WO2018121434A1 - 芳香烃受体调节剂 - Google Patents

芳香烃受体调节剂 Download PDF

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Publication number
WO2018121434A1
WO2018121434A1 PCT/CN2017/118004 CN2017118004W WO2018121434A1 WO 2018121434 A1 WO2018121434 A1 WO 2018121434A1 CN 2017118004 W CN2017118004 W CN 2017118004W WO 2018121434 A1 WO2018121434 A1 WO 2018121434A1
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Prior art keywords
formula
hydrocarbon receptor
aryl hydrocarbon
compound
receptor modulator
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PCT/CN2017/118004
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English (en)
French (fr)
Inventor
杨录青
李国栋
张所明
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上海正基医药科技有限公司
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Application filed by 上海正基医药科技有限公司 filed Critical 上海正基医药科技有限公司
Priority to EP17885769.4A priority Critical patent/EP3564239B9/en
Priority to KR1020227002623A priority patent/KR102536298B1/ko
Priority to US16/473,616 priority patent/US11547698B2/en
Priority to KR1020197016871A priority patent/KR20190093198A/ko
Priority to JP2019555540A priority patent/JP2020503385A/ja
Priority to AU2017389794A priority patent/AU2017389794B2/en
Publication of WO2018121434A1 publication Critical patent/WO2018121434A1/zh
Priority to PCT/IB2018/001559 priority patent/WO2019123007A1/zh
Priority to US16/229,408 priority patent/US20190307731A1/en
Priority to AU2021200452A priority patent/AU2021200452B2/en
Priority to JP2021184480A priority patent/JP2022024049A/ja

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    • A—HUMAN NECESSITIES
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    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A61K31/4025—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil not condensed and containing further heterocyclic rings, e.g. cromakalim
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    • A61K31/403—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with carbocyclic rings, e.g. carbazole
    • A61K31/404—Indoles, e.g. pindolol
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    • A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
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    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
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    • A61K31/4965—Non-condensed pyrazines
    • A61K31/497—Non-condensed pyrazines containing further heterocyclic rings
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    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
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    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A61K31/5375—1,4-Oxazines, e.g. morpholine
    • A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
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    • A61K31/7052—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides
    • A61K31/7056—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing five-membered rings with nitrogen as a ring hetero atom
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Definitions

  • the present invention belongs to the technical field of antitumor compounds and relates to a class of compounds having modulating aromatic hydrocarbon receptor (AhR) activity and pharmaceutically acceptable salts thereof.
  • AhR aromatic hydrocarbon receptor
  • Aryl hydrocarbon receptor is a class of intracellular transcriptional regulators that can sense xenobiotic stimuli in the external environment and mediate toxic reactions.
  • the activated AhR can regulate the expression of genes on many chromosomes and promote the decomposition of heterogeneous substances. Previous studies have found that this signal is also involved in some important biological processes such as signal transduction, cell differentiation, and apoptosis. The relationship between AhR and immune regulation has also been a hot topic. Previous studies have shown that AhR can participate in the differentiation and function of T cells, macrophages and DCs. In addition, AhR also plays a key role in immune rejection after organ transplantation. .
  • DIM and its derivatives have tumor suppressor activity (Breast Cancer Res. Treat. 2001, 66, 147), and DIM is currently in Phase II clinical studies for the treatment of prostate cancer and cervical cancer.
  • the natural products ICZ and FICZ are both AhR agonists and are resistant to asthma (Chem. Rev., 2002, 102, 4303; Chem. Rev., 2012, 112, 3193; J. Biol. chem. 2009, 284, 2690). Malassezin (Bioorg. Med. Chem. 2001, 9, 955).
  • Aminoflavonone was developed by NCI and is in Phase I clinical. 3-hydroxymethyl hydrazine (Indole-3-carbinol) is in phase II clinical use as a chemical protectant and immunostimulant. Phortress is an AhR agonist developed by Pharminox Univ. of Nottingham, Phase I clinically for the treatment of solid tumors (Br. J. Cancer, 2003, 88, 599; Mol. Cancer Ther. 2004, 3, 1565). Tanshinone I is a natural AhR ligand for anti-tumor chemical protective agents (Toxicol Appl Pharmacol. 2011 Apr 1; 252(1): 18-27). 2-(Indolyl-3-yl)furan (Food Chem. 2011, 127, 1764 - 1772).
  • ITE is a natural endogenous AhR activator with anti-liver cancer, prostate cancer, breast cancer and ovarian cancer (Proc. Natl. Acad. Sci. 2002, 99, 14694-9; CN102573470; WO2016040553).
  • R' is H, CN, CH 2 (OH)R 0 , C m H 2m+1 , C n H 2n-1 , C n H 2n-3 , Wherein W 0 is O or NH; W 1 is a linkage, C(R 0 ) 2 , C(R 0 ) 2 O, C(R 0 ) 2 OC(R 0 ) 2 or C(R 0 ) 2 OC ( R 0 ) 2 C(R 0 ) 2 ; when W is C, S or S(O), W 2 is a linkage, O, NR 0 , CH(N(R 0 ) 2 ) or OCH 2 C(O When W is P(OR 0 ), W 2 is O or NR 0 ; each R 0 is independently H, C m H 2m+1 , C m H 2m+1 OC(O), C m H 2m +1-r X r , C m H 2m+1 OC(O)C
  • A is an unsubstituted or 1 to 3 R-substituted C 6 -C 10 aromatic ring, or an unsubstituted or 1 to 3 R-substituted hetero 1 to 5 C selected from N, O and S hetero atoms a C-N 4- to 7-membered non-aromatic heterocyclic ring having 2 to C 10 heteroaromatic rings or 1 to 3 heteroatoms selected from N, O and S heteroatoms;
  • Q is R, or an unsubstituted or 1 to 3 R-substituted C 6 -C 10 aromatic ring, or an unsubstituted or 1 to 3 R-substituted hetero 1 to 5, preferably 1 to 3, more preferably 2 to 3 selected from N, O and S heteroatoms, preferably 3 to 10 members, preferably 4 to 7 members, more preferably 5 to 6 membered heterocyclic rings, preferably heteroaromatic rings;
  • R is R C attached to C or R N attached to N , wherein each R C is independently X, CN, R", -Y-OR", -YC(O)R", -Y-OC(O R", -YC(O)OR", -Y-OC(O)OR", -Y-NR" 2 , -YC(O)NR" 2 , -Y-NR"C(O)R", -Y-NR"C(O)NR” 2 , -Y-OC(O)NR" 2 , -Y-NR"C(O)OR", -YS(O) 1 ⁇ 2 R", -YS( O) 1 to 2 NR" 2 or -Y-NR"S(O) 1 to 2 R"; each R N is independently CN, R", -Y-OR", -YC(O)R", - Y-OC(O)R", -YC(O)OR", -Y-OC(O)OR", -Y-NR” 2 ,
  • R" is H, D, C m H 2m+1 , C n H 2n-1 , C n H 2n-3 , C m H 2m+1-r X r , C n H 2n-1-s X s or C n H 2n-3-t X t ;
  • Y is a linkage, -C m H 2m -, -C n H 2n-2 -, -C n H 2n-4 -, -C m H 2m-i X i -, -C n H 2n-2-j X j - or -C n H 2n-4-k X k -;
  • (a cyclic C 4 H 8 NO) C m H 2m is a cyclic C 4 H 8 NO is a six-membered ring, N and O in a meta or para position, preferably N-substituted morpholine.
  • C m H 2m+1 , C m H 2m+1-r X r , -C m H 2m - and -C m H 2m-i X i - may be linear or branched saturated hydrocarbon groups, C n H 2n-1 , C n H 2n-1-s X s , -C n H 2n-2 - and -C n H 2n-2-j X j - may be linear or branched
  • the olefin group, C n H 2n-3 , C n H 2n-3-t X t , -C n H 2n-4 - and -C n H 2n-4-k X k may be linear or A branched alkyne group.
  • C n H 2n-1 , C n H 2n-1-s X s , -C n H 2n-2 - and -C n H 2n-2-j X j - may also be A cycloalkane group.
  • C n H 2n-3 , C n H 2n-3-t X t , -C n H 2n-4 ⁇ and -C n H 2n-4-k X k may also be double An olefinic group or a cyclic olefin group.
  • A is At this time, the formula (I) becomes the formula (I1),
  • one of A 1 , A 2 and A 3 is O, S or N(R), and the other two are independently C(R) or N, which are specifically divided into three cases, that is, A 1 is O, S or N(R), and A 2 and A 3 are each independently C(R) or N; if A 2 is O, S or N(R), A 1 and A 3 are each independently C(R) or N; if A 3 is O, S or N(R), A 1 and A 2 are each independently C(R) or N.
  • the present invention is further preferably based on the formula (I1), wherein one of A 1 , A 2 and A 3 is O, S or N(R), and the other two are each independently N, in which case A 1 , Both A 2 and A 3 are heteroatoms.
  • a 3 is fixed to N, and the formula (I1) becomes the formula (Ia).
  • a 1 is O, S or N(R), and A 2 is N; or A 2 is O, S or N(R), and A 1 is N.
  • the present invention is further preferably further based on the formula (I1), wherein A 2 is CH, and the formula (I1) is changed to the formula (Ib).
  • a 1 is N or C(R), A 3 is O, S or N(R); or A 1 is O, S or N(R), and A 3 is N or C(R) .
  • a 2 is O, S or N(R).
  • the present invention may further preferably further on the basis of the formula (I1), wherein A 1 is N, A 3 is C(R), and R' is At this time, the formula (I1) becomes the formula (Ie),
  • a 2 is O, S or N(R).
  • the present invention may further preferably further on the basis of the formula (I1), wherein A 1 is N, A 3 is C(R), and R' is At this time, the formula (I1) becomes the formula (If),
  • a 2 is O, S or N(R), and each R 0 is independently H or Ac.
  • Q is One of B 1 , B 2 , B 3 and B 4 is O, S or N(R), and the other three are independently C(R) or N, ie
  • B 1 is O, S or N(R), and B 2 , B 3 and B 4 are each independently C(R) or N;
  • B 2 is O, S or N(R), and B 1 , B 3 and B 4 are each independently C(R) or N;
  • B 3 is O, S or N(R), and B 1 , B 2 and B 4 are each independently C(R) or N;
  • B 4 is O, S or N(R), and B 1 , B 2 and B 3 are each independently C(R) or N.
  • Q is B 5 to B 9 are C(R), that is, Q is a benzene ring; or one or two of B 5 to B 9 are N, and the others are each independently C(R), that is,
  • Q may also be a pyridine ring, in which case B 5 is N, B 6 to B 9 are each independently C(R); or B 6 is N, and B 5 and B 7 to B 9 are each independently C(R). Or B 7 is N, B 5 , B 6 , B 8 and B 9 are each independently C(R);
  • Q may also be a pyridazine ring, in which case B 5 and B 6 are N, B 7 to B 9 are each independently C(R); or B 6 and B 7 are N, and B 5 , B 8 and B 9 are respectively Independently C(R);
  • Q may also be a pyrimidine ring, in which case B 5 and B 7 are N, and B 6 , B 8 and B 9 are each independently C(R);
  • Q may also be a pyrazine ring, in which case B 5 and B 8 are N, and B 6 , B 7 and B 9 are each independently C(R).
