WO2019034179A1 - Indole ido inhibitor and method for preparing the same - Google Patents

Abstract

The present invention discloses an indole IDO inhibitor and a method for preparing the same. The indole IDO inhibitor serves as active ingredient for a drug, and can be used for treating, for example but not limited to, immune activation related to indolamine-2,3-dioxygenase activity, inflammatory diseases and cardiovascular diseases.

Description

IDO inhibitor containing anthracene ring and preparation method thereof Technical field

The present invention relates to a class of tetrazolium phenyl hydrazine derivatives, which are useful as active ingredients for the treatment of immune activation and inflammation associated with indoleamine-2,3-dioxygenase activity. Diseases and cardiovascular diseases.

Background technique

Tryptophan, the essential amino acid in the human body, has two pathways: the serotonin pathway (about 5%) and the kynurenine pathway (about 95%) (Neuroch em Res, 1980, 5(3): 223-239). Indoleamine-2,3-dioxygenase (IDO) and tryptophan-2,3-dioxygenase (TDO) are the rate-limiting enzymes of the tryptophan/kynurenine pathway, and IDO is widely present in In mammalian tissue cells other than the liver, TDO is mostly expressed in the liver.

Indoleamine-2,3-dioxygenase is the only one outside the liver that can catalyze the epoxidation of ruthenium in tryptophan molecules, thereby decomposing along the canine uric acid pathway into L-kynurenine, picolinic acid and quinolinic acid. And a variety of metabolites. The expression of the enzyme and its related metabolites is mainly distributed in the T cell region of the thymic medulla and secondary lymphoid organs, and is scattered in some immune tolerance or immune special tissues, such as thymus, gastrointestinal mucosa, placenta and the like.

Under normal physiological conditions, IDO and TDO protect tissues from immune response by immunosuppression. INF-γ produced by activated T cells induces activation of indoleamine-2,3-dioxygenase expression, thereby negatively regulating CD4+ T cells, CD8+ T cells, and NK cells. However, IDO and TDO have high expression in a variety of tumor tissues, and their high expression is one of the causes of tumor immune tolerance, and is closely related to the poor prognosis of cancer patients. Both IDO and TDO can inactivate the tumor surveillance of the immune system and prevent tumor rejection. Tumor cells and specific types of immune cells use this mechanism to limit anti-tumor immune responses.

Studies have shown that inhibition of indoleamine-2,3-dioxygenase can modulate immunosuppressive function and thereby inhibit tumor growth (Nat. ReV. Immunol 2004, 4, 762-74; Nat. ReV. Cancer, 2006, 6,613-625).

Numerous studies have confirmed that IDO is also associated with other chronic diseases associated with inflammation, cardiovascular diseases, neurodegenerative diseases, psychiatric diseases, viral infections, autoimmune diseases, and the like.

However, most of the IDO small molecule inhibitors that have entered the clinical research stage are only micromolar (such as Newlink Genetics' Indoximod), and some have poor oral bioavailability (such as Incyte Corporation). Epacadostat), so there is a need for drugs with better inhibition and bioavailability to meet current clinical needs.

At the same time, the mechanism of action of IDO small molecule inhibitors entering clinical research is different. Epacadostat has affinity for IDO holoenzyme; Indoximod can relieve T cell function inhibition caused by decreased mTORC1 activity due to tryptophan deletion; Navoximod pair Simultaneous expression of IDO1/TDO tumors has an inhibitory effect; PF-06840003 is a non-competitive inhibitor of tryptophan, does not bind to the hemoglobin of the IDO enzyme; BMS-986205 binds to apo-IDO1 without cofactor And it produces inhibition.

definition

According to standard practice in the art, the formula representing the chemical structure in the terms used in the present invention may include a single dash "-", a double dash "=" or a symbol.

Used to indicate the chemical bond structure between a chemical element or a named substituent and its parent moiety: a single dash "-" indicates a single bond, and a double dash "=" indicates a double bond, symbol

A bond that is a point of attachment of a moiety or substituent to the core or core of a compound structure. If there is no single or double dashes in the formula representing the chemical structure, it is understood that a single bond is formed between the substituent and its parent moiety.

According to standard practice in the art, a hetero (atomic, alkyl, aryl, cyclic group) refers to a corresponding chemical structure containing atoms other than carbon atoms.

Summary of the invention

The present invention provides a tetrazolium phenyl hydrazine derivative which is a guanamine-2,3-dioxygenase inhibitor whose main function is by inhibiting guanamine-2,3-bis Oxygenase activity plays a role in regulating immune system function and inflammatory factors, specifically compounds of formula (I):

And / or its stereoisomers, tautomers or pharmaceutically acceptable salts, solvates, wherein:

R ¹ is an optionally substituted straight or branched alkyl group, a substituted or unsubstituted alkenyl group, a substituted or unsubstituted alkynyl group, a substituted or unsubstituted heteroalkyl group, a substituted or unsubstituted one with or without a hetero atom aryl group, a substituted or unsubstituted cycloalkyl group, a substituted or unsubstituted heterocyclic group, a substituted or unsubstituted alkanoyl group, a substituted or unsubstituted amide group, a substituted or unsubstituted amide alkyl group, the aforementioned The hetero atom is an oxygen, sulfur or nitrogen atom.

R ^{2 is} selected from substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted alkoxy, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclic, substituted or Unsubstituted alkynyl group.

A is a carbon chain with or without a hetero atom, and its structure is -(CH ₂ ) _n -, wherein n = 0 to 5; or -NH(CH ₂ ) _n -, n = 0 to 5, wherein the NH terminal is The ring is connected.

R ³ is a substituted or unsubstituted aryl group, and the aryl group may be an all-carbon skeleton or a skeleton containing one or more hetero atoms such as oxygen, sulfur, nitrogen, etc.; wherein the substitution on the aryl group may be a mono- or poly-substitution, substitution The group is independently selected from the group consisting of halogen, hydroxy, amino, nitro, cyano, trifluoromethyl, azido, sulfonyl, sulfonylamino, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted Or unsubstituted alkynyl, substituted or unsubstituted heteroalkyl, C ₁ -C ₈ substituted or unsubstituted alkoxy, substituted or unsubstituted aryl, substituted or unsubstituted cycloalkyl, substituted or not Substituted heterocyclic group, substituted or unsubstituted alkanoyl group, substituted or unsubstituted amide group, substituted or unsubstituted amide alkyl group.

The substituents described above are independently selected from the group consisting of halogen, hydroxy, amino, nitro, cyano, trifluoromethyl, azide, sulfonyl, acyl.

Which the alkyl is C ₁ -C ₈ substituted or unsubstituted alkyl _{group, - (CH 2) n -Ar} -, - (CH 2) n -Cy-, wherein Ar is a substituted or unsubstituted substituted Aryl or heteroaryl, Cy is substituted or unsubstituted cycloalkyl or heterocycloalkyl.

The alkenyl group described above is a C ₂ -C ₈ chain alkyl group containing one or more -(C=C)-.

The alkynyl group described above is a C ₂ -C ₈ chain alkyl group containing one or more -(C≡C)-.

The heteroalkyl group described above is a substituted or unsubstituted C ₁ -C ₈ chain alkyl group containing one or more atoms other than carbon (oxygen, sulfur or nitrogen atom).

The alkoxy group described above is -OR ⁴ wherein R ⁴ is a linear or branched substituted or unsubstituted C ₁ -C ₈ alkyl, alkenyl or alkynyl group.

The aryl group described above is a skeleton which may be an all carbon skeleton or a hetero atom containing one or more of oxygen, sulfur, nitrogen or the like, and may have one or more substituents thereon, and in some cases, any adjacent ones. The two substituents may form a cyclic structure in which C ₁ -C _{6 has} or does not contain a hetero atom (oxygen, sulfur or nitrogen).

The cycloalkyl group described above is a C ₃ -C ₇ carbocyclic group.

The heterocyclic group described above is a substituted or unsubstituted C ₃ -C ₇ carbocyclic group containing one or more atoms other than carbon (oxygen, sulfur or nitrogen atom).

The alkanoyl group described above is -(C=O)-R ⁵ wherein R ⁵ is a linear or branched substituted or unsubstituted C ₁ -C ₇ alkyl group.

The amide group described above is -(C=O)-NH-R ⁶ wherein R ⁶ is hydrogen, a linear or branched substituted or unsubstituted C ₁ -C ₇ alkyl group.

The amide alkyl group described above is -R ⁷ -(C=O)-NH-R ⁸ wherein R ⁷ is a linear or branched substituted or unsubstituted C ₁ -C ₇ alkyl group, and R ⁸ is a substituted or unsubstituted hydrogen, a linear or branched C _1- C ₅ alkyl group.

The sulfonyl group described above is a substituted or unsubstituted C ₁ -C ₆ alkylsulfonyl group.

The compound (I) provided by the present invention is characterized in that R ³ is a substituted or unsubstituted phenyl group or a six-membered aromatic group containing one or more hetero atoms, wherein the hetero atom is N, O or S.

In certain embodiments, the invention provides a compound of formula (II):

And / or its stereoisomers, tautomers or pharmaceutically acceptable salts, solvates, wherein:

R ¹ is an optionally substituted straight or branched alkyl group, a substituted or unsubstituted alkenyl group, a substituted or unsubstituted alkynyl group, a substituted or unsubstituted heteroalkyl group, a substituted or unsubstituted one with or without a hetero atom aryl group, a substituted or unsubstituted cycloalkyl group, a substituted or unsubstituted heterocyclic group, a substituted or unsubstituted alkanoyl group, a substituted or unsubstituted amide group, a substituted or unsubstituted amide alkyl group, the aforementioned The hetero atom is an oxygen, sulfur or nitrogen atom.

