CN110407765B - 1,2,5-oxadiazole derivative, preparation method and medical application thereof - Google Patents
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- 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
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Abstract
The invention relates to a1,2,5-oxadiazole derivative, a preparation method thereof and application thereof in medicines. Specifically, the invention discloses a compound shown as a general formula A, or a stereoisomer or an optical isomer thereof, or a pharmaceutically acceptable salt thereof. The invention also discloses a preparation method of the compound and application of the compound as an IDO inhibitor.
Description
Technical Field
The invention belongs to the field of biological medicines, and particularly relates to a1,2,5-oxadiazole derivative, a preparation method thereof and application thereof in medicines.
Background
Tryptophan (Trp) is an essential amino acid required for the biosynthesis of proteins, nicotinic acid and the neurotransmitter 5-hydroxytryptamine (serotonin). The enzyme indoleamine 2,3-dioxygenase (also known as INDO or IDO) catalyzes the first and rate-limiting step in the degradation of L-tryptophan to N-formyl-kynurenine. In human cells, trp depletion by IDO activity is a well-known gamma interferon (IFN- γ) -induced antimicrobial effector mechanism. IFN- γ stimulation induces activation of IDO, which leads to Trp depletion, thus inhibiting the growth of Trp-dependent intracellular pathogens such as Toxoplasma murine (Toxoplasma gondii) and Chlamydia trachomatis (Chlamydia trachomatis).
IDO activity also has antiproliferative effects on a variety of tumor cells, and IDO induction can be observed in vivo during allogeneic tumor rejection, suggesting that this enzyme may play a role in the tumor rejection process (Daubener et al, 1999, adv.exp.med.biol.,467, 517-24, taylor et al, 1991, faeb J., 5.
It has been observed that HeLa cells co-cultured with Peripheral Blood Lymphocytes (PBLs) acquire an immunosuppressive phenotype through upregulation of IDO activity. It has also been suggested that IDO activity in tumor cells can be used to attenuate the anti-tumor response (Logan et al, 2002, immunology, 105. Recently, the immunomodulatory role of Trp depletion, IDO, has received much attention in the immunosuppressive process of preventing fetal rejection in the uterus.
In view of experimental data indicating a role for IDO in immunosuppression, tumor resistance and/or rejection, chronic infections, HIV infection, AIDS (including its manifestations such as cachexia, dementia and diarrhea), autoimmune diseases or disorders (such as rheumatoid arthritis) and immune tolerance and prevention of uterine fetal rejection, there is a need for therapeutic agents directed to inhibiting tryptophan degradation by inhibiting IDO activity. IDO inhibitors can be used to activate T cells when they are inhibited by pregnancy, malignancies and viruses such as HIV, thereby enhancing T cell activation. Inhibition of IDO can also be an important treatment strategy in patients with neurological or neuropsychiatric diseases or disorders (e.g., depression).
As can be seen, IDO inhibitors remain a focus and focus of research in this field.
Disclosure of Invention
The invention aims to provide a novel 1,2,5-oxadiazole derivative serving as an IDO inhibitor.
The invention aims to provide a preparation method of the compound.
It is also an object of the present invention to provide the use of the above compounds as inhibitors of indoleamine 2,3-dioxygenase (dioxygenase) for the treatment of cancer and other disorders.
In a first aspect, the present invention provides a compound represented by formula a, or a stereoisomer or an optical isomer thereof, or a pharmaceutically acceptable salt thereof:
wherein: w is CH 2 NH, O, S, SO or SO 2 ；
m is 1,2, 3 or 4;
r1 is selected from the group consisting of: halogen, cyano, nitro, C1-C6 alkyl, haloC 1-C6 alkyl, C1-C6 alkoxy, haloC 1-C6 alkoxy; t is 1,2, 3 or 4;
m is SO 2 、S(＝O)(＝NH)、PO 2 Y is NH or CH when P (= O) (= NH), C = O, S = O or P = O 2 (ii) a n is 1,2, 3, 4 or 5; r2 is a substituent on a ring;
or
M is SO 2 When, Y is nothing; n is 0; r2 is connected with the sulfur atom in M; and
r2 is hydrogen, halogen, C1-C6 alkyl, C3-C6 cycloalkyl, C3-C6 cycloalkenyl, C2-C6 alkenyl or C2-C6 alkynyl; wherein said C1-C6 alkyl, C3-C6 cycloalkyl, C3-C6 cycloalkenyl, C2-C6 alkenyl or C2-C6 alkynyl is optionally substituted with one or more substituents selected from halogen, nitro, cyano, amine or hydroxyl.
In another preferred embodiment, W is CH 2 NH, O, S, SO or SO 2 ；
m is 1,2, 3 or 4;
r1 is selected from the group consisting of: halogen, cyano, nitro, C1-C6 alkyl, haloC 1-C6 alkyl, C1-C6 alkoxy, haloC 1-C6 alkoxy; t is 1,2, 3 or 4;
m is SO 2 、S(＝O)(＝NH)、PO 2 Y is NH or CH when P (= O) (= NH), C = O, S = O or P = O 2 (ii) a n is 1,2, 3, 4 or 5; r2 is a substituent on a ring;
or
M is SO 2 When, Y is nothing; n is 0; r2 is connected with the sulfur atom in M; and
r2 is hydrogen, C1-C6 alkyl, C3-C6 cycloalkyl, C3-C6 cycloalkenyl, C2-C6 alkenyl or C2-C6 alkynyl; wherein said C1-C6 alkyl, C3-C6 cycloalkyl, C3-C6 cycloalkenyl, C2-C6 alkenyl or C2-C6 alkynyl is optionally substituted with one or more substituents selected from halogen, nitro, cyano, amine or hydroxyl.
In another preferred embodiment, the compound is represented by formula B:
each group is as defined above.
In another preferred embodiment, the compound is of formula I:
wherein:
w is CH 2 NH, O, S, SO or SO 2 ；
m is 1,2, 3 or 4;
when X is O or NH; when Z is S or P; y is NH or CH 2 (ii) a n is 1,2, 3, 4 or 5; r2 is a substituent on a ring;
or
When X is O; when Z is S; y is nothing; n is 0; r2 is connected with Z;
r2 is hydrogen, halogen, C1-C6 alkyl, C3-C6 cycloalkyl, C3-C6 cycloalkenyl, C2-C6 alkenyl or C2-C6 alkynyl; wherein said C1-C6 alkyl, C3-C6 cycloalkyl, C3-C6 cycloalkenyl, C2-C6 alkenyl or C2-C6 alkynyl is optionally substituted with one or more substituents selected from halogen, nitro, cyano, amine or hydroxyl.
