Substituted phenyl group-containing 2, 3-dihydroquinazoline derivative as well as preparation method and application thereof

Abstract

The invention belongs to the technical field of medicine development, and discloses a substituted phenyl group-containing 2, 3-dihydroquinazoline derivative as well as a preparation method and application thereof. Specifically, the invention relates to a compound in claim 1, and a stereoisomer and a pharmaceutically acceptable salt thereof, as described in the specification. The invention also relates to a pharmaceutical composition comprising the compound of the invention, the use of the compound of the invention in the preparation of a medicament for a method for treating and / or preventing diseases or conditions related to overexpression of indoleamine 2, 3-dioxygenase (IDO-1), and a method for treating related diseases by using the compound of the invention. The compound provided by the invention has effective IDO-1 inhibitory activity.

Description

Technical Field

[0001] The present invention belongs to the technical field of pharmaceutical development, and particularly relates to a class of substituted phenyl 2,3-dihydroquinazoline derivatives having IDO-1 inhibitory activity as shown in claim 1, a preparation method thereof, a pharmaceutical composition containing them, and their use as IDO-1 small molecule inhibitors, and the use of such compounds in the preparation of anti-tumor drugs. Background Art

[0002] Tryptophan is one of the essential amino acids for human growth and metabolism, and is a necessary nutrient for the synthesis of proteins and neurotransmitters in the human body. Tryptophan in the body is mainly degraded through two metabolic pathways: (1) about 5% of tryptophan is metabolized by tryptophan hydroxylase to generate 5-hydroxytryptamine; (2) about 95% of tryptophan is metabolized to generate kynurenine under the action of indoleamine 2,3-dioxygenase or tryptophan 2,3-dioxygenase, and kynurenine is further decomposed into 3-hydroxyanthranilic acid, quinolinic acid or kynurenic acid through different pathways. Kynurenine and 3-hydroxyanthranilic acid participate in the regulation of lymphocyte activity and thus cause immunosuppression.

[0003] Indoleamine 2,3-dioxygenase 1 (IDO-1, EC1.13.11.42) is a protease related to tryptophan metabolism. The IDO-1 gene of humans is encoded on human chromosome 8, consists of 10 exons and 9 introns, and has a length of about 15 kb. The human IDO-1 protein is composed of 403 amino acid residues and has a molecular weight of about 42 kDa. IDO-1 contains a heme monomer protein, uses superoxide anion as a cofactor, and catalyzes the cleavage of the indole ring of L-tryptophan by oxidation. In 2007, scientists discovered indoleamine 2,3-dioxygenase 2 (IDO-2). The IDO-2 gene is located downstream of the IDO-1 gene, and the gene sequences of IDO-2 and IDO-1 are highly similar. IDO-2 can also catalyze the degradation of tryptophan, but compared with IDO-1, the activity of IDO-2 is lower and it does not play a leading role. IDO-2 is closely related to IDO-1 and may jointly regulate some physiological functions.

[0004] The IDO of mammals is distributed in tissue cells other than the liver, including macrophages, dendritic cells DC, monocytes, astrocytes, microglia, tumor cells and tumor-related cells, etc. TDO is mainly expressed in the liver. In healthy human bodies, the expression level of IDO is relatively low.

[0005] Studies in pregnant mouse models have found that syncytiotrophoblast cells and antigen-presenting cells at the maternal-fetal interface can synthesize IDO, and the dynamic changes in IDO expression are consistent with embryo formation. If the synthesis of IDO is specifically blocked, it can lead to miscarriage in mice, indicating that the high expression of indoleamine 2,3-dioxygenase in placental tissue can prevent immune rejection of the fetus. The experimental results prove that the high expression of indoleamine 2,3-dioxygenase in tissue cells can lead to the inhibition of the immune system in the tissue microenvironment, or immune suppression or immune checkpoint. One of the mechanisms leading to immune suppression is that the high expression of indoleamine 2,3-dioxygenase causes local L-tryptophan depletion, which is then sensed by surrounding lymphocytes through mechanisms such as GCN2, causing CD8 + cytotoxic T cells to undergo cell cycle arrest or apoptosis. Another mechanism leading to immune suppression may be that the high expression of indoleamine 2,3-dioxygenase causes an increase in kynurenine. After kynurenine is formed, it leaves the cell and enters the extracellular matrix, and then enters nearby lymphocytes to regulate CD8 + T cells and regulatory Treg cells. The activity of CD8+ cytotoxic T cells is inhibited, while the number of regulatory Treg cells increases and is activated, resulting in immune suppression.

