TW201912636A - Pomalidomide derivatives and the preparing method thereof - Google Patents

Abstract

The invention relates to pomalidomide derivatives and their stereoisomers or pharmaceutically acceptable salts, and their use in preparing medicaments for treating cancers.

Description

Pomodamine derivative and preparation method thereof

The present invention relates to a pomacilamine derivative or a pharmaceutically acceptable salt thereof, and the use thereof in the manufacture of a medicament for treating cancer.

Pomamide (formula A) was developed by the American Xaar Gene Company and was first approved for marketing in the United States in February 2013. Pomodamin is the third immunoprecipitator listed after thalidomide, lenalidomide, which enhances T cell and natural killer cell-mediated immune responses while inhibiting monocyte production of pro-inflammatory cells. Factor (such as TNF-α, IL-6, etc.). In addition, pomicamide inhibits tumor cell proliferation and induces apoptosis, and has a strong proliferation inhibitory effect on lenalidomide-resistant multiple myeloma cell lines. Formula A

Common adverse reactions to pomamide include neutropenia, fatigue, anemia, constipation, diarrhea, thrombocytopenia, upper respiratory tract infections, back pain, fever, and possibly thrombosis, which can cause severe birth defects in the fetus.

According to the literature, pomamide is a poorly soluble drug, and its solubility in purified water, pH 6.8 phosphate buffer, pH 4.5 acetate buffer and 0.1 mol/L hydrochloric acid was determined, and the results were 17.8, 17.0, respectively. , 18.7 and 18.9 μg/mL. The low solubility of pomicamide not only increases the difficulty of the preparation process, but also limits the dissolution and absorption process of the active ingredient in the gastrointestinal tract, thereby affecting the oral bioavailability.

The currently marketed pomoloproline oral capsule, sold under the trade name POMALYST, is formulated with a surfactant sodium lauryl sulfate in order to increase the dissolution of the drug, but sodium lauryl sulfate has a certain Gastrointestinal irritancy.

It is an object of the present invention to provide a novel pomamide prodrug having high stability, good solubility, improved bioavailability, low toxic side effects or long-term potential.

In one aspect, the invention provides a compound of formula (I), including stereoisomers thereof, or a pharmaceutically acceptable salt thereof, Formula (I) wherein: R1 is selected from H, substituted or unsubstituted C1-6 alkyl, substituted or unsubstituted C1-6 alkoxy, substituted or unsubstituted C2-6 alkenyl, substituted or unsubstituted a C2-6 alkynyl group, wherein the aforementioned substituted substituent is selected from C1-6 alkyl, C1-6 alkoxy; \R2 is selected from H, -OR3, -SR3, -NHR3, substituted or unsubstituted C3-10 a heterocyclic group, a substituted or unsubstituted C3-10 heterocyclic aryl group, a substituted or unsubstituted C3-10 cycloalkyl group, wherein the aforementioned substituted substituent is selected from a C1-6 alkyl group, a C1-6 alkoxy group, Carbonyl, carboxyl, amino, hydroxy; R3 is selected from -C(O)(R4)(R5), -P(O)(OR6)(OR7), -P(O)2(OR6)M, -P(O 3MY; R4 is selected from the group consisting of hydrogen, amino, hydroxy, halogen, C1-6 alkyl; R5 is selected from hydrogen, substituted or unsubstituted C1-16 alkyl, substituted or unsubstituted C1-6 alkoxy, substituted or Unsubstituted C3-10 heterocyclic group, substituted or unsubstituted C3-10 heterocyclic aryl, substituted or unsubstituted C3-10 cycloalkyl, phenyl, benzyl, -(CH2)nSCH3, -(CH2 mNHCH3, -(CH2)mN(CH3)2, wherein the previously substituted substituent is selected from the group consisting of amino, hydroxy, carboxy, -SH, -C(O)NH2, C1-6 alkyl; R6 and R7 are each independently It is selected from hydrogen, C1-6 alkyl; M and Y are each independently selected from a monovalent cation, or MY is a divalent cation; and m and n are each independently selected from 1, 2, 3, 4, 5, 6.

In a particular embodiment, R1 is selected from H, substituted or unsubstituted methyl, substituted or unsubstituted ethyl, substituted or unsubstituted propyl, substituted or unsubstituted butyl, substituted or unsubstituted pentyl a substituted, unsubstituted or unsubstituted hexyl group wherein the substituents previously substituted are selected from the group consisting of methyl, ethyl or propyl.

In a particular embodiment, R2 is selected from the group consisting of H, -OR3, substituted or unsubstituted tetrahydrofuranyl, substituted or unsubstituted tetrahydropyrrolyl, substituted or unsubstituted furyl, substituted or unsubstituted thiophenyl, substituted Or an unsubstituted pyrrolyl group, a substituted or unsubstituted imidazolyl group, a substituted or unsubstituted pyrazolyl group, a substituted or unsubstituted thiazolyl group, a substituted or unsubstituted oxazolyl group, a substituted or unsubstituted pyridyl group, substituted Or unsubstituted pyrimidinyl, substituted or unsubstituted pyridazinyl, substituted or unsubstituted pyrazinyl, substituted or unsubstituted fluorenyl, substituted or unsubstituted quinolinyl, substituted or unsubstituted isoquinoline a substituted or unsubstituted fluorenyl group, a substituted or unsubstituted cyclopropyl group, a substituted or unsubstituted cyclohexyl group, a substituted or unsubstituted cyclobutyl group, a substituted or unsubstituted cyclopentyl group, wherein the aforementioned substitution The substituent is selected from the group consisting of methyl, ethyl, propyl, carbonyl, carboxyl, amino, hydroxy.

In a preferred embodiment, R3 is selected from the group consisting of -C(O)(R4)(R5) wherein R4 is selected from the group consisting of hydrogen, amino, methyl, ethyl, propyl; and R5 is selected from hydrogen, substituted or unsubstituted Tetrahydrofuranyl, substituted or unsubstituted tetrahydropyrrolyl, substituted or unsubstituted furanyl, substituted or unsubstituted thienyl, substituted or unsubstituted pyrrolyl, substituted or unsubstituted imidazolyl, substituted or unsubstituted Pyrazolyl, substituted or unsubstituted thiazolyl, substituted or unsubstituted oxazolyl, substituted or unsubstituted pyridyl, substituted or unsubstituted pyrimidinyl, substituted or unsubstituted pyridazinyl, substituted or not Substituted pyrazinyl, substituted or unsubstituted indenyl, substituted or unsubstituted quinolyl, substituted or unsubstituted isoquinolinyl, substituted or unsubstituted fluorenyl, substituted or unsubstituted cyclopropyl , substituted or unsubstituted cyclohexyl, substituted or unsubstituted cyclobutyl, substituted or unsubstituted cyclopentyl, phenyl, benzyl, -(CH2)nSCH3, -(CH2)mNHCH3, -(CH2)mN (CH3)2, wherein the previously substituted substituent is selected from the group consisting of amino, hydroxy, carboxy, -SH, -C(O)NH2, methyl, ethyl Propyl.

