KR20120079274A - A novel deguelin derivatives or its pharmaceutically acceptable salts and pharmaceutical composition containing the same as an active ingredient - Google Patents

Abstract

PURPOSE: A pharmaceutical composition containing a compound which suppresses HIF-1 activation is provided to selectively suppress HIF-1alpha protein accumulation and VEGF(vascular endothelial growth factor) activation. CONSTITUTION: A compound which suppresses HIF-1 activation is denoted by chemical formula 1 or 2. A pharmaceutical composition for preventing or treating cancer contains the compound of chemical formula 1 or 2. A pharmaceutical composition for preventing or treating diabetic retinopathy contains the compound of chemical formula 1 or 2. A pharmaceutical composition for preventing or treating rheumatic arthritis contains the compound of chemical formula 1 or 2.

Description

Novel deguelin derivatives or its pharmaceutically acceptable salts and pharmaceutical compositions containing the same as active ingredients

The present invention relates to a deguelin derivative that inhibits Hsp90 and a pharmaceutical composition containing the same as an active ingredient.

Molecular chaperones, such as heat-shock protein families (HSPs), regulate the folding of client proteins through ATP-dependent structural changes to help activate nascent proteins, refold or degrade damaged proteins. Protein. In addition, client proteins avoid aggregation by binding to molecular chaperones, and their binding aids intracellular deposition through membrane translocation of client proteins.

The molecular chaperone function of Hsp90, a family of heat shock proteins, is known to be necessary for the stability and activation of various client proteins involved in cell signaling pathways. Under normal conditions without external stimulation, the amount of Hsp90 accounts for 1-2% of the intracellular protein, but under external stimulation, the amount of Hsp90 doubles. Cancer-causing mutations in client proteins require higher levels of Hsp90 function and lead to overexpression of Hsp90, and overexpressed Hsp90 compared to normal tissue is a common feature of cancer cells [Bagatell, R .; Whitesell, L. Altered Hsp90 function in cancer: A unique therapeutic opportunity. Mol . Cancer Ther . 2004, 3 , 1021-1030.

ErbB2, Src, Met tyrosine kinase, MEK 1/2 (mitogen-activated protein kinase kinase), Akt, Raf-1, Cyclin-dependent serine kinases, steroid hormone receptors, telomerases, Hsp90 client proteins, including metalloprotein-2 (MMP-2) and hypoxia-inducible factor-1α (HIF-1α), are available on a variety of signaling pathways, including cell survival, proliferation, invasion, metastasis, and neovascularization. Present and are known to contribute to malignant phenotypes [Eustace, BK; Sakurai, T .; Stewart, JK; Yimlamai, D .; Unger, C .; Zehetmeier, C .; Lain, B .; Torella, C .; Henning, SW; Beste, G .; Scroggins, BT; Neckers, L .; Ilag, LL; Jay, DG Functional proteomic screens reveal an essential extracellular role for hsp90 alpha in cancer cell invasiveness. Nat . Cell Biol . 2004, 6 , 507-514.

In particular, HIF-1α, together with HIF-1β, constitutes a subunit of the hypoxia-inducible factor (HIF), which is an oxygen-labile transcription factor and is one of the neovascularization-regulatory proteins. Induces neovascularization in terms of vascular destruction and vascular dysfunction. Angiogenesis is the process of creating new blood vessels and is required for repair, regeneration and development of blood vessels or metabolically activated tissue.

However, pathological neovascularization not only plays an important role in the growth and expansion of cancer through metastasis, but also induces bleeding, blood vessel leakage, and tissue destruction by abnormally fast neovascularization. As a result, pathological neovascularization can lead to various neovascularization dependent diseases including diabetic retinopathy and macular degeneration, as well as cancer, and are known to be associated with chronic infectious diseases such as psoriasis and rheumatoid arthritis.

Therefore, inhibition of Hsp90 can be considered as a new and effective treatment for angiogenesis-related diseases, and Hsp90 inhibitors are potential chemotherapeutic agents for angiogenesis-related diseases [Eccles, S .; Massey, A .; Raynaud, F .; Sharp, S .; Box, G .; Valenti, M .; Patterson, L .; de Haven Brandon, A .; Gowan, S .; Boxall, F. NVP-AUY922: a novel heat shock protein 90 inhibitor active against xenograft tumor growth, angiogenesis, and metastasis. Cancer Res . 2008, 68 , 2850].

Hsp90 exists mostly as a homodimer and consists of an N-terminal region, an intermediate region, and a C-terminal region. In particular, the N-terminal region has an adenine nucleotide-binding pocket, which includes a unique structural motif, also known as the Bergerrat fold, that distinguishes Hsp90 from Hsp70 or other kinases. Have an ATP-binding region. This structural specificity suggests the possibility of developing highly selective Hsp90 inhibitors and several Hsp90 inhibitors are known as shown below.

Geldanamycin ( 2 ) and its less toxic derivative 17-AAG (17-arylamino-17-dimethoxy geldanamycin), radicicol ( 3 ) and more stable oxime derivatives, and synthetic derivatives PU3 ( 4) Most Hsp90 inhibitors, such as), are known to interact with the ATP-binding pockets of the N-terminal region of Hsp90, whereas the novel antibiotic novobiocin ( 5 ) is known to inhibit Hsp90. It interacts with the ATP-binding pocket of the C-terminal region to show an effective Hsp90 inhibitory effect. These Hsp90 inhibitors showed significant chemopreventive effects in preclinical models of various cancer cell lines by promoting the degradation of various cancer-induced Hsp90 client proteins. In addition, some Hsp90 inhibitors, including 17-AAG, have entered the clinical stage.

Deguelin ( 1 ) [Clark, E., A relation between rotenone, deguelin and tephrosin. 1931; Vol. 73, pp 17-18.] Is a rotenoid compound isolated from the plant of African origin mundulea sericea, and is known to prevent lung carcinogenesis induced by tobacco carcinogens by blocking Akt activation. In vitro experiments with various transformed and cancer cell lines showed cell death and angiogenesis inhibition [Lee, H. Molecular mechanisms of deguelin-induced apoptosis in transformed human bronchial epithelial cells. Biochem . Pharmacol . 2004, 68 , 1119-1124.

Although deguelin's potential as an anticancer or angiogenesis inhibitor has been identified in terms of efficacy, toxicity, low solubility and chemical instability have shown deguelin's limitation as a drug.

Accordingly, the present inventors synthesized derivatives having low toxicity and improved physicochemical properties while maintaining the activity of deguelin based on the three-dimensional conformation of deguelin and confirmed the Hsp90 inhibitory effect of the novel deguelin derivatives. The present invention was completed.

It is an object of the present invention to provide novel compounds that inhibit Hsp90.

Another object of the present invention to provide a pharmaceutical composition for treating cancer containing the novel compound as an active ingredient.

Another object of the present invention to provide a pharmaceutical composition for treating diabetic retinopathy containing the novel compound as an active ingredient.

Another object of the present invention to provide a pharmaceutical composition for treating rheumatoid arthritis containing the novel compound as an active ingredient.

In order to achieve the above object, there is provided a novel compound represented by the following formula (1) or a pharmaceutically acceptable salt thereof:

[Formula 1]

(In Formula 1, R ¹ to R ⁵ are as defined herein).

The present invention also provides a novel compound represented by the following formula (2) or a pharmaceutically acceptable salt thereof:

[Formula 2]

(In Formula 2, R ^a and R ^b are as defined herein).

Furthermore, the present invention provides a pharmaceutical composition for preventing or treating cancer, containing the compound of Formula 1 and Formula 2 or a pharmaceutically acceptable salt thereof as an active ingredient.

The present invention also provides a pharmaceutical composition for preventing or treating diabetic retinopathy containing the compound of Formula 1 and Formula 2 or a pharmaceutically acceptable salt thereof as an active ingredient.

Furthermore, the present invention provides a pharmaceutical composition for preventing or treating rheumatoid arthritis, containing the compound of Formula 1 and Formula 2 or a pharmaceutically acceptable salt thereof as an active ingredient.

Compounds of Formula 1 and Formula 2 according to the present invention inhibit Hsp90 expression, inhibit the accumulation of Hsp-1 client protein HIF-1α protein and effectively inhibit the activity of angiogenesis factor (VEGF), anticancer agent, diabetic retinopathy And it can be used as an active ingredient of arthritis therapeutics.

1 is a Western blot diagram showing the extent to which the compounds according to an embodiment of the present invention inhibits HIF-1α accumulation.
Figure 2 is a photograph showing the effect of compound 53 on neovascularization according to an embodiment of the present invention.
3 is a photograph showing the effect of compound 69 on neovascularization according to an embodiment of the present invention.
Figure 4 is a photograph showing the effect of compound 72 on neovascularization according to an embodiment of the present invention.

Hereinafter, the present invention will be described in detail.

The present invention provides a novel deguelin derivative represented by the following formula (1) or a pharmaceutically acceptable salt thereof.

In Formula 1,

R ¹ And R ² are each independently -H, -OH, C _{1 - 4} alkoxy, and, _{- 4} straight or branched chain alkyl, or C ₁

R ³ is -H, -OH, = O, -OR ⁶ Or = NOR ⁷ ,

R ⁴ is -H, -OH, C _{1 - 4} alkoxy is, acetate or phenylmethoxy,

R ⁵ is C _{1 - 6} is straight or branched chain alkyl or alkenyl,

,

또는

이고, 및R ⁶ is C _{1 - 6} straight or branched chain alkyl or alkenyl, C _{5 - 8} aryl,

,

or

And

R ⁷ is -H, C _{1 -4} straight or branched chain alkyl, or C _{5 - 8} is aryl.

In this case, R ⁴ and R ⁵ may be achieved for each heterocyclic ring containing 5-8 to each other in the O ring greater than or equal to 1, this ring is -OH or C _{1 - 2} alkyl group may be substituted with more than a 1.

는 단일결합 또는 이중결합이다.
Also,

Is a single bond or a double bond.

Preferably,

R ¹ and R ² are each independently —OH or —OMe,

R ³ is -H, -OH, = O, -OR ⁶ Or = NOR ⁷ ,

R ⁴ is -OH, C _{1 -} and _3-alkoxy, phenyl acetate or methoxy,

R ⁵ is C _{1 - 5,} and a straight chain or branched chain alkyl or alkenyl,

,

또는

이고, 및R ⁶ is C _{1 - 3} linear or branched alkyl or alkenyl, C _{5 - 6} arylalkyl,

,

or

And

R ⁷ is -H, C _{1 -3} straight or branched chain alkyl, or C _{5 - 6} is arylalkyl.

In this case, R ⁴ and R ⁵ may be achieved for each heterocyclic ring containing five or six to one another within the at least one O ring, the ring is -OH or C _{1 - 2} alkyl group may be substituted with more than a 1.

More preferably,

,

,

, =N-OH, =N-OMe 또는 =N-OBn이고,R ³ is —H, —OH, ═O, methoxy, ethoxy, propoxy, propenoxy, benzyloxy,

,

,

, = N-OH, = N-OMe or = N-OBn,

R ⁴ is -OH, methoxy, Pro phenoxy, benzyloxy, genus with lactate or R ⁵ forms a 6 each hetero ring containing another one in the O ring, the ring is -OH or C _{1 - 2} An alkyl group may be substituted one or more,

또는 R⁴와 함께 서로 고리 내 O를 1개 함유하는 6각 헤테로고리를 형성하며, 이 고리에는 -OH 또는 C_{1 - 2}알킬기가 1 이상 치환될 수 있고,R ⁵ is

Or together with R ⁴ forms a 6 to each other, each hetero ring containing one O in the ring, this ring is -OH or C _{1 - 2} alkyl group can be optionally substituted with at least 1,

,

또는

이다.
Ring formed by R ⁴ and R ⁵ is

,

or

to be.

Specific examples of the compound of Formula 1 are as follows.

(6a S , 12a S ) -9-hydroxy-2,3-dimethoxy-8- (3-methyl-2-butenyl) -6a, 12a-dihydrochromeno [3,4- b ] chromen -12 ( 6H ) -on,

(7a S , 13a S ) -9-hydroxy-13,13a-dihydro-10-methoxy-3,3-dimethyl- 3H -chromeno [3,4- b ] pyrano [2,3- h ] chromen-7 (7a H ) -on,

(7a S , 13a S ) -10-hydroxy-13,13a-dihydro-9-methoxy-3,3-dimethyl- 3H -chromeno [3,4- b ] pyrano [2,3- h ] chromen-7 (7a H ) -on,

(7a S , 13a S ) -13,13a-dihydro-9,10-dihydroxy-3,3-dimethyl-3 H -chromeno [3,4- b ] pyrano [2,3- h ] Chromen-7 (7a H ) -on,

9,10-Dimethoxy-3,3-dimethyl -3 H - chroman Agate [3,4- b] pyrano [2,3- h] chromen -7- (13 H) - one,

(7 S, 7a R, 13a S) -9,10- dimethoxy-3,3-dimethyl -7,7a, 13,13a- tetrahydro -3 H - chroman Agate [3,4- b] pyrano [ 2,3- h ] chromen-7-ol,

(7a S , 13a S ) -9,10-dimethoxy-3,3-dimethyl-7,7a, 13,13a-tetrahydro-3 H -chromeno [3,4- b ] pyrano [2,3 h ] chromen,

(7 S, 7a R, 3a S) -7,9,10- -trimethoxy-3,3-dimethyl -7,7a, 13,13a- tetrahydro -3 H - chroman Agate [3,4- b] Pyrano [2,3- h ] chromen,

(7 S, 7a R, 3a S) to 9,10-dimethoxy-3,3-dimethyl-7-ethoxy -7,7a, 13,13a- tetrahydro -3 H - chroman Agate [3,4- b ] pyrano [2,3- h ] chromen,

(7 S, 7a R, 3a S) -9,10- dimethoxy-3,3-dimethyl-7-propoxy -7,7a, 13,13a- tetrahydro -3 H - chroman Agate [3,4- b ] pyrano [2,3- h ] chromen,

(7 S, 7a R, 3a S) -7- benzyloxy-9,10-dimethoxy-3,3-dimethyl -7,7a, 13,13a- tetrahydro -3 H - chroman Agate [3,4- b ] pyrano [2,3- h ] chromen,

(7 S , 7a S , 13a S ) -9,10-dimethoxy-3,3-dimethyl-7- (tetrahydro-2 H -pyran-2-yloxy) -7,7a, 13,13a-tetra Hydro- 3H -chromeno [3,4- b ] pyrano [2,3- h ] chromen,

(7 S , 7a S , 13a S ) -9,10-dimethoxy-3,3-dimethyl-7,7a, 13,13a-tetrahydro-3 H -chromeno [3,4- b ] pyrano [ 2,3, h ] chromen-7-yl acetate,

(7 S , 7a S , 13a S ) -9,10-dimethoxy-3,3-dimethyl-7,7a, 13,13a-tetrahydro-3 H -chromeno [3,4-b] pyrano [ 2,3- h ] chromen-7-yl carbamate,

(13a S ) -9,10-dimethoxy-3,3-dimethyl-13,13a-dihydro-3 H -chromeno [3,4- b ] pyrano [2,3- h ] chromen,

(7a R , 13a S ) -9,10-dimethoxy-3,3-dimethyl-13,13a-dihydro-3 H -chromeno [3,4- b ] pyrano [2,3- h ] chrome Men-7 (7a H ) -one oxime,

(7a R , 13a S ) -9,10-dimethoxy-3,3-dimethyl-13,13a-dihydro-3 H -chromeno [3,4- b ] pyrano [2,3- h ] chrome Mentioned -7 (7a H) - one O - methyl oxime,

(7a R , 13a S ) -9,10-dimethoxy-3,3-dimethyl-13,13a-dihydro-3 H -chromeno [3,4- b ] pyrano [2,3- h ] chrome Men-7 (7a H ) -on O -benzyloxime,

(7a S , 13a S ) -9,10-dimethoxy-3,3-dimethyl-2,3,13,13a-tetrahydro-1 H -chromeno [3,4- b ] pyrano [2,3 h ] chromen-7 (7a H ) -on,

(7a S , 13a S ) -1,2-dihydroxy-9,10-dimethoxy-3,3-dimethyl-2,3,13,13a-tetrahydro-1 H -chromeno [3,4- b ] pyrano [2,3- h ] chromen-7 (7a H ) -one,

2,3,9- trimethoxy-8- (3-methyl-boot-2-enyl) -6a, 12a- dihydro -6 H-chroman Agate [3,4- b] chromen -12- one,

9-aryloxy-2,3-dimethoxy-8- (3-methyl-boot-2-enyl) -6a, 12a- dihydro -6 H-chroman Agate [3,4- b] chromen -12- On,

9-benzyloxy-2,3-dimethoxy-8- (3-methyl-boot-2-enyl) -6a, 12a- dihydro -6 H-chroman Agate [3,4- b] chromen -12- On,

Acetic acid 2,3-dimethoxy-8- (3-methyl-but-2-enyl) -12-oxo-6,6a, 12,12a-tetrahydrochromeno [3,4- b ] chromen-9- One ester, and

(7 S, 7a R, 3a S) -9,10- dimethoxy-3,3-dimethyl-7- (prop-2-en-oxy) -7,7a, 13,13a- tetrahydro -3H- croissant Meno [3,4- b ] pyrano [2,3- h ] chromen.

