Organic selenium compound for preventing and treating cancer

文档序号：1871289 发布日期：2021-11-23 浏览：28次中文

阅读说明：本技术 用于预防和治疗癌症的有机硒化合物 (Organic selenium compound for preventing and treating cancer ) 是由贺贤然李少磊李晓龙聂友松于 2020-05-16 设计创作，主要内容包括：本发明提供了用于预防和治疗癌症的化合物,其具有式(I)的结构式：R-(a)-R-(b)-C(W)-O-L-SeCN(I)其中各变量如说明书中所定义。本发明还提供了所述式(I)化合物的制备方法、包含所述式(I)化合物的药物组合物以及所述式(I)化合物在制备用于预防和治疗癌症的药物中的用途。(The present invention provides compounds for the prevention and treatment of cancer, having the structural formula of formula (I): r a ‑R b -c (w) -O-L-secn (i) wherein the variables are as defined in the specification. The invention also provides a preparation method of the compound of the formula (I), a pharmaceutical composition containing the compound of the formula (I) and application of the compound of the formula (I) in preparation of medicines for preventing and treatingThe use in medicaments for treating cancer.)

1. A compound of formula (I):

R_a-R_b-C(W)-O-L-SeCN

(I)

or a pharmaceutically acceptable salt thereof;

wherein

R_aRepresents aryl, aryl C_1-4Alkyl-or heteroaryl, said aryl, aryl C_1-4Alkyl or heteroaryl is optionally substituted with one, two or three substituents selected from: phenyl, methylsulfonylphenyl C_1-4Alkyl-, halophenyl-formyl-, phenyl-formyl-, C_1-4Alkylphenylamino-, halogen, C_1-4Alkyl radical, C_1-4Alkoxy-, halo-C_1-4Alkoxy-, amino, acyl, C_1-4Alkyl acyl-, acyloxy, C_1-2Alkyl acyloxy-, C_1-2Alkylamino-, halo-C_1-4Alkyl-;

w is selected from O, S and Se;

R_bis a straight or branched alkylene or alkenylene chain of 1 to 4 carbon atoms, or is a direct covalent bond;

l is a straight or branched alkylene chain of 1 to 4 carbon atoms.

2. The compound of claim 1, wherein R_aSelected from the group consisting of unsubstituted or substituted phenyl, naphthyl, benzopyrrole, benzopyrrolidinyl and benzocyclopentenyl,

wherein the substituent is selected from phenyl and methylsulfonylphenyl C_1-4Alkyl-, halophenyl-formyl-, phenyl-formyl-, C_1-4Alkylphenylamino-, halogen, C_1-4Alkyl radical, C_1-4Alkoxy-, halo-C_1-4Alkyl-, halo-C_1-4Alkoxy-, acyl, C_1-4Alkyl acyl-, acyloxy, C_1-2Alkyl acyloxy-, C_1-2Alkylamino-; and is

Wherein the heteroaryl group is selected from the group consisting of a benzopyrrole group, a benzopyrrolidinyl group, and a benzocyclopentenyl group.

3. The compound of claim 1 or 2, wherein W is O.

4. A compound according to any one of claims 1 to 3, wherein R_aSelected from: phenyl, naphthyl, benzocyclopentenyl, benzopyrryl and benzopyrrolidinyl, and R_aOptionally substituted with one or two substituents selected from: halogen selected from fluorine, chlorine, bromine, iodine, phenyl, methanesulfonylphenylmethine-, phenylamino-, benzoyl, methoxy, straight or branched alkylene of 1 to 4 carbon atoms, trifluoromethyl.

5. The compound of any one of claims 1 to 4, wherein L is (CH)₂)₂Or (CH)₂)₃。

6. The compound of claim 1, which is a specific compound selected from the group consisting of:

or a pharmaceutically acceptable salt thereof.

7. A process for the preparation of a compound according to any one of claims 1 to 6, comprising the steps of: r is to be_a-R_bA compound represented by-C (W) -OH and NCSe (CH)₂)_nOH in an organic solvent, wherein the variable R_a、R_bAnd W is as defined in claim 1, the variable n being an integer selected from 1,2,3 and 4.

8. The process according to claim 7, wherein the reaction is carried out under catalysis of N, N' -Dicyclohexylcarbodiimide (DCC).

9. The method of claim 7 or 8, wherein R is_a-R_b-C (W) -OH and NCSe (CH)₂)_nThe molar ratio of OH is 1:1 to 1: 3.

10. The method of any of claims 7-9, wherein DCC and R are_a-R_b-C (W) -OH in a molar ratio of 1:1 to 1: 2.

11. The process of any one of claims 7-10, wherein the reaction is carried out at a temperature of less than 0 ℃.

12. A pharmaceutical composition comprising a compound according to any one of claims 1 to 6 and optionally a carrier.

13. The pharmaceutical composition of claim 12, further comprising an additional active pharmaceutical compound.

14. The pharmaceutical composition of claim 12 or 13, which is in a dosage form selected from the group consisting of: tablets, pills, powders, lozenges, suspensions, emulsions, solutions, syrups, aerosols, ointments, creams, lotions, capsules, suppositories, eye drops, injections and powder injections.

15. Use of a compound according to any one of claims 1 to 6 in the manufacture of a medicament for the prevention or treatment of cancer or for the prevention, treatment and/or alleviation of complications and/or symptoms associated with cancer.

16. The use of claim 15, wherein the cancer is selected from the group consisting of brain cancer, breast cancer, colon cancer, rectal cancer, skin cancer, head and neck cancer, cervical cancer, renal cancer, lung cancer, liver cancer, ovarian cancer, pancreatic cancer, prostate cancer, thyroid cancer, gastric cancer, leukemia, lymphoma, sarcoma, and melanoma.

17. The use of claim 15 or 16, wherein the cancer is selected from cervical cancer, prostate cancer, colon cancer and gastric cancer.

Technical Field

The application relates to the field of pharmaceutical chemistry, in particular to a selenium-containing organic compound for preventing and treating cancer, a preparation method of the compound, a pharmaceutical composition containing the compound and pharmaceutical application of the compound.

Background

Cancer is a significant lethal disease affecting the population worldwide. During the life of a cell, small changes in DNA called "mutations" occasionally occur. Among these mutations, some (referred to as "silent mutations") do not result in any substantial change in cell function, while others may alter the mode of action of the cell. Various mechanisms can prevent cells that have mutated from continuing the cell cycle and if genetic errors are not corrected, these cells will "suicide" through a process called "apoptosis". However, if mutations occur in proteins involved in cell cycle regulation, this can lead to uncontrolled cell proliferation (known as tumor formation), which can further progress to cancer.

