CN110540521A

CN110540521A - Octahydro pentalene compound, preparation method and application thereof in medicine and pharmacology

Info

Publication number: CN110540521A
Application number: CN201810521853.8A
Authority: CN
Inventors: 不公告发明人
Original assignee: Beijing Nuocheng Jianhua Pharmaceutical Technology Co Ltd
Current assignee: Beijing Nuocheng Jianhua Pharmaceutical Technology Co Ltd; Beijing Innocare Pharma Tech Co Ltd
Priority date: 2018-05-28
Filing date: 2018-05-28
Publication date: 2019-12-06
Also published as: WO2019228170A1

Description

Octahydro pentalene compound, preparation method and application thereof in medicine and pharmacology

Technical Field

The invention relates to a novel octahydropentalene compound or a pharmaceutically acceptable salt thereof for regulating or inhibiting the activity of indoleamine 2, 3-dioxygenase (IDO), a pharmaceutical composition containing the compound or the pharmaceutically acceptable salt thereof, a preparation method of the compound or the pharmaceutically acceptable salt thereof, and application of the compound or the pharmaceutically acceptable salt thereof or the pharmaceutical composition containing the compound or the pharmaceutically acceptable salt thereof in preparing medicaments for treating and/or preventing IDO-mediated related diseases, particularly tumors and a using method thereof.

Background

Indoleamine 2, 3-dioxygenase (IDO) is a heme-containing monomeric protein widely distributed in tissues other than liver, catalyzes the oxidative degradation of tryptophan into kynurenine, and is a rate-limiting enzyme of the kynurenine metabolic pathway. Tryptophan is an essential amino acid for T cell proliferation and is also a precursor for the synthesis of neurotransmitters. If the tryptophan concentration in the microenvironment of the cells is reduced and the kynurenine level is increased, the T cells are arrested in the metaphase of G1, thereby affecting the proliferation, differentiation and activity of the T cells.

IDO is expressed at a low level in normal cells, but is over-expressed in a plurality of tumor tissues, so that the local tryptophan metabolism abnormality of the tumor and the formation of regulatory T cells are caused, the local T cell immune tolerance of the tumor is further mediated, and the IDO plays an important role in the generation, development and metastasis processes of malignant tumors. If IDO activity is inhibited, tryptophan metabolism around tumor cells is effectively prevented, and T cell growth is promoted, thereby enhancing the function of the immune system of the body against tumors. Therefore, the development of IDO inhibitors has become a leading hotspot in the research of tumor immunotherapy drugs. Preclinical studies have shown that a single dose of the selective inhibitor INCB-024360 of IDO effectively inhibits plasma IDO activity in naive mice at the level of IDO-deficient mice, and that repeated doses hamper expansion of CT26 tumors (Koblish et al, mol.

The IDO inhibitor can also be combined with other antitumor small molecule drugs and immune checkpoint inhibitors, such as antibodies of CTLA-4, PD-1 and PD-L1, to enhance the antitumor effect of the drugs. Combination immunotherapy of small molecule IDO inhibitors with immune checkpoint inhibitors is in clinical trials, such as combination therapy clinical trials of indoximod/ipilimumab, epacadostat/pembrolizumab, epacadostat/nivolumab, indoximod/MEDI-4736, and the like. Preliminary clinical results show that the combination of the IDO small-molecule inhibitor and the PD-1 has additional effect, achieves good disease control rate on the treatment of various tumors, has less side effect than PD-1/CTLA-4, and shows wide tumor immunotherapy prospect (AACR, 2017; ASCO, 2017).

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

small molecule IDO inhibitor drugs are currently in clinical trials, in addition to Incyte's INCB-024360(epacadostat), also New Link Genetics ' indoximod and Po-Mei-Shi Guibao ' BMS-986205, among others.

Because of the promise exhibited by IDO inhibitors in the immunotherapy of a variety of tumors and other diseases, both alone and in combination, the development of IDO inhibitors has attracted attention from numerous biopharmaceutical companies, a range of IDO inhibitors have been published including WO2006122150a1, WO2011056652a1, WO2013069765a1, WO2014186035a1, WO2015002918a1, WO2016073738a2, WO2016073770a1, WO2016181348a1, WO2016161960a1, WO2017079669a1, and the like, but there remains a need to develop new compounds that are better druggability and have a higher response rate in immunotherapy. Through continuous efforts, the invention designs the compound with the structure shown in the general formula (I), and finds that the compound with the structure shows excellent effect and action of inhibiting IDO activity.

Disclosure of Invention

The invention provides a compound shown as a general formula (I) as an IDO inhibitor:

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

Ring D is an optionally substituted phenyl ring or a 5-6 membered heteroaromatic ring;

R1 and R2 are each independently selected from H or optionally substituted C1-4 alkyl, C3-6 cycloalkyl or 4-7 membered heterocyclyl; or, R1 and R2 taken together with the carbon atom to which they are attached form a 3-7 membered ring optionally containing a heteroatom selected from O, N and S;

R3 and R4 are each independently selected from H or C1-4 alkyl;

A is N or CR 5;

B is N or CR 6;

L is a bond, -O-or-CR 7R 8-;

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

r5 and R6 are each independently selected from H, halogen, OH, or optionally substituted C1-4 alkyl or-O-C1-4 alkyl;

R7 and R8 are each independently selected from H or optionally substituted C1-4 alkyl.

One embodiment of the present invention relates to compounds represented by the above general formula (I) or pharmaceutically acceptable salts, prodrugs, stable isotopic derivatives, isomers and mixtures thereof, wherein:

Ring D is an optionally substituted phenyl ring or a 6-membered heteroaromatic ring;

R1 and R2 are each independently selected from H or optionally substituted C1-4 alkyl;

r3 and R4 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 4-7 membered heterocyclyl, 6-10 membered aryl or 5-10 membered heteroaryl optionally substituted with halogen, cyano, C1-4 alkyl or haloC 1-4 alkyl.

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

Wherein:

Ring D is an optionally substituted benzene or pyridine ring;

r1 and R2 are each independently selected from H or C1-4 alkyl;

a is N or CH;

C is a 5-10 membered heteroaryl optionally substituted with halogen, cyano, C1-4 alkyl or haloC 1-4 alkyl.

Another embodiment of the present invention is directed to compounds of any of the above embodiments or pharmaceutically acceptable salts, prodrugs, stable isotopic derivatives, isomers and mixtures thereof, wherein ring D is a phenyl ring or a pyridyl ring optionally substituted with halogen, cyano, -SF5, C1-4 alkyl, haloc 1-4 alkyl, -O-C1-4 alkyl or-O-haloc 1-4 alkyl.

Another embodiment of the present invention relates to compounds according to any of the preceding embodiments, wherein C is quinolinyl or pyridinyl, particularly fluoroquinolinyl, optionally substituted with halogen, cyano, C1-4 alkyl or halo C1-4 alkyl.

another embodiment of the invention is directed to compounds according to any of the above embodiments, wherein R1 is C1-4 alkyl, R2 is H, particularly R1 is methyl and R2 is H.