In addition, the present invention provides a compound represented by the following formula (2) or a pharmaceutically acceptable salt thereof.

In Formula 2,

또는

이고,R ^a is

or

ego,

R ^b is -H, -OH or C _{1 - 3} alkoxy and,

R ^c and R ^d are each independently -H, C _{1 - 3} is straight or branched chain alkyl,

R ^e is independently -H or C ₁ to each other _- and the _3-alkoxy,

, -NH- 또는 C_{1 - 3}알킬 또는 알케닐이고, 및X is

, -NH-, or C _{1 - 3} alkyl or alkenyl, and

,

,

,

,

,

, -NH-,

,

또는 -SO₂Ph이다.Y is -H, C _{1 - 3} alkyl or alkenyl,

,

,

,

,

,

, -NH-,

,

Or -SO ₂ Ph.

In this case, R ^a and R ^b may form a 5-8 hexaheterocycle containing one or more O in a ring, and at least one oxo or dimethoxyphenyl group may be substituted on the ring.

는 단일결합 또는 이중결합이다.
Also,

Is a single bond or a double bond.

Preferably,

또는

이고,R ^a is

or

ego,

R ^b is -H, -OH or C _{1 - 2} alkoxy and,

R ^c and R ^d are each independently -H, C _{1 -} a _divalent straight or branched chain alkyl,

R ^e is independently -H or C ₁ to each other _- and _two alkoxy,

, -NH- 또는 C_{1 - 2}알킬 또는 알케닐이고, 및X is

, -NH-, or C _{1 - 2} alkyl or alkenyl, and

,

,

,

,

,

, -NH-,

,

또는 -SO₂Ph이다.Y is -H, C _{1 - 2} alkyl or alkenyl,

,

,

,

,

,

, -NH-,

,

Or -SO ₂ Ph.

In this case, R ^a and R ^b may form a 5-6 hexaheterocycle containing one or more O in a ring, and at least one oxo or dimethoxyphenyl group may be substituted on the ring.

More preferably,

,

,

,

,

,

,

,

,

또는 R^b와 서로 고리 내 O를 1개 함유하는 6각 헤테로고리를 형성하며, 이 고리에는 옥소 및 디메톡시페닐기가 각각 하나씩 치환될 수 있고,R ^a is

,

,

,

,

,

,

,

,

Or R ^b and a hexagonal heterocyclic ring containing one O in the ring, and each ring may be substituted with one oxo and dimethoxyphenyl group,

R ^{b and} -H, -OH, methoxy or R ^a and each other form a hexagonal heterocycle containing one O in the ring, in which each oxo and dimethoxyphenyl group may be substituted,

또는

이다.
The ring is

or

to be.

Specific examples of the compound of Formula 2 are as follows.

(3 S) -3- (3,4- dimethoxy-phenyl) -8,8- dimethyl-2,3-dihydro -4 H, 8 H - pyrano [2,3- f] chromene-4 On,

(6,7-dimethoxychroman-4-yl) (2,2-dimethyl- 2H -chromen-6-yl)

2- (3,4-dimethoxyphenyl) -1- (2,2-dimethyl- 2H -chromen-6-yl) ethanone,

2- (3,4-dimethoxyphenyl) -1- (5-methoxy-2,2-dimethyl- 2H -chromen-6-yl) ethanone,

2- (3,4-dimethoxyphenyl-1- (5-methoxy-2,2-dimethyl- 2H -chromen-6-yl) propan-1-one

2- (3,4-dimethoxyphenyl) -1- (5-methoxy-2,2-dimethyl- 2H -chromen-6-yl) -2-methylpropan-1-one,

2- (3,4-dimethoxyphenyl) -1- (5-methoxy-2,2-dimethyl- 2H -chromen-6-yl) prop-2-en-1-one,

1- (3,4-dimethoxyphenyl) cyclopropyl) (5-methoxy-2,2-dimethyl- 2H -chromen-6-yl) methanone,

( S ) -2- (3,4-dimethoxyphenyl) -1- (5-methoxy-2,2-dimethyl- 2H -chromen-6-yl) propan-1-one,

( R ) -2- (3,4-dimethoxyphenyl) -1- (5-methoxy-2,2-dimethyl- 2H -chromen-6-yl) propan-1-one,

3- (3,4-dimethoxyphenyl) -8,8- dimethyl -4 H, 8 H - pyrano [2,3- f] chromene-4-one,

6,7-dimethoxy- 2H -chromen-4-yl (2,2-dimethyl- 2H -chromen-6-yl) methanone,

6,7-dimethoxy-2,2-dimethyl- 2H -chromen-4-yl) (4-methoxy-2,2-dimethyl- 2H -chromen-6-yl) methanone,

6,7-dimethoxy-2,2-dimethyl- 2H -chromen-4-yl) (2,2-dimethyl- 2H -chromen-6-yl) methanone,

6,7-dimethoxy- 2H -chromen-4-yl) (4-methoxy-2,2-dimethyl- 2H -chromen-6-yl) methanone,

2- (3,4-dimethoxyphenyl) -1- (5-hydroxy-2,2-dimethyl- 2H -chromen-6-yl) -2- (phenylsulfonyl) ethanone,

(3,4-dimethoxyphenyl) (2,2-dimethyl- 2H -chromen-6-yl) methanone,

( E ) -1- (3,4-dimethoxyphenyl) -3- (2,2-dimethyl- 2H -chromen-6-yl) prop-2-en-1-one,

( E ) -3- (3,4-dimethoxyphenyl) -1- (5-hydroxy-2,2-dimethyl- 2H -chromen-6-yl) prop-2-en-1-one,

( E ) -3- (3,4-dimethoxyphenyl) -1- (2,2-dimethyl- 2H -chromen-6-yl) prop-2-en-1-one,

( E ) -1- (5-hydroxy-2,2-dimethyl- 2H -chromen-6-yl) -3- (2,4,5-trimethoxyphenyl) prop-2-ene-1 -On,

( E ) -3- (3,4-dimethoxyphenyl) -1- (5-methoxy-2,2-dimethyl- 2H -chromen-6-yl) prop-2-en-1-one,

( E ) -1- (5-methoxy-2,2-dimethyl-2H-chromen-6-yl) -3- (2,4,5-trimethoxyphenyl) prop-2-ene-1- On,

2- (3,4-dimethoxy-phenyl) -8,8- dimethyl -4 H, 8 H - pyrano [2,3- f] chromene-4-one,

2- (3,4-dimethoxyphenyl) - N - (5- methoxy-2,2-dimethyl -2 H-chromen-6-yl) acetamido-amide,

N- (3,4-dimethoxybenzyl) -2,2-dimethyl- 2H -chromen-6-carboxamide,

N- (3,4-dimethoxyphenyl) -2,2-dimethyl- 2H -chromen-6-carboxamide,

N- (2,2-dimethyl- 2H -chromen-6-yl) -3,4-dimethoxybenzamide,

( R ) -2- (3,4-dimethoxyphenyl) -1- (2,2-dimethyl- 2H -chromen-6-yl) propan-1-one,

( S ) -2- (3,4-dimethoxyphenyl) -1- (2,2-dimethyl- 2H -chromen-6-yl) propan-1-one.

Specific examples of the novel deguelin derivatives of Formula 1 and Formula 2 according to the present invention are summarized in Table 1 below.

compound rescue

Deguelin
(Deguelin)

Compound 8

Compound 9

Compound 10

Compound 11

Compound 12

Compound 13

Compound 14

Compound 15


Compound 16

Compound 17

Compound 18

Compound 19

Compound 20

Compound 21

Compound 22

Compound 23

Compound 24

Compound 25

Compound 26

Compound 27

Compound 28

Compound 29

Compound 30

Compound 31

Compound 37

Compound 45

Compound 53

Compound 54

Compound 56

Compound 57

Compound 58

Compound 59

Compound 69

Compound 72

Compound 80

Compound 81

Compound 82

Compound 83

Compound 84

Compound 86

Compound 87

Compound 88

Compound 89

Compound 90

Compound 91

Compound 92

Compound 93

Compound 94

Compound 95

Compound 96

Compound 97

Compound 98

Compound 99

Compound 100

Compound 101

The present invention includes all of the novel compounds represented by Formula 1 and Formula 2 or pharmaceutically acceptable salts thereof, as well as possible solvates, hydrates or prodrugs that can be prepared therefrom.

The novel compounds represented by formulas (1) and (2) of the present invention can be used in the form of pharmaceutically acceptable salts, and acid addition salts formed by pharmaceutically acceptable free acids are useful as salts. . Acid addition salts include those derived from inorganic acids such as hydrochloric acid, nitric acid, phosphoric acid, sulfuric acid, hydrobromic acid, hydroiodic acid, nitrous acid or phosphorous acid, and aliphatic mono- and dicarboxylates, phenyl-substituted alkanoates, hydroxyalkanoates, Dioleate, aromatic acid, aliphatic and aromatic sulfonic acids. Such pharmaceutically innocuous salts include, but are not limited to, sulfate, pyrosulfate, bisulfate, sulfite, bisulfite, nitrate, phosphate, monohydrogenphosphate, dihydrogenphosphate, metaphosphate, pyrophosphate chloride, bromide, Butyrate, caprate, heptanoate, propiolate, oxalate, malonate, succinate, succinate, maleic anhydride, maleic anhydride, , Sebacate, fumarate, maleate, butyne-1,4-dioate, hexane-1,6-dioate, benzoate, chlorobenzoate, methylbenzoate, dinitrobenzoate, hydroxybenzoate, Methoxybenzoate, phthalate, terephthalate, benzene sulfonate, toluene sulfonate, chlorobenzene sulfide Propyl sulphonate, naphthalene-1-yne, xylenesulfonate, phenylsulfate, phenylbutyrate, citrate, lactate,? -Hydroxybutyrate, glycolate, maleate, Sulfonate, naphthalene-2-sulfonate or mandelate.

The acid addition salts according to the present invention are dissolved in conventional methods, for example, the novel compounds represented by the formulas (1) and (2) in an excess of aqueous acid solution, and the salts are water-miscible organic solvents such as methanol and ethanol. It may be prepared by precipitation with acetone or acetonitrile. Equivalent amounts of the novel compounds represented by the formulas (1) and (2) and acids or alcohols in water may be heated and then the mixture is evaporated to dryness or the precipitated salts may be produced by suction filtration.

Bases can also be used to make pharmaceutically acceptable metal salts. The alkali metal or alkaline earth metal salt is obtained, for example, by dissolving the compound in an excess amount of an alkali metal hydroxide or an alkaline earth metal hydroxide solution, filtering the insoluble 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. Corresponding silver salts are also obtained by reacting alkali or alkaline earth metal salts with a suitable silver salt (eg, silver nitrate).

The novel deguelin derivatives according to the present invention are [a) Caboni, P .; Sherer, T .; Zhang, N .; Taylor, G .; Na, H .; Greenamyre, J .; Casida, J. Rotenone, deguelin, their metabolites, and the rat model of Parkinson's disease. Chem . Res . Toxicol 2004, 17 , 1540-1548; (b) Anzeveno, P. Rotenoid interconversion. Synthesis of deguelin from rotenone. J. Org . Chem . 1979, 44 , 2578-2580 may be prepared by a method known in the art, but is not limited thereto. In addition, any known method as well as an unknown method may be used as long as it is capable of synthesizing the novel deguelin derivative. .

As described above, the novel deguelin derivatives prepared according to the present invention can be separated and purified by high-performance liquid chromatography after preparation, and the molecular structure can be confirmed by nuclear magnetic resonance.

The present invention also provides a pharmaceutical composition for preventing or treating cancer containing the compound of Formula 1 and Formula 2 or a pharmaceutically acceptable salt thereof as an active ingredient.

Compounds of Formula 1 and Formula 2 or pharmaceutically acceptable salts thereof of the present invention inhibit Hsp90 expression, inhibit the accumulation of Hsp90 client protein HIF-1α protein and effectively inhibit the activity of angiogenesis factor (VEGF). . The inhibition of HIF-1α activity includes both a series of phenomena that inhibit HIF-1α protein accumulation or inhibit the expression of HIF-1α target gene proteins.

As a result of inhibition of accumulation of HIF-1α of the compounds of Formulas 1 and 2 according to the present invention, the compounds according to the present invention were HIF-dependently in a hypoxic condition without affecting the production of comparative tubulin. It has been shown to inhibit -1α accumulation. In particular, the compound 14 of Example 6 according to the present invention was found to be about 10 times more superior to HIF-1α accumulation inhibitory IC ₅₀ value than the conventional material deguelin (Deguelin) (see Table 2 and Figure 1).

In addition, the compounds of the compounds of formulas (1) and (2) according to the present invention are important for cancer growth and metastasis to other tissues, which are known to contribute to cancer proliferation and metastasis among the target genes of HIF-1α. It was shown to inhibit the expression of neovascularization factor VEGF (Vascular endothelial growth factor A) in a concentration-dependent manner (see FIGS. 2 to 4).

Therefore, the compounds of Formula 1 and Formula 2 of the present invention inhibit Hsp90 expression and inhibit Hsp-1 client protein HIF-1α accumulation and effectively inhibit the activity of angiogenesis factor (VEGF), thus, colon cancer, liver cancer, Stomach cancer, breast cancer, colon cancer, bone cancer, pancreatic cancer, head or neck cancer, uterine cancer, ovarian cancer, rectal cancer, esophageal cancer, small intestine cancer, anal muscle cancer, colon cancer, fallopian tube carcinoma, endometrial carcinoma, cervical carcinoma, vaginal carcinoma, vulvar carcinoma, It can be used for treating various cancers such as Hodgkin's disease, prostate cancer, bladder cancer, kidney cancer, ureter cancer, renal cell carcinoma, renal pelvic carcinoma and central nervous system tumor.

Furthermore, the present invention provides a pharmaceutical composition exhibiting a therapeutic effect on diabetic retinopathy or arthritis through inhibition of Hsp90 containing the compound of Formula 1 and Formula 2 or a pharmaceutically acceptable salt thereof as an active ingredient.

Hsp90 may be used as a target in the development of therapeutics for diseases in which activation of angiogenesis is associated with exacerbation of the disease. In particular, angiogenic factors such as VEGF induced by HIF-1α, a client protein of Hsp90 that is activated in the hypoxic state, are associated with the development of diabetic retinopathy or rheumatoid arthritis. Therefore, a compound that inhibits HIF-1α activated from the hypoxic state of diseased tissue is used as a therapeutic agent for diabetic retinopathy or arthritis.

Compounds of formulas (1) and (2) of the present invention have been shown to have an excellent effect of inhibiting blood vessel formation in zebrafish embryos (see FIGS. 2 to 4).

Therefore, since the expression of vasocular endothelial growth factor (VEGF), an angiogenesis factor, may be selectively inhibited, an active ingredient of a therapeutic agent for diabetic retinopathy or arthritis that is exacerbated by an increase in expression of VEGF by HIF-1α in a hypoxic state. Can be used as

The pharmaceutical compositions of the invention can be formulated in a variety of oral or parenteral dosage forms. Formulations for oral administration include, for example, tablets, pills, hard / soft capsules, solutions, suspensions, emulsifiers, syrups, granules, elixirs, etc. These formulations may contain, in addition to the active ingredients, diluents (e.g., lactose, dexter). Rose, sucrose, mannitol, sorbitol, cellulose and / or glycine), lubricants such as silica, talc, stearic acid and its magnesium or calcium salts and / or polyethylene glycols. Tablets may also contain binders such as magnesium aluminum silicate, starch paste, gelatin, methylcellulose, sodium carboxymethylcellulose and / or polyvinylpyrrolidine, and optionally such as starch, agar, alginic acid or its sodium salt. Disintegrant or boiling mixtures and / or absorbents, colorants, flavors, and sweeteners.