In another preferred embodiment, the compound is of formula I:
wherein:
w is CH 2 NH, O, S, SO or SO 2 ；
m is 1,2, 3 or 4;
when X is O or NH; when Z is S or P; y is NH or CH 2 (ii) a n is 1,2, 3, 4 or 5; r2 is a substituent on a ring;
or
When X is O; when Z is S; y is nothing; n is 0; r2 is connected with Z;
r2 is hydrogen, C1-C6 alkyl, C3-C6 cycloalkyl, C3-C6 cycloalkenyl, C2-C6 alkenyl or C2-C6 alkynyl; wherein said C1-C6 alkyl, C3-C6 cycloalkyl, C3-C6 cycloalkenyl, C2-C6 alkenyl or C2-C6 alkynyl is optionally substituted with one or more substituents selected from halogen, nitro, cyano, amine or hydroxyl.
In another preferred embodiment, the compound is of formula I:
wherein:
w is NH or O;
m is 1 or 2;
when X is O; when Z is S; y is NH; n is 2 or 3; r2 is a substituent on a ring;
or
When X is O; when Z is S; y is nothing; n is 0; r2 is connected with Z;
r2 is hydrogen, halogen or C1-C6 alkyl.
In another preferred embodiment, the compound is represented by formula II:
wherein:
w is CH 2 NH, O, S, SO or SO 2 ；
m is 1,2, 3 or 4;
a is C, S or P;
y is NH or CH 2 ；
n is 1,2, 3, 4 or 5;
r2 is a substituent on a ring; r2 is hydrogen, C1-C6 alkyl, C3-C6 cycloalkyl, C3-C6 cycloalkenyl, C2-C6 alkenyl or C2-C6 alkynyl; wherein said C1-C6 alkyl, C3-C6 cycloalkyl, C3-C6 cycloalkenyl, C2-C6 alkenyl or C2-C6 alkynyl is optionally substituted with one or more substituents selected from halogen, nitro, cyano, amine or hydroxyl.
In another preferred embodiment, the compound is selected from the group consisting of:
in another preferred embodiment, the compound is selected from the group consisting of:
in a second aspect, the present invention provides a pharmaceutical composition comprising a compound according to the first aspect of the present invention, or a stereoisomer or an optical isomer thereof, or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable carrier.
In a third aspect, the present invention provides a use of a compound according to the first aspect of the present invention, or a stereoisomer or an optical isomer thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to the second aspect of the present invention, for the preparation of an IDO inhibitor; and/or for the manufacture of a medicament for the prevention or treatment of IDO related diseases.
In another preferred embodiment, the disease is selected from the group consisting of: cancer, alzheimer's disease, viral infections, neurodegenerative disorders, trauma, organ transplant rejection, autoimmune diseases, depression, anxiety, cataracts, psychological disorders and aids.
In another preferred embodiment, the disease is a disease characterized by IDO-mediated tryptophan metabolic pathway pathology.
In a fourth aspect, the present invention provides a process for the preparation of a compound according to the first aspect of the present invention, or a stereoisomer or an optical isomer thereof, or a pharmaceutically acceptable salt thereof, which process comprises the steps of: reacting compound A1 and compound A2 in an inert solvent, thereby forming compound a;
wherein n, M, M, Y, R1, R2 and t are as defined above;
w' is NH 2 When G is CHO or NO 2 (ii) a Or G is NO when W' is OH or SH 2 (ii) a Or G is NH when W' is CHO 2 ；
W is NH, O or S.
In another preferred example, when Y is NH, the method comprises the steps of:
(a) Reacting compound A1' and compound A2 in an inert solvent, thereby forming compound A3;
(b) Subjecting compound A3 to a deprotection reaction in an inert solvent, thereby forming compound a;
wherein Y' is an N-amino protecting group selected from the group consisting of: p-methoxyphenyl, benzyl, tert-butoxycarbonyl, acetyl, benzyloxycarbonyl, fluorenyl methoxycarbonyl (Fmoc); the other groups are as defined above.
In another preferred example, the method comprises the steps of: reacting compound A1 and compound A2' in an inert solvent to form compound B;
in the above formulae, the respective groups are as defined above.
The present invention also provides a method for preventing or treating an IDO-related disease, the method comprising administering to a subject in need thereof a compound or a pharmaceutical composition of the present invention.
It is to be understood that within the scope of the present invention, the above-described features of the present invention and those specifically described below (e.g., in the examples) may be combined with each other to form new or preferred embodiments. Not to be reiterated herein, but to the extent of space.
Detailed Description
The inventor of the invention through extensive and intensive research, unexpectedly found a kind of structure novel 1,2,5-oxadiazole derivatives for the first time, have excellent IDO inhibitory activity, can be used for the treatment of diseases such as cancer. The present invention has been completed based on this finding.
Term(s)
Unless otherwise indicated, reference to "or" herein has the same meaning as "and/or" (meaning "or" and ").
Unless otherwise specified, each chiral carbon atom (chiral center) in all compounds of the invention may optionally be in the R configuration or the S configuration, or a mixture of the R configuration and the S configuration.
As used herein, the term "alkyl", alone or as part of another substituent, refers to a straight-chain (i.e., unbranched) or branched-chain saturated hydrocarbon group containing only carbon atoms, or a combination of straight-chain and branched-chain groups. When an alkyl group is preceded by a carbon atom number limitation (e.g., C1-C6 alkyl), it is meant that the alkyl group contains 1-6 carbon atoms. Including methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, or the like.
As used herein, the term "C1-C6 alkoxy" refers to C1-C6 alkyl-oxy-and includes methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy, tert-butoxy, or the like.
As used herein, the term "C3-C6 cycloalkyl", alone or as part of another substituent, refers to a cyclic saturated hydrocarbon group having 3 to 6 carbon atoms, including, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, or the like.
As used herein, the term "C3-C6 cycloalkenyl" alone or as part of another substituent refers to cyclic partially unsaturated hydrocarbon radicals having 3-6 carbon atoms, including, for example, cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, or the like.
As used herein, the term "C2-C6 alkenyl" alone or as part of another substituent refers to a branched or straight chain alkenyl-containing unsaturated hydrocarbon group having 2 to 6 carbon atoms, including, for example, ethenyl, propenyl, butenyl, pentenyl, hexenyl, or the like.
As used herein, the term "C2-C6 alkynyl" alone or as part of another substituent refers to a branched or straight chain alkynyl-containing unsaturated hydrocarbon group having 2 to 6 carbon atoms and includes, for example, ethynyl, propynyl, butynyl, pentynyl, hexynyl, or the like.
"halogen" is fluorine, chlorine, bromine or iodine. "halo" means fluoro, chloro, bromo, or iodo.
As used herein, a symbol
Represents a single bond.
Active ingredient
The compound of the invention refers to a compound shown in a general formula A, or a stereoisomer or an optical isomer thereof, or a pharmaceutically acceptable salt thereof.
