than carbon and hydrogen. Non-limiting examples include: -CH (CH)₂)₂(cyclopropyl), cyclobutyl, cyclopentyl or cyclohexyl (Cy). As used herein, the term does not preclude the presence of one or more alkyl groups (where carbon number limitations allow) attached to carbon atoms of the non-aromatic ring structure. The term "cycloalkandiyl", when used without the "substituted" modifier, refers to a divalent saturated aliphatic group having two carbon atoms as points of attachment, no carbon-carbon double or triple bonds, and no other atoms besides carbon and hydrogen. Radical (I)Are non-limiting examples of cycloalkanediyl groups. "cycloalkane" refers to a class of compounds having the formula H-R, wherein R is cycloalkyl, as that term is defined above. When any of these terms is used with the "substituted" modifier, one or more hydrogen atoms have been independently replaced with-OH, -F, -Cl, -Br, -I, -NH₂、-NO₂、-CO₂H、-CO₂CH₃、-CN、-SH、-OCH₃、-OCH₂CH₃、-C(O)CH₃、-NHCH₃、-NHCH₂CH₃、-N(CH₃)₂、-C(O)NH₂、-C(O)NHCH₃、-C(O)N(CH₃)₂、-OC(O)CH₃、-NHC(O)CH₃、-S(O)₂OH or-S (O)₂NH₂And (4) substitution.

The term "alkenyl", when used without the "substituted" modifier, refers to a monovalent unsaturated aliphatic group having a carbon atom as the point of attachment, being a straight or branched chain acyclic structure, having at least one nonaromatic carbon-carbon double bond, no carbon-carbon triple bonds, and no atoms other than carbon and hydrogen. Non-limiting examples include: -CH ═ CH₂(vinyl), -CH ═ CHCH₃、-CH＝CHCH₂CH₃、-CH₂CH＝CH₂(allyl)、-CH₂CH＝CHCH₃and-CH ═ CHCH ═ CH₂. The term "alkenediyl" when substituted withoutThe term "modifier" when used herein means a divalent unsaturated aliphatic group having two carbon atoms as points of attachment, is a straight or branched chain acyclic structure, has at least one nonaromatic carbon-carbon double bond, has no carbon-carbon triple bond, and has no atoms other than carbon and hydrogen. The radicals-CH-, -CH-C (CH)₃)CH₂-、-CH＝CHCH₂-and-CH₂CH＝CHCH₂Similarly, the terms "terminal olefin" and "α -olefin" are synonymous and refer to an olefin having only one carbon-carbon double bond, where the double bond is part of a vinyl group at the end of the molecule₂、-NO₂、-CO₂H、-CO₂CH₃、-CN、-SH、-OCH₃、-OCH₂CH₃、-C(O)CH₃、-NHCH₃、-NHCH₂CH₃、-N(CH₃)₂、-C(O)NH₂、-C(O)NHCH₃、-C(O)N(CH₃)₂、-OC(O)CH₃、-NHC(O)CH₃、-S(O)₂OH or-S (O)₂NH₂And (4) substitution. The groups-CH ═ CHF, -CH ═ CHCl and-CH ═ CHBr are non-limiting examples of substituted alkenyl groups.

The term "alkynyl", when used without the "substituted" modifier, refers to a monovalent unsaturated aliphatic group having a carbon atom as the point of attachment, being a straight or branched chain acyclic structure, having at least one carbon-carbon triple bond, and having no atoms other than carbon and hydrogen. As used herein, the term alkynyl does not preclude the presence of one or more non-aromatic carbon-carbon double bonds. The group-C.ident.CH, -C.ident.CCH₃and-CH₂C≡CCH₃Are non-limiting examples of alkynyl groups. "alkyne" means having the formulaClass of compounds of H-R, wherein R is alkynyl. When any of these terms is used with the "substituted" modifier, one or more hydrogen atoms have been independently replaced with-OH, -F, -Cl, -Br, -I, -NH₂、-NO₂、-CO₂H、-CO₂CH₃、-CN、-SH、-OCH₃、-OCH₂CH₃、-C(O)CH₃、-NHCH₃、-NHCH₂CH₃、-N(CH₃)₂、-C(O)NH₂、-C(O)NHCH₃、-C(O)N(CH₃)₂、-OC(O)CH₃、-NHC(O)CH₃、-S(O)₂OH or-S (O)₂NH₂And (4) substitution.

The term "aryl," when used without the "substituted" modifier, refers to a monovalent unsaturated aromatic group having an aromatic carbon atom as the point of attachment, said carbon atom forming part of one or more aromatic ring structures, each aromatic ring structure having six ring atoms all carbon, and wherein the group has no atoms other than carbon and hydrogen. If more than one ring is present, the rings may be fused or unfused. The non-fused rings are linked by covalent bonds. As used herein, the term aryl does not exclude the presence of one or more alkyl groups (where carbon number limitations allow) attached to the first aromatic ring or any other aromatic ring present. Non-limiting examples of aryl groups include phenyl (Ph), tolyl, (dimethyl) phenyl, -C₆H₄CH₂CH₃(ethylphenyl), naphthyl and a monovalent group derived from biphenyl (e.g., 4-phenylphenyl). The term "aryldiyl," when used without the "substituted" modifier, refers to a divalent aromatic group having two aromatic carbon atoms as points of attachment, the carbon atoms forming part of one or more six-membered aromatic ring structures, each six-membered aromatic ring structure having six ring atoms that are all carbon, and wherein the divalent group contains no other atoms than carbon and hydrogen. As used herein, the term aryldiyl does not exclude the presence of one or more alkyl groups (where carbon number limitations allow) attached to the first aromatic ring or any other aromatic ring present. If there is more than oneThe rings of (b) may be fused or unfused. The non-fused rings are linked by covalent bonds. Non-limiting examples of aryldiyl groups include:

"arene" refers to a class of compounds having the formula H-R, where R is aryl, the term being as defined above. Benzene and toluene are non-limiting examples of aromatic hydrocarbons. When any of these terms is used with the "substituted" modifier, one or more hydrogen atoms have been independently replaced with-OH, -F, -Cl, -Br, -I, -NH₂、-NO₂、-CO₂H、-CO₂CH₃、-CN、-SH、-OCH₃、-OCH₂CH₃、-C(O)CH₃、-NHCH₃、-NHCH₂CH₃、-N(CH₃)₂、-C(O)NH₂、-C(O)NHCH₃、-C(O)N(CH₃)₂、-OC(O)CH₃、-NHC(O)CH₃、-S(O)₂OH or-S (O)₂NH₂And (4) substitution.

The term "aralkyl" when used without the "substituted" modifier refers to the monovalent group-alkanediyl-aryl, wherein the terms alkanediyl and aryl are each used in a manner consistent with the definition provided above. Non-limiting examples are: benzyl (benzyl, Bn) and 2-phenylethyl. When the term aralkyl is used in conjunction with the "substituted" modifier, one or more hydrogen atoms from the alkanediyl and/or aryl group have been independently replaced by-OH, -F, -Cl, -Br, -I, -NH₂、-NO₂、-CO₂H、-CO₂CH₃、-CN、-SH、-OCH₃、-OCH₂CH₃、-C(O)CH₃、-NHCH₃、-NHCH₂CH₃、-N(CH₃)₂、-C(O)NH₂、-C(O)NHCH₃、-C(O)N(CH₃)₂、-OC(O)CH₃、-NHC(O)CH₃、-S(O)₂OH or-S (O)₂NH₂And (4) substitution. Non-limiting examples of substituted aralkyl groups are: (3-chloro)Phenyl) -methyl and 2-chloro-2-phenyl-eth-1-yl.