Another embodiment of the present invention relates to compounds according to any one of the above embodiments, which are of the following general formulae (IIIa) to (IIIc):

Another embodiment of the present invention relates 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 compounds represented by the above general formula (IV) wherein R1 is methyl.

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

or a prodrug, stable isotope derivative, pharmaceutically acceptable salt, isomer, and mixture thereof.

The compound of the invention has a significant inhibitory effect on the activity of IDO in Hela cells, preferably with an IC50 of less than 200nM, more preferably with an IC50 of less than 50 nM.

The compounds of the invention are therefore useful for treating or preventing IDO-mediated related diseases, including but not limited to cancer, immunosuppression, chronic infection, viral infection, autoimmune diseases or disorders (e.g., rheumatoid arthritis), neurological or neuropsychiatric diseases or disorders (e.g., depression), and the like. The compounds of the present invention are useful for treating or preventing IDO-associated tumors, including but not limited to prostate, colon, rectal, membrane adenocarcinoma, cervical, gastric, endometrial, brain, liver, bladder, ovarian, testicular, head and neck, skin (including melanoma and basal), mesothelial, lymphoma, leukemia, esophageal, breast, muscle, connective tissue, lung (including small cell lung and non-small cell), adrenal, thyroid, renal, bone, glioblastoma, mesothelioma, sarcoma (including kaposi's sarcoma), choriocarcinoma, basal cell carcinoma of the skin, or seminoma of the testes, and the like. Accordingly, in a further aspect, the present invention provides a method for treating or preventing IDO-mediated diseases (e.g., such as such tumors) comprising administering to a patient in need thereof a therapeutically effective amount of a compound of the present invention or a pharmaceutically acceptable salt, prodrug, stable isotopic derivative, isomer or mixture thereof, or a pharmaceutical composition comprising said compound.

another aspect of the invention relates to compounds of formula (I) or pharmaceutically acceptable salts, prodrugs, stable isotopic derivatives, isomers and mixtures thereof, for use as a medicament or for use in medicine in the treatment or prevention of IDO mediated diseases, such as cancer, immunosuppression, chronic infection, viral infection, autoimmune diseases or disorders (e.g., rheumatoid arthritis), neurological or neuropsychiatric diseases or disorders (e.g., depression), and the like.

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

Another aspect of the present invention relates to the use of a compound represented by the general formula (I) or a pharmaceutically acceptable salt, prodrug, stable isotope derivative, isomer, and mixture thereof, or the pharmaceutical composition thereof for the preparation of a medicament for the treatment or prevention of IDO-mediated diseases such as tumors and immunosuppression.

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

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

the pharmaceutical preparations of the present invention may be administered in dosage units containing a predetermined amount of the active ingredient per dosage unit. Such units may contain, for example, from 0.5 mg to 1g, preferably from 1mg to 700 mg, particularly preferably from 5 mg to 300 mg, of a compound of the 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 a daily dose or sub-dose, or corresponding fraction thereof, of the active ingredient as indicated above. In addition, pharmaceutical formulations of this type may be prepared using methods well known in the pharmaceutical art.

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

Detailed Description

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

The expression "Cx-y" as used herein denotes a range of numbers of carbon atoms, wherein x and y are both integers, e.g. C3-8 cycloalkyl denotes cycloalkyl having 3-8 carbon atoms, i.e. cycloalkyl having 3, 4,5, 6, 7 or 8 carbon atoms. It is also understood that "C3-8" also includes any subrange therein, such as C3-7, C3-6, C4-7, C4-6, C5-6, and the like.

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

"cycloalkyl" refers to a saturated cyclic hydrocarbyl substituent containing from 3 to 14 carbon ring atoms. Cycloalkyl groups may be monocyclic, typically containing 3 to 8, 3 to 7, or 3 to 6 carbon ring atoms. Non-limiting examples of monocyclic cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cycloheptyl. Cycloalkyl groups may alternatively be bi-or tricyclic fused together, such as decahydronaphthyl. The cycloalkyl group may be optionally substituted.

"Heterocyclyl or heterocycle" refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic group comprising 3 to 20 ring atoms, which may be, for example, 3 to 14, 3 to 12, 3 to 10, 3 to 8, 3 to 6 or 5 to 6 ring atoms, wherein one or more ring atoms are selected from nitrogen, oxygen or S (O) m (wherein m is an integer from 0 to 2), but not including the ring portion of-O-O-, -O-S-or-S-S-, the remaining ring atoms being carbon. Preferably 3 to 12 ring atoms, more preferably 3 to 10 ring atoms, more preferably 4 to 7 ring atoms, most preferably 5 or 6 ring atoms, of which 1 to 4 are heteroatoms, more preferably 1 to 3 are heteroatoms, most preferably 1 to 2 are heteroatoms. Non-limiting examples of monocyclic heterocyclyl groups include pyrrolidinyl, piperidinyl, piperazinyl, pyranyl, morpholinyl, thiomorpholinyl, homopiperazinyl, oxacyclohexanyl, and azetidinyl. Polycyclic heterocyclic groups include fused, bridged or spiro polycyclic heterocyclic groups such as octahydrocyclopenta [ c ] pyrrole, octahydropyrrolo [1,2-a ] pyrazine, 3, 8-diazabicyclo [3.2.1] octane, 5-azaspiro [2.4] heptane, 2-oxa-7-azaspiro [3.5] nonane and the like. The heterocyclic group or heterocycle may be optionally substituted.

"aryl or aromatic ring" means an aromatic monocyclic or fused polycyclic group containing 6 to 14 carbon atoms, preferably 6 to 10 membered, such as phenyl and naphthyl, most preferably phenyl. The aryl ring may be fused to a heteroaryl, heterocyclyl or cycloalkyl ring, wherein the ring attached to the parent structure is an aryl ring, non-limiting examples of which include:

The aryl or aromatic ring may be optionally substituted.

"heteroaryl or heteroaromatic ring" refers to a heteroaromatic system comprising 5 to 14 ring atoms, wherein 1 to 4 ring atoms are selected from heteroatoms including oxygen, sulfur and nitrogen. The heteroaryl group is preferably 5 to 10 membered. 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, heterocyclyl or cycloalkyl ring, wherein the ring joined together with the parent structure is a heteroaryl ring, non-limiting examples of which include:

The heteroaryl or heteroaryl ring may be optionally substituted.

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

"cyano" means-CN.

"optional" means that the subsequently described event or circumstance may, but need not, occur, and that the description includes instances where the event or circumstance occurs or does not. For example, "a heterocyclic group optionally substituted with an alkyl" means that an alkyl may, but need not, be present, and the expression includes the case where the heterocyclic group is substituted with an alkyl and the case where the heterocyclic group is not substituted with an alkyl.