In a more preferred embodiment, n is selected from 1, 2 or 3 and m is selected from 1, 2, 3, 4 or 5.

In a specific embodiment, R3 is selected from the group consisting of -P(O)(OR6)(OR7), -P(O)2(OR6)M, -P(O)3MY, wherein R6 and R7 are each independently selected from hydrogen , methyl, ethyl, propyl, butyl, pentyl, hexyl, M and Y are each independently selected from sodium ion, potassium ion, or MY is a divalent cation selected from calcium ion, magnesium ion.

In a particular embodiment, R1 is selected from H, methyl, ethyl or propyl; R2 is selected from H, -OR3, substituted or unsubstituted furyl, substituted or unsubstituted thienyl, substituted or unsubstituted Pyrrolyl, substituted or unsubstituted imidazolyl, substituted or unsubstituted pyrazolyl, substituted or unsubstituted thiazolyl, substituted or unsubstituted oxazolyl, substituted or unsubstituted pyridyl, substituted or unsubstituted Pyrimidinyl, substituted or unsubstituted pyridazinyl, substituted or unsubstituted pyrazinyl, substituted or unsubstituted fluorenyl, substituted or unsubstituted quinolinyl, substituted or unsubstituted isoquinolinyl, substituted or An unsubstituted fluorenyl group, wherein the aforementioned substituted substituent is selected from the group consisting of methyl, ethyl, and propyl; and R3 is selected from -C(O)(R4)(R5), -P(O)(OR6)(OR7) , -P(O)2(OR6)M, -P(O)3MY; R4 is selected from the group consisting of hydrogen, amino, methyl, ethyl, propyl; R5 is selected from the group consisting of hydrogen, methyl, ethyl, propyl, butyl , pentyl, hexyl, heptyl, octyl, decyl, decyl, tetrahydrofuranyl, tetrahydropyrrolyl, furyl, thienyl, pyrrolyl, imidazolyl, pyrazolyl, thiazolyl, oxazolyl, Pyridyl Pyrimidinyl, pyridazinyl, pyrazinyl, fluorenyl, quinolyl, isoquinolinyl, fluorenyl, phenyl, benzyl, -(CH2)nSCH3, -(CH2)mNHCH3, -(CH2)mN (CH3)2; R6 and R7 are each independently selected from the group consisting of hydrogen, methyl, ethyl, and propyl; and M and Y are each independently selected from sodium ion, potassium ion, or MY is a divalent cation selected from calcium ions. Magnesium ions; and m and n are each independently selected from 1, 2, 3, 4, 5, 6.

In a preferred embodiment, wherein: R1 is selected from the group consisting of H, methyl; and R2 is selected from the group consisting of H, -OR3, Wherein the substituent is selected from the group consisting of methyl, ethyl, propyl; R3 is selected from -C(O)(R4)(R5), -P(O)(OR6)(OR7), -P(O)2(OR6 M,-P(O)3MY; R4 is selected from hydrogen, amino; R5 is selected from the group consisting of hydrogen, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, decyl, decyl ,tetrahydrofuranyl, tetrahydropyrrolyl, furyl, thienyl, pyrrolyl, imidazolyl, pyrazolyl, thiazolyl, oxazolyl, pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl, fluorenyl, quin Polinyl, isoquinolyl, decyl, phenyl, benzyl, -(CH2)nSCH3, -(CH2)mNHCH3, -(CH2)mN(CH3)2; R6 and R7 are hydrogen; M and Y are each Independently selected from sodium ion, potassium ion, or MY is a divalent cation selected from calcium ion, magnesium ion; and m and n are each independently selected from 1, 2, 3, 4, 5, 6.

According to the invention, the compounds of the formula (I), the preferred compounds of which: , , , , , , , , , , .

Pharmaceutically acceptable salts as described in the present invention include, but are not limited to, hydrochloride or tromethamine salts.

In another aspect, the present invention provides a pharmaceutical composition comprising a therapeutically effective amount of a compound (including a stereoisomer thereof) as described above, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier and/or excipient.

In a further aspect, the invention provides the use of a compound according to the foregoing (including stereoisomers thereof), or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for the treatment of cancer. Such cancers include, but are not limited to, prostate cancer.

Unless otherwise stated, the terms used in the specification and claims are intended to have the following meanings.

The compound represented by the formula (I) according to the present invention includes stereoisomers thereof.

The carbon, hydrogen, oxygen, sulfur, nitrogen or halogen involved in the groups and compounds of the present invention include their isotopes, and the carbon, hydrogen, oxygen, sulfur, and the groups and compounds involved in the present invention. Nitrogen or halogen, optionally further replaced by one or more of their corresponding isotopes, wherein the carbon isotopes include ¹² C, ¹³ C, and ¹⁴ C, and the hydrogen isotopes include ruthenium (H), strontium (D, also known as heavy Hydrogen), strontium (T, also known as super-heavy hydrogen), oxygen isotopes include ¹⁶ O, ¹⁷ O and ¹⁸ O, sulfur isotopes include ³² S, ³³ S, ³⁴ S and ³⁶ S, nitrogen isotopes include ¹⁴ N and ¹⁵ N, the fluorine isotope includes ¹⁹ F, the chlorine isotope includes ³⁵ Cl and ³⁷ Cl, and the bromine isotope includes ⁷⁹ Br and ⁸¹ Br.

"Alkyl" means a straight-chain or branched saturated aliphatic hydrocarbon group, and the main chain includes 1 to 20 carbon atoms, preferably 1 to 12 carbon atoms, further preferably 1 to 8 carbon atoms. More preferably, it is a linear or branched group of 1 to 6 carbon atoms, still more preferably 1 to 4 carbon atoms, most preferably 1 to 2 carbon atoms; and examples of the alkyl group include, but are not limited to, a methyl group. , ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, 2-pentyl, 3-pentyl, 2-methyl-2-butyl , 3-methyl-2-butyl, 3-methyl-1-butyl, 2-methyl-1-butyl, n-hexyl, 2-hexyl, 3-hexyl, 2-methyl-2- Pentyl, 3-methyl-2-pentyl, 4-methyl-2-pentyl, 3-methyl-3-pentyl, 2-methyl-3-pentyl, 2,3-dimethyl -2-butyl, 3,3-dimethyl-2-butyl, n-heptyl, 2-methylhexyl, 3-methylhexyl, 4-methylhexyl, 5-methylhexyl, 2,2 - dimethylpentyl, 2,3-dimethylpentyl, 2,4-dimethylpentyl, 3,3-dimethylpentyl, 2-ethylpentyl, 3-ethylpentyl , n-octyl, 2,2-dimethylhexyl, 2,3-dimethylhexyl, 2,4-dimethylhexyl, 2,5-dimethyl Hexyl, 3,3-dimethylhexyl, 4,4-dimethylhexyl, 2-ethylhexyl, 3-ethylhexyl, 4-ethylhexyl, 2-methyl-2-ethylpentyl 2-methyl-3-ethylpentyl, n-decyl, 2-methyl-2-ethylhexyl and n-decyl.

