WO2021000862A1 - Akr1c3抑制剂及医药用途 - Google Patents

Akr1c3抑制剂及医药用途 Download PDF

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WO2021000862A1
WO2021000862A1 PCT/CN2020/099353 CN2020099353W WO2021000862A1 WO 2021000862 A1 WO2021000862 A1 WO 2021000862A1 CN 2020099353 W CN2020099353 W CN 2020099353W WO 2021000862 A1 WO2021000862 A1 WO 2021000862A1
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substituted
membered
cancer
compound
group
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French (fr)
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段建新
李安蓉
孟繁英
蔡晓宏
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Ascentawits Pharmaceuticals Ltd
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Ascentawits Pharmaceuticals Ltd
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Priority claimed from CN201910585317.9A external-priority patent/CN112174865A/zh
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Priority to KR1020227002569A priority Critical patent/KR20220030256A/ko
Priority to CN202080001496.8A priority patent/CN112004799B/zh
Priority to US17/623,666 priority patent/US20220251021A1/en
Priority to CN202310332716.0A priority patent/CN116554071A/zh
Priority to JP2021577319A priority patent/JP2022538602A/ja
Priority to EP20834153.7A priority patent/EP3995480A4/en
Publication of WO2021000862A1 publication Critical patent/WO2021000862A1/zh
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/04—Nitro compounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/045—Hydroxy compounds, e.g. alcohols; Salts thereof, e.g. alcoholates
    • A61K31/05—Phenols
    • A61K31/06—Phenols the aromatic ring being substituted by nitro groups
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/66—Phosphorus compounds
    • A61K31/664—Amides of phosphorus acids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B55/00—Racemisation; Complete or partial inversion
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C205/00—Compounds containing nitro groups bound to a carbon skeleton
    • C07C205/27—Compounds containing nitro groups bound to a carbon skeleton the carbon skeleton being further substituted by etherified hydroxy groups
    • C07C205/35—Compounds containing nitro groups bound to a carbon skeleton the carbon skeleton being further substituted by etherified hydroxy groups having nitro groups and etherified hydroxy groups bound to carbon atoms of six-membered aromatic rings of the carbon skeleton
    • C07C205/36—Compounds containing nitro groups bound to a carbon skeleton the carbon skeleton being further substituted by etherified hydroxy groups having nitro groups and etherified hydroxy groups bound to carbon atoms of six-membered aromatic rings of the carbon skeleton to carbon atoms of the same non-condensed six-membered aromatic ring or to carbon atoms of six-membered aromatic rings being part of the same condensed ring system
    • C07C205/38—Compounds containing nitro groups bound to a carbon skeleton the carbon skeleton being further substituted by etherified hydroxy groups having nitro groups and etherified hydroxy groups bound to carbon atoms of six-membered aromatic rings of the carbon skeleton to carbon atoms of the same non-condensed six-membered aromatic ring or to carbon atoms of six-membered aromatic rings being part of the same condensed ring system the oxygen atom of at least one of the etherified hydroxy groups being further bound to a carbon atom of a six-membered aromatic ring, e.g. nitrodiphenyl ethers
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C33/00—Unsaturated compounds having hydroxy or O-metal groups bound to acyclic carbon atoms
    • C07C33/18—Monohydroxylic alcohols containing only six-membered aromatic rings as cyclic part
    • C07C33/20—Monohydroxylic alcohols containing only six-membered aromatic rings as cyclic part monocyclic
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
    • C07F9/02—Phosphorus compounds
    • C07F9/06—Phosphorus compounds without P—C bonds
    • C07F9/22—Amides of acids of phosphorus
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
    • C07F9/02—Phosphorus compounds
    • C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
    • C07F9/553—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having one nitrogen atom as the only ring hetero atom
    • C07F9/564—Three-membered rings

Definitions

  • the present invention relates to an AKR1C3 inhibitor and the medical use of the inhibitor.
  • the DNA alkylating agent cancer therapeutic compound prodrug developed by our company targeting the highly expressed aldehyde ketone reductase 1C3 (AKR1C3) (application number PCT/US2016/021581, publication number WO2016/145092; application number PCT/US2016/062114 , Publication No. WO2017/087428) specifically undergoes metabolic activation under the action of AKR1C3 in the body.
  • ARR1C3 application number PCT/US2016/021581, publication number WO2016/145092; application number PCT/US2016/062114 , Publication No. WO2017/087428
  • S configuration of TH-2870, AST-3424 as an example:
  • a DNA alkylating agent that targets the highly expressed aldehyde ketone reductase AKR1C3 will bind to AKR1C3 in the body, and then undergo a metabolic reaction, and finally produce a cytotoxic DNA alkylating agent.
  • the present invention provides the following technical solutions.
  • R 1 and R 2 are each independently hydrogen, deuterium, aryl or Z substituted aryl, heteroaryl or Z substituted heteroaryl, C 1 -C 6 alkyl or Z substituted alkyl, C 2 -C 6 alkenyl or Z substituted alkenyl, C 2 -C 6 alkynyl or Z substituted alkynyl, C 3 -C 8 cycloalkyl or Z substituted cycloalkyl;
  • R 3 is hydrogen, halogen, cyano or isocyano, hydroxyl, mercapto, amine, oxime, hydrazone, OTs, OMs, C 1 -C 6 alkyl or Z substituted alkyl, C 2 -C 6 alkene Group or Z-substituted alkenyl, C 2 -C 6 alkynyl or Z-substituted alkynyl, C 3 -C 8 cycloalkyl or Z-substituted cycloalkyl, C 6 -C 10 aryl or Z-substituted aryl, 4- 15-membered heterocycle or Z-substituted heterocycle, 5-15-membered heteroaryl or Z-substituted heteroaryl, C 1 -C 6 alkoxy or Z substituted C 1 -C 6 alkoxy or R 3 is -CONR 6 R 7 , -SO 2 NR 6 R 7 , -SO 2 R 6 ,
  • R 6 and R 7 are each independently hydrogen, cyano or isocyano, C 1 -C 6 alkyl or Z substituted alkyl, C 2 -C 6 alkenyl or Z substituted alkenyl, C 2 -C 6 alkyne Group or Z substituted alkynyl, C 3 -C 8 cycloalkyl or Z substituted cycloalkyl, C 6 -C 10 aryl or Z substituted aryl, 4-15 membered heterocycle or Z substituted heterocycle, 5-15 Member heteroaryl or Z-substituted heteroaryl, C 1 -C 6 alkoxy or Z-substituted C 1 -C 6 alkoxy, or R 6 and R 7 groups together with the atoms to which they are bonded form 3- 7-membered heterocyclic group or Z-substituted 3-7-membered heterocyclic group;
  • a 0, 1, 2, 3;
  • X is C, N;
  • R 3 can be located on different atoms of the benzene ring or pyridine ring, that is, there may be no R 3 group.
  • a is 0, that is, the benzene ring or the pyridine ring is hydrogen; it can be 1 R 3 groups, where a is 1, that is, the remaining 2 (in this case, pyridine ring) or 3 (in this case, benzene ring) hydrogen positions on the benzene ring or pyridine ring are replaced by 1 R 3 group ;
  • One R 3 group is substituted; it can be 3 R 3 groups, in which case a is 3, that is, the 3 hydrogen positions of the benzene ring are replaced by 3 R 3 groups.
  • Y is O or S
  • Cx is selected from C 6 -C 10 aryl or Z substituted aryl, 4-15 membered heterocycle or Z substituted 4-15 membered heterocycle, 5-15 membered heteroaryl or Z substituted heteroaryl, 7-15 -Membered fused ring or Z-substituted fused ring and -CONR 6 R 7 , -SO 2 NR 6 R 7 , -SO 2 R 6 , -OCOO-R 6 , -COOR 6 , -NR 6 COR 7 , -OCOR 6 , -NR 6 SO 2 R 7 , -NR 6 SO 2 NR 6 R 7 , -COR 6 , -NR 6 CONR 6 R 7 substituted C 6 -C 10 aryl, 4-15 membered heterocyclic ring, 5-15 membered Heteroaryl, 7-15 membered fused ring, and R 6 , R 7 and N may or may not form 4-8 membered Z-substituted heterocyclic
  • L is selected from -O-, -S-, -OCOO-, -NR 6 CO-, -OCO-, -NR 6 SO 2 -, -OCONR 6 -, quaternary ammonium group, sulfonate group -OSO 2 -;
  • Cy is selected from hydrogen, deuterium, C 6 -C 10 aryl or Z substituted aryl, 4-15 membered heterocycle or Z substituted heterocycle, 5-15 membered heteroaryl or Z substituted heteroaryl, 7-15 Membered fused ring or Z substituted fused ring, C 1 -C 6 alkyl or Z substituted alkyl, C 2 -C 6 alkenyl or Z substituted alkenyl, C 2 -C 6 alkynyl or Z substituted alkynyl, C 3- C 8 cycloalkyl or Z-substituted C 3 -C 8 cycloalkyl;
  • Cy is selected from The 5-10 membered ring group formed by two OR 6 and P atom, The 5-10 membered ring group formed by OR 6 and NR 6 R 7 and P atom, 5-10 membered ring group formed by two NR 6 R 7 and P atoms;
  • -L-Cy residues does not include those :-P the amine phosphates H atoms lose an alkylating agent (Z 1) (NR 9 CH 2 CH 2 X 1) 2, -P (Z 1) (NR 9 2 )(N(CH 2 CH 2 X 1 )2), -P(Z 1 )(N(CH 2 CH 2 X 1 )) 2 or -P(Z 1 )(N(CH 2 CH 2 X 1 ) 2 ) 2 , each R 9 is independently hydrogen or a C1-C6 alkyl group, or 2 R 9 and the nitrogen atom to which it is bound together form a 5- to 7-membered heterocyclic group, Z 1 is O or S, and X 1 is Cl, Br or OMs, -L-Cy does not include -OH and -SH;
  • the Z substituent is halogen, cyano or isocyano, hydroxyl, mercapto, amine, oxime, hydrazone, OTs, OMs, C 1 -C 3 alkyl or substituted alkyl, C 1 -C 3 alkoxy Or substituted alkoxy, C 2 -C 3 alkenyl or substituted alkenyl, C 2 -C 3 alkynyl or substituted alkynyl, C 3 -C 8 cycloalkyl or substituted cycloalkyl, aromatic ring, heterocycle, Heteroaromatic ring and fused ring or substituted aromatic ring, heterocyclic ring, heteroaromatic ring and fused ring, the mode of substitution is mono-substituted or gem-disubstituted;
  • the Cz group is a group containing C, P, S and the group can be hydrolyzed by a hydrolase to break the corresponding C-N, P-N, S-N bond.
  • R 1 and R 2 are each independently hydrogen, deuterium, aryl or Z substituted aryl, heteroaryl or Z substituted heteroaryl, C 1 -C 6 alkyl or Z substituted alkyl, C 2 -C 6 alkene Group or Z-substituted alkenyl, C 2 -C 6 alkynyl or Z-substituted alkynyl, C 3 -C 8 cycloalkyl or Z-substituted cycloalkyl;
  • R 3 is hydrogen, halogen, cyano or isocyano, hydroxyl, mercapto, amine, oxime, hydrazone, OTs, OMs, C 1 -C 6 alkyl or Z substituted alkyl, C 2 -C 6 alkene Group or Z-substituted alkenyl, C 2 -C 6 alkynyl or Z-substituted alkynyl, C 3 -C 8 cycloalkyl or Z-substituted cycloalkyl, C 6 -C 10 aryl or Z-substituted aryl, 4- 15-membered heterocycle or Z-substituted heterocycle, 5-15-membered heteroaryl or Z-substituted heteroaryl, C 1 -C 6 alkoxy or Z substituted C 1 -C 6 alkoxy or R 3 is -CONR 6 R 7 , -SO 2 NR 6 R 7 , -SO 2 R 6 ,
  • R 4 and R 5 are each independently hydrogen, halogen, cyano or isocyano, hydroxyl, mercapto, amine, oxime, hydrazone, OTs, OMs, C 1 -C 6 alkyl or Z substituted alkyl, C 2 -C 6 alkenyl or Z substituted alkenyl, C 2 -C 6 alkynyl or Z substituted alkynyl, C 3 -C 8 cycloalkyl or Z substituted cycloalkyl, C 6 -C 10 aryl or Z Substituted aryl, 4-15 membered heterocycle or Z substituted heterocycle, 5-15 membered heteroaryl or Z substituted heteroaryl, C 1 -C 6 alkoxy or Z substituted C 1 -C 6 alkoxy Or R 4 and R 5 are -CONR 6 R 7 , -SO 2 NR 6 R 7 , -SO 2 R 6 , -OCOO-R 6 , -COOR 6
  • R 6 and R 7 are each independently hydrogen, cyano or isocyano, C 1 -C 6 alkyl or Z substituted alkyl, C 2 -C 6 alkenyl or Z substituted alkenyl, C 2 -C 6 alkyne Group or Z substituted alkynyl, C 3 -C 8 cycloalkyl or Z substituted cycloalkyl, C 6 -C 10 aryl or Z substituted aryl, 4-15 membered heterocycle or Z substituted heterocycle, 5-15 Member heteroaryl or Z-substituted heteroaryl, C 1 -C 6 alkoxy or Z-substituted C 1 -C 6 alkoxy, or R 6 and R 7 groups together with the atoms to which they are bonded form 3- 7-membered heterocyclic group or Z-substituted 3-7-membered heterocyclic group;
  • Y is O or S
  • Cx is selected from C 6 -C 10 aryl or Z substituted aryl, 4-15 membered heterocycle or Z substituted 4-15 membered heterocycle, 5-15 membered heteroaryl or Z substituted heteroaryl, 7-15 -Membered fused ring or Z-substituted fused ring and -CONR 6 R 7 , -SO 2 NR 6 R 7 , -SO 2 R 6 , -OCOO-R 6 , -COOR 6 , -NR 6 COR 7 , -OCOR 6 , -NR 6 SO 2 R 7 , -NR 6 SO 2 NR 6 R 7 , -COR 6 , -NR 6 CONR 7 substituted C 6 -C 10 aryl, 4-15 membered heterocyclic ring, 5-15 membered heteroaromatic Group, a 7-15 membered fused ring, and R 6 , R 7 and N may or may not form a 4-8 membered Z-substituted hetero
  • L is selected from -O-, -S-, -OCOO-, -NR 6 CO-, -OCO-, -NR 6 SO 2 -, -OCONR 6 -, quaternary ammonium group, sulfonate group -OSO 2 -;
  • Cy is selected from hydrogen, deuterium, C 6 -C 10 aryl or Z substituted aryl, 4-15 membered heterocycle or Z substituted heterocycle, 5-15 membered heteroaryl or Z substituted heteroaryl, 7-15 Membered fused ring or Z substituted fused ring, C 1 -C 6 alkyl or Z substituted alkyl, C 2 -C 6 alkenyl or Z substituted alkenyl, C 2 -C 6 alkynyl or Z substituted alkynyl, C 3- C 8 cycloalkyl or Z-substituted C 3 -C 8 cycloalkyl;
  • Cy is selected from The 5-10 membered ring group formed by two OR 6 and P atom, The 5-10 membered ring group formed by OR 6 and NR 6 R 7 and P atom, 5-10 membered ring group formed by two NR 6 R 7 and P atoms;
  • the Z substituent is halogen, cyano or isocyano, hydroxyl, mercapto, amine, oxime, hydrazone, OTs, OMs, C 1 -C 3 alkyl or substituted alkyl, C 1 -C 3 alkoxy Or substituted alkoxy, C 2 -C 3 alkenyl or substituted alkenyl, C 2 -C 3 alkynyl or substituted alkynyl, C 3 -C 8 cycloalkyl or substituted cycloalkyl, aromatic ring, heterocycle, Heteroaromatic ring and fused ring or substituted aromatic ring, heterocyclic ring, heteroaromatic ring and fused ring, the mode of substitution is mono-substituted or gem-disubstituted;
  • the Cz group is a group containing C, P, S and the group can be hydrolyzed by hydrolase to break the corresponding CN, PN, SN bond, that is, Cz is an amino acid residue (-NH-Cz forms an amino acid peptide bond) , Organic carboxylic acid residue (-NH-Cz forms an amide structure), etc.
  • Hydrolase is classified as EC3 in the EC number, and subdivided into several sub-categories based on the bonds it breaks down:
  • hydrolases can hydrolyze and break many chemical bonds, especially the compounds disclosed in the present invention containing C, P, S Groups of atoms, especially these chemical bonds and hydrolases include EC3.4: peptide bond (peptidase), EC3.9: PN bond, EC3.10: SN bond, and the corresponding compounds include amides and phosphoramides , Thioamides.
  • Heterocycles and heteroaryl groups include three-membered, four-membered, five-membered, six-membered, and seven-membered rings. The following is an example.
  • Three-membered ring ethylene oxide, azathione, ethylene sulfide;
  • pyrrolidine pyrroline, 1-pyrroline, 3-pyrroline, 2-pyrroline, pyrrole, pyrazoline, 2-pyrazoline, imidazole, pyrazole, furan, THF, dihydrofuran, Tetrahydrothiophene, thiophene, sulfolane, phosphazene, oxazole, 1,2,3-triazole, 1,2,4-triazole, 1,3,4-thiadiazole;
  • Condensed ring is defined as the combination of the above heterocycles and heteroaryl groups or the combination with the cycloalkane structure.
  • the combination can be linked by a single bond or share one, two or even three atoms, as follows Give some common fused ring structures: naphthalene, quinoline, indole, isoindole, isoquinoline, quinoline, quinoxaline, biphenyl, coumarin, fluorene, dibenzocarban, carbazole, anthracene , Azaanthrene, Thiophenazine, Adamantane, Zulene, Phenanthrene, Anthraquinone, Flavonoids, Isoflavones.
  • the above compounds also include isotopically substituted compounds.
  • the typical substitution method is that the hydrogen atom H is replaced by the heavy hydrogen atom deuterium D.
  • the salt is a basic salt or an acid salt.
  • the compounds also include structural salts of formula I-1 to I-5 for use, that is, the present invention provides pharmaceutically acceptable salts of the compounds shown, and the salts may be basic salts, including
  • the compound is a salt formed with an inorganic base (for example, alkali metal hydroxide, alkaline earth metal hydroxide, etc.) or an organic base (for example, monoethanolamine, diethanolamine, or triethanolamine, etc.).
  • the salt may be an acid salt, including the compound and an inorganic acid (such as hydrochloric acid, hydrobromic acid, hydroiodic acid, nitric acid, perchloric acid, sulfuric acid or phosphoric acid, etc.) or an organic acid (such as methanesulfonic acid). , Trifluoromethanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, fumaric acid, oxalic acid, maleic acid, citric acid, etc.).
  • an inorganic acid such as hydrochloric acid, hydrobromic acid, hydroiodic acid, nitric acid, perchloric acid, sulfuric acid or phosphoric acid, etc.
  • organic acid such as methanesulfonic acid
  • the solvate is a hydrate or alcoholate.
  • the compound described herein can also be used in the form of a solvate, that is, the present invention provides a pharmaceutically acceptable solvate of the compound I shown, and the solvate is a hydrate, alcoholate, etc., alcoholate includes Ethanol hydrate.
  • CH-01 is a Hypoxia-Activated Prodrug That Sensitizes Cells to Hypoxia/Reoxygenation Through Inhibition of Chk1and Aurora A[J].
  • R 1 and R 2 are each independently hydrogen, deuterium, C 1 -C 6 alkyl or Z substituted alkyl, C 2 -C 6 alkenyl or Z substituted alkene
  • R 1 and R 2 are each independently hydrogen, deuterium, or methyl.
  • R 3 , R 4 , and R 5 are each independently hydrogen.
  • Cx is a phenyl group substituted by -CONR 6 R 7 , and R 6 , R 7 and N may or may not form a 4-8 membered Z-substituted heterocyclic ring.
  • L is selected from -O- and -S-.
  • Cy is selected from C 6 -C 10 aryl or halogen substituted aryl, 4-15 membered heterocycle or halogen substituted heterocycle, 5-15 membered heteroaryl or halogen substituted heteroaryl, 7- 15-membered fused ring or halogen substituted fused ring.
  • Cy is selected from fluorophenyl, difluorophenyl, and trifluorophenyl.
  • Cz in the prodrug I-5 at this time is -COR 6 and -COOR 6 .
  • the salt is a basic salt or an acid salt
  • the solvate is a hydrate or alcoholate
  • Aldehyde ketone reductase family 1 member C3 (AKR1C3, also known as type 5 17- ⁇ -hydroxysteroid dehydrogenase (17- ⁇ -HSD5)) is an enzyme of aldehyde/keto reductase (AKR) super A member of the family, which reduces the aldehyde/ketone group in steroid hormones to the corresponding alcohol, and therefore plays an important role in the metabolism/activation/deactivation of androgens, progesterone, estrogen, and prostaglandins.
  • a member of the family which reduces the aldehyde/ketone group in steroid hormones to the corresponding alcohol, and therefore plays an important role in the metabolism/activation/deactivation of androgens, progesterone, estrogen, and prostaglandins.
  • AKR1C3 has 3 ⁇ -HSD (hydroxysteroid dehydrogenase activity), 17 ⁇ -HSD, 20 ⁇ -HSD and prostaglandin (PG) F synthase activity. It catalyzes the conversion of estrone (weak estrogen activity) to estradiol (strong estrogen activity), the conversion of progesterone (strong antiestrogenic activity) to 20- ⁇ -hydroxyprogesterone (weak antiestrogenic activity) and Conversion of androstenedione to testosterone (Labrie F, Luu-T he V, Labrie C, et al. DHEA and Its Transformation into Androgens and Estrogens in Periphera Target Tissues: Intracrinology [J].
  • AKR1C3 catalyzes the conversion of PGH2 to PGF2 ⁇ and PGD2 to 11 ⁇ -PGF2, both of which are known to stimulate inflammation and proliferation.
  • AKR1C3 has also been shown to metabolize a wide range of carbonyl compounds and xenobiotics (including anthracycline administered clinically) (Bains O S, Grigliatti T A, Reid R E, et al. Naturally occurring variants of human aldo-keto reductases with reduced in vitro metabolism of daunorubicin and doxorubicin.[J].Journal of Pharmacology&Experimental Therapeutics, 2010,335(3):533-545.DOI: 10.1124/jpet.110.173179, Novotna G, et al.
  • aldo-keto reductase (AKR) 1C3[J].Toxicology Letters, 2008, 181(1):1-6.DOI:10.1016/j.toxlet.2008.06 .858; Hofman J, Malcekova B, Skarka A, et al. Anthracycline resistance mediated by reductive metabolism in cancer cells: The role of aldo-keto reductase 1 C3[J].Toxicology and 3), Applied, 2014, 278 :238-248. DOI: 10.1016/j.taap.2014.04.027).
  • AKR1C3 is closely related to endometriosis. AKR1C3 plays a role in several pathological conditions/diseases, including endometriosis.
  • Endometriosis is a chronic inflammatory disease dependent mainly on estrogen, which is characterized by the presence of endometrial tissue outside the uterine cavity.
  • the main symptoms of endometriosis are chronic pelvic pain and low fertility.
  • Estrogen (E2) deficiency is a clinically proven concept and basic mechanism of action for the pharmacological treatment of endometriosis.
  • E2 deficiency is a clinically proven concept and basic mechanism of action for the pharmacological treatment of endometriosis.
  • E2 deficiency is a clinically proven concept and basic mechanism of action for the pharmacological treatment of endometriosis.
  • In addition to the systemic estrogen content there are more and more signs of locally derived estrogen promoting the development of endometriosis.
  • the high tissue estrogen concentration in endometriotic lesions has recently been described, which indicates high local estrogen synthesis in endometriosis (Huhtinen K, Desai R, Stahlee M, e
  • Endomet rial and Endometriotic Concentrations of Estrone and Estradiol are Determined by Local Metaboli sm Rather than Circulating Levels[J].
  • AKR1C3 is largely manifested in endometriotic lesions and is only slightly detectable in the ovaries (Tina Hevir N, Martina et al. Disturbed estrogen and progesterone action in ovarian endometriosis [J].
  • AKR1C3 is expected to become a key enzyme for local E2 production in endometriotic lesions, thereby generating an estrogen environment, thereby stimulating endometriotic cells that are sensitive to estrogen The proliferation. Inhibition of AKR1C3 should therefore reduce the E2 content in local tissues and thereby reduce the proliferation of endometriotic lesions.
  • ovarian estrogen production is not expected because AKR1C3 is only slightly expressed in the ovary, and 17 ⁇ HSD1 is a dominant ovarian hydroxysteroid dehydrogenase.
  • AKR1C3 is also a PGF2 ⁇ synthetase, and in addition to the up-regulation of AKR1C3, it has been shown that the content of PGF2 ⁇ in women with peritoneal endometriosis and ectopic endometriosis is more effective than those of ectopic endometrium.
  • Significantly higher Sinreih, Anko M, Kene NH, et al. Expression of AKR1B1, AKR1C3 and other genes of prostaglandin F2 ⁇ biosynthesis and action in ovarian endometriosis tissue and in model cell lines[J].Chemico-Biological Interactions, 2015, 234(5-6) :320-331.
  • PGF2 ⁇ in endometriotic tissue is expected to cause inflammation, pain and hyperplasia in patients with endometriosis
  • AKR1C3 which is expected to manifest in endometriotic lesions, is expected to cause high local PGF2 ⁇ content in endometriotic tissue .
  • AK R1C3 inhibition has the potential to alleviate the proliferation, pain and inflammation of patients with endometriosis by locally reducing the content of E2, testosterone and PGF2 ⁇ in endometriosis tissue.
  • AKR1C3 is closely related to polycystic ovary syndrome (PCOS). AKR1C3 plays a role in several pathological conditions/diseases, including polycystic ovary syndrome (PCOS).