Cancer cells often have adverse effects on the body. Cancer can spread by invasion of adjacent tissues by malignant tumor cells, and can also spread by a process known as "metastasis" in which malignant cells detach from the tumor mass and spread to distant sites. Cancer appears in many different types of tissues in multiple forms and can be characterized by its degree of invasion and invasiveness.

Cancer occurs as a mass of abnormal tissue in a living host organism, which receives nutrients from the host without relying on host hyperproliferation and destroys the host organism. The human organ is composed of a large number of cells. Cancer occurs when normal cells of the human body become abnormal cells and the abnormal cells divide and proliferate without examination. Although genetic factors are closely related to the onset of cancer, environmental factors also have a significant impact on whether an individual develops cancer. Cancer is particularly prevalent in developed countries. It has been reported that the causes of cancer are increased use of pesticides, insecticides, etc. (and thus the amount of such substances remaining in foods) and consumption of processed foods containing additives such as food preservatives and colorants, increased pollution of water, soil and air, stress of modern life, reduction of activities, obesity caused by greasy dietary habits, and the like. In recent years, it has also been pointed out that cancer is caused when the cell signaling system of normal cells fails, when cancer genes are activated, or when cancer suppressor genes fail.

Various cancer treatment methods exist, such as surgical treatment, chemotherapy and radiotherapy. The surgical treatment method effectively removes cancer at an early stage, but has disadvantages in that organs have to be removed from time to time, which causes side effects, and there is uncertainty in spreading cancer to other organs. Radiation therapy is advantageous for effectively treating cancer occurring in a particular organ, but has the following disadvantages: exposure of the patient to other cancer risks due to radiation, failure to prevent the spread of cancer cells to other organs, and significant pain to the patient during treatment. Chemotherapy is generally performed using anticancer drugs, but it is known that toxicity of anticancer drugs acts not only on cancer cells but also on normal cells of patients, causing side effects. Therefore, development of new anticancer drugs having higher cancer cell selectivity and as little toxicity as possible is desired.

Selenium is a trace element essential for life activities of the body. In recent years, studies have been made on selenium compounds, particularly organic selenium compounds, in an attempt to find compounds having anticancer or antitumor activities therefrom. For example, EI-Baulomy et al (K El-Baulomy, Drugs Future,1997, 22(5): 539-545) have found that benzyl selenium cyanide exhibits anti-tumor effects in a mouse model of DMBA-induced breast cancer. Benzyl selencyanide has a higher anticancer activity than sodium selenite, but has a strong off-taste itself and has side effects that cause significant weight loss in patients.

The research shows that the action mechanism of ebselen is mainly to inhibit the activity of target enzyme thioredoxin reductase and regulate the downstream signal conduction path and the anti-tumor apoptosis path thereof to realize the anti-tumor action of the drug, and the biological activity and low toxicity may be related to the cyclic selenamide structure or the benzisoselenone-containing heterocyclic ring (H JReich, et al J.Am.chem.Soc., 1987, 109(18):5549-, has synergistic effect and activity superior to that of ebselen.

Despite the discovery of the above organic selenium compounds, the existing organic selenium compounds still have the problems of further improved anticancer efficacy, limited anticancer spectrum, and limited structural types of compounds, and are far from meeting the increasing demands of human beings for cancer prevention and treatment. Therefore, the development of more effective anticancer drugs, especially organic selenium compounds, has been urgently needed.

Therefore, there is still a strong need in the art for new and highly effective cancer preventives or remedies, particularly novel organoselenium compounds having a good anticancer effect and a broad anticancer spectrum.

Disclosure of Invention

Through a great deal of experimental research, the inventor unexpectedly finds that the organic compound containing selenocyanide has unexpected biological activity for preventing and treating cancer. The compounds are useful in the treatment and/or prevention of various cancers.

Based on the above findings, in a first aspect, the present invention provides a compound having the structure of the following formula (I):

R_a-R_b-C(W)-O-L-SeCN

(I)

or a pharmaceutically acceptable salt thereof,

wherein

w is selected from O, S and Se;

R_bis a straight or branched alkylene or alkenylene chain of 1 to 4 carbon atoms, or is a direct covalent bond;

l is a straight or branched alkylene chain of 1 to 4 carbon atoms.

In the compounds of formula (I) according to the invention, preferably R_aSelected from unsubstituted or substituted phenyl, naphthyl, benzopyrrole, benzopyrrolidine alkyl and benzocyclopentenyl.

In the compounds of formula (I) according to the invention, the substituents are selected from phenyl, mesylphenyl C_1-4Alkyl-, halophenyl-formyl-, phenyl-formyl-, C_1-4Alkylphenylamino-, halogen, C_1-4Alkyl radical, C_1-4Alkoxy-, halo-C_1-4Alkyl-, halo-C_1-4Alkoxy-, acyl, C_1-4Alkyl acyl-, acyloxy, C_1-2Alkyl acyloxy-, C_1-2Alkylamino-.

Preferably, the heteroaryl group is selected from the group consisting of a benzopyrrole group, a benzopyrrolidine group, a benzocyclopentene group, a benzothiophene group, a benzofuranyl group, a benzimidazolyl group, an azabenzimidazolyl group, a benzoxazolyl group, a benzothiazolyl group, a benzothiadiazolyl group, an imidazopyridinyl group, an isoxazolopyridinyl group; particularly preferably, the heteroaryl group is selected from the group consisting of a benzopyrrole group, a benzopyrrolidinyl group and a benzocyclopentenyl group.

In some preferred embodiments of the invention, R_aSelected from phenyl, naphthyl, benzocyclopentenyl, benzopyrryl and benzopyrrolidinyl, and R_aOptionally substituted with one or two substituents selected from: halogen selected from fluorine, chlorine, bromine and iodine, phenyl, methanesulfonylphenylphosphinyl-, phenylamino, benzoyl, methoxy, linear or branched alkylene of 1 to 4 carbon atoms, trifluoromethyl.

In the compounds of formula (I) according to the invention, W is preferably O or S; more preferably O.

In the compounds of the formula (I) according to the invention, L is preferably (CH)₂)₂Or (CH)₂)₃That is, L is a C2 or C3 chain, and the chain is not limited to a straight chain and may include a branched moiety.