The term "pharmaceutically acceptable salt" refers to a salt of a compound of the present invention with pharmaceutically acceptable inorganic and organic acids, wherein preferred inorganic acids include (but are not limited to): hydrochloric acid, hydrobromic acid, phosphoric acid, nitric acid, sulfuric acid; preferred organic acids include (but are not limited to): formic acid, acetic acid, propionic acid, succinic acid, naphthalenedisulfonic acid (1,5), asiatic acid, oxalic acid, tartaric acid, lactic acid, salicylic acid, benzoic acid, valeric acid, diethylacetic acid, malonic acid, succinic acid, fumaric acid, pimelic acid, adipic acid, maleic acid, malic acid, sulfamic acid, phenylpropionic acid, gluconic acid, ascorbic acid, nicotinic acid, isonicotinic acid, methanesulfonic acid, p-toluenesulfonic acid, citric acid, and amino acids.
The term "stereoisomer" or "optical isomer" means that the chiral carbon atom involved in the compound of the present invention may be in the R configuration, or may be in the S configuration, or a combination thereof.
Preparation method
The compounds of the present invention can be prepared by methods commonly used in the art, and can also be prepared according to the methods described herein. The reactions involved in the preparation process of the present invention may be carried out under conditions familiar to those skilled in the art
Pharmaceutical compositions and methods of administration
Since the compound of the present invention has excellent inhibitory activity against IDO, the compound of the present invention and a pharmaceutical composition containing the compound of the present invention as a main active ingredient can be used for the treatment, prevention and alleviation of diseases associated with IDO activity or expression level. According to the prior art, the compounds of the invention can be used for the treatment of the following diseases (but not limited to): various cancers such as lung cancer, bladder cancer, breast cancer, stomach cancer, liver cancer, salivary gland sarcoma, ovarian cancer, prostate cancer, cervical cancer, epithelial cell cancer, multiple myeloma, pancreatic cancer, lymphoma, chronic myelogenous leukemia, lymphocytic leukemia, cutaneous T cell lymphoma, etc.; alzheimer's disease, viral infections, neurodegenerative disorders, trauma, organ transplant rejection, autoimmune diseases, depression, anxiety, cataracts, psychological disorders and AIDS.
The pharmaceutical composition of the present invention comprises the compound of the present invention in a safe and effective amount range and a pharmacologically acceptable excipient or carrier.
The safe and effective amount refers to: the amount of the compound is sufficient to significantly improve the condition without causing serious side effects. Typically, the pharmaceutical composition contains 1-2000mg of a compound of the invention per dose, more preferably, 5-200mg of a compound of the invention per dose. Preferably, said "dose" is a capsule or tablet.
The "pharmaceutically acceptable carrier" refers to: one or more compatible solid or liquid fillers or gel substances which are suitable for human use and must be of sufficient purity and sufficiently low toxicity. By "compatibility" is meant that the components of the composition are compatible with the present inventionThe compounds of the invention and their intermingling without significantly reducing the efficacy of the compounds. Examples of pharmaceutically acceptable carrier moieties include cellulose and its derivatives (e.g., sodium carboxymethylcellulose, sodium ethylcellulose, cellulose acetate, etc.), gelatin, talc, solid lubricants (e.g., stearic acid, magnesium stearate), calcium sulfate, vegetable oils (e.g., soybean oil, sesame oil, peanut oil, olive oil, etc.), polyols (e.g., propylene glycol, glycerol, mannitol, sorbitol, etc.), emulsifiers (e.g., propylene glycol, glycerol, mannitol, sorbitol, etc.), and the like
) Wetting agents (e.g., sodium lauryl sulfate), coloring agents, flavoring agents, stabilizers, antioxidants, preservatives, pyrogen-free water, and the like.
The mode of administration of the compounds or pharmaceutical compositions of the present invention is not particularly limited, and representative modes of administration include (but are not limited to): oral, intratumoral, rectal, parenteral (intravenous, intramuscular or subcutaneous), and topical administration.
Solid dosage forms for oral administration include capsules, tablets, pills, powders and granules. In these solid dosage forms, the active compound is mixed with at least one conventional inert excipient (or carrier), such as sodium citrate or dicalcium phosphate, or with the following ingredients: (a) Fillers or extenders, for example, starch, lactose, sucrose, glucose, mannitol and silicic acid; (b) Binders, for example, hydroxymethyl cellulose, alginates, gelatin, polyvinylpyrrolidone, sucrose, and acacia; (c) humectants, for example, glycerol; (d) Disintegrating agents, for example, agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain complex silicates, and sodium carbonate; (e) slow solvents, such as paraffin; (f) absorption accelerators, e.g., quaternary ammonium compounds; (g) Wetting agents, such as cetyl alcohol and glycerol monostearate; (h) adsorbents, for example, kaolin; and (i) lubricants, for example, talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, or mixtures thereof. In capsules, tablets and pills, the dosage forms may also comprise buffering agents.
Solid dosage forms such as tablets, dragees, capsules, pills, and granules can be prepared using coatings and shells such as enteric coatings and other materials well known in the art. They may contain opacifying agents and the release of the active compound or compounds in such compositions may be delayed in release in a certain part of the digestive tract. Examples of embedding components which can be used are polymeric substances and wax-like substances. If desired, the active compound may also be in microencapsulated form with one or more of the above-mentioned excipients.
Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups or tinctures. In addition to the active compounds, the liquid dosage forms may contain inert diluents commonly employed in the art such as, for example, water or other solvents, solubilizing agents and emulsifiers such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, propylene glycol, 1,3-butylene glycol, dimethylformamide and oils, especially cottonseed, groundnut, corn germ, olive, castor and sesame oils or mixtures of such materials and the like.
In addition to these inert diluents, the compositions can also contain adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents.
Suspensions, in addition to the active compounds, may contain suspending agents as, for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum methoxide and agar, or mixtures of these substances, and the like.
Compositions for parenteral injection may comprise physiologically acceptable sterile aqueous or anhydrous solutions, dispersions, suspensions or emulsions, and sterile powders for reconstitution into sterile injectable solutions or dispersions. Suitable aqueous and nonaqueous carriers, diluents, solvents or vehicles include water, ethanol, polyols and suitable mixtures thereof. Dosage forms for topical administration of the compounds of the present invention include ointments, powders, patches, sprays, and inhalants. The active ingredient is mixed under sterile conditions with a physiologically acceptable carrier and any preservatives, buffers, or propellants which may be required if necessary.
The compounds of the present invention may be administered alone or in combination with other pharmaceutically acceptable compounds.
When using pharmaceutical compositions, a safe and effective amount of a compound of the present invention is administered to a mammal (e.g., a human) in need of treatment, wherein the administration is a pharmaceutically acceptable and effective dose, and the daily dose for a human of 60kg body weight is usually 1 to 2000mg, preferably 5 to 500mg. Of course, the particular dosage will depend upon such factors as the route of administration, the health of the patient, and the like, and is within the skill of the skilled practitioner.
The main advantages of the invention are:
the invention provides a compound which has a novel structure and can be used for IDO inhibitors.
The IDO inhibitors of the present invention have excellent activity.
