CN107033097B - Oxadiazole derivative, preparation method and medical application thereof - Google Patents

Oxadiazole derivative, preparation method and medical application thereof Download PDF

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CN107033097B
CN107033097B CN201710060610.4A CN201710060610A CN107033097B CN 107033097 B CN107033097 B CN 107033097B CN 201710060610 A CN201710060610 A CN 201710060610A CN 107033097 B CN107033097 B CN 107033097B
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CN107033097A (en
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吕贺军
费洪博
贺峰
陶维康
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Jiangsu Hengrui Medicine Co Ltd
Shanghai Hengrui Pharmaceutical Co Ltd
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Shanghai Hengrui Pharmaceutical Co Ltd
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D271/00—Heterocyclic compounds containing five-membered rings having two nitrogen atoms and one oxygen atom as the only ring hetero atoms
    • C07D271/02—Heterocyclic compounds containing five-membered rings having two nitrogen atoms and one oxygen atom as the only ring hetero atoms not condensed with other rings
    • C07D271/08—1,2,5-Oxadiazoles; Hydrogenated 1,2,5-oxadiazoles
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings

Abstract

The invention relates to oxadiazole derivatives, a preparation method thereof and application thereof in medicines. In particular, the invention relates to oxadiazole derivatives shown in a general formula (I), a preparation method thereof, a pharmaceutical composition containing the derivatives, and application of the oxadiazole derivatives in preparing a medicament for preventing and/or treating diseases with IDO (insulin-dependent diabetes mellitus) mediated tryptophan metabolic pathway pathological characteristics, wherein the diseases comprise cancer, Alzheimer disease, autoimmune diseases, depression, anxiety, cataract, mental disorder and AIDS. Wherein each substituent in the general formula (I) is defined as the specification.

Description

Oxadiazole derivative, preparation method and medical application thereof
Technical Field
The invention belongs to the field of medicines, and relates to an oxadiazole derivative, a preparation method thereof and application thereof in medicine research.
Background
The biological treatment of tumor is a new treatment method for preventing and treating tumor by applying modern biotechnology and related products, and is a fourth mode of tumor treatment after surgery, radiotherapy and chemotherapy (Clin Cancer Res, 1997; 3:2623-2629) due to the characteristics of safety, effectiveness, low adverse reaction and the like, and the biological treatment of tumor obtains the anti-tumor effect by mobilizing the natural defense mechanism of the host, such as the mechanism of inhibiting IDO-mediated tumor immune escape or giving naturally generated substances with strong targeting property.
Indoleamine 2,3-dioxygenase (IDO) is an iron-containing heme monomeric protein consisting of 403 amino acid residues, including two folded alpha-helical domains, the large domain containing a catalytic pocket in which a substrate can interact hydrophobically with IDO (Int J Biochem Cell biol.2007; 39(12): 2167-72). In mammals, there are two genes encoding unrelated heme-containing enzymes that catalyze the oxidative degradation of tryptophan: IDO and tryptophan 2,3-dioxygenase (TDO). Each enzyme catalyzes the same reaction: the oxidative breakdown of the 2, 3-double bond of the indole ring is promoted in tryptophan catabolism, the first rate-limiting step of the kynurenine pathway. TDO expression is primarily restricted to the liver and appears to be a homeostatic or "housekeeping" gene that cannot be induced or regulated by signals from the immune system (Nat Rev Immunol.2004; 4(10): 762-74). IDO is an enzyme that catalyzes the conversion of tryptophan into formylkynurenine, is widely distributed in tissues other than liver of human and other mammals (rabbits and mice), is the only rate-limiting enzyme that catalyzes the catabolism of tryptophan, and tryptophan is an amino acid essential for cell maintenance, activation and proliferation, and is also an essential component constituting proteins (Adv Exp Med biol. 2003; 527:455-63, Biochim biophysis acta. 2001; 1527(3): 167-75). IDO is closely related to various cytokines such as interferon (interferon), Interleukin (IL), tumor necrosis factor, etc., and can activate IDO (JPsychiatry neurosci.2004; 29(1): 11-17, Med Hypotheses.2003; 61(5-6):519-25) under certain conditions. On one hand, IDO causes local tryptophan depletion, so that T-cells are arrested in the middle stage of G1, and the proliferation of the T-cells is inhibited; on the other hand, the main product of canine urea produced by IDO catalysis of tryptophan metabolism induces T-cell apoptosis by oxygen free radical mediated changes in intracellular oxidants and antioxidants, which is an inherent immunosuppressive mechanism present in the body. A large number of studies at present show that IDO is highly expressed in leukemia cells, so that local T cell proliferation is inhibited, T-cell mediated immune reaction is inhibited, T-cell activation signal transduction is inhibited, and the attack of tumor cells escaping from an immune system is mediated. It has been found that most human tumors constitutively express IDO (J Exp Med.2002; 196(4):459-68, Nat Med.2003; 9(10):1269-74, Trends Mol Med.2004; 10(1): 15-8). Therefore, IDO is a potential target for cancer immunotherapy.
Disclosed inhibitor patent applications for selective inhibition of IDO include WO2004094409, WO2006122150, WO2007075598, WO200409387, WO2008147283, WO2013174947, WO2008075991, WO2004093871, WO2005051321, WO 200605638, WO2010005958, and WO2014066834, and the like.
The IDO inhibitor has good application prospect in the pharmaceutical industry as a medicine, but no good IDO inhibitor can be used as a medicine on the market at present, and in order to achieve the purpose of better tumor treatment effect and better meet the market demand, the inventor hopes to develop a new generation of high-efficiency low-toxicity selective IDO inhibitor. The present invention is to provide a selective IDO inhibitor of a novel structure, and to find that a compound having such a structure exhibits excellent effects and actions, particularly excellent drug absorption activity.
Disclosure of Invention
The invention aims to provide a compound shown in a general formula (I) or a tautomer, a meso form, a racemate, an enantiomer, a diastereoisomer or a mixture form thereof, or a pharmaceutically acceptable salt thereof,
Figure GDA0003352213010000021
wherein:
Figure GDA0003352213010000022
a mixture selected from the group consisting of cis-isomer, trans-isomer, and cis-trans-isomer;
ring a is selected from cycloalkyl, heterocyclyl, aryl and heteroaryl;
ring B is aryl or heteroaryl;
R1the same or different, and each is independently selected from the group consisting of hydrogen atom, alkyl, cyano, amino, halogen, alkenyl, alkynyl, hydroxyl, nitro, alkoxy, hydroxyalkyl, haloalkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl, wherein said alkyl, alkenyl, alkynyl, alkoxy, hydroxyalkyl, haloalkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl are each independently optionally further substituted with one or more substituents selected from the group consisting of hydroxyl, halogen, amino, cyano, alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, and heteroaryl;
R2are identical or different and are each independently selected from hydrogen atomsAlkyl, hydroxy, amino, alkoxy, hydroxyalkyl, haloalkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl, -OR3、-C(O)R3、-C(O)OR3、-S(O)mR3、-C(O)NR3R4、-OC(O)NR3R4、-NR3R4、-NR3C(O)R4、-NR3S(O)mR4and-NR3S(O)mNHR4Wherein said alkyl, alkoxy, hydroxyalkyl, haloalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are each independently optionally selected from alkyl, halogen, amino, nitro, cyano, hydroxy, hydroxyalkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl, -OR5、-C(O)R5、-C(O)OR5、-S(O)mR5、-NR5R6、-C(O)NR5R6、-NR5C(O)R6and-NR5S(O)mR6Is substituted with one or more substituents of (1);
R3and R4The same OR different, and each is independently selected from the group consisting of a hydrogen atom, an alkyl group, a hydroxyl group, an amino group, an alkoxy group, a hydroxyalkyl group, a haloalkyl group, a cycloalkyl group, a heterocyclic group, an aryl group, a heteroaryl group, -OR5、-C(O)R5、-C(O)OR5、-S(O)mR5、-NR5R6、-C(O)NR5R6、-NR5C(O)R6and-NR5S(O)mR6Wherein said alkyl, alkoxy, hydroxyalkyl, haloalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are each independently optionally selected from alkyl, haloalkyl, halogen, hydroxy, amino, nitro, cyano, alkoxy, hydroxyalkyl, cycloalkyl, heterocyclyl, -C (O) OR7Aryl and heteroaryl, substituted with one or more substituents;
R5and R6Are the same or different and are each independently selected from the group consisting of a hydrogen atom, an alkyl group, a hydroxyl group, an amino group, a carboxylate group, an alkoxy group, a hydroxyalkyl group, a haloalkyl group, a cycloalkyl group, a heterocyclic group, an aryl group and a heteroaryl group, wherein the groups areEach of the alkyl, amino, alkoxy, hydroxyalkyl, haloalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl of (a) is independently optionally substituted with one or more substituents selected from alkyl, halogen, hydroxy, amino, carboxylate, nitro, cyano, alkoxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl;
R7selected from the group consisting of hydrogen atoms, alkyl groups, hydroxyalkyl groups, haloalkyl groups, cycloalkyl groups, heterocyclic groups, aryl groups, and heteroaryl groups;
m is 0,1 or 2;
n is 0,1, 2,3, 4 or 5; and is
x is 0,1, 2,3, 4 or 5.
In a preferred embodiment of the present invention, the compound of formula (I) or a tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein ring B is aryl, preferably phenyl.
In a preferred embodiment of the present invention, the compound of formula (I) or a tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein R is1Is a hydrogen atom or a halogen.
In a preferred embodiment of the present invention, the compound of formula (I) or a tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein R is2Selected from the group consisting of hydrogen atom, alkyl group, hydroxyl group, amino group, -C (O) R3、-S(O)mR3、-C(O)NR3R4、-OC(O)NR3R4、-NR3R4、-NR3C(O)R4、-NR3S(O)mR4and-NR3S(O)mNHR4(ii) a preferably-NR3S(O)mNHR4；R3、R4And m is as defined in formula (I).
In a preferred embodiment of the present invention, the compound of formula (I) or a tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein n is 1 or 2.
In a preferred embodiment of the present invention, the compound of formula (I) or a tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein x is 1.
In a preferred embodiment of the present invention, the compound represented by the general formula (I) or a tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, is a compound represented by the general formula (II):
Figure GDA0003352213010000041
or a tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof,
wherein:
Figure GDA0003352213010000042
a mixture selected from the group consisting of cis-isomer, trans-isomer, and cis-trans-isomer;
g is selected from CH, O, N, S (O)mAnd S;
R2the same OR different, and each is independently selected from the group consisting of a hydrogen atom, an alkyl group, a hydroxyl group, an amino group, an alkoxy group, a hydroxyalkyl group, a haloalkoxy group, a cycloalkyl group, a heterocyclic group, an aryl group, a heteroaryl group, -OR3、-C(O)R3、-C(O)OR3、-S(O)mR3、-C(O)NR3R4、-OC(O)NR3R4、-NR3R4、-NR3C(O)R4、-NR3S(O)mNHR4and-NR3S(O)mR4Wherein said alkyl, alkoxy, hydroxyalkyl, haloalkyl, cycloalkyl, heterocyclyl, arylEach of which is independently optionally selected from alkyl, halogen, amino, nitro, cyano, hydroxy, hydroxyalkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl, -OR5、-C(O)R5、-C(O)OR5、-S(O)mR5、-NR5R6、-C(O)NR5R6、-NR5C(O)R6and-NR5S(O)mR6Is substituted with one or more substituents of (1);
x is 0 or 1;
y is 0,1, 2 or 3;
z is 0,1, 2 or 3; and is
Ring B, R1、R3～R6M and n are as defined in formula (I).
In a preferred embodiment of the invention, the compound of formula (I) or a tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein ring a is selected from the group consisting of cyclohexyl, indenyl, pyrazolyl, cyclopentyl, tetrahydrofuranyl, pyranyl, cyclobutyl, piperidinyl, oxetanyl, azetidinyl and pyrrolidinyl.
Typical compounds of formula (I) include, but are not limited to:
Figure GDA0003352213010000043
Figure GDA0003352213010000051
Figure GDA0003352213010000061
Figure GDA0003352213010000071
Figure GDA0003352213010000081
or a tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof.
The invention also provides an intermediate for preparing the compound shown in the general formula (I), wherein the intermediate is the compound shown in the general formula (III) or the tautomer, the mesomer, the racemate, the enantiomer, the diastereomer or the mixture form thereof, or the pharmaceutically acceptable salt thereof,
Figure GDA0003352213010000082
wherein:
ring B is selected from aryl and heteroaryl;
R1the same or different, and each is independently selected from the group consisting of hydrogen atoms, alkyl groups, cyano groups, amino groups, halogens, alkenyl groups, alkynyl groups, hydroxyl groups, nitro groups, alkoxy groups, hydroxyalkyl groups, haloalkyl groups, cycloalkyl groups, heterocyclic groups, aryl groups, and heteroaryl groups, wherein the alkyl groups, alkenyl groups, alkynyl groups, alkoxy groups, hydroxyalkyl groups, haloalkyl groups, cycloalkyl groups, heterocyclic groups, aryl groups, and heteroaryl groups are each independently optionally substituted with one or more substituents selected from the group consisting of hydroxyl groups, halogens, amino groups, cyano groups, alkyl groups, alkoxy groups, cycloalkyl groups, heterocyclic groups, aryl groups, and heteroaryl groups;
n is 0,1, 2,3, 4 or 5.
The invention also provides an intermediate for preparing the compound shown in the general formula (I), wherein the intermediate is the compound shown in the general formula (V) or a tautomer, a mesomer, a racemate, an enantiomer, a diastereoisomer or a mixture form thereof, or a pharmaceutically acceptable salt form thereof,
Figure GDA0003352213010000083
wherein:
ring A, ring B, R1、R2X and n are as defined in formula (I).
Typical compounds of formula (V) include, but are not limited to:
Figure GDA0003352213010000091
Figure GDA0003352213010000101
Figure GDA0003352213010000111
Figure GDA0003352213010000121
Figure GDA0003352213010000131
Figure GDA0003352213010000141
or a tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof.
The present invention also provides a process for preparing a compound of the general formula (I) or a tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, the process comprising:
Figure GDA0003352213010000151
reacting the compound of the general formula (III) with the general formula (IV) at room temperature under alkaline conditions to obtain a compound of the general formula (I);
wherein:
Figure GDA0003352213010000152
ring A, ring B, R1、R2X and n are as defined in formula (I).
The present invention also provides a process for preparing a compound of the general formula (I) or a tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, the process comprising:
Figure GDA0003352213010000153
opening the ring of the compound of the general formula (V) at room temperature under alkaline conditions to obtain a compound of a general formula (I);
wherein:
Figure GDA0003352213010000154
ring A, ring B, R1、R2X and n are as defined in formula (I).
The present invention also provides a process for preparing a compound of the general formula (I) or a tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, the process comprising:
Figure GDA0003352213010000155
the compound of the general formula (II-B) is subjected to ring opening under the alkaline condition at room temperature to obtain a compound of the general formula (II);
wherein:
Figure GDA0003352213010000156
ring B, G, R1、R2Y, z, x and n are as defined in formula (II).