In some particularly preferred embodiments of the invention, the compound of formula (I) is a specific compound selected from the group consisting of:

or a pharmaceutically acceptable salt thereof.

In another aspect of the invention, there is also provided a pharmaceutical composition comprising a compound of the invention and optionally a carrier.

In yet another aspect of the invention, the above-described pharmaceutical composition may further comprise an additional active pharmaceutical ingredient, i.e., a second medicament suitable for treating the same or a related condition medically indicated to be treatable or preventable by administration of a compound of the present invention.

In yet another aspect of the invention, there is provided a process for preparing a compound of the invention, said process comprising reacting DCC (N, N' -dicyclohexylcarbodiimide) with compound R_a-R_b-C (W) -OH in an organic solvent, wherein the variables are as defined above. Preferably, said compound R_a-R_bThe molar ratio of-C (W) -OH to DCC is 1:1 to 1: 3. Preferably, the reaction is carried out under catalysis of 4-Dimethylaminopyridine (DMAP); preferably, DMAP and R_a-R_b-C (W) -OH in a molar ratio of 1:1 to 1: 2. The reaction is preferably carried out at a temperature below 0 ℃, for example at a temperature of-5 ℃.

Various embodiments of the present invention provide methods of using a compound, composition or combination of the present invention comprising administering to a patient in need of treatment of a malcondition thereof the compound, composition or combination at a dose, frequency and duration sufficient to provide a beneficial effect to the patient.

In another aspect of the invention, there is provided the use of a compound or pharmaceutical composition of the invention in the manufacture of a medicament for the prevention or treatment of cancer or for the prevention, treatment and/or alleviation of complications and/or symptoms associated with cancer.

Detailed Description

The term "treatment" is defined as the treatment or care of a patient for the purpose of combating a disease, condition, or disorder (e.g., one of a number of types of conditions collectively referred to as "cancer"), which includes the administration of a compound of the present invention to prevent the onset of symptoms or complications, or to alleviate symptoms or complications, or to cure or eliminate the disease, condition, or disorder.

"treating" in the context of the present invention means alleviating the symptoms associated with a disorder or disease, or inhibiting the further development or worsening of these symptoms, or preventing the disease or disorder. Similarly, an "effective amount" or "therapeutically effective amount" of a compound of the invention as used herein refers to an amount of the compound that completely or partially alleviates the symptoms associated with the disorder or condition, or halts or slows further development or worsening of these symptoms, or prevents or provides prophylaxis for the disorder or condition.

The term "cancer" as used herein refers to any malignant solid tumor, metastatic tumor or other condition in which cell division is uncontrolled and cells lose differentiation.

When a group is defined as "covalent bond," it is meant that the groups immediately adjacent to the indicated group are attached to each other by a covalent bond.

Unless a particular stereochemistry or isomeric form is specifically indicated, the compounds of the present invention are intended to include all chiral, diastereomeric, racemic forms of the structure. The compounds used in the present invention may include any enriched or resolved degree of optical isomers of any or all asymmetric atoms as is apparent from the description. It is within the scope of the present invention that racemic and diastereomeric mixtures and individual optical isomers may be separated or synthesized so as to be substantially free of their enantiomers or diastereomers.

Generally, "substituted" means that an organic group, as defined herein, which contains one or more bonds to a hydrogen atom, is substituted with one or more bonds to a non-hydrogen atom, i.e., a substituent.

Substituents of the compounds of the invention (including R)_aSubstituents in the definition) include halogen, alkyl (preferably C)_1-4Alkyl, more preferably C_1-2Alkyl group), alkoxy group (preferably C)_1-4Alkoxy, more preferably C_1-2Alkoxy), halo C_1-4Alkoxy- (preferably halo C)_1-2Alkoxy-), amino, acyl, C_1-4Alkylacyl- (preferably C)_1-2Alkyl acyl-), acyloxy, C_1-4Alkanoyloxy- (preferably C)_1-2Alkyl acyloxy-), carboxyl, nitro, cyano, C_1-4Alkylamino- (preferably C)_1-2Alkylamino-), halogeno C_1-4Alkyl (preferably halogenated C)_1-2Alkyl group), C_1-4Alkylamino radical C_1-4Alkyl- (preferably C)_1-2Alkylamino radical C_1-2Alkyl-), hydroxy C_1-4Alkyl- (preferably hydroxy C)_1-2Alkyl-), hydroxy C_1-4Alkylamino- (preferably hydroxy C)_1-2Alkylamino-), C_3-6Cycloalkyl radical, C_2-4An alkenyl group.

In the definition of substituents of the present invention, the dash "-" represents a group or a bonding position where a substituent is attached to the rest of the structural formula. As will be appreciated by those skilled in the art, for the structures of formula (I), R_aHaving a bonding position, and R_bThere are two bonding sites at both ends.

Alkyl groups include straight and branched chain alkyl groups having from 1 to about 8 carbon atoms, or in certain embodiments from 1 to 4 and even more preferably from 1 to 2 carbon atoms. Examples of straight chain alkyl groups include those having 1 to 8, preferably 1 to 4, more preferably 1-2 carbon atoms, such as methyl, ethyl, n-propyl, n-butyl, n-pentyl, n-hexyl, n-heptyl, and n-octyl. Examples of branched alkyl groups include, but are not limited to, isopropyl, isobutyl, sec-butyl, tert-butyl, neopentyl, isoamyl, and 2, 2-dimethylpropyl. Representative substituted alkyl groups may be substituted one or more times with any of the aforementioned groups, for example, amino, hydroxyl, cyano, carboxyl, nitro, thio, alkoxy, and halogen groups.

Cycloalkyl is a cyclic alkyl group such as, but not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. In preferred embodiments, the cycloalkyl group has 3 to 8 ring members, while in other embodiments the number of ring carbon atoms is 3 to 5, 6 or 7. Cycloalkyl groups further include polycyclic cycloalkyl groups such as, but not limited to, norbornyl, adamantyl, bornyl, camphene, isobornene, and carenyl, and fused rings such as, but not limited to, decahydronaphthyl and the like. Cycloalkyl also includes rings substituted with straight or branched chain alkyl as defined above. Representative substituted cycloalkyl groups may be mono-substituted or substituted more than once, such as, but not limited to, 2-, 2,3-, 2,4-, 2,5-, or 2, 6-disubstituted cyclohexyl or mono-, di-, or tri-substituted norbornyl or cycloheptyl, which may be substituted with, for example, amino, hydroxy, cyano, carboxy, nitro, thio, alkoxy, and halo groups. The term "cycloalkenyl", alone or in combination, denotes cyclic alkenyl groups.

