RELATED APPLICATIONS

This application is a § 371 national stage of PCT International Application No. PCT/CN2019/072626, filed on Jan. 22, 2019, designating the United States and claiming priority of Chinese Application No. 201810581413.1, filed Jun. 7, 2018 and No. 201810067280.6, filed Jan. 24, 2018, the contents of each of which are hereby incorporated by reference into this application.

BACKGROUND

Technical Field

The present invention relates to a modulator of 1,2,5-oxadiazole indoleamine-(2,3)-dioxygenase, a preparation method and use thereof, sand belongs to the technical field of organic compound synthesis and medical application.

Related Art

Prodrug, also referred to as pro-drug, a drug precursor, a precursor drug and the like, refers to a compound which is obtained after chemical structure modification on drug, is inactive or less active in vitro, and release active drug through enzymatic or non-enzymatic conversion in vivo to achieve drug effects. At present, it has great effects on nervous system drugs, antitumor system drugs and antiviral drugs. The purpose of the prodrug is mainly to improve drug bioavailability, increase drug stability, reduce toxic and side effects, promote drug long-acting effects and the like. The prodrug is a very useful drug design method widely applied to administration route and dosage form design of various drug molecules. At present, clinically, the prodrug is not only used for improving lipophilicity of the drug to improve its transmembrane permeability, but also gradually used for improving water solubility of the drug. The prodrug has a great development space in tumor treatment. In summary, prodrug strategies have become an indispensable part of drug design and administration methods.

Tumors have specific tumor antigens, but in a natural state, the immune system sometimes cannot effectively control occurrence and development of the tumors. It is mainly because of immune tolerance to the tumor antigens in a tumor microenvironment, i.e. a specific non-responsive state of immunocompetent cells to tumor antigenic substances. Recent studies confirm that indoleamine-(2,3)-dioxygenase 1 (IDO1) is an initial and rate-limiting enzyme for catalyzing tryptophan metabolism along a kynurenine pathway outside human livers. Studies show that the IDO1 plays an important regulatory role in innate and adaptive immunity of a body by catalyzing the tryptophan metabolism. Abnormal tryptophan metabolism caused by overexpression of the IDO1 plays an important role in the immune tolerance of tumor patients. IDO1 expression is up-regulated in bodies of the tumor patients, and anti-tumor immunoreaction in the tumor microenvironment is inhibited through a series of complex mechanisms, promoting tumor angiogenesis. By inhibiting activity of IDO, the immune tolerance can be broken, and the anti-tumor immunoreaction can be enhanced. Therefore, an IDO pathway is one of key targets of tumor immunotherapy. Epacadostat, as an IDO inhibitor, is developed by Incyte Company and is used for treating cancers. The Epacadostat is in phase III clinical studies at present, and is used for treating cervical cancer, ovarian cancer, carcinoma tubae, peritoneal cancer, non-small cell lung cancer, triple negative breast cancer, urothelial cancer and other solid tumors.

However, it still needs to develop compounds with inhibitory activity on the IDO or with better pharmacodynamic performance in the art. The inventor found that an Epacadostat prodrug obtained by modifying active sites of the Epacadostat can improve the bioavailability of the Epacadostat. Therefore, the present invention is completed.

SUMMARY

Compounds of Formula I and Formula II, an isomer thereof, a pharmaceutically acceptable salt or a pharmaceutically acceptable solvate thereof are provided:



R1 is selected from H, —C(═O)Ra, —C(═O)ORb, —C(═O)CnPhRc and —P(═O)(ORd)(ORe). Ra is independently selected from C1-C18 alkyl, haloalkyl, and carboxyl and cyanogroup substituted alkyl. Rb is independently selected from C1-C18 alkyl, haloalkyl, and carboxyl and cyanogroup substituted alkyl. Rc is independently selected from C1-C18 alkyl, haloalkyl. H and halogen. Rd and Re are selected from identical or different groups, and are each independently hydrogen, C1-C16 saturated or unsaturated chain hydrocarbyl, C1-C16 saturated or unsaturated cyclohydrocarbyl, aromatic ring or heteroaromatic ring. A substituent on the ring may be selected from halogen, nitryl, cyanogroup, hydroxyl, amino group, C1-C16 alkyl and C1-C16 alkoxy. n is 0 or 1.