[0006] IDO activation is closely related to the pathogenesis of many diseases. Abnormal high expression of indoleamine 2,3-dioxygenase occurs in many different types of tumors, including hematological tumors and solid tumors such as colorectal cancer, liver cancer, lung cancer, pancreatic cancer, and throat cancer. Tumor cells can recruit dendritic cells expressing IDO-1 into the tumor microenvironment, so high expression of IDO-1 also exists in various tumor tissues and draining lymph nodes in humans, such as ovarian cancer, lung cancer, chronic lymphocytic leukemia, etc. Its expression plays an important regulatory role in inhibiting T cell immunity and inducing tumor immune tolerance. The abnormal high expression of indoleamine 2,3-dioxygenase is positively correlated with poor tumor prognosis. The abnormal high expression of indoleamine 2,3-dioxygenase in tumors may be a major mechanism for tumor cells to escape immune surveillance.

[0007] Inhibiting the activity of indoleamine 2,3-dioxygenase may activate the suppressed immune system and achieve the effect of inhibiting tumor growth. Therefore, indoleamine 2,3-dioxygenase inhibitors, as a type of immune checkpoint inhibitor, have attracted great interest in the medical community.

[0008] Many metabolites in the kynurenine metabolic pathway of tryptophan are related to schizophrenia, depression, and neuronal degeneration. Indoleamine 2,3-dioxygenase inhibitors may also be used for the treatment of these diseases. Kynurenine can be converted into kynurenic acid under the catalysis of kynurenine aminotransferase. Kynurenic acid is an NMDA antagonist, and higher levels of kynurenic acid are commonly found in the central nervous system of schizophrenia patients. Quinolinic acid has neurotoxicity and can lead to neuronal apoptosis and neurodegeneration. Indoleamine 2,3-dioxygenase not only participates in tryptophan metabolism but also participates in the metabolism of tryptamine, etc. Serotonin can be converted into 5-hydroxyindoleacetic acid under the catalysis of indoleamine 2,3-dioxygenase. The decrease in serotonin may be one of the factors leading to depression.

[0009] Therefore, IDO-1 inhibitors may be able to liberate the body's defense system, help T cells better attack tumors, and have the potential to treat a wide range of tumor types. Although IDO-1 inhibitors have broad application prospects, no IDO-1 inhibitor has been marketed so far. Therefore, searching for and developing novel and highly efficient IDO-1 inhibitors has important theoretical significance and application value. Currently, the research and development of indoleamine 2,3-dioxygenase inhibitors include Indoximod of NewLink, NLG-919 (IDO / TDO dual specificity), Epacadostat (INCB024360) of Incyte, and IDO or TDO inhibitors of companies such as BMS, Pfizer, Flexus, Iomet, Iteos, and Curadev.

[0010] In order to discover more drug-like and highly inhibitory IDO-1 small molecule inhibitors, the inventors found a class of 2,3-dihydroquinazoline derivatives containing substituted phenyl groups, which have high in vitro inhibitory activity against indoleamine 2,3-dioxygenase (IDO-1) and can be widely used in the treatment or prevention of diseases such as cancer or tumors. Summary of the Invention

[0011] The technical problem to be solved by the present invention is to provide a compound with a novel structure and strong activity that has an IDO-1 inhibitory effect. The inventors found that a class of 2,3-dihydroquinazoline derivatives containing substituted phenyl groups has IDO-1 inhibitory activity. We found that this class of compounds has good IDO-1 inhibitory activity and can be used for the preparation of drugs for the prevention and treatment of tumors related to IDO-1-mediated immune escape. The present invention is completed based on the above findings.

[0012] The first aspect of the present invention provides the compound shown in claim 1 and its pharmaceutically acceptable salts:

[0013]

[0014]

[0015]

[0016] A compound according to any one of the first aspect of the present invention, wherein the compound is the compound shown in claim 1 or a pharmaceutically acceptable salt thereof.

[0017] A compound according to any one of the first aspect of the present invention, which is the target compound of the present invention prepared in the examples (represented by a structural formula or described by a systematic name) and its stereoisomers, and pharmaceutically acceptable salts thereof.

[0018] The second aspect of the present invention provides a method for preparing the compound according to any one of the first aspect of the present invention, which comprises the following steps:

[0019] Method:

[0020]

[0021] Experimental conditions: (a) Using A as a raw material, reacting with compound B under alkaline conditions to obtain compound C

[0022] Preferably (a) N,N-diisopropylethylamine, ethanol, heating under reflux (90 °C)

[0023] R 1 、R 2 、R 3 、R 4 、R 5 have the same definitions as those defined above.

