Aromatic hydrocarbon receptor modulators and uses thereof

Abstract

The invention discloses an aromatic hydrocarbon receptor modulator, which has the following general formula (I) # imgabs0 # W: C = C or S, a1, A2 and A3 are independently connecting bonds or C, and m is an integer from 1 to 7; each R1 and R3 are independently H, D, halogen, CN, OR, SR, N (R) R,-C (O) R,-C (O) OR, RC (O) O-, S (O) nR, C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl or C3-C10 cycloalkyl, which are unsubstituted or substituted by 1-6 Ra; a4 is independently O or NR4; r2 is H, D or-(CH2O) aC (O) (CH2) b (O) c (CH (Rc)) d (CH2CH2O) eRc; and Rc is independently H, D, C1-C8 alkyl, NH2-, (C1-C8 alkyl) NH-, (C1-C8 alkyl) 2N-, and NH2 (C1-C8) alkyl-. The aromatic hydrocarbon receptor modulator provided by the invention has good activity in drugs for treating cancers and obesity or in immune regulation, hematopoiesis, cell cycle or intestinal barrier.

Description

Technical Field

[0001] The invention belongs to the technical field of drug synthesis, and specifically relates to an aryl hydrocarbon receptor modulator and application thereof. Background Art

[0002] Aryl hydrocarbon receptor (AHR) is a member of the bHLH-PAS (bHLH-PER-ARNT-SIM) subfamily of the basic helix-loop-helix (bHLH) superfamily and is the only receptor in the bHLH-PAS family that can be activated by ligands [Murray et al., Nat. Rev. Cancer, 2014, 14(12), 801-814; Bersten et al., Nat. Rev. Cancer, 2013, 13(12), 827-841].

[0003] AHR agonists are very extensive, including traditionally recognized aromatic hydrocarbon heterogeneities, such as 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD). In the past two decades, many endogenous agonists have been gradually discovered, such as 2-(1′H-indole-3′-carbonyl)-thiazole-4-carboxylic acid methyl ester (ITE) and tryptophan metabolite kynurenic acid. AHR agonists can also come from food intake, such as indole-3-carbinol (I3C) from the cruciferous family, and indoleacetic acid (IAA), a metabolite of intestinal flora. After being activated by agonists, AHR enters the nucleus from the cytoplasm and forms a heterodimer with the aryl hydrocarbon receptor nuclear translocator (ARNT), and binds to the xenobiotic response element (XRE) in DNA to start the transcription of XRE-regulated genes such as cytochrome CYP450 enzyme (CYP1A1). AHR can also regulate non-XRE-dependent gene expression and metabolism through protein interactions (such as with estrogen receptor, etc.).

[0004] The AHR pathway regulates many key innate and adaptive immune responses. Studies have found that some AHR agonists promote the differentiation of Th17 cells (T-helper cells) and the secretion of IL-17. Other AHR agonists can induce the horizontal differentiation of Th17 cells into Treg cells and enhance the inhibitory activity of Treg [Quintana et al., Nature, 2008, 453(7191), 65-71; Mezrich et al., J. Immunol., 2010, 185(6), 3190-3198;]. Studies have shown that AHR activation can inhibit the innate inflammatory response regulated by macrophages (for example, reducing the expression of IL-1b, IL-6, IL-12 and TNFalpha induced by lipopolysaccharide (LPS)) and inhibit dendritic cells (reducing the activation of dendritic cells and promoting the expression of IL-10) [Kimura et al., J. Exp. Med., 2009, 206(9), 2027-2035; Wang et al., Clin. Exp. Immunol., 2014, 177(2), 521-530; Wei et al., Lab. Invest., 2014, 94(5), 528-535; Nguyen et al., Proc. Natl. Acad. Sci. USA, 2010, 107(46), 19961-19966].

[0005] As an important key factor in immune regulation, AHR is considered to be a key target for immune-related diseases. Studies have shown that AHR has a regulatory effect in models such as septic shock, herpes simplex virus eye infection, and Toxoplasma gondii infection. AHR agonists also have a protective effect in immune diseases such as multiple sclerosis, inflammatory bowel disease, rheumatoid arthritis, and psoriasis. AHR-related immune regulatory activity also plays an important role in many inflammation-related metabolic diseases, such as atherosclerosis, type I diabetes, chronic kidney disease, bone metabolism-related diseases, and pulmonary hypertension. Therefore, the development of new agonists for AHR is of great significance in providing new drugs for the treatment of immune-related diseases. Summary of the invention

[0006] One aspect of the present invention is to provide an aromatic hydrocarbon receptor modulator, or an optical isomer, a prodrug or a pharmaceutically acceptable salt thereof, having the following general formula (I):

[0007]

[0008] W is C=C or S;

[0009] A1, A2, A3 are independently a connecting bond or C, m is an integer from 1 to 7; each R3 is independently H, D, halogen, CN, OR, SR, N(R)R, -C(O)R, -C(O)OR, RC(O)O-, S(O) n R, unsubstituted or substituted with 1 to 6 R a Substituted C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl or C3-C10 cycloalkyl; R a is D, halogen, OR, SR, N(R)R, -C(O)R, -C(O)OR, RC(O)O- or S(O) n R;

[0010] A4 is independently O or NR4; R4 is H, unsubstituted or substituted with 1 to 6 R b Substituted C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl or C3-C10 cycloalkyl; R b is D, halogen, OR, SR, N(R)R, -C(O)R, -C(O)OR, RC(O)O- or S(O) n R;

[0011] Each R1 is independently H, D, halogen, CN, OR, SR, N(R)R, -C(O)R, -C(O)OR, RC(O)O-, S(O) n R, unsubstituted or replaced by 1-6 R b Substituted C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl or C3-C10 cycloalkyl; R b is D, halogen, OR, SR, N(R)R, -C(O)R, -C(O)OR, RC(O)O- or S(O) n R; or two adjacent or alternate R1s form a 3-10 membered carbocyclic ring or a 3-10 membered heterocyclic ring containing 1-3 heteroatoms selected from N, O and S;

[0012] n is 1 or 2;

[0013] Each R is independently H, C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl or C3-C10 cycloalkyl;

[0014] R2 is H or -(CH2O) a C(O)(CH2) b (O) c (CH(R c )) d (CH2CH2O) e R c ; R cIndependently, they are H, D, C1~C8 alkyl, NH2-, (C1~C8 alkyl)NH-, (C1~C8 alkyl)2N-, NH2(C1~C8)alkyl-; a, b, c, d are independently 0 or 1; e is independently an integer from 0 to 3.

