WO2019228170A1 - Octahydropentene compound, preparation method therefor, and pharmaceutical application thereof - Google Patents

Abstract

Disclosed are an octahydropentene compound for regulating or inhibiting indoleamine 2,3-dioxygenase (IDO) activity, a preparation method therefor, and a pharmaceutical application thereof. Specifically, disclosed are a compound of formula (I) and pharmaceutically acceptable salts thereof, a pharmaceutical composition containing the compound or pharmaceutically acceptable salts thereof, a method for treating and/or preventing IDO-mediated related diseases, especially tumors, by applying the compound or pharmaceutically acceptable salts thereof, and a preparation method for the compound or pharmaceutically acceptable salts thereof. Also disclosed is use of the compound or pharmaceutically acceptable salts thereof or a pharmaceutical composition containing the compound or pharmaceutically acceptable salts thereof in the preparation of drugs for treating and/or preventing IDO-mediated related diseases, especially tumors. The definition of each substituent in formula (I) is the same as that in the description.

Description

Octahydropentalene compounds, preparation method thereof and application in medicine Technical field

The present invention relates to a novel octahydropentadiene-containing compound or a pharmaceutically acceptable salt thereof which regulates or inhibits the activity of indoleamine 2,3-dioxygenase (IDO), or contains the compound or a pharmaceutically acceptable salt thereof. A pharmaceutical composition of a salt, a method for preparing the compound or a pharmaceutically acceptable salt thereof, and a pharmaceutical composition containing the compound or a pharmaceutically acceptable salt thereof or a pharmaceutically acceptable salt thereof are prepared. Use in a medicament for the treatment and / or prevention of IDO-mediated related disorders, particularly tumors, and methods of using the same.

Background technique

Indoleamine 2,3-dioxygenase (IDO) is a heme-containing monomeric protein that is widely distributed in tissues other than the liver. It catalyzes the oxidative degradation of tryptophan to kynurenine, which is canine urine. The rate-limiting enzyme of the amino acid metabolic pathway. Tryptophan is an essential amino acid for T cell proliferation and is also a precursor substance for the synthesis of neurotransmitters. If the tryptophan concentration in the cell microenvironment is reduced and the kynurenine level is increased, T cells will stagnate in the middle stage of G1, which will affect the proliferation, differentiation and activity of T cells.

IDO is expressed at a low level in normal cells, but it is overexpressed in many tumor tissues, leading to abnormal tryptophan metabolism in the tumor and the formation of regulatory T cells, which in turn mediates the local T cell immune tolerance in tumors. Played an important role in the process of occurrence, development and transfer. If IDO activity is inhibited, tryptophan metabolism around tumor cells is effectively prevented, which can promote the growth of T cells, thereby enhancing the body's immune system's ability to fight tumors. Therefore, the research and development of IDO inhibitors has become the forefront of research on tumor immunotherapy drugs. Preclinical studies have shown that a single administration of INCO-024360, a selective inhibitor of IDO, can effectively suppress plasma IDO activity in blank mice at the level of IDO-deficient mice, and repeated administration hinders the expansion of CT26 tumors (Koblish et al., 2014). al, Mol. Cancer Ther. 2010, 9, 489-98).

IDO inhibitors can also be combined with other anti-tumor small molecule drugs and immune checkpoint inhibitors, such as CTLA-4, PD-1 and PD-L1 antibodies, to enhance the anti-tumor efficacy of the drug. The combined immunotherapy of small molecule IDO inhibitors and immune checkpoint inhibitors is in clinical trials, such as indoximod / ipilimumab, epacadostat / pembrolizumab, epacadostat / nivolumab, indoximod / MEDI-4736, etc. Preliminary clinical results show that the combination of IDO small molecule inhibitors and PD-1 has additional effects, achieves good disease control rates in a variety of tumor treatments, and has fewer side effects than PD-1 / CTLA-4, showing a broad tumor Prospects for immunotherapy (AACR, 2017; ASCO, 2017).

In addition to cancer, IDO is also associated with many other diseases, such as immunosuppression, chronic infections, viral infections, autoimmune diseases or conditions (such as rheumatoid arthritis), neurological or neuropsychiatric diseases or conditions (such as depression), and the like. Therefore, IDO inhibitors have great therapeutic value.

At present, small molecule IDO inhibitor drugs are still in clinical trials. In addition to INCY-024360 (epacadostat) of Incyte, Indoximod of NewLink Genetics and BMS-986205 of Bristol-Myers Squibb.

The development of IDO inhibitors has attracted the attention of many biopharmaceutical companies due to the prospects shown by them in the treatment of various tumors and other diseases individually and in combination with immunotherapy. A series of patent applications for IDO inhibitors have been published, including WO2006122150A1 , WO2011056652A1, WO2013069765A1, WO2014186035A1, WO2015002918A1, WO2016073738A2, WO2016073770A1, WO2016181348A1, WO2016161960A1, WO2017079669A1, etc., but there is still a need to develop new compounds that have better drugability and higher response rates in immunotherapy. Through continuous efforts, the present invention has designed compounds having a structure represented by the general formula (I), and found that compounds having such a structure exhibit excellent effects and effects of inhibiting IDO activity.

Summary of the Invention

The present invention provides a compound represented by the general formula (I) as an IDO inhibitor:

Or pharmaceutically acceptable salts, prodrugs, stable isotope derivatives, isomers and mixtures thereof, wherein:

Ring D is an optionally substituted benzene ring or a 5-6 membered heteroaryl ring;

R ¹ and R ² are each independently selected from H or optionally substituted C _1-4 alkyl, C _3-6 cycloalkyl, or 4-7 membered heterocyclyl; or, R ¹ and R ² and the attached carbon The atoms together form a 3-7 membered ring optionally containing heteroatoms selected from O, N and S;

R ³ and R ⁴ are each independently selected from H or C _1-4 alkyl;

A is N or CR ⁵ ;

B is N or CR ⁶ ;

L is a bond, -O- or -CR ⁷ R ^8- ;

C is optionally substituted 4-7 membered heterocyclic group, 6-10 membered aryl group or 5-10 membered heteroaryl group;

R ⁵ and R ⁶ are each independently selected from H, halogen, OH, or optionally substituted C _1-4 alkyl or -OC _1-4 alkyl;

R ⁷ and R ⁸ are each independently selected from H or optionally substituted C _1-4 alkyl.

An embodiment of the present invention relates to a compound represented by the above-mentioned general formula (I) or a pharmaceutically acceptable salt, prodrug, stable isotope derivative, isomer thereof, and a mixture thereof, wherein:

Ring D is an optionally substituted benzene ring or a 6-membered heteroaryl ring;

R ¹ and R ² are each independently selected from H or optionally substituted C _1-4 alkyl;

R ³ and R ⁴ are each independently selected from H or CH ₃ ;

A is N or CH;

B is N or CH;

L is a bond or -O-;

C is a 4-7 membered heterocyclic group, a 6-10 membered aryl group, or a 5-10 membered heteroaryl group optionally substituted with halogen, cyano, C _1-4 alkyl, or halogenated C _1-4 alkyl.

Another embodiment of the present invention relates to the compound according to any one of the above embodiments, or a pharmaceutically acceptable salt, prodrug, stable isotope derivative, isomer thereof, and a mixture thereof, the compound having the general formula (II) Compound shown:

among them:

Ring D is an optionally substituted benzene ring or a pyridine ring;

R ¹ and R ² are each independently selected from H or C _1-4 alkyl;

A is N or CH;

C is a 5-10 membered heteroaryl group optionally substituted with halogen, cyano, C _1-4 alkyl, or halo C _1-4 alkyl.

Another embodiment of the present invention relates to a compound or a pharmaceutically acceptable salt, prodrug, stable isotope derivative, isomer thereof, or a mixture thereof according to any one of the above embodiments, wherein ring D is optionally halogen, Cyano, -SF ₅ , C _1-4 alkyl, halo C _1-4 alkyl, -OC _1-4 alkyl or -O-halo C _1-4 alkyl substituted benzene ring or pyridine ring.

Another embodiment of this invention is directed to a compound according to any one of the preceding embodiments, wherein C is a quinolinyl group optionally substituted with halogen, cyano, C _1-4 alkyl or halo C _1-4 alkyl Pyridyl, especially fluoroquinolinyl.

Another embodiment of this invention is directed to a compound according to any one of the above embodiments, wherein R ¹ is C _1-4 alkyl and R ² is H, especially R ¹ is methyl and R ² is H.

Another embodiment of this invention is directed to a compound according to any one of the above embodiments, which is a compound of the following general formulae (IIIa)-(IIIc):

Another embodiment of this invention is directed to a compound according to any one of the above embodiments, which is a compound of the following general formula (IV):

Another embodiment of the present invention relates to a compound represented by the above-mentioned general formula (IV), wherein R ¹ is a methyl group.

One embodiment of the present invention relates to a compound represented by the above general formula (I), wherein the compound is selected from:

Or its prodrugs, stable isotope derivatives, pharmaceutically acceptable salts, isomers and mixtures thereof.

The compound of the present invention has a significant inhibitory effect on the activity of IDO in Hela cells, and preferably has an IC _{50 of} less than 200 nM, and more preferably an IC _{50 of} less than 50 nM.

The compounds of the invention are therefore useful in the treatment or prevention of IDO-mediated related diseases, including but not limited to cancer, immunosuppression, chronic infection, viral infection, autoimmune disease or disorder (e.g. rheumatoid arthritis), neurological or neuropsychiatric Diseases or conditions (e.g. depression) and the like. The compounds of the present invention are used to treat or prevent IDO-related tumors, including, but not limited to, prostate cancer, colon cancer, rectal cancer, glandular cancer, cervical cancer, gastric cancer, endometrial cancer, brain cancer, liver cancer, bladder cancer, ovary Cancer, testicular cancer, head and neck cancer, skin cancer (including melanoma and basal cancer), mesothelioma, lymphoma, leukemia, esophageal cancer, breast cancer, muscle cancer, connective tissue cancer, lung cancer (including small cell lung cancer and (Non-small cell cancer), adrenal cancer, thyroid cancer, kidney cancer, bone cancer, glioblastoma, mesothelioma, sarcoma (including Kaposi's sarcoma), choriocarcinoma, skin basal cell carcinoma, or testicular seminoma Tumor and so on. Therefore, in another aspect, the present invention provides a method for treating or preventing an IDO-mediated disease (such as the tumor), which comprises administering to a patient in need thereof a therapeutically effective amount of a compound of the present invention or a pharmaceutically acceptable Salts, prodrugs, stable isotope derivatives, isomers and mixtures thereof, or pharmaceutical compositions comprising said compounds.