Aryl is a cyclic aromatic hydrocarbon that does not contain heteroatoms. Thus, aryl groups include, but are not limited to, phenyl, azulenyl, heptenylyl (heptalenyl), biphenyl, dicyclopentadiene acenyl (indacenyl), fluorenyl, phenanthryl, triphenylenyl (triphenylenyl), pyrenyl, napthyl (napthylenyl), biphenylene, anthracenyl, and naphthyl. In certain embodiments, the aryl group contains 6 to 14 carbons in the ring portion of the group. The aryl group may be unsubstituted or substituted, as defined above. Representative substituted aryl groups may be monosubstituted or substituted more than once, such as but not limited to 2-, 3-, 4-, 5-, or 6-substituted phenyl or 2-8 substituted naphthyl, which may be substituted with carbon or non-carbon groups (such as those described above).

Heteroaryl is an aromatic ring compound containing 5 or more ring members, wherein one or more ring members are heteroatoms, such as, but not limited to N, O and S. Is named as C₂The heteroaryl group of the heteroaryl group may be a 5-membered ring having two carbon atoms and three heteroatoms, a 6-membered ring having two carbon atoms and four heteroatoms, or the like. Likewise, C₄The heteroaryl group may be a 5-membered ring having one heteroatom, a 6-membered ring having 2 heteroatoms, or the like. The sum of the number of carbon atoms plus the number of heteroatoms is equal to the total number of ring atoms. Heteroaryl groups include, but are not limited to, groups such as: pyrrolyl, pyrazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, thiazolyl, pyridyl, thienyl, benzothienyl, benzofuranyl, indolyl, azaindolyl, indazolyl, benzimidazolyl, azabenzimidazolyl, benzoxazolyl, benzothiazolyl, benzothiadiazolyl, imidazopyridinyl, isoxazolopyridyl, thianaphthyl, purinyl, xanthyl, adenine, guanine, quinolyl, isoquinolyl, tetrahydroquinolyl, quinoxalyl and quinazolinyl. Heteroaryl groups may be unsubstituted or may be substituted as described above. Representative substituted heteroaryl groups can be substituted one or more times with those groups described above.

Other examples of aryl and heteroaryl groups include, but are not limited to, phenyl, biphenyl, indenyl, naphthyl (1-naphthyl, 2-naphthyl), N-hydroxytetrazolyl, N-hydroxytriazolyl, N-hydroxyimidazolyl, anthracenyl (1-anthracenyl, 2-anthracenyl, 3-anthracenyl), thienyl (2-thienyl, 3-thienyl), furyl (2-furyl, 3-furyl), indolyl, oxadiazolyl, isoxazolyl, quinazolinyl, fluorenyl, xanthenyl, isoindolyl, benzhydryl, acridinyl, thiazolyl, pyrrolyl (2-pyrrolyl), pyrazolyl (3-pyrazolyl), imidazolyl (1-imidazolyl, 2-imidazolyl, 4-imidazolyl, 5-imidazolyl), triazolyl (1,2, 3-triazol-1-yl, 1,2, 3-triazol-2-yl, 1,2, 3-triazol-4-yl, 1,2, 4-triazol-3-yl), oxazolyl (2-oxazolyl, 4-oxazolyl, 5-oxazolyl), thiazolyl (2-thiazolyl, 4-thiazolyl, 5-thiazolyl), pyridyl (2-pyridyl, 3-pyridyl, 4-pyridyl), pyrimidinyl (2-pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl, 6-pyrimidinyl), pyrazinyl, pyridazinyl (3-pyridazinyl, 4-pyridazinyl, 5-pyridazinyl), quinolinyl (2-quinolinyl, 3-quinolinyl, 4-quinolinyl, 5-pyridazinyl), 5-quinolyl group, 6-quinolyl group, 7-quinolyl group, 8-quinolyl group), isoquinolyl group (1-isoquinolyl group, 3-isoquinolyl group, 4-isoquinolyl group, 5-isoquinolyl group, 6-isoquinolyl group, 7-isoquinolyl group, 8-isoquinolyl group), benzo [ b ] furyl group (2-benzo [ b ] furyl group, 3-benzo [ b ] furyl group, 4-benzo [ b ] furyl group, 5-benzo [ b ] furyl group, 6-benzo [ b ] furyl group, 7-benzo [ b ] furyl group), 2, 3-dihydro-benzo [ b ] furyl group (2- (2, 3-dihydro-benzo [ b ] furyl group), 3- (2, 3-dihydro-benzo [ b ] furyl group), 4- (2, 3-dihydro-benzo [ b ] furyl), 5- (2, 3-dihydro-benzo [ b ] furyl), 6- (2, 3-dihydro-benzo [ b ] furyl), 7- (2, 3-dihydro-benzo [ b ] furyl), benzo [ b ] thienyl (2-benzo [ b ] thienyl, 3-benzo [ b ] thienyl, 4-benzo [ b ] thienyl, 5-benzo [ b ] thienyl, 6-benzo [ b ] thienyl, 7-benzo [ b ] thienyl), 2, 3-dihydro-benzo [ b ] thienyl, (2- (2, 3-dihydro-benzo [ b ] thienyl), 3- (2, 3-dihydro-benzo [ b ] thienyl), 4- (2, 3-dihydro-benzo [ b ] thienyl), 5- (2, 3-dihydro-benzo [ b ] thienyl), 6- (2, 3-dihydro-benzo [ b ] thienyl), 7- (2, 3-dihydro-benzo [ b ] thienyl), indolyl (1-indolyl, 2-indolyl, 3-indolyl, 4-indolyl, 5-indolyl, 6-indolyl, 7-indolyl), indazole (1-indazolyl, 3-indazolyl, 4-indazolyl, 5-indazolyl, 6-indazolyl, 7-indazolyl), benzimidazolyl (1-benzimidazolyl, 2-benzimidazolyl, 4-benzimidazolyl, 5-benzimidazolyl, etc.), 6-benzimidazolyl, 7-benzimidazolyl, 8-benzimidazolyl), benzoxazolyl (1-benzoxazolyl, 2-benzoxazolyl), benzothiazolyl (1-benzothiazolyl, 2-benzothiazolyl, 4-benzothiazolyl, 5-benzothiazolyl, 6-benzothiazolyl, 7-benzothiazolyl), carbazolyl (1-carbazolyl, 2-carbazolyl, 3-carbazolyl, 4-carbazolyl) and the like.