  • PCOS polycystic ovary syndrome
  • PCOS is a common endocrine disorder that affects up to 10% of women of reproductive age. It is clinically associated with an egg-free infertility, dysfunctional bleeding, androgen overdose, hyperinsulinemia and insulin resistance, obesity and metabolic syndrome (Fang Y. In sulin resistance and the polycystic ovary syndrome:Mechanism) and implications for pathogenesis[J]. Endocrine Reviews, 1998, 18(6):774-800.DOI: 10.1210/edrv.18.6.0318).
  • PCOS cardiovascular disease 2019
  • abnormal ovulation and menstrual function abnormal ovulation and menstrual function
  • biochemical hyperandrogenemia for example, acne, hirsutism
  • clinical hyperandrogenism for example, acne, hirsutism
  • polycystic ovary Symptoms Azziz R, Carmina E, Dewailly D, Diamanti-Kandarakis E, Escobar-Morreale HF, Futterweit W, et al.Position stateme nt:criteria for defining polycystic ovary syndrome as a predominogeniclyhyperandrome ].
  • Hyperandrogenism, hirsutism and/or hyperandrogenism are the key components of this syndrome, and must be used to diagnose PCOS (Azziz R, Carmina E, Dew aid D, Diamanti-Kandarakis E, Escobar-Morreale HF, Futterweit W, et al. Position statement: criteria for defining polycystic ovary syndrome as a predominantly hyperandrogenic syndrome: an Androgen Excess Society. [J]. Clin Endocrinol Metab 2006/s 2003: 4237-43. ).
  • AKR1C3 is an androgen activating enzyme, which is known to convert androstenedione to testosterone.
  • AKR1C3 in the adipose tissue of PCOS patients has been described, which indicates that ARK1C3 in the fat significantly promotes the androgen formation of androstenedione in PCOS patients. It has also been shown that the expression of AKR1C3 in adipocytes is significantly increased by insulin, which indicates that higher insulin in PCOS can promote the formation of fat androgen by increasing the activity of AKR1C3 in the subcutaneous adipose tissue of women (O"Reilly M, Gathercole L, Capper F, et al.
  • AKR1C3 is also a PGF2 ⁇ synthetase, and plays a role in the formation of endogenous ligands for the peroxisome proliferator-activated receptor gamma (PPARgamma) Inhibitory effect, the peroxisome proliferation activation receptor ⁇ is the target of insulin sensitizing drugs (Spiegelman et.al, Diabetes 1998, 47:507-514. DOI:10.2337/diabetes.47.4.507).
  • Selective AKR1 C3 inhibition can provide novel therapeutic targets to reduce androgen burden and improve the metabolic phenotype in PCOS (O"Reilly M, Gathe rcole L, Capper F, et al.
  • AKR1C3 is closely related to cancer. AKR1C3 acts on several pathological conditions/diseases, including cancer.
  • AKR1C3 is overrepresented in a large number of cancers, such as prostate cancer, breast cancer, uterine cancer, blood cancer, lung cancer, brain cancer and kidney cancer such as the following: endometrial cancer (Rizner TL, Smuc T, Rupreht R, Sinkovec J, PenningTM AKR1C1and AKR1C3may determine progesterone and estrogen ratios in endometrial cancer.
  • endometrial cancer Rosner TL, Smuc T, Rupreht R, Sinkovec J, PenningTM AKR1C1and AKR1C3may determine progesterone and estrogen ratios in endometrial cancer.
  • AKR1C3 contrib utes to 7, 12-dimethylbenz(a)anthracene-3, 4-dihydrodiol mediated oxidative DNA damage in m yeloid cells: Implications for leukemogenesis[J]. Mutation Research, 2009, 662(1-2): 67-74. DOI: 10.1016/j.mrfmmm.2008.12.010), renal cell carcinoma (Azzarello J T, Lin H K, Gherezghiher A, et al. E xpression of AKR1C3 in renal cell carcinoma, papillary urothelial carcinoma, and Wilms' tumor[J].
  • aldo-keto reductase AK R1C3 contributes to 7,12-dimethylbenz(a) anthracene-3,4-dihydrodiol mediated oxidative DNA damage in myeloid cells: Implications for leukemogenesis[J].Mutation Research, 2009,662(1-2):67-74.DOI:10.1016/j.mrfmmm.2008.12.010; Miller et.al, Aldo-keto reductase family 1 member C3(AKR1C3) is expressed in adenocarcinoma and squamous cellcarcinoma but not small cellcarcinoma.[J].Int.J.Clin.Exp.Path.2012, 5:278- 289.PMID:22670171).
  • AKR1C3 can directly reduce estrone and progesterone to 17 ⁇ -estradiol and 20 ⁇ -hydroxyprogesterone respectively, thereby enhancing this pro-proliferative signal (Smuc, Rizner, Expression of 17 ⁇ -hydroxysteroid dehydrogenases and other estrogen-metabolizing enzymes) in different ca ncer cell lines[J].Chem Biol Interact.2009,178:228-33.DOI:10.1016/j.cbi.2008.10.038).
  • prostaglandin F synthase activity of AKR1C3 catalyzes the conversion of PGH2 to PGF2 ⁇ and PGD2 to 11 ⁇ -PGF2 ⁇ , both of which are known to stimulate inflammation and hyperplasia.
  • PGD2 alternatively converted to PGF2
  • AKR1C3 increases proliferative PGF2 isoforms and reduces anti-proliferative PGJ2 products, and therefore AKR1C3 has the possibility of affecting both hormone-dependent and hormone-independent cancers.
  • PSGFR prostaglandin F2 ⁇
  • AKR1C3 can produce the prostaglandin F2 ⁇ (PTGFR) ligand (YodaTet.al, 11 ⁇ -Prostaglandin F2 ⁇ , a bioactive metabolite catalyst by AKR1C3, stimulates and prostaglandin Freceptor induces slug expression in breast cancer[J].Mol Cell Endocrinol.15;413:236-247.DOI:10.1016/j.mce.2015.07.008).
  • AKR1C3 acts on several pathological conditions/diseases, especially prostate cancer.
  • the high level of AKR1C3 has been associated with the worsening and aggressiveness of prostate cancer (Stanbrough M et.al, Increased expression of genes converting in androgen-independent prostate cancer [J]. Cancer Res 2006, 66: 2815-25.
  • AKR1C3 converts androstenedione to testosterone, which in turn overactivates androgen receptors and promotes tumor growth (Penning T M, Steckelbroeck S, Bauman D R, et al. Aldo-keto reductase ( AKR)1C3: role in prostate disease and the development of specific inhibitors.[J].Molecular&Cellular Endocrinology, 2006,248(1):182-191.DOI:10.1016/j.mce.2005.12.009).
  • intratumoral androgen biosynthesis involves AKR1C3, which promotes the weak androgen androstenedione (A'diketone) to the more active androgens testosterone and 5 ⁇ -androgen, respectively.
  • Conversion of sterandione (5 ⁇ -diketone) to DHT Liu C, Lou W, Zhu Y, et al. Intracrine Androgens and AKR1C3 Activation Confer Resistance to Enzalutamide in Prostate Cancer[J].
  • AKR1C3-dependent androgen re-synthesis is a potential resistance mechanism to CYP17A1 inhibitors such as abiraterone (Mostaghel et.al, Clin Cancer Res 2011, 17:5913-5925.DOI:10.1158/ 1078-0432.CCR-11-0728; Cai et.al, Cancer Res 2011, 71:6503-6513.DOI:10.1158/0008-5472.CAN-11-0532). Therefore, AKR1C3 may be a promising therapeutic target in advance for patients with CRPC (Adeniji et.al, J Steroid Biochem Mol Biol 2013, 137:136-149. DOI: 10.1021/jm3017656).
  • AKR1C3 inhibitors were tested in patients with metastatic anti-castration prostate cancer.
  • the new androgen biosynthesis inhibitors did not show signs of clinical activity (Loriot et.al, Invest New Drugs 2014, 32:995-1004. DOI: 10.1007/s10637-014-0101-x).
  • the latest data indicate that the activation of AKR1C3 in CRPC is an important drug resistance mechanism associated with antiandrogen (enzalutamide) resistance.
  • androgen precursors such as cholesterol, DHEA, and progesterone
  • androgens can exhibit a high level of upregulation in enzalutamide-resistant prostate cancer cells.
  • AKR1C3 inhibitory pathway can act as enzalutamide sensitization treatment and has a restorative effect on patients with anti-enzalutamide CRPC (Liu C, Lou W, Zhu Y, et al. Intracrine Androgens and AKR1C3 Activation Confer Resistance to Enzalutamide in Prostate Cancer[J].Canc er Research, 2015, 75(7):1413-1422.DOI:10.1158/0008-5472.can-14-3080). It is assumed that co-treatment with AKR1C3 inhibitors will resolve enzalutamide resistance and improve the survival of patients with advanced prostate cancer (Thoma et.al, Nature Reviews Urology 2015, 12:124. DOI:10.1038/nrurol.2015.23).
  • AKR1C3 plays a role in several pathological conditions/diseases, especially including anthracycline-resistant cancer.
  • Anthracyclines or anthracycline antibiotics are a class of drugs used in cancer chemotherapy and are derived from the Streptomyces bacterium Streptomyces bacterium Streptomyces peucetius var. Caesius, Critical Revi ews in Biotechnology, 1985, 3(2): 133. DOI: 10.3109/07388558509150782). These compounds are used to treat many cancers, including leukemia, lymphoma, breast cancer, gastric cancer, uterine cancer, ovarian cancer, bladder cancer and lung cancer.
  • Anthracyclines are the most effective anti-cancer treatments ever developed. However, the clinical results of anthracyclines used in cancer treatment are weakened by drug resistance. It has become more and more generally recognized that the higher enzymatic reduction of anthracyclines to its weaker C13-hydroxy secondary metabolites constitutes one of the mechanisms that cause tumor-induced anthracycline resistance (Gavelova et.al. , 2008 Chem. Biol. Interact 176, 9-18. DOI: 10.1016/j.cbi.2008.07.011; Heibein et.al, 2012 BMC Cancer 12, 381. DOI: 10.1186/1471-2407-12-381).
  • AKR1C3 is involved in the metabolism of clinically administered anthracyclines such as doxorubicin and daunorubicin (Novotna et.al, Toxicol. Letter 2008, 181:1-6. DOI: 10.1016/j.toxlet.2008.06.858).
  • Asian breast cancer patients have demonstrated the correlation between the pharmacodynamics of doxorubicin and genetic variants of AKR1C3: a genetic variant is associated with longer progression-free survival and overall survival after doxorubicin-based therapy This indicates the potential interaction with doxorubicin metabolism (Voon et.al, British J of Cli n Pharmacology 2012, 75:1497-1505. DOI:10.1111/bcp.12021). Recently, it has been confirmed that AKR1C3 promotes the resistance of cancer cells to anthracycline therapy, and therefore, the concomitant administration of specific AKR1C3 inhibitors with anthracyclines can be used to successfully prevent and treat anti-anthracycline resistance. Effective strategies for tumors (Hofman et.al, Toxicology and Applied Pharmacology 2014, 278:238-248.DOI:10.1016/j.taap.2014.04.027).
  • AKR1C3 plays a key role in radiotherapy resistance to esophageal cancer, prostate cancer and non-small cell lung cancer (Sun et al Overexpression of AKR1C3 significantly enhances human prostate cancer cells resistance to ra diation. Oncotarget. 2016 Jul 26; 7 (30):48050-48058.DOI:10.18632/oncotarget.10347; Xiong et al.; E levated Expression of AKR1C3 Increases Resistance of Cancer Cells to Ionizing Radiation via Modul ation of Oxidative Stress.PLoS ONE 2014 9(11):e111911 .DOI:10.1371/journal.pone.0111911).
  • AKR1C3 The anti-radioactive effect of AKR1C3 in prostate cancer cells was studied using the prostate cell line DU145 and its corresponding cell line (AKR1C3-over) which stably expresses AKR1C3.
  • Indomethacin is a specific inhibitor of AKR1C3 activity, which can significantly enhance the sensitivity of prostate cells to radiotherapy.
  • PGF2 ⁇ can not only promote the proliferation of prostate cancer cells, but also enhance the resistance of prostate cancer cells to radiation.
  • the accumulation of PGF2 ⁇ in AKR1C3-over cells leads to the activation of MAPK pathway and inhibits the expression of PPAR ⁇ .
  • AKR1C3 can cause radiation resistance in NSCL (Xie et al; Aldo-keto reductase 1C3 may be a new radioresistance marker in non-small-cell lung cancer. Cancer Gene Ther. 2013 Apr; 20(4):260 -6.DOI:10.1038/cgt.2013.15).
  • AKR1C3 mRNA and protein levels were significantly up-regulated.
  • the AKR1C3 protein levels in A549/R and SPCA1/R were 6.2 times and 3.5 times higher than those in sensitive control cells, respectively.
  • the above studies have shown that reducing the expression of AKR1C3 can effectively increase the sensitivity of NSCLC cells to radiotherapy.
  • AKR1C3 The expression of AKR1C3 was significantly up-regulated in anti-immunotherapy patients. It has been reported in the literature that among 13 patients with renal cell carcinoma who received anti-PD-1 therapy, there were 4 responders (R) and 9 non-responders (NR); genome-wide analysis showed that 234 genes were in R and NR There are significant differences in expression. One of the significantly different genes is that the expression of AKR1C3 is significantly increased in non-responders (Ascierto 2015 The intratumoral balance between metabolic and immunological gene expression is associated with anti-PD-1 response in patients with renal cell cancerRecersImmunol4726 -733, doi: 10.1158/2326-6066. CIR-16-0072.)
  • AKR1C3 specific inhibitors and chemotherapy drugs such as daunorubicin or cytarabine can greatly increase the killing ability of blood cancer cells (Verma et al, Potent and Highly Selective Aldo-Keto Reductase 1C3 (AKR1C3) Inhibitors Act as Chemotherapeutic Potentiators in Leukemia and T-Cell Acute Lymph oblastic Leukemia.J.Med.Chem.2019, 62, 7: 3590-3616, DOI: 10.1021/acs.jmedchem.9b00090).
  • AKR1C3 acts on several pathological conditions/diseases, and these pathological conditions/diseases particularly include atopic dermatitis.
  • the antigen's attack on atopic individuals causes the release of PGD2 and histamine, which shows that PGD2 hardly promotes the real-time allergic reaction of human skin and PGD2 is a lipid mediator that promotes skin inflammation in atopic dermatitis (AD) (Barr et.al, Br J Pharmacol.1988,94:773-80.PMID:2460180; Satoh et.al,J Immunol.2006,177:2621-9.DOI:10.4049/jimmunol.177.4.2621; Shimuraet.al , Am J Pathol.
  • PGD2 is a relatively unstable pro-inflammatory mediator, which spontaneously transforms into a strong anti-inflammatory mediator 15d-PGJ2. This transformation is transferred by the metabolism of PGD2 through AKR1C3 to pro-inflammatory 9 ⁇ , 11 ⁇ -PGF2 (Mantel et.al, Exp Dermatol. 2016, 25(1): 38-43. DOI:10.1111/exd.12854).
  • AKR1C3 is up-regulated in human AD samples, and it has been assumed that AKR1C3 plays a role in regulating inflammation in skin pathology (especially atopic dermatitis) and keloids (Mantel et.al, J Invest Dermatol 2012, 132 ( 4):1103-1110.DOI:10.1038/jid.2011.412;Mantel et.al,Exp Dermatol.2016,25(1):38-43.DOI:10.1111/exd.12854). AKR1C3 inhibition may be a novel option for the treatment of AD and keloids.
  • AKR1C3 plays a role in several pathological conditions/diseases, and these pathological conditions/diseases particularly include inflammation.
  • Prostaglandin biosynthesis involves AKR1C3, which catalyzes the conversion of PGH2 to PGF2 ⁇ and PGD2 to 11 ⁇ -PGF2. It has been assumed that the performance and up-regulation of AKR1C3 supports inflammation by directly causing the increase in the synthesis rate of 9 ⁇ , 11 ⁇ -PGF2 and the spontaneous production of the powerful anti-inflammatory mediator 15d-PGJ2 (Mantel et.al, J Invest Dermatol 2012, 132 (4):1103-1110.DOI:10.1038/jid.2011.412).
  • AKR1C3 AKR1C3
  • 15d-PGJ2 anti-inflammatory lipid
  • AKR1C3 acts on several pathological conditions/diseases, and these pathological conditions/diseases include other diseases.
  • AKR1C3 inhibitors have the potential to treat the following: benign prostatic hyperplasia (Roberts et.al, Prostate 2006, 66(4), 392-404.DOI: 10.1002/pros.20362), alopecia (L. Colombe et.al) , Exp Dermatol 2007, 16(9), 762-769.
  • DOI:10.1111/j.1600-0625.2007.00639.x DOI:10.1111/j.1600-0625.2007.00639.x
  • obesity PASvensson et.al, Cell Mol Biol Lett 2008, 13(4), 599 -613.DOI: 10.2478/s11658-008-0025-6
  • premature sexual maturity C.He, Hum Genet 2010, 128(5), 515-527.
  • chronic obstructive pulmonary disease S. Pierrou, Am J Respir Crit Care 2007, 175(6), 577-586. DOI:10.1164/rccm.200607-931OC).
  • the compound of the present invention has the effect of inhibiting the activity of AKR1C3, and therefore can be used to treat or prevent AKR1C3 related disorders, such as gynecological disorders (specifically, endometriosis-related and polycystic ovarian syndrome-related gynecological disorders), pathologies And diseases, metabolic disorders, hyperproliferative disorders, conditions and diseases, and inflammatory disorders and other related diseases or disorders.
  • gynecological disorders specifically, endometriosis-related and polycystic ovarian syndrome-related gynecological disorders
  • pathologies And diseases such as metabolic disorders, hyperproliferative disorders, conditions and diseases, and inflammatory disorders and other related diseases or disorders.
  • Drugs containing the above-mentioned compounds and their pharmaceutically acceptable salts or solvates or isotopically substituted compounds are included in the above-mentioned compounds.
  • the drugs are drugs for preventing or treating diseases related to AKR1C3 inhibitors.
  • the medicine is used to prevent or treat diseases/disorders
  • diseases/disorders include endometriosis, uterine leiomyoma, uterine bleeding disorders, dysmenorrhea, prostate hyperplasia, acne, seborrhea, hair loss, Premature sexual maturation, polycystic ovary syndrome, chronic obstructive pulmonary disease COPD, obesity, inflammatory pain or cancer or inflammation or cancer pain.
  • the cancer includes prostate cancer, primary prostate cancer, advanced prostate cancer, metastatic prostate cancer, hormone-primary prostate cancer, refractory prostate cancer or castration-resistant prostate cancer CRPC and breast cancer, lung cancer, uterus Endometrial cancer, renal cell carcinoma, bladder cancer, non-Hodgkin's lymphoma and acute myeloid leukemia AML, T-cell acute lymphoblastic leukemia T-ALL, leukemia.
  • a drug for enhancing the sensitivity of cancer or tumor radiotherapy the drug containing the above-mentioned compound and its pharmaceutically acceptable salt or solvate or isotope substituted compound, which is used for: treating cancer or tumor patients Improve the efficacy of radiotherapy when radiotherapy is resistant; or treat cancer or tumor patients who are resistant to radiotherapy.
  • a drug for enhancing the sensitivity of cancer or tumor immunotherapy the drug containing the above-mentioned compound and its pharmaceutically acceptable salt or solvate or isotope substituted compound, which is used for: treating cancer or tumor patients Improve the efficacy of immunotherapy when immunotherapy is resistant; or treat cancer or tumor patients who are resistant to immunotherapy.
  • a medicine for enhancing the sensitivity of cancer or tumor chemotherapy which contains the above-mentioned compound and its pharmaceutically acceptable salt or solvate or isotope substituted compound, which is used for: Improve the efficacy of chemotherapy when it is resistant; or treat cancer or tumor patients who are resistant to chemotherapy.
  • the pharmaceutical use of the above-mentioned compound and its pharmaceutically acceptable salt or solvate or isotope substituted compound is also provided, which is used to improve the efficacy of immunotherapy when cancer or tumor patients are resistant to immunity; or the pharmaceutical use For the treatment of cancer or tumor patients who are resistant to immunotherapy.
  • a medicine for enhancing the sensitivity of cancer or tumor chemotherapy which contains the above-mentioned compound and its pharmaceutically acceptable salt or solvate or isotope substituted compound, which is used for: When it is resistant, the curative effect of chemotherapy is improved; or for the treatment of cancer or tumor patients resistant to chemotherapy, the medicine used in the chemotherapy contains daunorubicin or cytarabine.
  • the pharmaceutical application of the above-mentioned compound and its pharmaceutically acceptable salt or solvate or isotope substituted compound is also provided, which is an AKR1C3 enzyme inhibitor.
  • the pharmaceutical use of the above-mentioned compound and its pharmaceutically acceptable salt or solvate or isotope substituted compound is also provided, which is used to improve the therapeutic effect of radiotherapy when cancer or tumor patients are resistant to radiotherapy; or It is used to treat cancer or tumor patients who are resistant to radiation therapy.
  • the pharmaceutical use of the above-mentioned compound and its pharmaceutically acceptable salt or solvate or isotope substituted compound is also provided, the medicine is used to improve the efficacy of chemotherapy when cancer or tumor patients are resistant to chemotherapy; or the medicine is used for Treat cancer or tumor patients who are resistant to chemotherapy.
  • the medicine is used to improve the efficacy of chemotherapy when cancer or tumor patients are resistant to chemotherapy; or the medicine is used for For the treatment of cancer or tumor patients resistant to chemotherapy, the medicine used in the chemotherapy contains daunorubicin or cytarabine.
  • the prepared drugs contain the indicated compounds or their salts or solvates in a specific dosage range, and/or the prepared drugs are administered in a specific dosage form and a specific administration mode.
  • the prepared medicine may also contain pharmaceutically acceptable excipients or excipients.
  • the drug can be any dosage form for clinical administration, such as tablets, suppositories, dispersible tablets, enteric-coated tablets, chewable tablets, orally disintegrating tablets, capsules, sugar-coated agents, granules, dry powders, oral solutions, small injection needles , Lyophilized powder for injection or large infusion.
  • the pharmaceutically acceptable excipients or excipients in the drug may include one or more of the following: diluents, solubilizers, disintegrants, suspending agents, lubricants, viscosity Mixtures, fillers, correctives, sweeteners, antioxidants, surfactants, preservatives, wrappers and colors.
  • the patient is a mammal, more preferably a human.
  • Patient and “individual” are used interchangeably and refer to mammals in need of cancer treatment. Usually, the patient is a human. Generally, the patient is a human being diagnosed with cancer. In certain embodiments, “patient” or “individual” may refer to non-human mammals used for screening, characterizing, and evaluating drugs and therapies, such as non-human primates, dogs, cats, rabbits, pigs, mice Or rat.
  • Prodrug refers to a compound that is metabolized or otherwise converted into a compound (or drug) with at least one property of biological activity or higher activity after administration or administration.
  • prodrugs are chemically modified in such a way that they are less or inactive relative to the drug, but chemical modification allows the production of the corresponding drug through metabolism or other biological processes after the prodrug is administered.
  • Prodrugs can have altered metabolic stability or delivery characteristics, fewer side effects or lower toxicity, or improved flavor relative to the active drug (see, for example, Reference Nogrady, 1985, Medicinal Chemistry A Biochemical Approach, Oxford University Press, New York , Pages 388 to 392, which are incorporated herein by reference).
  • Prodrugs can be synthesized using reactants other than the corresponding drugs.
  • Solid tumor refers to a solid tumor including (but not limited to) metastatic tumors in bone, brain, liver, lung, lymph nodes, pancreas, prostate, skin, and soft tissue (sarcoma).
  • the "therapeutically effective amount" of a drug refers to a drug that, when administered or administered to a patient suffering from cancer, will have the expected therapeutic effect (for example, alleviation, improvement, alleviation or elimination of the clinical manifestations of one or more cancers in the patient) The amount.
  • the therapeutic effect does not have to occur through the administration or administration of one dose, and may only occur after administration or administration of a series of doses. Therefore, the therapeutically effective amount can be administered or administered one or more times.
  • Treatment of a condition or patient refers to taking steps to obtain beneficial or desired results (including clinical results).
  • beneficial or desired clinical results include (but are not limited to) alleviation or improvement of one or more cancer symptoms; reduction of disease degree; delay or reduction of disease progression; improvement, alleviation or stabilization of disease state; Or other beneficial results.
  • treatment of cancer can result in a partial response or stabilize the disease.
  • Tumor cells refer to tumor cells of any appropriate species (e.g., mammals such as murine, dog, cat, horse, or human).
  • Radiation therapy that is, radiation therapy for cancer. There are many ways to implement radiation therapy, the most commonly used are:
  • the photon ( ⁇ -ray) beam is emitted, and a large number of photon ( ⁇ -ray) beams are emitted by the linear accelerator;
  • Neutron beam radiation can be used to treat certain cancers with narrow tissue edges
  • Electron beam radiation is suitable for the treatment of skin or superficial cancer due to its superficial penetration of tissues;
  • Proton radiation although its uses are limited, it can provide a sharp ray periphery for a very narrow irradiation field that requires depth;
  • Brachytherapy a powerful radioactive source is implanted into the tumor tissue itself (such as the prostate or lung) through a needle, so as to achieve a small-scale high-dose effect;
  • Systemic radionuclide therapy can be used for organ receptors with nuclide uptake (such as thyroid cancer) or to inhibit receptors in the bones of the whole body (such as radioactive strontium for the treatment of metastatic prostate cancer).
  • nuclide uptake such as thyroid cancer
  • radioactive strontium for the treatment of metastatic prostate cancer
  • Curative radiation therapy generally requires the tumor or its local area to be included in the radiation field.