The term "heteroaryl," when used without the "substituted" modifier, refers to a monovalent aromatic group having an aromatic carbon or nitrogen atom as the point of attachment, said carbon or nitrogen atom forming part of one or more aromatic ring structures, each aromatic ring structure having from 3 to 8 ring atoms, wherein at least one ring atom of the aromatic ring structure is nitrogen, oxygen, or sulfur, and wherein the heteroaryl group contains no other atoms than carbon, hydrogen, aromatic nitrogen, aromatic oxygen, and aromatic sulfur. If more than one ring is present, the rings are fused; however, the term heteroaryl does not preclude the presence of one or more alkyl or aryl groups (where carbon number limitations allow) attached to one or more ring atoms. Non-limiting examples of heteroaryl groups include: furyl, imidazolyl, indolyl, indazolyl (Im), isoxazolyl, methylpyridinyl, oxazolyl, phenylpyridinyl, pyridyl, pyrrolyl, pyrimidinyl, pyrazinyl, quinolinyl, quinazolinyl, triazolyl, tetrazolyl, thienyl and triazolyl. The term "N-heteroaryl" refers to a heteroaryl group with a nitrogen atom as the point of attachment. "heteroarenes" refers to the class of compounds having the formula H-R, where R is heteroaryl. Pyridine and quinoline are non-limiting examples of heteroarenes. When these terms are used with the "substituted" modifier, one or more hydrogen atoms have been independently replaced with-OH, -F, -Cl, -Br, -I, -NH₂、-NO₂、-CO₂H、-CO₂CH₃、-CN、-SH、-OCH₃、-OCH₂CH₃、-C(O)CH₃、-NHCH₃、-NHCH₂CH₃、-N(CH₃)₂、-C(O)NH₂、-C(O)NHCH₃、-C(O)N(CH₃)₂、-OC(O)CH₃、-NHC(O)CH₃、-S(O)₂OH or-S (O)₂NH₂And (4) substitution.

The term "heterocycloalkyl", when used without the "substituted" modifier, refers to a monovalent non-aromatic group having as the point of attachment a carbon or nitrogen atom forming one or more than one pointA portion of non-aromatic rings, each non-aromatic ring having three to eight ring atoms, wherein at least one ring atom of the non-aromatic ring structure is nitrogen, oxygen, or sulfur, and wherein the heterocycloalkyl group consists only of carbon, hydrogen, nitrogen, oxygen, and sulfur atoms. If more than one ring is present, the rings are fused. As used herein, the term does not preclude the presence of one or more alkyl groups (where carbon number limitations allow) attached to one or more ring atoms. Also, the term does not exclude the presence of one or more double bonds in the ring or ring system, provided that the resulting group remains non-aromatic. Non-limiting examples of heterocycloalkyl groups include: aziridinyl, azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, tetrahydrofuryl, tetrahydrothiofuranyl, tetrahydropyranyl, pyranyl, oxiranyl and oxetanyl groups. The term "N-heterocycloalkyl" refers to a heterocycloalkyl group having a nitrogen atom as the point of attachment. N-pyrrolidinyl is an example of such a group. When these terms are used with the "substituted" modifier, one or more hydrogen atoms have been independently replaced with-OH, -F, -Cl, -Br, -I, -NH₂、-NO₂、-CO₂H、-CO₂CH₃、-CN、-SH、-OCH₃、-OCH₂CH₃、-C(O)CH₃、-NHCH₃、-NHCH₂CH₃、-N(CH₃)₂、-C(O)NH₂、-C(O)NHCH₃、-C(O)N(CH₃)₂、-OC(O)CH₃、-NHC(O)CH₃、-S(O)₂OH、or-S(O)₂NH₂And (4) substitution.

The term "acyl" when used without the "substituted" modifier refers to the group-c (o) R, wherein R is hydrogen, alkyl, cycloalkyl or aryl, as those terms are defined above. The group-CHO, -C (O) CH₃(acetyl, Ac), -C (O) CH₂CH₃、-C(O)CH(CH₃)₂、-C(O)CH(CH₂)₂、-C(O)C₆H₅and-C (O) C₆H₄CH₃Are non-limiting examples of acyl groups. "thioacyl" is defined in an analogous manner, soExcept that the oxygen atom of the group-C (O) R has been replaced by a sulfur atom, -C (S) R. The term "aldehyde" corresponds to an alkyl group as defined above attached to a — CHO group. When any of these terms is used with the "substituted" modifier, one or more hydrogen atoms (including the hydrogen atom directly attached to the carbon atom of the carbonyl or thiocarbonyl group (if any)) have been independently replaced with-OH, -F, -Cl, -Br, -I, -NH₂、-NO₂、-CO₂H、-CO₂CH₃、-CN、-SH、-OCH₃、-OCH₂CH₃、-C(O)CH₃、-NHCH₃、-NHCH₂CH₃、-N(CH₃)₂、-C(O)NH₂、-C(O)NHCH₃、-C(O)N(CH₃)₂、-OC(O)CH₃、-NHC(O)CH₃、-S(O)₂OH、or-S(O)₂NH₂And (4) substitution. group-C (O) CH₂CF₃、-CO₂H (carboxyl), -CO₂CH₃(methyl carboxyl), -CO₂CH₂CH₃、-C(O)NH₂(carbamoyl) and-CON (CH)₃)₂Are non-limiting examples of substituted acyl groups.

The term "alkoxy" when used without the "substituted" modifier refers to the group-OR, wherein R is alkyl, as that term is defined above. Non-limiting examples include: -OCH₃(methoxy), -OCH₂CH₃(ethoxy), -OCH₂CH₂CH₃、-OCH(CH₃)₂(isopropoxy) or-OC (CH)₃)₃(tert-butoxy). The terms "cycloalkoxy", "alkenyloxy", "alkynyloxy", "aryloxy", "aralkoxy", "heteroaryloxy", "heterocycloalkoxy", and "acyloxy", when used without the "substituted" modifier, refer to a group defined as-OR, wherein R is cycloalkyl, alkenyl, alkynyl, aryl, aralkyl, heteroaryl, heterocycloalkyl, and acyl, respectively. The terms "alkylthio" and "acylthio," when used without the "substituted" modifier, refer to the group-SR, wherein R is alkyl and acyl, respectively. Term(s) forAn "alcohol" corresponds to an alkane as defined above, wherein at least one hydrogen atom has been substituted by a hydroxyl group. The term "ether" corresponds to an alkane as defined above, wherein at least one hydrogen atom has been substituted by an alkoxy group. When any of these terms is used with the "substituted" modifier, one or more hydrogen atoms have been independently replaced with-OH, -F, -Cl, -Br, -I, -NH₂、-NO₂、-CO₂H、-CO₂CH₃、-CN、-SH、-OCH₃、-OCH₂CH₃、-C(O)CH₃、-NHCH₃、-NHCH₂CH₃、-N(CH₃)₂、-C(O)NH₂、-C(O)NHCH₃、-C(O)N(CH₃)₂、-OC(O)CH₃、-NHC(O)CH₃、-S(O)₂OH or-S (O)₂NH₂And (4) substitution.

The term "alkylamino", when used without a "substituted" modifier, refers to the group-NHR, where R is alkyl, as that term is defined above. Non-limiting examples include: -NHCH₃and-NHCH₂CH₃. The term "dialkylamino," when used without the "substituted" modifier, refers to the group-NRR ', where R and R' can be the same or different alkyl groups. Non-limiting examples of dialkylamino groups include: -N (CH)₃)₂and-N (CH)₃)(CH₂CH₃). The terms "cycloalkylamino", "alkenylamino", "alkynylamino", "arylamino", "aralkylamino", "heteroarylamino", "heterocycloalkylamino" and "alkoxyamino", when used without the "substituted" modifier, refer to a group defined as-NHR, wherein R is cycloalkyl, alkenyl, alkynyl, aryl, aralkyl, heteroaryl, heterocycloalkyl, and alkoxy, respectively. A non-limiting example of an arylamino group is-NHC₆H₅. The term "acylamino" (acylamino), when used without the "substituted" modifier, refers to the group-NHR, wherein R is acyl, the term being as defined above. A non-limiting example of an amide group is-NHC (O) CH₃. When any of these terms is anded with "When substituted "modifiers are used together, one or more hydrogen atoms attached to a carbon atom have been independently replaced by-OH, -F, -Cl, -Br, -I, -NH₂、-NO₂、-CO₂H、-CO₂CH₃、-CN、-SH、-OCH₃、-OCH₂CH₃、-C(O)CH₃、-NHCH₃、-NHCH₂CH₃、-N(CH₃)₂、-C(O)NH₂、-C(O)NHCH₃、-C(O)N(CH₃)₂、-OC(O)CH₃、-NHC(O)CH₃、-S(O)₂OH、or-S(O)₂NH₂And (4) substitution. The group-NHC (O) OCH₃And NHC (O) NHCH₃Are non-limiting examples of substituted amide groups.

The use of the word "a" or "an" when used in conjunction with the word "comprising" in the claims and/or the specification may mean "one," but is also consistent with the meaning of "one or more," at least one, "and" one or more than one.

Throughout this application, the term "about" is used to indicate that a value includes the inherent variation of error in the equipment, methods used to determine the value, or variation that exists between study subjects.

An "active ingredient" (AI) (also referred to as an active compound, active substance, active agent, pharmaceutical agent, bioactive molecule, or therapeutic compound) is a biologically active drug or pesticide. The analogous terms active pharmaceutical ingredient (APl) and drug substance are also used in medicine, and the term active substance may be used in pesticide formulations.