  • the present invention may further preferably further comprise, based on the formula (I1), A 1 is N, A 2 is S, A 3 is CH, and Q is a 5-membered heteroaryl ring, and at this time, the formula (I) is changed to the formula (Ig). )
  • one of B 2 , B 3 or B 4 is O, S or N(R), and the others are C(R) or N, ie
  • B 2 is O, S or N(R), B 3 and B 4 are each independently C(R) or N;
  • B 3 is O, S or N(R), B 2 and B 4 are each independently C(R) or N;
  • B 4 is O, S or N(R), B 2 and B 3 are each independently C(R) or N.
  • the present invention may further preferably further comprise, based on the formula (I1), A 1 is N, A 2 is S, A 3 is CH, and Q is a 5-membered heterocyclic ring, and the formula (I) is changed to the formula (Ih).
  • B 4 is O, S or N(R).
  • A is a non-aromatic heterocyclic ring heterozygous with N and S, and Q is R, wherein formula (I) is changed to formula (I2)
  • A is At this time, the formula (I) becomes the formula (I3),
  • Z 1 to Z 5 are C(Q), that is, A is a benzene ring;
  • one or two of Z 1 to Z 5 are N, and the others are independently C(Q), that is,
  • A may also be a pyridine ring, in which Z 1 is N, Z 2 to Z 5 are each independently C(Q); or Z 2 is N, and Z 1 and Z 3 to Z 5 are each independently C(Q). Or Z 3 is N, Z 1 , Z 2 , Z 4 and Z 5 are each independently C(Q);
  • A may also be a pyridazine ring, in which Z 1 and Z 2 are N, Z 3 - Z 5 are each independently C(Q); or Z 2 and Z 3 are N, Z 1 , Z 4 and Z 5 respectively Independently C(Q);
  • A may also be a pyrimidine ring, in which Z 1 and Z 3 are N, Z 2 , Z 4 and Z 5 are each independently C(Q);
  • A may also be a piperazine ring, in which Z 1 and Z 4 are N, Z 2 , Z 3 and Z 5 are each independently C(Q);
  • two adjacent Z 1 to Z 5 are C(Q) together to form a 5- to 6-membered carbocyclic ring or a heterocyclic one to three 5- to 6-membered heterocyclic ring selected from N, O and S heteroatoms.
  • the other three are independently C (Q), or the other two are independently C (Q), one is N, or one of the other three is C (Q) and the remaining two are N;
  • the classification according to the position classification of the loop is divided into the following two cases: when Z 1 and Z 2 are C(Q) and form a 5- to 6-membered carbocyclic ring or a heterocyclic 1 to 3 hetero atom selected from N, O and S
  • Z 3 to Z 5 are each independently C(Q), or Z 3 and Z 4 are independently C(Q) and Z 5 is N, or Z 3 and Z 5 Independently C(Q) and Z 4 are N, respectively, or Z 4 and Z 5 are independently C(Q) and Z 3 is N,
  • Z 4 and Z 5 are independently C(Q) and Z 1 is N, or Z 1 is C(Q) and Z 4 and Z 5 are N, or Z 4 is C(Q) and Z 1 and Z 5 are N, or Z 5 is C(Q) and Z 1 and Z 4 are N.
  • R' is W 1 is a linkage, C(R 0 ) 2 O or C(R 0 ) 2 OC(R 0 ) 2 ; W 2 is O or CH(N(R 0 ) 2 )R 0 .
  • R' may be one of the following substituents:
  • a compound satisfying formula (Ia) can be any compound satisfying formula (Ia)
  • the compound satisfying formula (Ib) can be any compound satisfying formula (Ib).
  • a compound satisfying formula (Ic) can be any compound satisfying formula (Ic).
  • the compound satisfying formula (Id) can be any compound satisfying formula (Id).
  • a compound satisfying formula (Ie) can be any compound satisfying formula (Ie).
  • a compound satisfying the formula (If) can be any compound satisfying the formula (If)
  • a compound satisfying the formula (Ig) can be any compound satisfying the formula (Ig)
  • a compound satisfying formula (Ih) can be any compound satisfying formula (Ih).
  • the compound satisfying the formula (I1) may also be any compound satisfying the formula (I1).
  • the compound satisfying the formula (I2) can be any compound satisfying the formula (I2).
  • the compound satisfying the formula (I3) can be any compound satisfying the formula (I3).
  • aromatic hydrocarbon receptor modulators of the formula (I) of the present invention are classified into the following five types of compounds:
  • Step one the raw material S ( ⁇ or ⁇ derivative) and the acid halide compound (ClC(O)AQ), the alcohol or the olefin compound are subjected to Fourier's reaction to obtain the target compound I A substituted at the 3-position;
  • Step two reacting with R'X or R'OH in the target compound I A to obtain the target compound I B ;
  • Step 3 the target compound I A or the target compound I B is reacted with H 2 NW 3 R 1 to obtain the target compound I C or the target compound I D ;
  • Step 4 the target compound I A or the target compound I B is subjected to a reduction reaction to obtain the target compound I E or the target compound I F .
  • the compounds of formula (I) of the present invention bind to AhR, 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 of the formula (I) can be used as an AhR inhibitor or a non-constitutive AhR agonist, which can be used for inhibiting the growth of cancer cells and inhibiting the metastasis and invasion of tumor cells.
  • Triethylene glycol monomethyl ether (2.0 g, 12.2 mmol) was dissolved in tetrahydrofuran (20 mL), and triphosgene (1.8 g, 6.1 mmol) was added with stirring, and the mixture was cooled to zero temperature in an ice bath, and pyridine (1.5 g, 19.0) was slowly added dropwise. Methyl), reacted at room temperature for 1 hour. Filtration and concentration of the mother liquid under reduced pressure gave a colorless liquid intermediate 5a (2.1 g, yield: 75.9%).
  • the starting material S-1 (2.0 g, 7.0 mmol) was dissolved in tetrahydrofuran (80 ml), triethylamine (1.5 g, 14.9 mmol) was added dropwise, and the mixture was cooled to zero temperature in an ice bath, and the intermediate 5-1 (2.1 g, 9.3) was added dropwise.
  • Methylene chloride solution (20 mL) was reacted at room temperature for 1 hour. Pour into ice water, dilute with methylene chloride, EtOAc (EtOAc) (2.5 g, yield 75.8%).
  • Triethylene glycol monomethyl ether (10 g, 60.9 mmol) was dissolved in tetrahydrofuran (100 mL), sodium hydrogen (3.2 g, 60% content, 79.17 mmol) was added portionwise at 0 ° C, and stirred at room temperature for 1 h after the addition.
  • Ethyl bromoacetate (20.1 g, 122 mmol) was added, and the mixture was evaporated to dryness.
  • the starting material S2 (188 mg, 1 mmol) was dissolved in dichloromethane (20 mL), 1 drop of DMF was added dropwise, cooled to 0-5 ° C, oxalyl chloride (151 mg, 1.2 mmol) was added dropwise, the ice bath was removed and stirred at room temperature 1 hour. Concentrate to dryness under reduced pressure, dichloromethane (20 mL) was evaporated and evaporated.
  • the intermediate 19b (10 g, 45.8 mmol) was suspended in 150 mL of ethyl acetate, pyridine (10.87 g, 137.5 mmol) was added, and the mixture was cooled to below 10 ° C, and trifluoroacetic anhydride (14.43 g, 68.7 mmol) was slowly added dropwise. After about 30 minutes, the mixture was dropped, and the reaction was continued at 10 ° C for 2 h. The reaction mixture was poured into 100 mL of ice water, and the mixture was combined with EtOAc EtOAc.
  • the synthesis route of the compound 20-1 and the compound 20-2 was the same as that of the example 19, and the starting material was replaced by 5-fluoroindole instead of 5-methoxyindole.
  • the relevant structure identification data is as follows.
  • the raw material S4 (4.0 g, 23.5 mmol) was dissolved in methanol (50 mL), and the temperature was lowered to below 0 ° C.
  • the dry hydrogen chloride gas was continuously introduced, and the reaction was continued for 8 hours, the aeration was stopped, the mixture was stirred overnight, and 5.4 g of a yellow solid was obtained by filtration. That is, the intermediate 23a was used directly for the subsequent reaction.
  • the starting material S1 (1.0 g, 3.5 mmol) was dissolved in pyridine (15 mL), methoxyamine hydrochloride (1.75 g, 21 mmol) was added, heated to 90 ° C for 24 h, cooled to room temperature, diluted with water, with ethyl acetate The ester was extracted twice, and the organic phase was washed with EtOAc EtOAc EtOAc. ⁇ 5:17) Purified compound 25-1 (410 mg) and compound 25-2 (300 mg), yield 64.3%.
  • the starting material S1 (7 g, 24 mmol) was dissolved in a mixed solvent of THF (42 mL) and methanol (168 mL), and cooled to 0 ° C with an ice salt bath, then sodium borohydride (4.6 g, 122. ), remove the ice salt bath, and raise to room temperature for 1 hour.
  • the reaction solution was poured into ice water, filtered, and the filter cake was washed with methanol and dried to afford Intermediate 28a (6.8 g, yield 98%).
  • the compound 43-1 (1.5 g, 4.3 mmol) was dissolved in ethanol (25 mL), thiourea (327 mg, 4.3 mmol) was added, and the reaction was carried out at 80 ° C for 3 h, the reaction was completed, cooled, filtered, washed with aqueous sodium hydrogen carbonate and dried. It was dissolved in THF, filtered through silica gel, and the filtrate was concentrated, and then washed with EA to give the compound 44 1.2 g (yield 85.6%).
  • Plasmids AhR receptor reporter cells expressing native (Human Hepatoma Huh-7), which contain a firefly luciferase gene linked to upstream receptor-specific genetic response element (GRE) functionality in a reporter vector.
  • native Human Hepatoma Huh-7
  • GRE genetic response element
  • the AhR stimulation test consists of the following three steps:
  • Implanted cells A suspension of AhR receptor reporter cells was prepared in a cell recovery medium (CRM; FBS containing 10% activated carbon treatment). The prepared suspension (100 ⁇ L) was then dispensed into the wells of a white 96-well culture plate.
  • CCM cell recovery medium
  • Master Stocks is diluted to a "2X concentration" of treatment medium using appropriate compound screening assay media (CSM: FBS containing 10% activated carbon).
  • CSM compound screening assay media
  • Test compounds were diluted in a gradient with 0.2% DMSO in CSM medium such that the final concentration of DMSO in each well of each treatment group was 0.1%.