The invention will be further illustrated with reference to the following specific examples. It should be understood that these examples are for illustrative purposes only and are not intended to limit the scope of the present invention. The experimental procedures, in which specific conditions are not noted in the following examples, are generally carried out under conventional conditions or conditions recommended by the manufacturers. Unless otherwise indicated, percentages and parts are percentages and parts by weight.
The test materials and reagents used in the following examples are commercially available without specific reference.
EXAMPLE 1 preparation of Compound 201
Step one, 2-N- (4-methoxyphenyl) sulfonylamino) methyl acetate (compound 2)
4-methoxyaniline (1.8g, 14.6 mmol) and pyridine (1.4g, 17.4mmol) were dissolved in acetonitrile (35 mL), the solution was cooled on an ice bath and methyl 2- (chlorosulfonyl) acetate (compound 1,2.5g, 14.5mmol) was slowly added dropwise. The reaction was stirred at room temperature overnight. The reaction mixture was subjected to solvent removal on a rotary vacuum evaporator, and the residue was dissolved in methylene chloride (100 mL), washed with 1N hydrochloric acid (40 mL) and saturated brine (40 mL), respectively, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to give crude compound 2 as a purple oil (3.46 g, yield: 92%).
1 H NMR(400MHz,CDCl 3 ):δ7.30-7.28(m,2H),6.97(brs,1H),6.90-6.88(m,2H),3.92(s,2H),3.83(s,3H),3.80(s,3H).MS(ESI):Calcd.for C 10 H 13 NO 5 S 259；Found 282[M+Na] + .
Step two, 2- (4-methoxyphenyl) -1,1-isothiazolidine dioxide-5-methyl formate (3)
To a mixture of compound 2 (3.2g, 14.5 mmol) and potassium carbonate (5.1g, 36.9 mmol) in N, N-dimethylformamide (40 mL) was added 1,2-dibromoethane (4.2g, 22.3 mmol) at room temperature. The reaction mixture was heated to 70 ℃ and stirred overnight. The reaction was cooled to room temperature, diluted with water (150 mL) and extracted with ethyl acetate (100mL x 3). The ethyl acetate phase was washed with saturated brine (200 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was spin-dried and purified by a silica gel column to give Compound 3 (1.8 g, yield: 50%) as a pale yellow solid.
1 H NMR(400MHz,CDCl 3 ):δ7.28-7.25(m,2H),6.92-6.89(m,2H),4.27-4.23(dd,J＝6.8Hz,2.0Hz,1H),3.89(s,3H),3.85-3.79(m,4H),3.72-3.65(m,1H),2.91-2.81(m,1H),2.67-2.57(m,1H).MS(ESI):Calcd.for C 12 H 15 NO 5 S 285；Found 286[M+H] + ,308[M+Na] + .
Step three, 5-hydroxymethyl-2- (4-methoxyphenyl) -1,1-isothiazolidine dioxide (4)
Compound 3 (1.7g, 6.0mmol) was dissolved in methanol (60 mL), and sodium borohydride (0.5g, 12mmol) was added in portions under ice bath. The reaction mixture was stirred at room temperature overnight. The reaction mixture was quenched by slowly adding 1N hydrochloric acid, the temperature was controlled below 20 ℃ and the pH was adjusted to about 7. The resulting mixture was concentrated in vacuo to remove methanol and extracted with ethyl acetate (100mL. Times.3). The ethyl acetate phase was washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered and concentrated. The mixture was separated and purified by a silica gel column to obtain Compound 4 (1.3 g, yield: 80%) as a pale yellow oil.
1 H NMR(400MHz,CDCl 3 ):δ7.30-7.20(m,2H),6.95-6.86(m,2H),4.16-4.09(m,1H),4.04-3.97(m,1H),3.82(s,3H),3.72-3.60(m,2H),3.60-3.50(m,1H),2.74(brs,1H),2.58-2.48(m,1H),2.42-2.30(m,1H).MS(ESI):Calcd.for C 11 H 15 NO 4 S 257；Found 258[M+H] + ,280[M+Na] + .
Step four, 2- (4-methoxyphenyl) -1,1-isothiazolidine dioxide-5-formaldehyde (5)
Compound 4 (0.7g, 2.7mmo) was dissolved in dichloromethane (10 mL) and Dess-Martin oxidant (1.2g, 2.8mmol) was added to the solution in portions while cooling on ice. The reaction mixture was stirred at room temperature overnight. The reaction solution was subjected to solvent removal in a rotary vacuum evaporator, and the residue was purified by a silica gel column to give 5 (0.4 g, yield: 58%) as a yellow oil.
MS(ESI):Calcd.for C 11 H 13 NO 4 S 255；Found 256[M+H] + .
Step five, 4- (3-bromo-4-fluorophenyl) -3- (4- (((2- (4-methoxyphenyl) -1,1-dihydroxyisothiazolidin-5-yl) methyl) amino) -1,2,5-oxadiazol-3-yl) -1,2,4-oxadiazol-5 (4H) -one (7)
To a solution of compound 6 (0.36g, 1.05mmol), triethylsilane (0.5g, 4.3mmol) and methanesulfonic acid (0.41g, 4.26mmol) in dichloromethane (10 mL) was added compound 5 (0.4 g, 1.56mmol) at room temperature. The reaction mixture was stirred at 30 ℃ overnight. The reaction mixture was diluted with water (25 mL), extracted with dichloromethane (40mL. Times.3), the organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated and purified by a silica gel column to give compound 7 (290 mg, yield: 47%) as a white solid.
MS(ESI):Calcd.for C 21 H 18 BrFN 6 O 6 S 580；Found 581[M+H] + .
Step six, 4- (3-bromo-4-fluorophenyl) -3- (4- (((1,1-dihydroxyisothiazolidin-5-yl) methyl) amino) -1,2,5-oxadiazol-3-yl) -1,2,4-oxadiazol-5 (4H) -one (8)
Compound 7 (290mg, 0.5 mmol) was dissolved in acetonitrile (5 mL), and a solution of ceric ammonium nitrate (820 mg,1.5 mmol) in water (5 mL) was added dropwise to the solution in ice bath. The reaction mixture was stirred for an additional 1 hour under ice bath. The reaction was diluted with water (20 mL) and extracted with ethyl acetate (20mL × 4). The ethyl acetate phase was dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated in vacuo. The resulting mixture was purified on a preparative TLC plate to give Compound 8 as a white solid (140 mg, yield: 58%).
MS(ESI):Calcd.for C 14 H 12 BrFN 6 O 5 S 474；Found 475[M+H] + .
Step seven, (Z) -N- (3-bromo-4-fluorophenyl) -4- (((1,1-dihydroxyisothiazolidin-5-yl) methyl) amino) -N' -hydroxy-1,2,5-oxadiazole-3-carbooxaamidine (201)
To a solution of compound 8 (140mg, 0.29mmol) in methanol (2 mL) was added an aqueous solution of sodium hydroxide (2N, 0.5mL) at room temperature. The reaction mixture was stirred at room temperature for an additional 2 hours. The reaction was diluted with water (20 mL) and extracted with ethyl acetate (25mL. Times.3). The ethyl acetate phase was dried over anhydrous sodium sulfate, filtered and the filtrate concentrated in vacuo. The crude product was purified by preparative high performance liquid chromatography to give the objective compound 201 (10 mg, yield: 7.7%) as a colorless oil.