"optionally substituted" means that one or more, preferably 5, more preferably 1 to 3, hydrogen atoms in the group are independently substituted with a corresponding number of substituents. It goes without saying that the substituents are only in their possible chemical positions, and that the person skilled in the art is able to determine (experimentally or theoretically) possible or impossible substitutions without undue effort. For example, amino or hydroxyl groups having free hydrogen may be unstable in combination with carbon atoms having unsaturated (e.g., olefinic) bonds. Such substituents include, but are not limited to, halogen, cyano, nitro, oxo, -SF5, C1-4 alkyl, C3-7 cycloalkyl, 4-7 membered heterocyclyl, phenyl, 5-6 membered heteroaryl, -OR ', -NR ' 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)2R ', -S (O) mR ' (m is 1 OR 2), -S (O)2NR ' R ', and the like, wherein the alkyl, cycloalkyl, OR heteroaryl is substituted with one OR more substituents selected from the group consisting of C, and C (O), C (R ') OR C (O) R ' -S, Heterocyclyl, phenyl OR heteroaryl are optionally substituted with one OR more substituents selected from halogen, cyano, C1-4 alkyl, C3-7 cycloalkyl, 4-7 membered heterocyclyl, 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) (') C (O) NR' R ', -N (R') S (O)2R ', -S (O) 2R', -S (O)2NR 'R', and the like. R ', R ", and R'" are each independently selected from H, C1-4 alkyl optionally containing a heteroatom selected from N, O and S, C3-7 cycloalkyl, 4-7 membered heterocyclyl, phenyl, or 5-6 membered heteroaryl, wherein said alkyl, cycloalkyl, heterocyclyl, phenyl, or heteroaryl is optionally substituted with one or more substituents selected from halogen, cyano, C1-4 alkyl, halo C1-4 alkyl, -O-C1-4 alkyl, and the like; r 'and R' on the same nitrogen atom optionally form together with the nitrogen atom to which they are attached a 4-7 membered heterocyclic ring optionally containing an additional heteroatom selected from O, S and N.

"isomers" refer to compounds having the same molecular formula but differing in the form or order of their atomic associations or the spatial arrangement of their atoms. Isomers differing in the arrangement of their atoms in space are referred to as "stereoisomers". Stereoisomers include optical isomers, geometric isomers and conformational isomers.

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

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

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

it is to be understood that the present invention includes any tautomeric or stereoisomeric form and mixtures thereof, and is not to be limited solely to any one tautomeric or stereoisomeric form used in the nomenclature or chemical structural formulae of the compounds.

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

by "prodrug" is meant that the compounds of the present invention can be administered in the form of a prodrug. Prodrugs refer to derivatives that are converted to the biologically active compounds of the present invention under physiological conditions in vivo, e.g., by oxidation, reduction, hydrolysis, and the like, each of which utilizes or proceeds without the participation of an enzyme. Examples of prodrugs are the following compounds: wherein an amino group in a compound of the invention is acylated, alkylated or phosphorylated, e.g. eicosanoylamino, alanylamino, pivaloyloxymethylamino, or wherein a hydroxyl group is acylated, alkylated, phosphorylated or converted to a borate, e.g. acetoxy, palmitoyloxy, pivaloyloxy, succinyloxy, fumaroyloxy, alanyloxy, or wherein a carboxyl group is esterified or amidated, or wherein a sulfhydryl group forms a disulfide bridge with a carrier molecule, e.g. a peptide, that selectively delivers a drug to a target and/or to the cytosol of a cell. These compounds can be prepared from the compounds of the present invention according to known methods.

"pharmaceutically acceptable salt" or "pharmaceutically acceptable salt" refers to salts prepared from pharmaceutically acceptable bases or acids, including inorganic bases or acids and organic bases or acids. 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 be present 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 can be present in the form of salts and can 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, propionic 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 also includes inner salts or betaine salts in addition to the salt forms mentioned. The salts can be obtained by conventional methods known to the person skilled in the art, for example by contacting these with organic or inorganic acids or bases in solvents or dispersants or by anion exchange or cation exchange with other salts.

"pharmaceutical composition" refers to a composition containing one or more of the compounds described herein, or pharmaceutically acceptable salts, prodrugs, stable isotopic derivatives, isomers, and mixtures thereof, as well as other components, such as pharmaceutically acceptable carriers and excipients. The purpose of the pharmaceutical composition is to facilitate administration to an organism, facilitate absorption of the active ingredient and exert biological activity.

Thus, when reference is made herein to "a compound", "a compound of the invention" or "a compound of the invention", all such compound forms are included, for example, pharmaceutically acceptable salts, prodrugs, stable isotopic derivatives, isomers and mixtures thereof.

as used herein, the term "tumor" includes both benign tumors and malignant tumors (e.g., cancers).

as used herein, the term "therapeutically effective amount" is meant to include an amount of a compound of the present invention that is effective to inhibit the function of IDO and/or treat or prevent the disorder in question.

Synthesis method

The invention also provides a method for preparing the compound. The preparation of the compounds of the general formula (I) according to the invention can be carried out by the following exemplary methods and examples, which should not be construed as limiting the scope of the invention in any way. The compounds of the invention may also be synthesized by synthetic techniques known to those skilled in the art, or a combination of methods known in the art and those described herein may be used. The product from each reaction step is obtained by separation techniques known in the art, including but not limited to extraction, filtration, distillation, crystallization, chromatography, and the like. The starting materials and chemicals required for the synthesis can be routinely synthesized or purchased according to the literature (available from SciFinder).

the octahydropentalene compound shown in the general formula (I) can be synthesized according to the route shown in the method A: the intermediate acid A2 is changed into acyl chloride or activated by an amide condensing agent, and then coupled with (hetero) arylamine A1 to obtain the target product amide compound A3.

The method A comprises the following steps:

Synthesizing achiral intermediate acid A2 according to a conventional method; chiral intermediate acid a2 can be synthesized according to the route described in method B: one ketone in B1 was protected with ethylene glycol and the other ketone was reacted with trifluoromethanesulfonic anhydride under basic conditions to give hydrocarbyl triflate B2; b2 is reacted with boric acid ester or boric acid C-B (OR)2 through Suzuki coupling reaction to obtain B3, which is hydrogenated, reduced and deprotected to generate B4; b4 carrying out Wittig reaction to generate mono-alkene (ester is hydrolyzed into acid in the reaction, otherwise, alkali is added to promote ester hydrolysis), and then hydrogenating and reducing to obtain acid B5; b5 is firstly reacted with acyl chloride (such as pivaloyl chloride) to generate anhydride under the catalysis of alkali, and then substituted by chiral auxiliary agent ((R) -4-benzyl oxazolidine-2-one lithium salt) to generate B6; b6 is dehydrogenated with strong base, reacted with methyl iodide to obtain B7, and finally hydrolyzed under the catalysis of base to obtain acid A2.

the method B comprises the following steps:

examples

The structure of the compounds is determined by Nuclear Magnetic Resonance (NMR) or Mass Spectrometry (MS). NMR was measured using a Bruker ASCEND-400 NMR spectrometer using deuterated dimethyl sulfoxide (DMSO-d6), deuterated chloroform (CDC13), and deuterated methanol (CD3OD) as solvents, Tetramethylsilane (TMS) as an internal standard, and chemical shifts given in units of 10-6 (ppm).