Another aspect of the present invention relates to a pharmaceutical composition comprising a therapeutically effective amount of a compound of formula (I) or a tautomer, mesomer, racemate, enantiomer, or diastereomer thereof, or mixture thereof, or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers, diluents, or excipients. The invention also relates to a method for preparing the composition, which comprises the step of mixing the compound shown in the general formula (I) or the tautomer, the mesomer, the racemate, the enantiomer, the diastereomer or the mixture form thereof, or the pharmaceutically acceptable salt thereof with a pharmaceutically acceptable carrier, diluent or excipient.
The invention further relates to the use of a compound of general formula (I) or a tautomer, mesomer, racemate, enantiomer, diastereomer or mixture thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising same, for the preparation of a medicament for the prophylaxis and/or treatment of a disease characterized by a pathology of the IDO-mediated tryptophan metabolic pathway. IDO inhibitors may be used for inhibition of cardiac disorders and treatment of other diseases with pathological features of IDO-mediated tryptophan metabolic pathway, including infection with viruses such as AIDS, cell infections such as AIDS, lyme disease and streptococcal infection, myelodysplastic syndrome, neurodegenerative disorders (e.g., alzheimer's disease, huntington's disease and parkinson's disease), autoimmune diseases, depression, anxiety, psychological disorders, cancer (including T-cell leukemia and colon cancer), ocular diseases (e.g., cataracts and age-related yellowing), wherein the cancer may be selected from breast cancer, cervical cancer, colon cancer, lung cancer, stomach cancer, rectal cancer, pancreatic cancer, brain cancer, skin cancer, oral cancer, prostate cancer, bone cancer, kidney cancer, ovarian cancer, bladder cancer, liver cancer, fallopian tube tumor, ovarian tumor, Peritoneal tumors, stage IV melanoma, solid tumors, glioma, glioblastoma, hepatocellular carcinoma, mastoid renal tumor, head and neck tumors, leukemia, lymphoma, myeloma, and non-small cell lung cancer.
The invention also relates to a compound of general formula (I) or a tautomer, mesomer, racemate, enantiomer, diastereomer or mixture thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising same, for use in the prevention and/or treatment of a disease characterized by a pathology of the IDO-mediated tryptophan metabolic pathway. These diseases include infection by a virus such as AIDS, cell infection such as AIDS, Lyme disease and streptococcal infection, myelodysplastic syndrome, neurodegenerative disorders (e.g., Alzheimer's disease, Huntington's disease and Parkinson's disease), autoimmune diseases, depression, anxiety, psychological disorders, cancer (including T-cell leukemia and colon cancer), eye diseases (e.g., cataract and age-related yellowing), wherein the cancer may be selected from breast cancer, cervical cancer, colon cancer, lung cancer, gastric cancer, rectal cancer, pancreatic cancer, brain cancer, skin cancer, oral cancer, prostate cancer, bone cancer, kidney cancer, ovarian cancer, bladder cancer, liver cancer, fallopian tube tumor, ovarian tumor, peritoneal tumor, stage IV melanoma, solid tumor, glioma, glioblastoma, hepatocellular carcinoma, papillary renal tumor, head and neck tumor, Leukemia, lymphoma, myeloma, and non-small cell lung cancer.
The present invention also relates to a method for the treatment and/or prophylaxis of diseases which are characterized by pathologies of the IDO-mediated tryptophan metabolic pathway, which comprises administering to a patient a therapeutically effective dose of a compound of the general formula (I) or a tautomer, mesomer, racemate, enantiomer, diastereomer or mixture thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising same. The disease includes infection by a virus such as AIDS, cell infection such as AIDS, Lyme disease and streptococcal infection, myelodysplastic syndrome, neurodegenerative disorders (e.g., Alzheimer's disease, Huntington's disease and Parkinson's disease), autoimmune diseases, depression, anxiety, psychological disorders, cancer (including T cell leukemia and colon cancer), eye diseases (e.g., cataract and age-related yellowing), wherein the cancer may be selected from breast cancer, cervical cancer, colon cancer, lung cancer, stomach cancer, rectal cancer, pancreatic cancer, brain cancer, skin cancer, oral cancer, prostate cancer, bone cancer, kidney cancer, ovarian cancer, bladder cancer, liver cancer, fallopian tube tumor, ovarian tumor, peritoneal tumor, stage IV melanoma, solid tumor, glioma, glioblastoma, hepatocellular carcinoma, papillary renal tumor, head and neck tumor, Leukemia, lymphoma, myeloma, and non-small cell lung cancer.
Another aspect of the present invention relates to a method for treating cancer, which comprises administering to a patient a therapeutically effective amount of a compound of formula (I) of the present invention, or a tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof. The method shows outstanding therapeutic effects and fewer side effects, wherein the cancer may be selected from breast cancer, cervical cancer, colon cancer, lung cancer, stomach cancer, rectal cancer, pancreatic cancer, brain cancer, skin cancer, oral cancer, prostate cancer, bone cancer, kidney cancer, ovarian cancer, bladder cancer, liver cancer, fallopian tube tumor, ovarian tumor, peritoneal tumor, stage IV melanoma, solid tumor, glioma, glioblastoma, hepatocellular carcinoma, papillary renal tumor, head and neck tumor, leukemia, lymphoma, myeloma, and non-small cell lung cancer, preferably fallopian tube tumor, peritoneal tumor, stage IV melanoma, myeloma, and breast cancer, more preferably breast cancer.
The pharmaceutical compositions containing the active ingredient may be in a form suitable for oral use, for example, as tablets, troches, lozenges, aqueous or oily suspensions, dispersible powders or granules, emulsions, hard or soft capsules, or syrups or elixirs. Oral compositions may be prepared according to any method known in the art for preparing pharmaceutical compositions, and such compositions may contain one or more ingredients selected from the group consisting of: sweetening agents, flavoring agents, coloring agents and preserving agents in order to provide a pleasant to the eye and palatable pharmaceutical preparation. Tablets contain the active ingredient in admixture with non-toxic pharmaceutically acceptable excipients which are suitable for the manufacture of tablets. These excipients may be inert excipients, granulating and disintegrating agents, binding agents and lubricating agents. These tablets may be uncoated or they may be coated by known techniques which mask the taste of the drug or delay disintegration and absorption in the gastrointestinal tract and thereby provide a sustained action over a longer period. For example, water soluble taste masking substances or time extending substances may be used.
Oral formulations may also be provided in soft gelatin capsules wherein the active ingredient is mixed with an inert solid diluent or wherein the active ingredient is mixed with a water soluble carrier or an oil vehicle.
Aqueous suspensions contain the active materials in admixture with excipients suitable for the manufacture of aqueous suspensions. Such excipients are suspending, dispersing or wetting agents. Aqueous suspensions may also contain one or more preservatives, one or more coloring agents, one or more flavoring agents, and one or more sweetening agents.
Oil suspensions may be formulated by suspending the active ingredient in a vegetable or mineral oil. The oil suspension may contain a thickening agent, for example beeswax, hard paraffin or cetyl alcohol. Sweetening agents such as those set forth above, and flavoring agents may be added to provide a palatable preparation. These compositions can be preserved by the addition of antioxidants.
Dispersible powders and granules suitable for preparation of an aqueous suspension by the addition of water provide the active ingredient in admixture with a dispersing or wetting agent, suspending agent or one or more preservatives. Suitable dispersing or wetting agents and suspending agents are illustrative of the examples given above. Other excipients, for example sweetening, flavoring and coloring agents, may also be present. These compositions are preserved by the addition of an antioxidant such as ascorbic acid.
The pharmaceutical compositions of the invention may also be in the form of oil-in-water emulsions. The oily phase may be a vegetable oil or a mineral oil or a mixture thereof. Suitable emulsifiers may be naturally occurring phospholipids, partial esters and condensation products of the said partial esters with ethylene oxide. The emulsions may also contain sweetening agents, flavouring agents, preservatives and antioxidants. Such formulations may also contain a demulcent, a preservative, a colorant and an antioxidant.
The pharmaceutical compositions may be in the form of a sterile injectable aqueous solution. Among the acceptable vehicles or solvents that may be employed are water, ringer's solution and isotonic sodium chloride solution. The sterile injectable preparation may be a sterile injectable oil-in-water microemulsion in which the active ingredient is dissolved in the oil phase. The injection solution or microemulsion may be injected into the bloodstream of a patient by local bulk injection. Alternatively, it may be desirable to administer the solutions and microemulsions in a manner that maintains a constant circulating concentration of the compounds of the present invention. To maintain such a constant concentration, a continuous intravenous delivery device may be used. An example of such a device is an intravenous pump model Deltec CADD-PLUS. TM.5400.
The pharmaceutical compositions may be in the form of sterile injectable aqueous or oleaginous suspensions for intramuscular and subcutaneous administration. The suspension may be formulated according to the known art using those suitable dispersing or wetting agents and suspending agents which have been mentioned above. The sterile injectable preparation may also be a sterile injectable solution or suspension in a parenterally-acceptable, non-toxic diluent or solvent. In addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium. For this purpose, any blend fixed oil may be used, including synthetic mono-or diglycerides. In addition, fatty acids can also be prepared into injections.
The compounds of the present invention may be administered in the form of suppositories for rectal administration. These pharmaceutical compositions can be prepared by mixing the drug with a suitable non-irritating excipient which is solid at ordinary temperatures but liquid in the rectum and therefore will melt in the rectum to release the drug.
As is well known to those skilled in the art, the dosage of a drug administered depends on a variety of factors, including, but not limited to: the activity of the particular compound employed, the age of the patient, the weight of the patient, the health condition of the patient, the patient's integument, the patient's diet, the time of administration, the mode of administration, the rate of excretion, the combination of drugs, and the like; in addition, the optimal treatment regimen, such as the mode of treatment, the daily amount of compound (I) of the formula or the type of pharmaceutically acceptable salt, can be verified according to conventional treatment protocols.
Detailed description of the invention
Unless stated to the contrary, terms used in the specification and claims have the following meanings.
The term "alkyl" refers to a saturated aliphatic hydrocarbon group which is a straight or branched chain group containing 1 to 20 carbon atoms, preferably an alkyl group containing 1 to 12 carbon atoms, more preferably an alkyl group containing 1 to 6 carbon atoms. Non-limiting examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1-dimethylpropyl, 1, 2-dimethylpropyl, 2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2-methylpropyl, 1, 2-trimethylpropyl, 1-dimethylbutyl, 1, 2-dimethylbutyl, 2-dimethylbutyl, 1, 3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2, 3-dimethylbutyl, n-heptyl, 2-methylhexyl, 3-methylhexyl, 4-methylhexyl, 5-methylhexyl, 2, 3-dimethylpentyl, 2, 4-dimethylpentyl, 2-dimethylpentyl, 3-dimethylpentyl, 2-ethylpentyl, 3-ethylpentyl, n-octyl, 2, 3-dimethylhexyl, 2, 4-dimethylhexyl, 2, 5-dimethylhexyl, 2-dimethylhexyl, 3-dimethylhexyl, 4-dimethylhexyl, 2-ethylhexyl, 3-ethylhexyl, 4-ethylhexyl, 2-methyl-2-ethylpentyl, 2-methyl-3-ethylpentyl, n-nonyl, 2-methyl-2-ethylhexyl, 2-methyl-3-ethylhexyl, 2-dimethylpentyl, 2-dimethylhexyl, 3-dimethylpentyl, 2-ethylhexyl, 3-dimethylhexyl, 2-ethylhexyl, 2-dimethylhexyl, 2-ethylhexyl, 2-dimethylhexyl, 2-dimethylhexyl, 2-dimethylhexyl, 2-ethylhexyl, 2-ethyl, 2-2, 2-2, 2-2, or, 2, 2-diethylpentyl, n-decyl, 3-diethylhexyl, 2-diethylhexyl, and various branched isomers thereof. More preferred are lower alkyl groups having 1 to 6 carbon atoms, non-limiting examples of which include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1-dimethylpropyl, 1, 2-dimethylpropyl, 2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2-methylpropyl, 1, 2-trimethylpropyl, 1-dimethylbutyl, 1, 2-dimethylbutyl, 2-dimethylbutyl, 1, 3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2, 3-dimethylbutyl and the like. The alkyl group may be substituted or unsubstituted, and when substituted, the substituent may be substituted at any available point of attachment, preferably one or more groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halo, mercapto, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, oxo, carboxy or carboxylate.
The term "alkylene" means that one hydrogen atom of an alkyl group is further substituted, for example: "methylene" means-CH2-, "ethylene" means- (CH)2)2-, "propylene" means- (CH)2)3-, "butylene" means- (CH)2)4-and the like.
The term "alkenyl" refers to an alkyl group as defined above consisting of at least two carbon atoms and at least one carbon-carbon double bond, e.g., ethenyl, 1-propenyl, 2-propenyl, 1-, 2-or 3-butenyl, and the like. The alkenyl group may be substituted or unsubstituted, and when substituted, the substituents are preferably one or more groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio.
The term "alkynyl" refers to an alkyne that does not include a C.ident.C into an alkyne in a molecule, such as: acetylene, propyne, 1-butyne, 2-butyne, 3-methyl-1-butyne, 2-pentyne, or the like. Alkynyl groups may be substituted or unsubstituted, and when substituted, the substituents are preferably one or more groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio.
The term "cycloalkyl" refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent, the cycloalkyl ring containing from 3 to 20 carbon atoms, preferably from 3 to 12 carbon atoms, more preferably from 3 to 6 carbon atoms. Non-limiting examples of monocyclic cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cycloheptatrienyl, cyclooctyl, and the like; polycyclic cycloalkyl groups include spiro, fused and bridged cycloalkyl groups.
