WO2023185673A1 - Cdk8 inhibitors, preparation method therefor and use thereof - Google Patents

Abstract

Provided in the present invention are CDK8 inhibitors, a preparation method therefor and the use thereof, belonging to the field of biological medicines. The CDK8 inhibitors of the present invention are compounds represented by formula (I), or optical isomers, pharmaceutically acceptable salts, hydrates or solvates thereof. The compounds of the present invention have excellent CDK8 inhibiting effect, can be clinically used as CDK8 inhibitors, provide a new choice for treating tumor-related diseases, such as leukemia, and have great application prospects.

Description

A CDK8 inhibitor and its preparation method and use Technical field

The invention belongs to the field of biomedicine, and specifically relates to a CDK8 inhibitor and its use.

Background technique

Cyclin-dependent kinases (CDKs) are a family of serine/threonine protein kinases that control key regulatory events during the cell cycle and DNA transcription. Cyclin-dependent kinase 8 (CDK8) is a widely expressed transcriptional member of the CDK family. CDK8 plays an important role in transcriptional regulation by binding to the mediator complex or by phosphorylating transcription factors (such as NOTCH, STAT1 and SMADs, etc.). Its deregulation has been implicated in several types of human cancers. The gene encoding CDK8 was first identified as an oncogene in colorectal cancer in 2008. Genetic and biochemical studies to date have confirmed that CDK8 is also a key oncogenic factor in a variety of other cancers, including prostate cancer, melanoma, breast cancer, acute myeloid leukemia, and pancreatic cancer. In addition, phosphorylation of serine S727 in the transcription factor STAT1 by CDK8 inhibits the activity of natural killer (NK) cells, and S727-mutated NK cells show increased release of cytotoxic proteins (such as granzyme B and perforin) and are resistant to cancer. cells are more cytotoxic. This suggests that inhibition of CDK8 expression may play an important role in cancer immunotherapy, a role that was further verified using several exogenous CDK8 small molecule inhibitors. Taken together, these studies provide a theoretical basis for CDK8 to become an important target for cancer treatment. Therefore, there is an urgent need to find effective and selective small molecule CDK8 inhibitors. Since the report of the marine steroidal alkaloid cortistatin A as a high-affinity ligand for CDK8 in 2009, various naturally derived or chemically synthesized molecular scaffolds and their derivatives have been used to search for CDK8 inhibitors. Two of the compounds, BCD-115 and SEL120, have been approved to enter phase I clinical trials for the treatment of advanced metastatic breast cancer, colon cancer, acute myeloid leukemia or high-risk myelodysplastic syndrome and some other solid tumors.

Until now, although many CDK8 inhibitor compounds have been reported, there is still a need for more structurally novel CDK8 inhibitors (especially selective CDK8 inhibitors) for the treatment of diseases, especially tumors, with better effects. The search for CDK8 inhibitor compounds continues.

For example, patent application WO2019/160889A1 discloses a series of compounds with the following structures that have inhibitory effects on CDK8:

However, the inhibitory effect of most of these compounds is still poor and further improvement research is needed.

Contents of the invention

The purpose of the present invention is to provide a new CDK8 inhibitor and its preparation method and use.

The invention provides the compound represented by formula I or its optical isomer, pharmaceutically acceptable salt, water Compound or solvate:

Wherein, X is -OR, =O or -NR ₁ R ₂ ;

R is H or C1～C6 alkyl;

R ₁ and R ₂ are independently selected from H, C1 to C6 alkyl, -C(O)-R, or R ₁ and R ₂ together with the N atom to which they are connected form a substituted or unsubstituted 3 to 7-membered heterogeneous group. Ring or 5-, 8-, or 9-membered aromatic heterocycle, the heteroatoms on the heterocycle or aromatic heterocycle are N and/or O, S, the number of heteroatoms is at least 1; the substituted substituent It is C1～C6 alkyl;

u, v, w are connected to form the following structure:

y and z are connected to form the following structure:

Het is a substituted or unsubstituted aromatic heterocycle or paraaromatic heterocycle, the heteroatom of the aromatic heterocycle or paraaromatic heterocycle is N, O or S, and the number of heteroatoms is any integer from 1 to 4; The number of substituted substituents is any integer from 1 to 5, and the substituents are cyano, halogen, hydroxyl-substituted or unsubstituted C1-C5 alkyl, C1-C5 alkyl or =O substituted or unsubstituted 5-10 membered heterocycle, phenyl, amino, -C(O)-R _a or -C(O)OR _a , the heteroatom of the heterocyclic ring is N, O or S, and the number of heteroatoms is 1 to 10 Any integer of 4; the number of substituted hydroxyl groups is any integer of 1 to 4; the number of substituted C1 to C5 alkyl groups or =O is any integer of 1 to 3;

R _a is a substituted or unsubstituted amino group, a substituted or unsubstituted C1-C5 alkoxy group, a C1-C5 alkyl group or a 3-6 membered carbocyclic ring; the number of substituted substituents is any one from 1 to 5 Integer, the substituted substituent is halogen, C1-C3 alkyl or C1-C3 alkoxy.

further,

The X is -OR or -NR ₁ R ₂ ;

R is H or C1～C3 alkyl;

R ₁ and R ₂ are each independently selected from H, C1-C3 alkyl, or R ₁ and R ₂ together with the N atom to which they are connected form a substituted or unsubstituted 5-7 membered heterocyclic ring. The heteroatoms are N and/or O, and the number of heteroatoms is any integer from 1 to 3; the substituted substituent is C1 to C3 alkyl.

further,

The X is -OH or -NR ₁ R ₂ ;

R ₁ and R ₂ are independently selected from H, methyl, or R ₁ and R ₂ together with the N atom to which they are connected form a substituted or unsubstituted 6-membered heterocyclic ring, and the heteroatoms on the heterocyclic ring are N and / or O, the number of heteroatoms is 1 or 2; the substituted substituent is methyl.

further,

The R ₁ and R ₂ are independently selected from H and methyl, or R ₁ and R ₂ together with the N atom to which they are connected form a methyl substituted or unsubstituted

Preferably, R ₁ and R ₂ are independently selected from H, methyl, or R ₁ and R ₂ together with the N atoms to which they are connected form

further,

Het is a substituted or unsubstituted nitrogen-containing aromatic heterocycle or nitrogen-containing aromatic heterocycle, and the number of heteroatoms of the nitrogen-containing aromatic heterocycle or nitrogen-containing aromatic heterocycle is 1, 2 or 3;

The number of the substituted substituents is any integer from 1 to 3, and the substituents are cyano, halogen, hydroxyl substituted or unsubstituted C1~C4 alkyl, C1~C3 alkyl or =O substituted or unsubstituted Substituted 5-10 membered heterocycle, phenyl, amino, -C(O)-R _a or -C(O)OR _a , the heteroatom of the heterocyclic ring is N, and the number of heteroatoms is 1, 2 or 3; the number of substituted hydroxyl groups is 1 or 2; the number of substituted C1~C3 alkyl or =O is 1 or 2;

R _a is a substituted or unsubstituted amino group, a substituted or unsubstituted C1-C4 alkoxy group, a C1-C4 alkyl group or a 5-6 membered carbocyclic ring; the number of substituted substituents is any of 1 to 3 Integer, the substituted substituent is halogen, C1-C3 alkyl or C1-C3 alkoxy.

further,

Het is a substituted or unsubstituted nitrogen aromatic heterocycle or nitrogen aromatic heterocycle, and the number of heteroatoms of the nitrogen aromatic heterocycle or nitrogen aromatic heterocycle is 1, 2 or 3;

The number of the substituted substituents is 1 or 2, and the substituents are cyano, chlorine, hydroxyl substituted or unsubstituted C1-C3 alkyl, C1-C3 alkyl or =O substituted or unsubstituted 6-10 membered heterocycle, phenyl, amino, -C(O)-R _a or -C(O)OR _a , the heteroatom of the heterocyclic ring is N, and the number of heteroatoms is 2; the hydroxyl group The number of substitutions is 1; the number of C1~C3 alkyl or =O substitutions is 1;

R _a is a substituted or unsubstituted amino group, a substituted or unsubstituted C1-C3 alkoxy group, a methyl group or a 5-membered carbocyclic ring; the number of the substituted substituents is 1, 2 or 3, and the Substituted substituents are fluorine, methyl or methoxy.

further,

Het is substituted or unsubstituted

further,

Het is substituted or unsubstituted

Preferably substituted or unsubstituted or replace

further,

The number of the substituted substituents is 1, and the substituents are: 1 hydroxyl-substituted C1-C3 alkyl group, 1 methyl-substituted 6-membered heterocycle, and 1 =O-substituted 10-membered heterocycle , cyano group, -C(O)-R _a or -C(O)OR _a , the heteroatom of the heterocyclic ring is N, and the number of heteroatoms is 2;

R _a is a substituted or unsubstituted amino, methyl, 5-membered carbocyclic ring or C1-C3 alkoxy group; the number of the substituted substituents is 1 or 2, and the substituted substituents are methyl or Methoxy.

further,

The number of the substituted substituents is 1, and the substituents are: 1 hydroxyl-substituted C1-C3 alkyl group, or -C(O)-R _a ;

R _a is a substituted or unsubstituted amino, methyl, 5-membered carbocyclic ring or C1-C3 alkoxy group; the number of substituted substituents is 1, and the substituted substituent is methyl or methoxy .

Further, the compound has a structure shown in formula IA:

Among them, X, u, v, w, y, z, Het are as mentioned above.