  • Radiation irradiation cell damage is non-selective and non-specific, and has a complex effect on DNA. The effect is determined by how much the damage of the cell exceeds its repair ability. Generally speaking, the repair efficiency of normal tissues is higher than that of cancer cells, so that radiation therapy can benefit patients.
  • Chemotherapy is the abbreviation of chemotherapy, which is achieved by using chemotherapy drugs to kill cancer cells.
  • Chemotherapy is currently one of the most effective treatments for cancer, and is called the three major treatments for cancer together with surgery and radiotherapy.
  • Surgery and radiotherapy are local treatments, which are only effective for tumors at the treatment site, for potential metastatic lesions (cancer cells have actually metastasized, but because of the current technical limitations, they cannot be detected and detected clinically) and clinical metastases have occurred It’s difficult to effectively treat cancers.
  • Chemotherapy is a method of systemic treatment. No matter what route is used (oral, intravenous and body cavity administration, etc.), chemotherapy drugs will circulate throughout most of the organs and tissues of the body.
  • chemotherapy is the main treatment method for some tumors with a tendency to spread throughout the body and for metastatic tumors.
  • chemotherapy drugs are cytotoxic drugs, which can directly kill cells.
  • chemotherapy drugs due to the different characteristics of cancer cells and normal cells, chemotherapy drugs often have a greater killing effect on cancer cells, which can make patients Benefit.
  • chemotherapy still has serious side effects, including digestive system reactions, bone marrow suppression, hair loss, etc. Certain side effects may prevent some patients from receiving chemotherapy or certain chemotherapy drugs.
  • tumor-immune cycle The process by which the human immune system recognizes and eliminates tumor cells (tumor-immune cycle) has multiple links, any link being inhibited can cause tumor cells to not be eliminated normally. Different tumors can effectively inhibit the effective recognition and killing of tumor cells by the immune system through different links of abnormalities, thereby generating immune tolerance, and even promoting the occurrence and development of tumors.
  • Tumor immunotherapy is a treatment method that restores the body's normal anti-tumor immune response by restarting and maintaining the tumor-immune cycle, thereby controlling and eliminating tumors. Including monoclonal antibody immune checkpoint inhibitors, therapeutic antibodies, cancer vaccines, cell therapy and small molecule inhibitors. In recent years, the good news of tumor immunotherapy has continued. At present, it has shown strong anti-tumor activity in the treatment of solid tumors such as melanoma, non-small cell lung cancer, kidney cancer and prostate cancer. Immunotherapy drugs have been approved for clinical use.
  • MTBE methyl tert-butyl ether
  • DMAP 4-dimethylaminopyridine
  • T 3 P propyl phosphoric anhydride
  • THF tetrahydrofuran
  • DCM dichloromethane
  • EA or EtOAC ethyl acetate
  • TEA triethylamine
  • HPLC high performance liquid chromatography
  • DBAD di-tert-butyl azodicarboxylate
  • TFA trifluoroacetic acid
  • LCMS liquid-mass spectrometry
  • EtOH ethanol
  • t-BuOH tert-butanol
  • DMF dimethyl Formamide
  • PE petroleum ether, petroleum ether
  • eq equivalent is the molar ratio
  • TBAF tetrabutylammonium fluoride
  • DIPEA N,N-diisopropylethylamine
  • reflux reflux
  • rt room temperature
  • TBAF tetrabuty
  • the chemical reagents and medicines whose sources are not indicated are all analytical or chemically pure, and they are all purchased from commercial reagent companies.
  • 2-A1 500 mg, 1.51 mmol, synthesized with reference to No. 29 compound synthesis method
  • 2-A2 336 mg, 2.27 mmol, commercially available
  • THF 10 mL
  • triphenylphosphorus 991mg, 3.78mmol
  • di-tert-butyl azodicarboxylate 870mg, 3.78mmol
  • 3-A1 200 mg, 0.632 mmol, synthesized with reference to No. 29 compound synthesis method
  • 3-A2 140 mg, 0.948 mmol, commercially available
  • Methylamine (1.6 g, 12.8 mmol, 25% inTHF) was added dropwise, and then TEA (1.29 g, 12.85 mmol) in DCM (5 mL) was added dropwise. Keep it at -40°C for half an hour, then naturally rise to room temperature and stir overnight. After the reaction, the temperature was lowered to 0°C, potassium carbonate solution (1g, 10mL) was added dropwise, DCM extraction (10mL ⁇ 3), water washing (5mL ⁇ 2), drying and concentration, the pure product (380mg, yield 57.7%), a light yellow viscous oil.
  • tris(dimethylamino)phosphine (179mg, 1.1mmol, commercially available) and tetrazolium (0.64mg, 0.009mmol) were added to acetonitrile (3mL), and then 6-A1 (300mg, 0.914 mmol, refer to the synthesis method of compound No. 29) in acetonitrile solution (2mL), stir at room temperature for two hours, add TEA (277mg, 2.74mmol) and tert-butanol peroxide (329mg, 3.66mmol) dropwise, stir at room temperature for three hours, react complete.
  • tris(dimethylamino)phosphine (124mg, 0.76mmol, purchased commercially) and tetrazolium (0.4mg, 0.0057mmol) were added to acetonitrile (3mL), and then 7-A1 (200mg, 0.63 mmol, refer to the synthesis method of compound 29) in acetonitrile (2mL), stir at room temperature for 2 hours, add TEA (192mg, 1.90mmol) and tert-butanol peroxide (228mg, 2.53mmol) dropwise, stir at room temperature for 3 hours, and react complete.
  • TEA 192mg, 1.90mmol
  • tert-butanol peroxide (228mg, 2.53mmol
  • 8-A1 300 mg, 0.91 mmol, synthesized with reference to No. 29 compound synthesis method
  • 8-A2 202 mg, 1.36 mmol
  • THF 5 mL
  • triphenylphosphorus 600mg, 2.30mmol
  • di-tert-butyl azodicarboxylate 530mg, 2.30mmol
  • water 5mL was added dropwise at 0°C, extracted with DCM (5mL ⁇ 3), washed with water (2mL ⁇ 2), dried and concentrated.
  • Methylamine (960 mg, 7.70 mmol, 25% inTHF) was added dropwise, and then TEA (782 mg, 7.70 mmol) in DCM (5 mL) was added dropwise. Keep the temperature at -40°C for 0.5h, then naturally rise to room temperature and stir overnight. The temperature was lowered to 0°C, potassium carbonate solution (1g, 10mL) was added dropwise, DCM extraction (10mL ⁇ 3), water washing (5mL ⁇ 2), drying and concentration, HPLC prepared 10 pure compounds (60mg, yield 15.2%) ), is a light yellow viscous oil.
  • tris(dimethylamino)phosphine (179mg, 1.1mmol, commercially available) and tetrazolium (0.64mg, 0.009mmol) were added to acetonitrile (3mL), and then 12-A1 (300mg, 0.91 mmol, refer to the synthesis method of compound No. 29) in acetonitrile solution (2mL), stir at room temperature for 2h, add TEA (277mg, 2.74mmol) and tert-butanol peroxide (329mg, 3.66mmol) dropwise, stir at room temperature for 3h, the reaction is complete.
  • tris(dimethylamino)phosphine (124mg, 0.76mmol, purchased commercially) and tetrazolium (0.4mg, 0.0057mmol) were added to acetonitrile (3mL), and then 13-A1 (200mg, 0.63 mmol, refer to the synthesis method of compound 29) in acetonitrile solution (2mL), stir at room temperature for 2h, add TEA (192mg, 1.90mmol) and tert-butanol peroxide (228mg, 2.53mmol) dropwise, stir at room temperature for 2h, the reaction is complete.
  • TEA 192mg, 1.90mmol
  • tert-butanol peroxide (228mg, 2.53mmol
  • N,N'-dimethyl-1,3-propanediamine (130mg, 1.27mmol, commercially available) in DCM (2mL) was added dropwise, then TEA (130mg, 1.266mmol) in DCM was added dropwise
  • the solution (2ml) was incubated at -40°C for one hour, and the intermediate conversion was completed.
  • the temperature was naturally raised to 0°C, saturated aqueous ammonium chloride solution (5mL) was added dropwise, DCM extraction (10mL ⁇ 3), purified water washing (3ml ⁇ 3), drying and concentration, HPLC prepared No. 14 compound and product (8.5mg, yield Rate 2.9%), it is light yellow oily liquid.
  • phosphorus oxychloride (53.4mg, 0.348mmol) was added dropwise to anhydrous DCM (5mL), the temperature was lowered to -40°C, and 17-A1 (100mg, 0.316mmol) was added dropwise, according to the synthesis method of No. 29 compound ) In DCM (2ml), then TEA (35.2mg, 0.348mmol) was added dropwise and kept at -40°C for 1.5 hours. The raw material was completely converted into an intermediate.
  • 19-A1 2.0g, 11.69mmol
  • 19-A2 6.4g, 46.76mmol, commercially available
  • DMF 10mL
  • potassium carbonate 6.5g, 46.76mmol
  • cool to room temperature add water (20ml) dropwise, EA extraction (20mL ⁇ 3), water wash (8mL ⁇ 5), brine wash (8mL3), dry and concentrate, column separation (300-400 mesh silica gel, n-heptane Alkane: EA, 25%-35% EA) to obtain 19-A3 (1.05 g, 31.3%) as a pale yellow solid.
  • phosphorus oxychloride (59mg, 0.382mmol) was added dropwise to anhydrous DCM (10mL), the temperature was reduced to -40°C, and 19-A3 (100mg, 0.347mmol) in DCM (2mL) was added dropwise, Then TEA (39mg, 0.382mmol) was added dropwise, and the temperature was kept at -40°C to -35°C for two hours. HPLC and LC-MS detected that 19-A3 disappeared and converted into an intermediate.
  • N,N'-dimethyl-1,3-propanediamine 39mg, 0.382mmol, commercially available
  • TEA 105mg, 1.041mmol
  • the solution (2ml) was incubated at -40°C for one hour, and the intermediate conversion was completed.
  • the temperature was naturally raised to 0°C, saturated aqueous ammonium chloride solution (5mL) was added dropwise, DCM extraction (10mL ⁇ 3), purified water washing (3m ⁇ 3), drying and concentration, preparative HPLC to obtain No. 19 compound (34.5mg, yield 20.8 %), is a light yellow oily liquid.
  • phosphorus oxychloride (59mg, 0.382mmol) was added dropwise to anhydrous DCM (10mL), the temperature was reduced to -40°C, and 20-A1 (100mg, 0.347mmol, ie 19-A3) DCM was added dropwise Solution (2mL), TEA (39mg, 0.382mmol) was then added dropwise, incubated at -40°C to -35°C for two hours, monitored by HPLC and LC-MS, 20-A1 disappeared and converted into an intermediate.
  • phosphorus oxychloride (59mg, 0.382mmol) was added dropwise to anhydrous DCM (10mL), the temperature was lowered to -40°C, and 21-A1 (100mg, 0.347mmol, ie 19-A3) DCM was added dropwise Solution (2mL), then TEA (39mg, 0.382mmol) was added dropwise, kept at -40°C to -35°C for 3.5 hours, and then at -40°C, 3-(methylamino)-1-propanol (34mg , 0.382mmol) in DCM (2mL), then TEA (105mg, 1.041mmol) in DCM (2ml) was added dropwise, incubated at -40°C for 30 minutes, naturally warmed to room temperature, reacted overnight, at 0°C, saturated Aqueous ammonium chloride solution (5 mL), DCM extraction (8 mL ⁇ 3), pure water washing (3 ml ⁇ 3), drying and
  • phosphorus oxychloride (59.0mg, 0.382mmol) was added dropwise to anhydrous DCM (5mL), the temperature was lowered to -40°C, and 23-A1 (100mg, 0.347mmol, ie 19-A3) DCM was added dropwise Solution (2ml), then TEA (39.0mg, 0.382mmol) was added dropwise and kept at -40°C for 1.5 hours. The raw material was completely converted into an intermediate.
  • Triphosgene (3g, 10.1mmol) was dissolved in DCM (300ml) at 0°C, then 26-A1 (1.52g, 20.2mmol, 2eq) was dissolved in DCM (60ml) and added dropwise to the system for 20min. After 4 hours of reaction, the system was spin-dried, and the slurry was beaten with MTBE (20 ml). After suction filtration, the mother liquor was spin-dried to obtain 1.2 g of 26-A2 crude product, light brown liquid. Invest directly in the next reaction.
  • TEA 480mg, 4.744mmol, 5eq
  • DMAP 29.1mg, 0.237mmol, 0.25eq
  • 27-A1 120mg, 0.358mmol, refer to the synthesis method of compound 29
  • DMF 5mL
  • 2,4 difluorothiophenol 104mg, 0.716mmol, 2eq
  • Cs 2 CO 3 291.6 mg, 0.895 mmol
  • the reaction was completed in 1h.
  • EA 50mL
  • wash with saturated sodium carbonate aqueous solution (20mlx3) wash with brine (10mlx2), dry and concentrate, and prepare the product (41mg, yield 25.7%) by HPLC, which is a yellow oily liquid.
  • Dissolve 24-A1 (100mg, 0.32mmol, refer to the synthesis method of No. 29 compound) and pyridine (55.7mg, 0.70mmol, 2.2eq) in DCM (3ml), then reduce the temperature to 0°C, and add isopropyl chloroformate dropwise (129.6mg, 1.2mmol, 3.6eq, commercial purchase) was added to the system, reacted at 20°C for 18h, cooled to 0°C-5°C, 1N hydrochloric acid (3ml) was added dropwise, extracted with DCM (10mLx2), the organic phase was washed with hydrochloric acid (1N , 10mLx5), washed with water (5mLx3), washed with brine (5mLx2), dried over sodium sulfate, concentrated the organic phase, and obtained the product (27mg, 21.2%) by neutral preparation, which was an off-white solid.
  • 30-A4 (500mg, 1.27mmol) was dissolved in THF (2ml), cooled to 0°C, NaBH 4 (193mg, 5.10mmol, 4eq) was added to the system in batches, then the system was heated to 60°C and refluxed, monitored by HPLC for 15h The reaction is complete. Reduce to 0°C, quench with water (20ml), extract with DCM (20ml ⁇ 3), dry and spin dry to concentrate and mix the sample, 300-400 silica gel and flash column chromatography to obtain 30-A5 pure product (140mg, yield 30.2%) is off-white solid.
  • 31-A2 (1.8g, 10.5mmol) was added to H 2 O (18ml), a white suspension, and then NaOH (923mg, 23.1mmol, 2.2eq) was slowly added to the system in batches, and then the reaction The system gradually became clear.
  • the desired product was monitored by LCMS. After reacting overnight, MeCN (20ml) was added and mixed, and part of the water was spun off. The remaining mixture was adjusted to acidity with 12N HCl, and a large amount of solids precipitated out. After suction filtration, MeCN (10ml) was used for beating to remove water. After suction filtration, MeCN (10ml) was added and spin-dried to obtain a total of 800mg of 31-A3, which was a white solid, which was directly thrown into the next reaction.
  • 31-A4 (100mg, 0.299mmol, Refer to the synthesis method of compound No. 29). Dissolve it in DMF (2ml), then add 31-A3 (91.5mg, 0.597mmol, 2eq) and TEA (90.7mg, 0.896mmol, 3eq) to the system, and the system is now light orange Yellow, reacted at 20°C overnight, the reaction is complete.
  • Nitrogen protection will 34-A4 (50mg, 0.149mmol, Synthesize with reference to No. 29 compound synthesis method) Dissolve in DMF (1mL), then add 34-A3 (418.6mg, 1.194mmol, 8eq) and TEA (120.8mg, 1.194mmol, 8eq) to the system, and warm the system to 30°C ,overnight.
  • 35-A4 (100mg, 0.299mmol, Synthesize with reference to No. 29 compound synthesis method) Dissolve in DMF (2ml), then add 35-A3 (182mg, 1.196mmol, 4eq) and TEA (121mg, 1.196mmol, 4eq) into the system, and then heat the system to 25°C After overnight, HPLC monitored the completion of the reaction. Add saturated NaHCO 3 aqueous solution (5ml), EA extraction (5mLx3), organic phase washing (10mlx2), aqueous EA extraction (5mlx2), organic phase spin-drying, HPLC neutral conditions preparation and separation, to obtain 35 total 23.1mg, The yield was 17.2% and it was a pale yellow solid.
  • Step 2 Pre-incubate the above duplicate mixture at 37°C for 30 minutes.
  • Step 3 Add another 10 ⁇ L of 20 mM NADPH PBS phosphate buffered saline solution and 2 ⁇ L of 250 ⁇ M progesterone 50% MeOH/H 2 O solution to each Eppendorf tube and mix gently.
  • Step 4 Immediately transfer 50 ⁇ L of the mixture in the above step to 100 ⁇ L of 1 ⁇ g/mL propranolol (propranolol, internal standard IS) 100% acetonitrile solution.
  • propranolol propranolol, internal standard IS
  • Step 5 Incubate the remaining samples at 37°C for 30 minutes, and add 100 ⁇ L of 1 ⁇ g/mL propranolol (propranolol, internal standard IS) 100% acetonitrile solution.
  • propranolol propranolol, internal standard IS
  • Step 6 For all samples, add 100 ⁇ L of reagent water, vortex and mix at 1100 rpm for 5 minutes, and centrifuge at 15000 rpm for 10 minutes at room temperature.
  • Step 7 Load all samples on LC/MS to determine the content of reduced progesterone, namely 20 ⁇ -dihydroprogesterone.
  • test conditions of the LC-MS instrument are the test conditions of the LC-MS instrument.
  • Step 9 calculation of reduced progesterone (20 ⁇ -dihydroprogesterone): Determine the peak area of reduced progesterone, namely 20 ⁇ -dihydroprogesterone and propranolol in each sample by LC/MS. Calculate the peak area ratio of reduced progesterone to propranolol, and set the ratio when the time is 0 to 0%.
  • ND means not detected
  • the activity data of the above compounds are obtained from four tests: 2019/5/29, 2019/5/31, 2019/6/13, 2019/6/14, which corresponds to the control compound AST-3424, indomethacin There are also four values. The arithmetic average of these four times is used in the above table.
  • the specific test results and time are as follows:
  • Indomethacin is a typical AKR1C3 inhibitor, and it is clinically used to relieve and treat cancer pain.
  • the compound disclosed in the present invention has a higher ability to inhibit the AKR1C3 enzyme than indomethacin at a concentration of 5 ⁇ M/L, which shows that the compound disclosed in the present invention is a more efficient AKR1C3 inhibitor.

