阅读说明：本技术 芳香烃受体调节剂 (Aromatic hydrocarbon receptor modulators ) 是由 杨录青 李国栋 张所明 于 2016-12-26 设计创作，主要内容包括：本发明公开了一种式(Ⅰ)所示的芳香烃受体调节剂,及其药学上可接受的盐,式(Ⅰ)中各个基团的定义如说明书中所述。本发明的式(Ⅰ)的化合物可调节AhR活性,可用于抑制癌细胞生长,抑制肿瘤细胞的转移和侵袭。(The invention discloses an aromatic hydrocarbon receptor modulator shown in a formula (I) and pharmaceutically acceptable salts thereof, wherein each group in the formula (I) is defined in the specification. The compound of formula (I) can regulate AhR activity, and can be used for inhibiting cancer cell growth and inhibiting metastasis and invasion of tumor cells.)

1. An aromatic hydrocarbon receptor modulator of formula (I), and pharmaceutically acceptable salts thereof,

r' is H, CN, CH₂(OH)R₀、C_mH_2m+1、C_nH_2n-1、C_nH_2n-3、 Wherein W₀Is O or NH; w₁Is a connecting bond, C (R)₀)₂、C(R₀)₂O、C(R₀)₂OC(R₀)₂Or C (R)₀)₂OC(R₀)₂C(R₀)₂(ii) a When W is C, S or S (O), W₂Is a connecting key, O, NR₀、CH(N(R₀)₂) Or OCH₂C (O); when W is P (OR)₀) When W is₂Is O or NR₀(ii) a Each R₀Independently H, C_mH_2m+1、C_mH_2m+1OC(O)、C_mH_2m+1-rX_r、C_mH_2m+1OC(O)C_mH_2mAnd (Ring-shaped C)₄H₈NO)C_mH_2m、CH₃(OCH₂CH₂)_uOr CH₃(OCH₂CH₂)_uOCH₂；

Two R_aIndependently is H or two R_aTogether form ═ O, ═ N-CN or ═ N-W₃-R₁，W₃Is O or NH, R₁Is H, C_mH_2m+1、C_mH_2m+1C(O)、C_mH_2m+1OC (O) or C_mH_2m+1S(O)_1～2；

A is unsubstituted or 1-3R-substituted C₆～C₁₀An aromatic ring, or C which is unsubstituted or substituted with 1 to 3R, 1 to 5 hetero atoms selected from N, O and S₂～C₁₀A heteroaromatic ring or a 4-to 7-membered C ═ N non-aromatic heterocyclic ring containing 1-3 heteroatoms selected from N, O and S;

q is R, or unsubstituted or 1-3R-substituted C₆～C₁₀An aromatic ring, or a 3-10 membered, preferably 4-7 membered, more preferably 5-6 membered heterocyclic ring, preferably a heteroaromatic ring, which is unsubstituted or 1-3R substituted hetero 1-5, preferably 1-3, more preferably 2-3 heteroatoms selected from N, O and S heteroatoms;

r is R linked to C_COr R attached to N_NWherein each R is_CIndependently X, X,CN、R”、-Y-OR”、-Y-C(O)R”、-Y-OC(O)R”、-Y-C(O)OR”、-Y-OC(O)OR”、-Y-NR”₂、-Y-C(O)NR”₂、-Y-NR”C(O)R”、-Y-NR”C(O)NR”₂、-Y-OC(O)NR”₂、-Y-NR”C(O)OR”、-Y-S(O)_1～2R”、-Y-S(O)_1～2NR”₂or-Y-NR' S (O)_1～2R "; each R is_NIndependently CN, R ", -Y-OR", -Y-C (O) R ", -Y-OC (O) R", -Y-C (O) OR ", -Y-OC (O) OR", -Y-NR "₂、-Y-C(O)NR”₂、-Y-NR”C(O)R”、-Y-NR”C(O)NR”₂、-Y-OC(O)NR”₂、-Y-NR”C(O)OR”、-Y-S(O)_1～2R”、-Y-S(O)_1～2NR”₂or-Y-NR' S (O)_1～2R”；

R' is H, D, C_mH_2m+1、C_nH_2n-1、C_nH_2n-3、C_mH_2m+1-rX_r、C_nH_2n-1-sX_sOr C_nH_2n-3-tX_t；

Y is a connecting bond, -C_mH_2m-、-C_nH_2n-2-、-C_nH_2n-4-、-C_mH_2m-iX_i-、-C_nH_2n-2-jX_j-or-C_nH_2n-4-kX_k-；

m is 1-8, n is 2-8, u is 1-5, r is less than or equal to 2m +1, s is less than or equal to 2n-1, t is less than or equal to 2n-3, i is less than or equal to 2m, j is less than or equal to 2n-2, k is less than or equal to 2n-4, and X is halogen; preferably, m is 1 to 5, more preferably 1 to 3, n is 2 to 6, more preferably 2 to 4, u is 1 to 4, more preferably 1 to 3, and X is F, Cl or Br.

2. The aromatic hydrocarbon receptor modulator of claim 1, wherein a isFormula (I) is changed into formula (I1),

in the formula (I1), A₁、A₂And A₃One of the three is O, S or N (R), and the other two are independently C (R) or N.

3. The aromatic hydrocarbon receptor modulator of claim 2, wherein a is₁、A₂And A₃One of the three is O, S or N (R), and the other two are N independently.

4. The aromatic hydrocarbon receptor modulator of claim 3, wherein A is₃Is N, formula (I1) is changed to formula (Ia),

in the formula (Ia), A₁O, S or N (R), A₂Is N; or A₂O, S or N (R), A₁Is N.

5. The aromatic hydrocarbon receptor modulator of claim 2, wherein a is₂Is CH, formula (I1) is changed to formula (Ib),

in the formula (Ib), A₁Is N or C (R), A₃O, S or N (R); or A₁O, S or N (R), A₃Is N or C (R).

6. The aromatic hydrocarbon receptor modulator of claim 2, wherein a is₁Is N, A₃Is C (R), two R_aTogether form ═ N-W₃-R₁Formula (I1) is changed to formula (ic),

in the formula (ic), A₂O, S or N (R).

7. The aromatic hydrocarbon receptor modulator of claim 2, wherein a is₁Is N, A₃Is C (R), two R_aIs H, formula (I1) is changed to formula (Id),

in the formula (Id), A₂O, S or N (R).

8. The aromatic hydrocarbon receptor modulator of claim 2, wherein a is₁Is N, A₃Is C (R), R' isFormula (I1) is changed to formula (ie),

a in the formula (ie)₂O, S or N (R).

9. The aromatic hydrocarbon receptor modulator of claim 2, wherein a is₁Is N, A₃Is C (R), R' isFormula (I1) is changed to formula (if),

in the formula (if) A₂Is O, S or N (R), each R₀Independently H or Ac.

10. The aromatic hydrocarbon receptor modulator of claim 1, wherein Q isB₁、B₂、B₃And B₄One of the four is O, S or N (R), the other three are independently C (R) or N;

or Q isB₅～B₉Is C (R); or B₅～B₉One or two are N, the others are independently C (R).

Technical Field

The invention belongs to the technical field of anti-tumor compounds, and relates to a compound with the function of regulating the activity of an aromatic hydrocarbon receptor (AhR) and pharmaceutically acceptable salts thereof.

Background

Due to the change of environment and life style, the incidence rate of cancer is increasing day by day, and the high fatality rate seriously threatens the health of human beings. Although significant advances have been made in the medical treatment of certain cancers, targeted drug and immunotherapy have greatly improved patient survival, the overall 5-year survival rate for all cancer patients has increased by only 10% of a month over the last 20 years. Moreover, cancer discovery and treatment is extremely difficult due to drug resistance or metastasis and rapid growth in an uncontrolled manner in malignant tumors.

Aromatic hydrocarbon receptors (AhR) are a class of heterogeneous species that can sense the environmentc) Intracellular transcriptional regulators that stimulate, and mediate, toxic responses. The activated AhR can regulate the expression of genes on a plurality of chromosomes and promote the decomposition of heterogeneous substances. Previous studies found that this signal is also involved in some important biological processes, such as signal transduction, cell differentiation, apoptosis, etc. The relationship between AhR and immunoregulation is a hot spot of research, and previous researches show that AhR can participate in the differentiation and function of T cells, macrophages and DCs, and has a key role in immune rejection after organ transplantation. Researches show that the survival rate of mice after virus infection can be reduced by using Dioxin to activate AhR in mice, and the differentiation and proliferation rates of virus-specific CD 8T cells are also influenced. As another example, DIM and its derivatives have tumor-inhibiting activity (Breast Cancer Res. treat.2001,66, 147), which is currently in phase II clinical studies for the treatment of prostate and cervical Cancer. Both natural products ICZ and FICZ are AhR agonists and are anti-asthmatics (chem. rev.,2002,102,4303; chem. rev.,2012, 112, 3193; j.biol. chem.2009,284, 2690). Malassezin (bioorg.med.chem.2001,9, 955). Aminoflavone (aminoflavanone) was developed by NCI and is in phase I clinical use. 3-hydroxymethyl Indole (Indole-3-carbanol) is in phase II clinical use as a chemoprotectant and as an immunostimulant. Phortress is an AhR agonist developed by Pharminox Univ.of Nottingham, and is clinically used in the treatment of solid tumors in phase I (Br. J. cancer,2003,88, 599; mol. cancer Ther.2004,3,1565). Tanshinone I as one natural AhR ligand for antitumor chemoprotectantToxicol Appl Pharmacol.2011Apr 1; 252(1):18-27). 2- (Indoleacetyl-3-yl) furan (Food chem.2011,127, 1764-1772). ITE A natural endogenous AhR activator with effects of resisting hepatocarcinoma, prostatic cancer, breast cancer and ovarian cancer: (ITE)Proc.Natl.Acad.Sci.2002，99，14694-9；CN102573470；WO2016040553)。