  • the treatment medium was added to a culture plate (100 uL/well) in which the reporter gene-containing cells had been pre-plated, and double duplicate wells. The plate was placed in a 37 ° C incubator for 24 hours.
  • the data processing method is referred to J. Biomol. Screen, 1999, 4(2), 67-73.
  • each of the above compounds can bind to AhR and regulate those functions and signaling pathways controlled by AhR, thereby affecting the growth and proliferation of cancer cells and the invasiveness of tumor cells, and thus the formula (I) of the present invention is shown.
  • the pharmaceutical composition of the compound can be used as an AhR inhibitor or a non-constitutive AhR agonist, which can be used to inhibit cancer cell growth and inhibit tumor cell metastasis and invasion.
  • the present invention discloses an aromatic hydrocarbon receptor modulator represented by the formula (I), and a pharmaceutically acceptable salt thereof,
  • Q is R Or a C 6 -C 10 aromatic ring substituted with 1 to 3 R or 1 to 5 C 2 -C 10 heteroaryl rings selected from N, O and S hetero atoms;
  • R is C connected R C or R N connected to N.
  • the compound of the formula (I) of the present invention can modulate AhR activity and can be used for inhibiting the growth of cancer cells and inhibiting the met

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Abstract

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， R'为H、CN、CH2(OH)R0、CmH2m+1、CnH2n-1、CnH2n-3、式(A)、式(B)、或式(C)；两Ra独立地为H或两Ra共同形成＝O或＝N-W3-R1；A为未取代的或1～3个R取代的C6～C10芳环、1～5个选自N、O和S杂原子的C2～C10杂芳环或杂1～3个选自N、O和S杂原子的含有C＝N的4～7元非芳香杂环；Q为R、或者、为未取代的或1～3个R取代的C6～C10芳环或杂1～5个选自N、O和S杂原子的C2～C10杂芳环；R为与C连接的RC或与N连接的RN。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。

Description

芳香烃受体调节剂 技术领域
本发明属于抗肿瘤化合物技术领域，涉及一类具有调节芳香烃受体(AhR)活性的化合物及其药学上可接受的盐。
背景技术
由于环境以及生活方式的变化，癌症发病率日趋升高，加上其较高的致死率，严重威胁人类健康。虽然在某些癌症的医学治疗方面取得了显著的进步，靶向药物及免疫治疗大大提高了患者的生存率，但是在过去的20年里，所有癌症患者的总的5年生存率仅提高了月10％。而且由于恶性肿瘤的耐药性或以不受控制方式的转移和快速生长，使得癌症的发现与治疗极其困难。
芳香烃受体(AhR，Aryl hydrocarbon receptor)是一类能够感受外界环境中的异质物(xenobiotic)刺激，并介导毒性反应的胞内转录调控因子。激活后的AhR能够调控许多染色体上基因的表达，并促进对异质物的分解。之前的研究发现该信号还参与一些重要的生物学过程，如信号转导、细胞分化、细胞凋亡等。AhR与免疫调节的关系也是一直以来研究的热点，此前的研究表明AhR能够参与T细胞、巨噬细胞以及DC的分化与功能，另外，在器官移植后的免疫排斥反应中AhR也具有关键的作用。研究发现，利用Dioxin激活小鼠体内的AhR，能够降低小鼠在病毒感染后的存活率，病毒特异性CD8T细胞的分化与增殖速率也受到了影响。再比如下列化合物中，DIM及其衍生物具有抑制肿瘤活性(Breast Cancer Res.Treat.2001,66,147)，DIM目前处于II期临床研究，用于治疗前列腺癌和子宫颈癌。天然产物ICZ和FICZ都是AhR激动剂，可以抗哮喘(Chem.Rev.,2002,102,4303；Chem.Rev.,2012,112,3193；J.Biol.chem.2009,284,2690)。Malassezin(Bioorg.Med.Chem.2001,9,955)。氨基黄酮(aminoflavonone)由NCI开发，处于I期临床。3-羟甲基吲哚(Indole-3-carbinol)处于II期临床，用做化学保护剂及免疫兴奋剂。Phortress是Pharminox Univ.of Nottingham开发的AhR激动剂，I期临床用于实体瘤的治疗(Br.J.Cancer,2003,88,599；Mol.Cancer Ther.2004,3,1565)。丹参酮I(Tanshinone I)是一个天然的AhR配体，用于抗肿瘤化学保护剂(Toxicol Appl Pharmacol.2011Apr 1；252(1):18-27)。2-(吲哚乙酰-3-基)呋喃(Food Chem.2011,127,1764–1772)。ITE一个天然的内源性AhR激活剂，具有抗肝癌、前列腺癌、乳腺癌和卵巢癌(Proc.Natl.Acad.Sci.2002，99，14694-9；CN102573470；WO2016040553)。
Figure PCTCN2017118004-appb-000001
发明内容
本发明的目的在于提供一种新的具有AhR活性的如式(Ⅰ)所示的芳香烃受体调节剂，及其药学上可接受的盐，
Figure PCTCN2017118004-appb-000002
R'为H、CN、CH 2(OH)R 0、C mH 2m+1、C nH 2n-1、C nH 2n-3、
Figure PCTCN2017118004-appb-000003
Figure PCTCN2017118004-appb-000004
其中W 0为O或NH；W 1为连接键、C(R 0) 2、C(R 0) 2O、C(R 0) 2OC(R 0) 2或C(R 0) 2OC(R 0) 2C(R 0) 2；当W为C、S或S(O)时，W 2为连接键、O、NR 0、CH(N(R 0) 2)或OCH 2C(O)；当W为P(OR 0)时，W 2为O或NR 0；各R 0独立地为H、C mH 2m+1、C mH 2m+1OC(O)、C mH 2m+1-rX r、C mH 2m+1OC(O)C mH 2m、(环状C 4H 8NO)C mH 2m、CH 3(OCH 2CH 2) u或者CH 3(OCH 2CH 2) uOCH 2；
两R a独立地为H或两R a共同形成＝O、＝N-CN或＝N-W 3-R 1，W 3为O或NH，R 1为H、C mH 2m+1、C mH 2m+1C(O)、C mH 2m+1OC(O)或C mH 2m+1S(O) 1～2；
A为未取代的或1～3个R取代的C 6～C 10芳环、或者为未取代的或1～3个R取代的杂1～5个选自N、O和S杂原子的C 2～C 10杂芳环或杂1～3个选自N、O和S杂原子的含有C＝N的4～7元非芳香杂环；
Q为R，或者为未取代的或1～3个R取代的C 6～C 10芳环，或者为未取代的或1～3个R取代的杂1～5个优选1～3个更优选2～3选自N、O和S杂原子的3～10元优选4～7元更优选5～6元杂环优选杂芳环；
R为与C连接的R C或与N连接的R N，其中各个R C独立地为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” 2或-Y-NR”S(O) 1～2R”；各个R N独立地为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” 2或-Y-NR”S(O) 1～2R”；
R”为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 s或C nH 2n-3-tX t；
Y为连接键、-C mH 2m-、-C nH 2n-2-、-C nH 2n-4-、-C mH 2m-iX i-、-C nH 2n-2-jX j-或-C nH 2n-4-kX k-；
m＝1～8，n＝2～8，u＝1～5，r≤2m+1，s≤2n-1，t≤2n-3，i≤2m，j≤2n-2，k≤2n-4，X为卤素；优选地，m＝1～5更优选＝1～3，n＝2～6更优选＝2～4，u＝1～4更优选1～3，X为F、Cl或Br。
其中，(环状C 4H 8NO)C mH 2m中的环状C 4H 8NO为六元环，N和O处于间位或对位，优选N取代吗啡啉。
C mH 2m+1、C mH 2m+1-rX r、-C mH 2m-和-C mH 2m-iX i-可以是直链的也可以是含有支链的饱和烃基，C nH 2n-1、C nH 2n-1-sX s、-C nH 2n-2-和-C nH 2n-2-jX j-可以是直链的也可以是含有支链的烯烃基，C nH 2n-3、C nH 2n-3-tX t、-C nH 2n-4-和-C nH 2n-4-kX k可以是直链的也可以是含有支链的炔烃基。
当n＝3～8时，C nH 2n-1、C nH 2n-1-sX s、-C nH 2n-2-和-C nH 2n-2-jX j-还可以是环烷烃基。当n＝5～8时，C nH 2n-3、C nH 2n-3-tX t、-C nH 2n-4-和-C nH 2n-4-kX k还可以是双烯烃基或环状烯烃基。
本发明的一些较佳实施例中，A为
Figure PCTCN2017118004-appb-000005
此时式(Ⅰ)变为式(Ⅰ1)，
Figure PCTCN2017118004-appb-000006
式(Ⅰ1)中，A 1、A 2和A 3三者之一为O、S或N(R)，其他二者分别独立地为C(R)或N，具体分三种情形，即若A 1为O、S或N(R)，A 2和A 3分别独立地为C(R)或N；若A 2为O、S或N(R)，A 1和A 3分别独立地为C(R)或N；若A 3为O、S或N(R)，A 1和A 2分别独立地为C(R)或N。
本发明在式(Ⅰ1)的基础上进一步优选的，A 1、A 2和A 3三者之一为O、S或N(R)，其他二者分别独立地为N，此时A 1、A 2和A 3三者均为杂原子。而在此基础上更进一步优选的，A 3固定为N，此时式(Ⅰ1)变为式(Ⅰa)，
Figure PCTCN2017118004-appb-000007
式(Ⅰa)中，A 1为O、S或N(R)，A 2为N；或者A 2为O、S或N(R)，A 1为N。
本发明在式(Ⅰ1)的基础上还可进一步优选的，A 2为CH，此时式(Ⅰ1)变为式(Ⅰb)，
Figure PCTCN2017118004-appb-000008
式(Ⅰb)中，A 1为N或C(R)，A 3为O、S或N(R)；或者A 1为O、S或N(R)，A 3为N或C(R)。
本发明在式(Ⅰ1)的基础上还可进一步优选的，A 1为N，A 3为C(R)，两R a共同形成＝N-W 3-R 1或者独立地为H，此时式(Ⅰ1)变为式(Ⅰc)或(Ⅰd)，