Further, the compound has a structure shown in formula IB:

Among them, R ₁ , R ₂ , u, v, w, y, z are as mentioned above;

R' is a substituent on the pyridine ring, forming R' is selected from cyano, halogen, hydroxyl substituted or unsubstituted C1~C5 alkyl, C1~C5 alkyl or =O substituted or unsubstituted 5~10 membered heterocycle, phenyl, amino, -C(O )-R _a or -C(O)OR _a , the heteroatom of the heterocyclic ring is N, O or S, the number of heteroatoms is any integer from 1 to 4; the number of hydroxyl groups substituted is 1 to 4 any integer; the number of C1-C5 alkyl or =O substituted is any integer from 1 to 3;

R _a is a substituted or unsubstituted amino group, a substituted or unsubstituted C1-C5 alkoxy group, a C1-C5 alkyl group or a 3-6 membered carbocyclic ring; the number of substituted substituents is any one from 1 to 5 Integer, the substituted substituent is halogen, C1～C3 alkyl or C1～C3 alkoxy;

Preferably,

R' is selected from cyano, halogen, hydroxyl substituted or unsubstituted C1~C4 alkyl, C1~C3 alkyl or =O substituted or unsubstituted 5~10 membered heterocycle, phenyl, amino, -C(O )-R _a or -C(O)OR _a , the heteroatom of the heterocyclic ring is N, and the number of heteroatoms is 1, 2 or 3; the number of hydroxyl groups substituted is 1 or 2; so The number of C1~C3 alkyl or =O substituted groups is 1 or 2;

R _a is a substituted or unsubstituted amino group, a substituted or unsubstituted C1-C4 alkoxy group, a C1-C4 alkyl group or a 5-6 membered carbocyclic ring; the number of substituted substituents is any of 1 to 3 Integer, the substituted substituent is halogen, C1～C3 alkyl or C1～C3 alkoxy;

More preferably,

R' is selected from cyano, chlorine, hydroxyl substituted or unsubstituted C1~C3 alkyl, C1~C3 alkyl or =O substituted or unsubstituted 6~10 membered heterocycle, phenyl, amino, -C(O )-R _a or -C(O)OR _a , the heteroatom of the heterocyclic ring is N, and the number of heteroatoms is 2; the number of hydroxyl groups substituted is 1; the C1~C3 alkyl group or =The number of O substitutions is 1;

R _a is a substituted or unsubstituted amino group, a substituted or unsubstituted C1-C3 alkoxy group, a methyl group or a 5-membered carbocyclic ring; the number of the substituted substituents is 1, 2 or 3, and the The substituted substituent is fluorine, methyl or methoxy;

More preferably,

R' is selected from 1 hydroxyl-substituted C1~C3 alkyl group, 1 methyl-substituted 6-membered heterocycle, 1 =O-substituted 10-membered heterocycle, cyano group, -C(O)-R _a or - C(O)OR _a , the heteroatom of the heterocyclic ring is N, and the heteroatom of the heterocyclic ring is N. The number of atoms is 2;

R _a is a substituted or unsubstituted amino, methyl, 5-membered carbocyclic ring or C1-C3 alkoxy group; the number of the substituted substituents is 1 or 2, and the substituted substituents are methyl or methoxy;

More preferably,

R' is selected from C1～C3 alkyl substituted by 1 hydroxyl group, or -C(RO)-R _a ;

R _a is a substituted or unsubstituted amino, methyl, 5-membered carbocyclic ring or C1-C3 alkoxy group; the number of substituted substituents is 1, and the substituted substituent is methyl or methoxy .

Further, the compound has a structure shown in formula IA-a:

Where, X is -OR or -NR ₁ R ₂ ;

R, R ₁ , R ₂ and Het are as described above.

Further, the compound has a structure represented by formula IA-a1:

Among them, R ₁ , R ₂ and Het are as mentioned above.

Further, the compound has a structure shown in formula IA-a2:

Where, X is -OR or -NR ₁ R ₂ ;

R, R ₁ and R ₂ are as mentioned above;

R' is a substituent on the pyridine ring, forming R' is as mentioned above.

Further, the compound has a structure shown in formula IA-a3:

Among them, R ₁ and R ₂ are as mentioned above;

R' is a substituent on the pyridine ring, forming R' is as mentioned above.

Further, the compound has a structure shown in formula IA-a4:

Among them, R' is as mentioned above.

Further, the compound has any of the following structures:

Further, the compound has a structure represented by formula IA-b:

Where, X is -OR or -NR ₁ R ₂ ;

R, R ₁ , R ₂ and Het are as described above.

Further, the compound has a structure shown in formula IA-b1:

Among them, R _a , R ₁ and R ₂ are as mentioned above.

Further, the compound has any of the following structures:

The present invention also provides a method for preparing the aforementioned compound, which includes the following steps of preparing compound Ia:

(1) Compound 1 reacts with lead acetate in an organic solvent under the action of a catalyst to obtain compound 2;

(2) Compound 2 reacts in an organic solvent under the action of a reducing agent to obtain compound 3;

(3) Compound 3 reacts in an organic solvent under the action of an oxidant to obtain compound 4;

(4) Compound 4 reacts with Gilbert's reagent in an organic solvent under the action of an inorganic base to obtain compound 5;

(5) Compound 5 reacts with X-Het in an organic solvent under the action of a catalyst to obtain compound Ia;

The reaction formula is as follows:

Among them, u, v, w, y, z, Het are as mentioned above;

X is halogen.

further,

The solvent described in step (1) is a mixed solvent of benzene and methanol, and the volume ratio of benzene and methanol is (15～20): 1, the catalyst is boron trifluoride ether; the molar ratio of compound 1 to lead acetate is 1: (1.5～2);

And/or, the organic solvent in step (2) is tetrahydrofuran, and the reducing agent is lithium aluminum hydride; the molar ratio of the compound 2 and the reducing agent is 1: (3-5);

And/or, the organic solvent described in step (3) is a mixed solvent of methanol and water, and the volume ratio of methanol and water is (3-5):1; the oxidizing agent is sodium periodate; the compound 3 and The molar ratio of oxidant is 1:(0.8～1.2);

And/or, the organic solvent in step (4) is methanol, and the inorganic base is potassium carbonate; the molar ratio of compound 4 to Gilbert's reagent is 1: (1.5-2.5);

And/or, the organic solvent in step (5) is tetrahydrofuran, and the catalyst is a palladium carbon catalyst and cuprous iodide.

further,

The reaction in step (1) is carried out at 20-30°C for 1.5-3 hours;

And/or, the reaction in step (2) is carried out at 20-30°C for 3-5 hours;

And/or, the reaction in step (3) is carried out at 20-30°C for 0.5-1.5 hours;

And/or, the reaction in step (4) is carried out at 20-30°C for 10-15 hours;

And/or, the reaction in step (5) is carried out at 75-85°C for 10-15 hours.

The present invention also provides the use of the aforementioned compound or its optical isomer, pharmaceutically acceptable salt, hydrate or solvate in the preparation of CDK8 inhibitors.

Further, the CDK8 inhibitor is an anti-cancer drug.

Further, the anti-cancer drug is a drug for preventing and treating colorectal cancer, prostate cancer, melanoma, breast cancer, acute myeloid leukemia and/or pancreatic cancer.

The invention also provides an anti-cancer drug, which uses the aforementioned compound or its optical isomer, pharmaceutically acceptable salt, hydrate or solvate as an active ingredient, plus pharmaceutically acceptable excipients and carriers. or preparations made with excipients.

The present invention provides a new compound, which has excellent CDK8 inhibitory effect and can be used as a CDK8 inhibitor in clinical applications. It provides a new choice for the treatment of tumor-related diseases, such as leukemia, and has broad application prospects.

Explanation of terminology of the present invention:

Aromatic ring: an all-carbon monocyclic or fused polycyclic (that is, a ring that shares pairs of adjacent carbon atoms) groups with a conjugated π electron system, such as phenyl and naphthyl. The aromatic ring can be fused to other cyclic groups (including saturated and unsaturated rings), but it cannot contain heteroatoms such as O, N or S, and the point of connection to the parent must be in a ring with a conjugated π electron system on the carbon atoms.

Aromatic heterocycle: an aryl group in which at least one carbon atom on the ring of the conjugated π electron system is replaced by a heteroatom, and the heteroatom is O, N or S. The 5-, 8-, and 9-membered aromatic heterocycles refer to 5, 8, or 9 atoms (carbon atoms and heteroatoms) constituting the conjugated skeleton of the aromatic heterocycle.

Carbocyclic ring: A saturated or unsaturated all-carbon monocyclic ring that does not have a conjugated π electron system. For example, a 5-membered carbocyclic ring refers to a ring composed of 5 carbon atoms.

Heterocycle: A saturated or unsaturated all-carbon monocyclic ring that does not have a conjugated π electron system, and the At least one carbon atom is replaced by a heteroatom, which is O, N or S. 3-7 membered heterocycle refers to a heterocycle composed of 3, 4, 5, 6 or 7 carbon atoms.

Nitrogen-containing aromatic heterocycle, nitrogen-containing heteroaromatic ring: an aryl or aryl group in which at least one carbon atom on the ring of the conjugated π electron system is replaced by a heteroatom (that is, an aryl group that shares two adjacent atoms on the ring Aryl), the heteroatom must contain N, and may contain O or S.

Nitroaromatic heterocycle, nitrogen heteroaromatic ring: an aryl or aryl group in which at least one carbon atom on the ring of the conjugated π electron system is replaced by a heteroatom (that is, an aryl group that shares two adjacent atoms on the ring ), the heteroatom is N, and does not contain heteroatoms O or S.