"Alkoxy" means an -O-alkyl group wherein alkyl is as defined above. The alkoxy group may be substituted or unsubstituted, and specific examples of the alkoxy group include, but are not limited to, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, Tert-butoxy, sec-butoxy, n-pentyloxy and n-hexyloxy.

"Alkenyl" means an alkyl group as defined herein above containing at least one carbon-carbon double bond, preferably having 2 to 20 carbon atoms, further preferably 2 to 12 carbon atoms, more preferably 2 in the main chain. Alkenyl groups may be substituted or unsubstituted to 8 carbon atoms; non-limiting specific examples include vinyl, allyl, 1-propenyl, 2-propenyl, 1-butenyl, 2-butyl Alkenyl, 3-butenyl, 1-pentenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, 1-methyl-1-butenyl, 2-methyl-1 -butenyl, 2-methyl-3-butenyl, 1-hexenyl, 2-hexenyl, 3-hexenyl, 4-hexenyl, 5-hexenyl, 1-methyl 1-pentenyl, 2-methyl-1-pentenyl, 1-heptenyl, 2-heptenyl, 3-heptenyl, 4-heptenyl, 1-octenyl, 3- Octenyl, 1-decenyl, 3-decenyl, 1-decenyl, 4-decenyl, 1,3-butadiene, 1,3-pentadiene, 1,4-pentane Alkene, 1,4-hexadiene, 3-undecyl, 4-dodecenyl and 4,8,12-tetradecatriene.

"Alkynyl" means an alkyl group as defined herein above containing at least one carbon-carbon triple bond, preferably having from 2 to 20 carbon atoms, further preferably from 2 to 8 carbon atoms, more preferably An alkynyl group having 2 to 4 carbon atoms in the main chain; the alkynyl group may be substituted or unsubstituted; non-limiting specific examples include ethynyl, 1-propynyl, 2-propynyl, butynyl , 2-butynyl, 3-butynyl, 1-methyl-2-propynyl, 4-pentynyl, 3-pentynyl, 1-methyl-2-butynyl, 2-hexyl Alkynyl, 3-hexynyl, 2-heptynyl, 3-heptynyl, 4-heptynyl, 3-octynyl, 3-decynyl, 4-decynyl, 3-undynyl And 4-dodecynyl.

"Cycloalkyl" means a ring of monocyclic, fused, spiro or bridged rings all carbon, including, but not limited to, cyclopropane, cyclobutane, cyclopentane, spiro[3.4]octane, bicyclic [3.1.1] Hexane, etc.

"Heterocyclic" or "heterocyclic group" means substituted or unsubstituted saturated or unsaturated containing at least 1 to 5 selected from N, O, S, S(=O) or S(=O)2 atoms. Or a non-aromatic ring system of a group, the non-aromatic ring system comprising 3 to 20 ring atoms, preferably 3 to 10 ring atoms, more preferably 3 to 8 ring atoms; and optionally substituted in the heterocyclic ring N, S can be oxidized to various oxidation states; non-limiting specific examples include oxiranyl, oxetanyl, oxetanyl, oxetanyl, oxetanyl, oxetane , azacyclopropane, azetidinyl, azacyclopentyl, azacyclohexyl, azacyclopropenyl, 1,3 dioxocyclopentyl, 1,4-dioxocyclopentyl, 1,3-Dioxycyclopentyl, 1,3-dioxocyclohexyl, 1,3-dithiocyclohexyl, azepanyl, morpholinyl, pyridazinyl, pyridyl, furyl, thiophene , pyrrolyl, pyranyl, N-alkylpyrrolyl, pyrimidinyl, pyrazinyl, pyridazinyl, imidazolyl, acridinyl, thiomorpholinyl, dihydropyran, thiadiazolyl, Oxazolyl, oxadiazolyl, pyrazolyl, 1,4-dioxane , 2H-1,2- oxazin-yl or 2,5-dihydro-thienyl and the like.

"Heteroaryl" means a substituted or unsubstituted 5 to 14 membered aromatic ring and contains 1 to 5 atoms selected from N, O or S(=O)n or a group, preferably 5 to 10 members. The aromatic ring is further preferably 5 to 6 members; non-limiting examples of heteroaryl groups include, but are not limited to, pyridinyl, furyl, thienyl, pyridyl, pyranyl, N-alkylpyrrolyl, pyrimidine. Base, pyrazinyl, pyridazinyl, imidazolyl, acridine, morpholine, thiomorpholine, 1,3-dithiane, benzimidazole, decyl, benzimidazole, benzopyridine, pyrrole And pyridine; the heteroaryl ring may be fused to an aryl, heterocyclic or cycloalkyl ring, wherein the ring to which the parent structure is attached is a heteroaryl ring.

"Substitution" means a case where one or more hydrogen atoms in a group are substituted by another group, and if the group is substituted by a hydrogen atom, the group formed is the same as the group substituted by a hydrogen atom.

"Substituted or unsubstituted" refers to a situation in which a group may be substituted or unsubstituted, and if it is not indicated in the present invention that a group may be substituted, it means that the group is unsubstituted.

"Each independently selected from" means that the substituents may be the same or different, and even the different substituents represented by the same substituent symbol in the same embodiment may be the same or different.

"Pharmaceutically acceptable salt" means the bioavailability and properties of the free acid or free base, and the free acid is passed through with non-toxic inorganic or organic salts, or the free acid described, and non-toxic. Those salts obtained by the reaction of inorganic or organic acids.

The invention will be further described in conjunction with the specific embodiments thereof, and the present invention may be more fully understood by those skilled in the art, without limiting the invention in any way.

Example 1

Preparation of Compound 1

Step 1: Under a nitrogen atmosphere, S.M.B (20 g, 73.2 mmol, 1.00 eq) and DMF (400 ml) were added to a 1000 mL three-necked reaction flask and stirred magnetically. Sodium hydride (3.5 g, 87.5 mmol, 1.2 eq) was then added slowly. After stirring for 30 min, potassium iodide (12 g, 72.2 mmol, 0.99 eq) and TBAB (tetrabutylammonium bromide) (3.52 g, 10.9 mmol, After stirring for 15 minutes, SM1 (23.8 g, 72.8 mmol, 0.99 eq) was added and stirred for 12 hours. The reaction was stopped, the reaction system was poured into 2 L of water, and the mixture was stirred for 1 hour. A solid precipitated and filtered to give a yellow solid cake. The filter cake was washed with 500 ml of DCM (dichloromethane), and the organic phase was concentrated under reduced pressure. Chromatography (PE: EA = 1.5:1) gave 13.20 g of a yellow solid product with a yield of 35.8%.

Step 2: Add 100 ml of Int 1-01 (500 mg, 1 mmol, 1.00 eq), DCM 5 ml to a 100 ml three-necked reaction flask under nitrogen atmosphere. After stirring at room temperature for 10 minutes, add HCl/EA (10 ml, 10 mmol). , 10.0 eq), stirring was continued for 40 minutes. The reaction was quenched and dried by filtration to give 380 mg (yel.