Figure PCTCN2017118004-appb-000009
式(Ⅰc)和(Ⅰd)中，A 2为O、S或N(R)。
本发明在式(Ⅰ1)的基础上还可进一步优选的，A 1为N，A 3为C(R)，R'为
Figure PCTCN2017118004-appb-000010
此时式(Ⅰ1)变为式(Ⅰe)，
Figure PCTCN2017118004-appb-000011
式(Ⅰe)中，A 2为O、S或N(R)。
本发明在式(Ⅰ1)的基础上还可进一步优选的，A 1为N，A 3为C(R)，R'为
Figure PCTCN2017118004-appb-000012
此时式(Ⅰ1)变为式(Ⅰf)，
Figure PCTCN2017118004-appb-000013
式(Ⅰf)中A 2为O、S或N(R)，各R 0独立地为H或Ac。
本发明的一些较佳实施例中，Q为
Figure PCTCN2017118004-appb-000014
B 1、B 2、B 3和B 4四者之一为O、S或N(R)，其他三者分别独立地为C(R)或N，即
B 1为O、S或N(R)，B 2、B 3和B 4分别独立地为C(R)或N；
或者B 2为O、S或N(R)，B 1、B 3和B 4分别独立地为C(R)或N；
或者B 3为O、S或N(R)，B 1、B 2和B 4分别独立地为C(R)或N；
或者B 4为O、S或N(R)，B 1、B 2和B 3分别独立地为C(R)或N。
本发明的一些较佳实施例中，Q为
Figure PCTCN2017118004-appb-000015
B 5～B 9为C(R)，即Q为苯环；或者B 5～B 9之一或之二为N，其他的分别独立地为C(R)，即
Q还可为吡啶环，此时B 5为N，B 6～B 9分别独立地为C(R)；或B 6为N，B 5、B 7～B 9分别独立地为C(R)；或B 7为N，B 5、B 6、B 8和B 9分别独立地为C(R)；
Q还可为哒嗪环，此时B 5、B 6为N，B 7～B 9分别独立地为C(R)；或B 6和B 7为N，B 5、B 8和B 9分别独立地为C(R)；
Q还可为嘧啶环，此时B 5和B 7为N，B 6、B 8和B 9分别独立地为C(R)；
Q还可为吡嗪环，此时B 5和B 8为N，B 6、B 7和B 9分别独立地为C(R)。
本发明在式(Ⅰ1)的基础上还可进一步优选的，A 1为N，A 2为S，A 3为CH，Q为5元杂芳环，此时式(Ⅰ)变为式(Ⅰg)
Figure PCTCN2017118004-appb-000016
其中，B 2、B 3或B 4之一为O、S或N(R)，其他为C(R)或N，即
若B 2为O、S或N(R)，B 3和B 4分别独立地为C(R)或N；
若B 3为O、S或N(R)，B 2和B 4分别独立地为C(R)或N；
若B 4为O、S或N(R)，B 2和B 3分别独立地为C(R)或N。
本发明在式(Ⅰ1)的基础上还可进一步优选的，A 1为N，A 2为S，A 3为CH，Q为5元杂环，此时式(Ⅰ)变为式(Ⅰh)
Figure PCTCN2017118004-appb-000017
B 4为O、S或N(R)。
本发明的一些较佳实施例中，A为杂有N和S的非芳香杂环，Q为R，此时式(Ⅰ)变为式(Ⅰ2)
Figure PCTCN2017118004-appb-000018
本发明的一些较佳实施例中，A为
Figure PCTCN2017118004-appb-000019
此时式(Ⅰ)变为式(Ⅰ3)，
Figure PCTCN2017118004-appb-000020
式(Ⅰ3)中，Z 1～Z 5为C(Q)，即A为苯环；
或者，Z 1～Z 5之一或之二为N，其他的分别独立地为C(Q)，即
A还可为吡啶环，此时Z 1为N，Z 2～Z 5分别独立地为C(Q)；或Z 2为N，Z 1、Z 3～Z 5 分别独立地为C(Q)；或Z 3为N，Z 1、Z 2、Z 4和Z 5分别独立地为C(Q)；
A还可为哒嗪环，此时Z 1和Z 2为N，Z 3～Z 5分别独立地为C(Q)；或Z 2和Z 3为N，Z 1、Z 4和Z 5分别独立地为C(Q)；
A还可为嘧啶环，此时Z 1和Z 3为N，Z 2、Z 4和Z 5分别独立地为C(Q)；
A还可为哌嗪环，此时Z 1和Z 4为N，Z 2、Z 3和Z 5分别独立地为C(Q)；
或者，Z 1～Z 5中相邻的两个为C(Q)一起共同形成5～6元碳环或杂1～3个选自N、O和S杂原子的5～6元杂环，其他三者分别独立地为C(Q)，或者其他三者之二分别独立地为C(Q)剩下一个为N，或者其他三者之一为C(Q)剩下两个为N；按成环的位置分类进行描述具体分以下两种情形：当Z 1和Z 2为C(Q)并形成5～6元碳环或杂1～3个杂原子选自N、O和S杂原子的5～6元杂环时，Z 3～Z 5分别独立地为C(Q)，或者Z 3和Z 4分别独立地为C(Q)而Z 5为N，或者Z 3和Z 5分别独立地为C(Q)而Z 4为N，或者Z 4和Z 5分别独立地为C(Q)而Z 3为N，或者Z 3为C(Q)而Z 4和Z 5为N，或者Z 4为C(Q)而Z 3和Z 5为N，或者Z 5为C(Q)而Z 3和Z 4为N；当Z 2和Z 3为C(Q)并形成5～6元碳环或杂1～3个杂原子选自N、O和S杂原子的5～6元杂环时，Z 1、Z 4和Z 5分别独立地为C(Q)，或者Z 1和Z 4分别独立地为C(Q)而Z 5为N，或者Z 1和Z 5分别独立地为C(Q)而Z 4为N，或者Z 4和Z 5分别独立地为C(Q)而Z 1为N，或者Z 1为C(Q)而Z 4和Z 5为N，或者Z 4为C(Q)而Z 1和Z 5为N，或者Z 5为C(Q)而Z 1和Z 4为N。
本发明的一些较佳实施例中，R'为
Figure PCTCN2017118004-appb-000021
W 1为连接键、C(R 0) 2O或C(R 0) 2OC(R 0) 2；W 2为O或CH(N(R 0) 2)R 0。
在具体的实施例中，各个独立的官能团或取代基可在描述的范围内任意选择以及组合，比如
式(Ⅰ)中R'可为下列取代基之一：
Figure PCTCN2017118004-appb-000022
Figure PCTCN2017118004-appb-000023
式(Ⅰ1)中的
Figure PCTCN2017118004-appb-000024
可为下列取代基之一：
Figure PCTCN2017118004-appb-000025
Figure PCTCN2017118004-appb-000026
式(Ⅰb)中的
Figure PCTCN2017118004-appb-000027
可为下列取代基之一：
Figure PCTCN2017118004-appb-000028
Figure PCTCN2017118004-appb-000029
式(Ⅰc)～(Ⅰf)中的
Figure PCTCN2017118004-appb-000030
可为下列取代基之一：
Figure PCTCN2017118004-appb-000031
满足式(Ⅰa)的化合物可为
Figure PCTCN2017118004-appb-000032
满足式(Ⅰb)的化合物可为
Figure PCTCN2017118004-appb-000033
满足式(Ⅰc)的化合物可为
Figure PCTCN2017118004-appb-000034
满足式(Ⅰd)的化合物可为
Figure PCTCN2017118004-appb-000035
满足式(Ⅰe)的化合物可为
Figure PCTCN2017118004-appb-000036
满足式(Ⅰf)的化合物可为
Figure PCTCN2017118004-appb-000037
满足式(Ⅰg)的化合物可为
Figure PCTCN2017118004-appb-000038
满足式(Ⅰh)的化合物可为
Figure PCTCN2017118004-appb-000039
满足式(Ⅰ1)的化合物还可为
Figure PCTCN2017118004-appb-000040
满足式(Ⅰ2)的化合物可为
Figure PCTCN2017118004-appb-000041
满足式(Ⅰ3)的化合物可为
Figure PCTCN2017118004-appb-000042
本发明式(Ⅰ)所示的芳香烃受体调节剂分为如下5类化合物：
Figure PCTCN2017118004-appb-000043
式(Ⅰ A)(R'为H时)、
Figure PCTCN2017118004-appb-000044
式(Ⅰ B)(R'不为H时)、
Figure PCTCN2017118004-appb-000045
式(Ⅰ C)(R'为H时)、
Figure PCTCN2017118004-appb-000046
式(Ⅰ D)(R'不为H时)、
Figure PCTCN2017118004-appb-000047
式(Ⅰ E)(R'为H时)
Figure PCTCN2017118004-appb-000048
式(Ⅰ F)(R'不为H)。
其中，式(Ⅰ A)～式(Ⅰ F)的合成流程如下所示：
Figure PCTCN2017118004-appb-000049
步骤一，原料S(吲哚或者吲哚衍生物)和酰卤化合物(ClC(O)AQ)、醇类或烯类化合物经傅氏反应得到吲哚3位取代的目标化合物I A；
步骤二，目标化合物I A中与R'X或R'OH反应得到目标化合物I B；
步骤三，目标化合物I A或目标化合物I B与H 2NW 3R 1反应得到目标化合物I C或目标化合物I D；
步骤四，目标化合物I A或目标化合物I B经过还原反应得到目标化合物I E或目标化合物I F。
本发明的积极进步效果：本发明的式(Ⅰ)的化合物可结合至AhR，调控由AhR控制的那些功能和信号通路，从而影响着癌细胞的生长与增殖以及肿瘤细胞的侵袭力。式(Ⅰ)所示的化合物的药物组合物能够用作AhR抑制剂或非组成型AhR激动剂(non-constitutive AhR  agonists)，可用于抑制癌细胞生长，抑制肿瘤细胞的转移和侵袭。
具体实施方式
实施例1 化合物1-1和化合物1-2
Figure PCTCN2017118004-appb-000050
中间体1a的合成
向Boc-L-缬氨酸(0.8g,3.68mmol)的二氯甲烷和水(12mL/12mL)的悬浮液中，在搅拌状态下加入碳酸氢钠(1.546g,18.411mmol)及四丁基溴化铵(0.237g,0.736mmol)，冷却至0℃以下，将氯甲基氯磺酸酯(0.91g,5.52mmol)慢慢的滴加到反应液中，然后搅拌过夜。反应液用二氯甲烷萃取2次，有机相用水、饱和食盐水各洗1次，再用无水硫酸钠干燥并减压浓缩得粗品，粗品经硅胶柱层析(PE/EA＝20/1)纯化，得油状的中间体1a(0.97g,收率99％)。
化合物1-1的合成
向原料S1(1g,3.763mmol)的二甲基甲酰胺(DMF)(10mL)溶液中在搅拌状态下分批次加入氢化钠(0.165g,4.139mmol)，然后升温至40℃反应1小时，降至室温，慢慢滴加中间体1a(0.97g,3.6mmol)的DMF(2mL)溶液，室温搅拌过夜。将反应液倒入60mL的冰水中，过滤得粗品，粗品用硅胶柱层析(PE/EA＝20/1～10/1)纯化得到化合物1-1(0.5g,收率28％)。MS(ESI)m/z:516[M+1] +。
化合物1-2的合成
将化合物1-1(0.5g,0.97mmol)溶于二氧六环(2mL)中，滴加氯化氢二氧六环溶液(5mL)，室温反应过夜，过滤得到化合物1-2(0.24g,收率55％)。 1H NMR(400MHz,CDCl 3):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] +。
实施例2 化合物2-1和化合物2-2
Figure PCTCN2017118004-appb-000051
中间体2a的合成
方法同中间体1a的合成，由Boc-L-叔亮氨酸(2g,8.647mmol)制得油状的中间体2a(2.3g,收率95％)。
化合物2-1的合成
方法同化合物1-1的合成，由中间体2a(1g,3.6mmol)制得化合物2-1(1.4g,收率74％)。 1H NMR(400MHz,CDCl 3):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] +。
化合物2-2的合成
方法同化合物1-2的合成，由化合物2-1(1.4g,2.6mmol)制得化合物2-2(0.85g,收率70％)。 1H NMR(400MHz,CDCl 3):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] +。