Pharmaceutical compositions comprising the compounds of Formulas 1 and 2 according to the present invention as an active ingredient may be parenterally administered. Parenteral administration may be by subcutaneous injection, intravenous injection, intramuscular injection or intrathoracic injection. . In this case, in order to formulate into a parenteral dosage form, the compound of Formula 1 and Formula 2 or a pharmaceutically acceptable salt thereof is mixed with water together with a stabilizer or buffer to prepare a solution or suspension, which is administered in ampoules or vials. It can be manufactured in a mold. The compositions may contain sterile and / or preservatives, stabilizers, hydrating or emulsifying accelerators, auxiliaries such as salts and / or buffers for the control of osmotic pressure, and other therapeutically useful substances, and conventional methods of mixing, granulating It may be formulated according to the formulation or coating method. As an active ingredient, the compounds of formulas (1) and (2) may be divided or divided once a day in an amount of 0.1 to 500 mg / kg body weight, preferably 0.5 to 100 mg / kg body weight, for mammals including humans. Administration can be via oral or parenteral routes.

The composition of the present invention may be used alone or in combination with methods using surgery, radiation therapy, hormone therapy, chemotherapy and biological response modifiers.

Hereinafter, the present invention will be described in more detail with reference to examples. However, the following examples are merely to illustrate the present invention, but the content of the present invention is not limited thereto.

< Manufacturing example  1> methyl  2- (3,4- Dimethoxyphenyl Acetate ( Methyl  2- (3,4- dimethoxyphenyl ) acetate Manufacture of 32

Carboxylic acid (1 equiv) and anhydrous DMF (catalyst amount) were dissolved in anhydrous CH ₂ Cl ₂ (0.1 M) and cooled to 0 ° C., then oxalic acid (3 equiv) was added dropwise. After stirring for 30 minutes at room temperature, anhydrous methanol (50 equivalents) was added dropwise and stirred for 10 minutes. The mixture was then treated with water, the aqueous layer was extracted with CH ₂ Cl ₂ , the organic layer was dried over MgSO ₄ , filtered and concentrated under reduced pressure and the residue obtained by flash column chromatography (EtOAc: n-hexane = 1: Purification with 3) gave compound 32.

1 H NMR (CDCl 3, 300 MHz) δ6.79 (s, 3H), 3.85 (s, 3H), 3.83 (s, 3H), 3.54 (s, 2H).

< Manufacturing example  2> methyl 2- (3,4-dimethoxyphenyl) -3- (4-methoxybenzyloxy) propanoate (Methyl 2- (3,4-dimethoxyphenyl) -3- (4-methoxybenzyloxy) propanoate) ( Manufacture of 33

Compound 32 (500 mg, 2.38 mmol) and paraformaldehyde (76 mg, 2.50 mmol) prepared in Preparation Example 1 were dissolved in anhydrous DMSO (5.0 mL) and treated with sodium methoxide (6.8 mg, 0.12 mmol). The mixture was stirred at room temperature for 24 hours, then poured into ice water (10 mL) and neutralized with 2N aqueous hydrochloric acid with stirring, poured into water and extracted with EtOAc (× 3). The organic layer was washed once with saturated brine aqueous solution, dried over MgSO ₄ , filtered and concentrated under reduced pressure. The residue obtained was purified by silica gel elution chromatography (EtOAc: n -hexane = 1: 1) to give the aldol product pale. Obtained as a yellow solid (yield 58%, 331 mg).

¹ H NMR (CDCl _3, 300 MHz) δ6.74 (m, 3H), 4.05 (m, 1H), 3.81 (s, 3H), 3.79 (s, 3H), 3.73 (m, 2H), 3.65 (s, 3H)

P -methoxybenzyl 2,2,2-trichloroacetamidate (84 mg, 0.30 mmol) in anhydrous CH ₂ Cl ₂ (1.0 mL) solution containing the obtained aldol product (36 mg, 0.15 mmol) and The catalytic amount of CSA was added at room temperature. The reaction mixture was stirred overnight under argon atmosphere, filtered and the remaining filter cake was washed with CH ₂ Cl ₂ . The filtered liquid is extracted with saturated NaHCO ₃ solution and brine. The organic layer was dried over MgSO ₄ , filtered and evaporated. The residue was purified by flash column chromatography (EtOAc: n-hexane = 1: 3) to give compound 33 of Preparation Example 2 as a white solid (yield 100). %, 54 mg).

¹ H NMR (CDCl _3, 500 MHz) δ 7.19 (d, 2H, J = 8.5 Hz), 6.84 (d, 2H, J = 8.5 Hz), 6.78 (m, 3H), 4.46 (AB quartet, 2H, J = 33.4, 11.7 Hz), 3.98 (m, 1H), 3.83 (s, 6H), 3.80 (m, 2H), 3.77 (s, 3H), 3.67 (s, 3H)

< Manufacturing example  3> 2- (3,4- Dimethoxyphenyl ) -3- (4- Methoxybenzyloxy ) Propanal  Preparation of (2- (3,4-Dimethoxyphenyl) -3- (4-methoxybenzyloxy) propanal) 34

Compound 33 (20 mg, 0.055 mmol) obtained in Preparation Example 2 was dissolved in anhydrous THF (1.0 mL), treated with methanol (0.06 mmol, 1.1 equiv), cooled to -78 ° C and DIBAL-H (0.16 mL, 0.16 mmol) was added slowly. The reaction mixture was monitored by TLC and stirred at -78 ° C until the reaction was complete. Rochelle's aqueous solution was carefully added for 15 minutes and the mixture of the two layers was vigorously stirred at 0 ° C. for 1 hour and then poured into water. The aqueous layer was extracted with EtOAc (× 2) and the organic layer was extracted with anhydrous NaSO ₄ , filtered and concentrated under reduced pressure. The residue obtained was purified by flash column chromatography (EtOAc: n-hexane = 1: 4 to 1: 1). And primary alcohol was obtained. (Yield 88%, 16 mg).

¹ H NMR (CDCl _3, 500 MHz) δ 7.21 (d, 2H, J = 8.5 Hz), 6.85 (d, 2H, J = 8.5 Hz), 6.77 (d, 1H, J = 8.6 Hz), 6.73 (m, 2H), 4.46 (s , 2H), 3.93 (m, 1H), 3.83 (s. 6H), 3.81 (m, 1H), 3.78 (s, 3H), 3.72 (m, 2H), 3.10 (quin, 1H, J = 6.5 Hz) ; HRMS (FAB) Calcd for C ₁₉ H ₂₄ O ₅ (M + H ⁺ ): 332.1624, Found: 332.1628.

Dess-Martin periodinan (2.0 equiv) was added to a solution of CH ₂ Cl ₂ (0.03 M) containing the primary alcohol (1.0 equiv) obtained above, followed by stirring for 1 hour. The mixture was diluted with CH ₂ Cl ₂ and sodium thiosulfate (10%) was added. The mixture was stirred for 10 minutes until it was separated into two layers at room temperature. The organic layer obtained above was washed with saturated NaHCO ₃ aqueous solution, dried over MgSO ₄ , filtered, and concentrated under reduced pressure. The residue obtained was purified by flash column chromatography (EtOAc: n-hexane = 1: 3) to prepare. Compound 34 of Example 3 was obtained (yield 71%, 11 mg).

¹ H NMR (CDCl _3, 300 MHz) δ9.66 (d, 1H, J = 1.65 Hz), 7.14 (d, 1H, J = 8.4 Hz), 6.78 (m, 3H), 6.66 (m. 2H), 4.40 (d, 2H, J = 3.5 Hz), 3.99 (dd, 1H, J = 6.9, 6.9 Hz), 3.80 (s, 3H), 3.77 (s, 3H), 3.73 (s, 3H), 3.70 (m, 2H).

< Manufacturing example  4> ( S ) -2- (3,4- Dimethoxyphenyl ) -1- (5- Methoxy -2,2-dimethyl-2 H - Chromen -6-yl) -3- (4-meth Oxybenzyl jade Propane-1-one (( S ) -2- (3,4- Dimethoxyphenyl ) -1- (5- methoxy -2,2-dimethyl-2 H -chromen-6-yl) -3- (4-methoxybenzyl oxy ) propan -One- one Manufacture of 35

To the anhydrous THF solution containing aryl bromide (1.5 equiv), n- BuLi (1.4 equiv) was added dropwise at −78 ° C. and stirred at −78 ° C. to generate aryl anions. After stirring at −78 ° C. for 20 minutes, aldehyde (1.0 equiv) was added and stirring continued for 30 minutes to bring the reaction temperature to room temperature. The reaction mixture was treated with saturated aqueous NH ₄ Cl solution and extracted with EtOAc. The extract was washed with brine, dried over MgSO 4 and the solvent was evaporated and the residue was purified by flash column chromatography (EtOAc: n-hexane = 1: 2) to give a secondary alcohol (yield 72%, 34 mg). ).

HRMS (FAB) Calcd for C ₃₁ H ₃₆ O ₇ (M + H ⁺ ): 543.2359, Found: 543.2365.

Dess-Martin periodinan (3.0 equiv) was added to a solution of CH ₂ Cl ₂ (0.03 M) containing the secondary alcohol (1.0 equiv) obtained above, followed by stirring for 1 hour. The mixture was diluted with CH ₂ Cl ₂ and sodium thiosulfate (10%) was added. The mixture was stirred for 10 minutes until it was separated into two layers at room temperature. The organic layer obtained above was washed with saturated NaHCO ₃ aqueous solution, dried over MgSO ₄ , filtered, and concentrated under reduced pressure. The residue obtained was purified by flash column chromatography (EtOAc: n-hexane = 1: 3) to prepare. Compound 35 of Example 4 was obtained (yield 84%, 26 mg).

¹ H NMR (CDCl _{3 ,} 300 MHz) δ7.34 (d, 1H, J = 8.6 Hz), 7.11 (d, 2H, J = 8.6 Hz), 6.73 (m, 5H), 6.50 (d, 1H, J = 10.0 Hz), 6.45 (d, 1H, J = 8.2 Hz), 5.57 (d, 1H, J = 9.9 Hz), 4.83 (dd, 1H, J = 8.9, 5.1 Hz), 4.39 (q, 2H, J = 11.5 Hz), 4.12 (t, 1H, J = 9.1 Hz), 3.75 (s, 6H), 3.71 (s, 1H), 3.57 (dd, 1H, J = 9.1, 5.1 Hz), 3.52 (s, 3H ), 1.34 (s, 6 H); HRMS (FAB) Calcd for C ₃₁ H ₃₄ 0 ₇ (M + H ⁺ ): 519.2383, Found: 519.2373.

< Manufacturing example  5> ( S ) -2- (3,4- Dimethoxyphenyl ) -3-hydroxy-1- (5-hydroxy-2,2-dimethyl-2 H -Chromen-6-yl) propan-1-one (( S ) -2- (3,4- Dimethoxyphenyl ) -3- hydroxy -1- (5-hydroxy-2,2-dimethyl-2 H -chromen-6-yl) propan-1-one) (36)

In a 10 mL round bottom flask, Compound 35 (23 mg, 0.044 mmol) and CH ₂ Cl ₂ (1.0 mL) obtained in Preparation Example 4 were added and dried by heating. The solution was cooled to -78 ° C and boron trichloride (0.16 mL, 0.16 mmol, 1.0 M solution in CH ₂ Cl ₂ ) was added. After stirring for 1 h, the reaction was cooled with saturated aqueous NH ₄ Cl solution, extracted with CH ₄ Cl ₂ , dried over MgSO ₄ , and concentrated under reduced pressure. The resulting residue was purified by flash column chromatography (EtOAc: n-hexane = 1). It refine | purified in: 2) and obtained the compound 36 of the manufacture example 5 as a pale yellow solid (yield 75%, 12 mg).

HRMS (FAB) Calcd for C ₂₂ H ₂₄ O ₆ (M + H ⁺ ): 384.1573, Found: 384.1570.

< Manufacturing example  6> Preparation of methyl 2- (2-bromo-4,5-dimethoxyphenyl) acetate (38)

N -bromosuccinimide (449 mg, 2.50 mmol) was poured into anhydrous THF (12.0 mL) solution containing compound 32 (500 mg, 2.38 mmol) obtained in Preparation Example 1 at -78 ° C. The reaction mixture was stirred at −78 ° C. for 30 minutes, the reaction temperature was brought to room temperature, filtered, and the residue obtained by concentration under reduced pressure was purified by flash column chromatography (EtOAc: n-hexane = 1: 3). Compound 38 of Example 6 was obtained as a pale yellow solid (yield 96%, 660 mg).

¹ H NMR (CDCl ₃ , 300 MHz) δ 6.96 (s, 1H), 6.72 (s, 1H), 3.79 (s, 6H), 3.62 (s, 2H).

< Manufacturing example  7> Methyl 2- (2-bromo-4,5-dimethoxyphenyl) pent-4-enoate (methyl 2- (2-bromo-4,5-dimethoxyphenyl) pent-4-enoate) of (39) Produce

Compound 38 (150 mg, 0.52 mmol) obtained in Preparation Example 6 was dissolved in dry THF (6.0 mL) at −78 ° C., and LHMDS (0.63 mL, 0.93 mmol, 1.0 M solution in THF) was added dropwise. After stirring for 20 minutes, allyl bromide (0.044 mL, 0.52 mmol) was added dropwise, then stirred for 1 hour and warmed to -40 ° C. The mixture was treated with saturated aqueous NH ₄ Cl solution (5.0 mL) and poured into water (5.0 mL). Extract the aqueous layer with EtOAc (2 × 15 mL), dry the organic layer with MgSO ₄ , filter, and concentrate under reduced pressure to purify the residue by flash column chromatography (EtOAc: n-hexane = 1: 8), Compound 39 of Preparation Example 7 was obtained. (Yield 53%, 90 mg).

^{_{1 H NMR (CDCl 3, 300MHz}} ) δ6.94 (s, 1H), 6.81 (s, 1H), 5.68 (m, 1H), 4.98 (m, 1H), 4.11 (dd, 1H, J = 8.2, 7.2 Hz), 3.78 (s, 6H), 3.61 (s, 3H), 2.69 (m, 1H), 2.42 (m, 1H).

< Manufacturing example  8> 1- (1- ( Benzyloxy ) Pent -4-en-2-yl) -2- Bromo -4,5- Dimethoxybenzene  Preparation of (1- (1- (Benzyloxy) pent-4-en-2-yl) -2-bromo-4,5-dimethoxybenzene) 40

Compound 39 (84 mg, 0.25 mmol) obtained in Preparation Example 7 was dissolved in anhydrous THF (2.0 mL) and cooled to 0 ° C. Lithium aluminum hydride (10 mg, 0.25 mmol) was added and stirred at room temperature for 1 hour until the reaction was completed, then cooled to 0 ° C. and NaHCO ₃ (saturated aqueous solution) was carefully added for 30 minutes. The mixture of two phases was vigorously stirred at 0 ° C. for 1 hour and then poured into water. The aqueous layer was extracted with EtOAc (× 2) and the organic layer was dried over NaSO ₄ , filtered and concentrated under reduced pressure to purify the residue by flash column chromatography (EtOAc: n-hexane = 1: 6) to give the primary alcohol. Obtained (yield 88%).

¹ H NMR (CDCl _{3 ,} 500z MHz) δ 7.01 (s, 1H), 6.73 (s, 1H), 5.73 (m, 1H), 5.03 (d, 1H, J = 17.1 Hz), 4.97 (d, 1H, J = 10.1 Hz), 3.84 (s, 3H), 3.83 (s, 3H), 3.77 (d, 2H, J = 5.7 Hz), 3.41 (quin, 1H, J = 7.1 Hz), 2.50 (quin, 1H, J = 7.1 Hz), 2.37 (quin, 1H, J = 7.1 Hz).