Disclosure of Invention

The invention aims to provide a novel aromatic hydrocarbon receptor regulator with AhR activity as shown in a formula (I), and pharmaceutically acceptable salts thereof,

r' is H, CN, CH₂(OH)R₀、C_mH_2m+1、C_nH_2n-1、C_nH_2n-3、 Wherein W₀Is O or NH; w₁Is a connecting bond, C (R)₀)₂、 C(R₀)₂O、C(R₀)₂OC(R₀)₂Or C (R)₀)₂OC(R₀)₂C(R₀)₂(ii) a When W is C, S or S (O), W₂Is a connecting key, O, NR₀、CH(N(R₀)₂) Or OCH₂C (O); when W is P (OR)₀) When W is₂Is O or NR₀(ii) a Each R₀Independently H, C_mH_2m+1、C_mH_2m+1OC(O)、C_mH_2m+1-rX_r、C_mH_2m+1OC(O)C_mH_2mAnd (Ring-shaped C)₄H₈NO)C_mH_2m、CH₃(OCH₂CH₂)_uOr CH₃(OCH₂CH₂)_uOCH₂；

Two R_aIndependently is H or two R_aTogether form ═ O, ═ N-CN or ═ N-W₃-R₁，W₃Is O or NH, R₁Is H, C_mH_2m+1、C_mH_2m+1C(O)、C_mH_2m+1OC (O) or C_mH_2m+1S(O)_1～2；

A is unsubstitutedOr 1 to 3R-substituted C₆～C₁₀An aromatic ring, or C which is unsubstituted or substituted with 1 to 3R, 1 to 5 hetero atoms selected from N, O and S₂～C₁₀A heteroaromatic ring or a 4-to 7-membered C ═ N non-aromatic heterocyclic ring containing 1-3 heteroatoms selected from N, O and S;

q is R, or unsubstituted or 1-3R-substituted C₆～C₁₀An aromatic ring, or a 3-10 membered, preferably 4-7 membered, more preferably 5-6 membered heterocyclic ring, preferably a heteroaromatic ring, which is unsubstituted or 1-3R substituted hetero 1-5, preferably 1-3, more preferably 2-3 heteroatoms selected from N, O and S heteroatoms;

r is R linked to C_COr R attached to N_NWherein each R is_CIndependently X, CN, R ", -Y-OR", -Y-C (O) R ", -Y-OC (O) R", -Y-C (O) OR ", -Y-OC (O) OR", -Y-NR "₂、-Y-C(O)NR”₂、 -Y-NR”C(O)R”、-Y-NR”C(O)NR”₂、-Y-OC(O)NR”₂、-Y-NR”C(O)OR”、-Y-S(O)_1～2R”、 -Y-S(O)_1～2NR”₂or-Y-NR' S (O)_{1～ 2}R "; each R is_NIndependently CN, R ", -Y-OR", -Y-C (O) R ", -Y-OC (O) R", -Y-C (O) OR ", -Y-OC (O) OR", -Y-NR "₂、-Y-C(O)NR”₂、-Y-NR”C(O)R”、 -Y-NR”C(O)NR”₂、-Y-OC(O)NR”₂、-Y-NR”C(O)OR”、-Y-S(O)_1～2R”、-Y-S(O)_1～2NR”₂or-Y-NR' S (O)_1～2R”；

R' is H, D, C_mH_2m+1、C_nH_2n-1、C_nH_2n-3、C_mH_2m+1-rX_r、C_nH_2n-1-sX_sOr C_nH_2n-3-tX_t；

Y is a connecting bond, -C_mH_2m-、-C_nH_2n-2-、-C_nH_2n-4-、-C_mH_2m-iX_i-、-C_nH_2n-2-jX_j-or-C_nH_2n-4-kX_k-；

m is 1-8, n is 2-8, u is 1-5, r is less than or equal to 2m +1, s is less than or equal to 2n-1, t is less than or equal to 2n-3, i is less than or equal to 2m, j is less than or equal to 2n-2, k is less than or equal to 2n-4, and X is halogen; preferably, m is 1 to 5, more preferably 1 to 3, n is 2 to 6, more preferably 2 to 4, u is 1 to 4, more preferably 1 to 3, and X is F, Cl or Br.

Wherein (Cyclic C)₄H₈NO)C_mH_2mIn (2) cyclic C₄H₈NO is a six-membered ring, N and O are in the meta or para positions, and N-substituted morpholine is preferred.

C_mH_2m+1、C_mH_2m+1-rX_r、-C_mH_2m-and-C_mH_2m-iX_iSaturated hydrocarbon radicals, which may be linear or branched, C_nH_2n-1、C_nH_2n-1-sX_s、-C_nH_2n-2-and-C_nH_2n-2-jX_jAlkylene which may be linear or branched, C_nH_2n-3、C_nH_2n-3-tX_t、-C_nH_2n-4-and-C_nH_2n-4-kX_kThe alkynyl group may be a straight chain or branched chain.

When n is 3-8, C_nH_2n-1、C_nH_2n-1-sX_s、-C_nH_2n-2-and-C_nH_2n-2-jX_j-may also be a cycloalkyl group. When n is 5-8, C_nH_2n-3、C_nH_2n-3-tX_t、-C_nH_2n-4-and-C_nH_2n-4-kX_kIt may also be a dienyl or cycloalkenyl group.

In some preferred embodiments of the present invention, A isFormula (I) is changed to formula (I1),

in the formula (I1), A₁、A₂And A₃One of the three is O, S or N (R), the other two are independently C (R) or N, in three cases, if A₁O, S or N (R), A₂And A₃Each independently is C (R) or N; if A₂O, S or N (R), A₁And A₃Each independently is C (R) or N; if A₃O, S or N (R), A₁And A₂Each independently is C (R) or N.

The invention is further preferred on the basis of formula (I1), A₁、A₂And A₃One of the three is O, S or N (R), the other two are N independently, when A is₁、A₂And A₃All three are hetero atoms. And further preferred on this basis, A₃Fixed to N, at which time formula (I1) becomes formula (Ia),

in the formula (Ia), A₁O, S or N (R), A₂Is N; or A₂O, S or N (R), A₁Is N.

According to the invention, it is further preferred, based on formula (I1), that A₂Is CH, at which time formula (I1) is changed to formula (Ib),

in the formula (Ib), A₁Is N or C (R), A₃O, S or N (R); or A₁O, S or N (R), A₃Is N or C (R).

According to the invention, it is further preferred, based on formula (I1), that A₁Is N, A₃Is C (R), two R_aTogether form ═ N-W₃-R₁Or independently of one another is H, in which case formula (I1) is changed to formula (ic) or (id),

in the formulae (ic) and (id), A₂O, S or N (R).

According to the invention, it is further preferred, based on formula (I1), that A₁Is N, A₃Is C (R), R' isFormula (I1) is now changed to formula (ie),

in the formula (ie), A₂O, S or N (R).

According to the invention, it is further preferred, based on formula (I1), that A₁Is N, A₃Is C (R), R' isFormula (I1) is now changed to formula (if),

in the formula (if) A₂Is O, S or N (R), each R₀Independently H or Ac.

In some preferred embodiments of the present invention, Q isB₁、B₂、B₃And B₄One of the four is O, S or N (R), the other three are independently C (R) or N, i.e.

B₁O, S or N (R), B₂、B₃And B₄Each independently is C (R) or N;

or B₂O, S or N (R), B₁、B₃And B₄Each independently is C (R) or N;

or B₃O, S or N (R), B₁、B₂And B₄Each independently is C (R) or N;

or B₄O, S or N (R), B₁、B₂And B₃Each independently is C (R) or N.

In some preferred embodiments of the present invention, Q isB₅～B₉Is C (R), namely Q is a benzene ring; or B₅～B₉One or two are N, the others are independently C (R), i.e.

Q may also be a pyridine ring, in which case B₅Is N, B₆～B₉Each independently is C (R); or B₆Is N, B₅、 B₇～B₉Each independently is C (R); or B₇Is N, B₅、B₆、B₈And B₉Each independently is C (R);

q may also be a pyridazine ring, in which case B₅、B₆Is N, B₇～B₉Each independently is C (R); or B₆And B₇Is N, B₅、B₈And B₉Each independently is C (R);

q may also be a pyrimidine ring, in which case B₅And B₇Is N, B₆、B₈And B₉Each independently is C (R);

q may also be a pyrazine ring, in which case B₅And B₈Is N, B₆、B₇And B₉Are each independently C (R).

According to the invention, it is further preferred, based on formula (I1), that A₁Is N, A₂Is S, A₃Is CH, Q is a 5-membered heteroaromatic ring, at which time formula (I) is changed to formula (Ig)

Wherein, B₂、B₃Or B₄One is O, S or N (R), the other is C (R) or N, i.e.