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

HPLC measurements were carried out using an Agilent 1260DAD high pressure liquid chromatograph (Poroshell120EC-C18, 50X 3.0mm, 2.7 μm column) or a Waters Arc high pressure liquid chromatograph (Sunfirc C18, 150X 4.6mm, 5 μm column).

The thin-layer chromatography silica gel plate adopts a Qingdao ocean GF254 silica gel plate, the specification of the silica gel plate used by the thin-layer chromatography (TLC) is 0.15-0.2 mm, and the specification of the thin-layer chromatography separation and purification product is 0.4-0.5 mm.

Column chromatography generally uses Qingdao ocean silica gel of 200-300 meshes as a carrier.

known starting materials of the present invention can be synthesized by or according to methods known in the art, or can be purchased from companies such as ABCR GmbH & Co. KG, Acros Organics, Aldrich Chemical Company, Shao Yuan Chemical technology (Accela ChemBio Inc.), Beijing coupling chemistry, and the like.

In the examples, unless otherwise specified, the reaction was carried out under an argon atmosphere or a nitrogen atmosphere.

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

The hydrogen atmosphere refers to a reaction flask connected with a hydrogen balloon with a volume of about 1L.

The hydrogenation reaction was usually evacuated and charged with hydrogen and repeated 3 times.

The microwave reaction was carried out using a CEM Discover-SP type microwave reactor.

in the examples, the reaction temperature was room temperature and the temperature range was 20 ℃ to 30 ℃ unless otherwise specified.

The progress of the reaction in the examples was monitored using an Agilent LC Mass spectrometer (1260/6120). The progress of the reaction can also be monitored by Thin Layer Chromatography (TLC) using a system of A: dichloromethane and methanol systems; b: petroleum ether and ethyl acetate, the volume ratio of the solvent is adjusted according to the polarity of the compound.

The system of eluents for column chromatography and developing agents for thin layer chromatography used for purifying compounds include a: dichloromethane and methanol systems; b: the volume ratio of the petroleum ether to the ethyl acetate is adjusted according to the polarity of the compound, or a small amount of triethylamine, an acidic or basic reagent and the like can be added for adjustment, or other solvent systems can be adopted. Purification of the Compounds Using Waters' Mass Spectrometry guided automated preparation System (Mass Spectroscopy: SQD2), reversed phase high pressure columns (Xbridge-C18, 19X 150mm, 5 μm) were eluted with appropriate acetonitrile/water (containing 0.1% trifluoroacetic acid or formic acid) or acetonitrile/water (containing 0.05% ammonia) gradients at flow rates of 20mL/min depending on the polarity of the compound.

Example 1

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

First step of

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

To a mixture of (3as,6as) -tetrahydro-pentalene-2, 5(1H,3H) -dione 1a (100g, 725mmol), ethylene glycol (40.4g, 652mmol) and toluene (1.6L) was added p-toluenesulfonic acid (12.4g, 72.4mmol), and the reaction mixture was heated to 100 ℃ and stirred for 10H. Cooled to room temperature and the solvent removed under reduced pressure. Water was added to the residue, which was extracted with ethyl acetate (500 mL. times.3). The organic phases were combined and dried over anhydrous sodium sulfate, filtered to remove the drying agent, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate ═ 3/1) to give the desired product (3aR,6aS) -tetrahydro-1H-spiro [ pentalene-2, 2' - [1,3] dioxan ] -5(3H) -one 1b (53g, yellow oil) in yield: 40 percent.

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

second step of

(3aR,6aS) -3,3a,4,6 a-tetrahydro-1H-spiro [ pentalene-2, 2' - [1,3] dioxan-5-yl trifluoromethanesulfonate

the compound (3aR,6aS) -tetrahydro-1H-spiro [ pentalene-2, 2' - [1,3] dioxolane ] -5(3H) -one 1b (52g, 287mmol) was dissolved in tetrahydrofuran (480mL), cooled to-50 deg.C, a solution of sodium bis (trimethylsilyl) amide in tetrahydrofuran (2M, 176.5mL, 344.3mmol) was added and stirred for 1 hour. N-phenylbis (trifluoromethanesulfonyl) imide (123g, 344.3mmol) was added, and the reaction was warmed to room temperature and stirred for 5 hours. Quenched with saturated ammonium chloride solution (350mL) and extracted with ethyl acetate (300 mL. times.3). The organic phases were combined and dried over anhydrous sodium sulfate, filtered to remove the drying agent, and concentrated under reduced pressure to give the desired product (3aR,6aS) -3,3a,4,6 a-tetrahydro-1H-spiro [ pentalene-2, 2' - [1,3] dioxan ] -5-yl trifluoromethanesulfonate 1c (72g, brown oil), yield: 80 percent.

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

the third step

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

The reaction mixture (3aR,6aS) -3,3a,4,6 a-tetrahydro-1H-spiro [ pentalene-2, 2'- [1,3] dioxan-5-yl trifluoromethanesulfonate 1c (9.55g, 30.4mmol), (2-methylpyridin-4-yl) boronic acid (5g, 36.5mmol), (1, 1' -bis (diphenylphosphino) ferrocene ] dichloropalladium dichloromethane complex (1.24g, 1.52mmol), sodium carbonate (6.44g, 60.8mmol), N-dimethylformamide (100mL) and water (10mL) were heated to 110 ℃ under nitrogen and stirred overnight. Cooled to room temperature and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (dichloromethane/methanol ═ 10/1) to give the desired product 2-methyl-4- ((3aR,6aS) -3,3a,4,6 a-tetrahydro-1H-spiro [ pentalene-2, 2' - [1,3] dioxolan ] -5-yl) pyridine 1d (6g, yellow oil) in yield: 77 percent.

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

The fourth step

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

the reaction mixture 2-methyl-4- ((3aR,6aS) -3,3a,4,6 a-tetrahydro-1H-spiro [ pentalene-2, 2' - [1,3] dioxolan ] -5-yl) pyridine 1d (6g, 23.3mmol), palladium on carbon (10%, 1.0g) and methanol (200mL) were stirred under a hydrogen atmosphere at room temperature overnight. Filtration and concentration under reduced pressure, and purification of the residue by silica gel column chromatography (petroleum ether/ethyl acetate ═ 2/1) gave the desired product 4- ((3aR,6aS) -hexahydro-1H-spiro [ pentalene-2, 2' - [1,3] dioxan ] -5-yl) -2-methylpyridine 1e (5g, light yellow oil) in yield: 83 percent.