The terms "comprising," "having," and "including" are open-ended linking verbs. Any form or tense of one or more of these verbs, such as "comprising", "having", "including" and "including", is also open-ended. For example, any method that "comprises," "has," or "includes" one or more steps is not limited to having only those one or more steps, and also encompasses other unlisted steps.

The term "effective" as used in the specification and/or claims refers to being sufficient to achieve a desired, expected, or intended result. When used in the context of treating a patient or subject with a compound, "effective amount," "therapeutically effective amount," or "pharmaceutically effective amount" refers to the amount of the compound that, when administered to a subject or patient, is sufficient to effect such treatment or prevention of a disease as these terms define hereinafter.

An "excipient" is a pharmaceutically acceptable substance formulated with an active ingredient of a drug, pharmaceutical composition, formulation or drug delivery system. For example, excipients may be used to stabilize the composition, to fill the composition (often referred to for this purpose as "filling agents", "fillers" or "diluents"), or to impart therapeutic enhancements to the active ingredient in the final dosage form, such as promoting drug absorption, reducing viscosity, or increasing solubility. Excipients include antiadherents, binders, coatings, pigments, disintegrants, flavoring agents, glidants, lubricants, preservatives, adsorbents, sweeteners, and carriers in a pharmaceutically acceptable form. The main excipients that act as vehicles for the delivery of the active ingredient are called carriers. Excipients may also be used in the manufacturing process to further aid in the handling of the active substance, for example by promoting flowability or non-stick properties of the powder, on the basis of aiding in-vitro stability, such as denaturation or aggregation upon standing for the expected shelf life. The suitability of an excipient typically varies depending on the route of administration, the dosage form, the active ingredient, and other factors.

The term "hydrate," when used as a modifier of a compound, means that the compound has less than one (e.g., hemihydrate), one (e.g., monohydrate), or more than one (e.g., dihydrate) water molecule associated with each molecule of the compound (e.g., in the solid form of the compound).

As used herein, the term "IC₅₀By "is meant an inhibitory dose that achieves 50% of the maximal response. Such quantitative measures indicate how much of a particular drug or other substance (inhibitor) is required to link a given biological, biochemical or chemical process (or component of a process, i.e., enzyme, cell)Receptor or microorganism) inhibits half.

An "isomer" of a first compound is a separate compound in which each molecule contains the same constituent atoms as the first compound, but the three-dimensional configuration of these atoms is different.

As used herein, the term "patient" or "subject" refers to a living mammalian organism, such as a human, monkey, cow, sheep, goat, dog, cat, mouse, rat, guinea pig, or transgenic species thereof. In certain embodiments, the patient or subject is a primate. Non-limiting examples of human patients are adults, adolescents, infants and fetuses.

As generally used herein, "pharmaceutically acceptable" refers to those compounds, materials, compositions, and/or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues, organs, and/or bodily fluids of humans and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit/risk ratio.

"pharmaceutically acceptable salt" refers to a salt of a compound of the invention as defined above which is pharmaceutically acceptable and has the desired pharmacological activity. Non-limiting examples of such salts include acid addition salts formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, and phosphoric acid; or an acid addition salt with an organic acid such as 1, 2-ethanedisulfonic acid, 2-hydroxyethanesulfonic acid, 2-naphthalenesulfonic acid, 3-phenylpropionic acid, 4' -methylenebis (3-hydroxy-2-ene-1-carboxylic acid), 4-methylbicyclo [2.2.2] non-2-ene-1-carboxylic acid, acetic acid, aliphatic monocarboxylic acid, aliphatic dicarboxylic acid, aliphatic sulfuric acid, aromatic sulfuric acid, benzenesulfonic acid, benzoic acid, camphorsulfonic acid, carbonic acid, cinnamic acid, citric acid, cyclopentanepropionic acid, ethanesulfonic acid, fumaric acid, glucoheptonic acid, gluconic acid, glutamic acid, glycolic acid, heptanoic acid, hexanoic acid, hydroxynaphthoic acid, lactic acid, lauryl sulfuric acid, maleic acid, malic acid, malonic acid, mandelic acid, methanesulfonic acid, muconic acid, o- (4-hydroxybenzoyl) benzoic acid, Oxalic acid, p-chlorobenzenesulfonic acid, phenyl-substituted alkanoic acids, propionic acid, p-toluenesulfonic acid, pyruvic acid, salicylic acid, stearic acid, succinic acid, tartaric acid, tert-butylacetic acid and trimethylacetic acid. Pharmaceutically acceptable salts also include base addition salts which may be formed when an acidic proton present is capable of reacting with an inorganic or organic base. Acceptable inorganic bases include sodium hydroxide, sodium carbonate, potassium hydroxide, aluminum hydroxide, and calcium hydroxide. Non-limiting examples of acceptable organic bases include ethanolamine, diethanolamine, triethanolamine, tromethamine, and N-methylglucamine. It should be recognized that the particular anion or cation forming part of any salt of the invention is not critical so long as the salt as a whole is pharmaceutically acceptable. Additional examples of pharmaceutically acceptable Salts and methods of making and using the same are described in Handbook of pharmaceutical Salts: properties, and Use (P.H.Stahl & C.G.Wermuth eds., VerlagHelvetica Chimica Acta, 2002).

A "pharmaceutically acceptable carrier," "pharmaceutical carrier," or simply "carrier" is a pharmaceutically acceptable substance formulated with an active ingredient drug that is involved in carrying, delivering, and/or transporting a chemical agent. Pharmaceutical carriers can be used to improve the delivery and effectiveness of drugs, including, for example, controlled release techniques to modulate drug bioavailability, reduce drug metabolism, and/or reduce drug toxicity. Some drug carriers can improve the effectiveness of drug delivery to a specific target site. Examples of the carrier include: liposomes, microspheres (e.g., made of poly (lactic-co-glycolic acid)), albumin microspheres, synthetic polymers, nanofibers, protein-DNA complexes, protein conjugates, erythrocytes, virosomes, and dendrimers.

"drug" (also referred to as a drug (pharmaceutical), a pharmaceutical agent (pharmaceutical agent), a pharmaceutical product (pharmaceutical preparation), a pharmaceutical composition (pharmaceutical composition), a pharmaceutical preparation (pharmaceutical formulation), a pharmaceutical product (pharmaceutical product), a drug (medicine), a medicine (medicine), a drug (medicine) or a drug (drug) for short) is a drug for diagnosing, curing, treating or preventing a disease. Active Ingredients (AI) (as defined above) are ingredients in drugs or pesticides that have biological activity. Similar terms Active Pharmaceutical Ingredient (API) and drug substance are also used in medicine, the term active substance being applicable to pesticide formulations. Some pharmaceutical and agrochemical products may contain more than one active ingredient. In contrast to active ingredients, inactive ingredients are often referred to in the pharmaceutical context as excipients (defined above).

"prevention" or "preventing" includes: (1) inhibiting the onset of a disease in a subject or patient who may be at risk and/or at risk of developing a disease but who has not experienced or exhibited any or all of the pathologies or symptoms of the disease, and/or (2) slowing the rate of onset of a pathology or symptom of a disease in a subject or patient who may be at risk and/or at risk of developing a disease but who has not experienced or exhibited any or all of the pathologies or symptoms of the disease.

Non-limiting examples of suitable esters that may be converted in vivo to a hydroxy compound include acetate, citrate, lactate, phosphate, tartrate, malonate, oxalate, salicylate, propionate, succinate, fumarate, maleate, methylene-bis- β -hydroxynapthenate, behenate, isethionate, di-p-toluoyl tartrate, methane sulfonate, ethane sulfonate, benzene sulfonate, p-toluene sulfonate, cyclohexyl sulfonate, quinic acid ester, and esters of amino acids.