The minimum and maximum carbon atom content in a hydrocarbon group are represented by prefixes. For example, the alkyl group of C1 to C6 refers to an alkyl group of C1, C2, C3, C4, C5, and C6, that is, the alkyl group has 1 to 6 Straight-chain or branched alkyl groups with carbon atoms, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, sec-butyl, pentyl, hexyl, etc. Similarly, alkoxy groups of C1 to C5 refer to alkoxy groups of C1, C2, C3, C4, and C5; Alkyl group: Alkyl group refers to a hydrocarbon group formed by missing one hydrogen atom in a straight-chain or branched alkane molecule.

Substitution: refers to the replacement of 1, 2 or more hydrogen atoms in a molecule by other different atoms, molecules, or groups, including 1, 2 or more on isotopic atoms or ectopic atoms in the molecule replace.

Obviously, according to the above content of the present invention, according to the common technical knowledge and common means in the field, without departing from the above basic technical idea of the present invention, various other forms of modifications, replacements or changes can also be made.

The above contents of the present invention will be further described in detail below through specific implementation methods in the form of examples. However, this should not be understood to mean that the scope of the above subject matter of the present invention is limited to the following examples. All technologies implemented based on the above contents of the present invention belong to the scope of the present invention.

Detailed ways

The raw materials and equipment used in the present invention are all known products and are obtained by purchasing commercially available products.

Example 1. Preparation of compounds I-1 to I-17 of the present invention

1): β-ketoester compound (2)

Under ice bath, add Pb(OAc) ₄ (103 mg, 0.43 mmol) to a solution of pregnenolone 1 (100 mg, 0.23 mmol) in benzene (2.8 mL) and methanol (0.16 mL), and slowly add 48% of BF ₃ Et ₂ O solution (41.0 μL, 0.34 mmol). After the dripping is completed, the mixture is raised to room temperature and reacted for 2 hours. The reaction solution was extracted three times with ethyl acetate (15 mL), the organic layers were combined, dried (anhydrous sodium sulfate), filtered with suction, and concentrated. The obtained crude product was purified by flash silica gel column chromatography (petroleum ether/ethyl acetate = 4:1) to obtain a white solid, which was the title compound 2 (60 mg, 69%). ¹ H NMR (400MHz, CDCl ₃ , ppm) δ5.35 (d, J = 5.3Hz, 1H), 4.71 (d, J = 16.9Hz, 1H), 4.53 (d, J = 16.9Hz, 1H), 3.52 (s,1H),2.50(t,J＝8.7Hz,1H),2.35–2.27(m,1H),2.24(dd,J＝11.4,3.5Hz,2H),2.20(s,1H),2.17( d,J＝0.7Hz,3H),2.08–1.96(m,2H),1.90–1.80(m,2H),1.72(t,J＝6.2Hz,2H),1.52(d,J＝3.9Hz,2H ),1.49(d,J＝4.4Hz,1H),1.44(m,2H),1.39(d,J＝4.1Hz,1H),1.32–1.23(m,1H),1.20–1.11(m,2H) ,1.11–1.04(m,1H),1.01(s,3H),0.67(s,3H).

2): Ortho-diol compound (3)

To a solution of 2 (560 mg, 1.49 mmol) in dry THF (15 mL) was added _LiAlH4 (227 mg, 5.98 mmol) in an ice bath. After the addition is completed, the mixture is raised to room temperature and reacted for 4 hours. The reaction solution was extracted three times with ethyl acetate (60 mL), the organic layers were combined, dried (anhydrous sodium sulfate), filtered with suction, and concentrated. The obtained crude product was purified by flash silica gel column chromatography (dichloromethane/methanol=20:1) to obtain a white solid, which was the title compound 3 (420 mg, 79%). ¹ H NMR (400MHz, CDCl ₃ , ppm) δ5.35 (dd, J＝4.8, 2.6Hz, 1H), 3.67 (dd, J＝10.0, 6.5Hz, 2H), 3.53 (m, 1H), 3.39 ( dd,J＝11.4,7.7Hz,1H),2.30–2.25(m,1H),2.25–2.18(m,1H),2.10(dt,J＝12.5,3.4Hz,1H),2.02–1.94(m, 1H),1.89–1.83(m,3H),1.65(d,J＝7.6Hz,3H),1.52(dd,J＝5.1,2.7Hz,2H),1.51–1.48(m,1H),1.47(d ,J＝3.3Hz,2H),1.29(d,J＝5.6Hz,1H),1.25(s,2H),1.22(d,J＝2.2Hz,1H),1.18–1.11(m,1H),1.09 (d,J＝4.1Hz,1H),1.05(d,J＝4.8Hz,1H),1.02(s,3H),0.96(dt,J＝11.1,5.6Hz,1H),0.79(s,3H) .

3): Steroidal C-17 aldehyde compound (4)

To a solution of 3 (350 mg, 1.05 mmol) in methanol (10 mL) and _H2O (2.5 mL) was added _NaIO4 (224 mg, 1.05 mmol) at room temperature. After the addition is completed, the mixture is raised to room temperature and allowed to react for 1 hour. The reaction solution was extracted three times with ethyl acetate (60 mL), the organic layers were combined, dried (anhydrous sodium sulfate), filtered with suction, and concentrated. The obtained crude product was purified by flash silica gel column chromatography (petroleum ether/ethyl acetate = 6:1) to obtain a white solid, which was the title compound 4 (260 mg, 82%). ¹ H NMR (400MHz, CDCl ₃ , ppm) δ9.78 (d, J＝2.1Hz, 1H), 5.36 (dt, J＝5.7, 2.0Hz, 1H), 3.53 (m, 1H), 2.32 (q, J＝2.3Hz,1H),2.31–2.25(m,2H),2.23(t,J＝2.7Hz,1H),2.19–2.08(m,2H),2.05–1.96(m,3H),1.90–1.80 (m,3H),1.80–1.69(m,3H),1.47(s,3H),1.25(s,3H),1.02(s,3H),0.77(s,3H).

4): Steroidal C-17 alkynyl compound (5)

To a solution of Gilbert's reagent (0.35 mL, 2.33 mmol) in dry methanol (9 mL) was added _K2CO3 (645 _mg , 4.66 mmol) in an ice bath. After stirring for 5 minutes, anhydrous methanol solution (16 mL) of 4 (470 mg, 1.56 mmol) was slowly added dropwise. After the dropping is completed, the mixture is raised to room temperature and reacted for 12 hours. The reaction solution was extracted three times with ethyl acetate (60 mL), the organic layers were combined, dried (anhydrous sodium sulfate), filtered with suction, and concentrated. The obtained crude product was purified by flash silica gel column chromatography (petroleum ether/ethyl acetate = 3:1) to obtain a white solid, which was the title compound 5 (440 mg, 95%). ¹ H NMR (400MHz, CDCl ₃ , ppm) δ5.35 (dd, J＝4.9, 2.4Hz, 1H), 3.58–3.47 (m, 1H), 2.28 (dt, J＝7.1, 3.5Hz, 1H), 2.23(s,1H),2.18(d,J＝2.5Hz,1H),2.09(d,J＝2.4Hz,1H),2.06–2.00(m,1H),1.98(m,J＝4.9,2.5Hz ,1H),1.92–1.80(m,3H),1.73(d,J＝1.6Hz,1H),1.70(s,1H),1.67(d,J＝3.3Hz,1H),1.54–1.44(m, 4H), 1.25 (dd, J = 7.2, 5.0Hz, 2H), 1.15–1.05 (m, 2H), 1.02 (s, 3H), 1.00–0.90 (m, 2H), 0.81 (s, 3H).

5): Steroidal C-17 pyridine compound (I-1)

To 3-bromopyridine (10 μL, 0.11 mmol), Cs ₂ CO ₃ (55 mg, 0.18 mmol), CuI (1 mg, 0.005 mmol), PPh ₃ (2 mg, 0.006 mmol) and 10% Pd/C ( 5 (20 mg, 0.07 mmol) was added to a mixed solution of DME (2.5 mL) and H ₂ O (2.5 mL) (0.5 mg, 0.002 mmol). After the addition is completed, the temperature is raised to 80°C and allowed to react for 12 hours. Filter, wash three times with ethyl acetate (20 mL), combine the organic layers, dry (anhydrous sodium sulfate), filter with suction, and concentrate. The obtained crude product was purified by flash silica gel column chromatography (petroleum ether/ethyl acetate = 4:1) to obtain a white solid, which was the title compound I-1 (10 mg, 40%). ¹ H NMR (400MHz, CDCl ₃ , ppm) δ8.62 (s, 1H), 8.51–8.42 (m, 1H), 7.67 (dt, J＝7.9, 1.9Hz, 1H), 7.20 (dd, J＝7.9 ,4.8Hz,1H),5.34(dd,J＝5.1,2.6Hz,1H),3.58–3.46(m,1H),2.39(t,J＝9.6Hz,1H),2.34–2.18(m,2H) ,2.10(m,1H),1.99(d,J＝2.6Hz,1H),1.96–1.91(m,1H),1.89–1.85(m,1H),1.80–1.68(m,2H),1.59(dd ,J＝7.8,3.1Hz,2H),1.57–1.42(m,4H),1.32(t,J＝3.0Hz,1H),1.24(s,2H),1.19–1.07(m,2H),1.02( s, 3H), 0.98 (d, J = 5.5Hz, 1H), 0.86 (s, 3H).