[0024] The third aspect of the present invention provides a pharmaceutical composition, which comprises a therapeutically and / or prophylactically effective amount of the compound according to any one of the first aspect of the present invention, a pharmaceutically acceptable salt thereof, and optionally one or more pharmaceutically acceptable carriers or excipients.

[0025] The fourth aspect of the present invention provides the use of the compound according to any one of the first aspect of the present invention, a pharmaceutically acceptable salt thereof, or the pharmaceutical composition according to any one of the third aspect of the present invention in the preparation of a drug for treating and / or preventing a disease or disorder related to overactive IDO-1 activity or overexpression of IDO-1. In one embodiment, the disease or disorder related to overactive IDO-1 activity or overexpression of IDO-1 is a disease or disorder selected from the following: tumors.

[0026] The fourth aspect of the present invention also provides the use of the compound according to any one of the first aspect of the present invention, a pharmaceutically acceptable salt thereof, or the pharmaceutical composition according to any one of the third aspect of the present invention in the preparation of a drug for treating and / or preventing tumors.

[0027] The fourth aspect of the present invention further provides the use of the compound according to any one of the first aspect of the present invention, its pharmaceutically acceptable salt, or the pharmaceutical composition according to any one of the third aspect of the present invention in the preparation of a drug as an IDO-1 inhibitor.

[0028] The fifth aspect of the present invention provides a method for treating and / or preventing a disease or disorder associated with excessive IDO-1 activity or IDO-1 overexpression in a subject in need thereof, the method comprising administering to the subject in need thereof a therapeutically and / or prophylactically effective amount of the compound according to any one of the first aspect of the present invention, its pharmaceutically acceptable salt, or the pharmaceutical composition according to any one of the third aspect of the present invention. According to the method of any one of the fifth aspect of the present invention, wherein the disease or disorder associated with excessive IDO-1 activity or IDO-1 overexpression is selected from tumors.

[0029] The fifth aspect of the present invention further provides a method for treating and / or preventing tumors in a subject in need thereof, the method comprising administering to the subject in need thereof a therapeutically and / or prophylactically effective amount of the compound according to any one of the first aspect of the present invention, its pharmaceutically acceptable salt, or the pharmaceutical composition according to any one of the third aspect of the present invention.

[0030] The sixth aspect of the present invention provides the compound according to any one of the first aspect of the present invention, its pharmaceutically acceptable salt, for treating and / or preventing a disease or disorder associated with excessive IDO-1 activity or IDO-1 overexpression. According to the compound of the sixth aspect of the present invention, wherein the disease or disorder associated with excessive IDO-1 activity or IDO-1 overexpression is selected from: tumors.

[0031] The sixth aspect of the present invention further provides the compound according to any one of the first aspect of the present invention, its pharmaceutically acceptable salt, for treating and / or preventing tumors.

[0032] Any feature possessed by any aspect of the present invention or any item of that aspect equally applies to any other aspect or any item of that other aspect, provided that they do not conflict with each other. Of course, when applicable to each other, the corresponding features may be appropriately modified if necessary. In the present invention, for example, when referring to "any one of the first aspect of the present invention", the "any one" refers to any sub-aspect of the first aspect of the present invention, and when referred to in a similar manner in other aspects, it has a similar meaning.

[0033] Beneficial technical effects

[0034] Some of the compounds in the present invention all have strong in vitro IDO-1 inhibitory activity (IC 50(<10 μM), indicating that such compounds have significant IDO-1 inhibitory activity. The content of this study provides a class of IDO-1 inhibitors with novel structures and strong activities, which can be used to prepare drugs for preventing and treating cancer or tumors and their related diseases. Detailed implementation manners

[0035] The present invention can be further described by the following examples. However, the scope of the present invention is not limited to the following examples. Those skilled in the art can understand that various changes and modifications can be made to the present invention without departing from the spirit and scope of the present invention. The present invention generally and / or specifically describes the materials and test methods used in the experiments.

[0036] For all the following examples, standard operations and purification methods known to those skilled in the art can be used. Unless otherwise specified, all temperatures are expressed in °C (degrees Celsius). The structures of the compounds are determined by nuclear magnetic resonance spectroscopy (NMR).

