TW202136201A - Akr1c3 inhibitor and medical use - Google Patents

Abstract

The present invention provides an AKR1C3 inhibitor of compounds of the following formulas and pharmaceutically acceptable salts or solvates or isotopically substituted compounds thereof and medical use.

Description

AKR1C3 inhibitor and medical use

The present invention relates to an AKR1C3 inhibitor and the medical use of the inhibitor.

The DNA alkylating agent cancer treatment compound prodrug developed by our company with high expression of aldehyde ketone reductase 1C3 (AKR1C3) as the target (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. Take the S configuration AST-3424 of TH-2870 as an example:

As a prodrug form, the 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.

During the research and development process, it was discovered that when attempting to substitute various groups for these compounds, it was found that when the benzyl carbon atom at the para position of the nitro group on the benzene ring is connected to the benzyl carbon atom, it is not similar to the application number PCT/US2016/021581, and the publication number WO2016/ 145092; application number PCT/US2016/062114, publication number WO2017/087428; application number PCT/US2016/025665, publication number WO2016/161342 as a cytotoxic alkylating agent, the compound exhibits the ability to inhibit the activity of AKR1C3 enzyme, for this reason The R&D team designed and synthesized a series of AKR1C3 inhibitors with new chemical structures.

To this end, the present invention provides the following technical solutions, a compound of the following formula and its pharmaceutically acceptable salt or solvate or isotope substituted compound:

Wherein, 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 , -OCO-R ⁶ , -OCOO-R ⁶ , -COOR ⁶ , -NR ⁶ COR ⁷ ,-NR ⁶ SO ₂ R ⁷ , -NR ⁶ CONR ⁶ R ⁷ , and R ⁶ , R ⁷ and N may or may not form a 4- to 8-membered Z-substituted heterocyclic ring;

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 is 0, 1, 2, 3;

X is C, N;

In the above chemical structural formula, R ₃ can be located on different atoms of the benzene ring or pyridine ring, that is, there may be no R ₃ group. In this case, a is 0, that is, hydrogen is on the benzene ring or the pyridine ring; it can be 1 R ₃ group, at this time 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 Substitution; can be 2 R ₃ groups, at this time a is 2, 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 2 R ₃ groups are substituted; it can be 3 R ₃ groups, in this 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 membered heteroaryl, 7-15 Member 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 heterocycle, 5-15 member Heteroaryl, a 7-15 membered fused ring, 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-, -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 Member 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;

、

、

、

； Or Cy is selected from

,

,

,

；

中兩個OR⁶與P原子所形成的5-10員 環基團、

中OR⁶與NR⁶R⁷與P原子所形成的5-10員環基團、

中兩個NR⁶R⁷與P原子所形成5-10員環基團； Or Cy is selected from

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;}

And -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 C ₁ -C ₆ alkyl group, or 2 R ⁹ and the nitrogen atom to which they are 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-substitution or gem-di-substitution;

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.

The compound of formula I or its pharmaceutically acceptable salt or solvate or isotopically substituted compound,

Or can be converted into the prodrug of the above I-3 in the organism

Wherein, 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 , -OCO-R ⁶ , -OCOO-R ⁶ , -COOR ⁶ , -NR ⁶ COR ⁷ , -NR ⁶ SO ₂ R ⁷ , -NR ⁶ CONR ⁶ R ⁷ , and R ⁶ , R ⁷ and N may or may not form a 4- to 8-membered Z-substituted heterocyclic ring;

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, C1-C6 alkoxy or Z substituted C1-C6 alkoxy or R ₄ , R ₅ is -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 CONR ⁷ or R ₄ , R ₅ and the atoms on the benzene ring to which they are bonded together form a 7-15 membered fused ring or a Z-substituted fused ring, and R ⁶ , R ⁷ and N are formed or not formed 4-8 member Z substituted heterocycle;

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 membered heteroaryl, 7-15 Member 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 heterocycle, 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 heterocyclic ring;

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 Member 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;

、

、

、

； Or Cy is selected from

,

,

,

；

中兩個OR6與P原子所形成的5-10員 環基團、

中OR⁶與NR⁶R⁷與P原子所形成的5-10員環基團、

中兩個NR⁶R⁷與P原子所形成5-10員環基團； Or Cy is selected from

5-10 membered ring group formed by two OR6 and P atoms,

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;}

And the above H-L-Cy does not form a phosphate alkylating agent;

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-substitution or gem-di-substitution;

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.

Hydrolases are classified as EC3 in the EC number, and are subdivided into several sub-categories based on the bonds it breaks down:

EC3.1: Ester bond (esterase)

EC3.2: Sugar (glycosylase)

EC3.3: ether bond

EC3.4: Peptide bond (peptidase)

EC3.5: C-N bond, but not including peptide bond

EC3.6: acid anhydride

EC3.7: C-C key

EC3.8: Halogen bond

EC3.9: P-N key

EC3.10: S-N key

EC3.11: S-P key

EC3.12: S-S key

EC3.13: C-S key

In the physiological environment of the human body, there are many enzymes that can cleave -NH-Cz in the above prodrugs. In particular, hydrolase can hydrolyze and break many chemical bonds, especially the compounds disclosed in the present invention containing C, P, S Atomic groups, 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, phosphatidyl Amines, thioamides.

Heterocycle and heteroaryl include three-membered ring, four-membered ring, five-membered ring, six-membered ring, and seven-membered ring. The following is an example.

Three-membered ring: ethylene oxide, azathione, ethylene sulfide;

Four-membered ring: azetidine, oxetidine, thiabutidine, butidine;

Five-membered ring: pyrrolidine, pyrroline, 1-pyrroline, 3-pyrroline, 2-pyrroline, pyrrole, pyrazoline, 2-pyrazoline, imidazole, pyrazole, furan, THF, dihydrofuran, Tetrahydrothiophene, thiophene, cyclobutane, phosphazone, oxazole, 1,2,3-triazole, 1,2,4-triazole, 1,3,4-thiadiazole;

Six-membered ring: pyridine, tetrahydropyran, tetrahydrothiopyran, pyridine, pyran, thiopyran, dihydropyridine, morpholine, pyrazine, pyridazine, pyrazine, 1,3,5-triazine, 1,3,5-Trithiane;

、氧雜

、硫雜

。 Seven-membered ring: azepine (azacycloheptane), oxheptane, thiaheptane, aza

Oxa

Thia

.

Fused ring is defined as the combination of the above heterocycles and heteroaryl groups or the combination with the cycloalkane structure. The combination can be connected by a single bond or share one, two or even three atoms, as follows Give some common fused ring structures: naphthalene, quinoline, indole, isoindole, iso Quinoline, cinnoline, quinoxaline, biphenyl, coumarin, fluorene, dibenzofuran, oxazole, anthracene, anthracene, thiophenazine, adamantane, azulene, phenanthrene, anthraquinone, flavonoid, isoflavone.

Obviously, 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.

In particular, the position substituted by deuterium is located on Ph-C*- in formula I, as shown in the following formula:

Further, in the compound provided above, the salt is a basic salt or an acid salt.

Regarding the compounds described herein, the compounds also include the forms of structural salts of formula I-1 to I-5, 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.). Alternatively, 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 Acid, citric acid, etc.). The selection and preparation of acceptable salts, solvates, etc. of the compound are techniques well known in the art.

Further, in the compound provided above, the solvate is a hydrate or an alcoholate.

In the technical field of drug design and organic chemistry, compounds, especially those with more active groups, such as phosphamide, amide, amine, salt or ester, etc., due to their resistance to solvents, such as alcohols such as water and ethanol. Solvent-like solvents have good affinity, and there are often combinations of solvents and compounds (typically inorganic salts such as hydrated copper sulfate), especially when the compound is a solid obtained from the solvent by crystallization, precipitation, concentration, etc. At this time, it will inevitably get a solvate that is combined with the solvent due to binding and wrapping with the solvent. Since the compound provided by the present invention has active groups such as phosphamide, amide, and hydroxyl, it is naturally possible to generate corresponding solvates based on the above-mentioned reasons and actual conditions.

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. The solvate is a hydrate, alcoholate, etc., and alcoholate includes Ethanol hydrate.

It has been confirmed through experiments that in the above compound I:

Has AKR1C3 enzyme inhibitory activity.

Literature investigation and research show that these compounds undergo the following metabolic reactions under the action of AKR1C3 enzyme:

The nitro compound in the above formula I will be obtained during the two reduction processes of AKR1C3 enzyme:

Intermediates of these three structures (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-Körner,Isabel M.Pires,I.Diane Swallow,et al. CH-01 is a Hypoxia-Activated Prodrug That Sensitizes Cells to Hypoxia/Reoxygenation Through Inhibition of Chk1 and 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 MB, Rischin D, Pegram M, et al. A phase I trial of PR-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 FW, Wouters BG, 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 monother apy and in combination with sorafenib in hepatocellular carcinoma[J].Cancer Biology & Therapy,2015,16(4):610-622.DOI:0.1080/15384047.2015.1017171), so these three intermediates (nitroso, hydroxylamine , Amine group) correspondingly can exert the AKR1C3 enzyme inhibitory activity similar to the nitro compound in formula I.

Due to prodrug

It can be hydrolyzed by various enzymes in the body (amide hydrolase, phosphamide hydrolase) to obtain the corresponding amine form, i.e. I-3, so the prodrugs I-5 and I-3 can be similar to the AKR1C3 inhibitor in the body. effect.

Further, the 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 alkenyl, C ₂ -C ₆ Alkynyl or Z-substituted alkynyl, C ₃ -C ₈ cycloalkyl or Z-substituted cycloalkyl.

Further, wherein, the R ₁ and R ₂ are each independently hydrogen, deuterium, or methyl.

Further, wherein R ₃ , R ₄ , and R ₅ are each independently hydrogen.

Further, 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- to 8-membered Z-substituted heterocyclic ring.

Further, where L is selected from -O- and -S-.

Further, where 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.

Further, wherein, Cy is selected from fluorophenyl, difluorophenyl, and trifluorophenyl.

、

、

、

Z取代的

、

、

、

、

、

、

、

Further, where Cy is selected from

,

,

,

Z replaced

,

,

,

,

,

,

,

Further, where the prodrug

Selected from

、

。即此時的前藥I-5中Cz為-COR⁶、- COOR⁶。

,

. That is, Cz in the prodrug I-5 at this time is -COR ⁶ and -COOR ⁶ .

Further, where -NH-Cz is a phosphamide group.

Further, compounds selected from the following structures

Wherein, the salt is a basic salt or an acid salt, and the solvate is a hydrate or alcoholate.

Literature investigation and research, according to the patent document TW201742868A (publication date 2017-12-16) in Taiwan, China, the content of the document is also (Disclosed in WO2017202817A1, AU2017269871A1, US20180319807A2, US20170342082A1, etc.) The public content can be known:

The aldehyde keto reductase family 1 member C3 (AKR1C3, also known as type 5 17-β-hydroxysteroid dehydrogenase (17-β-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.