实施例3 化合物3
Figure PCTCN2017118004-appb-000052
中间体3a的合成
称取羟基乙酸甲酯(3g,33.3mmol)，加入二氯甲烷(50mL)和多聚甲醛(1.3g,43.3mmol)，降温到-20℃以下，持续通入现制的氯化氢气体，保持-20℃反应30分钟，撤去氯化氢气体，加入无水硫酸镁和无水硫酸钠，继续保温反应1小时，室温过夜。过滤除去固体，母液室温下浓缩至干后经硅胶柱层析纯化得到中间体3a(1.2g,收率26％)。
化合物3的合成
方法同化合物1-1的合成，由原料S1(286mg,1mmol)及中间体3a(500mg,3.6mmol) 制得淡黄色固体化合物3(280mg,收率74％)。 1H NMR(400MHz,CDCl 3):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] +。
实施例4 化合物4-1和化合物4-2
Figure PCTCN2017118004-appb-000053
化合物4-1的合成
向Boc-L-缬氨酸(2.17g,10mmol)的DMF(20mL)溶液中加入原料S1(2.86g,10mmol)，搅拌下加入HATU(4.56g,12mmol)及DIEA(2.6g,20mmol)，搅拌过夜。反应液倒入水中，用乙酸乙酯萃取2次，有机相用水、饱和盐水各洗涤1次，再用无水硫酸钠干燥并减压浓缩得粗品，粗品经硅胶柱层析(PE/EA＝4/1)纯化得到化合物4-1(3.01g,收率62％)。 1H NMR(400MHz,CDCl 3):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] +。
化合物4-2的合成
方法同化合物1-2的合成，由化合物4-1(486mg,1mmol)制得化合物4-2(348mg,收率77％)。 1H NMR(400MHz,CDCl 3):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] +。
实施例5 化合物5
Figure PCTCN2017118004-appb-000054
中间体5a的合成
三乙二醇单甲醚(2.0g,12.2mmol)溶解在四氢呋喃(20mL)中，搅拌下加入三光气(1.8g,6.1mmol)，冰浴降温至零度，缓慢滴入吡啶(1.5g,19.0mmol)，室温反应1小时。过滤，母液减压浓缩得到无色液体中间体5a(2.1g,收率75.9％)。
化合物5的合成
原料S-1(2.0g,7.0mmol)溶解在四氢呋喃(80ml)中，滴入三乙胺(1.5g,14.9mmol)，冰浴降温至零度，滴入中间体5-1(2.1g,9.3mmol)的二氯甲烷溶液(20mL)，室温反应1小时。倒入冰水中，二氯甲烷萃取，有机相用饱和盐水洗涤，无水硫酸钠干燥，减压浓缩至干，粗品用硅胶柱层析(PE/EA＝3/1)纯化得白色固体化合物5(2.5g,收率75.8％)。 1H NMR(400MHz,CDCl 3):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]+。
实施例6 化合物6
Figure PCTCN2017118004-appb-000055
中间体6a的合成
将三乙二醇单甲醚(10g,60.9mmol)溶于四氢呋喃(100mL)中，0℃下分批加入钠氢(3.2g,60％含量,79.17mmol)，加完后室温搅拌1h，滴入溴乙酸乙酯(20.1g,122mmol)，室温反应3h，直接向反应液中加入水(100mL)，用二氯甲烷萃取，有机相用无水硫酸钠干燥并减压浓缩至干。然后加水(100mL)和氢氧化钠固体(3g,73mmol)，室温搅拌1h，用乙酸乙酯萃取2次，水相用稀盐酸调节至pH＝2～3，再用二氯甲烷/异丙醇(V/V＝10:1)混合溶剂萃取5次，有机相用无水硫酸钠干燥并减压浓缩干得粗品，粗品经硅胶柱层析(DCM:CH 3OH＝100:1～20:1)纯化得化合物6a(10g,收率74％)。
中间体6b的合成
将化合物6a(2g,8.99mmol)溶于二氯甲烷(20mL)中，加入碳酸氢钠(3.1g,36mmol)、四丁基溴化铵(289mg,0.899mmol)和水(20mL)。降温到0℃以下，滴入氯甲基氯磺酸酯(1.48g，8.99mmol)的二氯甲烷溶液(10mL)，室温搅拌过夜，静置分层，水相用二氯甲烷萃取2次，有机相用无水硫酸钠干燥并减压浓缩干得粗品，粗品经硅胶柱层析(DCM:CH 3OH＝50：1)纯化得油状液体6b(300mg,收率12.3％)。LCMS(ESI)m/z：271[M+1] +。
化合物6的合成
将原料S1(1g,3.49mmol)溶于DMF(15mL)中，0℃下加入氢化钠(153mg,60％含量，3.84mmol)，加完后搅拌10min，升温至50℃搅拌1h，冷却到室温，加入化合物6b(0.944mg，3.49mmol)室温反应4h，加入水和二氯甲烷，并用二氯甲烷萃取3次，有机相用无水硫酸 钠干燥并减压浓缩干得粗品，粗品经硅胶柱层析(CH 3OH:DCM＝0-2％)纯化得化合物6(650mg,收率35.8％)。 1H NMR(400MHz,CDCl 3):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] +。
实施例7 化合物7
Figure PCTCN2017118004-appb-000056
中间体7a的合成
方法同6a，起始原料为中间体6a。收率75％。LCMS(ESI)m/z:337.2[M+1] +。
中间体7b的合成
将中间体7a(3.4g,10mmol)溶解在二氯甲烷(5mL)中，加入三氟乙酸(5mL)，室温搅拌过夜，减压浓缩至干，粗品经硅胶柱层析(CH 3OH:DCM＝0-2％)纯化得油状物7b(2.6g,收率76％)。LCMS(ESI)m/z:281.2[M+1] +。
化合物7
方法同化合物6。收率55％。 1H NMR(400MHz,CDCl 3):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] +。
实施例8 化合物8
Figure PCTCN2017118004-appb-000057
中间体8a的合成
将原料S2(188mg,1mmol)溶于二氯甲烷(20mL)中，滴加1滴DMF，冷却到0-5℃，滴加草酰氯(151mg,1.2mmol)，移去冰浴，室温搅拌1小时。减压浓缩至干，加入二氯甲烷(20mL)溶解，减压浓缩至干得中间体8a，直接用于下一步反应。
化合物8的合成
将中间体8a(1mmol)的二氯甲烷(30mL)溶液滴入到含有无水三氯化铝(164mg,1.2mmol)的二氯甲烷(30mL)悬浊液中，搅拌2小时，将吲哚(143mg,1.2mmol)的二氯甲烷(30mL)溶液慢慢滴入上述反应液中，反应过夜。加入饱和碳酸氢钠溶液洗涤，有机相用饱和盐水洗涤，在用无水硫酸钠干燥并减压浓缩得粗品，粗品经硅胶柱层析(PE/EA＝4/1)纯化得浅黄色固体化合物8(120mg,收率42％)。 1H NMR(400MHz,DMSO-d 6):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] +。
实施例9～18 化合物9～18
Figure PCTCN2017118004-appb-000058
Figure PCTCN2017118004-appb-000059
化合物9～18制备方法同实施例8，分别使用对应的酸代替原料S-2，其他原料同实施例8。
化合物9：MS(ESI)m/z:271.1[M+1] +。
化合物10： 1H NMR(400MHz,CDCl 3)：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)。
化合物11： 1H NMR(400MHz,DMSO-d 6):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)。
化合物12： 1H NMR(400MHz,CDCl 3):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＝4.2Hz,1H),4.25(s,3H),3.90(s,3H)。
化合物13： 1H NMR(400MHz,DMSO-d 6):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] +。
化合物14： 1H NMR(400MHz,DMSO-d 6):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] +。
化合物15： 1H NMR(400MHz,CDCl 3):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] +。
化合物16： 1H NMR(400MHz,DMSO-d 6):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] +。
化合物17： 1H NMR(400MHz,CDCl 3):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] +。
化合物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] +。
实施例19 化合物19-1、19-2
Figure PCTCN2017118004-appb-000060
中间体19a的合成
将5-甲氧基吲哚(10g,68mmol)加入250mL的三口瓶中，加入甲基叔丁基醚(75mL)溶解，降温到-10℃，慢慢滴入草酰氯(9.5g,74mmol)，控制滴入温度低于-5℃，滴完后继 续低温搅拌1h，撤去冰浴室温搅拌30分钟，加入石油醚100mL，搅拌30分钟，过滤，滤饼用石油醚和甲基叔丁基醚混合液洗涤，干燥得中间体19a(15.5g,收率97％)。LCMS(ESI)m/z：234[M+1] +(将产物用甲醇稀释，酰氯转化成甲酯)。
中间体19b的合成
在0℃下，将中间体19a(15.5g)分批加入到52.3g浓氨水(25％)和100mL乙醇的混合物中，加毕，在10℃反应2h。反应混合物倒入100mL冰水，搅拌30分钟，过滤，滤饼烘干得到浅灰色固体，即中间体19b(10.5g)。LCMS(ESI)m/z：219[M+1] +。
中间体19c的合成
将中间体19b(10g,45.8mmol)悬浮在150mL乙酸乙酯中，加入吡啶(10.87g,137.5mmol)，降温至10℃以下，慢慢滴入三氟乙酸酐(14.43g,68.7mmol)，约30分钟滴完，滴毕，继续10℃反应2h。反应液倒入100mL冰水中，用乙酸乙酯萃取2次，有机相合并，用饱和碳酸氢钠洗涤2次，0.5N的稀盐酸洗涤2次，无水硫酸钠干燥，过滤，减压浓缩得到粗品固体8.8g，用乙酸乙酯：二氯甲烷＝5:1的混合溶剂洗涤，过滤得中间体19c(7.2g,收率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] +。
化合物19-1的合成
将中间体19c(2g,10mmol)溶解在N,N’-二甲基酰胺(15mL)中，加入L-半胱氨酸甲酯盐酸盐(1.72g,10mmol)，DBU(152mg,1mmol)，升温到40℃反应3h。冷却到室温，将反应液滴入80mL冰稀盐酸(含0.1mmol HCl)中，搅拌20分钟，过滤，滤饼压干，用少量二氯甲烷洗涤，干燥得中间体19-1(3.1g,收率97％)。 1H NMR(400MHz,CDCl 3):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] +。
化合物19-2的合成
将化合物19-1(2.6g,8.16mmol)溶解在N,N-二甲基甲酰胺(30mL)中，在80℃下鼓空气泡反应12h。将反应液滴入到冰水中搅拌20分钟，过滤，滤饼水洗，干燥得到化合物19-2(2.5g，收率96)。 1H NMR(400MHz,CDCl 3):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] +。
实施例20 化合物20-1、20-2
Figure PCTCN2017118004-appb-000061