"stereoisomers" or "optical isomers" are isomers of a given compound in which the same atom is bonded to the same other atom, but the three-dimensional configuration of the atoms is different. "enantiomers" are stereoisomers of a given compound that are mirror images of each other (e.g., left and right handed). "diastereomer" means that a given compound is not enantiomericStereoisomers of the body. Chiral molecules contain a chiral center, also referred to as a stereocenter or stereogenic center, which is any point, although not necessarily an atom, in the molecule with groups such that the interchange of any two groups results in a stereoisomer. In organic compounds, the chiral center is typically a carbon, phosphorus or sulfur atom, but other atoms may also be stereogenic centers in organic and inorganic compounds. A molecule may have multiple stereocenters, giving it many stereoisomers. In compounds where the stereoisomerism is due to tetrahedral stereogenic centres (e.g. tetrahedral carbons), it is assumed that the total number of possible stereoisomers will not exceed 2ⁿWhere n is the number of tetrahedral stereocenters. Molecules with symmetry are generally less than the maximum possible number of stereoisomers. A50: 50 mixture of enantiomers is referred to as a racemic mixture. Alternatively, a mixture of enantiomers may be enantiomerically enriched such that one enantiomer is present in an amount greater than 50%. In general, enantiomers and/or diastereomers may be resolved or separated using techniques known in the art. It is contemplated that any stereocenter or chiral axis for which stereochemistry is not defined may exist in its R form, S form, or a mixture of the R and S forms (including racemic and non-racemic mixtures). As used herein, the phrase "substantially free of other stereoisomers" means that the composition contains 15% or less, more preferably 10% or less, even more preferably 5% or less, or most preferably 1% or less of another stereoisomer.

"treating" or "treating" includes (1) inhibiting a disease (e.g., arresting further development of the pathology and/or symptom) in a subject or patient experiencing or exhibiting the pathology or symptom of the disease, (2) ameliorating the disease (e.g., such as reversing the pathology and/or symptom) in a subject or patient experiencing or exhibiting the pathology or symptom of the disease, and/or (3) achieving any measurable reduction in the disease in a subject or patient experiencing or exhibiting the pathology or symptom of the disease.

In the event that there is any conflicting definition in any reference incorporated by reference herein, the above definition controls. However, the fact that certain terms have been defined should not be taken to mean that any terms that are not defined are indefinite. Rather, all terms used are to be construed as describing the invention in terms that would allow a person of ordinary skill in the art to understand the scope and practice the invention.

V. examples

The following examples are included to illustrate preferred embodiments of the present disclosure. It should be appreciated by those of skill in the art that the techniques disclosed in the examples which follow represent techniques discovered by the inventor to function well in the practice of the disclosure, and thus can be considered to constitute preferred modes for its practice. However, those of skill in the art should, in light of the present disclosure, appreciate that many changes can be made in the specific embodiments which are disclosed and still obtain a like or similar result without departing from the spirit and scope of the present disclosure.

Design and synthesis of caffeic acid derivatives

TABLE 1 structure of caffeic acid derivatives.

Synthesis of Compound of type (2)

The appropriate 4-hydroxyalkylbenzophenone (40mmol), dibromoethane (200mmol), potassium carbonate (15g) and acetone (150m L) were mixed together and the resulting reaction mixture was refluxed until the reaction was judged complete by T L C the reaction mixture was then cooled, the inorganic salts were removed by filtration and the solvent was evaporated to dryness.

1- (4- (2-Bromoethoxy) phenyl) propan-1-one (2a, R)₁＝R₁′＝Et)：

The yield is 85 percent,¹H NMR(CDCl₃，300MHz，)ppm，7.98-7.93(m，2H)，6.97-6.92(m，2H)，4.35(dd，2H，J＝6.1Hz，J＝6.3Hz)，3.66(dd，1H，J＝6.3Hz，J＝6.2Hz)，2.95(q，2H，J＝7.2Hz)，1.22(t，3H，J＝7.2Hz)

1- (4- (2-Bromoethoxy) phenyl) butan-1-one (2b, R)₁＝R₁′＝Pr)：

The yield was 83%,¹H NMR(CDCl₃，300MHz，)ppm，7.98-7.92(m，2H)，6.97-6.91(m，2H)，4.35(dd，2H，J＝6.1Hz，J＝6.2Hz)，3.66(dd，1H，J＝6.2Hz，J＝6.3Hz)，1.83-1.69(m，2H)，1.0(t，3H，J＝7.2Hz，J＝7.4Hz)

synthesis of Compounds of type (3)

The appropriate alkyl magnesium bromide (14mmol) was added dropwise to a vigorously stirred solution of the appropriate 1- (4- (2-bromoethoxy) phenyl) alkyl-1-one (12mmol) in THF (90m L). the resulting reaction mixture was stirred at room temperature for 1 hour, and the progress of the reaction was monitored by T L C.after judging that the reaction was complete, the reaction mixture was poured into ice-cold 1N HCl solution (60 ml). after stirring for 20 minutes, the product was extracted with ethyl acetate. the organic extract was washed with 10% sodium bicarbonate solution followed by brine, and the resulting solution was washed with anhydrous Na₂SO₄The drying agent and solvent were removed and the product was purified by L C using a toluene/ethyl acetate gradient with elution the fractions containing the product were pooled together and evaporated to dryness.

3- (4- (2-Bromoethoxy) phenyl) pentan-3-ol (3a, R)₁＝R₁′＝Et)：

The yield was 72%,¹H NMR(CDCl₃，300MHz，)ppm，7.32-7.27(m，2H)，6.91-6.85(m，2H)，4.29(dd，2H，J＝6.4Hz，J＝6.3Hz)，3.64(dd，2H，J＝6.3Hz，J＝6.3Hz)，1.90-1.71(m，4H)，0.75(t.6H，J＝7.4Hz)

4- (4- (2-Bromoethoxy) phenyl) heptan-4-ol (3b, R)₁＝R₁′＝Pr)

The yield was 65%,¹H NMR(CDCl₃，300MHz，)ppm；7.33-7.24(m，2H)，6.91-6.83(m，2H)，4.22(dd，2H，J＝6.3Hz，J＝6.3Hz)，3.63(dd，2H，J＝6.3Hz，J＝6.3Hz)，1.85-1.66(m，4H)，1.40-1.18(m，2H)，1.153-0.97(m，2H)，0.85(t.6H，J＝7.2Hz)

synthesis of Compound of type (4)

Preparation of Compound (3) (6mmol), NaN₃(24mmol) and chloroform (20m L), vigorously stirred and cooled to 0 ℃. trifluoroacetic acid (40mmol) was added and the reaction mixture was stirred at 0 ℃. after judging that the reaction was complete by T L C, the mixture was diluted with chloroform (30m L) and then water (30m L) was added.

1- (3-azidopent-3-yl) -4- (2-bromoethoxy) benzene (4a, R)₁＝R₁′＝Et)：

The yield is 85.6 percent,¹H NMR(CDCl₃，300MHz，)ppm，7.29-7.21(m，2H)，6.94-6.85(m，2H)，4.29(dd，2H，J＝6.3Hz，J＝6.3Hz)，3.64(dd，2H，J＝6.3Hz，J＝6.3Hz)，2.05-1.82(m，4H)，0.78(t.6H，J＝7.4Hz)

1- (4-azido (azldo) hept-4-yl) -4- (2-bromoethoxy) benzene (4b, R)¹＝R¹＝Pr)：

The yield was 84.8%,¹H NMR(CDC₃，300MHz，)ppm；7.28-7.21(m，2H)，6.91-6.84(m，2H)，4.28(dd，2H，J＝6.3Hz，J＝6.3Hz)，3.63(dd，2H，J＝6.3Hz，J＝6.3Hz)，1.96-1.75(m，4H)，1.40-1.18(m，2H)，1.40-1.16(m，2H)，1.16-1.00(m，2H)，0.88(t，6H，J＝7.2Hz)

synthesis of Compound of type (5)

A mixture of the appropriate compound (4) (2mmol), amine (2.2mmol), potassium carbonate (20mmol) and acetonitrile (10m L) was prepared and the mixture was refluxed under vigorous stirring the reaction progress was monitored by T L C after judged complete the reaction mixture was cooled then diluted with chloroform the inorganic salts were removed by filtration, the solvent was evaporated off and the crude product was purified by using L C eluting with chloroform/methanol gradient the product containing fractions were pooled together and evaporated to dryness the following compounds were prepared according to this step:

4- (2- (4- (3-azidopent-3-yl) phenoxy) ethyl) morpholine (5a, R)₁＝R₁′＝Et，R₂Morpholinyl):

the yield was 80%.¹H NMR(CDCl₃，300MHz，)ppm；7.25-7.20(m，2H)，6.92-6.85(m，2H)，4.11(dd，2H，J＝5.7Hz，J＝5.7Hz)，3.74(dd，2H，J＝4.4Hz，J＝4.6Hz)，2.81(dd，2H，J＝5.7Hz，J＝5.7Hz)，2.58(dd，2H，J＝4.7Hz，J＝4.6Hz)，2.03-1.82(m，4H)，0.78(t.6H，J＝7.4Hz)