[0037] Example Part

[0038] I. Synthesis of compounds

[0039] The structures of the compounds are determined by proton nuclear magnetic resonance spectroscopy (NMR). The nuclear magnetic resonance chemical shift (δ) is given in parts per million (ppm). The nuclear magnetic resonance spectra are measured using a Mercury-400 nuclear magnetic resonance spectrometer, with deuterated methanol (CD 3 OD) or deuterated chloroform (CDCl 3 ) or deuterated dimethyl sulfoxide (DMSO-d6) as the solvent and tetramethylsilane (TMS) as the internal standard.

[0040] The electronic balance uses the PL303 electronic balance of METTLER TOLEDO. Column chromatography generally uses silica gel with 200 - 300 mesh as the carrier. Anhydrous solvents are all treated by standard methods. Other reagents are all commercially available analytical pure. Among them, DIPEA is N,N-diisomromylethylamine, that is, N,N-diisopropylethylamine.

[0041] In the synthesis steps of Examples 1 - 20 in the patent application, specific implementations are slightly modified according to the final products:

[0042]

[0043] Experimental conditions: (a) N,N-diisopropylethylamine, ethanol, heating under reflux (90 °C)

[0044] Step a: To a solution of Compound 1 (1.05 mmol) in anhydrous ethanol (10 mL) was added DIPEA (258.5 mg, 2.00 mmol), followed by the addition of Compound 2 (1.00 mmol). The reaction mixture was heated under reflux for 4 hours. The reaction was monitored by TLC until completion. After the reaction mixture was cooled to room temperature, the mother liquor was filtered to obtain a filter cake, which was washed with ethanol to obtain the crude product with a yield of 82.1% - 89.3%.

[0045] Example 1: 3-Phenyl-2-thioxo-2,3-dihydroquinazolin-4(1H)-one (Compound 1)

[0046]

[0047] Step a: To a solution of phenyl isothiocyanate (141.9 mg, 1.05 mmol) in anhydrous ethanol (10 mL) was added DIPEA (258.5 mg, 2.00 mmol), followed by the addition of anthranilic acid (137.1 mg, 1.00 mmol). The reaction mixture was heated under reflux for 4 hours. The reaction was monitored by TLC until completion. After the reaction mixture was cooled to room temperature, the mother liquor was filtered to obtain a filter cake, which was washed with ethanol to obtain the product 3-phenyl-2-thioxo-2,3-dihydroquinazolin-4(1H)-one with a yield of 83.4%.

[0048] 1 H NMR (400 MHz, DMSO-D 6 ) δ 13.03 (s, 1H), 7.95 (d, J = 7.4 Hz, 1H), 7.78 (ddd, J = 8.5, 7.4, 1.5 Hz, 1H), 7.50–7.38 (m, 4H), 7.37–7.32 (m, 1H), 7.28 (s, 2H).

[0049] Example 2: 5-Bromo-3-phenyl-2-thioxo-2,3-dihydroquinazolin-4(1H)-one (Compound 2)

[0050]

[0051] Step a: Anthranilic acid was replaced with 2-amino-6-bromobenzoic acid. The method was similar to that of Step a in Example 1 to prepare 5-bromo-3-phenyl-2-thioxo-2,3-dihydroquinazolin-4(1H)-one with a yield of 85.2%.

[0052] 1 H NMR (400 MHz, DMSO-D 6)δ13.04(s,1H),7.59(q,J=4.3Hz,2H),7.52–7.44(m,3H),7.40(t,J=7.4Hz,1H),7.27(d,J=7.2Hz,2H).

[0053] Example 3: N-(4-oxo-3-phenyl-2-thioxo-1,2,3,4-tetrahydroquinazolin-6-yl)acetamide (Compound 3)

[0054]

[0055] Step a: Replace anthranilic acid with 2-amino-5-acetamidobenzoic acid. The method is similar to that of Step a in Example 1, and N-(4-oxo-3-phenyl-2-thioxo-1,2,3,4-tetrahydroquinazolin-6-yl)acetamide is prepared. The yield is 88.1%.

[0056] 1 H NMR(400MHz,DMSO-D 6 )δ13.02(s,1H),10.23(s,1H),8.25(d,J=2.4Hz,1H),7.91(dd,J=8.9,2.4Hz,1H),7.47(t,J=7.4Hz,2H),7.43–7.37(m,2H),7.30–7.23(m,2H),2.06(s,3H).

[0057] Example 4: 7-Methyl-3-phenyl-2-thioxo-2,3-dihydroquinazolin-4(1H)-one (Compound 4)

[0058]

[0059] Step a: Replace anthranilic acid with 2-amino-4-methylbenzoic acid. The method is similar to that of Step a in Example 1, and 7-methyl-3-phenyl-2-thioxo-2,3-dihydroquinazolin-4(1H)-one is prepared. The yield is 89.3%.

