KR20200124630A - chromane derivatives, and pharmaceutical composition for preventing or treating neovascular eye disease or cancer containing the same as an active ingredient - Google Patents

Abstract

The present invention provides a pharmaceutical composition for treating cancer or neovascular-related diseases containing a compound of chemical formula 1, which is a chromane derivative, a hydrate thereof, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof. In the chemical formula 1, R^1, R^2, R^3, R^4, R^5, R^6, and R^7 are as defined in the description of the invention.

Description

Chroman derivatives, and pharmaceutical composition for preventing or treating neovascular eye disease or cancer containing the same as an active ingredient}

It relates to a chroman derivative and a pharmaceutical composition for preventing or treating neovascular eye disease or cancer comprising the same.

Angiogenesis does not occur in the body except during development and wound healing. However, angiogenesis during a number of pathological conditions is particularly evident in ocular diseases such as Retinopathy of Prematurity (ROP), Diabetic Retinopathy (DR), and Age-related Macular Disease (AMD). It happens. After pathologic angiogenesis has occurred, the newly formed blood vessels are fragile, porous and not sufficiently differentiated. This formation of new blood vessels in the eye can lead to bleeding with rapid and permanent vision loss, rapid photoreceptor degeneration, and eventual fibrotic scarring.

The clinical symptoms of DR appear in 75% of diabetic patients, and 10% of these eventually develop into visual impairment (Non-Patent Document 1, Indian J Ophthalmol. 2009 Jul-Aug; 57(4): 293-298). DR is currently the leading cause of blindness among working-age adults in the United States and accounts for 8% of legal blindness. Also, nearly 2 million Americans have AMD. AMD represents an estimated loss of productivity burden of $5.4 billion per year in the United States. Severely ill patients have a very inferior quality of life compared to catastrophic stroke victims or patients with chronic pain advanced cancer.

Established treatment modalities for AMD include thermal laser photocoagulation or photodynamic therapy with verteporfin. More recently, anti-vascular endothelial growth factor therapies such as pegaptanib, ranibizumab, aflibercept and bevacizumab have been shown to be successful in slowing or even reversing vision loss in some elderly macular degeneration patients. However, significant acute systemic side effects (extraocular hemorrhage, myocardial infarction, and stroke) indicate that these therapies can act outside the eye even when delivered intravitreal. There are also possible blinding intraocular side effects, and the long-term risk burden of these drugs is still unclear. In addition, since they are biological drugs, the cost-benefit ratio of these drugs is also poor. For example, ranibizumab costs about $2,000 per month dose, which makes this treatment unacceptable for many patients. Since relapses can also occur after discontinuation of treatment, treatment with drug combinations targeting different pathways to truly eradicate the disease has been touted as a future therapy for this disease.

A similar situation exists for retinopathy of prematurity (ROP). Retinopathy of prematurity (ROP) is characterized by abnormal blood vessel growth in the neonatal retina. The disease progresses in two stages. In the hyperoxygen phase of the first, 22 to 30 week gestational age, high oxygen levels (as experienced in a ventilated ectopic environment compared to intrauterine) prevented a decrease in VEGF production and thus a cessation of vascularization. cause. In the second stage, the photoreceptors mature and the avascular retina grows and becomes hypoxic, triggering VEGF production. VEGF is essential for signaling normal blood vessel growth during development, but abnormally expressed at high levels results in inadequate neovascular growth. New blood vessels extending into the vitreous cannot supply oxygen to the retinal wall and are easily ruptured, leading to loss of retinal ganglion cells and photoreceptors, retinal detachment, and blindness.

In 2010, 12% of children in the United States were born premature, and 1.5% had very low birth weight (VLBW; ≤500 g). Almost 70% of these VLBW infants are prone to developing ROP, which is caused by abnormal angiogenesis after exposure to postpartum hyperoxia. The disease is estimated to cause vision loss in 1300 children per year in the United States and serious visual impairment in an additional 500 children per year. Overall, 6% to 18% of pediatric blindness can be attributed to ROP. In addition, as more and more children survive preterm birth in the developed world due to improvements in neonatal intensive care, ROP is becoming more prevalent worldwide. In addition to the acute risk of blindness, in childhood and even in adults, ROP survivors are more prone to posterior segment pathology, retinal detachment, myopia, amblyopia, strabismus, early cataracts and glaucoma than the general population.

In particular, since these drugs can exhibit systemic action even when delivered locally, biopharmaceutical treatment is effective against retinopathy of prematurity and has fewer side effects than surgical treatment. Considerable concern remains. Therefore, in order to complement existing approaches and to allow low-dose combination therapy, there is a very important and unmet need for novel small molecules to treat intraocular angiogenesis disorders as well as other angiogenesis-mediated diseases. do.

1. Chinese Patent Publication No. 105153100 2. US Patent Publication No. 2017-0333516

1. Indian J Ophthalmol. 2009 Jul-Aug; 57(4): 293-298.

An object in one aspect of the present invention is a compound, a hydrate thereof, a stereoisomer thereof, or a pharmaceutically acceptable compound thereof, which can be used for the prevention or treatment of cancer or neovascular eye disease due to its excellent angiogenesis inhibitory activity. It is to provide salt.

Another object of the present invention is to provide a pharmaceutical composition for the prevention or treatment of cancer or neovascular eye disease, including the compound, a hydrate thereof, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof.

Another object of the present invention is to provide a health functional food composition for preventing or improving cancer or neovascular eye disease, including the compound, a hydrate thereof, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof. will be.

Another object of the present invention is to administer the compound, a hydrate thereof, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof to an individual or subject in need thereof, for cancer or neovascularization. It is to provide a method of treating diseases.

Another object of the present invention is to provide the compound, a hydrate thereof, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof for use in the treatment of cancer or neovascular eye disease.

Another object of the present invention is to provide a use of the compound, a hydrate thereof, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof for use in the manufacture of a drug for the treatment of cancer or neovascular eye disease. will be.

To achieve the above object,

One aspect of the present invention provides a compound represented by the following Formula 1, a hydrate thereof, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof.

[Formula 1]

(In Formula 1,

는 단일결합, 또는 이중결합이고;remind

Is a single bond or a double bond;

X is CH or N;

The R ¹ , R ² , R ³ , R ⁴ , R ⁵ and R ⁶ are independently -H, -OH, =O, halogen, nitro, nitrile, C _1-10 straight or branched chain alkyl, C _1-10 straight or branched alkoxy, C _3-10 cycloalkyl, C _1-5 straight or branched alkoxy, or -0-(CH ₂ ) _n -CH=CH ₂ , wherein n is 1 to Is an integer of 10; And

R ⁷ is -H, -OH, halogen, C _1-10 straight or branched chain alkyl, C _1-10 straight or branched chain alkoxy, C _1-10 straight or branched alkylcarbonyloxy,

, 또는

이고;

, or

ego;

, 또는

이고,The A ¹ and A ² are independently -H, -(CH ₂ ) _m -O(C=O)-CH=CH ₂ , C _1-10 linear or branched alkoxycarbonyl C _1-5 linear or Branched chain alkyl, -(CH ₂ ) _p -CH=CH ₂ , 5 to 6 membered unsubstituted or substituted heterocycloalkyl containing one or more heteroatoms selected from the group consisting of N, O and S, C _{1 -5} straight or branched chain alkylcarbonyloxy C _1-5 straight or branched chain alkyl, unsubstituted or substituted C _6-8 aryl C _1-5 straight or branched chain alkyl,

, or

ego,

Here, m is an integer of 1 to 10, p is an integer of 1 to 10,

The substituted heterocycloalkyl is a C _6-8 aryl C _1-5 straight or branched chain alkyl substituted heterocycloalkyl, and the substituted C _6-8 aryl is C _{6- Is} an aryl of ₈ ,

_Wherein A ³ is a C _6-8 aryl C _1-5 straight or branched chain alkyl,

_Wherein A ⁴ is C _1-10 straight or branched chain alkyl,

_Wherein A ⁵ is C _1-10 straight or branched chain alkyl,

A ⁶ is a C _6-8 aryl C _1-5 straight or branched chain alkyl, C _1-5 straight or branched chain alkylsulfanyl C _1-5 straight or branched chain alkyl, or C _1-5 Straight or branched alkoxycarbonylamino C _1-5 straight or branched alkyl;

The B ¹ and B ² are unsubstituted or single C _1-10 of 5 to 6 atoms including one or more heteroatoms selected from the group consisting of N, O and S by being linked together with the carbon atom to which they are attached. Or to form 7 heterocycloalkyl substituted with a branched alkoxycarbonyl group, or

Wherein B ¹ and B ² are independently -H, C _1-10 straight or branched chain alkyl, 5 to 6 membered heterocycloalkyl C containing at least one heteroatom selected from the group consisting of N, O and S _1-5 straight or branched chain alkyl, unsubstituted or substituted C _6-8 aryl C _1-5 straight or branched chain alkyl, C _1-5 straight or branched chain alkylcarbonylamino, N, O and 5- to 10-membered heteroaryl C _1-5 straight or branched chain alkyl containing one or more heteroatoms selected from the group consisting of S, C _1-5 straight or branched alkoxycarbonylamino, diC _{1- 10} straight or branched chain alkylamino, or

이고,

ego,

Here, B ³ is C _1-10 straight or branched chain alkyl, or C ₆ aryl C _1-10 straight or branched chain alkyl,

The substituted C _6-8 aryl is C ₆ aryl C _1-5 straight or branched alkoxy, C _1-5 straight or branched alkoxy, C _1-5 straight or branched alkyl, halogen and At least one substituent selected from the group consisting of nitro is substituted C _6-8 aryl.

Another aspect of the present invention provides a pharmaceutical composition for the prevention or treatment of cancer or neovascular eye disease, including the compound, a hydrate thereof, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof.

Another aspect of the present invention provides a health functional food composition for preventing or improving cancer or neovascular eye disease, including the compound, a hydrate thereof, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof.

Another aspect of the present invention is a method for treating cancer or neovascular eye disease, comprising administering the compound, a hydrate thereof, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof to an individual or subject in need thereof. Provides.

Another aspect of the present invention provides the compound, a hydrate thereof, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof for use in the treatment of cancer or neovascular eye disease.

Another aspect of the present invention provides a use of the compound, a hydrate thereof, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof for use in the manufacture of a medicament for the treatment of cancer or neovascular eye disease.

Synthesis Example compounds provided in one aspect of the present invention, since it has excellent angiogenesis inhibitory activity, can be usefully used in the prevention or treatment of cancer or neovascular eye disease.

1 to 5 are results confirming the ability of the compound of the present invention to inhibit angiogenesis.

Hereinafter, the present invention will be described in detail.

On the other hand, embodiments of the present invention may be modified in various other forms, and the scope of the present invention is not limited to the embodiments described below. In addition, embodiments of the present invention are provided in order to more completely explain the present invention to those having average knowledge in the art. Furthermore, "including" a certain component throughout the specification means that other components may be further included, rather than excluding other components unless specifically stated to the contrary.

One aspect of the present invention provides a compound represented by the following [Formula 1], a hydrate thereof, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof.

[Formula 1]

(In Formula 1,

는 단일결합, 또는 이중결합이고;remind

Is a single bond or a double bond;

X is CH or N;

The R ¹ , R ² , R ³ , R ⁴ , R ⁵ and R ⁶ are independently -H, -OH, =O, halogen, nitro, nitrile, C _1-10 straight or branched chain alkyl, C _1-10 straight or branched alkoxy, C _3-10 cycloalkyl, C _1-5 straight or branched alkoxy, or -0-(CH ₂ ) _n -CH=CH ₂ , wherein n is 1 to Is an integer of 10; And

R ⁷ is -H, -OH, halogen, C _1-10 straight or branched chain alkyl, C _1-10 straight or branched chain alkoxy, C _1-10 straight or branched alkylcarbonyloxy,

, 또는

이고;

, or

ego;

, 또는

이고,The A ¹ and A ² are independently -H, -(CH ₂ ) _m -O(C=O)-CH=CH ₂ , C _1-10 linear or branched alkoxycarbonyl C _1-5 linear or Branched chain alkyl, -(CH ₂ ) _p -CH=CH ₂ , 5 to 6 membered unsubstituted or substituted heterocycloalkyl containing one or more heteroatoms selected from the group consisting of N, O and S, C _{1 -5} straight or branched chain alkylcarbonyloxy C _1-5 straight or branched chain alkyl, unsubstituted or substituted C _6-8 aryl C _1-5 straight or branched chain alkyl,

, or

ego,

Here, m is an integer of 1 to 10, p is an integer of 1 to 10,

The substituted heterocycloalkyl is a C _6-8 aryl C _1-5 straight or branched chain alkyl substituted heterocycloalkyl, and the substituted C _6-8 aryl is C _{6- Is} an aryl of ₈ ,

_Wherein A ³ is a C _6-8 aryl C _1-5 straight or branched chain alkyl,

_Wherein A ⁴ is C _1-10 straight or branched chain alkyl,

_Wherein A ⁵ is C _1-10 straight or branched chain alkyl,

A ⁶ is a C _6-8 aryl C _1-5 straight or branched chain alkyl, C _1-5 straight or branched chain alkylsulfanyl C _1-5 straight or branched chain alkyl, or C _1-5 Straight or branched alkoxycarbonylamino C _1-5 straight or branched alkyl;

The B ¹ and B ² are unsubstituted or single C _1-10 of 5 to 6 atoms including one or more heteroatoms selected from the group consisting of N, O and S by being linked together with the carbon atom to which they are attached. Or a branched alkoxycarbonyl group to form a substituted heterocycloalkyl, or

Wherein B ¹ and B ² are independently -H, C _1-10 straight or branched chain alkyl, 5 to 6 membered heterocycloalkyl C containing at least one heteroatom selected from the group consisting of N, O and S _1-5 straight or branched chain alkyl, unsubstituted or substituted C _6-8 aryl C _1-5 straight or branched chain alkyl, C _1-5 straight or branched chain alkylcarbonylamino, N, O and 5- to 10-membered heteroaryl C _1-5 straight or branched chain alkyl containing one or more heteroatoms selected from the group consisting of S, C _1-5 straight or branched alkoxycarbonylamino, diC _{1- 10} straight or branched chain alkylamino, or

이고,

ego,

Here, B ³ is C _1-10 straight or branched chain alkyl, or C ₆ aryl C _1-10 straight or branched chain alkyl,

The substituted C _6-8 aryl is C ₆ aryl C _1-5 straight or branched alkoxy, C _1-5 straight or branched alkoxy, C _1-5 straight or branched alkyl, halogen and At least one substituent selected from the group consisting of nitro is substituted C _6-8 aryl).

On the other side,

The R ¹ , R ² , R ³ , R ⁴ , R ⁵ and R ⁶ are independently -H, -OH, =O, halogen, nitro, nitrile, C _1-5 straight or branched chain alkyl, C _1-5 linear or branched alkoxy, C _3-6 cycloalkyl C _1-3 linear or branched alkoxy, or -0-(CH ₂ ) _n -CH=CH ₂ , wherein n is 1 to Is an integer of 5; And

R ⁷ is -H, -OH, halogen, C _1-5 straight or branched chain alkyl, C _1-5 straight or branched chain alkoxy, C _1-5 straight or branched alkylcarbonyloxy,

, 또는

이고;

, or

ego;

, 또는

이고,The A ¹ and A ² are independently -H, -(CH ₂ ) _m -O(C=O)-CH=CH ₂ , C _1-5 linear or branched alkoxycarbonyl C _1-5 linear or Branched chain alkyl, -(CH ₂ ) _p -CH=CH ₂ , 5 to 6 membered unsubstituted or substituted heterocycloalkyl containing one or more heteroatoms selected from the group consisting of N, O and S, C _{1 -5} straight or branched chain alkylcarbonyloxy C _1-5 straight or branched chain alkyl, unsubstituted or substituted C _6-8 aryl C _1-5 straight or branched chain alkyl,

, or

ego,

Here, m is an integer of 1 to 5, p is an integer of 1 to 5,

The substituted heterocycloalkyl is a C _6-8 aryl C _1-5 straight or branched chain alkyl substituted heterocycloalkyl, and the substituted C _6-8 aryl is C _{6- Is} an aryl of ₈ ,

_Wherein A ³ is a C _6-8 aryl C _1-5 straight or branched chain alkyl,

Wherein A ⁴ is C _1-5 straight or branched chain alkyl,

Wherein A ⁵ is C _1-5 straight or branched chain alkyl,

A ⁶ is a C _6-8 aryl C _1-5 straight or branched chain alkyl, C _1-5 straight or branched chain alkylsulfanyl C _1-5 straight or branched chain alkyl, or C _1-5 Straight or branched alkoxycarbonylamino C _1-5 straight or branched alkyl;

The B ¹ and B ² are unsubstituted or single C _1-5 of 5 to 6 atoms including one or more heteroatoms selected from the group consisting of N, O and S by being linked together with the carbon atom to which they are attached. Or a branched alkoxycarbonyl group to form a substituted heterocycloalkyl, or

B ¹ and B ² are independently -H, C _1-5 straight or branched chain alkyl, 5 to 6 membered heterocycloalkyl C containing at least one heteroatom selected from the group consisting of N, O and S _1-5 straight or branched chain alkyl, unsubstituted or substituted C _6-8 aryl C _1-5 straight or branched chain alkyl, C _1-5 straight or branched chain alkylcarbonylamino, N, O and 5- to 10-membered heteroaryl C _1-5 straight or branched chain alkyl containing one or more heteroatoms selected from the group consisting of S, C _1-5 straight or branched alkoxycarbonylamino, diC _{1- 5} straight or branched chain alkylamino, or

이고,

ego,

Here, B ³ is C _1-5 straight or branched chain alkyl, or C ₆ aryl C _1-5 straight or branched chain alkyl,

The substituted C _6-8 aryl is C ₆ aryl C _1-5 straight or branched alkoxy, C _1-5 straight or branched alkoxy, C _1-5 straight or branched alkyl, halogen and One or more substituents selected from the group consisting of nitro may be substituted C _6-8 aryl.

In another aspect, [Formula 1] is

X is CH or N;

R ¹ is -H, or -OCH ₃ ;

이고;R ² is -H, -F, -Cl, -OCH ₃ , -OH, or

ego;

R ³ is -H, -CI, -OCH ₃ , or -OCH ₂ CH=CH ₂ ;

R ⁴ is -H, -F, -CI, or -OCH ₃ ;

R ⁵ is -H, -CH ₃ , or =O;

R ⁶ is -H, -F, -Cl, -OCH ₃ , -OCH ₂ CH ₃ , -OCH ₂ CH ₂ CH ₃ , -OCH(CH ₃ ) ₂ , -OCH ₂ CH=CH ₂ or -OH ; And

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인 화합물, 이의 수화물, 이의 입체 이성질체, 또는 이의 약학적으로 허용 가능한 염을 제공한다.R ⁷ is -H, -F, -OH, -OCH ₃ , -CF ₃ ,

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Phosphorus compounds, hydrates thereof, stereoisomers thereof, or pharmaceutically acceptable salts thereof are provided.

In another aspect, the compound provides a compound represented by the following [Chemical Formula 1-1], a hydrate thereof, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof.

[Formula 1-1]

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이다.R ⁷ is -H, -F, -OH, -OCH ₃ ,

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to be.

In another aspect, the compound provides a compound represented by the following [Formula 1-2], a hydrate thereof, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof.

[Formula 1-2]

이고;R ² is -OCH ₃ , or

ego;

R ³ is -OCH ₃ or -OCH ₂ CH=CH ₂ .

In another aspect, the compound provides a compound represented by [Chemical Formula 1-3] below, a hydrate thereof, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof.

[Formula 1-3]

R ¹ is -H, or -OCH ₃ ;

이고;R ² is -H, -F, -Cl, -OCH ₃ , -OH, or

ego;

R ³ is -H, -CI, -OCH ₃ , or -OCH ₂ CH=CH ₂ ;

R ⁵ is -H or -CH ₃ ;

R ⁶ is -H, -F, -Cl, -OCH ₃ , -OCH ₂ CH ₃ , -OCH ₂ CH ₂ CH ₃ , -OCH(CH ₃ ) ₂ , -OCH ₂ CH=CH ₂ or -OH ; And

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또는

이다.R ⁷ is -F, -OH, -CF ₃ , -OCH ₃ ,

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or

to be.

In another aspect, the compound provides a compound represented by the following [Formula 1-4], a hydrate thereof, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof.

[Formula 1-4]

R ¹ is -H, -Cl, -F, or -OMe;

R ² is -H, -Cl, -F, or -OMe;

R ³ is -H, -Cl, -F, or -OMe;

R ⁴ is -H, -Cl, -F, or -OMe.

In another aspect, the compound provides a compound represented by the following [Formula 1-5], a hydrate thereof, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof.

[Formula 1-5]

R ¹ is -H, -Cl, -F, or -OMe;

R ² is -H, -Cl, -F, or -OMe;

R ³ is -H, -Cl, -F, or -OMe;

R ⁴ is -H, -Cl, -F, or -OMe.

으로 표시되는 화합물, 이의 수화물, 이의 입체 이성질체, 또는 이의 약학적으로 허용 가능한 염을 제공한다.In another aspect, the compound is

It provides a compound represented by, a hydrate thereof, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof.

In another aspect, the compound may be any one compound selected from the following compound group.

(1) 5-((6,8-dichlorochroman-3-yl)methyl)-2-methoxyphenol;

(2) 5-(chroman-3-ylmethyl)-2-methoxyphenol;

(3) 5-((5,7-dimethoxychroman-3-yl)methyl)-2-methoxyphenol;

(4) (R)-2-methoxy-5-((5,6,7-trimethoxychroman-3-yl)methyl)phenol;

(5) (S)-2-methoxy-5-((5,6,7-trimethoxychroman-3-yl)methyl)phenol;

(6) 3-(3,4-dimethoxybenzyl)-5,6,7-trimethoxychroman;

(7) 5-((7,8-dimethoxychroman-3-yl)methyl)-2-methoxyphenol;

(8) 5-((6,7-dimethoxychroman-3-yl)methyl)-2-methoxyphenol;

(9) 3-(3-hydroxy-4-methoxybenzyl)-5,7-dimethoxychroman-6-ol;

(10) 2-methoxy-4-((5,6,7-trimethoxychroman-3-yl)methyl)phenol;

(11) 3-(3-fluoro-4-methoxybenzyl)-5,6,7-trimethoxychrome;

(12) 2-methoxy-5-((5,6,7-trimethoxychroman-3-yl)methyl)phenyl 5-(1,2-dithiolan-3-yl)pentanoate;

(13) 3-benzyl-5,6,7-trimethoxychroman;

(14) 2-methoxy-6-((5,6,7-trimethoxychroman-3-yl)methyl)pyridine;

(15) 2-methoxy-5-((5,6,7-trimethoxy-4-oxochroman-3-yl)methyl)phenyl (tert-butoxycarbonyl)-L-leucinate;

(16) 2-methoxy-5-((5,6,7-trimethoxy-4-oxochroman-3-yl)methyl)phenyl (2S)-3-(4-(benzyloxy)phenyl) -2-((tert-butoxycarbonyl)amino)propanoate;

(17) 2-methoxy-5-((5,6,7-trimethoxy-4-oxochroman-3-yl)methyl)phenyl (2S)-3-(4-(tert-butoxy) Phenyl)-2-((tert-butoxycarbonyl)amino)propanoate;

(18) 2-methoxy-5-((5,6,7-trimethoxy-4-oxochroman-3-yl)methyl)phenyl ((benzyloxy)carbonyl)-L-phenylalaninate ;

(19) 2-methoxy-5-((5,6,7-trimethoxy-4-oxochroman-3-yl)methyl)phenyl (2S)-2-((tert-butoxycarbonyl) Amino)-4-phenylbutanoate;

(20) 6,8-difluoro-3-(3-hydroxy-4-methoxybenzyl)chroman-4-one;

(21) 6-fluoro-3-(3-hydroxy-4-methoxybenzyl)chroman-4-one;

(22) (E)-6-chloro-3-(3-hydroxy-4-methoxybenzylidene)chroman-4-one;

(23) (E)-7-chloro-3-(3-hydroxy-4-methoxybenzylidene)chroman-4-one;

(24) (E)-6-fluoro-3-(3-hydroxy-4-methoxybenzylidene)chroman-4-one;

(25) 6,8-dichloro-3-(3-hydroxy-4-methoxybenzyl)chroman-4-one;

(26) 2-methoxy-5-((5,6,7-trimethoxy-4-oxochroman-3-yl)methyl)phenyl (2S)-2-((tert-butoxycarbonyl) Amino)-3-(4-fluorophenyl)propanoate;

(27) 2-methoxy-5-((5,6,7-trimethoxy-4-oxochroman-3-yl)methyl)phenyl (2S)-2-((tert-butoxycarbonyl) Amino)-3-(4-nitrophenyl)propanoate;

(28) 2-methoxy-5-((5,6,7-trimethoxy-4-oxochroman-3-yl)methyl)phenyl (2S)-2-((tert-butoxycarbonyl) Amino)-3-(p-tolyl)propanoate;

(29) 2-methoxy-5-((5,6,7-trimethoxy-4-oxochroman-3-yl)methyl)phenyl acetyl-L-phenylalaninate;

(30) 2-methoxy-5-((5,6,7-trimethoxy-4-oxochroman-3-yl)methyl)phenyl (tert-butoxycarbonyl)-L-tryptophanate;

(31) 5-((6,8-dichloro-4-oxochroman-3-yl)methyl)-2-methoxyphenyl (tert-butoxycarbonyl)-L-phenylalaninate;

(32) 2-methoxy-5-((5,6,7-trimethoxy-4-oxochroman-3-yl)methyl)phenyl (tert-butoxycarbonyl)-D-phenylalaninate ;

(33) 2-methoxy-5-((5,6,7-trimethoxy-4-oxochroman-3-yl)methyl)phenyl (2S)-3-(4-bromophenyl)-2 -((tert-butoxycarbonyl)amino)propanoate;

(34) 1-(tert-butyl) 3-(2-methoxy-5-((5,6,7-trimethoxy-4-oxochroman-3-yl)methyl)phenyl)piperidine- 1,3-dicarboxylate;

(35) 2-methoxy-5-(((S)-5,6,7-trimethoxy-4-oxochroman-3-yl)methyl)phenyl (tert-butoxycarbonyl)-L- Phenylalaninate;

(36) 2-methoxy-5-(((R)-5,6,7-trimethoxy-4-oxochroman-3-yl)methyl)phenyl (tert-butoxycarbonyl)-L- Phenylalaninate;

(37) (S)-3-(3-hydroxy-4-methoxybenzyl)-5,6,7-trimethoxychroman-4-one;

(38) (R)-3-(3-hydroxy-4-methoxybenzyl)-5,6,7-trimethoxychroman-4-one;

(39) 2-methoxy-5-((5,6,7-trimethoxy-4-oxochroman-3-yl)methyl)phenyl pivalate;

(40) tert-butyl (2-methoxy-5-((5,6,7-trimethoxy-4-oxochroman-3-yl)methyl)phenyl) ((R)-3-phenylpropane- 1,2-diyl)dicarbamate;

(41) 7-(allyloxy)-3-(3-hydroxy-4-methoxybenzyl)-5,6-dimethoxychroman-4-one;

(42) 2-methoxy-5-((5,6,7-trimethoxy-4-oxochroman-3-yl)methyl)phenyl dimethyl-L-phenylalaninate;

(43) 2-methoxy-5-((5,6,7-trimethoxy-4-oxochroman-3-yl)methyl)phenyl ((S)-1-phenylethyl)carbamate;

(44) 2-methoxy-5-((5,6,7-trimethoxy-4-oxochroman-3-yl)methyl)phenyl ((R)-1-phenylethyl)carbamate;

(45) 2-methoxy-5-((5,6,7-trimethoxy-4-oxochroman-3-yl)methyl)phenyl (4-fluorophenethyl)carbamate;

(46) 2-methoxy-5-((5,6,7-trimethoxy-4-oxochroman-3-yl)methyl)phenyl (1-benzylpiperidin-4-yl)carbamate;

(47) methyl ((2-methoxy-5-((5,6,7-trimethoxy-4-oxochroman-3-yl)methyl)phenoxy)carbonyl)-L-phenylalaninate ;

(48) ethyl ((2-methoxy-5-((5,6,7-trimethoxy-4-oxochroman-3-yl)methyl)phenoxy)carbonyl)glycinate;

(49) 2-methoxy-5-((5,6,7-trimethoxy-4-methylchroman-3-yl)methyl)phenol;

(50) 5,6,7-trimethoxy-3-(4-methoxybenzyl)chroman-4-one;

(51) (E)-6-(cyclopropylmethoxy)-3-(3-hydroxy-4-methoxybenzylidene)-5,7-dimethoxychroman-4-one;

(52) 6-(cyclopropylmethoxy)-3-(3-hydroxy-4-methoxybenzyl)-5,7-dimethoxychroman-4-one;

(53) 2-methoxy-5-((5,6,7-trimethoxy-4-oxochroman-3-yl)methyl)phenyl 5-(1,2-dithiolan-3-yl) Pentanoate;

(54) tert-butyl ((2-methoxy-5-((5,6,7-trimethoxy-4-oxochroman-3-yl)methyl)phenoxy)carbonyl)-L-alani Nate;

(55) tert-butyl ((2-methoxy-5-((5,6,7-trimethoxy-4-oxochroman-3-yl)methyl)phenoxy)carbonyl)-L-valinate ;