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Abstract

本发明提供下式化合物及其药学上可接受的盐或溶剂合物或同位素取代化合物的AKR1C3抑制剂及医药用途。

Description

AKR1C3抑制剂及医药用途 技术领域
本发明涉及AKR1C3抑制剂以及该抑制剂的医药用途。
背景技术
我公司开发的以高表达醛酮还原酶1C3(AKR1C3)为标靶的DNA烷化剂癌症治疗化合物前药(申请号PCT/US2016/021581，公开号WO2016/145092；申请号PCT/US2016/062114，公开号WO2017/087428)特异性的在体内AKR1C3的作用下发生代谢活化，以其中TH-2870的S构型AST-3424为例：
Figure PCTCN2020099353-appb-000001
作为前药形式的以高表达醛酮还原酶AKR1C3为标靶的DNA烷化剂在体内会和AKR1C3结合，然后发生代谢反应，最终产生具有细胞毒性的DNA烷化剂。
发明内容
研发过程中发现对该类化合物进行各个基团取代的尝试时，发现当苯环上硝基对位上的苄基碳原子上连接的不是类似于申请号PCT/US2016/021581，公开号WO2016/145092；申请号PCT/US2016/062114，公开号WO2017/087428；申请号PCT/US2016/025665，公开号WO2016/161342的细胞毒性的烷化剂时，化合物表现出抑制AKR1C3酶活性的能力，为此研发团队设计并合成了一系列新化学结构的AKR1C3抑制剂。
为此本发明提供以下的技术方案。
下式的化合物以及其药学上可接受的盐或溶剂合物或同位素取代化合物：
Figure PCTCN2020099353-appb-000002
其中，R 1、R 2各自独立地为氢、氘、芳基或Z取代芳基、杂芳基或Z取代杂芳基、C 1-C 6烷基或Z取代烷基、C 2-C 6烯基或Z取代烯基、C 2-C 6炔基或Z取代炔基、C 3-C 8环烷基或Z取代环烷基；
R 3是氢、卤素、氰基或异氰基、羟基、巯基、胺基、肟基、腙基、OTs、OMs、C 1-C 6烷基或Z取代烷基、C 2-C 6烯基或Z取代烯基、C 2-C 6炔基或Z取代炔基、C 3-C 8环烷基或Z取代环烷基、C 6-C 10芳基或Z取代芳基、4-15元杂环或Z取代杂环、5-15元杂芳基或Z取代杂芳基、C 1-C 6烷氧基或Z取代的C 1-C 6烷氧基或者R 3是-CONR 6R 7、-SO 2NR 6R 7、-SO 2R 6、-OCO-R 6、-OCOO-R 6、-COOR 6、-NR 6COR 7、-NR 6SO 2R 7、-NR 6CONR 6R 7，且R 6,R 7与N形成或不形成4-8元Z取代杂环；
R 6和R 7各自独立地是氢、氰基或异氰基、C 1-C 6烷基或Z取代烷基、C 2-C 6烯基或Z取代烯基、C 2-C 6炔基或Z取代炔基、C 3-C 8环烷基或Z取代环烷基、C 6-C 10芳基或Z取代芳基、4-15元杂环或Z取代杂环、5-15元杂芳基或Z取代杂芳基、C 1-C 6烷氧基或Z取代的C 1-C 6烷氧基，或者R 6、R 7基团与其所键结的原子一起形成3-7元杂环基或Z取代3-7元杂环基；
a为0、1、2、3；
X为C、N；
在上述的化学结构式中，R 3可以位于苯环或吡啶环的不同原子上，即可以没有R 3基团，此时a为0，即苯环或吡啶环上为氢；可以是1个R 3基团，此时a为1，即苯环或吡啶环上剩下的2个(此时为吡啶环)或3个(此时为苯环)氢的位置被1个R 3基团取代；可以是2个R 3基团，此时a为2，即苯环或吡啶环上剩下的2个(此时为吡啶环)或3个(此时为苯环)氢的位置被2个R 3基团取代；可以是3个R 3基团，此时a为3，即苯环3个氢的位置被3个R 3基团取代。
Y为O或者S；
Cx选自C 6-C 10芳基或Z取代芳基、4-15元杂环或Z取代4-15元杂环、5-15元杂芳基或Z取代元杂芳基、7-15元的稠环或Z取代稠环以及-CONR 6R 7、-SO 2NR 6R 7、-SO 2R 6、-OCOO-R 6、-COOR 6、-NR 6COR 7、-OCOR 6、-NR 6SO 2R 7、-NR 6SO 2NR 6R 7、-COR 6、-NR 6CONR 6R 7取代的C 6-C 10芳基、4-15元杂环、5-15元杂芳基、7-15元的稠环，且R 6,R 7与N形成或不形成4-8元Z取代杂环；
L选自-O-、-S-、-OCOO-、-NR 6CO-、-OCO-、-NR 6SO 2-、-OCONR 6-、季铵根、磺酸酯基-OSO 2-；
Cy选自氢、氘、C 6-C 10芳基或Z取代的芳基、4-15元杂环或Z取代杂环、5-15元杂芳基或Z取代杂芳基、7-15元的稠环或Z取代稠环，C 1-C 6烷基或Z取代烷基、C 2-C 6烯基或Z取代烯基、C 2-C 6炔基或Z取代炔基、C 3-C 8环烷基或Z取代C 3-C 8环烷基；
或
Cy选自
Figure PCTCN2020099353-appb-000003
或Cy选自
Figure PCTCN2020099353-appb-000004
中两个OR 6与P原子所形成的5-10元环基团、
Figure PCTCN2020099353-appb-000005
中OR 6与NR 6R 7与P原子所形成的5-10元环基团、
Figure PCTCN2020099353-appb-000006
中两个NR 6R 7与P原子所形成5-10元环基团；
并且-L-Cy不包括这些胺基磷酸酯烷化剂的失去H原子后的残基：-P(Z 1)(NR 9CH 2CH 2X 1) 2、-P(Z 1)(NR 9 2)(N(CH 2CH 2X 1)2)、-P(Z 1)(N(CH 2CH 2X 1)) 2或-P(Z 1)(N(CH 2CH 2X 1) 2) 2，每个R 9独立地为氢或C1-C6烷基，或2个R 9与其所结合的氮原子一起形成5至7元杂环基，Z 1为O或S，且X 1为Cl、Br或OMs，-L-Cy也不包括-OH和-SH；
Z取代基为卤素、氰基或异氰基、羟基、巯基、胺基、肟基、腙基、OTs、OMs、C 1-C 3烷基或取代烷基、C 1-C 3烷氧基或取代烷氧基、C 2-C 3烯基或取代烯基、C 2-C 3炔基或取代炔基、C 3-C 8环烷基或取代环烷基、芳环、杂环、杂芳环和稠环或取代芳环、杂环、杂芳环和稠环，取代的方式为单取代或偕二取代；
Cz基团为含有C、P、S的基团且该基团能被水解酶水解而使得对应的C-N，P-N，S-N键断裂。
式I化合物或者其药学上可接受的盐或溶剂合物或同位素取代化合物，
Figure PCTCN2020099353-appb-000007
或
在生物体内能被转化为上述I-3的前药
Figure PCTCN2020099353-appb-000008
其中，
R 1、R 2各自独立地为氢、氘、芳基或Z取代芳基、杂芳基或Z取代杂芳基、C 1-C 6烷基或Z取 代烷基、C 2-C 6烯基或Z取代烯基、C 2-C 6炔基或Z取代炔基、C 3-C 8环烷基或Z取代环烷基；
R 3是氢、卤素、氰基或异氰基、羟基、巯基、胺基、肟基、腙基、OTs、OMs、C 1-C 6烷基或Z取代烷基、C 2-C 6烯基或Z取代烯基、C 2-C 6炔基或Z取代炔基、C 3-C 8环烷基或Z取代环烷基、C 6-C 10芳基或Z取代芳基、4-15元杂环或Z取代杂环、5-15元杂芳基或Z取代杂芳基、C 1-C 6烷氧基或Z取代的C 1-C 6烷氧基或者R 3是-CONR 6R 7、-SO 2NR 6R 7、-SO 2R 6、-OCO-R 6、-OCOO-R 6、-COOR 6、-NR 6COR 7、-NR 6SO 2R 7、-NR 6CONR 6R 7，且R 6,R 7与N形成或不形成4-8元Z取代杂环；
R 4、R 5各自独立地是氢、卤素、氰基或异氰基、羟基、巯基、胺基、肟基、腙基、OTs、OMs、C 1-C 6烷基或Z取代烷基、C 2-C 6烯基或Z取代烯基、C 2-C 6炔基或Z取代炔基、C 3-C 8环烷基或Z取代环烷基、C 6-C 10芳基或Z取代芳基、4-15元杂环或Z取代杂环、5-15元杂芳基或Z取代杂芳基、C 1-C 6烷氧基或Z取代的C 1-C 6烷氧基或者R 4、R 5是-CONR 6R 7、-SO 2NR 6R 7、-SO 2R 6、-OCOO-R 6、-COOR 6、-NR 6COR 7、-OCOR 6、-NR 6SO 2R 7、-NR 6CONR 7或者R 4、R 5和与其所键结的苯环上的原子一起形成7-15元的稠环或Z取代稠环，且R 6,R 7与N形成或不形成4-8元Z取代杂环；
R 6和R 7各自独立地是氢、氰基或异氰基、C 1-C 6烷基或Z取代烷基、C 2-C 6烯基或Z取代烯基、C 2-C 6炔基或Z取代炔基、C 3-C 8环烷基或Z取代环烷基、C 6-C 10芳基或Z取代芳基、4-15元杂环或Z取代杂环、5-15元杂芳基或Z取代杂芳基、C 1-C 6烷氧基或Z取代的C 1-C 6烷氧基，或者R 6、R 7基团与其所键结的原子一起形成3-7元杂环基或Z取代3-7元杂环基；
Y为O或者S；
Cx选自C 6-C 10芳基或Z取代芳基、4-15元杂环或Z取代4-15元杂环、5-15元杂芳基或Z取代元杂芳基、7-15元的稠环或Z取代稠环以及-CONR 6R 7、-SO 2NR 6R 7、-SO 2R 6、-OCOO-R 6、-COOR 6、-NR 6COR 7、-OCOR 6、-NR 6SO 2R 7、-NR 6SO 2NR 6R 7、-COR 6、-NR 6CONR 7取代的C 6-C 10芳基、4-15元杂环、5-15元杂芳基、7-15元的稠环，且R 6,R 7与N形成或不形成4-8元Z取代杂环；
L选自-O-、-S-、-OCOO-、-NR 6CO-、-OCO-、-NR 6SO 2-、-OCONR 6-、季铵根、磺酸酯基-OSO 2-；
Cy选自氢、氘、C 6-C 10芳基或Z取代的芳基、4-15元杂环或Z取代杂环、5-15元杂芳基或Z取代杂芳基、7-15元的稠环或Z取代稠环，C 1-C 6烷基或Z取代烷基、C 2-C 6烯基或Z取代烯基、C 2-C 6炔基或Z取代炔基、C 3-C 8环烷基或Z取代C 3-C 8环烷基；
或
Cy选自
Figure PCTCN2020099353-appb-000009
或Cy选自
Figure PCTCN2020099353-appb-000010
中两个OR 6与P原子所形成的5-10元环基团、
Figure PCTCN2020099353-appb-000011
中OR 6与NR 6R 7与P原子所形成的5-10元环基团、
Figure PCTCN2020099353-appb-000012
中两个NR 6R 7与P原子所形成5-10元环基团；
并且以上H-L-Cy不形成磷酸酯烷化剂；
Z取代基为卤素、氰基或异氰基、羟基、巯基、胺基、肟基、腙基、OTs、OMs、C 1-C 3烷基或取代烷基、C 1-C 3烷氧基或取代烷氧基、C 2-C 3烯基或取代烯基、C 2-C 3炔基或取代炔基、C 3-C 8环烷基或取代环烷基、芳环、杂环、杂芳环和稠环或取代芳环、杂环、杂芳环和稠环，取代的方式为单取代或偕二取代；
Cz基团为含有C、P、S的基团且该基团能被水解酶水解而使得对应的C-N，P-N，S-N键断裂，即Cz为氨基酸残基(-NH-Cz形成氨基酸肽键)、有机羧酸残基(-NH-Cz形成酰胺结构)等。
水解酶在EC编号中分类为EC3，并以它分解的键再细分为几个子类：
EC3.1：酯键(酯酶)
EC3.2：糖(糖基酶)
EC3.3：醚键
EC3.4：肽键(肽酶)
EC3.5：C-N键，但不包括肽键
EC3.6：酸酐
EC3.7：C-C键
EC3.8：卤键
EC3.9：P-N键
EC3.10：S-N键
EC3.11：S-P键
EC3.12：S-S键
EC3.13：C-S键
在人体生理环境中，存在着许多酶能够将上述前药中的-NH-Cz断裂，特别的例如水解酶能够将许多化学键水解而断开，特别是本发明公开化合物的含有C、P、S原子的基团，特别的这些化学键、水解酶包括EC3.4：肽键(肽酶)、EC3.9：P-N键、EC3.10：S-N键，其所对应的化合物包括酰胺类、磷酰胺类、硫代酰胺类。
杂环、杂芳基包括三元环、四元环、五元环、六元环、七元环。以下举例说明。
三元环：环氧乙烷、环氮乙烷、环硫乙烷；
四元环：吖丁啶、噁丁啶、噻丁啶、丁啶；
五元环：吡咯烷、吡咯啉、1-吡咯啉、3-吡咯啉、2-吡咯啉、吡咯、吡唑烷、2-吡唑啉、咪唑、吡唑、呋喃、THF、二氢呋喃、四氢噻吩、噻吩、环丁砜、磷杂茂、噁唑、1，2，3-三唑、1，2，4-三唑、1，3，4-噻二唑；
六元环：哌啶、四氢吡喃、四氢噻喃、吡啶、吡喃、噻喃、二氢吡啶、吗啉、哌嗪、哒嗪、吡嗪、1，3，5-三嗪、1，3，5-三噻烷；
七元环：吖庚烷(氮杂环庚烷)、噁庚烷、噻庚烷、氮杂
Figure PCTCN2020099353-appb-000013
氧杂
Figure PCTCN2020099353-appb-000014
硫杂
Figure PCTCN2020099353-appb-000015
稠环定义为以上的杂环、杂芳基之间的骈合或者与环烷结构的骈合，骈合可以是通过单键的链接或者是共用一个、两个甚至三个原子的形式，以下给出一些常见的稠环结构：萘、喹啉、吲哚、异吲哚、异喹啉、噌啉、喹喔啉、联苯、香豆素、芴、二苯咔喃、咔唑、蒽、氮蒽、噻吩嗪、金刚烷、薁、菲、蒽醌、黄酮、异黄酮。
显然以上的化合物，其也包括同位素取代化合物，典型的取代方式为氢原子H被重氢原子氘D取代。
特别的，被氘取代的部位位于I式中Ph-C *-上，如下式所示：
Figure PCTCN2020099353-appb-000016
进一步的，上述提供的化合物，所述盐为碱式盐或酸式盐。
关于本文所述化合物，所述化合物还包括式I-1至I-5结构盐的形式使用，即本发明提供所示化合物的药学上可接受的盐，所述盐可以为碱式盐，包括所述化合物与无机碱(例如碱金属氢氧化物、碱土金属氢氧化物等)或与有机碱(例如单乙醇胺、二乙醇胺或三乙醇胺等)形成的盐。或者，所述盐可以为酸式盐，包括所述化合物与无机酸(例如盐酸、氢溴酸、氢碘酸、硝酸、高氯酸、硫酸或磷酸等)或与有机酸(例如甲磺酸、三氟甲磺酸、乙磺酸、苯磺酸、对甲苯磺酸、富马酸、草酸、 马来酸、柠檬酸等)形成的盐。选择和制备化合物的可接受的盐和溶剂化物等是本领域公知技术。
进一步的，上述提供的化合物，其中，所述溶剂合物为水合物或醇合物。
在药物设计和有机化学这一技术领域，化合物特别是具有较活泼基团的化合物，比如磷酰胺、酰胺、胺、盐或是酯等基团，由于对溶剂，比如水、乙醇等醇类溶剂具有较好的亲和性，经常会出现溶剂和化合物的结合物(典型如水合硫酸铜这类无机盐)，特别是当化合物为通过结晶或是沉淀、浓缩等方式自溶剂中得到之固体时，会不可避免的与溶剂因为结合、包裹而得到与溶剂发生结合的溶剂化物。本发明提供的化合物具有磷酰胺、酰胺、羟基等活性基团就，自然也可以通过上述之理由和实际情况而生成对应的溶剂化物。
关于本文所述化合物还可以溶剂合物的形式使用，即本发明提供所示I化合物的药学上可接受的溶剂合物，所述溶剂合物为水合物、醇合物等，醇合物包括乙醇合物。
通过实验已经证实上述化合物I中：
Figure PCTCN2020099353-appb-000017
具有AKR1C3酶抑制活性。
文献调研可知，该类化合物在AKR1C3酶作用下发生以下的代谢反应：
Figure PCTCN2020099353-appb-000018
上述的I式中的硝基化合物在AKR1C3酶的两次还原过程中会得到
Figure PCTCN2020099353-appb-000019
这三种结构的中间体(Roger M.Phillips，Targeting the hypoxic fraction of tumours using hypoxia-activated prodrugs[J].Cancer Chemother Pharmacol(2016)77:441-457.DOI 10.1007/s00280-015-2920-7；Baran N，Konopleva M.Molecular Pathways:Hypoxia-activated prodrugs in cancer therapy[J].Clinical Cancer Research，2017:clincanres.0895.2016.DOI： 10.1158/1078-0432.CCR-16-0895；Cindy Cazares-
Figure PCTCN2020099353-appb-000020
Isabel M.Pires，I.Diane Swallow，et al.CH-01 is a Hypoxia-Activated Prodrug That Sensitizes Cells to Hypoxia/Reoxygenation Through Inhibition of Chk1and Aurora A[J].ACS Chem.Biol.2013，8(7):1451.DOI:10.1021/cb4001537；Potent and Highly Selective Hypoxia-Activated Achiral Phosphoramidate Mustards as Anticancer Drugs[J].Journal of Medicinal Chemistry，2008，51(8):2412-2420.DOI:10.1021/jm701028q；Jameson M B，Rischin D，Pegram M，et al.A phase I trial ofPR-104，a nitrogen mustard prodrug activated by both hypoxia and aldo-keto reductase 1C3，in patients with solid tumors[J].Cancer Chemotherapy&Pharmacology，2010，65(4):791-801.DOI:10.1007/s00280-009-1188-1；Hunter F W，Wouters B G，Wilson W R.Hypoxia-activated prodrugs:paths forward in the era of personalised medicine[J].British Journal of Cancer，2016.DOI:10.1038/bjc.2016.79；Pre-clinical activity of PR-104 as monotherapy and in combination with sorafenib in hepatocellular carcinoma[J].Cancer Biology&Therapy，2015，16(4):610-622.DOI：10.1080/15384047.2015.1017171)，所以这三个中间体(亚硝基、羟胺、胺基)也对应的能发挥和式I中的硝基化合物类似的AKR1C3酶抑制活性。
由于前药
Figure PCTCN2020099353-appb-000021
能通过体内的各种酶(酰胺水解酶、磷酰胺水解酶)来水解得到对应的胺形式即I-3，所以前药I-5和I-3类似也能在体内发挥AKR1C3抑制剂的作用。
进一步的，所述R 1、R 2各自独立地为为氢、氘、C 1-C 6烷基或Z取代烷基、C 2-C 6烯基或Z取代烯
基、C 2-C 6炔基或Z取代炔基、C 3-C 8环烷基或Z取代环烷基。
进一步的，其中，所述R 1、R 2各自独立地为为氢、氘、甲基。
进一步的，其中，R 3、R 4、R 5各自独立地为氢。
进一步的，其中，Cx为-CONR 6R 7取代的苯基，且R 6,R 7与N形成或不形成4-8元Z取代杂环。
进一步的，其中，L选自-O-、-S-。
进一步的，其中，Cy选自C 6-C 10芳基或卤素取代的芳基、4-15元杂环或卤素取代杂环、5-15元杂芳基或卤素取代杂芳基、7-15元的稠环或卤素取代稠环。
进一步的，其中，Cy选自氟苯基、二氟苯基、三氟苯基。
进一步的，其中，Cy选自
Figure PCTCN2020099353-appb-000022
Figure PCTCN2020099353-appb-000023
或Z取代的
Figure PCTCN2020099353-appb-000024
Figure PCTCN2020099353-appb-000025
进一步的，其中，前药
Figure PCTCN2020099353-appb-000026
选自
Figure PCTCN2020099353-appb-000027
即此时的前药I-5中Cz为-COR 6、-COOR 6。
进一步的，其中，-NH-Cz为磷酰胺基团。
进一步的，选自以下结构的化合物
Figure PCTCN2020099353-appb-000028
Figure PCTCN2020099353-appb-000029
其中，所述盐为碱式盐或酸式盐，所述溶剂合物为水合物或醇合物。
文献调研，根据中国台湾地区专利文献TW201742868A(公开日2017-12-16，该文献内容也在WO2017202817A1、AU2017269871A1、US20180319807A2、US20170342082A1等文件中公开)公开内容可知：
醛基酮基还原酶族1成员C3(AKR1C3，亦被称作5型17-β-羟基类固醇去氢酶(17-β-HSD5))为酶类之醛/酮基还原酶(AKR)超家族的成员，其将类固醇激素中之醛/酮基还原成对应醇，且因此在雄激素、孕酮、雌激素及及前列腺素的代谢/活化/去活化中起重要作用。
AKR1C3具有3α-HSD(羟基类固醇去氢酶活性)、17β-HSD、20α-HSD及前列腺素(PG)F合成酶活性。其催化雌酮(弱雌激素活性)至雌二醇(强雌激素活性)之转化、孕酮(强抗雌激素活性)至20-α-羟基孕酮(弱抗雌激素活性)之转化及雄烯二酮至睾固酮之转化(Labrie F，Luu-T he V，Labrie C，et al.DHEA and Its Transformation into Androgens and Estrogens in Periphera l Target Tissues:Intracrinology[J].Frontiers in Neuroendocrinology，2001，22(3):185-212.DOI：10.1006/frne.2001.0216)。此外，AKR1C3催化PGH2至PGF2α及PGD2至11β-PGF2之转化，已知两者刺激发炎及增生。
此外，亦已展示AKR1C3使广泛范围之羰基化合物及异生物质(包括临床上投与之蒽环类霉素anthracycline)代谢(Bains O S，Grigliatti T A，Reid R E，et al.Naturally occurring variants of human aldo-keto reductases with reduced in vitro metabolism of daunorubicin and doxorubicin.[J].Journal of Pharmacology&Experimental Therapeutics，2010，335(3):533-545.DOI：10.1124/jpet.110.173179；Novotna R，Wsol V，Xiong G，et al.Inactivation of the anticancer drugs dox orubicin and oracin by aldo–keto reductase(AKR)1C3[J].Toxicology Letters，2008，181(1):1-6.DOI:10.1016/j.toxlet.2008.06.858；Hofman J，Malcekova B，Skarka A，et al.Anthracycl ine resistance mediated by reductive metabolism in cancer cells：The role of aldo-keto reductase 1 C3[J].Toxicology and Applied Pharmacology，2014，278(3):238-248.DOI：10.1016/j.taap.2014.04.027)。
AKR1C3与子宫内膜异位密切相关。AKR1C3对若干病理性病状/疾病起作用，这些病理性病状/疾病包括子宫内膜异位。
子宫内膜异位为主要雌激素相依之慢性发炎疾病，其表征为子宫腔外存在子宫内膜组织。子宫内膜异位之主要症状为慢性骨盆疼痛及低生育力。雌激素(E2)缺乏为用于药理治疗子宫内膜异位之临床上经证实之概念及基础主要作用机制。除全身雌激素含量以外，局部衍生的雌激素促进子宫内膜异位病变之发展的迹象愈来愈多。最近已描述子宫内膜异位病变之高组织内雌激素浓度，其表明在子宫内膜异位中的高局部雌激素合成(Huhtinen K，Desai R，Stahlee M，et al.Endomet rial and Endometriotic Concentrations of Estrone and Estradiol Are Determined by Local Metaboli sm Rather than Circulating Levels[J].The Journal of Clinical Endocrinology&Metabolism，2012，97(11):4228-4235.DOI：10.1210/jc.2012-1154)。因此，在子宫内膜异位病变中抑制局部E2之产生被视为用于治疗子宫内膜异位之极具吸引力的作用机制。AKR1C3很大程度上在子宫内膜异位病变中表现，且仅可在卵巢中略微可侦测到(Tina
Figure PCTCN2020099353-appb-000030
Hevir N，Martina
Figure PCTCN2020099353-appb-000031
et al.Disturbed estrogen and progesterone action in ovarian endometriosis[J].Molecular&Cellular Endocrinology，2009，301(1):59-64.DOI：10.1016/j.mce.2008.07.020)。在与CYP19A1(芳香酶)协同作用时，预期AKR1C3成为子宫内膜异位病变中之局部E2产生之关键酶，从而产生促雌激素环境，藉此刺激对雌激素敏感的子宫内膜异位细胞之增生。对AKR1C3之抑制应因此使得局部组织内E2含量下降，且藉此使子宫内膜异位病变之增生减少。不预期在卵巢雌激素产生方面之效果，此系因为AKR1C3在卵巢中仅略微表现，且17βHSD1为显性卵巢羟基类固醇去氢酶。
AKR1C3亦为PGF2α合成酶，且除AKR1C3之调升之外，已展示PGF2α之含量在来自患有腹膜 子宫内膜异位之女性之正位及异位子宫内膜两者中相比在来自患有卵巢子宫内膜瘤之女性之类似组织中明显更高(
Figure PCTCN2020099353-appb-000032
Sinreih，Anko M，Kene N H，et al.Expression of AKR1B1，AKR1C3 and other genes of prostaglandin F2αbiosynthesis and action in ovarian endometriosis tissue and in model cell lines[J].Chemico-Biological Interactions，2015，234(5-6):320-331.DOI：10.1016/j.cbi.2014.11.009)。预期子宫内膜异位组织中之PGF2α造成子宫内膜异位患者的发炎、疼痛及增生，且预期在子宫内膜异位病变中表现之AKR1C3造成子宫内膜异位组织中之高局部PGF2α含量。AK R1C3抑制具有藉由局部减少子宫内膜异位组织中之E2、睪固酮及PGF2α含量来缓解子宫内膜异位患者之增生、疼痛及发炎的潜能。
AKR1C3与多囊性卵巢症候群(PCOS)密切相关。AKR1C3对若干病理性病状/疾病起作用，这些病理性病状/疾病包括多囊性卵巢症候群(PCOS)。
PCOS为常见内分泌病症，其影响高达10％的生殖年龄女性。其临床上与无卵性不孕症、功能不良性出血、雄激素过量、高胰岛素血症及抗胰岛素症、肥胖症及代谢症候群相关联(Fang Y.In sulin resistance and the polycystic ovary syndrome:Mechanism and implications for pathogenesis[J].Endocrine Reviews，1998，18(6):774-800.DOI：10.1210/edrv.18.6.0318)。PCOS之四个主要特征已由雄激素过量学会(Androgen Excess Society)确认：排卵及月经功能异常、生物化学高雄激素血症、临床雄激素过多症(例如，痤疮、多毛症)及多囊性卵巢症(Azziz R，Carmina E，Dewailly D，Diamanti-Kandarakis E，Escobar-Morreale HF，Futterweit W，et al.Position stateme nt:criteria for defining polycystic ovary syndrome as a predominantly hyperandrogenic syndrome:an Androgen Excess Society.[J].Clin Endocrinol Metab 2006；91:4237-45.DOI：10.1055/s-2003-43304)。患有PCOS的绝大部分女性会呈现雄激素过多症之临床症状，例如痤疮、多毛症或主要藉由低生育力或月经过少显现之无排卵(LegroRichard S，Brzyski Robert G，Diamond Michae P，et.al，Letrozole versus Clomiphene for Infertility in the Polycystic Ovary Syndrome[J].New England Jo urnal of Medicine，2014，371(2):119-129.DOI：10.1056/nejmoa1313517)。患有PCOS的女性易患葡萄糖不耐及代谢症候群(Taponen S，Martikainen H，Jarvelin M R.Metabolic Cardio vascular Disease Risk Factors in Women With Self-Reported Symptoms of Oligomenorrhea and/or Hirsutism:Northern Finland Birth Cohort 1966Study[J].Journal of Clinical Endocrinology&Met abolism，2004，89(5):2114-8.DOI:10.1210/jc.2003-031720)，具有心血管疾病相关联之风险因素及很可能增加的未来心血管事件之风险(Mani H，Levy MJ，Davies MJ，et al.Diabetes and car diovascular events in women with polycystic ovary syndrome；a 20-year retrospective cohort study[J].Clin Endocrinol，2013，78(6):926-934.DOI：10.1111/cen.12068)。雄激素过多症、多毛症及/或高雄激素血症为该症候群之关键组成部分，且必选用于诊断PCOS(Azziz R，Carmina E，Dew ailly D，Diamanti-Kandarakis E，Escobar-Morreale HF，Futterweit W，et al.Position statement:criteria for defining polycystic ovary syndrome as a predominantly hyperandrogenic syndrome:an Androgen Excess Society.[J].Clin Endocrinol Metab 2006；91:4237-45.DOI：10.1055/s-2003-43304)。虽然血清睪固酮为高雄激素血症之生物化学评估之关键因素，但最近建议将雄烯二酮作为PCOS相关雄激素过量之更可靠标记物，此系因为雄烯二酮在PCOS女性体内高浓度循环(O’Reilly，Micha el W，Taylor A E，Crabtree N J，et al.Hyperandrogenemia predicts metabolic phenotype in poly cystic ovary syndrome:the utility of serum androstenedione[J].The Journal of Clinical Endocrinol ogy&Metabolism，2014:jc.2013-3399.DOI：10.1210/jc.2013-3399)。PCOS在传统上已被视为卵巢病症(Franks S，Gharani N，Gilling-Smith C.Polycystic ovary syndrome:evidence for a primary disorder of ovarian steroidogenesis[J].Journal of Steroid Biochemistry and Molecular Biology，19 99，69:269-272.DOI：10.1016/s0960-0760(99)00044-8)。然而，对PCOS之卵巢外及肾上腺外雄激素形成增加的关注已突显周围组织的作用，诸如脂肪雄激素形成(Quinkler M，Sinha B，Tom linson JW，Bujalska IJ，Stewart PM，Arlt W(2004)Androgen generation in adipose tissue in women with simple obesity a site-specific role for 17{beta}-hydroxysteroid dehydrogenase type 5.[J].J Endocrinol，2004，183:331-342.DOI:10.1677/joe.1.05762)。AKR1C3为雄激素活化酶，已知其主要系将雄烯二酮转化成睪固酮。已描述PCOS患者之脂肪组织中之AKR1C3的调升，其指示脂肪中之ARK1C3表现明显促进PCOS患者之雄烯二酮的雄激素形成。已另外展示脂肪细胞中之AK R1C3表现藉由胰岛素明显增加，其指示在PCOS中较高的胰岛素能够藉由增加女性皮下脂肪组织中 之AKR1C3活性来推进脂肪雄激素形成(O"Reilly M，Gathercole L，Capper F，et al.Effect of i nsulin on AKR1C3 expression in female adipose tissue:in-vivo and in-vitro study of adipose andr ogen generation in polycystic ovary syndrome[J].The Lancet，2015，385:S16.DOI：10.1016/S0140-6736(15)60331-2)。AKR1C3亦为PGF2α合成酶，且在用于过氧化体增生物活化受体γ(PPARg amma)之内源性配位体的形成中起抑止作用，该过氧化体增生物活化受体γ为胰岛素敏化药物之标靶(Spiegelman et.al，Diabetes 1998，47:507-514.DOI:10.2337/diabetes.47.4.507)。选择性AKR1 C3抑制可提供新颖治疗标靶以减小雄激素负担及改良PCOS中之代谢表现型(O"Reilly M，Gathe rcole L，Capper F，et al.Effect of insulin on AKR1C3 expression in female adipose tissue:in-vivo and in-vitro study of adipose androgen generation in polycystic ovary syndrome[J].The Lancet，2015，385:S16.DOI：10.1016/S0140-6736(15)60331-2；Du et.al，J Clin Endocrinol Metab.2009，94(7):2594-2601.DOI:10.1210/jc.2009-0139)。
AKR1C3与癌症密切相关。AKR1C3对若干病理性病状/疾病起作用，这些病理性病状/疾病包括癌症。