[0060] 1 H NMR(400MHz,DMSO-D 6 )δ12.97(s,1H),7.84(d,J=8.1Hz,1H),7.47(t,J=7.5Hz,2H),7.40(t,J=7.3Hz,1H),7.30–7.21(m,3H),7.18(d,J=8.1Hz,1H),2.43(s,3H).

[0061] Example 5: 8-Methoxy-3-phenyl-2-thioxo-2,3-dihydroquinazolin-4(1H)-one (Compound 5)

[0062]

[0063] Step a: Replace anthranilic acid with 2-amino-3-methoxybenzoic acid. The method is similar to that of Step a in Example 1 to prepare 8-methoxy-3-phenyl-2-thioxo-2,3-dihydroquinazolin-4(1H)-one. The yield is 83.7%.

[0064] 1 H NMR (400 MHz, DMSO-D 6 ) δ 11.73 (s, 1H), 7.52 (dd, J = 7.9, 1.0 Hz, 1H), 7.50–7.37 (m, 4H), 7.31 (t, J = 8.0 Hz, 1H), 7.29–7.23 (m, 2H), 3.95 (s, 3H).

[0065] Example 6: 8-Methyl-3-phenyl-2-thioxo-2,3-dihydroquinazolin-4(1H)-one (Compound 6)

[0066]

[0067] Step a: Replace anthranilic acid with 2-amino-3-methylbenzoic acid. The method is similar to that of Step a in Example 1 to prepare 8-methyl-3-phenyl-2-thioxo-2,3-dihydroquinazolin-4(1H)-one. The yield is 83.1%.

[0068] 1 H NMR (400 MHz, DMSO-D 6 ) δ 11.82 (s, 1H), 7.83 (d, J = 8.8 Hz, 1H), 7.62 (d, J = 7.4 Hz, 1H), 7.48 (td, J = 6.7, 1.6 Hz, 2H), 7.44–7.37 (m, 1H), 7.30–7.23 (m, 3H), 2.52 (s, 3H).

[0069] Example 7: 7,8-Dimethyl-3-phenyl-2-thioxo-2,3-dihydroquinazolin-4(1H)-one (Compound 7)

[0070]

[0071] Step a: Replace anthranilic acid with 2-amino-3,4-dimethylbenzoic acid. The method is similar to that of step a in Example 1, and 7,8-dimethyl-3-phenyl-2-thioxo-2,3-dihydroquinazolin-4(1H)-one is prepared. The yield is 88.4%.

[0072] 1 H NMR(400MHz,DMSO-D 6 )δ11.63(s,1H),7.74(d,J=8.1Hz,1H),7.48(t,J=7.4Hz,2H),7.40(t,J=7.4Hz,1H),7.26(dd,J=8.3,1.3Hz,2H),7.22(d,J=8.1Hz,1H),2.40(s,3H),2.39(s,3H).

[0073] Example 8: 6-Methoxy-3-phenyl-2-thioxo-2,3-dihydroquinazolin-4(1H)-one (Compound 8)

[0074]

[0075] Step a: Replace anthranilic acid with 2-amino-5-methoxybenzoic acid. The method is similar to that of step a in Example 1, and 6-methoxy-3-phenyl-2-thioxo-2,3-dihydroquinazolin-4(1H)-one is prepared. The yield is 83.4%.

[0076] 1 H NMR(400MHz,DMSO-D 6 )δ13.00(s,1H),7.51–7.34(m,6H),7.26(d,J=7.1Hz,2H),3.82(s,3H).

[0077] Example 9: 6-Methyl-3-phenyl-2-thioxo-2,3-dihydroquinazolin-4(1H)-one (Compound 9)

[0078]

[0079] Step a: Replace anthranilic acid with 2-amino-5-methylbenzoic acid. The method is similar to that of step a in Example 1, and 6-methyl-3-phenyl-2-thioxo-2,3-dihydroquinazolin-4(1H)-one is prepared. The yield is 85.8%.

[0080] 1 H NMR(400MHz,DMSO-D 6)δ 12.99 (s, 1H), 7.75 (s, 1H), 7.61 (dd, J = 8.4, 1.9 Hz, 1H), 7.47 (t, J = 7.4 Hz, 2H), 7.41 (d, J = 7.4 Hz, 1H), 7.36 (d, J = 8.4 Hz, 1H), 7.26 (d, J = 7.0 Hz, 2H), 2.37 (s, 3H).