(56) tert-Butyl N ⁶ -(t-butoxycarbonyl)-N ² -((2-methoxy-5-((5,6,7-trimethoxy-4-oxochroman-3- I)methyl)phenoxy)carbonyl)-L-lysinate;

(57) tert-butyl ((2-methoxy-5-((5,6,7-trimethoxy-4-oxochroman-3-yl)methyl)phenoxy)carbonyl)glycinate;

(58) methyl ((2-methoxy-5-((5,6,7-trimethoxy-4-oxochroman-3-yl)methyl)phenoxy)carbonyl)-L-methioninate;

(59) (2-methoxy-5-((5,6,7-trimethoxychroman-3-yl)methyl)phenyl(tert-butoxycarbonyl)-L-phenylalaninate;

(60) 2-methoxy-5-((5,6,7-trimethoxy-4-oxochroman-3-yl)methyl)phenyl)benzylcarbamate;

(61) 2-methoxy-5-((5,6,7-trimethoxy-4-oxochroman-3-yl)methyl)phenyl diethylcarbamate;

(62) 3-3(fluoro-4-methoxybenzyl)-5,6,7-trimethoxychroman-4-one;

(63) 5-(1,2-dithiolan-3-yl)-H-(2-methoxy-5-((5,6,7-trimethoxy-4-oxochroman-3-yl) Methyl)phenyl)pentanamide;

(64) 2-(((2-methoxy-5-((5,6,7-trimethoxychroman-3-yl)methyl)phenoxy)carbonyl)amino)ethyl acrylate;

(65) butyl ((2-methoxy-5-((5,6,7-trimethoxychroman-3-yl)methyl)phenoxy)carbonyl)glycinate;

(66) 2-methoxy-5-((5,6,7-trimethoxychroman-3-yl)methyl)phenyl allylcarbamate;

(67) 2-methoxy-5-((5,6,7-trimethoxychroman-3-yl)methyl)phenyl (1-benzylpiperidin-4-yl)carbamate;

(68) 2-(((2-methoxy-5-((5,6,7-trimethoxychroman-3-yl)methyl)phenoxy)carbonyl)amino)ethyl propionate;

(69) tert-butyl (2-methoxy-5-((5,6,7-trimethoxychroman-3-yl)methyl)phenyl) ((R)-3-phenylpropane-1,2- Diyl) dicarbamate;

(70) 3-(4-ethoxy-3-fluorobenzyl)-5,6,7-triethoxychroman;

(71) 3-(3-fluoro-4-propoxybenzyl)5,6,7-trimethoxychroman;

(72) 3-(3-fluoro-4-isopropoxybenzyl)-5,6,7-trimethoxychroman;

(73) 3-4(-(allyloxy)3-fluorobenzyl)-5,6,7-trimethoxychroman;

(74) 3-(4-chloro-3-(trifluorobetyl)benzyl)-5,6,7-trimethoxychroman;

(75) 3-(3-fluoro-5-methoxybenzyl)-5,6,7-trimethoxychroman;

(76) 2-methoxy-5-((5,6,7-trimethoxy-4-ketylchroman-3-yl)methyl)phenyl 5-(1,2-dithiolan-3-yl)penta No eight;

(77) 5-((6-(cyclopropylmethoxy)-5,7-dimethoxychroman-3-yl)methyl)-2-methoxyphenol

(78) 2-methoxy-5-(((R)-5,6,7-trimethoxychroman-3-yl)methyl)phenyl-(tert-butoxycarbonyl)-L-phenylalani Nate;

(79) (R)-3-(3-fluoro-4-methoxybenzyl)-5,6,7-trimethoxychroman-4-one;

(80) (S)-3-(3-fluoro-4-methoxybenzyl)-5,6,7-trimethoxychroman;

(81) 2-methoxy-5-((( R )-5,6,7-trimethoxychroman-3-yl)methyl)phenyl ( tert -butoxycarbonyl)-L-phenylalaninate ;

(82) ( S )-3-(3-fluoro-4-methoxybenzyl)-5,6,7-trimethoxychroman; And

(83) ( R )-3-(3-fluoro-4-methoxybenzyl)-5,6,7-trimethoxychroman;

The compound represented by Formula 1 of the present invention can be used in the form of a pharmaceutically acceptable salt, and an acid addition salt formed by a pharmaceutically acceptable free acid is useful. Acid addition salts include inorganic acids such as hydrochloric acid, nitric acid, phosphoric acid, sulfuric acid, hydrobromic acid, hydroiodic acid, nitrous acid, phosphorous acid, etc., aliphatic mono and dicarboxylates, phenyl-substituted alkanoates, hydroxy alkanoates and alkanes. Non-toxic organic acids such as dioates, aromatic acids, aliphatic and aromatic sulfonic acids, trifluoroacetic acid, acetate, benzoic acid, citric acid, lactic acid, maleic acid, gluconic acid, methanesulfonic acid, 4-toluenesulfonic acid, tartaric acid, fumaric acid, etc. Get from Examples of such pharmaceutically non-toxic salts include sulfate, pyrosulfate, bisulfate, sulfite, bisulfite, nitrate, phosphate, monohydrogen phosphate, dihydrogen phosphate, metaphosphate, pyrophosphate chloride, bromide, i. Odide, fluoride, acetate, propionate, decanoate, caprylate, acrylate, formate, isobutyrate, caprate, heptanoate, propiolate, oxalate, malonate, succinate, sube Rate, sebacate, fumarate, maleate, butine-1,4-dioate, hexane-1,6-dioate, benzoate, chlorobenzoate, methylbenzoate, dinitro benzoate, hydroxybenzoate, Methoxybenzoate, phthalate, terephthalate, benzenesulfonate, toluenesulfonate, chlorobenzenesulfonate, xylenesulfonate, phenylacetate, phenylpropionate, phenylbutyrate, citrate, lactate, β-hydroxybutyrate, Glycolate, malate, tartrate, methanesulfonate, propanesulfonate, naphthalene-1-sulfonate, naphthalene-2-sulfonate, mandelate, and the like.

The acid addition salt according to the present invention can be prepared by a conventional method, for example, a precipitate formed by dissolving the derivative of Formula 1 in an organic solvent such as methanol, ethanol, acetone, methylene chloride, acetonitrile, etc. and adding an organic or inorganic acid May be prepared by filtration and drying, or may be prepared by distilling off a solvent and an excess of acid under reduced pressure and then drying to crystallize under an organic solvent.

In addition, a pharmaceutically acceptable metal salt can be made using a base. The alkali metal or alkaline earth metal salt is obtained, for example, by dissolving the compound in an excess alkali metal hydroxide or alkaline earth metal hydroxide solution, filtering the undissolved compound salt, and evaporating and drying the filtrate. At this time, it is pharmaceutically suitable to prepare sodium, potassium or calcium salt as the metal salt. In addition, the corresponding salt is obtained by reacting an alkali metal or alkaline earth metal salt with a suitable silver salt (eg, silver nitrate).

Further, the present invention includes not only the compound represented by Formula 1 and its pharmaceutically acceptable salts, but also solvates, optical isomers, hydrates, etc. that may be prepared therefrom.

Another aspect of the present invention is as shown in Scheme 1 below,

A method of preparing a compound represented by Formula 1a by reacting a compound represented by Formula 2 with a compound represented by Formula 3 in the presence of an acid is provided.

[Scheme 1]

(In the above Scheme 1,

R ¹ to R ⁷ and X are as defined herein;

The compound represented by Formula 1a is a compound included in the compound represented by Formula 1).

In the method for preparing a compound represented by Formula 1a according to Scheme 1 provided in an aspect of the present invention, the reaction may be carried out in a known reaction solvent such as toluene, and p -toluenesulfonic acid is used as the acid. Can be used.

The reaction temperature is from room temperature to 120° C. The reaction time may be performed for 6 to 24 hours, but is not particularly limited thereto.

The C=C unsaturated bond present in the compound represented by Formula 1a can be converted into a C-C saturated bond through a hydrogenation reaction using a Pd/C catalyst.

Another aspect of the present invention provides a pharmaceutical composition for the prevention or treatment of neovascular eye diseases comprising the compound, a hydrate thereof, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof. At this time, the neovascular eye disease may be macular degeneration, retinopathy of prematurity, or diabetic retinopathy.

The compound represented by Formula 1 or a pharmaceutically acceptable salt thereof may be administered in various oral and parenteral formulations upon clinical administration.

In the case of formulation, it is prepared using diluents or excipients such as fillers, extenders, binders, wetting agents, disintegrants, and surfactants that are usually used. Solid preparations for oral administration include tablets, pills, powders, granules, capsules, and the like, and these solid preparations include at least one excipient, such as starch, calcium carbonate, sucrose, or lactose ( lactose), gelatin, etc. In addition, in addition to simple excipients, lubricants such as magnesium stearate and talc are also used.

Liquid preparations for oral administration include suspensions, liquid solutions, emulsions, and syrups.In addition to water and liquid paraffin, which are commonly used simple diluents, various excipients such as humectants, sweeteners, fragrances, and preservatives may be included. have. Formulations for parenteral administration include sterile aqueous solutions, non-aqueous solvents, suspensions, and emulsions. As the non-aqueous solvent and the suspension solvent, propylene glycol, polyethylene glycol, vegetable oil such as olive oil, and injectable ester such as ethyl oleate may be used.

A pharmaceutical composition containing the compound represented by [Chemical Formula 1] or a pharmaceutically acceptable salt thereof as an active ingredient can be administered parenterally, and parenteral administration is subcutaneous injection, intravenous injection, intramuscular injection, or intrathoracic injection By the method of injecting.

At this time, in order to formulate a formulation for parenteral administration, the compound represented by Formula 1 or a pharmaceutically acceptable salt thereof is mixed in water together with a stabilizer or buffer to prepare a solution or suspension, and the ampoule or vial unit dosage form It can be manufactured with The composition may be sterilized and/or contain adjuvants such as preservatives, stabilizers, hydrating agents or emulsification accelerators, salts and/or buffers for controlling osmotic pressure, and other therapeutically useful substances, which are conventional methods of mixing, granulation. It can be formulated according to the method of painting or coating.

Formulations for oral administration include, for example, tablets, pills, hard/soft capsules, solutions, suspensions, emulsifiers, syrups, granules, elixirs, and troches.These formulations include diluents (e.g., lactose) in addition to the active ingredients. , Dextrose, sucrose, mannitol, sorbitol, cellulose and/or glycine), lubricants (e.g. silica, talc, stearic acid and its magnesium or calcium salt and/or polyethylene glycol). Tablets may contain a binder such as magnesium aluminum silicate, starch paste, gelatin, methylcellulose, sodium carboxymethylcellulose and/or polyvinylpyrrolidine, and in some cases, boron such as starch, agar, alginic acid or sodium salt thereof. It may contain release or boiling mixtures and/or absorbents, colorants, flavoring agents, and sweetening agents.

Another aspect of the present invention provides a food for preventing cancer or neovascular eye disease, including the compound, a hydrate thereof, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof. At this time, the neovascular eye disease may be macular degeneration, retinopathy of prematurity, or diabetic retinopathy.

The compound represented by Formula 1 according to the present invention may be added to food as it is or may be used together with other foods or food ingredients, and may be appropriately used according to a conventional method. The mixing amount of the compound may be suitably determined depending on the purpose of use (for prevention or improvement). In general, the amount of the compound in the health food may be added in 0.1 to 90 parts by weight of the total food weight. However, in the case of long-term intake for the purpose of health and hygiene or for the purpose of health control, the amount may be below the above range, and since there is no problem in terms of safety, the compound may be used in an amount above the above range.

In addition, the health functional beverage composition of the present invention is not particularly limited to other ingredients other than containing the compound as an essential ingredient in the indicated ratio, and may contain various flavoring agents or natural carbohydrates, etc. as additional ingredients, as in ordinary beverages. have. Examples of the above-described natural carbohydrates include monosaccharides such as glucose, fructose, and the like; Disaccharides such as maltose, sucrose, and the like; And polysaccharides, for example, common sugars such as dextrin and cyclodextrin, and sugar alcohols such as xylitol, sorbitol, and erythritol. As flavoring agents other than those described above, natural flavoring agents (taumatin, stevia extract (for example, rebaudioside A, glycyrrhizin, etc.)) and synthetic flavoring agents (saccharin, aspartame, etc.) can be advantageously used. The proportion of the natural carbohydrate is generally about 1 to 20 g, preferably about 5 to 12 g per 100 g of the composition of the present invention.

Further, in addition to the above, the compound represented by Formula 1 according to the present invention includes various nutrients, vitamins, minerals (electrolytes), flavoring agents such as synthetic flavors and natural flavoring agents, coloring agents and heavy weight agents (cheese, chocolate, etc.), pect Acids and salts thereof, alginic acid and salts thereof, organic acids, protective colloidal thickeners, pH adjusters, stabilizers, preservatives, glycerin, alcohols, carbonates used in carbonated beverages, and the like. In addition, the compound represented by Chemical Formula 1 of the present invention may contain flesh for the manufacture of natural fruit juice and fruit juice beverages and vegetable beverages.

Another aspect of the present invention provides a pharmaceutical composition for preventing or treating cancer comprising the compound of Formula I, a hydrate thereof, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof.

At this time, the cancer may be a solid cancer.

More specifically, the cancer is pseudomyxoma, intrahepatic biliary tract cancer, hepatoblastoma, liver cancer, thyroid cancer, colon cancer, testicular cancer, myelodysplastic syndrome, glioblastoma, oral cancer, cleft lip cancer, mycosis fungoides, acute myeloid leukemia, acute lymphoblastoma. Constituent leukemia, basal cell carcinoma, ovarian epithelial carcinoma, ovarian germ cell carcinoma, male breast cancer, brain cancer, pituitary adenoma, multiple myeloma, gallbladder cancer, biliary tract cancer, colon cancer, chronic myelogenous leukemia, chronic lymphocytic leukemia, retinoblastoma, choroidal melanoma, Barter Bulge cancer, bladder cancer, peritoneal cancer, parathyroid cancer, adrenal cancer, non-sinus cancer, non-small cell lung cancer, tongue cancer, astrocytoma, small cell lung cancer, pediatric brain cancer, pediatric lymphoma, pediatric leukemia, small intestine cancer, meningioma, esophageal cancer, glioma, renal cow cancer , Kidney cancer, heart cancer, duodenal cancer, malignant soft tissue cancer, malignant bone cancer, malignant lymphoma, malignant mesothelioma, malignant melanoma, eye cancer, vulvar cancer, ureteral cancer, urethral cancer, primary site unknown cancer, gastric lymphoma, stomach cancer, stomach Carcinoid carcinoma, gastrointestinal interstitial cancer, Wilms cancer, breast cancer, triple negative breast cancer, sarcoma, penile cancer, pharyngeal cancer, gestational chorionic disease, cervical cancer, endometrial cancer, uterine sarcoma, prostate cancer, metastatic bone cancer, metastatic brain cancer, mediastinal cancer, rectal cancer , Rectal carcinoma, vaginal cancer, spinal carcinoma, auditory neuroma, pancreatic cancer, salivary gland cancer, Kaposi's sarcoma, Paget's disease, tonsil cancer, squamous cell carcinoma, lung adenocarcinoma, lung cancer, lung squamous cell carcinoma, skin cancer, anal cancer, rhabdomyosarcoma , Laryngeal cancer, pleural cancer, thymic cancer, etc.

The pharmaceutical composition of the present invention may further include an anticancer agent as a second therapeutic agent in addition to the compound of [Formula 1] or a salt thereof. The second therapeutic agent may be used in combination or sequentially with the pharmaceutical composition of the present invention.

Specifically, anticancer agents included in the second therapeutic agent include alkylating agents, antimetabolites, folic acid analogs, pyrimidine analogs, purine analogs and related inhibitors, vinca alkaloids, epipodophyllotoxins, antibiotics, L-asparaginase, topoisomerase inhibitors, Interferon, platinum coordination complex, anthracendione-substituted urea, methyl hydrazine derivatives, adrenocortical inhibitors, adrenocorticosteroids, progestins, estrogens, antiestrogens, androgens, antiandrogens, gonadotropin-releasing hormone analogs, and the like. Specifically, gemcitabine, gefinitib, cisplatin, oxaliplatin, paclitaxel, capecitabine, vorinistat, entinostat ) And 5-FU (5-fluorouracil) may be one or more selected from, but is not limited thereto.

Synthetic compound provided in one aspect of the present invention is excellent in angiogenesis inhibitory activity, so it is useful for the prevention or treatment of neovascular eye disease including cancer or macular degeneration, retinopathy of prematurity, or diabetic retinopathy. It can be used, and this is supported by Examples and Experimental Examples described later.

Hereinafter, the present invention will be described in detail through examples and experimental examples.

However, the examples and experimental examples described below are only to specifically illustrate the present invention in one aspect, and the present invention is not limited thereto.

<Synthesis Example>

Substance and method

All starting materials and reagents used in the following examples were obtained from commercial suppliers and used without further purification. Reactions sensitive to air and moisture were carried out under a nitrogen atmosphere. Flash column chromatography was performed using silica gel 60 (230-400 mesh, Merck) with the indicated solvent. Thin layer chromatography (TLC) was performed using a 0.25 mm silica gel plate (Merck). ¹ H and ¹³ C{ ¹ H} NMR spectra are CDCl ₃ or DMSO- d ₆ Recorded on Bruker 600 MHz as heavy solution. ¹ H NMR data were recorded in the order of chemical shift, multiplicity (s, singlet; d, doublet; t, triplet; m, multiplet and/or multiple resonance), number of protons, and binding constant ( J ; Hz).

1-(6-hydroxy-2,3,4-trimethoxyphenyl)ethan-1-one (2a)

BF ₃ ·Et ₂ O (0.07 ml) was added to a solution of 3,4,5-trimethoxyphenol (1a) (1.2 g, 6.6 mmol) in acetic anhydride (2 ml) at 0°C. The resulting mixture was stirred at 60° C. for 3 hours. The mixture was diluted with ethyl acetate (10 ml) at 0°C, and water (10 ml) and TEA (1 ml) were added at room temperature, followed by stirring for 1 hour. The mixture was diluted with ethyl acetate (10 mL) and washed with water. The organic layer was dried over anhydrous Na ₂ SO ₄ and concentrated under reduced pressure. The residue was purified through flash column chromatography using silica gel (ethyl acetate: n -hexane = 1: 5) to obtain 1-(6-hydroxy-2,3,4-trimethoxyphenyl)ethan-1-one. (2a) (1.4 g, 95%) was obtained.

¹ H NMR (600 MHz, CDCl ₃ ) δ 6.22 (s, 1H), 3.97 (s, 3H), 3.87 (s, 3H), 3.77 (s, 3H), 2.64 (s, 3H). ¹³ C{ ¹ H} NMR (150 MHz, CDCl ₃ ) δ 203.4, 161.9, 160.1, 155.2, 134.7, 108.4, 96.1, 61.0, 60.9, 56.1, 31.9.

1-(3,6-dihydroxy-2,4-dimethoxyphenyl)ethan-1-one (2b)

In a solution of 2,6-dimethoxybenzene-1,4-diol (1b) (3.0 g, 17.63 mmol) in chloroform (20 ml) at 0°C, acetic anhydride (1.7 ml, 17.98 mmol) and BF ₃ ·Et ₂ O (11 mL, 88.15 mmol) was added. After stirring at 70° C. for 24 hours, the mixture was cooled at room temperature and mixed with ice-cold water. The mixture was diluted with ethyl acetate (10 mL) and washed with water. The organic layer was dried over anhydrous Na ₂ SO ₄ and concentrated under reduced pressure. The residue was purified through flash column chromatography using silica gel (ethyl acetate: n -hexane = 1: 5) to obtain 1-(3,6-dihydroxy-2,4-dimethoxyphenyl)ethan-1-one. (2b) (3.15 g, 84%) was obtained.

¹ H NMR (600 MHz, CDCl ₃ ) δ 13.18 (s, 1H), 6.26 (s, 1H), 5.13 (s, 1H), 3.95 (s, 3H), 3.92 (s, 4H), 2.67 (s, 3H). ¹³ C{ ¹ H} NMR (150 MHz, CDCl ₃ ) δ 203.6, 159.1, 154.2, 147.5, 131.4, 108.7, 95.7, 60.9, 56.4, 31.8

5,6,7-trimethoxroman-4-one (3a)

1-(6-hydroxy-2,3,4-trimethoxyphenyl)ethan-1-one (2a) (766 mg, 3.39 mmol) was dissolved in toluene (5 ml) solution N,N -dimethoxy Formamide dimethylacetal (0.9 ml, 9.79 mmol) was added. After the mixture was stirred at 80°C for 20 hours, cooled at room temperature, and concentrated hydrochloric acid (6 ml) was added at 0°C. After stirring for 1 hour at 50° C., the mixture was diluted with ethyl acetate (10 ml) and washed with water. The organic layer was dried over anhydrous Na ₂ SO ₄ and concentrated under reduced pressure. The residue was 5,6,7-trimethoxy- 4H -chromen-4-one (612 mg) through flash column chromatography using silica gel (ethyl acetate: n -hexane:methanol=1:5:0.1). , 83%) was obtained.

5,6,7-trimethoxy-4 H -chromen-4-one (500 mg, 2.11 mmol) and 10% Pd/C (22 mg, 0.2 mmol) in anhydrous methanol (3 ml) solution Replaced with hydrogen gas. After stirring at room temperature for 1 hour, the mixture was diluted with ethyl acetate (10 ml) and filtered with a celite pad. The organic layer was concentrated under reduced pressure, and the residue was purified through flash column chromatography using silica gel (ethyl acetate: n -hexane = 1: 3), and 5,6,7-trimethoxchroman-4-one (3a) ( 469 mg, 94%) was obtained.

¹ H NMR (CDCl ₃ , 600 MHz) δ 6.22 (s, 1H), 4.42 (t, 2H, J = 6.6 Hz), 3.88 (s, 3H), 3.84 (s, 3H), 3.77 (s, 3H) , 2.69 (t, 2H, J = 6.6 Hz). ¹³ C{ ¹ H} NMR (150 MHz, CDCl ₃ ) δ 189.1, 160.0, 159.3, 154.3, 137.3, 109.6, 96.0, 66.8, 61.5, 61.3, 56.0, 38.7.

6-hydroxy-5,7-dimethoxy-4 H -Chroman-4-one (3b)

1-(3,6-dihydroxy-2,4-dimethoxyphenyl)ethan-1-one (2b) (3.15 g, 14.85 mmol) was dissolved in DME (20 mL) solution of N,N -dime Toxicformamide dimethylacetal (5.92 mL, 44.5 mmol) was added. After stirring at 80°C for 20 hours, the mixture was cooled at room temperature, and concentrated hydrochloric acid (6 ml) was added at 0°C. After stirring for 1 hour at 50° C., the mixture was diluted with ethyl acetate and washed with water. The organic layer was dried over anhydrous Na ₂ SO ₄ and concentrated under reduced pressure. The residue was purified through flash column chromatography using silica gel (ethyl acetate: n -hexane:methanol=1:5:0.1), and 6-hydroxy-5,7-dimethoxy- 4H -chroman-4- On (2.5 g, 77%) was obtained.

¹ H NMR (600 MHz, CDCl ₃ ) δ 7.67 (d, 1H, J = 5.9 Hz), 6.70 (s, 1H), 6.20 (d, 1H, J = 5.9 Hz), 5.97 (s, 1H), 3.98 (s, 3H), 3.98 (s, 3H). ¹³ C{ ¹ H} NMR (150 MHz, CDCl ₃ ) δ 176.3, 153.4, 152.4, 152.4, 144.1, 136.9, 113.6, 113.5, 62.6, 56.6.

6-hydroxy-5,7-dimethoxy-4 H -chromen-4-one (2.5 g, 11.25 mmol) and 10% Pd/C (22 mg, 0.2 mmol) dissolved in anhydrous methanol (3 ml) The solution was replaced with hydrogen gas. After stirring for 1 hour at room temperature, the mixture was diluted with ethyl acetate (10 ml) and filtered with a celite pad. The organic layer was concentrated under reduced pressure, and the residue was purified through flash column chromatography using silica gel (ethyl acetate: n -hexane = 1: 2), and 6-hydroxy-5,7-dimethoxy-4 H -chromen-4 -On (3b) (2.29 g, 91%) was obtained.

¹ H NMR (600 MHz, CDCl ₃ ) δ 6.28 (s, 1H), 5.45 (s, 1H), 4.43 (t, 2H, J = 6.4 Hz), 3.92 (s, 3H), 3.92 (s, 3H) , 2.72 (t, 2H, J = 6.5 Hz). ¹³ C{ ¹ H} NMR (150 MHz, CDCl ₃ ) δ 189.4, 157.6, 153.9, 146.1, 133.8, 109.0, 96.2, 67.0, 61.9, 56.4, 38.8.

7-(benzyloxy)-5,6-dimethoxychroman-4-one (3c)

1- (4- (benzyloxy) -6-hydroxy-2,3-dimethoxy-phenyl) ethane-1-one (511 ㎎, 1.69 mmol) is dissolved in the DME (3 ㎖) was added N, N - dimethoxyethane Toxicformamide dimethylacetal (0.44 ml, 3.31 mmol) was added. After the mixture was stirred at 80°C for 20 hours, cooled at room temperature, and concentrated hydrochloric acid (6 ml) was added at 0°C. After stirring for 1 hour at 50° C., the mixture was diluted with ethyl acetate (10 ml) and washed with water. The organic layer was dried over anhydrous NaSO ₄ and concentrated under reduced pressure. The residue was subjected to flash column chromatography using silica gel (ethyl acetate: n -hexane: methanol = 1: 5: 0.1) to 7-benzyloxy-5,6-dimethoxy-4 H -chromen-4-one ( 500.3 mg, 95%) was obtained.

¹ H NMR (600 MHz, CDCl ₃ ) δ 7.62 (d, 1H, J = 5.4 Hz), 7.46 (d, 2H, J = 7.8 Hz), 7.42 (t, 2H, J = 7.2 Hz), 7.37 (t , 1H, J = 7.8 Hz), 6.71 (s, 1H), 6.17 (d, 1H, J = 6 Hz), 5.19 (s, 2H), 3.97 (s, 3H), 3.91 (s, 3H). ¹³ C{ ¹ H} NMR (150 MHz, CDCl ₃ ) δ 176.3, 156.8, 154.6, 153.0, 152.8, 140.7, 135.6, 128.8, 128.4, 127.3, 114.2, 113.8, 97.7, 70.9, 62.2, 61.5.

Anhydrous tetrahydrofuran (5 ml) solution in which 7-benzyloxy-5,6-dimethoxy-4H-chromen-4-one (500.3 mg, 1.6 mmol) and LiAlH (121 mg, 3.2 mmol) were dissolved After nitrogen substitution, the mixture was stirred at -60°C for 1 hour. After stopping the reaction by adding ice-cold water to the reaction mixture, it was diluted with ethyl acetate, washed with water and brine, dried over MgSO ₄ and concentrated under reduced pressure. The residue was purified through flash column chromatography using silica gel (ethyl acetate: n -hexane = 1: 3), and 7-(benzyloxy)-5,6-dimethoxychroman-4-one (3c) (415.5 Mg, 82.5%) was obtained.

¹ H NMR (600 MHz, CDCl ₃ ) δ 7.43 (t, 2H, J = 7.2 Hz), 7.40 (t, 2H, J = 7.2 Hz), 7.35 (t, 1H, J = 7.2 Hz), 6.29 (s , 1H), 5.12 (s, 2H), 4.42 (t, 2H, J = 6 Hz), 3.92 (s, 3H), 3.82 (s, 3H), 2.70 (t, 2H, J = 6.6 Hz). ¹³ C{ ¹ H} NMR (150 MHz, CDCl ₃ ) δ 189.2, 159.8, 158.4, 154.5, 137.7, 135.8, 128.7, 128.3, 127.2, 109.8, 97.4, 70.6, 66.9, 61.6, 61.3, 38.7.

6-(cyclopropylmethyl)-5,7-dimethoxychroman-4-one (3d)

In a solution of 6-hydroxy-5,7-dimethoxychroman-4-one (3b) (500 mg, 2.23 mmol) in acetonitrile (10 ml), cyclopropyl bromide (0.23 ml, 2.4 mmol) and Potassium carbonate (1.5 g, 11.15 mmol) was added. The mixture was refluxed for 3 hours. After cooling at room temperature, the mixture was diluted with ethyl acetate (10 mL) and washed with water. The organic layer was dried over anhydrous Na ₂ SO ₄ and concentrated under reduced pressure. The residue was purified through flash column chromatography using silica gel (ethyl acetate: n -hexane = 1: 2), and 6-(cyclopropylmethyl)-5,7-dimethoxychroman-4-one (3d) ( 571 mg, 92%) was obtained.

¹ H NMR (600 MHz, CDCl ₃ ) δ 6.22 (s, 1H), 4.41 (t, 2H, J = 6.4 Hz), 3.90 (s, 3H), 3.84 (s, 3H), 3.71 (d, 2H, J = 7.2 Hz), 2.69 (t, 2H, J = 6.4 Hz), 1.25 (m, 1H), 0.54 (m, 2H), 0.26 (m, 2H). ¹³ C{ ¹ H} NMR (150 MHz, CDCl ₃ ) δ 189.3, 160.0, 159.7, 154.6, 136.5, 109.7, 96.1, 78.7, 66.9, 61.5, 56.1, 38.8, 11.0, 3.1.