The term "spirocycloalkyl" refers to a 5 to 20 membered polycyclic group sharing one carbon atom (referred to as a spiro atom) between monocyclic rings, which may contain one or more double bonds, but none of the rings have a completely conjugated pi-electron system. Preferably 6 to 14, more preferably 7 to 10. Spirocycloalkyl groups are classified into a single spirocycloalkyl group, a double spirocycloalkyl group or a multi spirocycloalkyl group, preferably a single spirocycloalkyl group and a double spirocycloalkyl group, according to the number of spiro atoms shared between rings. More preferably 4-membered/4-membered, 4-membered/5-membered, 4-membered/6-membered, 5-membered/5-membered or 5-membered/6-membered. Non-limiting examples of spirocycloalkyl groups include:
Figure GDA0003352213010000201
the term "fused cyclic alkyl" refers to a 5 to 20 membered all carbon polycyclic group in which each ring in the system shares an adjacent pair of carbon atoms with other rings in the system, wherein one or more of the rings may contain one or more double bonds, but none of the rings has a completely conjugated pi-electron system. Preferably 6 to 14, more preferably 7 to 10. They may be classified into bicyclic, tricyclic, tetracyclic or polycyclic fused ring alkyls according to the number of constituent rings, preferably bicyclic or tricyclic, more preferably 5-or 6-membered bicycloalkyl. Non-limiting examples of fused ring alkyl groups include:
Figure GDA0003352213010000202
the term "bridged cycloalkyl" refers to a 5 to 20 membered all carbon polycyclic group in which any two rings share two carbon atoms not directly attached, which may contain one or more double bonds, but none of the rings have a completely conjugated pi-electron system. Preferably 6 to 14, more preferably 7 to 10. They may be classified as bicyclic, tricyclic, tetracyclic or polycyclic bridged cycloalkyl groups, preferably bicyclic, tricyclic or tetracyclic, more preferably bicyclic or tricyclic, depending on the number of constituent rings. Non-limiting examples of bridged cycloalkyl groups include:
Figure GDA0003352213010000203
the cycloalkyl ring may be fused to an aryl, heteroaryl or heterocycloalkyl ring, wherein the ring to which the parent structure is attached is cycloalkyl, non-limiting examples of which include indenyl, tetrahydronaphthyl, benzocycloheptanyl, and the like. Cycloalkyl groups may be optionally substituted or unsubstituted, and when substituted, the substituents are preferably one or more groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, oxo, carboxy or carboxylate.
The term "heterocyclyl" refers to a saturated or partially unsaturated mono-or polycyclic cyclic hydrocarbon substituent containing from 3 to 20 ring atoms wherein one or more of the ring atoms is selected from nitrogen, oxygen, or S (O)m(wherein m is an integer from 0 to 2) but excludes the ring moiety of-O-O-, -O-S-, or-S-S-, the remaining ring atoms being carbon. Preferably 3 to 12 ring atoms, of which 1 to 4 are heteroatoms; most preferably 3 to 8 ring atoms, of which 1 to 3 are heteroatoms; most preferably 5 to 6 ring atoms, of which 1-2 or 1-3 are heteroatoms. Non-limiting examples of monocyclic heterocyclyl groups include pyrrolidinyl, imidazolidinyl, tetrahydrofuranyl, tetrahydrothienyl, dihydroimidazolyl, dihydrofuranyl, dihydropyrazolyl, dihydropyrrolyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, homopiperazinyl, pyranyl, azetidinyl, and the like, preferably 1,2, 5-oxadiazolyl, pyranyl, piperidinyl, azetidinyl, pyrrolidinyl, or morpholinyl. Polycyclic heterocyclic groups include spiro, fused and bridged heterocyclic groups.
The term "spiroheterocyclyl" refers to a 5-to 20-membered polycyclic heterocyclic group in which one atom (referred to as the spiro atom) is shared between monocyclic rings, and in which one or more ring atoms is selected from nitrogen, oxygen, or S (O)m(wherein m is an integer of 0 to 2) and the remaining ring atoms are carbon. It may contain one or more double bonds, but no ring has a completely conjugated pi-electron system. Preferably 6 to 14, more preferably 7 to 10. According to the ring andthe number of spiro atoms shared between the rings divides the spiro heterocyclic group into a single spiro heterocyclic group, a double spiro heterocyclic group or a multi spiro heterocyclic group, and preferably the single spiro heterocyclic group and the double spiro heterocyclic group. More preferred are 4-membered/4-membered, 4-membered/5-membered, 4-membered/6-membered, 5-membered/5-membered or 5-membered/6-membered mono spiroheterocyclic groups. Non-limiting examples of spiro heterocyclic groups include:
Figure GDA0003352213010000211
the term "fused heterocyclyl" refers to a 5 to 20 membered polycyclic heterocyclic group in which each ring in the system shares an adjacent pair of atoms with other rings in the system, one or more rings may contain one or more double bonds, but none of the rings has a fully conjugated pi-electron system in which one or more ring atoms is selected from nitrogen, oxygen or S (O)m(wherein m is an integer of 0 to 2) and the remaining ring atoms are carbon. Preferably 6 to 14, more preferably 7 to 10. They may be classified into bicyclic, tricyclic, tetracyclic or polycyclic fused heterocyclic groups according to the number of constituent rings, preferably bicyclic or tricyclic, more preferably 5-or 6-membered bicyclic fused heterocyclic groups. Non-limiting examples of fused heterocyclic groups include:
Figure GDA0003352213010000212
the term "bridged heterocyclyl" refers to a 5 to 14 membered polycyclic heterocyclic group in which any two rings share two atoms not directly attached which may contain one or more double bonds, but none of the rings have a fully conjugated pi-electron system in which one or more of the ring atoms is selected from nitrogen, oxygen or S (O)m(wherein m is an integer of 0 to 2) and the remaining ring atoms are carbon. Preferably 6 to 14, more preferably 7 to 10. They may be classified into bicyclic, tricyclic, tetracyclic or polycyclic bridged heterocyclic groups according to the number of constituent rings, preferably bicyclic, tricyclic or tetracyclic, more preferably bicyclic or tricyclic. Non-limiting examples of bridged heterocyclic groups include:
Figure GDA0003352213010000221
the heterocyclyl ring may be fused to an aryl, heteroaryl or cycloalkyl ring, wherein the ring to which the parent structure is attached is heterocyclyl, non-limiting examples of which include:
Figure GDA0003352213010000222
and the like.
The heterocyclyl group may be optionally substituted or unsubstituted, and when substituted, the substituents are preferably one or more groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, oxo, carboxy or carboxylate.
The term "aryl" refers to a 6 to 14 membered all carbon monocyclic or fused polycyclic (i.e., rings which share adjacent pairs of carbon atoms) group having a conjugated pi-electron system, preferably 6 to 10 membered, such as phenyl and naphthyl. More preferably phenyl. The aryl ring may be fused to a heteroaryl, heterocyclyl or cycloalkyl ring, wherein the ring attached to the parent structure is an aryl ring, non-limiting examples of which include:
Figure GDA0003352213010000223
the aryl group may be substituted or unsubstituted, and when substituted, the substituent is preferably one or more groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, carboxy or carboxylate.
The term "heteroaryl" refers to a heteroaromatic system comprising 1 to 4 heteroatoms, 5 to 14 ring atoms, wherein the heteroatoms are selected from oxygen, sulfur and nitrogen. Heteroaryl is preferably 5 to 10 membered, containing 1 to 3 heteroatoms; more preferably 5 or 6 membered, containing 1 to 2 heteroatoms; preferably, for example, imidazolyl, furyl, thienyl, thiazolyl, pyrazolyl, oxazolyl, pyrrolyl, tetrazolyl, pyridyl, pyrimidinyl, thiadiazole, pyrazinyl and the like, preferably imidazolyl, thiazolyl, pyrazolyl or pyrimidinyl, thiazolyl; more preferably pyrazolyl or thiazolyl. The heteroaryl ring may be fused to an aryl, heterocyclyl or cycloalkyl ring, wherein the ring joined together with the parent structure is a heteroaryl ring, non-limiting examples of which include:
Figure GDA0003352213010000231
heteroaryl groups may be optionally substituted or unsubstituted, and when substituted, the substituents are preferably one or more groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, carboxyl or carboxylate groups.
The term "alkoxy" refers to-O- (alkyl) and-O- (unsubstituted cycloalkyl), wherein alkyl and cycloalkyl are as defined above. Non-limiting examples of alkoxy groups include: methoxy, ethoxy, propoxy, butoxy, cyclopropoxy, cyclobutoxy, cyclopentyloxy, cyclohexyloxy. Alkoxy groups may be optionally substituted or unsubstituted, and when substituted, the substituents are preferably one or more groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, carboxy or carboxylate groups.
The term "haloalkyl" refers to an alkyl group substituted with one or more halogens wherein alkyl is as defined above.
The term "haloalkoxy" refers to an alkoxy group substituted with one or more halogens, wherein the alkoxy group is as defined above.
The term "hydroxyalkyl" refers to an alkyl group substituted with a hydroxy group, wherein alkyl is as defined above.
The term "hydroxy" refers to an-OH group.
The term "halogen" refers to fluorine, chlorine, bromine or iodine.
The term "amino" refers to the group-NH2。
The term "cyano" refers to — CN.
The term "nitro" means-NO2。
The term "oxo" refers to ═ O.
The term "carbonyl" refers to C ═ O.
The term "carboxy" refers to-C (O) OH.
The term "isocyanato" refers to-NCO.
The term "oximino" refers to N-OH.
The term "mercapto" refers to-SH.
The term "alkenyl" refers to a hydrocarbon group having one or more fewer hydrogen atoms in the olefin molecule.
The term "alkynyl" refers to a hydrocarbon containing a carbon-carbon triple bond in the molecule.
The term "carboxylate" refers to-C (O) O (alkyl) or-C (O) O (cycloalkyl), wherein alkyl, cycloalkyl are as defined above.
The term "acyl halide" refers to a compound containing a group that is-C (O) -halogen.
"optional" or "optionally" means that the subsequently described event or circumstance may, but need not, occur, and that the description includes instances where the event or circumstance occurs or does not. For example, "a heterocyclic group optionally substituted with an alkyl" means that an alkyl may, but need not, be present, and the description includes the case where the heterocyclic group is substituted with an alkyl and the heterocyclic group is not substituted with an alkyl.
"substituted" means that one or more, preferably up to 5, more preferably 1 to 3, hydrogen atoms in the group are independently substituted with a corresponding number of substituents. It goes without saying that the substituents are only in their possible chemical positions, and that the person skilled in the art is able to determine (experimentally or theoretically) possible or impossible substitutions without undue effort. For example, amino or hydroxyl groups having free hydrogen may be unstable in combination with carbon atoms having unsaturated (e.g., olefinic) bonds.
"pharmaceutical composition" means a mixture containing one or more compounds described herein or a physiologically/pharmaceutically acceptable salt or prodrug thereof in admixture with other chemical components, as well as other components such as physiologically/pharmaceutically acceptable carriers and excipients. The purpose of the pharmaceutical composition is to facilitate administration to an organism, facilitate absorption of the active ingredient and exert biological activity.
"pharmaceutically acceptable salts" refers to salts of the compounds of the present invention which are safe and effective for use in the body of a mammal and which possess the requisite biological activity.
In the invention, different terms such as "X is selected from A, B or C", "X is selected from A, B and C", "X is A, B or C", "X is A, B and C" and the like all express the same meaning, that is, X can be any one or more of A, B, C.
Synthesis of the Compounds of the invention
In order to achieve the purpose of the invention, the invention adopts the following technical scheme:
scheme one
The invention relates to a method for preparing a compound shown as a general formula (I) or a tautomer, a mesomer, a racemate, an enantiomer, a diastereoisomer or a mixture form thereof, or a pharmaceutically acceptable salt form thereof, which comprises the following steps:
Figure GDA0003352213010000251
under the heating acidic condition, the compound of the general formula (A) is oxidized to obtain a compound of a general formula (III); reacting the obtained compound of the general formula (III) with a general formula (VI) at room temperature under alkaline conditions to obtain a compound of a general formula (I); or reacting the obtained compound of the general formula (III) with the general formula (VI) at room temperature under alkaline conditions to obtain a compound of the general formula (V); the obtained compound of the general formula (V) is subjected to ring opening under alkaline conditions to obtain the compound of the general formula (I).
The agent that provides basic conditions includes organic bases including, but not limited to, triethylamine, N-diisopropylethylamine, N-butyllithium, lithium diisopropylamide, potassium acetate, sodium tert-butoxide, or potassium tert-butoxide, and inorganic bases including, but not limited to, sodium hydride, potassium phosphate, sodium carbonate, potassium carbonate, or cesium carbonate. The agent providing alkaline conditions is preferably sodium hydroxide.
Oxidants used include, but are not limited to: selenium dioxide, hydrogen peroxide, potassium permanganate or manganese dioxide, preferably 30% hydrogen peroxide solution.
Reagents that provide acidic conditions include, but are not limited to, trifluoroacetic acid, formic acid, acetic acid, hydrochloric acid, sulfuric acid, or methanesulfonic acid, with trifluoroacetic acid being preferred.
Wherein:
ring A, ring B, R1、R2X and n are as defined in formula (I).
Scheme two
The invention relates to a method for preparing a compound shown as a general formula (II) or a tautomer, a mesomer, a racemate, an enantiomer, a diastereomer or a mixture form thereof, or a pharmaceutically acceptable salt form thereof, which comprises the following steps:
Figure GDA0003352213010000252
under the heating acidic condition, the compound of the general formula (A) is oxidized to obtain a compound of a general formula (III); reacting the obtained compound of the general formula (III) with the general formula (II-A) at room temperature under alkaline conditions to obtain a compound of the general formula (II-B); the obtained compound of the general formula (II-B) is subjected to ring opening under alkaline conditions to obtain the compound of the general formula (II).
The agent that provides basic conditions includes organic bases including, but not limited to, triethylamine, N-diisopropylethylamine, N-butyllithium, lithium diisopropylamide, potassium acetate, sodium tert-butoxide, or potassium tert-butoxide, and inorganic bases including, but not limited to, sodium hydride, potassium phosphate, sodium carbonate, potassium carbonate, or cesium carbonate. The agent providing alkaline conditions is preferably sodium hydroxide.
Oxidants used include, but are not limited to: selenium dioxide, hydrogen peroxide, potassium permanganate or manganese dioxide, preferably 30% hydrogen peroxide solution.
Reagents that provide acidic conditions include, but are not limited to, trifluoroacetic acid, formic acid, acetic acid, hydrochloric acid, sulfuric acid, or methanesulfonic acid, with trifluoroacetic acid being preferred.
Wherein:
Figure GDA0003352213010000261
ring B, G, R1、R2Y, z, x and n are as defined in formula (II).
Detailed Description
The present invention is further described below with reference to examples, which are not intended to limit the scope of the present invention.
Examples
The structure of the compounds is determined by Nuclear Magnetic Resonance (NMR) or/and Mass Spectrometry (MS). NMR shift (. delta.) of 10-6The units in (ppm) are given. NMR was measured using a Bruker AVANCE-400 NMR spectrometer using deuterated dimethyl sulfoxide (DMSO-d)6) Deuterated chloroform (CDCl)3) Deuterated methanol (CD)3OD), internal standard Tetramethylsilane (TMS).
MS was determined using a FINNIGAN LCQAD (ESI) mass spectrometer (manufacturer: Thermo, model: Finnigan LCQ advantage MAX).
HPLC was carried out using an Agilent 1200DAD high pressure liquid chromatograph (Sunfire C18150X 4.6mm column) and a Waters 2695-2996 high pressure liquid chromatograph (Gimini C18150X 4.6mm column).
Chiral HPLC analytical determination using LC-10A vp (Shimadzu) or SFC-analytical (Berger Instruments Inc.);
the thin layer chromatography silica gel plate adopts HSGF254 of tobacco yellow sea or GF254 of Qingdao, the specification of the silica gel plate used by Thin Layer Chromatography (TLC) is 0.15 mm-0.2 mm, and the specification of the thin layer chromatography separation and purification product is 0.4 mm-0.5 mm.