If B is₂O, S or N (R), B₃And B₄Each independently is C (R) or N;

if B is₃O, S or N (R), B₂And B₄Each independently is C (R) or N;

if B is₄O, S or N (R), B₂And B₃Each independently is C (R) or N.

According to the invention, it is further preferred, based on formula (I1), that A₁Is N, A₂Is S, A₃Is CH and Q is a 5-membered heterocyclic ring, at which time formula (I) is changed to formula (ih)

B₄O, S or N (R).

In some preferred embodiments of the invention, A is a non-aromatic heterocyclic ring which is interrupted by N and S, and Q is R, when formula (I) is changed to formula (I2)

In some preferred embodiments of the present invention, A isFormula (I) is changed to formula (I3),

in the formula (I3), Z₁～Z₅Is C (Q), namely A is a benzene ring;

or, Z₁～Z₅One or two are N, the others are independently C (Q), i.e.

A may also be a pyridine ring, in which case Z₁Is N, Z₂～Z₅Each independently is C (Q); orZ₂Is N, Z₁、 Z₃～Z₅Each independently is C (Q); or Z₃Is N, Z₁、Z₂、Z₄And Z₅Each independently is C (Q);

a may also be a pyridazine ring, in which case Z₁And Z₂Is N, Z₃～Z₅Each independently is C (Q); or Z₂And Z₃Is N, Z₁、Z₄And Z₅Each independently is C (Q);

a may also be a pyrimidine ring, in which case Z₁And Z₃Is N, Z₂、Z₄And Z₅Each independently is C (Q);

a may also be a piperazine ring, in which case Z₁And Z₄Is N, Z₂、Z₃And Z₅Each independently is C (Q);

or, Z₁～Z₅Two adjacent C (Q) S are C (Q) S and form 5-6-membered carbocycle or 1-3 hetero 5-6-membered heterocycle selected from N, O and S heteroatom together, the other three are C (Q) S respectively, or two of the other three are C (Q) S respectively, the rest one is N, or one of the other three is C (Q) and the rest two is N; the description is classified into the following two cases in terms of the position of the loop: when Z is₁And Z₂Z is C (Q) and forms a 5-6 membered carbocyclic ring or a 5-6 membered heterocyclic ring containing 1-3 hetero atoms selected from N, O and S₃～Z₅Each independently C (Q), or Z₃And Z₄Independently of one another are C (Q) and Z₅Is N, or Z₃And Z₅Independently of one another are C (Q) and Z₄Is N, or Z₄And Z₅Independently of one another are C (Q) and Z₃Is N, or Z₃Is C (Q) and Z₄And Z₅Is N, or Z₄Is C (Q) and Z₃And Z₅Is N, or Z₅Is C (Q) and Z₃And Z₄Is N; when Z is₂And Z₃Z is C (Q) and forms a 5-6 membered carbocyclic ring or a 5-6 membered heterocyclic ring containing 1-3 hetero atoms selected from N, O and S₁、Z₄And Z₅Each independently C (Q), or Z₁And Z₄Independently of one another are C (Q) and Z₅Is N, or Z₁And Z₅Independently of one another are C (Q) and Z₄Is N, or Z₄And Z₅Independently of one another are C (Q) and Z₁Is N, or Z₁Is C (Q) and Z₄And Z₅Is N, or Z₄Is C (Q) and Z₁And Z₅Is N, or Z₅Is C (Q) and Z₁And Z₄Is N.

In some preferred embodiments of the invention, R' isW₁Is a connecting bond, C (R)₀)₂O or C (R)₀)₂OC(R₀)₂；W₂Is O or CH (N (R)₀)₂)R₀。

In particular embodiments, each individual functional group or substituent can be arbitrarily selected and combined within the ranges described, such as

R' in formula (I) may be one of the following substituents:

in formula (I1)May be one of the following substituents:

in formula (Ib)May be as followsOne of the substituents:

in formulae (ic) to (if)May be one of the following substituents:

the compound satisfying the formula (Ia) may be

The compound satisfying the formula (Ib) may be

The compound satisfying formula (ic) may be

The compound satisfying the formula (Id) may be

The compound satisfying the formula (ie) may be

The compound satisfying formula (if) may be

The compound satisfying formula (Ig) may be

The compound satisfying formula (ih) may be

The compound satisfying the formula (I1) may also be

The compound satisfying the formula (I2) may be

The compound satisfying the formula (I3) may be

The aromatic hydrocarbon receptor modulators of formula (I) of the present invention are classified into the following 5 groups of compounds:

formula (I)_A) (when R' is H),Formula (I)_B) (when R' is not H),Formula (I)_C) (when R' is H),Formula (I)_D) (when R' is not H),Formula (I)_E) (when R' is H)Formula (I)_F) (R' is not H).

Wherein, formula (I)_A) Equation (I)_F) The synthetic scheme of (a) is as follows:

firstly, performing Friedel-crafts reaction on raw materials S (indole or indole derivatives) and acyl halide (ClC (O) AQ), alcohols or alkene compounds to obtain a target compound I substituted by 3-position indole_A；

Step two, target compound I_AReacting with R 'X or R' OH to obtain target compound I_B；

Step three, the target compound I_AOr the object compound I_BAnd H₂NW₃R₁Reacting to obtain a target compound I_COr the object compound I_D；

Step four, the target compound I_AOr the object compound I_BObtaining a target compound I through reduction reaction_EOr the object compound I_F。

The positive progress effect of the invention is as follows: the compounds of formula (i) of the present invention bind to AhR and modulate those functions and signaling pathways controlled by AhR, thereby affecting the growth and proliferation of cancer cells and the invasiveness of tumor cells. The pharmaceutical composition of the compound shown in the formula (I) can be used as an AhR inhibitor or a non-constitutive AhR agonist (non-constitutive AhR agonists), and can be used for inhibiting the growth of cancer cells and inhibiting the metastasis and invasion of the cancer cells.

Detailed Description

EXAMPLE 1 Compounds 1-1 and 1-2

Synthesis of intermediate 1a

To a suspension of Boc-L-valine (0.8g,3.68mmol) in methylene chloride and water (12mL/12mL) were added sodium bicarbonate (1.546g,18.411mmol) and tetrabutylammonium bromide (0.237g,0.736mmol) with stirring, and the mixture was cooled to 0 ℃ or below, chloromethyl chlorosulfonate (0.91g,5.52mmol) was slowly added dropwise to the reaction mixture, followed by stirring overnight. The reaction mixture was extracted 2 times with dichloromethane, and the organic phase was washed with water and saturated brine 1 times, dried over anhydrous sodium sulfate and concentrated under reduced pressure to give a crude product, which was purified by silica gel column chromatography (PE/EA ═ 20/1) to give intermediate 1a as an oil (0.97g, yield 99%).

Synthesis of Compound 1-1

To a solution of raw material S1(1g,3.763mmol) in Dimethylformamide (DMF) (10mL) was added sodium hydride (0.165g,4.139mmol) portionwise with stirring, then warmed to 40 ℃ for reaction for 1 hour, cooled to room temperature, and a solution of intermediate 1a (0.97g,3.6mmol) in DMF (2mL) was slowly added dropwise with stirring at room temperature overnight. The reaction mixture was poured into 60mL of ice water, and the crude product was obtained by filtration and purified by silica gel column chromatography (PE/EA ═ 20/1 to 10/1) to obtain compound 1-1(0.5g, yield 28%). MS (ESI) M/z 516[ M +1 ]]⁺。

Synthesis of Compound 1-2

Compound 1-1(0.5g,0.97mmol) was dissolved in dioxane (2mL), a hydrogen chloride dioxane solution (5mL) was added dropwise, the reaction was allowed to proceed overnight at room temperature, and then, compound 1-2(0.24g, yield 55%) was obtained by filtration.¹H NMR(400MHz, CDCl₃):δ9.24(s,1H),8.94(s,1H),8.41(brs,3H),8.35(d,J＝7.6Hz,1H),7.81(d,J＝7.6Hz, 1H),7.39～7.47(m,2H),6.63(d,J＝10.8Hz,1H),6.58(d,J＝10.8Hz,1H),4.02(d,J＝7.6Hz, 1H),3.94(s,3H),2.07～2.12(m,1H),0.84(d,J＝7.2Hz,1H),0.80(d,J＝7.2Hz,1H)。 MS(ESI)m/z:416[M+1]⁺。

EXAMPLE 2 Compound 2-1 and Compound 2-2

Synthesis of intermediate 2a

The procedure was as for the synthesis of intermediate 1a, and Boc-L-tert-leucine (2g,8.647mmol) gave intermediate 2a as an oil (2.3g, 95% yield).