Another aspect of the present invention relates to a compound represented by the general formula (I) or a pharmaceutically acceptable salt thereof, a prodrug, a stable isotope derivative, an isomer, and a mixture thereof, which is used as a medicine or for medical use. Treat or prevent IDO-mediated diseases, such as cancer, immunosuppression, chronic infections, viral infections, autoimmune diseases or conditions (such as rheumatoid arthritis), neurological or neuropsychiatric diseases or conditions (such as depression), and the like.

The invention further relates to a pharmaceutical composition comprising the compound of the invention or a pharmaceutically acceptable salt thereof, a prodrug, a stable isotope derivative, an isomer and a mixture thereof, and a pharmaceutically acceptable carrier And excipients.

Another aspect of the present invention relates to a compound represented by the general formula (I) or a pharmaceutically acceptable salt, prodrug, stable isotope derivative, isomer and mixture thereof, or a pharmaceutical composition in the preparation of a medicament. Use, wherein the medicament is used to treat or prevent IDO-mediated diseases such as tumors and immunosuppression.

Another aspect of the present invention relates to a pharmaceutical composition comprising a compound represented by the general formula (I) or a pharmaceutically acceptable salt thereof, a prodrug, a stable isotope derivative, an isomer, and a mixture thereof And at least one additional drug, wherein the at least one additional drug is a chemotherapeutic agent, an immune and / or inflammation modulator (such as an immune checkpoint inhibitor), a neuro-related disease modulator, or an anti-infective agent.

According to the present invention, the medicament may be any pharmaceutical dosage form, including but not limited to tablets, capsules, solutions, lyophilized preparations, injections.

The pharmaceutical preparation of the present invention may be administered in the form of a dosage unit containing a predetermined amount of an active ingredient per dosage unit. Such a unit may contain, for example, 0.5 mg to 1 g, preferably 1 mg to 700 mg, and particularly preferably 5 mg to 300 mg of a compound of the present invention depending on the condition to be treated, the method of administration and the age, weight and condition of the patient. Preferred dosage unit formulations are those containing the daily or divided dose or active fraction thereof as indicated above. In addition, this type of pharmaceutical preparation can be prepared using methods known in the pharmaceutical art.

The pharmaceutical formulations of the present invention may be suitable for administration by any desired suitable method, such as by oral (including oral or sublingual), rectal, nasal, topical (including oral, sublingual or transdermal), vaginal or parenteral (Including subcutaneous, intramuscular, intravenous or intradermal) methods. Such formulations can be prepared using all methods known in the pharmaceutical art, for example, by combining the active ingredient with one or more excipients or one or more adjuvants.

Detailed ways

Unless stated to the contrary, the following terms used in the specification and claims have the following meanings.

The expression “C _xy ” used herein means the range of the number of carbon atoms, where x and y are integers, for example, C _3-8 cycloalkyl represents a cycloalkyl group having 3-8 carbon atoms, that is, having 3 , 4, 5, 6, 7, or 8 carbon atom cycloalkyl. It should also be understood that " _C3-8 " also includes any sub-ranges thereof, such as _C3-7 , _C3-6 , _C4-7 , _C4-6 , _C5-6, and the like.

"Alkyl" refers to a saturated straight or branched chain hydrocarbon group containing 1 to 20 carbon atoms, such as 1 to 8 carbon atoms, 1 to 6 carbon atoms, or 1 to 4 carbon atoms. Non-limiting examples of alkyl include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1,1-dimethylpropyl Methyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl 2-methylpropyl, 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1,3-dimethylbutyl and 2-ethylbutyl. The alkyl group may be optionally substituted.

"Cycloalkyl" refers to a saturated cyclic hydrocarbon substituent having 3 to 14 carbon ring atoms. A cycloalkyl group can be a single carbocyclic ring and typically contains 3 to 8, 3 to 7, or 3 to 6 carbon ring atoms. Non-limiting examples of monocyclic cycloalkyl include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cycloheptyl. Cycloalkyl can optionally be bi or tricyclic fused together, such as decahydronaphthyl. The cycloalkyl group may be optionally substituted.

"Heterocyclyl or heterocyclic" refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic group, which includes 3 to 20 ring atoms, and may be 3 to 14, 3 to 12, 3 to 10, for example Three, eight, three to six, or five to six ring atoms, one or more of which are selected from nitrogen, oxygen, or S (O) _m (where m is an integer from 0 to 2), but does not include The ring part of -OO-, -OS- or -SS-, and the remaining ring atoms are carbon. It preferably includes 3 to 12 ring atoms, more preferably 3 to 10 ring atoms, more preferably 4 to 7 ring atoms, and most preferably 5 or 6 ring atoms, of which 1 to 4 are heteroatoms, and more preferably 1 to 3 Are heteroatoms, and most preferably one or two are heteroatoms. Non-limiting examples of monocyclic heterocyclyl include pyrrolidinyl, piperidinyl, piperazinyl, pyranyl, morpholinyl, thiomorpholinyl, homopiperazinyl, oxetanyl, and nitrogen Heterocycloalkyl. Polycyclic heterocyclyls include fused, bridged, or spiro polycyclic heterocyclyls, such as octahydrocyclopentadieno [c] pyrrole, octahydropyrrolo [1,2-a] pyrazine, 3,8-bis Azabicyclo [3.2.1] octane, 5-azaspiro [2.4] heptane, 2-oxa-7-azaspiro [3.5] nonane, etc. The heterocyclyl or heterocyclic ring may be optionally substituted.

"Aryl or aromatic ring" refers to an aromatic monocyclic or fused polycyclic group containing 6 to 14 carbon atoms, preferably 6 to 10 members, such as phenyl and naphthyl, and most preferably phenyl. The aryl ring may be fused to a heteroaryl, heterocyclic or cycloalkyl ring, wherein the ring connected to the parent structure is an aryl ring, and non-limiting examples include:

The aryl or aromatic ring may be optionally substituted.

"Heteroaryl or heteroaryl ring" refers to a heteroaromatic system containing 5 to 14 ring atoms, wherein 1 to 4 ring atoms are selected from heteroatoms including oxygen, sulfur, and nitrogen. Heteroaryl is preferably 5 to 10 members. More preferably heteroaryl is 5- or 6-membered, such as furyl, thienyl, pyridyl, pyrrolyl, N-alkylpyrrolyl, pyrimidinyl, pyrazinyl, pyrazolyl, imidazolyl, tetrazolyl, Oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, quinolinyl and the like. The heteroaryl ring may be fused to an aryl, heterocyclic or cycloalkyl ring, wherein the ring connected to the parent structure is a heteroaryl ring, and non-limiting examples include:

The heteroaryl or heteroaryl ring may be optionally substituted.

"Halogen" means fluorine, chlorine, bromine or iodine.

"Cyano" refers to -CN.

"Optional" means that the event or environment described later can, but need not, occur, and that expression includes situations where the event or environment occurs or does not occur. For example, "an heterocyclic group optionally substituted with an alkyl group" means that an alkyl group may but need not exist, and the expression includes a case where the heterocyclic group is substituted with an alkyl group and a case where the heterocyclic group is not substituted with an alkyl group .

"Optionally substituted" refers to one or more hydrogen atoms in a group, preferably 5 and more preferably 1 to 3 hydrogen atoms, independently of one another, with a corresponding number of substituents. It goes without saying that the substituents are only at their possible chemical positions, and those skilled in the art can determine (by experiment or theory) possible or impossible substitutions without undue effort. For example, an amino or hydroxyl group with free hydrogen may be unstable when combined with a carbon atom having an unsaturated (eg, olefinic) bond. The substituents include, but are not limited to, halogen, cyano, nitro, oxo, -SF ₅ , C _1-4 alkyl, C _3-7 cycloalkyl, 4-7 membered heterocyclyl, phenyl, 5 -6 membered heteroaryl, -OR ', -NR'R ", -C (O) R', -C (O) OR ', -C (O) NR'R", -C (O) N ( R ′) OR ″, -OC (O) R ′, -OC (O) NR′R ″, -N (R ′) C (O) OR ″, -N (R ′) C (O) R ″, -N (R ′ ″) C (O) NR′R ″, -N (R ′) S (O) ₂ R ″, -S (O) _m R ′ (m is 1 or 2), -S (O ) ₂ NR'R "and the like, wherein said alkyl, cycloalkyl, heterocyclyl, phenyl or heteroaryl is optionally substituted with one or more groups selected from halo, cyano, C _{1- 4} alkyl, C _3-7 cycloalkyl, 4-7 membered heterocyclic group, phenyl, 5-6 membered heteroaryl, -OR ', -NR'R ", -C (O) R', -C (O) OR ′, -C (O) NR′R ″, -OC (O) NR′R ″, -N (R ′) C (O) OR ″, -N (R ′) C (O) R ″, -N (R ′ ″) C (O) NR′R ″, -N (R ′) S (O) ₂ R ″, -S (O) ₂ R ′, -S (O) ₂ NR′R ″ and other substituents Substituted. R ′, R ″, and R ′ ″ are each independently selected from H, C _1-4 alkyl, C _3-7 cycloalkyl, optionally containing heteroatoms selected from N, O, and S, 4- 7-membered heterocyclyl, phenyl, or 5- to 6-membered heteroaryl, wherein the alkane Group, cycloalkyl, heterocyclyl, phenyl or heteroaryl is optionally selected from one or more of halogen, cyano, C _1-4 alkyl, halo C _1-4 alkyl, -OC _{1- 4} alkyl and other substituents; R ′ and R ″ on the same nitrogen atom are optionally combined with the nitrogen atom to which they are attached to form a 4- atom optionally containing another heteroatom selected from O, S and N 7-membered heterocyclic ring.