AKR1C3在大量癌症中过度表现，该等癌症包括诸如以下之彼等前列腺癌、乳癌、子宫癌、血癌、肺癌、脑癌及肾癌：子宫内膜癌(Rizner TL，Smuc T，Rupreht R，Sinkovec J，Penning TM AKR1C1and AKR1C3may determine progesterone and estrogen ratios in endometrial cancer.[J].Molecular&Cellular Endocrinology，2005，248(1-2):126-135.DOI：10.1016/j.mce.2005.10.009)、肺癌(Lan Q，Mumford JL，Shen M，Demarini DM，Bonner MR，He X，Yeager M，Welch R，Chanock S，Tian L，Chapman RS，Zheng T，Keohavong P，Caporaso N，Rothman N.Oxidativ e damage-related genes AKR1C3 and OGG1modulate risks for lung cancer due to exposure to P AH-rich coal combustion emissions.Carcinogenesis.2004，25(11):2177–2181.DOI:10.1093/carc in/bgh240)、非霍奇金淋巴瘤(Lan Q，Zheng T，Shen M，et al.Genetic polymorphisms in th e oxidative stress pathway and susceptibility to non-Hodgkin lymphoma.Hum Genet.2007；121:161–168.DOI:10.1007/s00439-006-0288-9)、膀胱癌(Figueroa J D，Núria Malats，Montserrat Ga rcía-Closas，et al.Bladder cancer risk and genetic variation in AKR1C3 and other metabolizing g enes[J].Carcinogenesis，2008，29(10):1955-62..DOI：10.1093/carcin/bgn163)、慢性骨髓白血病(Birtwistle J，Hayden R E，Khanim F L，et al.The aldo-keto reductase AKR1C3 contrib utes to 7，12-dimethylbenz(a)anthracene-3，4-dihydrodiol mediated oxidative DNA damage in m yeloid cells:Implications for leukemogenesis[J].Mutation Research，2009，662(1-2):67-74.DOI:10.1016/j.mrfmmm.2008.12.010)、肾细胞癌(Azzarello J T，Lin H K，Gherezghiher A，et al.E xpression of AKR1C3 in renal cell carcinoma，papillary urothelial carcinoma，and Wilms'tumor[J].International Journal of Clinical&Experimental Pathology，2010，3(2):147.PMID:20126582)、乳癌(Byrns M C，Duan L，Lee S H，et al.Aldo-keto reductase 1C3 expression in MCF-7 cel ls reveals roles in steroid hormone and prostaglandin metabolism that may explain its over-expres sion in breast cancer[J].J Steroid Biochem Mol Biol，2010，118(3):0-187.DOI:10.1016/j.jsbmb.2009.12.009)，然而其调升与肿瘤侵袭性及攻击性通常相关(Azzarello J T，Lin H K，Gherezgh iher A，et al.Expression of AKR1C3 in renal cell carcinoma，papillary urothelial carcinoma，and Wilms'tumor[J].International Journal of Clinical&Experimental Pathology，2010，3(2):147.PMID:20126582；Birtwistle J，Hayden R E，Khanim F L，et al.The aldo-keto reductase AK R1C3 contributes to 7，12-dimethylbenz(a)anthracene-3，4-dihydrodiol mediated oxidative DNA damage in myeloid cells:Implications for leukemogenesis[J].Mutation Research，2009，662(1-2):67-74.DOI:10.1016/j.mrfmmm.2008.12.010；Miller et.al，Aldo-keto reductase family 1 member C3(AKR1C3)is expressed in adenocarcinoma and squamous cell carcinoma but not small cell carcinoma.[J].Int.J.Clin.Exp.Path.2012，5:278-289.PMID:22670171)。AKR1C3能够直接将雌酮及孕酮分别还原成17β-雌二醇及20α-羟孕酮，藉此增强此促增生性信号(Smuc，Rizner，Express ion of 17β-hydroxysteroid dehydrogenases and other estrogen-metabolizing enzymes in different ca ncer cell lines[J].Chem Biol Interact.2009，178:228-33.DOI:10.1016/j.cbi.2008.10.038)。
另外，AKR1C3之前列腺素F合成酶活性催化PGH2至PGF2α及PGD2至11β-PGF2α之转化，已知两者刺激发炎及增生。在缺乏AKR1C3活性之情况下，PGD2(替代转化成PGF2)自发地脱水 及重排以形成抗增生性及抗发炎性PGJ2异构体，包括15d-PGJ2。
概言之，AKR1C3增加增生性PGF2异构体并减少抗增生性PGJ2产物，且因此AKR1C3具有影响激素依赖性及激素非依赖性癌症两者之可能性。在乳癌中，假定AKR1C3之作用可产生其活化导致癌细胞存活之前列腺素F2α(PTGFR)配体(Yoda T et.al，11β-Prostaglandin F2α，a bioacti ve metabolite catalyzed by AKR1C3，stimulates prostaglandin F receptor and induces slug expres sion in breast cancer[J].Mol Cell Endocrinol.15；413:236-247.DOI:10.1016/j.mce.2015.07.008)。
AKR1C3对若干病理性病状/疾病起作用，这些病理性病状/疾病特别的包括前列腺癌。AKR1C3之高度表现已与前列腺癌恶化及攻击性相关联(Stanbrough M et.al，Increased expression of genes converting in androgen-independent prostate cancer[J].Cancer Res 2006，66:2815-25.DOI:10.1158/0008-5472.can-05-4000；Wako K，Kawasaki T，Yamana K.et al.Expression of androgen receptor through androgen-converting enzymes is associated with biological aggressiveness in prostate can cer.J Clin Pathol.2008 Apr；61(4):448–54.DOI:10.1136/jcp.2007.050906)。在激素依赖性前列腺癌中，AKR1C3将雄烯二酮转化成睪固酮，其转而过度活化雄激素受体且促进肿瘤生长(Penning T M，Steckelbroeck S，Bauman D R，et al.Aldo-keto reductase(AKR)1C3:role in p rostate disease and the development of specific inhibitors.[J].Molecular&Cellular Endocrinology，2006，248(1):182-191.DOI:10.1016/j.mce.2005.12.009)。在抗去势性前列腺癌(CRPC)中，瘤内雄激素生物合成中涉及AKR1C3，其分别促进弱雄激素雄烯二酮(A'二酮)至更具活性的雄激素睪固酮及5α-雄固烷二酮(5α-二酮)至DHT之转化(Liu C，Lou W，Zhu Y，et al.Intracrine Androgens and AKR1C3 Activation Confer Resistance to Enzalutamide in Prostate Cancer[J].Cancer Research，2015，75(7):1413-1422.DOI:10.1158/0008-5472.can-14-3080；Fung，K-M.Increased expression of type 2 3-hydroxysteroid dehydrogenase/type 5 17-hydroxysteroid de hydrogenase(AKR1C3)and its relationship with androgen receptor in prostate carcinoma[J].En docrine Related Cancer，2006，13(1):169-180.DOI:10.1677/erc.1.01048)。重要的是，相较于在患有原发性前列腺癌之患者体内，AKR1C3表达在患有CRPC之患者体内展示增加(Stanbrough et.al，Cancer Res 2006，66:2815-2825.DOI:10.1158/0008-5472.CAN-05-4000；Hamid AR，Pfeiff er MJ，Verhaegh GW，Schaafsma E，Brandt A，Sweep FC，Sedelaar JP，Schalken JA.Al do-keto reductase family 1 member C3(AKR1C3)is a biomarker and therapeutic target for cas tration-resistant prostate cancer.Mol.Med.2012；18:1449–1455.DOI:10.2119/molmed.2012.00296；Pfeiffer MJ，Smit FP，Sedelaar JP et al(2011)Steroidogenic enzymes and stem cell markers are upregulated during androgen deprivation in prostate cancer.Mol Med 17:657–664.DOI:10.2119/molmed.2010.00143)。遗传多态性在AKR1C3之AKR1C3基因写码中亦展示为前列腺癌之非依赖性预测子(Yu et.al，PLoS One 2013，8(1):e54627.DOI:10.1371/journal.pone.0054627)。此外，表明了AKR1C3依赖性雄激素重新合成是对诸如阿比特龙(abiraterone)之CYP17A1抑制剂之潜在抗药机制(Mostaghel et.al，Clin Cancer Res 2011，17:5913-5925.DOI:10.1158/1078-0432.CCR-11-0728；Cai et.al，Cancer Res 2011，71:6503-6513.DOI:10.1158/0008-5472.CAN-11-0532)。因此，AKR1C3可为患有CRPC的患者提前具有前景的治疗标靶(Adeniji et.al，J Steroid Biochem Mol Biol 2013，137:136-149.DOI:10.1021/jm3017656)。在多中心阶段I/II研究中，对患有转移性抗去势性前列腺癌之患者测试AKR1C3抑制剂。然而，新颖雄激素生物合成抑制剂并未展示对临床活性之相关迹象(Loriot et.al，Invest New Drugs 2014，32:995-1004.DOI:10.1007/s10637-014-0101-x)。最新资料指示CRPC中之AKR1C3活化为与抗雄激素(恩杂鲁胺enzalutamide)抗药性相关联之重要抗药机制。相较于在亲代细胞中，雄激素前驱体(诸如，胆固醇、DHEA及孕酮)以及雄激素在抗恩杂鲁胺前列腺癌细胞中可展示高度调升。资料表明AKR1C3抑制路径可充当恩杂鲁胺敏化治疗且对患有抗恩杂鲁胺CRPC之患者有恢复功效(Liu C，Lou W，Zhu Y，et al.Intracrine Androgens and AKR1C3 Activation Confer Resistance to Enzalutamide in Prostate Cancer[J].Canc er Research，2015，75(7):1413-1422.DOI:10.1158/0008-5472.can-14-3080)。假定使用AKR1C3抑制剂共同治疗将解决恩杂鲁胺抗性且提高晚期前列腺癌患者之存活期(Thoma et.al，Nature Re views Urology 2015，12:124.DOI:10.1038/nrurol.2015.23)。
AKR1C3对若干病理性病状/疾病起作用，这些病理性病状/疾病特别的包括抗蒽环类霉素癌。蒽环类霉素(或蒽环类抗生素)为用于癌症化学疗法之一类药物，且衍生自链霉菌细菌波塞链霉菌青 灰变种(Fujiwara et.al，Streptomyces bacterium Streptomyces peucetius var.Caesius，Critical Revi ews in Biotechnology，1985，3(2):133.DOI：10.3109/07388558509150782)。此等化合物用于治疗许多癌症，包括白血病、淋巴瘤、乳癌、胃癌、子宫癌、卵巢癌、膀胱癌及肺癌。蒽环类霉素为曾经所研发之抗癌治疗当中最有效的。然而，用于癌症治疗的蒽环类霉素之临床成果被抗药性弱化。已越来越普遍认可蒽环类霉素至其较弱C13-羟基次级代谢物的较高酶还原构成了引起肿瘤之蒽环类霉素抗性的机制中之一者(Gavelova et.al，2008 Chem.Biol.Interact 176，9-18.DOI:10.1016/j.cbi.2008.07.011；Heibein et.al，2012 BMC Cancer 12，381.DOI:10.1186/1471-2407-12-381)。阿霉素之酶代谢是造成在阿霉素化学疗法后观测到的心肌病的原因。已有文献展示诸如阿霉素及道诺霉素(daunorubicin)之临床上投与的蒽环类霉素之代谢中涉及AKR1C3(Novotna et.al，Toxicol.Letter 2008，181:1-6.DOI:10.1016/j.toxlet.2008.06.858)。在2012年，亚洲乳癌患者已展示阿霉素药效学与AKR1C3遗传变异体之相关性：一种遗传变异体与较长无进展存活期及在基于阿霉素之疗法之后的整体存活期相关联，从而表明与阿霉素代谢之潜在交互作用(Voon et.al，British J of Cli n Pharmacology 2012，75:1497-1505.DOI:10.1111/bcp.12021)。最近，可证实AKR1C3促进癌细胞对蒽环类霉素治疗之抗性，且因此具有蒽环类霉素的特定AKR1C3抑制剂之伴随投与可为用于成功预防及治疗抗蒽环类霉素抵肿瘤之有效策略(Hofman et.al，Toxicology and Applied Pharmacology 2014，278:238-248.DOI:10.1016/j.taap.2014.04.027)。
研究还表明，AKR1C3在食管癌，前列腺癌和非小细胞肺癌的放射治疗抵抗性中起关键作用(Sun et al Overexpression of AKR1C3 significantly enhances human prostate cancer cells resistance to ra diation. Oncotarget.2016 Jul 26；7(30):48050-48058.DOI:10.18632/oncotarget.10347；Xiong et al.；E levated Expression of AKR1C3 Increases Resistance of Cancer Cells to Ionizing Radiation via Modul ation of Oxidative Stress.PLoS ONE 2014 9(11):e111911.DOI:10.1371/journal.pone.0111911)。使用来自前列腺细胞系DU145及其稳定高表达AKR1C3的相应细胞系(AKR1C3-over)研究了前列腺癌细胞中的AKR1C3抗放射性的作用。吲哚美辛是AKR1C3活性的特异性抑制剂，它可明显增强前列腺细胞对放射治疗的敏感性。研究发现PGF2α不仅可以促进前列腺癌细胞的增殖，还可以增强前列腺癌细胞对辐射的抵抗力。PGF2α在AKR1C3-over细胞中的积累导致激活MAPK通路的激活并抑制PPARγ的表达。同时研究发现AKR1C3高表达可引起NSCL抗辐射性(Xie et al；Aldo-keto reductase 1C3 may be a new radioresistance marker in non-small-cell lung cancer. Cancer Gene Ther.2013 Apr；20(4):260-6.DOI:10.1038/cgt.2013.15)。在A549/R和SPCA1/R细胞中，AKR1C3mRNA和蛋白水平显着上调。A549/R和SPCA1/R中的AKR1C3蛋白水平比敏感型的对照细胞要分别高6.2倍和3.5倍。以上研究表明，降低AKR1C3表达可有效增加NSCLC细胞对放射治疗的敏感性。
AKR1C3表达在抗免疫治疗患者中明显上调。已有文献报导13例接受抗PD-1治疗的肾细胞癌患者中，有4名有反应者(R)，9名无反应者(NR)；全基因组分析显示234个基因在R与NR中表达具有显著差异。其中之一的显著差异基因是在无反应者中AKR1C3表达明显增高(Ascierto 2015 The intratumoral balance between metabolic and immunologic gene expression is associated with anti-PD-1 response in patients with renal cell carcinoma Cancer Immunol Res 2016 4 726-733，doi:10.1158/2326-6066.CIR-16-0072.)
研究表明联合使用AKR1C3特异性抑制剂和daunorubicin或cytarabine等化疗药物可大幅度增加血癌细胞的杀伤能力(Verma et al，Potent and Highly Selective Aldo-Keto Reductase 1C3(AKR1C3)Inhibitors Act as Chemotherapeutic Potentiators in Acute Myeloid Leukemia and T-Cell Acute Lymph oblastic Leukemia.J.Med.Chem.2019，62，7：3590-3616，DOI：10.1021/acs.jmedchem.9b00090)。
AKR1C3对若干病理性病状/疾病起作用，这些病理性病状/疾病特别的包括异位性皮肤炎。抗原对异位性个体的攻击造成PGD2及组织胺之释放，其展示PGD2几乎不促进人类皮肤之实时过敏反应且PGD2为异位性皮肤炎(AD)中促使皮肤发炎的脂质介体(Barr et.al，Br J Pharmacol.1988，94:773-80.PMID:2460180；Satoh et.al，J Immunol.2006，177:2621-9.DOI:10.4049/jimmunol.177.4.2621；Shimura et.al，Am J Pathol.2010，176:227-37.DOI:10.2353/ajpath.2010.090111)。PGD2为相对不稳定的促炎性介体，其自发地转化成强抗炎性介体15d-PGJ2。彼转化藉由PGD2藉AKR1C3至促炎性9α，11β-PGF2之代谢来转移(Mantel et.al，Exp Dermatol.2016，25(1):38-43.DOI:10.1111/exd.12854)。经证实，AKR1C3在人类AD样本中调升，且已假定AKR1C3在皮肤病理学(尤其是异位性皮肤炎)及瘢痕瘤中调节发炎之作用(Mantel et.al，J Invest Dermatol 2012，132 (4):1103-1110.DOI:10.1038/jid.2011.412；Mantel et.al，Exp Dermatol.2016，25(1):38-43.DOI:10.1111/exd.12854)。AKR1C3抑制可为用于治疗AD及瘢痕瘤之新颖选项。
AKR1C3对若干病理性病状/疾病起作用，这些病理性病状/疾病特别的包括发炎。前列腺素生物合成中涉及AKR1C3，其催化PGH2至PGF2α及PGD2至11β-PGF2之转化。已假定AKR1C3之表现及调升藉由直接引起9α，11β-PGF2合成速率提高以及转移强抗炎性介体15d-PGJ2之自发性产生来支援发炎(Mantel et.al，J Invest Dermatol 2012，132(4):1103-1110.DOI:10.1038/jid.2011.412)。亦已在HL-60细胞中(Desmond et.al，Cancer Res 2003，63:505-512.PubMed:12543809)及MCF-7细胞中(Byrns et.al，J Steroid Biochem Mol Biol 2010，118:177-187.DOI:10.1016/j.jsbmb.2009.12.009)涉及AKR1C3之此功能。假定对AKR1C3之抑制增加15d-PGJ2(抗炎性脂质)，其主要经由过氧化体增殖剂活化受体γ(PPAR-γ)之活化及/或对在免疫细胞中传信之NF-κB之抑制直接调节其作用(Maggi et.al，Diabetes 2000，49:346-355.DOI:10.2337/diabetes.49.3.346；Scher et.al，Clinical Immunology 2005，114:100-109.DOI:10.1016/j.clim.2004.09.008)。先前资料已展示PPAR-γ活化减轻小鼠之皮肤及肺脏中之过敏原诱发性发炎(Ward et.al，Carcinogenesis.2006，27(5):1074-80.DOI:10.1093/carcin/bgi329；Dahten et.al，J Invest Dermatol.2008，128(9):2211-8.DOI:10.1038/jid.2008.84)。此表明AKR1C3抑制在抑制发炎方面之作用。
AKR1C3对若干病理性病状/疾病起作用，这些病理性病状/疾病包括其他疾病。此外，AKR1C3抑制剂具有用于治疗以下之潜能：前列腺增生(Roberts et.al，Prostate 2006，66(4)，392-404.DOI:10.1002/pros.20362)、脱发(L.Colombe et.al，Exp Dermatol 2007，16(9)，762-769.DOI:10.1111/j.1600-0625.2007.00639.x)、肥胖症(P.A.Svensson et.al，Cell Mol Biol Lett 2008，13(4)，599-613.DOI:10.2478/s11658-008-0025-6)、过早性成熟(C.He，Hum Genet 2010，128(5)，515-527.DOI:10.1007/s00439-010-0878-4.)及慢性阻塞性肺病(S.Pierrou，Am J Respir Crit Care2007，175(6)，577-586.DOI:10.1164/rccm.200607-931OC)。
现已发现本发明之化合物具有抑制AKR1C3活性的效果，因此可用于治疗或预防AKR1C3相关病症，诸如妇科病症(特定言之，子宫内膜异位相关及多囊性卵巢症候群相关妇科病症)、病状及疾病，代谢病症，过度增生性病症、病状及疾病，及发炎病症以及其他相关疾病或病症。
基于此，还提供以下医药用途相关的技术方案。
含有上述的化合物以及其药学上可接受的盐或溶剂合物或同位素取代化合物的药品。
所述药品为预防或治疗与AKR1C3抑制剂相关的疾病的药品。
进一步的，所述药品用于预防或治疗疾病/病症，所述疾病/病症包括子宫内膜异位症、子宫平滑肌瘤、子宫出血性病症、痛经、前列腺增生、痤疮、皮脂溢、脱发、过早性成熟、多囊卵巢综合征、慢性阻塞性肺病COPD、肥胖、炎性疼痛或癌症或炎症或癌性疼痛。
更进一步，所述癌症包括前列腺癌、原发性前列腺癌、晚期前列腺癌、转移性前列腺癌、激素原初前列腺癌，难治性前列腺癌或去势抗性前列腺癌CRPC和乳腺癌、肺癌、子宫内膜癌、肾细胞癌、膀胱癌、非霍奇金淋巴瘤以及急性髓性白血病AML、T细胞急性淋巴细胞白血病T-ALL、白血病。
上述的化合物以及其药学上可接受的盐或溶剂合物或同位素取代化合物在制备治疗活预防相关疾病/病症的药品中的用途，所述疾病/病症包括子宫内膜异位症、子宫平滑肌瘤、子宫出血性病症、痛经、前列腺增生、痤疮、皮脂溢、脱发、过早性成熟、多囊卵巢综合征、慢性阻塞性肺病COPD、肥胖、炎性疼痛或癌症或炎症或癌性疼痛。
还提供一种用于增强癌症或肿瘤放射疗法敏感性的药品，该药品含有上述的化合物以及其药学上可接受的盐或溶剂合物或同位素取代化合物，其用于：在癌症或肿瘤患者对放射疗法具有抗性时提高放射疗法的疗效；或治疗对放射疗法具有抗性的癌症或肿瘤患者。
还提供一种用于增强癌症或肿瘤免疫疗法敏感性的药品，该药品含有上述的化合物以及其药学上可接受的盐或溶剂合物或同位素取代化合物，其用于：在癌症或肿瘤患者对免疫疗法具有抗性时提高免疫疗法的疗效；或治疗对免疫疗法具有抗性的癌症或肿瘤患者。
还提供一种用于增强癌症或肿瘤化疗敏感性的药品，该药品含有上述的化合物以及其药学上可接受的盐或溶剂合物或同位素取代化合物，其用于：在癌症或肿瘤患者对化疗具有抗性时提高化疗的疗效；或治疗对化疗具有抗性的癌症或肿瘤患者。
还提供上述的化合物以及其药学上可接受的盐或溶剂合物或同位素取代化合物的制药用途，该药用于在癌症或肿瘤患者对免疫具有抗性时提高免疫疗法的疗效；或者该药用于治疗对免疫疗法具 有抗性的癌症或肿瘤患者。
还提供一种用于增强癌症或肿瘤化疗敏感性的药品，该药品含有上述的化合物以及其药学上可接受的盐或溶剂合物或同位素取代化合物，其用于：在癌症或肿瘤患者对化疗具有抗性时提高化疗的疗效；或治疗对化疗具有抗性的癌症或肿瘤患者，所述化疗使用的药品含有柔红霉素daunorubicin或阿糖胞苷cytarabine。
上述的化合物以及其药学上可接受的盐或溶剂合物或同位素取代化合物的用途，其用于增强癌症或肿瘤放射疗法敏感性或用于增强含有柔红霉素daunorubicin或阿糖胞苷cytarabine的药品化疗癌症或肿瘤的敏感性。
还提供上述的化合物以及其药学上可接受的盐或溶剂合物或同位素取代化合物的作为AKR1C3酶抑制剂的用途。
还提供上述的化合物以及其药学上可接受的盐或溶剂合物或同位素取代化合物的制药用途，该药为AKR1C3酶抑制剂。
还提供上述的化合物以及其药学上可接受的盐或溶剂合物或同位素取代化合物的制药用途，该药用于在癌症或肿瘤患者对放射疗法具有抗性时提高放射疗法的疗效；或者该药用于治疗对放射疗法具有抗性的癌症或肿瘤患者。
还提供上述的化合物以及其药学上可接受的盐或溶剂合物或同位素取代化合物的制药用途，该药用于在癌症或肿瘤患者对化疗具有抗性时提高化疗的疗效；或者该药用于治疗对化疗具有抗性的癌症或肿瘤患者。
还提供上述的化合物以及其药学上可接受的盐或溶剂合物或同位素取代化合物的制药用途，该药用于在癌症或肿瘤患者对化疗具有抗性时提高化疗的疗效；或者该药用于治疗对化疗具有抗性的癌症或肿瘤患者，所述化疗使用的药品含有柔红霉素daunorubicin或阿糖胞苷cytarabine。
关于本文所述药品或制剂，所制得的药物包含特定剂量范围的所示化合物或其盐或溶剂合物，和/或，所制得的药物为特定剂型、特定给药方式施用。
关于本文所述用途，所制得的药物还可包含药学上可接受的辅料或赋形剂。所述药物可以为临床施用的任何剂型，例如片剂、栓剂、分散片、肠溶片、咀嚼片、口崩片、胶囊、糖衣剂、颗粒剂、干粉剂、口服溶液剂、注射用小针、注射用冻干粉针或大输液。根据具体剂型和施用方式，所述药物中的药学上可接受的辅料或赋形剂可以包括下述的一种或多种：稀释剂、增溶剂、崩解剂、悬浮剂、润滑剂、粘合剂、填充剂、矫味剂、甜味剂、抗氧化剂、表面活性剂、防腐剂、包裹剂和色素等。
优选地，所述患者是哺乳动物，更优选是人。
具体实施方式
以下参照具体的实施例来说明本发明。本领域技术人员能够理解，这些实施例仅用于说明本发明，其不以任何方式限制本发明的范围。
下述实施例中的实验方法，如无特殊说明，均为常规方法。下述实施例中所用的药材原料、试剂材料等，如无特殊说明，均为市售购买产品。
“患者”及“个体”可互换使用，是指需要癌症治疗的哺乳动物。通常，患者是人类。通常，患者是诊断患有癌症的人类。在某些实施例中，“患者”或“个体”可指用于筛选、表征及评估药物及疗法的非人类哺乳动物，例如非人类灵长类动物、狗、猫、兔、猪、小鼠或大鼠。
“前药”是指投与或施用之后经新陈代谢或以其他方式转化为关于至少一种性质的生物学活性或活性更高的化合物(或药物)的化合物。相对于药物，前药以使其相对于药物活性较低或无活性的方式化学修饰，但化学修饰使得在前药投与之后通过代谢或其他生物过程产生相应药物。前药可相对于活性药物具有改变的代谢稳定性或输送特征、较少副作用或较低毒性或经改良的风味(参见(例如)参考文献Nogrady，1985，Medicinal Chemistry A BiochemicalApproach，Oxford University Press，NewYork，第388页至392页，其以引用式并入本文中)。前药可使用除相应药物以外的反应物来合成。
“实体肿瘤”是指包括(但不限于)骨、脑、肝、肺、淋巴结、胰脏、前列腺、皮肤及软组织(肉瘤)中的转移肿瘤的实体肿瘤。
药物的“治疗有效量”是指当向患有癌症的患者投与或施用时，将具有预期的治疗效应(例如患者中一或多种癌症的临床表现的缓和、改善、缓解或消除)的药物的量。治疗效应不必通过投与或施用一个剂量而出现，且可仅在投与或施用一系列剂量后出现。因此，治疗有效量可以一或多次来投与或施用。
病况或患者的“治疗”是指采取步骤以获得有益或期望结果(包括临床结果)。出于本发明的目的，有益或期望临床结果包括(但不限于)一或多种癌症症状的缓和或改善；疾病程度的减弱；疾病进展的延迟或减缓；疾病状态的改善、缓解或稳定；或其他有益结果。在一些情形下，癌症的治疗可使得部分反应或稳定疾病。
“肿瘤细胞”是指任何适当物种(例如，哺乳动物，例如鼠类、犬、猫、马或人类)的肿瘤细胞。
放射疗法，即癌症的放射疗法，放射治疗有多种实施方法，最常用的是：
光子(γ-射线)束放射，由直线加速器发射大量光子(γ-射线)束；
中子束放射，可用于治疗组织边缘狭窄的某些癌肿；
电子束放射，因具有穿透组织极浅的特性，适用于治疗皮肤或表浅癌肿；
质子放射，虽用途有限，但对需要深度而范围极狭小的照射野可提供锐利的射线周缘；
近距放射，将强力放射源，通过针头植入肿瘤组织本身(如前列腺或肺部)，从而达到小范围高剂量的效应；
全身性放射性核素治疗，可用于有核素摄吸的器官受体(如甲状腺癌)或抑制全身骨骼部位的受体(如治疗转移性前列腺癌的放射性锶)。
痊愈性放射治疗一般需将肿瘤局部或其局部区域包含在照射野之内。
放射性照射细胞损伤是无选择性的和非特异性的，对DNA产生复杂的作用，疗效优劣按细胞损伤程度超越其修复能力的多少而定。一般来说，正常组织的修复效率高于癌细胞，从而是的放射疗法能使得病人获益。
化疗，化疗是化学药物治疗的简称，通过使用化学治疗药物杀灭癌细胞达到治疗目的。化疗是目前治疗癌症最有效的手段之一，和手术、放疗一起并称癌症的三大治疗手段。手术和放疗属于局部治疗，只对治疗部位的肿瘤有效，对于潜在的转移病灶(癌细胞实际已经发生转移，但因为目前技术手段的限制在临床上还不能发现和检测到)和已经发生临床转移的癌症就难以发挥有效治疗了。而化疗是一种全身治疗的手段，无论采用什么途径给药(口服、静脉和体腔给药等)，化疗药物都会随着血液循环遍布全身的绝大部分器官和组织。因此，对一些有全身播撒倾向的肿瘤及已经转移的中晚期肿瘤，化疗都是主要的治疗手段。一般而言化疗的药物都是细胞毒性药物，其能直接杀死细胞，但由于癌细胞、正常细胞的某些特性不同，常常使得化疗药物对癌细胞的杀灭作用更大，从而能使得病人获益。但化疗依然存在严重的毒副作用，包括消化系统反应、骨髓抑制、脱发等，某些毒副作用会然部分患者无法再继续接受化疗或某种化疗药物。
免疫疗法。正常情况下，人体的免疫系统可以识别并清除肿瘤微环境中的肿瘤细胞，但为了生存和生长，肿瘤细胞能够采用不同策略，使人体的免疫系统受到抑制，不能正常的杀伤肿瘤细胞，从而在抗肿瘤免疫应答的各阶段得以幸存。人体免疫系统识别并清除肿瘤细胞的过程(肿瘤-免疫循环)具有多个环节，任一环节被抑制，都能导致肿瘤细胞不能被正常的清除。不同肿瘤可以通过不同环节的异常抑制免疫系统对肿瘤细胞的有效识别和杀伤从而产生免疫耐受，甚至促进肿瘤的发生、发展。
肿瘤免疫治疗就是通过重新启动并维持肿瘤-免疫循环，恢复机体正常的抗肿瘤免疫反应，从而控制与清除肿瘤的一种治疗方法。包括单克隆抗体类免疫检查点抑制剂、治疗性抗体、癌症疫苗、细胞治疗和小分子抑制剂等。近几年，肿瘤免疫治疗的好消息不断，目前已在多种肿瘤如黑色素瘤，非小细胞肺癌、肾癌和前列腺癌等实体瘤的治疗中展示出了强大的抗肿瘤活性，多个肿瘤免疫治疗药物已经获批准临床应用。
以上对本发明具体实施方式的描述并不限制本发明，本领域技术人员可以根据本发明作出各种改变或变形，只要不脱离本发明的精神，均应属于本发明所附权利要求的范围。
以下是本发明的具体试验和实施例部分。
以下试验将揭示申请人研发的AKR1C3抑制剂的体外抑制活性，申请人在此声明，以下的实验数据的权利属于申请人。
申请人声明以下试验中公开的部分具体化合物在本发明已公开的化合物的具体合成方法以及合成路线的基础上，参考专利公开文献(比如申请号PCT/US2016/021581，公开号WO2016/145092；申请号PCT/US2016/062114，公开号WO2017/087428)或其他公开文献揭露的类似方法和操作(虽然底物不同，产率有高有低但本领域即药物化学、有机化学等掌握有机合成技能的技术人员依然能合成得到)能够合成得到，并且申请人已经过核磁、质谱确证结构，本次申请提供代表性的化合物合成方法、核磁数据以及对AKR1C3酶的体外抑制活性。
化合物合成实验
合成方法概述
Figure PCTCN2020099353-appb-000033
路线1
Figure PCTCN2020099353-appb-000034
路线2
Figure PCTCN2020099353-appb-000035
路线3
英文简写解释
MTBE，甲基叔丁基醚；DMAP，4-二甲氨基吡啶；T 3P，丙基磷酸酐；THF，四氢呋喃；DCM，二氯甲烷；EA或EtOAC，乙酸乙酯；TEA，三乙胺；HPLC，高效液相色谱仪；DBAD，偶氮二甲酸二叔丁酯；TFA，三氟乙酸；LCMS，液质联用；EtOH，乙醇；t-BuOH，叔丁醇；DMF，二甲基甲酰胺；PE，石油醚，petroleum ether；eq，当量即摩尔比；TBAF，四丁基氟化铵；DIPEA，N,N-二异丙基乙胺；reflux，回流；rt，室温；
合成过程中未注明来源的化学试剂、药品均为分析纯或化学纯，均从商业的试剂公司购买得到。
其他出现的英文简写以有机化学领域中的解释为准。
2号化合物的合成
Figure PCTCN2020099353-appb-000036
氮气保护下，将2-A1(500mg，1.51mmol，参照29号化合物合成方法合成)与2-A2(336mg，2.27mmol，商业购买)溶于无水THF中(10mL)。降温至0℃，加入三苯基磷(991mg，3.78mmol)，然后缓慢滴加偶氮二甲酸二叔丁酯(870mg，3.78mmol)的THF溶液(5mL)，保温0℃半小时，然后室温搅拌2.5小时。反应完毕之后，0℃滴加入水(5mL)，DCM萃取(10mL×3)，水洗(3mL×2)，干燥浓缩，高效液相制备得2号化合物纯品(340mg，48.9％)，为淡黄色油状物。 1H-NMR(400M，CD 3OD)：δ8.01(d，J＝8.4Hz，1H)，7.52-7.47(m，2H)，7.45(s，2H)，7.30(d，J＝1.2Hz，1H)，7.25-7.23(m，1H)，7.10-7.07(m，2H)，5.54-5.52(m，1H)，3.08(s，3H)，2.98(s，3H)，1.61(d，J＝6.4Hz，3H).