[0015] In a preferred embodiment of the present invention, when W is S, the general formula (I) is the general formula (Ia)

[0016]

[0017] In a further preferred embodiment of the present invention,

[0018] When A4 is O, the general formula (Ia) is the general formula (Ia1)

[0019]

[0020] When A4 is NR4, the general formula (Ia) is the general formula (Ia2)

[0021]

[0022] In a preferred embodiment of the present invention, when W is C=C, the general formula (I) is the general formula (Ib)

[0023]

[0024] In a further preferred embodiment of the present invention,

[0025] When A4 is O, the general formula (Ib) is the general formula (Ib1)

[0026]

[0027] When A4 is NR4, the general formula (Ib) is the general formula (Ib2)

[0028]

[0029] In the general formula (I) of the present invention, the structure In the figure, the double dashed line bond between A2 and A3 indicates that there is either a single bond or a double bond between A2 and A3. Similarly, the double dashed line bond between C and A1 indicates that there is either a single bond or a double bond between C and A1. In addition, "whether there is a single bond or a double bond between A2 and A3" is independent of "whether there is a single bond or a double bond between C and A1" and there is no necessary connection.

[0030] In the general formula (I) of the present invention, the substituents Can be connected to the structure R3 can be any substitutable position on the atom, that is, it can be connected to C, or to A1, A2 or A3. R3 can be one or more, and two R3 can be connected to the same atom or different atoms at the same time, which is not particularly limited in the present invention.

[0031] In a preferred embodiment of the present invention,

[0032] A1, A2, A3 are independently a connecting bond or C, m is an integer from 1 to 5; each R3 is independently H, D, halogen, CN, OR, SR, N(R)R, -C(O)R, -C(O)OR, RC(O)O-, S(O) n R, unsubstituted or substituted with 1 to 3 R a Substituted C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl or C3-C8 cycloalkyl; R a is D, halogen, OR, SR, N(R)R, -C(O)R, -C(O)OR, RC(O)O- or S(O) n R;

[0033] n is 1 or 2;

[0034] Each R is independently H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl or C3-C8 cycloalkyl;

[0035] Preferably,

[0036] A1, A2, A3 are independently a connecting bond or C, m is an integer from 1 to 3; each R3 is independently H, D, halogen, CN, OR, SR, N(R)R, -C(O)R, -C(O)OR, RC(O)O-, S(O) n R, unsubstituted or replaced by 1-2 R a Substituted C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl or C3-C7 cycloalkyl; R a is D, halogen, OR, SR, N(R)R, -C(O)R, -C(O)OR, RC(O)O- or S(O) n R;

[0037] n is 1 or 2;

[0038] Each R is independently H, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl or C3-C7 cycloalkyl;

[0039] More preferably,

[0040] A1, A2, A3 are independently a connecting bond or C, m is an integer of 1 to 2; each R3 is independently H, D, halogen, CN, OR, SR, N(R)R, -C(O)R, -C(O)OR, RC(O)O-, S(O) n R, unsubstituted or replaced by 1 R a Substituted C1-C3 alkyl, C2-C3 alkenyl, C2-C3 alkynyl or C5-C6 cycloalkyl; R a is D, halogen, OR, SR, N(R)R, -C(O)R, -C(O)OR, RC(O)O- or S(O) n R;

[0041] n is 1 or 2;

[0042] Each R is independently H, C1-C3 alkyl, C2-C3 alkenyl, C2-C3 alkynyl or C5-C6 cycloalkyl.

[0043] In another preferred embodiment of the present invention,

[0044] Each R1 is independently H, D, halogen, CN, OR, SR, N(R)R, -C(O)R, -C(O)OR, RC(O)O-, S(O) n R, unsubstituted or replaced by 1-3 R b Substituted C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl or C3-C8 cycloalkyl; R b is D, halogen, OR, SR, N(R)R, -C(O)R, -C(O)OR, RC(O)O- or S(O) n R; or two adjacent or alternate R1s form a 3-8 membered carbocyclic ring or a 3-8 membered heterocyclic ring containing 1-3 heteroatoms selected from N, O and S;

[0045] n is 1 or 2;

[0046] Each R is independently H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl or C3-C8 cycloalkyl;

[0047] Preferably,

[0048] Each R1 is independently H, D, halogen, CN, OR, SR, N(R)R, -C(O)R, -C(O)OR, RC(O)O-, S(O) n R, unsubstituted or replaced by 1-2 R b Substituted C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl or C3-C7 cycloalkyl; R b is D, halogen, OR, SR, N(R)R, -C(O)R, -C(O)OR, RC(O)O- or S(O)n R; or two adjacent or alternate R1s form a 3-7 membered carbocyclic ring or a 3-7 membered heterocyclic ring containing 1-2 heteroatoms selected from N, O and S;

[0049] n is 1 or 2;

[0050] Each R is independently H, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl or C3-C7 cycloalkyl;

[0051] More preferably,

[0052] Each R1 is independently H, D, halogen, CN, OR, SR, N(R)R, -C(O)R, -C(O)OR, RC(O)O-, S(O) n R, unsubstituted or replaced by 1 R b Substituted C1-C3 alkyl, C2-C3 alkenyl, C2-C3 alkynyl or C5-C6 cycloalkyl; R b is D, halogen, OR, SR, N(R)R, -C(O)R, -C(O)OR, RC(O)O- or S(O) n R; or two adjacent or alternate R1s form a 5-6 membered carbocyclic ring or a 5-6 membered heterocyclic ring containing 1-2 heteroatoms selected from N, O and S;

[0053] n is 1 or 2;

[0054] Each R is independently H, C1-C3 alkyl, C2-C3 alkenyl, C2-C3 alkynyl or C5-C6 cycloalkyl.

[0055] In another preferred embodiment of the present invention,

[0056] R2 is H or -(CH2O) a C(O)(CH2) b (O) c (CH(R c )) d (CH2CH2O) e R c ; R c independently H, D, C1-C6 alkyl, NH2-, (C1-C6 alkyl)NH-, (C1-C6 alkyl)2N-, NH2(C1-C6)alkyl-; a, b, c, d are independently 0 or 1; e is independently an integer from 0 to 2;

[0057] Preferably,

[0058] R2 is H or -(CH2O) a C(O)(CH2) b (O) c (CH(R c ))d (CH2CH2O) e R c ; R c independently H, D, C1-C4 alkyl, NH2-, (C1-C4 alkyl)NH-, (C1-C4 alkyl)2N-, NH2(C1-C4)alkyl-; a, b, c, d are independently 0 or 1; e is independently an integer of 0 or 1;

[0059] More preferably,

[0060] R2 is H or -(CH2O) a C(O)(CH2) b (O) c (CH(R c )) d (CH2CH2O) e R c ; R c Independently represent H, D, C1~C3 alkyl, NH2-, (C1~C3 alkyl)NH-, (C1~C3 alkyl)2N-, NH2(C1~C3)alkyl-; a, b, c, d are independently 0 or 1; e is independently an integer of 0 or 1.