R ^{2 is} selected from substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted alkoxy, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclic, substituted or Unsubstituted alkynyl group.

n = 0 to 5.

R ³ is a substituted or unsubstituted aromatic phenyl group or a six-membered aromatic group containing one or more hetero atoms (nitrogen, oxygen or sulfur), wherein the substitution on the aryl group may be a mono- or poly-substitution, and the substituents are independently Selected from halogen, hydroxy, amino, nitro, cyano, trifluoromethyl, azido, sulfonyl, sulfonylamino, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted Alkynyl, substituted or unsubstituted heteroalkyl, C ₁ -C ₈ substituted or unsubstituted alkoxy, substituted or unsubstituted aryl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted A cycloalkyl, substituted or unsubstituted alkanoyl group, a substituted or unsubstituted amide group, a substituted or unsubstituted amide alkyl group.

The substituents described above are independently selected from the group consisting of halogen, hydroxy, amino, nitro, cyano, trifluoromethyl, azide, sulfonyl, acyl.

Which the alkyl is C ₁ -C ₈ substituted or unsubstituted alkyl _{group, - (CH 2) n -Ar} -, - (CH 2) n -Cy-, wherein Ar is a substituted or unsubstituted substituted Aryl or heteroaryl, Cy is substituted or unsubstituted cycloalkyl or heterocycloalkyl.

The alkenyl group described above is a C ₂ -C ₈ chain alkyl group containing one or more -(C=C)-.

The alkynyl group described above is a C ₂ -C ₈ chain alkyl group containing one or more -(C≡C)-.

The heteroalkyl group described above is a substituted or unsubstituted C ₁ -C ₈ chain alkyl group containing one or more atoms other than carbon (oxygen, sulfur or nitrogen atom).

The alkoxy group described above is -OR ⁴ wherein R ⁴ is a linear or branched substituted or unsubstituted C ₁ -C ₈ alkyl, alkenyl or alkynyl group.

The aryl group described above is a skeleton which may be an all carbon skeleton or a hetero atom containing one or more of oxygen, sulfur, nitrogen or the like, and may have one or more substituents thereon, and in some cases, any adjacent ones. The two substituents may form a cyclic structure in which C ₁ -C _{6 has} or does not contain a hetero atom (oxygen, sulfur or nitrogen).

The cycloalkyl group described above is a C ₃ -C ₇ carbocyclic group.

The heterocyclic group described above is a substituted or unsubstituted C ₃ -C ₇ carbocyclic group containing one or more atoms other than carbon (oxygen, sulfur or nitrogen atom).

The alkanoyl group described above is -(C=O)-R ⁵ wherein R ⁵ is a linear or branched substituted or unsubstituted C ₁ -C ₇ alkyl group.

The amide group described above is -(C=O)-NH-R ⁶ wherein R ⁶ is hydrogen, a linear or branched substituted or unsubstituted C ₁ -C ₇ alkyl group.

The amide alkyl group described above is -R ⁷ -(C=O)-NH-R ⁸ wherein R ⁷ is a linear or branched substituted or unsubstituted C ₁ -C ₇ alkyl group, and R ⁸ is a substituted or unsubstituted hydrogen, a linear or branched C _1- C ₅ alkyl group.

The sulfonyl group described above is a substituted or unsubstituted C ₁ -C ₆ alkylsulfonyl group.

In certain embodiments, the invention provides a compound of formula (III):

And / or its stereoisomers, tautomers or pharmaceutically acceptable salts, solvates, wherein:

R ¹ is an optionally substituted straight or branched alkyl group, a substituted or unsubstituted alkenyl group, a substituted or unsubstituted alkynyl group, a substituted or unsubstituted heteroalkyl group, a substituted or unsubstituted one with or without a hetero atom aryl group, a substituted or unsubstituted cycloalkyl group, a substituted or unsubstituted heterocyclic group, a substituted or unsubstituted alkanoyl group, a substituted or unsubstituted amide group, a substituted or unsubstituted amide alkyl group, the aforementioned The hetero atom is an oxygen, sulfur or nitrogen atom.

R ^{2 is} selected from substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted alkoxy, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclic, substituted or Unsubstituted alkynyl group.

n = 0 to 5.

R ³ is a substituted or unsubstituted aromatic phenyl group or a six-membered aromatic group containing one or more hetero atoms (nitrogen, oxygen or sulfur), wherein the substitution on the aryl group may be a mono- or poly-substitution, and the substituents are independently Selected from halogen, hydroxy, amino, nitro, cyano, trifluoromethyl, azido, sulfonyl, sulfonylamino, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted Alkynyl, substituted or unsubstituted heteroalkyl, C ₁ -C ₈ substituted or unsubstituted alkoxy, substituted or unsubstituted aryl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted A cycloalkyl, substituted or unsubstituted alkanoyl group, a substituted or unsubstituted amide group, a substituted or unsubstituted amide alkyl group.

The substituents described above are independently selected from the group consisting of halogen, hydroxy, amino, nitro, cyano, trifluoromethyl, azide, sulfonyl, acyl.

Which the alkyl is C ₁ -C ₈ substituted or unsubstituted alkyl _{group, - (CH 2) n -Ar} -, - (CH 2) n -Cy-, wherein Ar is a substituted or unsubstituted substituted Aryl or heteroaryl, Cy is substituted or unsubstituted cycloalkyl or heterocycloalkyl.

The alkenyl group described above is a C ₂ -C ₈ chain alkyl group containing one or more -(C=C)-.

The alkynyl group described above is a C ₂ -C ₈ chain alkyl group containing one or more -(C≡C)-.

The heteroalkyl group described above is a substituted or unsubstituted C ₁ -C ₈ chain alkyl group containing one or more atoms other than carbon (oxygen, sulfur or nitrogen atom).

The alkoxy group described above is -OR ⁴ wherein R ⁴ is a linear or branched substituted or unsubstituted C ₁ -C ₈ alkyl, alkenyl or alkynyl group.

The aryl group described above is a skeleton which may be an all carbon skeleton or a hetero atom containing one or more of oxygen, sulfur, nitrogen or the like, and may have one or more substituents thereon, and in some cases, any adjacent ones. The two substituents may form a cyclic structure in which C ₁ -C _{6 has} or does not contain a hetero atom (oxygen, sulfur or nitrogen).

The cycloalkyl group described above is a C ₃ -C ₇ carbocyclic group.

The heterocyclic group described above is a substituted or unsubstituted C ₃ -C ₇ carbocyclic group containing one or more atoms other than carbon (oxygen, sulfur or nitrogen atom).

The alkanoyl group described above is -(C=O)-R ⁵ wherein R ⁵ is a linear or branched substituted or unsubstituted C ₁ -C ₇ alkyl group.

The amide group described above is -(C=O)-NH-R ⁶ wherein R ⁶ is hydrogen, a linear or branched substituted or unsubstituted C ₁ -C ₇ alkyl group.

The amide alkyl group described above is -R ⁷ -(C=O)-NH-R ⁸ wherein R ⁷ is a linear or branched substituted or unsubstituted C ₁ -C ₇ alkyl group, and R ⁸ is a substituted or unsubstituted hydrogen, a linear or branched C _1- C ₅ alkyl group.

The sulfonyl group described above is a substituted or unsubstituted C ₁ -C ₆ alkylsulfonyl group.

The present invention surprisingly finds that a class of tetrazolium phenyl hydrazine derivatives can regulate the biological activity of IDO by inhibiting the IDO enzyme in biological cells, and can have other mechanisms of action due to slight differences in mechanism of action. IDO inhibitors work synergistically to meet current demand for IDO modulators.

resolve resolution

In the compound (II) according to the present invention, when n = 0, the structure of the oxime skeleton can be carried out by using 4-bromo-2-iodoaniline and R ² -substituted ethyl acylacetate, and then passing the hydrogen on the N. Base substitution, amidation reaction and Suzuki reaction are obtained. The synthetic route is shown in the following figure:

In compound (II), when n=0, the target compound can also be prepared by Suzuki reaction and amidation reaction after alkyl substitution on 吲哚N:

The compound (II) (where n = 0) can also be obtained by coupling cyclohexylamine with ethyl acetoacetate and then constructing an anthracene ring with p-benzoquinone, followed by a Suzuki reaction and an amidation reaction.