Referring to the synthesis method of compound I-1, compounds I-2 (11 mg, 0.02 mmol, 36%), I-3 (12 mg, 0.03 mmol, 40%), I-4 ( 12mg, 0.02mmol, 38%), I-5 (8mg, 0.02mmol, 28%), I-6 (12mg, 0.02mmol, 33%), I-7 (12mg, 0.02mmol, 36%), I- 8 (13mg, 0.03mmol, 40%), I-9 (15mg, 0.04mmol, 55%), I-10 (12mg, 0.02mmol, 32%), I-11 (13mg, 0.03mmol, 43%), I-12 (12mg, 0.03mmol, 36%), I-13 (10mg, 0.03mmol, 36%), I-14 (8mg, 0.02mmol, 30%), I-15 (8mg, 0.02mmol, 28% ), I-16 (12 mg, 0.03 mmol, 43%), I-17 (15 mg, 0.04 mmol, 55%). The structures and hydrogen spectrum characterization data of compounds I-2 to I-17 are shown in Table 1.

Table 1. Structure and hydrogen spectrum characterization data of compounds I-2～I-17

Example 2. Preparation of compounds I-18 to I-26 of the present invention

1): Isopropyl alcohol derivative (I-18)

Methyl format reagent (1 M in THF, 0.17 mL, 0.17 mmol) was added dropwise to I-7 (15 mg, 0.03 mmol) in THF (0.5 mL) under ice bath. After the dripping is completed, the mixture is raised to room temperature and reacted for 2 hours. The reaction solution was extracted three times with ethyl acetate (30 mL), the organic layers were combined, dried (anhydrous sodium sulfate), filtered with suction, and concentrated. The obtained crude product was purified by flash silica gel column chromatography (petroleum ether/acetone = 1:1) to obtain a white solid, which was the title compound I-18 (6 mg, 40%). ¹ H NMR (400MHz, CDCl ₃ , ppm) δ8.60 (s, 1H), 8.43 (d, J = 5.3Hz, 1H), 7.40 (d, J = 5.2Hz, 1H), 5.35 (dd, J = 5.2,2.6Hz,1H),3.52(dq,J＝11.0,5.4,4.9Hz,1H),3.34(s,1H),2.49(t,J＝9.6Hz,1H),2.30(dtd,J＝10.8 ,5.2,2.8Hz,1H),2.26–2.19(m,1H),2.14(ddd,J＝13.1,6.7,3.7Hz,1H),2.02(m,1H),1.93(dt,J＝12.4,3.5 Hz,1H),1.85(td,J＝12.4,3.7Hz,3H),1.81–1.73(m,1H),1.70(s,6H),1.65–1.56(m,3H),1.56–1.47(m, 2H),1.39–1.27(m,1H),1.25(s,1H),1.23–1.16(m,1H),1.10(ddd,J＝14.3,12.0,3.8Hz,2H),1.03(s,3H) ,0.98(dd,J＝11.5,4.7Hz,1H),0.89(s,3H).

2): Reduced derivatives (I-19)

LiAlH ₄ (1 M in THF, 0.30 mL, 0.30 mmol) was added dropwise to I-7 (20 mg, 0.05 mmol) in THF (2 mL) under ice bath. After the dripping is completed, the mixture is raised to room temperature and reacted for 2 hours. The reaction solution was extracted three times with ethyl acetate (30 mL), the organic layers were combined, dried (anhydrous sodium sulfate), filtered with suction, and concentrated. The obtained crude product was purified by flash silica gel column chromatography (dichloromethane/methanol=20:1) to obtain a white solid, which was the title compound I-19 (5 mg, 27%). ¹ H NMR (400MHz, CDCl ₃ , ppm) δ8.59 (d, J＝5.8Hz,1H),8.52(d,J＝5.2Hz,1H),7.47(d,J＝5.1Hz,1H),5.42–5.33(m,1H),4.84(s,2H),3.53( s,1H),2.45(t,J＝9.5Hz,1H),2.29(dt,J＝20.7,10.1Hz,3H),2.20–2.09(m,3H),2.03(d,J＝14.4Hz,2H ),1.87(m,5H),1.75(t,J＝13.1Hz,3H),1.52(s,2H),1.25(s,3H),1.03(s,3H),0.87(s,3H).

3): Condensation derivatives (I-20)

LiOH (22 mg, 0.92 mmol) was added to compound I-7 (100 mg, 0.23 mmol) in THF (5.0 mL) at room temperature, and the reaction was carried out for 3 hours. The reaction solution was extracted three times with ethyl acetate (30 mL), and the organic layers were combined. , dried (anhydrous sodium sulfate), filtered, and concentrated. The obtained crude product I-7a (75 mg) was directly used in the next reaction.

To hydrolyzate I-7a (20 mg, 0.05 mmol) in dichloromethane (2.0 mL) was added isopropyl alcohol (6 μL, 0.07 mmol), DMAP (13 mg, 0.10 mmol) and EDCHCl (18 mg, 0.10 mmol) at room temperature. ). After the dripping is completed, the mixture is raised to room temperature and reacted for 2 hours. The reaction solution was extracted three times with ethyl acetate (30 mL), the organic layers were combined, dried (anhydrous sodium sulfate), filtered with suction, and concentrated. The crude product was purified by flash silica gel column chromatography (petroleum ether/ethyl acetate = 2:1) to obtain a white solid, which was the title compound I-20 (12 mg, 53%).

Referring to the synthesis method of compound I-20, compounds I-21 (11 mg, 0.02 mmol, 36%), I-22 (12 mg, 0.03 mmol, 38%), I-7a (20 mg, 0.07 mmol) were prepared. 23 (15 mg, 0.02 mmol, 49%), I-24 (11 mg, 0.02 mmol, 48%), I-25 (11 mg, 0.02 mmol, 46%). The structures and hydrogen spectrum characterization data of compounds I-20 to I-25 are shown in Table 2.

Table 2. Structure and hydrogen spectrum characterization data of compounds I-20～I-25

4): Amide derivative (I-26)

To 1-7a (20 mg, 0.05 mmol) in ethanol (2.0 mL) was added 30% NH ₃ H ₂ O (2 mL) at room temperature. After the addition is completed, the temperature is raised to 80°C, and the tube is sealed for 15 hours. The reaction solution was extracted three times with ethyl acetate (30 mL), the organic layers were combined, dried (anhydrous sodium sulfate), filtered with suction, and concentrated. The obtained crude product was purified by flash silica gel column chromatography (petroleum ether/ethyl acetate = 1:3) to obtain a white solid, which was the title compound I-26 (11 mg, 57%). ¹ H NMR (400MHz, CDCl ₃ , ppm) δ8.76 (s, 1H), 8.62 (d, J = 5.2Hz, 1H), 7.94 (d, J = 5.2Hz, 1H), 7.68 (d, J = 6.0Hz,1H),6.02(s,1H),5.36(dd,J＝5.2,2.6Hz,1H),3.53(m,1H),2.50(t,J＝9.5Hz,1H),2.30(dd, J＝5.2,2.2Hz,1H),2.26(dd,J＝11.0,2.7Hz,1H),2.22–2.11(m,1H),2.04(s,2H),1.90(m,2H),1.87–1.75 (m,2H),1.62(m,1H),1.52(m,1H),1.44–1.31(m,1H),1.22–1.17(m,1H),1.12(dd,J＝13.1,3.3Hz,1H ),1.03(s,3H),0.89(s,3H).

Example 3. Preparation of compounds I-27 to I-31 of the present invention

1): Steroidal C-3 β-azide compound (I-20a)

To 1-20 (200 mg, 0.37 mmol) in anhydrous DCM (12 mL) was added triethylamine (0.08 mL, 0.56 mmol) and methanesulfonyl chloride (28 μL, 0.45 mmol) under ice bath. After the dropping is completed, move to room temperature and react for 1 hour. The reaction solution was concentrated and used in the next step. At room temperature, add to the obtained concentration TMSN ₃ (0.10 mL, 1.12 mmol) and BF ₃ ·OEt ₂ (0.22 mL, 1.50 mmol) were added to the anhydrous DCM (12 mL) of the condensate. After the dripping is completed, the reaction lasts for 12 hours. The reaction solution was extracted three times with ethyl acetate (90 mL), the organic layers were combined, dried (anhydrous sodium sulfate), filtered with suction, and concentrated. The obtained crude product was purified by flash silica gel column chromatography (petroleum ether/ethyl acetate = 50:1) to obtain a white solid, which was the title compound I-20a (115 mg, 68%). ¹ H NMR (400MHz, CDCl ₃ , ppm) δ8.74 (s, 1H), 8.53 (d, J = 5.1Hz, 1H), 7.61 (d, J = 5.1Hz, 1H), 5.38 (d, J = 5.1Hz,1H),5.31–5.23(m,1H),3.25–3.15(m,1H),2.45(t,J＝9.6Hz,1H),2.29(d,J＝7.3Hz,2H),2.13( ddt,J＝9.4,7.3,4.7Hz,1H),2.07–1.96(m,2H),1.96–1.82(m,4H),1.80–1.68(m,2H),1.57(d,J＝14.8Hz, 3H),1.50(dt,J＝11.6,3.4Hz,3H),1.37(d,J＝6.3Hz,6H),1.32–1.23(m,2H),1.15(ddd,J＝24.9,12.9,4.1Hz ,3H),1.02(s,3H)

2): Steroidal C-3 β-amino compound (I-27)

To 1-20a (80 mg, 0.17 mmol) in THF (4 mL) was added P(Me) ₃ (61 μL, 0.70 mmol) and H ₂ O (16 μL, 0.87 mmol) at room temperature. After the dropping is completed, move to room temperature and react for 12 hours. The reaction solution was extracted three times with ethyl acetate (15 mL), the organic layers were combined, dried (anhydrous sodium sulfate), filtered with suction, and concentrated. The obtained crude product was purified by flash silica gel column chromatography (dichloromethane/methanol=25:1) to obtain a white solid, which was the title compound I-27 (80 mg, 53%). ¹ H NMR (400MHz, CDCl ₃ , ppm) δ8.73 (s, 1H), 8.52 (d, J = 5.2Hz, 1H), 7.61 (d, J = 5.1Hz, 1H), 5.33–5.29 (m, 1H),5.26(s,1H),2.59(m,1H),2.43(d,J＝9.5Hz,1H),2.14(m,J＝5.0,4.2Hz,2H),2.10–2.00(m,2H ),1.96(dt,J＝12.4,3.4Hz,2H),1.71(tt,J＝10.2,3.2Hz,3H),1.60(td,J＝12.2,10.6,3.0Hz,3H),1.37(d, J＝6.2Hz, 6H), 1.31 (d, J＝4.8Hz, 3H), 1.14 (ddd, J＝26.0, 13.2, 4.0Hz, 3H), 1.00 (s, 3H), 0.89 (s, 3H).