6,7-dimethoxychroman-4-one (3e)

1-(2-hydroxy-4,5-dimethoxyphenyl)ethan-1-one (2e) and N,N -dimethoxyformamide dimethylacetal for formation of chromen-4-one, followed by the above synthesis method By carrying out a hydrogenation reaction, 75% of 6,7-dimethoxychroman-4-one (3e) was obtained.

¹ H NMR (CDCl ₃ , 600 MHz) δ 7.30 (s, 1H), 6.43 (s, 1H), 4.52 (t, 2H, J = 6.6 Hz), 3.91 (s, 3H), 3.88 (s, 3H) , 2.76 (d, 2H, J = 6.6 Hz). ¹³ C{ ¹ H} NMR (150 MHz, CDCl ₃ ) δ 190.6, 158.4, 156.1, 144.5, 113.6, 106.8, 100.0, 67.6, 56.3, 56.2, 37.3.

(E)-3-(3'-hydroxy-4'-methoxybenzylidene)-5,6,7-trimethoxychroman-4-one (4a)

Isovanillin (170 mg, 1.1 mmol) and p -toluenesulfonic acid in a solution of 5,6,7-trimethoxroman-4-one (3a) (238 mg, 1.0 mmol) in benzene (25 ml) (20 mg, 0.1 mmol) was added at 0°C. After the mixture was refluxed for 12 hours and cooled at room temperature, the reaction mixture was concentrated under reduced pressure. The residue was purified through flash column chromatography using silica gel (ethyl acetate: n -hexane=1:1) to obtain (E)-3-(3'-hydroxy-4'-methoxybenzylidene)-5, 6,7-trimethoxychroman-4-one (4a) (215 mg, 58%) was obtained.

1H NMR (600 MHz, CDCl3) δ 7.74 (s, 1H), 6.85 (m, 3H), 6.26 (s, 1H), 5.67 (s, 1H), 5.24 (d, 2H, J = 1.8 Hz), 3.98 (s, 3H), 3.94 (s, 3H), 3.88 (s, 3H), 3.83 (s, 3H). 13C{1H} NMR (150 MHz, CDCl3) δ 179.5, 159.3, 159.1, 154.7, 147.5, 145.5, 137.8, 136.2, 130.1, 128.1, 123.2, 115.7, 110.5, 96.1, 67.6, 61.6, 61.3, 60.3, 60.3, 56.0, 55.9. HRMS (EI): mass calcd for C ₂₀ H ₂₀ O ₇ [M] ⁺ , 372.1209; found, 372.1208.

(E)-6-hydroxy-3-(3-hydroxy-4-methoxybenzylidene)-5,7-dimethoxychroman-4-one (4b)

6-hydroxy-5,7-dimethoxychroman-4-one (3b) (33.5 mg, 0.15 mmol) was dissolved in toluene (3 ml) solution, isovanillin (23 mg, 0.15 mmol) and p -toluene Sulfonic acid (3.0 mg, 0.02 mmol) was added at 0°C. After the mixture was refluxed for 12 hours and cooled at room temperature, the reaction mixture was concentrated under reduced pressure. The residue was purified through flash column chromatography using silica gel (ethyl acetate: n -hexane = 1: 1) to obtain (E)-6-hydroxy-3-(3-hydroxy-4-methoxybenzylidene) -5,7-dimethoxychroman-4-one (4b) (42 mg, 26%) was obtained.

¹ H NMR (600 MHz, CDCl ₃ ) δ 7.74 (s, 1H), 6.88 (m, 3H), 6.28 (s, 1H), 5.77 (s, 1H), 5.56 (s, 1H), 5.23 (d, 2H, J = 1.7 Hz), 3.98 (s, 3H), 3.93 (s, 3H), 3.91 (s, 3H). ¹³ C{ ¹ H} NMR (150 MHz, CDCl ₃ ) δ 179.7, 156.7, 153.6, 147.6, 146.5, 145.6, 136.4, 134.0, 130.1, 128.1, 123.3, 115.8, 110.6, 96.0, 77.3, 77.0, 76.8, 67.6 , 61.7, 56.3, 56.0.

(E)-7-(benzyloxy)-3-(3-hydroxy-4-methoxybenzylidene)-5,6-dimethoxychroman-4-one (4c)

7-(benzyloxy)-5,6-dimethoxychroman-4-one (3c) (271.6 mg, 0.86 mmol) was dissolved in toluene (3 ml) solution, isovanillin (156.3 mg, 0.99 mmol) and p -Toluenesulfonic acid (19.3 mg, 0.10 mmol) was added at 0°C. The mixture was refluxed for 12 hours, cooled at room temperature, and the reaction mixture was concentrated under reduced pressure. The residue was purified through flash column chromatography using silica gel (ethyl acetate: n -hexane = 1: 3) to obtain (E)-7-(benzyloxy)-3-(3-hydroxy-4-methoxybenzyl Liden)-5,6-dimethoxychroman-4-one (4c) (227.1 mg, 59%, BORSM 76%) was obtained.

¹ H NMR (600 MHz, CDCl ₃ ) δ 7.74 (s, 1H), 7.44 (d, 2H, J = 7.1 Hz), 7.40 (t, 2H, J = 7.5 Hz), 7.34 (m, 1H), 6.90 (d, 1H, J = 8.3 Hz), 6.87 (d, 1H, J = 2.0 Hz), 6.84 (q, 1H, J = 3.5 Hz), 6.31 (s, 1H), 5.68 (s, 1H), 5.22 (d, 2H, J = 1.7 Hz), 5.14 (s, 2H), 4.00 (s, 3H), 3.94 (s, 3H), 3.85 (s, 3H). ¹³ C{ ¹ H} NMR (150 MHz, CDCl ₃ ) δ 179.6, 159.2, 158.3, 154.9, 147.5, 145.6, 138.2, 136.3, 135.9, 130.2, 128.7, 128.3, 128.2, 127.3, 123.3, 115.8, 110.9, 110.6 , 97.5, 70.7, 67.7, 61.7, 61.4, 56.0.

( E )-3-(3-hydroxy-4-methoxybenzylidene)-6,7-dimethoxychroman-4-one (4e)

6,7-dimethoxychroman-4-one (3e) (396 mg, 1.9 mmol) was dissolved in toluene (10 ml) in isovanillin (234 mg, 1.54 mmol) and p -toluenesulfonic acid (38 mg). , 0.2 mmol) was added at 0°C. After the mixture was refluxed for 12 hours and cooled at room temperature, the reaction mixture was concentrated under reduced pressure. The residue was purified through flash column chromatography using silica gel (ethyl acetate: n -hexane=1:1) to ( E )-3-(3-hydroxy-4-methoxybenzylidene)-6,7- Dimethoxychroman-4-one (4e) (383 mg, 59%, BORSM, 95%) was obtained.

¹ H NMR (600 MHz, CDCl ₃ ) δ 7.76 (s, 1H), 6.92 (d, 1H, J = 7.8 Hz), 6.90 (d, 1H, J = 2.4 Hz), 6.87 (dd, 1H, J = 7.8 and 1.8 Hz), 6.43 (s, 1H), 5.68 (s, 1H), 5.35 (d, 2H, J = 1.8 Hz), 3.95 (s, 3H), 3.92 (s, 3H), 3.92 (s, 3H). ¹³ C{ ¹ H} NMR (150 MHz, CDCl ₃ ) δ 180.9, 157.6, 156.1, 147.6, 145.6, 144.9, 136.6, 129.4, 128.1, 123.3, 115.9, 114.2, 110.6, 107.5, 100.1, 68.1, 56.3, 56.3 , 56.0.

(E)-6-(cyclopropylmethoxy)-3-(3-hydroxy-4-methoxybenzylidene)-5,7-dimethoxychroman-4-one (20) (SH-19019)

6-(cyclopropylmethoxy)-5,7-dimethoxychroman-4-one (3d) (571 mg, 2.05 mmol) was dissolved in toluene (10 ml) solution isovanillin (312 mg, 2.05 mmol) And p -toluenesulfonic acid (36 mg, 0.21 mmol) were added at 0°C. After the mixture was refluxed for 12 hours and cooled at room temperature, the reaction mixture was concentrated under reduced pressure. The residue was purified through flash column chromatography using silica gel (ethyl acetate: n -hexane = 1: 1) to obtain (E)-6-(cyclopropylmethoxy)-3-(3-hydroxy-4-me). Toxoxybenzylidene)-5,7-dimethoxychroman-4-one (20) (250 mg, 30%) was obtained.

6-(cyclopropylmethoxy)-3-(3-hydroxy-4-methoxybenzyl)-5,7-dimethoxychroman-4-one (21) (SH-19020)

To a solution of 3-benzylidene-chroman-4-one (20) (72 mg, 0.17 mmol) in anhydrous methanol (10 ml) was added 10% Pd/C (9 mg, 0.09 mmol) and hydrogenated. . After stirring at room temperature for 2 hours, the reaction mixture was diluted with ethyl acetate, filtered with a Celite pad, and concentrated under reduced pressure. The residue was purified through flash column chromatography using silica gel (ethyl acetate: n -hexane = 1: 2) to obtain 6-(cyclopropylmethoxy)-3-(3-hydroxy-4-methoxybenzyl)- 5,7-dimethoxychroman-4-one (21) (SH-19020) (49 mg, 70%) was obtained.

5-((6-(cyclopropylmethoxy)-5,7-dimethoxychroman-3-yl)methyl)-2-methoxyphenol ((38) (SH-19021)

To a solution of 3-benzylidene-chroman-4-one (20) (252.3 mg, 0.61 mmol) in anhydrous methanol (10 mL) was added 10% Pd/C (325 mg, 0.3 mmol) and hydrogenated. . After stirring at room temperature for 17 hours, the reaction mixture was diluted with ethyl acetate, filtered with a Celite pad, and concentrated under reduced pressure. The residue was purified through flash column chromatography using silica gel (ethyl acetate: n -hexane = 1: 2), and 5-((6-(cyclopropylmethoxy)-5,7-dimethoxychroman-3- Il)methyl)-2-methoxyphenol (38) (SH-19021) (109.2 mg, 45%) was obtained.

3-(3-hydroxy-4-methoxybenzyl)-5,7-dimethoxychroman-6-ol (39) (SH-19018)

(E)-6-hydroxy-3-(3-hydroxy-4-methoxybenzylidene)-5,7-dimethoxychroman-4-one (4b) (33 mg, 0.09 mmol) was dissolved 10% Pd/C (21 mg, 0.02 mmol) was added to anhydrous methanol (3 ml) solution, followed by hydrogen substitution. After stirring at room temperature for 17 hours, the reaction mixture was diluted with ethyl acetate, filtered with a Celite pad, and concentrated under reduced pressure. The residue was purified through flash column chromatography using silica gel (ethyl acetate: n -hexane = 1: 3) to obtain 3-(3-hydroxy-4-methoxybenzyl)-5,7-dimethoxychroman- 6-ol (39) (20 mg, 60%) was obtained.

7-hydroxy-3-(3-hydroxy-4-methoxybenzyl)-5,6-dimethoxychroman-4-one (5c).

(E)-7-(benzyloxy)-3-(3-hydroxy-4-methoxybenzylidene)-5,6-dimethoxychroman-4-one (4c) (0.27 g, 0.60 mmol) 10% Pd/C (64 mg, 0.06 mmol) was added to the dissolved anhydrous methanol (3 ml) solution, followed by hydrogen substitution. After stirring at room temperature for 17 hours, the reaction mixture was diluted with ethyl acetate, filtered with a Celite pad, and concentrated under reduced pressure. The residue was purified through flash column chromatography using silica gel (ethyl acetate: n -hexane = 1: 3) to obtain 7-hydroxy-3-(3-hydroxy-4-methoxybenzyl)-5,6- Dimethoxychroman-4-one (5c) (0.20 mg, 94%) was obtained.

¹ H NMR (600 MHz, CDCl ₃ ) δ 6.79 (q, 2H, J = 4.9 Hz), 6.71 (d, 1H, J = 2.0 Hz), 6.33 (d, 1H, J = 5.9 Hz), 6.31 (s , 1H), 5.59 (t, 1H, J = 2.0 Hz), 4.25 (q, 1H, J = 5.2 Hz), 4.07 (q, 1H, J = 6.3 Hz), 3.92 (s, 3H), 3.91 (s , 3H), 3.87 (s, 3H), 3.16 (q, 1H, J = 6.1 Hz), 2.73 (m, 1H), 2.59 (q, 1H, J = 8.2 Hz). ¹³ C{ ¹ H} NMR (150 MHz, CDCl ₃ ) δ 191.6, 159.9, 155.6, 153.5, 145.7, 145.3, 135.2, 131.7, 120.6, 115.2, 110.8, 108.7, 98.9, 68.9, 61.6, 61.5, 56.0, 48.4 , 32.2. HRMS (ESI): mass calcd for C ₁₉ H ₂₀ O ₇ [M + H] ⁺ , 361.1287; found, 361.1270.

5-((6,7-dimethoxychroman-3-yl)methyl)-2-methoxyphenol (41) (SH-18089)

(E)-3-(3-hydroxy-4-methoxybenzylidene)-6,7-dimethoxychroman-4-one (4e) (12.6 mg, 0.04 mmol) dissolved in anhydrous methanol (3 ml) ) 10% Pd/C (7.8 mg, 0.01 mmol) was added to the solution, followed by hydrogen substitution. After stirring at room temperature for 17 hours, the reaction mixture was diluted with ethyl acetate, filtered with a Celite pad, and concentrated under reduced pressure. The residue was purified through flash column chromatography using silica gel (ethyl acetate: n -hexane = 1: 3) to obtain 5-((6,7-dimethoxychroman-3-yl)methyl)-2-methoxy Phenol (41) (8.7 mg, 72%) was obtained.

3-(3'-hydroxy-4'-methoxybenzyl)-5,6,7-trimethoxychroman-4-one (SH-11008).

3-(3'-hydroxy-4'-methoxybenzyl)-5,6,7-trimethoxychroman- 4-one (4a) (415 mg, 1.2 mmol) dissolved in anhydrous methanol (3 ml) ) 5% Pd/C (59 mg) was added to the solution, followed by hydrogen substitution. After stirring at room temperature for 17 hours, the reaction mixture was diluted with ethyl acetate, filtered with a Celite pad, and concentrated under reduced pressure. The residue was purified through flash column chromatography using silica gel (ethyl acetate: n -hexane = 1: 1) to obtain 3-(3'-hydroxy-4'-methoxybenzyl)-5,6,7-tri Methoxychroman-4-one (SH-11008) (327 mg, 78%) was obtained.

¹ H NMR (400 MHz, CDCl ₃ ) δ 7.24 (s, 1H), 6.83 (d, 1H, J = 7.8 Hz), 6.71 (d, 2H, J = 1.9 Hz), 6.23 (s, 1H), 5.53 (s, 1H), 4.23 (m, 1H), 4.10 (m, 1H), 3.91 (s, 3H), 3.85 (d, 6H, J = 1.9 Hz), 3.79 (s, 3H), 3.16 (m, 1H), 2.70 (m, 1H), 2.63 (m, 1H). ¹³ C{ ¹ H} NMR (100 MHz, CDCl ₃ ) δ 191.3, 159.6, 159.2, 154.4, 146.5, 144.2, 137.4, 130.2, 121.8, 114.3, 111.4, 108.6, 95.9, 69.0, 61.5, 61.2, 56.0, 55.9 , 48.5, 32.5. HRMS (ESI): mass calcd for C ₂₀ H ₂₂ O ₇ [M] ⁺ , 375.1444; found, 375.1432.

2-methoxy-5-((5,6,7-trimethoxy-4-oxochroman-3-yl)methyl)phenyl dimethyl-L-phenylalaninate (1) (SH-18070)

3-(3-hydroxy-4-methoxybenzyl)-5,6,7-trimethoxychroman-4-one (SH-11008) (21.2 mg, 0.06 mmol) in dichloromethane (1 ml) ) N,N -dimethyl-L-phenylalanine (13 mg, 0.07 mmol), EDCI (11 mg, 0.084 mmol) and DMAP (1.4 mg, 0.01 mmol) were added to the solution. After stirring for 17 hours, the reaction mixture was diluted with dichloromethane, washed with water and brine, dried over MgSO ₄ and concentrated under reduced pressure. The residue was purified through flash column chromatography using silica gel (ethyl acetate: n -hexane = 1: 2) to obtain 2-methoxy-5-((5,6,7-trimethoxy-4-oxochroman). -3-yl)methyl)phenyl dimethyl-L-phenylalaninate (1) (27.8 mg, 89%) was obtained.

2-methoxy-5-((5,6,7-trimethoxy-4-oxochroman-3-yl)methyl)phenyl5-(1,2-dithiolane-3-yl)pentano Eight(2) (SH-19028)

3-(3'-hydroxy-4'-methoxybenzyl)-5,6,7-trimethoxychroman-4-one (SH-11008) (21.7 mg, 0.06 mmol) in dichloromethane ( 1 ml) solution was added α -lipoic acid (75 mg, 0.19 mmol), EDCI (16.5 mg, 0.09 mmol) and DMAP (1.5 mg, 0.01 mmol). After stirring for 17 hours, the reaction mixture was diluted with dichloromethane, washed with water and brine, dried over MgSO ₄ and concentrated under reduced pressure. The residue was purified through flash column chromatography using silica gel (ethyl acetate: n -hexane = 1: 3) to obtain 2-methoxy-5-((5,6,7-trimethoxy-4-oxochroman). -3-yl)methyl)phenyl5-(1,2-dithiolane-3-yl)pentanoate(2) (SH-19028) (31 mg, 95%) was obtained.

2-methoxy-5-((5,6,7-trimethoxychroman-3-yl)methyl)phenol (SH-17059)

(E)-3-(3'-hydroxy-4'-methoxybenzylidene)-5,6,7-trimethoxychroman-4-one (4a) (22 0 mg, 0.59 mmol) is dissolved 10% Pd/C (60 mg, 0.06 mmol) was added to the resulting anhydrous methanol (1 ml) solution, followed by hydrogen substitution. After stirring at room temperature for 17 hours, the reaction mixture was diluted with ethyl acetate, filtered through a Celite pad, and concentrated under reduced pressure. The residue was purified through flash column chromatography using silica gel (ethyl acetate: n -hexane = 1: 3) to obtain 2-methoxy-5-((5,6,7-trimethoxychroman-3-yl). )Methyl)phenol (SH-17059) (190 mg, 89%) was obtained.

¹ H NMR (600 MHz, CDCl ₃ ) δ 6.79 (m, 2H), 6.67 (dd, 1H, J = 7.8 and 1.8 Hz), 6.19 (s, 1H), 5.62 (s, 1H), 4.09 (d, 1H, J = 10.8 Hz), 3.87 (s, 3H), 3.85 (s, 3H), 3.79 (s, 6H), 3.74 (dd, 1H, J = 10.2 and 8.4 Hz), 2.77 (dd, 1H, J = 16.8 and 5.4 Hz), 2.58 (m, 2H), 2.34 (dd, 1H, J = 16.2 and 8.4 Hz), 2.23 (m, 1H). ¹³ C { ¹ H} NMR (150 MHz, CDCl ₃ ) δ 152.2, 151.6, 150.7, 145.5, 145.1, 135.8, 132.7, 120.4, 115.2, 110.6, 107.3, 95.9, 69.6, 61.0, 60.6, 56.0, 55.8, 37.6 , 33.6, 25.5.

2-methoxy-5-((5,6,7-trimethoxychroman-3-yl)methyl)phenyl-5-(1,2-dithiolan-3-yl)pentanoate (22) (SH-19029)

2-methoxy-5-((5,6,7-trimethoxychroman-3-yl)methyl)phenol (SH-17059) (192 mg, 0.53 mmol) in dichloromethane (5 ml) solution To α-lipoic acid (165 mg, 0.80 mmol), EDCI (153 mg, 0.80 mmol) and DMAP (13 mg, 0.1 mmol) were added. After stirring for 17 hours, the reaction mixture was diluted with dichloromethane, washed with water and brine, dried over MgSO ₄ and concentrated under reduced pressure. The residue was purified through flash column chromatography using silica gel (ethyl acetate: n -hexane = 1: 2) to obtain 2-methoxy-5-((5,6,7-trimethoxychroman-3-yl). )Methyl)phenyl-5-(1,2-dithiolan-3-yl)pentanoate (22) (269.5 mg, 90%) was obtained.

2-methoxy-5-((5,6,7-trimethoxychroman-3-yl)methyl)phenyl( tert -Butoxycarbonyl)-L-phenylalaninate (23) (SH-17060)

2-methoxy-5-((5,6,7-trimethoxychroman-3-yl)methyl)phenol (SH-17059) (407 mg, 1.13 mmol) in dichloromethane (10 ml) solution To Boc- L- Phe-OH (583 mg, 1.69 mmol), EDCI (325 mg, 1.69 mmol) and DMAP (28 mg, 0.2 mmol) were added. After stirring for 17 hours, the reaction mixture was diluted with dichloromethane, washed with water and brine, dried over MgSO ₄ and concentrated under reduced pressure. The residue was purified through flash column chromatography using silica gel (ethyl acetate: n -hexane = 1: 2) to obtain 2-methoxy-5-((5,6,7-trimethoxychroman-3-yl). )Methyl)phenyl (tert-butoxycarbonyl)-L-phenylalaninate (23) (SH-17060) (653 mg, 93%) was obtained.

Carbamate

2-methoxy-5-((5,6,7-trimethoxy-4-oxochroman-3-yl)methyl)phenyl(( S )-1-phenylethyl)carbamate (3) (SHA-001)

3-(3-hydroxy-4-methoxybenzyl)-5,6,7-trimethoxychroman-4-one (SH-11008) (40 mg, 0.11 mmol) in dichloromethane (2 ml) ) To the solution, ( S )-(-)-α-methoxybenzyl isocyanate (19 mg, 0.13 mmol) and Et ₃ N (62 μl, 0.43 mmol) were added at 0°C. After the mixture was stirred at room temperature for 3 hours, the reaction mixture was diluted with ethyl acetate, dried over MgSO ₄ and concentrated under reduced pressure. The residue was purified through flash column chromatography using silica gel (ethyl acetate: n -hexane = 1: 3) to obtain 2-methoxy-5-((5,6,7-trimethoxy-4-oxochroman). -3-yl)methyl)phenyl(( S )-1-phenylethyl)carbamate (3) (52.9 mg, 95%) was obtained.

2-methoxy-5-((5,6,7-trimethoxy-4-oxochroman-3-yl)methyl)phenyl benzylcarbamate (4) (SHA-003)

3-(3-hydroxy-4-methoxybenzyl)-5,6,7-trimethoxybenzyl-4-one (SH-11008) (40 mg, 0.12 mmol) in dichloromethane (2 ml) Benzyl isocyanate (17 mg, 0.13 mmol) and Et ₃ N (62 µl, 0.43 mmol) were added to the solution at 0°C. After the mixture was stirred at room temperature for 3 hours, the reaction mixture was diluted with ethyl acetate, dried over MgSO ₄ and concentrated under reduced pressure. The residue was purified through flash column chromatography using silica gel (ethyl acetate: n -hexane = 1: 3) to obtain 2-methoxy-5-((5,6,7-trimethoxy-4-oxochroman). -3-yl)methyl)phenyl benzylcarbamate (4) (51.5 mg, 95%) was obtained.

2-methoxy-5-((5,6,7-trimethoxy-4-oxochroman-3-yl)methyl)phenyl(( R )-1-phenylethyl)carbamate (5) (SHA-004)

3-(3-hydroxy-4-methoxybenzyl)-5,6,7-trimethoxychroman-4-one (SH-11008) (40 mg, 0.11 mmol) in dichloromethane (2 ml) ) To the solution ( R )-(+)- α -methyl benzyl isocyanate (19 mg, 0.13 mmol) and Et ₃ N (62 µl, 0.43 mmol) were added at 0°C. After the mixture was stirred at room temperature for 3 hours, the reaction mixture was diluted with ethyl acetate, dried over MgSO ₄ and concentrated under reduced pressure. The residue was purified through flash column chromatography using silica gel (ethyl acetate: n -hexane = 1: 2) to obtain 2-methoxy-5-((5,6,7-trimethoxy-4-oxochroman). -3-yl)methyl)phenyl(( R )-1-phenylethyl)carbamate (5) (51.8 mg, 93%) was obtained.

2-methoxy-5-((5,6,7-trimethoxy-4-oxochroman-3-yl)methyl)phenyl(4-fluorophenethyl)carbamate (6) (SHA-007)

3-(3-hydroxy-4-methoxybenzyl)-5,6,7-trimethoxychroman-4-one (SH-11008) (40 mg, 0.11 mmol) in dichloromethane (2 ml) ) 4-fluorophenethyl isocyanate (21 mg, 0.13 mmol) and Et ₃ N (62 µl, 0.43 mmol) were added to the solution at 0°C. After the mixture was stirred at room temperature for 3 hours, the reaction mixture was diluted with ethyl acetate, dried over MgSO ₄ and concentrated under reduced pressure. The residue was purified through flash column chromatography using silica gel (ethyl acetate: n -hexane = 1: 3) to obtain 2-methoxy-5-((5,6,7-trimethoxy-4-oxochroman). -3-yl)methyl)phenyl(4-fluorophenethyl)carbamate (6) (55.9 mg, 97%) was obtained.

2-methoxy-5-((5,6,7-trimethoxy-4-oxochroman-3-yl)methyl)phenyl(1-benzylpiperidin-4-yl)carbamate (7) ( SHA-014)

3-(3-hydroxy-4-methoxybenzyl)-5,6,7-trimethoxychroman-4-one (SH-11008) (20 mg, 0.05 mmol) in dichloromethane (2 ml) ) Triphosgene (19 mg, 0.06 mmol) and TEA (30 µl, 0.21 mmol) were added to the solution at 0°C. After stirring at room temperature for 1 hour, 1-benzyl piperidin-4-amine (13 µl, 0.06 mmol) was added, followed by stirring at room temperature for 48 hours. After the mixture was concentrated under reduced pressure, the residue was purified through flash column chromatography using silica gel (ethyl acetate: n -hexane = 1: 3) to obtain 2-methoxy-5-((5,6,7-trimethoxy). -4-oxochroman-3-yl)methyl)phenyl(1-benzylpiperidin-4-yl)carbamate (7) (11 mg, 34%) was obtained.

Methyl ((2-methoxy-5-((5,6,7-trimethoxy-4-oxochroman-3-yl)methyl)phenoxy)carbonyl)-L-phenylalaninate (8) (SHA-028)

3-(3-hydroxy-4-methoxybenzyl)-5,6,7-trimethoxychroman-4-one (SH-11008) (42 mg, 0.11 mmol) in dichloromethane (2 ml) ) TEA (62 µl, 0.44 mmol) and methyl (S)-2-isocyanato-3-phenylpropanoate (26 mg, 0.13 mmol) were added to the solution at 0°C. The mixture was stirred at room temperature for 5 hours and then concentrated under reduced pressure. The residue was purified through flash column chromatography using silica gel (ethyl acetate: n -hexane = 1: 3) to obtain methyl ((2-methoxy-5-((5,6,7-trimethoxy-4- Oxochroman-3-yl)methyl)phenoxy)carbonyl)-L-phenylalaninate (8) (48 mg, 74%) was obtained.

2-methoxy-5-((5,6,7-trimethoxy-4-oxochroman-3-yl)methyl)phenyl diethylcarbamate (9) (SHA-029)

3-(3-hydroxy-4-methoxybenzyl)-5,6,7-trimethoxychroman-4-one (SH-11008) (31 mg, 0.08 mmol) in dichloromethane (2 ml) ) Triphosgene (12 mg, 0.04 mmol) and TEA (22 µl, 0.16 mmol) were added to the solution at room temperature. The mixture was stirred at room temperature for 12 hours and then concentrated under reduced pressure. The residue was purified through flash column chromatography using silica gel (ethyl acetate: n -hexane = 1: 3) to obtain 2-methoxy-5-((5,6,7-trimethoxy-4-oxochroman). -3-yl)methyl)phenyl diethylcarbamate (9) (32 mg, 82%) was obtained.

Ethyl ((2-methoxy-5-((5,6,7-trimethoxy-4-oxochroman-3-yl)methyl)phenoxy)carbonyl)glycinate (10) (SHA-030 )

3-(3-hydroxy-4-methoxybenzyl)-5,6,7-trimethoxychroman-4-one (SH-11008) (50 mg, 0.13 mmol) in dichloromethane (2 ml) ) TEA (75 µl, 0.53 mmol) and ethyl 2-cyanatoacetate (21 mg, 0.16 mmol) were added to the solution at 0°C. The mixture was stirred at room temperature for 12 hours and then concentrated under reduced pressure. The residue was purified through flash column chromatography using silica gel (ethyl acetate: n -hexane = 1: 3) to obtain ethyl ((2-methoxy-5-((5,6,7-trimethoxy-4- Oxochroman-3-yl) Methyl)phenoxy)carbonyl)glycinate (10) (61 mg, 90%) was obtained.

tert-butyl ((2-methoxy-5-((5,6,7-trimethoxy-4-oxochroman-3-yl)methyl)phenoxy)carbonyl)-L-alaninate (11 ) (SH-19032).