2- (4- (3-azidopent-3-yl) phenoxy) -N, N-diethylethan-1-amine (5b, R)₁＝R₁′＝Et，R₂Diethylamine):

the yield was 95%.¹H NMR(CDCl₃，300MHz，)ppm；7.25-7.18(m，2H)，6.92-6.83(m，2H)，4.04(dd，2H，J＝6.3Hz，J＝6.3Hz)，2.89(dd，2H，J＝6.3Hz，J＝6.3Hz)，2.65(q，4H，J＝7.1Hz)，2.14-1.80(m，4H)，1.80(t，6H，J＝7.1Hz)，0.78(t，6H，J＝7.4Hz)

4- (2- (4- (4-azidohept-4-yl) phenoxy) ethyl) morpholine (5c, R)₁＝R₁′＝Pr，R₂Morpholinyl):

the yield was 95.3%.¹H NMR(CDCl₃，300MHz，)ppm；7.25-7.20(m，2H)，6.92-6.83(m，2H)，4.10(dd，2H，J＝5.7Hz，J＝5.7Hz)，3.73(dd，2H，J＝4.6Hz，J＝4.7Hz)，2.80(dd，2H，J＝5.7Hz，J＝5.7Hz)，2.58(dd，2H，J＝4.7Hz，J＝4.7Hz)，1.95-1.74(m，4H)，1.38-1.00(m，4H)，0.86(t.6H，J＝7.3Hz)

1- (2- (4- (4-azidohept-4-yl) phenoxy) ethyl) -4-methylpiperazine (5d, R)₁＝R₁′＝Pr，R₂4-methyl-piperazinyl):

the yield was 78.3%.¹H NMR(CDCl₃，300MHz，)ppm；7.25-7.18(m，2H)，6.90-6.83(m，2H)，4.10(dd，2H，J＝5.9Hz，J＝5.9Hz)，2.81(dd，2H，J＝5.9Hz，J＝5.9Hz)，2.70-2.36(m，SH)，2.39(s，3H)，1.96-1.75(m，4H)，1.38-1.00(m，4H)，0.86(t，6H，J＝7.3Hz)

Synthesis of Compound of type (6)

The appropriate compound (5) (1g) was dissolved in a mixture of THF/EtOH (1: 1v/v) (15ml) Pd/C (10% wet Degussa type, 100mg) was added and the reaction mixture was exposed to hydrogen overnight (40p.s.i.) using a Paar apparatus after completion of the reaction, the reaction mixture was filtered through celite, the solvent was evaporated and the product was purified by L C system using a chloroform/methanol gradient as eluent.

3- (4- (2- (diethylamino) ethoxy) phenyl) pentan-3-amine (6a, R)₁＝R₁′＝Et，R₂Diethylamine):

the yield was about 100%.¹H NMR(CDCl₃，300MHz，)ppm；7.32-7.25(m，2H)，6.89-6.83(m，2H)，4.04(dd，2H，J＝6.5Hz，J＝6.4Hz)，2.89(dd，2H，J＝6.4Hz，J＝6.4Hz)，2.65(q，4H，J＝7.1Hz)，1.87-1.73(m，2H)，1.72-1.55(m，2H)，1.07(t，6H，J＝7.1Hz)，0.72(t，6H，J＝7.4Hz)

4- (4- (2-morpholinoethoxy) phenyl) hept-4-amine (6b, R)₁＝R₁′＝Pr，R₂Morpholinyl):

the yield was 75.4%.¹H NMR(CDC₃，300MHz，)ppm；7.32-7.26(m，2H)，6.88-6.83(m，2H)，4.10(dd，2H，J＝5.7Hz，J＝5.7Hz)，3.73(dd，2H，J＝4.5Hz，J＝4.8Hz)，2.80(dd，2H，J＝5.7Hz，J＝5.7Hz)，2.58(dd，2H，J＝4.7Hz，J＝4.7Hz)，1.85-1.58(m，2H)，1.30-1.00(m，2H)，0.84(t.6H，J＝7.2Hz)

4- (4- (2- (diethylamino) ethoxy) phenyl) hept-4-amine (6c, R)₁＝R₁′＝Pr，R₂Diethylamino):

the yield was 73.8%.¹H NMR(CDCl₃，300MHz，)ppm；7.32-7.26(m，2H)，6.88-6.81(m，2H)，4.04(dd，2H，J＝6.4Hz，J＝6.4Hz)，2.87(dd，2H，J＝6.4Hz，J＝6.4Hz)，2.64(q，4H，J＝7.1Hz)，1.80-1.54(m，8H)，1.30-1.12(m，2H)，1.12-0.90(m，2H)，1.07(t，3H，J＝7.1Hz)，0.83(t，3H，J＝7.1Hz)

4- (4- (2- (4-methylpiperazin-1-yl) ethoxy) phenyl) hept-4-amine (6d, R)₁＝R₁′＝Pr，R₂4-methyl-piperidinyl)

The yield was 65.7%.¹H NMR(DMSO-d₆，300MHz，)ppm；8.52(bs，2H)，7.40-7.30(m，2H)，7.72-6.95(m，2H)，4.20-4.0(m，2H)，3.50-3.30(m，2H)，3.33(s，3H)，3.20-2.55(m，8H)，2.00-1.72(m，2H)，1.28-1.00(m，2H)，1.07(t，3H，J＝7.0Hz)，0.83(t，3H，J＝7.3Hz)

Synthesis of Compound of type (7)

EDC (2.0mmol) and DMAP (0.01mmol) were added successively to a solution of the appropriate compound (6) (1mmol) and cyanoacetic acid (2.5mmol) in DCM (10m L) and the resulting mixture was stirred at room temperature overnight the crude product was purified by L C using a chloroform/methanol gradient as eluent.

2-cyano-N- (3- (4- (2- (morpholinoethoxy) phenyl) pent-3-yl) acetamide (7a, R)₁＝R₁′＝Et，R₂Armour morpholino)

The yield was 60%.¹H NMR(CDCl₃，300MHz，)ppm；7.25-7.17(m，2H)，6.92-6.85(m，2H)，6.14(bs，1H，4.10(dd，2H，J＝5.7Hz，J＝5.7Hz)，3.73(dd，2H，J＝4.6Hz，J＝4.8Hz)，3.34(s，2H)，2.79(dd，2H，J＝5.6Hz，J＝5.8Hz)，2.58(dd，2H，J＝4.7Hz，J＝4.6Hz)，2.22-1.95(m，2H)，0.75(t，6H，J＝7.4Hz)

2-cyano-N- (3- (4- (2- (diethylamino) ethoxy) phenyl) pent-3-yl) acetamide (7b, R)₁＝R₁′＝Et，R₂Diethylamino group)

The yield was 70.4%.¹H NMR(CDCl₃，300MHz，)ppm；7.25-7.17(m，2H)，6.92-6.85(m，2H)，6.15(bs，1H，4.03(dd，2H，J＝6.4Hz，J＝6.4Hz)，3.37(s，2H)，2.87(dd，2H，J＝6.4Hz，J＝6.4Hz)，2.65(q，2H，J＝7.1Hz)，2.22-2.00(m，2H)，1.07(t，6H，J＝7.1Hz)，0.74(t，6H，J＝7.4Hz)

2-cyano-N- (4- (4- (2- (diethylamino) ethoxy) phenyl) hept-4-yl) acetamide (7c, R)₁＝R₁′＝Pr，R₂Diethylamino group)

The yield was 60.4%.¹H NMR(CDCl₃，300MHz，)ppm；7.25-7.17(m，2H)，6.92-6.85(m，2H)，6.18(bs，1H，4.04(dd，2H，J＝6.4Hz，J＝6.4Hz)，3.33(s，2H)，2.90(dd，2H，J＝6.3Hz，J＝6.3Hz)，2.68(q，2H，J＝7.1Hz)，2.22-1.98(m，4H)，1.22-1.08(m，4H)，1.08(t，6H，J＝7.1Hz)，0.87(t，6H，J＝7.3Hz)

2-cyano-N- (4- (4- (2- (morpholinoethoxy) phenyl) hept-4-yl) acetamide (7d, R)₁＝R₁′＝Pr，R₂Morpholinyl)

The yield was 93.4%.¹H NMR(CDCl₃，300MHz，)ppm；7.25-7.17(m，2H)，6.92-6.85(m，2H)，6.14(bs，1H，4.10(dd，2H)，J＝5.7Hz，J＝5.7Hz)，3.73(dd，2H，J＝4.7Hz，J＝4.7Hz)，3.33(s，2H)，2.80(dd，2H，J＝5.7Hz，J＝5.7Hz)，2.58(dd，4H，J＝4.7Hz，J＝4.7Hz)，2.19-1.90(m，4H)，1.22-1.03(m，4H)，0.88(t，6H，J＝7.1Hz)