3): Steroid C-3 β-dimethylamino compound (I-28)

To 1-27 (15 mg, 0.03 mmol) in methanol (2 mL) was added paraformaldehyde (14 mg, 0.17 mmol) and NaBH ₃ CN (17 mg, 0.10 mmol). React for 24 hours, extract the reaction solution three times with ethyl acetate (30 mL), combine the organic layers, dry (anhydrous sodium sulfate), filter with suction, and concentrate. The obtained crude product was purified by flash silica gel column chromatography (dichloromethane/methanol=15:1) to obtain a white solid, which was the title compound I-28 (8 mg, 50%). ¹ H NMR (400MHz, CD ₃ OD, ppm) δ8.66 (s, 1H), 8.53 (d, J = 5.1Hz, 1H), 7.70 (d, J = 5.1Hz, 1H), 5.40 (d, J ＝5.0Hz,1H),5.24(p,J＝6.3Hz,1H),2.49(t,J＝9.6Hz,1H),2.42(s,6H),2.29(s,3H),2.20–2.10(m ,1H),1.98(dt,J＝13.0,3.6Hz,3H),1.89–1.83(m,2H),1.67–1.59(m,2H),1.59–1.51(m,4H),1.39(d,J ＝6.3Hz,6H),1.35–1.29(m,2H),1.27–1.11(m,3H),1.04(s,3H),0.93(s,3H).

Referring to the synthesis method of compound I-28, compound I-29 (8 mg, 0.02 mmol, 29%) was prepared from I-7 (26 mg, 0.06 mmol), and compound I- was prepared from I-17 (50 mg, 0.12 mmol). 30 (25 mg, 0.06 mmol, 48%), and compound I-31 (8 mg, 0.02 mmol, 22%) was prepared from I-25 (35 mg, 0.07 mmol). The structures and hydrogen spectrum characterization data of compounds I-29 to I-31 are shown in Table 3.

Table 3. Structure and hydrogen spectrum characterization data of compounds I-29～I-31

Example 4. Preparation of compounds I-32 to I-47 of the present invention

1): Steroidal C-17 alkynyl coupling compound (I-7b)

At room temperature, add 3-bromoisonicotinic acid methyl ester (0.14mL, 1.00mmol), PdCl ₂ (PPh ₃ ) ₂ (47mg, 0.06mmol), CuI (26mg, 0.13mmol), PPh ₃ (18mg, 0.06mmol). ) was added to a mixed solvent of 8 mL triethylamine and 1 mL THF. Compound 5b (200 mg, 0.67 mmol) was added. After the addition is completed, the temperature is raised to 55°C and allowed to react for 5 hours. Filter, wash three times with ethyl acetate (20 mL), combine the organic layers, dry (anhydrous sodium sulfate), filter with suction, and concentrate. The obtained crude product was purified by flash silica gel column chromatography (petroleum ether/ethyl acetate = 4:1) to obtain a yellow solid, which was the title compound I-7b (105 mg, 36%). ¹ H NMR (400MHz, CDCl _3, ppm) δ8.75 (s, 1H), 8.54 (d, J = 5.2Hz, 1H), 7.66 (d, J = 5.1Hz, 1H), 3.93 (s, 3H) ,3.59(tt,J＝10.7,4.8Hz,1H),2.45(t,J＝9.6Hz,1H),2.17–2.06(m,1H),1.92(dt,J＝12.4,3.4Hz,1H), 1.83–1.77(m,2H),1.71(td,J＝9.6,4.9Hz,4H),1.58(td,J＝13.8,6.0Hz,2H),1.39(dddd,J＝23.9,12.3,8.9,3.2 Hz,3H),1.31–1.25(m,4H),1.16–1.11(m,2H),1.04–0.98(m,2H),0.97–0.88(m,2H),0.87(s,3H),0.82( s,3H).

2): Steroidal C-3 carbonyl compound (6)

To a solution of compound 1-7b (350 mg, 0.80 mmol) in dichloromethane (6.5 mL) and pyridine (1.3 mL) was added Dess-Martin oxidant (513 mg, 1.21 mmol) at room temperature. After addition, react for 1 hour. The reaction solution was extracted three times with dichloromethane (60 mL), the organic layers were combined, dried (anhydrous sodium sulfate), filtered, and concentrated. The obtained crude product was purified by flash silica gel column chromatography (petroleum ether/ethyl acetate = 4:1) to obtain a white solid, which was the title compound 6 (295 mg, 84%). ¹ H NMR (400MHz, CDCl _3, ppm) δ8.78 (s, 1H), 8.57 (d, J = 5.2Hz, 1H), 7.68 (d, J = 5.1Hz, 1H), 3.95 (s, 3H) ,2.48(t,J＝9.6Hz,1H),2.43–2.35(m,1H),2.30(d,J＝14.8Hz,1H),2.19–2.10(m,2H),2.09–2.04(m,1H ),1.96(dt,J＝12.5,3.5Hz,1H),1.85(ddt,J＝13.6,7.2,3.6Hz,1H),1.75(m,3H),1.68–1.61(m,1H),1.59– 1.48(m,2H),1.42(td,J＝7.3,6.7,3.2Hz,2H),1.38–1.33(m,3H),1.32–1.26 (m,2H),1.23–1.12(m,2H),1.04(s,3H),0.91(s,3H).

3): Steroidal C-3β-dimethylamino compound (I-32) and α-dimethylamino compound (I-33)

To a solution of compound 6 (20 mg, 0.05 mmol) in methanol (1 mL) and dimethylaminemethanol (0.2 mL) was added NaBH ₃ CN (9 mg, 0.13 mmol) under ice bath. After the addition is completed, the mixture is raised to room temperature and reacted for 12 hours. The reaction solution was extracted three times with ethyl acetate (30 mL), the organic layers were combined, dried (anhydrous sodium sulfate), filtered with suction, and concentrated. The obtained crude product was purified by flash silica gel column chromatography (petroleum ether/ethyl acetate/triethylamine=8:1:1) to obtain the white solid title compound I-32 (18 mg, 82%) and the white solid title compound I- 33 (2mg, 9.2%). Characterization data of I-32: ¹ H NMR (400MHz, CDCl ₃ , ppm) δ8.75 (s, 1H), 8.54 (d, J = 5.1Hz, 1H), 7.65 (dd, J = 5.2, 0.8Hz, 1H),3.93(s,3H),2.53(q,J＝7.2Hz,1H),2.45(t,J＝9.5Hz,1H),2.27(s,6H),2.12(dddd,J＝15.9,12.3 ,6.9,3.0Hz,2H),1.92(dt,J＝12.3,3.4Hz,1H),1.80–1.67(m,5H),1.61(dq,J＝12.0,3.2,2.4Hz,1H),1.55– 1.44(m,2H),1.40–1.33(m,3H),1.31–1.25(m,4H),1.20(d,J＝1.5Hz,1H),1.15(s,1H),0.94–0.89(m, 2H),0.86(s,3H),0.78(s,3H). Characterization data of I-33: ¹ H NMR (400MHz, CD ₃ OD, ppm) δ8.66 (d, J = 0.8Hz, 1H), 8.54 (d, J = 5.1Hz, 1H), 7.74 (dd, J ＝5.2,0.8Hz,1H),3.93(s,3H),2.49(t,J＝9.5Hz,1H),2.29(s,6H),2.17–2.09(m,2H),1.93(dt,J＝ 12.2,3.4Hz,2H),1.82(ddt,J＝11.3,3.6,1.7Hz,1H),1.75(ddd,J＝12.6,7.7,3.2Hz,2H),1.66–1.57(m,3H),1.50 –1.40(m,4H),1.39–1.28(m,4H),1.23(dd,J＝9.9,6.2Hz,2H),1.18–1.11(m,2H),1.02(dd,J＝12.2,5.5Hz ,1H),0.90(s,3H),0.89(s,3H).