R2 is selected from hydrogen, substituted or unsubstituted C1-C10 alkyl, substituted or unsubstituted C3-C10 cycloalkyl, substituted or unsubstituted C2-C10 alkenyl, substituted or unsubstituted C3-C10 alkynyl, substituted or unsubstituted C5-C20 aryl, and substituted or unsubstituted C3-C14 heteroaryl. Heteroatoms may be S, O, NH or NRf.

Rf and the “substituted” refer to having one or more of substituents selected from a group below: halogen, hydroxyl, —NH2, nitryl, —CN, substituted or unsubstituted C1-C10 alkyl, substituted or unsubstituted C1-C10 haloalkyl, substituted or unsubstituted C1-C10 alkoxy, substituted or unsubstituted C1-C10 cycloalkyl, substituted or unsubstituted C2-C10 alkenyl, substituted or unsubstituted C3-C10 alkynyl, substituted or unsubstituted C5-C20 aryl, and substituted or unsubstituted C3-C14 heteroaryl. Heteroatoms may be S. O and NH.

R3 is selected from —C(═O)Ra, —C(═O)ORb, —C(═O)CnPhRc and —P(═O)(ORd)(ORe). Ra is independently selected from C9-C18 alkyl, haloalkyl, and carboxyl and cyanogroup substituted alkyl. Rb is independently selected from C9-C18 alkyl, haloalkyl, and carboxyl and cyanogroup substituted alkyl. Re is independently selected from C1-C18 alkyl, haloalkyl, H and halogen. Rd and Re are selected from identical or different groups, and are each independently hydrogen, C1-C16 saturated or unsaturated chain hydrocarbyl, C1-C16 saturated or unsaturated cyclohydrocarbyl, aromatic ring or heteroaromatic ring. A substituent on the ring may be selected from halogen, nitryl, cyanogroup, hydroxyl, amino group, C1-C16 alkyl and C1-C16 alkoxy. n is 0 or 1.

In another aspect, the present invention provides a pharmaceutical composition, including compounds of Formula I and/or Formula II, an isomer thereof, a pharmaceutically acceptable salt or a pharmaceutically acceptable solvate thereof according to claim1, and a pharmaceutically acceptable carrier.

In another aspect, the present invention provides a preparation method of compounds of Formula I and Formula II. 1, according to a preparation method of the compound I, a compound 1 and a compound 2 are prepared into the compound of Formula I through a condensation dehydration reaction under a room temperature or heating condition in no solvent or an organic solvent.

According to a preparation method of the compound II, a compound 1 and a compound 3 are prepared into a compound of Formula 4 through a condensation dehydration reaction under a room temperature or heating condition in no solvent or an organic solvent. The compound of Formula 4 and a compound 5 are prepared into the compound of Formula II through a condensation dehydration reaction under a room temperature or heating condition in no solvent or an organic solvent.



R1 is selected from H, —C(═O)Ra, —C(═O)ORb, —C(═O)CnPhRc, and —P(═O)(ORd)(ORe). Ra is independently selected from C1-C18 alkyl, haloalkyl, and carboxyl and cyanogroup substituted alkyl. Rb is independently selected from C1-C18 alkyl, haloalkyl, and carboxyl and cyanogroup substituted alkyl. Rc is independently selected from C1-C18 alkyl, haloalkyl. H and halogen. Rd and Re are selected from identical or different groups and are each independently hydrogen, C1-C16 saturated or unsaturated chain hydrocarbyl, C1-C16 saturated or unsaturated cyclohydrocarbyl, aromatic ring or heteroaromatic ring. A substituent on the ring may be selected from halogen, nitryl, cyanogroup, hydroxyl, amino group, C1-C16 alkyl and C1-C16 alkoxy. n is 0 or 1.

R2 is selected from hydrogen, substituted or unsubstituted C1-C10 alkyl, substituted or unsubstituted C3-C10 cycloalkyl, substituted or unsubstituted C2-C10 alkenyl, substituted or unsubstituted C3-C10 alkynyl, substituted or unsubstituted C5-C20 aryl, and substituted or unsubstituted C3-C14 heteroaryl. Heteroatoms may be S, O, NH or NRf.