"Isomer" refers to a compound that has the same molecular formula but differs in the form or order in which its atoms are bound or the arrangement of their atoms in space. Isomers whose atomic arrangement is different are called "stereoisomers". Stereoisomers include optical isomers, geometric isomers, and conformers.

The compounds of the invention may exist as optical isomers. Depending on the configuration of the substituents around the chiral carbon atom, these optical isomers are in the "R" or "S" configuration. Optical isomers include enantiomers and diastereomers. Methods for preparing and separating optical isomers are known in the art.

The compounds of the invention may also exist as geometric isomers. The present invention contemplates various geometric isomers and mixtures thereof resulting from the distribution of substituents around carbon-carbon double bonds, carbon-nitrogen double bonds, cycloalkyl or heterocyclic groups. The substituents around the carbon-carbon double bond or carbon-nitrogen bond are designated as the Z or E configuration, and the substituents around the cycloalkyl or heterocyclic ring are designated as the cis or trans configuration.

The compounds of the invention may also exhibit tautomerism, such as keto-enol tautomerism.

It should be understood that the present invention includes any tautomeric or stereoisomeric form and mixtures thereof, and is not limited to any one of the tautomeric or stereoisomeric forms used in the nomenclature or chemical structural formula of the compound.

"Isotopes" include all isotopes of the atoms present in the compounds of the invention. Isotopes include those atoms that have the same atomic number but different mass numbers. Examples of isotopes suitable for incorporation in the compounds of the invention are hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine and chlorine, such as, but not limited to, ² H, ³ H, ¹³ C, ¹⁴ C, ¹⁵ N, ¹⁸ O, ¹⁷ O, ³¹ P, ³² P, ³⁵ S, ¹⁸ F, and ³⁶ Cl. Isotopically-labeled compounds of the invention can generally be prepared by conventional techniques known to those skilled in the art or by methods similar to those described in the appended examples, using appropriate isotopically-labeled reagents instead of non-isotopically-labeled reagents. Such compounds have a variety of potential uses, such as standards and reagents in determining biological activity. In the case of stable isotopes, such compounds have the potential to beneficially alter biological, pharmacological or pharmacokinetic properties.

"Prodrug" means that a compound of the invention can be administered in the form of a prodrug. Prodrugs refer to derivatives of biologically active compounds of the present invention that are transformed under physiological conditions in vivo, such as by oxidation, reduction, hydrolysis, etc. (they are each performed with or without the participation of an enzyme). Examples of prodrugs are compounds in which an amino group in a compound of the invention is acylated, alkylated, or phosphorylated, such as eicosanoylamino, alanylamino, pivaloyloxymethylamino, or Where the hydroxyl group is acylated, alkylated, phosphorylated, or converted to a borate such as acetoxy, palmitoyloxy, pivaloyloxy, succinyloxy, fumaroyloxy, alanyloxy Group, or where the carboxyl group is esterified or amidated, or where the thiol group forms a disulfide bridge with a carrier molecule, such as a peptide, that selectively delivers the drug to the target and / or to the cytosol of the cell. These compounds can be prepared from a compound of the present invention according to a known method.

"Pharmaceutically acceptable salt" or "pharmaceutically acceptable salt" refers to a salt made from a pharmaceutically acceptable base or acid, including an inorganic base or acid and an organic base or acid. Where the compounds of the invention contain one or more acidic or basic groups, the invention also includes their corresponding pharmaceutically acceptable salts. Thus, the compounds of the invention containing acidic groups can exist in the form of salts and can be used according to the invention, for example as alkali metal salts, alkaline earth metal salts or as ammonium salts. More specific examples of such salts include sodium, potassium, calcium, magnesium, or salts with ammonia or organic amines, such as ethylamine, ethanolamine, triethanolamine, or amino acids. The compounds of the invention containing basic groups may exist in the form of salts and may be used according to the invention in the form of their addition salts with inorganic or organic acids. Examples of suitable acids include hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, nitric acid, methanesulfonic acid, p-toluenesulfonic acid, naphthalenedisulfonic acid, oxalic acid, acetic acid, tartaric acid, lactic acid, salicylic acid, benzoic acid, formic acid, propylene Acid, pivalic acid, malonic acid, succinic acid, pimelic acid, fumaric acid, maleic acid, malic acid, sulfamic acid, phenylpropionic acid, gluconic acid, ascorbic acid, isonicotinic acid, citric acid, Adipic acid and other acids known to those skilled in the art. If the compounds of the invention contain both acidic and basic groups in the molecule, the invention includes, in addition to the salt forms mentioned, internal salts or internal ammonium salts. Each salt can be obtained by conventional methods known to those skilled in the art, such as by contacting these with organic or inorganic acids or bases in a solvent or dispersant or by anion exchange or cation exchange with other salts.

"Pharmaceutical composition" refers to a compound containing one or more of the compounds described herein, or a pharmaceutically acceptable salt, prodrug, stable isotope derivative, isomer and mixture thereof, and other components such as a pharmaceutically acceptable carrier And excipient composition. The purpose of the pharmaceutical composition is to promote the administration to the organism, which is beneficial to the absorption of the active ingredient and then exerts the biological activity.

Therefore, when referring to "compounds", "compounds of the present invention" or "compounds of the present invention" in this application, all such compound forms are included, such as their pharmaceutically acceptable salts, prodrugs, stable isotope derivatives , Isomers and mixtures thereof.

As used herein, the term "tumor" includes benign and malignant tumors (eg, cancer).

As used herein, the term "therapeutically effective amount" means an amount that includes a compound of the invention that is effective to inhibit the function of IDO and / or treat or prevent the disease.

resolve resolution

The present invention also provides a method for preparing the compound. The preparation of the compound of the general formula (I) of the present invention can be accomplished by the following exemplary methods and examples, but these methods and examples should not be considered as limiting the scope of the present invention in any way. The compounds of the present invention can also be synthesized by synthetic techniques known to those skilled in the art, or a method known in the art and a method of the present invention can be used in combination. The products obtained in each step are obtained using separation techniques known in the art, including, but not limited to, extraction, filtration, distillation, crystallization, chromatographic separation, and the like. The starting materials and chemical reagents required for the synthesis can be routinely synthesized or purchased according to the literature (available from SciFinder).

The octahydropentadiene compound of the general formula (I) of the present invention can be synthesized according to the route described in Method A: firstly, the intermediate acid A2 is changed into an acid chloride or activated with an amide condensing agent, and then the (hetero) arylamine A1 Coupling gave the target amide compound A3.

Method A:

The achiral intermediate acid A2 is synthesized according to the conventional method; the chiral intermediate acid A2 can be synthesized according to the route described in Method B: one ketone in B1 is protected with ethylene glycol, and the other ketone is reacted with trifluoro under basic conditions Methanesulfonic anhydride reacts to form alkenyl trifluoromethanesulfonate B2; B2 and borate or CB (OR) _{2 are} obtained by Suzuki coupling reaction to obtain B3, which is reduced to hydrogenation and deprotected to form B4; B4 undergoes Wittig reaction Monoene is formed (the ester is hydrolyzed to acid in the reaction, otherwise alkali is added to promote ester hydrolysis), and then hydrogenated to obtain acid B5; B5 first forms acid anhydride with acid chloride (such as pivaloyl chloride) under base catalysis, and is then used as a chiral auxiliary (Lithium salt of ((R) -4-benzyloxazolidin-2-one)) is substituted to form B6; B6 is dehydrogenated with a strong base, and then reacted with methyl iodide to obtain B7, and finally hydrolyzed under base to obtain acid A2.

Method B:

Examples

The structure of the compound is determined by nuclear magnetic resonance (NMR) or mass spectrometry (MS). The NMR measurement was performed using a Bruker ASCEND-400 nuclear magnetic analyzer. The measurement solvents were deuterated dimethyl sulfoxide (DMSO-d ₆ ), deuterated chloroform (CDC1 ₃ ), and deuterated methanol (CD ₃ OD). For methylsilyl (TMS), the chemical shift is given in units of 10 ^-6 (ppm).

The MS was measured using an Agilent SQD (ESI) mass spectrometer (manufacturer: Agilent, model: 6120).

For HPLC measurement, an Agilent 1260DAD high pressure liquid chromatography (Poroshell 120EC-C18, 50 × 3.0 mm, 2.7 μm column) or a Waters Arc high pressure liquid chromatography (Sunfirc C18, 150 × 4.6 mm, 5 μm column) was used.

The thin-layer chromatography silica gel plate uses Qingdao Ocean GF254 silica gel plate. The thin-layer chromatography (TLC) silica gel plate uses a size of 0.15 to 0.2mm. The thin-layer chromatography separation and purification product uses a size of 0.4 to 0.5mm silica gel plate. .

Column chromatography generally uses Qingdao Ocean 200-300 mesh silica gel as the carrier.

The known starting materials of the present invention can be synthesized by or in accordance with methods known in the art, or can be purchased from ABCR GmbH & Co. KG, Acros Organics, Aldrich Chemical Company, Accela ChemBio Inc., Beijing Coupling chemicals and other companies.

Unless otherwise specified in the examples, the reaction is performed in an argon atmosphere or a nitrogen atmosphere.

An argon or nitrogen atmosphere means that the reaction flask is connected to an argon or nitrogen balloon with a volume of about 1 L.

The hydrogen atmosphere means that a reaction balloon is connected to a hydrogen balloon with a volume of about 1 L.

The hydrogenation reaction is usually evacuated and charged with hydrogen, and the operation is repeated 3 times.

For the microwave reaction, a CEM Discover-SP microwave reactor was used.

Unless otherwise specified in the examples, the reaction temperature is room temperature, and the temperature range is 20 ° C-30 ° C.

The reaction progress in the examples was monitored using an Agilent LC / MS instrument (1260/6120). The reaction progress can also be monitored by thin-layer chromatography (TLC). The systems used as the eluent are A: dichloromethane and methanol; B: petroleum ether and ethyl acetate. The volume ratio of the solvent depends on the polarity of the compound. Adjust differently.