3号化合物的合成
Figure PCTCN2020099353-appb-000037
氮气保护下，将3-A1(200mg，0.632mmol，参照29号化合物合成方法合成)与3-A2(140mg，0.948mmol，商业购买)溶于无水THF中(5mL)。降温至0℃，加入三苯基磷(414mg，1.58mmol)，然后缓慢滴加偶氮二甲酸二叔丁酯(363mg，1.58mmol)的THF溶液(2mL)，保温0℃半小时，然后室温搅拌2.5小时。反应完毕之后，0℃滴加入水(5mL)，DCM萃取(5mL×3)，水洗(2mL×2)，干燥浓缩，高效液相制备得3号化合物纯品(160mg，收率56.7％)，为淡黄色油状物。 1H-NMR(400M，CDCl 3)：δ7.95(d，J＝8.4Hz，1H)，7.38-7.32(m，2H)，7.25(s，1H)，7.20-7.16(m，3H)，7.05-7.02(m，2H)，4.94(s，2H)，3.02(s，3H)，2.90(s，3H)。
4号化合物的合成
Figure PCTCN2020099353-appb-000038
氮气保护下，将三氯氧磷(580mg，3.78mmol)滴加入无水DCM中(5mL)，降温至-40℃，滴加入4-A1(500mg，1.51mmol，参照29号化合物合成方法合成)的DCM溶液(3mL)，然后滴加入TEA(397mg，3.9mmol)的DCM溶液(2mL)，保温-40℃6小时，原料消失。滴加入甲胺(1.6g，12.8mmol，25％inTHF)，然后滴加入TEA(1.29g，12.85mmol)的DCM溶液(5mL)。保温-40℃半小时，自然升至常温搅拌过夜。反应完毕之后，降温至0℃，滴加入碳酸钾溶液(1g，10mL)，DCM萃取(10mL×3)，水洗(5mL×2)，干燥浓缩，高效液相制备得纯品(380mg，收率57.7％)，为淡黄色粘稠油状物。 1H-NMR(400MHz，CDCl 3)：δ7.95(d，J＝8.4Hz，1H)，7.42(t，J＝7.9Hz，1H)，7.21-7.18(m，2H)，7.12–7.07(m，2H)，7.04(s，1H)，5.47-5.44(m，1H)，3.08(s，3H)，2.97(s，3H)，2.59(d，J＝12.2Hz，3H)，2.51(m，2H)，2.38(d，J＝12.2Hz，3H)，1.53(d，J＝6.5Hz，3H)。MS：Calculated 436.2，found 437.1([M+H] +)。
5号化合物的合成
Figure PCTCN2020099353-appb-000039
氮气保护下，将三氯氧磷(242mg，1.58mmol)滴加入无水DCM中(5mL)，降温至-40℃，滴加入5-A1(200mg，0.63mmol，参照29号化合物合成方法合成)的DCM溶液(3mL)，然后滴加入TEA(166mg，1.64mmol)的DCM溶液(2mL)，保温-40℃6小时，原料消失。滴加入甲胺(670g，5.40mmol，25％inTHF)，然后滴加入TEA(546g，5.4mmol)的DCM溶液(5mL)。保温-40℃半小时，自然升至常温搅拌过夜。反应完毕之后，降温至0℃，滴加入碳酸钾溶液(1g，10mL)，DCM萃取(10mL×3)，水洗(5mL×2)，干燥浓缩，高效液相制备得5号化合物纯品(130mg，收率48.9％)，为淡黄色油状物。 1H-NMR(400M，CDCl 3)δ7.99(d，J＝8.4Hz，1H)，7.47-7.44(m，2H)，7.24(d，J＝1.6Hz，1H)，7.07-7.04(m，3H)，4.94(d，J＝7.9Hz，2H)，3.11-3.02(m，6H)，2.62(s，3H)，2.59(s，3H)。MS：Calculated 422.1，found 423.2([M+H] +)。
6号化合物的合成
Figure PCTCN2020099353-appb-000040
氮气保护下，三(二甲胺基)膦(179mg，1.1mmol，商业购买)与四氮唑(0.64mg，0.009mmol)加入到乙腈中(3mL)，然后滴加入6-A1(300mg，0.914mmol，参照29号化合物合成方法合成)的乙腈溶液(2mL)，室温搅拌两小时，滴加入TEA(277mg，2.74mmol)，过氧化叔丁醇(329mg，3.66mmol)，常温搅拌三小时，反应完毕。滴加入硫代硫酸钠水溶液(4mL)，DCM萃取(5mL×3)，干燥浓缩，高效液相制备分离得到6号化合物(120mg，收率28.3％)，为淡黄色油状物。 1H-NMR(400M，CDCl 3):δ7.97(d，J＝8.4Hz，1H)，7.42-7.38(m，1H)，7.23-7.20(m，2H)，7.10-7.05(m，3H)，5.41-5.38(m，1H)，3.08(s，3H)，2.98(s，3H)，2.64(d，J＝10.0Hz，6H)，2.43(d，J＝10.0Hz，6H)，1.52(d，J＝6.5Hz，3H)。MS：Calculated 464.2，found 465.2([M+H] +)。
7号化合物的合成
Figure PCTCN2020099353-appb-000041
氮气保护下，三(二甲胺基)膦(124mg，0.76mmol，商业购买)与四氮唑(0.4mg，0.0057mmol)加入到乙腈中(3mL)，然后滴加7-A1(200mg，0.63mmol，参照29号化合物合成方法合成)的乙腈溶液(2mL)，室温搅拌2小时，滴加入TEA(192mg，1.90mmol)，过氧化叔丁醇(228mg，2.53mmol)，常温搅拌3小时，反应完毕。滴加入硫代硫酸钠水溶液(4mL)，DCM萃取(5mL×3)，干燥浓缩，高效液相制备分离得到7号化合物(90mg，收率31.6％)，为淡黄色油状物。 1H-NMR(400M，CDCl 3):δ8.00(d，J＝8.4Hz，1H)，7.46-7.42(m，1H)，7.28-7.23(m，2H)，7.12-7.08(m，3H)，4.97-4.95(m，2H)，3.11(s，3H)，3.00(s，3H)，2.60(d，J＝10.0Hz，12H)。MS：Calculated 450.2，found 451.2([M+H] +)。
8号化合物的合成
Figure PCTCN2020099353-appb-000042
氮气保护下，将8-A1(300mg，0.91mmol，参照29号化合物合成方法合成)与8-A2(202mg，1.36mmol)溶于无水THF中(5mL)。降温至0℃，加入三苯基磷(600mg，2.30mmol)，然后缓慢滴加偶氮二甲酸二叔丁酯(530mg，2.30mmol)的THF溶液(3mL)，保温0℃半小时，然后室温搅拌2.5小时。反应完毕之后，0℃滴加入水(5mL)，DCM萃取(5mL×3)，水洗(2mL×2)，干燥浓缩，高效液相制备得8号化合物纯品(230mg，收率54.9％)，为淡黄色固体。 1H-NMR(400M，DMSO-d6)：δ8.13(d，J＝8.4Hz，1H)，7.68(s，2H)，7.56(dd，J＝8.4，2.0Hz，1H)，7.47(dd，J＝6.8，2.0Hz，2H)，7.33(d，J＝1.6Hz，1H)，7.05-7.03(m，2H)，5.52-5.50(m，1H)，2.95(s，6H)，1.57(d，J＝6.5Hz，3H)。
9号化合物的合成
Figure PCTCN2020099353-appb-000043
氮气保护下，将9-A1(300mg，0.95mmol，参照29号化合物合成方法合成)和2，4，6-三氟苯酚(210mg，1.40mmol)溶于干燥THF(5mL)中，加入三苯基膦(622mg，2.40mmol)，降温至0℃，滴加入偶氮二甲酸二叔丁基酯(550mg，2.40mmol)的THF溶液(4mL)，反应2.5h完毕，加入水(5mL)，DCM萃取(3x15mL)，盐水洗，干燥，除去溶剂，高效液相制备得到9号化合物(210mg，收率为49.5％)，为类白色固体。 1H-NMR(400M，CDCl 3):δ8.02(d，J＝8.4Hz，1H)，7.46(d，J＝8.8Hz，2H)，7.40(d，J＝8.4Hz，1H)，7.32(s，2H)，7.24(s，1H)，7.07(d，J＝8.8Hz，2H)，5.01(s，2H)，3.11(s，3H)，3.02(s，3H)。
10号化合物
Figure PCTCN2020099353-appb-000044
氮气保护下，将三氯氧磷(348mg，2.30mmol)滴加入无水DCM中(5mL)，降温至-40℃，滴加入10-A1(300mg，0.91mmol，参照29号化合物合成方法合成)的DCM溶液(3mL)，然后滴加入TEA(240mg，2.40mmol)的DCM溶液(2mL)，保温-40℃6小时，原料消失。滴加入甲胺(960mg，7.70mmol，25％inTHF)，然后滴加入TEA(782mg，7.70mmol)的DCM溶液(5mL)。保温-40℃0.5h，自然升至常温搅拌过夜。降温至0℃，滴加入碳酸钾溶液(1g，10mL)，DCM萃取(10mL×3)，水洗(5mL×2)，干燥浓缩，高效液相制备得10化合物纯品(60mg，收率15.2％)，为淡黄色粘稠油状物。 1H-NMR(400MHz，CDCl 3)：δ7.97(d，J＝8.4Hz，1H)，7.46(d，J＝8.5Hz，2H)，7.24-7.22(m，1H)，7.09(s，1H)，7.05(d，J＝8.5Hz，2H)，5.48-5.44(m，1H)，3.07(s，6H)，2.61(d，J＝12.1Hz，3H)，2.42(d，J＝12.1Hz，3H)，1.54(d，J＝6.4Hz，3H)。MS：Calculated 436.2，found 437.2([M+H] +)。
11号化合物
Figure PCTCN2020099353-appb-000045
氮气保护下，将三氯氧磷(242mg，1.58mmol)滴加入无水DCM中(5mL)，降温至-40℃，滴加入11-A1(200mg，0.63mmol，参照29号化合物合成方法合成)的DCM溶液(3mL)，然后滴加入TEA(166mg，1.64mmol)的DCM溶液(2mL)，保温-40℃6小时，原料消失。滴加入甲胺(670mg，5.40mmol，25％inTHF)，然后滴加入TEA(546mg，5.4mmol)的DCM溶液(5mL)。保温-40℃0.5h，自然升至常温搅拌过夜。降温至0℃，滴加入碳酸钾溶液(1g，10mL)，DCM萃取(10mL×3)，水洗(5mL×2)，干燥浓缩，高效液相制备得11号化合物纯品(95mg，收率35.7％)，为淡黄色粘稠油状物。 1H-NMR(400，MeOD)：δ8.04(d，J＝8.4Hz，1H)，7.49(d，J＝8.7Hz，2H)，7.40(d，J＝8.5Hz，1H)，7.27(s，1H)，7.09(d，J＝8.6Hz，2H)，4.99(d，J＝7.9Hz，2H)，3.12(s，3H)，3.07(s，3H)，2.50(d，J＝12.4Hz，6H)。MS：Calculated 422.1，found 423.2([M+H] +)。
12号化合物
Figure PCTCN2020099353-appb-000046
氮气保护下，三(二甲胺基)膦(179mg，1.1mmol，商业购买)与四氮唑(0.64mg，0.009mmol)加入到乙腈中(3mL)，然后滴加入12-A1(300mg，0.91mmol，参照29号化合物合成方法合成)的乙腈溶液(2mL)，室温搅拌2h，滴加入TEA(277mg，2.74mmol)，过氧化叔丁醇(329mg，3.66mmol)，常温搅拌3h，反应完毕。滴加入硫代硫酸钠水溶液(4mL)，DCM萃取(5mL×3)，干燥浓缩，高效液相制备分离得到12号化合物76.5mg，收率18.2％，为淡黄色油状物。 1H-NMR(400M，CDCl 3):δ7.98(d，J＝8.4Hz，1H)，7.45(d，J＝8.6Hz，2H)，7.24(d，J＝1.5Hz，1H)，7.09(d，J＝1.4Hz，1H)，7.04(d，J＝8.6Hz，2H)，5.43-5.39(m，1H)，3.07(s，6H)，2.65(d，J＝10.0Hz，6H)，2.44(d，J＝10.0Hz，6H)，1.52(d，J＝6.5Hz，3H)。MS:Calculated 464.2，found 465.2([M+H] +)。
13号化合物
Figure PCTCN2020099353-appb-000047
氮气保护下，三(二甲胺基)膦(124mg，0.76mmol，商业购买)与四氮唑(0.4mg，0.0057mmol)加入到乙腈中(3mL)，然后滴加入13-A1(200mg，0.63mmol，参照29号化合物合成方法合成)的乙腈溶液(2mL)，室温搅拌2h，滴加入TEA(192mg，1.90mmol)，过氧化叔丁醇(228mg，2.53mmol)，常温搅拌2h，反应完毕。滴加入硫代硫酸钠水溶液(4mL)，DCM萃取(5mL×3)，干燥浓缩，高效液相制备分离得到13号化合物(31mg，收率9.0％)，为淡黄色油状物。 1H-NMR(400M，CDCl 3):δ7.99(d，J＝8.4Hz，1H)，7.45(d，J＝8.8Hz，2H)，7.24(m，1H)，7.06-7.04(m，3H)，4.93(d，J＝7.6Hz，2H)，3.11(s，3H)，3.02(s，3H)，2.62(s，6H)，2.59(s，6H)。MS：Calculated 450.2，found 451.1([M+H] +)。
14号化合物
Figure PCTCN2020099353-appb-000048
氮气保护下，将三氯氧磷(246mg，0.949mmol)滴加到无水DCM中(10mL)，降温至-40℃，滴加入14-A1(200mg，0.633mmol，参照29号化合物合成方法合成)的DCM溶液(4mL)，然后滴加入TEA(96mg，0.949mmol)，保温-40℃--35℃两小时，HPLC跟踪检测14-A1消失，转化为中间体。-40℃，滴加入N，N’-二甲基-1，3-丙二胺(130mg，1.27mmol，商业购买)的DCM溶液(2mL)，然后滴加入TEA(130mg，1.266mmol)的DCM溶液(2ml)，保温-40℃一小时，中间体转化完毕。自然升温至0℃，滴加入饱和氯化铵水溶液(5mL)，DCM萃取(10mL×3)，纯净水洗(3ml×3)，干燥浓缩，HPLC制备得14号化合物和产品(8.5mg，收率2.9％)，为淡黄色油状液体。 1H-NMR(400MHz，CDCl 3)：δ7.98(d，J＝8.4Hz，1H)，7.45(d，J＝8.4Hz，2H)，7.23(d，J＝8.5Hz，1H)，7.11-7.02(m，3H)，4.92(d，J＝7.5Hz，2H)，3.15-2.86(m，10H)，2.65(s，3H)，2.63(s，3H)，2.03-1.97(m，1H)，1.52-1.50(m，1H)。MS：Calculated 462.2，found 463.1([M+H] +)。
15号化合物
Figure PCTCN2020099353-appb-000049
氮气保护下，将三氯氧磷(53mg，0.348mmol)滴加到无水DCM中(10mL)，降温至-40℃，滴加入15-A1(100mg，0.316mmol，参照29号化合物合成方法合成)的DCM溶液(2mL)，然后滴加入TEA(35mg，0.348mmol)，保温-40℃至-35℃下2h，HPLC、LC-MS监测，15-A1消失，转化为中间体。于-40℃，滴加入3-胺基-1-丙醇(26mg，0.348mmol)的DCM溶液(2mL)，然后滴加入TEA(96mg，0.948mmol)的DCM溶液(2ml)，保温-40℃1h，中间体转化完毕。自然升温至0℃，滴加入饱和氯化铵水溶液(5mL)，DCM萃取(10mL×3)，纯净水洗(3ml×3)，干燥浓缩，HPLC制备得15号化合物产品(44.5mg，收率32.3％)，为白色固体。 1H-NMR(400M，CDCl 3):δ7.99(d，J＝8.4Hz，1H)，7.46(dd，J＝9.0，2.2Hz，2H)，7.27-7.25(m，1H)，7.08(s，2H)，7.06(d，J＝2.5Hz，1H)，5.03-5.00(m，2H)，4.45-4.30(m，1H)，4.23-4.16(m，1H)，3.30-3.24(m，1H)，3.12-3.07(m，7H)，2.07–1.98(m，2H)，1.67-1.62(m，1H)。MS：Calculated 435.1，found 436.1([M+H] +)。
16号化合物
Figure PCTCN2020099353-appb-000050
氮气保护下，将三氯氧磷(54mg，0.35mmol)滴加到无水DCM中(10mL)，降温至-40℃，滴加入16-A1(100mg，0.32mmol，参照29号化合物合成方法合成)的DCM溶液(2mL)，然后滴加入TEA(36mg，0.35mmol)，在40℃保温-3小时。-40℃，滴加入3-(甲胺基)-1-丙醇(31mg，0.35mmol，商业购买)的DCM溶液(2mL)，然后滴加入TEA(107mg，1.05mmol)的DCM溶液(2ml)，-40℃保温3小时，自然升温至室温，反应过夜，0℃下，滴加入饱和氯化铵水溶液(5mL)，DCM萃取(8mL×3)，纯净水洗(3ml×3)，干燥浓缩，HPLC制备得16号化合物(33mg，收率为22.9％)，为半固体。 1H-NMR(400M，CDCl 3):δ7.99(d，J＝8.4Hz，1H)，7.46(d，J＝8.4Hz，2H)，7.23-7.25(m，1H)，7.06-7.08(m，3H)，4.94-5.12(m，2H)，4.22-4.31(m，1H)，4.05-4.12(m，1H)，2.97-3.12(m，8H)，2.65(d，J＝10.8Hz，3H)，2.10-2.19(m，1H)，1.71-1.76(m，1H)。MS：CalculatedMS，449.1，found，450.1([M+H] +)。
17号化合物
Figure PCTCN2020099353-appb-000051
氮气保护下，三氯氧磷(53.4mg，0.348mmol)滴加入到无水DCM中(5mL)，降温至-40℃，滴加入17-A1(100mg，0.316mmol，参照29号化合物合成方法合成)的DCM溶液(2ml)，然后滴加入TEA(35.2mg，0.348mmol)，保温-40℃1.5小时，原料完全转化为中间体。-40℃，滴加入1，3-丙二醇(26.5mg，0.348mmol)的DCM溶液(2mL)，然后滴加入TEA(106mg，1.043mmol)的DCM溶液(2mL)，保温-40℃，反应完毕。0℃，滴加入饱和氯化铵水溶液(3mL)，DCM萃取(5mL×3)，纯净水洗(3mL×3)，干燥浓缩，制备HPLC得到17号化合物(23.9mg，收率17.3％.)，为淡黄色油状液体。 1H-NMR(400M，CDCl 3):δ8.00(d，J＝8.4Hz，1H)，7.47(d，J＝8.5Hz，2H)，7.27-7.25(m，1H)，7.11-7.04(m，3H)，5.10(d，J＝8.5Hz，2H)，4.47-4.35(m，2H)，4.27(m，2H)，3.07(s，6H)，2.27(dd，J＝10.9，4.4Hz，1H)，1.80(m，1H)，1.34-1.18(m，2H)。MS：Calculated 436.1，found 437.1([M+H] +)。
19号化合物
Figure PCTCN2020099353-appb-000052
氮气保护下，将19-A1(2.0g，11.69mmol)与19-A2(6.4g，46.76mmol，商业购买)溶于DMF中(10mL)，然后加入碳酸钾(6.5g，46.76mmol)，40℃搅拌过夜。反应完毕之后，降至常温，滴加入水(20ml)，EA萃取(20mL×3)，水洗(8mL×5)，盐水洗(8mL3)，干燥浓缩，柱分离(300-400目硅胶，正庚烷：EA，25％-35％EA)得到19-A3(1.05g，31.3％)，为淡黄色固体。 1H-NMR(400MHz，CDCl 3)：δ8.02(d，J＝8.4Hz，1H)，7.99-7.95(m，2H)，7.32-7.28(m，1H)，7.18(d，J＝0.6Hz，1H)，7.06-7.00(m，2H)，4.77(s，2H)，2.58(s，3H)。MS：Calculated 287.1，found288.0([M+H] +)。
氮气保护下，将三氯氧磷(59mg，0.382mmol)滴加到无水DCM中(10mL)，降温至-40℃，滴加入19-A3(100mg，0.347mmol)的DCM溶液(2mL)，然后滴加入TEA(39mg，0.382mmol)，保温-40℃至-35℃两小时，HPLC、LC-MS检测19-A3消失，转化为中间体。-40℃，滴加入N，N’-二甲基-1，3-丙二胺(39mg，0.382mmol，商业购买)的DCM溶液(2mL)，然后滴加入TEA(105mg，1.041mmol)的DCM溶液(2ml)，保温-40℃一小时，中间体转化完毕。自然升温至0℃，滴加入饱和氯化铵水溶液(5mL)，DCM萃取(10mL×3)，纯净水洗(3m×3)，干燥浓缩，制备HPLC得到19号化合物(34.5mg，收率20.8％)，为淡黄色油状液体。 1H-NMR(400MHz，CDCl 3):δ8.02(d，J＝8.4Hz，1H)，7.97(dd，J＝11.2，2.4Hz，2H)，7.30(dd，J＝8.4，1.0Hz，1H)，7.15(s，1H)，7.04(dd，J＝11.2，2.4Hz，2H)，4.95(d，J＝7.6Hz，2H)，3.10-3.04(m，2H)，3.01-2.88(m，2H)，2.65(s，3H)，2.63(s，3H)，2.58(s，3H)，2.04-2.01(m，1H)，1.51-1.47(m，1H)。MS：Calculated 433.1，found 434.1([M+H] +)。
20号化合物
Figure PCTCN2020099353-appb-000053
氮气保护下，将三氯氧磷(59mg，0.382mmol)滴加到无水DCM中(10mL)，降温至-40℃，滴加入20-A1(100mg，0.347mmol，即19-A3)的DCM溶液(2mL)，然后滴加入TEA(39mg，0.382mmol)，保温-40℃到-35℃两小时，HPLC、LC-MS监测，20-A1消失，转化为中间体。-40℃，滴加入3-胺基-1-丙醇(29mg，0.382mmol，商业购买)的DCM溶液(2mL)，然后滴加入TEA(105mg，1.041mmol)的DCM溶液(2ml)，保温-40℃一小时，中间体转化完毕。自然升温至0℃，滴加入饱和氯化铵水溶液(5mL)，DCM萃取(10mL×3)，纯净水洗(3ml×3)，干燥浓缩，HPLC制备得到产品(13.3mg，收率9.4％)，为淡黄色油状液体。 1H-NMR(400M，CDCl 3):δ8.03(d，J＝8.4Hz，1H)，7.98(d，J＝8.8Hz，2H)，7.35(dd，J＝8.4，1.1Hz，1H)，7.18(s，1H)，7.04(d，J＝8.8Hz，2H)，5.05(d，J＝7.6Hz，2H)，4.33-4.41(m，1H)，4.19-4.26(m，1H)，3.14-3.34(m，2H)，2.58(s，3H)，1.97-2.09(m，1H)，1.61-1.65(m，1H)。MS：Calculated 406.1.，found 407.1([M+H] +)。