More particularly, aryl and heteroaryl groups may include phenyl, isoindolinyl, imidazolyl, oxazolyl, benzimidazolyl and benzoxazolyl groups; wherein any aryl or heteroaryl group may be unsubstituted, mono-substituted or, independently, poly-substituted, for example with a J group as defined herein.

The term "alkoxy" means that the oxygen atom is attached to an alkyl group as defined above, including cycloalkyl groups. Examples of linear alkoxy groups include, but are not limited to, methoxy, ethoxy, propoxy, butoxy, pentoxy, hexoxy, and the like. Examples of branched alkoxy groups include, but are not limited to, isopropoxy, sec-butoxy, tert-butoxy, isopentoxy, isohexoxy, and the like. Examples of cycloalkoxy groups include, but are not limited to, cyclopropoxy, cyclobutoxy, cyclopentoxy, cyclohexyloxy, and the like.

The term "halogen" as used herein includes fluorine, chlorine, bromine and iodine. "haloalkyl" includes monohaloalkyl and polyhaloalkyl (wherein all halogen atoms may be the same or different). Partially halogenated alkyl is "haloalkyl" within the meaning of the present disclosure. Examples of haloalkyl groups include trifluoromethyl, 1-dichloroethyl, 1, 2-dichloroethyl, 1, 3-dibromo-3, 3-difluoropropyl, and the like.

The term "acyl" as used herein refers to a group comprising a carbonyl moiety, wherein the group is bonded via the carbonyl carbon atom. The carbonyl carbon atom is also bonded to other carbon atoms, which may be part of an alkyl, aryl, aralkylcycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, heteroarylalkyl, or the like. In the particular case where the carbonyl carbon atom is bonded to hydrogen, the group is "formyl", which is an acyl group (the term being as defined herein). Other examples include acetyl, benzoyl, phenylacetyl, pyridylacetyl, cinnamoyl, acryloyl, and the like. When a group containing a carbon atom bonded to a carbonyl carbon atom contains a halogen, the group is referred to as a "haloacyl". One example is trifluoroacetyl.

"salts" as is well known in the art include organic compounds such as carboxylic acids, sulfonic acids or amines in ionic form in combination with a counter ion. For example, an acid in anionic form may form a salt with: cations such as metal cations, e.g., sodium, potassium, and the like; ammonium salts such as NH₄ ⁺Or cations of various amines, including tetraalkylammonium salts such as tetramethylammonium, or other cations such as trimethylsulfonium, and the like. A "pharmaceutically acceptable" salt is a salt formed from ions that are approved for human use and are generally non-toxic, such as the hydrochloride or sodium salt. "zwitterions" are internal salts, which can be formed, for example, in molecules having at least two ionizable groups, one forming an anion and the other forming a cation, which are in equilibrium with one another. For example, amino acids (e.g. glycine)) May be present in zwitterionic form. "zwitterion" is a salt within the meaning herein.

A "hydrate" is a compound that exists in combination with a water molecule. The composition may contain a stoichiometric amount of water, such as a monohydrate or dihydrate, or may contain any amount of water.

A "solvate" is a similar composition except that water is replaced with a solvent different from water. For example, methanol or ethanol may form "alcoholates", which may also be stoichiometric or non-stoichiometric.

"tautomers" are two forms of matter that differ only in the position of a hydrogen atom in the molecular structure.

Another aspect of the present invention provides a pharmaceutical composition comprising a compound of the present invention and optionally a carrier or a pharmaceutical composition further comprising a further pharmaceutically active ingredient in addition to a compound of the present invention and optionally a carrier. The pharmaceutical compositions of the invention may be prepared by conventional techniques, for example as described in Remington: the method described in The Science and Practice of Pharmacy, 19 th edition, 1995, which is incorporated herein by reference. The compositions may be presented in conventional forms, such as capsules, tablets, aerosols, solutions, suspensions or topical application forms.

Typical compositions comprise a compound of the invention and a carrier. For example, the active compound is typically mixed with a carrier, or diluted by a carrier, or enclosed within a carrier which may be in the form of an ampoule, capsule, sachet (sachet), paper or other container. When the active compound is mixed with a carrier, or when the carrier serves as a diluent, the carrier can be a solid, semi-solid, or liquid material that serves as a carrier, excipient, or medium for the active compound. The active compound may be adsorbed on a particulate solid carrier (e.g. contained in a sachet). Some examples of suitable carriers are water, salt solutions, alcohols, polyethylene glycols, polyhydroxyethoxylated castor oil, peanut oil, olive oil, gelatin, lactose, terra alba, sucrose, dextrin, magnesium carbonate, sugars, cyclodextrins, amylose, magnesium stearate, talc, gelatin, agar, pectin, acacia, stearic acid or lower alkyl ethers of cellulose, silicic acid, fatty acids, fatty acid amines, fatty acid mono-and diglycerides, pentaerythritol fatty acid esters, polyoxyethylene, hydroxymethylcellulose and polyvinylpyrrolidone. Similarly, the carrier or diluent may include any sustained release material known in the art, such as glyceryl monostearate or glyceryl distearate alone or with a wax.

The formulations may be mixed with adjuvants which do not deleteriously react with the active compound. These additives may include wetting agents, emulsifying and suspending agents, salts for influencing osmotic pressure, buffering and/or coloring substances, preservatives, sweeteners or flavorings. The composition may also be sterilized, if desired.

The route of administration may be any route which is effective for transporting the active compounds of the invention to the appropriate or desired site of action, for example the oral, nasal, pulmonary, buccal, subcutaneous, intradermal, transdermal or parenteral routes, for example the rectal, depot (depot), subcutaneous, intravenous, intraurethral, intramuscular, intranasal, ophthalmic solutions or ointments route, the oral route being preferred.

If a solid carrier is used for oral administration, the formulation may be tableted, placed in a hard gelatin capsule as a powder or pellet, or it may be in the form of a lozenge or troche. If a liquid carrier is used, the formulation may be in the form of a syrup, emulsion, soft gelatin capsule, or sterile injectable liquid, such as an aqueous or non-aqueous liquid suspension or solution.