HPLC: 97.05%

LCMS: 403.2 (M+H-HCl)

¹ H NMR (400 MHz, DMSO) δ 8.56-8.51 (d, 3H), 7.51-7.47 (dd, 1H), 7.06–7.04 (d, 1H), 7.01-7.02 (d, 1H), 6.56 (bs, 2 H), 5.91-5.85 (dd, 1H), 5.74-5.69 (t, 1H), 5.28-5.23 (m, 1H), 3.92 (s, 1H), 2.25 (m, 1H), 2.88-2.84 (d , 1H), 2.61-2.51 (m, 1H), 2.16-2.10 (m, 2H), 0.96 -0.92 (m, 6H).

Example 2

Preparation of Compound 2

Step 1: To a 2000 mL three-necked reaction flask was added SM2 (50 g, 285.4 mmol, 1.00 eq), H ₂ O (1000 ml), sodium bicarbonate (95.9 g, 1141.6 mmol, 4.00 eq), stirred for 30 minutes, then added DCM and Bu ₄ NHSO ₄ (9.7 g, 28.5 mmol, 0.1 eq). After stirring for 20 minutes, SMA (56.5 g, 342.5 mmol, 1.2 eq) was added and the reaction was stirred for 15 hours. The reaction was stopped, and the organic layer was concentrated under reduced pressure to give 60 g of colorless oil.

Step 2: Under a nitrogen atmosphere, add SMB (5.0 g, 18.3 mmol, 1.00 eq) to a 100 ml single-mouth reaction flask, 50 ml of DMF, and stir for 10 minutes in an ice water bath, then add NaH (0.9 g, 22.0 mmol, 1.2 eq) in one portion. After stirring for 20 minutes, TBAB (0.6 g, 1.8 mmol, 0.1 eq), and KI (3.0 g, 18.3 mmol, 1.00 eq) were added, and the reaction was carried out for 10 minutes in an ice water bath to give Int. 2-01 (6.2). G, 27.5 mmol, 1.50 eq) was added and stirred at room temperature overnight. The reaction was stopped, the liquid was separated, and the organic phase was concentrated under reduced pressure. <RTI ID=0.0>>

Step 3: Into a 25 ml three-necked reaction flask was added Int 2-02 (0.1 g, 0.2 mmol, 1.00 eq), hydrochloric acid / dioxane 20 ml, and stirred at room temperature overnight. The reaction was quenched and dried by filtration to give a product (yield: 73 mg). HPLC: 96.24%

LCMS: 361.1 (M+H ⁺ )

¹ H NMR (400 MHz, DMSO) δ = 8.50 (s, 2H), 7.49 (t, 1H), 7.04 (dd, 2H), 5.79 (q, J = 9.7, 2H), 5.24 (dd, 4.5, 1H ), 3.82 (d, 2H), 3.57 (s, 1H), 3.14 – 3.01 (m, 1H), 2.85 (d, 1H), 2.60 (d, 1H).

Specific embodiment 3

Preparation of Compound 3

Step 1: To a 500 mL three-necked reaction flask was added SM1 (6 g, 31.7 mmol, 1.00 eq), H ₂ O (130 ml), sodium bicarbonate (10.6 g, 126.8 mmol, 4.00 eq), and stirred for 30 minutes. Then DCM and Bu ₄ NHSO ₄ (1.08 g, 3.2 mmol, 0.1 eq) were added and stirred for 20 minutes; SMA (6.3 g, 38.0 mmol, 1.2 eq) was added and the reaction was stirred for 15 hours. The reaction was stopped, the liquid was separated, and the organic phase was concentrated under reduced pressure to yield 7.2 g of colorless oil.

Step 2: To a 250 mL one-necked reaction flask was added EtOAc (EtOAc, EtOAc, EtOAc (EtOAc) The reaction was stopped, and the organic phase was concentrated under reduced pressure to give 9.2 g of product as colorless oil.

Step 3: Under a nitrogen atmosphere, add SMB (3 g, 10.98 mmol, 1.00 eq) to a 250 ml three-neck reaction flask, and DMF 65 mL, cool the reaction system to below -20 ° C, and add LiHMDS (11 ml, 11 mmol, After stirring for 10 minutes, a solution of Int. 3-02 (4.34 g, 13.17 mmol, 1.20 eq) in DMF was added and stirring was continued. Ice-water solution to stop the reaction, the reaction system was poured into 1% NH ₄ Cl (300ml), the precipitated solid was stirred, filtered, and the filter cake was dissolved in EtOAc, concentrated under reduced pressure, column chromatography (PE / EtOAc = 10: 1- 2:1) Get 1.6 grams of product with a recovery rate of 30%.

Step 4: To a 25 ml three-necked reaction flask was added Int 3-03 (0.5 g, 1.05 mmol, 1.00 eq), hydrochloric acid / dioxane 20 ml, and stirred at room temperature overnight. The reaction was quenched, filtered and dried to give 235 mg of yd. HPLC: 96.4%

LCMS: 375.1 (M+H ⁺ )

¹ H NMR (400 MHz, DMSO-d6) δ 8.56 (s, 1H), 7.48 (t, J = 7.8 Hz, 1H), 7.05 (d, J = 8.4 Hz, 1H), 7.01 (d, J = 7.1 Hz, 1H), 5.86 (t, J = 9.1 Hz, 1H), 5.74 (d, J = 9.5 Hz, 1H), 5.24 (dd, J = 13.0, 5.3 Hz, 1H), 4.11 – 4.02 (m, 3H ), 3.11– 3.03 (m, 3H), 2.87 – 2.74 (m, 1H), 2.68 – 2.57 (m, 1H), 2.14 – 2.08 (m, 1H), 1.38 (d, J = 7.0 Hz, 3H).

Specific embodiment 4

Preparation of Compound 4

Step 1: To a 500 mL three-necked reaction flask SM4 (6.3g, 25.27 mmol, 1.00eq ), H 2 O (110ml), sodium bicarbonate (8.48g, 101.08 mmol, 4.00eq) was added, stirred for 10 minutes Then, DCM and Bu ₄ NHSO ₄ (0.86 g, 2.52 mmol, 0.1 eq) were added, and after stirring for 10 minutes, SMA (5 g, 30.32 mmol, 1.2 eq) was added dropwise under ice bath, and the reaction was stirred at room temperature for 15 h. The reaction was stopped, and the organic layer was concentrated under reduced pressure to give 7.4 g (yel.

Step 2: Under a nitrogen atmosphere, add SMB (2.7 g, 9.88 mmol, 1.00 eq), DMF 70 ml to a 250 ml three-neck reaction flask, and cool the reaction system to below -20 °C, and add LiHMDS (9.88 ml, 9.88 mmol, 1.00). Eq) Stirring was continued for 10 minutes, then a solution of Int. 4-01 (3.8 g, 12.84 mmol, 1.3 eq) in DMF was added and kept stirring at low temperature. The reaction was stopped, and the reaction system was poured into a 1% aqueous solution of NH ₄ Cl (315 ml) in ice. The solid was separated and filtered, filtered, and then filtered and evaporated. 800mg product, the recovery rate is 15%.