The eluent system for column chromatography and the eluent system for thin-layer chromatography used to purify compounds include A: dichloromethane and methanol systems; B: petroleum ether and ethyl acetate systems. It can be adjusted by different polarities. It can also be adjusted by adding a small amount of triethylamine and acidic or alkaline reagents, or using other solvent systems. The purified compounds also used Waters' mass spectrometry-oriented automatic preparation system (mass detector: SQD2). Depending on the polarity of the compound, appropriate acetonitrile / water (containing 0.1% trifluoroacetic acid or formic acid) or acetonitrile / water (containing 0.05% ammonia) A reverse phase high pressure column (XBridge-C18, 19 × 150 mm, 5 μm) was eluted with a gradient at a flow rate of 20 mL / min.

Example 1

(R) -N- (4-chlorophenyl) -2-((2s, 3aR, 5R, 6aS) -5- (2-methylpyridin-4-yl) octahydropentadien-2-yl) Propionamide

first step

(3aR, 6aS) -tetrahydro-1H-spiro [pentaene-2,2 '-[1,3] dioxolane] -5 (3H) -one

To a mixture of (3as, 6as) -tetrahydropentadiene-2,5 (1H, 3H) -dione 1a (100 g, 725 mmol), ethylene glycol (40.4 g, 652 mmol) and toluene (1.6 L) With p-toluenesulfonic acid (12.4 g, 72.4 mmol), the reaction mixture was heated to 100 ° C and stirred for 10 hours. Cool to room temperature and remove the solvent under reduced pressure. The residue was added with water and extracted with ethyl acetate (500 mL × 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered to remove the drying agent, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 3/1) to obtain the target product (3aR, 6aS)- Tetrahydro-1H-spiro [pentadiene-2,2 '-[1,3] dioxolane] -5 (3H) -one 1b (53 g, yellow oil), yield: 40%.

MS m / z (ESI): 183 [M + 1]

Second step

(3aR, 6aS) -3,3a, 4,6a-tetrahydro-1H-spiro [pentaene-2,2 '-[1,3] dioxolane] -5-yltrifluoromethanesulfonate

Compound (3aR, 6aS) -tetrahydro-1H-spiro [pentaene-2,2 '-[1,3] dioxolane] -5 (3H) -one 1b (52g, 287mmol) was dissolved in tetrahydrofuran (480 mL), cooled to -50 ° C, and a tetrahydrofuran solution of sodium bis (trimethylsilyl) amino (2M, 176.5 mL, 344.3 mmol) was added and stirred for 1 hour. N-phenylbis (trifluoromethanesulfonyl) imine (123 g, 344.3 mmol) was added, and the reaction solution was warmed to room temperature and stirred for 5 hours. It was quenched with a saturated ammonium chloride solution (350 mL), and extracted with ethyl acetate (300 mL × 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered to remove the desiccant, and concentrated under reduced pressure to obtain the target product (3aR, 6aS) -3,3a, 4,6a-tetrahydro-1H-spiro [pentalene-2, 2 '-[1,3] dioxolane] -5-yltrifluoromethanesulfonate 1c (72 g, brown oil), yield: 80%.

MS m / z (ESI): 315 [M + 1]

third step

2-methyl-4-((3aR, 6aS) -3,3a, 4,6a-tetrahydro-1H-spiro [pentane-2,2 '-[1,3] dioxolane] -5 -Yl) pyridine

The reaction mixture (3aR, 6aS) -3,3a, 4,6a-tetrahydro-1H-spiro [pentaene-2,2 '-[1,3] dioxolane] -5-yltrifluoromethyl Sulfonate 1c (9.55g, 30.4mmol), (2-methylpyridin-4-yl) boronic acid (5g, 36.5mmol), [1,1'-bis (diphenylphosphine) ferrocene] dichloro Palladium dichloromethane complex (1.24g, 1.52mmol), sodium carbonate (6.44g, 60.8mmol), N, N-dimethylformamide (100mL) and water (10mL) heated to 110 ° C under nitrogen , And stirred overnight. Cool to room temperature and concentrate under reduced pressure. The residue was purified by silica gel column chromatography (dichloromethane / methanol = 10/1) to obtain the target product 2-methyl-4-((3aR, 6aS) -3,3a, 4,6a-tetrahydro-1H- Spiro [pentaene-2,2 '-[1,3] dioxolane] -5-yl) pyridine 1d (6 g, yellow oil), yield: 77%.

MS m / z (ESI): 258 [M + 1]

the fourth step

4-((3aR, 6aS) -hexahydro-1H-spiro [pentaene-2,2 '-[1,3] dioxolane] -5-yl) -2-methylpyridine

Reaction mixture 2-methyl-4-((3aR, 6aS) -3,3a, 4,6a-tetrahydro-1H-spiro [pentaene-2,2 '-[1,3] dioxolane] -5-yl) pyridine 1d (6 g, 23.3 mmol), palladium on carbon (10%, 1.0 g), and methanol (200 mL) were stirred at room temperature overnight under a hydrogen atmosphere. Filtration and concentration under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 2/1) to obtain the target product 4-((3aR, 6aS) -hexahydro-1H-spiro [pentalene- 2,2 '-[1,3] dioxolane] -5-yl) -2-methylpyridine 1e (5 g, pale yellow oil), yield: 83%.

MS m / z (ESI): 260 [M + 1]

the fifth step

(3aR, 6aS) -5- (2-methylpyridin-4-yl) hexahydropentalene-2 (1H) -one

The compound 4-((3aR, 6aS) -hexahydro-1H-spiro [pentaene-2,2 '-[1,3] dioxolane] -5-yl) -2-methylpyridine 1e ( 5 g, 19.3 mmol) was dissolved in a solution of hydrogen chloride in dioxane (4M, 20 mL) and methanol (20 mL), and stirred at room temperature for 12 hours. Concentrated under reduced pressure to give the target product (3aR, 6aS) -5- (2-methylpyridin-4-yl) hexahydropentadiene-2 (1H) -one 1f (4 g, yellow solid), yield: 96 %.

MS m / z (ESI): 216 [M + 1]

Step Six

2-((3aR, 6aS, E) -5- (2-methylpyridin-4-yl) hexahydropentadiene-2 (1H) -idene) acetic acid

Dissolve ethyl 2- (diethoxyphospho) acetate (6.25g, 27.9mmol) in tetrahydrofuran (100mL), cool to 0 ° C, add sodium hydride (60%, 1.5g, 37.2mmol), at 0 ° C Stir for 2 hours. A solution of (3aR, 6aS) -5- (2-methylpyridin-4-yl) hexahydropentadiene-2 (1H) -one 1f (4g, 18.6mmol) in tetrahydrofuran (100mL) was added, and the temperature was raised to room temperature. Stir for 11.5 hours. The pH of the solution was adjusted to weakly acidic and concentrated under reduced pressure. The residue was dissolved in a mixed solvent of dichloromethane and methanol (10/1), filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (dichloromethane / methanol = 10/1) to obtain the target product 2- ( (3aR, 6aS, E) -5- (2-methylpyridin-4-yl) hexahydropentadiene-2 (1H) -subunit) acetic acid 1g (1.5g, pale yellow oil), Yield: 31%.

MS m / z (ESI): 258 [M + 1]

Step Seven

2-((3aR, 6aS) -5- (2-methylpyridin-4-yl) octahydropentalen-2-yl) acetic acid

Reaction mixture 2-((3aR, 6aS, E) -5- (2-methylpyridin-4-yl) hexahydropentadiene-2 (1H) -idene) acetic acid 1 g (1.5 g, 5.83 mmol), Palladium on carbon (10%, 0.3 g) and methanol (30 mL) were stirred at room temperature for 8 hours under a hydrogen atmosphere. Filtration and concentration under reduced pressure gave the target product 2-((3aR, 6aS) -5- (2-methylpyridin-4-yl) octahydropentadien-2-yl) acetic acid for 1 h (1.2 g, pale green oil) ), Yield: 79%.

MS m / z (ESI): 260 [M + 1]

Step eight

(4R) -4-benzyl-3- (2-((3aR, 6aS) -5- (2-methylpyridin-4-yl) octahydropentadien-2-yl) acetyl) oxazole Alkan-2-one

2-((3aR, 6aS) -5- (2-methylpyridin-4-yl) octahydropentalen-2-yl) acetic acid was dissolved in methylene chloride (50 mL) for 1 h (1.2 g, 4.63 mmol). Then, oxalyl chloride (2.94 g, 23.1 mmol) was added at 0 ° C, the temperature was raised to room temperature, and the mixture was stirred for 1 hour. The solvent was removed under reduced pressure to obtain an acid chloride intermediate. (R) -4-benzyloxazolidin-2-one (0.985 g, 5.56 mmol) was dissolved in tetrahydrofuran (80 mL), cooled to -78 ° C, and n-butyl lithium n-hexane solution (2.5 M, 2.8 mL, 6.95 mmol). After the dropwise addition, the mixture was stirred at the same temperature for 1 hour. Then, a solution of the above-mentioned acid chloride in tetrahydrofuran (20 mL) was added, and stirring was continued at -78 ° C for 1.5 hours. The reaction was quenched with a saturated ammonium chloride solution and extracted with dichloromethane (50 mL x 5). The organic phases were combined, dried over anhydrous sodium sulfate, and then dissolved under reduced pressure. The residue was purified by silica gel column chromatography (dichloromethane / methanol = 5/1) to obtain the target product (4R) -4-benzyl-3. -(2-((3aR, 6aS) -5- (2-methylpyridin-4-yl) octahydropentadien-2-yl) acetyl) oxazolidin-2-one 1i (1.4 g, light Yellow solid), yield: 72%.

MS m / z (ESI): 419 [M + 1]

Step Nine

(4R) -4-benzyl-3-((2R) -2-((3aR, 6aS) -5- (2-methylpyridin-4-yl) octahydropentadien-2-yl) propene (Acyl) oxazolidin-2-one

(4R) -4-benzyl-3- (2-((3aR, 6aS) -5- (2-methylpyridin-4-yl) octahydropentadien-2-yl) acetyl) oxazine The oxazolidin-2-one 1i (0.5 g, 1.2 mmol) was dissolved in tetrahydrofuran (30 mL), cooled to -70 ° C, and a tetrahydrofuran solution of sodium bis (trimethylsilyl) amine (2M, 0.9 mL, 1.8 mmol). After the dropwise addition, the mixture was stirred at the same temperature for 1.5 hours. Methyl iodide (170 mg, 1.2 mmol) was added, and stirring was continued at -70 ° C for 3 hours. The reaction was quenched with a saturated ammonium chloride solution (10 mL), warmed to room temperature, diluted with water (50 mL), and extracted with ethyl acetate (30 mL × 3). The organic phases were combined and dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 1/1) to obtain the target product (4R) -4-benzyl- 3-((2R) -2-((3aR, 6aS) -5- (2-methylpyridin-4-yl) octahydropentadien-2-yl) propionyl) oxazolidin-2-one 1j (0.35 g, colorless oil), yield: 68%.