AKR1C3 has 3α-HSD (hydroxysteroid dehydrogenase activity), 17β-HSD, 20α-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-α-hydroxyprogesterone (weak antiestrogenic activity) and Conversion of androstenedione to testosterone (Labrie F, Luu-The V, Labrie C, et al. DHEA and Its Transformation into Androgens and Estrogens in Peripheral Target Tissues: Intracrinology[J]. Frontiers in Neuroendocrinology, 2001, 22 (3): 185-212. DOI: 10.1006/frne.2001.0216). In addition, AKR1C3 catalyzes the conversion of PGH2 to PGF2α and PGD2 to 11β-PGF2, both of which are known to stimulate inflammation and proliferation.

In addition, AKR1C3 has also been shown to metabolize a wide range of carbonyl compounds and xenobiotics (including clinically administered anthracycline anthracycline) (Bains OS, Grigliatti TA, Reid RE, 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 doxorubicin 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.Anthracycline resistance mediated by reductive metabolism in cancer cells: The role of aldo-keto reductase 1C3[J].Toxicology and Applied Pharmacology,2014,278(3):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.

muc,Hevir N,Martina Ribi

Pucelj,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)。在與CYP19A1(芳香酶)協同作用時，預期AKR1C3成為子宮內膜異位員病變中之局部E2產生之關鍵酶，從而產生促雌激素環境，藉此刺激對雌激素敏感的子宮內膜異位細胞之增生。對AKR1C3之抑制應因此使得局部組織內E2含量下降，且藉此使子宮內膜異位病變之增生減少。不預期在卵巢雌激素產生方面之效果，此系因為AKR1C3在卵巢中僅略微表現，且17βHSD1為顯性卵巢羥基類固醇去氫酶。 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. In addition to the systemic estrogen content, there are more and more signs of locally derived estrogen promoting the development of endometriotic lesions. Recently, the high tissue estrogen concentration in endometriotic lesions has been described, which indicates high local estrogen synthesis in endometriosis (Huhtinen K, Desai R, Stahlee M, et al. Endometrial and Endometriotic Concentrations of Estrone and Estradiol Are Deter mined by Local Metabolism Rather than Circulating Levels[J]. The Journal of Clinical Endocrinology & Metabolism, 2012, 97(11): 4228-4235. DOI: 10.1210/jc.2012-1154). Therefore, the inhibition of local E2 production in endometriosis lesions is regarded as an attractive mechanism for the treatment of endometriosis. AKR1C3 is largely manifested in endometriotic lesions and is only slightly detectable in the ovaries (Tina

muc,Hevir N,Martina Ribi

Pucelj, 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). When synergistically with CYP19A1 (aromatase), AKR1C3 is expected to become a key enzyme for local E2 production in endometriotic lesions, thereby generating an estrogen environment, thereby stimulating endometriosis that is sensitive to estrogen Proliferation of cells. Inhibition of AKR1C3 should therefore reduce the E2 content in local tissues and thereby reduce the proliferation of endometriotic lesions. The effect on ovarian estrogen production is not expected because AKR1C3 is only slightly expressed in the ovary, and 17βHSD1 is a dominant ovarian hydroxysteroid dehydrogenase.

a Sinreih,Anko M,Kene N H,et al.Expression of AKR1B1,AKR1C3 and other genes of prostaglandin F2α biosynthesis 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)。預期子宮內膜異位員組織中之PGF2α造成子宮內膜異位患者的發炎、疼痛及增生，且預期在子宮內膜異位病變中表現之AKR1C3造成子宮內膜異位員組織中之高局部PGF2α含量。AKR1C3抑制具有藉由局部減少子宮內膜異位員組織中之E2、睪固酮及PGF2α含量來緩解子宮內膜異位患者之增生、疼痛及發炎的潛能。 AKR1C3 is also a PGF2α synthetase, and in addition to the up-regulation of AKR1C3, it has been shown that the content of PGF2α in women with peritoneal endometriosis and ectopic endometriosis are more effective than those of ectopic endometrium. Women with ovarian endometrioma have significantly higher levels in similar tissues (Ma

a Sinreih,Anko M,Kene NH,et al.Expression of AKR1B1,AKR1C3 and other genes of prostaglandin F2α biosynthesis 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). PGF2α in the tissues of endometriosis is expected to cause inflammation, pain and hyperplasia in patients with endometriosis, and AKR1C3, which is expected to manifest in endometriosis lesions, is expected to cause high localities in the tissues of endometriosis. PGF2α content. AKR1C3 inhibition has the potential to alleviate the proliferation, pain and inflammation of endometriosis patients by locally reducing the content of E2, testosterone and PGF2α in endometriosis tissues.

AKR1C3 is closely related to polycystic ovary syndrome (PCOS). AKR1C3 acts on several pathological conditions or diseases, including polycystic ovary syndrome (PCOS).

PCOS is a common endocrine disorder that affects up to 10% of women of reproductive age. It is clinically associated with an ovarian infertility, dysfunctional bleeding, androgen excess, hyperinsulinemia and insulin resistance, obesity and metabolic syndrome (Fang Y. Insulin 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). The four main characteristics of PCOS have been confirmed by the Androgen Excess Society: abnormal ovulation and menstrual function, biochemical hyperandrogenemia, clinical hyperandrogenism (eg, acne, hirsutism), and polycystic ovary disease (Azziz R,Car mina E,Dewailly D,Diamanti-Kandarakis E,Escobar-Morreale HF,Futterweit W,et al.Position statement: criteria for defining polycystic ovary syndrome as a predo minantly hyperandrogenic syndrome: an Androgen Excess Society.[J ]. Clin Endocrinol Metab 2006; 91: 4237-45. DOI: 10.1055/s-2003-43304). The vast majority of women with PCOS will present clinical symptoms of hyperandrogenism, such as acne, hirsutism, or anovulation mainly due to low fertility or oligomenorrhea (LegroRichard S, Brzyski Robert G, Diamond Michae P, et.al,Letrozole versus Clomiphene for Infertility in the Polycystic Ovary Syndrome[J].New England Journal of Medicine,2014,371(2):119-129.DOI:10.1056/nejmoa1313517). Women with PCOS are susceptible to glucose intolerance and metabolic disorders Syndrome (Taponen S, Martikainen H, Jarvelin M R. Metabolic Cardiovascular Disease Risk Factors in Women With Self-Reported Symptoms of Oligomenorrhea and/or Hirsutism: Northern Finland Birth Cohort 1966 Study[J]. Journal of Clinical Endocrinology & Metabolism, 2004 ,89(5):2114-8.DOI:10.1210/jc.2003-031720), with risk factors associated with cardiovascular disease and the likely increased risk of future cardiovascular events (Mani H, Levy MJ, Davies MJ ,et al.Diabetes and cardiovascular 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). Hyperandrogenism, hirsutism and/or hyperandrogenism are the key components of this syndrome, and must be used to diagnose PCOS (Azziz R, Car mina E, Dewailly D, Diamanti-Kandarakis E, Escobar-Morreale HF, Futterweit W,et al.Position statement: criteria for defining polycystic ovary syndrome as a predo minantly hyperandrogenic syndrome: an Androgen Excess Society.[J].Clin Endocrinol Metab 2006;91:4237-45.DOI:10.1055/s-2003-43304 ). Although serum testosterone is a key factor in the biochemical evaluation of hyperandrogenemia, androstenedione has recently been suggested as a more reliable marker for PCOS-related androgen excess. This is because androstenedione has a high concentration in women with PCOS.圈(O'Reilly, Michael W, Taylor AE, Crabtree NJ, et al. Hyperandrogenemia predicts metabolic phenotype in polycystic ovary syndrome: the utility of serum androstenedione[J]. The Journal of Clinical Endocrinology & Metabolism, 2014: jc.2013- 3399.DOI: 10.1210/jc.2013-3399). PCOS has traditionally been regarded as an ovarian disorder (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, 1999, 69: 269-272. DOI: 10.1016/s0960-0760(99)00044-8). However, attention to increased extraovarian and extraadrenal androgen formation in PCOS has highlighted the role of surrounding tissues, such as fat androgen formation (Quinkler M, Sinha B, To mLinson 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 is an androgen activating enzyme, which is known to convert androstenedione into testosterone. The up-regulation of AKR1C3 in the adipose tissue of PCOS patients has been described, which indicates that the performance of ARK1C3 in fat significantly promotes 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.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). AKR1C3 is also a PGF2α synthase, and plays a role in inhibiting the formation of endogenous ligands for the peroxisome proliferation activated receptor γ (PPARga mma), The peroxisome proliferative activation receptor γ is the target of insulin sensitizing drugs (Spiegelman et.al, Diabetes 1998, 47:507-514. DOI: 10.2337/diabetes.47.4.507). Selective AKR1C3 inhibition can provide Novel therapeutic targets to reduce the burden of androgens and improve the metabolic phenotype in PCOS (O"Reilly M, Gathercole 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 is closely related to cancer. AKR1C3 plays a role in several pathological conditions/disease 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: endometrial cancer (Rizner TL, Smuc T, Rupreht R, Sinkovec J,Penning TM AKR1C1 and AKR1C3 may deter mine 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), lung cancer (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. Oxidative damage-related genes AKR1C3 and OGG1 modulate risks for lung cancer due to exposure to PAH-rich coal combustion emissions.Carcinogenesis.2004,25(11):2177-2181.DOI:10.1093/carcin/bgh240), non-Hodgkin Lymphoma (Lan Q, Zheng T, Shen M, et al. Genetic polymorphisms in the oxidative stress pathway and susceptibility to non-Hodgkin lymphoma. Hum Genet. 2007; 121: 161-168. DOI: 10.1007/s00439-006-0288 -9), bladder cancer (Figueroa JD, Núria Malats, Montserrat García-Closas, et al. Bladder cancer risk and genetic variation in AKR1C3 and other metabolizing genes[J].Carcinogenesis,2008,29(10):1955-62..DOI:10.1093/carcin/bgn163), chronic bone marrow leukemia (Birtwistle J, Hayden RE, Khanim FL, et al. The aldo-keto reductase AKR1C3 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.mrf mmm.2008.12.010), renal cell carcinoma (Azzarello JT, Lin HK, Gherezghiher 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), breast cancer (Byrns MC, Duan L, Lee SH, et al. Aldo-keto reductase 1C3 expression in MCF-7 cells reveals roles in steroid hormone and prostaglandin metabolism that may explain its over-expression in breast cancer[J].J Steroid Biochem Mol Biol,2010,118(3):0-187.DOI:10.1016/j.jsbmb.2009.12. 009), however, its upscaling is usually associated with tumor aggressiveness and aggressiveness (Azzarello JT, Lin HK, Gherezghiher A, et al. Expression o f 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 RE,Khanim FL,et al.The aldo-keto reductase AKR1C3 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.mrf mmm.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 can directly reduce estrone and progesterone to 17β-estradiol and 20α-hydroxyprogesterone respectively, thereby enhancing this proliferative signal (Smuc, Rizner, Expression of 17β-hydroxysteroid dehydrogenases and other estrogen-metabolizing enzymes in different cancer cell lines[J].Chem Biol Interact.2009,178:228-33.DOI:10.1016/j.cbi.2008.10.038).