Step 3: To a 25 ml three-necked reaction flask was added Int 4-02 (0.2 g, 0.37 mmol, 1.00 eq), 2N hydrochloric acid / EA 4 ml 4 ml, and stirred at room temperature overnight. The reaction was stopped, filtered and dried to give 80 mg of a yellow solid product.

HPLC: 98.24%.

LCMS: 417.4 (M+H ⁺ )

¹ H NMR (400 MHz, DMSO) δ 8.43 (s, 2H), 7.50 (t, J = 7.7 Hz, 1H), 7.09 - 6.95 (m, 2H), 6.55 (s, 2H), 5.87 (d, J = 9.6 Hz, 1H), 5.74 (d, J = 9.8 Hz, 1H), 5.24 (d, J = 12.9 Hz, 1H), 4.00 (s, 1H), 3.09 (t, J = 15.2 Hz, 1H), 2.86 (d, J = 18.2 Hz, 1H), 1.76 – 1.64 (m, 1H), 1.57 (dd, J = 14.0, 6.9 Hz, 2H), 1.24 (s, 2H), 0.89 (d, J = 6.2 Hz , 6H).

Specific embodiment 5

Preparation of compound 5

Step 1: The preparation method is different from Step 1 of Concrete Example 4 in that S.M.4 is changed to S.M.5. Preparation 7.6 g of a colorless oil was obtained with a yield of 99.2%.

Step 2: The preparation method was the same as Step 2 of Specific Example 4, except that Int. 4-01 was changed to Int. 5-01. Preparation of 800 mg of product, the recovery rate of 15%.

Step 3: The preparation method was the same as Step 3 of Specific Example 4, except that Int. 4-02 was changed to Int. 5-02. 83.6 mg of a yellow solid product were obtained with a recovery of 52%.

HPLC: 99.5%

LCMS: 417.4 (M+H ⁺ )

¹ H NMR (400 MHz, DMSO) δ 8.47 (s, 3H), 7.49 (s, 1H), 7.05 (d, J = 8.5 Hz, 2H), 6.52 (s, 2H), 5.87 (d, J = 9.8 Hz, 1H), 5.71 (dd, J = 9.7, 4.3 Hz, 1H), 5.29 – 5.16 (m, 1H), 3.97 (s, 1H), 3.08 (ddd, J = 18.7, 12.7, 6.1 Hz, 1H) , 2.86 (d, J = 17.5 Hz, 1H), 2.63 (dd, J = 26.7, 13.6 Hz, 1H), 2.20 – 2.05 (m, 1H), 1.41 (dt, J = 13.3, 6.6 Hz, 1H), 1.32 – 1.07 (m, 2H), 0.93 – 0.70 (m, 6H).

LCMS: 417.4 (M+H ⁺ )

Specific embodiment 6

Preparation of compound 6

Step 1: The preparation method is different from Step 1 of Concrete Example 4 in that S.M.4 is changed to S.M.6. 6.3 g of a colorless oil was obtained with a yield of 94.2%.

Step 2: The preparation method was the same as Step 2 of Specific Example 4, except that Int. 4-01 was changed to Int. 6-01. Preparation 100 mg of product was obtained with a recovery of 2%.

Step 3: The preparation method was the same as Step 3 of Specific Example 4, except that Int. 4-02 was changed to Int. 6-02. The product product of 45 mg of a yellow solid was obtained with a yield of 56.2%.

HPLC: 96.53%.

LCMS: 401.4 (M+H ⁺ )

¹ H NMR (400 MHz, DMSO) δ 10.00 (s, 1H), 9.00 (s, 1H), 7.48 (s, 1H), 7.03 (dd, J = 11.8, 7.8 Hz, 2H), 6.53 (s, 2H) ), 5.86 (s, 2H), 5.24 (dd, J = 13.0, 5.2 Hz, 1H), 4.40 (s, 1H), 3.16 (d, J = 32.7 Hz, 2H), 3.13 – 2.98 (m, 1H) , 2.91 – 2.78 (m, 1H), 2.22 (dd, J = 14.8, 7.1 Hz, 1H), 2.16 – 2.04 (m, 1H), 1.91 (s, 4H), 0.85 (s, 0H).

Specific embodiment 7

Preparation of Compound 7

Step 1: The preparation method is the same as Step 1 of Specific Example 4, in that S. M.4 is changed to S.M.7. 7 g of a colorless oil was obtained, and the recovery was 88.6%.

Step 2: The preparation method is the same as Step 2 of Specific Example 4, except that Int. 4-01 is changed to Int. 7-01. 2.1 g of product was prepared, and the recovery was 40.2%.

Step 3: The preparation method is the same as Step 3 of Specific Example 4 except that Int. 4-02 is changed to Int. 7-02. The product product of 45 mg of a yellow solid was obtained with a yield of 56.2%.

HPLC: 96.41%

LCMS: 451.4 (M+H ⁺ )

¹ H NMR (400 MHz, DMSO) δ 8.64 (s, 3H), 7.48 (dd, J = 10.3, 4.3 Hz, 1H), 7.38 – 7.15 (m, 5H), 7.14 – 6.92 (m, 2H), 5.94 – 5.78 (m, 1H), 5.66 (dd, J = 9.6, 3.1 Hz, 1H), 5.20 (d, J = 13.0 Hz, 1H), 4.33 (s, 1H), 3.09 (dt, J = 21.8, 11.7 Hz, 3H), 2.86 (d, J = 16.2 Hz, 1H), 2.77 – 2.51 (m, 1H), 2.12 (d, J = 6.2 Hz, 1H).

Specific embodiment 8

Preparation of Compound 8

Under a nitrogen atmosphere, add SMB (2.5g, 9.15mmol, 1.00 eq) to a 250 ml three-neck reaction flask, DMF 65 mL, cool the reaction system to below -20 °C, and add LiHMDS (9.15 ml, 9.15 mmol, 1.00 eq). The mixture was stirred at low temperature for 10 minutes, then a solution of SM8 (2.72 g, 11.89 mmol, 2.00 eq) in DMF. The reaction was stopped, the reaction was poured into 1% NH ₄ Cl (300 mL) ice water and stirred to precipitate a solid, the filter cake was dissolved in EtOAc in, concentrated under reduced pressure, column chromatography (PE: EtOAc = 2: 1 ) Get 290 mg of product.

HPLC: 82.4%

LCMS: 386.1 (M+H ⁺ )

¹ H NMR (400 MHz, DMSO) δ 8.64 (s, 3H), 7.48 (dd, J = 10.3, 4.3 Hz, 1H), 7.38 – 7.15 (m, 5H), 7.14 – 6.92 (m, 2H), 5.94 – 5.78 (m, 1H), 5.66 (dd, J = 9.6, 3.1 Hz, 1H), 5.20 (d, J = 13.0 Hz, 1H), 4.33 (s, 1H), 3.09 (dt, J = 21.8, 11.7 Hz, 3H), 2.86 (d, J = 16.2 Hz, 1H), 2.77 – 2.51 (m, 1H), 2.12 (d, J = 6.2 Hz, 1H).