Rf and the “substituted” refer to having one or a plurality of substituents selected from a group below: halogen, hydroxyl, —NH2, nitryl, —CN, substituted or unsubstituted C1-C10 alkyl, substituted or unsubstituted C1-C10 haloalkyl, substituted or unsubstituted C1-C10 alkoxy, substituted or unsubstituted C3-C10 cycloalkyl, substituted or unsubstituted C2-C10 alkenyl, substituted or unsubstituted C3-C10 alkynyl, substituted or unsubstituted C5-C20 aryl, and substituted or unsubstituted C3-C14 heteroaryl. Heteroatoms may be S, O and NH.

R3 is selected from —C(═O)Ra, —C(═O)ORb, —C(═O)CnPhRc, and —P(═O)(ORd)(ORe). Ra is independently selected from C9-C18 alkyl, haloalkyl, and carboxyl and cyanogroup substituted alkyl. Rb is independently selected from C9-C18 alkyl, haloalkyl, and carboxyl and cyanogroup substituted alkyl. Rc is independently selected from C1-C18 alkyl, haloalkyl, H and halogen. Rd and Re are selected from identical or different groups and are each independently hydrogen, C1-C16 saturated or unsaturated chain hydrocarbyl, C1-C16 saturated or unsaturated cyclohydrocarbyl, aromatic ring or heteroaromatic ring. A substituent on the ring may be selected from halogen, nitryl, cyanogroup, hydroxyl, amino group, C1-C16 alkyl and C1-C16 alkoxy. n is 0 or 1.

The selected solvent is selected from one or more of methyl alcohol, ethyl alcohol, dichloromethane, trichloromethane, acetonitrile, DMF, DMA, DMSO, THF and toluene, including but not limited to the above solvents.

A reaction temperature ranges from 0° C. to 200° C.

Reference may be made to embodiments for the above specific reaction conditions.

In another aspect, the present invention provides compounds of Formula I and Formula II, an isomer thereof, a pharmaceutically acceptable salt or a pharmaceutically acceptable solvate thereof or use of a pharmaceutical composition according to claim5in preparing an indoleamine-(2,3)-dioxygenase inhibitor, or a use in preparing drugs for preventing and/or treating indoleamine-(2.3)-dioxygenase-mediated diseases, or use in preparing anti-inflammatory drugs.

The indoleamine-(2,3)-dioxygenase-mediated diseases are cancers, neurodegenerative diseases, eye diseases, mental disorders, depression, anxiety disorders, Alzheimer's diseases and/or autoimmune diseases.

In an embodiment of the present invention, when R1 is selected from H a compound of General Formula II, an isomer thereof, a pharmaceutically acceptable salt or a pharmaceutically acceptable solvate thereof are as follows:



R2 is selected from hydrogen, and substituted or unsubstituted C1-C10alkyl, including but not limited to methyl, ethyl, n-propyl, isopropyl, n-butyl, etc.; substituted or unsubstituted C3-C10cycloalkyl, including but not limited to cyclopropyl, cyclopentyl, cyclohexyl, etc.; substituted or unsubstituted C2-C10alkenyl, including but not limited to ethenyl, propenyl, butenyl, etc.; substituted or unsubstituted C3-C10alkynyl, including but not limited to propinyl, butynyl, etc.; substituted or unsubstituted C5-C20aryl, including but not limited to phenyl, tolyl, methoxyphenyl, naphthyl, etc.; and substituted or unsubstituted C3-C14heteroaryl. Heteroatoms may be S, O, NH or NRf, including but not limited to thiofuran, furfuran, pyran, pyrrole, pyridine, pyridazine, etc.