To anhydrous THF (7.0 mL) solution containing the primary alcohol (400 mg, 1.33 mmol) was added sodium hydride (64 mg, 1.59 mmol, 60% in mineral oil) at 0 ° C. and stirred for 30 minutes at room temperature. Tetrabutyl ammonium bromide (23 mg, 0.066 mmol) and benzyl bromide (0.19 ml, 0.59 mmol) were added and the mixture was stirred at room temperature overnight. The mixture was treated with saturated NH ₄ Cl (5.0 mL) solution, extracted with EtOAc (10 mL × 2), washed with brine, dried over MgSO ₄ , filtered and concentrated under reduced pressure to flash column chromatography. Purification by chromatography (EtOAc: n-hexane = 1: 8) afforded compound 40 of Preparation 8 as a colorless solid (yield 86%, 448 mg).

¹ H NMR (CDCl _{3 ,} 300 MHz) δ7.23 (m, 5H), 6.94 (s, 1H), 6.71 (s, 1H), 5.65 (m, 1H), 4.93 (m, 2H), 4.43 (s , 2H), 3.78 (s, 3H), 3.72 (s, 3H), 3.53 (m, 3H), 2.53 (m, 1H), 2.30 (m, 1H); HRMS (FAB) Calcd for C ₂₀ H ₂₃ BrO ₃ (M + H ⁺ ): 390.0831, Found: 390.0839.

Preparation Example 9 4- (benzyloxy) -3- (2-bromo-4,5-dimethoxyphenyl) butan-1-ol (4- (benzyloxy) -3- (2-bromo-4,5) -dimethoxyphenyl) butan-1-ol) (41)

NMO (233 mg, 1.93 mmol) was added to 40 (252 mg, 0.64 mmol) obtained in Preparation Example 8, and dissolved in an acetone: water (4: 1, 25 mL) solution at 0 ° C. OsO ₄ (0.32 mL, 0.032 mmol, 0.1 M solution in toluene) was added to the mixture, stirred at room temperature for 6 hours, extracted with EtOAc (3 × 15 mL), washed with saturated sodium sulfite solution, The crude product, which was dried over MgSO ₄ , removed the solvent under reduced pressure, was dissolved in a solution of acetone: water (4: 1, 25 mL), stirred at room temperature, and then slowly stirred NaIO ₄ (413 mg, 1.93 mmol) Added. The mixture was stirred at room temperature for 30 minutes, extracted with EtOAc (3 × 15 mL), washed with saturated sodium thiosulfate solution, and the solvent was removed under reduced pressure to obtain crude aldehyde. The crude aldehyde was used in the next step without further purification.

To methanol (6.0 mL) containing the crude aldehyde (0.64 mmol) obtained above was added sodium borohydride (49 mg, 1.29 mmol) at −100 ° C. and maintained at temperature for 1 hour. The mixture was cooled with a saturated NH ₄ Cl aqueous solution, extracted with EtOAc, dried over MgSO ₄ , and concentrated under reduced pressure, and the residue obtained was purified by flash column chromatography (EtOAc: n-hexane = 1: 1). Compound 41 of 9 was obtained as a colorless solid (yield 73%, 184 mg).

¹ H NMR (CDCl _{3 ,} 300 MHz) δ7.23 (m, 5H), 6.94 (s, 1H), 6.69 (s, 1H), 4.47 (s, 2H), 3.78 (s, 3H), 3.73 (s , 3H), 3.54 (m, 4H), 2.01 (m, 2H), 1.81 (m, 1H); HRMS (FAB) Calcd for C ₁₉ H ₂₃ BrO ₄ (M + H ⁺ ): 394.0780, Found: 394.0774.

< Manufacturing example  10> 4- ( Benzyloxymethyl ) -6,7- Dimethoxy Chroma  (4-( Benzyloxymethyl ) -6,7-dimethoxychroman) Preparation of 42

Compound 41 (379 mg, 0.96 mmol) and sodium t -butoxide (124 mg, 1.25 mmol) obtained in Preparation Example 9 were diluted with Pd ₂ (dba) ₃ (13 mg, 0.0143 mmol) and 2- (di-) under argon atmosphere. To a heat dried two necked round bottom flask containing toluene (10 mL) containing t -butylphosphino) biphenyl (7.0 mg, 0.024 mmol) was added. The reaction was heated to 50-55 [deg.] C. overnight and cooled to room temperature, diluted with EtOAc (10 mL), filtered through celite and the solvent removed under reduced pressure to yield a dark yellow crude product obtained by flash column chromatography. Purification by chromatography (EtOAc: n-hexane = 1: 6) afforded Compound 42 of Preparation 10 as a pale yellow solid (yield 75%, 226 mg).

¹ H NMR (CDCl _{3 ,} 300 MHz) δ7.24 (m, 5H), 6.61 (s, 1H), 6.30 (s, 1H), 4.48 (q, 2H, J = 11.9 Hz), 4.03 (m, 2H ), 3.73 (s, 3H), 3.70 (s, 3H), 3.54 (m, 4H), 2.39 (m, 1H), 1.95 (m, 2H); HRMS (FAB) Calcd for C ₁₉ H ₂₂ O ₄ (M + H ⁺ ): 314.1518, Found: 314.1518.

< Manufacturing example  11> 6,7- Dimethoxy Chroma -4- Kavaldehyde  (6,7- Dimethoxychroman Preparation of -4-carbaldehyde (43)

Methanol (5 mL) mixture containing Compound 42 (191 mg, 0.61 mmol) and 20% Pd (OH) ₂ / C (38 mg) obtained in Preparation Example 10 was stirred under a hydrogen atmosphere at room temperature for 5 hours. The mixture was filtered through celite, washed with methanol (10 mL) and the residue obtained by evaporation of methanol under reduced pressure was purified by flash column chromatography (EtOAc: n-hexane = 1: 1) to give the primary alcohol. Obtained (yield 100%, 158 mg).

¹ H NMR (CDCl _{3 ,} 300 MHz) δ6.61 (s, 1H), 6.33 (s, 1H), 4.08 (m, 2H), 3.78 (m, 2H), 3.74 (s, 6H), 2.85 (m , 1H), 1.98 (m, 2H); LRMS (FAB) m / z 225 (M + H ⁺ ).

Dess-Martin periodinan (3.0 equiv) was added to a solution of CH ₂ Cl ₂ (0.03 M) containing the primary alcohol (1.0 equiv) obtained above, followed by stirring for 1 hour. Was diluted with CH ₂ Cl ₂ and sodium thiosulfate (10%) was added. The mixture was stirred for 10 minutes until it was separated into two layers at room temperature. The organic layer obtained above was washed with saturated NaHCO ₃ aqueous solution, dried over MgSO ₄ , filtered, and concentrated under reduced pressure. The residue obtained was purified by flash column chromatography (EtOAc: n-hexane = 1: 2) to prepare. Compound 43 of Example 11 was obtained (yield 60%, 15 mg).

¹ H NMR (CDCl _{3 ,} 300 MHz) δ9.67 (d, 1H, J = 1.8 Hz), 6.58 (s, 1H), 6.42 (s, 1H), 4.13 (m, 3H), 3.81 (s, 6H ), 2.32 (m, 1 H), 2.06 (m, 1 H).

< Manufacturing example  12> (6,7- Dimethoxy Chroma -4-yl) (2,2-dimethyl-2 H - Chromen -6-yl) methanol ((6,7-Dimethoxychroman-4-yl) (2,2-dimethyl-2 H Preparation of -chromen-6-yl) methanol (44)

To anhydrous THF solution containing 6-bromo-2,2-dimethyl-2 H -chromen (1.5 equiv), n- BuLi (1.4 equiv) was added dropwise at -78 deg. C and stirred at -78 deg. An aryl anion was produced. After stirring at −78 ° C. for 20 minutes, Compound 43 (1.0 equiv) obtained in Preparation Example 11 was added and stirring was continued for 30 minutes, thereby allowing the reaction temperature to reach room temperature. The reaction mixture was treated with saturated aqueous NH ₄ Cl solution and extracted with EtOAc. The extract was washed with brine, dried over MgSO ₄ and the solvent was evaporated. The residue was purified by flash column chromatography (EtOAc: n-hexane = 1: 4) to give compound 44 of Preparation 12 (yield 75). %, 18 mg).

HRMS (FAB) Calcd for C ₂₃ H ₂₆ O ₅ (M + H ⁺ ): 382.1780, Found: 382.1793.

< Manufacturing example  13> 2- (3,4- Dimethoxyphenyl Acetaldehyde (2- (3,4-Dimethoxyphenyl) acetaldehyde Manufacture of 52

Anhydrous diethyl ether solution containing methyl 3 ', 4'-dimethoxyphenyl acetate (1.94 g, 9.24 mmol) was stirred and DIBAL-H (11.1 mL, 1 M solution in THF) was kept at -78 ° C. Dropwise was added and stirred at the same temperature for 1 hour. Rochelle's aqueous solution was carefully added for 15 minutes and the mixture of the two phases was vigorously stirred at 0 ° C. for 1 hour and then poured into water. The aqueous layer was extracted with EtOAc (× 2), the organic layer was dried over MgSO ₄ , filtered and concentrated under reduced pressure to give a residue obtained by flash column chromatography (EtOAc: n-hexane = 1: 2), which was prepared. Compound 52 of Example 13 was obtained (yield 68%, 1.13 g).

¹ H NMR (CDCl _{3 ,} 300 MHz) δ9.66 (t, 1H , J = 2.5 Hz), 6.80 (d, 1H, J = 8.0 Hz), 6.68 (m, 1H), 6.64 (d, 1H, J = 1.8 Hz), 3.81 ( s, 6H), 3.56 (d, 1H, J = 2.5 Hz).

< Manufacturing example  14> 2- (3,4- Dimethoxyphenyl ) Propanal  (2- (3,4- Dimethoxyphenyl ) propanal Manufacture of 55

To anhydrous THF (5 mL) solution containing methyl 3 ', 4'-dimethoxyphenyl acetate (4.76 g, 22.63 mmol) LDA (18.1 mL, 36.21 mmol, 2 M solution in THF) under argon atmosphere at -78 ° C. Was added dropwise and the mixture was stirred for 30 minutes at the same temperature. Next, methyl iodide (2.82 mL, 45.26 mmol) was added and the mixture was stirred for 1 hour. The reaction mixture was acidified by addition of 2N-HCl aqueous solution and extracted with EtOAc. The organic layer was washed with brine, dried over MgSO ₄ , and concentrated under reduced pressure. The residue obtained was purified by silica gel column chromatography (EtOAc: n -hexane = 1: 4) to give compound 55 of Preparation 14 as a colorless oil. Obtained (yield 79%, 4.01 g).

¹ H NMR (CDCl _{3 ,} 500 MHz) δ6.80 (m, 3H), 3.85 (s, 3H), 3.83 (s, 3H), 3.64 (q, 1H, J = 7.1 Hz), 3.63 (s, 3H ), 1.46 (d, 1H, J = 7.1 Hz); ¹³ C NMR (CDCl ₃ , 125 MHz) δ 175.7, 148.9, 148.1, 133.0, 119.5, 111.2, 110.6, 55.8, 51.9, 44.9, 18.6.

< Manufacturing example  15> 2- (3,4- Dimethoxyphenyl Propanoic acid (2- (3,4- Dimethoxyphenyl ) propanoic  acid) (64)

Hydroxide monohydrate (230 mg, 5.35 mmol) was added to a THF / water (2/1, 9.0 mL) solution containing Compound 63 (400 mg, 1.78 mmol) at room temperature and stirred for 5 hours. After the reaction was completed, the reaction mixture was extracted with EtOAc (× 2) and the organic layer was basified with 2N-NaOH aqueous solution. The aqueous layer was acidified with 2N-HCl aqueous solution, extracted with EtOAc (× 2) and the organic layer was washed with brine. The product obtained by drying the organic layer with MgSO ₄ and concentrating under reduced pressure was used in Preparation Examples 16 and 17.

¹ H NMR (CDCl _{3 ,} 300 MHz) δ6.83 (m, 3H), 3.85 (s, 3H), 3.84 (s, 3H), 3.66 (q, 1H, J = 7.3 Hz), 1.48 (d, 3H , J = 7.3 Hz).

< Manufacturing example  16--17> ( S ) -2- (3,4- Dimethoxyphenyl ) - N -(( R ) -2-hydroxy-1- Phenylethyl ) Propane Amide (( S ) -2- (3,4- Dimethoxyphenyl ) - N -(( R )-2- hydroxy -One- phenylethyl propanamide) 65 and

( R ) -2- (3,4- Dimethoxyphenyl ) - N -(( R ) -2-hydroxy-1- Phenylethyl ) Propanamide  (( R ) -2- (3,4-Dimethoxyphenyl)- N -(( R ) -2-hydroxy-1-phenylethyl) propanamide) (66)

(3-dimethylaminopropyl) - - N '- ethyl car body imide hydrochloride (EDCI) (N in the compound obtained in Preparation Example 15 64 (282 mg, 1.34 mmol ) is CH ₂ Cl ₂ (10 mL) solution containing 287 mg, 1.47 mmol), ( R )-(-)-2-phenylglycinol (207 mg, 1.47 mmol) and HOBt (230 mg, 1.47 mmol) were added. Finally, (230 mg, 1.47 mmol). Finally, diisopropylethylamine (0.26 mL, 1.47 mmol) was added dropwise at 0 ° C. The reaction mixture was stirred at room temperature overnight, the reaction was terminated with saturated aqueous NH ₄ Cl solution and diluted with CH ₂ Cl ₂ . The organic layer was washed with water, dried over MgSO ₄ , filtered and concentrated under reduced pressure. The residue obtained was purified by flash column chromatography (EtOAc: CH ₂ Cl ₂ : n -hexane = 3: 2: 1) and prepared. Compound 65 (yield 42%, 187 mg) of Example 16 and compound 66 (yield 42%, 186 mg) of Preparation Example 17 were obtained as a pale yellow solid.

( S ) -Diastereomer (65) : ¹ H NMR (CDCl _{3 ,} 300 MHz) δ 7.26 (m, 3H), 7.03 (m, 2H), 6.81 (m, 2H), 6.73 (s, 1H), 6.05 (m, 1H), 5.02 (m , 1H), 3.86 (s, 3H), 3.80 (m, 2H), 3.78 (s, 3H), 3.58 (q, 1H, J = 7.1 Hz) 1.48 (d, 3H, J = 7.1 Hz);

( R ) -Diastereomer (66) : ¹ H-NMR (CDCl ₃ , 300 MHz) δ7.23 (m, 3H), 7.10 (m, 2H), 6.78 (m, 3H), 5.97 (m, 1H), 4.96 (m, 1H), 3.82 (s, 3H), 3.80 (s, 3H), 3.72 (d, 2H, J = 5.0 Hz), 3.50 (q, 1H, J = 7.1 Hz) 1.46 (d, 3H, J = 7.1 Hz).

< Manufacturing example  18> ( S ) -2- (3,4- Dimethoxyphenyl Propanoic acid S ) -2- (3,4- Dimethoxyphenyl ) propanoic acid  Manufacture of 67

To a 1,4-dioxane (5.0 mL) solution containing compound 65 (186 mg, 0.56 mmol) obtained in Preparation Example 16, an aqueous sulfonic acid solution (5.0 mL, 4.0 M in water) was slowly added at 0 ° C. The reaction mixture was refluxed for 2 hours, cooled to room temperature, diluted with EtOAc, the organic layer washed with water, dried over MgSO ₄ , filtered and concentrated under reduced pressure to give compound 67 as a brown oil (yield 100%, 117 mg).

¹ H-NMR (CDCl ₃ , 300 MHz) δ6.83 (m, 3H), 3.86 (s, 3H), 3.84 (s, 3H), 3.67 (q, 1H, J = 7.1 Hz), 1.47 (d, 3H, J = 7.1 Hz).