[0061] In another preferred embodiment of the present invention,

[0062] R4 is H, unsubstituted or substituted with 1 to 3 R b Substituted C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl or C3-C8 cycloalkyl; R b is D, halogen, OR, SR, N(R)R, -C(O)R, -C(O)OR, RC(O)O- or S(O) n R;

[0063] Each R is independently H, D, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl or C3-C8 cycloalkyl;

[0064] Preferably,

[0065] R4 is H, unsubstituted or substituted with 1 to 2 R b Substituted C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl or C3-C7 cycloalkyl; R b is D, halogen, OR, SR, N(R)R, -C(O)R, -C(O)OR, RC(O)O- or S(O) n R;

[0066] Each R is independently H, D, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl or C3-C7 cycloalkyl;

[0067] More preferably,

[0068] R4 is H, unsubstituted or replaced by 1 R b Substituted C1-C3 alkyl, C2-C3 alkenyl, C2-C3 alkynyl or C5-C6 cycloalkyl; R b is D, halogen, OR, SR, N(R)R, -C(O)R, -C(O)OR, RC(O)O- or S(O) n R;

[0069] Each R is independently H, D, C1-C3 alkyl, C2-C3 alkenyl, C2-C3 alkynyl or C5-C6 cycloalkyl.

[0070] The aromatic hydrocarbon receptor modulator of the present invention is the following compound:

[0071]

[0072]

[0073]

[0074] Another aspect of the present invention is to provide the use of the aromatic hydrocarbon receptor modulator described in the general formula (I) of the present invention in the preparation of drugs for treating cancer and obesity or in the preparation of drugs for immunomodulation, hematopoiesis, cell cycle or intestinal barrier.

[0075] Another aspect of the present invention is to provide the use of the aromatic hydrocarbon receptor modulator described in the general formula (I) of the present invention as a drug for treating cancer, obesity, or in immunoregulation, hematopoiesis, cell cycle or intestinal barrier.

[0076] The synthesis process of the aromatic hydrocarbon receptor modulator described in the general formula (I) of the present invention is as follows:

[0077]

[0078] Wherein X is a halogen. DETAILED DESCRIPTION

[0079] Synthesis of intermediate Int-1

[0080]

[0081] Step 1: 2-(1H-indol-3-yl)-2-oxalyl chloride (Int-1A)

[0082] At room temperature, indole (131 g, 1118 mmol) was dissolved in MTBE (983 mL), cooled to -10 °C, and oxalyl chloride (149 g, 1174 mmol) was slowly added dropwise. The temperature was maintained between -10 °C and 5 °C during the addition. After the addition was completed, the temperature was naturally raised to room temperature for 1 hour. Petroleum ether (983 mL) was added, stirred at room temperature for 30 minutes, filtered, and the filter cake was rinsed with petroleum ether (200 mL). The filter cake solid was decompressed to obtain a yellow solid Int-1A (228 g).

[0083] Step 2: 2-(1H-indol-3-yl)-2-oxalamide (Int-1B)

[0084] Mix ammonia water (content 25%, 749 mL) and ethanol (1140 mL) and cool to -5~14°C, then slowly add Int-1A (228 g, 1101 mmol) in batches. After the addition is completed, the reaction solution is kept at -5~14°C for 2 hours. The reaction solution is added to water (1140 mL), stirred at room temperature for 30 minutes, filtered, washed with water, and dried in an oven at 60°C overnight to obtain a white solid product Int-1B (170 g).

[0085] Step 3: 1H-Indole-3-carbonyl cyanide (Int-1C)

[0086] Int-1B (170 g, 904 mmol) was dissolved in ethyl acetate (2000 mL), pyridine (214 g, 2712 mmol) was added at room temperature, the temperature was lowered to 0°C to 5°C, trifluoroacetic anhydride (284 g, 1356 mmol) was slowly added dropwise for 1.5 hours, and then the reaction solution was kept at 5°C to 18°C ​​for 1.5 hours. After the reaction was completed, it was quenched with saturated sodium bicarbonate aqueous solution (1700 mL), stirred for 10 minutes, and extracted with ethyl acetate twice. The organic phases were combined, washed with 0.5N dilute hydrochloric acid (650 mL×2), washed once with saturated brine (650 mL), dried over anhydrous sodium sulfate, and concentrated to dryness to obtain a crude product. The crude product was treated with PE / EA=10 / 1 (400 mL) and filtered to obtain a brown solid Int-1C (145 g).

[0087] Step 4: Intermediate Int-1

[0088] Triethylamine (88.4 g, 873 mmol) was added to a solution of Int-1C (135 g, 794 mmol) in pyridine (1350 mL) at 60°C, and then ammonium sulfide (108 g, 1588 mmol) was added. The reaction solution was kept at 60°C for 1.5 hours. The reaction solution was cooled to room temperature and slowly added to 1N hydrochloric acid (7 L). It was then extracted with ethyl acetate (2 L × 3). The organic phases were combined, washed with saturated brine (2 L), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to dryness. The crude Int-1 was stirred and washed twice with PE / EA = 10 / 1 (500 mL), and filtered to obtain a yellow solid Int-1 (90 g).

[0089] LCMS [M+H] + =205.2.

[0090] 1 H NMR (400MHz, DMSO-d6) δ12.15(s,1H),10.23(s,1H),10.02(s,1H),8.20(d,J=3.2Hz,1H),8.14(dd,J=5.8,3.2Hz,1H),7.58 -7.47(m,1H),7.31-7.19(m,2H).

[0091] Table 1 The following intermediates Int-2 to Int-9 were prepared by the same method as that of intermediate Int-1.

[0092]

[0093]

[0094] Example 1 Synthesis of Compound 1

[0095]

[0096] Step 1: Synthesis of Intermediate 1-A

[0097] At room temperature, add acetic acid (2.40 g, 40.0 mmol, 1.00 eq.) to a solution of 2-acetylbutyrolactone (5.12 g, 40.0 mmol, 1.00 eq.) in dichloromethane (100 mL), cool the reaction solution to below 0°C, and dropwise add a solution of bromine (12.8 g, 80.0 mmol, 2.00 eq.) in dichloromethane (50 mL) (dropping time is 45 minutes). After the dropwise addition, the reaction solution is warmed to room temperature and stirred for 1 hour. The reaction solution is filtered, and the filtrate is concentrated under reduced pressure to obtain a brown oily intermediate 1-A (1.50 g, 18.2%), which is directly used in the next step.

[0098] Step 2: Synthesis of compound 1

[0099] At room temperature, add intermediate 1-A (2.50 g, 12.1 mmol, 1.00 eq.) to a tetrahydrofuran (30 mL) solution of intermediate Int-1 (3.00 g, 14.6 mmol, 1.20 eq.). Stir overnight at room temperature under nitrogen protection. Concentrate to dryness under reduced pressure, add ice water and stir, solid precipitates, filter to obtain a crude product (2.50 g); recrystallize from ethyl acetate to obtain compound 1 (yellow solid, 2.30 g, yield 51%).

[0100] LCMS(ESI): [M+H] + =313.0.

[0101] 1 H NMR(400MHz,DMSO-d6)δ12.25(s,1H),8.99(d,J=2.1Hz,1H),8.38-8.27(m,1H),8.03(s,1H),7 .61-7.55(m,1H),7.33-7.25(m,2H),4.58-4.53(m,1H),4.47-4.35(m,2H),2.80-2.60(m,2H).