Injectable dosage forms typically comprise an aqueous or oily suspension, which may be formulated using suitable dispersing or wetting agents and suspending agents. Injectable forms may be in the form of a solution phase or a suspension prepared with a solvent or diluent. Acceptable solvents or carriers include sterile water, ringer's solution, or isotonic saline solution. Alternatively, sterile oils may be employed as a solvent or suspending agent. Preferably, the oil or fatty acid is non-volatile and comprises a natural or synthetic oil, a fatty acid, a monoglyceride, diglyceride, or triglyceride.

For injection, the formulation may also be a powder suitable for reconstitution with a suitable solution as described above. Examples of these include, but are not limited to, freeze-dried, spin-dried or spray-dried powders, amorphous powders, granules, precipitates or microparticles. For injections, the formulation may optionally include stabilizers, pH modifiers, surfactants, bioavailability modifiers, and combinations of these agents. The compounds may be formulated for parenteral administration by injection, for example by bolus injection or continuous infusion. Unit dosage forms for injection may be in ampoules or in multi-dose containers.

The formulations of the present invention may be designed to provide rapid, sustained or delayed release of the active ingredient after administration to a patient by methods well known in the art. Thus, the formulation may also be formulated for controlled release or slow release.

The compounds of the present invention are effective over a wide dosage range. For example, in the treatment of adults, a dose of about 0.05 to about 5000mg, preferably about 1 to about 2000mg, more preferably about 2 to about 2000mg per day may be used. Typical dosages are from about 10mg to about 1000mg per day. When selecting a patient treatment regimen, it may often be necessary to start with a higher dose and reduce the dose when the condition is controlled. The precise dosage will depend upon the activity of the compound, the mode of administration, the desired treatment, the form of administration, the subject to be treated and the weight of the subject to be treated, as well as the preferences and experience of the attending physician or veterinarian.

Typically, the compounds of the present invention are dispensed in unit dosage forms containing from about 0.05mg to about 1000mg of the active ingredient per unit dose and a pharmaceutically acceptable carrier.

In general, dosage forms suitable for oral, nasal, pulmonary or transdermal administration include from about 125 μ g to about 1250mg, preferably from about 250 μ g to about 500mg, more preferably from about 2.5mg to about 250mg of the compound in admixture with a pharmaceutically acceptable carrier or diluent.

The dosage form may be administered once daily, or more than once daily, e.g., twice daily or three times daily. Alternatively, the dosage form may be administered less frequently than once daily, for example every other day or weekly, if deemed appropriate by the prescribing physician.

The pharmaceutical compositions may be in the form of tablets, capsules, powders, granules, lozenges, liquids or gels. Tablets and capsules for oral administration may be in a form suitable for unit dose administration and may contain conventional excipients, such as: binders such as syrup, gum arabic, gelatin, sorbitol, tragacanth, polyvinylpyrrolidone (PVP); fillers such as lactose, sugars, corn flour, calcium phosphate, sorbitol or glycine; tablet lubricants such as magnesium stearate, silicon dioxide, talc, polyethylene glycol or silicon dioxide; disintegrants such as potato starch; acceptable lubricants such as sodium lauryl sulfate. The tablets may be coated according to known methods of conventional pharmaceutical practice. Oral liquid preparations may be in the form of aqueous or oily suspensions, solutions, emulsions, syrups or tinctures, or may be presented as a dry substance for reconstitution with water or other suitable vehicle before use. These liquid preparations may contain conventional additives such as suspending agents (e.g., sorbitol, syrup, methyl cellulose, glucose syrup, gelatin, hydrogenated edible fats and oils). Emulsifying agents (e.g. lecithin, sorbitol monooleate or acacia), non-aqueous vehicles (including edible oils such as almond oil, fractionated coconut oil, fats and oils such as glycerol, propylene glycol or ethanol), preservatives (e.g. methyl or propyl p-hydroxybenzoic acid or sorbic acid), and if desired conventional flavouring or colouring agents.

The percentage of active substance in the pharmaceutical composition of the present invention is variable because the pharmaceutical formulation must be formulated in a suitable proportion of the dosage to achieve the desired therapeutic effect. In general, the pharmaceutical preparations according to the invention should be administered orally or by injection in a dose of 1 to 15mg of active substance per 70kg of body weight per day. Some examples are given below by way of illustration and not by way of limitation.

The present invention provides, in various embodiments, methods of synthesizing the compounds of the invention herein. The general method comprises reacting R_a-R_bA compound represented by-C (W) -OH with 2-selenocyanolethanol or 3-selenocyanopropanol (NCSe (CH)₂)_nOH) (n is 2 or 3) inAnd (3) reacting in an organic solvent. The reaction can be carried out at low temperature, under catalysts (DCC and DMAP). In some preferred embodiments, the compound of formula R_a-R_bDissolving a (C) (W) -OH compound in tetrahydrofuran or dichloromethane, adding 4-dimethylaminopyridine, adding N, N' -Dicyclohexylcarbodiimide (DCC) under stirring, and reacting under stirring in ice bath to generate a target compound R_a-R_b-C(W)-O-L-SeCN。

Examples

The technical solution and applications of the present invention are further illustrated by the following specific examples:

examples of synthetic preparations

Example 1: preparation of Compound I-a

The reaction formula is as follows:

a50 ml flask was charged with Compound II-a (100mg, 1.0eq) and 10ml of anhydrous tetrahydrofuran, and 2-selenoethanol (54mg, 1.2eq), DCC (62mg, 1.0eq) and DMAP (44mg, 1.2eq) were added in this order under ice-cooling, and the reaction was stirred for 12 hours and monitored by TLC for completion. The solvent was distilled off under reduced pressure, and the extract was separated by silica gel column chromatography using ethyl acetate (V): petroleum ether (V) ═ 1:3 as the mobile phase, gave a pale yellow solid, compound I-a 120mg, in 86% yield.

Nuclear magnetic resonance¹H NMR(400MHz,CDCl₃):δ2.24(s,3H,-CH₃),2.88(s,3H,CH₃),3.16(t,2H,J＝8.00Hz,CH₂),3.64(s,2H,CH₂),3.85(t,2H,J＝8.00Hz,CH₂),6.55(t,1H,J＝8.00Hz,ArH),6.80(d,1H,J＝8.00Hz,ArH),7.11(d,1H,J＝4.00Hz,ArH),7.17(s,1H,CH),7.58(d,2H,J＝8.00Hz,ArH),7.73(d,2H,J＝8.00Hz,ArH).¹³C NMR(100MHz,CDCl₃):δ11.3,26.2,34.9,43.3,51.2,107.1(d,J＝24Hz),113.9(d,J＝22Hz),122.9,129.4,129.8,130.9,132.4,138.3,140.2,141.4,145.6,147.8(d,J＝9.5Hz),163.2,163.9,165.5,174.8.¹⁹F NMR(CDCl₃,376MHz):δ＝-112.1(s,F).