化合物20-1和化合物20-2的合成路线同实施例19，起始原料用5-氟吲哚代替5-甲氧基吲哚，相关结构鉴定数据如下，
中间体20b:MS(ESI)m/z:207.2[M+1] +。
中间体20c: 1H NMR(400MHz,DMSO-d 6):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] +。
化合物20-1: 1H NMR(400MHz,DMSO-d 6):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] +。
化合物20-2: 1H NMR(400MHz,DMSO-d 6):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] +。
实施例21 化合物21
Figure PCTCN2017118004-appb-000062
化合物21的合成
将1-溴-3-甲基-2-丁酮(0.8g,4.89mmol)溶于乙醇(25mL)中，搅拌下加入原料S3(1.0g,4.89mmol)，加热至80℃，反应2h，冷却至室温，过滤并乙醇洗涤得化合物21(0.6g,收率45％)。 1H NMR(400MHz,DMSO-d 6):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)。
实施例22 化合物22
Figure PCTCN2017118004-appb-000063
化合物22的合成同化合物21的合成,由原料S3(1.0g,4.89mmol)制得化合物22(1.2g，收率80％)。 1H NMR(400MHz,DMSO-d 6):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)。
实施例23 化合物23
Figure PCTCN2017118004-appb-000064
中间体23a的合成
将原料S4(4.0g,23.5mmol)溶于甲醇(50mL)中，降温到0℃以下，持续通入干燥的氯化氢气体，反应8小时，停止通气，密封搅拌过夜，过滤得到5.4g黄色固体，即中间体23a，直接用于后续反应。
中间体23b的合成
将中间体23a(5.4g,19.6mmol)溶于乙腈(15mL)中，加入2,3-二氨基丙酸甲酯盐酸盐(3.7g,19.6mmol)，滴入三乙胺(10g,98mmol)，回流反应5h，减压除去溶剂，加入水和二氯甲烷溶解、分层，水相用二氯甲烷萃取2次，有机相合并后用饱和食盐水洗涤，再用无水硫酸钠干燥并减压浓缩得粗品，粗品经硅胶柱层析纯化得中间体23b(2.4g,收率45％)。 1H NMR(400MHz,CDCl 3):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] +。
化合物23的合成
将中间体23b(1.2g,4.42mmol)溶解在DMF(20mL)中，加氢氧化钠(530mg,13.3mmol)，60℃下通入空气搅拌反应3h，冷却，倒入冰水中，用乙酸乙酯萃取三次，有机相用饱和盐水洗涤，再用无水硫酸钠干燥并减压浓缩得粗品，粗品用PE:EA＝2:1混合溶剂洗涤得到化合物23(960mg,收率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] +。
实施例24 化合物24
Figure PCTCN2017118004-appb-000065
中间体24a的合成
将原料S1(2.86g,10mmol)溶于混合溶剂THF/MeOH/H 2O(16/15/15mL)中，室温下搅拌过夜。反应液用4N的盐酸调节至pH＝4-5，然后过滤，滤饼用水洗涤并真空干燥得中间体24a(2.6g,收率96％)。MS(ESI)m/z:271[M-1] -。
中间体24b的合成
将中间体24a(1.36g,5mmol)溶于THF(20mL)中，加2滴DMF，滴加草酰氯(755mg,6mmol)，室温反应2h，减压浓缩至干后溶于THF(20mL)中，然后滴加到80％的水合肼(2mL,57mmol)中，搅拌过夜，反应液减压浓缩至5mL后过滤，滤饼用THF洗涤，干燥得中间体24b(1.38g,收率97％)。
化合物24的合成
将中间体24b(1.0g,3.5mmol)、对甲苯磺酸一水合物(20mg)和原甲酸三甲酯(5mL)的混合物加热至80℃，搅拌过夜，倒入冰水中，过滤，滤饼用乙酸乙酯洗涤，干燥得化合物24(280mg,收率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] +。
实施例25 化合物25-1、25-2
Figure PCTCN2017118004-appb-000066
化合物25-1和25-2的合成
将原料S1(1.0g,3.5mmol)溶于吡啶(15mL)中，加入甲氧基胺盐酸盐(1.75g,21mmol)，加热至90℃反应24h，冷却至室温，加水稀释，用乙酸乙酯萃取2次，有机相用1N的盐酸洗涤2次，饱和盐水洗涤，再用无水硫酸钠干燥并减压浓缩得粗品，粗品用硅胶柱层析(石油醚：乙酸乙酯＝20:1～5:17)纯化得化合物25-1(410mg)和化合物25-2(300mg)，收率64.3％。
化合物25-1： 1H NMR(400MHz,CDCl 3):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] +。
化合物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] +。
实施例26 化合物26-1、26-2
Figure PCTCN2017118004-appb-000067
化合物26-1和26-2的合成
方法同化合物25-1和25-2的合成,由原料S1(324mg,1.13mmol)和盐酸羟胺(696mg,10mmol)制得化合物26-1和26-2(149mg,收率44％)。
化合物26-1： 1H NMR(400MHz,CDCl 3):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] +。
化合物26-2： 1H NMR(400MHz,CDCl 3):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] +。
实施例27 化合物27
Figure PCTCN2017118004-appb-000068
向中间体24a(1.36g,5mmol)的DMF(20mL)溶液中，加入甘氨酸甲酯盐酸盐(753mg,6mmol)及HATU(2.26g,6mmol)及DIEA(2.3g,10mmol)，室温搅拌2小时，反应混合物倒入100mL冰水中，过滤，滤饼经乙酸乙酯洗涤后干燥得化合物27(1.45g,收率84.5％)。 1H NMR(400MHz,DMSO-d 6):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)。
实施例28 化合物28
Figure PCTCN2017118004-appb-000069
中间体28a的合成
将原料S1(7g,24mmol)溶于THF(42mL)和甲醇(168mL)的混合溶剂中，用冰盐浴降温到0℃，然后分批次慢慢加入硼氢化钠(4.6g,122.mmol)，再移去冰盐浴，升至室温反应1小时。将反应液倒入冰水中，过滤，滤饼经甲醇洗涤后干燥得中间体28a(6.8g,收率98％)。 1H NMR(400MHz,DMSO-d 6):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] +。
化合物28的合成
将中间体28a(3g,10.4mmol)溶于甲醇(25mL)中，搅拌下加入锌粉(2g,31.2mmol)，氮气保护，100℃回流1小时，然后将反应液滴加到冰水中，过滤得到粗品1.8g。取粗品(200mg)用硅胶柱层析(PE/EA＝4/1～2/1)纯化得化合物28(20mg)。 1H NMR(400MHz,DMSO-d 6):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] +。
实施例29 化合物29
Figure PCTCN2017118004-appb-000070
中间体29a的合成
将中间体24a(1.36g,5mmol)溶于THF(20mL)中，加2滴DMF，滴加草酰氯(755mg,6mmol)，室温反应2小时，减压浓缩至干，溶解在THF(20mL)中后滴加到浓氨水(10mL)中，搅拌过夜。减压浓缩至5mL，过滤，滤饼经THF洗涤后干燥得中间体29a(1.3g,收率95％)。 1H NMR(400MHz,DMSO-d 6):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] +。
化合物29的合成
将中间体29a(17g,62.66mmol)溶于乙酸乙酯(250mL)中，加入吡啶14.87g(187.9mmol)，室温下滴加三氟乙酸酐(19.7g,93.99mmol)，室温搅拌4小时，减压浓缩至干，用乙酸乙酯重结晶得化合物29(14g,收率88％)。 1H NMR(400MHz,DMSO-d 6):δ12.44(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] +。
实施例30 化合物30-1、30-2
Figure PCTCN2017118004-appb-000071
化合物30-1的合成
将化合物29(1g,3.9mmol)溶于甲醇(100mL)中，氮气置换三次，滴加甲醇钠溶液(金属钠0.23g,10mmol,甲醇50mL)，室温搅拌4小时，滴加L-丝氨酸甲酯盐酸盐(1.8g，11.6mmol)的甲醇(50mL)溶液，加热至55℃，搅拌2小时，倒入冰水，过滤得粗品，粗品经硅胶柱层析(PE:EA＝1：1)纯化得化合物30-1(0.4g收率29％)。 1H NMR(400MHz,DMSO-d 6):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] +。
化合物30-2的合成
将化合物30-1(200mg，0.56mmol)溶于四氢呋喃(50mL)中，加入二氧化锰(1000mg，11.56mmol)回流过夜，冷却，过滤，滤液减压浓缩至干得粗品，粗品经硅胶柱层析(PE:EA＝2：1)纯化得化合物30-2(25mg收率12％)。 1H NMR(400MHz,DMSO-d 6):δ12.37(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] +。
实施例31 化合物31-1、31-2
Figure PCTCN2017118004-appb-000072
化合物31-1：方法同化合物30-1。 1H NMR(400MHz,DMSO-d 6):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] +。
化合物31-2：方法同化合物30-2。 1H NMR(400MHz,DMSO-d 6)：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＝3.2Hz,1H),7.65～7.57(m,1H),7.35～7.27(m,2H)。MS(ESI)m/z:312.0[M+1] +。
实施例32 化合物32-1、32-2
Figure PCTCN2017118004-appb-000073
化合物32-1：方法同化合物30-1。 1H NMR(400MHz,DMSO-d 6):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] +。
化合物32-2：方法同化合物30-2。MS(ESI)m/z:370.0[M+1] +。
实施例33 化合物33-1、33-2
Figure PCTCN2017118004-appb-000074
化合物33-1：方法同化合物30-1。MS(ESI)m/z:298.0[M+1] +。
化合物33-2：方法同化合物30-2。 1H NMR(400MHz,DMSO-d 6)：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] +。
实施例34 化合物34
Figure PCTCN2017118004-appb-000075