Synthesis of Compound 2-1

The same procedure was followed as for the synthesis of Compound 1-1, and Compound 2-1(1.4g, 74% yield) was obtained from intermediate 2a (1g,3.6 mmol).¹H NMR(400MHz,CDCl₃):δ9.24(s,1H),8.50～8.52(m,1H),8.46(s,1H), 7.57～7.60(m,1H),7.39～7.43(m,1H),6.42(d,J＝11.2Hz,1H),6.17(d,J＝11.2Hz,1H), 5.05(d,J＝9.2Hz,1H),4.10(d,J＝8.4Hz,1H),4.04(s,3H),1.42(s,9H),0.83(s,9H)。 MS(ESI)m/z:530[M+1]⁺。

Synthesis of Compound 2-2

The same procedure as described for the synthesis of Compound 1-2 gave Compound 2-2(0.85g, 70% yield) from Compound 2-1(1.4g,2.6 mmol).¹H NMR(400MHz,CDCl₃):δ9.24(s,1H),8.94(s,1H),8.36(d,J＝7.2Hz,1H), 8.27(brs,3H),7.82(d,J＝7.6Hz,1H),7.39～7.47(m,2H),6.61(s,1H),3.93(s,3H),3.86(s, 3H),0.89(s,9H)。MS(ESI)m/z:430[M+1]⁺。

EXAMPLE 3 Compound 3

Synthesis of intermediate 3a

Weighing methyl glycolate (3g,33.3mmol), adding dichloromethane (50mL) and paraformaldehyde (1.3g, 43.3mmol), cooling to below-20 ℃, continuously introducing the prepared hydrogen chloride gas, keeping the temperature at-20 ℃ for reaction for 30 minutes, removing the hydrogen chloride gas, adding anhydrous magnesium sulfate and anhydrous sodium sulfate, continuing the heat preservation reaction for 1 hour, and standing at room temperature overnight. The solid was removed by filtration, and the mother liquor was concentrated to dryness at room temperature and purified by silica gel column chromatography to give intermediate 3a (1.2g, yield 26%).

Synthesis of Compound 3

The same procedure as that for the synthesis of compound 1-1 gave compound 3(280mg, 74% yield) as a pale yellow solid from starting material S1(286mg,1mmol) and intermediate 3a (500mg, 3.6 mmol).¹H NMR(400MHz,CDCl₃):δ9.19(s,1H),8.55～8.56(m,1H),8.45(s,1H),7.63～7.65(m,1H),7.41～7.45(m,2H),5.82(s, 2H),4.12(s,2H),4.03(s,3H),3.77(s,3H)。MS(ESI)m/z:389[M+1]⁺。

EXAMPLE 4 Compound 4-1 and Compound 4-2

Synthesis of Compound 4-1

To a solution of Boc-L-valine (2.17g,10mmol) in DMF (20mL) was added the starting material S1(2.86g,10mmol), HATU (4.56g,12mmol) and DIEA (2.6g,20mmol) with stirring and stirred overnight. The reaction solution was poured into water, extracted 2 times with ethyl acetate, and the organic phase was washed with water and saturated brine 1 times each, dried over anhydrous sodium sulfate and concentrated under reduced pressure to give a crude product, which was purified by silica gel column chromatography (PE/EA ═ 4/1) to give compound 4-1(3.01g, yield 62%).¹H NMR(400MHz,CDCl₃):δ9.75(s,1H),8.48～8.55(m,3H), 7.47～7.52(m,2H),5.44(d,J＝8.8Hz,1H),5.27(dd,J＝4.0,8.8Hz,1H),4.05(s,3H), 2.37～2.42(m,1H),1.48(s,9H),1.25(d,J＝6.8Hz,3H),1.01(d,J＝6.4Hz,3H)。MS(ESI) m/z:508[M+23]⁺。

Synthesis of Compound 4-2

The same procedure as that for the synthesis of Compound 1-2 gave Compound 4-2(348mg, 77% yield) from Compound 4-1(486mg,1 mmol).¹H NMR(400MHz,CDCl₃):δ9.56(s,1H),9.04(s,1H),8.81(brs,3H), 8.46～8.48(m,1H),8.35～8.37(s,1H),7.54～7.60(m,2H),5.01(d,J＝4.8Hz,1H),3.99(s,3H), 2.42～2.47(m,1H),1.17(d,J＝6.8Hz,3H),1.07(d,J＝6.8Hz,3H)。MS(ESI)m/z:386[M+1] ⁺。

EXAMPLE 5 Compound 5

Synthesis of intermediate 5a

Triethylene glycol monomethyl ether (2.0g,12.2mmol) is dissolved in tetrahydrofuran (20mL), triphosgene (1.8g,6.1mmol) is added with stirring, the temperature is reduced to zero in an ice bath, pyridine (1.5g,19.0mmol) is slowly dropped, and the reaction is carried out at room temperature for 1 hour. Filtration and concentration of the mother liquor under reduced pressure gave intermediate 5a (2.1g, yield 75.9%) as a colorless liquid.

Synthesis of Compound 5

The starting material S-1(2.0g,7.0mmol) was dissolved in tetrahydrofuran (80mL), triethylamine (1.5g,14.9mmol) was added dropwise, the temperature was lowered to zero in an ice bath, a dichloromethane solution (20mL) of intermediate 5-1(2.1g,9.3mmol) was added dropwise, and the reaction was carried out at room temperature for 1 hour. Poured into ice water, extracted with dichloromethane, the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, concentrated to dryness under reduced pressure, and the crude product was purified by silica gel column chromatography (PE/EA ═ 3/1) to give compound 5(2.5g, yield 75.8%) as a white solid.¹H NMR(400MHz,CDCl₃):δ9.56(s,1H),8.49(s,2H),8.33～8.24(m,1H),7.51～7.39(m, 2H),4.75～4.67(m,2H),4.03(s,3H),4.01～3.94(m,2H),3.80(dd,J＝5.9,3.4Hz,2H), 3.74～3.69(m,2H),3.67～3.62(m,2H),3.53～3.48(m,2H),3.35(s,3H)。LCMS(ESI) m/z:477.2[M+1]+。

EXAMPLE 6 Compound 6

Synthesis of intermediate 6a

Dissolving triethylene glycol monomethyl ether (10g,60.9mmol) in tetrahydrofuran (100mL), adding sodium hydrogen (3.2g, 60% content, 79.17mmol) in batches at 0 ℃, stirring at room temperature for 1h after the addition is finished, dropwise adding ethyl bromoacetate (20.1g,122mmol), reacting at room temperature for 3h, directly adding water (100mL) into the reaction liquid, extracting with dichloromethane, drying the organic phase with anhydrous sodium sulfate, and concentrating under reduced pressure to dryness. Adding water (100mL) and a sodium hydroxide solid (3g,73mmol), stirring at room temperature for 1h, extracting with ethyl acetate for 2 times, adjusting the pH of the aqueous phase to 2-3 with dilute hydrochloric acid, extracting with a dichloromethane/isopropanol (V/V-10: 1) mixed solvent for 5 times, drying the organic phase with anhydrous sodium sulfate, concentrating under reduced pressure to obtain a crude product, and performing silica gel column chromatography (DCM: CH) on the crude product₃OH 100:1 to 20:1) to obtain compound 6a (10g, yield 74%).

Synthesis of intermediate 6b

Compound 6a (2g,8.99mmol) was dissolved in dichloromethane (20mL), and sodium bicarbonate (3.1g,36mmol), tetrabutylammonium bromide (289mg,0.899mmol), and water (20mL) were added. Cooling to below 0 deg.C, adding dropwise dichloromethane solution (10mL) of chloromethyl chlorosulfonate (1.48g, 8.99mmol), stirring at room temperature overnight, standing for layering, extracting the aqueous phase with dichloromethane for 2 times, drying the organic phase with anhydrous sodium sulfate, concentrating under reduced pressure to obtain crude product, and performing silica gel column chromatography (DCM: CH) on the crude product₃OH 50: 1) purification gave 6b as an oily liquid (300mg, yield 12.3%). LCMS (ESI) m/z:271[ M +1 ]]⁺。

Synthesis of Compound 6

Dissolving raw material S1(1g,3.49mmol) in DMF (15mL), adding sodium hydride (153mg, 60% content, 3.84mmol) at 0 deg.C, stirring for 10min after adding, heating to 50 deg.C, stirring for 1h, cooling to room temperature, adding compound 6b (0.944mg, 3.49mmol), reacting at room temperature for 4h, adding water and dichloromethane, extracting with dichloromethane for 3 times, drying organic phase with anhydrous sodium sulfate, concentrating under reduced pressure to obtain crude product, and performing silica gel column Chromatography (CH)₃OH DCM ═ 0-2%) was purified to give compound 6(650mg, yield 35.8%).¹H NMR(400MHz,CDCl₃):δ9.25(s,1H),8.52～8.54(m,1H),8.46(s, 1H),7.59～7.61(m,1H),7.41～7.44(m,2H),6.32(s,2H),4.21(s,2H),4.04(s,3H),3.70～3.72(m, 2H),3.65～3.68(m,2H),3.60～3.64(m,6H),3.52～3.54(m,2H),3.37(s,3H)。LCMS(ESI)m/z: 521[M+1]⁺。

EXAMPLE 7 Compound 7

Synthesis of intermediate 7a

The procedure is as in 6a, starting from intermediate 6 a. The yield thereof was found to be 75%. LCMS (ESI) M/z 337.2[ M +1 ]]⁺。

Synthesis of intermediate 7b

Intermediate 7a (3.4g,10mmol) was dissolved in dichloromethane (5mL), trifluoroacetic acid (5mL) was added, stirring overnight at room temperature, concentrated to dryness under reduced pressure, and the crude product was purified by silica gel column Chromatography (CH)₃OH DCM ═ 0-2%) purified to give oil 7b (2.6g, 76% yield). LCMS (ESI) M/z 281.2[ M +1 ]]⁺。

Compound 7

Methods are described for compound 6. The yield thereof was found to be 55%.¹H NMR(400MHz,CDCl₃):δ9.20(s,1H),8.50～8.52(m, 1H),8.44(s,1H),7.53～7.56(m,1H),7.40～7.42(m,2H),6.31(s,2H),4.70(s,2),4.25(s,2H), 4.02(s,3H),3.63～3.71(m,10H),3.53～3.55(m,2H),3.37(s,3H)。LCMS(ESI)m/z:579.2 [M+1]⁺。

EXAMPLE 8 Compound 8

Synthesis of intermediate 8a

The starting material S2(188mg,1mmol) was dissolved in dichloromethane (20mL), 1 drop of DMF was added dropwise, cooled to 0-5 deg.C, oxalyl chloride (151mg,1.2mmol) was added dropwise, the ice bath was removed, and the mixture was stirred at room temperature for 1 hour. Concentrated to dryness under reduced pressure, dissolved in dichloromethane (20mL) and concentrated to dryness under reduced pressure to give intermediate 8a, which is used directly in the next reaction.