Referring to the synthetic methods of compounds I-32 and I-33, compounds I-34 (10 mg, 0.02 mmol, 49%) and I-35 (5 mg, 0.01 mmol, 24%) were prepared from compound 6 (20 mg, 0.05 mmol). , I-36 (11mg, 0.02mmol, 47%), I-37 (6mg, 0.01mmol, 26%), I-38 (15mg, 0.03mmol, 57%), I-39 (5mg, 0.01mmol, 19 %). Compounds I-40 (11 mg, 0.02 mmol, 9%), I-41 (3 mg, 0.01 mmol, 4%), and I-42 (11 mg, 0.02 mmol, 9%) were prepared from compound 5b (65 mg, 0.22 mmol). , I-43 (7mg, 0.01mmol, 4%), I-44 (14mg, 0.03mmol, 14%), I-45 (5mg, 0.01mmol, 4%), I-46 (15mg, 0.03mmol, 14 %), I-47 (5 mg, 0.01 mmol, 4%). The structures and hydrogen spectrum characterization data of compounds I-34 to I-47 are shown in Table 4.

Table 4. Structure and hydrogen spectrum characterization data of compounds I-34～I-47

Example 5. Preparation of compounds I-48 to I-52 of the present invention

Compound I-29 (20 mg, 0.04 mmol) was dissolved in 3 mL of ammonia methanol solution (7 mol/L), and the tube was sealed for 4 hours at 100°C. The reaction solution was concentrated, and the crude product was purified by flash silica gel column chromatography (dichloromethane/methanol=30:1) to obtain a white solid, which was the title compound I-48 (15 mg, 79%). ¹ H NMR (400MHz, CD ₃ OD, ppm) δ8.76 (s, 1H), 8.62 (d, J = 5.2Hz, 1H), 7.94 (d, J = 5.2Hz, 1H), 7.73–7.67 (m ,1H),6.02(s,1H),5.35(d,J＝5.1Hz,1H),2.50(t,J＝9.5Hz,1H),2.34(s,6H),2.23(t,J＝4.9Hz ,5H),2.11–1.99(m,2H),1.91(dd,J＝12.8,3.7Hz,3H),1.85–1.78(m,3H),1.64(dd,J＝14.0,3.2Hz,2H), 1.45(d,J＝8.3Hz,2H),1.38–1.30(m,2H),1.25(s,1H),1.00(s,3H),0.88(s,3H).

Referring to the synthesis method of compound I-48, compound I-49 (10 mg, 0.02 mmol, 74%) was prepared from I-32 (15 mg, 0.03 mmol). Compound I-50 (12 mg, 0.03 mmol, 62%) was prepared from I-34 (20 mg, 0.04 mmol). Compound I-51 (15 mg, 0.03 mmol, 76%) was prepared from I-36 (20 mg, 0.04 mmol). Compound I-52 (20 mg, 0.04 mmol, 94%) was prepared from I-38 (22 mg, 0.04 mmol). The structures and hydrogen spectrum characterization data of compounds I-49 to I-52 are shown in Table 5.

Table 5. Structure and hydrogen spectrum characterization data of compounds I-49～I-52

Example 6. Preparation of Compound I-53 of the Invention

1): Steroidal C-3N-Boc piperazinyl substituted compound (I-53a)

Referring to the synthesis method of compound I-32, compound I-53a (10 mg, 0.01 mmol, 25%) was prepared from compound 6 (20 mg, 0.05 mmol).

2): Steroidal C-3 piperazinyl substituted compound (I-53b)

To a solution of compound 1-53a (15 mg, 0.03 mmol) in dichloromethane was added 4 M HCl (31 μL, 1.50 mmol) at room temperature. After addition, react for 12 hours. The reaction solution was extracted three times with ethyl acetate (30 mL), the organic layers were combined, dried (anhydrous sodium sulfate), filtered with suction, and concentrated. The obtained crude product was purified by flash silica gel column chromatography (dichloromethane/methanol=20:1) to obtain a white solid, which was the title compound I-53b (10 mg, 80%).

3): Amide derivative compound (I-53)

Referring to the synthesis method of compound I-48, compound I-53 (5 mg, 0.01 mmol, 64%) was prepared from I-53b (8 mg, 0.02 mmol). The structure and hydrogen spectrum characterization data of compound I-53 are shown in Table 6.

Table 6. Structural and hydrogen spectrum characterization data of compound I-53

Example 7. Preparation of compound I-54 of the present invention

Methyl format reagent (3M in THF, 80 μL, 0.24 mmol) was added dropwise to I-29 (22 mg, 0.05 mmol) in THF (1 mL) under ice bath. After the dropping is completed, the mixture is raised to room temperature and reacted for 12 hours. The reaction solution was extracted three times with ethyl acetate (30 mL), the organic layers were combined, dried (anhydrous sodium sulfate), filtered with suction, and concentrated. The obtained crude product was purified by flash silica gel column chromatography (dichloromethane/methanol=30:1) to obtain a white solid, which was the title compound I-54 (12 mg, 52%). ¹ H NMR (400MHz, CDCl ₃ , ppm) δ8.59 (s, 1H), 8.43 (d, J = 5.3Hz, 1H), 7.41 (d, J = 5.3Hz, 1H), 5.37 (d, J = 5.0Hz,1H),2.49(d,J＝9.6Hz,1H),2.42(s,6H),2.29(d,J＝7.6Hz,3H),2.14(qd,J＝9.7,9.3,5.1Hz, 2H),2.06–2.00(m,1H),1.97–1.91(m,3H),1.83(d,J＝13.6Hz,2H),1.70(s,6H),1.63–1.58(m,2H),1.55 –1.50(m,1H),1.43–1.35(m,2H),1.24(s,2H),1.10(dd,J＝13.7,3.7Hz,2H),1.00(s,3H),0.88(s,3H ).

Example 8. Preparation of compounds I-55 to I-59 of the present invention

To 1-17 (30 mg, 0.073 mmol) in NMP (0.5 mL) was added 2,8-diazaspiro[4,5]decan-3-one hydrochloride (21 mg, 0.10 mmol) at room temperature. ), Et ₃ N (31 μL, 0.20 mmol). After the addition is completed, the tube is sealed and reacted at 160°C for 12 hours. The reaction solution was washed with water (3×10 mL), dried (anhydrous sodium sulfate), filtered, and concentrated. The obtained crude product was purified by flash silica gel column chromatography (dichloromethane/methanol=30:1) to obtain a gray solid, which was the title compound I-55 (22 mg, 58%). ¹ H NMR (400MHz, CDCl ₃ , ppm) δ8.42 (s, 1H), 8.24 (d, J = 5.7Hz, 1H), 6.67 (d, J = 5.8Hz, 1H), 5.60 (s, 1H),5.36(dd,J＝4.8,2.5Hz,1H),3.57–3.51(m,1H),3.47(dt,J＝12.8,4.9Hz,3H),3.31(td,J＝7.5,6.8, 4.1Hz,2H),3.27(d,J＝0.8Hz,2H),2.46(t,J＝9.5Hz,1H),2.29(s,3H),2.12(ddd,J＝12.9,6.5,3.6Hz, 1H),2.05–1.99(m,1H),1.89(s,2H),1.84(s,5H),1.78–1.71(m,2H),1.66–1.61(m,3H),1.50(dd,J＝ 10.2,4.8Hz,2H),1.45–1.37(m,1H),1.30(ddd,J＝19.1,12.2,6.6Hz,3H),1.19(dd,J＝12.8,4.3Hz,1H),1.03(s ,3H),0.86(s,3H).

Referring to the synthesis method of compound I-55, compounds I-56 (20 mg, 0.04 mmol, 52%) and I-57 (23 mg, 0.05 mmol, 66%) were prepared from I-17 (30 mg, 0.07 mmol). Compounds I-58 (8 mg, 0.01 mmol, 32%) and I-59 (6 mg, 0.01 mmol, 25%) were prepared from I-30 (20 mg, 0.05 mmol). The structures and hydrogen spectrum characterization data of compounds I-56 to I-59 are shown in Table 7.

Table 7. Structure and hydrogen spectrum characterization data of compounds I-53～I-59

The beneficial effects of the compounds of the present invention are demonstrated below through experimental examples.

Experimental Example 1. Inhibitory effect of compounds of the present invention on CDK8/cyclin C complex

1. Experimental methods

CDK8 used in experiments method for activity detection. Transfer 10 nL 1mM and 10nL 0.1mM compound to the assay plate. The final test concentration of the test compound ranged from 1 μM to 0.017 nM, with 3-fold gradient dilution, for a total of 11 concentrations. Dilute the 10mM compound solution to 1mM and use a pipette to transfer the compound to the assay plate in 2.5nL increments. Compounds were spotted into the wells of the assay plate in a total volume of 100 nL DMSO at a final concentration of 1% v/v. The detection buffer was prepared as follows: 50mM HEPES (pH 7.5), 1mM EDTA, 0.01% Brij-35, 10mM MgCl ₂ . Use a pipette to place 5μL of 2x (10nM) CDK8/CyclinC, 2x Eu-Streptavidin (4nM) and Biotin anti-His Tag Antibody (4nM) mixture into the above detection buffer (prepared 30 minutes in advance) and transfer to per assay plate. Transfer 5 μL of 2x (8 nM) Kinase Tracer 236 buffer to each assay well. Place the detection plate at 23°C and 1000rpm Centrifuge for 1 minute, shake to mix, and incubate at 23°C for 2 hours. Read data on Perkin Elmer Envision instruments. The calculation formula is %inhibition=(AVG Low-sample data)/(AVG Low-AVG High)*100; according to %inhibition vs.log[compound concentration], use XLfit5 software mode205 for data analysis and plot drawing. Fit=(A+((BA)/(1+((C/x)^D)))); Res=(y-fit); Finally, the IC50 (nM) of the test compound was obtained.