ESI-MS:471.4([M+1]⁺).

Example 2: preparation of Compound I-b

The reaction formula is as follows:

a50 ml flask was charged with Compound II-b (100mg, 1.0eq) and 10ml of anhydrous tetrahydrofuran, and 3-selenocyanopropanol (59mg, 1.2eq), DCC (62mg, 1.0eq) and DMAP (44mg, 1.2eq) were added in this order under ice-cooling and the reaction was stirred for 12 hours and monitored by TLC for completion. The solvent was distilled off under reduced pressure, and the extract was separated by silica gel column chromatography using ethyl acetate (V): petroleum ether (V) ═ 1:3 as the mobile phase, gave a white solid, i.e. compound I-b 110mg, in 75% yield.

Nuclear magnetic resonance¹H NMR(400MHz,CDCl₃):δ2.04(t,2H,J＝4.00Hz,CH₂),2.20(s,3H,CH₃),2.84(s,3H,–CH₃),3.00(t,2H,J＝4.00Hz,CH₂),3.33–3.40(m,2H,CH₂),3.48(s,2H,CH₂),6.50-6.58(m,1H,ArH),6.88(d,1H,J＝8.00Hz,ArH),7.17–7.20(m,2H,ArH),7.70(d,2H,J＝13Hz,8.00Hz,ArH),7.77(d,2H,J＝8.00Hz,ArH).¹³C NMR(100MHz,CDCl₃):δ10.4,26.6,31.1,34.3,37.9,44.2,101.3,104.9(d,J＝24Hz),112.5(d,J＝22Hz),125.0(d,J＝12Hz),129.3,129.8(d,J＝3.0Hz),131.5,133.4(d,J＝2.0Hz),139.2,139.8,142.6,146.8,147.9(d,J＝9.0Hz),164.1,165.6,170.3.¹⁹F NMR(CDCl₃,376MHz):δ＝-112.3(s,F).

ESI-MS:486.4([M+1]⁺).

Example 3: the preparation reaction of compounds I-c is as follows:

a50 ml flask was charged with Compound II-c (100mg, 1.0eq) and 10ml of anhydrous tetrahydrofuran, and 2-selenoethanol (72mg, 1.2eq), DCC (82mg, 1.0eq) and DMAP (59mg, 1.2eq) were added in this order under ice-cooling, and the reaction was stirred for 12 hours and monitored by TLC for completion. The solvent was distilled off under reduced pressure, and the extract was separated by silica gel column chromatography using ethyl acetate (V): petroleum ether (V) ═ 1:3 as the mobile phase, gave a white solid, i.e. compound I-c 100mg, in 66% yield.

Nuclear magnetic resonance¹H NMR(400MHz,CDCl₃)：δ1.50(d,3H,J＝7.20Hz,CH₃),3.13(t,2H,J＝4.00Hz,CH₂),3.70(q,1H,J＝7.20Hz,CH),3.81(t,2H,J＝4.00Hz,CH₂),7.04-7.11(m,2H,ArH),7.31-7.42(m,4H,ArH),7.46-7.50(m,2H,ArH).¹³C NMR(100MHz,CDCl₃):δ18.3,24.2,48.4,53.8,114.7(d,J＝24Hz),124.2,129.1,129.3,129.5,130.4,131.8,136.4,144.5(d,J＝8Hz),159.8,162.5,165.3,178.6.¹⁹F NMR(CDCl₃,376MHz):δ＝-112.2(s,F).

ESI-MS:377.3([M+1]⁺).

Example 4: preparation of Compounds I-d

The reaction formula is as follows:

a50 ml flask was charged with Compound II-d (100mg, 1.0eq) and 10ml of anhydrous tetrahydrofuran, and 3-selenocyanopropanol (79mg, 1.2eq), DCC (82mg, 1.0eq) and DMAP were added in this order under ice bath

(59mg, 1.2eq) the reaction was stirred for 12 hours and monitored by TLC for completion. The solvent was distilled off under reduced pressure, and the extract was separated by silica gel column chromatography using ethyl acetate (V): petroleum ether (V) ═ 1:3 as the mobile phase, gave a white solid, i.e. compound I-d 110mg, in 70% yield.

Nuclear magnetic resonance¹H NMR(400MHz,CDCl₃):δ1.52(d,3H,J＝8.00Hz,CH₃),1.83-1.88(m,2H,CH₂),2.85(t,2H,J＝8.00Hz,CH₂),3.34(t,2H,J＝8.00Hz,CH₂),3.61(q,1H,J＝8.00Hz,CH),7.08-7.13(m,2H,ArH),7.33-7.42(m,4H,ArH),7.47(d,2H,J＝8.00Hz,ArH).¹³C NMR(100MHz,CDCl₃):δ18.0,27.5,32.1,39.4,45.6,101.3,117.2(d,J＝24Hz),124.7,128.9,128.3(d,J＝13Hz),128.7,129.1,132.0,136.2,144.7,159.2,162.1,175.8.¹⁹F NMR(CDCl₃,376MHz):δ＝-114.9(s,F).

ESI-MS:391.0([M+1]⁺).

EXAMPLE 5 preparation of Compounds I-e

The reaction formula is as follows:

a50 ml flask was charged with Compound II-e (100mg, 1.0eq) and 10ml of anhydrous tetrahydrofuran, and 2-selenoethanol (54mg, 1.2eq), DCC (62mg, 1.0eq) and DMAP (44mg, 1.2eq) were added in this order under ice-cooling, and the reaction was stirred for 12 hours and monitored by TLC for completion. The solvent was distilled off under reduced pressure, and the extract was separated by silica gel column chromatography using ethyl acetate (V): petroleum ether (V) ═ 1:3 as the mobile phase, gave a white solid, i.e. compound I-e 120mg, 84% yield.