[0102] Compounds 1-isomer-A and 1-isomer-B

[0103] Compound 1 (800 mg) was separated by chiral preparation to obtain compound 1-isomer-A (340 mg, component 1, retention time 1.163 minutes) and compound 1-isomer-B (340 mg, component 2, retention time 1.418 minutes).

[0104] Analytical methods:

[0105] Instrument: UPCC (waters)

[0106] Column: Regis (R, R) Whelk-O1 (4.6×100mm, 3.5μm)

[0107] Temperature: 40℃

[0108] Fluidity: CO2 / MeOH [0.2% NH3 (7M in MeOH)] = 45 / 55

[0109] Flow rate: 3mL / min

[0110] H back pressure: 2000psi

[0111] Preparation method:

[0112] Instrument: SFC-150mgm(waters)

[0113] Column: Regis (R, R) Whelk-O1 (25×250, 10μm)

[0114] Temperature: 30℃

[0115] Mobile phase: CO2 / MeOH [0.2% NH3 (7M in MeOH)] = 50 / 50

[0116] Flow rate: 100mL / min

[0117] Back pressure: 100bar

[0118] Detection wavelength: 214nm

[0119] Compound 1-isomer-A

[0120] LCMS(ESI): [M+H] + =313.0.

[0121] 1 H NMR(400MHz,MeOH-d4)δ9.04(s,1H),8.38-8.35(m,1H),7.82(s,1H),7.52-7.49(m,1 H),7.28-7.26(m,2H),4.64-4.59(m,1H),4.50-4.44(m,1H),4.32-4.28(m,1H),2.80 -2.60(m,2H).

[0122] Compound 1-isomer-B

[0123] LCMS(ESI): [M+H] + =313.0.

[0124] 1 H NMR(400MHz,MeOH-d4)δ9.04(s,1H),8.38-8.35(m,1H),7.82(s,1H),7.52-7.49(m,1H),7.2 8-7.26(m,2H),4.64-4.59(m,1H),4.50-4.44(m,1H),4.32-4.28(m,1H),2.80-2.60(m,2H).

[0125] Table 2 Preparation of Compounds 1-2 to 1-9 using the synthetic method of Compound 1

[0126]

[0127]

[0128]

[0129] Example 2 Synthesis of Compound 2

[0130]

[0131] At room temperature, TBD (5.00 mg, 0.032 mmol, 0.10 eq.) was added to a DMF (5 mL) solution of compound 1 (0.10 g, 0.32 mmol, 1.00 eq.). The solution was heated to 45°C and stirred overnight. The reaction solution was concentrated to dryness under reduced pressure and purified by silica gel column chromatography (ethyl acetate: petroleum ether = 0% to 50%) to obtain a yellow solid compound 2 (70 mg, 70%).

[0132] LCMS(ESI): [M+H] + =329.0.

[0133] 1 H NMR (400MHz, DMSO-d6) δ12.26(s,1H),8.93(d,J=3.3Hz,1H),8.31(dd,J=5.9,3.2Hz,1H),8.09(s,1H),7. 68-7.50(m,1H),7.40-7.20(m,2H),6.98(s,1H),4.64-4.43(m,2H),2.94-2.88(m,1H),2.62-2.52(m,1H).

[0134] Table 3 Preparation of Compounds 2-2 to 2-5 using the synthetic method of Compound 2 in Example 2

[0135]

[0136] Example 3 Synthesis of Compound 3

[0137]

[0138] Under nitrogen protection, NaH (60.0 mg, 2.50 mmol, 2.50 eq.) was added to a tetrahydrofuran (5 mL) solution of compound 1 (0.312 g, 1.00 mmol, 1.00 eq.) at room temperature. After stirring for half an hour, N-fluorobisbenzenesulfonamide (378 mg, 1.20 mmol, 1.20 eq.) was added and stirred at room temperature for 1 hour. The mixture was concentrated to dryness under reduced pressure and purified by silica gel column chromatography (methanol: dichloromethane = 0% to 100%) to obtain yellow solid compound 3 (40 mg, 10%).

[0139] LCMS(ESI): [M+H] + =331.0.

[0140] 1 H NMR(400MHz,DMSO-d6)δ12.31(s,1H),8.97(s,1H),8.41(s,1H),8.34-8.11(m,1H),7.59-7.56(m,1 H),7.41-7.08(m,2H),4.70-4.64(m,1H),4.62-4.41(m,1H),3.29-3.19(m,1H),3.10-2.93(m,1H).

[0141] Table 4 Preparation of Compounds 3-2 to 3-5 using the synthetic method of Compound 3 in Example 3

[0142]

[0143]

[0144] Example 4 Synthesis of Compound 4

[0145]

[0146] Step 1: Synthesis of intermediate 4-A

[0147] At zero degrees Celsius and under nitrogen protection, add sulfonyl chloride (5.49 g, 41.0 mmol, 1.05 eq.) dropwise to α-acetyl-γ-butyl ester (5.00 g, 39.0 mmol, 1.00 eq.). Stir the reaction at room temperature for 5 hours. Pour the mixture into water (100 mL) and extract with ethyl acetate (50 mL × 3). Combine the organic phases and wash with saturated brine, dry over anhydrous sodium sulfate, filter and concentrate under reduced pressure to obtain a brown oily intermediate 4-A (6.00 g, 95%), which is used directly in the next step without purification.

[0148] Step 2: Synthesis of intermediate 4-B

[0149] Under nitrogen protection, a solution of bromine (9.88 g, 61.7 mmol, 2.00 eq.) in dichloromethane (30 mL) was added dropwise to a solution of intermediate 4-A (5.00 g, 30.9 mmol, 1.00 eq.) in dichloromethane (20 mL) at 0°C and stirred overnight at room temperature. The mixture was concentrated under reduced pressure to obtain a brown oil 4-B (6.70 g, 90%), which was used directly in the next step without purification.

[0150] Step 3: Synthesis of compound 4

[0151] Under nitrogen protection, add intermediate Int-1 (2.1 g, 10.3 mmol, 1.03 eq.) to a solution of intermediate 4-B (2.41 g, 10.0 mmol, 1.00 eq.) in tetrahydrofuran (20 mL) at room temperature. Stir overnight at room temperature. Pour the mixture into ice water (100 mL), extract with ethyl acetate (50 mL × 3), combine the organic phases and wash with saturated brine, dry over anhydrous sodium sulfate, filter and concentrate to dryness under reduced pressure. The crude product was purified by silica gel paper chromatography (methanol: dichloromethane = 0% to 30%) to obtain compound 4 (yellow solid, 2.3 g, yield 67%).

[0152] LCMS(ESI):347[M+H] + .