In the compound (II), when n≥1, the citric acid intermediate can be prepared into an acid chloride, and the carboxylic acid which grows one carbon chain is obtained by Arndt-Eister reaction, and is condensed with the corresponding amine to be coupled with tetrazolium by the Suzuki reaction. The azole group can obtain the target product; after the ring structure is constructed, the ester can be reduced and oxidized to form an aldehyde, and the carboxylic acid having a growth of 2 to 5 carbons can be obtained by a ylide reaction, and then the target compound can be obtained by amidation and Suzuki reaction. The synthetic route is shown in the figure below:

In the compound (III) according to the present invention, when n=0, the cyclohexylamine and the ethyl acetoacetate may be coupled to form an anthracene ring with p-benzoquinone, and then sequentially subjected to a Suzuki reaction and a Cruz rearrangement. The synthetic route is shown in the figure below:

In the compound (III), when n = 0, the ruthenium skeleton can also be constructed by using 4-bromo-2-iodoaniline and ethyl acetoacetate, and then the tetrazolium phenyl moiety is connected by the Suzuki reaction, and the cruss weight is The row is constructed by the urea bond, and the synthetic route is shown in the following figure:

In the compound (III), when n=1 to 5, the oxime carboxylate intermediate may be hydrolyzed and the crus rearranged to form an amine, and then linked to a bromo ester having a different length of methylene straight chain, the ester After hydrolysis, it is coupled with the corresponding amine, and finally obtained by Suzuki reaction. The synthetic route is shown in the following figure:

Instructions

The compounds of the present invention can modulate the activity of indoleamine-2,3-dioxygenase (IDO). As used herein, "modulation" refers to the ability to increase or decrease the activity of an enzyme or receptor. The compounds described herein are useful in methods of modulating IDO by contacting the enzyme with any one or more of the compounds or compositions described herein. In some embodiments, the compounds described herein can be used as inhibitors of IDO. In a further embodiment, the compounds described herein are useful for modulating the IDO activity of a cell or individual in need of modulation of the enzyme by administering a modulatory (e.g., inhibitory) dose of a compound of the invention.

The present invention provides a method of altering (e.g., increasing) the level of extracellular tryptophan in a mammal in a system comprising a cell-expressed IDO, such as a tissue, cell or living organism culture, comprising administering an effective amount of the present invention. Compound or ingredient. Methods for determining tryptophan levels and tryptophan degradation are routine methods in the art.

The invention provides methods of inhibiting immunosuppression (e.g., IDO-mediated immunosuppression) in a patient by administering to the patient an effective amount of a compound or component of the invention. IDO-mediated immunosuppression is associated with cancer, tumor growth, metastasis, infectious diseases (such as viral infections), viral replication, and the like.

The present invention treats diseases associated with abnormal IDO activity or expression in an individual (e.g., a patient) by administering to the patient an effective amount of a compound or component of the present invention. The disease includes any disease, disorder or condition that is directly or indirectly associated with abnormal expression or activity of the IDO enzyme. Examples of diseases related to IDO include cancer, neurodegenerative disorders (eg, Alzheimer's disease, Huntington's disease, etc.), viral infections (eg, HIV infection, etc.), depression, trauma, cataracts, autoimmune diseases (eg, rheumatoid joints) Inflammation, asthma, multiple sclerosis, psoriasis, systemic lupus erythematosus, inflammatory bowel disease, etc.), organ transplantation (eg organ transplant rejection, etc.).

Examples of cancer-associated tumor-specific immunosuppression treatable by the methods of the invention include colon, pancreas, breast, prostate, lung, brain, ovary, cervix, testis, kidney, head and neck cancer, lymphoma , immunosuppression related to leukemia, melanoma, etc.

The IDO-mediated immunosuppression associated with viral infections of the present invention is associated with viral infections selected from the group consisting of hepatitis C virus (HCV), human papillomavirus (HPV), and cytomegalovirus (CMV). , Epstein-Barr virus (EBV), poliovirus, varicella zoster virus, Coxsackie virus, human immunodeficiency virus (HIV).

In another embodiment, IDO-mediated immunosuppression associated with an infectious disease is associated with tuberculosis or leishmaniasis.

For example, a patient undergoing or having completed a course of chemotherapy and/or radiation therapy for a disease state (e.g., cancer) may administer a therapeutically effective amount of a compound or component of the invention to a patient to inhibit immunosuppression due to a disease state. And / or its treatment benefits.

Further provided is a method of treating a disease associated with IDO activity or expression (including abnormal activity and/or overexpression) by administering to a subject (eg, a patient) in need of a related treatment a therapeutically effective amount of a compound of the present invention or a pharmaceutical composition thereof. Methods. Examples of diseases can include any disease, disorder, or condition, such as overexpression or activity abnormality, that is directly or indirectly related to the expression or activity of an IDO enzyme. IDO-related diseases can also include any disease, disorder, or condition that can be prevented, ameliorated, or cured by modulating enzyme activity.

As used herein, "contacting" refers to the association of a specified portion with an in vitro system or an in vivo system. For example, "contacting" an IDO enzyme with a compound or ingredient of the invention includes administering to a subject or patient (e.g., a human) having the IDO a compound of the invention, or introducing a compound of the invention into a sample comprising the IDO enzyme-containing cell or purified preparation.

The term "individual" or "patient" as used in the present invention refers to any animal or human including a mammal, preferably a mouse, a rat, another rodent, a rabbit, a dog, a cat, a pig, a cow, a sheep, a horse. Or primate, most preferably human.

As used herein, "therapeutically effective amount" refers to the amount of active compound or drug that a researcher, physician, or veterinarian seeks in a tissue, system, animal, individual, or human to cause a biological or medical response, including disease prevention, relief. One or more of diseases and diseases.

Combination therapy

The compounds of the invention may be combined with one or more other therapeutic methods (eg, antiviral, chemotherapeutic or other anticancer drugs, immunopotentiators, immunosuppressants, radiation, anti-tumor and anti-viral vaccines, cytokine therapies) Combination of drugs such as IL2, GM-CSF, etc. and/or tyrosine kinase inhibitors to treat IDO-related diseases, disorders or conditions (as described above) or to improve the treatment of disease states or conditions (eg cancer) Efficacy. These drugs may be used in combination with a compound of the present invention in one dosage form, or these drugs may be administered simultaneously or sequentially in different dosage forms.

Suitable antiviral drugs contemplated for use in combination with the compounds of the invention may include nucleoside and nucleotide reverse transcriptase inhibitors (NRTIs), non-nucleoside reverse transcriptase inhibitors (NNRTIs), protease inhibitors, and others. Antiviral drugs.

Examples of suitable nucleoside reverse transcriptase inhibitors include, but are not limited to, zidovudine (AZT); didanosine (ddI); zalcitabine (ddC); stavudine (d4T); Mifidine (3TC); abacavir (1592U89); adefovir dipivoxil [bisacrylamide (POM)-PMEA]; lobucarb (BMS-180194); BCH-10652; emtricitabine [ (-)-FTC]; β-L-FD4 (also known as β-L-D4C and the name β-L-2', 3'-dideoxy-5-fluoro-cytidine); DAPD((-) -β-D-2,6-diamino-decanedioxolane; and Lord's adenosine (FddA). Typical suitable non-nucleoside reverse transcriptase inhibitors include, but are not limited to, nevirapine (BI-RG-587); delavirdine (BHAP, U-90152); efavirenz (DMP-266); PNU-142721; AG- 1549; MKC-442[1-(ethoxy-methyl)-5-(1-methylethyl)-6-(benzyl)-(2,4-(1H,3H)-pyrimidine-II Ketone]; and (+)-caolin A (NSC-675451) and B. Typical suitable protease inhibitors include, but are not limited to, saquinavir (Ro31-8959); ritonavir (ABT-538); Indo Nawei (MK-639); nelfinavir (AG-1343); amprenavir (141W94); rasinavir (BMS-234475); DMP-450; BMS-2322623; ABT-378; -1549. Other antiviral drugs include, but are not limited to, hydroxyurea, ribavirin, IL-2, IL-12, pentafoxif and Yissum (item number 11607).

Suitable chemotherapy or other anti-cancer drugs include, but are not limited to, alkylating agents (including, without limitation, nitrogen mustard, aziridine derivatives, alkyl sulfonates, nitrosoureas, and triazenes), such as uramus Tet, piperacin, cyclophosphamide (CytoxanTM), ifosfamide, melphalan, chlorambucil, piperac bromide, triethylene-melamine, triethylene thiophosphoramide, busulfan, Carmustine, lomustine, streptozotocin, dacarbazine, and temozolomide; antimetabolites (including, without limitation, f-folate antagonists, pyrimidine analogs, purine analogs, and adenosine deaminase inhibitors) Such as methotrexate, 5-fluorouracil, fluorouridine, cytarabine, 6-anthracene, 6-thioguanine, fludarabine phosphate, pentastatin and gemcitabine; some natural Products and their derivatives (such as vinca alkaloids, anti-tumor antibiotics, enzymes, lymphokines and epipodophyllotoxin), such as vinblastine, vincristine, vindesine, bleomycin, dactinomycin, soft red , doxorubicin, epirubicin, demethoxydaunorubicin, cytarabine, paclitaxel (TaxolTM), light god Mycin, deoxy-assisin, mitomycin-C, L-asparaginase, interferon, etoposide and teniposide.

Other suitable cytotoxic drugs include, but are not limited to, noviben, CPT-11, anastrozole, letrozole, capecitabine, raloxifene, cyclophosphamide, ifosfamide, and droloxifene.

The following cytotoxic drugs (including drugs of the same mechanism) are also suitable: such as epiphyllotoxin; tumor enzyme; topoisomerase inhibitor; procarbazine; mitoxantrone; platinum complexes such as cisplatin and carboplatin; Biological response modifier; growth inhibitor; anti-hormone therapeutic; calcium leucovorin; tegafur; and hematopoietic growth factor.

Suitable other anticancer drugs include antibody therapy such as trastuzumab (Herceptin), costimulatory molecules such as CTLA-4, 4-1BB and PD-1 or cytokine antibodies (IL-10, TGF-β) Etc.; drugs that block the migration of immune cells, such as chemokine receptor antagonists (CCR2, CCR4, and CCR6); drugs that enhance the immune system, such as adjuvant or adaptive T cell metastases.