中间体34a的合成参考J.Am.Chem.Soc.,2002,124(44).13179-13184。
中间体34b的合成见J.Med.Chem.,1961,4,259-296。
中间体34c的合成
将化合物34b(1.18g,10mmol)和三乙胺(3.03g,30mmol)溶解在二氯甲烷(15mL)中,在0℃下滴加化合物34a(2.07g,10mmol)的二氯甲烷(10mL)溶液。反应混合物在室温下搅拌过夜。加30mL水稀释，二氯甲烷萃取3次，合并有机相，无水硫酸钠干燥，过滤，减压浓缩得中间体34c(2.8g，收率97％)。MS(ESI)m/z:290.0[M+1] +。
化合物34的合成
将中间体34c(5g,17.286mmol)溶于DMF(200mL)中，搅拌下加入三乙胺(5.2g，51.86mmol)，然后加入THF(100mL)，氮气保护下，慢慢滴加二氯甲烷(50mL)溶解的对甲苯磺酰氯(9.88g,51.86mmol)，1h加毕，然后室温反应过夜。减压浓缩除去二氯甲烷和THF后，滴加到冰水中，搅拌，过滤得粗品，粗品经硅胶柱层析纯化(二氯甲烷/甲醇＝50/1～10/1)得到化合物34(0.5g,收率10％)。 1H NMR(400MHz,DMSO-d 6):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] +。
实施例35 化合物35
Figure PCTCN2017118004-appb-000076
将化合物29(2g,7.9mmol)加入到密封反应器中，加入DMF(30mL)搅拌，氯化铵(0.49g,9.2mmol)，叠氮化钠(0.6g,9.2mmol)，将反应器密封，油浴120℃反应过夜，将反应液降至室温滴加到200mL冰水中，用乙酸乙酯萃取(150mL)，水相用2N的盐酸调pH为酸性；析出固体，然后过滤，水洗，干燥，得到化合物35(1.8g,77％)。 1H NMR(400MHz,DMSO-d 6):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] +。
实施例36 化合物36
Figure PCTCN2017118004-appb-000077
将化合物29(0.5g,1.7mmol)悬浮在10mL乙二醇甲醚中，加入2mL醋酸及醋酸甲脒 (0.215g,2.07mmol)，氮气保护，油浴回流24小时，减压蒸馏，粗品经硅胶柱层析(DCM/甲醇＝200/1～20/1)纯化得化合物35(0.32g,收率55％)。 1H NMR(400MHz,DMSO-d 6):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] +。
实施例37 化合物37
Figure PCTCN2017118004-appb-000078
将化合物1-1(500mg,0.97mmol)溶于甲醇(2mL)中，滴加0.1N甲醇钠溶液(2mL)，室温反应过夜，过滤，固体用甲醇洗涤，干燥得到化合物37(153mg,收率50％)。 1H NMR(400MHz,CDCl 3):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] +。
实施例38 化合物38-1～化合物38-4
Figure PCTCN2017118004-appb-000079
化合物38-1、38-2的合成
原料S-1(1.07g,3.78mmol)溶解在THF(50mL)中，加入2,3,4,6-四乙酰基葡萄糖(2.6g，7.55mmol)，氮气保护下，加入三苯基膦(2g,7.55mmol)，降温至-15℃，滴加偶氮二甲酸二异丙酯(1.53g,7.55mmol),反应液倒入冰水中，乙酸乙酯萃取(100mL X2)，无水硫酸钠干燥，减压浓缩至干，硅胶柱层析纯化(石油醚/乙酸乙酯：10/1-2/1)，得化合物38-1(650mg)和化合物38-2(600mg)(收率54％)。化合物38-1： 1H NMR(400MHz,CDCl 3): 1H NMR(400MHz,CDCl 3):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] +。化合物38-2：δ9.20(s,1H),8.56～8.49(m,1H),8.45(s,1H),7.87～7.80(m,1H),7.44～7.35(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),4.38～4.25(m,2H),4.21～4.12(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] +。
化合物38-3、38-4的合成
将化合物38-1(200mg,0.325mmol)溶解在甲醇(10mL)中，加入甲醇钠(190mg，3.57mmol)，室温搅拌5h。反应液倒入饱和氯化钠水溶液中，加入乙酸乙酯50mL，用枸橼酸调节pH至中性，分离有机相，水相用乙酸乙酯再萃取一次，合并有机相，无水硫酸钠干燥，过滤，减压浓缩至干，硅胶柱层析纯化(甲醇/二氯甲烷：5％-10％)得化合物38-3(40mg)和化合物38-4(5mg)。化合物38-3：MS(ESI)m/z:491.1[M+1] +。化 合物38-4：MS(ESI)m/z:449.1[M+1] +。
实施例39 化合物39
Figure PCTCN2017118004-appb-000080
制备方法同实施例21，得到化合物39(收率65％)。 1H NMR(400MHz,DMSO-d 6):δ12.25(s,1H),9.58(d,J＝0.8Hz,1H),9.38(d,J＝3.2Hz,1H),8.79(s,1H),8.76(d,J＝1.2Hz,1H),8.72(d,J＝2.4Hz,1H),8.34～8.36(m,1H),7.60～7.63(m,1H),7.28～7.33(m,2H)。MS(ESI)m/z:307[M+1] +。
实施例40 化合物40
Figure PCTCN2017118004-appb-000081
制备方法同实施例21，得到化合物40(收率58％)。 1H NMR(400MHz,DMSO-d 6):δ12.29(s,1H),9.23(d,J＝3.2Hz,1H),8.33～8.36(m,1H),8.21(s,1H)，7.85(d,J＝0.8,1H),7.59～7.61(m,1H),7.27～7.33(m,2H),7.13(d,J＝2.8Hz,1H),6.69～6.71(m,1H)。MS(ESI)m/z:295[M+1] +。
实施例41 化合物41
Figure PCTCN2017118004-appb-000082
制备方法同实施例21，得到化合物41(收率58％)。 1H NMR(400MHz,DMSO-d 6):δ12.19(s,1H),8.99(d,J＝3.2Hz,1H),8.30(m,1H),7.71(s,1H),7.60(m,1H),7.27(m,2H),2.24(m,1H),1.01(d,J＝6.8Hz,4H)。MS(ESI)m/z:269[M+1] +。
实施例42 化合物42-1～化合物42-2
Figure PCTCN2017118004-appb-000083
合成方法同实施例4，化合物42-1的收率83％，MS(ESI)m/z:511.1[M+1] +。
化合物42-2，收率90％， 1H NMR(400MHz,CDCl 3):δ9.58(s,1H),9.04(s,1H),8.89(brs,3H),8.78(m,1H),8.46～8.51(m,1H),8.35～8.38(m,1H)，8.03(d,J＝3.2Hz,1H)，7.96(d,J＝3.2Hz，1H),7.54～7.62(m,2H),5.13(m,1H),2.54～2.59(m,1H),1.15(d,J＝7.2Hz,3H),1.07(d,J＝7.2Hz,3H)。MS(ESI)m/z:411.1[M+1] +。
实施例43 化合物43-1～化合物43-2
Figure PCTCN2017118004-appb-000084
化合物43-1的合成方法同实施例21，收率78，MS(ESI)m/z:349[M+1] +
化合物43-1(1.8g,5.15mmol)加入乙二醇(35mL)中，加入醋酸甲脒(2.68g,25.77mmol)，N 2保护下140℃(外温)反应2h，冷却，加入冰水中，加入氢氧化钠水溶液调节pH＝9～10，用EA萃取，有机相合并干燥减蒸脱溶，固体用EA和少量乙醇混合液洗涤，过滤，粗产物用THF溶解，用硅胶过滤，THF洗涤，浓缩后再用THF/石油醚混合液洗涤，过滤得到化合物43-2 380mg。 1H NMR(400MHz,DMSO)δ＝12.37(s,1H),12.45(s,1H),9.38(s,1H),8.33～8.38(m,1H)，8.04(s,1H),7.79(s,2H),7.58～7.63(m,1H),7.26～7.33(m,2H)。MS(ESI)m/z：295[M+1] +
实施例44 化合物44
Figure PCTCN2017118004-appb-000085
化合物43-1(1.5g，4.3mmol)溶于乙醇(25mL)中，加入硫脲(327mg,4.3mmol)，80℃反应3h，反应完全，冷却，过滤，用碳酸氢钠水溶液洗涤，干燥后用THF溶解，通过硅胶过滤，滤液浓缩后，用EA洗涤得化合物44 1.2g(收率85.6％)。 1H NMR(400MHz,CDCl 3)δ＝12.26(d,J＝2.4Hz,1H),9.27(d,J＝3.2Hz,1H),8.32～8.36(m,1H), 7.99(s,1H),7.58～7.61(m,1H),7.26～7.32(m,3H),7.21(s,2H)。MS(ESI)m/z：327[M+1] +。
效果实施例1
AhR激动试验(参考激动剂MeBio的活性测定：Oncogene(2004)23,4400–4412)
试验材料(plasmids)：表达天然(Human Hepatoma Huh-7)的AhR受体报告基因细胞，在报告载体包含连接于上游受体特异性遗传应答元素(GRE)功能性的萤火虫荧光素酶基因。
AhR激动试验包括以下三个步骤：
1、植入细胞：在细胞恢复培养基(CRM；含有10％活性炭处理的FBS)中制备AhR受体报告细胞的悬浮液。然后将制备好的悬浮液(100μL)分配到一个白色的96孔培养板的孔中。
2、在实验即将开始前，将Master Stocks用适当的化合物筛选实验培养基(CSM：含有10％活性炭处理的FBS)稀释成“2X浓度”的处理培养基。测试化合物用含0.2％DMSO的CSM培养基梯度稀释，使得各处理组各实验孔中DMSO的终浓度均为0.1％。将处理培养基加入到已经预先铺好含报告基因细胞的培养板中(100uL/孔)，双复孔。将实验板放入37℃培养箱培养24小时。
3、荧光检测及分析：孵化完成后，弃去处理培养基并加入100μL/孔的萤光素酶检测试剂，测定每一个孔的Ave RLU(平均相对荧光强度)和各组实验的变异系数，由实验组的不同浓度的测试化合物的Ave RLU Test Cmpd和空白对照组的Ave RLU Vehicle的比值，定量确定不同浓度的测试化合物作用下的AhR受体的活性，确定激活倍数以及EC 50。
Figure PCTCN2017118004-appb-000086
数据处理方法参考J.Biomol.Screen,1999,4(2),67-73。
各化合物的EC 50如表1所示，其中A表示0.001μM＜EC 50≤1.0μM，B表示1.0μM＜EC 50≤10.0μM，C表示10.0μM＜EC 50≤100μM。
表1 各化合物的EC 50
Figure PCTCN2017118004-appb-000087
Figure PCTCN2017118004-appb-000088
由表1可知，上述各化合物可结合至AhR并调控由AhR控制的那些功能和信号通路，进而可影响癌细胞的生长与增殖以及肿瘤细胞的侵袭力，因此本发明的式(Ⅰ)所示的化合物的药物组合物能够用作AhR抑制剂或非组成型AhR激动剂(non-constitutive AhR agonists)，可用于抑制癌细胞生长，抑制肿瘤细胞的转移和侵袭。
工业实用性
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，
Figure PCTCN2017118004-appb-000089