The column chromatography generally uses 200-300 mesh silica gel of the Tibet Huanghai silica gel as a carrier.
Chiral preparative column chromatography Using Prep Star SD-1(Varian Instruments Inc.) or SFC-Multigram (Berger Instruments Inc.)
Average inhibition rate of kinase and IC50The values were determined with a NovoStar microplate reader (BMG, Germany).
Known starting materials of the present invention may be synthesized by or according to methods known in the art, or may be purchased from companies such as ABCR GmbH & Co.KG, Acros Organics, Aldrich Chemical Company, Shao Yuan Chemical technology (Accela ChemBio Inc), Darri Chemicals, and the like.
In the examples, the reaction can be carried out in an argon atmosphere or a nitrogen atmosphere, unless otherwise specified.
An argon atmosphere or nitrogen atmosphere means that the reaction flask is connected to a balloon of argon or nitrogen with a volume of about 1L.
The hydrogen atmosphere refers to a reaction flask connected with a hydrogen balloon with a volume of about 1L.
The pressure hydrogenation reaction used a hydrogenation apparatus of Parr 3916EKX type and a hydrogen generator of Qinglan QL-500 type or a hydrogenation apparatus of HC2-SS type.
The hydrogenation reaction was usually evacuated and charged with hydrogen and repeated 3 times.
The microwave reaction was carried out using a CEM Discover-S908860 type microwave reactor.
In the examples, the solution means an aqueous solution unless otherwise specified.
In the examples, the reaction temperature is, unless otherwise specified, from 20 ℃ to 30 ℃ at room temperature.
The progress of the reaction in the examples was monitored by Thin Layer Chromatography (TLC) using a developing solvent system of: a: dichloromethane and methanol system, B: n-hexane and ethyl acetate system, C: petroleum ether and ethyl acetate system, D: the volume ratio of acetone and solvent is adjusted according to the polarity of the compound.
The eluent system for column chromatography and the developing agent system for thin-layer chromatography used for purifying compounds comprise: a: dichloromethane and methanol system, B: n-hexane and ethyl acetate system, C: the volume ratio of the solvent is adjusted according to the polarity of the compound, and a small amount of basic or acidic reagents such as triethylamine, acetic acid and the like can be added for adjustment.
Examples 1 and 2
N- (3-bromo-4-fluorophenyl) -N' -hydroxy-4- (((1s,3s) -3- (sulfamoylamino) cyclobutane) thio) -1,2, 5-oxadiazole-3-carboxamidine 1
N- (3-bromo-4-fluorophenyl) -N' -hydroxy-4- (((1r,3r) -3- (sulfamoylamino) cyclobutane) thio) -1,2, 5-oxadiazole-3-carboxamidine 2
Figure GDA0003352213010000271
Figure GDA0003352213010000281
First step of
3- ((tert-Butoxycarbonyl) amino) cyclobutylmethanesulfonate 1b
Tert-butyl (3-hydroxycyclobutane) carbamate 1a (1.2g, 6.94mmol, prepared by the method disclosed in patent application "WO 2013107405") was dissolved in 5mL dichloromethane, cooled to 0 ℃, methanesulfonyl chloride (953mg, 8.32mmol) was added dropwise, warmed to room temperature and stirred for reaction for 30 minutes. The reaction was poured into 30mL of ice water, extracted with dichloromethane (30mL), and the organic phase was washed successively with saturated sodium bicarbonate solution (30mL), saturated sodium chloride solution (30mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give the crude title product 1b (1.84g), which was directly subjected to the next reaction without purification.
Second step of
S- (3- ((tert-butoxycarbonyl) amino) cyclobutyl) thioacetic acid 1c
Crude 1b (1.84g, 6.93mmol) was dissolved in 30mL of N, N-dimethylformamide, potassium thioacetate (1.58g, 13.9mmol) was added, and the reaction was stirred at 70 ℃ for 12 hours. The reaction solution was cooled to room temperature, poured into 50mL of water, extracted with ethyl acetate (50mL × 2), the organic phases were combined, washed with saturated sodium chloride solution (50mL × 2), dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography with eluent system B to give the title product 1c (1.4g), yield: 82.3 percent.
The third step
(3-mercaptocyclobutane) carbamic acid tert-butyl ester 1d
Dissolve 1c (1.3g, 2.3mmol) in 20mL of methanol, cool to 0 deg.C and add potassium carbonate (1.09g, 7.9mmol) and stir for 20 minutes. To the reaction solution was added 50mL of dichloromethane, washed with saturated sodium chloride solution (50 mL. times.2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give the crude title product 1d (1.07g), which was directly subjected to the next reaction without purification.
The fourth step
4- (3-bromo-4-fluorophenyl) -3- (4-nitro-1, 2, 5-oxadiazol-3-yl) -1,2, 4-oxadiazol-5 (4H) -one 1f
Reacting 3- (4-amino-1, 2, 5-oxadiazole-3-yl) -4- (3-bromo-4-fluorophenyl) -1,2, 4-oxadiazole-5 (4H) -one 1e
(13.0g, 41.1mmol, prepared by the method disclosed in patent application "WO 2014066834") was added to 150mL of trifluoroacetic acid, and 90mL of an aqueous hydrogen peroxide solution (30%) was added and reacted at 45 ℃ for 48 hours. After the reaction was completed, the reaction mixture was cooled, 300mL of a saturated sodium thiosulfate solution and 150mL of ethyl acetate were added, the reaction was stirred for 20 minutes, and the peroxide was detected by a potassium iodide paper. The phases were separated and the aqueous phase was extracted with ethyl acetate (100mL × 2), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography with eluent system B to give the title product 1f (4.5g) in 30% yield.
The fifth step
(3- ((4- (4- (3-bromo-4-fluorophenyl) -5-oxo-4, 5-dihydro-1, 2, 4-oxadiazol-3-yl) -1,2, 5-oxadiazol-3-yl) thio) cyclobutane) carbamic acid tert-butyl ester 1g
1f (1.76g, 4.74mmol) was dissolved in 20mL tetrahydrofuran, crude 1d (1.07g, 5.26mmol) and potassium carbonate (1.45g, 1.05mmol) were added and the reaction stirred for 1 hour. The reaction solution was poured into 50mL of water, extracted with ethyl acetate (30mL × 2), the organic phases were combined, washed with a saturated sodium chloride solution (30mL × 2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a residue, which was slurried with a mixed solvent of n-hexane and ethyl acetate (V: V ═ 1:1) to obtain 1g (2g) of the crude title product, which was directly subjected to the next reaction without purification.
The sixth step
3- (4- ((3-Aminocyclobutane) thio) -1,2, 5-oxadiazol-3-yl) -4- (3-bromo-4-fluorophenyl) -1,2, 4-oxadiazol-5 (4H) -one 1H
Crude 1g (1g, 1.89mmol) was dissolved in 10mL of dichloromethane, 4mL of trifluoroacetic acid was added, and the reaction was stirred for 1 hour. The reaction was concentrated under reduced pressure to give the crude title product 1h (700mg) which was directly used in the next reaction without purification.
Seventh step
N- (3- ((4- (4- (3-bromo-4-fluorophenyl) -5-oxo-4, 5-dihydro-1, 2, 4-oxadiazol-3-yl) -1,2, 5-oxadiazol-3-yl) thio) cyclobutyl) sulfamoylcarbamic acid tert-butyl ester 1j
The crude product was dissolved in 50mL of dichloromethane for 1h (700mg, 1.64mmol), cooled to 0 deg.C and triethylamine (469mg, 4.92mmol) was added, the reaction was stirred for 10min and tert-butyl chlorosulfonylcarbamate 1i (526mg, 2.45mmol, prepared as disclosed in the patent application "US 2015133674") was added and the reaction was stirred at room temperature for 1 h. The reaction solution was poured into 30mL of water. Extraction with dichloromethane (30 mL. times.2) and combining the organic phases, washing successively with saturated sodium bicarbonate solution (30mL), saturated sodium chloride solution (30mL), drying over anhydrous sodium sulfate, filtration and concentration of the filtrate under reduced pressure gave the crude title product 1j (900mg) which was directly subjected to the next reaction without purification.
Eighth step
N- [3- ({4- [4- (3-bromo-4-fluorophenyl) -5-oxo-4, 5-dihydro-1, 2, 4-oxadiazol-3-yl ] -1,2, 5-oxadiazol-3-yl } thio) cyclobutane ] aminosulfonamide 1k
Crude 1j (900mg, 1.48mmol) was dissolved in 10mL of dichloromethane, 4mL of trifluoroacetic acid was added, and the reaction was stirred for 1 hour. The reaction was concentrated under reduced pressure to give the crude title product 1k (700mg), which was directly used in the next reaction without purification.
The ninth step
N- (3-bromo-4-fluorophenyl) -N' -hydroxy-4- (((1s,3s) -3- (sulfamoylamino) cyclobutane) thio) -1,2, 5-oxadiazole-3-carboxamidine 1
N- (3-bromo-4-fluorophenyl) -N' -hydroxy-4- (((1r,3r) -3- (sulfamoylamino) cyclobutane) thio) -1,2, 5-oxadiazole-3-carboxamidine 2
Crude 1k (400mg, 0.79mmol) was dissolved in 10mL tetrahydrofuran, 0.63mL of 2.5M sodium hydroxide solution was added, and the reaction was stirred for 1 hour. The reaction solution was poured into 30mL of water, extracted with ethyl acetate (30mL × 2), the organic phases were combined, washed with a saturated ammonium chloride solution (40mL × 2), dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the resulting residue was purified by high performance liquid chromatography to give title product 1(40mg) and title product 2(100mg), yield: 36.9 percent.
Example 1:
MS m/z(ESI):481.2[M+1]
1HNMR(400MHz,DMSO-d6)δ11.71(s,1H),8.96(s,1H),7.15-7.20(m,1H),7.05-7.07(m,2H),6.68-6.70(m,1H),6.56(s,2H),3.79-3.83(m,1H),3.70-3.76(m,1H),2.85-2.87(m,2H),2.06-2.11(m,2H).
example 2:
MS m/z(ESI):481.2[M+1]
1HNMR(400MHz,DMSO-d6)δ11.72(s,1H),8.97(s,1H),7.15-7.20(m,1H),7.06-7.10(m,2H),6.71-6.73(m,1H),6.56(s,2H),3.99-4.06(m,2H),2.58-2.64(m,2H),2.32-2.36(m,2H).
examples 3 and 4
4- (((1r,3r) -3-aminocyclobutane) thio) -N- (3-bromo-4-fluorophenyl) -N' -hydroxy-1, 2, 5-oxadiazole-3-carboxamidine 3
4- (((1s,3s) -3-aminocyclobutane) thio) -N- (3-bromo-4-fluorophenyl) -N' -hydroxy-1, 2, 5-oxadiazole-3-carboxamidine 4
Figure GDA0003352213010000301
Figure GDA0003352213010000311
The crude product was dissolved in 10mL of tetrahydrofuran for 1h (200mg, 0.47mmol), and 0.38mL of 2.5M sodium hydroxide solution was added and the reaction stirred for 1 h. The reaction solution was poured into 30mL of water, extracted with ethyl acetate (30mL × 2), the organic phases were combined, washed with a saturated ammonium chloride solution (30mL × 2), dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the resulting residue was purified by high performance liquid chromatography to give title product 3(30mg) and title product 4(30mg), yield: 32.1 percent.
Example 3:
MS m/z(ESI):402.2[M+1]
1HNMR(400MHz,DMSO-d6)δ8.96(s,1H),7.15-7.20(m,1H),7.04-7.06(m,1H),6.67-6.70(m,1H),3.65-3.69(m,1H),3.26-3.28(m,1H),2.73-2.75(m,2H),1.73-1.80(m,2H).
example 4:
MS m/z(ESI):402.1[M+1]
1HNMR(400MHz,DMSO-d6)δ8.98(s,1H),7.16-7.21(m,1H),7.05-7.08(m,1H),6.69-6.73(m,1H),4.00-4.04(m,1H),3.59-3.63(m,1H),2.20-2.28(m,4H).
examples 5 and 6
N- (3-bromo-4-fluorophenyl) -N' -hydroxy-4- (((1s,3s) -3- (methylsulfonamido) cyclobutane) thio) -1,2, 5-oxadiazole-3-carboxamidine 5
N- (3-bromo-4-fluorophenyl) -N' -hydroxy-4- (((1r,3r) -3- (methylsulfonamido) cyclobutane) thio) -1,2, 5-oxadiazole-3-carboxamidine 6
Figure GDA0003352213010000312
Figure GDA0003352213010000321
First step of
N- (3- ((4- (4- (3-bromo-4-fluorophenyl) -5-oxo-4, 5-dihydro-1, 2, 4-oxadiazol-3-yl) -1,2, 5-oxadiazol-3-yl) thio) cyclobutane) methanesulfonamide 5a
The crude product was dissolved for 1h (200mg, 0.47mmol) in 30mL of dichloromethane, cooled to 0 deg.C, triethylamine (95mg, 0.94mmol) was added, followed by dropwise addition of methanesulfonyl chloride (64mg, 0.56mmol), and the reaction was stirred at room temperature for 1 h. The reaction was poured into 30mL of water, extracted with dichloromethane (30mL), and the organic phase was washed successively with saturated sodium bicarbonate solution (30mL), saturated sodium chloride solution (30mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give the crude title product 5a (200mg) which was directly subjected to the next reaction without purification.
Second step of
N- (3-bromo-4-fluorophenyl) -N' -hydroxy-4- (((1s,3s) -3- (methylsulfonamido) cyclobutane) thio) -1,2, 5-oxadiazole-3-carboxamidine 5
N- (3-bromo-4-fluorophenyl) -N' -hydroxy-4- (((1r,3r) -3- (methylsulfonamido) cyclobutane) thio) -1,2, 5-oxadiazole-3-carboxamidine 6
Crude 2a (200mg, 0.4mmol) was dissolved in 10mL tetrahydrofuran, 0.32mL of 2.5M sodium hydroxide solution was added, and the reaction was stirred for 1 hour. The reaction solution was poured into 30mL of water, extracted with ethyl acetate (30mL × 2), and the organic phases were combined, washed with a saturated ammonium chloride solution (30mL × 2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure and the resulting residue was purified by high performance liquid chromatography to give title product 5(30mg) and title product 6(30mg), yield: 31.7 percent.