< Manufacturing example  19> ( S ) -2- (3,4- Dimethoxyphenyl ) Propanal  (( S ) -2- (3,4- Dimethoxyphenyl ) manufacture of propanal 68

Anhydrous diethyl ether (8.0 mL) solution containing Compound 67 (115 mg, 0.55 mmol) obtained in Preparation Example 17 was cooled to 0 ° C., and BH ₃ −SMe ₂ complex (1.5 mL, 3.00 mmol) was added dropwise. Added. The solution was stirred at 0 ° C. for 1 hour and then further stirred at room temperature for 3 hours. The reaction mixture was quenched by dropwise addition of water at 0 ° C. When no hydrogen gas bubbles were observed any more, 2N-NaOH aqueous solution was added dropwise. The aqueous layer was extracted with ether (× 2) and the ether layer was washed with brine, dried over MgSO ₄ , filtered and concentrated under reduced pressure and the residue obtained by flash column chromatography (EtOAc: n-hexane = 1: 2). Purification with, yielded the primary alcohol as a pale yellow solid (yield 85%, 104 mg).

¹ H-NMR (CDCl ₃ , 500 MHz) δ6.78 (m, 3H), 3.87 (s, 3H), 3.85 (s, 3H), 3.66 (m, 2H), 2.88 (sex, 1H, J = 6.9 Hz), 1.24 (d, 3H, J = 6.9 Hz).

Dess-Martin periodinan (3.0 equiv) was added to a solution of CH ₂ Cl ₂ (0.03 M) containing the primary alcohol (1.0 equiv) obtained above, followed by stirring for 1 hour. The mixture was diluted with CH ₂ Cl ₂ and sodium thiosulfate (10%) was added. The mixture was stirred for 10 minutes until it was separated into two layers at room temperature. The organic layer obtained above was washed with saturated NaHCO ₃ aqueous solution, dried over MgSO ₄ , filtered, and concentrated under reduced pressure. The residue obtained was purified by flash column chromatography (EtOAc: n-hexane = 1: 3) to prepare. Compound 68 of Example 19 was obtained (yield 81%, 21 mg).

¹ H-NMR (CDCl ₃ , 300 MHz) δ9.63 (d, 1H, J = 1.5 Hz), 6.86 (d, 1H, J = 8.2 Hz), 6.74 (dd, 1H, J = 8.2, 2.0 Hz) , 6.66 (d, 1H, J = 2.0 Hz), 3.86 (s, 6H), 3.55 (q, 1H, J = 7.1 Hz), 1.40 (d, 3H, J = 7.1 Hz).

< Manufacturing example  20> ( R ) -2- (3,4- Dimethoxyphenyl Propanoic acid R ) -2- (3,4- Dimethoxyphenyl ) propanoic acid Manufacture of 70

To a 1,4-dioxane (5.6 mL) solution containing compound 66 (217 mg, 0.66 mmol) obtained in Preparation Example 17, an aqueous sulfonic acid solution (5.6 mL, 4.0 M in water) was slowly added at 0 ° C. The reaction mixture was refluxed for 2 hours, cooled to room temperature, diluted with EtOAc, the organic layer was washed with water, dried over MgSO ₄ , filtered and concentrated under reduced pressure to give compound 70 as a brown oil (yield 100%, 138 mg).

¹ H-NMR (CDCl ₃ , 300 MHz) δ6.83 (m, 3H), 3.86 (s, 3H), 3.84 (s, 3H), 3.67 (q, 1H, J = 7.1 Hz), 1.47 (d, 3H, J = 7.1 Hz).

< Manufacturing example  21> ( R ) -2- (3,4- Dimethoxyphenyl ) Propanal  (( R ) -2- (3,4- Dimethoxyphenyl ) manufacture of propanal 71

Anhydrous diethyl ether (10 mL) solution containing Compound 70 (115 mg, 0.55 mmol) obtained in Preparation Example 20 was cooled to 0 ° C. and BH ₃ −SMe ₂ complex (1.8 mL, 3.61 mmol) was added dropwise. Added. The solution was stirred at 0 ° C. for 1 hour and then further stirred at room temperature for 3 hours. The reaction mixture was quenched by dropwise addition of water at 0 ° C. When no hydrogen gas bubbles were observed any more, 2N-NaOH aqueous solution was added dropwise. The aqueous layer was extracted with ether (× 2) and the ether layer was washed with brine, dried over MgSO ₄ , filtered and concentrated under reduced pressure and the residue obtained by flash column chromatography (EtOAc: n-hexane = 1: 2). Purification with, gave the primary alcohol as a pale yellow solid (yield 81%, 104 mg).

¹ H-NMR (CDCl ₃ , 500 MHz) δ6.78 (m, 3H), 3.87 (s, 3H), 3.85 (s, 3H), 3.66 (m, 2H), 2.88 (sex, 1H, J = 6.9 Hz), 1.24 (d, 3H, J = 6.9 Hz).

Dess-Martin periodinan (3.0 equiv) was added to a solution of CH ₂ Cl ₂ (0.03 M) containing the primary alcohol (1.0 equiv) obtained above, followed by stirring for 1 hour. The mixture was diluted with CH ₂ Cl ₂ and sodium thiosulfate (10%) was added. The mixture was stirred for 10 minutes until it was separated into two layers at room temperature. The organic layer obtained above was washed with saturated NaHCO ₃ aqueous solution, dried over MgSO ₄ , filtered, and concentrated under reduced pressure. The residue obtained was purified by flash column chromatography (EtOAc: n-hexane = 1: 3) to prepare. Compound 71 of Example 21 was obtained (yield 79%, 16 mg).

¹ H-NMR (CDCl ₃ , 300 MHz) δ9.63 (d, 1H, J = 1.5 Hz), 6.86 (d, 1H, J = 8.2 Hz), 6.74 (dd, 1H, J = 8.2, 2.0 Hz) , 6.66 (d, 1H, J = 2.0 Hz), 3.86 (s, 6H), 3.55 (q, 1H, J = 7.1 Hz), 1.40 (d, 3H, J = 7.1 Hz).

< Manufacturing example  22> 4-nitrobenzene-1,3- Dior  (4- Nitrobenzene -1,3- diol Manufacture of 46

Dissolve lysolinol (5.0 g, 44.96 mmol) in a mixture of chloroform: acetic acid (2: 1,270 mL), and slowly add acetic acid (70 mL) solution containing nitric acid (3.6 mL) at room temperature for 1 hour. Stirred. The reaction mixture was quenched with water (100 mL), extracted with CH ₂ Cl ₂ (100 mL × 3), dried over MgSO ₄ , filtered under reduced pressure and the residue obtained by flash column chromatography (EtOAc: n−). Purification with hexane = 1: 4 in EtOAc: n -hexane: CH ₂ Cl ₂ = 1: 4: 2) afforded compound 46 as a yellow solid (yield 52%, 3.6 g).

¹ H NMR (CD ₃ OD, 300 MHz) δ 7.99 (d, 1H, J = 9.1 Hz), 6.43 (m, 2H).

< Manufacturing example  23> 5- (2- Methyl Boot 3-in-2- Sake ) -2-nitrophenol (5- (2- Methylbut -3- yn -2-yloxy) -2-nitrophenol) 47

To acetonitrile (18 mL) solution containing 2-methyl-3butyn-2-ol ((0.36 mL, 3.70 mmol) was added DBU (0.63 mL, 4.19 mmol) at 0 ° C., followed by trifluoroacetic anhydride. (0.58 mL, 4.19 mmol) was added dropwise over 30 minutes and the yellow solution was stirred for 40 minutes at 0 ° C. In another flask, acetonitrile containing Compound 46 (500 mg, 3.22 mmol) obtained in Preparation 22 was obtained. To the mixture obtained by adding DBU (0.63 mL, 4.19 mmol) to a solution of (18 mL) at 0 ° C., and adding CuC1 ₂ (8.65 mg, 0.064 mmol), the yellow solution prepared above (2-methyl-3- Butyn-2-yl trifluoroacetate) was added dropwise for 40 minutes at 0 ° C. The reaction mixture was stirred at 0 ° C. overnight and the residue obtained by concentration under reduced pressure was poured into water. Extracted with ethyl acetate, and the organic layer was extracted with 1N - HCI, 1N - KOH. And brine sequentially. The organic layer was dried over MgSO ₄ and concentrated under reduced pressure to give compound 47 (yield 45%, 320 mg).

¹ H NMR (CDCl ₃ , 300 MHz) δ7.90 (d, 1H, J = 9.4 Hz), 6.70 (d, 1H, J = 10.0 Hz), 6.38 (d, 1H, J = 9.4 Hz), 5.63 (d, 1H, J = 10.0 Hz), 1.45 (s, 6 H); HRMS (FAB) Calcd for C ₁₁ H ₁₁ NO ₄ (M + H ⁺ ): 206.1181, Found: 206.1186.

< Manufacturing example  24> 2,2-dimethyl-6-nitro-2 H - Chromen -5-ol (2,2- Dimethyl -6- nitro -2 H -chromen-5-ol) (48)

A solution of N , N -diethylaniline (28 mL) containing O -alkylated phenol (310 mg, 1.40 mmol) was monitored by TLC and heated to 130 ° C. under nitrogen atmosphere until the reaction was complete. The reaction mixture was poured into iced water and extracted with EtOAc. A - the organic layer 2 N- HCl aqueous solution, 2 N aqueous sodium hydroxide solution and washed with water, dried over MgSO _4, and chromatography of the residue obtained by concentration under reduced pressure, flash column Photography (15 EtOAc:: n- hexane = 1) Purification gave compound 48 of Preparation 24 as a pale yellow solid (yield 91%, 281 mg).

¹ H NMR (CDCl ₃ , 300 MHz) δ7.90 (d, 1H, J = 9.4 Hz), 6.70 (d, 1H, J = 10.0 Hz), 6.38 (d, 1H, J = 9.4 Hz), 5.63 (d, 1H, J = 10.0 Hz), 1.45 (s, 6 H); HRMS (FAB) Calcd for C ₁₁ H ₁₁ NO ₄ (M + H ⁺ ): 206.1181, Found: 206.1186.

< Manufacturing example  25> 5- Methoxy -2,2-dimethyl-6-nitro-2 H - Chromen  (5- Methoxy -2,2- dimethyl -6-nitro-2 H -chromene) (49) Preparation

Anhydrous acetone (7.0 mL) containing compound 48 (130 mg, 0.59 mmol), potassium carbonate (244 mg, 1.76 mmol) and iodine methane (0.11 mL, 1.76) obtained in Preparation Example 24 was heated to 55 ° C. overnight. It was. The mixture was concentrated, treated with water and extracted with EtOAc (× 3). The extract layer was washed with water, dried over MgSO ₄ , and concentrated under reduced pressure to yield compound 49.

¹ H NMR (CDCl ₃ , 300 MHz) δ7.77 (d, 1H, J = 8.9 Hz), 6.59 (m, 2H), 5.72 (d, 1H, J = 10.0 Hz), 3.89 (s, 3H), 1.44 (s, 6H); HRMS (FAB) Calcd for C ₁₂ H ₁₃ NO ₄ (M + H ⁺ ): 236.0923, Found: 236.0924.

< Manufacturing example  26> 5- Methoxy -2,2-dimethyl-2 H - Chromen -6-amine (5- Methoxy -2,2- dimethyl -2 H -chromen-6-amine) (50)

Boiling ethanol (2.0 mL) containing Compound 49 (136 mg, 0.663 mmol) and Tin (II) chloride dihydrate (740 mg, 3.21 mmol) obtained in Preparation Example 25 was stirred under nitrogen atmosphere for 1 hour. Ethanol was removed by vacuum evaporation and the residue obtained was extracted with ethyl acetate (× 3) and the organic layer was treated with 2N-NaOH solution (10 mL) and then treated with water (2 × 10 mL). The organic layer was washed with brine, dried over MgSO ₄ , and concentrated under reduced pressure. The residue was purified by flash column chromatography (EtOAc: n-hexane = 1: 15) to give compound 50 of Preparation 26 as a yellow solid. (Yield 79%, 100 mg).

¹ H NMR (CDCl ₃ , 300 MHz) δ 6.54 (m, 2H), 6.43 (d, 1H, J = 8.4 Hz), 5.63 (d, 1H, J = 9.9 Hz), 3.78 (s, 3H), 3.46 (br, 2H), 1.37 (s, 6 H); HRMS (FAB) Calcd for C ₁₂ H ₁₅ NO ₂ (M + H ⁺ ): 205.1103, Found: 205.1104.

< Manufacturing example  27> 6- Bromo -5- Methoxy -2,2-dimethyl-2 H - Chromen  (6- Bromo -5- methoxy -2,2-dimethyl-2 H -chromene (51)

Water (5.0 mL) containing Compound 50 (260 mg, 1.27 mmol) obtained in Preparation Example 26 was cooled to 0 ° C., and HBr (1.6 mL, 48% in water) was slowly added thereto. The reaction solid was vigorously stirred at 0 ° C. for 10 minutes. A slurry containing NaNO ₂ and HBr was slowly added to a water (1.0 mL) solution containing sodium nitrite and the temperature of the reaction mixture was below 5 ° C. Water (5.0 mL) containing copper (I) bromine (190 mg, 1.30 mmol) was added to a separatory funnel, heated to 60 ° C., and the aniline solution was added dropwise, and maintained at 60 ° C. After the reaction was completed, the reaction mixture was cooled to room temperature and extracted with EtOAc (× 2). The organic layer was washed with brine, dried over MgSO ₄ , and concentrated under reduced pressure. The residue obtained was purified by flash column chromatography (EtOAc: n-hexane = 1: 12) to give compound 51 of Preparation 27 as pale yellow oil. Obtained (yield 90%, 365 mg).

¹ H NMR (CDCl _{3 ,} 500 MHz) δ7.16 (d, 1H, J = 8.6 Hz), 6.52 (d, 1H, J = 10.0 Hz), 6.42 (d, 1H, J = 8.6 Hz), 5.59 ( d, 1H, J = 10.0 Hz), 3.74 (s, 3H), 1.35 (s, 6H); ¹³ C NMR (CDCl ₃ , 125 MHz) δ 153.3, 152.7, 132.1, 131.2, 116.9, 116.6, 113.9, 107.3, 76.1, 61.5, 30.9, 27.7.

< Manufacturing example  28> 1,2- Dimethoxy -4-( Phenylsulfonylmethyl ) Benzene (1,2- Dimethoxy Preparation of -4- (phenylsulfonylmethyl) benzene) (105)

4- (Bromoethyl) -1,2-dimethoxybenzene (100 mg, 0.43 mmol) and benzenesulfonate sodium salt dihydrate (87 mg, 0.52 mmol) were placed in anhydrous DMF (1.5 mL) solution and the mixture It was stirred at 80 ℃ for 12 hours, and cooled to room temperature. After general synthesis with water and EtOAc, the solvent was evaporated and the residue was purified by flash column chromatography (EtOAc: n-hexane: CH ₂ Cl ₂ = 1: 1: 1) to give compound 105 of Preparation 28. Obtained as a colorless oil (yield 93%, 118 mg).

¹ H NMR (CDCl ₃ , 300 MHz) δ 7.56 (m, 3H), 7.39 (m, 1H), 6.67 (d, 1H, J = 8.2 Hz), 6.55 (dd, 2H, J = 8.1, 2.0 Hz ), 6.47 (d, 1H, J = 2.0 Hz), 4.18 (s, 2H), 3.79 (s, 3H), 3.65 (s, 3H).

< Manufacturing example  29> 5-hydroxy-2,2-dimethyl-2 H - Chromen -6- Carbaaldehyde  (5- Hydroxy -2,2-dimethyl-2 H -chromene-6-carbaldehyde) (110)

A pyridine (0.01 M) solution containing 3-methyl-but-2-enal (2.0 equivalents) in anhydrous acetone (0.01 M) solution containing 2,4-dihydroxyaldehyde (1 equivalent) was 5.5 at 120.degree. Dropwise was added for an hour and heated for another 18 hours. After cooling to room temperature, the crude product obtained by removing solvent by rotary evaporator under reduced pressure and pyridine by azeotropic distillation with toluene was purified by flash column chromatography (EtOAc: n-hexane = 1: 8) to give Compound 119. Was obtained as a colorless solid (yield 32%, 1.12 g).

¹ H-NMR (CDCl ₃ , 300 MHz) δ 11.61 (s, 1H), 9.62 (s, 1H), 7.25 (d, 1H, J = 8.6 Hz), 6.39 (d, 1H, J = 8.6 Hz) , 5.58 (d, 1H, J = 10.0 Hz), 1.42 (s, 6H).