Synthesis of Compound 8

A solution of intermediate 8a (1mmol) in dichloromethane (30mL) was added dropwise to a suspension of anhydrous aluminum trichloride (164mg, 1.2mmol) in dichloromethane (30mL), the mixture was stirred for 2 hours, and a solution of indole (143mg,1.2mmol) in dichloromethane (30mL) was added dropwise slowly to the reaction mixture, and the reaction was allowed to proceed overnight. Saturated sodium bicarbonate solution was added for washing, the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure to give a crude product, which was purified by silica gel column chromatography (PE/EA ═ 4/1) to give compound 8(120mg, yield 42%) as a pale yellow solid.¹H NMR(400MHz, DMSO-d₆):δ12.4(brs,1H),9.05(s,1H),8.28～8.30(m,1H),7.62～7.64(m,1H),7.32～7.37 (m,2H),4.00(s,3H)。MS(ESI)m/z:288.0[M+1]⁺。

Examples 9 to 18 Compounds 9 to 18

The preparation methods of the compounds 9 to 18 were the same as in example 8, and the corresponding acids were used instead of the raw material S-2, respectively, and the other raw materials were the same as in example 8.

Compound 9: MS (ESI) M/z 271.1[ M +1 ]]⁺。

Compound 10:¹H NMR(400MHz,CDCl₃)：δ8.79(brs,1H),8.41～8.43(m,1H),8.24(s,1H), 7.98(d,J＝2.8Hz,1H),7.48～7.50(m,1H),7.31～7.37(m,2H),3.37～3.43(m,1H),1.49(d,J ＝6.8Hz,6H)。

compound 11:¹H NMR(400MHz,DMSO-d₆):δ12.49(brs,1H),9.09(s,1H),8.70(s,1H), 8.29～8.34(m,1H),7.58～7.60(m,1H),7.29～7.34(m,2H),3.98(s,3H)。

compound 12:¹H NMR(400MHz,CDCl₃):δ8.73(brs,1H),8.50～8.35(m,1H),7.83(d,J ＝3.1Hz,1H),7.55～7.41(m,1H),7.43～7.31(m,2H),6.96(d,J＝4.1Hz,1H),6.69(d,J＝4.2 Hz,1H),4.25(s,3H),3.90(s,3H)。

compound 13:¹H NMR(400MHz,DMSO-d₆):δ12.56(brs,1H),9.06(s,1H),7.94(dd, J＝2.8,9.6Hz,1H),7.65(dd,J＝4.8,8.8Hz,1H),7.20(dt,J＝2.8,9.6Hz,1H),4.00(s,3H)。 MS(ESI)m/z:306.0[M+1]⁺。

compound 14:¹H NMR(400MHz,DMSO-d₆):δ12.43(brs,1H),8.97(s,1H),7.9(d, J＝2.4Hz,1H),7.52(d,J＝8.8Hz,1H),6.97(dd,J＝2.4,8.8Hz,1H),3.99(s,3H),3.83(s, 3H)。MS(ESI)m/z:318.0[M+1]⁺。

compound 15:¹H NMR(400MHz,CDCl₃):δ9.07(brs,1H),8.41～8.44(m,1H),8.37(s, 1H),8.11(s,1H),7.95(d,J＝2.0Hz,1H),7.48～7.50(m,1H),7.34～7.37(m,2H),3.94(s,3H)。 MS(ESI)m/z:286.0[M+1]⁺。

compound 16:¹H NMR(400MHz,DMSO-d₆):δ12.22(brs,1H),9.10(s,1H), 8.39～8.42(m,1H),8.20～8.30(m,3H),7.53～7.57(m,1),7.26～7.30(m,2H),3.97(s,3H)。MS(ESI) m/z:281.0[M+1]⁺。

compound 17:¹H NMR(400MHz,CDCl₃):δ9.17(brs,1H),8.43～8.47(m,1H),8.30(brs, 2H),7.70(s,1H),7.54～7.56(m,2H),7.38～7.40(m,2H),4.09(s,3H)。MS(ESI)m/z:286.0 [M+1]⁺。

compound 18:¹H NMR(400MHz,DMSO):δ12.20(brs,1H),9.23～9.24(m,1H),8.76(s, 1H),8.51(dd,J＝8.0,J＝2.0,1H),8.35～8.52(m,1H),8.14(dd,J＝8.4,J＝0.8,1H), 7.53～7.56(m,1H),7.25～7.31(m,2H),3.95(s,3H)。MS(ESI)m/z:281[M+1]⁺。

EXAMPLE 19 Compounds 19-1, 19-2

Synthesis of intermediate 19a

Adding 5-methoxyindole (10g,68mmol) into 250mL three-necked flask, adding methyl tert-butyl ether (75mL) to dissolve, cooling to-10 deg.C, slowly dropping oxalyl chloride (9.5g,74mmol) at a temperature below-5 deg.CThen, stirring is continued for 1h at low temperature, the ice bath is removed, stirring is carried out for 30 min at room temperature, 100mL of petroleum ether is added, stirring is carried out for 30 min, filtering is carried out, a filter cake is washed by a mixed solution of the petroleum ether and the methyl tert-butyl ether, and drying is carried out to obtain an intermediate 19a (15.5g, the yield is 97%). LCMS (ESI) m/z: 234[ M +1 ]]⁺(the product was diluted with methanol and the acid chloride converted to the methyl ester).

Synthesis of intermediate 19b

Intermediate 19a (15.5g) was added portionwise to a mixture of 52.3g of concentrated aqueous ammonia (25%) and 100mL of ethanol at 0 ℃ and, after addition, reacted for 2h at 10 ℃. The reaction mixture was poured into 100mL of ice water, stirred for 30 minutes, filtered and the filter cake dried to give intermediate 19b (10.5g) as a pale gray solid. LCMS (ESI) m/z: 219[ M +1 ]]⁺。

Synthesis of intermediate 19c

Intermediate 19b (10g,45.8mmol) was suspended in 150mL ethyl acetate, pyridine (10.87g, 137.5mmol) was added, the temperature was reduced to below 10 ℃, trifluoroacetic anhydride (14.43g,68.7mmol) was added dropwise slowly over about 30 minutes, and the reaction was continued at 10 ℃ for 2h after completion of the dropwise addition. The reaction solution was poured into 100mL of ice water, extracted 2 times with ethyl acetate, the organic phases were combined, washed 2 times with saturated sodium bicarbonate, 2 times with 0.5N dilute hydrochloric acid, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give 8.8g of a crude solid, which was purified with ethyl acetate: the mixture was washed with 5:1 dichloromethane, and filtered to obtain intermediate 19c (7.2g, yield 78%).¹H NMR(400MHz,CDCl3):δ12.76(bis, 1H),8.53(s,1H)，7.48～7.51(m,2H)，6.99(dd,J＝8.8Hz,J＝2.4Hz,1H),3.80(s,3H)。 MS(ESI)m/z:201.0[M+1]⁺。

Synthesis of Compound 19-1

Intermediate 19c (2g,10mmol) was dissolved in N, N' -dimethylamide (15mL), L-cysteine methyl ester hydrochloride (1.72g,10mmol) and DBU (152mg,1mmol) were added, and the mixture was heated to 40 ℃ for reaction for 3 h. After cooling to room temperature, the reaction mixture was dropped into 80mL of ice-diluted hydrochloric acid (containing 0.1mmol of HCl), stirred for 20 minutes, filtered, the cake was dried under pressure, washed with a small amount of dichloromethane, and dried to give intermediate 19-1(3.1g, yield 97%).¹H NMR(400MHz,CDCl₃):δ8.78(brs,1H),8.71(d,J＝2.8Hz,1H),7.97(d,J＝2.8Hz,1H), 7.33(d,J＝8.8Hz,1H),6.97(dd,J＝8.8Hz,J＝2.8Hz，1H),5.48(t，J＝8.8Hz,1H),3.92(s, 3H),3.89(t,3H),3.61(d,J＝9.6Hz,2H)。MS(ESI)m/z:319.0[M+1]⁺。

Synthesis of Compound 19-2

Compound 19-1(2.6g,8.16mmol) was dissolved in N, N-dimethylformamide (30mL) and reacted at 80 ℃ for 12h with bubbling air. The reaction solution was dropped into ice water and stirred for 20 minutes, followed by filtration, washing of the cake with water and drying to obtain compound 19-2(2.5g, yield 96).¹H NMR(400MHz,CDCl₃):δ9.23(d,J＝3.6Hz, 1H),9.02(brs,1H),8.44(s,1H),8.05(d,J＝2.4Hz,1H),7.37(d,J＝8.8Hz,1H),6.99(dd, J＝8.8Hz,J＝2.4Hz,1H),4.03(s,3H),3.95(s,3H)。MS(ESI)m/z:317.0[M+1]⁺。