1 H NMR(300MHz,DMSO-d 6 ):δ8.86(s,1H),7.17-7.06(m,2H),6.93(s,1H),6.78-6.71(m,1H),6.54-6.47(m,1H),3.65-3.53(m,1H),3.54-3.38(m,1H),3.20-3.02(m,3H),2.84-2.74(m,1H),2.45-2.30(m,1H),2.08-1.90(m,1H).MS(ESI):Calcd.for C 13 H 14 BrFN 6 O 4 S 448；Found 449[M+H] + .HPLC purity:98.8％(214nm)/99.6％(254nm).
EXAMPLE 2 preparation of Compound 201-P1 and Compound 201-P2
The compound 201-P1 and the compound 201-P2 are enantiomers of each other and can be obtained by chiral resolution of the compound 201 by chiral HPLC. The chiral resolution conditions were as follows: the chromatographic column is OJ-H; the size of the chromatographic column is 5 mu m,
the mobile phase is CO 2 IPA (0.2% dea) =70/30; flow rate =40g/min; the temperature is 37.8 ℃; the pressure is 150-160bar. Safening of Compound 201-P1The retention time was 5.9min, and the retention time of compound 201-P2 was 5.34min.
Compound 201-P1 1 H NMR(300MHz,DMSO-d 6 ):δ8.86(s,1H),7.17-7.06(m,2H),6.93(s,1H),6.78-6.71(m,1H),6.54-6.47(m,1H),3.65-3.53(m,1H),3.54-3.38(m,1H),3.20-3.02(m,3H),2.84-2.74(m,1H),2.45-2.30(m,1H),2.08-1.90(m,1H).MS(ESI):Calcd.for C 13 H 14 BrFN 6 O 4 S 448；Found 449[M+H] + .
Compound 201-P2 1 H NMR(300MHz,DMSO-d 6 ):δ8.86(s,1H),7.17-7.06(m,2H),6.93(s,1H),6.78-6.71(m,1H),6.54-6.47(m,1H),3.65-3.53(m,1H),3.54-3.38(m,1H),3.20-3.02(m,3H),2.84-2.74(m,1H),2.45-2.30(m,1H),2.08-1.90(m,1H).MS(ESI):Calcd.for C 13 H 14 BrFN 6 O 4 S 448；Found 449[M+H] + .
EXAMPLE 3 preparation of Compound 202
Step one, 2-N- (4-methoxyphenyl) sulfonamido) methyl acetate (compound 2)
Methyl 2- (chlorosulfonyl) acetate (compound 1,12.5g,72.4 mmol) was slowly added dropwise to a solution of 4-methoxyaniline (9.0 g,72.4 mmol) and pyridine (7.0 g,88.6 mmol) in acetonitrile (160 mL) with cooling in an ice bath. The reaction was stirred at room temperature for 3 hours. The reaction mixture was evaporated in a rotary vacuum evaporator to remove the solvent, and the residue was dissolved in methylene chloride (300 mL), washed with 1N hydrochloric acid (100mL. Times.2), saturated brine (100 mL), dried over anhydrous sodium sulfate, and then concentrated to give Compound 2 as a purple oil (15.5 g, yield: 82.5%).
HNMR(400MHz,CDCl3):δ7.29(d,J＝8.8Hz,2H),6.97(s,1H),6.89(d,2H,J＝8.8Hz),3.92(s,2H),3.83(s,3H),3.80(s,3H).MS(ESI):Calcd.for C10H13NO5S 259；Found 260[M+H]+,282[M+Na]+.
Step two, 2- (4-methoxyphenyl) -1,2-thiazahexane-6-carboxylic acid methyl ester-1,1-dioxide (Compound 3)
To a mixture of compound 2 (1.4g, 5.4mmol) and potassium carbonate (2.2g, 16.2mmol) in N, N-dimethylformamide (30 mL) was added 1,3-dibromopropane (1.53g, 7.56mmol) at room temperature. The reaction was heated to 70 ℃ and stirred overnight. The reaction was cooled to room temperature, diluted with water (200 mL), the mixture was extracted with ethyl acetate (100mL x 3), and the combined organic phases were dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by a silica gel column to give compound 3 (1.2 g, yield: 69%) as a yellow oil.
HNMR(400MHz,CDCl3):δ7.24(d,J＝8.8Hz,2H),6.87(d,J＝8.8Hz,2H),3.95-3.86(m,1H),3.82(s,3H),3.80(s,3H),3.67-3.60(m,1H),2.64-2.45(m,2H),2.14-2.06(m,1H),1.97-1.87(m,1H),1.65-1.55(m,1H).MS(ESI):Calcd.for C13H17NO5S 299；Found 300[M+H]+,322[M+Na]+.
Step three, 2- (4-methoxyphenyl) -1,2-thiazahexan-6-hydroxymethyl-1,1-dioxide (Compound 4)
To a solution of compound 3 (1.1g, 3.7 mmol) in methanol (20 mL) was added sodium borohydride (0.4 g,10.5 mmol) in portions under ice-bath cooling. The reaction was stirred at room temperature overnight. The reaction was quenched with 1N hydrochloric acid at a temperature below 20 ℃ and the pH was adjusted to about 7. The reaction mixture was evaporated off methanol in a rotary vacuum evaporator, the residue was diluted with dichloromethane (30 mL) and water (20 mL), the aqueous phase was extracted with dichloromethane (30 mL), and the combined organic phases were dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by a silica gel column to give compound 4 (1.0 g, yield: 99%) as a yellow oil.
HNMR(400MHz,CDCl3):δ7.26(d,J＝8.8Hz,2H),6.99(d,J＝8.8Hz,2H),4.19-4.12(m,1H),4.03-3.95(m,1H),3.80(s,3H),3.60-3.52(m,1H),3.37-3.29(m,1H),2.52-2.35(m,1H),2.32-2.22(m,2H),2.00-1.87(m,2H),1.65-1.50(m,1H).MS(ESI):Calcd.for C12H17NO4S 271；Found 272[M+H]+,294[M+Na]+.
Step four, 2- (4-methoxyphenyl) -1,2-thiazahexan-6-carbaldehyde-1,1-dioxide (Compound 5)
To a solution of compound 4 (0.9g, 3.3mmol) in dichloromethane (15 mL) was added Dess-Martin reagent (2.1g, 4.95mmol) in portions with ice-bath cooling. The reaction was stirred at room temperature for 3 hours. The reaction was quenched with aqueous sodium thiosulfate (50mL x 2) and extracted with dichloromethane (30mL x 3). The combined organic phases were dried over anhydrous sodium sulfate, filtered and spin-dried to give crude compound 5 (0.9 g) as a yellow oil, which was used in the next step without further purification of compound 5.