MS m / z (ESI): 433 [M + 1]

Step ten

(2R) -2-((3aR, 6aS) -5- (2-methylpyridin-4-yl) octahydropentadien-2-yl) propionic acid

(4R) -4-benzyl-3-((2R) -2-((3aR, 6aS) -5- (2-methylpyridin-4-yl) octahydropentalen-2-yl) Propionyl) oxazolidin-2-one 1j (0.35 g, 0.81 mmol) was dissolved in tetrahydrofuran (10 mL) and water (2 mL), cooled to 0 ° C, and a hydrogen peroxide solution (30%, 2 mL) and lithium hydroxide ( 78 mg, 3.24 mmol) and refluxed for 10 hours. The pH was adjusted to 6 with dilute hydrochloric acid (2M), and the solvent was removed under reduced pressure. The residue was added with a mixed solvent of dichloromethane / methanol = 5/1 (20 mL), and filtered. The filtrate was desolvated under reduced pressure, and the residue was purified by reversed-phase high performance liquid chromatography to obtain the target product (2R) -2-((3aR, 6aS) -5- (2-methylpyridin-4-yl) octahydropentyl 1-Phen-2-yl) propanoic acid 1k (100 mg, colorless oil), yield: 45%.

MS m / z (ESI): 274 [M + 1]

Eleventh step

(R) -N- (4-chlorophenyl) -2-((2s, 3aR, 5R, 6aS) -5- (2-methylpyridin-4-yl) octahydropentadien-2-yl) Propionamide

(2R) -2-((3aR, 6aS) -5- (2-methylpyridin-4-yl) octahydropentadien-2-yl) propanoic acid 1k (40 mg, 0.15 mmol) was dissolved in dichloride Methane (10 mL), 2- (7-azabenzotriazole) -N, N, N ', N'-tetramethylurenium hexafluorophosphate (67 mg, 0.18 mmol) and N, N- Diisopropylethylamine (28 mg, 0.22 mmol) was stirred at room temperature for 1 hour. Concentrated under reduced pressure to obtain an active ester intermediate. 4-chloroaniline (21 mg, 0.16 mmol) was dissolved in N, N-dimethylformamide (2 mL), sodium hydride (60%, 12 mg, 0.29 mmol) was added, and the mixture was stirred at room temperature for 0.5 hours. A solution of the above-mentioned active ester intermediate in N, N-dimethylformamide (3 mL) was added and stirred at room temperature for 3 hours. The solvent was removed under reduced pressure, and the residue was purified by reversed-phase high performance liquid chromatography to obtain the target product (R) -N- (4-chlorophenyl) -2-((2s, 3aR, 5R, 6aS) -5- ( 2-methylpyridin-4-yl) octahydropentadien-2-yl) propanamide 1 (7 mg, white solid), yield: 12%.

MS m / z (ESI): 383 [M + 1]

¹ H NMR (400MHz, CD ₃ OD) δ8.15 (d, J = 5.3Hz, 1H), 7.49–7.42 (m, 2H), 7.23–7.16 (m, 2H), 7.07 (s, 1H), 7.01 (d, J = 5.3 Hz, 1H), 3.05 (tt, J = 12.2, 6.2 Hz, 1H), 2.64-2.43 (m, 2H), 2.38 (s, 3H), 2.21-2.06 (m, 5H), 1.96–1.91 (m, 1H), 1.35–1.25 (m, 2H), 1.10 (d, J = 6.7Hz, 3H), 1.07–0.92 (m, 2H).

Example 2

(R) -N- (4-chlorophenyl) -2-((2s, 3aR, 5R, 6aS) -5- (6-fluoroquinolin-4-yl) octahydropentalen-2-yl) Propionamide

first step

6-fluoro-4-((3aR, 6aS) -3,3a, 4,6a-tetrahydro-1H-spiro [pentaene-2,2 '-[1,3] dioxolane] -5- ) Quinoline

The reaction mixture (3aR, 6aS) -3,3a, 4,6a-tetrahydro-1H-spiro [pentaene-2,2 '-[1,3] dioxolane] -5-yltrifluoromethyl Sulfonate 1c (66 g, 210 mmol), (6-fluoroquinolin-4-yl) boronic acid (47 g, 250 mmol), sodium carbonate (56 g, 525 mmol), [1,1'-bis (diphenylphosphine) di Ferrocene] palladium dichloride dichloromethane complex (8.5 g, 10.5 mmol), dioxane (1.2 L) and water (250 mL) were heated to 90 ° C. and reacted for 6 hours under nitrogen protection. It was cooled to room temperature, diluted with water (200 mL), and extracted with ethyl acetate (300 mL × 3). The organic phases were combined and purified by silica gel column chromatography (petroleum ether / ethyl acetate = 1/1) to obtain the target product 6-fluoro-4-((3aR, 6aS) -3,3a, 4,6a-tetrahydro- 1H-spiro [pentaene-2,2 '-[1,3] dioxolane] -5-yl) quinoline 2a (47.3 g, brownish yellow oil), yield: 73%.

MS m / z (ESI): 312 [M + 1]

Second step

6-fluoro-4-((3aR, 5s, 6aS) -hexahydro-1H-spiro [pentaene-2,2 '-[1,3] dioxolane] -5-yl) quinoline

Reaction mixture 6-fluoro-4-((3aR, 6aS) -3,3a, 4,6a-tetrahydro-1H-spiro [pentaene-2,2 '-[1,3] dioxolane]- 5-yl) quinoline 2a (47.3 g, 152 mmol), palladium on carbon (10%, 5 g), and methanol (250 mL) were stirred at room temperature under a hydrogen atmosphere for 4 hours. It was filtered and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 1/1) to obtain the target product 6-fluoro-4-((3aR, 5s, 6aS) -hexahydro-1H-spiro [pentalene- 2,2 '-[1,3] dioxolane] -5-yl) quinoline 2b (31 g, yellow oil), yield: 66%.

MS m / z (ESI): 314 [M + 1]

third step

(3aR, 5s, 6aS) -5- (6-fluoroquinolin-4-yl) hexahydropentadiene-2 (1H) -one

The compound 6-fluoro-4-((3aR, 5s, 6aS) -hexahydro-1H-spiro [pentaene-2,2 '-[1,3] dioxolane] -5-yl) quinoline 2b (31 g, 99 mmol) was dissolved in tetrahydrofuran (400 mL), hydrochloric acid (6M, 10 mL) was added, and the mixture was stirred at room temperature for 3 hours. The solution was adjusted to pH = 8 with a saturated sodium bicarbonate solution (130 mL), and extracted with ethyl acetate (200 mL × 3). The organic phases were combined and concentrated under reduced pressure to give the target product (3aR, 5s, 6aS) -5- (6-fluoroquinolin-4-yl) hexahydropentadiene-2 (1H) -one 2c (22.0 g, crude ), Yield: 83%.

MS m / z (ESI): 270 [M + 1]

the fourth step

2-((3aR, 5R, 6aS, E) -5- (6-fluoroquinolin-4-yl) hexahydropentadiene-2 (1H) -ylidene) ethyl acetate

Dissolve ethyl 2- (diethoxyphospho) acetate (22 g, 98.1 mmol) in tetrahydrofuran (400 mL), cool to 0 ° C, slowly add sodium hydride (60%, 2.9 g, 122.7 mmol), and protect with nitrogen. The reaction was continued for 0.5 hours. This reaction solution was then slowly added with (3aR, 5s, 6aS) -5- (6-fluoroquinolin-4-yl) hexahydropentadiene-2 (1H) -one 2c (22 g, 81.7 mmol) in tetrahydrofuran ( 50 mL) solution, reacted at room temperature for 6 hours. Dilute with water (300 mL), and extract with ethyl acetate (200 mL x 3). The organic phases were combined and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 1/1) to obtain the target product 2-((3aR, 5R, 6aS, E) -5- (6- Fluoroquinolin-4-yl) hexahydropentadiene-2 (1H) -ylidene) acetate 2d (17 g, yellow oil), yield: 61%.

MS m / z (ESI): 340 [M + 1]

the fifth step

2-((3aR, 5r, 6aS) -5- (6-fluoroquinolin-4-yl) octahydropentadien-2-yl) ethyl acetate

Reaction mixture 2-((3aR, 5R, 6aS, E) -5- (6-fluoroquinolin-4-yl) hexahydropentadiene-2 (1H) -ylidene) acetate 2d (17g, 50.15 mmol), palladium on carbon (10%, 1 g) and methanol (200 mL) were reacted at room temperature under a hydrogen atmosphere for 4 hours. It was filtered and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 1/1) to obtain the target product 2-((3aR, 5r, 6aS) -5- (6-fluoroquinolin-4-yl) octahydro Pentenen-2-yl) ethyl acetate 2e (16.7 g, yellow oil), yield: 98%.

MS m / z (ESI): 342 [M + 1]

Step Six

2-((3aR, 5r, 6aS) -5- (6-fluoroquinolin-4-yl) octahydropentalen-2-yl) acetic acid

Dissolve 2-((3aR, 5r, 6aS) -5- (6-fluoroquinolin-4-yl) octahydropentadien-2-yl) ethyl acetate 2e (15.3 g, 45 mmol) in ethanol (200 mL ) And water (50 mL), sodium hydroxide (3.6 g, 90 mmol) was added, and the mixture was heated to 70 ° C. and reacted for 4 hours. The organic solvent was removed by concentration under reduced pressure, the pH of the reaction solution was adjusted to 4 with dilute hydrochloric acid (2M), and extracted with dichloromethane (30 mL x 3). The organic phases were combined and concentrated under reduced pressure to give the target product 2-((3aR, 5r, 6aS) -5- (6-fluoroquinolin-4-yl) octahydropentalen-2-yl) acetic acid 2f (12.1 g , Yellow solid), yield: 87%.