In addition, the prostaglandin F synthase activity of AKR1C3 catalyzes the conversion of PGH2 to PGF2α and PGD2 to 11β-PGF2α, both of which are known to stimulate inflammation and hyperplasia. In the absence of AKR1C3 activity, PGD2 (alternatively converted to PGF2) spontaneously dehydrates and rearranges to form anti-proliferative and anti-inflammatory PGJ2 isoforms, including 15d-PGJ2.

In summary, 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. In breast cancer, it is assumed that the action of AKR1C3 can produce prostaglandin F2α (PTGFR) ligands (Yoda T et.al, 11β-Prostaglandin F2α, a bioactive metabolite catalyzed by AKR1C3, stimulates prostaglandin F receptor and induces) which activates the survival of cancer cells. slug expression in breast cancer[J].Mol Cell Endocrinol.15;413:236-247.DOI:10.1016/j.mce.2015.07.008).

AKR1C3 plays a role in 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.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 cancer.J Clin Pathol.2008 Apr; 61(4 ): 448-54. DOI: 10.1136/jcp.2007.050906). In hormone-dependent prostate cancer, AKR1C3 converts androstenedione to testosterone, which in turn overactivates the androgen receptor and promotes tumor growth (Penning TM, Steckelbroeck S, Bauman DR, 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). In anti-castration prostate cancer (CRPC), intratumoral androgen biosynthesis involves AKR1C3, which promotes the weak androgen androstenedione (A'diketone) to the more active androgens testosterone and 5α-androgen, respectively Conversion of alkanedione (5α-diketone) to DHT (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,KM. Increased expression of type 2 3-hydroxysteroid dehydrogenase/type 5 17-hydroxysteroid dehydrogenase(AKR1C3)and its relationship with androgen receptor in prostate carcinoma[J].Endocrine Related Cancer,2006,13(1):169-180.DOI: 10.1677/erc.1.01048). Importantly, AKR1C3 expression is shown to increase in patients with CRPC compared to patients with primary prostate cancer (Stanbrough et.al, Cancer Res 2006, 66: 2815-2825. DOI: 10.1158/ 0008-5472.CAN-05-4000; Hamid AR, Pfeiffer MJ, Verhaegh GW, Schaafsma E, Brandt A, Sweep FC, Sedelaar JP, Schalken JA. Aldo-keto reductase family 1 member C3(AKR1C3) is a biomarker and therapeutic target for castration-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). Genetic polymorphism is also shown as an independent predictor of prostate cancer in the AKR1C3 gene coding of AKR1C3 (Yu et.al, PLoS One 2013, 8(1): e54627.DOI: 10.1371/journal.pone.0054627) . In addition, it has been shown that 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). In a multicenter phase I/II study, AKR1C3 inhibitors were tested on patients with metastatic anti-castration prostate cancer. However, novel androgen biosynthesis inhibitors have not shown any 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 resistance mechanism associated with antiandrogen (enzalutamide) resistance. Compared to parental cells, androgen precursors (such as cholesterol, DHEA, and progesterone) and androgens can exhibit a high level of upregulation in enzalutamide-resistant prostate cancer cells. Data indicate that the AKR1C3 inhibitory pathway can act as enzalutamide sensitization therapy 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]. Cancer 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, including in particular anti-anthracycline cancer. Anthracyclines (or anthracycline antibiotics) are a class of drugs used in cancer chemotherapy, and are derived from the Streptomyces bacterium Streptomyces bacterium Streptomyces bacterium Streptomyces bacterium Streptomyces peucetius var. Caesius, Critical Reviews 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-hydroxyl 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). The enzymatic metabolism of adriamycin is responsible for the cardiomyopathy observed after adriamycin chemotherapy. The literature has shown that 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). In 2012, 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 , Thereby indicating a potential interaction with doxorubicin metabolism (Voon et.al, British J of Clin Pharmacology 2012, 5: 14971505. DOI: 10.1111/bcp.12021). Recently, it has been confirmed that AKR1C3 promotes the resistance of cancer cells to anthracycline treatment, and therefore the concomitant administration of specific AKR1C3 inhibitors with anthracyclines can be used to successfully prevent and treat anti-anthracyclines Effective strategies against tumors (Hofman et.al, Toxicology and Applied Pharmacology 2014,278:238-248.DOI:10.1016/j.taap.2014.04.027).

Studies have also shown that AKR1C3 plays a key role in the resistance to radiation therapy of esophageal cancer, prostate cancer and non-small cell lung cancer (Sun et al Overexpression of AKR1C3 significantly enhances human prostate cancer cells resistance to radiation.Oncotarget.2016 Jul 26; 7( 30): 48050-48058. DOI: 10.18632/oncotarget.10347; Xiong et al.; Elevated Expression of AKR1C3 Increases Resistance of Cancer Cells to Ionizing Radiation via Modulation of Oxidative Stress.PLoS ONE 2014 9(11): e111911.DOI: 10.1371/journal.pone.0111911). Use DU145 cell line from prostate and its stable The corresponding cell line (AKR1C3-over) with high expression of AKR1C3 has been studied for the anti-radioactive effect of AKR1C3 in prostate cancer cells. Indomethacin is a specific inhibitor of AKR1C3 activity, which can significantly enhance the sensitivity of prostate cells to radiotherapy. Studies have found that PGF2α can not only promote the proliferation of prostate cancer cells, but also enhance the resistance of prostate cancer cells to radiation. The accumulation of PGF2α in AKR1C3-over cells leads to the initiation of the MAPK pathway and inhibits the expression of PPARγ. At the same time, studies have found that high expression of AKR1C3 can cause radiation resistance of 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). In A549/R and SPCA1/R cells, AKR1C3 mRNA and protein levels increased significantly. 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 showed a significant increase in anti-immune therapy 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 is a significant difference in expression. One of the significantly different genes is that AKR1C3 expression is significantly increased in non-responders (Ascierto 2015 The intratumoral balance between metabolic and i mmunologic gene expression is associated with anti-PD-1 response in patients with renal cell carcinoma Cancer I mrmunol Res 2016 4 726-733, doi: 10.1158/2326-6066. CIR-16-0072.).

Studies have shown that the combined use of AKR1C3 specific inhibitors and chemotherapeutics 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 Acute Myeloid Leukemia and T-Cell Acute Lymphoblastic Leukemia. J. Med. Chem. 2019, 62, 7: 3590-3616, DOI: 10.1021/acs.jmedchem. 9b00090).

AKR1C3 acts on several pathological conditions or diseases, which especially include atopic dermatitis. The attack of antigens on atopic individuals causes the release of PGD2 and histamine, which shows that PGD2 hardly promotes immediate allergic reactions in human skin and PGD2 is a lipid mediator that promotes skin inflammation in atopic dermatitis (AD) (Barr et al. .al,Br J Pharmacol.1988,94:773-80.PMID:2460180; Satoh et.al,JI mmunol.2006,177:2621-9.DOI: 10.4049/ji mmunol.177.4.2621; Shimura et.al , Am J Pathol. 2010, 176: 227-37. DOI: 10.2353/ajpath.2010.090111). PGD2 is a relatively unstable pro-inflammatory mediator, which spontaneously transforms into a strong anti-inflammatory mediator 15d-PGJ2. Its transformation is transferred by the metabolism of PGD2 through AKR1C3 to pro-inflammatory 9α, 11β-PGF2 (Mantel et.al, Exp Dermatol. 2016, 25(1): 38-43. DOI: 10.1111/exd. 12854). It has been confirmed that AKR1C3 is up-regulated in human AD samples, and it has been assumed that AKR1C3 regulates 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 can be a novel option for the treatment of AD and keloids.

AKR1C3 plays a role in several pathological conditions or diseases, which especially include inflammation. AKR1C3 is involved in prostaglandin biosynthesis, which catalyzes the conversion of PGH2 to PGF2α and PGD2 to 11β-PGF2. It has been postulated that the performance and upscaling of AKR1C3 supports inflammation by directly causing an increase in the synthesis rate of 9α, 11β-PGF2 and transferring the spontaneous production of the strong anti-inflammatory mediator 15d-PGJ2 (Mantel et.al, J Invest Dermatol 2012, 132 (4): 1103-1110. DOI: 10.1038/jid.2011.412). It has also been used in HL-60 cells (Desmond et.al, Cancer Res 2003, 63: 505-512. PubMed: 12543809) and MCF-7 cells (Byrns et. al, J Steroid Biochem Mol Biol 2010, 118: 177 -187.DOI: 10.1016/j.jsbmb.2009.12.009) involves this function of AKR1C3. It is assumed that the inhibition of AKR1C3 increases by 15d-PGJ2 (anti-inflammatory lipid), which is mainly through the activation of peroxisome proliferator activated receptor γ (PPAR-γ) and/or the inhibition of NF-κB that is transmitted in immune cells Directly regulate its effects (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). Previous data has pointed out that PPAR-γ activation reduces allergen-induced inflammation in the skin and lungs of mice (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). This shows the effect of AKR1C3 inhibition in suppressing inflammation.

AKR1C3 acts on several pathological conditions or diseases, and these pathological conditions or diseases include other diseases. In addition, AKR1C3 inhibitors have the potential to treat the following: prostate 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), 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. DOI: 10.1007/s00439-010-0878-4.), and chronic obstructive pulmonary disease (S. Pierrou , Am J Respir Crit Care 2007, 175(6), 577-586. DOI: 10.1164/rccm.200607-931OC).

It has now been found that 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 (especially 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.

Based on this, the following technical solutions related to medical applications are further provided.

Drugs containing the above-mentioned compounds and their pharmaceutically acceptable salts or solvates or isotopically substituted compounds.

The medicines are medicines for preventing or treating diseases related to AKR1C3 inhibitors.

Further, the medicine is used to prevent or treat diseases or conditions, the diseases or conditions include endometriosis, uterine leiomyoma, uterine bleeding disorders, dysmenorrhea, prostate hyperplasia, acne, seborrhea, hair loss, Premature sexual maturity, polycystic ovary syndrome, chronic obstructive pulmonary disease COPD, obesity, inflammatory pain or cancer or inflammation or cancer pain.