THF (2 ml) in which 3-(3-hydroxy-4-methoxybenzyl)-5,6,7-trimethoxychroman-4-one (SH-11008) (42 mg, 0.11 mmol) was dissolved To the solution, tert-butyl((4-nitroethoxy)carbonyl)-L-alaninate (69 mg, 0.22 mmol) and DIEA (0.08 ml, 0.45 mmol) were added at room temperature. After refluxing for 17 hours, the reaction mixture was diluted with dichloromethane, washed with water and brine, dried over MgSO ₄ and concentrated under reduced pressure. The residue was purified through flash column chromatography using silica gel (ethyl acetate: n -hexane = 1: 2) to obtain tert-butyl ((2-methoxy-5-((5,6,7-trimethoxy- 4-oxochroman-3-yl)methyl)phenoxy)carbonyl)-L-alaninate (11) (24.6 mg, 40%) was obtained.

tert-butyl ((2-methoxy-5-((5,6,7-trimethoxy-4-oxochroman-3-yl)methyl)phenoxy)carbonyl)-L-valinate (12) (SH-19033)

THF (2 mL) in which 3-(3-hydroxy-4-methoxybenzyl)-5,6,7-trimethoxychroman-4-one (SH-11008) (41.3 mg, 0.11 mmol) was dissolved To the solution, tert -butyl((4-nitroethoxy)carbonyl)-L-valinate (74 mg, 0.22 mmol) and DIEA (0.08 ml, 0.44 mmol) were added at room temperature. After refluxing for 17 hours, the reaction mixture was diluted with dichloromethane, washed with water and brine, dried over MgSO ₄ and concentrated under reduced pressure. The residue was purified via flash column chromatography using silica gel (ethyl acetate: n -hexane = 1: 2) to obtain tert -butyl ((2-methoxy-5-((5,6,7-trimethoxy- 4-oxochroman-3-yl)methyl)phenoxy)carbonyl)-L-valinate (12) (42.8 mg, 68%) was obtained.

tert -Butyl N ⁶ -( tert -Butoxycarbonyl)-N ² -((2-methoxy-5-((5,6,7-trimethoxy-4-oxochroman-3-yl)methyl)phenoxy)carbonyl)-L-lysinate (13) (SH -19034))

1-옥시다인(1:1) (86 ㎎, 0.18 mmol)와 DIEA (0.065 ㎖, 0.37 mmol)를 상온에서 첨가하였다. 17시간 교반한 후에, 반응 혼합물을 디클로로메탄으로 희석하고 물 및 염수로 세척한 후, MgSO₄로 건조시키고 감압 하에서 농축시켰다. 잔여물은 실리카겔을 사용한 플래시 컬럼 크로마토그래피 (에틸 아세테이트: n-헥산 = 1 : 3)를 통해 정제하여 tert-부틸 N⁶-(tert-부톡시카보닐)-N²-((2-메톡시-5-((5,6,7-트리메톡시-4- 옥소크로만-3-일)메틸)페녹시)카보닐)-L-리시네이트 (13) (31.6 ㎎, 50%)를 수득하였다. THF (2 mL) in which 3-(3-hydroxy-4-methoxybenzyl)-5,6,7-trimethoxychroman-4-one (SH-11008) (35 mg, 0.09 mmol) was dissolved In solution tert -butyl N ⁶ -(tert-butoxycarbonyl)-N ² -((4-nitrophenoxy)carbonyl)-L-lysinate, methyl-

1-oxidyne (1:1) (86 mg, 0.18 mmol) and DIEA (0.065 ml, 0.37 mmol) were added at room temperature. After stirring for 17 hours, the reaction mixture was diluted with dichloromethane, washed with water and brine, dried over MgSO ₄ and concentrated under reduced pressure. The residue was purified through flash column chromatography using silica gel (ethyl acetate: n -hexane = 1: 3) to obtain tert -butyl N ⁶ -( tert -butoxycarbonyl) -N ² -((2-methoxy -5-((5,6,7-trimethoxy-4-oxochroman-3-yl)methyl)phenoxy)carbonyl)-L-lysinate (13) (31.6 mg, 50%) was obtained. I did.

tert -Butyl ((2-methoxy-5-((5,6,7-trimethoxy-4-oxochroman-3-yl)methyl)phenoxy)carbonyl)glycinate (14) (SH- 19035)

THF (5 ml) in which 3-(3-hydroxy-4-methoxybenzyl)-5,6,7-trimethoxychroman-4-one (SH-11008) (111 mg, 0.30 mmol) was dissolved To the solution, tert-butyl((4-nitrophenoxy)carbonyl)glycinate (176 mg, 0.60 mmol) and DIEA (0.2 ml, 1.2 mmol) were added at room temperature. After stirring for 17 hours, the reaction mixture was diluted with dichloromethane, washed with water and brine, dried over MgSO ₄ and concentrated under reduced pressure. The residue was purified via flash column chromatography using silica gel (ethyl acetate: n -hexane = 1: 2) to obtain tert -butyl ((2-methoxy-5-((5,6,7-trimethoxy- 4-oxochroman-3yl)methyl)phenoxy)carbonyl)glycinate (14) (69.7 mg, 44%) was obtained.

Methyl ((2-methoxy-5-((5,6,7-trimethoxy-4-oxochroman-3-yl)methyl)ethoxy)carbonyl)-L-methioninate (48) ( SH-19036 )

THF (2 ml) in which 3-(3-hydroxy-4-methoxybenzyl)-5,6,7-trimethoxychroman-4-one (SH-11008) (40 mg, 0.1 mmol) was dissolved Methyl((4-nitrophenoxy)carbonyl) -L -methioninate (66 mg, 0.2 mmol) and DIEA (0.051 mL, 0.3 mmol) were added to the solution at room temperature. After stirring for 17 hours, the reaction mixture was diluted with dichloromethane, washed with water and brine, dried over MgSO ₄ and concentrated under reduced pressure. The residue was purified through flash column chromatography using silica gel (ethyl acetate: n -hexane = 1: 4) to obtain methyl ((2-methoxy-5-((5,6,7-trimethoxy-4-)). Oxochroman-3-yl)methyl)ethoxy)carbonyl)-L-methioninate (48) (33.6 mg, 60%) was obtained.

¹ H NMR (600 MHz, CDCl ₃ ) δ 7.04 (d, 1H, J = 8.4 Hz), 6.97 (s, 1H), 6.89 (d, 1H, J = 7.8 Hz), 6.24 (s, 1H), 5.82 (bs, 1H), 4.54 (q, 1H, J = 6 Hz), 4.28 (dd, 1H, J = 11.4 and 3.6 Hz), 4.07 (m, 1H), 3.91 (s, 3H), 3.87 (s, 3H), 3.81 (s, 3H), 3.80 (s, 3H), 3.78 (s, 3H); 3.18 (dd, 1H, J =13.8 and 3.6 Hz), 2.74-2.70 (m, 1H), 2.63 (m , 3H), 2.24-2.21 (m, 1H), 2.11 (s, 3H), 2.07 (m, 1H); ¹³ C { ¹ H} NMR (150 MHz, CDCl ₃ ) δ 191.2, 172.2, 159.7, 159.4, 154.4, 153.9, 150.2, 139.7, 137.5, 130.9, 127.2, 123.8, 112.6, 108.6, 96.0, 69.0, 61.6, 61.3 , 56.1, 56.0, 53.3, 52.7, 48.2, 32.0, 31.8, 28.8, 15.5.

2-(((2-methoxy-5-((5,6,7-trimethoxychroman-3-yl)methyl)phenoxy)carbonyl)amino)ethyl)acrylate (24) (SHA- 031)

2-methoxy-5-((5,6,7-trimethoxychroman-3-yl)methyl)phenol (SH-17059) (200 mg, 0.55 mmol) in dichloromethane (10 ml) solution 2-isocyanatoethyl acrylate (117 mg, 0.83 mmol) and TEA (0.8 ml, 5.55 mmol) were added at 0°C. The reaction mixture was stirred at room temperature for 1 hour. The mixture was diluted with ethyl acetate (10 mL) and washed with water and brine. The organic layer was dried over anhydrous Na ₂ SO ₄ and concentrated under reduced pressure. The residue was purified through flash column chromatography using silica gel (ethyl acetate: n -hexane = 1: 5) to obtain 2-(((2-methoxy-5-((5,6,7-trimethoxy)). Man-3-yl)methyl)phenoxy)carbonyl)amino)ethyl) acrylate (24) (210 mg, 75%) was obtained.

2-(((2-methoxy-5-((5,6,7-trimethoxychroman-3-yl)methyl)phenoxy)carbonyl) glycinate (25) (SHA-032)

2-methoxy-5-((5,6,7-trimethoxychroman-3-yl)methyl)phenol (SH-17059) (200 mg, 0.55 mmol) in dichloromethane (10.0 ml) solution To butyl-2-isocyanatoacetate (130 mg, 0.83 mmol) and Et ₃ N (0.8 ml, 5.55 mmol) were added at 0°C. The reaction mixture was stirred at room temperature for 1 hour. The mixture was diluted with ethyl acetate (10.0 mL) and washed with water and brine. The organic layer was dried over anhydrous Na ₂ SO ₄ and concentrated under reduced pressure. The residue was purified through flash column chromatography using silica gel (ethyl acetate: n -hexane = 1: 5) to obtain 2-(((2-methoxy-5-((5,6,7-trimethoxy)). Man-3-yl)methyl)phenoxy)carbonyl) glycinate (25) (220 mg, 77%) was obtained.

2-methoxy-5-((5,6,7-trimethoxychroman-3-yl)methyl) phenyl allylcarbamate (26) (SHA-033)

2-methoxy-5-((5,6,7-trimethoxychroman-3-yl)methyl)phenol (SH-17059) (200 mg, 0.55 mmol) in dichloromethane (10.0 ml) solution 2-allyl isocyanate (69 mg, 0.83 mmol) and Et ₃ N (0.8 ml, 5.55 mmol) were added thereto at 0°C. The reaction mixture was stirred at room temperature for 1 hour. The mixture was diluted with ethyl acetate (10.0 mL) and washed with water and brine. The organic layer was dried over anhydrous Na ₂ SO ₄ and concentrated under reduced pressure. The residue was purified through flash column chromatography using silica gel (ethyl acetate: n -hexane = 1: 5) to obtain 2-methoxy-5-((5,6,7-trimethoxychroman-3-yl). )Methyl) phenyl allylcarbamate (26) (200 mg, 81%) was obtained.

2-methoxy-5-((5,6,7-trimethoxychroman-3-yl)methyl) phenyl (1-benzylpiperidin-4-yl) carbamate (27) (SHA-034)

2-methoxy-5-((5,6,7-trimethoxychroman-3-yl)methyl)phenol (SH-17059) (273 mg, 0.76 mmol) in dichloromethane (10 ml) solution Triphosgene (270 mg, 0.91 mmol) and triethylamine (0.4 mL, 3.04 mmol) were added at 0°C. After stirring at room temperature for 20 minutes, 1-benzyl piperidin-4-amine (0.19 mL, 0.95 mmol) was added, followed by stirring for 10 minutes. The mixture was concentrated under reduced pressure. The residue was purified through flash column chromatography using silica gel (ethyl acetate: n -hexane:methanol=1:1:0.1), and 2-methoxy-5-((5,6,7-trimethoxychroman). -3-yl)methyl) phenyl (1-benzylpiperidin-4-yl) carbamate (27) (271 mg, 61%) was obtained.

2-(((methoxy-5-((5,6,7-trimethoxychroman-3-yl)methyl))phenoxy)carbonyl)amino)ethyl propionate (28) (SHA-035 )

2-(((methoxy-5-((5,6,7-trimethoxychroman-3-yl)methyl))phenoxy)carbonyl)amino)ethyl acrylate (24) (180 mg, 0.32 mmol) dissolved in ethyl acetate (10 ml) was added with 10% Pd/C (100 mg), followed by hydrogen substitution. After stirring at room temperature for 17 hours, the reaction mixture was diluted with dichloromethane, filtered through a pad of Celite, and concentrated under reduced pressure. The residue was purified through flash column chromatography using silica gel (ethyl acetate: n -hexane = 1: 3) and 2-(((methoxy-5-((5,6,7-trimethoxychroman- 3-yl)methyl))phenoxy)carbonyl)amino)ethyl propionate (28) (150 mg, 83%) was obtained.

tert -Butyl(2-methoxy-5-((5,6,7-trimethoxychroman-3-yl)methyl)phenyl) (( R )-3-phenylpropane-1,2-diyl)dicarbamate (29) (SH-19039)

2-methoxy-5-((5,6,7-trimethoxychroman-3-yl)methyl)phenol (SH-17059) (227 mg, 0.63 mmol) in dichloromethane (10 ml) solution 4-nitrophenyl chloroformate (190 mg, 0.94 mmol) and Et ₃ N (263 µl, 11.88 mmol) were added at 0°C. After stirring at room temperature for 2 hours, the reaction mixture was diluted with dichloromethane, washed with saturated ammonium chloride solution, dried over MgSO ₄ and concentrated under reduced pressure. The residue was purified through flash column chromatography using silica gel (ethyl acetate: n -hexane = 1: 2) to obtain 2-methoxy-5-((5,6,7-trimethoxychroman-3-yl). )Methyl)phenyl(4-nitrophenyl) carbonate (281mg, 83%) was obtained.

2-methoxy-5-((5,6,7-trimethoxychroman-3-yl)methyl)phenyl(4-nitrophenyl) carbonate (180 mg, 0.343 mmol) in dichloromethane (5 ml) ) Tert -butyl ( R )-(1-amino-3-phenylpropan-2-yl)carbamate (270 mg, 0.91 mmol) and Et ₃ N (150 uL, 1.0 mmol) were added to the solution at 0°C. . After stirring at room temperature for 17 hours, the reaction mixture was diluted with dichloromethane, washed with water and brine, dried over MgSO ₄ and concentrated under reduced pressure. The residue was purified through flash column chromatography using silica gel (ethyl acetate: n -hexane = 1: 2) to obtain tert -butyl (2-methoxy-5-((5,6,7-trimethoxychroman). -3-yl)methyl)phenyl) ((R)-3-phenylpropane-1,2-diyl)dicarbamate (29) (157 mg, 72%) was obtained.

( E )-3-(3-fluoro-4-hydroxybenzylidene)-5,6,7-trimethoxychroman-4-one (28a).

5,6,7-trimethoxychroman-4-one (3a) (119 mg, 0.5 mmol) was dissolved in toluene (5 ml) solution, 3-fluoro-4-hydroxybenzaldehyde (70 mg, 0.5 mmol) and p -toluenesulfonic acid (10 mg, 0.05 mmol) were added at 0°C. The mixture was refluxed for 12 hours and cooled at room temperature, then diluted with ethyl acetate and washed with water. The organic layer was dried over anhydrous Na ₂ SO4 and concentrated under reduced pressure. The residue was purified through flash column chromatography using silica gel (ethyl acetate: n -hexane=1:3) to obtain ( E )-3-(3-fluoro-4-hydroxybenzylidene)-5,6, 7-trimethoxychroman-4-one (28a) (84 mg, 47%,) was obtained.

¹ H NMR (600 MHz, CDCl ₃ ) δ 7.70 (s, 1H), 7.08 (t, 1H, J = 8.4 Hz), 7.02 (d, 1H, J = 11.4 Hz), 6.97 (d, 1H, J = 8.4 Hz), 6.26 (s, 1H), 5.21 (d, 2H, J = 1.8 Hz), 3.98 (s, 3H), 3.88 (s, 3H), 3.82 (s, 3H). ¹³ C{ ¹ H} NMR (150 MHz, CDCl ₃ ) δ 179.6, 159.5 (d), 154.7, 151.7, 150.1, 145.1 (d), 137.8, 135.4, 130.6, 127.5 (d), 127.2 (d), 117.8 , 117.2 (d), 110.4, 96.2, 67.4, 61.7, 61.4, 56.2.

(E)-3-(3-fluoro-4-methoxybenzylidene)-5,6,7-trimethoxychroman-4-one (28b).

In a solution of 5,6,7-trimethoxychroman-4-one (3a) (238 mg, 1 mmol) in toluene (5 ml), 3-fluoro-4-methoxycibenzaldehyde (174 mg, 1.1 mmol) and p -toluenesulfonic acid (20 mg, 0.1 mmol) were added at 0°C. The mixture was refluxed for 12 hours and cooled at room temperature, then diluted with ethyl acetate (10 ml) and washed with water. The organic layer was dried over anhydrous Na ₂ SO ₄ and concentrated under reduced pressure. The residue was purified through flash column chromatography using silica gel (ethyl acetate: n -hexane = 1: 3) to obtain ( E )-3-(3-fluoro-4-methoxybenzylidene)-5,6, 7-trimethoxychroman-4-one (28b) (243 mg, 65%) was obtained.

¹ H NMR (600 MHz, CDCl ₃ ) δ 7.71 (s, 1H), 7.03 (m, 3H), 6.26 (s, 1H), 5.21 (s, 2H), 3.98 (s, 3H), 3.93 (s, 3H), 3.89 (s, 3H), 3.83 (s, 3H). ¹³ C{ ¹ H} NMR (150 MHz, CDCl ₃ ) δ 179.3, 159.4, 154.8, 152.8, 151.2, 148.6, 137.9, 134.9, 130.9, 127.7, 126.9, 117.4, 113.2, 110.5, 96.2, 67.4, 61.7, 61.3 , 56.3, 56.2.

3-(3-fluoro-4-methoxybenzyl)-5,6,7-trimethoxychroman-4-one (15) (SH-19056)

(E)-3-(3-fluoro-4-methoxybenzylidene)-5,6,7-trimethoxychroman-4-one (28b) (63 mg, 0.17 mmol) in methanol ( 3 ml) solution was added with 10% Pd/C (18 mg), followed by hydrogen substitution. After stirring at room temperature for 1 hour, the reaction mixture was diluted with ethyl acetate, filtered with a Celite pad, and concentrated under reduced pressure. The residue was purified through flash column chromatography using silica gel (ethyl acetate: n -hexane = 1: 3) to obtain 3-(3-fluoro-4-methoxybenzyl)-5,6,7-trimethoxy. Chroman-4-one (15) (47 mg, 75%) was obtained.

2-fluoro-4-((5,6,7-trimethoxychroman-3-yl)methyl)phenol (30a)

(E)-3-(3-fluoro-4-hydroxybenzylidene)-5,6,7-trimethoxychroman-4-one (28a) (60 mg, 0.17 mmol) in methanol ( 3 ml) solution was added with 10% Pd/C (25 mg), followed by hydrogen substitution. After stirring at room temperature for 1 hour, the reaction mixture was diluted with ethyl acetate, filtered with a Celite pad, and concentrated under reduced pressure. The residue was purified through flash column chromatography using silica gel (ethyl acetate: n -hexane = 1: 3) to obtain 2-fluoro-4-((5,6,7-trimethoxychroman-3-yl). )Methyl)phenol (30a) (55 mg, 93%) was obtained.

¹ H NMR (600 MHz, CDCl ₃ ) δ 6.92 (m, 2H), 6.84 (dd, 1H, J =7.8Hz and 1.2Hz), 6.19 (s, 1H), 5.45 (br, 1H), 4.07 (m , 1H), 3.85 (s, 3H), 3.80 (s, 3H), 3.79 (s, 3H), 3.72 (dd, 1H, J =10.8Hz and J =7.8Hz), 2.76 (m, 1H), 2.58 (d, 2H, J =7.2Hz), 2.31 (q, 1H, J =8.4Hz), 2.20 (m, 1H). ¹³ C{ ¹ H} NMR (150 MHz, CDCl ₃ ) δ 152.2, 151.7, 151.6, 150.6, 150.1, 141.9, 141.9, 135.9, 132.3, 132.3, 125.2, 125.2, 117.2, 117.2, 116.0, 115.9, 107.0, 96.0 , 69.4, 61.1, 60.6, 55.9, 37.2, 33.6, 25.4.

3-(3-fluoro-4-methoxybenzyl)-5,6,7-trimethoxychroman (30) (SH-19027)

( E )-3-(3-fluoro-4-methoxybenzylidene)-5,6,7-trimethoxychroman-4-one (28b) (11 mg, 0.029 mmol) in methanol ( 3 ml) solution was added with 10% Pd/C (3 mg), followed by hydrogen substitution. After stirring at room temperature for 17 hours, the reaction mixture was diluted with ethyl acetate, filtered with a Celite pad, and concentrated under reduced pressure. The residue was purified through flash column chromatography using silica gel (ethyl acetate: n -hexane = 1: 3) to obtain 3-(3-fluoro-4-methoxybenzyl)-5,6,7-trimethoxy. Chroman (30) (10 mg, 95%) was obtained.

General procedure General procedure (31~34)

K ₂ in acetone solution (5 ml) in which 2-fluoro-4-((5,6,7-trimethoxychroman-3-yl)methyl)phenol (30a) (50 mg, 0.143 mmol) was dissolved CO ₃ (200 mg, 1.43 mmol) and alkyl halide (0.172 mmol) were added. The reaction mixture was refluxed for 6 hours. After cooling to room temperature, the reaction mixture was concentrated under reduced pressure. The residue was purified through flash column chromatography using silica gel (ethyl acetate: n -hexane = 1: 2) to give compounds 31 to 34 .

3-(4-ethoxy-3-fluorobenzyl)-5,6,7-trimethoxychroman (31) (SH-19048)

(51mg, 95%)

3-(3-fluoro-4-propoxybenzyl)-5,6,7-trimethoxychroman (32) (SH-19049)

(53mg, 95%)

3-(3-fluoro-4-isopropoxybenzyl)-5,6,7-trimethoxychroman (33) (SH-19050)

(53mg, 95%)

3-(4-(allyloxy)-3-fluorobenzyl)-5,6,7-trimethoxychroman (34) (SH-19052)

(52mg, 95%)

3-(4-chloro-3-(trifluoromethyl)benzyl)-5,6,7-trimethoxychroman (35) (SH-19055).

5,6,7-trimethoxychroman-4-one (3a) (50 mg, 0.22 mmol) was dissolved in toluene (4 ml) in a solution of 4-chloro-3- (trifluoromethyl) benzaldehyde (53 Mg, 0.22 mmol) and p-toluenesulfonic acid (4 mg, 0.02 mmol) were added at 0°C. The reaction mixture was refluxed for 12 hours. After cooling to room temperature, the reaction mixture was concentrated under reduced pressure. The residue was purified by flash column chromatography using silica gel (ethyl acetate: n -hexane = 1: 2) to obtain (E)-3-(4-chloro-3-(trifluoromethyl)benzylidene)-5. ,6,7-trimethoxychroman-4-one (63 mg, 70%) was obtained.

¹ H NMR (600 MHz, CDCl ₃ ) δ 7.70 (s, 1H), 7.46 (t, 1H, J = 7.8 Hz), 7.06 (dd, 1H, J = 9.6 and 1.8 Hz), 7.01 (dd, 1H, J = 8.4 and 1.8 Hz), 6.26 (s, 1H), 5.16 (d, 2H, J = 1.8 Hz), 3.98 (s, 3H), 3.89 (s, 3H), 3.83 (s, 3H). ¹³ C{ ¹ H} NMR (150 MHz, CDCl ₃ ) δ 178.9, 159.6 (d), 158.8 (d), 154.8, 138.0, 135.1 (d), 133.7 (d), 133.1, 130.9, 126.2, 126.2, 122.0 , 121.9, 117.6 (d), 110.4, 96.2, 67.2, 61.6, 61.3, 56.2.

(E)-3-(4-chloro-3-(trifluoromethyl)benzylidene)-5,6,7-trimethoxychroman-4-one (19.5 mg, 0.05 mmol) and 10% Pd/ A solution of methanol (5 ml) in which C (5 mg) was dissolved was subjected to hydrogen substitution. After stirring for 40 minutes, the reaction mixture was diluted with ethyl acetate, filtered with a Celite pad, and concentrated under reduced pressure. The residue was purified by flash column chromatography using silica gel (ethyl acetate: n -hexane = 1: 2), and 3-(4-chloro-3-(trifluoromethyl)benzyl)-5,6,7- Trimethoxychroman (35) (4.1 mg, 22%) was obtained.

(E)-3-(3-fluoro-5-methoxybenzylidene)-5,6,7-trimethoxychroman-4-one

5,6,7-trimethoxychroman-4-one (3a) (238 mg, 1 mmol) was dissolved in toluene (5 ml) solution, 3-fluoro-4-methoxybenzaldehyde (174 mg, 1.1 mmol) and p -toluenesulfonic acid (20 mg, 0.1 mmol) were added at 0°C. The mixture was refluxed for 12 hours and cooled at room temperature, then diluted with ethyl acetate (10 ml) and washed with water. The organic layer was dried over anhydrous Na ₂ SO ₄ and concentrated under reduced pressure. The residue was purified through flash column chromatography using silica gel (ethyl acetate: n -hexane = 1: 2) to obtain (E)-3-(3-fluoro-5-methoxybenzylidene)-5,6, 7-trimethoxychroman-4-one (243 mg, 65%) was obtained.

¹ H NMR (600 MHz, CDCl ₃ ) δ 7.73 (s, 1H), 6.60 (m, 3H), 6.27 (s, 1H), 5.19 (d, 2H, J =1.8Hz), 3.99 (s, 3H) , 3.90 (s, 3H), 3.85 (s, 3H), 3.84 (s, 3H). ¹³ C{ ¹ H} NMR (150 MHz, CDCl ₃ ) δ 179.1, 162.6, 161.0, 160.9, 159.5, 159.5, 154.8, 137.9, 137.0, 136.9, 135.0, 135.0, 132.8, 111.5, 111.4, 110.4, 108.6, 108.4 , 102.3, 102.1, 96.2, 67.3, 61.6, 61.3, 56.1, 55.7.

3-(3-fluoro-5-methoxybenzyl)-5,6,7-trimethoxychroman (42) (SH-19058)

( E )-3-(3-fluoro-5-methoxybenzylidene)-5,6,7-trimethoxychroman-4-one (11 mg, 0.03 mmol) and 10% Pd/C (3 Methanol (3 mL) in which mg) was dissolved was subjected to hydrogen substitution. After stirring at room temperature for 17 hours, the reaction mixture was diluted with ethyl acetate, filtered with a Celite pad, and concentrated under reduced pressure. The residue was purified through flash column chromatography using silica gel (ethyl acetate: n -hexane = 1: 2) to obtain 3-(3-fluoro-5-methoxybenzyl)-5,6,7-trimethoxy. Chroman (42) (10 mg, 95%) was obtained.

7-(Allyloxy)-3-(3-hydroxy-4-methoxybenzyl)-5,6-dimethoxychroman-4-one (19) (SH-18063)

7-(hydroxy)-3-(3-hydroxy-4-methoxybenzyl)-5,6-dimethoxychroman-4-one (5c) (35 mg, 0.1 mmol) dissolved in acetone ( 3mL) solution was added with allyl bromide (13 uL, 0.15 mmol), K ₂ CO ₃ (41 g, 0.29 mmol) and KI (24 mg, 0.15 mmol). The reaction mixture was refluxed for 7 hours. After cooling to room temperature, the reaction mixture was diluted with ethyl acetate (10 ml) and washed with a saturated aqueous solution of ammonium chloride. The organic layer was dried over anhydrous Na ₂ SO ₄ and concentrated under reduced pressure. The residue was purified through flash column chromatography using silica gel (ethyl acetate: n -hexane = 1: 21) to obtain 7-(allyloxy)-3-(3-hydroxy-4-methoxybenzyl)-5, 6-dimethoxychroman-4-one (19) (5.5 mg, 14%; BORSM 25%) was obtained.

3-(3,4-dimethoxybenzyl)-5,6,7-trimethoxychroman (40) (SH-18078)

In a solution of 2-methoxy-5-((5,6,7-trimethoxychroman-3-yl)methyl)phenol (SH-17059) (20 mg, 0.06 mmol) in DMF (1 ml) Iodomethane (15 mg, 0.11 mmol) and K ₂ CO ₃ (38 mg, 0.28 mmol) were added. The mixture was refluxed for 3 hours and cooled at room temperature, then diluted with ethyl acetate and washed with water. The organic layer was dried over anhydrous Na ₂ SO ₄ and concentrated under reduced pressure. The residue was purified through flash column chromatography using silica gel (ethyl acetate: n -hexane = 1: 2), and 3-(3,4-dimethoxybenzyl)-5,6,7-trimethoxychroman ( 40) (19.5 mg, 95%) was obtained.

5-(1,2-dithioran-3-yl)-N-(2-methoxy-5-((5,6,7-trimethoxy-4-oxochroman-3-yl)methyl) Phenyl)pentanamide (16) (SH-19030)

In a solution of benzene (2 ml) in which chroman-4-one (3a) (17 mg, 0.07 mmol) was dissolved, 4-methoxy-3-nitrobenzaldehyde (13 mg, 0.07 mmol) and p-toluenesulfonic acid (2) Mg, 0.1 mmol) was added at 0°C. After refluxing for 12 hours using a Dean-Stark apparatus, the reaction mixture was cooled and the reaction was completed with a saturated sodium hydrogen carbonate solution. The reaction was diluted with ethyl acetate and washed with water. The organic layer was dried over anhydrous Na ₂ SO ₄ and concentrated under reduced pressure. The residue was purified through flash column chromatography using silica gel (ethyl acetate: n -hexane = 1: 2) to 3-(3-nitro-4-methoxybenzyl)-5,6,7-trimethoxy. Man-4-one (17 mg, 60%) was obtained.