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

The fifth step

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

compound 4- ((3aR,6aS) -hexahydro-1H-spiro [ pentalene-2, 2' - [1,3] dioxolan ] -5-yl) -2-methylpyridine 1e (5g, 19.3mmol) was dissolved in hydrogen chloride in dioxane (4M, 20mL) and methanol (20mL) and stirred at room temperature for 12H. Concentration under reduced pressure gave the desired product (3aR,6aS) -5- (2-methylpyridin-4-yl) hexahydropentalen-2 (1H) -one 1f (4g, yellow solid) in yield: 96 percent.

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

The sixth step

2- ((3aR,6aS, E) -5- (2-methylpyridin-4-yl) hexahydro-pent-2 (1H) -ylidene) acetic acid

Ethyl 2- (diethoxyphosphoryl) acetate (6.25g, 27.9mmol) was dissolved in tetrahydrofuran (100mL), cooled to 0 deg.C, added sodium hydride (60%, 1.5g, 37.2mmol), and stirred at 0 deg.C for 2 hours. A solution of (3aR,6aS) -5- (2-methylpyridin-4-yl) hexahydropentalen-2 (1H) -one 1f (4g, 18.6mmol) in tetrahydrofuran (100mL) was added, the mixture was warmed to room temperature, and the mixture was stirred for 11.5 hours. Adjusting the pH value of the solution to be weakly acidic, and concentrating under reduced pressure. The residue was dissolved in a mixed solvent of dichloromethane and methanol (10/1), filtered, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (dichloromethane/methanol ═ 10/1) to give the aimed product 2- ((3aR,6aS, E) -5- (2-methylpyridin-4-yl) hexahydropentalen-2 (1H) -ylidene) acetic acid 1g (1.5g, pale yellow oil), yield: 31 percent.

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

seventh step

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

The reaction mixture, 2- ((3aR,6aS, E) -5- (2-methylpyridin-4-yl) hexahydropentalen-2 (1H) -ylidene) acetic acid, 1g (1.5g, 5.83mmol), palladium on carbon (10%, 0.3g) and methanol (30mL) was stirred under a hydrogen atmosphere at room temperature for 8 hours. Filtration and concentration under reduced pressure gave the desired product, 2- ((3aR,6aS) -5- (2-methylpyridin-4-yl) octahydropentalen-2-yl) acetic acid, 1h (1.2g, light green oil), yield: 79 percent.

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

Eighth step

(4R) -4-benzyl-3- (2- ((3aR,6aS) -5- (2-methylpyridin-4-yl) octahydro-pentalen-2-yl) acetyl) oxazolidine-2-one

2- ((3aR,6aS) -5- (2-methylpyridin-4-yl) octahydropentalen-2-yl) acetic acid 1h (1.2g, 4.63mmol) was dissolved in dichloromethane (50mL), oxalyl chloride (2.94g, 23.1mmol) was added at 0 ℃, warmed to room temperature, and stirred for 1 h. The solvent was removed under reduced pressure to give the acid chloride intermediate. (R) -4-Benzyloxazolidin-2-one (0.985g, 5.56mmol) was dissolved in tetrahydrofuran (80mL), cooled to-78 deg.C, and a solution of n-butyllithium in n-hexane (2.5M, 2.8mL, 6.95mmol) was slowly added dropwise, after which time it was stirred at the same temperature for 1 hour. A solution of the above acid chloride in tetrahydrofuran (20mL) was then added and stirring continued at-78 deg.C for 1.5 hours. The reaction was quenched with saturated ammonium chloride solution and extracted with dichloromethane (50 mL. times.5). The organic phases were combined and dried over anhydrous sodium sulfate, desolventized under reduced pressure, and the residue was purified by silica gel column chromatography (dichloromethane/methanol ═ 5/1) to give the desired product (4R) -4-benzyl-3- (2- ((3aR,6aS) -5- (2-methylpyridin-4-yl) octahydropenten-2-yl) acetyl) oxazolidin-2-one 1i (1.4g, pale yellow solid), yield: 72 percent.

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

the ninth step

(4R) -4-benzyl-3- ((2R) -2- ((3aR,6aS) -5- (2-methylpyridin-4-yl) octahydro-pentalen-2-yl) propionyl) oxazolidine-2-one

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

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

The tenth step

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

(4R) -4-benzyl-3- ((2R) -2- ((3aR,6aS) -5- (2-methylpyridin-4-yl) octahydropent-2-yl) propionyl) oxazolidin-2-one 1j (0.35g, 0.81mmol) was dissolved in tetrahydrofuran (10mL) and water (2mL), cooled to 0 ℃ and aqueous hydrogen peroxide (30%, 2mL) and lithium hydroxide (78mg, 3.24mmol) were added 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 (20mL), and filtered. The filtrate was desolventized under reduced pressure, and the residue was purified by reverse phase high performance liquid chromatography to give the target product (2R) -2- ((3aR,6aS) -5- (2-methylpyridin-4-yl) octahydropentalen-2-yl) propanoic acid 1k (100mg, colorless oil), yield: 45 percent.

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

The eleventh step

(2R) -2- ((3aR,6aS) -5- (2-methylpyridin-4-yl) octahydropent-2-yl) propanoic acid 1k (40mg, 0.15mmol) was dissolved in dichloromethane (10mL), 2- (7-azabenzotriazole) -N, N, N ', N' -tetramethyluronium hexafluorophosphate (67mg, 0.18mmol) and N, N-diisopropylethylamine (28mg, 0.22mmol) were added and stirred at room temperature for 1 hour. Concentrating under reduced pressure to obtain active ester intermediate. 4-chloroaniline (21mg, 0.16mmol) was dissolved in N, N-dimethylformamide (2mL), and sodium hydride (60%, 12mg, 0.29mmol) was added and stirred at room temperature for 0.5 hour. A solution of the above active ester intermediate in N, N-dimethylformamide (3mL) was added and stirred at room temperature for 3 hours. The solvent was removed under reduced pressure, and the residue was purified by reverse phase high performance liquid chromatography to give the objective product (R) -N- (4-chlorophenyl) -2- ((2s,3aR,5R,6aS) -5- (2-methylpyridin-4-yl) octahydropentalen-2-yl) propionamide 1(7mg, white solid), yield: 12 percent.