Furthermore, 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, endometrial cancer, renal cell carcinoma, bladder cancer, non-Hodgkin lymphoma and acute myeloid leukemia A ML, T-cell acute lymphoblastic leukemia T-ALL, leukemia.

Use of the above-mentioned compounds and their pharmaceutically acceptable salts or solvates or isotopes substituted compounds in the preparation of medicines for the treatment or prevention of related diseases/disorders, the diseases/disorders including endometriosis, uterine smooth muscle Tumors, uterine bleeding disorders, dysmenorrhea, prostate hyperplasia, acne, seborrhea, hair loss, premature sexual maturity, polycystic ovary syndrome, chronic obstructive pulmonary disease COPD, obesity, inflammatory pain or cancer or inflammation or cancer pain.

There is also provided a medicine for enhancing the sensitivity of cancer or tumor radiotherapy, the medicine containing the above-mentioned compound and its pharmaceutically acceptable salt or solvate or isotope substituted compound, which is used for: Improve the efficacy of radiotherapy when the therapy is resistant; or treat cancer or tumor patients who are resistant to radiotherapy.

There is also provided 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: immune response in cancer or tumor patients Improve the efficacy of immunotherapy when the therapy is resistant; or treat cancer or tumor patients who are resistant to immunotherapy.

There is also provided a medicine for enhancing the sensitivity of cancer or tumor chemotherapy. The medicine contains the above-mentioned compound and its pharmaceutically acceptable salt or solvate or isotope substituted compound, which is used to: 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. Improve the efficacy of immunotherapy when it is resistant; or the drug is used to treat cancer or tumor patients who are resistant to immunotherapy.

There is also provided a medicine for enhancing the sensitivity of cancer or tumor chemotherapy. The medicine contains the above-mentioned compound and its pharmaceutically acceptable salt or solvate or isotope substituted compound, which is used to: When it is resistant, the curative effect of chemotherapy is improved; or for the treatment of cancer or tumor patients who are resistant to chemotherapy, the medicine used in the chemotherapy contains daunorubicin or cytarabine.

The use of the above-mentioned compounds and their pharmaceutically acceptable salts or solvates or isotopes substituted compounds for enhancing the sensitivity of cancer or tumor radiotherapy or for enhancing drugs containing daunorubicin or cytarabine Sensitivity of drugs to chemotherapy for cancer or tumors.

The use of the above-mentioned compound and its pharmaceutically acceptable salt or solvate or isotopically substituted compound as an AKR1C3 enzyme inhibitor is also provided.

The pharmaceutical application of the above-mentioned compound and its pharmaceutically acceptable salt or solvate or isotope substituted compound is also provided. The medicine 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 efficacy 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, which is used for radiotherapy in cancer or tumor patients Improve the efficacy of radiotherapy when it is resistant; or the drug is used to treat cancer or tumor patients who are resistant to radiotherapy.

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 For the treatment of cancer or tumor patients resistant to chemotherapy, the medicine used in the chemotherapy contains daunorubicin or cytarabine.

Regarding the drugs or formulations described herein, the prepared drugs contain the indicated compound or its 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.

Regarding the use described herein, 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, injection needles, Lyophilized powder for injection or large infusion. According to the specific dosage form and mode of administration, the pharmaceutically acceptable excipients or excipients in the drug may include one or more of the following: diluents, solubilizers, disintegrants, suspending agents, lubricants, binders , Fillers, flavoring agents, sweeteners, antioxidants, surfactants, preservatives, wrapping agents and pigments.

Since the patient is a mammal, it is more preferably a human.

Hereinafter, the present invention will be explained with reference to specific embodiments. Those skilled in the art can understand that these embodiments are only used to illustrate the present invention, and they do not limit the scope of the present invention in any way.

The experimental methods in the following examples, unless otherwise specified, are all conventional methods. The medicinal materials, reagent materials, etc. used in the following examples are all commercially available products unless otherwise specified.

"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" and "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 being administered or administered.

Compared with drugs, prodrugs are chemically modified in such a way that they are less active or inactive relative to the drug, but chemical modification allows the corresponding drug to be produced through metabolism or other biological processes after the prodrug is injected. Prodrugs may 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 the amount of a drug that will have the expected therapeutic effect (for example, the alleviation, improvement, alleviation or elimination of the clinical manifestations of one or more cancers in the patient) when administered or administered to a patient suffering from cancer quantity. 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). For the purposes of the present invention, 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.

In some cases, the 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 (γ-ray) beam is emitted, and a large number of photon (γ-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 cancers due to its superficial penetration of tissues;

Proton radiation, although its usefulness is limited, 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).

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 effectiveness of the effect depends on 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 it is called the three major treatments for cancer together with surgery and radiotherapy. Surgery and radiotherapy are local treatments, which are only effective for the tumor at the treatment site, and 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 is difficult to effectively treat the cancer. Chemotherapy is a method of systemic treatment. No matter what route is used for administration (oral, intravenous and body cavity administration, etc.), chemotherapeutic drugs will circulate throughout most of the organs and tissues of the body with blood circulation. Therefore, chemotherapy is the main treatment method for some tumors that have a tendency to spread throughout the body and for metastatic tumors. Generally speaking, chemotherapy drugs are cytotoxic drugs, which can directly kill cells. However, 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 Get beneficial. However, chemotherapy still has serious toxic side effects, including digestive system reactions, bone marrow suppression, hair loss, etc. Certain toxic side effects will prevent some patients from continuing to receive chemotherapy or certain chemotherapy drugs.

Immunotherapy. Under normal circumstances, the human body’s immune system can recognize and eliminate tumor cells in the tumor microenvironment. However, in order to survive and grow, tumor cells can adopt different strategies to suppress the body’s immune system and cannot normally kill tumor cells. All stages of the anti-tumor immune response survived. The process by which the human immune system recognizes and eliminates tumor cells (tumor-immune loop) 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 loop, 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. 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. The therapeutic drugs have been approved for clinical use.

The above description of the specific embodiments of the present invention does not limit the present invention. Those skilled in the art can make various changes or modifications according to the present invention, as long as they do not deviate from the spirit of the present invention, they shall fall within the scope of the appended claims of the present invention.

The following are specific tests and examples of the present invention.

The following test will reveal the in vitro inhibitory activity of the AKR1C3 inhibitor developed by the applicant. The applicant hereby declares that the right to the following experimental data belongs to the applicant.

The applicant declares that part of the specific compounds disclosed in the following experiments are based on the specific synthetic methods and synthetic routes of the compounds disclosed in the present invention, with reference to patent publications (for example, application number PCT/US2016/021581, publication number WO2016/145092; No. PCT/US2016/062114, Publication No. WO2017/087428) or similar methods and operations disclosed in other public documents (although the substrates are different, the yields are high or low, but the field of pharmaceutical chemistry, organic chemistry, etc. masters the skills of organic synthesis Technicians can still synthesize it) can be synthesized, and the applicant has confirmed the structure by nuclear magnetic and mass spectrometry. This application provides representative compound synthesis methods, nuclear magnetic data and in vitro inhibitory activity against AKR1C3 enzyme.

Compound synthesis experiment

Synthetic method overview

English abbreviation explanation

MTBE, methyl tert-butyl ether; DMAP, 4-dimethylaminopyridine; T3P, 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, dimethylformate Amine; PE, petroleum ether, petroleum ether; eq, equivalent is the molar ratio; TBAF, tetrabutylammonium fluoride; DIPEA, N,N-diisopropylethylamine; reflux, reflux; rt, room temperature;

The chemical reagents and drugs that are not indicated in the synthesis process are all analytical or chemically pure, and they are all purchased from commercial reagent companies. Other English abbreviations that appear are subject to the interpretation in the field of organic chemistry.

Synthesis of compound 2

Under the protection of nitrogen, 2-A1 (500 mg, 1.51 mmol, synthesized with reference to No. 29 compound synthesis method) and 2-A2 (336 mg, 2.27 mmol, commercially available) were dissolved in anhydrous THF (10 mL). Cool down to 0°C, add triphenylphosphorus (991mg, 3.78mmol), then slowly add di-tert-butyl azodicarboxylate (870mg, 3.78mmol) in THF (5mL) dropwise, keep it at 0°C for half an hour, then chamber Warm stirring for 2.5 hours. After the reaction was completed, water (5mL) was added dropwise at 0°C, extracted with DCM (10mL×3), washed with water (3mL×2), dried and concentrated. The pure compound No. 2 (340mg, 48.9%) was prepared by HPLC, which was light. Yellow oil. ¹ H-NMR(400M,CD ₃ OD): 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).

Synthesis of compound 3

Under the protection of nitrogen, 3-A1 (200 mg, 0.632 mmol, refer to the synthesis method of compound 29) and 3-A2 (140 mg, 0.948 mmol, commercially available) were dissolved in anhydrous THF (5 mL). Cool down to 0°C, add triphenylphosphorus (414mg, 1.58mmol), then slowly add di-tert-butyl azodicarboxylate (363mg, 1.58mmol) in THF (2mL) dropwise, keep at 0°C for half an hour, then chamber Warm stirring for 2.5 hours. After the reaction was completed, water (5mL) was added dropwise at 0°C, extracted with DCM (5mL×3), washed with water (2mL×2), dried and concentrated. The pure compound No. 3 (160mg, yield 56.7%) was prepared by HPLC. It is light yellow oil. ¹ H-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).

Synthesis of compound No. 4

Under the protection of nitrogen, phosphorus oxychloride (580mg, 3.78mmol) was added dropwise to anhydrous DCM (5mL), the temperature was lowered to -40℃, and 4-A1 (500mg, 1.51mmol, synthesized with reference to No. 29 compound synthesis method) was added dropwise. DCM solution (3 mL), then TEA (397 mg, 3.9 mmol) in DCM solution (2 mL) was added dropwise, incubated at -40°C for 6 hours, and the raw materials disappeared. 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 the temperature 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%), it is a pale yellow viscous oil. ¹ H-NMR (400M Hz, 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=12.2 Hz, 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] ⁺ ).

Synthesis of compound 5

Under the protection of nitrogen, phosphorus oxychloride (242mg, 1.58mmol) was added dropwise to anhydrous DCM (5mL), the temperature was reduced to -40℃, and 5-A1 (200mg, 0.63mmol, synthesized with reference to No. 29 compound synthesis method) was added dropwise. DCM solution (3 mL), then TEA (166 mg, 1.64 mmol) in DCM solution (2 mL) was added dropwise, incubated at -40°C for 6 hours, and the raw material disappeared. Methylamine (670 g, 5.40 mmol, 25% inTHF) was added dropwise, and then TEA (546 g, 5.4 mmol) in DCM (5 mL) was added dropwise. Keep the temperature 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, HPLC prepared pure compound No. 5 (130mg , The yield is 48.9%), it is a pale yellow oil. ¹ H-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] ⁺ ).