Step five, 4- (3-bromo-4-fluorophenyl) -3- (4 (- (2 (4-methoxyphenyl) -1,1-dihydroxy-1,2-thiazepin-6-yl) methyl) amino-1,2,5-oxadiazol-3-yl) -1,2,4-oxadiazol-5 (4H) -one (Compound 7)
To a solution of compound 6 (0.78g, 2.3mmol), triethylsilane (2.1g, 18.0mmol) and methanesulfonic acid (1.6g, 16.6mmol) in dichloromethane (20 mL) at room temperature was added crude compound 5 (0.9g, 3.3mmol). The reaction was heated to 30 ℃ and stirred overnight. The reaction solution was directly concentrated, and the residue was purified by a silica gel column to give compound 7 (450 mg, yield: 33%) as a white solid.
HNMR(400MHz,CDCl3):δ8.10-7.97(m,1H),7.67-7.61(m,1H),7.38-7.31(m,1H),7.30-7.22(m,2H),6.94-6.85(m,2H),5.98-5.95(m,1H),4.05-3.93(m,2H),3.82(s,3H),3.86-3.74(m,1H),3.65-3.48(m,2H),2.36-2.26(m,1H),2.24-2.12(m,1H),2.00-1.90(m,2H).MS(ESI):Calcd.for C22H20BrFN6O6S 594；Found 595[M+H]+.
Step six, 4- (3-bromo-4-fluorophenyl) -3- (4- (((1,1-dihydroxy-1,2-thiazepin-6-yl) methyl) amino-1,2,5-oxadiazol-3-yl) -1,2,4-oxadiazol-5 (4H) -one (Compound 8)
To a solution of compound 7 (450mg, 0.76mmol) in acetonitrile (5 mL) was added dropwise a solution of ceric amine nitrate (1.25g, 2.28mmol) in water (5 mL) with cooling in an ice bath. The reaction was stirred for an additional 1 hour while cooling on ice. The reaction was quenched by the addition of water (40 mL), extracted with ethyl acetate (25mL x 3), and the combined organic phases were dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by preparative TLC plate to give Compound 8 (300 mg, yield: 81%) as a yellow solid.
HNMR(400MHz,d6-DMSO):δ8.12-8.07(m,1H),7.76-7.68(m,1H),7.65-7.57(m,1H),7.02-6.95(m,1H),6.83-6.76(m,1H),3.78-3.69(m,1H),3.52-3.40(m,2H),3.20-3.05(m,2H),2.09-2.01(m,1H),1.80-1.55(m,2H),1.51-1.38(m,1H).MS(ESI):Calcd.for C15H14BrFN6O5S 488；Found 489[M+H]+.
Step seven, N- (3-bromo-4-fluorophenyl) -4- (((1,1-dihydroxy-1,2-thiazepin-6-yl) methyl) amino) -N' -hydroxy-1,2,5-oxadiazole-3-carbooxaamidine (Compound 202)
To a solution of compound 8 (300mg, 0.61mmol) in methanol (6 mL) was slowly added aqueous sodium hydroxide (2N, 2mL) dropwise at room temperature. The reaction was stirred at room temperature for 2 hours. Water (25 mL) was added to dilute the reaction and extracted with ethyl acetate (30mL x 3). The combined organic phases were dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by preparative TLC plate to give compound 202 (150 mg, yield: 53%) as a white solid.
HNMR(400MHz,d6-DMSO):δ11.48(s,1H),8.93(s,1H),7.21-7.16(m,1H),7.14-7.09(m,1H),7.00-6.93(m,1H),6.80-6.72(m,1H),6.52-6.46(m,1H),3.72-3.63(m,1H),3.45-3.35(m,1H),3.29-3.20(m,1H),3.17-3.03(m,2H),1.98-1.86(m,1H)，1.71-1.54(m,2H),1.50-1.35(m,1H).MS(ESI):Calcd.for C14H16BrFN6O4S 462；Found 463[M+H]+.HPLC:95.3％(214nm)/96.5％(254nm).
EXAMPLE 4 preparation of Compound 203
Step one, 4- (3-bromo-4-fluorophenyl) -3- (4-nitroso-1,2,5-oxadiazol-3-yl) -1,2,4-oxadiazol-5 (4H) -one (Compound 2)
To a mixed solution of compound 1 (1.0 g,2.9 mmol) in trifluoroacetic acid (6 mL) and dichloroethane (10 mL) was added urea peroxide (urea. H) under water bath 2 O 2 ) (2.2g, 23.4mmol). The reaction was stirred at room temperature overnight. Monitoring revealed that about 50% of the starting material remained, urea peroxide (2.2g, 23.4 mmol) was added again and the reaction was allowed to continue stirring overnight at room temperature. The reaction was quenched with ice water, the aqueous phase was extracted with dichloromethane (50mL x 3), the combined organic phases were dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by a silica gel column to obtain Compound 4 (0.8 g, yield: 74%) as a white solid.
HNMR(400MHz,CDCl3):δ7.64-7.60(m,2H),7.28-7.26(m,1H).
Step two, 4- (3-bromo-4-fluorophenyl) -3- (4- ((2- (4-methoxyphenyl) -1,1-dihydroxyisothiazolidin-5-yl) methoxy) -1,2,5-oxadiazol-3-yl) -1,2,4-oxadiazol-5 (4H) -one (compound 4)
To a solution of compound 3 (200mg, 0.78mmol) in anhydrous tetrahydrofuran (10 mL) was added dropwise a 1mol/L potassium tert-butoxide tetrahydrofuran solution (0.66mL, 0.66mmol) at room temperature, and after stirring at room temperature for 2 minutes, compound 2 (227 mg, 0.61mmol) was added, and the reaction was continued to stir at room temperature for 30 minutes. The reaction was directly spin dried to give crude compound 4 (0.4 g, ca. 20% content) as a yellow oil, which was used in the next step without purification.
MS(ESI):Calcd.for C21H17BrFN5O7S 581；Found 582[M+H]+.
Step three, 4- (3-bromo-4-fluorophenyl) -3- (4- ((1,1-dihydroxyisothiazolin-5-yl) methoxy) -1,2,5-oxadiazol-3-yl) -1,2,4-oxadiazol-5 (4H) -one (compound 5)
To a solution of crude compound 4 (400mg, 0.6 mmol) in acetonitrile (15 mL) was added dropwise a solution of ceric amine nitrate (1.64g, 3 mmol) in water (6 mL) with cooling in an ice bath. The reaction was stirred for an additional 1 hour while cooling on ice. The reaction was diluted with water (30 mL), extracted with ethyl acetate (25mL x 3), and the organic phase was dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by preparative TLC plate to give crude compound 5 as a yellow oil (60 mg, yield: 20%).
MS(ESI):Calcd.for C14H12BrFN5O6S 475；Found 476[M+H]+.