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

H NMR(400MHz,CDOD)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＝5.3Hz,1H),3.05(tt,J＝12.2,6.2Hz,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 of

6-fluoro-4- ((3aR,6aS) -3,3a,4,6 a-tetrahydro-1H-spiro [ pentalene-2, 2' - [1,3] dioxolan ] -5-yl) quinoline

The reaction mixture (3aR,6aS) -3,3a,4,6 a-tetrahydro-1H-spiro [ pentalene-2, 2'- [1,3] dioxan-5-yl trifluoromethanesulfonate 1c (66g, 210mmol), (6-fluoroquinolin-4-yl) boronic acid (47g, 250mmol), sodium carbonate (56g, 525mmol), [1,1' -bis (diphenylphosphino) ferrocene ] dichloropalladium dichloromethane complex (8.5g, 10.5mmol), dioxane (1.2L) and water (250mL) was heated to 90 ℃ and reacted for 6 hours under nitrogen protection. Cooled to room temperature, diluted with water (200mL) and extracted with ethyl acetate (300 mL. times.3). The organic phases were combined and purified by silica gel column chromatography (petroleum ether/ethyl acetate ═ 1/1) to give the desired product 6-fluoro-4- ((3aR,6aS) -3,3a,4,6 a-tetrahydro-1H-spiro [ pentalene-2, 2' - [1,3] dioxan ] -5-yl) quinoline 2a (47.3g, tan oil) in yield: 73 percent.

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

second step of

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

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

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

The third step

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

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

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

The fourth step

2- ((3aR,5R,6aS, E) -5- (6-fluoroquinolin-4-yl) hexahydropentalen-2 (1H) -ylidene) acetic acid ethyl ester

Ethyl 2- (diethoxyphosphoryl) acetate (22g, 98.1mmol) was dissolved in tetrahydrofuran (400mL), cooled to 0 deg.C, and sodium hydride (60%, 2.9g, 122.7mmol) was slowly added and reacted under nitrogen for 0.5 h. Then, the reaction mixture was slowly added to a solution of (3aR,5s,6aS) -5- (6-fluoroquinolin-4-yl) hexahydropentalen-2 (1H) -one 2c (22g, 81.7mmol) in tetrahydrofuran (50mL) and reacted at room temperature for 6 hours. Water (300mL) was added to dilute the solution, and the solution was extracted with ethyl acetate (200 mL. times.3). The organic phases were combined and concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate ═ 1/1) to give the desired product ethyl 2- ((3aR,5R,6aS, E) -5- (6-fluoroquinolin-4-yl) hexahydropentalen-2 (1H) -ylidene) acetate 2d (17g, yellow oil), yield: 61 percent.

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

The fifth step

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

The reaction mixture was ethyl 2- ((3aR,5R,6aS, E) -5- (6-fluoroquinolin-4-yl) hexahydropentalen-2 (1H) -ylidene) acetate 2d (17g, 50.15mmol), palladium on carbon (10%, 1g) and methanol (200mL) reacted under a hydrogen atmosphere at room temperature for 4 hours. Filtering, and concentrating the filtrate under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate ═ 1/1) to give the desired product ethyl 2- ((3aR,5r,6aS) -5- (6-fluoroquinolin-4-yl) octahydropentalen-2-yl) acetate 2e (16.7g, yellow oil), yield: 98 percent.

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

The sixth step

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

ethyl 2- ((3aR,5r,6aS) -5- (6-fluoroquinolin-4-yl) octahydropentalen-2-yl) acetate 2e (15.3g, 45mmol) was dissolved in ethanol (200mL) and water (50mL), and sodium hydroxide (3.6g, 90mmol) was added, heated to 70 ℃ and reacted for 4 hours. The organic solvent was removed by concentration under reduced pressure, the reaction mixture was adjusted to pH 4 with dilute hydrochloric acid (2M), and extracted with methylene chloride (30 mL. times.3). The organic phases were combined and concentrated under reduced pressure to give the desired product 2- ((3aR,5r,6aS) -5- (6-fluoroquinolin-4-yl) octahydropentalen-2-yl) acetic acid 2f (12.1g, yellow solid), yield: 87 percent.

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

seventh step

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

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

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

The suspension was cooled to-78 ℃ and then a pale yellow solution which had been cooled to-78 ℃ was added. The reaction mixture was gradually warmed to room temperature and stirring was continued for 3 hours. To the reaction mixture was added a saturated ammonium chloride solution (100mL), and extracted with ethyl acetate (100 mL. times.3). The organic phases were combined and washed with saturated brine (20 mL. times.2). After drying over anhydrous sodium sulfate and filtration, the solvent was removed from the filtrate under reduced pressure, and the residue was purified by silica gel column chromatography (dichloromethane/methanol ═ 9/1) to give the desired product (4R) -4-benzyl-3- (2- ((3aR,5R,6aS) -5- (6-fluoroquinolin-4-yl) octahydropentalen-2-yl) acetyl) oxazolidin-2-one 2g (510mg, off-white solid) in yield: 85 percent.

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

Eighth step

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

2g (510mg, 1.08mmol) of compound (4R) -4-benzyl-3- (2- ((3aR,5R,6aS) -5- (6-fluoroquinolin-4-yl) octahydropental-2-yl) acetyl) oxazolidin-2-one was dissolved in anhydrous tetrahydrofuran (30mL), cooled to-50 ℃ and then a solution of sodium bis (trimethylsilyl) amide in tetrahydrofuran (2M, 1.1mL, 2.2mmol) was added. After stirring for 30 minutes, methyl iodide (460mg, 3.24mmol) was added at this temperature and stirring was continued for 3 hours. After quenching with saturated ammonium chloride solution (10mL), the temperature was gradually raised to room temperature, followed by extraction with ethyl acetate (50 mL. times.2). The organic phases were combined and washed with saturated brine (20 mL). After drying over anhydrous sodium sulfate and filtration, the solvent was removed from the filtrate under reduced pressure, and the residue was purified by silica gel column chromatography (dichloromethane/methanol ═ 9/1) to give the desired product (4R) -4-benzyl-3- ((2R) -2- ((3aR,5R,6aS) -5- (6-fluoroquinolin-4-yl) octahydropenten-2-yl) propionyl) oxazolidin-2-one 2h (450mg, off-white solid), yield: 86 percent.

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

The ninth step

(2R) -2- ((3aR,5R,6aS) -5- (6-fluoroquinolin-4-yl) octahydropentalen-2-yl) propanoic acid

Compound (4R) -4-benzyl-3- ((2R) -2- ((3aR,5R,6aS) -5- (6-fluoroquinolin-4-yl) octahydropentalen-2-yl) propionyl) oxazolidin-2-one 2h (450mg, 0.92mmol) and tetrahydrofuran (15mL) were mixed, cooled to 0 ℃ and then 35% hydrogen peroxide solution (0.5mL) and aqueous lithium hydroxide solution (1N, 1mL, 1mmol) were added in that order. After gradually warming to room temperature, stirring was continued for 1 hour. It was cooled again to 0 ℃ and formic acid (0.5mL) was added slowly, and then the solvent was removed under reduced pressure. The residue was purified by reverse phase high performance liquid chromatography to give the desired product (2R) -2- ((3aR,5R,6aS) -5- (6-fluoroquinolin-4-yl) octahydropentalen-2-yl) propanoic acid 2i (250mg, light yellow solid), yield: 83 percent.