Synthesis of compound 6

Under nitrogen protection, 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, The reaction is complete. Aqueous sodium thiosulfate solution (4 mL) was added dropwise, extracted with DCM (5 mL×3), dried and concentrated, and prepared and separated by HPLC to obtain compound 6 (120 mg, yield 28.3%) as a pale yellow oil. ¹ H-NMR (400M, CDCl ₃ ): δ7.97 (d, J=8.4 Hz, 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] ⁺ ).

Synthesis of compound 7

Under nitrogen protection, 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, The reaction is complete. An aqueous sodium thiosulfate solution (4 mL) was added dropwise, extracted with DCM (5 mL×3), dried and concentrated, and prepared and separated by HPLC to obtain compound 7 (90 mg, yield 31.6%) as a pale yellow oil. ¹ H-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] ⁺ ).

Synthesis of compound 8

Under the protection of nitrogen, 8-A1 (300 mg, 0.91 mmol, refer to the synthesis method of compound 29) and 8-A2 (202 mg, 1.36 mmol) were dissolved in anhydrous THF (5 mL). Cool down to 0°C, add triphenylphosphonium (600mg, 2.30mmol), then slowly add di-tert-butyl azodicarboxylate (530mg, 2.30mmol) in THF (3mL) dropwise, keep at 0°C for half an hour, then room Warm stirring for 2.5 hours. After the reaction was completed, water (5mL) was added dropwise at 0°C, extracted with DCM (5mL×3), washed with water (2mL×2), dried and concentrated. The pure compound No. 8 (230mg, yield 54.9%) was prepared by HPLC. It is a pale yellow solid. ¹ H-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).

Synthesis of compound 9

Under nitrogen protection, dissolve 9-A1 (300mg, 0.95mmol, refer to the synthesis method of compound 29) and 2,4,6-trifluorophenol (210mg, 1.40mmol) in dry THF (5mL), and add triphenyl Di-tert-butyl azodicarboxylate (550mg, 2.40mmol) in THF (4mL) was added dropwise, the reaction was completed for 2.5h, and water (5mL), DCM was added. Extraction (3×15 mL), brine washing, drying, and removal of solvent, high performance liquid preparation to obtain No. 9 compound (210 mg, yield 49.5%), as an off-white solid. ¹ H-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).

Compound No. 10

Under the protection of nitrogen, phosphorus oxychloride (348mg, 2.30mmol) was added dropwise to anhydrous DCM (5mL), the temperature was reduced to -40℃, and 10-A1 (300mg, 0.91mmol, synthesized with reference to No. 29 compound synthesis method) was added dropwise. DCM solution (3mL), then TEA (240mg, 2.40mmol) in DCM solution (2mL) was added dropwise, incubated at -40°C for 6 hours, the raw material disappeared. 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℃, 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. ¹ H-NMR(400M Hz,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] ⁺ ).

Compound 11

Under the protection of nitrogen, phosphorus oxychloride (242mg, 1.58mmol) was added dropwise to anhydrous DCM (5mL), the temperature was lowered to -40℃, and 11-A1 (200mg, 0.63mmol, synthesized with reference to No. 29 compound synthesis method) was added dropwise. DCM solution (3 mL), then TEA (166 mg, 1.64 mmol) in DCM solution (2 mL) was added dropwise, incubated at -40°C for 6 hours, and the raw material disappeared. Methylamine (670 mg, 5.40 mmol, 25% inTHF) was added dropwise, and then TEA (546 mg, 5.4 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℃, potassium carbonate solution (1g, 10mL) was added dropwise, DCM extraction (10mL×3), water washing (5mL×2), drying and concentration, HPLC prepared pure compound No. 11 (95mg, yield 35.7 %), is a light yellow viscous oily substance. ¹ H-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=12.4 Hz,6H).MS: Calculated 422.1,found 423.2([M+H] ⁺ ).

Compound No. 12

Under nitrogen protection, tris(dimethylamino)phosphine (179mg, 1.1mmol, purchased commercially) 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 . An aqueous sodium thiosulfate solution (4 mL) was added dropwise, extracted with DCM (5 mL×3), dried and concentrated, and prepared and separated by HPLC to obtain 76.5 mg of compound 12 with a yield of 18.2%, which was a pale yellow oil. ¹ H-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] ⁺ ).

Compound No. 13

Under nitrogen protection, tris(dimethylamino)phosphine (124mg, 0.76mmol, commercially available) 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 No. 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 . An aqueous sodium thiosulfate solution (4 mL) was added dropwise, extracted with DCM (5 mL×3), dried and concentrated, and prepared and separated by HPLC to obtain compound 13 (31 mg, yield 9.0%) as a pale yellow oil. ¹ H-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] ⁺ ).

Compound 14

Under nitrogen protection, add phosphorus oxychloride (246mg, 0.949mmol) to anhydrous DCM (10mL) dropwise, cool to -40℃, dropwise add 14-A1 (200mg, 0.633mmol, refer to No. 29 compound synthesis method) Then TEA (96mg, 0.949mmol) was added dropwise in DCM solution (4mL), and the temperature was kept at -40°C-35°C for two hours. HPLC tracked detection of 14-A1 disappeared and converted into an intermediate. At -40°C, N,N'-dimethyl-1,3-propanediamine (130mg, 1.27mmol, commercially available) in DCM (2mL) was added dropwise, and 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. ¹ H-NMR(400M Hz, 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] ⁺ ).

Compound 15

Under nitrogen protection, add phosphorus oxychloride (53mg, 0.348mmol) to anhydrous DCM (10mL) dropwise, cool to -40℃, dropwise add 15-A1 (100mg, 0.316mmol, refer to the synthesis method of No. 29 compound) Then TEA (35mg, 0.348mmol) was added dropwise in DCM solution (2mL), and the mixture was incubated at -40°C to -35°C for 2h, monitored by HPLC and LC-MS, 15-A1 disappeared and converted into an intermediate. At -40°C, 3-amino-1-propanol (26mg, 0.348mmol) in DCM (2mL) was added dropwise, then TEA (96mg, 0.948mmol) in DCM (2mL) was added dropwise, and the temperature was kept at -40°C 1h, the intermediate conversion is completed. Spontaneously warm to 0°C, add dropwise saturated aqueous ammonium chloride solution (5mL), extract with DCM (10mL×3), wash with pure water (3mL×3), dry and concentrate, and prepare compound No. 15 by HPLC (44.5mg, yield 32.3%), a white solid. ¹ H-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] ⁺ ).

Compound 16

Under the protection of nitrogen, add phosphorus oxychloride (54mg, 0.35mmol) to anhydrous DCM (10mL) dropwise, reduce the temperature to -40℃, dropwise add 16-A1 (100mg, 0.32mmol, refer to the synthesis method of No. 29 compound) DCM solution (2mL), TEA (36mg, 0.35mmol) was then added dropwise, and incubated at 40°C for -3 hours. At -40°C, 3-(methylamino)-1-propanol (31mg, 0.35mmol, commercially available) in DCM (2mL) was added dropwise, and then TEA (107mg, 1.05mmol) in DCM (2mL) was added dropwise Incubate at -40°C for 3 hours, naturally warm to room temperature, react overnight, add saturated ammonium chloride aqueous solution (5mL) dropwise at 0°C, extract with DCM (8mL×3), wash with pure water (3mL×3), and dry Concentrated and prepared by HPLC to obtain compound No. 16 (33 mg, yield 22.9%) as a semi-solid. ¹ H-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] ⁺ ).

Compound 17

Under the protection of nitrogen, phosphorus oxychloride (53.4mg, 0.348mmol) was added dropwise to anhydrous DCM (5mL), the temperature was reduced to -40℃, and 17-A1 (100mg, 0.316mmol, synthesized by referring to the synthesis method of No. 29 compound) was added dropwise. DCM solution (2mL), TEA (35.2mg, 0.348mmol) was added dropwise, and the temperature was kept at -40°C for 1.5 hours. The raw material was completely converted into an intermediate. At -40°C, 1,3-propanediol (26.5mg, 0.348mmol) in DCM (2mL) was added dropwise, and then TEA (106mg, 1.043mmol) in DCM (2mL) was added dropwise, warmed at -40°C, and the reaction was completed. At 0°C, saturated aqueous ammonium chloride solution (3mL) was added dropwise, extracted with DCM (5mL×3), washed with pure water (3mL×3), dried and concentrated. Preparative HPLC gave compound No. 17 (23.9mg, yield 17.3%.) , It is light yellow oily liquid. ¹ H-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] ⁺ ).

Compound No. 19

Under the protection of nitrogen, 19-A1 (2.0g, 11.69mmol) and 19-A2 (6.4g, 46.76mmol, commercially available) were dissolved in DMF (10mL), and then potassium carbonate (6.5g, 46.76mmol) was added. Stir at °C overnight. After the reaction is completed, cool to room temperature, add dropwise water (20mL), EA extraction (20mL×3), water washing (8mL×5), brine washing (8mL3), drying and concentration, 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. ¹ H-NMR(400M Hz, 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, found 288.0([M+H] ⁺ ).

Under the protection of nitrogen, phosphorus oxychloride (59mg, 0.382mmol) was added dropwise to anhydrous DCM (10mL), the temperature was lowered to -40°C, 19-A3 (100mg, 0.347mmol) in DCM solution (2mL) was added dropwise, and then TEA (39mg, 0.382mmol) was added dropwise and kept at -40°C to -35°C for two hours. HPLC and LC-MS detected that 19-A3 disappeared and was converted into an intermediate. At -40°C, N,N'-dimethyl-1,3-propanediamine (39mg, 0.382mmol, commercially available) in DCM (2mL) was added dropwise, and then TEA (105mg, 1.041mmol) 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 (3m×3), drying and concentration, preparative HPLC to obtain compound No. 19 (34.5mg, yield 20.8 %), is a light yellow oily liquid. ¹ H-NMR(400M Hz,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] ⁺ ).

Compound No. 20

Under the protection of nitrogen, phosphorus oxychloride (59mg, 0.382mmol) was added dropwise to anhydrous DCM (10mL), the temperature was lowered to -40°C, and 20-A1 (100mg, 0.347mmol, ie 19-A3) in DCM was added dropwise (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. At -40°C, 3-amino-1-propanol (29 mg, 0.382 mmol, commercially available) in DCM (2 mL) was added dropwise, and then TEA (105 mg, 1.041 mmol) in DCM (2 mL) was added dropwise, and incubated- One hour at 40°C, the intermediate conversion is complete. Spontaneously warm to 0°C, add dropwise saturated aqueous ammonium chloride solution (5mL), extract with DCM (10mL×3), wash with pure water (3mL×3), dry and concentrate, and prepare the product by HPLC (13.3mg, yield 9.4%) , It is light yellow oily liquid. ¹ H-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] ⁺ ) .