Specific embodiment 9

Preparation of compound 9

Step 1: Under nitrogen protection, add SMB (1 g, 3.66 mmol, 1.00 eq), DMF 25 mL to a 100 mL three-neck reaction flask, and cool the reaction system to below -20 °C, and add LiHMDS (3.66 ml, 3.66). Methanol, 1.00 eq), stirred for 10 min, then a solution of EtOAc (1. <RTI ID=0.0></RTI></RTI><RTIgt; The reaction was stopped, the reaction was poured into 1% NH ₄ Cl (120 mL) ice water and stirred precipitated solid was filtered, the filter cake was dissolved with EtOAc, concentrated under reduced pressure, column chromatography (PE: EA = 2: 1 ) With 310 mg product, the recovery rate is 18.3%.

HPLC: 98.2%

LCMS: 480.2 (M+Na ⁺ )

¹ H NMR (400 MHz, DMSO) δ 7.48 (t, J = 7.7 Hz, 1H), 7.02 (t, J = 8.1 Hz, 2H), 6.53 (s, 2H), 5.64 (d, J = 2.3 Hz, 2H), 5.23 (dd, J = 13.0, 5.3 Hz, 1H), 3.05 (td, J = 13.9, 13.4, 6.9 Hz, 1H), 2.82 (dt, J = 17.8, 3.2 Hz, 1H), 2.72 – 2.51 (m, 2H), 2.27 (t, J = 7.3 Hz, 2H), 2.15 – 2.02 (m, 1H), 1.49 (t, J = 7.1 Hz, 2H), 1.22 (s, 1H), 0.84 (t, J = 6.6 Hz, 3H).

Specific embodiment 10

Preparation of Compound 10

Step 1: Under a nitrogen atmosphere, add SM10 (15g, 107.9 mmol, 1.00 eq), DCM (150 ml), DMF (4 drops) to a 500 mL three-necked reaction flask. Continue to add the grass and chlorine to the ice bath. (15.07 g, 118.74 mmol, 1.1 eq), stirred at room temperature for 2 h. The reaction was stopped, and the reaction mixture was concentrated under reduced pressure to yield 14.56 g of oil.

Step 2: To a 100 ml single-mouth reaction flask was added Int. 10-01 (14.56 g, 92.06 mmol, 1.00 eq), paraformaldehyde (2.78 g, 92.06 mmol, 1.00 eq), zinc chloride (2.52 g, 18.41 mmol, 0.2 eq), the temperature of the reaction system was raised to 90 ° C and stirred. The reaction was stopped, and the reaction liquid was concentrated under reduced pressure.

Step 3: Under a nitrogen atmosphere, add SMB (4.48g, 16.4mmol, 1.00 eq), DMF 65ml, and cool the reaction system to below -20 °C. Add LiHMDS (16.4ml, 16.4mmol). After stirring for 10 minutes, a solution of Int. 10-02 (4.0 g, 21.3 mmol, 1.3 eq) in DMF. The reaction system was poured into a 1% aqueous solution of NH ₄ Cl (360 ml) in ice, and the solid was separated, filtered, and filtered, EtOAc was evaporated, EtOAc evaporated. With 3.3g product, the recovery rate is 47.5%.

Step 4: To a 250 ml three-neck reaction flask was added Int. 10-03 (3.33 g, 7.85 mmol, 1.00 eq), THF 66 ml, dimethylamine (1.41 g, 31.4 mmol, 4.00 eq), KI (33 mg), room temperature Stir. The reaction was stopped, and the system was directly dried with a vacuum pump to dissolve a small amount of EA, and then precipitated with 3N HCl/EA. The product was filtered to obtain 500 mg of product, and the recovery was 15%.

HPLC: 98.6%

LCMS: 451.4 (M+H ⁺ )

¹ H NMR (400 MHz, DMSO) δ 10.78 (s, 0H), 7.48 (dd, J = 8.4, 7.1 Hz, 1H), 7.04 (dd, J = 21.7, 7.6 Hz, 2H), 6.59 (s, 2H ), 5.81 (q, J = 9.7 Hz, 1H), 5.26 (dd, J = 13.0, 5.4 Hz, 1H), 3.61 – 3.18 (m, 1H), 2.83 (s, 3H), 2.51 (dt, J = 3.8, 1.9 Hz, 1H), 2.22 – 1.98 (m, 1H).

Specific embodiment 11

Preparation of Compound 11

Step 1: To a 100 mL 3-neck reaction flask was added SM11 (2.50 g, 10 mmol, 1.00 eq), sodium bicarbonate (3.78 g, 45 mmol, 4.50 eq), tetrabutylammonium hydrogen sulfate (169 mg, 0.5 mmol) , 0.05 eq), water (12 ml), isopropyl acetate (14 ml). After stirring for 30 minutes, SMA (2.97 g, 18 mmol, 1.80 eq) was added dropwise and the reaction was stirred for about 13 h. The reaction was stopped, the liquid was separated, and the organic phase was concentrated under reduced pressure to give 2.20 g of a colorless liquid. The recovery was 85.2%.

Step 2: To a 100 ml three-neck reaction flask, pomeloamine (1.00 g, 3.66 mmol, 1.00 eq) and DMF 10 ml were added under a nitrogen atmosphere. After stirring for 1 h, sodium hydride (60%) (175 mg, 4.39 mmol, 1.20 eq), stirring was continued for 40 minutes; then Int. 11.01 (0.95 g, 3.66 mmol, 1.00 eq) was added and stirring was continued for 27 h. The reaction was stopped, the system was poured into a 5% solution of ammonium chloride (200 ml), and the solid was precipitated, filtered, and the filter cake was dissolved in 200 ml of DCM, concentrated under reduced pressure, and purified by column chromatography (PE: EA = 1.5:1) Solid product. The recovery rate is 35.9%.

Step 3: To a 100 ml three-necked reaction flask was added Int1. 02 (490 mg, 1 mmol, 1.00 eq), DCM 20 ml, stirred at room temperature for 10 min, then HCl/EA (20 ml, 20 mmol, 20.0 eq) Continue stirring for 45 minutes. The reaction was stopped, and the hydrochloric acid in the reaction system was evacuated by a water pump for 20 minutes, and then filtered under a nitrogen atmosphere to obtain a yellow solid product which was directly dissolved in methanol (10 ml) and used as the next material. Under a nitrogen atmosphere, a methanol solution of the above intermediate was added to a 100 ml three-neck reaction flask, and a solution of tributylamine (243 mg, 2 mmol, 2.00 eq) in 20 ml of methanol was added dropwise with stirring at room temperature, and the mixture was stirred for 10 minutes, and 25 ml of acetone was dropped. In the system, a large amount of solid was precipitated in the system and stirred for 40 minutes. The filter cake was filtered and dried in vacuo to give &lt

HPLC: 99.73

LCMS: 382 (M-H-2tris)

¹ H NMR (400 MHz, DMSO), δ 7.52-7.48 (t, 1H), 7.05-7.03 (t, 2H), 5.92 (m, 2H), 5.16-5.11 (dd, 1H), 3.37 (s, 12H), 3.03-2.95 (m, 1H), 2.82-2.78 (d, 1H), 2.64-2.53 (m, 1H), 2.10-2.03 (m, 1H)

Specific Example 12 Determination of Solubility of Compounds of the Invention

1 mg of the compound 1 was mixed with 1 ml of water, stirred at room temperature, completely dissolved, and the supernatant was taken as a test sample solution. The test sample solution was measured by HPLC, and the results are shown in Table 1.