Suitable anti-cancer vaccines include dendritic cells, synthetic peptides, DNA vaccines, and recombinant viruses.

Those skilled in the art are aware of ways to safely and effectively administer most of these chemotherapeutic drugs. In addition, its administration is always described in the standard literature. For example, many methods of administering chemotherapeutic drugs are described in the "Physicians' Desk Reference" (PDR, eg, 1996 edition, Medical Economics Company, Montvale, NJ), which is incorporated herein by reference. As listed in its full text.

Drug formula and dosage form

When the compound of the present invention is used as a medicament, it can be administered in the form of a pharmaceutical composition which is a combination of the compound of the present invention and a pharmaceutically acceptable carrier. These compositions can be prepared in a manner well known in the pharmaceutical art and administered by a variety of routes depending on the area used for topical or systemic treatment and treatment. Administration may be topical (including ocular administration and mucosal administration such as intranasal, vaginal and rectal), pulmonary (such as by nebulizer, intratracheal, intranasal, epidermal and transdermal) inhalation or injection of powder Or aerosol), eye, oral or parenteral.

Methods of ocular administration may include topical administration (eye drops), subconjunctival, periocular or intravitreal injection, introduction of an ocular insert through a balloon catheter or surgical placement in the conjunctival sac, and the like.

Methods for parenteral administration include intravenous, intraarterial, subcutaneous, intraperitoneal or intramuscular injection or infusion; or intracranial, such as intrathecal or intraventricular administration. Parenteral administration can be in the form of a single bolus dose or can be in the form of a continuous infusion pump or the like.

Methods for topical administration may include transdermal patches, ointments, lotions, creams, gels, drops, suppositories, sprays, creams, powders, liquids, and powders. It may be necessary or desirable to use conventional pharmaceutical carriers, water, powder or oily bases, thickeners, and the like.

The pharmaceutical composition of the present invention may contain, as an active ingredient, one or more of the above compounds of the present invention in combination with one or more pharmaceutically acceptable carriers. In making the compositions of the present invention, the active ingredient will generally be mixed with the adjuvant, diluted by the adjuvant or contained in a carrier such as a capsule, sachet, paper or other container. When the adjuvant is used as a diluent, the adjuvant may be a solid, semi-solid or liquid material, as an excipient, carrier or vehicle for the active ingredient. The composition may be in the form of a tablet, a pill, a powder, a lozenge, a sachet, a cachet, an elixir, a suspension, an emulsion, a solution, a syrup, an aerosol (as a solid or liquid medium), and contains the highest activity. An ointment, a soft and hard gel capsule, a suppository, a sterile injectable solution, and a sterile packaged powder having a compound weight of 10%.

In making the preparation of the formulation, the active compound of the present invention can be pulverized to provide a suitable particle size prior to combining with the other ingredients. If the active compound is substantially insoluble, it can be ground to a particle size of less than 200 mesh. If the active compound is soluble in water, the particle size can be adjusted by comminution to provide a substantially uniform distribution in the formulation, such as about 40 mesh.

Some examples of excipients used in the present invention include lactose, dextrose, sucrose, sorbitol, mannitol, starch, gum arabic, calcium phosphate, alginate, tragacanth, gelatin, calcium silicate, microcrystals. Cellulose, polyvinylpyrrolidone, cellulose, water, syrup and methylcellulose. Formulations may also include, but are not limited to, lubricants (such as talc, magnesium stearate, mineral oil, etc.), wetting agents, emulsifying and suspending agents, preservatives (such as methylparaben, propyl ester, etc.), Sweeteners and flavorings. The compositions of the present invention can be formulated using procedures known in the art to provide rapid, slow or delayed release of the active ingredient after administration to a patient.

The compositions of the present invention may also be formulated in unit dosage form such that they contain from about 5 to about 200 mg per dose, more usually from about 10 to about 100 mg of the active ingredient. The above "unit dosage form" refers to a physically discrete unit suitable as a single dose for human subjects and other mammals, each unit containing a predetermined amount of active material calculated to produce the desired therapeutic effect.

The active compounds of the present invention can be effective in a wide variety of dosage forms and are generally administered in a pharmaceutically effective amount. It is to be understood that the actual dose of the compound is usually determined by the physician according to the circumstances, including the condition to be treated, the route of administration selected, the actual compound administered, the age, weight and response of the individual patient, the severity of the patient's symptoms, etc. .

In the preparation of a solid composition such as a tablet, the main active ingredient is mixed with a pharmaceutical adjuvant to form a pre-formulation composition containing a homogeneous mixture of the compounds described herein. By "homogeneous" as used in the appeal, it is meant that the active ingredient will generally be homogeneously dispersed in the composition such that the compositions are readily divided into equivalent unit dosage forms such as tablets, pills, capsules and the like. This solid preformulation is then subdivided into unit dosage forms of the type described above containing, for example, from 0.1 to about 500 mg of the active compound of the invention.

The tablets or pills may be coated or otherwise compounded to obtain a dosage form that has the advantage of prolonged action. For example, a tablet or pill can contain both an inner dose and an outer dose component, the latter being in the form of the former. The two components can be separated by an enteric layer which serves to prevent disintegration in the stomach and complete passage of the inner component through the duodenum or delayed release. A variety of materials are available for this enteric layer or coating, including but not limited to various polymeric acids and mixtures of polymeric acids with shellac, cetyl alcohol, and cellulose acetate.

Liquid forms which may be added to the compounds and compositions of the present invention for oral or parenteral administration include: aqueous solutions, suitable flavored syrups, aqueous or oily suspensions, and edible oils such as cottonseed oil, sesame oil, coconut oil or peanut oil. Flavored emulsions, elixirs and similar pharmaceutically acceptable carriers.

Compositions for inhalation or insufflation include dissolving a compound of the invention in a pharmaceutically acceptable solution, suspension, water or organic solvent, or mixtures and powders thereof. Suitable pharmaceutically acceptable excipients may be included in the liquid or solid compositions. In some embodiments, the composition is administered by the oral or nasal respiratory route to produce a local or systemic effect. The composition can be atomized using an inert gas. The nebulizing solution can be directly inhaled by the atomizing device, or the nebulizing device can be connected to a mask or a intermittent positive pressure ventilator. Solutions, suspensions or powder compositions can be administered orally or nasally by means of a device for releasing the formulation in a suitable manner.

The amount of the compound or composition to be administered to a patient varies depending on the ingredient to be administered, the purpose of administration (e.g., prevention or treatment), the state of the patient, the mode of administration, and the like. In therapeutic applications, the composition can be administered to a patient already suffering from a disease in an amount sufficient to cure or at least partially arrest the symptoms of the disease and its complications. The effective dose depends on the condition being treated and the judgment of the attending physician based on factors such as the severity of the disease, the age, weight and general condition of the patient.

The composition administered to the patient may be in the form of the above pharmaceutical composition. These compositions can be sterilized or sterile filtered by conventional sterilization techniques. The aqueous solution may be packaged as it is or as a lyophilized preparation, and the lyophilized preparation is used after mixing with a sterile aqueous carrier prior to administration. The pH of the compound formulation is generally between 3 and 11, more preferably between 5 and 9, and most preferably between 7 and 8. It will be appreciated that the use of some of the above-described excipients, carriers or stabilizers will result in the presence of the drug in the form of a salt.

The therapeutic dose of the compound of the present invention may vary depending on the particular use of the treatment, the manner in which the compound is administered, the health and condition of the patient, and the judgment of the prescribing physician. The proportion or concentration of the compound of the present invention in a pharmaceutical composition may vary depending on various factors including dosage, chemical characteristics (e.g., hydrophobicity), route of administration, and the like. For example, the compounds of the invention may be provided in a physiologically buffered aqueous solution containing from about 0.1 to about 10% w/v of the compound for parenteral administration. Some typical dosage ranges range from about 1 [mu]g/kg to about 1 g/kg body weight per day. In some embodiments, the dosage range is between about 0.01 mg/kg to about 100 mg/kg body weight per day. The dosage may depend on factors such as the type and progression of the disease or disorder, the overall health of the particular patient, the relative biological efficacy of the selected compound, the formulation of the adjuvant, and the route of administration. The effective dose can be inferred by a dose response curve from an in vitro or animal model test system.

The compounds of the present invention may also be formulated in combination with one or more other active ingredients, and other active ingredients may include any drug, such as antiviral drugs, vaccines, antibodies, immunopotentiators, immunosuppressive agents, anti-inflammatory agents, and the like.

Labeling compounds and measuring methods

Another aspect related to the present invention relates to fluorescent dyes, spin labels, heavy metals or radiolabeled derivatives of said compounds which are useful not only for imaging but also for in vivo and in vivo detection for localization and quantification of tissue specimens ( The IDO enzyme in humans is included and used to recognize IDO enzyme ligands by inhibiting binding to the labeled compound. The invention further provides IDO enzyme assays containing such labeled compounds.