Compound 21

Under the protection of nitrogen, 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) in DCM was added dropwise (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, warmed to -40°C for 30 minutes, naturally warmed to room temperature, reacted overnight, at 0°C, saturated solution was added dropwise Aqueous ammonium chloride solution (5 mL), DCM extraction (8 mL×3), purified water washing (3 mL×3), drying and concentration, HPLC prepared compound No. 21 (41 mg, yield 27.2%), which was a semi-solid. ¹ H-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] ⁺ ).

Compound 23

Under nitrogen protection, 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) in DCM was added dropwise (2mL), then TEA (39.0mg, 0.382mmol) was added dropwise and incubated at -40°C for 1.5 hours. The raw material was completely converted into an intermediate. At -40°C, 4-amino-1-butanol (34.0 mg, 0.382 mmol, commercially available) in DCM (2 mL) was added dropwise, then TEA (116 mg, 1.145 mmol) in DCM (2 mL) was added dropwise, and incubated -40°C, the reaction is complete in 5 hours. At 0°C, saturated aqueous ammonium chloride solution (3mL) was added dropwise, extracted with DCM (5mL×3), washed with pure water (3mL×3), dried and concentrated to prepare pure compound No. 23 (15.7mg, 10.7%), which is Light yellow oily liquid. ¹ H-NMR(400M Hz,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] ⁺ ).

Synthesis of compound 24

Dissolve 24-A1 (100 mg, 0.32 mmol) in DCM (3 mL). The temperature was lowered to 0°C, and sulphurous acid chloride (57.12mg, 4.8mmol, 1.5eq) was added dropwise and stirred at room temperature, and the reaction was completed in 1.5h. Reduce the temperature to 0-5°C, add dropwise saturated sodium bicarbonate solution, adjust to weak alkaline (pH=7-8), extract with DCM (10mL×2), dry and concentrate to obtain 24-A2 (130mg) as a yellow oil The substance is directly thrown into the next reaction.

Dissolve 24-A2 (130mg, 0.388mmol) in DMF (3mL), add 3-hydroxypyridazine (74.57mg, 0.776mmol, 2eq), add cesium carbonate (316mg, 0.96mmol, 2.5eq) and stir at room temperature. The reaction was completed in 40 minutes. Add EA (20 times the volume), wash with saturated sodium carbonate (5 mL×3), brine, and dry and concentrate to prepare the product (26 mg, 17.0%) as a yellow oil. ¹ H-NMR (400M Hz, 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] ⁺ ).

Synthesis of compound 25

Dissolve 24-A1 (50mg, 0.16mmol) in DCM (3mL), add 29-B1 (141.8mg, 0.96mmol, 6eq) to lower the temperature to 0℃, drop TEA (95.9mmol, 0.96mmol, 6eq), add DMAP ( 4.85mg, 0.04mmol, 0.25eq) was heated at 40°C and stirred overnight. After the reaction was completed, the solvent was removed, and 14.1mg of the product was prepared by HPLC, which was a white solid, and the yield was 20.5%. ¹ H-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] ⁺ ).

Synthesis of compound 26

Dissolve triphosgene (3g, 10.1mmol) in DCM (300mL) at 0°C, then dissolve 26-A1 (1.52g, 20.2mmol, 2eq) in DCM (60mL) and add the system dropwise, After 20min, the drip is finished. 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. Directly invest in the next reaction.

，參照29號化合物合成方法合成)溶於 DCM(12mL)，降溫至0℃後將TEA(480mg，4.744mmol，5eq)與DMAP(29.1mg，0.237mmol，0.25eq)加入至體系，將體系升溫至35℃，大約12h反應完畢。HPLC與LCMS監測反應完畢後降至室溫，加入飽和NaHCO3(15mL×2)洗滌，有機相水洗(10mL×2)，水相DCM萃取(20mL×1)，有機相旋幹，高效液相製備得到26號化合物(150mg，收率37.8%)，為黃色油狀液體。¹H-NMR(400M,CDCl₃)：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,found 418.0([M+1]⁺). The 26-A2 (300mg, 0.949mmol) and 26-A3 (652.5mg, 4.744mmol, 5eq,

, Refer to the synthesis method of compound No. 29) Dissolve in DCM (12mL), add TEA (480mg, 4.744mmol, 5eq) and DMAP (29.1mg, 0.237mmol, 0.25eq) to the system after cooling to 0°C, and increase the temperature of the system The reaction is complete in about 12 hours to 35°C. After the reaction was monitored by HPLC and LCMS, the reaction was lowered to room temperature, saturated NaHCO3 (15mL×2) was added to wash, the organic phase was washed with water (10mL×2), the aqueous phase was extracted with DCM (20mL×1), the organic phase was spin-dried, and HPLC was prepared. The compound No. 26 (150 mg, yield 37.8%) was obtained as a yellow oily liquid. ¹ H-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,found 418.0([M+1] ⁺ ).

Synthesis of compound 27

Under the protection of nitrogen, 27-A1 (120mg, 0.358mmol, refer to the synthesis method of compound No. 29) was dissolved in DMF (5mL), 2,4 difluorothiophenol (104mg, 0.716mmol, 2eq) was added to Cs2CO3 (291.6 mg, 0.895mmol) 2.5eq). Stir at room temperature. The reaction was completed in 1h. Add 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. ¹ H-NMR (400M, CDCl ₃ ): δ 7.89 (d, J = 8.4 Hz, 1H), 7.44 (d, J = 8.4 Hz, 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] ⁺ ).

Synthesis of compound 28

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℃, and add isopropyl chloroformate dropwise (129.6mg, 1.2mmol, 3.6eq, commercially purchased) 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. ¹ H-NMR(400M,CDCl ₃ ): δ7.98(d,J=8.4 Hz,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] ⁺ ).

Synthesis of compound 29

29-A1 (1g, 5.84mmol) and 3-hydroxy-N,N-dimethylbenzamide (2.8g, 17.53mmol, 3eq) were dissolved in MeCN (30mL), and then K2CO3 (2.8g, 20.45 mmol, 3.5eq) was added to the system, the temperature of the system was raised to 65°C, the temperature was reduced to 20°C after 3h of reaction, H2O (15mL) was added, EA extraction (30mL×3), the organic phase was washed with 1N NaOH solution (50mL×3) , The organic phase is dried and spin-dried to mix samples, 200-300 silica gel (EA:PE, 1:3) to obtain 29-A2 (m=950mg, yield 51.4%). ¹ H-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) ⁺ ].

29-A2 (50mg, 0.158mmol) and piperidine-1-methyl chloride (141.9mg, 0.948mmol, 6eq) were dissolved in DCM (2mL), then TEA (32.0mg, 0.316mmol, 2eq) and DMAP ( 4.9mg, 0.04mmol, 0.25eq) was added to the system. At this time, the system was light yellow. The system was heated to 40° C., and the reaction was completed in 12 hours. The solvent was removed and prepared by high performance liquid chromatography to obtain 16.5 mg of pure product with a yield of 24.3%. ¹ H-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] ⁺ ).

Synthesis of compound 30

Under nitrogen protection, 30-A1 (1.76g, 7.72mmol) and 3,3-difluorotrimethyleneimine hydrochloride (1.0g, 7.72mmol, 1eq) were dissolved in DCM (20mL), and T3P EA solution ( 10g, 15.4mmol, 2eq, 50%), cool the system to 5°C, add DIEA dropwise, stir at room temperature after completion, HPLC monitoring for 2h, add water (5mL) to the system after the reaction is complete, and extract with DCM (15mL×3). The organic phase was washed with water (10 mL×2), dried and spin-dried to obtain the crude product (m=2.5g, yield 100%) as a pale yellow solid. ¹ H-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] ⁺ ).

Under nitrogen protection, dissolve 30-A2 (2.5g, 8.242mmol) in EtOH (37mL), then add Pd/C (630mg, 25% A2) to the system, and purge the system with N2 three times to make the system full of N2 , And then pump H2 three times to make the system full of H2, then stir at room temperature, and HPLC monitors that the reaction is completed for 8 hours. H2 was extracted under N2 protection, then Pd/C was filtered off with suction, washed with DCM (30 mL×3), and the mother liquor was spin-dried to obtain crude 30-A3 (1.5 g, yield 85.4%) as an off-white solid. ¹ H-NMR (400M, DMSO-d6): δ 7.24-7.28 (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] ⁺ ).

30-A3 (1.5g, 7.04mmol) and methyl 3-fluoro-4-nitrobenzoate (2.8g, 14.06mmol, 2eq) were dissolved in ACN (15mL), and then K2CO3 (2.9g, 21.01mmol, 3eq) was added to the system, refluxed overnight at 60°C, the next day the reaction was monitored by HPLC, cooled to room temperature, water (10mL) was added, extracted with DCM (20mL×4), the organic phase was washed with water (10mL×2), washed with brine, and dried. It was spin-dried to obtain crude 30-A4 (m=1.8g, yield 65.2%) as a yellow solid. ¹ H-NMR(400M,CDCl ₃ ): δ7.99(d,J=8.4Hz,1H),7.92(dd,J1=8.4Hz,J2=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] ⁺ ).

Dissolve 30-A4 (500mg, 1.27mmol) in THF (2mL), cool to 0°C, add NaBH4 (193mg, 5.10mmol, 4eq) to the system in batches, then heat the system to 60°C and reflux, and monitor the reaction by HPLC for 15h complete. Reduce to 0℃, quench with water (20mL), extract with DCM (20mL×3), dry and spin-dry to concentrate and mix the sample, 300-400 silica gel is subjected to fast Flash column chromatography to obtain 30-A5 pure product (140mg, yield 30.2%) is off-white solid. ¹ H-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,J1=8.4Hz,J2=2.0Hz,1H), 4.63-4.68(m,4H),3.67-3.76(m,2H).Calculated 364.1,found 365.1([M+H] ⁺ ) .

Dissolve 30-A5 (140mg, 0.384mmol) and piperidine-1-carbochloride (287.4mg, 1.92mmol, 5eq) in DCM (6mL). After cooling to 0°C, TEA (194.3mg, 1.92mmol, 5eq ) And DMAP (11.8 mg, 0.096 mmol, 0.25 eq) were added to the system and the system was heated to 35° C., and the reaction was completed in about 12 hours. After the reaction was monitored by HPLC and LCMS, it was lowered to room temperature, saturated NaHCO3 (10mL×2) was added for washing, the organic phase was washed with water (10mL×2), and the aqueous phase was extracted with DCM (10mL). After separation under neutral conditions, pure product (22.5 mg, yield 12.3%) was obtained as a white solid. ¹ H-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] ⁺ ).