50 mg of the hydrochloride or tromethamine salt of the compound was mixed with 150 μl of water, stirred at room temperature, completely dissolved, and the supernatant was taken as a test sample solution. The test sample solution was measured by HPLC, and the results are shown in Table 1.

Table 1

In this test, the saturation solubility of the sample is not determined, but the appropriate amount of the sample is selected to determine the solubility of the sample. From the test, it was found that the compound (1 mg) or the salt (300 mg) of the present invention can be completely dissolved in 1 ml of water, the solubility of the compound is not less than 1 mg/ml, and the salt solubility is not less than 300 mg/ml. The solubility of pomamide in water is about 0.01 mg/ml, which is much lower than the solubility of the compound of the present invention or a salt thereof.

Specific Example 13 Determination of Stability of Compounds of the Invention

Appropriate samples were placed independently under different environmental conditions, and the percentage of samples at 0, 5, 10 or 30 days was determined to evaluate the stability of the samples.

Note: RT = room temperature, RH = relative humidity

Specific Example 14 Pharmacokinetic data

The male SD rats (SPF grade) used in this example, weighing 250-330 g, were purchased from Beijing Weitong Lihua Experimental Animal Technology Co., Ltd., more than 8 weeks old, and the animals were raised in polycarbonate with litter. In the ester cage (up to 5 animals/gender/cage). Free drinking water, free access to qualified feed 5CC4 daily (same as 5CR4, PMI Nutrition International LLC, USA)

The SD rats tested were divided into the hydrochloride group of the compound 1, the tromethamine group of the compound 11, and the possumamine group by a group design of a randomized block design. Each group was administered by intragastric administration (i.g.) at a dose of 2 mg/kg (based on posuleamine).

Test method: Before administration, blood samples were collected at 0.25, 0.5, 1, 2, 3, 4, 6, 8, 12, 24, 36 and 48 hours after administration, and collected into the anticoagulant tube containing EDTA-2K. Blood was stored on wet ice and plasma samples were obtained by centrifugation at 3500 rpm for 5 minutes at 4 ° C for 30 minutes. The plasma samples obtained by separation were immediately placed in dry ice and then transferred to a -60 to -80 ° C refrigerator. The hydrochloride salt of Compound 1 in the plasma, the tromethamine salt of Compound 11, and the possumamine were detected by LC/MS/MS, and the pharmacokinetics of the rats after administration were calculated using the non-compartment model of soft WinNonlin. Learning parameters.

DATA RESULTS: The pharmacokinetic parameters of the concentration of pomamide in plasma over time after administration of equimolar doses of each compound of pomamide (2 mg/kg) in rats are shown in the table below.

Conclusion: It can be seen from the above test results that after administration of each group, only pomicamine was detected in the body, indicating that they were rapidly metabolized to pomicamine after entering the body. At a dose of 2 mg/kg, after administration, the _Cmax value of the compound of the present invention was increased by more than 3 times and the AUC _{last was} more than 2 times higher than that of the _{posocinamine. The Cmax of the} compound 1 and the compound 11 indicates the present invention. The compound has better oral bioavailability compared to pomamide.

no

Figure 1 shows the relationship between drug concentration and time in plasma after administration of rats in each group of compounds.

Claims (13)