[0153] Table 5: Preparation of Compounds 4-2 to 4-5 using the synthetic method of Compound 4 in Example 4

[0154]

[0155] Example 5 Synthesis of Compound 5

[0156]

[0157] At room temperature and under nitrogen protection, triethylamine (58.5 mg, 0.578 mmol, 2.00 eq.) and triethylamine trihydrofluoride (93.2 mg, 0.578 mmol, 2.00 eq.) were added to a solution of compound 4 (0.100 g, 0.289 mmol, 1.00 eq.) in acetonitrile (3 mL). Stir and reflux overnight. After cooling to room temperature, the mixture was concentrated to dryness under reduced pressure and purified by silica gel column chromatography (methanol: dichloromethane = 0% to 30%) to obtain a yellow solid compound 5 (0.01 g, 11%).

[0158] LCMS(ESI): [M+H] + =311.2. 1 H NMR (400MHz, DMSO-d6) δ12.30(s,1H),9.27(s,1H),8.51(s,2H),8.33(dd,J=5.8, 3.2Hz, 1H), 7.59 (dd, J = 5.8, 2.8Hz, 1H), 7.37-7.16 (m, 2H), 5.17 (d, J = 1.3Hz, 2H).

[0159] Example 6

[0160]

[0161] Step 1: Synthesis of intermediate 6-A

[0162] The method is the same as the second step of compound 1, with a yield of 78%.

[0163] Step 2: Synthesis of compound 6

[0164] At room temperature and under nitrogen protection, ethyl glycolate (0.13 g, 1.27 mmol, 4.00 eq.) and potassium tert-butoxide (0.29 g, 2.55 mmol, 8.00 eq.) were added to a solution of intermediate 6-A (0.10 g, 0.32 mmol, 1.00 eq.) in tetrahydrofuran (5 mL), and stirred overnight at room temperature. The mixture was poured into ice water (10 mL), the pH was adjusted to 7 with saturated tartaric acid aqueous solution, and extracted with ethyl acetate (10 mL × 3). The organic phases were combined and washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to dryness under reduced pressure. The crude product was purified by preparative HPLC to obtain yellow solid compound 6 (45.00 mg, 43%). LCMS [M + H] + =327.0. 1 H NMR (400MHz, MeOH-d4) δ9.50(s,1H),8.39-8.37(m,1H),7.96(s,1H),7.53-7.44(m,1H),7.30-7.19(m,2H),4.54(s,2H).

[0165] Example 7

[0166]

[0167] Step 1: Synthesis of intermediate 7-A

[0168] Freshly prepared LDA solution [n-BuLi (4.04 mL, 10.09 mmol, 2.5 M in THF) was added dropwise to diisopropylamine (1.42 mL, 10.09 mmol) in anhydrous THF (20 mL) at -78°C] was slowly added dropwise to a solution of N-methyl-2-pyrrolidone (1.0 g, 10.09 mmol) in anhydrous THF (15.0 mL) at -78°C and stirred at the same temperature for 1 hour. Ethyl bromoacetate (1.34 mL, 12.11 mmol) was added dropwise at -78°C over 5 minutes and continued at the same temperature for 3 hours. The temperature was slowly raised to -20°C, 1N HCl (20 mL) was added dropwise, the temperature was controlled not to exceed -20°C, and stirred for 10 to 15 minutes. The reaction mixture was diluted with ice water (30-40 g) and the layers were separated, and the aqueous layer was extracted with EtOAc (3×30 mL). The ethyl acetate phases were combined, dried over Na2SO4 and concentrated under reduced pressure. The crude residue was purified by column chromatography to obtain compound 7-A in a yield of 69% (1.230 g) as a light yellow oil.

[0169] LCMS [M+H]+ =220,222.

[0170] Step 2: Synthesis of compound 7

[0171] The method is the same as the second step of compound 1: At room temperature, add intermediate 7-A (330 mg, 1.5 mmol) to a solution of intermediate Int-1 (300 mg, 1.46 mmol, 1.20 eq.) in tetrahydrofuran (10 mL). Stir overnight at room temperature under nitrogen protection. Concentrate to dryness under reduced pressure, add ice water and stir, solid precipitates, filter to obtain a crude product (152 mg); recrystallize from ethyl acetate to obtain compound 7 (yellow solid, 120 mg, yield 54%). LCMS (ESI): [M+H] + =326.1. 1 H NMR(400MHz, DMSO-d6)δ12.25(s,1H),8.99(d,J=3.2Hz,1H),8.36–8.25(m,1H),7.90(s,1H),7.66–7.49(m,1H), 7.38–7.16(m,2H),3.99(t,J=8.7Hz,1H),3.61–3.41(m,2H),2.84(s,3H),2.55–2.49(m,1H),2.38-2.33(m,1H).

[0172] Table 6 Preparation of Compounds 7-2 to 7-6 using the synthetic method of Compound 7 in Example 7

[0173]

[0174]

[0175]

[0176] Example 8

[0177]

[0178] Step 1: Synthesis of intermediate 8-A

[0179] Freshly prepared LDA solution [n-BuLi (4.04 mL, 10.09 mmol, 2.5 M in THF solution) was added dropwise to diisopropylamine (1.42 mL, 10.09 mmol) in anhydrous THF (20 mL) at -78°C] was slowly added dropwise to a solution of γ-valerolactone (1.1 g, 11 mmol) in anhydrous THF (15.0 mL) at -78°C and stirred at the same temperature for 1 hour. Ethyl bromoacetate (1.34 mL, 12.11 mmol) was added dropwise at -78°C over 5 minutes and continued at the same temperature for 3 hours. The temperature was slowly raised to -20°C, 1N HCl (20 mL) was added dropwise, the temperature was controlled not to exceed -20°C, and stirred for 10 to 15 minutes. The reaction mixture was diluted with ice water (30-40 g) and the layers were separated. The aqueous layer was extracted with EtOAc (3×30 mL). The ethyl acetate phases were combined, dried over Na2SO4 and concentrated under reduced pressure. The crude residue was purified by column chromatography to obtain compound 7-A in a yield of 69% (1.230 g) as a light yellow oil.

[0180] LCMS [M+H] + =221,223.

[0181] Step 2: Synthesis of compound 8

[0182] The method is the same as the second step of compound 1: At room temperature, add intermediate 8-A (332 mg, 1.5 mmol) to a tetrahydrofuran (10 mL) solution of intermediate Int-1 (300 mg, 1.46 mmol, 1.20 eq.). Stir overnight at room temperature under nitrogen protection. Concentrate to dryness under reduced pressure, add ice water and stir, solid precipitates, filter to obtain a crude product (152 mg); recrystallize from ethyl acetate to obtain compound 8 (yellow solid, 343 mg, yield 72%).

[0183] LCMS(ESI): [M+H] + =327.1.