Example 5:
MS m/z(ESI):480.1[M+1]
1HNMR(400MHz,DMSO-d6)δ8.98(s,1H),7.15-7.20(m,1H),7.07-7.09(m,1H),6.73-6.75(m,1H),4.02-4.08(s,2H),2.87(s,3H),2.58-2.61(m,2H),2.36-2.40(m,2H).
example 6:
MS m/z(ESI):480.1[M+1]
1HNMR(400MHz,DMSO-d6)δ11.72(s,1H),8.97(s,1H),7.56-7.58(m,1H),7.16-7.20(m,1H),7.06-7.08(m,1H),6.70-6.72(m,1H),3.79-3.84(m,2H),2.85-2.91(m,5H),2.03-2.11(m,2H).
example 7
N- (3- ((4- (N- (3-bromo-4-fluorophenyl) -N' -hydroxycarbamimidoyl) -1,2, 5-oxadiazol-3-yl) thio) cyclobutane) acetamide 7
Figure GDA0003352213010000331
First step of
N- (3- ((4- (4- (3-bromo-4-fluorophenyl) -5-oxo-4, 5-dihydro-1, 2, 4-oxadiazol-3-yl) -1,2, 5-oxadiazol-3-yl) thio) cyclobutane) acetamide 7a
The crude product was dissolved in 20mL of dichloromethane for 1h (200mg, 0.47mmol), cooled to 0 deg.C, triethylamine (71mg, 0.71mmol) was added, acetic anhydride (48mg, 0.47mmol) was added dropwise, the reaction was stirred at room temperature, and the reaction was terminated by LC-MS detection. The reaction was poured into 30mL of water, extracted with dichloromethane (30mL), and the organic phase was washed successively with saturated sodium bicarbonate solution (30mL), saturated sodium chloride solution (30mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give the crude title product 7a (200mg) which was directly subjected to the next reaction without purification.
Second step of
N- (3- ((4- (N- (3-bromo-4-fluorophenyl) -N' -hydroxycarbamimidoyl) -1,2, 5-oxadiazol-3-yl) thio) cyclobutane) acetamide 7
Crude 7a (200mg, 0.45mmol) was dissolved in 10mL tetrahydrofuran, 0.45mL of 2.5M sodium hydroxide solution was added, and the reaction was stirred for 1 hour. The reaction solution was poured into 50mL of a saturated ammonium chloride solution, extracted with ethyl acetate (50mL × 2), the organic phases were combined, washed with a saturated sodium chloride solution (50mL × 2), dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the resulting residue was purified by thin layer chromatography with developer system a to give the title product 7(30mg), yield: 15.9 percent.
MS m/z(ESI):444.2[M+1]
Example 8
4- ((1-Acetylazetidin-3-yl) thio) -N- (3-bromo-4-fluorophenyl) -N' -hydroxy-1, 2, 5-oxadiazole-3-carboxamidine 8
Figure GDA0003352213010000341
First step of
3- ((4- (4- (3-bromo-4-fluorophenyl) -5-oxo-4, 5-dihydro-1, 2, 4-oxadiazol-3-yl) -1,2, 5-oxadiazol-3-yl) thio) azetidine-1-carboxylic acid tert-butyl ester 8b
1f (1g, 2.7mmol) was dissolved in 30mL tetrahydrofuran, 3-mercaptoazetidinecarboxylic acid tert-butyl ester 8a (1.02g, 5.4mmol, prepared by the method disclosed in patent application "WO 201084767") and potassium carbonate (745mg, 5.4mmol) were added, and the reaction was stirred for 12 hours. The reaction solution was poured into 50mL of water, extracted with ethyl acetate (30mL × 2), the organic phases were combined, washed with a saturated sodium chloride solution (30mL × 2), dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography with eluent system B, slurried with diethyl ether to give the title product 8B (850mg), yield: 61.6 percent.
Second step of
3- (4- (azetidin-3-ylthio) -1,2, 5-oxadiazol-3-yl) -4- (3-bromo-4-fluorophenyl) -1,2, 4-oxadiazol-5 (4H) -one 8c
8b (750mg, 1.46mmol) was dissolved in 10mL of dichloromethane, 2mL of trifluoroacetic acid was added, and the reaction was stirred for 1 hour. The reaction was concentrated under reduced pressure to give the crude title product 8c (604mg), which was directly used in the next reaction without purification.
The third step
3- (4- ((1-Acetylazetidin-3-yl) thio) -1,2, 5-oxadiazol-3-yl) -4- (3-bromo-4-fluorophenyl) -1,2, 4-oxadiazol-5 (4H) -one 8d
Crude 8c (100mg, 0.24mmol) was dissolved in 100mL of dichloromethane, cooled to 0 deg.C, triethylamine (48mg, 0.48mmol) was added, acetic anhydride (29mg, 0.29mmol) was added dropwise, and the reaction was stirred at room temperature for 12 hours. The reaction was poured into saturated sodium bicarbonate solution, extracted with dichloromethane (30mL), the organic phase washed with saturated ammonium chloride solution (30mL), dried over anhydrous sodium sulfate, filtered and the filtrate concentrated under reduced pressure to give the crude title product 8d (80mg) which was directly used in the next reaction without purification.
The fourth step
4- ((1-Acetylazetidin-3-yl) thio) -N- (3-bromo-4-fluorophenyl) -N' -hydroxy-1, 2, 5-oxadiazole-3-carboxamidine 8
Crude 8d (80mg, 0.18mmol) was dissolved in 10mL tetrahydrofuran, 0.14mL of 2.5M sodium hydroxide solution was added, and the reaction was stirred for 12 hours. The reaction solution was poured into 30mL of a saturated ammonium chloride solution, extracted with ethyl acetate (30mL × 2), the organic phases were combined, washed with a saturated sodium chloride solution (30mL × 2), dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography with eluent system a to give the title product 8(10mg), yield: 13.3 percent.
MS m/z(ESI):430.2[M+1]
1H NMR(400MHz,DMSO-d6)δ11.80(s,1H),8.98(s,1H),7.11-7.20(m,2H),6.75-6.78(m,1H),4.64-4.66(m,1H),4.30-4.38(m,2H),4.06-4.09(m,1H),3.77-3.80(m,1H),1.77(s,3H).
Example 9
N- (3-bromo-4-fluorophenyl) -N' -hydroxy-4- ((1-aminosulfonylazetidin-3-yl) thio) -1,2, 5-oxadiazole-3-carboxamidine 9
Figure GDA0003352213010000351
First step of
(3- ((4- (4- (3-bromo-4-fluorophenyl) -5-oxo-4, 5-dihydro-1, 2, 4-oxadiazol-3-yl) -1,2, 5-oxadiazol-3-yl) thio) azetidin-1-yl) sulfonylcarbamic acid tert-butyl ester 9a
Crude 8c (400mg, 0.97mmol) was dissolved in 30mL of dichloromethane, cooled to 0 deg.C, triethylamine (294mg, 2.91mmol) was added, 1i (415mg, 1.93mmol) was added dropwise, and the reaction was stirred at room temperature for 1 hour. The reaction was poured into 50mL of saturated sodium bicarbonate solution, extracted with dichloromethane (30 mL. times.2), the organic phases combined, washed with saturated sodium chloride solution (30 mL. times.2), dried over anhydrous sodium sulfate, filtered, and the filtrate concentrated under reduced pressure to give the crude title product 9a (400mg) which was directly subjected to the next reaction without purification.
Second step of
3- ((4- (4- (3-bromo-4-fluorophenyl) -5-oxo-4, 5-dihydro-1, 2, 4-oxadiazol-3-yl) -1,2, 5-oxadiazol-3-yl) thio) azetidine-1-sulfonamide 9b
Crude 9a (400mg, 0.67mmol) was dissolved in 10mL of dichloromethane, 2mL of trifluoroacetic acid was added, and the reaction was stirred for 1 hour. The reaction was concentrated under reduced pressure to give the crude title product 9b (400mg), which was carried on to the next reaction without purification.
The third step
N- (3-bromo-4-fluorophenyl) -N' -hydroxy-4- ((1-aminosulfonylazetidin-3-yl) thio) -1,2, 5-oxadiazole-3-carboxamidine 9
Crude 9b (400mg, 0.81mmol) was dissolved in 20mL tetrahydrofuran, 0.65mL of 2.5M sodium hydroxide solution was added, and the reaction was stirred for 12 hours. The reaction solution was poured into 100mL of a saturated ammonium chloride solution, extracted with ethyl acetate (50mL × 2), the organic phases were combined, washed with a saturated sodium chloride solution (50mL × 2), dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography with eluent system a to give the title product 9(200mg), yield: 52.9 percent.
MS m/z(ESI):467.1[M+1]
1HNMR(400MHz,DMSO-d6)δ11.81(s,1H),8.98(s,1H),7.11-7.20(m,4H),6.74-6.77(m,1H),4.33-4.37(m,1H),4.19-4.24(m,2H),3.72-3.76(m,2H).
Example 10
N- (3-bromo-4-fluorophenyl) -N' -hydroxy-4- ((1- (methylsulfonyl) azetidin-3-yl) thio) -1,2, 5-oxadiazole-3-carboxamidine 10
Figure GDA0003352213010000361
First step of
4- (3-bromo-4-fluorophenyl) -3- (4- ((1- (methylsulfonyl) azetidin-3-yl) thio) -1,2, 5-oxadiazol-3-yl) -1,2, 4-oxadiazol-5 (4H) -one 10a
Crude 8c (100mg, 0.24mmol) was dissolved in 10mL of dichloromethane, cooled to 0 deg.C, triethylamine (48mg, 0.48mmol) was added, methanesulfonyl chloride (33mg, 0.29mmol) was added dropwise, and the reaction was stirred for 1 hour. The reaction was poured into 30mL of saturated sodium bicarbonate solution, extracted with dichloromethane (30mL), and the organic phase was washed with saturated ammonium chloride solution (30mL), saturated sodium chloride solution (30mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give the crude title product 10a (100mg) which was directly subjected to the next reaction without purification.
Second step of
N- (3-bromo-4-fluorophenyl) -N' -hydroxy-4- ((1- (methylsulfonyl) azetidin-3-yl) thio) -1,2, 5-oxadiazole-3-carboxamidine 10
Crude 10a (100mg, 0.2mmol) was dissolved in 10mL tetrahydrofuran, 0.16mL of 2.5M sodium hydroxide solution was added, and the reaction was stirred for 1 hour. The reaction solution was poured into 30mL of a saturated ammonium chloride solution, extracted with ethyl acetate (30mL × 2), the organic phases were combined, washed with a saturated sodium chloride solution (30mL × 2), dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography with eluent system a to give the title product 10(40mg), yield: 42 percent.
MS m/z(ESI):466.2[M+1]
1H NMR(400MHz,DMSO-d6)δ11.81(s,1H),8.98(s,1H),7.13-7.18(m,2H),6.75-6.77(m,1H),4.39-4.42(m,3H),3.91-3.92(m,2H),3.08(s,3H).
Example 11
N- (3-bromo-4-fluorophenyl) -N' -hydroxy-4- ((1-sulfamoylpiperidin-4-yl) thio) -1,2, 5-oxadiazole-3-carboxamidine 11
Figure GDA0003352213010000371
First step of
4- ((4- (4- (3-bromo-4-fluorophenyl) -5-oxo-4, 5-dihydro-1, 2, 4-oxadiazol-3-yl) -1,2, 5-oxadiazol-3-yl) thio) piperidine-1-carboxylic acid tert-butyl ester 11b
1f (1.54g, 4.2mmol) was dissolved in 20mL tetrahydrofuran, and 4-mercaptopiperidine-1-carboxylic acid tert-butyl ester 11a (1.8g, 8.3mmol, prepared by the method disclosed in patent application "WO 200730366") and potassium carbonate (1.15g, 8.3mmol) were added and the reaction was stirred for 1 hour. The reaction solution was poured into 50mL of water, extracted with ethyl acetate (30 mL. times.2), the organic phases were combined, washed with saturated sodium chloride solution (30 mL. times.2), dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the resulting residue was slurried with diethyl ether to give the crude title product 11b (2.1g), which was directly subjected to the next reaction without purification.
Second step of
4- (3-bromo-4-fluorophenyl) -3- (4- (piperidin-4-ylsulfanyl) -1,2, 5-oxadiazol-3-yl) -1,2, 4-oxadiazol-5 (4H) -one 11c
Crude 11b (542mg, 0.1mmol) was dissolved in 15mL of dichloromethane, 5mL of trifluoroacetic acid was added, and the reaction was stirred for 1 hour. The reaction was concentrated under reduced pressure to give the crude title product 11c (450mg), which was directly used in the next reaction without purification.
The third step (tert-butyl 4- ((4- (4- (3-bromo-4-fluorophenyl) -5-oxo-4, 5-dihydro-1, 2, 4-oxadiazol-3-yl) -1,2, 5-oxadiazol-3-yl) thio) piperidin-1-yl) sulfonylcarbamate 11d
Crude 11c (450mg, 0.1mmol) was dissolved in 10mL of dichloromethane, cooled to 0 deg.C, triethylamine (202mg, 0.2mmol) was added, 1i (323.5mg, 0.15mmol) was added dropwise, and the reaction was stirred for 1 hour. The reaction solution was poured into water. Extraction with dichloromethane (30 mL. times.2) and combining the organic phases, washing with water (30 mL. times.2), saturated sodium chloride solution (30 mL. times.2), drying over anhydrous sodium sulfate, filtration and concentration of the filtrate under reduced pressure gave the crude title product 11d (600mg) which was directly subjected to the next reaction without purification.
The fourth step
4- ((4- (4- (3-bromo-4-fluorophenyl) -5-oxo-4, 5-dihydro-1, 2, 4-oxadiazol-3-yl) -1,2, 5-oxadiazol-3-yl) thio) piperidine-1-sulfonamide 11e
Crude 11d (600mg, 0.97mmol) was dissolved in 15mL of dichloromethane, 5mL of trifluoroacetic acid was added, and the reaction was stirred for 30 minutes. The reaction was concentrated under reduced pressure, the resulting residue was dissolved in dichloromethane, saturated sodium carbonate solution was added dropwise under ice-bath conditions to pH 7, extracted with dichloromethane (30mL × 2), the organic phases were combined, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography with eluent system a to give the title product 11e (200mg), yield: 39.8 percent.
The fifth step
N- (3-bromo-4-fluorophenyl) -N' -hydroxy-4- ((1-sulfamoylpiperidin-4-yl) thio) -1,2, 5-oxadiazole-3-carboxamidine 11
11e (200mg, 0.38mmol) was dissolved in 10mL tetrahydrofuran, and 0.5mL of 2.5M sodium hydroxide solution was added thereto, followed by stirring and completion of the reaction by TLC. The aqueous phase was separated, 1M hydrochloric acid was added dropwise to neutral PH, extracted with dichloromethane (30mL × 2), the organic phases were combined, washed with saturated sodium chloride solution (30mL × 2), dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure and the resulting residue was purified by silica gel column chromatography with eluent system a to give the title product 11(110mg), yield: 58 percent.
MS m/z(ESI):495.2[M+1]
1H NMR(400MHz,DMSO-d6)δ11.74(s,1H),9.01(s,1H),7.16-7.21(t,1H),7.05-7.08(dd,1H),6.83(s,2H),6.70-6.71(m,1H),3.78-3.69(m,1H),3.36-3.43(m,2H),2.79-2.84(t,2H),2.18-2.21(m,2H),1.75-1.79(m,2H).