¹ H NMR (600 MHz, CDCl ₃ ) δ 7.76 (d, 1H, J = 2.4 Hz), 7.72 (s, 1H), 7.51 (dd, 1H, J = 9.0 and 2.4 Hz), 7.17 (d, 1H, J = 8.4 Hz), 6.26 (s, 1H), 5.20 (d, 2H, J = 1.8 Hz), 4.02 (s, 3H), 3.98 (s, 3H), 3.89 (s, 3H), 3.83 (s, 3H). ¹³ C { ¹ H}NMR (150 MHz, CDCl ₃ ) δ 178.8, 159.5, 159.4, 154.8, 153.3, 139.5, 138.0, 135.7, 133.0, 132.4, 127.1, 126.5, 113.8, 110.3, 96.2, 67.1, 61.6, 61.3 , 56.7, 56.2. HRMS (EI): mass calcd for C ₂₀ H ₁₉ NO ₈ [M] ⁺ , 401.1111; found, 401.1113.

3-(3-nitro-4-methoxybenzyl)-5,6,7-trimethoxychroman-4-one (12 mg, 0.05 mmol) and 10% Pd/C (4 mg) in methanol The solution was subjected to hydrogen substitution. After stirring at room temperature for 1 hour, the reaction mixture was diluted with ethyl acetate, filtered with a Celite pad, and concentrated under reduced pressure. The residue was purified through flash column chromatography using silica gel (ethyl acetate: n -hexane = 1: 2) to obtain 3-(3-amino-4-methoxybenzyl)-5,6,7-trimethoxy. Man-4-one (13 mg, 73%) was obtained.

¹ H NMR (600 MHz, CDCl ₃ ) δ 6.70 (d, 1H, J = 8.4 Hz), 6.58 (d, 1H, J = 1.8 Hz), 6.56 (dd, 1H, J = 8.4 and 2.4 Hz), 4.26 (dd, 1H, J = 10.8 and 4.2 Hz), 4.11 (m, 1H), 3.91 (s, 3H), 3.85 (s, 3H), 3.81 (s, 3H), 3.79 (s, 3H), 3.12 ( dd, 1H, J = 14.4 and 4.2 Hz), 2.71 (m, 1H), 2.54 (dd, 1H, J = 13.8 and 10.8 Hz). ¹³ C{ ¹ H} NMR (150 MHz, CDCl ₃ ) δ 191.7, 166.4, 159.8, 159.2, 136.1, 133.5, 131.2, 125.7, 118.9, 115.6, 110.4, 108.9, 95.9, 69.1, 61.6, 61.3, 56.0, 55.5 , 48.4, 32.1. HRMS (EI): mass calcd for C ₂₀ H ₂₃ NO ₆ [M] ⁺ , 373.1525; found, 373.1519.

3-(3-amino-4-methoxybenzyl)-5,6,7-trimethoxychroman-4-one (17.6 mg, 0.05 mmol) in dichloromethane (1 ml) solution Acid (12 mg, 0.06 mmol), EDCI (14 mg, 0.07 mmol) and DMAP (1 mg, 0.01 mmol) were added. After the mixture was stirred for 17 hours, it was diluted with dichloromethane and washed with water and brine. The organic layer was dried over anhydrous mgSO ₄ and concentrated under reduced pressure. The residue was purified through flash column chromatography using silica gel (ethyl acetate: n -hexane = 1: 2) to obtain 5-(1,2-dithiolan-3-yl)-N-(2-methoxy- 5-((5,6,7-trimethoxy-4-oxochroman-3-yl)methyl)phenyl)pentanamide (16) (SH-19030) (11 mg, 42%) was obtained.

2-methoxy-5-((5,6,7-trimethoxy-4-methylchroman-3-yl)methyl)phenol (36) (SH-18075)

To a THF (5 ml) solution in which 3-(benzyloxy)-4-methoxybenzylchromanone (46 mg, 0.1 mmol) was dissolved was added MeMgBr (3.0 M) (0.13 ml, 0.4 mmol) at -40°C. . The reaction mixture was stirred at -40°C for 15 minutes, and saturated ammonium chloride solution (3 ml) was added to complete the reaction. The reaction was extracted three times with ethyl acetate. The organic extract was washed with brine, dried over Na ₂ SO ₄ and concentrated under reduced pressure. The residue was purified through flash column chromatography using silica gel (ethyl acetate: n -hexane=1:5) to give trimethoxy-4-methylchroman-4-ol (47 mg, 98%).

¹ H NMR (600 MHz, CDCl ₃ ) δ 7.46 (dd, 2H, J = 7.9 and 0.9 Hz), 7.35 (m, 2H), 7.30 (m, 1H), 6.83 (m, 3H), 6.19 (s, 1H), 5.15 (d, 2H, J = 1.3 Hz), 4.26 (s, 1H), 4.09 (s, 3H), 3.90 (dd, 1H, J = 11.3 and 1.5 Hz), 3.87 (s, 3H), 3.82 (s, 3H), 3.80 (s, 3H), 3.76 (dd, 1H, J = 11.4 and 3.8 Hz), 3.19 (dd, 1H, J = 14.0 and 3.9 Hz), 2.34 (dd, 1H, J = 14.0 and 11.8 Hz), 1.88 (dtd, 1H, J = 11.7, 3.8 and 2.2 Hz), 1.69 (s, 3H). ¹³ C{ ¹ H} NMR (150 MHz, CDCl ₃ ) δ 153.4, 152.6, 149.9, 148.2, 148.1, 137.4, 136.0, 133.5, 128.6, 127.9, 127.7, 122.3, 115.8, 113.4, 112.1, 96.1, 71.1, 69.9 , 65.5, 61.5, 61.0, 56.3, 56.0, 46.4, 32.5, 30.8.

AcOH/H ₂ O (4/1, 5 mL) was added to the above trimethoxy-4-methylchroman-4-ol (40 mg, 0.08 mmol) compound. The reaction mixture was refluxed at 90° C. for 12 hours, then cooled at room temperature and diluted with water. The mixture was extracted three times with ethyl acetate, dried over Na ₂ SO ₄ and concentrated under reduced pressure. The residue was purified through flash column chromatography using silica gel (ethyl acetate: n -hexane = 1: 5) to give trimethoxy-4-methyl-2H-chromene (47 mg, 98%).

¹ H NMR (600 MHz, CDCl ₃ ) δ 7.40 (m, 4H), 7.24 (m, 1H), 6.79 (dd, 2H, J = 35.7 and 8.1 Hz), 6.73 (s, 1H), 6.29 (s, 1H), 5.12 (s, 2H), 4.19 (s, 2H), 3.88 (s, 3H), 3.86 (s, 3H), 3.84 (s, 6H), 3.46 (s, 2H), 2.12 (s, 3H ). ¹³ C{ ¹ H} NMR (150 MHz, CDCl ₃ ) δ 153.0, 151.6, 151.4, 148.3, 148.2, 137.4, 137.3, 131.3, 128.6, 127.9, 127.4, 127.0, 125.2, 121.0, 114.6, 113.1, 112.1, 96.2 , 71.2, 68.2, 61.4, 61.2, 56.2, 56.1, 35.4, 15.4.

A solution of methanol (3 ml) in which trimethoxy-4-methyl-2H-chromene (7.3 mg, 0.016 mmol) and 10% Pd/C (1 mg) were dissolved was subjected to hydrogen substitution. After stirring at room temperature for 17 hours, the reaction mixture was diluted with ethyl acetate, filtered with a Celite pad, and concentrated under reduced pressure. The residue was purified through flash column chromatography using silica gel (ethyl acetate: n -hexane = 1: 4) to obtain 2-methoxy-5-((5,6,7-trimethoxy-4-methylchroman). -3-yl)methyl)phenol (36) (SH-18075) (4.4 mg, 74%) was obtained.

2-methoxy-5-((5,6,7-trimethoxy-4-methylchroman-3-yl)methyl)phenyl 5-(1,2-dithiolan-3-yl)pentanoate (37) (SH-19031).

In a solution of 2-methoxy-5-((5,6,7-trimethoxy-4-methylchroman-3-yl)methyl)phenol (20 mg, 0.05 mmol) in dichloromethane (1.0 ml) α-lipoic acid (13 mg, 0.06 mmol), EDCI (15 mg, 0.08 mmol) and DMAP (1.5 mg, 0.01 mmol) were added. After the mixture was stirred for 17 hours, it was diluted with dichloromethane, and washed with water and brine. The organic layer was dried over anhydrous MgSO ₄ and concentrated under reduced pressure. The residue was purified through flash column chromatography using silica gel (ethyl acetate: n -hexane = 1: 2) to obtain 2-methoxy-5-((5,6,7-trimethoxy-4-methylchroman). -3-yl)methyl)phenyl 5-(1,2-dithiolan-3-yl)pentanoate (37) (SH-19031) (17.1 mg, 58%) was obtained.

2-methoxy-5-((( R )-5,6,7-trimethoxychroman-3-yl)methyl)phenyl ( tert -Butoxycarbonyl)-L-phenylalaninate (43) (SH-20002)

( R )-2-methoxy-5-((5,6,7-trimethoxychroman-3-yl)methyl)phenyl (50 mg, 0.13 mmol) in dichloromethane (3.0 ml) solution Boc-L-Phe-OH (58 mg, 0.17 mmol), EDCI (33 mg, 0.17 mmol) and DMAP (2 mg, 0.016 mmol) were added. After the mixture was stirred for 12 hours, it was diluted with dichloromethane and washed with water and brine. The organic layer was dried over anhydrous MgSO ₄ and concentrated under reduced pressure. The residue was purified through flash column chromatography using silica gel (ethyl acetate: n -hexane = 1: 2) to obtain 2-methoxy-5-((( R )-5,6,7-trimethoxychroman -3-yl)methyl)phenyl ( tert -butoxycarbonyl)-L-phenylalaninate (72 mg, 91%) was obtained.

( S )-3-(3-fluoro-4-methoxybenzyl)-5,6,7-trimethoxychroman (44) (SH-19123).

(3R,4R)-3-(3-fluoro-4-methoxybenzyl)-5 in a mixed solution of trifluoroacetic acid (1.6 ml) and triethylsilane (0.3 ml, 1.85 mmol) at 40°C, Anhydrous THF (5 ml) solution in which 6,7-trimethoxychroman-4-ol (( R,R )-1) (140 mg, 0.37 mmol) was dissolved was added dropwise over 20 minutes. After stirring for 1 hour, the reaction mixture was diluted with ethyl acetate, and washed with water and saturated sodium hydrogencarbonate solution. The organic layer was dried over anhydrous MgSO ₄ and concentrated under reduced pressure. The residue was purified through flash column chromatography using silica gel (ethyl acetate: n -hexane = 1: 3) to obtain (S)-3-(3-fluoro-4-methoxybenzyl)-5,6,7 -Trimethoxychroman (44) ((S)-SH-19027) (120 mg, 90%) was obtained. [α] _D ²⁵ = -38 (c 0.08, CH ₃ OH). enantiomeric excess = 73%ee.

( R )-3-(3-fluoro-4-methoxybenzyl)-5,6,7-trimethoxychroman (45) (SH-19121)

In a mixed solution of trifluoroacetic acid (1.6 ml) and triethylsilane (0.4 ml, 2.39 mmol) at 40 °C ( 3S,4S )-3-(3-fluoro-4-methoxybenzyl)-5, Anhydrous THF (5 ml) solution in which 6,7-trimethoxychroman-4-ol (( S,S )-1) (181 mg, 0.48 mmol) was dissolved was added dropwise over 20 minutes. After stirring for 1 hour, the reaction mixture was diluted with ethyl acetate, and washed with water and saturated sodium hydrogencarbonate solution. The organic layer was dried over anhydrous MgSO ₄ and concentrated under reduced pressure. The residue was purified by flash column chromatography using silica gel (ethyl acetate: n -hexane = 1: 3), and then ( R )-3-(3-fluoro-4-methoxybenzyl)-5,6,7-trimethoxychromane ( 45) (( R )-SH-19027) (161 mg, 89%) was obtained. [α] _D ²⁵ = +50 (c 0.1, CH ₃ OH). enantiomeric excess = 77%ee.

2-methoxy-5-((5,6,7-trimethoxy-4-oxochroman-3-yl)methyl)phenyl( tert -butoxycarbonyl )-L- tritopanate (46) ( SH-17031 ).

3-(3-hydroxy-4-methoxybenzyl)-5,6,7-trimethoxychroman-4-one (SH-11008) (18.8 mg, 0.05 mmol) in dichloromethane (1.0 mL) ) Boc-Trp-OH (23 mg, 0.075 mmol), EDCI (15 mg, 0.075 mmol) and DMAP (1.0 mg, 0.01 mmol) were added to the solution. After stirring for 17 hours, the reaction mixture was diluted with dichloromethane, washed with water and brine, dried over MgSO ₄ and concentrated under reduced pressure. The residue was purified through flash column chromatography using silica gel (ethyl acetate: n -hexane = 1: 2) to obtain 2-methoxy-5-((5,6,7-trimethoxy-4-oxochroman). -3-yl)methyl)phenyl ( tert -butoxycarbonyl )-L- trittophanate (46) (30 mg, 91%) was obtained.

One-( tert- Butyl) 3-(2-methoxy-5-((5,6,7-trimethoxy-4-oxochroman-3-yl)methyl)phenyl) piperidine-1,3-dicarboxylate ( 47) (SH-17040)

3-(3-hydroxy-4-methoxybenzyl)-5,6,7-trimethoxychroman-4-one (SH-11008) (25.8 mg, 0.068 mmol) in dichloromethane (1.0 mL) ) 1-( tert -butoxycarbonyl)-3-piperidinecarboxylic acid (24 mg, 0.103 mmol), EDCI (20 mg, 0.103 mmol) and DMAP (2.0 mg, 0.01 mmol) were added to the solution. After stirring for 17 hours, the reaction mixture was diluted with dichloromethane, washed with water and brine, dried over MgSO ₄ and concentrated under reduced pressure. The residue was purified through flash column chromatography using silica gel (ethyl acetate: n -hexane = 1: 2) to obtain 1-( tert- butyl) 3-(2-methoxy-5-((5,6,7 -Trimethoxy-4-oxochroman-3-yl)methyl)phenyl) piperidine-1,3-dicarboxylate (47) (30 mg, 91%) was obtained.

( 3R,4R )-3-(3-fluoro-4-methoxybenzyl)-5,6,7-trimethoxychroman-4-ol (( R,R )-One)

3-(3-fluoro-4-methoxybenzyl)-5,6,7-trimethoxychroman-4-one (SH-19056) (450 mg, 1.19 mmol) and RuCl(p-cymene)[ ( R,R )-Ts-DPEN] (227 mg, 0.35 mmol) was added dropwise DBU/formic acid (150 uL: 50 uL) dissolved in acetonitrile (5 ml) to a solution of acetonitrile (5 ml). . After stirring at 50° C. for 24 hours, the reaction was finished with saturated ammonium chloride solution. Extracted with diethyl ether, the organic extract was washed with saturated sodium hydrogencarbonate solution, dried over anhydrous MgSO ₄ and concentrated under reduced pressure. The residue was purified through flash column chromatography using silica gel (diethyl ether: n -hexane = 1: 4) to ( 3R,4R )-3-(3-fluoro-4-methoxybenzyl)-5, 6,7-trimethoxychroman-4-ol (( R,R )-1) (370 mg, 82%) was obtained.

[α] _D ²⁰ = -103 (c 0.1, CH ₂ Cl ₂ ). enantiomeric excess = 93%ee.

¹ H NMR (600 MHz, CDCl ₃ ) δ 6.85 (d, 1H, J = 2.0 Hz), 6.79 (d, 1H, J = 8.2 Hz), 6.74 (q, 1H, J = 3.4 Hz), 6.16 (s , 1H), 5.63 (d, 1H, J = 5.0 Hz), 4.69 (t, 1H, J = 3.0 Hz), 3.96 (s, 5H), 3.87 (s, 3H), 3.79 (s, 3H), 3.78 (s, 3H), 2.85 (q, 1H, J = 7.2 Hz), 2.58 (q, 1H, J = 7.3 Hz), 2.15 (m, 2H). ¹³ C{ ¹ H} NMR (150 MHz, CDCl ₃ ) δ 153.4, 150.8, 149.8, 144.5, 144.0, 134.3, 131.7, 119.4, 114.2, 109.7, 109.5, 94.6, 63.9, 60.3, 59.9, 59.4, 54.9, 54.8 , 39.0, 31.3.

( 3S,4S )-3-(3-fluoro-4-methoxybenzyl)-5,6,7-trimethoxychroman-4-ol ((S,S)-1)

3-(3-fluoro-4-methoxybenzyl)-5,6,7-trimethoxychroman-4-one (SH-19056) (400 mg, 1.06 mmol) and RuCl(p-cymene)[ ( S,S )-Ts-DPEN] (202 mg, 0.32 mmol) was added dropwise DBU/formic acid (150uL: 50uL) dissolved in acetonitrile (5 ml) to a solution of acetonitrile (5 ml). After stirring at 50° C. for 24 hours, the reaction was finished with saturated ammonium chloride solution. Extracted with diethyl ether, the organic extract was washed with saturated sodium hydrogencarbonate solution, dried over anhydrous MgSO ₄ and concentrated under reduced pressure. The residue was purified through flash column chromatography using silica gel (diethyl ether: n -hexane = 1: 4) to ( 3S,4S )-3-(3-fluoro-4-methoxybenzyl)-5, 6,7-trimethoxychroman-4-ol (( S,S )-1) (19.1 mg, 90%) was obtained.

[α] _D ²⁰ = -103 (c 0.1, CH ₂ Cl ₂ ). enantiomeric excess = 93%ee.

¹ H NMR (600 MHz, CDCl ₃ ) δ 6.85 (d, 1H, J = 2.0 Hz), 6.79 (d, 1H, J = 8.2 Hz), 6.74 (q, 1H, J = 3.4 Hz), 6.16 (s , 1H), 5.63 (d, 1H, J = 5.0 Hz), 4.69 (t, 1H, J = 3.0 Hz), 3.96 (s, 5H), 3.87 (s, 3H), 3.79 (s, 3H), 3.78 (s, 3H), 2.85 (q, 1H, J = 7.2 Hz), 2.58 (q, 1H, J = 7.3 Hz), 2.15 (m, 2H). ¹³ C{ ¹ H} NMR (150 MHz, CDCl ₃ ) δ 153.4, 150.8, 149.8, 144.5, 144.0, 134.3, 131.7, 119.4, 114.2, 109.7, 109.5, 94.6, 63.9, 60.3, 59.9, 59.4, 54.9, 54.8 , 39.0.

( R )-3-(3-fluoro-4-methoxybenzyl)-5,6,7-trimethoxychroman-4-one (17) (SH-19122)

, 171 ㎎)와 N-메틸몰포린-N-옥사이드 (191 ㎎, 1.63 mmol)를 첨가하여 15분 동안 교반하였다. 다음에 테트라프로필암모늄 퍼루티네이트 (167 ㎎, 0.48 mmol) 를 첨가하고 30분 동안 실온에서 교반하였다. 반응 혼합물을 디에틸 에테르로 희석하고 실리카겔 여과 한 후에 유기층을 갑압 농축하였다. 잔여물은 실리카겔을 사용한 플래시 컬럼 크로마토그래피 (디에틸 에테르: n-헥산 = 1 : 3)를 통해 정제하여 (R)-3-(3- 플루오로-4-메톡시벤질)-5,6,7-트리메톡시크로만-4-온 (17) ((R)-SH-19056) (150 ㎎, 86%)을 수득하였다. [α]_D ²⁵ = -36 (c 0.08, CH₃OH). enantiomeric excess = 75%ee. ( 3R,4R )- 3-(3-fluoro-4-methoxybenzyl)-5,6,7-trimethoxychroman-4-ol (( R,R )-1) (176 mg, 0.47 mmol) in dichloromethane (8 ml) in molecular sieve (4

, 171 mg) and N-methylmorpholine-N-oxide (191 mg, 1.63 mmol) were added and stirred for 15 minutes. Next, tetrapropylammonium perrutinate (167 mg, 0.48 mmol) was added and stirred at room temperature for 30 minutes. The reaction mixture was diluted with diethyl ether, filtered through silica gel, and the organic layer was concentrated under reduced pressure. The residue was purified through flash column chromatography using silica gel (diethyl ether: n -hexane = 1: 3) to obtain ( R )-3-(3-fluoro-4-methoxybenzyl)-5,6, 7-trimethoxychroman-4-one (17) (( R )-SH-19056) (150 mg, 86%) was obtained. [α] _D ²⁵ = -36 (c 0.08, CH ₃ OH). enantiomeric excess = 75%ee.

( S )-3-(3-fluoro-4-methoxybenzyl)-5,6,7-trimethoxychroman-4-one (18) (SH-19120).

, 190 ㎎)와 N-메틸몰포린N-옥사이드 (206 ㎎, 1.76 mmol)를 첨가하여 15분 동안 교반하였다. 다음에 테트라프로필암모늄 퍼루티네이트 (181 ㎎, 0.52 mmol) 를 첨가하고 30분 동안 실온에서 교반하였다. 반응 혼합물을 디에틸 에테르로 희석하고 실리카겔 여과 한 후에 유기층을 갑압 농축하였다. 잔여물은 실리카겔을 사용한 플래시 컬럼 크로마토그래피 (디에틸 에테르: n-헥산 = 1 : 3)를 통해 정제하여 (S)- 3-(3-플루오로-4-메톡시벤질)-5,6,7-트리메톡시크로만-4-온 (18) ((S)-SH-19056) (167 ㎎, 88%)를 수득하였다. [α]_D ²⁵ = +38 (c 0.08, CH₃OH). enantiomeric excess = 74%ee. ( 3S,4S )-3-(3-fluoro-4-methoxybenzyl)-5,6,7-trimethoxychroman-4-ol ((S,S)-1) (190 mg, 0.50 mmol) in dichloromethane (6 ml) in a molecular sieve (4

, 190 mg) and N-methylmorpholine N-oxide (206 mg, 1.76 mmol) were added and stirred for 15 minutes. Next, tetrapropylammonium perrutinate (181 mg, 0.52 mmol) was added and stirred at room temperature for 30 minutes. The reaction mixture was diluted with diethyl ether, filtered through silica gel, and the organic layer was concentrated under reduced pressure. The residue was purified through flash column chromatography using silica gel (diethyl ether: n -hexane = 1: 3) to obtain ( S )-3-(3-fluoro-4-methoxybenzyl)-5,6, 7-trimethoxychroman-4-one (18) (( S )-SH-19056) (167 mg, 88%) was obtained. [α] _D ²⁵ = +38 (c 0.08, CH ₃ OH). enantiomeric excess = 74%ee.

The structure and NMR data of the Synthesis Example compound are shown in Table 1 below.

Synthesis example rescue NMR Data One
(SH-18070)

2-methoxy-5-((5,6,7-trimethoxy-4-oxochroman-3-yl)methyl)phenyl dimethyl-L-phenylalaninate

2-methoxy-5-((5,6,7-trimethoxy-4-oxochroman-3-yl)methyl)phenyl dimethyl-L-phenylalaninate ¹ H NMR (600 MHz, CDCl ₃ ) δ 7.33 (m, 4H), 7.26 (t, 1H, J = 7.2 Hz), 7.03 (d, 1H, J = 8.4 Hz), 6.54 (s, 1H), 6.25 (d, 1H, J = 2.4 Hz), 4.26 (dd, 1H, J = 11.4 and 4.2 Hz), 4.05 (m, 1H), 3.92 (s, 3H), 3.88 (s, 3H), 3.81 (s, 3H), 3.73 (m, 1H), 3.72(s, 3H), 3.18 (m, 2H), 3.07 (dd, 1H, J = 13.2 and 5.4 7Hz), 2.6 (m, 1H), 2.59 (dd, 1H , J = 13.8 and 10.8 Hz), 2.53 (s, 6H). ¹³ C{ ¹ H} NMR (150 MHz, CDCl ₃ ) δ 191.1, 169.3, 159.7, 159.4, 154.5, 149.6, 139.4, 137.9, 137.5, 130.9, 129.4, 128.4, 127.4, 126.6, 123.4, 112.5, 108.7, 96.0 , 69.3, 69.0, 61.6, 61.3, 56.1, 55.7, 48.2, 41.8, 36.3, 31.8. 2
(SH-19028)

2-methoxy-5-((5,6,7-trimethoxy-4-oxochroman-3-yl)methyl)phenyl 5-(1,2-dithiolan-3-yl)pentanoate ¹ H NMR (600 MHz, CDCl ₃ ) δ 7.06 (dd, 1H, J = 8.4 and 1.8 Hz), 6.90 (s, 1H), 6.89 (m, 1H), 6.24 (s, 1H), 4.28 (d, 1H, J = 11.4 Hz), 4.09 (m, 1H), 3.91 (s, 3H), 3.87 (s, 3H), 3.80 (s, 3H), 3.60 (t, 1H, J = 6.6 Hz), 3.18 ( d, 2H, J = 12.6 Hz), 3.10 (m, 1H), 2.74 (m, 1H), 2.60 (m, 3H), 2.48 (m, 1H), 1.92 (m, 1H), 1.75 (m, 4H) ), 1.58 (m, 2H). ¹³ C{ ¹ H} NMR (150 MHz, CDCl ₃ ) δ 191.1, 171.5, 159.7, 159.3, 154.4, 149.8, 139.7, 137.5, 131.0, 127.3, 123.5, 112.5, 108.7, 96.0, 69.0, 61.6, 61.3, 56.4 , 56.1, 56.0, 48.3, 40.3, 38.5, 34.6, 33.8, 31.8, 28.7, 24.7. 3
(SHA-001)

2-methoxy-5-((5,6,7-trimethoxy-4-oxochroman-3-yl)methyl)phenyl ((S)-1-phenylethyl)carbamate ¹ H NMR (600 MHz, CDCl ₃ ) δ 7.38 (q, 4H, J = 7.8 Hz), 7.29 (td, 1H, J = 6.6 and 1.2 Hz), 7.02 (d, 1H, J = 8.4 Hz), 6.97 (s, 1H), 6.87 (d, 1H, J = 7.8 Hz), 6.23 (s, 1H), 5.41 (d, 1H, J = 7.8 Hz), 4.92 (t, 1H, J = 7.2 Hz), 4.28 (dd, 1H, J = 11.4 and 4.2 Hz), 4.10 (dd, 1H, J = 10.8 and 7.8 Hz), 3.92 (d, 3H, J = 1.8 Hz), 3.87 (s, 3H), 3.80 (s, 3H), 3.79 (s, 3H), 3.18 (dd, 1H, J = 13.8 and 4.2 Hz), 2.73 (m, 1H), 2.63 (td, 1H, J = 13.8 and 3 Hz), 1.57 (d, 3H , J = 1.2 Hz). ¹³ C{ ¹ H} NMR (150 MHz, CDCl ₃ ) δ 191.2, 159.7, 159.3, 154.5, 153.5, 150.3, 143.1, 140.0, 137.5, 130.9, 128.7, 127.4, 129.9, 126.1, 123.9, 112.5, 108.7, 96.0 , 69.0, 61.6, 61.3, 56.1, 56.0, 51.0, 48.2, 31.8, 22.2. 4
(SHA-003)

2-methoxy-5-((5,6,7-trimethoxy-4-oxochroman-3-yl)methyl)phenyl benzylcarbamate ¹ H NMR (600 MHz, CDCl ₃ ) δ 7.30 (m, 5H), 7.05 (d, 1H, J =7.8Hz), 7.01 (s, 1H), 6.91 (d, 1H, J =7.8Hz), 6.25 (s, 1H), 4.46 (d, 2H, J = 6Hz), 4.30 (dd, 1H, J =11.4Hz and 4.2Hz), 4.11 (dd, 1H, J =11.4Hz and 7.8Hz), 3.93 (s , 3H), 3.88 (s, 3H), 3.84 (s, 3H), 3.81 (s, 3H), 3.18 (dd, 1H, J =14.4Hz and 4.2Hz ), 2.75 (m, 1H), 2.63 (dd , 1H, J =13.8Hz and 10.2Hz). ¹³ C{ ¹ H} NMR (150 MHz, CDCl ₃ ) δ 191.2, 159.7, 159.3, 154.4, 154.4, 150.3, 139.9, 138.1, 137.5, 130.9, 128.7, 127.6, 127.6, 127.0, 123.9, 112.5, 108.7, 96.0 , 69.0, 61.6, 61.3, 56.1, 56.0, 48.2, 45.3, 31.8 5
(SHA-004)

2-methoxy-5-((5,6,7-trimethoxy-4-oxochroman-3-yl)methyl)phenyl ((R)-1-phenylethyl)carbamate ¹ H NMR (600 MHz, CDCl ₃ ) δ 7.38 (q, 4H, J = 7.8 Hz), 7.29 (td, 1H, J = 6.6 and 1.2 Hz), 7.02 (d, 1H, J = 8.4 Hz), 6.97 (s, 1H), 6.88 (d, 1H, J = 7.8 Hz), 6.24 (s, 1H), 5.41 (d, 1H, J = 7.8 Hz), 4.92 (t, 1H, J = 7.2 Hz), 4.28 (dd, 1H, J = 11.4 and 4.2 Hz), 4.10 (dd, 1H, J = 10.8 and 7.8 Hz), 3.92 (d, 3H, J = 1.8 Hz), 3.87 (s, 3H), 3.81 (s, 3H), 3.79 (s, 3H), 3.18 (dd, 1H, J = 13.8 and 4.2 Hz), 2.73 (m, 1H), 2.63 (td, 1H, J = 13.8 and 3 Hz), 1.57 (d, 3H , J = 1.2 Hz). ¹³ C{ ¹ H} NMR (150 MHz, CDCl ₃ ) δ 191.2, 159.7, 159.3, 154.5, 153.5, 150.3, 143.1, 140.0, 137.5, 130.9, 128.7, 127.4, 129.9, 126.1, 123.9, 112.5, 108.7, 96.0 , 69.0, 61.6, 61.3, 56.1, 56.0, 51.0, 48.2, 31.8, 22.2. 6
(SHA-007)