[0081] Example 10: 7-Trifluoromethyl-3-phenyl-2-thioxo-2,3-dihydroquinazolin-4(1H)-one (Compound 10)

[0082]

[0083] Step a: Replace anthranilic acid with 2-amino-4-trifluoromethylbenzoic acid. The method is similar to that of step a in Example 1, and 7-trifluoromethyl-3-phenyl-2-thioxo-2,3-dihydroquinazolin-4(1H)-one is prepared. The yield is 87.2%.

[0084] 1 H NMR (400 MHz, DMSO-D 6 )δ 13.21 (s, 1H), 8.15 (d, J = 8.2 Hz, 1H), 7.75 (s, 1H), 7.69–7.61 (m, 1H), 7.49 (t, J = 7.4 Hz, 2H), 7.42 (t, J = 6.7 Hz, 1H), 7.32–7.26 (m, 2H).

[0085] Example 11: 3-(4-Fluorophenyl)-8-methyl-2-thioxo-2,3-dihydroquinazolin-4(1H)-one (Compound 11)

[0086]

[0087] Step a: Replace phenyl isothiocyanate with 4-fluorophenyl isothiocyanate and anthranilic acid with 2-amino-3-methylbenzoic acid. The method is similar to that of step a in Example 1, and 3-(4-fluorophenyl)-8-methyl-2-thioxo-2,3-dihydroquinazolin-4(1H)-one is prepared. The yield is 84.6%.

[0088] 1 H NMR (400 MHz, DMSO-D 6 )δ 11.85 (s, 1H), 7.83 (d, J = 7.9 Hz, 1H), 7.62 (d, J = 7.3 Hz, 1H), 7.35–7.24 (m, 5H), 2.51 (s, 3H).

[0089] Example 12: 3-(4-Fluorophenyl)-2-thioxo-2,3-dihydroquinazolin-4(1H)-one (Compound 12)

[0090]

[0091] Step a: Replace phenyl isothiocyanate with 4-fluorophenyl isothiocyanate. The method is similar to that of Step a in Example 1, and 3-(4-fluorophenyl)-2-thioxo-2,3-dihydroquinazolin-4(1H)-one is prepared. The yield is 88.7%.

[0092] 1 H NMR (400 MHz, DMSO-D 6 ) δ 13.05 (s, 1H), 7.95 (dd, J = 7.9, 1.2 Hz, 1H), 7.82–7.74 (m, 1H), 7.45 (d, J = 8.2 Hz, 1H), 7.38–7.26 (m, 5H).

[0093] Example 13: N-(3-(4-Fluorophenyl)-4-oxo-2-thioxo-1,2,3,4-tetrahydroquinazolin-6-yl)acetamide (Compound 13)

[0094]

[0095] Step a: Replace phenyl isothiocyanate with 4-fluorophenyl isothiocyanate and anthranilic acid with 2-amino-5-acetamidobenzoic acid. The method is similar to that of Step a in Example 1, and N-(3-(4-fluorophenyl)-4-oxo-2-thioxo-1,2,3,4-tetrahydroquinazolin-6-yl)acetamide is prepared. The yield is 83.0%.

[0096] 1 H NMR (400 MHz, DMSO-D 6 ) δ 13.04 (s, 1H), 10.23 (s, 1H), 8.26 (d, J = 2.2 Hz, 1H), 7.91 (dd, J = 8.9, 2.3 Hz, 1H), 7.40 (d, J = 8.9 Hz, 1H), 7.36–7.26 (m, 4H), 2.06 (s, 3H).

[0097] Example 14: 3-(4-Fluorophenyl)-7-methyl-2-thioxo-2,3-dihydroquinazolin-4(1H)-one (Compound 14)

[0098]

[0099] Step a: Replace phenyl isothiocyanate with 4-fluorophenyl isothiocyanate, and replace anthranilic acid with 2-amino-4-methylbenzoic acid. The method is similar to that of step a in Example 1, and 3-(4-fluorophenyl)-7-methyl-2-thioxo-2,3-dihydroquinazolin-4(1H)-one is prepared. The yield is 86.3%.

[0100] 1 H NMR(400MHz,DMSO-D 6 )δ12.99(s,1H),7.84(d,J=8.1Hz,1H),7.38–7.25(m,4H),7.23(s,1H),7.18(d,J=8.2Hz,1H),2.43(s,3H).