< Manufacturing example  30> 5- ( Methoxyethoxy ) -2,2-dimethyl-2 H - Chromen -6- Carbaaldehyde  (5- (Methoxymethoxy) -2,2-dimethyl-2 H -chromene-6-carbaldehyde) (108)

To a solution of acetone (5 mL) containing Compound 110 (200 mg, 0.98 mmol) and potassium carbonate (406 mg, 2.94 mmol) obtained in Preparation Example 29, chloromethylmethyl ether (0.11 mL, 1.47 mmol) was added at room temperature. . The mixture was refluxed for 3 hours and then concentrated under reduced pressure, and the resulting crude residue was extracted with EtOAc and the organic layer was washed with brine. The extract was dried over anhydrous MgSO ₄ and concentrated under reduced pressure, and the crude residue was purified by flash column chromatography (EtOAc: n-hexane = 1: 10) to give compound 108 of Preparation 30 as a pale yellow solid ( Yield 100%, 231 mg).

¹ H NMR (CDCl ₃ , 300 MHz) δ 10.07 (s, 1 H), 7.59 (d, J = 8.6 Hz, 1 H), 6.61 (d, J = 8.6 Hz, 1 H), 6.53 (d, J = 10.0) Hz, 1H), 5.63 (d, J = 10.0 Hz, 1H), 5.02 (s, 2H), 3.52 (s, 3H).

< Manufacturing example  31> 2- (3,4- Dimethoxyphenyl ) -1- (5-hydroxy-2,2-dimethyl-2 H - Chromen -6-day) -2- (pe Nilsulfonyl ) Ethanone  (2- (3,4- Dimethoxyphenyl ) -1- (5- hydroxy -2,2- dimethyl -2 H -chromen-6-yl) -2- (phenylsulfonyl) ethanone) (106)

To anhydrous THF (5.0 mL) solution containing compound 105 (119 mg, 0.407 mmol) obtained in Preparation Example 28 was added n- BuLi (0.26 mL, 0.444 mmol, 1.6 M in hexane) at -78 ° C and at the same temperature. Stir for 1 hour. Anhydrous THF (3.0 mL) containing Compound 108 (121 mg, 0.448 mmol) of Preparation 30 was added slowly to the reaction mixture at -78 ° C. After 1 hour of addition, water was added to the reaction mixture to terminate the reaction and extracted with EtOAc (× 3). The extract was washed with brine, dried over anhydrous MgSO ₄ and concentrated under reduced pressure to obtain the intermediate residue (secondary alcohol) which was used in the next step without further purification.

To anhydrous CH ₂ Cl ₂ (5.0 mL) solution containing the obtained secondary alcohol (183 mg, 0.339 mmol) was added Dess-Martin periodinan (286 mg, 0.660 mmol) at room temperature. After stirring for 1 hour, the reaction mixture was treated with saturated aqueous sodium carbonate solution: saturated aqueous sodium thiosulfate solution (1: 1, 4 mL) and stirred for 30 minutes, and then the reaction mixture was poured into water and CH ₂ Cl ₂ (× Extracted with 3). The organic layer was dried over MgSO ₄ , filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography (EtOAc: n-hexane = 1: 2) to give compound 106 of Preparation 31 (yield 63%). , 137 mg).

¹ H NMR (CDCl _{3 ,} 300 MHz) δ 7.95 (dd, 1H, J = 20.0, 7.9 Hz), 7.58 (m, 3H), 7.34 (m, 3H), 6.81 (dd, 1H, J = 8.4, 2.2 Hz), 6.74 (d, 1H, J = 2.2 Hz), 6.70 (d, 1H, J = 8.4 Hz), 6.60 (d, 1H, J = 10.0 Hz), 5.85 (s, 1H), 5.50 (d , 1H, J = 10.0 Hz), 3.78 (s, 3H), 3.63 (s, 3H), 1.37 (s, 3H), 1.33 (s, 3H).

< Manufacturing example  32> 2- (3,4- Dimethoxyphenyl ) -1- (5-hydroxy-2,2-dimethyl-2 H - Chromen -6- days) Ethanone  (2- (3,4- Dimethoxyphenyl ) -1- (5- hydroxy -2,2- dimethyl -2 H - chromen -6-yl) ethanone) (107) Preparation

To anhydrous THF (1.0 mL) containing Compound 106 (10 mg, 0.0202 mmol) obtained in Preparation Example 31, SmI ₂ (0.81 mL, 0.081 mmol, 0.1 M in THF) was added at -20 ° C. The reaction mixture was stirred at −20 ° C. for 10 minutes and then quenched with saturated aqueous ammonium chloride solution (2.0 mL). The mixture was filtered through a pad of celite and extracted with EtOAc (4.0 mL × 3). The organic layer was dried over 20% saturated aqueous sodium thiosulfate solution, filtered, and the residue obtained by concentration under reduced pressure was purified by flash column chromatography (EtOAc: n-hexane = 1: 3) to prepare compound 107 of Preparation 32. Obtained as a yellow solid (yield 87%, 77 mg).

¹ H NMR (CDCl _{3 ,} 300 MHz) δ 12.88 (s, 1H), 7.58 (d, 1H, J = 8.8 Hz), 7.74 (s, 1H), 6.71 (s, 1H), 6.63 (d, 1H , J = 10.0 Hz), 6.25 (d, 1H, J = 8.8 Hz), 5.50 (d, 1H, J = 10.0 Hz), 4.15 (s, 2H), 3.79 (s, 6H), 1.37 (s, 6H ).

< Manufacturing example  33> 1,2- Dimethoxy -4-( Prop -2- Iniloxy ) Benzene (1,2- Dimethoxy -4-( prop -2-ynyloxy) benzene) 115

Propargyl bromine (225 mg, 1.51 mmol) and potassium carbonate (211 mg, 1.51 mmol) were added to a DMF (0.2M) solution containing 3,4-dimethoxyphenol and stirred at room temperature for 12 hours. The reaction mixture was quenched with saturated aqueous ammonium chloride solution and extracted with diethyl ether. The organic layer was washed with water (× 2), brine and dried over anhydrous MgSO ₄ , and the residue obtained by concentration under reduced pressure was purified by flash column chromatography (n-hexane: CH ₂ Cl ₂ = 1: 1), Compound 115 of Preparation Example 33 was obtained as a pale yellow oil (yield 100%, 241 mg).

¹ H NMR (CDCl ₃ , 300 MHz) δ6.79 (d, 1H, J = 8.8 Hz), 6.60 (d, 1H, J = 2.7 Hz), 6.49 (dd, 1H, J = 8.8, 2.7 Hz), 4.65 (d, 2H, J = 2.4 Hz), 3.86 (s, 3H), 3.84 (s, 3H), 2.52 (t, 1H, J = 2.4 Hz).

< Manufacturing example  34> 4- (3- Bromoprop -2- Iniloxy ) -1,2- Dimethoxybenzene  (4- (3- Bromoprop Preparation of -2-ynyloxy) -1,2-dimethoxybenzene) 116

To the saturated aqueous sodium hydroxide solution (0.5 mL, 5.0 M) was added cold bromine (1.12 mmol, 0.03 mL), followed by dimethoxyethane containing compound 115 (108 mg, 0.56 mmol) obtained in Preparation 33. 1.0 mL) was added. Next, the flask was filled with nitrogen gas and stirred vigorously at room temperature for 5 hours. The reaction mixture was poured into iced water and extracted with n-hexane (5.0 mL). The extract was washed with water, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by flash column chromatography (EtOAc: n-hexane = 1: 5) to give compound 116 of Preparation 34 as a pale yellow oil. (Yield 86%, 130 mg).

¹ H NMR (CDCl ₃ , 300 MHz) δ6.79 (d, 1H, J = 8.6 Hz, 1H), 6.58 (d, 1H, J = 2.9 Hz), 6.47 (dd, 1H, J = 8.6, 2.9 Hz ), 4.66 (s, 2H), 3.86 (s, 3H), 3.84 (s, 3H).

< Manufacturing example  35> 4- Bromo -6,7- Dimethoxy -2 H - Chromen  (4- Bromo -6,7- dimethoxy -2 H -chromene) Preparation of 118

Compound 116 (130 mg, 0.48 mmol) obtained in Preparation Example 34 was placed in N , N -diethylaniline (7.0 mL), monitored by TLC, and heated to 210 ° C. under a nitrogen atmosphere until completion of the reaction. The reaction mixture was poured into iced water and extracted with EtOAc (10 mL). The organic layer was washed with 2N- HCl aqueous solution, 2N- NaOH aqueous solution and water, the organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure, and the residue obtained by flash column chromatography (EtOAc: n-hexane = 1: 8) was purified. Compound 118 of Preparation Example 35 was obtained as a pale yellow solid (yield 77%, 100 mg).

¹ H NMR (CDCl ₃ , 300 MHz): δ6.73 (s, 1H), 6.42 (s, 1H), 6.01 (t, 1H, J = 4.2 Hz), 4.72 (d, 2H, J = 4.2 Hz) , 3.88 (s, 3 H), 3.86 (s, 3 H).

< Manufacturing example  36> 4- Bromo -6,7- Dimethoxy -2,2-dimethyl-2 H - Chromen  (4- Bromo -6,7-dimethoxy-2,2-dimethyl-2 H- chromene) 119

Anhydrous trichloroethylene (1.5 mL) solution containing anhydrous DMF (0.05 mL, 0.62 mmol) and phosphorus oxybromide (188 mg, 0.62 mmol) contains 2,2-dimethylchromonone (100 mg, 0.41 mmol) Anhydrous trichloroethylene (1.5 mL) solution was added at 0 ° C. The reaction mixture was monitored by TLC and heated to 60 ° C. until the reaction was complete and concentrated under reduced pressure to give an orange gum. The gum was extracted with CH ₂ Cl ₂ (× 5) and the extract was washed with brine. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by flash column chromatography (EtOAc: n-hexane = 1: 5) to give compound 119 of Preparation 36 as a yellow solid (yield 91%, 9 mg).

¹ H NMR (CDCl ₃ , 300 MHz) δ 6.95 (s, 1H), 6.38 (s, 1H), 5.82 (s, 1H), 3.85 (s, 3H), 3.83 (s, 3H), 1.41 (s , 6H).

< Manufacturing example  37> 2,2-dimethyl-2H- Chromen -6- Carbaaldehyde  (2,2- dimethyl -2H- chromene -6-carbaldehyde) Preparation of 120

A suspension of DMF (1.0 M) containing phenol (1 equiv), potassium carbonate (2 equiv), potassium iodine (1.7 equiv) and copper (I) iodine (0.02 equiv) was prepared at room temperature. 3-Chloro-3-methyl-1-butyne (1.8 equiv) was added to the mixture, the reaction mixture was heated to 65 ° C. for 2 hours, cooled to room temperature and poured into diethyl ether, 10% sodium hydroxide (× 3) and brine. The extract was dried over anhydrous MgSO ₄ , and the resulting residue was purified by silica gel column chromatography (EtOAc: n-hexane) to give o -alkylated phenol.

N , N -diethylaniline (0.05 M) solution containing o -alkylated phenol (1 equiv) was monitored by TLC at 190 ° C. under nitrogen atmosphere and heated until the reaction was complete. The reaction mixture was poured into iced water and extracted with EtOAc. The organic layer was washed with 2N- HCl aqueous solution, 2N- NaOH aqueous solution and water. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure, and the crude residue was purified by flash column chromatography (EtOAc: n-hexane) to give compound 120 (yield 46%, 326 mg).

¹ H NMR (CDCl ₃ , 300 MHz) δ 9.80 (s, 1H), 7.15 (dd, 1H, J = 8.2, 2.0 Hz), 7.49 (d, 1H, J = 2.0 Hz), 6.84 (d, 1H, J = 8.4 Hz), 6.35 (d, 1H, J = 9.8 Hz), 5.67 (d, 1H, J = 9.8 Hz), 1.45 (s, 6H); HRMS (FAB) Czalcd for C 12 H 13 r O 2 (M + H ⁺ ): 189.0916, Found: 189.0916.

< Manufacturing example  38> 5- ( Methoxy ) -2,2-dimethyl-2 H - Chromen -6- Carbaaldehyde  (5- ( Methoxy ) -2,2-dimethyl-2 H -chromene-6-carbaldehyde) (121)

To acetone (5 mL) solution containing Compound 110 (200 mg, 0.98 mmol) and potassium carbonate (406 mg, 2.94 mmol) obtained in Preparation Example 29, iodine methane (0.11 mL, 1.47 mmol) was added at room temperature. The mixture was refluxed for 3 hours, and then the crude residue obtained by concentration under reduced pressure was extracted with EtOAc and the organic layer was washed with brine. The extracts were dried over anhydrous MgSO ₄ and the residue obtained by concentration under reduced pressure was purified by flash column chromatography (EtOAc: n- hexane = 1: 10) to yield compound 121 as a light yellow solid (yield: 91%, 231 mg ).

¹ H NMR (CDCl ₃ , 300 MHz) δ 10.07 (s, 1 H), 7.59 (d, J = 8.6 Hz, 1 H), 6.61 (d, J = 8.6 Hz, 1 H), 6.53 (d, J = 10.0) Hz, 1H), 5.63 (d, J = 10.0 Hz, 1H), 5.02 (s, 2H), 3.52 (s, 3H).

< Manufacturing example  39> 6- Bromo -2,2-dimethyl-2 H - Chromen  (6- Bromo -2,2- dimethyl -2 H - chromene 131)

To acetonitrile (0.02 M) solution containing 2-methyl-3-butyn-2-ol (1.15 equiv) was added DBU (1.3 equiv) at 0 ° C. through a syringe for 30 minutes. The resulting yellow solution was stirred at 0 ° C. for 40 minutes. To another flask, 4-bromophenol (1 equiv) was added to acetonitrile (0.03 M) at 0 ° C. and treated with DBU (1.3 equiv), followed by addition of CuC1 ₂ H ₂ 0 (0.02 equiv). The mixture was added dropwise at 0 ° C., the yellow solution prepared above (2-methyl-3-butyn-2-yl trifluoroacetate) dropwise through the cannula for 40 minutes. The reaction mixture was stirred at 0 ° C. for 5 hours and the residue obtained by concentration under reduced pressure was poured into water. The aqueous layer is extracted with hexane; The organic layer was washed with 1 N -HCI, 1 N -KOH (x2), and brine. The organic layer was dried over anhydrous MgSO ₄ and concentrated under reduced pressure to afford o -alkylated phenol (1.0 equiv). The product was used for the next step.

The N , N -diethylaniline (0.05 M) solution containing the o -alkylated phenol (1.0 equiv) was monitored by TLC and heated to 190 ° C. under nitrogen atmosphere until the reaction was complete. The reaction mixture was poured into iced water and extracted with EtOAc. The organic layer was washed with 2N- HCl aqueous solution, 2N- NaOH aqueous solution, and water. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude residue was purified by flash column chromatography (EtOAc: n-hexane = 1: 20) to give compound 131 as a pale yellow oil (yield 68%, 464). mg).

¹ H NMR (CDCl ₃ , 300 MHz) δ 7.15 (d, 1H, J = 8.4 Hz), 7.06 (d, 1H, J = 2.3 Hz), 6.63 (d, 1H, J = 8.4 Hz), 6.23 (d, 1H, J = 9.9 Hz), 5.62 (d, 1H, J = 9.9 Hz), 1.39 (s, 6H).

< Manufacturing example  40> (3,4- Dimethoxyphenyl ) (2,2-dimethyl-2 H - Chromen -6-yl) methanol ((3,4-Dimethoxyphenyl) (2,2-dimethyl-2 H -chromen-6-yl) methanol) (132)

To anhydrous THF (3.0 mL) solution containing compound 131 (60 mg, 0.25 mmol) obtained in Preparation Example 39 was added n- BuLi (0.17 mL, 0.28 mmol, 1.6 M solution in n-hexane) at -78 ° C. Then, stirred for 30 minutes. Next, anhydrous THF (1.0 mL) containing 3,4-dimethoxybenzaldehyde (83 mg, 0.50 mmol) was added dropwise to the mixture, stirred for 30 minutes, and maintained at -78 ° C. Aqueous solution of saturated ammonium chloride was added to the reaction mixture to terminate the reaction, extracted with EtOAc (× 2), and washed with brine. The organic layer was dried over anhydrous MgSO ₄ , filtered, and concentrated under reduced pressure. The residue obtained was purified by flash column chromatography (EtOAc: n-hexane = 1: 4) to give compound 132 as a white solid (yield 66%). , 108 mg).