Example 12
(R) -N- (3-bromo-4-fluorophenyl) -N' -hydroxy-4- ((1-aminosulfonylpiperidin-3-yl) thio) -1,2, 5-oxadiazole-3-carboxamidine 12
Figure GDA0003352213010000391
First step of
(R) -3-mercaptopiperidine-1-carboxylic acid tert-butyl ester 12b
(R) -3- (acetylthio) piperidine-3-carboxylic acid tert-butyl ester 12a (1.7g, 6.56mmol, prepared by the method disclosed in patent application "WO 2012138678") was dissolved in 20mL of methanol, cooled to 0 ℃ and added with potassium carbonate (1.36g, 9.84mmol), and the reaction was stirred for 10 min. The reaction was quenched by adding 5mL of saturated ammonium chloride solution to the reaction solution, extracted with dichloromethane (50mL), the organic phase was washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography with eluent system B to give the title product 12B (1.4g), yield: 98 percent.
Second step of
(S) -3- ((4- (4- (3-bromo-4-fluorophenyl) -5-oxo-4, 5-dihydro-1, 2, 4-oxadiazol-3-yl) -1,2, 5-oxadiazol-3-yl) thio) piperidine-1-carboxylic acid tert-butyl ester 12c
12b (1.4g, 6.215mmol) and 1f (1.68g, 4.52mmol) were dissolved in 20mL of tetrahydrofuran, and potassium carbonate (1.78g, 12.9mmol) was added to stir the reaction for 12 hours. Filtration, concentration of the filtrate under reduced pressure and purification of the resulting residue by silica gel column chromatography with eluent system B gave the title product 12c (800mg), yield: 32.6 percent.
The third step is (S) -4- (3-bromo-4-fluorophenyl) -3- (4- (piperidin-3-ylsulfanyl) -1,2, 5-oxadiazol-3-yl) -1,2, 4-oxadiazol-5 (4H) -one 12d
12c (800mg, 1.48mmol) was dissolved in 5mL of 1, 4-dioxane, 10mL of 4M hydrochloric acid was added, and the reaction was stirred for 24 hours. To the reaction solution was added 50mL of ethyl acetate, a saturated sodium carbonate solution was added dropwise to neutral pH, the organic phase was separated, concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography with eluent system a to give the title product 12d (500mg), yield: 76.7 percent.
Fourth step (R) - (3- ((4- (4- (3-bromo-4-fluorophenyl) -5-oxo-4, 5-dihydro-1, 2, 4-oxadiazol-3-yl) -1,2, 5-oxadiazol-3-yl) thio) piperidin-1-yl) sulfonylcarbamic acid tert-butyl ester 12e
Crude 12d (490mg, 1.11mmol) was dissolved in 10mL of dichloromethane, triethylamine (224mg, 2.22mmol) was added, 1i (238mg, 1.11mmol) was added dropwise, the reaction was stirred and the reaction was complete by TLC. The reaction solution was poured into water, extracted with dichloromethane (30mL × 2), the organic phases were combined, washed successively with water (30mL), saturated sodium chloride solution (30mL × 2), dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography with eluent system B to give the title product 12e (420mg), yield: 60.9 percent.
The fifth step
(R) -3- ((4- (4- (3-bromo-4-fluorophenyl) -5-oxo-4, 5-dihydro-1, 2, 4-oxadiazol-3-yl) -1,2, 5-oxadiazol-3-yl) thio) piperidine-1-sulfonamide 12f
12e (420mg, 0.676mmol) was dissolved in 5mL of 4M hydrochloric acid/1, 4-dioxane solution and the reaction was stirred for 12 hours. The reaction was concentrated under reduced pressure to give the crude title product 12f (400mg, brown solid) which was directly used in the next reaction without purification.
The sixth step
(R) -N- (3-bromo-4-fluorophenyl) -N' -hydroxy-4- ((1-aminosulfonylpiperidin-3-yl) thio) -1,2, 5-oxadiazole-3-carboxamidine 12
Crude 12f (400mg, 0.768mmol) was dissolved in 5mL tetrahydrofuran, 5mL of 2M sodium hydroxide solution was added, and the reaction was stirred for 2 hours. To the reaction solution was added 2mL of water, extracted with ethyl acetate (10mL × 2), the organic phases were combined, concentrated under reduced pressure and the resulting residue was purified by high performance liquid chromatography to give the title product 12(200mg), yield: 52.6 percent.
MS m/z(ESI):495.0[M+1]
1H NMR(400MHz,DMSO-d6):δ11.80(s,1H),9.00(s,1H),7.18(t,1H),7.11-7.09(m,1H),6.86(s,2H),6.73-6.69(m,1H),3.96(m,1H),3.52-3.49(m,1H),3.11-3.01(m,2H),2.01(m,1H),1.86(m,1H),1.70(m,2H),1.24(m,1H).
Example 13
(S) -N- (3-bromo-4-fluorophenyl) -N' -hydroxy-4- ((1-sulfamoylpiperidin-3-yl) thio) -1,2, 5-oxadiazole-3-carboxamidine 13
Figure GDA0003352213010000401
Figure GDA0003352213010000411
First step of
(R) -3- ((4- (4- (3-bromo-4-fluorophenyl) -5-oxo-4, 5-dihydro-1, 2, 4-oxadiazol-3-yl) -1,2, 5-oxadiazol-3-yl) thio) piperidine-1-carboxylic acid tert-butyl ester 13b
1f (171.2mg, 0.46mmol) was dissolved in 10mL of tetrahydrofuran, and (S) -3-mercaptopiperidine-1-carboxylic acid tert-butyl ester 13a (200mg, 0.92mmol, prepared by a known method "Bioorganic and Medicinal Chemistry Letters,2009,19(10),2742 and 2746") and potassium carbonate (95.22mg, 0.69mmol) were added and reacted with stirring for 1 hour. The reaction was poured into water, extracted with ethyl acetate (30mL × 2), the organic phases combined, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered and the filtrate concentrated under reduced pressure to give the crude title product 13b (360mg) which was directly subjected to the next reaction without purification.
Second step of
(R) -4- (3-bromo-4-fluorophenyl) -3- (4- (piperidin-3-ylthio) -1,2, 5-oxadiazol-3-yl) -1,2, 4-oxadiazol-5 (4H) -one 13c
Crude 13b (360mg, 0.7mmol) was dissolved in 15mL of dichloromethane, 5mL of trifluoroacetic acid was added, and the reaction was stirred for 30 minutes. The reaction was concentrated under reduced pressure to give the crude title product 13c (350mg), which was directly used in the next reaction without purification.
The third step
(S) - (3- ((4- (4- (3-bromo-4-fluorophenyl) -5-oxo-4, 5-dihydro-1, 2, 4-oxadiazol-3-yl) -1,2, 5-oxadiazol-3-yl) thio) piperidin-1-yl) sulfonylcarbamic acid tert-butyl ester 13d
Crude 13c (350mg, 0.79mmol) was dissolved in 5mL of dichloromethane, triethylamine (160mg, 1.58mmol) was added, after cooling to 0 deg.C, 1i (256mg, 1.2mmol) was added dropwise, and the reaction was stirred for 1 hour. The reaction solution was poured into water. Extraction with dichloromethane (30mL × 2), combining the organic phases, washing with saturated sodium chloride solution, drying over anhydrous sodium sulfate, filtration, concentration of the filtrate under reduced pressure, and purification of the resulting residue by silica gel column chromatography with eluent system a gave the title product 13d (300mg), yield: 61 percent.
The fourth step
(S) -3- ((4- (4- (3-bromo-4-fluorophenyl) -5-oxo-4, 5-dihydro-1, 2, 4-oxadiazol-3-yl) -1,2, 5-oxadiazol-3-yl) thio) piperidine-1-sulfonamide 13e
13d (300mg, 0.48mmol) was dissolved in 15mL of dichloromethane, 5mL of trifluoroacetic acid was added, and the reaction was stirred for 1 hour. The reaction was concentrated under reduced pressure, the resulting residue was dissolved in dichloromethane, saturated sodium bicarbonate solution was added dropwise to a basic pH, extracted with dichloromethane (30mL × 2), the organic phases were combined, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give the crude title product 13e (150mg) which was directly subjected to the next reaction without purification.
The fifth step
(S) -N- (3-bromo-4-fluorophenyl) -N' -hydroxy-4- ((1-sulfamoylpiperidin-3-yl) thio) -1,2, 5-oxadiazole-3-carboxamidine 13
Crude 13e (100mg, 0.19mmol) was dissolved in 5mL tetrahydrofuran, 0.23mL of 2.5M sodium hydroxide solution was added, and the reaction was stirred for 30 minutes. The aqueous phase was separated, 1M hydrochloric acid was added dropwise to pH 7, extracted with ethyl acetate (10mL × 2), the organic phases were combined, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the resulting residue was purified by high performance liquid chromatography to give the title product 13(50mg), yield: 52.7 percent.
MS m/z(ESI):495.1[M+1]
1H NMR(400MHz,DMSO-d6)δ11.78(s,1H),8.99(s,1H),7.15-7.19(t,1H),7.08-7.10(dd,1H),6.85(s,2H),6.67-6.82(m,1H),3.48-3.50(m,1H),3.00-3.10(m,2H),1.97-2.00(t,2H),1.67-1.82(m,2H),1.17-1.33(m,2H).
Example 14
N- (3-bromo-4-fluorophenyl) -N' -hydroxy-4- (((1s,4s) -4- (sulfamoylamino) cyclohexyl) thio) -1,2, 5-oxadiazole-3-carboxamidine 14
Figure GDA0003352213010000421
Figure GDA0003352213010000431
First step of
((1s,4s) -4-mercaptocyclohexyl) carbamic acid tert-butyl ester 14b
S- ((1S,4S) -4- ((t-butoxycarbonyl) amino) cyclohexyl) thioacetic acid 14a (800mg, 2.93mmol, prepared by a known method "Journal of Medicinal Chemistry,1993,36(19), 2788-2800") was dissolved in 20mL of methanol, potassium carbonate (605.7mg, 4.39mmol) was added, and the reaction was stirred for 20 minutes. To the reaction solution was added 20mL of saturated ammonium chloride solution, extracted with ethyl acetate (15 mL. times.2), the organic phases were combined, washed with saturated sodium chloride solution (20mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give the crude title product 14b (800mg) which was directly subjected to the next reaction without purification.
Second step of
((1r,4r) - (4- ((4- (4- (3-bromo-4-fluorophenyl) -5-oxo-4, 5-dihydro-1, 2, 4-oxadiazol-3-yl) -1,2, 5-oxadiazol-3-yl) thio) cyclohexane) carbamic acid tert-butyl ester 14c
Crude 14b (600mg, 2.59mmol) was dissolved in 20mL tetrahydrofuran, 1f (200mg, 0.54mmol) and potassium carbonate (149.04mg, 1.08mmol) were added, and the reaction was stirred for 16 h. The reaction solution was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography with eluent system B to give the title product 14c (260mg), yield: 86.7 percent.
The third step
3- (4- (((1r,4r) -4-aminocyclohexyl) thio) -1,2, 5-oxadiazol-3-yl) -4- (3-bromo-4-fluorophenyl) -1,2, 4-oxadiazol-5 (4H) -one 14d
14c (300.5mg, 0.54mmol) was dissolved in 5mL of dichloromethane, 1mL of trifluoroacetic acid was added, and the reaction was stirred for 2 hours. The reaction was concentrated under reduced pressure to give the crude title product 14d (280mg), which was directly used in the next reaction without purification.
The fourth step
N- ((1r,4r) -4- ((4- (4- (3-bromo-4-fluorophenyl) -5-oxo-4, 5-dihydro-1, 2, 4-oxadiazol-3-yl) -1,2, 5-oxadiazol-3-yl) thio) cyclohexane) sulfamoylcarbamic acid tert-butyl ester 14e
Crude 14d (126.4mg, 0.54mmol) was dissolved in 20mL of dichloromethane, cooled to 0 deg.C and triethylamine (0.224mL, 1.62mmol) and 1i (0.54mL, 0.54mmol) were added and the reaction was stirred at room temperature for 16 h. To the reaction solution was added 1mL of methanol, concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography with eluent system a to give the title product 14e (280mg), yield: 81.6 percent.
The fifth step
N- [4- ({4- [4- (3-bromo-4-fluorophenyl) -5-oxo-4, 5-dihydro-1, 2, 4-oxadiazol-3-yl ] -1,2, 5-oxadiazol-3-yl } thio) cyclohexyl ] aminosulfonamide 14f
14e (300mg, 0.47mmol) was dissolved in 9mL of dichloromethane, 2mL of trifluoroacetic acid was added, and the reaction was stirred for 3 hours. The reaction was concentrated under reduced pressure to give the crude title product 14f (260mg), which was directly used in the next reaction without purification.
The sixth step
N- (3-bromo-4-fluorophenyl) -N' -hydroxy-4- (((1s,4s) -4- (sulfamoylamino) cyclohexyl) thio) -1,2, 5-oxadiazole-3-carboxamidine 14
Crude 14f (200mg, 0.37mmol) was dissolved in 10mL tetrahydrofuran, 0.59mL of 2.5M sodium hydroxide solution was added, and the reaction was stirred for 1 hour. To the reaction solution was added 20mL of saturated ammonium chloride solution, extracted with ethyl acetate (15mL × 3), the organic phases were combined, washed with saturated sodium chloride solution (20mL), dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography with eluent system a to give the title product 14(100mg), yield: 53.1 percent.
MS m/z(ESI):509.1[M+1]
1H NMR(400MHz,DMSO-d6)δ11.71(s,1H),9.00(s,1H),7.16-7.21(m,1H),7.02-7.04(m,1H),6.70-6.71(m,1H),6.61-6.62(m,1H),6.49-6.50(m,2H),3.84-3.86(m,1H),3.25-3.27(m,1H),1.89-1.91(m,4H),1.76-1.79(m,2H),1.61-1.64(m,2H)
Example 15
(R) -N- (3-bromo-4-fluorophenyl) -N' -hydroxy-4- ((1-sulfamoylpyrrolidin-3-yl) thio) -1,2, 5-oxadiazole-3-carboxamidine
Figure GDA0003352213010000441
Figure GDA0003352213010000451
First step (R) -3- ((4- (4- (3-bromo-4-fluorophenyl) -5-oxo-4, 5-dihydro-1, 2, 4-oxadiazol-3-yl) -1,2, 5-oxadiazol-3-yl) thio) pyrrolidine-1-carboxylic acid tert-butyl ester 15b
1f (280mg, 0.72mmol) was dissolved in 10mL of tetrahydrofuran, and (R) -3-mercaptopyrrolidine-1-carboxylic acid tert-butyl ester 15a (306mg, 1.5mmol, prepared by a known method "Bioorganic and Medicinal Chemistry Letters,2009,19(1), 170-174") and potassium carbonate (207mg, 1.5mmol) were added and reacted with stirring for 16 hours. The reaction solution was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography with eluent system B to give the title product 15B (300mg), yield: 81.5 percent.