2-cyano-N- (4- (4- (2- (4-methylpiperazin-1-yl) ethoxy) phenyl) hept-4-yl) acetamide (7e, R)₁＝R₁′＝Pr，R₂4-methylpiperazino group)

The yield was 65.5%.¹H NMR(CDCl₃，300MHz，)ppm；7.25-7.17(m，2H)，6.88-6.85(m，2H)，6.21(bs，1H)，4.10(dd，2H，J＝5.7Hz，J＝5.7Hz)，3.49(s，2H)，3.29(s，3H)，3.13(dd，8H，J＝J＝5.7Hz)，2.91(dd 2H，J＝5.0Hz，J＝5.1Hz)，2.19-1.90(m，4H)，1.22-1.03(m，4H)，0.88(t，6H，J＝7.1Hz)

Synthesis of Compound of type (8)

A mixture of the appropriate compound (7) (lmmol), the appropriate 6-substituted pyridylaldehyde (1.2mmol), piperidine (0.1mmol) and acetonitrile (20m L) was prepared and refluxed with stirring the reaction progress was monitored by T L C after judged complete, the reaction mixture was evaporated to dryness and the crude product was purified by L C using a chloroform/methanol gradient as eluent.

(E) -3- (6-Chloropyridin-2-yl) -2-cyano-N- (3- (4- (2-morpholinoethoxy) phenyl) pent-3-yl) acrylamide (WP1721)

The yield was 86.3%.¹H NMR(CDCl₃，300MHz，)ppm；8.13(s，1H)，7.76(dd，1H，J＝J＝7.7Hz)，7.48(d，1H，J＝7.1Hz)，7.42(dd，1H，J＝8.0Hz，J＝0.6Hz)，7.30-7.20(m，2H)，6.92-6.85(m，2H)，6.71(bs，1H)，4.10(dd，2H，J＝5.7Hz，J＝5.7Hz)，3.73(dd，2H，J＝4.6Hz，J＝4.7Hz)，2.79(dd，2H，J＝5.7Hz，J＝5.7Hz)，2.57(dd，4H，J＝4.7Hz，J＝4.7Hz)，2.30-2.23(m，4H)，0.78(t，6H，J＝7.3Hz)

(E) -3- (6-chloropyridin-2-yl) -2-cyano-N- (3- (4- (2- (diethylamino) ethoxy) phenyl) pent-3-yl) acrylamide (WP1722)

The yield was 84.2%.¹H NMR(CDCl₃，300MHz，)ppm；8.14(s，1H)，7.76(dd，1H，J＝J＝7.7Hz)，7.49(d，1H，J＝7.2Hz)，7.42(dd，1H，J＝8.0Hz，J＝0.8Hz)，7.30-7.20(m，2H)，6.92-6.86(m，2H)，6.71(bs，1H)，4.03(dd，2H，J＝6.4Hz，J＝6.4Hz)，2.88(dd，2H，J＝6-4Hz，J＝6.4Hz)，2.63(q，4H，J＝7.1Hz)，2.29-2.04(m，4H)，1.05(t，6H，J＝7.1Hz)，0.77(t，6H，J＝7.3Hz)

(E) -2-cyano-N- (3- (4- (2- (diethylamino) ethoxy) phenyl) pent-3-yl) -3- (pyridin-2-yl) acrylamide (WP1727)

The yield was 65.3%.¹H NMR(CDCl₃，300MHz，)ppm；8.82(dd，1H，J＝4.7Hz，J＝0.8Hz)，8.21(s，1H)，7.80(ddd，1H，J＝J＝7.7Hz，J＝1.8Hz)，7.55(d，1H，J＝7.8Hz)，7.39(ddd，1H，J＝7.7Hz，J＝4.7Hz，J＝1.0Hz)，7.30-7.22(m，2H)，6.93-6.85(m，2H)，6.72(bs，1H)，4.03(dd，2H，J＝6.4Hz，J＝6.4Hz)，2.86(dd，2H，J＝6.4Hz，J＝6.4Hz)，2.63(q，4H，J＝7.2Hz)，2.28-2.21(m，4H)，1.06(t，6H，J＝7.2Hz)，0.78(t，6H，J＝7.3Hz)

(E) -3- (6-Chloropyridin-2-yl) -2-cyano-N- (4- (4- (2-morpholinoethoxy) phenyl) hept-4-yl) acrylamide (WP1733)

The yield was 83.7%.¹H NMR(CDCl₃，300MHz，)ppm；8.13(s，1H)，7.76(dd，1H，J＝J＝7.8Hz)，7.49(d，1H，J＝7.2Hz)，7.42(d，1H，J＝8.0Hz)，7.29-7.22(m，2H)，6.92-6.86(m，2H)，6.73(bs，1H)，4.10(dd，2H，J＝6.7Hz，J＝6.7Hz)，3.73(dd，2H，J＝4.7Hz，J＝4.7Hz)，2.79(dd，2H，J＝4.7Hz，J＝4.7Hz)，2.58(dd，4H，J＝4.6Hz，J＝4.7Hz)，2.22-1.97(m，4H)，0.89(t，6H，J＝7.1Hz)

(E) -3- (6-chloropyridin-2-yl) -2-cyano-N- (4- (4- (2- (diethylamino) ethoxy) phenyl) hept-4-yl) acrylamide (WP1734)

The yield was 74%.¹H NMR(CDCl₃，300MHz，)ppm；8.14(s，1H)，7.76(dd，1H，J＝J＝7.7Hz)，7.49(d，1H，J＝7.2Hz)，7.42(d，1H，J＝8.0Hz)，7.28-7.21(m，2H)，6.92-6.86(m，2H)，6.73(bs，1H)，4.07(dd，2H，J＝6.4Hz，J＝6.4Hz)，2.90(dd，2H，J＝6.3Hz，J＝6.3Hz)，2.67(q，4H，J＝7.1Hz)，2.23-1.97(m，4H)，1.30-1.07(m，4H)，1.08(t，6H，J＝7.2Hz)，0.87(t，6H，J＝7.1Hz)

(E) -3- (6-chloropyridin-2-yl) -2-cyano-N- (4- (4- (2- (diethylamino) ethoxy) phenyl) hept-4-yl) acrylamide (WP1735)

The yield was 84%.¹H NMR(CDCl₃，300MHz，)ppm；8.13(s，1H)，7.76(dd，1H，J＝J＝7.7Hz)，7.49(d，1H，J＝7.4Hz)，7.42(dd，1H，J＝8.0Hz，J＝0.5Hz)，7.28-7.20(m，2H)，6.92-6.86(m，2H)，6.72(bs，1H)，4.09(dd，2H，J＝5.8Hz，J＝5.8Hz)，2.81(dd，2H，J＝5.6Hz，J＝5.6Hz)，2.75-2.40(m，4H)，2.30(s，3H)，2.20-1.97(m，4H)，1.30-1.07(m，4H)，0.87(t，6H，J＝7.4Hz)

Synthesis of 1- (4- (2- (2-chloroethoxy) ethoxy) phenyl) propan-1-one (9)

Intermediate 9 was obtained according to the literature (Koning et al, 2011. in brief, a mixture of 4-hydroxypropiophenone (20mmol), potassium carbonate (33mmol), KI (2.2mmol) and 2-chloroethyl ether (20m L) was prepared and refluxed under vigorous stirring for 48 hours the reaction mixture was diluted with ethyl acetate (50m L), the inorganic salts were removed by filtration and the filtrate was washed with water and then dried over anhydrous sodium sulfate, the drying agent and solvent were removed and the crude product was purified by L C. yield was 83.7%.¹H NMR(CDCl₃，300MHz，)ppm；7.98-7.89(m，2H)，6.98-6.92(m，2H)，4.21(dd，2H，J＝6.0Hz，J＝4.9Hz)，3.91(dd，2H，J＝4.8Hz，J＝4.9Hz)，3.83(dd，2H，J＝6.0Hz，J＝5.4Hz)，3.67(dd，2H，J＝5.9Hz，J＝5.4Hz)，2.95(q，2H，J＝7.3Hz)，1.21(t，3H，J＝7.2Hz)

Synthesis of 3- (4- (2- (2-chloroethoxy) ethoxy) phenyl) pentan-3-ol (10)