¹ H NMR (CDCl _{3 ,} 300 MHz) δ 7.06 (d, 1H, J = 8.2 Hz), 7.85 (m, 4H), 6.71 (d, 1H, J = 8.2 Hz), 6.26 (d, 1H, J = 9.8 Hz), 5.70 (s, 1H), 5.58 (d, 1H, J = 9.8 Hz), 3.84 (s, 3H), 3.83 (s, 3H), 2.09 (d, 1H, J = 3.2 Hz), 1.39 (s, 6 H).

< Manufacturing example  41> 1- (5-hydroxy-2,2-dimethyl-2 H - Chromen -6- days) Ethanone  (1- (5- hydroxy -2,2- dimethyl -2 H - chromen -6-yl) ethanone) (112) Preparation

To the anhydrous THF solution containing aryl bromide (1.5 equiv), n-BuLi (1.4 equiv) was added dropwise at −78 ° C. and stirred at −78 ° C. to generate aryl anions. After stirring at −78 ° C. for 20 minutes, 2 ′, 4′-dihydroxyacetophenone (1.0 equiv) was added and stirring continued for 30 minutes to allow the reaction temperature to room temperature. The reaction mixture was treated with saturated aqueous NH ₄ Cl solution and extracted with EtOAc. The extract was washed with brine, dried over MgSO ₄ and the solvent was evaporated and the residue obtained was purified by flash column chromatography (EtOAc: n-hexane = 1: 15 to 1:10) to afford compound 112 as a pale yellow solid. Obtained (yield 32%, 460 mg).

¹ H-NMR (CDCl ₃ , 300 MHz) δ 12.94 (s, 1H), 7.50 (d, 1H, J = 8.7 Hz), 6.79 (d, 1H, J = 10.0 Hz), 6.31 (d, 1H, J = 8.7 Hz), 5.56 (d, 1H, J = 8.7 Hz), 1.42 (s, 6H).

< Manufacturing example  42> 1- (2,2-dimethyl-2H- Chromen -6- days) Ethanone  (1- (2,2- Dimethyl -2H-chromen-6-yl) ethanone) (134)

A suspension of DMF (1.0 M) containing Compound 133 (1 equiv), potassium carbonate (2 equiv), potassium iodine (1.7 equiv) and copper (I) iodine (0.02 equiv) was prepared at room temperature. 3-Chloro-3-methyl-1-butyne (1.8 equiv) was added to the mixture, the reaction mixture was heated to 65 ° C. for 2 hours, cooled to room temperature and poured into diethyl ether, 10% sodium hydroxide (× 3) and brine. The extract was dried over anhydrous MgSO ₄ , and the resulting residue was purified by silica gel column chromatography to give o -alkylated phenol.

A solution of N, N-diethylaniline (0.05 M) containing o -alkylated phenol (1 equiv) was monitored by TLC at 190 ° C. under a nitrogen atmosphere and heated until the reaction was complete. The reaction mixture was poured into iced water and extracted with EtOAc. The organic layer was washed with 2N- HCl aqueous solution, 2N- NaOH aqueous solution and water. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude residue was purified by flash column chromatography (EtOAc: n-hexane = 1: 15) to give compound 134 as a colorless oil (yield 65%, 248 mg). ).

¹ H NMR (CDCl ₃ , 300 MHz) δ7.32 (dd, 1H, J = 8.4, 2.1 Hz), 6.60 (d, 1H, J = 2.4 Hz), 6.77 (d, 1H, J = 8.4 Hz), 6.34 (d, 1H, J = 9.9 Hz), 5.65 (d, 1H, J = 9.9 Hz), 2.51 (s, 3H), 1.43 (s, 6H); LRMS (FAB) m / z 203 (M + H ⁺ ).

< Example  1> (6 a S , 12 a S ) -9-hydroxy-2,3- Dimethoxy -8- (3- methyl -2- Butenyl ) -6a, 12a-D Hydrochromeno [3,4- b ] Chrome-12 (6 H ) -On ((6 a S , 12 a S ) -9- Hydroxy -2,3-dimethoxy-8- (3-methyl-2-butenyl) -6a, 12a-dihydrochromeno [3,4- b ] chromen -12 (6 H ) - one Manufacture of 8

Rotenone (Sigma-Aldrich, To anhydrous CH ₂ Cl ₂ (5.0 mL) solution in which 200 mg, 0.50 mmol) is dissolved, add BBr ₃ (0.53 mL, 0.53 mmol, 1.0 M solution in CH ₂ Cl ₂ ) under argon atmosphere at −10 ° C., The reaction mixture was mixed for 5 minutes. Next, methanol (1.0 mL) was added, the solvent was removed under reduced pressure, and the crude residue (Compound 7) obtained by filtration was used in the next step without further purification. Compound 7 and NaBH ₃ CN (69 mg, 1.1 mmol) were added to a hexamethylphosphoamide (HMPA) solution, heated to 70 ° C., stirred for 3 hours, and poured into water. The extract of the mixture was washed with brine, dried over MgSO ₄ and concentrated under reduced pressure. Then, the residue was purified by flash column chromatography (EtOAc: n -hexane = 1: 2) to obtain compound 8 of Example 1 as a pale yellow solid (yield 50%, 55 mg).

¹ H-NMR (CDCl ₃ , 500 MHz) δ7.68 (d, 1H, J = 8.7 Hz), 6.76 (s, 1H), 6.50 (d, 1H, J = 8.7 Hz), 6.41 (s, 1H) , 5.19 (m, 1H), 4.87 (t, 1H, J = 2.97 Hz), 4.60 (dd, 1H, J = 11.9, 3.1 Hz), 4.14 (d, 1H, J = 11.9 Hz), 3.80 (m, 1H), 3.75 (s, 3H), 3.70 (s, 3H), 3.34 (m 2H), 1.74 (s, 3H), 1.65 (s, 3H); ¹³ H-NMR (CDCl ₃ , 125 MHz) δ 190.4, 162.1, 160.1, 149.3, 147.5, 143.6, 134.0, 126.9, 121.1, 114.8, 112.5, 110.7, 110.5, 108.5, 104.7, 100.8, 72.0, 66.2, 56.2 , 55.7, 44.1, 25.7, 22.0, 17.7; HRMS (FAB) Calcd for C ₂₃ H ₂₄ O ₆ (M + H ⁺ ): 396.1573, Found: 396.1575.

< Example  2 ~ 4> (7 a S , 13 a S ) -9-hydroxy-13,13a- Dihydro -10- Methoxy -3,3-dimethyl-3 H -Chromeno [ 3,4- b ] Pyrano [2,3- h ] Chromen -7 (7 a H ) -On ((7a S , 13a S ) -9-Hydroxy-13,13a- dihydro -10- methoxy -3,3- dimethyl -3 H - chromeno [3,4- b ] pyrano [2,3- h ] chromen -7 (7a H ) -one) (9);

(7 a S , 13 a S ) -10-hydroxy-13,13a- Dihydro -9- Methoxy -3,3-dimethyl-3 H -Chromeno [3,4- b ] Pyrano [ 2,3- h ] Chrome -7 (7 a H ) -On ((7 a S , 13 a S ) -10- Hydroxy -13,13a- dihydro -9- methoxy -3,3-dimethyl-3 H -chromeno [3,4- b ] pyrano [2,3- h ] chromen -7 (7 a H ) - one ) (10); And

(7 a S , 13 a S ) -13,13a- Dihydro -9,10-dihydroxy-3,3-dimethyl-3 H - Chromeno [3,4- b ] Pyrano [2,3-] chromen-7 (7 a H ) -On ((7 a S , 13 a S ) -13,13a- Dihydro -9,10- dihydroxy -3,3- dimethyl -3 H -chromeno [3,4- b ] pyrano [2,3- h ] chromen-7 (7a H ) -one) Preparation of 11

In anhydrous CH ₂ Cl ₂ (7.0 mL) solution containing deguelin (100 mg, 0.25 mmol) in Comparative Example 1, 1.0 in BBr ₃ (0.25 mL, 0.25 mmol, CH ₂ Cl ₂ ) under argon atmosphere at −78 ° C. M solution) was added and stirred for 1 hour and then left until 0 ° C. After stirring for an additional 30 minutes, the reaction mixture was cooled with water, extracted with CH ₂ Cl ₂ and washed with brine. The organic layer obtained above was dried over MgSO ₄ , filtered and concentrated to obtain a residue obtained by flash column chromatography (EtOAc: n -hexane: CH ₂ Cl ₂ = 1: 3: 1 to 1: 2: 1). , Compound 9 of Example 2 was obtained as a pale yellow solid (yield 16%, 16 mg).

¹ H-NMR (acetone-d ₆ , 400 MHz) δ7.64 (d, 1H, J = 8.7 Hz), 7.60 (s, 1H), 6.67 (s, 1H), 6.59 (d, 1H, J = 10.1 Hz), 6.40 (d, 1H, J = 8.7 Hz), 6.30 (s, 1H), 5.66 (d, 1H, J = 10.1 Hz), 5.06 (m, 1H), 4.57 (dd, 1H, J = 12.2 , 2.9 Hz), 4.22 (d, 1H, J = 12.2 Hz), 3.85 (d, 1H, J = 4.0 Hz), 3.62 (s, 3H), 2.00 (m, 1H), 1.39 (s, 3H), 1.30 (s, 3 H); ¹³ C-NMR (acetone-d ₆ , 100 MHz) δ 190.2, 160.8, 158.2, 149.6, 148.6, 143.7, 130.4, 129.4, 116.6, 114.3, 112.2, 112.1, 110.3, 105.8, 105.2, 78.8, 74.0, 67.3 , 57.3, 45.4, 29.0, 28.6; HRMS (FAB) Calcd for C ₂₂ H ₂₁ O ₆ (M + H ⁺ ): 381.1321, Found: 381.1327.

In addition, compound 10 of Example 3 was obtained as a pale yellow solid (yield 14%, 14 mg).

¹ H-NMR (acetone-d ₆ , 300 MHz) δ7.64 (d, 1H, J = 8.6 Hz), 7.07 (s, 1H), 6.60 (s, 1H), 6.59 (d, 1H, J = 10.1 Hz), 6.39 (d, 1H, J = 8.6 Hz), 6.38 (s, 1H), 5.67 (d, 1H, J = 10.1 Hz), 5.06 (m, 1H), 4.59 (dd, 1H, J = 12.2 , 2.9 Hz), 4.23 (d, 1H, J = 12.2 Hz), 3.82 (d, 1H, J = 4.0 Hz), 3.71 (s, 3H), 2.00 (m, 1H), 1.39 (s, 3H), 1.30 (s, 3 H); ¹³ C-NMR (acetone-d ₆ , 75 MHz) δ 190.0, 160.8, 158.2, 149.1, 148.2, 142.1, 130.4, 129.4, 116.6, 114.5, 114.3, 112.1, 110.3, 107.2, 102.1, 78.8, 73.9, 67.4 , 56.6, 45.4, 29.0, 28.6; HRMS (FAB) Calcd for C ₂₂ H ₂₁ O ₆ (M + H ⁺ ): 381.1338, Found: 381.1335.

Furthermore, compound 11 of Example 4 was obtained as a pale yellow solid (33% yield, 32 mg).

¹ H-NMR (acetone-d ₆ , 400 MHz) δ7.75 (s, 1H), 7.63 (d, 1H, J = 8.7 Hz), 7.38 (s, 1H), 6.59 (s, 1H), 6.58 ( d, 1H, J = 10.1 Hz), 6.39 (d, 1H, J = 8.7 Hz), 6.29 (s, 1H), 5.65 (d, 1H, J = 10.1 Hz), 5.03 (m, 1H), 4.55 ( dd, 1H, J = 12.2, 2.9 Hz), 4.20 (d, 1H, J = 12.2 Hz), 3.79 (d, 1H, J = 4.0 Hz), 1.99 (m, 1H), 1.38 (s, 3H), 1.30 (s, 3 H); ¹³ C-NMR (acetone-d ₆ , 100 MHz) δ 190.1, 160.8, 158.2, 148.4, 146.9, 140.7, 160.8, 158.2, 148.4, 146.9, 140.7, 130.4, 129.3, 116.6, 114.9, 114.2, 112.1, 110.3 , 106.2, 105.1, 78.8, 74.0, 67.2, 45.4, 29.0, 28.6; HRMS (FAB) Calcd for C ₂₁ H ₁₉ O ₆ (M + H ⁺ ): 367.1182, Found: 367.1179.

< Example  5> 9,10- Dimethoxy -3,3-dimethyl-3 H - Chromeno [3,4- b ] Pyrano [2,3- h ] Chromen -7- (13 H ) -On (9,10- Dimethoxy -3,3- dimethyl -3 H - chromeno [3,4- b ] pyrano [2,3- h ] chromen -7- (13 H ) -one) Preparation of 12

Sodium acetate (21 mg, 0.25 mmol) and I ₂ (290 mg, 1.14 mmol) were added at room temperature to a solution of ethyl alcohol (2.0 mL) in which Daeguline (50 mg, 0.13 mmol) was dissolved. The mixture was refluxed for 12 h, then cooled to room temperature and extracted with EtOAc. The organic layer of the extract was washed with brine, dried over MgSO ₄ , and concentrated under reduced pressure to crystallize from EtOAc: n -hexane = 1: 1 solution to give compound 12 of Example 5 as a pale yellow solid ( Yield 35%, 17 mg).

¹ H-NMR (CDCl ₃ , 500 MHz) δ 8.42 (s, 1H), 8.01 (d, 1H, J = 8.7 Hz), 6.84 (d, 1H, J = 8.7 Hz), 6.73 (d, 1H, J = 10.0 Hz), 6.52 (s, 1H), 5.70 (d, 1H, J = 8.7 Hz), 4.99 (s, 2H), 3.93 (s, 3H), 3.84 (s, 3H), 1.47 (s, 6H) .; ¹³ C-NMR (CDCl ₃ , 125 MHz) δ174.2, 157.1, 156.1, 151.0, 148.9, 146.2, 144.0, 130.5, 126.4, 118.4, 115.3, 114.6, 111.7, 110.5, 109.9, 109.0, 100.3, 77.7, 64.8 , 56.2, 55.8, 28.1; HRMS (FAB) Calcd for C ₂₃ H ₂₀ O ₆ (M + H ⁺ ): 392.1260, Found: 392.1263.

< Example  6> (7 S , 7 a R , 13 a S ) -9,10- Dimethoxy -3,3-dimethyl-7,7a, 13,13a- Tetrahydro -3 H -Big Romeno [3,4- b ] Pyrano [2,3- h ] Chromen -7-all ((7 S , 7a R , 13a S ) -9,10-Dimethoxy-3,3- dimethyl -7,7a, 13,13a- tetrahydro -3 H - chromeno [3,4- b ] pyrano [2,3- h ] chromen -7-ol) (14) Preparation

NaBH ₄ (43 mg, 1.13 mmol) was added to a methanol (10.0 mL) solution in which deguelin (300 mg, 0.76 mmol) was dissolved at 0 ° C., stirred for 30 minutes, and cooled with water. The mixture was extracted with diethyl ether, the organic layer was washed with brine, dried over MgSO ₄ and concentrated to obtain a residue obtained by flash column chromatography (EtOAc: n-hexane = 1: 1), and Example 6 Compound 14 was obtained as a white solid (yield 100%, 300 mg).

¹ H-NMR (CDCl ₃ , 400 MHz) δ 6.99 (d, 1H, J = 8.2 Hz), 6.68 (s, 1H), 6.64 (d, 1H, J = 10.0 Hz), 6.47 (s, 1H) , 6.41 (d, 1H, J = 8.2 Hz), 5.56 (d, 1H, J = 10.0 Hz), 4.80 (m, 2H), 4.57 (d, 1H, J = 10.0 Hz), 4.21 (m, 1H) , 3.84 (s, 3H), 3.82 (s, 3H), 3.36 (t, 1H, J = 4.9 Hz), 1.41 (s, 3H), 1.39 (s, 3H); ¹³ C-NMR (CDCl ₃ , 100 MHz) δ 154.3, 149.6, 149.4, 147.9, 143.8, 130.0, 129.1, 116.4, 113.6, 111.3, 109.8, 109.5, 108.7, 100.7, 76.0, 69.1, 66.3, 65.0, 56.5 , 55.8, 37.9, 27.8, 27.7; HRMS (FAB) Calcd for C ₂₃ H ₂₄ O ₆ (M + H ⁺ ): 396.1560, Found: 396.1562.