The invention further provides isotopically labeled compounds of the compounds. An "isotopically labeled" or "radiolabeled" compound is a compound of the invention in which one or more atoms are replaced or substituted with an atomic mass or mass number of atoms different from the atomic mass or mass number normally found in nature (ie, naturally occurring). . Suitable radionuclides include, but are not limited to, ² H, ³ H, ¹¹ C, ¹³ C, ¹⁴ C, ¹³ N, ¹⁵ N, ¹⁵ O, ¹⁷ O, ¹⁸ O, ¹⁸ F, ³⁵ S, ³⁶ Cl, ⁸² Br, ⁷⁵ Br, ⁷⁶ Br, ⁷⁷ Br, ¹²³ I, ¹²⁴ I, ¹²⁵ I and ¹³¹ I. The radionuclide contained in the radiolabeled compound will depend on the particular application of the radiolabeled compound. For example, for in vitro IDO enzyme labeling and competitive detection, compounds containing ³ H, ¹⁴ C, ⁸² Br, ¹²⁵ I, ¹³¹ I or ³⁵ S are generally used. For radiographic applications, compounds containing ¹¹ C, ¹⁸ F, ¹²⁵ I, ¹²³ I, ¹²⁴ I, ¹³¹ I, ⁷⁵ Br, ⁷⁶ Br or ⁷⁷ Br are generally employed.

The above-mentioned "radiolabel" or "labeled compound" is a compound containing at least one radionuclide. In some embodiments, the radionuclide is selected from the group consisting of ³ H, ¹⁴ C, ¹²⁵ I, ³⁵ S or ⁸² Br.

Methods of incorporating a radioisotope into an organic compound are suitable for use in the compounds described herein and are well known in the art.

The radiolabeled compounds of the invention can be used to identify or evaluate screening assays for compounds. In general, a newly synthesized or discovered compound (i.e., a test compound) can be evaluated to reduce the ability of the radiolabeled compound of the present invention to bind to an IDO enzyme. The ability of a test compound to compete with a radiolabeled compound for binding to an IDO enzyme is directly related to its binding affinity.

Kit

The invention also encompasses kits for treating diseases, such as treating or preventing diseases or conditions associated with IDO, obesity, diabetes, and other diseases of the invention. Such a kit is a container comprising one or more of the pharmaceutical compositions of the present invention, comprising a pharmaceutical composition having a therapeutically effective amount. Such kits may also include suitable one or more of various conventional kit components, such as containers containing one or more pharmaceutically acceptable carriers, other containers readily apparent to those skilled in the art, and the like. Instructions for indicating the amount of the compound, administration of the drug, and/or compounding instructions for the compound may also be included in the kit as an insert or label.

General abbreviations and symbols

g: g

Mg: mg

mL: ml

Mol: Moore

°C: Celsius

BINOL: 1,1'-binaphthol

BOP: benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate

DCM: dichloromethane

DMAP: 4-dimethylaminopyridine

DMF: dimethylformamide

DMSO: dimethyl sulfoxide

DPBS: Dunsen's phosphate buffer

EA: ethyl acetate

EDTA: ethylenediaminetetraacetic acid

H ₂ O: water

LDA: lithium diisopropylamide

NBS: N-bromosuccinimide

Min: minute

PCC: Pyridyl chlorochromate

SOCl ₂ : chlorosulfoxide

TEA: Triethylamine

THF: tetrahydrofuran

TLC: thin layer chromatography

Trypan Blue: Trypan Blue

Trypsin: Trypsin

DRAWINGS

Figure 1 is a graph showing the antitumor effect of the compound.

Detailed ways

Reagents and solvents were purchased from commercial sources, and the reaction was monitored using a 0.25 mm HSGF254 thin layer chromatography silica gel plate and flash column chromatography using 200-300 mesh particle size thin layer chromatography silica gel. Nuclear magnetic resonance spectroscopy was performed using a Bruker Avance III NMR spectrometer. Mass spectrometry was performed using Agilent LC/MS chromatographs 1260-6110 and 1260-6120. All reactions were magnetically stirred at room temperature unless otherwise stated.

The following specific examples are merely illustrative of the invention and are not intended to limit the invention in any way. Those skilled in the art will readily recognize that various non-critical parameters can be changed or adjusted to produce substantially the same results. According to one or more of the detection methods of the present invention, the compounds of the following examples were found to be IDO inhibitors.

Example 1 : 5-(2-(1H-tetrazol-5-yl)phenyl)-N-(4-methylphenyl)-1-isobutyl-2-methyl-1H-indole- 3-carboxamide

1A, 5-bromo-2-methyl-1H-indole-3-carboxylic acid ethyl ester

4-Bromo-2-iodoaniline (10 g, 33.57 mmol), ethyl acetoacetate (6.55 g, 50.35 mmol), cuprous iodide (640 mg, 3.36 mmol), BINOL (1.922 g, 6.71 mmol), cesium carbonate (10.94 g, 33.57 mmol) and DMSO (60 mL) were added to the reaction flask. The reaction was stirred by heating to 55 ° C and monitored by TLC. After the completion of the reaction, the reaction mixture was diluted with a large amount of water, and extracted with EA (200 mL×4). The organic phase was combined, washed with a large amount of water, and then washed with saturated brine, dried over anhydrous sodium sulfate and mixed. The liquid was concentrated to give a crude brown oil (yield: EtOAc: EtOAc: _{^{1 H NMR (400MHz, CDCl 3}} ) δppm: 8.41 (s, 1H); 8.10 (d, 1H); 7.14 (d, 1H); 4.40 (q, 2H); 2.38 (s, 3H); 1.39 (t, 3H). LCMS (ES-API): m/z = 282 [M+H] ⁺

1B, 5-bromo-1-isobutyl-2-methyl-1H-indole-3-carboxylic acid ethyl ester

Compound 2A (3 g, 11.5 mmol) and DMF (50 mL) were added to a reaction flask, and the temperature of the reaction mixture was lowered in an ice water bath, and sodium hydride (1.1 g, 46 mmol) and 1-bromo-2-methylpropane (6.3 g, 46 mmol) and potassium iodide (100 mg), the ice water bath was removed, and the reaction was warmed to 50 ° C and monitored by TLC. After the reaction is completed, the reaction solution is added with water to quench the reaction, and then diluted with a large amount of water, extracted with EA (150 mL×4), the organic phase is combined, DMF is washed away with a large amount of water, and then washed with saturated brine, anhydrous sulfuric acid The mixture was dried over sodium sulfate. EtOAc was evaporated. _{^{1 H NMR (400MHz, CDCl 3}} ) δppm: 7.86 (d, 1H); 7.63 (s, 1H); 7.34 (m, 2H); 7.18 (d, 1H); 4.40 (q, 2H); 4.13 (d, 2H); 2.71 (s, 3H); 2.15 (m, 1H); 1.39 (t, 3H); 1.01 (d, 6H). LCMS (ES-API): m/z = 338 [M+H] ⁺

1C, 5-bromo-1-isobutyl-2-methyl-1H-indole-3-carboxylic acid

Compound 2B (800 mg, 2.37 mmol) and 50% potassium hydroxide solution (15 mL, methanol: water = 4:1 v/v) were placed in a reaction flask and warmed to reflux. After the completion of the reaction, the reaction solution was cooled to room temperature, and the pH was adjusted to 5-6 with 10N hydrochloric acid, that is, a large amount of white solid was precipitated, and extracted with EA (100 mL×3), and the organic phase was combined, washed successively with water and saturated brine. The mixture was dried over sodium sulfate, and the mixture was evaporated. _{^{1 H NMR (400MHz, CDCl 3}} ) δppm: 11.2 (s, 1H); 7.97 (d, 1H); 7.49 (m, 2H); 4.23 (d, 2H); 2.81 (s, 3H); 2.25 (m, 1H); 1.11 (d, 6H). LCMS (ES-API): m/z = 308 [MH] ^-

1D, 5-bromo-N-(4-methylphenyl)-1-isobutyl-2-methyl-1H-indole-3-carboxamide

Compound 1C (400 mg, 1.29 mmol) was added to a reaction mixture. After cooling in an ice-water bath, thionyl chloride (6 mL) was added and the reaction was stirred and monitored by TLC. After the reaction was completed, the reaction mixture was concentrated. The residue was dissolved in dry THF (10 mL) EtOAc (EtOAc)EtOAc. After the reaction is completed, the reaction solution is dried, and the mixture is dissolved in water, and then extracted with EA (50 mL×3). The organic phase is combined, washed successively with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated. The solvent mixture of EA and hexane was purified by silica gel column chromatography as eluent to give product 479mg, yield 80%. _{^{1 H NMR (400MHz, CDCl 3}} ) δppm: 9.25 (s, 1H); 7.87 (d, 1H); 7.66 (d, 2H); 7.40 (d, 1H); 7.31 (d, 2H); 4.13 (d, 2H); 2.71 (s, 3H); 2.44 (s, 3H); 2.15 (m, 1H); 1.01 (m, 6H). LCMS (ES-API): m/z = 399 [M+H] ⁺

1, 5-(2-(1H-tetrazol-5-yl)phenyl)-N-(4-methylphenyl)-1-isobutyl-2-methyl-1H-indole-3- Formamide

Compound 1D (200 mg, 0.548 mmol), 2-(5-tetrapyrazole)benzeneboronic acid (200 mg, 1.096 mmol), potassium phosphate heptahydrate (920 mg, 2.74 mmol) and 10 mL of degassed solvent (DMF:H) ₂ O=10:1) After adding to the sealing tube, after replacing the gas in the sealing tube with nitrogen once, tetrakistriphenylphosphine palladium (60 mg, 0.05 mmol) was quickly added, and the gas in the sealing tube was replaced with nitrogen gas three times or more. The mixture was sealed and heated to 90 ° C for 7 hours. The reaction solution was cooled to room temperature, diluted with 10 g/L KOH solution, a small amount of solid was precipitated, washed with EA (100 mL), the organic phase was dark yellow, and the aqueous phase was light. The point plate organic phase product is less, retaining the aqueous phase. The aqueous phase was adjusted to pH 4-5 with 1N HCl. A large white solid was precipitated, which was extracted with EA (60 mL×3). The organic phase was combined, washed sequentially with water and brine, dried over anhydrous sodium sulfate, and concentrated. The product was purified by silica gel column chromatography using a solvent mixture of EA and hexanes as eluent. _{^{1 H NMR (400MHz, CDCl 3}} ) δppm: 7.97 (dd, 1H); 7.72 (s, 1H); 7.53 (m, 2H); 7.41 (dd, 1H); 7.18 (t, 3H); 6.89 (d, 2H); 6.77 (dd, 1H); 3.81 (d, 2H); 2.43 (s, 3H); 2.24 (s, 3H); 2.12 (m, 1H); 0.90 (m, 6H). LCMS (ES-API): m/z = 465 [M+H] ⁺

Examples 2 to 5 : The following compounds were obtained by a reaction method similar to that of Compound 1, by reacting Intermediate Compound 1C with the corresponding amine, and then by Suzuki reaction.