2. Experimental results

The IC50 values of the compounds of the present invention are shown in Table 8.

Table 8. IC50 values of compounds of the present invention

It can be seen from the above results that the compounds of the present invention have inhibitory effects on CDK8/cyclin C complex, among which compounds I-7, I-12, I-18, I-19, I-20, I-23, and I-26 , I-27, I-28, I-29, I-32, I-33, I-39, I-40, I-41, I-42, I-44, I-45, I-46, I -47, I-48, I-53, I-54, I-56, I-57, I-58 and I-59 have better inhibitory effects.

Experimental Example 2. Growth inhibitory effect of compounds of the present invention on human acute leukemia cell line MV-4-11

1. Experimental methods

The human acute leukemia cell line MV-4-11 was purchased from the American Model Organism Culture Collection (ATCC). MV-4-11 cells were cultured in RPMI 1640 medium at 37°C, 5% _CO2 , supplemented with 10% fetal bovine serum and 1% penicillin-streptomycin. The compound's inhibitory activity on the proliferation of MV-4-11 cells was detected by CellTiter-Glo reagent (CTG): the cells were evenly spread in a 96-well plate at 1000 cells/well, and the compound was diluted to different concentrations and added to the 96-well plate and cells. Incubate, and after 144 hours of incubation, perform cell viability testing according to the CTG reagent operating instructions, and use a multifunctional microplate reader to detect different The relative fluorescence intensity value in the concentration incubation wells. Fluorescence intensity values were corrected by DMSO-treated control wells, and three replicate wells were set up for parallel repetition. IC ₅₀ values were calculated using Grapgpad Prism 8.0.

2. Experimental results

The IC ₅₀ values of the compounds of the present invention are shown in Table 9.

Table 9. Growth inhibitory effect of compounds of the present invention on human acute leukemia cell line MV-4-11

From the above results, it can be seen that the compound of the present invention has a certain inhibitory effect on the growth of human acute leukemia cells.

In summary, the present invention provides a new compound that has excellent CDK8 inhibitory effect and can be used as a CDK8 inhibitor in clinical applications. It provides a new option for the treatment of tumor-related diseases, such as leukemia, and has a wide range of applications. prospect.

Claims (28)

1. The compound represented by formula I or its optical isomer, pharmaceutically acceptable salt, hydrate or solvate:
   

   Wherein, X is -OR, =O or -NR ₁ R ₂ ;

   R is H or C1～C6 alkyl;

   R ₁ and R ₂ are independently selected from H, C1 to C6 alkyl, -C(O)-R, or R ₁ and R ₂ together with the N atom to which they are connected form a substituted or unsubstituted 3 to 7-membered heterogeneous group. Ring or 5-, 8-, or 9-membered aromatic heterocycle, the heteroatoms on the heterocycle or aromatic heterocycle are N and/or O, S, the number of heteroatoms is at least 1; the substituted substituent It is C1～C6 alkyl;

   u, v, w are connected to form the following structure:
   

   y and z are connected to form the following structure:
   

   Het is a substituted or unsubstituted aromatic heterocycle or paraaromatic heterocycle, the heteroatom of the aromatic heterocycle or paraaromatic heterocycle is N, O or S, and the number of heteroatoms is any integer from 1 to 4; The number of substituted substituents is any integer from 1 to 5, and the substituents are cyano, halogen, hydroxyl-substituted or unsubstituted C1-C5 alkyl, C1-C5 alkyl or =O substituted or unsubstituted 5-10 membered heterocycle, phenyl, amino, -C(O)-R _a or -C(O)OR _a , the heteroatom of the heterocyclic ring is N, O or S, and the number of heteroatoms is 1 to 10 Any integer of 4; the number of substituted hydroxyl groups is any integer of 1 to 4; the number of substituted C1 to C5 alkyl groups or =O is any integer of 1 to 3;

   R _a is a substituted or unsubstituted amino group, a substituted or unsubstituted C1-C5 alkoxy group, a C1-C5 alkyl group or a 3-6 membered carbocyclic ring; the number of substituted substituents is any one from 1 to 5 Integer, the substituted substituent is halogen, C1-C3 alkyl or C1-C3 alkoxy.
2. The compound or its optical isomer, pharmaceutically acceptable salt, hydrate or solvate as claimed in claim 1, characterized in that:

   The X is -OR or -NR ₁ R ₂ ;

   R is H or C1～C3 alkyl;

   R ₁ and R ₂ are each independently selected from H, C1-C3 alkyl, or R ₁ and R ₂ together with the N atom to which they are connected form a substituted or unsubstituted 5-7 membered heterocyclic ring. The heteroatoms are N and/or O, and the number of heteroatoms is any integer from 1 to 3; the substituted substituent is C1 to C3 alkyl.
3. The compound or its optical isomer, pharmaceutically acceptable salt, hydrate or solvate as claimed in claim 2, characterized in that:

   The X is -OH or -NR ₁ R ₂ ;

   R ₁ and R ₂ are independently selected from H, methyl, or R ₁ and R ₂ together with the N atom to which they are connected form a substituted or unsubstituted 6-membered heterocyclic ring, and the heteroatoms on the heterocyclic ring are N and / or O, the number of heteroatoms is 1 or 2; the substituted substituent is methyl.
4. The compound or its optical isomer, pharmaceutically acceptable salt, hydrate or solvate as claimed in claim 3, characterized in that:

   The R ₁ and R ₂ are independently selected from H and methyl, or R ₁ and R ₂ together with the N atom to which they are connected form a methyl substituted or unsubstituted

   Preferably, R ₁ and R ₂ are independently selected from H, methyl, or R ₁ and R ₂ together with the N atoms to which they are connected form
5. The compound or its optical isomer, pharmaceutically acceptable salt, hydrate or solvate as claimed in claim 1, characterized in that:

   Het is a substituted or unsubstituted nitrogen-containing aromatic heterocycle or nitrogen-containing aromatic heterocycle, and the number of heteroatoms of the nitrogen-containing aromatic heterocycle or nitrogen-containing aromatic heterocycle is 1, 2 or 3;

   The number of the substituted substituents is any integer from 1 to 3, and the substituents are cyano, halogen, hydroxyl substituted or unsubstituted C1~C4 alkyl, C1~C3 alkyl or =O substituted or unsubstituted Substituted 5-10 membered heterocycle, phenyl, amino, -C(O)-R _a or -C(O)OR _a , the heteroatom of the heterocyclic ring is N, and the number of heteroatoms is 1, 2 or 3; the number of substituted hydroxyl groups is 1 or 2; the number of substituted C1~C3 alkyl or =O is 1 or 2;

   R _a is a substituted or unsubstituted amino group, a substituted or unsubstituted C1-C4 alkoxy group, a C1-C4 alkyl group or a 5-6 membered carbocyclic ring; the number of substituted substituents is any of 1 to 3 Integer, the substituted substituent is halogen, C1-C3 alkyl or C1-C3 alkoxy.
6. The compound or its optical isomer, pharmaceutically acceptable salt, hydrate or solvate as claimed in claim 5, characterized in that:

   Het is a substituted or unsubstituted nitrogen aromatic heterocycle or nitrogen aromatic heterocycle, and the number of heteroatoms of the nitrogen aromatic heterocycle or nitrogen aromatic heterocycle is 1, 2 or 3;

   The number of the substituted substituents is 1 or 2, and the substituents are cyano, chlorine, hydroxyl substituted or unsubstituted C1-C3 alkyl, C1-C3 alkyl or =O substituted or unsubstituted 6-10 membered heterocycle, phenyl, amino, -C(O)-R _a or -C(O)OR _a , the heteroatom of the heterocyclic ring is N, and the number of heteroatoms is 2; the hydroxyl group The number of substitutions is 1; the number of C1~C3 alkyl or =O substitutions is 1;

   R _a is a substituted or unsubstituted amino group, a substituted or unsubstituted C1-C3 alkoxy group, a methyl group or a 5-membered carbocyclic ring; the number of the substituted substituents is 1, 2 or 3, and the Substituted substituents are fluorine, methyl or methoxy.
7. The compound or its optical isomer, pharmaceutically acceptable salt, hydrate or solvate as claimed in claim 6, characterized in that:

   Het is substituted or unsubstituted
8. The compound or its optical isomer, pharmaceutically acceptable salt, hydrate or solvate as claimed in claim 7, characterized in that:

   Het is substituted or unsubstituted

   Preferably substituted or unsubstituted or replace
9. The compound or its optical isomer, pharmaceutically acceptable salt, hydrate or solvate as claimed in claim 6, characterized in that:

   The number of the substituted substituents is 1, and the substituents are: 1 hydroxyl-substituted C1-C3 alkyl group, 1 methyl-substituted 6-membered heterocycle, and 1 =O-substituted 10-membered heterocycle , cyano group, -C(O)-R _a or -C(O)OR _a , the heteroatom of the heterocyclic ring is N, and the number of heteroatoms is 2;

   R _a is a substituted or unsubstituted amino, methyl, 5-membered carbocyclic ring or C1-C3 alkoxy group; the number of the substituted substituents is 1 or 2, and the substituted substituents are methyl or Methoxy.
10. The compound or its optical isomer, pharmaceutically acceptable salt, hydrate or solvate as claimed in claim 9, characterized in that:

    The number of the substituted substituents is 1, and the substituents are: 1 hydroxyl-substituted C1-C3 alkyl group, or -C(O)-R _a ;