Rfand the “substituted” refer to having one or more of substituents selected from a group below: halogen, hydroxyl, —NH2, nitryl, —CN, and substituted or unsubstituted C1-C10alkyl, including but not limited to methyl, ethyl, n-propyl, isopropyl, n-butyl, etc.; substituted or unsubstituted C1-C10haloalkyl, including but not limited to fluoro/chloro/bromo/iodo methyl, fluoro/chloro/bromo/iodo ethyl, fluoro/chloro/bromo/iodo n-propyl, fluoro/chloro/bromo/iodo isopropyl, fluoro/chloro/bromo/iodo n-butyl, etc.; substituted or unsubstituted C1-C10alkoxy, including but not limited to methoxyl, ethyoxyl, propoxyl, butoxyl, etc.; substituted or unsubstituted C1-C10cycloalkyl, including but not limited to cyclopropyl, cyclopentyl, cyclohexyl, etc.; substituted or unsubstituted C1-C10alkenyl, including but not limited to ethenyl, propenyl, butenyl, etc.; substituted or unsubstituted C3-C10alkynyl, including but not limited to propinyl, butynyl, etc.; substituted or unsubstituted C5-C20aryl, including but not limited to phenyl, tolyl, methoxyphenyl, naphthyl, etc.; and substituted or unsubstituted C3-C14heteroaryl. Heteroatoms may be S, O, NH or NR2, including but not limited tothiofuran, furfuran, pyran, pyrrole, pyridine, pyridazine, etc.

In another aspect, the present invention provides a pharmaceutical composition, including a compound of General Formula II, an isomer thereof or a pharmaceutically acceptable salt or a pharmaceutically acceptable solvate thereof when R1 is selected from H. It includes but is not limited to alkali metal used by alkali addition salt, such as sodium, potassium, calcium, magnesium, etc. It includes but not limited to organic acid or inorganic acid used by alkali addition salt. The organic acid is, for example, formic acid, acetic acid, propionic acid, propandioic acid, methanesulfonic acid, oxalic acid, trifluoroacetic acid, lactic acid, tartaric acid, citric acid, maleic acid, fumaric acid, benzoic acid, benzene methane sulfonic acid, gluconic acid, succinic acid, salicylic acid and malic acid. The inorganic acid is, for example, hydrochloric acid, hydrobromic acid, sulfuric acid and phosphoric acid.

In another aspect, the present invention provides a preparation method of the compound of Formula II. A compound of Formula 2 and a compound of Formula 3 are prepared into the compound of Formula II through a condensation dehydration reaction in no solvent or an organic solvent.



R2 is selected from hydrogen, substituted or unsubstituted C1-C10alkyl, substituted or unsubstituted C3-C10cycloalkyl, substituted or unsubstituted C2-C10alkenyl, substituted or unsubstituted C3-C10alkynyl, substituted or unsubstituted C5-C20aryl, and substituted or unsubstituted C3-C14heteroaryl. Heteroatoms may be S, O, NH or NRf.

Rfand the “substituted” refer to having one or more of substituents selected from a group below: halogen, hydroxyl, —NH2, nitryl, —CN, substituted or unsubstituted C1-C10alkyl, substituted or unsubstituted C1-C10haloalkyl, substituted or unsubstituted C1-C10alkoxy, substituted or unsubstituted C1-C10cycloalkyl, substituted or unsubstituted C2-C10alkenyl, substituted or unsubstituted C3-C10alkynyl, substituted or unsubstituted C5-C20aryl, and substituted or unsubstituted C3-C14heteroaryl. Heteroatoms may be S, O or NH.

The selected solvent is selected from one or more of methyl alcohol, ethyl alcohol, dichloromethane, trichloromethane, acetonitrile, DMF, DMA, DMSO, THF and toluene, including but not limited to the above solvents.

A reaction temperature ranges from 0° C. to 200° C.

Reference may be made to embodiments for the above specific reaction conditions.

In another aspect, the present invention provides use of a compound of Formula II or a pharmaceutically acceptable salt thereof according to claim1, in (1) preparing an indoleamine-(2,3)-dioxygenase inhibitor, (2) preparing drugs for preventing and/or treating indoleamine-(2,3)-dioxygenase-mediated diseases, and (3) preparing anti-inflammatory drugs.

The indoleamine-(2,3)-dioxygenase-mediated diseases are cancers, neurodegenerative diseases, eye diseases, mental disorders, depression, anxiety disorders, Alzheimer's diseases and/or autoimmune diseases.

Beneficial effects: the present invention has the following advantages that an Epacadostat prodrug compound designed and obtained by the present invention can be fast converted into original drug Epacadostat. Additionally, compared with the original drug, the obtained prodrug compound has better solubility and higher bioavailability, and enhances the pharmaceutical effects.