Step four, N- (3-bromo-4-fluorophenyl) -4- ((1,1-dihydroxyisothiazolidin-5-yl) methoxy) -N' -hydroxy-1,2,5-oxadiazole-3-carbooxaamidine (Compound 203)
To a solution of compound 5 (60mg, 0.126mmol) in methanol (5 mL) was added an aqueous solution of sodium hydroxide (2N, 2mL,4 mmol) at room temperature. The reaction was stirred at room temperature for 2 hours. The reaction was concentrated to remove methanol, water (20 mL) was added and the pH adjusted to between 7-8 with 1N hydrochloric acid, extracted with ethyl acetate (25mL x 3), and the combined organic phases were dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by preparative TLC plate to give compound 203 as a clear oil (10 mg, yield: 53%).
HNMR(400MHz,CD3OD):δ7.98-7.94(m,1H),7.64-7.58(m,1H),7.21-7.14(t,J＝8.8Hz,1H),4.58-4.47(m,2H),3.64-3.56(m,1H),2.65-2.54(m,1H),2.23-2.10(m,2H),1.65-1.55(m,1H).MS(ESI):Calcd.for C13H14BrFN5O5S 449；Found 450[M+H]+.HPLC:87.6％(214nm)/96.7％(254nm).
EXAMPLE 5 preparation of Compound 204
Step one, 4-amino-N' -hydroxy-1,2,5-oxadiazole-3-carboxamidine (Compound 4)
Sodium nitrite (244g, 35.4 mol) and acetic acid (200 mL) were added portionwise to a solution of malononitrile (115g, 17.7 mol) in water (2.2L) with ice-bath cooling. The reaction was stirred for 30 minutes in an ice bath and then slowly warmed to room temperature to continue the reaction for 2 hours. The resulting mixed solution was cooled to 0-10 ℃ and a solution of hydroxylamine hydrochloride (368g, 53.1mol) in water (350 mL) was slowly added dropwise thereto, and the reaction was continued with stirring at that temperature for 1 hour. The pH of the resulting mixed solution was slowly adjusted to about 10 with sodium hydroxide. The reaction was heated to 100 ℃ and stirred overnight. The pH was adjusted to neutral with 6N hydrochloric acid while cooling on ice, and stirring was continued until a solid precipitated, which was filtered, and the filter cake was washed with water (400mL. Times.2) to obtain Compound 4 as a white solid after drying (170 g, yield: 68.2%).
MS(ESI):Calcd.for C3H5N5O2 143；Found 144[M+H]+.
Step two, 4-amino-N-hydroxy-1,2,5-oxadiazole-3-carboxamidine chloride (Compound 5)
Compound 4 (143g, 1.0 mol) was completely dissolved in a mixed solution of acetic acid (1L), 6N hydrochloric acid (500 mL) and water (2L) at about 45 ℃. To the clear mixed solution was added sodium chloride (175.5g, 3mol), the system was cooled with an ice bath, and a solution of sodium nitrite (67.6g, 980 mmol) in water (200 mL) was slowly added dropwise over 1 hour. The reaction was stirred for an additional 1.5 hours while cooling on ice. The solid precipitated, was filtered through a suction funnel, and the filter cake was washed with water (300mL. Times.2) and dried under vacuum to give Compound 5 (78.5 g, yield: 48.4%) as a white solid.
MS(ESI):Calcd.for C3H3ClN4O2 162；Found 163[M+H]+.
Step three, 4-amino-N' -hydroxy-N- (2- (methylsulfonyl) ethyl) -1,2,5-oxadiazole-3-carboxamidine (Compound 7)
To a solution of compound 5 (1g, 6.15mmol) and 2- (methylsulfonyl) ethylamine hydrochloride (6, 0.98g, 6.15mmol) in ethyl acetate (20 mL) was added triethylamine (1.56g, 15.37mmol) with cooling in an ice bath. The reaction was stirred at room temperature for 3 hours. The reaction mixture was diluted with water (25 mL), extracted with ethyl acetate (40mL. Times.3), and the combined organic phases were washed once with 1N hydrochloric acid (50 mL) and brine (25 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to give crude compound 7 (1.2 g) as a yellow oil, which was used in the next reaction without further purification
MS(ESI):Calcd.for C6H11N5O4S 249；Found 250[M+H]+.
Step four, N' -hydroxy-4- ((2- (methylsulfonyl) ethyl) amino) -1,2,5-oxadiazole-3-carboxamidine (Compound 8)
To a solution of compound 7 (1.2g, 4.8mmol) in water (20 mL) was added potassium hydroxide (0.84g, 15mmol) in portions at room temperature. The reaction was heated to 100 ℃ and stirred overnight. The reaction was diluted with water (40 mL), extracted with ethyl acetate (50mL × 4), and the combined organic phases were dried over anhydrous sodium sulfate, filtered and concentrated to give crude compound 8 (0.4 g) as a yellow oil which was used in the next reaction without further purification.
MS(ESI):Calcd.for C6H11N5O4S 249；Found 250[M+H]+.
Step five, N-hydroxy-4- ((2- (methylsulfonyl) ethyl) amino) -1,2,5-oxadiazole-3-carboxamidine chloride (Compound 9)
To a mixed solution of compound 8 (0.5g, 2.0 mmol) and sodium chloride (0.35g, 6.0 mmol) in acetic acid (8 mL) and 6N hydrochloric acid (10 mL) was slowly added dropwise a solution of sodium nitrite (140mg, 2.0 mmol) in water (5 mL) with cooling in an ice bath. The reaction was continued stirring for 1 hour under ice bath. The reaction was diluted with water (40 mL), extracted with ethyl acetate (50mL × 4), and the organic phase was dried over anhydrous sodium sulfate and concentrated to give crude compound 9 (250 mg) as a yellow oil, which was used in the next reaction without further purification.
MS(ESI):Calcd.for C6H9ClN4O4S 268；Found 269[M+H]+.
Step six, N- (3-bromo-4-fluorophenyl) -N' -hydroxy-4- ((2- (methylsulfonyl) ethyl) amino) -1,2,5-oxadiazole-3-carboxamidine (compound 204)
Add 3-bromo-4-fluoroaniline (10, 0.16g, 0.84mmol) and sodium bicarbonate (117mg, 1.40mmol) to a solution of Compound 9 (0.25g, 0.93mmol) in water (10 mL). The mixture was heated to 60 ℃ and stirred for 1 hour. The reaction was quenched by the addition of 0.5N hydrochloric acid (20 mL) and extracted with ethyl acetate (50mL. Times.4). The organic phase was dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by preparative TLC plate to give compound 204 (80 mg, yield: 22.6%) as a red oil.