2-methoxy-5-((5,6,7-trimethoxy-4-oxochroman-3-yl)methyl)phenyl (4-fluorophenethyl)carbamate ¹ H NMR (600 MHz, CDCl ₃ ) δ 7.20 (dd, 2H, J = 8.4 and 5.5 Hz), 7.03 (m, 3H), 6.96 (d, 1H, J = 1.9 Hz), 6.89 (d, 1H, J = 8.4 Hz), 6.25 (s, 1H), 5.11 (t, 1H, J = 6.0 Hz), 4.29 (dd, 1H, J = 11.3 and 4.1 Hz), 4.10 (dd, 1H, J = 11.3 and 7.4 Hz), 3.92 (s, 3H), 3.88 (s, 3H), 3.82 (s, 3H), 3.81 (s, 3H), 3.49 (q, 2H, J = 6.8 Hz), 3.18 (dd, 1H, J = 14.0 and 4.2 Hz), 2.87 (t, 2H, J = 7.0 Hz), 2.74 (ddd, 1H, J = 11.6, 8.1 and 4.2 Hz), 2.63 (dd, 1H, J = 14.0 and 10.7 Hz). ¹³ C{ ¹ H} NMR (150 MHz, CDCl ₃ ) δ 191.3, 162.6, 161.0, 159.8, 159.4, 154.6, 154.4, 150.5, 139.9, 137.6, 134.4, 131.1, 130.4, 130.4, 127.2, 124.1, 115.7, 115.5 , 112.6, 108.8, 96.1, 69.2, 61.8, 61.5, 56.2, 56.2, 48.4, 42.7, 35.2, 32.0, 29.8. 7
(SHA-014)

2-methoxy-5-((5,6,7-trimethoxy-4-oxochroman-3-yl)methyl)phenyl (1-benzylpiperidin-4-yl)carbamate ¹ H NMR (600 MHz, CDCl ₃ ) δ 7.32 (m, 3H), 7.26 (m, 2H), 7.03 (dd, 1H, J = 8.4 and 1.9 Hz), 6.98 (d, 1H, J = 1.9 Hz) , 6.89 (d, 1H, J = 8.4 Hz), 6.24 (s, 1H), 5.01 (d, 1H, J = 7.9 Hz), 4.28 (dd, 1H, J = 11.4 and 4.1 Hz), 4.10 (dd, 1H, J = 11.4 and 7.7 Hz), 3.92 (s, 3H), 3.87 (s, 3H), 3.82 (s, 3H), 3.81 (s, 3H), 3.60 (ddd, 1H, J = 19.2, 12.2 and 3.3 Hz), 3.51 (s, 2H), 3.18 (dd, 1H, J = 14.0 and 4.2 Hz), 2.84 (d, 2H, J = 10.8 Hz), 2.74 (ddd, 1H, J = 11.7, 8.2 and 4.2 Hz), 2.62 (dd, 1H, J = 14.0 and 10.7 Hz), 2.14 (t, 2H, J = 10.7 Hz), 2.01 (d, 2H, J = 11.1 Hz), 1.87 (s, 3H), 1.56 ( dd, 2H, J = 20.3 and 10.4 Hz). ¹³ C{ ¹ H} NMR (150 MHz, CDCl ₃ ) δ 191.3, 159.8, 159.4, 154.6, 153.6, 150.5, 140.0, 137.6, 131.0, 129.3, 128.4, 127.2, 124.1, 112.6, 108.8, 96.1, 69.2, 63.1 , 61.8, 61.5, 56.2, 56.2, .48.4, 32.4, 32.0, 29.8 8
(SHA-028)

methyl ((2-methoxy-5-((5,6,7-trimethoxy-4-oxochroman-3-yl)methyl)phenoxy)carbonyl)-L-phenylalaninate ¹ H NMR (600 MHz, CDCl ₃ ) δ 7.31 (t, 2H, J = 7.3 Hz), 7.26 (t, 1H, J = 7.1 Hz), 7.18 (d, 2H, J = 7.2 Hz), 7.03 (d , 1H, J = 8.3 Hz), 6.94 (s, 1H), 6.88 (d, 1H, J = 8.3 Hz), 6.24 (s, 1H), 5.64 (d, 1H, J = 8.0 Hz), 4.69 (dd , 1H, J = 12.9 and 5.9 Hz), 4.25 (m, 1H), 4.08 (ddd, 1H, J = 11.2, 7.5 and 1.8 Hz), 3.92 (s, 3H), 3.86 (s, 3H), 3.80 ( d, 6H, J = 2.6 Hz), 3.74 (s, 3H), 3.20 (m, 2H), 3.14 (dd, 1H, J = 12.5 and 4.3 Hz), 2.72 (ddt, 1H, J = 10.7, 7.5 and 3.7 Hz), 2.61 (dd, 1H, J = 13.9 and 10.7 Hz). ¹³ C{ ¹ H} NMR 150 MHz, CDCl ₃ ) δ 191.2, 171.6, 159.7, 159.3, 154.4, 153.5, 150.3, 139.7, 137.5, 135.6, 130.9, 129.4, 128.6, 127.2, 127.2, 127.1, 123.9, 112.6, 108.7, 96.0, 69.0, 61.6, 61.3, 56.1, 56.0, 55.0, 52.4, 48.3, 38.1, 38.0, 31.8. 9
(SHA-029)

2-methoxy-5-((5,6,7-trimethoxy-4-oxochroman-3-yl)methyl)phenyl diethylcarbamate ¹ H NMR (600 MHz, CDCl ₃ ) δ 7.01 (dd, J = 8.3, 2.1 Hz, 1H), 6.97 (d, 1H, J = 2.1 Hz), 6.88 (d, 1H, J = 8.3 Hz), 6.24 (s, 1H), 4.29 (dd, 1H, J = 11.4, 4.2 Hz), 4.11 (m, 1H), 3.92 (s, 3H), 3.87 (s, 3H), 3.81 (s, 6H), 3.45 ( m, 4H), 3.18 (dd, J = 14.0, 4.3 Hz, 1H), 2.74 (m, 1H), 2.62 (dd, J = 14.0, 10.7 Hz, 1H), 1.26 (m, 6H). ¹³ C{ ¹ H} NMR (150 MHz, CDCl3) δ 191.4, 159.9, 159.4, 154.6, 154.2, 150.6, 140.8, 137.6, 130.9, 126.7, 124.2, 112.7, 108.8, 96.1, 69.2, 61.8, 61.5, 60.5, 56.2, 56.2, 48.5, 42.4, 42.1, 32.0, 14.3. 10
(SHA-030)

ethyl ((2-methoxy-5-((5,6,7-trimethoxy-4-oxochroman-3-yl)methyl)phenoxy)carbonyl)glycinate ¹ H NMR (600 MHz, CDCl ₃ ) δ 7.02 (dd, 1H, J = 6.3 and 1.9 Hz), 6.96 (s, 1H), 6.88 (m, 1H), 6.23 (d, 1H, J = 2.5 Hz) , 5.75 (m, 1H), 4.20 (m, 3H), 4.08 (ddd, 1H, J = 11.3, 6.1 and 4.5 Hz), 4.03 (dd, 2H, J = 7.0 and 3.1 Hz), 3.90 (dd, 3H , J = 4.5 and 1.5 Hz), 3.85 (m, 3H), 3.81 (m, 3H), 3.79 (dd, 3H, J = 4.8 and 1.4 Hz), 3.15 (dd, 1H, J = 14.0 and 3.6 Hz) , 2.70 (m, 1H), 2.60 (m, 1H), 1.28 (dt, 3H, J = 7.0 and 3.7 Hz). ¹³ C{ ¹ H} NMR (150 MHz, CDCl ₃ ) δ 191.3, 169.8, 159.8, 159.4, 154.5, 150.4, 139.7, 137.5, 131.0, 127.2, 124.0, 112.7, 108.7, 96.1, 69.1, 61.7, 61.4, 56.2 , 56.1, 48.3, 43.1, 31.9, 14.2. 11
(SH-19032)

tert-butyl ((2-methoxy-5-((5,6,7-trimethoxy-4-oxochroman-3-yl)methyl)phenoxy)carbonyl)-L-alaninate ¹ H NMR (600 MHz, CDCl ₃ ) δ 7.06 (d, 1H, J = 8.4 Hz), 7.0 (s, 1H), 6.92 (d, 1H, J = 8.4 Hz), 6.27 (s, 1H), 5.74 (s, 1H), 4.33 (m, 1H), 4.32 (dd, 1H, J = 11.4 and 5.4 Hz), 4.12 (m, 1H), 3.94 (s, 3H), 3.89 (s,3H), 3.84 ( s, 3H), 3.83 (s, 3H), 3.21 (dd, 1H, J = 13.8 and 3.6 Hz), 2.76 (m, 1H), 2.66 (dd, 1H, J = 13.8 and 10.8 Hz), 1.51 (s , 9H), 1.46 (s, 3H). ¹³ C{ ¹ H} NMR (150 MHz, CDCl ₃ ) δ 191.2, 171.9, 159.7, 159.3, 154.5, 153.5, 150.3, 139.8, 137.5, 130.9, 127.0, 124.0, 112.6, 108.7, 96.0, 82.1, 69.0, 61.6 , 61.3, 56.1, 56.1, 50.4, 48.3, 31.8, 28.0, 18.9. 12
(SH-19033)

tert-butyl ((2-methoxy-5-((5,6,7-trimethoxy-4-oxochroman-3-yl)methyl)phenoxy)carbonyl)-L-valinate ¹ H NMR (600 MHz, CDCl ₃ ) δ 7.05 (d, 1H, J = 6 Hz), 6.99 (s, 1H), 6.90 (d, 1H, J = 8.4 Hz), 6.25 (s, 1H), 5.67 (d, 1H, J = 9 Hz), 4.29 (d, 1H, J = 10.8 Hz), 4.24 (s, 1H), 4.11 (m, 1H), 3.93 (s, 3H), 3.88 (s, 3H) , 3.82 (s, 6H), 3.19 (d, 1H, J = 13.8 Hz), 2.73 (m, 1H), 2.65 (t, 1H, J = 11.4 Hz), 2.23 (q, 1H, J = 6.6 Hz) , 1.50 (s, 9H), 1.04 (d, 3H, J = 6.6 Hz), 0.97 (d, 3H, J = 6.6 Hz). ¹³ C{ ¹ H} NMR (150 MHz, CDCl ₃ ) δ 191.2, 170.8, 159.7, 159.3, 154.4, 154.2, 150.3, 139.9, 137.5, 130.9, 127.0, 123.9, 112.6, 108.7, 96.0, 82.1, 69.0, 61.6 , 61.3, 59.5, 56.1, 56.0, 48.3, 31.8, 31.7, 28.1, 18.9 ,17.4. 13
(SH-19034)

tert-butyl N ⁶ -(tert-butoxycarbonyl)-N ² -((2-methoxy-5-((5,6,7-trimethoxy-4-oxochroman-3-yl)methyl)phenoxy)carbonyl)-L- lysinate ¹ H NMR (600 MHz, CDCl ₃ ) δ 7.03 (d, 1H, J = 8.4 Hz), 6.96 (s, 1H), 6.88 (d, 1H, J = 8.4 Hz), 6.23 (s, 1H), 5.71 (d, 1H, J = 7.8 Hz), 4.59 (bs, 1H), 4.28 (dd, 2H, J = 11.4 and 4.2 Hz), 4.09 (m, 1H), 3.90 (s, 3H), 3.86 (s, 3H), 3.80 (s, 3H), 3.79 (s, 3H), 3.17 (dd, 1H, J = 13.8 and 4.2 Hz), 3.11 (bs, 2H), 2.72 (m, 1H), 6.63 (t, 1H , J = 13.8 Hz), 1.88 (m, 2H), 1.74 (m, 1H), 1.51 (m, 2H), 1.47 (s, 9H), 1.44 (m, 2H), 1.41 (s, 9H). ¹³ C{ ¹ H} NMR (150 MHz, CDCl ₃ ) δ 159.7, 159.3, 156.0, 154.4, 153.8, 150.3, 139.8, 137.5, 130.9, 127.0, 123.9, 112.6, 108.7, 96.0, 82.3, 79.1, 69.0, 61.6 , 61.3, 56.1, 56.0, 54.4, 48.2, 40.3, 32.5, 31.8, 29.6, 28.4, 28.0, 22.2. 14
(SH-19035)

tert-butyl ((2-methoxy-5-((5,6,7-trimethoxy-4-oxochroman-3-yl)methyl)phenoxy)carbonyl)-glycinate
¹ H NMR (600 MHz, CDCl ₃ ) δ 7.05 (d, 1H, J = 8.4 Hz), 6.98 (d, 1H, J = 2.4 Hz), 6.90 (d, 1H, J = 7.8 Hz), 6.25 (s , 1H), 5.69 (bs, 1H), 4.29 (d, 1H, J = 11.4 Hz), 4.11 (m, 1H), 3.95 (t, 2H, J = 5.4 Hz), 3.92 (s, 3H), 3.87 (s, 3H), 3.82 (s, 3H), 3.81 (s, 3H), 3.18 (d, 1H, J = 13.8 Hz), 2.73 (m, 1H), 2.64 (t, 1H, J = 13.8 Hz) , 1.49 (s, 9H). ¹³ C{ ¹ H} NMR (150 MHz, CDCl ₃ ) δ 191.2, 168.8, 159.7, 159.3, 154.4, 154.2, 150.3, 139.7, 137.4, 130.9, 127.1, 124.0, 112.6, 108.6, 96.0, 82.4, 69.0, 61.6 , 61.3, 56.1, 56.0, 48.2, 43.6, 61.8, 28.0. 15
(SH-19056)

3-(3-fluoro-4-methoxybenzyl)-5,6,7-trimethoxychroman-4-one ¹ H NMR (600 MHz, CDCl ₃ ) δ 6.98 (d, 1H, J = 12 Hz), 6.90 (m, 2H), 6.25 (s, 1H), 4.29 (dd, 1H, J = 11.4 and 4.2 Hz) , 4.09 (dd, 1H, J = 10.8 and 7.8 Hz), 3.93 (s, 3H), 3.88 (s, 3H), 3.87 (s, 3H), 3.81 (s, 3H), 3.19 (dd, 1H, J = 13.8 and 4.2 Hz), 2.74 (m, 1H), 2.65 (dd, 1H, J = 13.8 and 10.2 Hz). ¹³ C{ ¹ H} NMR (150 MHz, CDCl ₃ ) δ 191.0, 159.7, 159.4, 154.5, 153.1, 146.3, 137.6, 131.5, 124.8, 116.7, 113.6, 108.7, 96.0, 69.1, 61.6, 61.3, 56.3, 56.1 , 48.2, 31.9. 16
(SH-19030)

5-(1,2-dithiolan-3-yl)-N-(2-methoxy-5-((5,6,7-trimethoxy-4-oxochroman-3-yl)methyl)phenyl)pentanamide ¹ H NMR (600 MHz, CDCl ₃ ) δ 8.21 (d, 1H, J = 1.2 Hz), 7.67 (bs, 1H), 6.85 (dd, 1H, J = 8.4 and 1.8 Hz), 6.75 (d, 1H, J = 8.4 Hz), 6.18 (bs, 1H), 4.24 (dd, 1H, J = 11.4 and 4.2 Hz), 4.07 (dd, 1H, J = 11.4 and 7.8 Hz), 3.86 (s, 3H), 3.81 ( s, 3H), 3.74 (s, 3H), 3.18 (dd, 1H, J = 13.8 and 4.2 Hz), 3.13 (m, 1H), 3.05 (m, 1H), 2.72 (m, 1H), 2.57 (d , 1H, J = 14.4 and 10.8 Hz), 2.40 (m, 1H), 2.35 (t, 2H, J = 7.2 Hz), 1.85 (m, 1H), 1.70 (m, 4H), 1.48 (m, 3H) . ¹³ C{ ¹ H} NMR (150 MHz, CDCl ₃ ) δ 191.3, 170.9, 159.8, 159.2, 154.4, 146.4, 137.4, 131.2, 127.7, 124.0, 120.3, 110.0, 108.7, 96.0, 69.3, 61.6, 61.3, 56.4 , 56.1, 55.8, 48.3, 40.3, 38.5, 37.7, 34.7, 32.3, 28.9, 25.2. 17
(SH-19122)

(R)-3-(3-fluoro-4-methoxybenzyl)-5,6,7-trimethoxychroman-4-one ¹ H NMR (600 MHz, CDCl ₃ ) δ 6.97 (dd, 1H, J = 12.0, 1.9 Hz), 6.93 (dd, 1H, J = 8.4, 1.9 Hz), 6.90 (m, 1H), 6.25 (s, 1H), 4.28 (dd, 1H, J = 11.3, 4.2 Hz), 4.08 (dd, 1H, J = 11.3, 7.7 Hz), 3.93 (s, 3H), 3.88 (s, 3H), 3.87 (s, 3H ), 3.81 (s, 3H), 3.18 (dd, 1H, J = 14.0, 4.5 Hz), 2.72 (m, 1H), 2.63 (dd, 1H, J = 14.0, 10.4 Hz). ¹³ C{ ¹ H} NMR (150 MHz, CDCl ₃ ) δ 191.1, 159.8, 159.5, 154.6, 151.6, 146.5, 137.7, 131.6, 124.,9 117.0, 113.7, 108.8, 96.1, 69.2, 61.7, 61.5, 56.5 , 56.2, 48.3, 32.0. 18
(SH-19120)

(S)-3-(3-fluoro-4-methoxybenzyl)-5,6,7-trimethoxychroman-4-one ¹ H NMR (600 MHz, CDCl ₃ ) δ 6.97 (dd, 1H, J = 12.0, 2.0 Hz), 6.93 (dd, 1H, J = 8.4, 1.9 Hz), 6.90 (m, 1H), 6.25 (s, 1H), 4.28 (dd, 1H, J = 11.3, 4.2 Hz), 4.08 (dd, 1H, J = 11.3, 7.7 Hz), 3.93 (s, 3H), 3.88 (s, 3H), 3.87 (s, 3H ), 3.81 (s, 3H), 3.18 (dd, 1H, J = 14.0, 4.5 Hz), 2.74 (m, 1H), 2.63 (dd, 1H, J = 14.0, 10.4 Hz). ¹³ C{ ¹ H} NMR (150 MHz, CDCl ₃ ) δ 191.1, 159.8, 159.5, 154.6, 151.6, 146.5, 137.7, 131.6, 124.9, 117.0, 113.7, 108.8, 96.1, 69.2, 61.7, 61.5, 56.5, 56.2 , 48.3, 32.0. 19
(SH-18063)

7-(allyloxy)-3-(3-hydroxy-4-methoxybenzyl)-5,6-dimethoxychroman-4-one ¹ H NMR (600 MHz, CDCl ₃ ) δ 6.80 (d, 1H, J = 2.4 Hz), 6.79 (d, 1H, J = 7.8 Hz), 6.71 (dd, 1H, J = 7.8 and 1.8 Hz), 6.23 (d, 1H), 6.08 (m, 1H), 5.60 (bs, 1H), 5.46 (qd, 1H, J = 17.4 and 1.2 Hz), 5.35 (qd, 1H, J = 16.8 and 1.2 Hz), 4.60 ( td, 2H, J = 4.8 and 1.2 Hz), 4.27 (dd, 1H, J = 11.4 and 4.2 Hz), 4.10 (dd, 1H, J = 11.4 and 7.8 Hz), 3.93 (s, 3H), 3.87 (s , 3H), 3.82 (s, 3H), 3.19 (dd, 1H, J = 14.4 and 4.8 Hz), 2.74 (m, 1H), 2.60 (dd, 1H, J = 13.8 and 10.8 Hz). ¹³ C{ ¹ H} NMR (150 MHz, CDCl ₃ ) δ 191.4, 159.6, 158.2, 154.6, 145.6, 145.3, 137.7, 132.1, 131.7, 120.6, 118.4, 115.2, 110.8, 108.8, 97.1, 69.5, 69.1, 61.7 , 61.3, 56.0, 48.4, 32.2. 20
(SH-19019)

(E)-6-(cyclopropylmethoxy)-3-(3-hydroxy-4-methoxybenzylidene)-5,7-dimethoxychroman-4-one ¹ H NMR (600 MHz, CDCl ₃ ) δ 7.73 (s, 1H), 6.86 (ddd, 3H, J = 14.5, 10.3 and 5.1 Hz), 6.24 (s, 1H), 5.70 (s, 1H), 5.24 ( d, 2H, J = 1.7 Hz), 3.99 (s, 3H), 3.94 (s, 3H), 3.86 (s, 3H), 3.77 (d, 2H, J = 7.2 Hz), 1.60 (m, 1H), 0.57 (m, 2H), 0.30 (m, 2H). ¹³ C{ ¹ H} NMR (150 MHz, CDCl ₃ ) δ 179.8, 159.7, 159.5, 155.1, 147.6, 145.7, 137.1, 136.3, 130.4, 128.3, 123.4, 115.9, 110.8, 110.7, 96.2, 78.8, 67.8, 61.7 , 56.2, 56.1, 11.1, 3.2. 21
(SH-19020)

6-(cyclopropylmethoxy)-3-(3-hydroxy-4-methoxybenzyl)-5,7-dimethoxychroman-4-one ¹ H NMR (600 MHz, CDCl ₃ ) δ 6.79 (d, 1H, J = 2.1 Hz), 6.77 (d, 1H, J = 8.2 Hz), 6.69 (dd, 1H, J = 8.2, 2.1 Hz), 6.22 (s, 1H), 5.67 (s, 1H), 4.25 (dd, 1H, J = 11.3, 4.2 Hz), 4.07 (dd, 1H, J = 11.3, 7.8 Hz), 3.93 (s, 3H), 3.85 ( s, 3H), 3.84 (s, 3H), 3.73 (d, 2H, J = 7.2 Hz), 3.17 (dd, 1H, J = 14.0, 4.3 Hz), 2.73 (m, 1H), 2.56 (dd, 1H , J = 14.0, 10.8 Hz), 1.26 (m, 1H), 0.55 (m, 2H), 0.27 (m, 2H). ¹³ C{ ¹ H} NMR (150 MHz, CDCl ₃ ) δ 191.5, 159.7, 159.7, 154.7, 145.7, 145.4, 136.6, 131.8, 120.7, 115.3, 110.9, 108.8, 96.0, 78.7, 69.2, 61.6, 56.1, 56.1 , 48.4, 32.3, 11.0, 3.2, 3.1. 22
(SH-19029)

2-methoxy-5-((5,6,7-trimethoxychroman-3-yl)methyl)phenyl 5-(1,2-dithiolan-3-yl)pentanoate ¹ H NMR (600 MHz, CDCl ₃ ) δ 6.95 (dd, 1H, J = 8.4 and 1.8 Hz), 6.84 (d, 1H, J = 8.4 Hz), 6.81 (d, 1H, J = 1.8 Hz), 6.12 (s, 1H), 4.02 (dd, 1H, J = 9 and 1.2 Hz), 3.78 (s, 3H), 3.75 (s, 3H), 3.72 (s, 3H), 3.72 (s, 3H), 3.68 ( dd, 1H, J = 10.8 and 8.4 Hz), 3.54 (m, 1H), 3.12 (m, 1H), 3.05 (m, 1H), 2.71 (dd, 1H, J = 16.2 and 4.8 Hz), 2.52 (m , 4), 2.42 (m, 1H), 2.28 (dd, 1H, J = 16.2 and 7.8 Hz), 2.13 (m, 1H), 1.89 (m, 1H), 1.70 (m, 4H), 1.57 (m, 2H). ¹³ C{ ¹ H} NMR (150 MHz, CDCl ₃ ) δ 171.5, 152.3, 151.6, 150.6, 149.5, 139.6, 135.9, 132.1, 127.1, 123.3, 112.4, 107.1, 95.9, 69.4, 61.0, 60.6, 56.4, 56.0 , 55.9, 40.3, 38.5, 37.1, 34.6, 33.8, 33.5, 28.7, 25.5, 24.8; HRMS (EI) mass calcd for C ₂₈ H ₃₆ O ₇ S ₂ [M] ⁺ : 548.1902; found, 548.1904. 23
(SH-17060)

2-methoxy-5-((5,6,7-trimethoxychroman-3-yl)methyl)phenyl (tert-butoxycarbonyl)-L-phenylalaninate ¹ H NMR (600 MHz, CDCl ₃ ) δ 7.34 (m, 5H), 7.03 (dd, 1H, J = 7.8 and 1.2 Hz), 6.91 (d, 1H, J = 8.4 Hz), 6.81 (s, 1H) , 6.20 (s, 1H), 5.04 (d, 1H, J = 8.4 Hz), 4.88 (q, 1H, J = 7.8 Hz), 4.09 (dd, 1H, J = 10.8 and 1.8 Hz), 3.85 (s, 3H), 3.81 (s, 3H), 3.80 (s, 3H), 3.79 (s, 3H), 3.75 (dd, 1H, J = 10.2 and 8.4 Hz), 3.35 (dd, 1H, J = 13.8 and 6 Hz ), 3.23 (dd, 1H, J = 14.4 and 6.6 Hz), 2.77 (dd, 1H, J = 16.8 and 5.4 Hz), 2.60 (d, 2H, J = 7.2 Hz), 2.35 (dd, 1H, J = 16.8 and 7.8 Hz), 2.18 (m, 1H), 1.41 (s, 9H). ¹³ C{ ¹ H} NMR (150 MHz, CDCl ₃ ) δ 170.2, 155.1, 152.3, 151.6, 150.6, 149.4, 139.2, 136.0, 135.9, 132.1, 129.6, 128.5, 127.5, 127.1, 123.2, 112.5, 107.1, 95.9 , 80.0, 69.3, 61.0, 60.6, 55.9, 55.9, 54.4, 38.3, 37.1, 33.5, 28.3, 25.5; HRMS (EI) mass calcd for C ₃₄ H ₄₁ NO ₉ [M] ⁺ : 607.2781; found, 607.2778. 24
(SHA-031)

2-(((2-methoxy-5-((5,6,7-trimethoxychroman-3-yl)methyl)phenoxy)carbonyl)amino)ethyl acrylate ¹ H NMR (600 MHz, CDCl ₃ ) δ 6.92 (dd, 1H, J = 7.8 and 1.2 Hz), 6.88 (d, 1H, J = 1.8 Hz), 6.82 (d, 1H, J = 7.8 Hz), 6.39 (dd, 1H, J = 17.4 and 0.6 Hz), 6.10 (m, 2H), 5.81 (dd, 1H, J = 10.8 and 1.2 Hz), 5.36 (t, 1H, J = 6 Hz), 4.24 (t, 1H, J = 5.4 Hz), 4.01 (dd, 1H, J = 10.2 and 1.2 Hz), 3.78(s, 3H), 3.76(s, 3H), 3.72(s, 6H), 3.66 (dd, 1H, J = 10.2 and 8.4 Hz), 3.51 (dd, 1H, J = 10.8 and 5.4 Hz), 2.68 (dd, 1H, J = 16.2 and 5.4 Hz), 2.50 (m, 2H), 2.26 (dd, 1H, J = 16.8 and 8.4 Hz), 2.13 (m, 1H). ¹³ C{ ¹ H} NMR (150 MHz, CDCl ₃ ) δ 166.1, 154.3, 152.2, 151.6, 150.7, 150.0, 139.7, 135.9, 132.0, 131.6, 128.0, 126.9, 123.7, 112.4, 107.1, 96.0, 69.4, 63.5 , 61.0, 60.6, 56.0, 55.9, 40.5, 37.1, 33.5, 25.5. 25
(SHA-032)

butyl ((2-methoxy-5-((5,6,7-trimethoxychroman-3-yl)methyl)phenoxy)carbonyl)glycinate ¹ HNMR (600 MHz, CDCl ₃ ) δ 7.00 (dd, 1H, J = 8.4 and 1.8 Hz), 6.96 (d, 1H, J = 2.4 Hz), 6.89 (d, 1H, J = 8.4 Hz), 6.18 ( s, 1H), 5.62 (t, 1H, J = 4.8 Hz), 4.19 (t, 2H, J = 7.2 Hz), 4.08 (m, 3H), 3.85 (s, 3H), 3.83 (s, 3H), 3.79 (s, 6H), 3.73 (dd, 1H, J = 10.8 and 8.4 Hz), 2.76 (ddd, 1H, J = 16.8 Hz, 5.4 and 1.2 Hz), 2.60 (m, 2H), 2.33 (q, 1H , J = 16.8 and 8.4 Hz), 2.20 (m, 1H), 1.65 (quint, 2H, J = 7.2 Hz), 1.40 (sext, 2H, J = 7.2 Hz), 0.95 (t, 1H, J = 7.2 Hz ). ¹³ C{ ¹ H} NMR (150 MHz, CDCl ₃ ) δ 169.7, 154.2, 152.2, 151.6, 150.7, 150.1, 139.6, 135.9, 132.0, 127.0, 123.7, 112.4, 107.1, 96.0, 69.4, 65.5, 61.0, 60.6 , 56.1, 55.9, 43.0, 37.1, 33.5, 30.5, 25.5, 19.0, 13.7; HRMS (EI) mass calcd for C ₂₇ H ₃₅ NO ₉ [M] ⁺ : 517.2312; found, 517.2318. 26
(SHA-033)