EXAMPLE 20 Compounds 20-1, 20-2

The synthetic routes of compound 20-1 and compound 20-2 are the same as in example 19, starting from 5-fluoroindole instead of 5-methoxyindole, the relevant structural identification data are as follows,

intermediate 20b MS (ESI) M/z 207.2[ M +1 ]]⁺。

Intermediate 20c:¹H NMR(400MHz,DMSO-d₆):δ12.94(brs,1H),8.68(s,1H),7.70(dd, J＝2.4,9.2Hz,1H),7.62(dd,J＝4.4,8.8Hz,1H),7.24(dt,J＝2.4,9.2Hz,1H)。MS(ESI) m/z:189[M+1]⁺。

compound 20-1:¹H NMR(400MHz,DMSO-d₆):δ12.42(brs,1H),8.69(d,J＝3.2Hz, 1H),7.87(dd,J＝2.4,8.8Hz,1H),7.59(dd,J＝4.4,8.8Hz,1H),7.16(dt,J＝2.4,9.2Hz, 1H),5.67(dd,J＝8.4,10.0Hz,1H),3.92(s,3H),3.68(dd,J＝11.2,10.0Hz,1H),3.55(dd, J＝8.4,11.2Hz,1H)。MS(ESI)m/z:307[M+1]⁺。

compound 20-2:¹H NMR(400MHz,DMSO-d₆):δ12.48(brs,1H),9.13(s,1H),8.89(s, 1H),7.97(dd,J＝2.4,9.6Hz,1H),7.62(dd,J＝4.4,8.8Hz,1H),7.17(dt,J＝2.4,9.2Hz, 1H),3.92(s,3H)。MS(ESI)m/z:305[M+1]⁺。

EXAMPLE 21 Compound 21

Synthesis of Compound 21

1-bromo-3-methyl-2-butanone (0.8g,4.89mmol) was dissolved in ethanol (25mL), and the starting material S3(1.0g,4.89mmol) was added with stirring, heated to 80 deg.C, reacted for 2h, cooled to room temperature, filtered, and washed with ethanol to give compound 21(0.6g, yield 45%).¹H NMR(400MHz,DMSO-d₆):δ12.22(brs,1H),9.10(d, J＝3.2Hz,1H),8.31～8.33(m,1H),7.77(s,1H),7.57～7.59(m,1H),7.25～7.31(m,2H), 3.16～3.23(m,1H),1.36(d,J＝6.8Hz,6H)。

EXAMPLE 22 Compound 22

Synthesis of Compound 22 with Synthesis of Compound 21, Compound 22(1.2g, yield 80%) was obtained from starting material S3(1.0g,4.89 mmol).¹H NMR(400MHz,DMSO-d₆):δ12.30(brs,1H),9.30(s,1H), 8.69(dd,J＝1.2,4.2Hz,1H),8.65(s,1H),8.34～8.36(m,1H),8.32(d,J＝1.2Hz,1H), 8.01(dt,J＝2.0,7.2Hz,1H),7.60～7.62(m,1H),7.44～7.47(m,1H),7.30～7.34(m,2H)。

EXAMPLE 23 Compound 23

Synthesis of intermediate 23a

Dissolving raw material S4(4.0g,23.5mmol) in methanol (50mL), cooling to below 0 ℃, continuously introducing dry hydrogen chloride gas, reacting for 8 hours, stopping introducing gas, sealing and stirring overnight, and filtering to obtain 5.4g yellow solid, namely intermediate 23a, which is directly used for subsequent reaction.

Synthesis of intermediate 23b

The intermediate 2 is3a (5.4g,19.6mmol) is dissolved in acetonitrile (15mL), 2, 3-diaminopropionic acid methyl ester hydrochloride (3.7g,19.6mmol) is added, triethylamine (10g,98mmol) is dropped, reflux reaction is carried out for 5h, the solvent is removed under reduced pressure, water and dichloromethane are added for dissolution and delamination, the water phase is extracted for 2 times by dichloromethane, the organic phase is combined and washed by saturated saline, dried by anhydrous sodium sulfate and concentrated under reduced pressure to obtain a crude product, and the crude product is purified by silica gel column chromatography to obtain an intermediate 23b (2.4g, yield 45%).¹H NMR(400MHz,CDCl₃):δ9.19(s,1H),8.91(d,J＝2.8Hz,1H), 8.44(dd,J＝6.8Hz,J＝1.6Hz,1H),7.41～7.43(m,1H),7.30～7.36(m,2H),4.67(brs,1H), 4.18(d,J＝7.6Hz,2H),3.82(s,3H),1.87(brs,1H)。MS(ESI)m/z:272[M+1]⁺。

Synthesis of Compound 23

Intermediate 23b (1.2g,4.42mmol) was dissolved in DMF (20mL), added sodium hydroxide (530mg, 13.3mmol), stirred with air at 60 ℃ for 3h, cooled, poured into ice water, extracted three times with ethyl acetate, the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure to give crude product, which was washed with mixed solvent PE: EA ═ 2:1 to give compound 23(960mg, yield 81%).¹H NMR(400MHz, DMSO):δ13.69(brs,1H),12.20(s,1H),9.15(s,1H),8.32～8.36(m,1H),8.03(s,1H), 7.55～7.59(m,1H),7.24～7.30(m,2H),3.83(s,3H)。MS(ESI)m/z:270[M+1]⁺。

EXAMPLE 24 Compound 24

Synthesis of intermediate 24a

Starting material S1(2.86g,10mmol) was dissolved in a mixed solvent THF/MeOH/H₂O (16/15/15mL), stirred at room temperature overnight. The reaction solution was adjusted to pH 4-5 with 4N hydrochloric acid, then filtered, and the filter cake was washed with water and dried in vacuo to give intermediate 24a (2.6g, yield 96%). MS (ESI) M/z 271[ M-1 ]]^-。

Synthesis of intermediate 24b

Intermediate 24a (1.36g,5mmol) was dissolved in THF (20mL), 2 drops of DMF were added, oxalyl chloride (755mg,6mmol) was added dropwise, reacted at room temperature for 2h, concentrated to dryness under reduced pressure, dissolved in THF (20mL), then added dropwise to 80% hydrazine hydrate (2mL,57mmol) and stirred overnight, the reaction was concentrated to 5mL under reduced pressure and filtered, the filter cake was washed with THF and dried to give intermediate 24b (1.38g, yield 97%).

Synthesis of Compound 24

A mixture of intermediate 24b (1.0g,3.5mmol), p-toluenesulfonic acid monohydrate (20mg) and trimethyl orthoformate (5mL) was heated to 80 deg.C, stirred overnight, poured into ice water, filtered, the filter cake washed with ethyl acetate and dried to give compound 24(280mg, yield 27%).¹H NMR(400MHz,DMSO-d6):δ12.45(brs,1H), 9.43(s,1H),9.15(s,1H),8.95(s,1H),8.32(m,1H),7.61(m,1H),7.32(m,2H)。MS(ESI) m/z:297[M+1]⁺。

EXAMPLE 25 Compounds 25-1, 25-2

Synthesis of Compounds 25-1 and 25-2

Dissolving a raw material S1(1.0g,3.5mmol) in pyridine (15mL), adding methoxylamine hydrochloride (1.75g,21 mmol), heating to 90 ℃ for reaction for 24h, cooling to room temperature, adding water for dilution, extracting with ethyl acetate for 2 times, washing an organic phase with 1N hydrochloric acid for 2 times, washing with saturated saline, drying with anhydrous sodium sulfate, concentrating under reduced pressure to obtain a crude product, and purifying the crude product by silica gel column chromatography (petroleum ether: ethyl acetate: 20: 1-5: 17) to obtain a compound 25-1(410mg) and a compound 25-2(300mg) with the yield of 64.3%.

Compound 25-1:¹H NMR(400MHz,CDCl₃):δ8.54(d,J＝3.2Hz,1H),8.51(brs,1H), 8.42(s,1H),8.37～8.39(m,1H),7.41～7.43(m,1H),7.25～7.29(m,2H),4.32(s,3H),4.00(s, 3H)。MS(ESI)m/z:316[M+1]⁺。

compound 25-2:¹H NMR(400MHz,CDCl3):δ8.94(bis,1H),8.24(s,1H),7.80(d, J＝2.8Hz,1H),7.40(d,J＝7.6Hz,1H),7.29～7.31(m,1H),7.14～7.18(m,1H),7.09～7.13(m, 1H),4.16(s,3H),3.92(s,3H)。MS(ESI)m/z:316[M+1]⁺。

EXAMPLE 26 Compounds 26-1, 26-2

Synthesis of Compounds 26-1 and 26-2

Synthesis of Compounds 25-1 and 25-2 was performed in a similar manner to that described above, and from the starting material S1(324mg,1.13mmol) and hydroxylamine hydrochloride (696mg, 10mmol), Compounds 26-1 and 26-2(149mg, yield 44%) were obtained.