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

The tenth step

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

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

H NMR(400MHz,CDOD)δ8.98(d,J＝5.5Hz,1H),8.29–8.19(m,2H),7.96(d,J＝ 5.5Hz,1H),7.90(ddd,J＝9.3,8.0,2.7Hz,1H),7.65–7.53(m,2H),7.37–7.26(m,2H),4.16– 4.03(m,1H),2.82(dt,J＝15.8,7.8Hz,2H),2.48(td,J＝17.3,8.5Hz,2H),2.40(dt,J＝ 15.7,6.8Hz,1H),2.31(dt,J＝13.6,7.4Hz,2H),2.12(dd,J＝12.5,6.5Hz,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) octahydropentalen-2-yl) -N- (4- (pentafluoro-lambda 6-sulfanyl) phenyl) propanamide

The compound (2R) -2- ((3aR,5R,6aS) -5- (6-fluoroquinolin-4-yl) octahydropentalen-2-yl) propanoic acid 2i (60mg, 0.18mmol) and 4- (pentafluoro-. lamda.6-sulfanyl) aniline 3a (118mg, 0.54mmol) were dissolved in dichloromethane (10mL) and 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (118mg, 0.54mmol) was added. After stirring at room temperature for 5 hours, the solvent was removed under reduced pressure, and the residue was purified by reverse phase high performance liquid preparative chromatography to give the objective product (R) -2- ((2s,3aR,5R,6aS) -5- (6-fluoroquinolin-4-yl) octahydropentalen-2-yl) -N- (4- (pentafluoro- λ 6-sulfanyl) phenyl) propionamide 3(12mg, white solid), yield: 12 percent.

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

H NMR(400MHz,CDOD)δ8.98(d,J＝5.5Hz,1H),8.23(dt,J＝10.0,3.7Hz,2H), 7.95(d,J＝5.5Hz,1H),7.89(ddd,J＝9.3,8.0,2.7Hz,1H),7.84–7.72(m,4H),4.14–4.02 (m,1H),2.82(dt,J＝15.8,7.9Hz,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＝11.9,8.4Hz,2H),1.31–1.15(m,5H)。

Example 4

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

The compound (2R) -2- ((3aR,5R,6aS) -5- (6-fluoroquinolin-4-yl) octahydropentalen-2-yl) propanoic acid 2i (100mg, 0.31mmol) and 6-methoxypyridin-3-amine 4a (114mg, 0.93mmol) were dissolved in dichloromethane (12mL) and 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (178mg, 0.93mmol) was added. After stirring at room temperature for 3 hours, the solvent was removed under reduced pressure, and the residue was purified by reverse phase high performance liquid preparative chromatography to give the objective product (R) -2- ((2s,3aR,5R,6aS) -5- (6-fluoroquinolin-4-yl) octahydropentalen-2-yl) -N- (6-methoxypyridin-3-yl) propionamide 4(57mg, white solid) in yield: 38 percent.

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

H NMR(400MHz,CDOD)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) octahydropentalen-2-yl) propanamide

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

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

H NMR(400MHz,CDOD)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＝9.1Hz,1H),4.27–4.12(m,1H),2.86(s,2H),2.64(dd,J ＝14.6,7.5Hz,1H),2.57–2.46(m,2H),2.35(ddd,J＝24.5,12.0,6.2Hz,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 all synthesized according to the procedure of example 5, but with a different aromatic amine being used instead of 5-chloropyridin-2-amine 5a, the characterization data being shown in the following table:

Example 6

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

First step of

(3aS,6aS) -5- (((trifluoromethyl) sulfonyl) oxo) -3,3a,4,6 a-tetrahydrocyclopenta [ c ] pyrrole-2 (1H) -carboxylic acid tert-butyl ester

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

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

Second step of

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

The compound (3aS,6aS) -5- (((trifluoromethyl) sulfonyl) oxo) -3,3a,4,6 a-tetrahydrocyclopenta [ c ] pyrrole-2 (1H) -carboxylic acid tert-butyl ester 6b (crude, 20g, 22.2mmol), 6-fluoro-4- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) quinoline (4.9g, 22.2mmol), sodium carbonate (4.8g, 44.4mmol), [1,1' -bis (diphenylphosphino) ferrocene ] dichloropalladium dichloromethane complex (726mg, 0.89mmol), 1, 4-dioxane (100mL) and water (20mL) were heated to 100 ℃ under nitrogen and reacted for 3 hours. Water (200mL) was added for dilution, and the mixture was extracted with methylene chloride (100 mL. times.2). The organic phases were combined and dried over anhydrous sodium sulfate, filtered to remove the drying agent, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate ═ 3/1) to give the target product (3aS,6aR) -5- (6-fluoroquinolin-4-yl) -3,3a,4,6 a-tetrahydrocyclopenta [ c ] pyrrole-2 (1H) -carboxylic acid tert-butyl ester 6c (7g, yellow oil) in yield: 89 percent.

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

The third step

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

The reaction mixture (3aS,6aR) -5- (6-fluoroquinolin-4-yl) -3,3a,4,6 a-tetrahydrocyclopenta [ c ] pyrrole-2 (1H) -carboxylic acid tert-butyl ester 6c (7g, 19.8mmol), palladium on carbon (10%, 1g) and methanol (100mL) was stirred at room temperature for 4 hours under a hydrogen atmosphere. Filtration and concentration of the filtrate under reduced pressure gave the desired product (3aR,6aS) -5- (6-fluoroquinolin-4-yl) hexahydrocyclopenta [ c ] pyrrole-2 (1H) -carboxylic acid tert-butyl ester 6d (6g, yellow solid) in yield: 85 percent.

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

The fourth step

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

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

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

The fifth step

Tert-butyl 2- ((3aR,6aS) -5- (6-fluoroquinolin-4-yl) hexahydrocyclopenta [ c ] pyrrol-2 (1H) -yl) propionate

The reaction mixture was stirred for 2h at room temperature for 6-fluoro-4- ((3aR,6aS) -octahydrocyclopenta [ c ] pyrrol-5-yl) quinoline 6e (61% content, 470mg, 0.98mmol), tert-butyl 2-bromopropionate (308mg, 1.47mmol), potassium carbonate (271mg, 1.96mmol) and acetonitrile (10 mL). Water (50mL) was added for dilution, and extraction was performed with methylene chloride (30 mL. times.3). The organic phases were combined and dried over anhydrous sodium sulfate, filtered to remove the drying agent, and concentrated under reduced pressure to give the desired product tert-butyl 2- ((3aR,6aS) -5- (6-fluoroquinolin-4-yl) hexahydrocyclopenta [ c ] pyrrol-2 (1H) -yl) propanoate 6f (780mg, yellow oil). The product was used directly in the next reaction without further purification.