Table 1 list of compounds

Example 6 : 5-(2-(1H-tetrazol-5-yl)phenyl)-N-(4-methylphenyl)-1-cyclohexyl-2-methyl-1H-indole-3 -formamide

6A, (3-cyclohexylamino)butenoic acid ethyl ester

Ethyl acetoacetate (4.85 mL, 38.4 mmol) was added to a 50 mL vial, and cyclohexylamine (5.50 mL, 48.0 mmol) was added dropwise to the reaction mixture at room temperature, and the mixture was stirred at the same temperature for 5 h. TLC showed that the reaction of the starting material was complete. 100 mL of petroleum ether was added to the reaction mixture, and the organic layer was separated. The organic layer was washed with water and brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure at 50 ° C. The oil was 8.25 g, and the crude material was used in the next step without purification. _{^{1 H NMR (400MHz, CDCl 3}} ) δppm: 4.82 (s, 1H); 4.40 (q, 2H); 2.77 (m, 1H); 2.46 (s, 3H); 1.94 (m, 2H); 1.69 (m, 4H); 1.56 (t, 3H); 1.37 (m, 4H). LCMS (ES-API): m/z = 212 [M+H] ⁺

6B, ethyl 1-cyclohexyl-5-hydroxy-2-methyl-1H-indole-3-carboxylate

Add p-benzoquinone (14.52g, 134.3mmol) and 200mL of absolute ethanol to a 500mL single-mouth bottle, stir and dissolve, then add intermediate 6A (8.25g, 39.0mmol) and absolute ethanol (25mL) under ice water bath cooling. The mixture was then transferred to room temperature for 18 h and TLC showed the starting material was completely. The reaction solution was stirred under ice-cooling for 30 min, and a large amount of brown solid was precipitated, filtered, and the filter cake was washed with a small amount of cold ethanol. The solid was dried in vacuo at 50 ° C to give 5.42 g of brown solid. One step reaction. _{^{1 H NMR (400MHz, CDCl 3}} ) δppm: 7.17 (s, 1H); 7.29 (d, 1H); 7.12 (d, 2H); 4.05 (q, 2H); 3.38 (m, 1H); 2.33 (s, 3H); 1.82 (m, 2H); 1.55 (m, 2H); 1.31 (m, 6H); 1.02 (t, 3H). LCMS (ES-API): m/z = 302 [M+H] ⁺

6C, ethyl 1-cyclohexyl-2-methyl-5-trifluoromethanesulfonyl-1H-indole-3-carboxylate

Intermediate 6B (5.4 g, 17.9 mmol) and 60 mL of dichloromethane were added to a 250 mL vial, 9 mL of pyridine was added with stirring, and trifluoromethanesulfonic anhydride (6.0 mL, 35.7 mmol) and dichloride were added dropwise with cooling in an ice water bath. A mixture of methane (30 mL) was then taken to room temperature for 18 h. The organic layer was separated, washed with EtOAc EtOAc EtOAc EtOAc EtOAc The mixture was purified by silica gel column chromatography as eluent to give 6.2 g of product (yield: 72.0%). _{^{1 H NMR (400MHz, CDCl 3}} ) δppm: 7.84 (s, 1H); 7.29 (d, 1H); 7.12 (d, 2H); 4.05 (q, 2H); 3.38 (m, 1H); 2.33 (s, 3H); 1.82 (m, 2H); 1.55 (m, 2H); 1.31 (m, 6H); 1.02 (t, 3H). LCMS (ES-API): m/z = 434 [M+H] ⁺

6D, 5-(2-(1H-tetrazol-5-yl)phenyl)-1-cyclohexyl-2-methyl-1H-indole-3-carboxylic acid ethyl ester

Intermediate 6C (2.0 g, 4.62 mmol), 2-(tetrazolyl-5-yl)benzeneboronic acid (1.05 g, 5.6 mmol), cesium carbonate (4.52 g, 13.9 mmol), and four were sequentially added to a 50 mL Schlenk bottle. Triphenylphosphine palladium (0.53 g, 0.46 mmol), 20 mL DMF and 2 mL water were then warmed to 90 ° C under N ₂ for 3 h. The reaction mixture was poured into 80 mL of water, and the mixture was adjusted to pH 1 with 10% EtOAc. EtOAc (EtOAc)EtOAc. 3.44 g of a yellow oil was purified by silica gel column chromatography using solvent mixture of EA and hexane as eluent to afford 1.39 g, yield 70.2%. _{^{1 H NMR (400MHz, CDCl 3}} ) δppm: 8.39 (d, 1H); 7.55 (m, 2H); 7.28 (s, 1H); 7.17 (d, 2H); 6.95 (d, 1H); 4.01 (q, 2H); 3.37 (m, 1H); 2.35 (s, 3H); 1.78 (m, 2H); 1.51 (m, 2H); 1.29 (m, 6H); 0.99 (t, 3H). LCMS (ES-API): m/z = 430 [M+H] ⁺

6E, 5-(2-(1H-tetrazol-5-yl)phenyl)-1-cyclohexyl-2-methyl-1H-indole-3-carboxylic acid

Intermediate 6D (1.3 g, 3.03 mmol) and 15 mL of methanol were added to a 100 mL vial, stirred and dissolved, and then 5 mL of 50% KOH solution was added, and then the temperature was raised to 65 ° C for 2 h, and TLC showed that the starting material was completely reacted. The methanol was removed under reduced pressure at 45 ° C, a solid precipitated, 20 mL of water was added to dissolve the solid, pH was adjusted to 5-6 with 10% HCl, a large amount of white solid was precipitated, filtered, and the filter cake was washed with 30 mL of water, and the solid was vacuum at 45 ° C. Drying gave 0.95 g of a white solid, yield 78.0%. _{^{1 H NMR (400MHz, CDCl 3}} ) δppm: 12.89 (s, 1H); 7.97 (d, 1H); 7.55 (d, 2H); 7.17 (m, 3H); 7.05 (s, 1H); 3.34 (m, 1H); 2.31 (s, 3H); 1.70 (m, 2H); 1.45 (m, 2H); 1.48 (m, 6H). LCMS (ES-API): m/z = 400 [MH] ^-

6, 5-(2-(1H-tetrazol-5-yl)phenyl)-N-(4-methylphenyl)-1-cyclohexyl-2-methyl-1H-indole-3-A Amide

Intermediate 6E (0.15 g, 0.37 mmol) and 5 ml of anhydrous dichloromethane were added to a 25 ml vial, and p-methylaniline (0.05 g, 0.45 mmol) and benzotriazol-1-yloxy were added sequentially with stirring. Tris(dimethylamino)phosphonium hexafluorophosphate (BOP reagent, 0.25 g, 0.56 mmol) and diisopropylethylamine (0.15 ml, 0.89 mmol), then reacted at room temperature for 4 h, TLC showed the starting material reaction complete. After adding 15 ml of dichloromethane, the organic layer was separated, washed sequentially with 10% EtOAc EtOAc EtOAc. After purifying by silica gel column chromatography, a white solid (0.16 g) was obtained. ¹ H NMR (400 MHz, CDCl ₃ ) δ ppm: 9.30 (s, 1H); 8.42 (d, 1H); 8.1 (m, 2H); 7.71 (d, 2H); 7.63 (m, 2H); 7.60 (d, 1H); 7.50 (s, 1H); 7.36 (d, 2H); 3.79 (m, 1H); 2.76 (s, 3H); 2.49 (s, 3H); 2.02 (m, 4H); 1.63 (m, 5H) ). LCMS (ES-API): m/z = 491 [M+H] ⁺

Example 7 : 4-Bromo-2-iodoaniline with corresponding

After the cyclization, the intermediate compound 6E is coupled with the corresponding amine using a synthetic method similar to that of the compound 6.