Compound 26-1:¹H NMR(400MHz,CDCl₃):δ9.00(s,1H),8.26(s,1H),8.19(d,J＝8.0Hz， 1H),7.80(d,J＝2.8Hz，1H),7.47(d,J＝8.0Hz，1H),7.09～7.19(m,2H),3.93(s,3H)。MS(ESI) m/z:302[M+1]⁺。

compound 26-2:¹H NMR(400MHz,CDCl₃):δ8.58(s,1H),8.45(s,1H),8.27(d,J＝3.2Hz， 1H),7.40(dd,J＝7.2Hz，J＝1.6Hz，1H),7.33(d,J＝8.0Hz，1H),7.20～7.28(m，2H),4.01(s, 3H)。MS(ESI)m/z:302[M+1]⁺。

EXAMPLE 27 Compound 27

To a solution of intermediate 24a (1.36g,5mmol) in DMF (20mL) was added glycine methyl ester hydrochloride (753mg,6mmol) and HATU (2.26g,6mmol) and DIEA (2.3g,10mmol), the mixture was stirred at room temperature for 2 hours, the reaction mixture was poured into 100mL of ice water, filtered, and the filter cake was washed with ethyl acetate and dried to give compound 27(1.45g, 84.5% yield).¹H NMR(400MHz,DMSO-d₆):δ12.40(d,J＝2.0Hz,1H),9.43(d, J＝3.2Hz,1H),9.29(t,J＝2.4Hz,1H),8.66(s,1H),8.32～8.35(m,1H),7.58～7.60(m,1H), 7.27～7.34(m,2H),4.13(d,J＝6.4Hz,2H),3.70(s,3H)。

EXAMPLE 28 Compound 28

Synthesis of intermediate 28a

The starting material S1(7g,24mmol) was dissolved in a mixed solvent of THF (42mL) and methanol (168mL), cooled to 0 ℃ with an ice salt bath, and then sodium borohydride (4.6g,122.mmol) was added slowly in portions, and the ice salt bath was removed and allowed to warm to room temperature for 1 hour. The reaction mixture was poured into ice water, filtered, and the filter cake was washed with methanol and dried to give intermediate 28a (6.8g, yield 98%).¹H NMR(400MHz,DMSO-d₆):δ11.07(s,1H),8.46(s,1H),7.48(d,J＝8.0Hz,1H), 7.37(d,J＝8.0Hz,1H),7.34(d,J＝2.4Hz,1H),7.07(dt,J＝0.8,8.0Hz,1H),6.96(dt,J＝0.8,8.0Hz, 1H),6.68(d,J＝4.0Hz,1H),6.18(d,J＝4.0Hz,1H),3.77(s,3H)。MS(ESI)m/z:291.0[M+1]⁺。

Synthesis of Compound 28

Intermediate 28a (3g,10.4mmol) was dissolved in methanol (25mL), zinc powder (2g,31.2mmol) was added with stirring, nitrogen blanketed, refluxed at 100 ℃ for 1 hour, and then the reaction was dropped into ice water and filtered to give crude 1.8 g. The crude product (200mg) was purified by silica gel column chromatography (PE/EA: 4/1-2/1) to obtain compound 28(20 mg).¹H NMR(400MHz,DMSO-d₆):δ11.06(s,1H),8.32(s,1H),7.39～7.44(m,3H),7.10(dt,J＝1.1, 8.0Hz,1H),6.98(dt,J＝1.1,8.0Hz,1H),4.05(s,2H),3.81(s,3H)。MS(ESI)m/z:275.0[M+1]⁺。

EXAMPLE 29 Compound 29

Synthesis of intermediate 29a

Intermediate 24a (1.36g,5mmol) was dissolved in THF (20mL), 2 drops of DMF were added, oxalyl chloride (755mg,6mmol) was added dropwise, reacted at room temperature for 2 hours, concentrated to dryness under reduced pressure, dissolved in THF (20mL), added dropwise to concentrated aqueous ammonia (10mL), and stirred overnight. Concentration to 5mL under reduced pressure, filtration, washing of the filter cake with THF and drying afforded intermediate 29a (1.3g, 95% yield).¹H NMR(400MHz,DMSO-d₆):δ12.27(s,1H),9.52(s,1H), 8.61(s,1H),8.31～8.35(m,1H),7.57～7.60(m,1H),8.28(s,1H),7.81(s,1H),7.26～7.34(m,2H). MS(ESI)m/z:272.0[M+1]⁺。

Synthesis of Compound 29

Intermediate 29a (17g,62.66mmol) was dissolved in ethyl acetate (250mL), pyridine 14.87g (187.9 mmol) was added, trifluoroacetic anhydride (19.7g,93.99mmol) was added dropwise at room temperature, stirred at room temperature for 4 hours, concentrated to dryness under reduced pressure, and recrystallized from ethyl acetate to give compound 29(14g, yield 88%).¹H NMR(400MHz,DMSO-d₆):δ 12.44(s,1H),9.15(s,1H),9.03(d,J＝3.6Hz,1H),8.28～8.31(m,1H),7.57～7.62(m,1H), 7.29～7.34(m,2H)。MS(ESI)m/z:254.0[M+1]⁺。

EXAMPLE 30 Compounds 30-1, 30-2

Synthesis of Compound 30-1

Compound 29(1g,3.9mmol) was dissolved in methanol (100mL), nitrogen was substituted three times, a sodium methoxide solution (sodium metal 0.23g,10mmol, methanol 50mL) was added dropwise, the mixture was stirred at room temperature for 4 hours, a methanol (50mL) solution of L-serine methyl ester hydrochloride (1.8g, 11.6mmol) was added dropwise, the mixture was heated to 55 ℃, stirred for 2 hours, poured into ice water, and filtered to obtain a crude product, which was purified by silica gel column chromatography (PE: EA ═ 1: 1) to obtain compound 30-1(0.4g yield 29%).¹H NMR(400MHz, DMSO-d₆):δ12.33(s,1H),9.10(d,J＝2.9Hz,1H),8.73(s,1H),8.44～8.21(m,1H),7.69～7.49 (m,1H),7.40～7.21(m,2H),5.06(dd,J＝10.0,8.0Hz,1H),4.76～4.57(m,2H),3.74(s,3H)。 MS(ESI)m/z:356.0[M+1]⁺。

Synthesis of Compound 30-2

Compound 30-1(200mg, 0.56mmol) was dissolved in tetrahydrofuran (50mL), manganese dioxide (1000mg, 11.56mmol) was added under reflux overnight, cooled, filtered, the filtrate was concentrated under reduced pressure to dryness to give a crude product, which was purified by silica gel column chromatography (PE: EA ═ 2: 1) to give compound 30-2(25mg yield 12%).¹H NMR(400MHz,DMSO-d₆):δ 12.37(s,1H),9.17(d,J＝2.7Hz,1H),9.09(s,1H),8.90(s,1H),8.37～8.29(m,1H),7.66～7.59 (m,1H),7.38～7.26(m,2H),3.89(s,3H)。MS(ESI)m/z:354[M+1]⁺。

EXAMPLE 31 Compounds 31-1, 31-2

Compound 31-1: method Compound 30-1.¹H NMR(400MHz,DMSO-d₆):δ12.41(s,1H), 9.08(d,J＝3.1Hz,1H),8.63(s,1H),8.42～8.24(m,1H),7.68～7.49(m,1H),7.31(m,2H),4.47 (t,J＝8.5Hz,2H),3.48(t,J＝8.5Hz,2H)。MS(ESI)m/z:314.0[M+1]⁺。

Compound 31-2: method Compound 30-2.¹H NMR(400MHz,DMSO-d₆)：δ12.41(s,1H), 9.13(d,J＝3.2Hz,1H),8.64(s,1H),8.37～8.30(m,1H),8.01(d,J＝3.2Hz,1H),7.91(d,J＝3.2 Hz,1H),7.65～7.57(m,1H),7.35～7.27(m,2H)。MS(ESI)m/z:312.0[M+1]⁺。

EXAMPLE 32 Compounds 32-1, 32-2

Compound 32-1: method Compound 30-1.¹H NMR(400MHz,DMSO-d₆):δ12.43(s,1H), 9.04(s,1H),8.70(s,1H),8.29～8.344(m,1H),7.57～7.60(m,1H),7.21～7.34(m,2H),5.48(dd, J＝9.2,8.4Hz,1H),3.78(dd,J＝6.0,11.6Hz,1H),3.75(s,3H),3.67(dd,J＝11.6,8.4Hz,1H)。MS (ESI)m/z:372.0[M+1]⁺。

Compound 32-2: method Compound 30-2. MS (ESI) M/z 370.0[ M +1 ]]⁺。

EXAMPLE 33 Compounds 33-1, 33-2

Compound 33-1: method Compound 30-1. MS (ESI) M/z 298.0[ M +1 ]]⁺。

Compound 33-2: method of making a chemical combinationSubstance 30-2.¹H NMR(400MHz,DMSO-d₆)：δ12.41(s,1H), 9.13(d,J＝3.2Hz,1H),8.64(s,1H),8.37～8.30(m,1H),7.65～7.57(m,1H),7.52(brs,1H), 7.35～7.27(m,2H),7.11(brs,1H)。MS(ESI)m/z:296.0[M+1]⁺。

EXAMPLE 34 Compound 34

The synthesis of intermediate 34a is described in J.Am.chem.Soc.,2002,124(44), 13179-13184.

Synthesis of intermediate 34b is described in j.med.chem.,1961,4, 259-.