R'为H、CN、CH 2(OH)R 0、C mH 2m+1、C nH 2n-1、C nH 2n-3、
Figure PCTCN2017118004-appb-000090
Figure PCTCN2017118004-appb-000091
Figure PCTCN2017118004-appb-000092
两R a独立地为H或两R a共同形成＝O或＝N-W 3-R 1；A为未取代的或1～3个R取代的C 6～C 10芳环、杂1～5个选自N、O和S杂原子的C 2～C 10杂芳环或杂 1～3个选自N、O和S杂原子的含有C＝N的4～7元非芳香杂环；Q为R、或者、为未取代的或1～3个R取代的C 6～C 10芳环或杂1～5个选自N、O和S杂原子的C 2～C 10杂芳环；R为与C连接的R C或与N连接的R N。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。

Claims (30)

  1. 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，
    Figure PCTCN2017118004-appb-100001
    R'为H、CN、CH 2(OH)R 0、C mH 2m+1、C nH 2n-1、C nH 2n-3、
    Figure PCTCN2017118004-appb-100002
    Figure PCTCN2017118004-appb-100003
    其中W 0为O或NH；W 1为连接键、C(R 0) 2、C(R 0) 2O、C(R 0) 2OC(R 0) 2或C(R 0) 2OC(R 0) 2C(R 0) 2；当W为C、S或S(O)时，W 2为连接键、O、NR 0、CH(N(R 0) 2)或OCH 2C(O)；当W为P(OR 0)时，W 2为O或NR 0；各R 0独立地为H、C mH 2m+1、C mH 2m+1OC(O)、C mH 2m+1-rX r、C mH 2m+1OC(O)C mH 2m、(环状C 4H 8NO)C mH 2m、CH 3(OCH 2CH 2) u或者CH 3(OCH 2CH 2) uOCH 2；
    两R a独立地为H或两R a共同形成＝O、＝N-CN或＝N-W 3-R 1，W 3为O或NH，R 1为H、C mH 2m+1、C mH 2m+1C(O)、C mH 2m+1OC(O)或C mH 2m+1S(O) 1～2；
    A为未取代的或1～3个R取代的C 6～C 10芳环、或者为未取代的或1～3个R取代的杂1～5个选自N、O和S杂原子的C 2～C 10杂芳环或杂1～3个选自N、O和S杂原子的含有C＝N的4～7元非芳香杂环；
    Q为R，或者为未取代的或1～3个R取代的C 6～C 10芳环，或者为未取代的或1～3个R取代的杂1～5个优选1～3个更优选2～3选自N、O和S杂原子的3～10元优选4～7元更优选5～6元杂环优选杂芳环；
    R为与C连接的R C或与N连接的R N，其中各个R C独立地为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” 2或-Y-NR”S(O) 1～2R”；各个R N独立地为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” 2或-Y-NR”S(O) 1～2R”；
    R”为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 s或C nH 2n-3-tX t；
    Y为连接键、-C mH 2m-、-C nH 2n-2-、-C nH 2n-4-、-C mH 2m-iX i-、-C nH 2n-2-jX j-或-C nH 2n-4-kX k-；
    m＝1～8，n＝2～8，u＝1～5，r≤2m+1，s≤2n-1，t≤2n-3，i≤2m，j≤2n-2，k≤2n-4，X为卤素；优选地，m＝1～5更优选＝1～3，n＝2～6更优选＝2～4，u＝1～4更优选1～3，X为F、Cl 或Br。
  2. 如权利要求1所述的芳香烃受体调节剂，其特征在于，A为
    Figure PCTCN2017118004-appb-100004
    式(Ⅰ)变为式(Ⅰ1)，
    Figure PCTCN2017118004-appb-100005
    式(Ⅰ1)中，A 1、A 2和A 3三者之一为O、S或N(R)，其他二者分别独立地为C(R)或N。
  3. 如权利要求2所述的芳香烃受体调节剂，其特征在于，A 1、A 2和A 3三者之一为O、S或N(R)，其他二者分别独立地为N。
  4. 如权利要求3所述的芳香烃受体调节剂，其特征在于，A 3为N，式(Ⅰ1)变为式(Ⅰa)，
    Figure PCTCN2017118004-appb-100006
    式(Ⅰa)中，A 1为O、S或N(R)，A 2为N；或者A 2为O、S或N(R)，A 1为N。
  5. 如权利要求2所述的芳香烃受体调节剂，其特征在于，A 2为CH，式(Ⅰ1)变为式(Ⅰb)，
    Figure PCTCN2017118004-appb-100007
    式(Ⅰb)中，A 1为N或C(R)，A 3为O、S或N(R)；或者A 1为O、S或N(R)，A 3为N或C(R)。
  6. 如权利要求2所述的芳香烃受体调节剂，其特征在于，A 1为N，A 3为C(R)，两R a共同形成＝N-W 3-R 1，式(Ⅰ1)变为式(Ⅰc)，
    Figure PCTCN2017118004-appb-100008
    式(Ⅰc)中，A 2为O、S或N(R)。
  7. 如权利要求2所述的芳香烃受体调节剂，其特征在于，A 1为N，A 3为C(R)，两R a为H，式(Ⅰ1)变为式(Ⅰd)，
    Figure PCTCN2017118004-appb-100009
    式(Ⅰd)中，A 2为O、S或N(R)。
  8. 如权利要求2所述的芳香烃受体调节剂，其特征在于，A 1为N，A 3为C(R)，R'为
    Figure PCTCN2017118004-appb-100010
    式(Ⅰ1)变为式(Ⅰe)，
    Figure PCTCN2017118004-appb-100011
    式(Ⅰe)中A 2为O、S或N(R)。
  9. 如权利要求2所述的芳香烃受体调节剂，其特征在于，A 1为N，A 3为C(R)，R'为
    Figure PCTCN2017118004-appb-100012
    式(Ⅰ1)变为式(Ⅰf)，
    Figure PCTCN2017118004-appb-100013
    式(Ⅰf)中A 2为O、S或N(R)，各R 0独立地为H或Ac。
  10. 如权利要求1所述的芳香烃受体调节剂，其特征在于，Q为
    Figure PCTCN2017118004-appb-100014
    B 1、B 2、B 3和B 4四者之一为O、S或N(R)，其他三者分别独立地为C(R)或N；
    或者Q为
    Figure PCTCN2017118004-appb-100015
    B 5～B 9为C(R)；或者B 5～B 9之一或之二为N，其他的分别独立地为C(R)。
  11. 如权利要求2所述的芳香烃受体调节剂，其特征在于，A 1为N，A 2为S，A 3为 CH，Q为5元杂芳环，式(Ⅰ1)变为式(Ⅰg)
    Figure PCTCN2017118004-appb-100016
    其中，B 2、B 3或B 4之一为O、S或N(R)，其他的分别独立地为C(R)或N。
  12. 如权利要求2所述的芳香烃受体调节剂，其特征在于，A 1为N，A 2为S，A 3为CH，Q为含有C＝N的5元非芳香杂环，式(Ⅰ1)变为(Ⅰh)
    Figure PCTCN2017118004-appb-100017
    B 4为O、S或N(R)。
  13. 如权利要求1所述的芳香烃受体调节剂，其特征在于，A为杂有N和S的非芳香杂环，Q为R，式(Ⅰ)变为(Ⅰ2)，
    Figure PCTCN2017118004-appb-100018
  14. 如权利要求1所述的芳香烃受体调节剂，其特征在于，A为
    Figure PCTCN2017118004-appb-100019
    式(Ⅰ)变为式(Ⅰ3)，
    Figure PCTCN2017118004-appb-100020
    式(Ⅰ3)中，Z 1～Z 5分别独立地为C(Q)；或者，Z 1～Z 5之一或之二为N，其他的分别独立地为C(Q)；或者，Z 1～Z 5中相邻的两个为C(Q)一起共同形成5～6元碳环或杂1～3个选自N、O和S杂原子的5～6元杂环，其他三者分别独立地为C(Q)，或者其他三者之二分别独立地为C(Q)剩下一个为N，或者其他三者之一为C(Q)剩下两个为N。
  15. 如权利要求1所述的芳香烃受体调节剂，其特征在于，式(Ⅰ)中R'为下列取代基之一：
    Figure PCTCN2017118004-appb-100021
  16. 如权利要求3所述的芳香烃受体调节剂，其特征在于，式(Ⅰ1)中的
    Figure PCTCN2017118004-appb-100022
    为下列取代基之一：
    Figure PCTCN2017118004-appb-100023
    Figure PCTCN2017118004-appb-100024
  17. 如权利要求5所述的芳香烃受体调节剂，其特征在于，式(Ⅰb)中的
    Figure PCTCN2017118004-appb-100025
    为下列取代基之一：
    Figure PCTCN2017118004-appb-100026
  18. 如权利要求6～9任一项所述的芳香烃受体调节剂，其特征在于，式(Ⅰc)～(Ⅰf)中的
    Figure PCTCN2017118004-appb-100027
    为下列取代基之一：
    Figure PCTCN2017118004-appb-100028
  19. 如权利要求3或4所述的芳香烃受体调节剂，其特征在于，所述芳香烃受体调节剂为
    Figure PCTCN2017118004-appb-100029
    Figure PCTCN2017118004-appb-100030
  20. 如权利要求5所述的芳香烃受体调节剂，其特征在于，所述芳香烃受体调节剂为
    Figure PCTCN2017118004-appb-100031
  21. 如权利要求6所述的芳香烃受体调节剂，其特征在于，所述芳香烃受体调节剂为
    Figure PCTCN2017118004-appb-100032
  22. 如权利要求7所述的芳香烃受体调节剂，其特征在于，所述芳香烃受体调节剂为
    Figure PCTCN2017118004-appb-100033
  23. 如权利要求8所述的芳香烃受体调节剂，其特征在于，所述芳香烃受体调节剂为
    Figure PCTCN2017118004-appb-100034
  24. 如权利要求9所述的芳香烃受体调节剂，其特征在于，所述芳香烃受体调节剂为
    Figure PCTCN2017118004-appb-100035
  25. 如权利要求10所述的芳香烃受体调节剂，其特征在于，所述芳香烃受体调节剂为
    Figure PCTCN2017118004-appb-100036
  26. 如权利要求12所述的芳香烃受体调节剂，其特征在于，所述芳香烃受体调节剂为
    Figure PCTCN2017118004-appb-100037
  27. 如权利要求2所述的芳香烃受体调节剂，其特征在于，所述芳香烃受体调节剂为
    Figure PCTCN2017118004-appb-100038
  28. 如权利要求13所述的芳香烃受体调节剂，其特征在于，所述芳香烃受体调节剂为
    Figure PCTCN2017118004-appb-100039
  29. 如权利要求14所述的芳香烃受体调节剂，其特征在于，所述芳香烃受体调节剂为
    Figure PCTCN2017118004-appb-100040
  30. 权利要求1～14任一项所述的芳香烃受体调节剂在制备抗肿瘤药物中的应用。
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