[0184] 1H NMR (400MHz, DMSO-d6) δ12.29(s,1H),9.00(d,J=3.2Hz,0.6H),8.99(d,J=3.2Hz,0.4H),8.31 –8.33(m,1H),8.02(s,0.6H),8.01(s,0.4H),7.55–7.58(m,1H),7.25–7.32(m,2H),4.95-5.00 (m,0.4H),4.72-4.77(m,0.6H),4.48-4.54(m,1H),2.83-2.90(m,0.6H),2.72-2.79(m,0.4H) ,2.32–2.44(m,0.4H),2.24-2.32(m,0.6H),1.48(d,J=8.0Hz,1.8H),1.44(d,J=8.0Hz,1.2H).

[0185] Step 3: Isomer separation

[0186] The compound 8 obtained in the second step was subjected to chromatographic separation, and the separation conditions were as follows:

[0187] Moisture (Co_Solvent): MeOH [0.2% NH3 (7M in MeOH)]

[0188] Column Name:AD-3 4.6*100mm 3um

[0189] Back Pressure:2000psi

[0190] Flow Rate: 3.0mL / min

[0191] Detector (Channel Name): PDA Ch1 MaxPlot (210-400) nm

[0192] Detection wavelength (Proc.Chnl.Descr.):PDA Ch1 MaxPlot(210-400)nm

[0193] Column Temperature: 40℃

[0194] Run Time: 6.0Minutes

[0195] After separation, four diastereoisomers were obtained, namely 8-cis-1, 8-cis-2, 8-trsns-1, and 8-trans-2.

[0196] Table 7 Preparation of Compounds 8-2 to 8-6 using the synthetic method of Compound 8 in Example 8

[0197]

[0198]

[0199]

[0200] Effect Example 1 Human Aryl Hydrocarbon Receptor (AhR) Agonist Luciferase Experiment

[0201] Cytochrome P450 family member A1 (CYP1A1) is one of the iconic genes regulated by the AhR signaling pathway. The upstream promoter of the CYP1A1 gene contains a specific sequence called dioxin responsive element (DRE), which can bind to the activated AhR to initiate CYP1A1 expression. In order to detect the activation of AhR, according to the conventional reporter gene plasmid construction method in the prior art, the gene sequence from -1200bp to 0bp upstream of CYP1A1 was placed in front of the Nano-luc luciferase reporter gene to construct the reporter gene plasmid. The reporter gene plasmid was introduced into human liver cancer cells HepG2 by the conventional liposome transfection method in the prior art, and the stable expression cells were selected by puromycin. The screened cells were diluted to a concentration of 5 cells / mL and inoculated into a 96-well plate at 100μl / well, and monoclones were obtained after growth. A monoclonal clone with normal morphology, normal growth and the highest induction signal was selected for the human AHR agonist luciferase experiment.

[0202] The HepG2 monoclonal cell line stably expressing the reporter gene was counted on the first day and the cells were 1-8×10 4 The cells were seeded at a density of 100 μL / well in a white opaque 96-well plate using complete culture medium without tryptophan and phenol red (basal culture medium MEM without tryptophan and phenol red, 10% fetal bovine serum, 1× non-essential amino acids, 1× sodium pyruvate and 1× GlutaMax) and cultured in an incubator maintained at 37°C and 5% carbon dioxide for 24 hours.

[0203] The test compounds were prepared into 10 mM stock solutions with dimethyl sulfoxide (DMSO) and stored at 4°C in the dark. Before treatment, the compound stock solution and the positive control compounds (such as dioxins, ITE, kynurenine, etc.) and the negative control (DMSO) were diluted with complete culture medium without tryptophan and phenol red for an initial dilution (determined according to preliminary experiments) and then diluted 3-20 times for 11 concentration points to obtain a 2× dilution. When treating cells, first aspirate 50 μL of culture medium from the 96-well plate inoculated with cells, and then add 50 μL of the serially diluted 2× dilution. Set up 2 replicates for each compound, and set one well of each replicate to a concentration of 0 (i.e., only culture medium) to determine the base number. After treatment, the reporter cells were returned to the incubator for incubation for 4 to 24 hours.

[0204] After treatment, add 100 μL / well of Nano-Glo luciferase assay reagent to the 96-well plate and measure the RLU (relative fluorescence intensity) of each well. The baseline Ave RLU is calculated by taking the average of the RLU with a concentration of 0 in each 96-well plate. Vehicle The RLU of the test compound at different concentrations in the experimental group Test Cmpd and baseline Ave RLU Vehicle The ratio of , was used to calculate the activity of AhR under the action of different concentrations of the test compound according to formula (1) to determine the activation multiple.

[0205] Formula (1)

[0206] The activation factor and the corresponding compound concentration were fitted using Graphpad Prism 9 [Agonist] vs. response-variable slope (four parameters) to calculate the EC of the compound to activate AhR 50 The EC of each compound 50 The values ​​are shown in Table 6, where A represents EC 50 ≤500nM, B means 500nM<EC 50 ≤2.0μM, C means 2.0μM<EC 50 ≤100μM.

[0207] Effect Example 2 Mouse-derived Aryl Hydrocarbon Receptor (AhR) Agonist Luciferase Experiment

[0208] In order to detect the activation of AhR, according to the conventional reporter gene plasmid construction method in the prior art, 6 tandem xenobiotic responsive elements (XRE, see Buckley, SMK et al., Sci. Rep. 2015; 5: 11842.) were placed in front of the Nano-luc luciferase reporter gene to construct the reporter gene plasmid. The reporter gene plasmid was introduced into mouse liver cancer cells Hepa1-6 by the conventional liposome transfection method in the prior art, and the stable expression cells were screened by puromycin for mouse AhR agonist luciferase experiment.

[0209] On the first day, the Hepa1-6 cell line stably expressing the reporter gene was counted and the number of cells was 1-8×10 4 The cells were seeded into a white opaque 96-well plate at a density of 100 μL / well using phenol red-free DMEM medium (phenol red-free DMEM, 10% fetal bovine serum), and cultured in an incubator maintained at 37° C. and 5% carbon dioxide for 24 hours.

[0210] The test compounds were prepared into 10 mM stock solutions with dimethyl sulfoxide (DMSO) and stored at 4°C in the dark. Before treatment, the compound stock solution and the positive control compounds (such as dioxins, ITE, kynurenine, etc.) and the negative control (DMSO) were diluted with complete culture medium without tryptophan and phenol red for an initial dilution (determined according to preliminary experiments) and then 3-20 times serial dilutions were made to obtain 11 concentration points to obtain a 10× dilution. When treating cells, 10 μL of culture medium was first aspirated from the 96-well plate inoculated with cells, and then 10 μL of the serially diluted 10× dilution was added. Two replicate experiments were set for each compound, and one well of each replicate experiment was set to a concentration of 0 (i.e., only culture medium) to determine the base number. After treatment, the reporter cells were returned to the incubator for incubation for 4-24 hours.