21号化合物
Figure PCTCN2020099353-appb-000054
氮气保护下，将三氯氧磷(59mg，0.382mmol)滴加到无水DCM中(10mL)，降温至-40℃，滴加入21-A1(100mg，0.347mmol，即19-A3)的DCM溶液(2mL)，然后滴加入TEA(39mg，0.382mmol)，保温-40℃至-35℃3.5小时，然后再-40℃下，滴加入3-(甲胺基)-1-丙醇(34mg，0.382mmol)的DCM溶液(2mL)，然后滴加入TEA(105mg，1.041mmol)的DCM溶液(2ml)，保温-40℃30分钟，自然升温至室温，反应过夜，0℃下，滴加入饱和氯化铵水溶液(5mL)，DCM萃取(8mL×3)，纯净水洗(3ml×3)，干燥浓缩，HPLC制备得21号化合物(41mg，收率为27.2％)，为半固体。 1H-NMR(400M，CDCl 3):δ8.03(d，J＝8.4Hz，1H)，7.98(d，J＝8.8Hz，2H)，7.30(dd，J＝8.4，1.6Hz，1H)，7.16(d，J＝1.6Hz，1H)，7.05(d，J＝8.8Hz，2H)，4.97-5.12(m，2H)，4.23-4.33(m，1H)，4.09-4.16(m，1H)，2.97-3.16(m，2H)，2.65(d，J＝10.8Hz，3H)，2.59(s，3H)，2.08-2.24(m，1H)，1.71-1.77(m，1H)。MS：Calculated 420.1，found 421.1([M+H] +)。
23号化合物
Figure PCTCN2020099353-appb-000055
氮气保护下，三氯氧磷(59.0mg，0.382mmol)滴加到无水DCM中(5mL)，降温至-40℃，滴加入23-A1(100mg，0.347mmol，即19-A3)的DCM溶液(2ml)，然后滴加入TEA(39.0mg，0.382mmol)，保温-40℃1.5小时，原料完全转化为中间体。-40℃，滴加入4-胺基-1-丁醇(34.0mg，0.382mmol，商业购买)的DCM溶液(2mL)，然后滴加入TEA(116mg，1.145mmol)的DCM溶液(2mL)，保温-40℃，5小时反应完毕。0℃，滴加入饱和氯化铵水溶液(3mL)，DCM萃取(5mL×3)，纯净水洗(3mL×3)，干燥浓缩，制备得到23号化合物纯品(15.7mg，10.7％)，为淡黄色油状液体。 1H-NMR(400MHz，CDCl 3):δ8.03(d，J＝8.4Hz，1H)，7.99(t，J＝5.7Hz，2H)，7.33(d，J＝8.5Hz，1H)，7.18(s，1H)，7.04(d，J＝8.7Hz，2H)，5.07(m，2H)，4.33-4.23(m，1H)，4.13(m，1H)，3.10-2.99(m，1H)，2.90-2.83(m，1H)，2.59(s，3H)，1.91-1.75(m，4H)。MS：Calculated 420.1，found 421.1([M+H] +)。
24号化合物的合成
Figure PCTCN2020099353-appb-000056
将24-A1(100mg，0.32mmol)溶于DCM(3ml)中。降温0℃度，滴加氯化亚砜(57.12mg，4.8mmol，1.5eq)常温搅拌，1.5h反应完毕。降温0-5℃，滴加饱和碳酸氢钠溶液，调至弱碱性(pH＝7-8)，DCM(10ml×2)萃取，干燥浓缩，得到24-A2(130mg)，为黄色油状物，直接投于下步反应。
将24-A2(130mg，0.388mmol)，溶于DMF(3ml)中，加入3-羟基哒嗪(74.57mg，0.776mmol，2eq)，加入碳酸铯(316mg，0.96mmol，2.5eq)常温搅拌。40min反应完毕。加入EA(20倍体积)，饱和碳酸钠洗(5ml×3)盐水洗，干燥浓缩制备得产物(26mg，17.0％)，为黄色油状物。 1H-NMR(400MHz，CDCl 3):δ8.05(s，1H)，8.00(d，J＝8.2Hz，1H)，7.94(s，1H)，7.49(d，J＝7.8Hz，2H)，7.13(d，J＝8.2Hz，1H)，7.09(d，J＝7.8Hz，2H)，6.94(s，1H)，6.72(s，1H)，5.18(s，2H)，3.15(s，3H),3.05(s，3H)。MS：Calculated 394.1，found 394.9([M+H] +)。
25号化合物的合成
Figure PCTCN2020099353-appb-000057
将24-A1(50mg，0.16mmol)溶于DCM(3ml)中，加入29-B1(141.8mg，0.96mmol，6eq)降温0℃，滴TEA(95.9mmol，0.96mmol，6eq)，加入DMAP(4.85mg，0.04mmol，0.25eq)升温40℃搅拌过夜，反应完毕后，除去溶剂，高效液相制备得产物14.1mg，为白色固体，收率为20.5％。 1H-NMR(400M，CDCl 3):δ7.99(d，J＝8.4Hz，1H)，7.46(d，J＝8.4Hz，2H)，7.21-7.23(m，1H)，7.06(d，J＝8.4Hz，2H)，7.01(m，1H)，5.11(s，2H)，3.46-3.65(m，8H)，3.11(s，3H)，3.02(s，3H)。MS：Calculated 429.2，found 429.9([M+H] +)。
26号化合物的合成
Figure PCTCN2020099353-appb-000058
将三光气(3g，10.1mmol)在0℃下溶于DCM(300ml)，然后将26-A1(1.52g，20.2mmol，2eq)溶于DCM(60ml)后滴加体系，20min滴毕。反应4h后将体系旋干，用MTBE(20ml)打浆，抽滤后母液旋干得26-A2粗品1.2g，浅棕色液体。直接投于下步反应。
将26-A2(300mg，0.949mmol)与26-A3(652.5mg，4.744mmol，5eq，
Figure PCTCN2020099353-appb-000059
参照29号化合物合成方法合成)溶于DCM(12ml)，降温至0℃后将TEA(480mg，4.744mmol，5eq)与DMAP(29.1mg，0.237mmol，0.25eq)加入至体系，将体系升温至35℃，大约12h反应完毕。HPLC与LCMS监测反应完毕后降至室温，加入饱和NaHCO 3(15ml×2)洗涤，有机相水洗(10ml×2)，水相DCM萃取(20ml×1)，有机相旋干，高效液相制备得到26号化合物(150mg，收率37.8％)，为黄色油状液体。 1H-NMR(400M，CDCl 3):δ7.94(d，J＝8.4Hz，1H)，7.43(t，J＝8.4Hz，2H)，7.19(d，J＝8.4Hz，1H)，7.02(t，J＝2.4Hz，3H)，5.24(s，1H)，5.06(s，2H)，3.42(t，J＝4.8Hz，2H)，3.34(d，J＝2.8Hz，2H)，3.32(d，J＝5.6Hz，3H)，3.08(s，3H)，3.00(s，3H)MS：Calculated 417.2，found418.0([M+1] +)。
27号化合物的合成
Figure PCTCN2020099353-appb-000060
氮气保护下，27-A1(120mg，0.358mmol，参照29号化合物合成方法合成)溶于DMF(5mL)中，加入2，4二氟苯硫酚(104mg，0.716mmol，2eq)加入Cs 2CO 3(291.6mg，0.895mmol)2.5eq)。常温搅拌。1h反应完毕。加入EA(50mL)，饱和碳酸钠水溶液洗(20mlx3)，盐水洗(10mlx2)干燥浓缩，高效液相制备得到产物(41mg，收率为25.7％)，为黄色油状液体。 1H-NMR(400M，CDCl 3):δ7.89(d，J＝8.4Hz，1H)，7.44(d，J＝8.4Hz，2H)，7.20-7.24(m，1H)，7.06-7.08(m，1H)，6.92(d，J＝8.4Hz，2H)，6.79-6.82(m，3H)，3.93(s，2H)，3.12(s，3H)，3.03(s，3H)。MS：Calculated 444.1，found 444.9([M+1] +)。
28号化合物的合成
Figure PCTCN2020099353-appb-000061
将24-A1(100mg，0.32mmol，参照29号化合物合成方法合成)与吡啶(55.7mg，0.70mmol，2.2eq)溶于DCM(3ml)，然后将降温0℃，滴加氯甲酸异丙酯(129.6mg，1.2mmol，3.6eq，商业购买)加入至体系，20℃反应18h，降温至0℃-5℃，滴加1N盐酸(3ml)，DCM萃取(10mLx2)，有机相用盐酸(1N，10mLx5)洗，水洗(5mLx3)，盐水洗(5mLx2)，硫酸钠干燥干燥，浓缩有机相，中性制备得到产物(27mg，21.2％)，为类白色固体。 1H-NMR(400M，CDCl 3):δ7.98(d，J＝8.4Hz，1H)，7.46(d，J＝8.4Hz，2H)，7.26(s，1H)，7.04-7.07(m，3H)，5.11(s，2H)，4.87(q，J＝6.4Hz，1H)，3.11(s，3H)，3.03(s，3H)，1.29(d，J＝6.4Hz，6H)。MS：Calculated 402.1，found 403.0([M+1] +)。
29号化合物的合成
Figure PCTCN2020099353-appb-000062
将29-A1(1g，5.84mmol)与3-羟基-N，N-二甲基苯甲酰胺(2.8g，17.53mmol，3eq)溶于MeCN(30ml)，然后将K 2CO 3(2.8g，20.45mmol，3.5eq)加入至体系，将体系升温至65℃，3h反应完毕后降温至20℃，加入H 2O(15ml)，EA萃取(30mL×3)，有机相用1NNaOH溶液洗涤(50ml×3)，有机相干燥旋干拌样，200-300硅胶(EA:PE，1:3)得到29-A2(m＝950mg，收率51.4％)。 1H-NMR(400M，CDCl 3):δ7.96(d，J＝8.4Hz，1H)，7.39-7.43(m，1H)，7.19-7.22(m，2H)，7.09-7.11(m，1H)，7.04-7.07(m，2H)，4.69(s，2H)，3.00(brs，6H)，1.97(s，1H)。MS：Calculated 316.1，found 317.1[(M+1) +].
将29-A2(50mg，0.158mmol)与哌啶-1-甲酰氯(141.9mg，0.948mmol，6eq)溶于DCM(2ml)，然后将TEA(32.0mg，0.316mmol，2eq)与DMAP(4.9mg，0.04mmol，0.25eq)加入至体系，此时体系呈淡黄色，将体系升温至40℃，12h反应完毕。除去溶剂，高效液相色谱制备，得到纯品16.5mg，收率24.3％。 1H-NMR(400M，CDCl 3):δ7.97(d，J＝8.4Hz，1H)，7.40-7.44(m，1H)，7.18-7.23(m，2H)，7.08-7.10(m，1H)，7.01-7.06(m，2H)，5.11(s，2H)，3.64(s，4H)，3.46(s，4H)，3.11(s，3H)，2.98(s，3H)。MS：Calculated:429.2，found 330.0([M+H] +)。
30号化合物的合成
Figure PCTCN2020099353-appb-000063
氮气保护，将30-A1(1.76g，7.72mmol)与3，3-二氟三甲叉亚胺盐酸盐(1.0g，7.72mmol，1eq)溶于DCM(20ml)，加入T 3P的EA溶液(10g，15.4mmol，2eq，50％)，将体系降温至5℃，滴加DIEA，完毕后常温搅拌，HPLC监测2h反应完毕后向体系中加入水(5ml)，DCM萃取(15ml×3)，有机相水洗(10ml×2)，干燥旋干得产物粗品(m＝2.5g，收率100％)淡黄色固体。 1H-NMR(400M，DMSO-d6):δ7.45-7.47(m，2H)，7.38-7.42(m，3H)，7.31-7.35(m，1H)，7.24-7.26(m，2H)，7.18-7.21(m，1H)，5.16(s，2H)，4.47-4.70(m，4H).Calculated 303.1，found 304.1([M+H] +)。
氮气保护，将30-A2(2.5g，8.242mmol)溶于EtOH(37ml)，然后将Pd/C(630mg，25％A2)加入至体系体系，先将体系抽冲N 2三次，使体系充满N 2，然后再抽冲H 2三次，使体系充满H 2，之后常温搅拌，HPLC监测8h反应完毕。在N 2保护下抽出H 2，然后抽滤掉Pd/C，DCM洗涤(30ml×3)，旋干母液得30-A3粗品(1.5g，收率为85.4％)为类白色固体。 1H-NMR(400M，DMSO-d6):δ7.24-7.28(m，1H)，7.05-7.09(m，2H)，6.92-6.94(m，1H)，4.46-4.69(m，4H).Calculated 213.1，found 214.1([M+H] +)。
将30-A3(1.5g，7.04mmol)与3-氟-4-硝基苯甲酸甲酯(2.8g，14.06mmol，2eq)溶于ACN(15ml)，后将K 2CO 3(2.9g，21.01mmol，3eq)加入至体系，60℃回流过夜，次日HPLC监测反应完毕，降至室温，加入水(10ml)，用DCM萃取(20mLx4)，有机相水洗(10ml×2)，食盐水洗，干燥，旋干，得30-A4粗品(m＝1.8g，收率为65.2％)，为黄色固体。 1H-NMR(400M，CDCl 3):δ7.99(d，J＝8.4Hz，1H)，7.92(dd，J 1＝8.4Hz，J 2＝1.6Hz，1H)，7.70(d，J＝1.6Hz，1H)，7.43-7.51(m，2H)，7.29-7.30(m，1H)，7.20-7.23(m，1H)，4.50-4.56(m，4H)，3.92(s，3H).Calculated MS:392.1，found 393.0([M+H] +)。
将30-A4(500mg，1.27mmol)溶于THF(2ml)，降温至0℃后分批将NaBH 4(193mg，5.10mmol，4eq)加入至体系后将体系升温至60℃回流，HPLC监测15h反应完毕。降至0℃，加水(20ml)淬灭，DCM萃取(20ml×3)，干燥并旋干浓缩拌样，300-400硅胶过快速Flash柱层析，得30-A5纯品(140mg，收率30.2％)为类白色固体。 1H-NMR(400M，CDCl 3):δ7.96(d，J＝8.4Hz，1H)，7.34-7.38(m，1H)，7.15-7.18(m，2H)，7.04-7.06(m，2H)，6.97(dd，J 1＝8.4Hz，J 2＝2.0Hz，1H)，4.63-4.68(m，4H)，3.67-3.76(m，2H).Calculated 364.1，found 365.1([M+H] +)。
将30-A5(140mg，0.384mmol)与哌啶-1-碳酰氯(287.4mg，1.92mmol，5eq)溶于DCM(6ml)，降温至0℃后将TEA(194.3mg，1.92mmol，5eq)与DMAP(11.8mg，0.096mmol，0.25eq)加入至体系后将体系升温至35℃，大约12h反应完毕。HPLC与LCMS监测反应完毕后降至室温，加入饱和NaHCO 3(10ml×2)洗涤，有机相水洗(10ml×2)，水相DCM萃取(10ml)，有机相旋干后使用高效液相色谱在中性条件分离，得到纯品(22.5mg，收率12.3％)，为白色固体。 1H-NMR(400M，CDCl 3):δ8.00(d，J＝8.8Hz，1H)，7.40-7.48(m，2H)，7.19-7.26(m，3H)，7.02(s，1H)，5.13(s，2H)，4.49-4.55(m，4H)，3.64(brs，4H)，3.46(s，4H).Calculated 477.1，found 478.0([M+H] +)。
31号化合物的合成
Figure PCTCN2020099353-appb-000064
将PSCl 3(4.5g，26.6mmol)溶于氯仿(50ml)，然后将31-A1(2g，26.6mmol)溶于氯仿(40ml)后滴加进体系，1h滴加完毕，搅拌1h后将DIEA(3.44g，26.6mmol)溶于氯仿(10ml)后滴加入至体系，将体系升温至20℃，过夜。加水萃取(20ml×4)，有机相干燥旋干得31-A2粗品(2.4g)，为类白色固体。
将31-A2(1.8g，10.5mmol)加入至H 2O(18ml)中，白色悬浊液，然后将NaOH(923mg，23.1mmol，2.2eq)缓慢分批加入至体系体系，在之后反应中体系逐渐变澄清。LCMS监测有所需产物，反应过夜后，加入MeCN(20ml)混合后旋去部分水分，剩余混合物用12N HCl将体系调至酸性，有大量固体析出，抽滤后用MeCN(10ml)打浆除水，抽滤后再加入MeCN(10ml)旋干后得31-A3共800mg，为白色固体，直接投于下步反应。
氮气保护下，将31-A4(100mg，0.299mmol，
Figure PCTCN2020099353-appb-000065
参照29号化合物合成方法合成)溶于DMF(2ml)，后将31-A3(91.5mg，0.597mmol，2eq)与TEA(90.7mg，0.896mmol，3eq)加入至体系，此时体系呈淡橘黄色，20℃反应过夜，反应完毕。加入饱和NaHCO 3水溶液(5ml)，EA萃取(5ml×3)，有机相水洗(10ml×5)，水相EA萃取(10ml×2)，有机相旋干后于中性条件下HPLC制备分离后冻干溶液得纯品67.4mg，收率为50.0％，为类白色固体。 1H-NMR(400M，CD 3OD):δ7.99(d，J＝8.4Hz，1H)，7.48-7.50(m，2H)，7.40(dd，J 1＝8.4Hz，J 2＝1.6Hz，1H)，7.27(d，J＝1.6Hz，1H)，7.08-7.10(m，2H)，4.21-4.26(m，2H)，4.03-4.07(m，2H)，3.16-3.25(m，2H)，3.10(s，3H)，3.05(s，3H)1.94-2.04(m，1H)，1.67-1.71(m，1H)。MS：Calculated 451.1，found 452.1([M+H] +)。
32号化合物的合成
Figure PCTCN2020099353-appb-000066
将31(20mg，0.044mmol)溶于DMF(1ml)中，紧接着将K 2CO 3(12.2mg，0.088mmol，2eq)加入反应体系室温搅拌1h，然后将MeI(22mg，0.132mmol，3eq)滴加进体系，之后监测转换45％之后不再变化。补加K 2CO 3(18.3mg，0.132mmol，2eq)，MeI(22mg，0.132mmol，3eq)，升温至35℃，过夜后转化达75％。降至10℃后向体系加入饱和NaHCO 3水溶液(2ml)，EA萃取(3ml×3)，有机相盐水洗(2ml×3)，干燥旋干后中性HPLC制备分离，得到32共6.1mg，为淡黄色固体。 1H-NMR(400M，CD 3OD):δ7.99(d，J＝8.4Hz，1H)，7.48-7.50(m，2H)，7.39-7.41(m，1H)，7.27(d，J＝1.6Hz，1H)，7.09-7.11(m，2H)，4.06-4.10(m，2H)，4.03-4.10(m，2H)，3.05-3.10(m，8H)，2.60(d，J＝7.2Hz，3H)，2.07-2.17(m，1H)，1.68-1.80(m，1H)。MS：Calculated 465.1，found 466.1([M+1] +)。
33号化合物的合成
Figure PCTCN2020099353-appb-000067
将PSCl 3(4.5g，26.3mmol，)溶于氯仿(50ml)，然后将33-A1(2g，26.3mmol)溶于氯仿(40ml)后滴加进体系，1h滴加完毕，搅拌1h后将DIEA(3.4g，26.3mmol)溶于氯仿(10ml)后滴加入至体系，将体系升温至20℃，过夜。加水萃取(20ml×4)，有机相干燥旋干得33-A2粗品(3.5g)，为类白色固体。直接投于下步反应。
将33-A2(1g，5.86mmol)加入至H 2O(10ml)中，然后将NaOH(281mg，7.03mmol，1.2eq)缓慢分批加入至体系体系，过夜。LCMS监测有所需产物，用12N HCl将体系调至pH＝3-4，无固体析出，旋去水分后得33-A3粗品500mg，为淡黄色液体。
氮气保护将33-A4(100mg，0.299mmol，
Figure PCTCN2020099353-appb-000068
参照29号化合物合成方法合成)溶于DMF(2ml)，后将33-A3(184.3mg，1.196mmol，4eq)与TEA(121.0mg，1.196mmol，4eq)加入至体系，室温过夜后HPLC监测反应完毕。加入饱和NaHCO 3(10mL)，EA萃取(5ml×3)，有机相水洗(5ml×2)，水相EA萃取(5ml×3)，有机相旋干，中性高效液相制备得到33共29.7mg，收率为22.0％，为黄色固体。 1H-NMR(400M，CD 3OD):δ8.00(d，J＝8.4Hz，1H)，7.48-7.51(m，2H)，7.42(dd，J＝8.4Hz，2.0Hz，1H)，7.28(d，J＝1.6Hz，1H)，7.10-7.11(m，2H)，4.34-4.41(m，4H)，4.15(d，J＝16.8Hz，2H)，3.10(s，3H)，3.05(s，3H)，2.22-2.27(m，1H)，1.79-1.85(m，1H)。MS：Calculated 452.1，found 453.0([M+1] +)。
34号化合物的合成
Figure PCTCN2020099353-appb-000069
0℃下，将PSCl 3(2g，11.8mmol)溶于氯仿(25ml)，然后将34-A1(11.8ml，23.6mmol，2eq，2MinTHF)滴加进体系，滴加完毕搅拌1h后将DIEA(3.44g，26.6mmol)溶于氯仿(10ml)后滴加入至体系，将体系升温至20℃，过夜。除去溶剂得34-A2粗品。加入水(20ml)搅拌30min后旋干可得34-A3粗品5g，为无色油状液体。
氮气保护将34-A4(50mg，0.149mmol，
Figure PCTCN2020099353-appb-000070
参照29号化合物合成方法合成)溶于DMF(1mL)，后将34-A3(418.6mg，1.194mmol，8eq)与TEA(120.8mg，1.194mmol，8eq)加入至体系，将体系升温至30℃，过夜。HPLC与LCMS监测反应完毕后降至室温，加入饱和NaHCO 3水溶液(5mL)，EA萃取(5mL×3)，有机相水洗(5mL×3)，盐水洗，硫酸钠干燥，旋干，高效液相中性制备，得纯品20.0mg，收率为30.6％，为淡黄色固体。 1H-NMR(400M，CD 3OD):δ7.99(d，J＝8.4Hz，1H)，7.48-7.50(m，2H)，7.40(dd，J＝8.4Hz，2.0Hz，1H)，7.26(d，J＝1.6Hz，1H)，7.07-7.10(m，2H)，3.96(d，J＝12.8Hz，2H)，3.10(s，3H)，3.05(s，3H)，2.51(s，3H)，2.48(s，3H)。MS：Calculated 438.1，found 439.1([M+1] +)。