2-methoxy-5-((5,6,7-trimethoxychroman-3-yl)methyl)phenyl allylcarbamate ¹ H-NMR (600 MHz, CDCl ₃ ) δ 7.00 (d, 1H, J = 8.4 Hz), 6.96 (s, 1H), 6.89 (d, 1H, J = 8.4 Hz), 6.11 (s, 1H), 5.90 (m, 1H), 5.29 (d, 1H, J = 17.4 Hz), 5.18 (m, 2H), 4.09 (d, 1H, J = 10.2 Hz), 3.90 (t, 2H, J = 5.4 Hz), 3.85 (s, 3H), 3.84 (s, 3H), 3.79 (s, 6H), 3.74 (t, 1H, J = 9 Hz), 2.76 (dd, 1H, J = 10.2 and 4.8Hz), 2.60 (m , 2H), 2.33 (q, 1H, J = 8.4 Hz), 2.20 (m, 1H). ¹³ C{ ¹ H} NMR (150 MHz, CDCl ₃ ) δ 154.3, 152.2, 151.6, 150.7, 150.1, 139.8, 135.9, 134.1, 132.0, 126.8, 123.8, 116.4, 112.4, 107.2, 96.0, 69.5, 61.0, 60.6 , 56.0, 55.9, 43.7, 37.1, 33.5, 25.5; HRMS (EI) mass calcd for C ₂₄ H ₂₉ NO ₇ [M] ⁺ : 443.1944; found, 443.1940. 27
(SHA-034)

2-methoxy-5-((5,6,7-trimethoxychroman-3-yl)methyl)phenyl (1-benzylpiperidin-4-yl)carbamate ¹ H NMR (600 MHz, CDCl ₃ ) δ 7.32 (m, 4H), 7.26 (s, 2H), 6.98 (d, 1H, J = 8.1 Hz), 6.95 (s, 1H), 6.88 (d, 1H, J = 8.3 Hz), 6.18 (s, 1H), 4.98 (s, 1H), 4.08 (d, 1H, J = 10.4 Hz), 3.85 (s, 3H), 3.83 (s, 3H), 3.79 (s, 6H), 3.73 (d, 1H, J = 8.6 Hz), 3.51 (s, 2H), 2.83 (d, 2H, J = 7.0 Hz), 2.76 (dd, 1H, J = 16.5 and 5.2 Hz), 2.60 ( m, 2H), 2.33 (dd, 1H, J = 16.5 and 8.1 Hz), 2.18 (m, 3H), 2.01 (d, 2H, J = 11.3 Hz), 1.56 (d, 2H, J = 8.5 Hz). ¹³ C{ ¹ H} NMR (150 MHz, CDCl ₃ ) δ 153.6, 152.4, 151.8, 150.8, 150.2, 139.9, 135.9, 132.1, 129.3, 128.4, 127.2, 126.8, 123.9, 112.5, 107.3, 96.1, 69.6, 63.2 , 61.2, 60.7, 56.2, 55.9, 52.3, 37.3, 33.6, 32.5, 25.6; HRMS (EI) mass calcd for C ₃₀ H ₄₀ N ₂ O ₇ [M] ⁺ : 576.2836; found, 576.2829. 28
(SHA-035)

2-(((2-methoxy-5-((5,6,7-trimethoxychroman-3-yl)methyl)phenoxy)carbonyl)amino)ethyl propionate ¹ H NMR (600 MHz, CDCl ₃ ) δ 6.3 (dd, 1H, J = 8.4 and 1.8 Hz), 6.88 (d, 1H, J = 2.4 Hz), 6.82 (d, 1H, J = 8.4 Hz), 6.11 (s, 1H), 5.28 (t, 1H, J = 6 Hz), 4.15 (t, 2H, J = 5.4 Hz), 4.02 (m, 1H), 3.78 (s, 3H), 3.77 (s, 3H) , 3.76 (s, 3H), 3.72 (s, 3H), 3.66 (dd, 1H, J = 10.8 and 7.8 Hz), 2.69 (ddd, 1H, J = 16.8, 5.4 and 1.2 Hz), 2.53 (m, 2H) ), 2.31 (q, 2H, J = 15 and 7.8 Hz), 2.26 (q, 1H, J = 8.4 Hz), 2.15 (m, 1H), 1.10 (t, 1H, J = 7.8 Hz). ¹³ C{ ¹ H} NMR (150 MHz, CDCl ₃ ) δ 166.1, 154.4, 152.2, 151.6, 150.7, 150.0, 139.7, 135.9, 132.0, 131.6, 126.9, 123.7, 112.4, 107.1, 95.9, 69.4, 63.2, 61.0 , 60.6, 56.0, 55.9, 40.5, 37.1, 33.5, 27.4, 25.5. HRMS (EI) mass calcd for C ₂₆ H ₃₃ NO ₉ [M] ⁺ : 503.2155; found, 503.2150. 29
(SH-19039)

tert-butyl (2-methoxy-5-((5,6,7-trimethoxychroman-3-yl)methyl)phenyl) ((R)-3-phenylpropane-1,2-diyl)dicarbamate ¹ H NMR (600 MHz, DMSO-d ₆ ) δ 7.74 (t, 1H, J = 6 Hz), 7.29 (q, 2H, J = 7.2 Hz), 7.22 (d, 2H, J = 7.2 Hz), 7.18 (m, 1H), 7.02 (s, 2H), 6.94 (s, 1H), 6.71 (d, 1H, J = 8.4 Hz), 6.23 (s, 1H), 4.04 (d, 1H, J = 7.8 Hz) , 3.75 (s, 3H), 3.74 (s, 3H), 3.72 (s, 3H), 3.68 (m, 2H), 3.64 (s, 3H), 3.10 (m,2H), 2.82 (dd, 1H, J = 13.8 and 4.2 Hz), 2.62 (m, 2H), 2.56 (m, 2H), 2.26 (dd, 1H, J = 16.8 and 9 Hz), 2.13 (m, 1H). ¹³ C{ ¹ H} NMR (150 MHz, DMSO-d ₆ ) δ 155.6, 154.9, 152.3, 151.6, 150.7, 150.3, 140.1, 139.4, 135.8, 132.1, 129.6, 128.5, 126.7, 126.4, 124.1, 113.1, 107.3 , 96.7, 78.0, 69.4, 60.9, 60.6, 56.1, 56.1, 52.1, 44.8, 37.9, 36.6, 33.4, 28.7, 25.1. 30
(SH-19027)

3-(3-fluoro-4-methoxybenzyl)-5,6,7-trimethoxychromane
¹ H NMR (600 MHz, CDCl ₃ ) δ 6.90 (m, 3H), 6.19 (s, 1H), 4.08 (d, 1H, J = 10.8 Hz), 3.88 (s, 3H), 3.85 (s, 3H) , 3.80 (s, 3H), 3.79 (s, 3H), 3.75 (dd, 1H, J = 10.8 and 8.4 Hz), 2.76 (dd, 1H, J = 16.2 and 5.4 Hz), 2.60 (d, 2H, J = 7.8 Hz), 2.34 (dd, 1H, J = 16.2 and 7.8 Hz), 2.20 (m, 1H). ¹³ C{ ¹ H} NMR (150 MHz, CDCl ₃ ) δ 152.3, 151.6, 150.6, 146.1, 135.9, 132.6, 124.6, 116.7, 116.6, 113.5, 106.9, 95.9, 69.4, 61.0, 60.6, 56.4, 55.9, 37.1 , 33.6, 25.4. 31
(SH-19048)

3-(4-ethoxy-3-fluorobenzyl)-5,6,7-trimethoxychromane ¹ H NMR (600 MHz, CDCl ₃ ) δ 6.90 (m, 3H), 6.19 (s, 1H), 4.10 (m, 3H), 3.85 (s, 3H), 3.80 (s, 3H), 3.80 (s, 3H), 3.73 (dd, 1H, J =10.2Hz and 7.8Hz), 2.75 (m, 1H), 2.60 (d, 2H, J =7.8Hz), 2.31 (dd, 1H, J =16.8Hz and 8.4Hz ), 2.20 (m, 1H), 1.45 (t, 3H, J =7.2Hz). ¹³ C{ ¹ H} NMR (150 MHz, CDCl ₃ ) δ 153.3, 152.3, 151.7, 151.6, 150.6, 145.3, 145.2, 135.8, 132.5, 132.5, 124.5, 124.5, 116.7, 116.6, 114.9, 114.9, 107.0, 95.9 , 69.4, 65.0, 61.0, 60.5, 55.8, 37.1, 33.5, 25.3, 14.8. 32
(SH-19049)

3-(3-fluoro-4-propoxybenzyl)-5,6,7-trimethoxychromane ¹ H NMR (600 MHz, CDCl ₃ ) δ 6.90 (m, 3H), 6.19 (s, 1H), 4.08 (m, 1H), 3.98 (t, 2H, J =6.6Hz), 3.85 (s, 3H) , 3.80 (s, 3H), 3.80 (s, 3H), 3.73 (dd, 1H, J =10.2Hz and 7.8Hz ), 2.75 (m, 1H), 2.60 (d, 2H, J =7.2Hz ), 2.32 (dd, 1H, J =16.8Hz and 8.4Hz), 2.19 (m, 1H), 1.85 (m, 2H), 1.05 (t, 3H, J =7.2Hz). ¹³ C{ ¹ H} NMR (150 MHz, CDCl ₃ ) δ 153.4, 152.2, 151.8, 151.6, 150.6, 145.5, 145.4, 135.8, 132.5, 132.4, 124.5, 124.4, 116.7, 116.6, 115.0, 115.0, 107.0, 95.9 , 71.1, 69.4, 61.0, 60.5, 55.8, 37.1, 33.5, 25.3, 22.6, 10.4. 33
(SH-19050)

3-(3-fluoro-4-isopropoxybenzyl)-5,6,7-trimethoxychromane ¹ H NMR (600 MHz, CDCl3) δ 6.85 (m, 2H), 6.78 (dd, 1H, J =8.4Hz and 1.2Hz ), 6.12 (s, 1H), 4.43 (q, 1H, J =6.0Hz) , 4.00 (m, 1H), 3.78 (s, 3H), 3.73 (s, 3H), 3.72 (s, 3H), 3.65 (dd, 1H, J =10.2Hz and 7.8Hz ), 2.68 (m, 1H) , 2.51 (d, 2H, J =7.2Hz), 2.32 (dd, 1H, J =16.8Hz and 9.1Hz), 2.14 (m, 1H), 1.29 (s, 3H), 1.28 (s, 3H). ¹³ C{ ¹ H} NMR (150 MHz, CDCl ₃ ) δ 154.4, 152.8, 152.3, 151.6, 150.6, 144.1, 144.0, 135.8, 133.1, 133.1, 124.5, 124.5, 118.0, 116.9, 116.8, 107.0, 95.9, 72.5 , 69.4, 61.0, 60.5, 55.8, 37.1, 33.5, 25.4, 22.1. 34
(SH-19052)

3-(4-(allyloxy)-3-fluorobenzyl)-5,6,7-trimethoxychromane ¹ H NMR (600 MHz, CDCl3) δ 6.83 (m, 3H), 6.12 (s, 1H), 6.00 (m, 1H), 5.34 (dq, 1H, J =16.8Hz and 1.8Hz and 1.2Hz), 5.23 (dq, 1H, J =16.8Hz and 1.8Hz and 1.2Hz), 4.52 (dt, 2H, J =5.4Hz and 1.2Hz ), 4.43 (q, 1H, J =6.0Hz), 4.00 (m, 1H) , 3.78 (s, 3H), 3.73 (s, 3H), 3.72 (s, 3H), 3.65 (dd, 1H, J =10.2Hz and 7.8Hz ), 2.68 (m, 1H), 2.51 (d, 2H, J =7.2Hz), 2.25 (dd, 1H, J =16.8Hz and 9.1Hz), 2.14 (m, 1H). ¹³ C{ ¹ H} NMR (150 MHz, CDCl ₃ ) δ 153.4, 152.3, 151.8, 151.6, 150.6, 144.9, 144.8, 135.8, 133.0, 132.9, 124.5, 124.4, 118.1, 116.8, 116.7, 115.5, 115.5, 106.9 , 95.9, 70.3, 69.4, 61.0, 60.5, 55.8, 37.1, 33.5, 25.3. 35
(SH-19055)

3-(4-chloro-3-(trifluoromethyl)benzyl)-5,6,7-trimethoxychromane ¹ H NMR (600 MHz, CDCl ₃ ) δ 7.33 (t, 1H, J = 7.8 Hz), 7.01 (dd, 1H, J = 10.2 and 1.8 Hz), 6.93 (dd, 1H, J = 7.8 and 1.8 Hz) , 6.19 (s, 1H), 4.07 (m, 1H), 3.85 (s, 3H), 3.80 (s, 3H), 3.79 (s, 3H), 3.76 (dd, 1H, J = 10.8 and 8.4 Hz), 2.77 (ddd, 1H, J = 16.2, 5.4 and 1.2 Hz), 2.65 (m, 2H), 2.36 (dd, 1H, J = 16.8 and 7.8 Hz), 2.23 (m, 1H). ¹³ C{ ¹ H} NMR (150 MHz, CDCl ₃ ) δ 152.4, 151.6, 150.5, 140.5, 135.9, 130.5, 125.5, 125.5, 117.2, 117.1, 106.6, 96.0, 69.1, 61.0, 60.6, 55.9, 37.3, 33.4 , 25.3. 36
(SH-18075)

2-methoxy-5-((5,6,7-trimethoxy-4-methylchroman-3-yl)methyl)phenol ¹ H NMR (600 MHz, CDCl ₃ ) δ 6.78 (dd, 2H, J = 5.2 and 3.0 Hz), 6.67 (dd, 1H, J = 8.2 and 2.1 Hz), 6.13 (s, 1H), 5.61 (s, 1H), 3.96 (ddd, 1H, J = 10.6, 3.7 and 1.4 Hz), 3.92 (s, 3H), 3.89 (d, 1H, J = 4.8 Hz), 3.87 (s, 3H), 3.78 (d, 6H , J = 1.6 Hz), 3.00 (m, 1H), 2.63 (dd, 1H, J = 14.0 and 6.9 Hz), 2.45 (dd, 1H, J = 14.0 and 8.6 Hz), 2.30 (m, 1H), 1.14 (d, 3H, J = 6.9 Hz). ¹³ C{ ¹ H} NMR (150 MHz, CDCl ₃ ) δ 152.4, 151.4, 149.8, 145.6, 145.0, 135.5, 132.8, 120.2, 115.0, 113.8, 110.7, 95.6, 65.0, 60.9, 60.8, 56.0, 55., 37.7, 34.3, 27.4, 16.1. 37
(SH-19031)

2-methoxy-5-((5,6,7-trimethoxy-4-methylchroman-3-yl)methyl)phenyl 5-(1,2-dithiolan-3-yl)pentanoate ¹ H NMR (600 MHz, CDCl ₃ ) δ 7.03 (d, 1H, J = 8.4 Hz), 6.91 (d, 1H, J = 8.4 Hz), 6.88 (m, 1H), 6.13 (s, 1H), 3.97 (dd, 1H, J = 10.8 and 3 Hz), 3.91 (s, 3H), 3.81 (s, 4H), 3.77 (s, 6H), 3.60 (m, 1H), 3.18 (m, 1H), 3.10 ( m, 1H), 2.98 (t, 1H, J = 6 Hz), 2.68 (dd, 1H, J = 14.4 and 6.6 Hz), 2.60 (t, 2H, J = 7.2 Hz), 2.48 (m, 2H), 2.32 (m, 1H), 1.95 (m, 1H), 1.75 (m, 4H), 1.60 (m, 3H), 1.14 (d, 3H). ¹³ C{ ¹ H} NMR (150 MHz, CDCl ₃ ) δ 171.5, 152.5, 151.3, 149.8, 149.5, 139.7, 135.6, 132.0, 126.9, 123.1, 113.7, 112.4, 95.5, 64.9, 60.9, 60.8, 56.4, 56.0 , 55.8, 40.3, 38.5, 37.6, 34.6, 33.9, 33.8, 28.7, 27.4, 24.8, 16.1. 38
(SH-19021)

5-((6-(cyclopropylmethoxy)-5,7-dimethoxychroman-3-yl)methyl)-2-methoxyphenol ¹ H NMR (600 MHz, CDCl ₃ ) δ 6.78 (dd, 2H, J = 5.1 and 3.0 Hz), 6.66 (dd, 1H, J = 8.2 and 2.1 Hz), 6.17 (s, 1H), 5.57 (s, 1H), 4.08 (ddd, 1H, J = 10.5, 3.0 and 1.5 Hz), 3.88 (s, 3H), 3.87 (s, 3H), 3.77 (s, 3H), 3.70 (m, 3H), 2.74 (ddd , 1H, J = 16.4, 5.4 and 1.3 Hz), 2.55 (m, 2H), 2.31 (dd, 1H, J = 16.5 and 8.5 Hz), 2.20 (m, 1H), 0.57 (m, 1H), 0.28 ( m, 1H). ¹³ C{ ¹ H} NMR (150 MHz, CDCl ₃ ) δ 152.6, 152.0, 150.7, 145.6, 145.2, 135.0, 132.9, 120.5, 115.3, 110.7, 107.3, 96.0, 78.6, 69.8, 60.7, 56.1, 56.0, 37.7 , 33.8, 25.6, 11.2, 3.2. 39
(SH-19018)

3-(3-hydroxy-4-methoxybenzyl)-5,7-dimethoxychroman-6-ol ¹ H NMR (600 MHz, CDCl ₃ ) δ 6.78 (dd, 2H, J = 5.1 and 3.0 Hz), 6.66 (dd, 1H, J = 8.2 and 2.0 Hz), 6.21 (s, 1H), 5.61 (s, 1H), 5.11 (s, 1H), 4.08 (dd, 1H, J = 10.5 and 1.4 Hz)), 3.88 (s, 3H), 3.83 (s, 3H), 3.82 (s, 3H), 3.72 (dd, 1H, J = 10.4 and 8.2 Hz), 2.78 (dd, 1H, J = 16.4 and 4.6 Hz), 2.60 (m, 2H), 2.36 (dd, 1H, J = 16.5 and 8.2 Hz), 2.20 (ddd, 1H , J = 13.1, 7.8 and 2.8 Hz). ¹³ C{ ¹ H} NMR (150 MHz, CDCl ₃ ) δ 147.6, 146.4, 145.6, 145.2, 144.9, 132.9, 132.4, 120.6, 115.3, 110.8, 107.6, 95.7, 69.7, 60.3, 56.2, 56.1, 37.7, 33.8 , 25.6. 40
(SH-18078)

3-(3,4-dimethoxybenzyl)-5,6,7-trimethoxychroman ¹ H NMR (600 MHz, CDCl ₃ ) δ 6.81 (d, 1H, J = 8.4 Hz), 6.73 (m, 2H), 6.20 (s, 1H), 4.09 (dd, 1H, J = 10.8 and 1.2 Hz) , 3.87 (s, 6H), 3.85 (s, 3H), 3.80 (s, 3H), 3.79 (s, 3H), 3.75 (dd, 1H, J = 10.8 and 3.6 Hz), 2.75 (dd, 1H, J = 16.2 and 4.8 Hz), 2.63 (m, 2H), 2.33 (q, 1H, J = 8.4 Hz), 2.24 (m, 1H). ¹³ C{ ¹ H} NMR (150 MHz, CDCl ₃ ) δ 152.3, 151.6, 150.7, 148.9, 147.5, 135.9, 132.1, 121.0, 112.1, 111.2, 107.2, 96.0, 69.7, 61.0, 60.6, 55.9, 55.9. 37.8, 33.7, 25.5. 41
(SH-18089)

5-((6,7-dimethoxychroman-3-yl)methyl)-2-methoxyphenol ¹ H NMR (600 MHz, CDCl ₃ ) δ 6.71 (m, 2H), 6.60 (dd, 1H, J = 7.8 and 1.8 Hz), 6.42 (s, 1H), 6.32 (s, 1), 5.55 (bs, 1H), 4.07 (d, 1H, J = 10.8 Hz), 3.81 (s, 3H), 3.75 (s, 3H), 3.72 (s, 3H), 3.70 (dd, 1H, J = 10.2 and 8.4 Hz), 2.65 (dd, 1H, J = 16.2 and 5.4 Hz), 2.57 (dd, 1H, J = 13.8 and 7.2 Hz), 2.46 (dd, 1H, J = 13.8 and 7.8 Hz), 2.38 (dd, 1H, J = 16.2 and 9 Hz), 2.19 (m, 1H). ¹³ C{ ¹ H} NMR (150 MHz, CDCl ₃ ) δ 148.3, 148.2, 145.5, 145.1, 143.1, 132.7, 120.4, 115.2, 112.6, 111.9, 110.6, 100.6, 69.9, 56.4, 56.0, 55.9, 37.5, 34.3 , 30.5. 42
(SH-19058)

3-(3-fluoro-5-methoxybenzyl)-5,6,7-trimethoxychromane ¹ H NMR (600 MHz, CDCl ₃ ) δ 6.46 (m, 3H), 6.14 (s, 1H), 4.03 (d, 1H, J = 10.5Hz), 3.81 (s, 3H), 3.75 (s, 3H) , 3.75 (s, 3H), 3.74 (s, 3H), 3.70 (t, 1H, J = 8.5Hz), 2.72 (dd, 1H, J =16.2Hz and 4.8Hz), 2.58 (d, 2H, J = 7.5Hz), 2.28 (dd, 1H, J = 16.4Hz and 8.1Hz), 2.20 (m, 1H). ¹³ C{ ¹ H} NMR (150 MHz, CDCl ₃ ) δ 164.4, 162.8, 160.9, 160.8, 152.3, 151.6, 150.5, 142.5, 142.5, 135.9, 110.7, 110.7, 108.1, 108.0, 106.9, 99.4, 99.2, 95.9 , 69.4, 61.0, 60.5, 55.8, 55.4, 38.0, 33.3, 25.4. 43
(SH-20002)

2-methoxy-5-(((R)-5,6,7-trimethoxychroman-3-yl)methyl)phenyl (tert-butoxycarbonyl)-L-phenylalaninate ¹ H NMR (600 MHz, CDCl ₃ ) δ 7.24 (m, 5H), 6.95 (d, 1H, J = 8.4 Hz), 6.84 (d, 1H, J = 8.4 Hz), 6.74 (s, 1H), 6.12 (s, 1H), 4.95 (d, 1H, J = 8.4 Hz), 4.78 (q, 1H, J = 7.8 Hz), 4.00 (dd, 1H, J = 10.8 and 1.8 Hz), 3.78 (s, 3H) , 3.74 (s, 3H), 3.73 (s, 3H), 3.73 (s, 3H), 3.65 (dd, 1H, J = 10.2 and 8.4 Hz), 3.25 (dd, 1H, J = 13.8 and 6 Hz), 3.13 (dd, 1H, J = 14.4 and 6.6 Hz), 2.58 (dd, 1H, J = 16.8 and 5.4 Hz), 2.52 (d, 2H, J = 7.2 Hz), 2.25 (dd, 1H, J = 16.8 and 7.8 Hz), 2.13 (m, 1H), 1.35 (s, 9H). ¹³ C{ ¹ H} NMR (150 MHz, CDCl ₃ ) δ 170.2, 155.1, 152.3, 151.6, 150.6, 149.4, 139.2, 136.0, 135.9, 132.1, 129.6, 128.5, 127.5, 127.1, 123.2, 112.5, 107.1, 95.9 , 80.0, 69.3, 61.0, 60.6, 55.9, 55.9, 54.4, 38.3, 37.1, 33.5, 28.3, 25.5; HRMS (EI) mass calcd for C ₃₄ H ₄₁ NO ₉ [M] ⁺ : 607.2781; found, 607.2778. 44
(SH-19123)

(S)-3-(3-fluoro-4-methoxybenzyl)-5,6,7-trimethoxychromane. ¹ H NMR (600 MHz, CDCl ₃ ) δ 6.90 (m, 3H), 6.19 (s, 1H), 4.07 (ddd, 1H, J = 10.6, 2.9, 1.4 Hz), 3.88 (s, 3H), 3.85 ( s, 3H), 3.80 (s, 3H), 3.79 (s, 3H), 3.73 (dd, 1H, J = 10.5, 8.1 Hz), 2.75 (ddd, 1H, J = 16.4, 5.5, 1.2 Hz), 2.60 (d, 2H, J = 7.5 Hz), 2.32 (dd, 1H, J = 16.5, 8.1 Hz), 2.20 (m, 1H). ¹³ C{ ¹ H} NMR (150 MHz, CDCl ₃ ) δ 153.2, 152.4, 151.7, 150.7, 146.2, 136.0, 132.7, 124.7, 116.8, 113.6, 107.1, 96.1, 69.5, 61.2, 60.7, 56.5, 56.0, 37.3 , 33.7, 25.5. 45
(SH-19121)

( R )-3-(3-fluoro-4-methoxybenzyl)-5,6,7-trimethoxychromane
¹ H NMR (600 MHz, CDCl ₃ ) δ 6.88 (m, 3H), 6.16 (d, 1H, J = 5.6 Hz), 4.04 (ddd, 1H, J = 10.5, 3.1, 1.6 Hz), 3.85 (s, 3H), 3.82 (s, 3H), 3.76 (s, 3H), 3.76 (s, 3H), 3.70 (dd, 1H, J = 10.3, 8.2 Hz), 2.71 (ddd, 1H, J = 16.6, 5.6, 1.6 Hz), 2.57 (d, 2H, J = 7.5 Hz), 2.29 (dd, 2H, J = 16.4, 8.1 Hz), 2.18 (m, 1H). ¹³ C{ ¹ H} NMR (150 MHz, CDCl ₃ ) δ 153.2, 152.4, 151.7, 150.7, 146.1, 135.9, 132.6, 124.6, 116.7, 113.5, 107.1, 96.0, 69.5, 61.1, 60.6, 56.4, 55.9, 37.2 , 33.6, 25.4. 46
(SH-17031)

2-methoxy-5-((5,6,7-trimethoxy-4-oxochroman-3-yl)methyl)phenyl(tert-butoxycarbonyl)- L -tryptophanate ¹ H NMR (600 MHz, CDCl ₃ ) δ 7.67 (dd, 1H, J = 7.8 and 4.2 Hz), 7.39 (d, 1H, J = 7.8 Hz), 7.29 (d, 2H, J = 4.2 Hz), 7.14 (dd, 1H, J = 11.4 and 7.2 Hz), 7.02 (d, 1H, J = 8.4 Hz), 6.87 (d, 1H, J = 8.4 Hz), 6.65 (d, H, J = 4.2 Hz), 6.26 (s, 1H), 5.19 (bs, 1H), 4.95 (d, 1H, J = 6.6 Hz), 4.29 (dd, 1H, J = 10.8 and 2.4 z), 4.08-4.03 (m, 1H), 3.96 ( s, 3H), 3.88 (s, 3H), 3.84 (d, 3H, J = 4.8 z), 3.75 (s, 3H), 3.46 (d, 2H, J = 4.8 Hz), 3.09 (dd, 1H, J = 13.8 and 4.2 Hz), 2.72-2.64 (m, 2H), 1.44 (s, 9H). ¹³ C{ ¹ H} NMR (150 MHz, CDCl ₃ ) δ 191.3, 170.5, 159.8, 159.4, 155.2, 154.3, 149.7, 139.3, 137.5, 136.2, 131.1, 131.0, 127.5, 123.5, 123.5, 122.0, 119.5, 119.0 , 112.5, 111.3, 110.0, 108.7, 96.1, 80.0, 69.3, 61.7, 61.4, 56.1, 55.9, 54.6, 48.0, 31.6, 28.4, 28.2. 47
(SH-17040)

1-( tert- butyl) 3-(2-methoxy-5-((5,6,7-trimethoxy-4-oxochroman-3-yl)methyl)phenyl) piperidine-1,3-dicarboxylate ¹ H NMR (600 MHz, CDCl ₃ ) δ 7.07 (dd, 1H, J = 8.4 and 1.8 Hz), 6.81 (d, 2H, J = 8.4 Hz), 6.25 (s, 1H), 4.30 (dd, 1H, J = 11.4 and 4.2 Hz), 4.11 (dd, 1H, J = 11.4 and 7.8 Hz), 3.96 (bs, 1H), 3.93 (s, 3H), 3.88 (s, 3H), 3.82 (s, 3H), 3.80 (s, 3H), 3.20 (dd, 1H, J = 13.8 and 10.2 Hz), 3.08 (bs, 1H), 2.89 (t, 1H, J = 11.4 Hz), 2.76 (m, 2H), 2.66 (dd , 1H, J = 13.2 and 11.4 Hz), 2.23 (d, 1H, J = 9 Hz), 1.79 (d, 1H, J = 10.8 Hz), 1.55 (bs, 2H), 1.48 (s, 9H). ¹³ C{ ¹ H} NMR (150 MHz, CDCl ₃ ) δ 191.1, 171.5, 159.7, 159.3, 154.7, 154.5, 149.7, 139.6, 137.5, 131.1, 127.4, 123.4, 112.5, 108.7, 96.0, 79.8, 69.0, 61.6 , 61.3, 56.1, 56.0, 49.3, 48.3, 41.4, 41.4, 31.8, 28.4, 27.5, 22.7. 48
(SH-19036)

methyl ((2-methoxy-5-((5,6,7-trimethoxy-4-oxochroman-3-yl)methyl)phenoxy)carbonyl)-L-methioninate ¹ H NMR (600 MHz, CDCl ₃ ) δ 7.04 (d, 1H, J = 8.4 Hz), 6.97 (s, 1H), 6.89 (d, 1H, J = 7.8 Hz), 6.24 (s, 1H), 5.82 (bs, 1H), 4.54 (q, 1H, J = 6 Hz), 4.28 (dd, 1H, J = 11.4 and 3.6 Hz), 4.07 (m, 1H), 3.91 (s, 3H), 3.87 (s, 3H), 3.81 (s, 3H), 3.80 (s, 3H), 3.78 (s, 3H); 3.18 (dd, 1H, J =13.8 and 3.6 Hz), 2.74-2.70 (m, 1H), 2.63 (m , 3H), 2.24-2.21 (m, 1H), 2.11 (s, 3H), 2.07 (m, 1H); ¹³ C { ¹ H} NMR (150 MHz, CDCl ₃ ) δ 191.2, 172.2, 159.7, 159.4, 154.4, 153.9, 150.2, 139.7, 137.5, 130.9, 127.2, 123.8, 112.6, 108.6, 96.0, 69.0, 61.6, 61.3 , 56.1, 56.0, 53.3, 52.7, 48.2, 32.0, 31.8, 28.8, 15.5.