[0211] After treatment, add 100 μL / well of Nano-Glo luciferase assay reagent to the 96-well plate and measure the RLU (relative fluorescence intensity) of each well. The baseline Ave RLU is calculated by taking the average of the RLU with a concentration of 0 in each 96-well plate. Vehicle The RLU of the test compound at different concentrations in the experimental group Test Cmpd and baseline Ave RLU Vehicle The ratio of , was used to calculate the activity of AhR under the action of different concentrations of the test compound according to formula (1) to determine the activation multiple.

[0212] Formula (1)

[0213] The activation fold and the corresponding compound concentration were fitted using Graphpad Prism 9 [Agonist] vs. response-variable slope (four parameters) to calculate the EC of the compound to activate AHR 50 The EC of each compound 50 The values ​​are shown in Table 8, where A represents EC 50 ≤100nM, B means 100nM<EC 50 ≤2.0μM, C means 2.0μM<EC 50 ≤100μM.

[0214] Effect Example 3 Rat-derived Aryl Hydrocarbon Receptor (AHR) Agonist Luciferase Experiment

[0215] In order to detect the activation of AhR, 6 Nano-luc luciferase reporter genes associated with xenobiotic responsive elements (XRE, see Buckley, SMK et al., Sci. Rep. 2015; 5: 11842.) were synthesized and cloned into the lentiviral transfer plasmid pGWLV11-new through two restriction sites, KpnI and Xbal. Through the conventional transfection method of the prior art, the transfer plasmid and the packaging plasmid were co-transfected into 293T cells and purified to obtain a lentivirus containing the reporter gene. The reporter gene was introduced into the rat hepatoma cell H-4-II-E genome by lentiviral infection, and the cells were stably expressed by puromycin to perform rat AhR agonist luciferase experiments.

[0216] The H-4-II-E cell line stably expressing the reporter gene was counted on the first day and seeded into a white opaque 96-well plate at a density of 1-8×104 / well using 100 μL of complete culture medium without tryptophan and phenol red (basal culture medium MEM without tryptophan and phenol red, 10% fetal bovine serum, 1× non-essential amino acids, 1× sodium pyruvate and 1× GlutaMax), and cultured in an incubator maintained at 37°C and 5% carbon dioxide for 24 hours.

[0217] The test compounds were prepared into 10 mM stock solutions with dimethyl sulfoxide (DMSO) and stored at 4°C in the dark. Before treatment, the compound stock solution and the positive control compounds (such as dioxins, ITE, kynurenine, etc.) and the negative control (DMSO) were diluted with complete culture medium without tryptophan and phenol red for an initial dilution (determined according to preliminary experiments) and then 3-20 times serial dilutions were made for 11 concentration points to obtain a 2× dilution. When treating cells, 50 μL of culture medium was first aspirated from the 96-well plate inoculated with cells, and then 50 μL of the serially diluted 2× dilution was added. Two replicate experiments were set for each compound, and one well of each replicate experiment was set to a concentration of 0 (i.e., only culture medium) to determine the base number. After treatment, the reporter cells were returned to the incubator for incubation for 4-24 hours.

[0218] After the treatment, 100 μL / well of Nano-Glo luciferase assay reagent was added to the 96-well plate, and the RLU (relative fluorescence intensity) of each well was measured. The RLU of each 96-well plate with a concentration of 0 was averaged to calculate the baseline Ave RLUVehicle. The activity of AhR under the action of different concentrations of the test compound was calculated according to formula (1) based on the ratio of the RLUTest Cmpd of the test compound at different concentrations in the experimental group and the baseline Ave RLUVehicle to determine the activation multiple.

[0219] Formula (1)

[0220] The activation fold and the corresponding compound concentration were fitted using Graphpad Prism 9 [Agonist] vs. response-variable slope (four parameters) to calculate the EC of the compound to activate AHR 50 The EC50 values ​​of each compound are shown in Table 8, where A represents EC 50 ≤10nM, B means 10nM<EC 50 ≤2.0M, C means 2.0M<EC 50 ≤100M.

[0221] Table 8 EC values ​​of each compound 50 value

[0222]

[0223]

[0224]

[0225] As can be seen from Table 8, the compounds of the present invention activate the expression of the gene of the cytochrome P450 family member A1 and have a strong stimulatory effect on the aryl hydrocarbon receptor.

Claims

1. An aromatic hydrocarbon receptor modulator, or a spin optical isomer, a prodrug or a pharmaceutically acceptable salt, characterized in that It has the following general formula (I) W is C=C or S; A1, A2, A3 are independently a connecting bond or C, m is an integer from 1 to 7; each R3 is independently H, D, halogen, CN, OR, SR, N(R)R, -C(O)R, -C(O)OR, RC(O)O-, S(O) n R, unsubstituted or substituted with 1 to 6 R a Substituted C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl or C3-C10 cycloalkyl; R a is D, halogen, OR, SR, N(R)R, -C(O)R, -C(O)OR, RC(O)O- or S(O) n R; A4 is independently O or NR4; R4 is H, unsubstituted or substituted with 1 to 6 R b Substituted C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl or C3-C10 cycloalkyl; R b is D, halogen, OR, SR, N(R)R, -C(O)R, -C(O)OR, RC(O)O- or S(O) n R; Each R1 is independently H, D, halogen, CN, OR, SR, N(R)R, -C(O)R, -C(O)OR, RC(O)O-, S(O) n R, unsubstituted or replaced by 1-6 R b Substituted C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl or C3-C10 cycloalkyl; R b is D, halogen, OR, SR, N(R)R, -C(O)R, -C(O)OR, RC(O)O- or S(O) n R; or two adjacent or alternate R1s form a 3-10 membered carbocyclic ring or a 3-10 membered heterocyclic ring containing 1-3 heteroatoms selected from N, O and S; n is 1 or 2; Each R is independently H, C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl or C3-C10 cycloalkyl; R2 is H or -(CH2O) a C(O)(CH2) b (O) c (CH(R c )) d (CH2CH2O) e R c ; R c Independently, they are H, D, C1~C8 alkyl, NH2-, (C1~C8 alkyl)NH-, (C1~C8 alkyl)2N-, NH2(C1~C8)alkyl-; a, b, c, d are independently 0 or 1; e is independently an integer from 0 to 3.