Synthesis of intermediate 34c

Compound 34b (1.18g,10mmol) and triethylamine (3.03g,30mmol) were dissolved in dichloromethane (15mL) and a solution of compound 34a (2.07g,10mmol) in dichloromethane (10mL) was added dropwise at 0 ℃. The reaction mixture was stirred at room temperature overnight. Dilution with 30mL of water, extraction with dichloromethane 3 times, combining the organic phases, drying over anhydrous sodium sulfate, filtration, and concentration under reduced pressure afforded intermediate 34c (2.8g, 97% yield). MS (ESI) M/z 290.0[ M +1 ]]⁺。

Synthesis of Compound 34

Intermediate 34c (5g,17.286mmol) was dissolved in DMF (200mL), triethylamine (5.2g, 51.86mmol) was added with stirring, then THF (100mL) was added, and p-toluenesulfonyl chloride (9.88g,51.86mmol) dissolved in dichloromethane (50mL) was slowly added dropwise under nitrogen, after 1h addition was complete, and then the reaction was allowed to proceed overnight at room temperature. After dichloromethane and THF were removed by concentration under reduced pressure, the mixture was added dropwise to ice water, stirred, and filtered to obtain a crude product, which was purified by silica gel column chromatography (dichloromethane/methanol: 50/1 to 10/1) to obtain compound 34(0.5g, yield 10%).¹H NMR(400MHz,DMSO-d₆):δ12.53(brs, 1H),8.90(s,1H),8.27～8.29(m,1H),7.60～7.62(m,1H),7.32～7.37(m,2H),4.02(s,3H)。MS(ESI) m/z:272.1[M+1]⁺。

EXAMPLE 35 Compound 35

Adding compound 29(2g,7.9mmol) into a sealed reactor, adding DMF (30mL) and stirring, adding ammonium chloride (0.49g,9.2mmol), sodium azide (0.6g,9.2mmol), sealing the reactor, carrying out oil bath at 120 ℃ for reaction overnight, cooling the reaction liquid to room temperature, dropwise adding the reaction liquid into 200mL of ice water, extracting with ethyl acetate (150mL), and adjusting the pH of an aqueous phase to be acidic by using 2N hydrochloric acid; the solid precipitated, which was then filtered, washed with water, and dried to give compound 35(1.8g, 77%).¹H NMR(400 MHz,DMSO-d₆):δ12.50(s,1H),9.48(d,J＝3.6Hz,1H),8.88(s,1H),8.36～8.34(m,1H), 7.62～7.60(m,1H),7.34～7.31(m,2H)。MS(ESI)m/z:297.0[M+1]⁺。

EXAMPLE 36 Compound 36

Compound 29(0.5g,1.7mmol) was suspended in 10mL of ethylene glycol methyl ether, 2mL of acetic acid and formamidine acetate (0.215g,2.07mmol) were added, under nitrogen protection, oil bath refluxing was carried out for 24 hours, distillation under reduced pressure was carried out, and the crude product was purified by silica gel column chromatography (DCM/methanol 200/1-20/1) to obtain compound 35(0.32g, yield 55%).¹H NMR(400MHz, DMSO-d₆):δ12.41(s,1H),10.6(s,1H),10.05(s,1H),9.55(s,1H),8.72(s,1H), 8.32～8.34(m,1H),7.58～7.59(m,1H),7.28～7.33(m,2H)。MS(ESI)m/z:296.0[M+1]⁺。

EXAMPLE 37 Compound 37

Compound 1-1(500mg,0.97mmol) was dissolved in methanol (2mL), and 0.1N sodium methoxide solution (2mL) was added dropwise, reacted at room temperature overnight, filtered, and the solid was washed with methanol and dried to give compound 37(153mg, yield 50%).¹H NMR(400MHz,CDCl₃):δ9.25(s,1H),8.93(s,1H),8.35(d,J＝7.6Hz,1H), 7.81(d,J＝7.6Hz,1H),7.39～7.47(m,2H),6.92(t,1H),5.6(d,2H),3.94(s,3H)。MS(ESI) m/z:317[M+1]⁺。

Example 38 Compound 38-1 to Compound 38-4

Synthesis of Compounds 38-1, 38-2

Raw material S-1(1.07g,3.78mmol) was dissolved in THF (50mL), 2,3,4, 6-tetraacetylglucose (2.6g, 7.55mmol) was added, triphenylphosphine (2g,7.55mmol) was added under nitrogen protection, the temperature was reduced to-15 ℃ and diisopropyl azodicarboxylate (1.53g,7.55mmol) was added dropwise, the reaction solution was poured into ice water, extracted with ethyl acetate (100mL X2), dried over anhydrous sodium sulfate, concentrated to dryness under reduced pressure, and purified by silica gel column chromatography (petroleum ether/ethyl acetate: 10/1-2/1) to give compound 38-1(650mg) and compound 38-2(600mg) (yield 54%). Compound 38-1:¹H NMR (400MHz,CDCl₃):¹H NMR(400MHz,CDCl₃):δ9.18(s,1H),8.52～8.54(m,1H),8.44 (s,1H),7.60～7.63(m,1H),7.38～7.42(m,2H),5.72(d,J＝9.2Hz,1H),5.64(t,J＝9.2Hz,1H), 5.50(t,J＝9.6Hz,1H),5.40(d,J＝9.6Hz,2H),4.35(dd,J＝4.8，12.4Hz，2H),4.27(dd, J＝2.4，12.4Hz,1H),4.07(s,3H),4.05～4.10(m,1H),2.16(s,3H),2.13(s,3H),2.05(s,3H), 1.74(s,3H)；MS(ESI)m/z:617.14[M+1]⁺. Compound 38-2: δ 9.20(s,1H),8.56 to 8.49(m,1H), 8.45(s,1H),7.87 to 7.80(m,1H),7.44 to 7.35(m,2H),5.92(d, J ═ 5.2Hz,1H),5.35(t, J ═ 2.3Hz, 1H),4.99(dt, J ═ 9.4,1.7Hz,1H),4.38 to 4.25(m,2H),4.21 to 4.12(m,2H),4.04(s,3H),2.21(s, 3H),2.18(s,3H),2.16(s,3H),2.07(s, 3H); MS (ESI) M/z 617.14[ M +1 ]]⁺。

Synthesis of Compounds 38-3, 38-4

Compound 38-1(200mg,0.325mmol) was dissolved in methanol (10mL), and sodium methoxide (190mg, 3.57mmol) was added, followed by stirring at room temperature for 5 h. Pouring the reaction solution into saturated sodium chloride aqueous solution, adding 50mL of ethyl acetate, adjusting pH to neutrality with citric acid, separating organic phase, extracting water phase with ethyl acetate once again, combining organic phases, drying with anhydrous sodium sulfate, filtering, concentrating under reduced pressure to dryness, and performing silica gel column chromatographyPurification (methanol/dichloromethane: 5% -10%) gave compound 38-3(40mg) and compound 38-4(5 mg). Compound 38-3: MS (ESI) M/z 491.1[ M +1 ]]⁺. Compound 38-4: MS (ESI) M/z 449.1[ M +1 ]]⁺。

Effect example 1

AhR agonist assay (Activity assay for reference agonist MeBio: Oncogene (2004)23, 4400-

Test materials (plasmids): expressing native (Human Hepatoma Huh-7) AhR receptor reporter gene cells comprising a firefly luciferase gene linked to an upstream receptor-specific Genetic Response Element (GRE) functionality in a reporter vector.

The AhR agonism assay comprises the following three steps:

1. implanting cells: a suspension of AhR receptor reporter cells was prepared in cell recovery medium (CRM; 10% charcoal-treated FBS). The prepared suspension (100. mu.L) was then dispensed into the wells of a white 96-well plate.

2. Master Stocks were diluted to "2 Xconcentration" treatment medium with the appropriate compound screening assay medium (CSM: FBS containing 10% charcoal treatment) just prior to the start of the experiment. Test compounds were gradient diluted with CSM medium containing 0.2% DMSO such that the final DMSO concentration in each experimental well was 0.1% for each treatment group. Treatment medium was added to plates (100 uL/well) that had been pre-plated with reporter-containing cells, duplicate wells. The plate was incubated in a 37 ℃ incubator for 24 hours.

3. Fluorescence detection and analysis: after incubation was complete, the treatment medium was discarded and 100. mu.L/well of luciferase detection reagent was added, and the Ave RLU (mean relative fluorescence intensity) of each well and the coefficient of variation for each set of experiments, from the Ave RLU of test compound at different concentrations in the experimental set, were determined^{Test Cmpd}Ave RLU with blank control group^VehicleQuantitative determination of the AhR receptor activity at different concentrations of the test compound, determination of fold activation and EC₅₀。

Data processing methods refer to j.biomol.screen,1999,4(2), 67-73.

EC of each compound₅₀As shown in Table 1, wherein A represents 0.001. mu.M < EC₅₀Less than or equal to 1.0 mu M, B represents 1.0 mu M < EC₅₀Less than or equal to 10.0 mu M, C represents 10.0 mu M < EC₅₀≤100μM。

TABLE 1 EC for the respective Compounds₅₀

As can be seen from table 1, each of the above compounds can bind to AhR and regulate those functions and signaling pathways controlled by AhR, which in turn can affect the growth and proliferation of cancer cells and the invasiveness of tumor cells, so that the pharmaceutical composition of the compound represented by formula (i) of the present invention can be used as an AhR inhibitor or a non-constitutive AhR agonist (non-constitutive AhR agonists), and can be used to inhibit the growth of cancer cells and inhibit the metastasis and invasion of tumor cells.