Ethyl magnesium bromide (33mmol) was added dropwise to a vigorously stirred solution of 9(10mmol) in THF (80m L). The mixture was stirred at room temperature for 1 hour, after judging completion of the reaction by T L C, the reaction mixture was poured into ice-cold 1N HCl solution (100m L). after stirring for 20 minutes, the product was extracted with ethyl acetate, the organic extract was washed with 10% sodium bicarbonate solution, then with brine, and the organic extract was washed with anhydrous Na₂SO₄Drying, removing the drying agent and solvent, and purifying the crude product by L C using a toluene/ethyl acetate gradient for elutionFractions of the material were pooled together and evaporated to dryness. The yield was 86.1%.¹H NMR(CDCl₃，300MHz，)ppm；7.32-7.23(m，2H)，6.92-6.85(m，2H)，4.14(dd，2H，J＝6.1Hz，J＝4.9Hz)，3.94-3.80(m，4H)，3.65(dd，2H，J＝6.1Hz，J＝5.6Hz)，1.9-1.7(m，4H)，1.60(d，1H，J＝7.1Hz)，0.75(t，3H，J＝7.4Hz)。

Synthesis of 1- (3-azidopent-3-yl) -4- (2- (2-chloroethoxy) ethoxy) benzene (11)

Preparation of Compound 3(8.6mmol), NaN₃(26mmol) and chloroform (20m L), and vigorously stirred and cooled to 0 ℃. trifluoroacetic acid (43mmol) was added and the reaction mixture was stirred at 0 ℃. after judging that the reaction was complete by T L C, the mixture was diluted with chloroform (30m L), then water (30m L) was added, the organic layer and the aqueous layer were separated, the organic layer was washed with water and dried.¹H NMR(CDCl₃，300MHz，)ppm；7.27-7.20(m，2H)，6.92-6.86(m，2H)，4.14(dd，2H，J＝6.0Hz，J＝4.9Hz)，3.92-3.80(m，4H)，3.66(dd，2H，J＝6.0Hz，J＝5.6Hz)，2.3-1.9(m，4H)，0.78(t，3H，J＝7.4Hz)

Synthesis of a Compound of type (12)

A mixture of the appropriate compound 11(2mmol), the appropriate amine (4.0mmol), potassium carbonate (20mmol) and acetonitrile (15m L) was prepared and the mixture was refluxed under vigorous stirring after judging the reaction to be complete by T L C, the reaction mixture was cooled and then diluted with chloroform the inorganic salts were removed by filtration, the solvent was evaporated and the crude product was purified by L C using a chloroform/methanol gradient for elution the product containing fractions were pooled together and evaporated to dryness.

4- (2- (2- (4- (3-azidopent-3-yl) phenoxy) ethoxy) ethyl) morpholine (12a, R)₁＝Et，R₂Armour morpholino)

The yield was 96%.¹H NMR(CDCl₃，300MHz，)ppm；7.27-7.19(m，2H)，6.92-6.85(m，2H)，4.12(dd，2H，J＝5.0Hz，J＝4.6Hz)，3.82(dd，2H，J＝5.9Hz，J＝5.0Hz)，3.75-3.67(m，4H)，2.67(dd，2H，J＝5.7Hz，J＝5.7Hz)，2.54(dd，2H，J＝4.7Hz，J＝4.6Hz)，2.3-1.8(m，4H)，0.78(t，3H，J＝7.4Hz)

1- (2- (2- (4- (3-azidopent-3-yl) phenoxy) ethoxy) ethyl) -4-methylpiperazine (12b, R)₁＝Et，R₂4-methylpiperazino group)

The yield was 98%.¹H NMR(CDCl₃，300MHz，)ppm；7.25-7.19(m，2H)，6.92-6.85(m，2H)，4.12(dd，2H，J＝5.0Hz，J＝4.7Hz)，3.82(dd，2H，J＝5.0Hz，J＝5.0Hz)，3.70(dd，2H，J＝5.8Hz，J＝5.8Hz)，2.62(dd，2H，J＝5.8Hz，J＝5.8Hz)，2.70-2.33(m，8H)，2.27(s，3H)，2.3-1.8(m，4H)，0.78(t，3H，J＝7.4Hz)

Synthesis of Compound of type (13)

Dissolve the appropriate compound 12(1g) in a mixture of THF/EtOH (1: 1v/v, 15m L) add Pd/C (10% wet Degussa type, 100mg) and expose the mixture to hydrogen overnight (40p.s.i.) using a Paar apparatusThe reaction mixture was filtered, the solvent was evaporated, and the crude product was purified by L C using a chloroform/methanol gradient as eluent.

3- (4- (2- (2-morpholinoethoxy) ethoxy) phenyl) pent-3-amine (13a, R)₁＝Et，R₂Armour morpholino)

The yield was 89%.¹H NMR(CDCl₃，300MHz，)ppm；7.35-7.27(m，2H)，6.90-6.83(m，2H)，4.16(dd，2H，J＝5.1Hz，J＝4.6Hz)，3.82(dd，2H，J＝5.8Hz，J＝5.0Hz)，3.75-3.68(m，6H)，2.62(dd，2H，J＝5.8Hz，J＝5.8Hz)，2.52(dd，4H，J＝4.7Hz，J＝4.6Hz)，1.92-1.65(m，4H)，0.74(t，3H，J＝7.4Hz)

3- (4- (2- (2- (-4-methylpiperazin-1-yl) ethoxy) phenyl) pentan-3-amine (13b, R)₁＝Et，R₂4-methylpiperazino group)

The yield was 86%.¹H NMR(CDCl₃，300MHz，)ppm；7.32-7.26(m，2H)，6.90-6.83(m，2H)，4.11(dd，2H，J＝5.1Hz，J＝4.7Hz)，3.81(dd，2H，J＝5.9Hz，J＝4.7Hz)，3.70(dd，2H，J＝5.9Hz，J＝5.9Hz)，2.63(dd，2H，J＝5.8Hz，J＝5.8Hz)，2.70-2.33(m，8H)，2.27(s，3H)，1.88-1.56(m，4H)，0.71(t，3H，J＝7.3Hz)

Synthesis of Compound of type (14)

EDC (1.7mmol) and DMAP (0.01mmol) were added successively to a solution of the appropriate compound 13(1.66mmol) and cyanoacetic acid (3.33mmol) in DCM (10m L) and the resulting mixture was stirred at room temperature overnight the crude product was purified by L C using a chloroform/methanol gradient as eluent the fractions containing the product were combined together and then evaporated to dryness the following compounds were prepared according to this step:

2-cyano-N- (3- (4- (2- (2-morpholinoethoxy) ethoxy) phenyl) pent-3-yl) acetamide (14a, R)₁＝Et，R₂Armour substituted morpholine)

The yield was 65%.¹H NMR(CDCl₃，300MHz，)ppm；7.26-7.17(m，2H)，6.93-6.85(m，2H)，6.12(bs，1H)，4.11(dd，2H，J＝5.1Hz，J＝4.6Hz)，3.82(dd，2H，J＝4.7Hz，J＝5.0Hz)，3.75-3.66(m，6H)，3.34(s，2H)，2.61(dd，2H，J＝5.8Hz，J＝5.8Hz)，2.51(dd，4H，J＝4.7Hz，J＝4.6Hz)，2.20-1.98(m，4H)，0.74(t，3H，J＝7.4Hz)

2-cyano-N- (3- (4- (2- (2- (4-methylpiperazin-1-yl) ethoxy) phenyl) pent-3-yl) acetamide (14b, R)₁＝Et，R₂4-methylpiperazino group)

The yield was 83%.¹H NMR(CDCl₃，300MHz，)ppm；7.26-7.17(m，2H)，6.92-6.84(m，2H)，6.33(bs，1H)，4.10(dd，2H，J＝4.9Hz，J＝3.5Hz)，3.79(dd，2H，J＝4.8Hz，J＝6.0Hz)，3.67(dd，2H，J＝4.6Hz，J＝5.5Hz)，3.37(s，2H)，2.64(dd，2H，J＝5.6Hz，J＝5.5Hz)，2.70-2.46(m，8H)，2.36(s，3H)，2.20-1.94(m，4H)，0.74(t，3H，J＝7.4Hz)

Synthesis of Compound of type (15)

A mixture of the appropriate compound 14(1mmol), the appropriate 6-substituted pyridylaldehyde (1.2mmol), piperidine (0.1mmol) and acetonitrile (20m L) was prepared and refluxed with stirring after judging the reaction was complete by T L C, the reaction mixture was evaporated to dryness and the crude product was purified by L C using a chloroform/methanol gradient as eluent.