HNMR(400MHz,d6-DMSO):δ11.50(s,1H),8.91(s,1H),7.22-7.15(t,J＝8.8Hz,1H),7.13-7.09(dd,J＝6.0Hz,J＝2.8Hz,1H),6.80-6.73(m,1H),6.53-6.46(t,J＝6.0Hz,1H),3.72–3.64(q,J＝2.4Hz,2H),3.48-3.43(t,J＝2.4Hz,2H),3.05(s,3H).MS(ESI):Calcd.for C12H13BrFN5O4S 421；Found 422/424[M+H]+.HPLC:98.1％(214nm)/98.1％(254nm).
EXPERIMENTAL EXAMPLE 1 indoleamine 2,3-dioxygenase 1 (IDO-1) Small molecule inhibitor screening assay
Gradient dilution of compound
The first step is as follows: test compounds were diluted from stock concentrations to 1mM with 100% DMSO.
The second step is that: 1mM of the compound was used as the first point, and DMSO was diluted 3-fold to 8 th point with 100%. Then transfer 1. Mu.L of diluted compound to 96-well plate with final DMSO concentration of 1% and final concentration of compound 10000nM, 3333.33nM, 1111.1nM, 370.4nM, 123.5nM, 41.2nM, 13.7nM, 4.6nM.
Experimental procedure
1, preparing a 50mM MES solution with pH 6.5;
2, preparing 6mL of 16.84ng/ul IDO enzyme solution (final enzyme concentration is 8.42 ng/ul) with 50mM MES solution of pH6.5, then adding 50ul enzyme solution to the 96-well plate which had been transferred with the compound, centrifuging at 1000rpm for 1 minute, and incubating at 25 ℃ for 30 minutes in an incubator;
3, preparing a 2X substrate solution containing 40mM ascorbic acid, 300 mu M L-tryptophan, 4500units/mL catalase and 20 mu M methylene blue;
4, adding 50ul 2X substrate solution into a reaction plate added with 1ul of the compound to be detected and 50ul of enzyme (the concentration of each component in the final substrate solution is 20mM ascorbic acid, 150 mu M L-tryptophan, 2250units/mL catalase and 10 mu M methylene blue), centrifuging at 2000rpm for 1 minute, and incubating in an incubator at 25 ℃ for 40 minutes;
5, preparation of a reaction termination solution: 1.8g of trichloroacetic acid are weighed out in 6ml of ddH 2 Dissolving O into trichloroacetic acid solution with the mass volume fraction of 30%;
adding 50ul of 30% trichloroacetic acid solution into a reaction plate added with 1ul of a compound to be detected, 50ul of enzyme and 50ul of substrate solution, incubating for 30 minutes in an incubator at 60 ℃, and centrifuging for 5 minutes at 2000 rpm;
7, aspirating 30ul of supernatant from the reaction plate into a new 96-well flat-bottom plate;
configuration of 8,2% ehrlichi reagent: weighing 0.12g of p-dimethylaminobenzaldehyde solution, and dissolving the p-dimethylaminobenzaldehyde solution into an ehrlichia reagent with the volume mass fraction of 2% by using 6ml of glacial acetic acid;
30ul 2% Ehrlich reagent was added to a 96-well plate containing 30ul of the supernatant, centrifuged at 1000rpm for 1 minute, allowed to stand at room temperature for 10 minutes, and read with Spark 10M (492 nm).
Results of the experiment
The results of the IDO enzyme inhibitory activity of each compound are shown in the following table:
| compound numbering | IC50(nM) |
| NLG919 (Positive control) | 83.77 |
| Compound 201 | 43.2 |
| Compound 201-P1 | 45.0 |
| Compound 201-P2 | 37.4 |
| Compound 202 | 50.3 |
The structure of NLG919 is as follows:
experimental example 2 pharmacokinetic study of Compound 201
Compound preparation: compound 201 was administered by gavage using a 0.5% aqueous solution of methylcellulose in a suspension of 0.5mg/mL, and intravenously using a solution of 10% DMSO/30% PEG 400/60% water in a concentration of 0.5 mg/mL.
Experiment design: healthy SD rats, 6 male, were cannulated with jugular vein and were tested at a weight of 200-250 g. The intravenous administration group had free diet and drinking water; the gavage group had fasted for 12 hours before administration, had free access to water, and had a uniform diet 4 hours after administration. The specific arrangement is shown in the following table:
collecting samples: SD rats were bled via jugular vein at the time points set above after administration, and about 0.25mL of whole blood, EDTA-K2 anticoagulated, centrifuged at 8000rpm for 6min, plasma separated, and frozen in a refrigerator at-80 ℃ per animal, 3 rats per time point. The concentration of the compound in plasma was determined by liquid chromatography tandem mass spectrometry.
The experimental results are as follows: based on the obtained plasma concentration data, pharmacokinetic parameters after administration were calculated using a non-compartmental model of Phoenix1.3 software (Pharsight, USA).
Pharmacokinetic parameters after intravenous injection of 1mg/kg and intragastric administration of 5mg/kg Compound 201 in SD rats:
and (4) experimental conclusion: compound 201 has good pharmacokinetic properties.
All documents referred to herein are incorporated by reference into this application as if each were individually incorporated by reference. Furthermore, it should be understood that various changes and modifications of the present invention can be made by those skilled in the art after reading the above teachings of the present invention, and these equivalents also fall within the scope of the present invention as defined by the appended claims.
Claims (9)
1. A compound represented by formula A or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof:
wherein:
w is NH;
m is 1;
r1 is halogen; t is 2;
m is SO 2 Y is NH; n is 2 or 3;
r2 is hydrogen.
2. The compound of claim 1, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein the compound is according to formula B:
each group is as defined above.
3. The compound of claim 1, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein the stereoisomer is an optical isomer.
4. The compound of claim 1 or 2, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, selected from the group consisting of:
5. a pharmaceutical composition comprising a compound of claim 1 or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable carrier.
6. Use of a compound according to claim 1 or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 5,
used for preparing IDO inhibitor.
7. Use of a compound according to claim 1 or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 5, for the manufacture of a medicament for the prevention or treatment of an IDO-related disease;
the disease is selected from the group consisting of: cancer, alzheimer's disease, viral infections, neurodegenerative disorders, trauma, organ transplant rejection, autoimmune diseases, depression, anxiety, cataracts, psychological disorders and aids.
8. A process for the preparation of a compound of claim 1, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, comprising the steps of: reacting compound A1 and compound A2 in an inert solvent, thereby forming compound a;
wherein n, M, M, Y, R1, R2 and t are as defined above;
w' is NH 2 G is CHO or NO 2 (ii) a W is NH.
9. The method of claim 8, wherein the method comprises the steps of:
(a) Reacting compound A1' and compound A2 in an inert solvent, thereby forming compound A3;
(b) Subjecting compound A3 to a deprotection reaction in an inert solvent, thereby forming compound a;
wherein Y' is an N-amino protecting group selected from the group consisting of: p-methoxyphenyl, benzyl, tert-butoxycarbonyl, acetyl, benzyloxycarbonyl, fluorenyl methoxycarbonyl (Fmoc); the other groups are as defined above.
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