Example 8 : 1-(5-(2-(1H-tetrazol-5-yl)phenyl)-1-cyclohexyl-2-methyl-1H-indol-3-yl)-3-methylphenyl Urea

According to the synthesis method of the compound 6, the intermediate compound 6E and DPPA were formed into an isocyanate, and then reacted with p-methylaniline to give a compound 8 in a yield of 23.8%. _{^{1 H NMR (400MHz, CDCl 3}} ) δppm: 7.87 (d, 1H); 7.39 (m, 4H); 7.07 (d, 2H); 6.97 (m, 3H); 6.72 (d, 1H); 4.07 (m, 1H); 2.28 (s, 3H); 2.23 (s, 3H); 2.10 (m, 2H); 1.93 (m, 2H); 1.80 (m, 2H); 1.42 (m, 2H); 1.27 (m, 2H) ). LCMS (ES-API): m/z = 506 [M+H] ⁺

Evaluation of biological activity of compounds

Experimental materials and instruments

The positive drug INCB024360 was purchased from MedChem Express. The Hela cells were obtained from the cell bank of the Chinese Academy of Sciences. The complete medium was prepared by our laboratory. DPBS, 0.25% Trypsin~EDTA and Trypan Blue were all from Thermo Fisher Scientific (China) Co., Ltd. Gibco ^TM , the microplate reader is Molecular Device's SpectraMax 190, the cell counter is the Countstar of Shanghai Ruiyi Biotech Co., Ltd., and the cell centrifuge is TDL-40B of Shanghai Anting Scientific Instrument Factory.

Reagent

INF-γ (R&D, 28-IF-100) was dissolved in sterile purified water to a concentration of 0.2 mg/mL;

4-dimethylaminobenzaldehyde solution (Sigma, CAT #100107) was formulated with glacial acetic acid (Kelong, CAT #64197) to a concentration of 2% (m/v);

The sample was dissolved in DMSO (Amresco, CAT #N182) to a concentration of 10 mM;

6.1 N trichloroacetic acid (Sigma, CAT #76039).

Cell line and culture conditions

Hela cells were cultured in MEM medium (Gibco), 90%;

Sodium Pyruvate (Gibco), 1 mM;

Fetal bovine serum (Hyclone), 10%;

Streptomycin solution (100×, Hyclone), 1%;

Gas phase: air, 95%; carbon dioxide, 5%;

The temperature is 37 °C.

Determination of IDO enzyme inhibition rate

Hela cells were plated in 96-well plates (2500/well, 200 ul/well), and after overnight adherence, INF-γ was diluted with medium to a final concentration of 50 ng/mL, and then medium containing 50 ng/mL INF-γ. Dilute the drug to 1 uM and 0.1 nM while setting the control: 50 ng/mL INF-γ medium + cell negative control and blank control containing 0.1% DMSO: 50 ng/mL INF-γ medium with only 0.1% DMSO; The original medium of the 96-well plate was aspirated, and 200 ul of the drug group and the control group were added to each well, and three replicate wells were set at each concentration, and the cells were incubated for 48 hours under normal culture conditions. After 48h, absorb 140ul/well of cell culture supernatant in 96-well round bottom plate, add 10ul of 6.1N trichloroacetic acid, mix and place at 50 °C for 30min; then centrifuge at 2500rpm for 10min; absorb 100ul of supernatant in new 96 well flat bottom plate; finally add 100ul 2% 4-dimethylaminobenzaldehyde solution, mix, stand at room temperature for 10min, and test at 480nm.

IDO inhibition rate = [1-(OD drug group - OD blank control group) / (OD negative control group - OD blank control group)] × 100%,

The OD drug group was a drug-added well; the OD-negative control group was a 50 ng/mL INF-γ medium cultured in 0.1% DMSO; the OD blank control group was a 50 ng/mL INF-γ medium without cells in 0.1% DMSO. .

Table 2 Percentage inhibition of IDO by some compounds and positive drugs at different concentrations

IDO kynurenine assay using human IDO cells

Hela cells were plated in 96-well plates (2500/well, 200 ul/well), and after overnight adherence, INF-γ was diluted with medium to a final concentration of

50 ng/mL, then dilute the drug to 1 uM in a medium containing 50 ng/mL INF-γ (10 times down to 5 concentrations to 0.1 nM).

At the same time set the control: 50 ng / mL INF-γ medium containing 0.1% DMSO + cell negative control and blank control: only

50 ng/mL INF-γ medium in 0.1% DMSO; the original medium in 96-well plates was aspirated, and 200 ul of drug group and pair were added per well.

According to the group, 3 replicate wells were set at each concentration, and the cells were incubated for 48 h under normal culture conditions. After 48h, absorb 140ul/well of cell culture

The supernatant was placed in a 96-well round bottom plate, 10 ul of 6.1 N trichloroacetic acid was added, mixed, placed at 50 ° C for 30 min; then at 2500 rpm

Centrifuge for 10 min; draw 100 ul of supernatant into a new 96-well flat bottom plate; finally add 100 ul of 2% 4-dimethylaminobenzaldehyde solution.

Mix well, place at room temperature for 10 min in the dark, detect at 480 nm on the plate reader, and calculate IC ₅₀ using GraphPad prism 5 software.

Table 3 IDO inhibition test results of Compounds 2 and 8

Determination of combined inhibition rate of IDO enzyme inhibitor

Hela cells were plated in 96-well plates (2500/well, 200 ul/well), and after overnight adherence, INF-γ was diluted with medium to a final concentration of 50 ng/mL, and then medium containing 50 ng/mL INF-γ. Dilute the drug, BL0019 and BL0030 are diluted 2 times from 120nM 2 times, INCB 024360 is diluted 2 times from 60nM 2 times; combined administration: BL0019: BL0030=1:1, BL0019: INCB 024360=2:1 , BL0030: INCB 024360 = 2:1, the starting concentration is started according to the single drug concentration, 2 times dilution, a total of 6 concentrations; at the same time set the control: 50 ng / mL INF-γ medium + cell negative with 0.1% DMSO Control and blank control: 50 ng/mL INF-γ medium in 0.1% DMSO; the original medium in 96-well plate was aspirated, 200 ul of drug group and control group were added to each well, and 3 replicate wells were set for each concentration. The cells were incubated for 48 h under normal culture conditions. After 48h, absorb 140ul/well of cell culture supernatant in 96-well round bottom plate, add 10ul of 6.1N trichloroacetic acid, mix and place at 50 °C for 30min; then centrifuge at 2500rpm for 10min; absorb 100ul of supernatant in new 96-well flat bottom plate; finally add 100ul 2% 4-dimethylaminobenzaldehyde solution, mix, stand at room temperature for 10min, avoid detection at 480nm, use Calcusyn software to calculate the CI value of the combination.

Table 4 Results of combined administration

Example number	Fa=50% corresponding CI
2:8	0.92
2: INCB 024360	0.89
8: INCB 024360	0.80

Detection of inhibition of T cell proliferation mediated by IDO expression

Human monocytes were collected from peripheral monocytes by leukocyte isolation, and human monocytes were added with 10% fetal bovine serum and 2 mM L- in 96-well culture plates at a density of 1 × 10 ⁶ cells/well. Glutamine was cultured overnight in RPMI 1640 medium. After adherent cells were retained, they were cultured for 7 days with 250 ng/ml IL-4, 100 ng/ml GM-CSF. The cells were matured for 2 days with a combination of 50 ng/mL INF-γ and 50 μg/mL LPS cytokines to induce dendritic cell maturation. The final concentration was obtained using 100-200 U/mL IL-2, 100 ng/mL anti-CD3 antibody and human RPMI 1640 replacement medium from normal donor human allogeneic T cells and different dilutions of IDO compounds. An IDO inhibitor between 500 and 1 μM was cultured for another two days. BrdU was added to an overnight shock and T cell proliferation was measured using a colorimetric cell proliferation ELISA kit. The cells were continuously cultured for 18 hours in a 10 μM BrdU labeling solution, the labeling medium was removed, 200 μL of FixDenat/well was added, and the mixture was incubated at room temperature for 30 minutes to remove the FixDenat solution, and incubated with 100 μL/well of anti-BrdU-POD antibody conjugate solution. In minutes, remove the antibody conjugate, wash the cells 3 times with 200 μL/well of washing solution, add 100 200 μL/well of substrate solution, read the plate data with a microplate reader, and record multiple readings at different time points to ensure data online. Within the scope of sex. Compounds of the invention having an IC50 of less than about 100 [mu]M are considered to be active compounds.

IDO inhibitory in vivo detection

A mouse CT26 xenograft model of colorectal cancer was established, and a certain concentration of compound 5, compound 161 and INCB024360 (positive drug) were administered to evaluate the effect of each compound on CT26 mouse xenografts. CT26 cells cultured in vitro were inoculated subcutaneously into the back of nude mice. After the tumors were grown, they were randomly divided into 6 groups, 7 to 8 per group. Different drugs were given (except for special instructions, 2 times a day), regular The body weight was measured, the tumor volume was measured, and the efficacy against the CT26 model was evaluated by examining the antitumor efficacy of each compound. The results showed that compound 8 was superior to compound 2 and positive drug, and had certain antitumor effect.