(E) -3- (6-chloropyridin-2-yl) -2-cyano-N- (3- (4- (2- (2-morpholinoethoxy) ethoxy) phenyl) pent-3-yl) acrylamide (WP1723)

The yield was 68.4%.¹H NMR(CDCl₃，300MHz，)ppm；8.13(s，1H)，7.76(dd，1H，J＝J＝7.8Hz)，7.49(d，1H，J＝7.3Hz)，7.43(dd，1H，J＝8.0Hz，J＝0.6Hz)，7.30-7.20(m，2H)，6.93-6.85(m，2H)，6.71(bs，1H)，4.11(dd，2H，J＝5.1Hz，J＝4.6Hz)，3.81(dd，2H，J＝4.7Hz，J＝5.0Hz)，3.74-3.66(m，6H)，2.61(dd，2H，J＝5.7Hz，J＝5.7Hz)，2.52(dd，4H，J＝4.7Hz，J＝4.6Hz)，2.30-2.02(m，4H)，0.77(t，3H，J＝7.3Hz)

(E) -2-cyano-N- (3- (4- (2- (2-morpholinoethoxy) ethoxy) phenyl) pent-3-yl) -3- (pyridin-2-yl) acrylamide (WP1724)

The yield was 73.5%.¹H NMR(CDCl₃，300MHz，)ppm；8.83(dd，1H，J＝4.7Hz，J＝0.9Hz)，8.21(s，1H)，7.79(ddd，1H，J＝J＝7.8Hz，J＝1.8Hz)，7.55(d，1H，J＝7.8Hz)，7.39(ddd，1H，J＝11.6Hz，J＝4.7Hz，J＝1.1Hz)，7.30-7.23(m，2H)，6.93-6.85(m，2H)，6.72(bs，1H)，4.15(dd，2H，J＝5.0Hz，J＝4.7Hz)，3.82(dd，2H，J＝4.7Hz，J＝5.0Hz)，3.75-3.65(m，6H)，2.61(dd，2H，J＝5.7Hz，J＝5.7Hz)，2.52(dd，4H，J＝4.7Hz，J＝4.6Hz)，2.30-2.03(m，4H)，0.77(t，3H，J＝7.3Hz)

(E) -3- (6-chloropyridin-2-yl) -2-cyano-N- (3- (4- (2- (2- (4-methylpiperazin-1-yl) ethoxy) phenyl) pent-3-yl) acrylamide (WP1731)

The yield was 64%.¹H NMR(CDCl₃，300MHz，)ppm；8.13(s，1H)，7.77(dd，1H，J＝J＝7.8Hz)，7.49(d，1H，J＝7.3Hz)，7.42(dd，1H，J＝8.0Hz，J＝0.6Hz)，7.28-7.20(m，2H)，6.98-6.85(m，2H)，6.71(bs，1H)，4.11(dd，2H，J＝5.1Hz，J＝4.7Hz)，3.88(dd，2H，J＝5.1Hz，J＝4.8Hz)，3.72-3.65(m，4H)，2.88(dd，2H，J＝4.7Hz，J＝4.7Hz)，2.62(dd，2H，J＝5.8Hz，J＝5.8Hz)，2.70-2.33(m，8H)，2.28(s，3H)，2.26-2.22(m，4H)，0.77(t，3H，J＝7.4Hz)

Synthesis of WP1732

A0.25M solution of maleic acid in acetonitrile (40M L) was added to a solution of WP1731(2.58g, 4.78mmol) in acetonitrile (5M L) diethyl ether (50M L) was added and the resulting off-white solid was filtered and washed with diethyl ether to pH about 7 the solid was dried under reduced pressure to give 2.48g of WP1732. yield 67%.¹H NMR(600MHz，DMSO，)ppm：8.18(s，1H)，8.07(dd，¹H，J＝J＝7.86Hz)，8.01(s，1H)，7.86(d，1H，J＝7.44Hz)，7.68(d，1H，J＝8.28Hz)，7.26(d，2H，J＝8.88Hz)，6.88(d，2H，J＝8.8Hz)，6.15(s，4H)，4.09(dd，2H，J＝4.74Hz，J＝4.38Hz)，3.74(dd，2H，J＝J＝4.55Hz)，3.64(dd，2H，J＝J＝5.28Hz)，3.50-2.80(m，8H)，2.74(bs，2H)，2.67(bs，3H)，2.13(m，2H)，1.94(m，2H)，0.69(t，6H，J＝7.32)。

Biological evaluation of synthetic caffeic acid derivatives

i. Cell culture

Glioblastoma U87 and pancreatic cancer cell lines AsPc-1, Panc-1, Colo357-FG and Colo 357-L3.6.6 were maintained at 37 ℃ with 5% CO in DMEM containing 10% Fetal Bovine Serum (FBS), 100mg/ml streptomycin and 100IU/ml penicillin₂。

Tumor cell lines were maintained at 37 ℃ in DMEM containing 10% Fetal Bovine Serum (FBS), 100. mu.g/ml streptomycin and 100IU/ml penicillin in 5% CO₂。

AsPc-1: a human pancreatic tumor cell line is established from ascites fluid of a patient with histopathologically confirmed pancreatic head adenocarcinoma. See Chen et al, (1982).

Panc-1, an epithelioid cell line, derived from human pancreatic ductal cell-derived carcinoma L ieber et al (1975).

Colo357 originates from metastases of pancreatic adenocarcinoma. See Morgan et al (1980).

Colo357-FG and Colo 357-L3 Colo357-FG are rapidly growing variants, 58% of nude mice developed regional lymph node metastasis after subcutaneous implantation and growth, 64% of nude mice developed liver metastasis and 43% of nude mice developed lung metastasis after implantation of tumor cells within the spleen, see Vezerilis et al (1990).

Colo 357-L3.5.5, established by serial passage of human pancreatic cancer cell lines through nude mouse liver see Vezeridis et al (1992).

WM793 human melanoma tumor cell line was used at different stages of progression and for biological and molecular analysis. See satyamoorthhy et al (1997).

Determination of cytotoxicity

For cytotoxicity assays, 1,500 tumor cells were seeded in 96-well flat-bottomed tissue culture plates in complete medium (see tables 2 and 3). After 20 hours, fresh medium containing various concentrations of the compounds disclosed herein was added. After 72 hours, the number of cells was counted by measuring the absorbance at 490nm with a 96-well plate reader using the MTS Assay (Promega CellTiter AQ Non-Radioactive cell promotion Assay kit, Madison, Wis., USA). Data representation as IC₅₀Values from eight measurements of relative proliferation inhibition + SD. The number of cells in the presence of DMSO was taken as 100%.

TABLE 2 cytotoxicity of WP compounds in tumor cell lines

TABLE 3 comparison of cytotoxicity of WP1732 and WP1066

*************

All of the compounds, compositions, and/or methods disclosed and claimed herein can be made and executed without undue experimentation in light of the present disclosure. While the compounds, compositions, and methods of this disclosure have been described in terms of preferred embodiments, it will be apparent to those of skill in the art that variations may be applied to the compositions and/or methods and in the steps or in the sequence of steps of the method disclosed herein without departing from the concept, spirit, and scope of the disclosure. More specifically, it will be apparent that certain agents which are both chemically and physiologically related may be substituted for the agents described herein while the same or similar results would be achieved. All such similar substitutes and modifications apparent to those skilled in the art are deemed to be within the spirit, scope and concept of the disclosure as defined by the appended claims.

Reference to the literature

The following references provide exemplary procedural or other details to a certain extent that are supplementary to those set forth herein and are expressly incorporated herein by reference:

U.S. Pat. No.6,426,366

U.S. Pat. No. 7,745,468

U.S. Pat. No. 8,143,412

U.S. Pat. No. 8,779,151

U.S. patent application publication 2003/0013748

Alas and Bonavida，Clin.Cancer Res.，9(1)：316-26，2003.

Bharti et al.，J.Immunol.，171(7)：3863-3871，2003.

Burdelya et al.，Mol.Cancer Ther.，1(11)：893-9，2002.

Catlett-Falcone et al.，Immunity，10(1)：105-15，1999.

Constantin et al.，Eur.J.Immunol.，28(11)：3523-9，1998.

Kerr et al.，FEBS Lett.，546(1)：1-5，2003.

Koning et al.，Toxicol.Lett.，206(1)：54-59，2011.

Kondo，et al.，Oncogene，26(17)：2435-44，2007.

Meydan et al.，Nature，379(6566)：645-8，1996.

Reagan-Shaw et al.，FASEB J.，22(3)：659-661，2008.

Verma et al.，Cancer Metastasis Rev.，22(4)：423-34，2003.

Yu and Jove，Nature Rev.Cancer，4(2)：97-105，2004.

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