2. The aryl hydrocarbon receptor modulator according to claim 1, characterized in that: When W is S, the general formula (I) is the general formula (Ia) 3. The aryl hydrocarbon receptor modulator according to claim 2, characterized in that: When A4 is O, the general formula (Ia) is the general formula (Ia1) When A4 is NR4, the general formula (Ia) is the general formula (Ia2) 4. The aryl hydrocarbon receptor modulator according to claim 1, characterized in that: When W is C=C, the general formula (I) is the general formula (Ib) 5. The aryl hydrocarbon receptor modulator according to claim 4, characterized in that: When A4 is O, the general formula (Ib) is the general formula (Ib1) When A4 is NR4, the general formula (Ib) is the general formula (Ib2) 6. The aryl hydrocarbon receptor modulator according to any one of claims 1 to 5, characterized in that A1, A2, A3 are independently a connecting bond or C, m is an integer from 1 to 5; each R3 is independently H, D, halogen, CN, OR, SR, N(R)R, -C(O)R, -C(O)OR, RC(O)O-, S(O) n R, unsubstituted or substituted with 1 to 3 R a Substituted C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl or C3-C8 cycloalkyl; R a is D, halogen, OR, SR, N(R)R, -C(O)R, -C(O)OR, RC(O)O- or S(O) n R; n is 1 or 2; Each R is independently H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl or C3-C8 cycloalkyl; Preferably, A1, A2, A3 are independently a connecting bond or C, m is an integer from 1 to 3; each R3 is independently H, D, halogen, CN, OR, SR, N(R)R, -C(O)R, -C(O)OR, RC(O)O-, S(O) n R, unsubstituted or replaced by 1-2 R a Substituted C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl or C3-C7 cycloalkyl; R a is D, halogen, OR, SR, N(R)R, -C(O)R, -C(O)OR, RC(O)O- or S(O) n R; n is 1 or 2; Each R is independently H, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl or C3-C7 cycloalkyl; More preferably, A1, A2, A3 are independently a connecting bond or C, m is an integer of 1 to 2; each R3 is independently H, D, halogen, CN, OR, SR, N(R)R, -C(O)R, -C(O)OR, RC(O)O-, S(O) n R, unsubstituted or replaced by 1 R a Substituted C1-C3 alkyl, C2-C3 alkenyl, C2-C3 alkynyl or C5-C6 cycloalkyl; R a is D, halogen, OR, SR, N(R)R, -C(O)R, -C(O)OR, RC(O)O- or S(O) n R; n is 1 or 2; Each R is independently H, C1-C3 alkyl, C2-C3 alkenyl, C2-C3 alkynyl or C5-C6 cycloalkyl.

7. The aryl hydrocarbon receptor modulator according to any one of claims 1 to 5, characterized in that Each R1 is independently H, D, halogen, CN, OR, SR, N(R)R, -C(O)R, -C(O)OR, RC(O)O-, S(O) n R, unsubstituted or replaced by 1-3 R b Substituted C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl or C3-C8 cycloalkyl; R b is D, halogen, OR, SR, N(R)R, -C(O)R, -C(O)OR, RC(O)O- or S(O) n R; or two adjacent or alternate R1s form a 3-8 membered carbocyclic ring or a 3-8 membered heterocyclic ring containing 1-3 heteroatoms selected from N, O and S; n is 1 or 2; Each R is independently H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl or C3-C8 cycloalkyl; Preferably, Each R1 is independently H, D, halogen, CN, OR, SR, N(R)R, -C(O)R, -C(O)OR, RC(O)O-, S(O) n R, unsubstituted or replaced by 1-2 R b Substituted C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl or C3-C7 cycloalkyl; R b is D, halogen, OR, SR, N(R)R, -C(O)R, -C(O)OR, RC(O)O- or S(O) n R; or two adjacent or alternate R1s form a 3-7 membered carbocyclic ring or a 3-7 membered heterocyclic ring containing 1-2 heteroatoms selected from N, O and S; n is 1 or 2; Each R is independently H, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl or C3-C7 cycloalkyl; More preferably, Each R1 is independently H, D, halogen, CN, OR, SR, N(R)R, -C(O)R, -C(O)OR, RC(O)O-, S(O) n R, unsubstituted or replaced by 1 R b Substituted C1-C3 alkyl, C2-C3 alkenyl, C2-C3 alkynyl or C5-C6 cycloalkyl; R b is D, halogen, OR, SR, N(R)R, -C(O)R, -C(O)OR, RC(O)O- or S(O) n R; or two adjacent or alternate R1s form a 5-6 membered carbocyclic ring or a 5-6 membered heterocyclic ring containing 1-2 heteroatoms selected from N, O and S; n is 1 or 2; Each R is independently H, C1-C3 alkyl, C2-C3 alkenyl, C2-C3 alkynyl or C5-C6 cycloalkyl.

8. The aryl hydrocarbon receptor modulator according to any one of claims 1 to 5, characterized in that R2 is H or -(CH2O) a C(O)(CH2) b (O) c (CH(R c )) d (CH2CH2O) e R c ; R c independently H, D, C1-C6 alkyl, NH2-, (C1-C6 alkyl)NH-, (C1-C6 alkyl)2N-, NH2(C1-C6)alkyl-; a, b, c, d are independently 0 or 1; e is independently an integer from 0 to 2; Preferably, R2 is H or -(CH2O) a C(O)(CH2) b (O) c (CH(R c )) d (CH2CH2O) e R c ; R c independently H, D, C1-C4 alkyl, NH2-, (C1-C4 alkyl)NH-, (C1-C4 alkyl)2N-, NH2(C1-C4)alkyl-; a, b, c, d are independently 0 or 1; e is independently an integer of 0 or 1; More preferably, R2 is H or -(CH2O) a C(O)(CH2) b (O) c (CH(R c )) d (CH2CH2O) e R c ; R c Independently represent H, D, C1~C3 alkyl, NH2-, (C1~C3 alkyl)NH-, (C1~C3 alkyl)2N-, NH2(C1~C3)alkyl-; a, b, c, d are independently 0 or 1; e is independently an integer of 0 or 1.

9. The aryl hydrocarbon receptor modulator according to any one of claims 1 to 5, characterized in that R4 is H, unsubstituted or substituted with 1 to 3 R b Substituted C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl or C3-C8 cycloalkyl; R b is D, halogen, OR, SR, N(R)R, -C(O)R, -C(O)OR, RC(O)O- or S(O) n R; Each R is independently H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl or C3-C8 cycloalkyl; Preferably, R4 is H, unsubstituted or substituted with 1 to 2 R b Substituted C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl or C3-C7 cycloalkyl; R b is D, halogen, OR, SR, N(R)R, -C(O)R, -C(O)OR, RC(O)O- or S(O) n R; Each R is independently H, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl or C3-C7 cycloalkyl; More preferably, R4 is H, unsubstituted or replaced by 1 R b Substituted C1-C3 alkyl, C2-C3 alkenyl, C2-C3 alkynyl or C5-C6 cycloalkyl; R b is D, halogen, OR, SR, N(R)R, -C(O)R, -C(O)OR, RC(O)O- or S(O) n R; Each R is independently H, C1-C3 alkyl, C2-C3 alkenyl, C2-C3 alkynyl or C5-C6 cycloalkyl.

10. The aryl hydrocarbon receptor modulator according to any one of claims 1 to 5, characterized in that The aromatic hydrocarbon receptor modulator is the following compound:

11. Use of the aryl hydrocarbon receptor modulator according to claim 1 in the preparation of drugs for treating cancer, obesity, or in the preparation of drugs for immunomodulation, hematopoiesis, cell cycle or intestinal barrier.

12. Use of the aryl hydrocarbon receptor modulator of claim 1 as a drug for treating cancer, obesity, or in immunoregulation, hematopoiesis, cell cycle or intestinal barrier.

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