Synthesis of compound 31

Dissolve PSCl3 (4.5g, 26.6mmol) in chloroform (50mL), then dissolve 31-A1 (2g, 26.6mmol) in chloroform (40mL) and add dropwise to the system. After 1h, the addition is complete. After stirring for 1h, DIEA( 3.44g, 26.6mmol) was dissolved in chloroform (10mL) and added dropwise to the system, and the system was heated to 20°C overnight. Water was added for extraction (20 mL×4), and the organic phase was dried and spin-dried to obtain crude 31-A2 (2.4 g), which was an off-white solid.

31-A2 (1.8g, 10.5mmol) was added to H2O (18mL), a white suspension, and then NaOH (923mg, 23.1mmol, 2.2eq) was slowly added to the system in batches, after which the system gradually changed during the reaction clarify. LCMS monitors the desired product. After reacting overnight, add MeCN (20mL) to mix and spin off part of the water. Use 12N HCl to adjust the system to acidity. A large amount of solids precipitate out. After suction filtration, use MeCN (10mL) to beat the water to remove water. After suction filtration, MeCN (10 mL) was added and spin-dried to obtain a total of 800 mg of 31-A3, which was a white solid, which was directly thrown into the next step of the reaction.

，參照29號化合物合成方法合成)溶於DMF(2mL)，後將 31-A3(91.5mg，0.597mmol，2eq)與TEA(90.7mg，0.896mmol，3eq)加入至體系，此時體系呈淡橘黃色，20℃反應過夜，反應完畢。加入飽和NaHCO3水溶液(5mL)，EA萃取(5mL×3)，有機相水洗(10mL×5)，水相EA萃取(10mL×2)，有機相旋幹後於中性條件下HPLC製備分離後凍幹溶液得純品67.4mg，收率為50.0%，為類白色固體。¹H-NMR(400M,CD₃OD)：δ7.99(d,J=8.4Hz,1H),7.48-7.50(m,2H),7.40(dd,J1=8.4Hz,J2=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]⁺). Under the protection of nitrogen, 31-A4 (100mg, 0.299mmol,

, Refer to the synthesis method of compound No. 29) was dissolved in DMF (2mL), and then 31-A3 (91.5mg, 0.597mmol, 2eq) and TEA (90.7mg, 0.896mmol, 3eq) were added to the system, the system was light at this time Orange, react overnight at 20°C, the reaction is complete. Add saturated aqueous NaHCO3 (5mL), extract with EA (5mL×3), wash the organic phase with water (10mL×5), extract with EA (10mL×2) in the aqueous phase, spin-dry the organic phase and HPLC preparation and separation under neutral conditions before freezing The dry solution yielded 67.4 mg of pure product, with a yield of 50.0%, which was an off-white solid. ¹ H-NMR(400M,CD ₃ OD): δ7.99(d,J=8.4Hz,1H),7.48-7.50(m,2H),7.40(dd,J1=8.4Hz,J2=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] ⁺ ).

Synthesis of compound 32

31 (20mg, 0.044mmol) was dissolved in DMF (1mL), then K2CO3 (12.2mg, 0.088mmol, 2eq) was added to the reaction system at room temperature and stirred for 1h, and then MeI (22mg, 0.132mmol, 3eq) was added dropwise After entering the system, the monitoring will not change after 45% conversion. Add K2CO3 (18.3mg, 0.132mmol, 2eq), MeI (22mg, 0.132mmol, 3eq), increase the temperature to 35°C, and the conversion reaches 75% overnight. After dropping to 10℃, add saturated NaHCO3 aqueous solution (2mL) to the system, extract with EA (3mL×3), wash the organic phase with brine (2mL×3), dry, spin dry and separate by neutral HPLC to obtain 32 6.1mg in total. Light yellow solid. ¹ H-NMR(400M,CD ₃ OD): 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] ⁺ ).

Synthesis of compound 33

Dissolve PSCl3 (4.5g, 26.3mmol,) in chloroform (50mL), then dissolve 33-A1 (2g, 26.3mmol) in chloroform (40mL) and add dropwise to the system. After 1 hour, the addition is complete. After stirring for 1 hour, DIEA (3.4 g, 26.3 mmol) was dissolved in chloroform (10 mL) and added dropwise to the system, and the system was heated to 20° C. overnight. Water was added for extraction (20 mL×4), and the organic phase was dried and spin-dried to obtain crude 33-A2 (3.5 g), which was an off-white solid. Directly invest in the next reaction.

33-A2 (1 g, 5.86 mmol) was added to H2O (10 mL), and then NaOH (281 mg, 7.03 mmol, 1.2 eq) was slowly added to the system in batches overnight. The desired product was detected by LCMS. The system was adjusted to pH=3-4 with 12N HCl, and no solid was precipitated. After spinning off the water, 500 mg of crude 33-A3 was obtained, which was a pale yellow liquid.

Under nitrogen protection, 33-A4 (100mg, 0.299mmol, synthesized by referring to No. 29 compound synthesis method) was dissolved in DMF (2mL), then 33-A3 (184.3mg, 1.196mmol, 4eq) and TEA (121.0mg, 1.196mmol) , 4eq) was added to the system. After overnight at room temperature, HPLC monitored the completion of the reaction. Add saturated NaHCO3 (10mL), extract with EA (5mL×3), wash the organic phase with water (5mL×2), extract the aqueous phase with EA (5mL×3), spin-dry the organic phase, and prepare 33 with a neutral high performance liquid phase to obtain a total of 29.7mg 33 The yield was 22.0%, and it was a yellow solid. ¹ H-NMR(400M,CD ₃ OD): 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] ⁺ ).

Synthesis of compound 34

At 0℃, dissolve PSCl3 (2g, 11.8mmol) in chloroform (25mL), and then add 34-A1 (11.8mL, 23.6mmol, 2eq, 2minTHF) dropwise into the system. After the addition is complete, stir for 1h and add DIEA (3.44 g, 26.6mmol) was dissolved in chloroform (10mL) and added dropwise to the system, and the system was heated to 20°C overnight. The solvent was removed to obtain crude product 34-A2. Water (20 mL) was added and stirred for 30 min and then spin-dried to obtain 5 g of 34-A3 crude product as a colorless oily liquid.

， 參照29號化合物合成方法合成)溶於DMF(1mL)，後將34-A3(418.6mg，1.194mmol，8eq)與TEA(120.8mg，1.194mmol，8eq)加入至體系，將體系升溫至30℃，過夜。HPLC與LCMS監測反應完畢後降至室溫，加入飽和NaHCO3水溶液(5mL)，EA萃取(5mL×3)，有機相水洗(5mL×3)，鹽水洗，硫酸鈉乾燥，旋幹，高效液相中性製備，得純品20.0mg，收率為30.6%，為淡黃色固體。¹H-NMR(400M,CD₃OD)：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]⁺). Nitrogen protection will 34-A4 (50mg, 0.149mmol,

, Refer to the synthesis method of compound No. 29) was dissolved in DMF (1mL), then 34-A3 (418.6mg, 1.194mmol, 8eq) and TEA (120.8mg, 1.194mmol, 8eq) were added to the system, and the system was heated to 30 ℃, overnight. After the reaction was monitored by HPLC and LCMS, it was lowered to room temperature, saturated NaHCO3 aqueous solution (5mL) was added, EA extraction (5mL×3), organic phase washed with water (5mL×3), brine washed, dried with sodium sulfate, spin-dried, HPLC Neutrally prepared, 20.0 mg of pure product was obtained, and the yield was 30.6%, which was a light yellow solid. ¹ H-NMR(400M,CD ₃ OD): 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] ⁺ ).

Synthesis of compound 35

PSCl3 (4.56g, 26.9mmol) was dissolved in chloroform (50mL), and then 35-A1 (2g, 26.9mmol) in chloroform (40mL) was added dropwise to the system. After 30min, the addition was completed. After stirring for 1h, DIEA( 3.48g, 26.9mmol) in chloroform (10mL) solution, the system was heated to 20°C overnight. After spin-drying, crude product 35-A2 was obtained. Water (20 mL) was added and stirred for 30 min. The water was removed to obtain a white solid. MeCN (3 mL) was slurried and filtered with suction to obtain 1.2 g of dry 35-A3, which was a white solid. Directly invest in the next reaction.

，參照29號化合物合成方法合成)溶於DMF(2mL)，後將 35-A3(182mg，1.196mmol，4eq)與TEA(121mg，1.196mmol，4eq)加入至體系，完畢後將體系升溫至25℃，過夜後HPLC監測反應完畢。加入飽和NaHCO3水溶液(5mL)，EA萃取(5mLx3)，有機相水洗(10mLx2)，水相EA萃取(5mLx2)，有機相旋幹，高效液相中性條件製備分離，得到35共23.1mg，收率為17.2%，為淡黃色固體。¹H- NMR(400M,CD₃OD)：δ7.98(d,J=8.4Hz,1H),7.47-7.50(m,2H),7.40(dd,J1=8.4Hz,J2=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]⁺). Under the protection of nitrogen, 35-A4 (100mg, 0.299mmol,

, Refer to the synthesis method of compound No. 29) was dissolved in DMF (2mL), and then 35-A3 (182mg, 1.196mmol, 4eq) and TEA (121mg, 1.196mmol, 4eq) were added to the system, and then the system was heated to 25 ℃, HPLC monitored the completion of the reaction overnight. Add saturated NaHCO3 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, yield The rate was 17.2%, and it was a pale yellow solid. ¹ H- NMR(400M,CD ₃ OD): δ7.98(d,J=8.4Hz,1H),7.47-7.50(m,2H),7.40(dd,J1=8.4Hz,J2=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] ⁺ ).

Compound No. 1

It is synthesized by referring to the method similar to the above compound 2/3.

¹ H-NMR(400M Hz,CDCl ₃ ): δ 7.91(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) ).

In vitro AKR1C3 enzyme activity inhibition test

laboratory apparatus:

The Waters Acquity I Class UPLC Ultra High Performance Liquid Chromatograph is equipped with a Xevo G2-XSQ Tof HRMS quadrupole time-of-flight high-resolution mass spectrometer.

Buffer and materials:

1. PBS phosphate buffered saline solution,

2.20mm NADPH PBS phosphate buffered saline solution

3.250μg/mL AKR1C3 in PBS phosphate buffered saline solution

4.250μM 50% MeOH/H2O solution of test compound

5.250μM progesterone (progesterone) in 50% MeOH/H2O solution

6.1μg/mL propranolol in 100% acetonitrile

Experimental operation process

In step 1, the reaction mixture was made into Eppendorf tubes in duplicate (n=2) according to the following table, and mixed gently.

Step 2. Pre-incubate the above duplicate mixture at 37°C for 30 minutes.

Step 3. Add another 10 μL of 20 mmNADPH PBS phosphate buffered saline solution and 2 μL of 250 μM progesterone 50% MeOH/H2O solution to each Eppendorf tube and mix gently.