<Example 1> Cell death ability analysis

In order to evaluate the apoptotic activity of the Example compounds provided in one aspect of the present invention, MTT cell viability assay (MTT viability assay) was performed.

Human retinal microvascular endothelial cells (HREC) and human umbilical vein endothelial cells (HUVEC) were purchased from Cell Systems (USA) and Lonza (Switzerland). The HREC and HUVEC cells were placed in a 96-well plate at a density of 2500 cells per well, and cultured in an incubator at 37°C and 5% CO ₂ for 16 hours. After treatment with the Synthesis Example compound, it was cultured for 44 hours again. 50 µl of MTT solution (2 mg/ml) was added to each well, and incubated at 37° C. for 4 hours. After discarding the supernatant from the plate, 50 µl of DMSO was added to each well and incubated for 10 minutes at room temperature. The absorption at 590 nm was measured using a microplate spectrometer Epoch2 (BioTek, USA), and the GI50 was calculated using the Prism (GraphPad) program, and the results are shown in Table 2 below.

The compounds of the present invention have a GI50 concentration of about 0.001 μM to 2.0 μM for HREC and/or HUVEC cells, and most of the compounds of Synthesis Examples have a GI50 concentration of 0.5 μM or less, especially Synthesis Examples 22, 24-29, 38 compounds They have a GI50 value of 0.005 μM or less.

<Example 2> Tube formation assay

After treatment of the example compound on microvascular endothelial cells, the ability to form a tubular structure was measured. More specifically, 96 well plates were coated with 50 μl of Matrigel (Corning, USA), and incubated at 37° C. for 30 minutes. HREC (25,000 cells/well), HUVEC (30,000 cells/well) cells were placed in 96 well plates coated with Matrigel, and the example compounds were treated in a CO ₂ incubator at 37° C. for 16 hours. Subsequently, the formed tubular structure was observed with an inverted microscope ECLIPSE TS100 (Nikon, Japan) (FIG. 5). Alternatively, after discarding the medium, 50 µl (8 µg/ml, Corning) of calcein AM (calcein AM; calcein acetoxymethyl) solution, which is a fluorescent cell-permeable derivative of calcein, was added to stain the cells. After incubation at 37°C for 30 minutes, cells were washed with Hank's Balanced Salt solution (HBSS), and observed using a fluorescence microscope ECLIPSE TS100 (Nikon, Japan) equipped with a C-SHG Mercury illuminator 50W (Nikon, Japan) (Fig. 1 to 4). The branch length was measured using the image J program.

In Table 2, when the tube formation of HREC and HUVEC cells was inhibited in 0.5 μM of the compound of Synthesis Example, it was indicated as "Ο". Most of the compounds inhibited tube formation below 0.5 μM.

In particular, in HREC cells, the analyzed Synthesis Example compounds inhibited tube formation in a concentration-dependent manner at 0.1 μM and 0.5 μM, respectively (Figs. 1 and 2), and concentration-dependently inhibited tube formation in HUVEC cells (Figs. 3 and 4). .

5 shows the results of inhibition of tube formation by the compounds of the synthesis example in HREC cells. SH-11008 hardly inhibited tube formation even by 0.1 μM treatment, whereas the compounds 23, 30, 43, and 45 of Synthesis Examples inhibited tube formation at 0.05 μM and 0.1 μM.

Synthesis example GI50 (HREC)
(μM) GI50 (HUVEC)
(μM) Inhibition of tube formation
(0.5 μM) 1 (SH-18070) 0.285 0.2518 ○ 2 (SH-19028) 0.05896 0.0693 ○ 3 (SHA-001) 0.4859 1.974 ○ 4 (SHA-003) 0.5728 3.123 ○ 5 (SHA-004) 0.2995 4.484 ○ 6 (SHA-007) 0.4639 1.695 ○ 7 (SHA-014) 0.1679 2.133 ○ 8 (SHA-028) 0.2495 0.4236 ○ 9 (SHA-029) 3.612 0.3739 ○ 10 (SHA-030) 0.1521 3.096 ○ 11 (SH-19032) 0.2198 0.1772 ○ 12 (SH-19033) 0.1465 0.09257 ○ 13 (SH-19034) 0.2468 0.1673 ○ 14 (SH-19035) 0.1443 0.1083 ○ 15 (SH-19056) 0.162 0.139 ○ 16 (SH-19030) 1.492 2.297 ○ 17 (SH-19122) 0.0078 N.D N.D 18 (SH-19120) 0.54 N.D N.D 19 (SH-18063) 0.3427 2.749 ○ 20 (SH-19019) 0.1623 0.2176 ○ 21 (SH-19020) 0.02199 0.01403 ○ 22 (SH-19029) 0.001772 0.001906 ○ 23 (SH-17060) 0.009876 N.D ○ 24 (SHA-031) 0.003616 0.001914 N.D 25 (SHA-032) 0.003398 0.001465 N.D 26 (SHA-033) 0.002882 0.001586 N.D 27 (SHA-034) 0.001425 0.001358 ○ 28 (SHA-035) 0.00091 0.001266 ○ 29 (SH-19039) 0.0021 0.002813 ○ 30 (SH-19027) 0.005498 0.002964 ○ 31 (SH-19048) 0.0308 0.02581 ○ 32 (SH-19049) 0.9219 0.5282 ○ 33 (SH-19050) 1.209 0.6667 ○ 34 (SH-19052) 0.4262 0.3643 ○ 35 (SH-19055) 0.3154 0.2063 ○ 36 (SH-18075) 0.059 0.03094 N.D 37 (SH-19031) 1.512 0.6434 ○ 38 (SH-19021) 0.00415 0.00226 ○ 39 (SH-19018) 0.2889 0.1622 ○ 40 (SH-18078) 0.2971 0.2481 N.D 41 (SH-18089) 0.08123 0.02727 N.D 42 (SH-19058) 0.4746 0.4341 ○ 43 (SH-20002) 0.0078 N.D ○ 44 (SH-19123) 0.1883 N.D N.D 45 (SH-19121) 0.021 N.D ○ 46 (SH-17031) 0.052 N.D N.D 47 (SH-17040) 0.098 N.D N.D 48 (SH-19036) 0.138 0.07608 ○

N.D was not measured

As shown in Table 2 above,

The example compounds provided in one aspect of the present invention have excellent angiogenesis inhibitory activity, so they are useful for the prevention or treatment of neovascular eye diseases such as cancer or macular degeneration, retinopathy of prematurity, or diabetic retinopathy. Can be used.

<Formulation Example 1> Preparation of pharmaceutical formulation

1-1. Preparation of powder

500 mg of the compound of formula 1

100 mg lactose

Talc 10 mg

The above ingredients are mixed and filled in an airtight cloth to prepare a powder.

1-2. Manufacture of tablets

500 mg of the compound of formula 1

Corn starch 100 mg

100 mg lactose

2 mg of magnesium stearate

After mixing the above ingredients, tablets are prepared by tableting according to a conventional tablet preparation method.

1-3. Preparation of capsules

500 mg of the compound of formula 1

Corn starch 100 mg

100 mg lactose

2 mg of magnesium stearate

According to a conventional capsule preparation method, the above ingredients are mixed and filled into gelatin capsules to prepare a capsule.

1-4. Preparation of injections

500 mg of the compound of formula 1

Suitable amount of sterile distilled water for injection

proper amount of pH adjuster

It is prepared with the above ingredients per ampoule (2 ml) according to a conventional injection preparation method.

1-5. Preparation of liquid

100 mg of the compound of formula 1

10 g of isomerized sugar

5 g of mannitol

Purified water appropriate amount

According to the usual preparation method of liquid preparation, add and dissolve each component in purified water, add lemon scent, mix the above ingredients, add purified water, add purified water, adjust the total to 100 ml, and fill in a brown bottle The liquid is prepared by sterilization.

In the above, the present invention has been described in detail through preferred manufacturing examples, examples and experimental examples, but the scope of the present invention is not limited to specific examples, and should be interpreted by the appended claims. In addition, those who have acquired ordinary knowledge in this technical field should understand that many modifications and variations can be made without departing from the scope of the present invention.

Claims (15)

A compound represented by the following Formula 1, a hydrate thereof, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof:
[Formula 1]

(In Formula 1,
remind

Is a single bond or a double bond;
X is CH or N;

The R ¹ , R ² , R ³ , R ⁴ , R ⁵ and R ⁶ are independently -H, -OH, =O, halogen, nitro, nitrile, C _1-10 straight or branched chain alkyl, C _1-10 straight or branched alkoxy, C _3-10 cycloalkyl, C _1-5 straight or branched alkoxy, or -0-(CH ₂ ) _n -CH=CH ₂ , wherein n is 1 to Is an integer of 10; And

R ⁷ is -H, -OH, halogen, C _1-10 straight or branched chain alkyl, C _1-10 straight or branched chain alkoxy, C _1-10 straight or branched alkylcarbonyloxy,

, or

ego;

The A ¹ and A ² are independently -H, -(CH ₂ ) _m -O(C=O)-CH=CH ₂ , C _1-10 linear or branched alkoxycarbonyl C _1-5 linear or Branched chain alkyl, -(CH ₂ ) _p -CH=CH ₂ , 5 to 6 membered unsubstituted or substituted heterocycloalkyl containing one or more heteroatoms selected from the group consisting of N, O and S, C _{1 -5} straight or branched chain alkylcarbonyloxy C _1-5 straight or branched chain alkyl, unsubstituted or substituted C _6-8 aryl C _1-5 straight or branched chain alkyl,

, or

ego,
Here, m is an integer of 1 to 10, p is an integer of 1 to 10,
The substituted heterocycloalkyl is a C _6-8 aryl C _1-5 straight or branched chain alkyl substituted heterocycloalkyl, and the substituted C _6-8 aryl is C _{6- Is} an aryl of ₈ ,
_Wherein A ³ is a C _6-8 aryl C _1-5 straight or branched chain alkyl,
_Wherein A ⁴ is C _1-10 straight or branched chain alkyl,
_Wherein A ⁵ is C _1-10 straight or branched chain alkyl,
A ⁶ is a C _6-8 aryl C _1-5 straight or branched chain alkyl, C _1-5 straight or branched chain alkylsulfanyl C _1-5 straight or branched chain alkyl, or C _1-5 Straight or branched alkoxycarbonylamino C _1-5 straight or branched alkyl;

The B ¹ and B ² are unsubstituted or single C _1-10 of 5 to 6 atoms including one or more heteroatoms selected from the group consisting of N, O and S by being linked together with the carbon atom to which they are attached. Or a branched alkoxycarbonyl group to form a substituted heterocycloalkyl, or
Wherein B ¹ and B ² are independently -H, C _1-10 straight or branched chain alkyl, 5 to 6 membered heterocycloalkyl C containing at least one heteroatom selected from the group consisting of N, O and S _1-5 straight or branched chain alkyl, unsubstituted or substituted C _6-8 aryl C _1-5 straight or branched chain alkyl, C _1-5 straight or branched chain alkylcarbonylamino, N, O and 5- to 10-membered heteroaryl C _1-5 straight or branched chain alkyl containing one or more heteroatoms selected from the group consisting of S, C _1-5 straight or branched alkoxycarbonylamino, diC _{1- 10} straight or branched chain alkylamino, or

ego,
Here, B ³ is C _1-10 straight or branched chain alkyl, or C ₆ aryl C _1-10 straight or branched chain alkyl,
The substituted C _6-8 aryl is C ₆ aryl C _1-5 straight or branched alkoxy, C _1-5 straight or branched alkoxy, C _1-5 straight or branched alkyl, halogen and At least one substituent selected from the group consisting of nitro is substituted C _6-8 aryl).
The method of claim 1,
R ¹ is -H, or -OCH ₃ ;
R ² is -H, -F, -Cl, -OCH ₃ , -OH, or

ego;
R ³ is -H, -CI, -OCH ₃ , or -OCH ₂ CH=CH ₂ ;
R ⁴ is -H, -F, -CI, or -OCH ₃ ;
R ⁵ is -H, -CH ₃ , or =O;
R ⁶ is -H, -F, -Cl, -OCH ₃ , -OCH ₂ CH ₃ , -OCH ₂ CH ₂ CH ₃ , -OCH(CH ₃ ) ₂ , -OCH ₂ CH=CH ₂ or -OH ; And
R ⁷ is -H, -F, -OH, -OCH ₃ , -CF ₃

_,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,,

,

,

,

,

,

,

,

,

,

, or

A phosphorus compound, a hydrate thereof, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof. The method of claim 1,
[Chemical Formula 1] is a compound represented by the following [Chemical Formula 1-1], a hydrate thereof, a stereoisomer thereof, or a pharmaceutically usable salt thereof
[Formula 1-1]

R ⁷ is -H, -F, -OH, -OCH ₃ ,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

, or

to be. The method of claim 1,
[Chemical Formula 1] is a compound represented by the following [Chemical Formula 1-2], a hydrate thereof, a stereoisomer thereof, or a pharmaceutically usable salt thereof
[Formula 1-2]

R ² is -OCH ₃ , or

ego;
R ³ is -OCH ₃ or -OCH ₂ CH=CH ₂ .
The method of claim 1,
[Chemical Formula 1] is a compound represented by the following [Chemical Formula 1-3], a hydrate thereof, a stereoisomer thereof, or a pharmaceutically usable salt thereof
[Formula 1-3]

R ¹ is -H, or -OCH ₃ ;
R ² is -H, -F, -Cl, -OCH ₃ , -OH, or

ego;
R ³ is -H, -CI, -OCH ₃ , or -OCH ₂ CH=CH ₂ ;
R ⁵ is -H or -CH ₃ ;
R ⁶ is -H, -F, -Cl, -OCH ₃ , -OCH ₂ CH ₃ , -OCH ₂ CH ₂ CH ₃ , -OCH(CH ₃ ) ₂ , -OCH ₂ CH=CH ₂ or -OH ; And
R ⁷ is -F, -OH, -CF ₃ , -OCH ₃ ,

,

,

,

,

,

,

,

,

,

,

,

,

,

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,

,

,

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,

,

,

,

,

,

,

,

,

,

,

, or

to be. The method of claim 1,
[Chemical Formula 1] is a compound represented by the following [Chemical Formula 1-4], a hydrate thereof, a stereoisomer thereof, or a pharmaceutically usable salt thereof.
[Formula 1-4]

R ¹ is -H, -Cl, -F, or -OMe;
R ² is -H, -Cl, -F, or -OMe;
R ³ is -H, -Cl, -F, or -OMe;
R ⁴ is -H, -Cl, -F, or -OMe. The method of claim 1,
[Chemical Formula 1] is a compound represented by the following [Chemical Formula 1-5], a hydrate thereof, a stereoisomer thereof, or a pharmaceutically usable salt thereof.
[Formula 1-5]

R ¹ is -H, -Cl, -F, or -OMe;
R ² is -H, -Cl, -F, or -OMe;
R ³ is -H, -Cl, -F, or -OMe;
R ⁴ is -H, -Cl, -F, or -OMe. The method of claim 1,
The compound is any one compound selected from the following compound group, a hydrate thereof, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof:
(1) 5-((6,8-dichlorochroman-3-yl)methyl)-2-methoxyphenol;
(2) 5-(chroman-3-ylmethyl)-2-methoxyphenol;
(3) 5-((5,7-dimethoxychroman-3-yl)methyl)-2-methoxyphenol;
(4) (R)-2-methoxy-5-((5,6,7-trimethoxychroman-3-yl)methyl)phenol;
(5) (S)-2-methoxy-5-((5,6,7-trimethoxychroman-3-yl)methyl)phenol;
(6) 3-(3,4-dimethoxybenzyl)-5,6,7-trimethoxychroman;
(7) 5-((7,8-dimethoxychroman-3-yl)methyl)-2-methoxyphenol;
(8) 5-((6,7-dimethoxychroman-3-yl)methyl)-2-methoxyphenol;
(9) 3-(3-hydroxy-4-methoxybenzyl)-5,7-dimethoxychroman-6-ol;
(10) 2-methoxy-4-((5,6,7-trimethoxychroman-3-yl)methyl)phenol;
(11) 3-(3-fluoro-4-methoxybenzyl)-5,6,7-trimethoxychrome;
(12) 2-methoxy-5-((5,6,7-trimethoxychroman-3-yl)methyl)phenyl 5-(1,2-dithiolan-3-yl)pentanoate;
(13) 3-benzyl-5,6,7-trimethoxychroman;
(14) 2-methoxy-6-((5,6,7-trimethoxychroman-3-yl)methyl)pyridine;
(15) 2-methoxy-5-((5,6,7-trimethoxy-4-oxochroman-3-yl)methyl)phenyl (tert-butoxycarbonyl)-L-leucinate;
(16) 2-methoxy-5-((5,6,7-trimethoxy-4-oxochroman-3-yl)methyl)phenyl (2S)-3-(4-(benzyloxy)phenyl) -2-((tert-butoxycarbonyl)amino)propanoate;
(17) 2-methoxy-5-((5,6,7-trimethoxy-4-oxochroman-3-yl)methyl)phenyl (2S)-3-(4-(tert-butoxy) Phenyl)-2-((tert-butoxycarbonyl)amino)propanoate;
(18) 2-methoxy-5-((5,6,7-trimethoxy-4-oxochroman-3-yl)methyl)phenyl ((benzyloxy)carbonyl)-L-phenylalaninate ;
(19) 2-methoxy-5-((5,6,7-trimethoxy-4-oxochroman-3-yl)methyl)phenyl (2S)-2-((tert-butoxycarbonyl) Amino)-4-phenylbutanoate;
(20) 6,8-difluoro-3-(3-hydroxy-4-methoxybenzyl)chroman-4-one;
(21) 6-fluoro-3-(3-hydroxy-4-methoxybenzyl)chroman-4-one;
(22) (E)-6-chloro-3-(3-hydroxy-4-methoxybenzylidene)chroman-4-one;
(23) (E)-7-chloro-3-(3-hydroxy-4-methoxybenzylidene)chroman-4-one;
(24) (E)-6-fluoro-3-(3-hydroxy-4-methoxybenzylidene)chroman-4-one;
(25) 6,8-dichloro-3-(3-hydroxy-4-methoxybenzyl)chroman-4-one;
(26) 2-methoxy-5-((5,6,7-trimethoxy-4-oxochroman-3-yl)methyl)phenyl (2S)-2-((tert-butoxycarbonyl) Amino)-3-(4-fluorophenyl)propanoate;
(27) 2-methoxy-5-((5,6,7-trimethoxy-4-oxochroman-3-yl)methyl)phenyl (2S)-2-((tert-butoxycarbonyl) Amino)-3-(4-nitrophenyl)propanoate;
(28) 2-methoxy-5-((5,6,7-trimethoxy-4-oxochroman-3-yl)methyl)phenyl (2S)-2-((tert-butoxycarbonyl) Amino)-3-(p-tolyl)propanoate;
(29) 2-methoxy-5-((5,6,7-trimethoxy-4-oxochroman-3-yl)methyl)phenyl acetyl-L-phenylalaninate;
(30) 2-methoxy-5-((5,6,7-trimethoxy-4-oxochroman-3-yl)methyl)phenyl (tert-butoxycarbonyl)-L-tryptophanate;
(31) 5-((6,8-dichloro-4-oxochroman-3-yl)methyl)-2-methoxyphenyl (tert-butoxycarbonyl)-L-phenylalaninate;
(32) 2-methoxy-5-((5,6,7-trimethoxy-4-oxochroman-3-yl)methyl)phenyl (tert-butoxycarbonyl)-D-phenylalaninate ;
(33) 2-methoxy-5-((5,6,7-trimethoxy-4-oxochroman-3-yl)methyl)phenyl (2S)-3-(4-bromophenyl)-2 -((tert-butoxycarbonyl)amino)propanoate;
(34) 1-(tert-butyl) 3-(2-methoxy-5-((5,6,7-trimethoxy-4-oxochroman-3-yl)methyl)phenyl)piperidine- 1,3-dicarboxylate;
(35) 2-methoxy-5-(((S)-5,6,7-trimethoxy-4-oxochroman-3-yl)methyl)phenyl (tert-butoxycarbonyl)-L- Phenylalaninate;
(36) 2-methoxy-5-(((R)-5,6,7-trimethoxy-4-oxochroman-3-yl)methyl)phenyl (tert-butoxycarbonyl)-L- Phenylalaninate;
(37) (S)-3-(3-hydroxy-4-methoxybenzyl)-5,6,7-trimethoxychroman-4-one;
(38) (R)-3-(3-hydroxy-4-methoxybenzyl)-5,6,7-trimethoxychroman-4-one;
(39) 2-methoxy-5-((5,6,7-trimethoxy-4-oxochroman-3-yl)methyl)phenyl pivalate;
(40) tert-butyl (2-methoxy-5-((5,6,7-trimethoxy-4-oxochroman-3-yl)methyl)phenyl) ((R)-3-phenylpropane- 1,2-diyl)dicarbamate;
(41) 7-(allyloxy)-3-(3-hydroxy-4-methoxybenzyl)-5,6-dimethoxychroman-4-one;
(42) 2-methoxy-5-((5,6,7-trimethoxy-4-oxochroman-3-yl)methyl)phenyl dimethyl-L-phenylalaninate;
(43) 2-methoxy-5-((5,6,7-trimethoxy-4-oxochroman-3-yl)methyl)phenyl ((S)-1-phenylethyl)carbamate;
(44) 2-methoxy-5-((5,6,7-trimethoxy-4-oxochroman-3-yl)methyl)phenyl ((R)-1-phenylethyl)carbamate;
(45) 2-methoxy-5-((5,6,7-trimethoxy-4-oxochroman-3-yl)methyl)phenyl (4-fluorophenethyl)carbamate;
(46) 2-methoxy-5-((5,6,7-trimethoxy-4-oxochroman-3-yl)methyl)phenyl (1-benzylpiperidin-4-yl)carbamate;
(47) methyl ((2-methoxy-5-((5,6,7-trimethoxy-4-oxochroman-3-yl)methyl)phenoxy)carbonyl)-L-phenylalaninate ;
(48) ethyl ((2-methoxy-5-((5,6,7-trimethoxy-4-oxochroman-3-yl)methyl)phenoxy)carbonyl)glycinate;
(49) 2-methoxy-5-((5,6,7-trimethoxy-4-methylchroman-3-yl)methyl)phenol;
(50) 5,6,7-trimethoxy-3-(4-methoxybenzyl)chroman-4-one;
(51) (E)-6-(cyclopropylmethoxy)-3-(3-hydroxy-4-methoxybenzylidene)-5,7-dimethoxychroman-4-one;
(52) 6-(cyclopropylmethoxy)-3-(3-hydroxy-4-methoxybenzyl)-5,7-dimethoxychroman-4-one;
(53) 2-methoxy-5-((5,6,7-trimethoxy-4-oxochroman-3-yl)methyl)phenyl 5-(1,2-dithiolan-3-yl) Pentanoate;
(54) tert-butyl ((2-methoxy-5-((5,6,7-trimethoxy-4-oxochroman-3-yl)methyl)phenoxy)carbonyl)-L-alani Nate;
(55) tert-butyl ((2-methoxy-5-((5,6,7-trimethoxy-4-oxochroman-3-yl)methyl)phenoxy)carbonyl)-L-valinate ;
(56) tert-Butyl N ⁶ -(t-butoxycarbonyl)-N ² -((2-methoxy-5-((5,6,7-trimethoxy-4-oxochroman-3- I)methyl)phenoxy)carbonyl)-L-lysinate;
(57) tert-butyl ((2-methoxy-5-((5,6,7-trimethoxy-4-oxochroman-3-yl)methyl)phenoxy)carbonyl)glycinate;
(58) methyl ((2-methoxy-5-((5,6,7-trimethoxy-4-oxochroman-3-yl)methyl)phenoxy)carbonyl)-L-methioninate;
(59) (2-methoxy-5-((5,6,7-trimethoxychroman-3-yl)methyl)phenyl(tert-butoxycarbonyl)-L-phenylalaninate;
(60) 2-methoxy-5-((5,6,7-trimethoxy-4-oxochroman-3-yl)methyl)phenyl)benzylcarbamate;
(61) 2-methoxy-5-((5,6,7-trimethoxy-4-oxochroman-3-yl)methyl)phenyl diethylcarbamate;
(62) 3-3(fluoro-4-methoxybenzyl)-5,6,7-trimethoxychroman-4-one;
(63) 5-(1,2-dithiolan-3-yl)-H-(2-methoxy-5-((5,6,7-trimethoxy-4-oxochroman-3-yl) Methyl)phenyl)pentanamide;
(64) 2-(((2-methoxy-5-((5,6,7-trimethoxychroman-3-yl)methyl)phenoxy)carbonyl)amino)ethyl acrylate;
(65) butyl ((2-methoxy-5-((5,6,7-trimethoxychroman-3-yl)methyl)phenoxy)carbonyl)glycinate;
(66) 2-methoxy-5-((5,6,7-trimethoxychroman-3-yl)methyl)phenyl allylcarbamate;
(67) 2-methoxy-5-((5,6,7-trimethoxychroman-3-yl)methyl)phenyl (1-benzylpiperidin-4-yl)carbamate;
(68) 2-(((2-methoxy-5-((5,6,7-trimethoxychroman-3-yl)methyl)phenoxy)carbonyl)amino)ethyl propionate;
(69) tert-butyl (2-methoxy-5-((5,6,7-trimethoxychroman-3-yl)methyl)phenyl) ((R)-3-phenylpropane-1,2- Diyl) dicarbamate;
(70) 3-(4-ethoxy-3-fluorobenzyl)-5,6,7-triethoxychroman;
(71) 3-(3-fluoro-4-propoxybenzyl)5,6,7-trimethoxychroman;
(72) 3-(3-fluoro-4-isopropoxybenzyl)-5,6,7-trimethoxychroman;
(73) 3-4(-(allyloxy)3-fluorobenzyl)-5,6,7-trimethoxychroman;
(74) 3-(4-chloro-3-(trifluorobetyl)benzyl)-5,6,7-trimethoxychroman;
(75) 3-(3-fluoro-5-methoxybenzyl)-5,6,7-trimethoxychroman;
(76) 2-methoxy-5-((5,6,7-trimethoxy-4-ketylchroman-3-yl)methyl)phenyl 5-(1,2-dithiolan-3-yl)penta No eight; (77) 5-((6-(cyclopropylmethoxy)-5,7-dimethoxychroman-3-yl)methyl)-2-methoxyphenol
(78) 2-methoxy-5-(((R)-5,6,7-trimethoxychroman-3-yl)methyl)phenyl-(tert-butoxycarbonyl)-L-phenylalani Nate;
(79) (R)-3-(3-fluoro-4-methoxybenzyl)-5,6,7-trimethoxychroman-4-one;
(80) (S)-3-(3-fluoro-4-methoxybenzyl)-5,6,7-trimethoxychroman;
(81) 2-methoxy-5-((( R )-5,6,7-trimethoxychroman-3-yl)methyl)phenyl ( tert -butoxycarbonyl)-L-phenylalaninate ;
(82) ( S )-3-(3-fluoro-4-methoxybenzyl)-5,6,7-trimethoxychroman; And
(83) ( R )-3-(3-fluoro-4-methoxybenzyl)-5,6,7-trimethoxychroman; A pharmaceutical composition for the prevention or treatment of cancer or neovascular eye disease, comprising the compound of any one of claims 1 to 8, a hydrate thereof, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof. . The method of claim 9,
The pharmaceutical composition is a pharmaceutical composition for preventing or treating cancer. The method of claim 10,
The cancer is a solid cancer, a pharmaceutical composition for preventing or treating cancer. The method of claim 11,
The pharmaceutical composition is a pharmaceutical composition for preventing or treating cancer used with a second therapeutic agent which is an anticancer agent. The method of claim 9,
The pharmaceutical composition is a pharmaceutical composition for the prevention or treatment of neovascular eye disease. The method of claim 13,
The neovascular eye disease is macular degeneration, retinopathy of prematurity, or diabetic retinopathy, a pharmaceutical composition for the prevention or treatment of neovascular eye disease. The method of claim 9,
The pharmaceutical composition further comprises a pharmaceutically acceptable carrier or excipient.

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