MS m / z (ESI): 314 [M + 1]

Step Seven

(4R) -4-benzyl-3- (2-((3aR, 5R, 6aS) -5- (6-fluoroquinolin-4-yl) octahydropentadien-2-yl) acetyl) Oxazolidin-2-one

The compound 2-((3aR, 5r, 6aS) -5- (6-fluoroquinolin-4-yl) octahydropentalen-2-yl) acetic acid 2f (400 mg, 1.27 mmol) was dissolved in anhydrous tetrahydrofuran ( 20 mL), triethylamine (259 mg, 2.55 mmol) was added and cooled to -78 ° C under a nitrogen atmosphere, and then pivaloyl chloride (190 mg, 1.59 mmol) was added dropwise. After stirring at 0 ° C for one hour, a suspension was obtained for use.

(R) -4-benzyloxazolidin-2-one (292 mg, 1.65 mmol) was dissolved in anhydrous tetrahydrofuran (20 mL), cooled to -78 ° C, and then n-butyllithium was added dropwise under a nitrogen atmosphere. Hexane solution (2.4M, 0.69 mL, 1.5 mmol). After stirring at -78 ° C for 15 minutes, the temperature was gradually raised to 0 ° C and stirred for 15 minutes. The resulting pale yellow solution was then cooled again to -78 ° C until use.

The above suspension was cooled to -78 ° C, and then a light yellow solution that had been cooled to -78 ° C was added. The reaction mixture was gradually warmed to room temperature and stirring was continued for 3 hours. A saturated ammonium chloride solution (100 mL) was added to the reaction mixture, and extracted with ethyl acetate (100 mL × 3). The organic phases were combined and washed with saturated brine (20 mL × 2). After drying over anhydrous sodium sulfate and filtering, the filtrate was freed from the solvent under reduced pressure, and the residue was purified by silica gel column chromatography (dichloromethane / methanol = 9/1) to obtain the target product (4R) -4-benzyl -3- (2-((3aR, 5R, 6aS) -5- (6-fluoroquinolin-4-yl) octahydropentadien-2-yl) acetyl) oxazolidin-2-one 2 g ( 510 mg, off-white solid), yield: 85%.

MS m / z (ESI): 473 [M + 1]

Step eight

(4R) -4-benzyl-3-((2R) -2-((3aR, 5R, 6aS) -5- (6-fluoroquinolin-4-yl) octahydropentalen-2-yl ) Propionyl) oxazolidin-2-one

Compound (4R) -4-benzyl-3- (2-((3aR, 5R, 6aS) -5- (6-fluoroquinolin-4-yl) octahydropentadien-2-yl) acetyl 2 g (510 mg, 1.08 mmol) of oxazolidin-2-one was dissolved in anhydrous tetrahydrofuran (30 mL), cooled to -50 ° C, and then a tetrahydrofuran solution of sodium bis (trimethylsilyl) amino (2M, 1.1 mL, 2.2 mmol). After stirring for 30 minutes, methyl iodide (460 mg, 3.24 mmol) was added at this temperature and stirring was continued for 3 hours. After quenching with a saturated ammonium chloride solution (10 mL), the temperature was gradually raised to room temperature, and then extracted with ethyl acetate (50 mL × 2). The organic phases were combined and washed with saturated brine (20 mL). After drying over anhydrous sodium sulfate and filtering, the filtrate was freed from the solvent under reduced pressure, and the residue was purified by silica gel column chromatography (dichloromethane / methanol = 9/1) to obtain the target product (4R) -4-benzyl -3-((2R) -2-((3aR, 5R, 6aS) -5- (6-fluoroquinolin-4-yl) octahydropentadien-2-yl) propionyl) oxazolidine-2 -Ketone 2h (450 mg, off-white solid), yield: 86%.

MS m / z (ESI): 487 [M + 1]

Step Nine

(2R) -2-((3aR, 5R, 6aS) -5- (6-fluoroquinolin-4-yl) octahydropentadien-2-yl) propionic acid

Compound (4R) -4-benzyl-3-((2R) -2-((3aR, 5R, 6aS) -5- (6-fluoroquinolin-4-yl) octahydropentadiene-2 -Yl) propanoyl) oxazolidin-2-one 2h (450mg, 0.92mmol) and tetrahydrofuran (15mL) were mixed, cooled to 0 ° C, and then 35% hydrogen peroxide solution (0.5mL) and lithium hydroxide aqueous solution were added in this order. (1N, 1 mL, 1 mmol). After gradually warming to room temperature, stirring was continued for 1 hour. After re-cooling to 0 ° C, formic acid (0.5 mL) was slowly added, and then the solvent was removed under reduced pressure. The residue was purified by reversed-phase high-performance liquid chromatography to obtain the target product (2R) -2-((3aR, 5R, 6aS) -5- (6-fluoroquinolin-4-yl) octahydropentadiene-2- Propyl) propanoic acid 2i (250 mg, pale yellow solid), yield: 83%.

MS m / z (ESI): 328 [M + 1]

Step ten

(R) -N- (4-chlorophenyl) -2-((2s, 3aR, 5R, 6aS) -5- (6-fluoroquinolin-4-yl) octahydropentalen-2-yl) Propionamide

Compound (2R) -2-((3aR, 5R, 6aS) -5- (6-fluoroquinolin-4-yl) octahydropentadien-2-yl) propanoic acid 2i (50 mg, 0.15 mmol) and 4-chloroaniline (57 mg, 0.45 mmol) was dissolved in dichloromethane (10 mL), and then 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (86 mg, 0.54 mmol) was added. . After stirring at room temperature for 3 hours, the solvent was removed under reduced pressure. The residue was purified by reversed-phase high-performance liquid chromatography to obtain the target product (R) -N- (4-chlorophenyl) -2-((2s, 3aR, 5R, 6aS) -5- (6-fluoroquinolin-4-yl) octahydropentalen-2-yl) propionamide 2 (18 mg, white solid), yield: 27%.

MS m / z (ESI): 437 [M + 1]

¹ H NMR (400 MHz, CD ₃ OD) δ 8.98 (d, J = 5.5 Hz, 1 H), 8.29–8.19 (m, 2 H), 7.96 (d, J = 5.5 Hz, 1 H), 7.90 (ddd, J = 9.3, 8.0, 2.7 Hz, 1H), 7.65–7.53 (m, 2H), 7.37–7.26 (m, 2H), 4.16–4.03 (m, 1H), 2.82 (dt, J = 15.8, 7.8 Hz, 2H ), 2.48 (td, J = 17.3, 8.5 Hz, 2H), 2.40 (dt, J = 15.7, 6.8 Hz, 1H), 2.31 (dt, J = 13.6, 7.4 Hz, 2H), 2.12 (dd, J = 12.5, 6.5 Hz, 1H), 1.73–1.59 (m, 2H), 1.32–1.14 (m, 5H).

Example 3

(R) -2-((2s, 3aR, 5R, 6aS) -5- (6-fluoroquinolin-4-yl) octahydropentadien-2-yl) -N- (4- (pentafluoro- λ ⁶ -sulfanyl) phenyl) propionamide

Compound (2R) -2-((3aR, 5R, 6aS) -5- (6-fluoroquinolin-4-yl) octahydropentadien-2-yl) propanoic acid 2i (60 mg, 0.18 mmol) and 4- (pentafluoro-λ ⁶ -sulfanyl) aniline 3a (118 mg, 0.54 mmol) was dissolved in dichloromethane (10 mL), and then 1- (3-dimethylaminopropyl) -3-ethylcarbodicarbonate was added. Imine hydrochloride (118 mg, 0.54 mmol). After stirring at room temperature for 5 hours, the solvent was removed under reduced pressure, and the residue was purified by reversed-phase high-performance liquid chromatography to obtain the target product (R) -2-((2s, 3aR, 5R, 6aS) -5- (6- Fluoroquinolin-4-yl) octahydropentadien-2-yl) -N- (4- (pentafluoro-λ ⁶ -sulfanyl) phenyl) propanamide 3 (12 mg, white solid), yield : 12%.

MS m / z (ESI): 529 [M + 1]

¹ H NMR (400MHz, CD ₃ OD) δ 8.98 (d, J = 5.5 Hz, 1H), 8.23 (dt, J = 10.0, 3.7 Hz, 2H), 7.95 (d, J = 5.5 Hz, 1H), 7.89 (ddd, J = 9.3, 8.0, 2.7 Hz, 1H), 7.84--7.72 (m, 4H), 4.14--4.02 (m, 1H), 2.82 (dt, J = 15.8, 7.9 Hz, 2H), 2.55-- 2.40 (m, 3H), 2.37-2.25 (m, 2H), 2.12 (dd, J = 12.1, 5.9Hz, 1H), 1.65 (qd, J = 11, 8.4Hz, 2H), 1.31-1.15 (m, 5H).

Example 4

(R) -2-((2s, 3aR, 5R, 6aS) -5- (6-fluoroquinolin-4-yl) octahydropentadien-2-yl) -N- (6-methoxypyridine -3-yl) propionamide

Compound (2R) -2-((3aR, 5R, 6aS) -5- (6-fluoroquinolin-4-yl) octahydropentadien-2-yl) propanoic acid 2i (100 mg, 0.31 mmol) and 6-methoxypyridin-3-amine 4a (114 mg, 0.93 mmol) was dissolved in dichloromethane (12 mL), and then 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride was added Salt (178 mg, 0.93 mmol). After stirring at room temperature for 3 hours, the solvent was removed under reduced pressure. The residue was purified by reversed-phase high-performance liquid chromatography to obtain the target product (R) -2-((2s, 3aR, 5R, 6aS) -5- (6- Fluoroquinolin-4-yl) octahydropentadien-2-yl) -N- (6-methoxypyridin-3-yl) propanamide 4 (57 mg, white solid), yield: 38%.