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

The sixth step

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

The compound tert-butyl 2- ((3aR,6aS) -5- (6-fluoroquinolin-4-yl) hexahydrocyclopenta [ c ] pyrrol-2 (1H) -yl) propanoate 6f (crude, 780mg, 0.98mmol) was dissolved in tetrahydrofuran (10mL) and concentrated hydrochloric acid (3mL), heated to 40 ℃ and stirred for 2H. Cooled to room temperature and concentrated under reduced pressure to give the desired product, 2- ((3aR,6aS) -5- (6-fluoroquinolin-4-yl) hexahydrocyclopenta [ c ] pyrrol-2 (1H) -yl) propionic acid, 6g (470mg, yellow oil). The product was used directly in the next reaction without further purification.

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

seventh step

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

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

HNMR(400MHz,CDOD)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＝8.5Hz,2H),4.56–3.34(m,8H),2.60(brs,2H),2.08 (brs,2H),1.75(brs,3H)。

IDO intracellular Activity inhibition assay

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

the experimental principle is summarized as follows: in the absence of any induction, the expression of IDO in Hela cells was low, but IFN-. gamma.at a certain concentration was able to induce the expression of IDO in Hela cells, causing them to catalyze tryptophan to form N-formyl kynurenine, which was hydrolyzed by trichloroacetic acid to form kynurenine, and then to undergo a color reaction with Ehrlich reagent, whereby the activity of IDO was detected, and the absorbance at 490nm (OD490) was proportional to the activity of IDO.

Compounds were dissolved and diluted to 5mM in DMSO (Sigma, cat # D5879) and then serially diluted 3-fold in DMSO to a minimum concentration of 2.29. mu.M, with 50-fold dilutions in FBS-free DMEM medium (ThermoFisher, cat # 11995073) at each concentration point. If compound IC50 values are very low, the initial concentration of compound can be reduced. Hela cells (ATCC, cat # CCL-2) were cultured in DMEM complete medium containing 10% FBS (GBICO, cat # 10099-141) and 100U/mL mixed solution of penicillin (ThermoFisher, cat # 15140122), when the coverage of the cells in the culture vessel reached 80-90%, they were seeded in 96-well plates (Corning, cat # 3599) after digestion with 0.25% trypsin (containing EDTA) (ThermoFisher, cat # 25200056), 30000 cells per well (80. mu.L of DMEM medium), and then the 96-well plates were cultured overnight (18-20 hours) in a 37 ℃ and 5% CO2 incubator.

After overnight, 10. mu.L of DMEM diluted compound, and 10. mu.L of 500ng/mL INF-. gamma.was added to each well and gently mixed. The 96-well plate was further incubated at 37 ℃ in an incubator containing 5% CO2, and after 24 hours, the plate was centrifuged at 2000 Xg for 5 minutes at room temperature, and then the supernatant was transferred to a reaction plate (Sigma; cat. No. CLS3695), and one twentieth of trichloroacetic acid (Sigma; cat. No. T9159) was added thereto, and the mixture was mixed well and incubated at 60 ℃. After 30 minutes, the plate was centrifuged at 2000 Xg for 5 minutes at room temperature, the supernatant was transferred to a clean plate, an equal volume of Ehrlich reagent was added, mixed and incubated at room temperature, and the OD490 was measured after 15 minutes for each well.

In the experiment, IFN-gamma is not added, and a DMEM culture medium is used for replacing OD490 of a group to be used as OD 490100% inhibition; OD490 of the group with IFN-. gamma.added and final DMSO concentration of 0.2% was taken as OD 4900% inhibition. The percentage of compound inhibition of IDO activity in Hela cells can be calculated using the following formula:

Percent inhibition 100-

Compound IC50 values were derived from 8 concentration points fitted with XLfit (ID Business Solutions ltd., UK) software using the following formula:

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

Wherein Y is the inhibition percentage, Bottom is the Bottom platform value of the S-shaped curve, Top is the Top platform value of the S-shaped curve, X is the logarithm value of the concentration of the compound to be detected, and slope factor is the slope coefficient of the curve.

Activity data for some representative example compounds are as follows:

Compound numbering	IC₅₀	Compound numbering	IC₅₀
				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 compounds of the examples of the present invention each had a significant inhibitory effect on the activity of IDO in cells, preferably with an IC50 of less than 200nM, more preferably with an IC50 of less than 50 nM.

Claims

1. A compound of the general formula (I):

r3 and R4 are each independently selected from H or C1-4 alkyl;

a is N or CR 5;

B is N or CR 6;

L is a bond, -O-or-CR 7R 8-;

2. the compound according to claim 1, or pharmaceutically acceptable salts, prodrugs, stable isotopic derivatives, isomers and mixtures thereof, wherein:

R3 and R4 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-;

3. The compound according to claim 1 or 2, or pharmaceutically acceptable salts, prodrugs, stable isotopic derivatives, isomers and mixtures thereof, which is a compound of the following general formula (II):

wherein:

ring D is an optionally substituted benzene or pyridine ring;

r1 and R2 are each independently selected from H or C1-4 alkyl;

A is N or CH;

4. The compound according to any one of the preceding claims, or pharmaceutically acceptable salts, prodrugs, stable isotopic derivatives, isomers and mixtures thereof, wherein ring D is a phenyl ring or a pyridine ring optionally substituted with halogen, cyano, -SF5, C1-4 alkyl, halo-substituted C1-4 alkyl, -O-C1-4 alkyl or-O-halo-substituted C1-4 alkyl.

5. The compound according to any one of the preceding claims, which is a compound of the following general formulae (IIIa) to (IIIc):

wherein:

ring D, R1, A and C are as defined in claims 1-4.

6. the compound according to any one of the preceding claims, which is a compound of the following general formula (IV):

Wherein:

The definition of ring D and R1 is as described in claims 1-4.

7. A compound according to any one of the preceding claims, or a pharmaceutically acceptable salt, prodrug, stable isotopic derivative, isomer and mixture thereof, selected from the group consisting of:

8. A pharmaceutical composition comprising a compound according to any one of claims 1 to 7 or a pharmaceutically acceptable salt, prodrug, stable isotope derivative, isomer and mixture forms thereof and a pharmaceutically acceptable carrier and excipient.

9. a pharmaceutical composition comprising a compound according to any one of claims 1-7 or a pharmaceutically acceptable salt, prodrug, stable isotope derivative, isomer, and mixture form thereof and at least one additional pharmaceutical agent, wherein the at least one additional pharmaceutical agent is a chemotherapeutic agent, an immune and/or inflammatory modulator, a neuro-related disorder modulator, or an anti-infective agent.

10. The pharmaceutical composition of claim 9, wherein the at least one additional drug is an immune checkpoint inhibitor.

11. Use of a compound according to any one of claims 1 to 7 or a pharmaceutically acceptable salt, prodrug, stable isotope derivative, isomer and mixture thereof or a pharmaceutical composition according to any one of claims 8 to 10 for the manufacture of a medicament for the treatment and/or prophylaxis of IDO-mediated diseases associated therewith, in particular tumors, wherein the tumor is selected from the group consisting of 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, mesothelial intimal cancer, 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.