35号化合物的合成
Figure PCTCN2020099353-appb-000071
将PSCl 3(4.56g，26.9mmol)溶于氯仿(50ml)，然后将35-A1(2g，26.9mmol)的氯仿溶液(40ml)滴加进体系，30min滴加完毕，搅拌1h后滴加入DIEA(3.48g，26.9mmol)的氯仿(10ml)溶液，将体系升温至20℃，过夜。旋干后得35-A2粗品。加入水(20ml)搅拌30min，除去水得到白色固体，MeCN(3ml)打浆后抽滤，得到干燥的35-A3共1.2g，为白色固体。直接投于下步反应。
氮气保护下，将35-A4(100mg，0.299mmol，
Figure PCTCN2020099353-appb-000072
参照29号化合物合成方法合成)溶于DMF(2ml)，后将35-A3(182mg，1.196mmol，4eq)与TEA(121mg，1.196mmol，4eq)加入至体系，完毕后将体系升温至25℃，过夜后HPLC监测反应完毕。加入饱和NaHCO 3水溶液(5ml)，EA萃取(5mLx3)，有机相水洗(10mlx2)，水相EA萃取(5mlx2)，有机相旋干，高效液相中性条件制备分离，得到35共23.1mg，收率为17.2％，为淡黄色固体。 1H-NMR(400M，CD 3OD):δ7.98(d，J＝8.4Hz，1H)，7.47-7.50(m，2H)，7.40(dd，J 1＝8.4Hz，J 2＝1.6Hz，1H)，7.28(d，J＝1.6Hz，1H)，7.07-7.10(m，2H)，3.99(d，J＝12.4Hz，2H)，3.05-3.24(m，10H)，1.69-1.82(m，1H)，1.60-1.65(m，1H)。MS：Calculated 450.1，found 451.1([M+1] +)。
1号化合物
参照以上化合物2/3类似的方法合成。
1H-NMR(400MHz，CDCl3)：δ7.91(d，J＝8.4Hz，1H)，7.41(t，J＝7.9Hz，1H)，7.33-7.27(m，1H)，7.21(d，J＝7.6Hz，1H)，7.15-6.98(m，3H)，4.55(s，2H)，3.54(s，3H)，3.36(s，3H)，3.09(s，3H)，2.97(s，3H)。
体外AKR1C3酶活性抑制实验
实验仪器：
Waters AcquityI Class UPLC超高效液相色谱仪配有Xevo G2-XSQ TofHRMS四极杆飞行时间高分辨率质谱仪。
缓冲液和物料：
1.PBS磷酸缓冲盐溶液，
2. 20mMNADPH的PBS磷酸缓冲盐溶液
3. 250μg/mL AKR1C3的PBS磷酸缓冲盐溶液
4. 250μM测试化合物的50％MeOH/H 2O溶液
5. 250μM黄体酮(progesterone)的50％MeOH/H 2O溶液
6. 1μg/mL普萘洛尔(propranolol)的100％乙腈溶液
实验操作流程
步骤1，将反应混合物按照下表一式二份(n＝2)制成Eppendorf管，轻轻混合。
物料 阴性对照(μL) 样本(μL)
PBS 68 66
NADPH(20mM) 10 10
AKR1C3(250μg/mL) 10 10
测试化合物(250μM) 0 2
步骤2，将以上一式两份混合物在37℃下预孵育30分钟。
步骤3，在每个Eppendorf管中加入另外10μL的20mMNADPH的PBS磷酸缓冲盐溶液和2μL的250μM黄体酮(progesterone)的50％MeOH/H 2O溶液并轻轻混合。
步骤4，立即将以上步骤中的50μL混合物转移到100μL的1μg/mL普萘洛尔(propranolol，内标IS)的100％乙腈溶液中。
步骤5，将剩余样品在37℃下孵育30分钟，并加入100μL1μg/mL普萘洛尔(propranolol，内标IS)的100％乙腈溶液。
步骤6，对于所有样品，加入100μL试剂水，以1100rpm涡旋混合5分钟，并在室温下以15000rpm离心10分钟。
步骤7，将所有样品加载到LC/MS上以测定还原的黄体酮即20α-二氢孕酮的含量。
LC-MS仪器的测试条件为
项目 条件
仪器: Waters Acquity IClass液相色谱仪
色谱柱: Acquity UPLC BEH C18色谱柱(50*2.1mm，1.7μm)
流速: 0.4mL/min
进样量: 3μL
流动相组成: A:0.1％(V/V)甲酸水溶液B:0.1％(V/V)甲酸乙腈溶液
柱温箱温度: 40℃
检测器: 四极杆飞行时间质谱仪Q-TOFMS
液相洗脱梯度
时间Time(min) A(％) B(％)
0.00 90.0 10.0
1.5 5.0 95.0
2.00 5.0 95.0
2.30 90.0 10.0
3.00 90.0 10.0
四极杆飞行时间质谱参数
项目 参数
毛细管电压(CapilarykV) 2.5
进样锥电压(SamplingConeV) 40
源温度Sourcetemperature(℃) 100
进样锥气体流速ConeGas(L/h) 50
脱溶剂气体流速DesolvationGas(L/h) 600
电离方式(InterfaceType) ES，Positive
分析器模式(AnalyserMode) Sensitivity
扫描范围(ScanRange) 50-800m/z
步骤9，还原黄体酮(20α-二氢孕酮)的计算：通过LC/MS测定每种样品中还原黄体酮即20α-二氢孕酮和普萘洛尔峰面积。计算还原黄体酮与普萘洛尔的峰面积比，并将时间为0时的比率设定为0％。
AKR1C3活性(％)＝[(样品标准化后的还原黄体酮量) 30min-(样品标准化后的还原黄体酮量) 0min]/[(阴性对照组标准化后的还原黄体酮量) 30min-(阴性对照组标准化后还原黄体酮量) 0min]*100。
根据以上计算得到下表的5μM/L化合物浓度的AKR1C3相对活性％活性结果。
Figure PCTCN2020099353-appb-000073
Figure PCTCN2020099353-appb-000074
Figure PCTCN2020099353-appb-000075
备注：
ND，表示未检测；
以上化合物的活性数据是四次测试得到的：2019/5/29、2019/5/31、2019/6/13、2019/6/14，对此对应的对照化合物AST-3424、吲哚美辛其值也有四个，上表中使用的是这四次的算术平均值，具体测试结果、时间如下：
化合物及测试浓度 2019/5/29 2019/5/31 2019/6/13 2019/6/14 平均
AST-3424，5μM/L 68.1 73.8 39.9 35 54.2
吲哚美辛，5μM/L 86.9 95 96.7 91 92.4
吲哚美辛是典型的AKR1C3的抑制剂，而且临床上被用来进行包括癌症疼痛在内的缓解和治疗。本发明公开的化合物其在5μM/L的浓度下抑制AKR1C3酶的能力较吲哚美辛高，显示本发明公开的化合物是一种较为高效的AKR1C3的抑制剂。

Claims (29)

  1. 下式的化合物以及其药学上可接受的盐或溶剂合物或同位素取代化合物：
    Figure PCTCN2020099353-appb-100001
    其中，R 1、R 2各自独立地为氢、氘、芳基或Z取代芳基、杂芳基或Z取代杂芳基、C 1-C 6烷基或Z取代烷基、C 2-C 6烯基或Z取代烯基、C 2-C 6炔基或Z取代炔基、C 3-C 8环烷基或Z取代环烷基；
    R 3是氢、卤素、氰基或异氰基、羟基、巯基、胺基、肟基、腙基、OTs、OMs、C 1-C 6烷基或Z取代烷基、C 2-C 6烯基或Z取代烯基、C 2-C 6炔基或Z取代炔基、C 3-C 8环烷基或Z取代环烷基、C 6-C 10芳基或Z取代芳基、4-15元杂环或Z取代杂环、5-15元杂芳基或Z取代杂芳基、C 1-C 6烷氧基或Z取代的C 1-C 6烷氧基或者R 3是-CONR 6R 7、-SO 2NR 6R 7、-SO 2R 6、-OCO-R 6、-OCOO-R 6、-COOR 6、-NR 6COR 7、-NR 6SO 2R 7、-NR 6CONR 6R 7，且R 6,R 7与N形成或不形成4-8元Z取代杂环，或者两个R 3和与其所键结的苯环上的原子一起形成7-15元的稠环或Z取代稠环；
    R 6和R 7各自独立地是氢、氰基或异氰基、C 1-C 6烷基或Z取代烷基、C 2-C 6烯基或Z取代烯基、C 2-C 6炔基或Z取代炔基、C 3-C 8环烷基或Z取代环烷基、C 6-C 10芳基或Z取代芳基、4-15元杂环或Z取代杂环、5-15元杂芳基或Z取代杂芳基、C 1-C 6烷氧基或Z取代的C 1-C 6烷氧基，或者R 6、R 7基团与其所键结的原子一起形成3-7元杂环基或Z取代3-7元杂环基；
    a为0、1、2、3；
    X为C、N；
    Y为O或者S；
    Cx选自C 6-C 10芳基或Z取代芳基、4-15元杂环或Z取代4-15元杂环、5-15元杂芳基或Z取代元杂芳基、7-15元的稠环或Z取代稠环以及-CONR 6R 7、-SO 2NR 6R 7、-SO 2R 6、-OCOO-R 6、-COOR 6、-NR 6COR 7、-OCOR 6、-NR 6SO 2R 7、-NR 6SO 2NR 6R 7、-COR 6、-NR 6CONR 6R 7取代的C 6-C 10芳基、4-15元杂环、5-15元杂芳基、7-15元的稠环，且R 6,R 7与N形成或不形成4-8元Z取代杂环；
    L选自-O-、-S-、-OCOO-、-NR 6CO-、-OCO-、-NR 6SO 2-、-OCONR 6-、季铵根、磺酸酯基-OSO 2-；
    Cy选自氢、氘、C 6-C 10芳基或Z取代的芳基、4-15元杂环或Z取代杂环、5-15元杂芳基或Z取代杂芳基、7-15元的稠环或Z取代稠环，C 1-C 6烷基或Z取代烷基、C 2-C 6烯基或Z取代烯基、C 2-C 6炔基或Z取代炔基、C 3-C 8环烷基或Z取代C 3-C 8环烷基；
    或
    Cy选自
    Figure PCTCN2020099353-appb-100002
    或Cy选自
    Figure PCTCN2020099353-appb-100003
    中两个OR 6与P原子所形成的5-10元环基团、
    Figure PCTCN2020099353-appb-100004
    中OR 6与NR 6R 7与P原子所形成的5-10元环基团、
    Figure PCTCN2020099353-appb-100005
    中两个NR 6R 7与P原子所形成5-10元环基团；
    并且-L-Cy不包括这些胺基磷酸酯烷化剂的失去H原子后的残基：-P(Z 1)(NR 9CH 2CH 2X 1) 2、-P(Z 1)(NR 9 2)(N(CH 2CH 2X 1)2)、-P(Z 1)(N(CH 2CH 2X 1)) 2或-P(Z 1)(N(CH 2CH 2X 1) 2) 2，每个R 9独立地为氢或C1-C6烷基，或2个R 9与其所结合的氮原子一起形成5至7元杂环基，Z 1为O或S，且X 1为Cl、Br或OMs，-L-Cy也不包括-OH和-SH；
    Z取代基为卤素原子、氰基或异氰基、羟基、巯基、胺基、肟基、腙基、OTs、OMs、C 1-C 3烷基或取代烷基、C 1-C 3烷氧基或取代烷氧基、C 2-C 3烯基或取代烯基、C 2-C 3炔基或取代炔基、C 3-C 8环烷 基或取代环烷基、芳环、杂环、杂芳环和稠环或取代芳环、杂环、杂芳环和稠环，取代的方式为单取代或偕二取代；
    Cz基团为含有C、P、S的基团且该基团能被水解酶水解而使得对应的C-N，P-N，S-N键断裂。
  2. 根据权利要求1所述化合物，其选自式I化合物，
    Figure PCTCN2020099353-appb-100006
    其中，
    I-5为在生物体内能被转化为上述I-3的前药，
    R 1、R 2各自独立地为氢、氘、芳基或Z取代芳基、杂芳基或Z取代杂芳基、C 1-C 6烷基或Z取代烷基、C 2-C 6烯基或Z取代烯基、C 2-C 6炔基或Z取代炔基、C 3-C 8环烷基或Z取代环烷基；
    R 3是氢、卤素、氰基或异氰基、羟基、巯基、胺基、肟基、腙基、OTs、OMs、C 1-C 6烷基或Z取代烷基、C 2-C 6烯基或Z取代烯基、C 2-C 6炔基或Z取代炔基、C 3-C 8环烷基或Z取代环烷基、C 6-C 10芳基或Z取代芳基、4-15元杂环或Z取代杂环、5-15元杂芳基或Z取代杂芳基、C 1-C 6烷氧基或Z取代的C 1-C 6烷氧基或者R 3是-CONR 6R 7、-SO 2NR 6R 7、-SO 2R 6、-OCO-R 6、-OCOO-R 6、-COOR 6、-NR 6COR 7、、-NR 6SO 2R 7、-NR 6CONR 6R 7，且R 6,R 7与N形成或不形成4-8元Z取代杂环；
    R 4、R 5各自独立地是氢、卤素、氰基或异氰基、羟基、巯基、胺基、肟基、腙基、OTs、OMs、C 1-C 6烷基或Z取代烷基、C 2-C 6烯基或Z取代烯基、C 2-C 6炔基或Z取代炔基、C 3-C 8环烷基或Z取代环烷基、C 6-C 10芳基或Z取代芳基、4-15元杂环或Z取代杂环、5-15元杂芳基或Z取代杂芳基、C 1-C 6烷氧基或Z取代的C 1-C 6烷氧基或者R 4、R 5是-CONR 6R 7、-SO 2NR 6R 7、-SO 2R 6、-OCOO-R 6、-COOR 6、-NR 6COR 7、-OCOR 6、-NR 6SO 2R 7、-NR 6CONR 6R 7或者R 4、R 5和与其所键结的苯环上的原子一起形成7-15元的稠环或Z取代稠环，且R 6,R 7与N形成或不形成4-8元Z取代杂环；
    R 6和R 7各自独立地是氢、氰基或异氰基、C 1-C 6烷基或Z取代烷基、C 2-C 6烯基或Z取代烯基、C 2-C 6炔基或Z取代炔基、C 3-C 8环烷基或Z取代环烷基、C 6-C 10芳基或Z取代芳基、4-15元杂环或Z取代杂环、5-15元杂芳基或Z取代杂芳基、C 1-C 6烷氧基或Z取代的C 1-C 6烷氧基，或者R 6、R 7基团与其所键结的原子一起形成3-7元杂环基或Z取代3-7元杂环基，且R 6,R 7与N形成或不形成4-8元Z取代杂环；
    Y为O或者S；
    Cx选自C 6-C 10芳基或Z取代芳基、4-15元杂环或Z取代4-15元杂环、5-15元杂芳基或Z取代元杂芳基、7-15元的稠环或Z取代稠环以及-CONR 6R 7、-SO 2NR 6R 7、-SO 2R 6、-OCOO-R 6、-COOR 6、-NR 6COR 7、-OCOR 6、-NR 6SO 2R 7、-NR 6SO 2NR 6R 7、-COR 6、-NR 6CONR 6R 7取代的C 6-C 10芳基、4-15元杂环、5-15元杂芳基、7-15元的稠环，且R 6,R 7与N形成或不形成4-8元Z取代杂环；
    L选自-O-、-S-、-OCOO-、-NR 6CO-、-OCO-、-NR 6SO 2-、-OCONR 6-、季铵根、磺酸酯基-OSO 2-；
    Cy选自氢、氘、C 6-C 10芳基或Z取代的芳基、4-15元杂环或Z取代杂环、5-15元杂芳基或Z取代杂芳基、7-15元的稠环或Z取代稠环，C 1-C 6烷基或Z取代烷基、C 2-C 6烯基或Z取代烯基、C 2-C 6炔基或Z取代炔基、C 3-C 8环烷基或Z取代C 3-C 8环烷基；
    或
    Cy选自
    Figure PCTCN2020099353-appb-100007
    或Cy选自
    Figure PCTCN2020099353-appb-100008
    中两个OR 6与P原子所形成的5-10元环基团、
    Figure PCTCN2020099353-appb-100009
    中OR 6与NR 6R 7 与P原子所形成的5-10元环基团、
    Figure PCTCN2020099353-appb-100010
    中两个NR 6R 7与P原子所形成5-10元环基团；
    Z取代基为卤素原子、氰基或异氰基、羟基、巯基、胺基、肟基、腙基、OTs、OMs、C 1-C 3烷基或取代烷基、C 1-C 3烷氧基或取代烷氧基、C 2-C 3烯基或取代烯基、C 2-C 3炔基或取代炔基、C 3-C 8环烷基或取代环烷基、芳环、杂环、杂芳环和稠环或取代芳环、杂环、杂芳环和稠环，取代的方式为单取代或偕二取代；
    Cz基团为含有C、P、S的基团且该基团能被水解酶水解而使得对应的C-N，P-N，S-N键断裂。
  3. 根据权利要求1-2所述的化合物，其中，
    所述R 1、R 2各自独立地为为氢、氘、C 1-C 6烷基或Z取代烷基、C 2-C 6烯基或Z取代烯基、C 2-C 6炔基或Z取代炔基、C 3-C 8环烷基或Z取代环烷基。
  4. 根据权利要求3所述的化合物，其中，
    所述R 1、R 2各自独立地为为氢、氘、甲基。
  5. 根据权利要求1-4所述的化合物，其中，
    R 3、R 4、R 5各自独立地为氢。
  6. 根据权利要求1-5所述的化合物，其中，
    Cx为-CONR 6R 7取代的苯基，且R 6,R 7与N形成或不形成4-8元Z取代杂环。
  7. 根据权利要求1-6所述的化合物，其中，
    L选自-O-、-S-。
  8. 根据权利要求1-7所述的化合物，其中，
    Cy选自C 6-C 10芳基或卤素取代的芳基、4-15元杂环或卤素取代杂环、5-15元杂芳基或卤素取代杂芳基、7-15元的稠环或卤素取代稠环。
  9. 根据权利要求8所述的化合物，其中，
    Cy选自氟苯基、二氟苯基、三氟苯基。
  10. 根据权利要求1-7所述的化合物，其中，
    Cy选自
    Figure PCTCN2020099353-appb-100011
    Figure PCTCN2020099353-appb-100012
    或Z取代的
    Figure PCTCN2020099353-appb-100013
    Figure PCTCN2020099353-appb-100014
  11. 根据权利要求1-2所述的化合物，其中，
    Cz选自-COR 6，-COOR 6。
  12. 根据权利要求1-10所述的化合物，其中，
    -NH-Cz为磷酰胺基团。
  13. 根据权利要求1-10所述的化合物，选自以下结构的化合物
    Figure PCTCN2020099353-appb-100015
    Figure PCTCN2020099353-appb-100016
  14. 根据权利要求1至13中任一项所述的化合物，其中，所述盐为碱式盐或酸式盐，所述溶剂合物为水合物或醇合物。
  15. 含有权利要求1至13中任一项所述的化合物以及其药学上可接受的盐或溶剂合物或同位素取代化合物的药品。
  16. 根据权利要求15所述的药品，该药品用于预防或治疗疾病/病症，所述疾病/病症包括子宫内膜异位症、子宫平滑肌瘤、子宫出血性病症、痛经、前列腺增生、痤疮、皮脂溢、脱发、过早性成熟、多囊卵巢综合征、慢性阻塞性肺病COPD、肥胖、炎性疼痛或癌症或炎症或癌性疼痛。
  17. 根据权利要求16所述的药品，其中，所述癌症包括前列腺癌、原发性前列腺癌、晚期前列腺癌、转移性前列腺癌、激素原初前列腺癌，难治性前列腺癌或去势抗性前列腺癌CRPC和乳腺癌、肺癌、子宫内膜癌、肾细胞癌、膀胱癌、非霍奇金淋巴瘤以及急性髓性白血病AML、T细胞急性淋巴细胞白血病T-ALL、白血病。
  18. 权利要求1至13中任一项所述的化合物以及其药学上可接受的盐或溶剂合物或同位素取代化合物在制备治疗活预防相关疾病/病症的药品中的用途，所述疾病/病症包括子宫内膜异位症、子宫平滑肌瘤、子宫出血性病症、痛经、前列腺增生、痤疮、皮脂溢、脱发、过早性成熟、多囊卵巢综合征、慢性阻塞性肺病COPD、肥胖、炎性疼痛或癌症或炎症或癌性疼痛。
  19. 一种用于增强癌症或肿瘤放射疗法敏感性的药品，该药品含有权利要求1至13中任一项所述的化合物以及其药学上可接受的盐或溶剂合物或同位素取代化合物，其用于：在癌症或肿瘤患者对放射疗法具有抗性时提高放射疗法的疗效；或治疗对放射疗法具有抗性的癌症或肿瘤患者。
  20. 一种用于增强癌症或肿瘤免疫疗法敏感性的药品，该药品含有权利要求1至13中任一项所述的化合物以及其药学上可接受的盐或溶剂合物或同位素取代化合物，其用于：在癌症或肿瘤患者对免疫疗法具有抗性时提高放射疗法的疗效；或治疗对免疫疗法具有抗性的癌症或肿瘤患者。
  21. 一种用于增强癌症或肿瘤化疗敏感性的药品，该药品含有权利要求1至13中任一项所述的化合物以及其药学上可接受的盐或溶剂合物或同位素取代化合物，其用于：在癌症或肿瘤患者对化疗具有抗性时提高化疗的疗效；或治疗对化疗具有抗性的癌症或肿瘤患者。
  22. 一种用于增强癌症或肿瘤化疗敏感性的药品，该药品含有权利要求1至13中任一项所述的化合物以及其药学上可接受的盐或溶剂合物或同位素取代化合物，其用于：在癌症或肿瘤患者对化疗具有抗性时提高化疗的疗效；或治疗对化疗具有抗性的癌症或肿瘤患者，所述化疗使用的药品含有柔红霉素daunorubicin或阿糖胞苷cytarabine。
  23. 权利要求1至13中任一项所述的化合物以及其药学上可接受的盐或溶剂合物或同位素取代化合物的用途，其用于增强癌症或肿瘤放射疗法敏感性或用于增强含有柔红霉素daunorubicin或阿糖胞苷cytarabine的药品化疗癌症或肿瘤的敏感性。
  24. 权利要求1至13中任一项所述的化合物以及其药学上可接受的盐或溶剂合物或同位素取代化合物的作为AKR1C3酶抑制剂的用途。
  25. 权利要求1至13中任一项所述的化合物以及其药学上可接受的盐或溶剂合物或同位素取代化合物的制药用途，该药为AKR1C3酶抑制剂。
  26. 权利要求1至13中任一项所述的化合物以及其药学上可接受的盐或溶剂合物或同位素取代化合物的制药用途，该药用于在癌症或肿瘤患者对放射疗法具有抗性时提高放射疗法的疗效；或者该药用于治疗对放射疗法具有抗性的癌症或肿瘤患者。
  27. 权利要求1至13中任一项所述的化合物以及其药学上可接受的盐或溶剂合物或同位素取代化合物的制药用途，该药用于在癌症或肿瘤患者对免疫疗法具有抗性时提高放射疗法的疗效；或者该药用于治疗对免疫疗法具有抗性的癌症或肿瘤患者
  28. 权利要求1至13中任一项所述的化合物以及其药学上可接受的盐或溶剂合物或同位素取代化合物的制药用途，该药用于在癌症或肿瘤患者对化疗具有抗性时提高化疗的疗效；或者该药用于治疗对化疗具有抗性的癌症或肿瘤患者。
  29. 权利要求1至13中任一项所述的化合物以及其药学上可接受的盐或溶剂合物或同位素取代化合物的制药用途，该药用于在癌症或肿瘤患者对化疗具有抗性时提高化疗的疗效；或者该药用于治疗对化疗具有抗性的癌症或肿瘤患者，所述化疗使用的药品含有柔红霉素daunorubicin或阿糖胞苷cytarabine。
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