    R _a is a substituted or unsubstituted amino, methyl, 5-membered carbocyclic ring or C1-C3 alkoxy group; the number of substituted substituents is 1, and the substituted substituent is methyl or methoxy .
11. The compound or its optical isomer, pharmaceutically acceptable salt, hydrate or solvate according to any one of claims 1 to 10, characterized in that: the compound has a structure represented by formula IA:
    

    Among them, X, u, v, w, y, z and Het are as described in any one of claims 1 to 10.
12. The compound or its optical isomer, pharmaceutically acceptable salt, hydrate or solvate as claimed in claim 11, characterized in that: the compound has a structure represented by formula IB:
    

    Wherein, R ₁ , R ₂ , u, v, w, y, z are as described in any one of claims 1 to 10;

    R' is a substituent on the pyridine ring, forming R' is selected from cyano, halogen, hydroxyl substituted or unsubstituted C1~C5 alkyl, C1~C5 alkyl or =O substituted or unsubstituted 5~10 membered heterocycle, phenyl, amino, -C(O )-R _a or -C(O)OR _a , the heteroatom of the heterocyclic ring is N, O or S, the number of heteroatoms is any integer from 1 to 4; the number of hydroxyl groups substituted is 1 to 4 any integer; the number of C1-C5 alkyl or =O substituted is any integer from 1 to 3;

    R _a is a substituted or unsubstituted amino group, a substituted or unsubstituted C1-C5 alkoxy group, a C1-C5 alkyl group or a 3-6 membered carbocyclic ring; the number of substituted substituents is any one from 1 to 5 Integer, the substituted substituent is halogen, C1～C3 alkyl or C1～C3 alkoxy;

    Preferably,

    R' is selected from cyano, halogen, hydroxyl substituted or unsubstituted C1~C4 alkyl, C1~C3 alkyl or =O substituted or unsubstituted 5~10 membered heterocycle, phenyl, amino, -C(O )-R _a or -C(O)OR _a , the heteroatom of the heterocyclic ring is N, and the number of heteroatoms is 1, 2 or 3; the number of hydroxyl groups substituted is 1 or 2; so The number of C1~C3 alkyl or =O substituted groups is 1 or 2;

    R _a is a substituted or unsubstituted amino group, a substituted or unsubstituted C1-C4 alkoxy group, a C1-C4 alkyl group or a 5-6 membered carbocyclic ring; the number of substituted substituents is any of 1 to 3 Integer, the substituted substituent is halogen, C1～C3 alkyl or C1～C3 alkoxy;

    More preferably,

    R' is selected from cyano, chlorine, hydroxyl substituted or unsubstituted C1~C3 alkyl, C1~C3 alkyl or =O substituted or unsubstituted 6~10 membered heterocycle, phenyl, amino, -C(O )-R _a or -C(O)OR _a , the heteroatom of the heterocyclic ring is N, and the number of heteroatoms is 2; the number of hydroxyl groups substituted is 1; the C1~C3 alkyl group or =The number of O substitutions is 1;

    R _a is a substituted or unsubstituted amino group, a substituted or unsubstituted C1-C3 alkoxy group, a methyl group or a 5-membered carbocyclic ring; the number of the substituted substituents is 1, 2 or 3, and the The substituted substituent is fluorine, methyl or methoxy;

    More preferably,

    R' is selected from 1 hydroxyl-substituted C1~C3 alkyl group, 1 methyl-substituted 6-membered heterocycle, 1 =O-substituted 10-membered heterocycle, cyano group, -C(O)-R _a or - C(O)OR _a , the heteroatom of the heterocyclic ring is N, and the number of heteroatoms is 2;

    R _a is a substituted or unsubstituted amino, methyl, 5-membered carbocyclic ring or C1-C3 alkoxy group; the number of the substituted substituents is 1 or 2, and the substituted substituents are methyl or methoxy;

    More preferably,

    R' is selected from C1～C3 alkyl substituted by 1 hydroxyl group, or -C(O)-R _a ;

    R _a is a substituted or unsubstituted amino, methyl, 5-membered carbocyclic ring or C1-C3 alkoxy group; the number of substituted substituents is 1, and the substituted substituent is methyl or methoxy .
13. The compound or its optical isomer, pharmaceutically acceptable salt, hydrate or solvate according to claim 11, characterized in that: the compound has a structure represented by formula IA-a:
    

    Where, X is -OR or -NR ₁ R ₂ ;

    R, R ₁ , R ₂ and Het are as described in any one of claims 1 to 10.
14. The compound or its optical isomer, pharmaceutically acceptable salt, hydrate or solvate according to claim 13, characterized in that: the compound has a structure represented by formula IA-a1:
    

    Among them, R ₁ , R ₂ and Het are as described in any one of claims 1 to 10.
15. The compound or its optical isomer, pharmaceutically acceptable salt, hydrate or solvate as claimed in claim 13, characterized in that: the compound has a structure represented by formula IA-a2:
    

    Where, X is -OR or -NR ₁ R ₂ ;

    R, R ₁ and R ₂ are as described in any one of claims 1 to 10;

    R' is a substituent on the pyridine ring, forming R' is as claimed in claim 12.
16. The compound or its optical isomer, pharmaceutically acceptable salt, hydrate or solvate according to claim 15, characterized in that: the compound has a structure represented by formula IA-a3:
    

    Wherein, R ₁ and R ₂ are as described in any one of claims 1 to 10;

    R' is a substituent on the pyridine ring, forming R' is as claimed in claim 12.
17. The compound or its optical isomer, pharmaceutically acceptable salt, hydrate or solvate according to claim 16, characterized in that: the compound has a structure represented by formula IA-a4:
    

    Wherein, R' is as described in claim 12.
18. The compound according to any one of claims 13 to 17 or its optical isomer, pharmaceutically acceptable The accepted salt, hydrate or solvate is characterized in that: the compound has any of the following structures:
    
    
    
19. The compound or its optical isomer, pharmaceutically acceptable salt, hydrate or solvate according to claim 11, characterized in that: the compound has a structure represented by formula IA-b:
    
    

    Where, X is -OR or -NR ₁ R ₂ ;

    R, R ₁ , R ₂ and Het are as described in any one of claims 1 to 10.
20. The compound or its optical isomer, pharmaceutically acceptable salt, hydrate or solvate as claimed in claim 19, characterized in that: the compound has a structure represented by formula IA-b1:
    

    Among them, R _a , R ₁ and R ₂ are as described in any one of claims 1 to 10.
21. The compound or its optical isomer, pharmaceutically acceptable salt, hydrate or solvate as claimed in claim 19 or 20, characterized in that: the compound has any of the following structures:
    
    
22. The method for preparing the compound according to any one of claims 1 to 21, characterized in that it includes the following steps of preparing compound Ia:

    (1) Compound 1 reacts with lead acetate in an organic solvent under the action of a catalyst to obtain compound 2;

    (2) Compound 2 reacts in an organic solvent under the action of a reducing agent to obtain compound 3;

    (3) Compound 3 reacts in an organic solvent under the action of an oxidant to obtain compound 4;

    (4) Compound 4 reacts with Gilbert's reagent in an organic solvent under the action of an inorganic base to obtain compound 5;

    (5) Compound 5 reacts with X-Het in an organic solvent under the action of a catalyst to obtain compound Ia;

    The reaction formula is as follows:
    

    Wherein, u, v, w, y, z and Het are as described in any one of claims 1 to 10;

    X is halogen.
23. The preparation method according to claim 22, characterized in that:

    The solvent described in step (1) is a mixed solvent of benzene and methanol, the volume ratio of benzene and methanol is (15-20):1, the catalyst is boron trifluoride ether; the molar ratio of compound 1 to lead acetate The ratio is 1:(1.5～2);

    And/or, the organic solvent in step (2) is tetrahydrofuran, and the reducing agent is lithium aluminum hydride; the molar ratio of the compound 2 and the reducing agent is 1: (3-5);

    And/or, the organic solvent described in step (3) is a mixed solvent of methanol and water, and the volume ratio of methanol and water is (3-5):1; the oxidizing agent is sodium periodate; the compound 3 and The molar ratio of oxidant is 1:(0.8～1.2);

    And/or, the organic solvent in step (4) is methanol, and the inorganic base is potassium carbonate; the molar ratio of compound 4 to Gilbert's reagent is 1: (1.5-2.5);

    And/or, the organic solvent in step (5) is tetrahydrofuran, and the catalyst is a palladium carbon catalyst and cuprous iodide.
24. The preparation method according to claim 22, characterized in that:

    The reaction in step (1) is carried out at 20-30°C for 1.5-3 hours;

    And/or, the reaction in step (2) is carried out at 20-30°C for 3-5 hours;

    And/or, the reaction in step (3) is carried out at 20-30°C for 0.5-1.5 hours;

    And/or, the reaction in step (4) is carried out at 20-30°C for 10-15 hours;

    And/or, the reaction in step (5) is carried out at 75-85°C for 10-15 hours.
25. Use of the compound according to any one of claims 1 to 21 or its optical isomer, pharmaceutically acceptable salt, hydrate or solvate in the preparation of a CDK8 inhibitor.
26. The application of claim 25, wherein the CDK8 inhibitor is an anti-cancer drug.
27. The application according to claim 26, wherein the anti-cancer drug is a drug for preventing and treating colorectal cancer, prostate cancer, melanoma, breast cancer, acute myeloid leukemia and/or pancreatic cancer.
28. An anti-cancer drug, characterized in that it uses the compound of any one of claims 1 to 21 or its optical isomer, pharmaceutically acceptable salt, hydrate or solvate as an active ingredient, plus Preparations made of pharmaceutically acceptable excipients, carriers or excipients.