[0101] Example 15: 3-(4-Fluorophenyl)-8-methoxy-2-thioxo-2,3-dihydroquinazolin-4(1H)-one (Compound 15)

[0102]

[0103] Step a: Replace phenyl isothiocyanate with 4-fluorophenyl isothiocyanate, and replace anthranilic acid with 2-amino-3-methoxybenzoic acid. The method is similar to that of step a in Example 1, and 3-(4-fluorophenyl)-8-methoxy-2-thioxo-2,3-dihydroquinazolin-4(1H)-one is prepared. The yield is 83.3%.

[0104] 1 H NMR(400MHz,DMSO-D 6 )δ11.78(s,1H),7.52(dd,J=8.0,1.2Hz,1H),7.43(dd,J=8.1,1.2Hz,1H),7.36–7.27(m,5H),3.95(s,3H).

[0105] Example 16: 2-Thioxo-3-(4-(trifluoromethyl)phenyl)-2,3-dihydroquinazolin-4(1H)-one (Compound 16)

[0106]

[0107] Step a: Replace phenyl isothiocyanate with 4-trifluoromethylphenyl isothiocyanate. The method is similar to that of step a in Example 1, and 2-thioxo-3-(4-(trifluoromethyl)phenyl)-2,3-dihydroquinazolin-4(1H)-one is prepared. The yield is 82.3%.

[0108] 1 H NMR(400MHz,DMSO-D 6)δ13.13(s,1H),7.97(dd,J=8.0,1.3Hz,1H),7.87(d,J=8.4Hz,2H),7.83–7.77(m,1H),7.58(d,J=8.2Hz,2H),7.46(d,J=8.3Hz,1H),7.37(t,J=7.6Hz,1H).

[0109] Example 17: N-(4-oxo-2-thioxo-3-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydroquinazolin-6-yl)acetamide (Compound 17)

[0110]

[0111] Step a: Replace phenyl isothiocyanate with 4-trifluoromethylphenyl isothiocyanate, and replace anthranilic acid with 2-amino-5-acetamidobenzoic acid. The method is similar to that of Step a in Example 1 to prepare N-(4-oxo-2-thioxo-3-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydroquinazolin-6-yl)acetamide. The yield is 82.8%.

[0112] 1 H NMR(400MHz,DMSO-D 6 )δ13.11(s,1H),10.24(s,1H),8.27(d,J=2.4Hz,1H),7.93(dd,J=8.9,2.4Hz,1H),7.87(d,J=8.4Hz,2H),7.56(d,J=8.2Hz,2H),7.42(d,J=8.9Hz,1H),2.06(s,3H).

[0113] Example 18: 7-Methyl-2-thioxo-3-(4-(trifluoromethyl)phenyl)-2,3-dihydroquinazolin-4(1H)-one (Compound 18)

[0114]

[0115] Step a: Replace phenyl isothiocyanate with 4-trifluoromethylphenyl isothiocyanate, and replace anthranilic acid with 2-amino-4-methylbenzoic acid. The method is similar to that of Step a in Example 1 to prepare 7-methyl-2-thioxo-3-(4-(trifluoromethyl)phenyl)-2,3-dihydroquinazolin-4(1H)-one. The yield is 85.8%.

[0116] 1 H NMR(400MHz,DMSO-D 6) δ 13.07 (s, 1H), 7.88–7.83 (m, 3H), 7.56 (d, J = 8.2 Hz, 2H), 7.25 (s, 1H), 7.20 (d, J = 8.5 Hz, 1H), 2.44 (s, 3H).

[0117] Example 19: 8-Methoxy-2-thioxo-3-(4-(trifluoromethyl)phenyl)-2,3-dihydroquinazolin-4(1H)-one (Compound 19)

[0118]

[0119] Step a: Replace phenyl isothiocyanate with 4-trifluoromethylphenyl isothiocyanate, and replace anthranilic acid with 2-amino-3-methoxybenzoic acid. The method is similar to that of step a in Example 1, and 8-methoxy-2-thioxo-3-(4-(trifluoromethyl)phenyl)-2,3-dihydroquinazolin-4(1H)-one is prepared. The yield is 82.6%.

[0120] 1 H NMR (400 MHz, DMSO-D 6 ) δ 11.93 (s, 1H), 7.87 (d, J = 8.3 Hz, 2H), 7.59–7.51 (m, 3H), 7.45 (dd, J = 8.1, 1.2 Hz, 1H), 7.32 (t, J = 8.0 Hz, 1H), 3.95 (s, 3H).