Step 4. Immediately transfer 50 μL of the mixture in the above step to 100 μL of 1 μg/mL propranolol (propranolol, internal standard IS) 100% acetonitrile solution.

Step 5: Incubate the remaining samples at 37° C. for 30 minutes, and add 100 μL of 1 μg/mL propranolol (propranolol, internal standard IS) 100% acetonitrile solution.

Step 6. For all samples, add 100 μL of reagent water, vortex at 1100 rpm for 5 minutes, and centrifuge at 15000 rpm for 10 minutes at room temperature.

Step 7. Load all samples onto LC/MS to determine the content of reduced progesterone, namely 20α-dihydroprogesterone.

The test conditions of the LC-MS instrument are

Liquid elution gradient

Quadrupole time-of-flight mass spectrometry parameters

Step 9. Calculation of reduced progesterone (20α-dihydroprogesterone): Determine the peak area of reduced progesterone, namely 20α-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%.

AKR1C3 activity (%)=[(reduced progesterone amount after sample standardization) 30min-(reduced progesterone amount after sample standardization) 0min]/[(reduced progesterone amount after normalization of negative control group) 30min-(negative control After group standardization, the amount of progesterone reduced) 0min]*100.

According to the above calculation, the AKR1C3 relative activity% activity result at a compound concentration of 5 μM/L in the following table is obtained.

Remarks: ND means not tested;

The activity data of the above compounds are obtained from four tests: 2019/5/29, 2019/5/31, 2019/6/13, 2019/6/14, the corresponding control compounds 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 inhibitor of AKR1C3, 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 μM/L, indicating that the compound disclosed in the present invention is a more efficient AKR1C3 inhibitor.

Claims (29)

Compounds of the following formula and their pharmaceutically acceptable salts or solvates or isotopically substituted compounds:

Wherein, 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 , -OCO-R ⁶ , -OCOO-R ⁶ , -COOR ⁶ , -NR ⁶ COR ⁷ , -NR ⁶ SO ₂ R ⁷ , -NR ⁶ CONR ⁶ R ⁷ , and R ⁶ , R ⁷ and N may or may not form a 4-8 membered Z-substituted heterocyclic ring, or two R3 and the atoms on the benzene ring to which they are bonded together form a 7-15 membered fused Ring or Z substituted fused ring; 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 is 0, 1, 2, 3; X is C, N; 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 membered heteroaryl, 7-15 Member 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 heterocycle, 5-15 member Heteroaryl, a 7-15 membered fused ring, 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-, -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 Member 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; or Cy is selected from

,

,

,

； Or Cy is selected from

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;} And -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 C ₁ -C ₆ alkyl group, or 2 R ⁹ and the nitrogen atom to which they are 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 a halogen atom, a cyano group or an isocyano group, a hydroxyl group, a mercapto group, an amino group, an oxime group, a hydrazone group, OTs, OMs, 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, heterocyclic ring, heteroaromatic ring and fused or substituted aromatic ring, Heterocyclic ring, heteroaromatic ring and fused ring, the mode of substitution is mono-substitution or gem-di-substitution; 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. The compound according to claim 1, which is selected from compounds of formula I,

Among them, I-5 is a prodrug that can be converted into the above-mentioned I-3 in the body, 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 , -OCO-R ⁶ , -OCOO-R ⁶ , -COOR ⁶ , -NR ⁶ COR ⁷ , -NR ⁶ SO ₂ R ⁷ , -NR ⁶ CONR ⁶ R ⁷ , and R ⁶ , R ⁷ and N may or may not form a 4- to 8-membered Z-substituted heterocyclic ring; 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, C1-C6 alkoxy or Z substituted C1-C6 alkoxy or R ₄ , R ₅ is -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 CONR ⁷ or R ₄ , R ₅ and the atoms on the benzene ring to which they are bonded together form a 7-15 membered fused ring or a Z-substituted fused ring, and R ⁶ , R ⁷ and N are formed or not formed 4-8 member Z substituted heterocycle; 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- A 7-membered heterocyclic group or Z-substituted 3-7-membered heterocyclic group, and R ⁶ , R ⁷ and N form or do not form a 4-8 membered Z-substituted heterocyclic ring; 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 membered heteroaryl, 7-15 Member 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 heterocycle, 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 heterocyclic ring; 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 Member 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; or Cy is selected from

,

,

,

； Or Cy is selected from

5-10 membered ring group formed by two OR6 and P atoms,

The 5-10 membered ring group formed by OR6 and NR6R7 and P atom,

5-10 membered ring group formed by two NR6R7 and P atoms; The Z substituent is a halogen atom, a cyano group or an isocyano group, a hydroxyl group, a mercapto group, an amino group, an oxime group, a hydrazone group, OTs, OMs, C ₁ -C ₃ alkyl or substituted alkyl, C ₁ -C ₃ alkoxy Group 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, heterocyclic ring , 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. The compound according to claims 1 to 2, wherein The 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 alkenyl, C ₂ -C ₆ alkynyl or Z substituted alkynyl, C ₃ -C ₈ cycloalkyl or Z substituted cycloalkyl. The compound according to claim 3, wherein the R ₁ and R ₂ are each independently hydrogen, deuterium, or methyl. The compound according to claims 1 to 4, wherein R ₃ , R ₄ , and R ₅ are each independently hydrogen. The compound according to claims 1 to 5, wherein Cx is -CONR6R7 substituted phenyl, and R ⁶ , R ⁷ and N may or may not form a 4- to 8-membered Z-substituted heterocyclic ring. The compound according to claims 1 to 6, wherein L is selected from -O- and -S-. The compound according to claims 1 to 7, wherein 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. The compound according to claim 8, wherein Cy is selected from fluorophenyl, difluorophenyl, and trifluorophenyl. The compound according to claims 1 to 7, wherein Cy is selected from

,

,

,

Or replaced by Z

,

,

,

The compound according to claims 1 to 2, wherein Cz is selected from -COR ⁶ and -COOR ⁶ . The compound according to claims 1 to 10, wherein -NH-Cz is a phosphamide group. The compounds described in claims 1 to 10, selected from compounds of the following structures

The compound according to any one of claims 1 to 13, wherein the salt is a basic salt or an acid salt, and the solvate is a hydrate or alcoholate. A drug containing the compound described in any one of claims 1 to 13 and its pharmaceutically acceptable salt or solvate or isotope substituted compound. The medicine according to claim 15, which is used for the prevention or treatment of diseases or conditions including endometriosis, uterine leiomyomas, uterine bleeding disorders, dysmenorrhea, prostate hyperplasia, acne, Seborrhea, hair loss, premature sexual maturity, polycystic ovary syndrome, chronic obstructive pulmonary disease COPD, obesity, inflammatory pain or cancer or inflammation or cancer pain. The medicine according to claim 16, wherein 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, endometrial cancer, renal cell carcinoma, bladder cancer, non-Hodgkin's lymphoma and acute myeloid leukemia A ML, T-cell acute lymphoblastic leukemia T-ALL, leukemia. Use of the compound according to any one of claims 1 to 13 and its pharmaceutically acceptable salt or solvate or isotope substituted compound in the preparation of a medicine for the treatment or prevention of related diseases/disorders, said diseases/disorders Including endometriosis, uterine leiomyoma, uterine bleeding disorders, dysmenorrhea, prostate hyperplasia, acne, seborrhea, alopecia, premature sexual maturity, polycystic ovary syndrome, chronic obstructive pulmonary disease COPD, obesity, inflammation Sexual pain or cancer or inflammation or cancer pain. A medicine for enhancing the sensitivity of cancer or tumor radiotherapy, the medicine containing the compound according to any one of claims 1 to 13 and its pharmaceutically acceptable salt or solvate or isotope substituted compound, which is used for : Improve the efficacy of radiotherapy when cancer or tumor patients are resistant to radiotherapy; 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 compound according to any one of claims 1 to 13 and its pharmaceutically acceptable salt or solvate or isotope substituted compound, which is used for : Improve the efficacy of radiotherapy when cancer or tumor patients are resistant to immunotherapy; or treat cancer or tumor patients who are resistant to immunotherapy. A medicine for enhancing the chemotherapeutic sensitivity of cancer or tumor, the medicine containing the compound according to any one of claims 1 to 13 and its pharmaceutically acceptable salt or solvate or isotope substituted compound, which is used for: Improve the efficacy of chemotherapy when cancer or tumor patients are resistant to chemotherapy; or treat cancer or tumor patients who are resistant to chemotherapy. A drug for enhancing the sensitivity of cancer or tumor chemotherapy, the drug containing the compound according to any one of claims 1 to 13 and a pharmaceutically acceptable salt or solvent thereof A compound or an isotope-substituting compound, which is used to: improve the efficacy of chemotherapy when cancer or tumor patients are resistant to chemotherapy; or to treat cancer or tumor patients resistant to chemotherapy, and the drugs used in the chemotherapy contain soft red Daunorubicin or cytarabine. The use of the compound according to any one of claims 1 to 13 and its pharmaceutically acceptable salt or solvate or isotope substituted compound for enhancing the sensitivity of cancer or tumor radiotherapy or for enhancing the content of soft red Sensitivity of drugs such as daunorubicin or cytarabine to chemotherapy for cancer or tumors. Use of the compound according to any one of claims 1 to 13 and its pharmaceutically acceptable salt or solvate or isotope substituted compound. The pharmaceutical use of the compound according to any one of claims 1 to 13 and its pharmaceutically acceptable salt or solvate or isotope substituted compound, which is an AKR1C3 enzyme inhibitor. Pharmaceutical use of the compound according to any one of claims 1 to 13 and its pharmaceutically acceptable salt or solvate or isotope substituted compound, which is used to increase the resistance of cancer or tumor patients to radiotherapy The efficacy of radiotherapy; or the drug is used to treat cancer or tumor patients who are resistant to radiotherapy. Pharmaceutical use of the compound according to any one of claims 1 to 13 and its pharmaceutically acceptable salt or solvate or isotope substituted compound, which is used to improve the resistance of cancer or tumor patients to immunotherapy The efficacy of radiotherapy; or the drug is used to treat cancer or tumor patients who are resistant to immunotherapy. The pharmaceutical use of the compound according to any one of claims 1 to 13 and its pharmaceutically acceptable salt or solvate or isotope substituted compound, which is used in cancer or Improve the efficacy of chemotherapy when tumor patients are resistant to chemotherapy; or the drug is used to treat cancer or tumor patients who are resistant to chemotherapy. Pharmaceutical use of the compound according to any one of claims 1 to 13 and its pharmaceutically acceptable salt or solvate or isotope substituted compound for improving chemotherapy when cancer or tumor patients are resistant to chemotherapy Or the medicine is used to treat cancer or tumor patients who are resistant to chemotherapy, and the medicine used in the chemotherapy contains daunorubicin or cytarabine.