MS m / z (ESI): 434 [M + 1]

¹ H NMR (400MHz, CD ₃ OD) δ9.14 (s, 1H), 8.99 (s, 1H), 8.57 (s, 1H), 8.44–8.31 (m, 2H), 8.23 (s, 1H), 8.05 (t, J = 7.7Hz, 1H), 7.66 (d, J = 8.6Hz, 1H), 4.22 (d, J = 24.9Hz, 4H), 2.85 (s, 2H), 2.64-2.42 (m, 3H) , 2.31 (s, 2H), 2.09 (s, 1H), 1.74 (s, 2H), 1.43–1.16 (m, 5H).

Example 5

(R) -N- (5-chloropyridin-2-yl) -2-((2s, 3aR, 5R, 6aS) -5- (6-fluoroquinolin-4-yl) octahydropentalene-2 -Yl) propionamide

The compound (2R) -2-((3aR, 5R, 6aS) -5- (6-fluoroquinolin-4-yl) octahydropentalen-2-yl) propionic acid 2i (100 mg, 0.31 mmol) was dissolved To dichloromethane (12 mL), then oxalyl chloride (0.5 mL) was added. After stirring for 3 hours, the solvent was removed under reduced pressure, and the residue was dissolved in dichloromethane (2 mL) to obtain a solution. This solution was added dropwise to a solution of 5-chloropyridin-2-amine 5a (119 mg, 0.93 mmol) and triethylamine (189 mg, 1.86 mmol) in tetrahydrofuran (6 mL). After stirring at room temperature for 15 hours, the solvent was removed under reduced pressure, and the residue was purified by reverse-phase preparative high-performance liquid chromatography to obtain the target product (R) -N- (5-chloropyridin-2-yl) -2-((2s, 3aR, 5R, 6aS) -5- (6-fluoroquinolin-4-yl) octahydropentalen-2-yl) propionamide hydrochloride 5 (10 mg, yellow solid), yield: 6.8%.

MS m / z (ESI): 438 [M + 1]

¹ H NMR (400MHz, CD ₃ OD) δ9.12 (d, J = 5.4Hz, 1H), 8.39–8.35 (m, 3H), 8.27–8.17 (m, 2H), 8.09–8.01 (m, 1H) , 7.87 (d, J = 9.1 Hz, 1H), 4.27-4.12 (m, 1H), 2.86 (s, 2H), 2.64 (dd, J = 14.6, 7.5 Hz, 1H), 2.57-2.46 (m, 2H ), 2.35 (ddd, J = 24.5, 12.0, 6.2 Hz, 2H), 2.21–2.08 (m, 1H), 1.82–1.66 (m, 2H), 1.37–1.26 (m, 5H).

The following examples (Examples 7-12) were synthesized with reference to the operation method of Example 5, but in the operation, different aromatic amines were used instead of 5-chloropyridin-2-amine 5a. The characterization data are shown in the following table:

Example 6

N- (4-chlorophenyl) -2-((3aR, 5r, 6aS) -5- (6-fluoroquinolin-4-yl) hexahydrocyclopentadieno [c] pyrrole-2 (1H) -Yl) propionamide

first step

(3aS, 6aS) -5-(((trifluoromethyl) sulfonyl) oxo) -3,3a, 4,6a-tetrahydrocyclopentadien (c) pyrrole-2 (1H) -carboxylic acid Tert-butyl ester

(3aR, 6aS) -5-carbonylhexahydrocyclopentadiene [c] pyrrole-2 (1H) -carboxylic acid tert-butyl ester 6a (5 g, 22.2 mmol) was dissolved in tetrahydrofuran (200 mL), and the temperature was reduced to- At 45 ° C., a tetrahydrofuran solution of sodium bis (trimethylsilyl) amino (2M, 17 mL, 34 mmol) was added and stirred for 1 hour. N-phenylbis (trifluoromethanesulfonyl) imide (12.7 g, 35.6 mmol) was added in portions, and the reaction solution was warmed to room temperature and stirred for 2 hours. It was quenched with a saturated ammonium chloride solution and extracted with ethyl acetate (100 mL × 2). The organic phases were combined, dried over anhydrous sodium sulfate, filtered to remove the drying agent, and concentrated under reduced pressure to obtain the target product (3aS, 6aS) -5-(((trifluoromethyl) sulfonyl) oxo) -3,3a, 4,6a-tetrahydrocyclopentadiene [c] pyrrole-2 (1H) -carboxylic acid tert-butyl ester 6b (20 g, brown oil). The product was used directly in the next reaction without further purification.

MS m / z (ESI): 358 [M + 1]

Second step

(3aS, 6aR) -5- (6-fluoroquinolin-4-yl) -3,3a, 4,6a-tetrahydrocyclopentadien (c) pyrrole-2 (1H) -carboxylic acid tert-butyl ester

The compound (3aS, 6aS) -5-(((trifluoromethyl) sulfonyl) oxo) -3,3a, 4,6a-tetrahydrocyclopentadieno [c] pyrrole-2 (1H)- Tert-butyl carboxylic acid 6b (crude, 20g, 22.2mmol), 6-fluoro-4- (4,4,5,5-tetramethyl-1,3,2-dioxoborolan-2-yl) Quinoline (4.9g, 22.2mmol), sodium carbonate (4.8g, 44.4mmol), [1,1'-bis (diphenylphosphine) ferrocene] palladium dichloromethane complex (726mg, 0.89 mmol), 1,4-dioxane (100 mL) and water (20 mL) under nitrogen, heated to 100 ° C., and reacted for 3 hours. Dilute with water (200 mL) and extract with dichloromethane (100 mL x 2). The organic phases were combined and dried over anhydrous sodium sulfate, filtered to remove the drying agent, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 3/1) to obtain the target product (3aS, 6aR)- 5- (6-fluoroquinolin-4-yl) -3,3a, 4,6a-tetrahydrocyclopentadiene [c] pyrrole-2 (1H) -carboxylic acid tert-butyl ester 6c (7g, yellow oily ), Yield: 89%.

MS m / z (ESI): 355 [M + 1]

third step

(3aR, 6aS) -5- (6-fluoroquinolin-4-yl) hexahydrocyclopentadieno [c] pyrrole-2 (1H) -carboxylic acid tert-butyl ester

Reaction mixture (3aS, 6aR) -5- (6-fluoroquinolin-4-yl) -3,3a, 4,6a-tetrahydrocyclopentadieno [c] pyrrole-2 (1H) -carboxylic acid tert Butyl 6c (7 g, 19.8 mmol), palladium on carbon (10%, 1 g), and methanol (100 mL) were stirred at room temperature under a hydrogen atmosphere for 4 hours. Filtration and concentration of the filtrate under reduced pressure gave the target product (3aR, 6aS) -5- (6-fluoroquinolin-4-yl) hexahydrocyclopentadiene [c] pyrrole-2 (1H) -carboxylic acid tert-butyl Ester 6d (6 g, yellow solid), yield: 85%.

MS m / z (ESI): 357 [M + 1]

the fourth step

6-fluoro-4-((3aR, 6aS) -octahydrocyclopentadieno [c] pyrrole-5-yl) quinoline

Compound (3aR, 6aS) -5- (6-fluoroquinolin-4-yl) hexahydrocyclopentadieno [c] pyrrole-2 (1H) -carboxylic acid tert-butyl ester 6d (6g, 16.8mmol) It was dissolved in methanol (80 mL) and concentrated hydrochloric acid (10 mL) and stirred at room temperature for 2 hours. The reaction solution was concentrated under reduced pressure to obtain the target product 6-fluoro-4-((3aR, 6aS) -octahydrocyclopentadieno [c] pyrrole-5-yl) quinoline 6e (8g, yellow oil, hydrochloric acid salt). The product was used directly in the next reaction without further purification.

MS m / z (ESI): 257 [M + 1]

the fifth step

2-((3aR, 6aS) -5- (6-fluoroquinolin-4-yl) hexahydrocyclopentadiene [c] pyrrole-2 (1H) -yl) propionic acid tert-butyl ester

Reaction mixture 6-fluoro-4-((3aR, 6aS) -octahydrocyclopentadieno [c] pyrrole-5-yl) quinoline 6e (61% content, 470 mg, 0.98 mmol), 2-bromopropionic acid Tert-butyl ester (308 mg, 1.47 mmol), potassium carbonate (271 mg, 1.96 mmol), and acetonitrile (10 mL) were stirred at room temperature for 2 hours. Dilute with water (50 mL) and extract with dichloromethane (30 mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered to remove the drying agent, and concentrated under reduced pressure to obtain the target product 2-((3aR, 6aS) -5- (6-fluoroquinolin-4-yl) hexahydrocyclopentane Tert-Butyl enc [c] pyrrole-2 (1H) -yl) propionate 6f (780 mg, yellow oil). The product was used directly in the next reaction without further purification.

MS m / z (ESI): 385 [M + 1]

Step Six

2-((3aR, 6aS) -5- (6-fluoroquinolin-4-yl) hexahydrocyclopentadieno [c] pyrrole-2 (1H) -yl) propionic acid

Compound 2-((3aR, 6aS) -5- (6-fluoroquinolin-4-yl) hexahydrocyclopentadieno [c] pyrrole-2 (1H) -yl) propionate 6f ( The crude product, 780 mg, 0.98 mmol) was dissolved in tetrahydrofuran (10 mL) and concentrated hydrochloric acid (3 mL), heated to 40 ° C, and stirred for 2 hours. Cool to room temperature and concentrate under reduced pressure to give the target product 2-((3aR, 6aS) -5- (6-fluoroquinolin-4-yl) hexahydrocyclopentadieno [c] pyrrole-2 (1H)- Base) Propionic acid 6 g (470 mg, yellow oil). The product was used directly in the next reaction without further purification.