Claims (19)

1. a compound of formula (I) or a stereoisomer, tautomer or pharmaceutically acceptable salt or solvate thereof:

   

   among them:

   R ¹ is an optionally substituted straight or branched alkyl group, a substituted or unsubstituted alkenyl group, a substituted or unsubstituted alkynyl group, a substituted or unsubstituted heteroalkyl group, a substituted or unsubstituted one with or without a hetero atom aryl group, a substituted or unsubstituted cycloalkyl group, a substituted or unsubstituted heterocyclic group, a substituted or unsubstituted alkanoyl group, a substituted or unsubstituted amide group, a substituted or unsubstituted amide alkyl group, Said hetero atom is an oxygen, sulfur or nitrogen atom;

   R ^{2 is} selected from substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted alkoxy, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclic, substituted or Unsubstituted alkynyl group;

   A is a carbon chain with or without a hetero atom, and its structure is -(CH ₂ ) _n -, wherein n = 0 to 5; or -NH(CH ₂ ) _n -, n = 0 to 5, wherein the NH terminal is The ring is connected.

   R ³ is a substituted or unsubstituted aryl group, and the aryl group may be an all-carbon skeleton or a skeleton containing one or more hetero atoms such as oxygen, sulfur, nitrogen, etc.; wherein the substitution on the aryl group may be a mono- or poly-substitution, substitution The group is independently selected from the group consisting of halogen, hydroxy, amino, nitro, cyano, trifluoromethyl, azido, sulfonyl, sulfonylamino, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted Or unsubstituted alkynyl, substituted or unsubstituted heteroalkyl, C ₁ -C ₈ substituted or unsubstituted alkoxy, substituted or unsubstituted aryl, substituted or unsubstituted cycloalkyl, substituted or not Substituted heterocyclic group, substituted or unsubstituted alkanoyl group, substituted or unsubstituted amide group, substituted or unsubstituted amide alkyl group.
2. The compound of claim 1 or a stereoisomer, tautomer or pharmaceutically acceptable salt or solvate thereof, wherein the substituent is independently selected from the group consisting of halogen, hydroxy, amino, nitro, and cyanide. A group, a trifluoromethyl group, an azide group, a sulfonyl group or an acyl group.
3. A compound according to claim 1 or a stereoisomer, tautomer or pharmaceutically acceptable salt or solvate thereof, wherein the alkyl group is a C ₁ -C ₈ substituted or unsubstituted alkyl group, -(CH ₂ ) _n -Ar-, -(CH ₂ ) _n -Cy-, wherein Ar is a substituted or unsubstituted aryl or heteroaryl group, and Cy is a substituted or unsubstituted cycloalkyl or heterocycloalkyl group .
4. A compound according to claim 1 or a stereoisomer, tautomer or pharmaceutically acceptable salt or solvate thereof, wherein the alkenyl group is C containing one or more -(C=C)- _2- C ₈ alkyl group.
5. A compound according to claim 1 or a stereoisomer, tautomer or pharmaceutically acceptable salt or solvate thereof, wherein the alkynyl group is C containing one or more -(C≡C)- _2- C ₈ alkyl group.
6. A compound according to claim 1 or a stereoisomer, tautomer or pharmaceutically acceptable salt or solvate thereof, wherein the heteroalkyl group contains one or more atoms other than carbon (oxygen, A substituted or unsubstituted C ₁ -C ₈ chain alkyl group of sulfur or a nitrogen atom.
7. A compound according to claim 1 or a stereoisomer, tautomer or pharmaceutically acceptable salt or solvate thereof, wherein the alkoxy group is -OR ⁴ , wherein R ⁴ is a straight chain or a branched chain. Substituted or unsubstituted C ₁ -C ₈ alkyl, alkenyl or alkynyl.
8. A compound according to claim 1 or a stereoisomer, tautomer or pharmaceutically acceptable salt or solvate thereof, wherein the aryl group is an all carbon skeleton or contains one or more oxygen and sulfur. a skeleton of a hetero atom such as nitrogen, which may have one or more substituents thereon, and in some cases, any two adjacent substituents may form a C ₁ -C _{6 group} with or without a hetero atom (oxygen, sulfur or Ring structure of nitrogen).
9. A compound according to claim 1, or a stereoisomer, tautomer or pharmaceutically acceptable salt or solvate thereof, wherein the cycloalkyl group is a C ₃ -C ₇ carbocyclic group.
10. A compound according to claim 1 or a stereoisomer, tautomer or pharmaceutically acceptable salt or solvate thereof, wherein the heterocyclic group is one or more atoms other than carbon (oxygen, A substituted or unsubstituted C ₃ -C ₇ carbocyclic group of sulfur or a nitrogen atom.
11. A compound according to claim 1 or a stereoisomer, tautomer or pharmaceutically acceptable salt or solvate thereof, wherein the alkanoyl group is -(C=O)-R ⁵ , wherein R ⁵ is A linear or branched, substituted or unsubstituted C ₁ -C ₇ alkyl group.
12. A compound according to claim 1 or a stereoisomer, tautomer or pharmaceutically acceptable salt or solvate thereof, wherein the amide group is -(C=O)-NH-R ⁶ wherein R ⁶ is a hydrogen, a straight or branched, substituted or unsubstituted C ₁ -C ₇ alkyl group.
13. A compound according to claim 1 or a stereoisomer, tautomer or pharmaceutically acceptable salt or solvate thereof, wherein the amide alkyl group is -R ⁷ -(C=O)-NH-R ⁸ wherein R ⁷ is a linear or branched substituted or unsubstituted C ₁ -C ₇ alkyl group, and R ⁸ is a hydrogen, straight or branched substituted or unsubstituted C ₁ -C ₅ alkyl group.
14. A compound according to claim 1 or a stereoisomer, tautomer or pharmaceutically acceptable salt or solvate thereof, wherein the sulfonyl group is a substituted or unsubstituted C ₁ -C ₆ alkylsulfonyl group. .
15. A compound according to claim 1 or a stereoisomer, tautomer or pharmaceutically acceptable salt or solvate thereof, characterized in that R ³ is a substituted or unsubstituted phenyl group or contains one or A six-membered aromatic group of a plurality of heteroatoms, wherein the hetero atom is N, O or S.
16. A compound according to claim 10, or a stereoisomer, tautomer or pharmaceutically acceptable salt or solvate thereof, which has the structural formula of formula (II):

    

    among them:

    R ¹ is an optionally substituted straight or branched alkyl group, a substituted or unsubstituted alkenyl group, a substituted or unsubstituted alkynyl group, a substituted or unsubstituted heteroalkyl group, a substituted or unsubstituted one with or without a hetero atom aryl group, a substituted or unsubstituted cycloalkyl group, a substituted or unsubstituted heterocyclic group, a substituted or unsubstituted alkanoyl group, a substituted or unsubstituted amide group, a substituted or unsubstituted amide alkyl group, the aforementioned The hetero atom is an oxygen, sulfur or nitrogen atom;

    R ^{2 is} selected from substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted alkoxy, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclic, substituted or Unsubstituted alkynyl group;

    N is selected from 0 to 5;

    R ³ is a substituted or unsubstituted aromatic phenyl group or a six-membered aromatic group containing one or more hetero atoms (nitrogen, oxygen or sulfur), wherein the substitution on the aryl group may be a mono- or poly-substitution, and the substituents are independently Selected from halogen, hydroxy, amino, nitro, cyano, trifluoromethyl, azido, sulfonyl, sulfonylamino, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted Alkynyl, substituted or unsubstituted heteroalkyl, C ₁ -C ₈ substituted or unsubstituted alkoxy, substituted or unsubstituted aryl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted A cycloalkyl, substituted or unsubstituted alkanoyl group, a substituted or unsubstituted amide group, a substituted or unsubstituted amide alkyl group.
17. A compound according to claim 11 or a stereoisomer, tautomer or pharmaceutically acceptable salt or solvate thereof, which has the structural formula of formula (III):

    

    among them:

    R ¹ is an optionally substituted straight or branched alkyl group, a substituted or unsubstituted alkenyl group, a substituted or unsubstituted alkynyl group, a substituted or unsubstituted heteroalkyl group, a substituted or unsubstituted one with or without a hetero atom aryl group, a substituted or unsubstituted cycloalkyl group, a substituted or unsubstituted heterocyclic group, a substituted or unsubstituted alkanoyl group, a substituted or unsubstituted amide group, a substituted or unsubstituted amide alkyl group, the aforementioned The hetero atom is an oxygen, sulfur or nitrogen atom;

    R ^{2 is} selected from substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted alkoxy, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclic, substituted or Unsubstituted alkynyl group;

    N is selected from 0 to 5;

    R ³ is a substituted or unsubstituted aromatic phenyl group or a six-membered aromatic group containing one or more hetero atoms (nitrogen, oxygen or sulfur), wherein the substitution on the aryl group may be a mono- or poly-substitution, and the substituents are independently Selected from halogen, hydroxy, amino, nitro, cyano, trifluoromethyl, azido, sulfonyl, sulfonylamino, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted Alkynyl, substituted or unsubstituted heteroalkyl, C ₁ -C ₈ substituted or unsubstituted alkoxy, substituted or unsubstituted aryl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted A cycloalkyl, substituted or unsubstituted alkanoyl group, a substituted or unsubstituted amide group, a substituted or unsubstituted amide alkyl group.
18. A compound according to any one of claims 1 to 17, or a stereoisomer, tautomer or pharmaceutically acceptable salt or solvate thereof, for treating cancer, inflammation, cardiovascular disease, neurodegenerative disease, spirit Use of sexually transmitted diseases, viral infections, autoimmune diseases, or other chronic diseases associated with disorders of tryptophan metabolism.
19. A pharmaceutical composition comprising a compound according to any one of claims 1-17, or a stereoisomer, tautomer or pharmaceutically acceptable salt or solvate thereof.

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