a compound of the formula (I) or a pharmaceutically acceptable salt thereof, Formula (I) wherein: R ^{1 is} selected from H, substituted or unsubstituted C _1-6 alkyl, substituted or unsubstituted C _1-6 alkoxy, substituted or unsubstituted C _2-6 alkenyl, substituted Or an unsubstituted C _2-6 alkynyl group, wherein the aforementioned substituted substituent is selected from a C _1-6 alkyl group, a C _1-6 alkoxy group; and R ^{2 is} selected from the group consisting of H, —OR ³ , —SR ³ , —NHR ^a substituted or unsubstituted C _3-10 heterocyclic group, a substituted or unsubstituted C _3-10 heterocyclic aryl group, a substituted or unsubstituted C _3-10 cycloalkyl group, wherein the aforementioned substituted substituent is selected from C _1-6 alkyl, C _1-6 alkoxy, carbonyl, carboxyl, amino, hydroxy; R ^{3 is} selected from -C(O)(R ⁴ )(R ⁵ ), -P(O)(OR ⁶ ) (OR ⁷ ), -P(O) ₂ (OR ⁶ )M, -P(O) ₃ MY; R ^{4 is} selected from the group consisting of hydrogen, amino, hydroxy, halogen, C _1-6 alkyl; R ^{5 is} selected from hydrogen, Substituted or unsubstituted C _1-16 alkyl, substituted or unsubstituted C _1-6 alkoxy, substituted or unsubstituted C _3-10 heterocyclyl, substituted or unsubstituted C _3-10 heterocyclic aryl a substituted, unsubstituted or substituted C _3-10 cycloalkyl group, phenyl, benzyl, -(CH ₂ ) nSCH ₃ , -(CH ₂ )mNHCH ₃ , -(CH ₂ )mN(CH ₃ ) ₂ , wherein The above substituted substituent is selected from the group consisting of an amino group, a hydroxyl group and a carboxyl group. _{-SH, -C (O) NH 2} , C 1-6 alkyl group; R ⁶ and R ⁷ are each independently selected from hydrogen, C _1-6 alkyl; M and Y are each independently selected from monovalent cations or for MY a divalent cation; and m and n are each independently selected from 1, 2, 3, 4, 5, 6. The compound of claim 1, wherein R ^{1 is} selected from H, substituted or unsubstituted methyl, substituted or unsubstituted ethyl, substituted or unsubstituted propyl, or a pharmaceutically acceptable salt thereof. a substituted or unsubstituted butyl group, a substituted or unsubstituted pentyl group, a substituted or unsubstituted hexyl group, wherein the aforementioned substituted substituent is selected from a methyl group, an ethyl group or a propyl group. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein R ^{2 is} selected from the group consisting of H, -OR ³ , substituted or unsubstituted tetrahydrofuranyl, substituted or unsubstituted tetrahydropyrrolyl, substituted Or unsubstituted furyl, substituted or unsubstituted thiophenyl, substituted or unsubstituted pyrrolyl, substituted or unsubstituted imidazolyl, substituted or unsubstituted pyrazolyl, substituted or unsubstituted thiazolyl, substituted or Non-substituted oxazolyl, substituted or unsubstituted pyridyl, substituted or unsubstituted pyrimidinyl, substituted or unsubstituted pyridazinyl, substituted or unsubstituted pyrazinyl, substituted or unsubstituted fluorenyl, substituted Or unsubstituted quinolyl, substituted or unsubstituted isoquinolyl, substituted or unsubstituted fluorenyl, substituted or unsubstituted cyclopropyl, substituted or unsubstituted cyclohexyl, substituted or unsubstituted ring Butyl, substituted or unsubstituted cyclopentyl, Wherein the aforementioned substituted substituent is selected from the group consisting of methyl, ethyl, propyl, carbonyl, carboxyl, amino, hydroxy. The compound of claim 3, wherein R ^{3 is} selected from -C(O)(R ⁴ )(R ⁵ ), wherein R ^{4 is} selected from the group consisting of hydrogen, amino, and A, or a pharmaceutically acceptable salt thereof. , ethyl, propyl; and R ^{5 is} selected from hydrogen, substituted or unsubstituted tetrahydrofuranyl, substituted or unsubstituted tetrahydropyrrolyl, substituted or unsubstituted furyl, substituted or unsubstituted thiophenyl, substituted Or an unsubstituted pyrrolyl group, a substituted or unsubstituted imidazolyl group, a substituted or unsubstituted pyrazolyl group, a substituted or unsubstituted thiazolyl group, a substituted or unsubstituted oxazolyl group, a substituted or unsubstituted pyridyl group, substituted Or unsubstituted pyrimidinyl, substituted or unsubstituted pyridazinyl, substituted or unsubstituted pyrazinyl, substituted or unsubstituted fluorenyl, substituted or unsubstituted quinolinyl, substituted or unsubstituted isoquinoline Base, substituted or unsubstituted fluorenyl, substituted or unsubstituted cyclopropyl, substituted or unsubstituted cyclohexyl, substituted or unsubstituted cyclobutyl, substituted or unsubstituted cyclopentyl, phenyl, benzyl Base, -(CH ₂ )nSCH ₃ , -(CH ₂ )mNHCH ₃ , -(CH ₂ )mN(CH ₃ ) ₂ , Wherein the aforementioned substituted substituent is selected from the group consisting of amino, hydroxy, carboxy, -SH, -C(O)NH ₂ , methyl, ethyl, propyl. The compound of claim 4, or a pharmaceutically acceptable salt thereof, wherein n is selected from 1, 2 or 3, and m is selected from 1, 2, 3, 4 or 5. The compound of claim 1, wherein R ^{3 is} selected from the group consisting of -P(O)(OR ⁶ )(OR ⁷ ), -P(O) ₂ (OR ⁶ )M, or a pharmaceutically acceptable salt thereof , -P(O) ₃ MY, wherein R ⁶ and R ⁷ are each independently selected from the group consisting of hydrogen, methyl, ethyl, propyl, butyl, pentyl, hexyl, and M and Y are each independently selected from sodium ion, potassium. The ion, or MY, is a divalent cation selected from the group consisting of calcium ions and magnesium ions. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein: R ^{1 is} selected from the group consisting of H, methyl, ethyl or propyl; and R ^{2 is} selected from H, -OR ³ , substituted or not Substituted furanyl, substituted or unsubstituted thienyl, substituted or unsubstituted pyrrolyl, substituted or unsubstituted imidazolyl, substituted or unsubstituted pyrazolyl, substituted or unsubstituted thiazolyl, substituted or unsubstituted Oxazolyl, substituted or unsubstituted pyridyl, substituted or unsubstituted pyrimidinyl, substituted or unsubstituted pyridazinyl, substituted or unsubstituted pyrazinyl, substituted or unsubstituted fluorenyl, substituted or unsubstituted Substituted quinolinyl, substituted or unsubstituted isoquinolinyl, substituted or unsubstituted fluorenyl, Wherein the aforementioned substituted substituent is selected from the group consisting of methyl, ethyl and propyl; R ^{3 is} selected from -C(O)(R ⁴ )(R ⁵ ), -P(O)(OR ⁶ )(OR ⁷ ), -P(O) ₂ (OR ⁶ )M, -P(O) ₃ MY; R ^{4 is} selected from the group consisting of hydrogen, amino, methyl, ethyl, propyl; R ^{5 is} selected from the group consisting of hydrogen, methyl, ethyl, and propyl , butyl, pentyl, hexyl, heptyl, octyl, decyl, decyl, tetrahydrofuranyl, tetrahydropyrrolyl, furyl, thienyl, pyrrolyl, imidazolyl, pyrazolyl, thiazolyl, cacao Azyl, pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl, fluorenyl, quinolyl, isoquinolinyl, fluorenyl, phenyl, benzyl, -(CH ₂ )nSCH ₃ ,-(CH ₂ ) mNHCH ₃ , -(CH ₂ )mN(CH ₃ ) ₂ ; R ⁶ and R ⁷ are each independently selected from the group consisting of hydrogen, methyl, ethyl and propyl; M and Y are each independently selected from sodium ion, potassium ion Or MY is a divalent cation selected from the group consisting of calcium ions and magnesium ions; and m and n are each independently selected from 1, 2, 3, 4, 5, and 6. The compound of claim 7 or a stereoisomer or pharmaceutically acceptable salt thereof, wherein R ^{1 is} selected from H, methyl; and R ^{2 is} selected from H, -OR ³ , Wherein the substituent is selected from the group consisting of methyl, ethyl, propyl; R ^{3 is} selected from -C(O)(R ⁴ )(R ⁵ ), -P(O)(OR ⁶ )(OR ⁷ ), -P( O) ₂ (OR ⁶ )M, -P(O) ₃ MY; R ^{4 is} selected from hydrogen, amino; R ^{5 is} selected from the group consisting of hydrogen, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl , octyl, decyl, decyl, tetrahydrofuranyl, tetrahydropyrrolyl, furyl, thienyl, pyrrolyl, imidazolyl, pyrazolyl, thiazolyl, oxazolyl, pyridyl, pyrimidinyl, pyridazinyl , pyrazinyl, fluorenyl, quinolyl, isoquinolinyl, fluorenyl, phenyl, benzyl, -(CH ₂ )nSCH ₃ , -(CH ₂ )mNHCH ₃ , -(CH ₂ )mN ( CH ₃ ) ₂ ; R ⁶ and R ⁷ are hydrogen; M and Y are each independently selected from sodium ion, potassium ion, or MY is a divalent cation selected from calcium ion and magnesium ion; and m and n are independently selected Since 1, 2, 3, 4, 5, 6. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein the compound has one of the following structures: , , , , , , , , , , . The compound of any one of claims 1 to 9 or a pharmaceutically acceptable salt thereof, wherein the pharmaceutically acceptable salt is a hydrochloride or a tromethamine salt. A pharmaceutical composition comprising a therapeutically effective amount of a compound according to any one of claims 1 to 9 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier and/or excipient . The use of a compound according to any one of claims 1 to 9 or a pharmaceutically acceptable salt thereof for the preparation of a medicament for treating cancer. The use of claim 1, wherein the cancer is prostate cancer.