MS m / z (ESI): 329 [M + 1]

Step Seven

N- (4-chlorophenyl) -2-((3aR, 5r, 6aS) -5- (6-fluoroquinolin-4-yl) hexahydrocyclopentadieno [c] pyrrole-2 (1H) -Yl) propionamide

6g of compound 2-((3aR, 6aS) -5- (6-fluoroquinolin-4-yl) hexahydrocyclopentadiene [c] pyrrole-2 (1H) -yl) propionic acid (crude, 470 mg , 0.98 mmol) was dissolved in dichloromethane (15 mL), 4-chloroaniline (161 mg, 1.27 mmol), 2- (7-azabenzotriazole) -N, N, N ', N'- Tetramethylurenium hexafluorophosphate (447 mg, 1.18 mmol) and N, N-diisopropylethylamine (253 mg, 1.96 mmol) were stirred at room temperature for 1 hour. Water (30 mL) was added and extracted with dichloromethane (30 mL × 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered to remove the drying agent, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (dichloromethane / methanol = 20/1), and the obtained product was further subjected to a reversed-phase high-performance liquid phase. Purification by preparative chromatography to give the target product N- (4-chlorophenyl) -2-((3aR, 5r, 6aS) -5- (6-fluoroquinolin-4-yl) hexahydrocyclopentadieno [c ] Pyrrole-2 (1H) -yl) propionamide 6 (17 mg, white solid), yield: 4%.

MS m / z (ESI): 438 [M + 1]

¹ HNMR (400MHz, CD ₃ OD) δ9.14 (s, 1H), 8.47–8.17 (m, 3H), 8.00 (t, J = 8.0Hz, 1H), 7.66 (d, J = 8.6Hz, 2H) , 7.36 (d, J = 8.5 Hz, 2H), 4.56-3.34 (m, 8H), 2.60 (brs, 2H), 2.08 (brs, 2H), 1.75 (brs, 3H).

IDO intracellular activity inhibition test

The effect of the compound of the present invention on the indoleamine 2,3-dioxygenase (IDO) activity in IFN-γ-induced Hela cells was evaluated by the Ehrlich method.

The experimental principle is summarized as follows: without any induction conditions, the expression of IDO in Hela cells is low, but a certain concentration of IFN-γ can induce Hela cells to express IDO and catalyze tryptophan to produce N-formyl kynurenine, which It can be hydrolyzed by trichloroacetic acid to generate kynurenine, and then develop a color reaction with Ehrlich reagent to detect the activity of IDO. The absorbance (OD490) at 490nm is directly proportional to the activity of IDO.

The compound was dissolved in DMSO (Sigma, Cat. No. D5879) and diluted to 5 mM, and then serially diluted 3 times with DMSO to a minimum concentration of 2.29 μM, and each concentration point was treated with FBS-free DMEM medium (ThermoFisher, Cat. 11995073) diluted 50-fold. If the compound is very low IC ₅₀ values, the concentration of the starting compound can be reduced. Hela cells (ATCC, article number CCL-2) were cultured in DMEM complete medium containing 10% FBS (GBICO, article number 10099-141) and 100 U / mL penicillin mixed solution (ThermoFisher, article number 15140122). When the cell coverage in the culture container reached 80-90%, the cells were digested with 0.25% trypsin (containing EDTA) (ThermoFisher, Cat. No. 25200056) and blown and planted in 96-well plates (Corning, Cat. No. 3599). 30,000 cells (80 μL DMEM medium), and then cultured in a 96-well plate in a 37 ° C, 5% CO ₂ incubator overnight (18-20 hours).

After overnight, 10 μL of DMEM diluted compound and 10 μL of 500ng / mL of INF-γ were added to each well, and mixed gently. The 96-well plate was placed in a 37 ° C, 5% CO ₂ incubator to continue culturing. After 24 hours, it was taken out and centrifuged at 2000 × g for 5 minutes at room temperature, and then the supernatant was transferred to a reaction plate (Sigma, article number CLS3695). Add one-twentieth of trichloroacetic acid (Sigma, article number T9159), mix well and incubate at 60 ° C. After 30 minutes, the reaction plate was taken out and centrifuged at 2000 × g for 5 minutes at room temperature. The supernatant was transferred to a clean reaction plate, and an equal volume of Ehrlich reagent was added, mixed and incubated at room temperature. After 15 minutes, the OD490 of each well was detected.

In the experiment, IFN-γ was not added, and OD490 of the group replaced with DMEM was used as _{100% inhibition of} OD490; IFN-γ was added, and the OD490 of the group with a final DMSO concentration of 0.2% was used as OD490 _{0% inhibition} . The percentage inhibition of IDO activity in Hela cells by the compound can be calculated using the following formula:

Percent inhibition = 100-100 * (OD490 _compound- OD490 _{100% inhibition} ) / (OD490 _{0% inhibition-} OD490 _{100% inhibition} )

Compound IC ₅₀ values were obtained from 8 concentration points using XLfit (ID Business Solutions Ltd., UK) software by the following formula:

Y = Bottom + (Top-Bottom) / (1 + 10 ^ ((logIC ₅₀ -X) * slope factor))

Where Y is the inhibition percentage, Bottom is the bottom plateau value of the S-shaped curve, Top is the top plateau value of the S-shaped curve, X is the logarithmic value of the concentration of the test compound, and slope factor is the slope coefficient of the curve.

The activity data of some representative example compounds are as follows:

Compound number	IC 50	Compound number	IC 50
1	A	2	A
3	A	4	A
5	A	6	A
7	A	8	A
9	B	10	B
11	A	12	A

A <50nM; 50nM≤B <200nM

The compound of the embodiment of the present invention has a significant inhibitory effect on the activity of IDO in the cells, respectively, preferably the IC _{50 is} less than 200 nM, and more preferably the IC _{50 is} less than 50 nM.

Claims (11)

1. Compounds represented by general formula (I):

   

   Or pharmaceutically acceptable salts, prodrugs, stable isotope derivatives, isomers and mixtures thereof, wherein:

   Ring D is an optionally substituted benzene ring or a 5-6 membered heteroaryl ring;

   R ¹ and R ² are each independently selected from H or optionally substituted C _1-4 alkyl, C _3-6 cycloalkyl, or 4-7 membered heterocyclyl; or, R ¹ and R ² and the attached carbon The atoms together form a 3-7 membered ring optionally containing heteroatoms selected from O, N and S;

   R ³ and R ⁴ are each independently selected from H or C _1-4 alkyl;

   A is N or CR ⁵ ;

   B is N or CR ⁶ ;

   L is a bond, -O- or -CR ⁷ R ^8- ;

   C is optionally substituted 4-7 membered heterocyclic group, 6-10 membered aryl group or 5-10 membered heteroaryl group;

   R ⁵ and R ⁶ are each independently selected from H, halogen, OH, or optionally substituted C _1-4 alkyl or -OC _1-4 alkyl;

   R ⁷ and R ⁸ are each independently selected from H or optionally substituted C _1-4 alkyl.
2. The compound according to claim 1 or a pharmaceutically acceptable salt, prodrug, stable isotope derivative, isomer and mixture thereof, wherein:

   Ring D is an optionally substituted benzene ring or a 6-membered heteroaryl ring;

   R ¹ and R ² are each independently selected from H or optionally substituted C _1-4 alkyl;

   R ³ and R ⁴ are each independently selected from H or CH ₃ ;

   A is N or CH;

   B is N or CH;

   L is a bond or -O-;

   C is a 4-7 membered heterocyclic group, a 6-10 membered aryl group, or a 5-10 membered heteroaryl group optionally substituted with halogen, cyano, C _1-4 alkyl, or halogenated C _1-4 alkyl.
3. The compound according to claim 1 or 2, or a pharmaceutically acceptable salt, prodrug, stable isotope derivative, isomer and mixture thereof, which is a compound of the following general formula (II):

   

   among them:

   Ring D is an optionally substituted benzene ring or a pyridine ring;

   R ¹ and R ² are each independently selected from H or C _1-4 alkyl;

   A is N or CH;

   C is a 5-10 membered heteroaryl group optionally substituted with halogen, cyano, C _1-4 alkyl, or halo C _1-4 alkyl.
4. The compound or a pharmaceutically acceptable salt, prodrug, stable isotope derivative, isomer thereof, or a mixture thereof according to any one of the preceding claims, wherein ring D is optionally substituted by halogen, cyano, -SF ₅ , C _1-4 alkyl, halo C _1-4 alkyl, -OC _1-4 alkyl or -O-halo C _1-4 alkyl substituted benzene ring or pyridine ring.
5. A compound according to any one of the preceding claims, which is a compound of the following general formulae (IIIa)-(IIIc):

   

   among them:

   Ring D, R ^1, A and C are defined as claimed in claims 1-4.
6. A compound according to any one of the preceding claims, which is a compound of the following general formula (IV):

   

   among them:

   Rings D and R ¹ are as defined in claims 1-4.
7. The compound according to any one of the preceding claims, or a pharmaceutically acceptable salt, prodrug, stable isotope derivative, isomer and mixture thereof, the compound is selected from:

   

   
8. A pharmaceutical composition comprising the compound according to any one of claims 1 to 7 or a pharmaceutically acceptable salt thereof, a prodrug, a stable isotope derivative, an isomer and a mixture thereof, and a pharmaceutically acceptable Accepted carriers and excipients.
9. A pharmaceutical composition comprising the compound according to any one of claims 1 to 7 or a pharmaceutically acceptable salt thereof, a prodrug, a stable isotope derivative, an isomer and a mixture thereof, and at least one Additional drugs, wherein the at least one additional drug is a chemotherapeutic agent, an immune and / or inflammation modulator, a neuro-related disease modulator or an anti-infective agent.
10. The pharmaceutical composition according to claim 9, wherein the at least one additional drug is an immune checkpoint inhibitor.
11. The compound according to any one of claims 1 to 7 or a pharmaceutically acceptable salt, prodrug, stable isotope derivative, isomer thereof, and a mixture thereof, or the medicament according to any one of claims 8 to 10 Use of the composition in the manufacture of a medicament for the treatment and / or prevention of IDO-mediated related diseases, in particular tumors, wherein said tumors are selected from prostate cancer, colon cancer, rectal cancer, membrane adenocarcinoma, cervical cancer , Gastric cancer, endometrial cancer, brain cancer, liver cancer, bladder cancer, ovarian cancer, testicular cancer, head and neck cancer, skin cancer, mesothelioma, lymphoma, leukemia, esophageal cancer, breast cancer, muscle cancer, connective tissue Cancer, lung cancer, adrenal cancer, thyroid cancer, renal cancer, bone cancer, glioblastoma, mesothelioma, sarcoma, choriocarcinoma, basal cell carcinoma of the skin, or testicular seminoma.