[0121] Example 20: 8-Methyl-2-thioxo-3-(4-(trifluoromethyl)phenyl)-2,3-dihydroquinazolin-4(1H)-one (Compound 20)

[0122]

[0123] Step a: Replace phenyl isothiocyanate with 4-trifluoromethylphenyl isothiocyanate, and replace anthranilic acid with 2-amino-3-methylbenzoic acid. The method is similar to that of step a in Example 1, and 8-methyl-2-thioxo-3-(4-(trifluoromethyl)phenyl)-2,3-dihydroquinazolin-4(1H)-one is prepared. The yield is 83.1%.

[0124] 1 H NMR (400 MHz, DMSO-D 6 ) δ 11.96 (s, 1H), 7.86 (t, J = 9.6 Hz, 3H), 7.64 (d, J = 7.3 Hz, 1H), 7.57 (d, J = 8.2 Hz, 2H), 7.28 (t, J = 7.6 Hz, 1H), 2.53 (s, 3H).

[0125] II. Determination of Compound Bioactivity

[0126] Experimental Example 1: Test for the Inhibitory Activity of Compounds against Human IDO-1

[0127] The recombinant protein of human indoleamine 2,3-dioxygenase 1 (IDO-1) is from the research group of Chen Xiaoguang. For the specific operation method, please refer to the references in the present invention (Protein Expr Purif 2004, 37(2), 392-8; Protein Expr Purif 2000, 19(1), 22-9; J Med Chem 2013, 56(21), 8321-31. J Med Chem 2009, 52(23), 7364-7). Prepare the IDO-1 reaction system, that is, in the final reaction of 100 μl, it contains 100 mM potassium phosphate solution (PH 6.5), 40 mM ascorbic acid (neutralized with sodium hydroxide), 200 μg / ml catalase, 20 μM methylene blue, a certain concentration of L-tryptophan and the test compound, and finally add the test compound. In the IDO-1 detection system, the final concentration of L-tryptophan is 800 μM, and the concentration of hIDO protein is 0.05 μM. After the reaction proceeds at 37 °C for 45 minutes, add 20 μl of 30% trichloroacetic acid to terminate the reaction. Then place the reacted 96-well plate in water at 65 °C for 1 minute. Finally, after the solution cools down, add 100 μl of 2% (w / v) p-dimethylaminobenzaldehyde acetic acid solution to the reaction solution. Detect the absorbance value at 492 nM with an enzyme-linked immunosorbent assay reader. The inhibition rate is calculated as (absorbance of the blank control group - absorbance of the test compound) / absorbance of the blank control group * 100%. After calculating the inhibition rate, use GraphPad to calculate IC 50 . The reference compounds used are NLG919 and INCB024360 which can be found in the literature.

[0128] Experimental Results:

[0129] Table 1: Results of the Inhibitory Activity of Compounds against IDO-1

[0130]

[0131]

[0132] Experimental Conclusion: The specific results are shown in Table 1. We measured the inhibitory activity of 20 compounds in the invention against IDO-1 and found that most of the compounds have strong in vitro IDO-1 inhibitory activity (IC 50 <10 μM), indicating that this type of compound has obvious IDO-1 inhibitory activity.

Claims

1. A class of 2,3-dihydroquinazoline compounds containing substituted phenyl or a pharmaceutically acceptable salt thereof, 2. A method for preparing the compound according to claim 1, which comprises the following steps: (a) Using A as a raw material, reacting with compound B under alkaline conditions to obtain compound C R 1 independently selected from hydrogen, fluorine, trifluoromethyl, R 2 , R 3 , R 4 , R 5 independently selected from halogen, acetamido, methyl, methoxy, trifluoromethyl.

3. A pharmaceutical composition, characterized in that it contains a therapeutically and / or prophylactically effective amount of the compound according to any one of claim 1 or a pharmaceutically acceptable salt thereof and optionally one or more pharmaceutically acceptable carriers or excipients.

4. Use of the compound according to any one of claim 1 or a pharmaceutically acceptable salt thereof or the pharmaceutical composition according to claim 3 in the preparation of a medicament for treating and / or preventing diseases related to IDO-1.

5. The use according to claim 4, characterized in that the diseases related to IDO-1 are selected from cancers.

6. The use according to claim 5, characterized in that the cancers are selected from colon cancer, pancreatic cancer, breast cancer, prostate cancer, lung cancer, brain cancer, ovarian cancer, cervical cancer, testicular cancer, kidney cancer, head or neck cancer, lymphoma, leukemia or melanoma.

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