Second step of
(R) -4- (3-bromo-4-fluorophenyl) -3- (4- (pyrrolidin-3-ylthio) -1,2, 5-oxadiazol-3-yl) -1,2, 4-oxadiazol-5 (4H) -one 15c
15b (300mg, 0.587mmol) was dissolved in 6mL of dichloromethane, 1.5mL of trifluoroacetic acid was added, and the reaction was stirred for 2 hours. The reaction was concentrated under reduced pressure to give the crude title product 15c (241.4mg), which was directly used for the next reaction without purification.
The third step
(R) - (3- ((4- (4- (3-bromo-4-fluorophenyl) -5-oxo-4, 5-dihydro-1, 2, 4-oxadiazol-3-yl) -1,2, 5-oxadiazol-3-yl) thio) pyrrolidin-1-yl) sulfonylcarbamic acid tert-butyl ester 15d
Crude 15c (241.4mg, 0.587mmol) was dissolved in 20mL of dichloromethane, cooled to 0 deg.C and triethylamine (0.162mL, 1.174mmol) and 1i (126.6mg, 0.587mmol) were added and the reaction stirred for 30 min. To the reaction solution was added 1mL of methanol, and after concentration under reduced pressure, the resulting residue was purified by silica gel column chromatography with eluent system a to give the title product 15d (300mg), yield: 86.6 percent.
The fourth step
(R) -3- ((4- (4- (3-bromo-4-fluorophenyl) -5-oxo-4, 5-dihydro-1, 2, 4-oxadiazol-3-yl) -1,2, 5-oxadiazol-3-yl) thio) pyrrolidine-1-sulfonamide 15e
15d (300mg, 0.494mmol) was dissolved in 6mL of dichloromethane, 1.5mL of trifluoroacetic acid was added, and the reaction was stirred for 2 hours. The reaction was concentrated under reduced pressure to give the crude title product 15e (260mg), which was directly used in the next reaction without purification.
The fifth step
(R) -N- (3-bromo-4-fluorophenyl) -N' -hydroxy-4- ((1-sulfamoylpyrrolidin-3-yl) thio) -1,2, 5-oxadiazole-3-carboxamidine 15
Crude 15e (250.5mg, 0.494mmol) was dissolved in 10mL tetrahydrofuran, 1mL of 2.5M sodium hydroxide solution was added, and the reaction was stirred for 1 hour. To the reaction solution was added 20mL of saturated ammonium chloride solution, extracted with ethyl acetate (15mL × 3), the organic phases were combined, washed with saturated sodium chloride solution (20mL), dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography with eluent system a to give the title product 15(150mg), yield: 63.1 percent.
MS m/z(ESI):481.1[M+1]
1H NMR(400MHz,DMSO-d6)δ11.77(s,1H),8.98(s,1H),7.16-7.18(m,1H),7.10-7.12(m,1H),6.92-6.94(m,2H),6.72-6.74(m,1H),4.19-4.20(m,1H),3.68-3.70(m,1H),3.16-3.27(m,4H),1.94-1.98(m,1H).
Example 16
(S) -N- (3-bromo-4-fluorophenyl) -N' -hydroxy-4- ((1-sulfamoylpyrrolidin-3-yl) thio) -1,2, 5-oxadiazole-3-carboxamidine
Figure GDA0003352213010000461
First step of
(S) -3- ((4- (4- (3-bromo-4-fluorophenyl) -5-oxo-4, 5-dihydro-1, 2, 4-oxadiazol-3-yl) -1,2, 5-oxadiazol-3-yl) thio) pyrrolidine-1-carboxylic acid tert-butyl ester 16b
1f (829.5mg, 2.21mmol) was dissolved in 10mL of tetrahydrofuran, and (S) -3-mercaptopyrrolidine-1-carboxylic acid tert-butyl ester 16a (0.9g, 4.43mmol, prepared by a known method "Bioorganic and Medicinal Chemistry Letters,2009,19(1),170 & 174") and potassium carbonate (611.3mg, 4.43mmol) were added and reacted with stirring for 1 hour. The reaction was poured into water, extracted with ethyl acetate (15 mL. times.3), the organic phases combined, washed with saturated sodium chloride solution (20mL), dried over anhydrous sodium sulfate, filtered and the filtrate concentrated under reduced pressure to give the crude title product 16b (1.5g) which was directly used in the next reaction without purification.
Second step of
(S) -4- (3-bromo-4-fluorophenyl) -3- (4- (pyrrolidin-3-ylthio) -1,2, 5-oxadiazol-3-yl) -1,2, 4-oxadiazol-5 (4H) -one 16c
Crude 16b (1.5g, 2.84mmol) was dissolved in 20mL of dichloromethane, 5mL of trifluoroacetic acid was added, and the reaction was stirred for 1 hour. The reaction was concentrated under reduced pressure to give the crude title product 16c (1g), which was directly used in the next reaction without purification.
The third step
(S) - (3- ((4- (4- (3-bromo-4-fluorophenyl) -5-oxo-4, 5-dihydro-1, 2, 4-oxadiazol-3-yl) -1,2, 5-oxadiazol-3-yl) thio) pyrrolidin-1-yl) sulfonylcarbamic acid tert-butyl ester 16d
Crude 16c (300mg, 0.7mmol) was dissolved in 10mL of dichloromethane, triethylamine (0.2mL, 1.4mmol) was added, after cooling to 0 deg.C 1i (226.7mg, 1.05mmol) was added dropwise and the reaction stirred for 30 min. The reaction solution was poured into water. Extraction with dichloromethane (30 mL. times.2) and combining the organic phases, washing with saturated sodium chloride solution, drying over anhydrous sodium sulfate, filtration and concentration of the filtrate under reduced pressure gave the crude title product 16d (350mg) which was directly used for the next step without purification.
The fourth step
(S) -3- ((4- (4- (3-bromo-4-fluorophenyl) -5-oxo-4, 5-dihydro-1, 2, 4-oxadiazol-3-yl) -1,2, 5-oxadiazol-3-yl) thio) pyrrolidine-1-sulfonamide 16e
Crude 16d (350mg, 0.58mmol) was dissolved in 15mL of dichloromethane, 5mL of trifluoroacetic acid was added, and the reaction was stirred for 1 hour. The reaction was concentrated under reduced pressure to give the crude title product 16e (230mg), which was directly used in the next reaction without purification.
The fifth step
(S) -N- (3-bromo-4-fluorophenyl) -N' -hydroxy-4- ((1-sulfamoylpyrrolidin-3-yl) thio) -1,2, 5-oxadiazole-3-carboxamidine 16
Crude 16e (230mg, 0.44mmol) was dissolved in 5mL tetrahydrofuran, 0.08mL of 1M sodium hydroxide solution was added, and the reaction was stirred for 30 minutes. The aqueous phase was separated, 1M hydrochloric acid was added dropwise to neutral pH, extracted with ethyl acetate (10mL × 2), the organic phases were combined, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure and the resulting residue was purified by thin layer chromatography with eluent system a to give the title product 16(25mg), yield: 63.1 percent.
MS m/z(ESI):481.1[M+1]
1H NMR(400MHz,DMSO-d6)δ11.77(s,1H),8.98(s,1H),7.16-7.20(t,1H),7.09-7.12(dd,1H),6.92(s,2H),6.72-6.74(m,1H),4.19-4.22(m,1H),3.68-3.72(m,1H),3.23-3.27(m,2H),3.16-3.19(t,1H),2.44-2.48(m,1H),1.92-1.99(m,1H).
Example 17
N- (3-bromo-4-fluorophenyl) -N' -hydroxy-4- ((1- ((2-hydroxyethyl) sulfonyl) azetidin-3-yl) thio) -1,2, 5-oxadiazole-3-carboxamidine
Figure GDA0003352213010000481
First step of
Ethyl 2- ((3- ((4- (N- (3-bromo-4-fluorophenyl) -N' -hydroxycarbamimidoyl) -1,2, 5-oxadiazol-3-yl) thio) azetidin-1-yl) sulfonyl) acetate 17b
The crude 8c (250mg, 0.6mmol) was dissolved in 20mL of dichloromethane, cooled to 0 deg.C, triethylamine (831.7mg, 6mmol) was added, 2- (chlorosulfonyl) acetic acid ethyl ester 17a (225.3mg, 1.21mmol, prepared by the method disclosed in the patent application "US 20090269305") was added dropwise, and the reaction was stirred for 0.5 hour. To the reaction solution was added 10mL of methanol, concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography with eluent system B to give the title product 17B (140mg), yield: 41.3 percent.
Second step of
N- (3-bromo-4-fluorophenyl) -N' -hydroxy-4- ((1- ((2-hydroxyethyl) sulfonyl) azetidin-3-yl) thio) -1,2, 5-oxadiazole-3-carboxamidine 17
17b (140mg, 0.25mmol) was dissolved in 5mL tetrahydrofuran, sodium borohydride (23.6mg, 0.62mmol) and methanol (16.02mg, 0.5mmol) were added, and the reaction was stirred at 65 ℃ for 1 hour. The reaction was cooled to room temperature, 20mL of water was added, extraction was performed with ethyl acetate (15mL × 2), the organic phases were combined, washed with saturated sodium chloride solution (20mL), dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography with eluent system a to give the title product 17(55mg), yield: 44.3 percent.
MS m/z(ESI):496.1[M+1]
1H NMR(400MHz,DMSO-d6)δ11.83(s,1H),8.99(s,1H),7.13-7.21(m,2H),6.75-6.79(m,1H),5.15-5.18(m,1H),4.41-4.46(m,3H),3.91-3.93(m,2H),3.75-3.80(m,2H),3.37-3.39(m,2H).
Biological evaluation
The present invention is further described and explained below in conjunction with test examples, which are not intended to limit the scope of the present invention.
Test example 1 determination of inhibitory Activity of the Compound of the present invention against human IDO1 protease
In vitro human IDO1 protease activity was tested by the following method.
This method was used to determine the inhibitory effect of the compounds of the present invention on the activity of human IDO1 protease.
First, experimental material and instrument
1. Enzyme mark instrument (Synergy HT, BIOTEK)
2. Tryptophan (T0254-5G, Sigma-Aldrich)
3. Catalase was derived from bovine liver (C1345-1G, Sigma-Aldrich)
4. Methylene blue (M9140-25G, Sigma-Aldrich)
5. L-ascorbic acid sodium salt (A7631-25G, Sigma-Aldrich)
6. 4- (dimethylamino) benzaldehyde (D2004-25G, Sigma-Aldrich)
7. Trichloroacetic acid (T9159-100G, Sigma-Aldrich)
8. Humanized IDO1 gene (SC126221, Origene)
Second, the experimental procedure
Homemade IDO1 protease:
the human IDO1 gene is transferred into a PET30a plasmid by a gene cloning technology, and then transferred into a competent Escherichia coli Rosetta (DE3) competent cell (KT1003, Shenzhen Huanyankang gene science and technology Limited); culturing in liquid LB (Luria-Bertani) culture medium (per liter of culture medium prepared according to molecular cloning's instruction (J. SammBruke D.W. Lassel.), collecting thallus, ultrasonicating, passing through hanging column, and eluting to obtain purified IDO1 protease.
Compound testing experiments:
mu.l of the enzyme (IDO1) was 100-fold diluted to 2400. mu.l with 50mM KPB, and 24. mu.l of the enzyme solution was added to each well of a 96-well reaction plate (AXYGEN, PCR-96-FLT-C) (hereinafter referred to as reaction plate). Blank wells were loaded with 24 μ l KPB [ preparation of KPB buffer (50 mM): weighing KH with analytical balance2PO46.805g of the powder is put into a 1000ml beaker, deionized water is added into a measuring cylinder to reach 900ml, the pH value is adjusted to 6.5 by using 1M KOH, the solution is poured into a 1L measuring cylinder, and water is added to reach 1L. Storage at 4 deg.C]. Mu.l of compound or DMSO was added to the corresponding wells in the reaction plate. Preparing a solution A: 200 μ L of 500mM L-sodium ascorbate was mixed with 1050 μ L KPB and mixed in a turbine mixer at maximum speed for 3 seconds. And B, liquid B: mu.l of 10mM tryptophan acid plus 100. mu.l of 100000 units/ml catalase, plus 5. mu.l of 10mM methylene blue, and finally 1050. mu.l of KPB, are mixed for 3 seconds at maximum speed in a turbine mixer. The 1200. mu. l A solution and 1200. mu. l B solution were mixed together at maximum speed in a turbine mixer for 3 seconds. This mixture was then added to the reaction plate at 24. mu.l per well. Placing the reaction plate in a plate centrifuge, centrifuging at the highest speed for 15 seconds to ensure that reaction liquid is gathered at the bottom, uniformly mixing the reaction liquid and the reaction liquid for 30 seconds in an oscillator, and incubating for 1 hour at 37 ℃ in a constant-temperature incubator. In the reaction plate, 10. mu.l of 30% (W/V) trichloroacetic acid was added to each well, and incubated at 65 ℃ for 15 minutes in an incubator. The reaction plate was centrifuged at 4700RPM on a centrifuge at room temperature for 5 minutes. Transfer 40. mu.l of supernatant from the reaction plate to the corresponding 96-well test plate (Corning, #3599) with a line gun. Add 40. mu.l of 2% (W/V) 4- (dimethylamino) benzaldehyde/glacial acetic acid solution per well and mix well for 1 min at maximum speed on a shaker. After incubation for 2 min at room temperature, the absorbance at 480nm was read on Synergy HT (BIOTEK).
The inhibitory activity of the compound of the present invention against human IDO1 protease was determined by the above assay, and the IC was determined50The values are shown in Table 1.
TABLE 1 inhibition of human IDO1 protease Activity IC by the Compounds of the invention50
Example numbering IC50(nM)
1 18
2 19
3 43
4 134
5 16
6 16
7 69
8 15
9 21
10 12
11 26
12 22
13 29
14 16
15 12
16 14
And (4) conclusion: the compound of the invention has obvious inhibition effect on the activity of human IDO1 protease.
Test example 2 determination of inhibitory Activity of Compounds of the present invention against human TDO protease
In vitro human TDO protease activity was tested by the following method.
This method was used to determine the inhibitory effect of the compounds of the invention on the activity of the human TDO protease.
First, experimental material and instrument
1. Enzyme mark instrument (Synergy HT, BIOTEK)
2. Tryptophan (T0254-5G, Sigma-Aldrich)
3. Catalase was derived from bovine liver (C1345-1G, Sigma-Aldrich)
4. Methylene blue (M9140-25G, Sigma-Aldrich)
5. L-ascorbic acid sodium salt (A7631-25G, Sigma-Aldrich)
6. 4- (dimethylamino) benzaldehyde (D2004-25G, Sigma-Aldrich)
7. Trichloroacetic acid (T9159-100G, Sigma-Aldrich)
8. Human TDO (U32989.1, Suzhou Jinweizhi Biotechnology Co., Ltd.)
9. Rossetta (CW0811A, Beijing kang is century Biotechnology Co., Ltd.)
10. Turbine mixer (6776, Corning)
11. Mini plate centrifuge (Mini-P25, ABSON life science equipment)
Second, the experimental procedure
Homemade TDO protease
Transferring the constructed plasmid containing the human TDO gene into competent escherichia coli Rosseta; the cells were cultured in a liquid LB (Luria-Bertani) medium (prepared per liter of the medium according to the molecular cloning Experimental guidelines, J. SammBruke D.W. Lassel.), amplified, the cells were harvested, sonicated, passed through a hanging column, and eluted to give purified TDO1 protease.