Nuclear magnetic resonance¹H NMR(400MHz,CDCl₃):δ2.12(s,3H,CH₃),3.03(t,2H,J＝8.00Hz,CH₂),3.60(t,2H,J＝8.00Hz,CH₂),3.64(s,3H,CH₃),6.68(d,1H,J＝8.00Hz,ArH),6.86(d,1H,J＝8.00Hz,ArH),7.11(m,1H,ArH),7.60(d,2H,J＝8.00Hz,ArH),7.65(d,2H,J＝8.00Hz,ArH).¹³C NMR(100MHz,CDCl₃):δ14.2,26.3,33.5,56.7,101.1,103.7,112.9,114.6,116.4,129.4,130.4,131.3,131.8,133.4,134.2,139.4,157.3,166.7.

ESI-MS:476.8([M+1]⁺).

EXAMPLE 6 preparation of Compounds I-f

The reaction formula is as follows:

a50 ml flask was charged with Compound II-f (100mg, 1.0eq) and 10ml of anhydrous tetrahydrofuran, and 3-selenocyanopropanol (49mg, 1.2eq), DCC (62mg, 1.0eq) and DMAP (44mg, 1.2eq) were added in this order under ice-cooling, and the reaction was stirred for 12 hours and monitored by TLC for completion. The solvent was distilled off under reduced pressure, and the extract was separated by silica gel column chromatography using ethyl acetate (V): petroleum ether (V) ═ 1:3 as the mobile phase gave white solid, compound I-f 105mg, 71% yield.

Nuclear magnetic resonance¹H NMR(400MHz,CDCl₃):δ2.08(t,2H,J＝8.00Hz,CH₂),2.41(s,3H,CH₃),3.05(t,2H,J＝8.00Hz,CH₂),3.30-3.34(m,2H,CH₂),3.67(s,2H,CH₂),3.88(s,3H,OCH₃),6.64-6.68(m,1H,ArH),6.80-6.82(m,2H,ArH),7.53(d,2H,J＝8.00Hz,ArH),7.69(d,2H,J＝8.00Hz,ArH).¹³C NMR(100MHz,CDCl₃):δ12.6,26.4,29.4,31.5,37.7,56.3,101.2,104.3,111.4,111.6,116.4,128.3,130.8,131.1,131.4,134.3,137.7,140.5,157.6,166.5,169.8.

ESI-MS:490.0([M+1]⁺).

Example 7 preparation of Compounds I-g

The reaction formula is as follows:

a50 ml flask was charged with Compound II-g (100mg, 1.0eq) and 10ml of anhydrous tetrahydrofuran, and 2-selenoethanol (72mg, 1.2eq), DCC (82mg, 1.0eq) and DMAP (59mg, 1.2eq) were added in this order under ice-cooling, and the reaction was stirred for 12 hours and monitored by TLC for completion. The solvent was distilled off under reduced pressure, and the extract was separated by silica gel column chromatography using ethyl acetate (V): petroleum ether (V) ═ 1:3 as the mobile phase, gave a pale yellow solid, compound I-g 100mg, 65% yield.

Nuclear magnetic resonance¹H NMR(400MHz,CDCl₃):δ1.48(d,3H,J＝8.00Hz,CH₃),2.12-2.16(m,2H,CH₂),3.03(m,2H,CH₂),3.68(q,1H,J＝8.00Hz,CH),7.40-7.46(m,3H,ArH),7.61-7.67(m,3H,ArH),7.76-7.82(m,3H,ArH).¹³C NMR(100MHz,CDCl₃):δ17.5,31.2,38.5,47.6,102.6,128.0,128.6,129.2,129.7,130.4,131.0,131.5,137.6,138.8,142.2,172.6,193.9.

ESI-MS:387.3([M+1]⁺).

EXAMPLE 8 preparation of Compounds I-h

The reaction formula is as follows:

a50 ml flask was charged with Compound II-h (100mg, 1.0eq) and 10ml of anhydrous tetrahydrofuran, and 3-selenocyanopropanol (79mg, 1.2eq), DCC (82mg, 1.0eq) and DMAP (59mg, 1.2eq) were added in this order under ice-cooling and the reaction was stirred for 12 hours and monitored by TLC for completion. The solvent was distilled off under reduced pressure, and the extract was separated by silica gel column chromatography using ethyl acetate (V): petroleum ether (V) ═ 1:3 as the mobile phase, gave a pale yellow solid, compound I-h 105mg, 65% yield.

Nuclear magnetic resonance¹H NMR(400MHz,CDCl₃):δ1.53(d,3H,J＝8.00Hz,CH₃),2.02-2.06(m,2H,CH₂),2.96(t,2H,J＝8.00Hz,CH₂),3.35-3.38(m,2H,CH₂),3.63(q,1H,J＝8.00Hz,CH),7.44-7.51(m,3H,ArH),7.56-7.61(m,3H,ArH),7.74-7.79(m,3H,ArH).¹³C NMR(100MHz,CDCl₃):δ18.6,27.2,31.1,38.4,46.9,102.3,128.4,128.9,129.0,129.3,130.1,131.4,132.7,137.3,138.1,141.7,174.5,196.6.

ESI-MS:402.3([M+1]⁺).

Example 9 preparation of Compounds I-I

The reaction formula is as follows:

a50 ml flask was charged with Compound II-i (100mg, 1.0eq) and 10ml of anhydrous tetrahydrofuran, and 2-selenoethanol (76mg, 1.2eq), DCC (86mg, 1.0eq) and DMAP (62mg, 1.2eq) were added in this order under ice-cooling, and the reaction was stirred for 12 hours and monitored by TLC for completion. The solvent was distilled off under reduced pressure, and the extract was separated by silica gel column chromatography using ethyl acetate (V): petroleum ether (V) ═ 1:3 as the mobile phase, gave a pale yellow solid, compound I-I115 mg, 73% yield.

Nuclear magnetic resonance¹H NMR(400MHz,DMSO):δ2.08(s,3H,CH₃),2.32(s,3H,CH₃),3.15(t,2H,J＝8.00Hz,CH₂),3.67(t,2H,J＝8.00Hz,CH₂),6.60–6.64(m,2H,ArH),6.96-6.99(m,1H,ArH),7.06-7.08(m,2H,ArH),7.15-7.17(m,1H,ArH),8.10(d,1H,J＝4.00Hz,ArH),9.67(s,1H,NH).¹³C NMR(100MHz,DMSO):δ13.8,21.2,23.8,48.4,114.8,117.7,119.2,124.4,126.2,126.8,131.1,131.4,134.8,137.3,138.6,147.2,172.5,174.6.

ESI-MS:374.1([M+1]⁺).

EXAMPLE 10 preparation of Compounds I-j