Compound testing experiments:
mu.l of enzyme (TDO) was 100-fold diluted to 2400. mu.l with 50mM KPB, and 24. mu.l of enzyme solution was added to each well of a 96-well reaction plate (AXYGEN, PCR-96-FLT-C) (hereinafter referred to as a reaction plate). Add 24. mu.l KPB buffer [ preparation of KPB buffer (50 mM): weighing KH with analytical balance2PO46.805g of the product was put into a 1000ml beaker, deionized water was added to 900ml in a measuring cylinder, the pH was adjusted to 6.5 with 1M KOH, and the mixture was introduced into a 1L measuring cylinder and water was added to 1L. Storage at 4 deg.C]. Mu.l of compound or DMSO was added to the corresponding wells in the reaction plate. Preparing a solution A: 200. mu.l of 500mM L sodium ascorbate was mixed with 1050. mu.l KPB and mixed in a turbine mixer at maximum speed for 3 seconds. And B, liquid B: mu.l 10mM Tryptophan acid 100. mu.l 100000unit/ml catalase, 5. mu.l 10mM methylene blue, finally 1050. mu.l KPB, mixed for 3 seconds at maximum speed in a turbine mixer. The 1200. mu. l A solution and 1200. mu. l B solution were mixed together at maximum speed in a turbine mixer for 3 seconds. This mixture was then added to the reaction plate at 24. mu.l per well. Placing the reaction plate in a plate centrifuge, centrifuging at the highest speed for 15 seconds to ensure that reaction liquid is gathered at the bottom, uniformly mixing the reaction liquid and the reaction liquid for 30 seconds in an oscillator, and incubating for 1 hour at 37 ℃ in a constant-temperature incubator. In the reaction plate, 10. mu.l of 30% (W/V) trichloroacetic acid was added to each well, and incubated at 65 ℃ for 15 minutes in an incubator. Centrifuge the reaction plate at 4700RPM offHeart, room temperature, 5 min. Transfer 40. mu.l of supernatant from the reaction plate to the corresponding 96-well test plate (Corning, #3599) with a line gun. Add 40. mu.l of 2% (W/V) 4- (dimethylamino) benzaldehyde/glacial acetic acid solution per well and mix well for 1 min at maximum speed on a shaker. After incubation for 2 min at room temperature, the absorbance at 480nm was read on a Synergy HT Reader.
The inhibitory Activity of the Compounds of the present invention against human TDO protease was determined by the above assay, and the IC was determined50The values are shown in Table 2.
TABLE 2 inhibition of human TDO protease Activity IC by Compounds of the invention50
Figure GDA0003352213010000511
Figure GDA0003352213010000521
And (4) conclusion: the weak inhibitory effect of the compounds of the present invention on the activity of human TDO protease indicates that the compounds of the present invention are selective IDO inhibitors.
Test example 3 determination of IDO protease inhibitory Activity of the Compound of the present invention in HeLa cells
IDO protease activity in HeLa cells was tested by the following method.
This method was used to determine the inhibitory effect of the compounds of the present invention on IDO protease activity in HeLa cells. (Note: HeLa cell line expresses indoleamine 2,3-dioxygenase (IDO) under induction of interferon gamma (INF-. gamma.))
First, experimental material and instrument
1. Enzyme mark instrument (Synergy HT, BIOTEK)
2. Tryptophan (T0254-5G, Sigma-Aldrich)
3. 4- (dimethylamino) benzaldehyde (D2004-25G, Sigma-Aldrich)
4. Trichloroacetic acid (T9159-100G, Sigma-Aldrich)
5. HeLa cell line (CCL-2, ATCC)
6. INF-gamma interferon (R & D Systems,285-IF-100)
Second, the experimental procedure
HeLa cell suspension was prepared from a fresh cell culture medium, and 10000 cells/well were added to a 96-well cell culture plate of 100. mu.l culture system, and cultured with 5% carbon dioxide at 37 ℃ for 24 hours. Removing supernatant, and adding 90 μ l of serum-free DMEM high-sugar medium into each well; then, 10. mu.l of the compound (final concentration: 10000, 1000, 100, 10, 1, 0.1nM) prepared in the medium containing INF-. gamma.and tryptophan was added to each well, and the mixture was incubated at 37 ℃ for 48 hours with 5% carbon dioxide, 80. mu.l of the supernatant from the 96-well cell culture plate was taken out to a 96-well round bottom plate, 16. mu.l of 30% (W/V) trichloroacetic acid was added to each well, and incubated at 65 ℃ for 25 minutes in an incubator. The reaction plate was centrifuged at 4700RPM for 5 minutes in a centrifuge. Transfer 50. mu.l of supernatant from the reaction plate to a 96-well flat-bottom transparent plate using a calandria, then add 50. mu.l of 2% (W/V) 4- (dimethylamino) benzaldehyde/glacial acetic acid solution per well and mix well on a shaker for 1 minute. After incubation for 2 min at room temperature, the absorbance at 480nm was read on a Synergy HT Reader.
The inhibitory activity of the compound of the present invention against HeLa intracellular IDO protease was measured by the above assay, and the IC was determined50The values are shown in Table 3.
TABLE 3 inhibition of IDO protease Activity IC in HeLa cells by the Compounds of the invention50
Example numbering IC50(nM)
1 5
2 5
3 29
4 39
5 11
6 10
7 11
8 5
9 8
10 5
11 21
12 40
13 16
14 32
15 8
16 11
And (4) conclusion: the compound has obvious inhibition effect on the activity of IDO protease in HeLa cells.
Pharmacokinetic evaluation
Test example 4 pharmacokinetic testing of Compounds of examples 1 and 2 of the invention
1. Abstract
The drug concentrations in plasma of SD rats at various times after intragastric administration of the compounds of examples 1 and 2 were determined by LC/MS/MS method using SD rats as test animals. The pharmacokinetic behavior of the compounds of the invention in SD rats was studied and evaluated for their pharmacokinetic profile.
2. Test protocol
2.1 test drugs
Compounds of examples 1 and 2
2.2 test animals
SD rats 8, male and female halves, were purchased from Shanghai Sphere-BiKai laboratory animals Co., Ltd.
2.3 pharmaceutical formulation
Weighing appropriate amount of sample, adding 0.15ml of dimethylacetamide, adding 10% 2-hydroxypropyl-b-cyclodextrin to the final volume, and ultrasonically treating to obtain 0.2mg/ml suspension.
2.4 administration
8 SD rats with half of male and female are averagely divided into 2 groups and 4 rats per group; after fasting overnight, the administration was performed by gavage with a volume of 10 ml/kg.
3. Operation of
8 SD rats with half male and half female; the gavage group was administered at 0.2ml per hour before and after administration at 0.5,1.0,2.0,4.0,6.0,8.0,11.0, and 24.0h, collected from the orbit, placed in heparinized tubes, centrifuged at 3500rpm for 10min to separate plasma, stored at-20 deg.C, and fed 2h after administration.
The LC/MS/MS method is used for measuring the content of the compound to be measured in the plasma of rats after the intragastric administration of different compounds.
4. Pharmacokinetic parameter results
The pharmacokinetic parameters of the compounds of examples 1 and 2 of the invention are as follows:
Figure GDA0003352213010000541
and (4) conclusion: the compound of the invention has good drug absorption and obvious drug absorption effect.
Test example 5 pharmacokinetic testing of Compounds of examples 1 and 2 of the invention
1. Abstract
The drug concentrations in the plasma of Beagle dogs at various times after intragastric administration of the compounds of examples 1 and 2 were determined by LC/MS/MS method using Beagle dogs as test animals. The pharmacokinetic behavior of the compounds of the invention in Beagle dogs was studied and their pharmacokinetic profile was evaluated.
2. Test protocol
2.1 test drugs
Compounds of examples 1 and 2
2.2 test animals
Beagle dogs, 6, male, were purchased from shanghai siepal-bikhaki laboratory animals ltd.
2.3 pharmaceutical formulation
Weighing appropriate amount of the medicine, adding 3% dimethylacetamide to dissolve, adding 10% 2-hydroxypropyl-b-cyclodextrin to the final volume, and ultrasonically treating to obtain a uniform solution.
2.4 administration
6 Beagle dogs, male, were divided equally into 2 groups, 3/group; after fasting overnight, the administration was effected by gavage in a volume of 5 ml/kg.
3. Operation of
Beagle dog 6, male; after fasting overnight, the administration was by gavage. The intragastric administration group collected blood of 1.0ml from jugular vein before and after administration at 0.5,1.0,2.0,4.0,6.0,8.0,12.0, and 24.0h, placed in heparinized test tube, centrifuged at 3500rpm for 10min to separate plasma, and stored at-20 deg.C. Food was consumed 3h after dosing.
And (3) determining the content of the compound to be tested in the blood plasma of Beagle dogs after the intragastric administration of different compounds by an LC/MS/MS method.
4. Pharmacokinetic parameter results
The pharmacokinetic parameters of the compounds of examples 1 and 2 of the invention are as follows:
Figure GDA0003352213010000551
and (4) conclusion: the compound of the invention has good drug absorption and obvious drug absorption effect.

Claims (16)

1. A compound of the general formula (I):
Figure FDA0003377335210000011
or a pharmaceutically acceptable salt thereof,
wherein:
Figure FDA0003377335210000012
a mixture selected from the group consisting of cis-isomer, trans-isomer, and cis-trans-isomer;
ring A is selected from the group consisting of cyclohexyl, cyclopentyl, tetrahydrofuranyl, pyranyl, cyclobutyl, piperidinyl, oxetanyl, azetidinyl and pyrrolidinyl;
ring B is phenyl;
R1are the same or different and are each independently selected from the group consisting of a hydrogen atom, C1-6Alkyl, halogen, C1-6Alkoxy radical, C1-6Hydroxyalkyl and C1-6A haloalkyl group;
R2are the same or different and are each independently selected from amino, -C (O) R3、-S(O)mR3、-NR3C(O)R4、-NR3S(O)mR4and-NR3S(O)mNHR4；
R3And R4Are the same or different and are each independently selected from the group consisting of a hydrogen atom, C1-6Alkyl, amino, C1-6Alkoxy, -C (O) OR5and-NR5C(O)R6Wherein said C1-6Alkyl is optionally selected from halogen, hydroxy and-C (O) OR7Is substituted with one or more substituents of (1);
R5is a hydrogen atom or C1-6An alkyl group;
R6selected from hydrogen atoms, C1-6Alkyl and C1-6An alkoxy group;
R7is a hydrogen atom or C1-6An alkyl group;
m is 0,1 or 2;
n is 0,1, 2,3, 4 or 5; and is
x is 1,2, 3,4 or 5.
2. A compound of formula (I) according to claim 1, wherein R1Are the same or different and are each independently a hydrogen atom or a halogen.
3. A compound of formula (I) according to claim 1, wherein R2is-NR3S(O)mNHR4；R3、R4And m is as defined in claim 1.
4. A compound of formula (I) according to claim 1, wherein n is 1 or 2.
5. A compound of formula (I) according to claim 1, wherein x is 1.
6. The compound of formula (I) according to claim 1, which is a compound of formula (II):
Figure FDA0003377335210000021
or a pharmaceutically acceptable salt thereof,
wherein:
Figure FDA0003377335210000022
a mixture selected from the group consisting of cis-isomer, trans-isomer, and cis-trans-isomer;
g is CH or N;
R2are the same or different and are each independently selected from amino, -C (O) R3、-S(O)mR3、-NR3C(O)R4、-NR3S(O)mNHR4and-NR3S(O)mR4；
x is 1;
y is 0 or 1;
z is 1 or 2; and is
Ring B, R1、R3、R4M and n are as defined in claim 1.
7. A compound of formula (I) according to claim 1, selected from:
Figure FDA0003377335210000023
Figure FDA0003377335210000031
8. a compound of the general formula (V):
Figure FDA0003377335210000032
or a pharmaceutically acceptable salt thereof,
wherein:
R2are the same or different and are each independently selected from the group consisting of a hydrogen atom, an amino group, -C (O) R3、-S(O)mR3、-NR3C(O)R4、-NR3S(O)mR4and-NR3S(O)mNHR4；
Ring A, ring B, R1、R3、R4M, x and n are as defined in claim 1.
9. The compound of formula (V) according to claim 8, selected from:
Figure FDA0003377335210000033
Figure FDA0003377335210000041
10. a process for the preparation of a compound of formula (I) according to claim 1, which process comprises:
Figure FDA0003377335210000042
opening the ring of the compound of the general formula (V) at room temperature under alkaline conditions to obtain a compound of a general formula (I);
wherein:
Figure FDA0003377335210000043
ring A, ring B, R1、R2X and n are as defined in claim 1.
11. A process for preparing a compound of formula (II) according to claim 6, which process comprises:
Figure FDA0003377335210000044
the compound of the general formula (II-B) is subjected to ring opening under the alkaline condition at room temperature to obtain a compound of the general formula (II);
wherein:
Figure FDA0003377335210000045
ring B, G, R1、R2Y, z, x and n are as defined in claim 6.
12. A pharmaceutical composition comprising a therapeutically effective amount of a compound of formula (I) according to any one of claims 1 to 7, together with one or more pharmaceutically acceptable carriers, diluents or excipients.
13. Use of a compound of general formula (I) according to any one of claims 1 to 7 or a pharmaceutical composition according to claim 12 for the preparation of a medicament for the prevention and/or treatment of a disease having a pathological feature of an IDO-mediated tryptophan metabolic pathway.
14. The use according to claim 13, wherein the disease having pathological features of IDO mediated tryptophan metabolic pathway is selected from the group consisting of cancer, myelodysplastic syndrome, alzheimer's disease, autoimmune diseases, depression, anxiety, cataracts, psychological disorders and aids.
15. The use according to claim 14, wherein the cancer is selected from the group consisting of breast cancer, cervical cancer, colon cancer, lung cancer, stomach cancer, rectal cancer, pancreatic cancer, brain cancer, skin cancer, oral cancer, prostate cancer, bone cancer, kidney cancer, ovarian cancer, bladder cancer, liver cancer, fallopian tube tumor, peritoneal tumor, stage IV melanoma, glioma, glioblastoma, papillary renal tumor, head and neck tumor, leukemia, lymphoma, and myeloma.
16. The use of claim 15, wherein the lung cancer is non-small cell lung cancer; wherein the liver cancer is hepatocellular carcinoma.
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