< Example  7> (7 a S , 13 a S ) -9,10- Dimethoxy -3,3-dimethyl-7,7a, 13,13a- Tetrahydro -3 H -Chromeno [3,4- b ] Pyrano [2,3- h ] Chromen  ((7 a S , 13 a S ) -9,10- Dimethoxy -3,3- dimethyl -7,7a, 13,13a-tetrahydro-3 H -chromeno [3,4- b ] pyrano [2,3- h ] chromene) (13) Preparation

To anhydrous THF (2.0 mL) solution in which Compound 14 (40 mg, 0.10 mmol) was prepared in Example 6 was added sodium hydride (16 mg, 0.40 mmol) under argon atmosphere at 0 ° C., and stirred for 30 minutes. Carbon disulfide (0.063 mL, 1.00 mmol) was then added at 0 ° C. Iodomethane (0.064 mL, 1.00 mmol) was added to the mixture at 0 ° C. and the reaction temperature was brought to room temperature. After confirming that the reaction was completed by TLC, the mixture was cooled with methanol (1.0 mL) and the solvent was removed under reduced pressure, and the residue obtained was extracted with EtOAc and washed with brine. The organic layer of the extract was dried over MgSO ₄ , filtered and the crude residue was purified by flash column chromatography (EtOAc: n-hexane = 1: 6) to afford the desired intermediate compound (yield 71%, 35 mg). ). This intermediate compound (21 mg, 0.043 mmol) was dissolved in anhydrous toluene (1.0 mL) and tri- n -butyltin hydride (0.024 mL, 0.086 mmol) and AIBN (catalyst amount) were added. The reaction mixture was monitored by TLC and refluxed until the reaction was completed and the residue obtained by removing the solvent under reduced pressure was purified by flash column chromatography (EtOAc: n-hexane = 1: 6) to obtain the compound of Example 7. 13 was obtained as a light yellow oil (yield 69%, 11 mg).

¹ H-NMR (CDCl ₃ , 300 MHz) δ6.75 (d, 1H, J = 8.2 Hz), 6.63 (d, 1H, J = 10.0 Hz), 6.62 (s, 1H), 6.38 (s, 1H) , 6.31 (d, 1H, J = 8.2 Hz), 5.52 (d, 1H, J = 10.0 Hz), 5.53 (d, 1H, J = 10.0 Hz), 4.67 (q, 1H, J = 4.7 Hz), 4.24 (d, 1H, J = 5.4 Hz), 3.79 (s, 6H), 3.26 (m, 1H), 2.99 (m, 2H), 1.38 (s, 3H), 1.37 (s, 3H); ¹³ C-NMR (CDCl ₃ , 75 MHz) δ 152.2, 148.9, 148.7, 147.7, 143.5, 128.9, 128.5, 116.7, 113.0, 111.4, 111.2, 109.7, 108.8, 100.6, 75.6, 69.7, 65.6, 56.6, 55.8 , 31.6, 29.6, 29.4, 27.8, 27.6; HRMS (FAB) Calcd for C ₂₃ H ₂₄ O ₅ (M + H ⁺ ): 380.1624, Found: 380.1631.

< Example  8> (7 S , 7 a R , 3 a S ) -7,9,10- Trimethoxy -3,3-dimethyl-7,7a, 13,13a- Tetrahydrate Rho-3 H - Chromeno [3,4- b ] Pyrano [2,3- h ] Chromen  ((7 S , 7a R , 3a S ) -7,9,10-Trimethoxy-3,3- dimethyl -7,7a, 13,13a- tetrahydro -3 H - chromeno [3,4- b ] pyrano [2,3- h ] chromene) Preparation of (15)

The compound 14 (1 equivalent) prepared in Example 7 was dissolved in anhydrous THF solution at 0 ° C. Iodomethane (1.5 equiv) was added and then at 0 ° C. t- BuOK solution (1 M in THF, 1 equiv) was added dropwise. The reaction mixture is monitored by TLC at 0 ° C. until the reaction is complete After stirring, it was cooled with saturated aqueous NH ₄ Cl solution and extracted with EtOAc. The organic layer in the extract was dried over MgSO ₄ , filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography (EtOAc: n-hexane = 1: 3) to give compound 15 of Example 8 as a colorless solid. (55 mg).

¹ H-NMR (CDCl ₃ , 400 MHz) δ6.93 (d, 1H, J = 8.2 Hz), 6.77 (s, 1H), 6.64 (d, 1H, J = 10.0 Hz), 6.42 (s, 1H) , 6.37 (d, 1H, J = 8.2 Hz), 6.31 (d, 1H, J = 8.2 Hz), 5.55 (d, 1H, J = 10.0 Hz), 4.78 (m, 1H), 4.51 (t, 1H, J = 10.0 Hz), 4.39 (d, 1H, J = 3.6 Hz), 4.22 (dd, 1H, J = 10.0, 3.9 Hz), 3.82 (s, 1H), 3.81 (s, 1H), 3.38 (m, 1H), 3.15 (s, 1H), 1.41 (s, 3H), 1.39 (s, 3H); ¹³ C-NMR (CDCl ₃ , 100 MHz) δ 154.2, 149.1, 149.0, 148.4, 143.5, 129.3, 129.0, 116.5, 113.6, 111.5, 110.3, 110.0, 108.4, 100.4, 76.7, 75.9, 70.0, 65.8, 57.0 , 56.5, 55.7, 37.2, 27.9, 27.8; HRMS (FAB) Calcd for C ₂₄ H ₂₄ O ₆ (M + H ⁺ ): 410.1729, Found: 410.1713.

< Example  9> (7 S , 7 a R , 3 a S ) -9,10- Dimethoxy -3,3-dimethyl-7- Ethoxy -7,7a, 13,13a- Tetrahydro -3 H - Chromeno [3,4- b ] Pyrano [2,3- h ] Chromen  ((7 S , 7 a R , 3 a S ) -9,10-Dimethoxy-3,3-dimethyl-7-ethoxy-7,7a, 13,13a-tetrahydro-3 H -chromeno [3,4- b pyrano [2,3- h ] chromene) Preparation of (16)

The compound 14 (1 equivalent) prepared in Example 7 was dissolved in anhydrous THF solution at 0 ° C. Iodoethane (1.5 equiv) was added and then at 0 ° C. t- BuOK solution (1 M in THF, 1 equiv) was added dropwise. The reaction mixture is monitored by TLC at 0 ° C. until the reaction is complete After stirring, it was cooled with saturated aqueous NH ₄ Cl solution and extracted with EtOAc. The organic layer in the extract was dried over MgSO ₄ , filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography (EtOAc: n-hexane = 1: 3) to give compound 16 of Example 9 as a colorless solid. (Yield 71%, 23 mg).

¹ H-NMR (CDCl ₃ , 300 MHz) δ6.94 (d, 1H, J = 8.3 Hz), 6.77 (s, 1H), 6.42 (s, 1H), 6.38 (d, 1H, J = 8.0 Hz) , 5.57 (d, 1H, J = 9.9 Hz), 4.81 (m, 1H), 4.55 (dd, 1H, J = 10.1, 9.9 Hz), 4.39 (d, 1H, J = 4.1 Hz), 4.24 (dd, 1H, J = 10.1, 3.8 Hz), 3.82 (s, 3H), 3.81 (s, 3H), 3.39 (m, 1H), 3.15 (s, 3H), 1.41 (s, 3H), 1.39 (s, 3H ). ¹³ C-NMR (CDCl ₃ , 75 MHz) δ 153.9, 149.1, 148.9, 148.4, 143.3, 128.9, 128.6, 116.6, 114.4, 111.7, 110.1, 109.8, 108.5, 100.3, 75.8, 75.0, 70.1, 66.0, 64.9 , 56.5, 55.7, 36.8, 29.6, 27.8, 27.8; HRMS (FAB) Calcd for C ₂₅ H ₂₈ O ₆ (M + H ⁺ ): 424.1886, Found: 424.1894.

< Example  10> (7 S , 7 a R , 3 a S ) -9,10- Dimethoxy -3,3-dimethyl-7- Propoxy -7,7a, 13,13a- Tetrahydro -3 H - Chromeno [3,4- b ] Pyrano [2,3- h ] Chromen  ((7 S , 7a R , 3a S ) -9,10-Dimethoxy-3,3- dimethyl -7- propoxy -7,7a, 13,13a- tetrahydro -3 H - chromeno [3,4- b ] pyrano [2,3- h ] chromene) Preparation of 17

The compound 14 (1 equivalent) prepared in Example 7 was dissolved in anhydrous THF solution at 0 ° C. Iodopropane (1.5 equiv) was added and then at 0 ° C. t- BuOK solution (1 M in THF, 1 equiv) was added dropwise. The reaction mixture is monitored by TLC at 0 ° C. until the reaction is complete After stirring, it was cooled with saturated aqueous NH ₄ Cl solution and extracted with EtOAc. The organic layer in the extract was dried over MgSO ₄ , filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography (EtOAc: n-hexane = 1: 5) to give compound 17 of Example 10 as a colorless solid. (Yield 68%, 15 mg).

¹ H-NMR (CDCl ₃ , 500 MHz) δ6.94 (d, 1H, J = 8.2 Hz), 6.83 (s, 1H), 6.39 (s, 1H), 6.34 (d, 1H, J = 8.2 Hz) , 5.53 (d, 1H, J = 9.9 Hz), 4.77 (m, 1H), 4.57 (t, 1H, J = 9.9 Hz), 4.50 (d, 1H, J = 3.7 Hz), 4.21 (dd, 1H, J = 9.9, 4.2 Hz), 3.80 (s, 6H), 3.39 (m, 1H), 3.10 (m, 1H), 1.39 (s, 8H), 0.69 (t, 3H, J = 7.3 Hz); ¹³ C-NMR (CDCl ₃ , 125 MHz) δ 153.9, 149.1, 148.9, 148.3, 143.3, 128.9, 128.7, 116.6, 114.3, 111.7, 110.2, 109.8, 108.4, 100.3, 75.8, 75.3, 71.3, 70.1, 65.9 , 56.5, 55.8, 36.8, 29.6, 27.9, 27.8, 22.9; HRMS (FAB) Calcd for C ₂₆ H ₃₁ O ₆ (M + H ⁺ ): 439.2121, Found: 439.2120.

< Example  11> (7 S , 7 a R , 3 a S ) -7- Benzyloxy -9,10- Dimethoxy -3,3-dimethyl-7,7a, 13,13a- Tetrahydro -3 H - Chromeno [3,4- b ] Pyrano [2,3- h ] Chromen  ((7 S , 7 a R , 3 a S ) -7- Benzyloxy -9,10- dimethoxy -3,3- dimethyl -7,7a, 13,13a- tetrahydro -3 H -chromeno [3,4- b ] pyrano [2,3- h ] chromene) (18) Preparation

The compound 14 (1 equivalent) prepared in Example 7 was dissolved in anhydrous THF solution at 0 ° C. Benzyl bromide (1.5 equiv) was added and then at 0 ° C. t- BuOK solution (1 M in THF, 1 equiv) was added dropwise. The reaction mixture is monitored by TLC at 0 ° C. until the reaction is complete After stirring, it was cooled with saturated aqueous NH ₄ Cl solution and extracted with EtOAc. The organic layer in the extract was dried over MgSO ₄ , filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography (EtOAc: n-hexane = 1: 6) to give compound 18 of Example 11 as a colorless solid. (Yield 88%, 22 mg).

¹ H-NMR (CDCl ₃ , 500 MHz) δ7.22 (m, 2H), 7.00 (d, 1H, J = 6.2 Hz), 6.87 (d, 1H, J = 8.2 Hz), 6.66 (d, 1H, J = 9.9 Hz), 6.62 (s, 1H), 6.45 (s, 1H), 6.37 (d, 1H, J = 8.2 Hz), 5.56 (d, 1H, J = 9.9 Hz), 4.81 (m, 1H) , 4.62 (t, 1H, J = 9.9 Hz), 4.54 (d, 1H, J = 3.2 Hz), 4.48 (AB quartet, 1H, J = 85.0, 12.5 Hz), 4.25 (dd, 1H, J = 14.2, 4.6 Hz), 3.84 (s, 3H), 3.72 (s, 3H), 3.36 (m, 1H), 1.42 (s, 3H), 1.40 (s, 3H); ¹³ C-NMR (CDCl ₃ , 125 MHz) δ 154.2, 149.1, 148.9, 148.7, 143.4, 137.9, 129.2, 129.0, 128.1, 127.6, 127.4, 127.2, 116.5, 113.8, 111.3, 110.1, 110.0, 108.4, 100.4 , 75.9, 72.8, 69.9, 69.8, 65.8, 64.9, 56.2, 55.8, 37.3, 27.9, 27.8; HRMS (FAB) Calcd for C ₃₀ H ₃₀ 0 ₆ (M + H ⁺ ): 486.2042, Found: 486.2050.

< Example  12> (7 S , 7 a S , 13 a S ) -9,10- Dimethoxy -3,3-dimethyl-7- ( Tetrahydro -2 H -Pyran-2-yl rock H) -7,7a, 13,13a- Tetrahydro -3 H - Chromeno [3,4- b ] Pyrano [2,3- h ] Chromen  ((7 S , 7 a S , 13 a S ) -9,10- Dimethoxy -3,3- dimethyl -7- ( tetrahydro -2 H - pyran -2- yloxy ) -7,7a, 13,13a-tetrahydro-3 H -chromeno [3,4- b ] pyrano [2,3- h ] chromene) (19) Preparation

P -toluenesulfonate (5.8 mg, 0.023 mmol) was dissolved in CH ₂ Cl ₂ (1.0 mL) in which Compound 14 (30 mg, 0.076 mmol) and DHP (13 mg, 0.15 mmol) prepared in Example 7 were dissolved. It was added and stirred at room temperature for 1 hour. Next, the reaction was cooled with water (0.5 mL) and the mixture was extracted with EtOAc. The organic layer of the extract was dried over MgSO ₄ , filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography (EtOAc: n-hexane = 1: 4) to give compound 19 of Example 12 as a colorless oil. (Yield 50%, diastereomeric mixture, 18 mg).

¹ H-NMR (CDCl ₃ , 500 MHz) δ 7.06 (d, 1H, J = 8.2 Hz), 6.91 (d, 1H, J = 8.2 Hz), 6.84 (s, 1H), 6.72 (s, 1H) , 6.63 (t, 1H, J = 9.9 Hz), 6.42 (s, 1H), 6.69 (s, 1H), 6.37 (d, 1H, J = 8.4 Hz), 6.33 (d, 1H, J = 8.2 Hz) , 5.54 (t, 1H, J = 9.3 Hz), 4.85 (m, 4H), 4.75 (m, 1H), 4.63 (t, 1H, J = 10.0 Hz), 4.55 (t, 1H, J = 10.0 Hz) , 4.33 (m, 1H), 4.21 (m, 2H), 3.81 (s, 3H), 3.80 (s, 3H), 3.79 (s, 3H), 3.78 (s, 3H), 3.70 (m, 1H), 3.40 (m, 3H), 3.29 (m, 1H), 3.11 (m, 1H), 1.71-1.19 (m, 12H), 1.40 (s, 12H); ¹³ C-NMR (CDCl ₃ , 125 MHz) δ 154.2, 153.7, 149.2, 149.1, 149.0, 148.9, 148.7, 148.7, 148.2, 148.2, 143.3, 143.2, 116.5, 116.4, 113.4, 113.1, 111.8, 111.7, 110.2 , 110.0, 109.6, 109.6, 109.3, 109.3, 109.1, 108.2, 100.3, 100.2, 99.1, 93.2, 75.9, 75.8, 72.4, 69.8, 69.4, 69.1, 65.8, 65.2, 61.6, 60.4, 56.5, 56.5, 55.8, 55.8 , 37.2, 36.8, 30.3, 30.2, 28.0, 27.9, 27.8, 27.7, 25.4, 25.3, 18.7, 18.1; HRMS (FAB) Calcd for C ₂₈ H ₃₂ O ₇ (M + H ⁺ ): 480.2148, Found: 480.2155.

< Example  13> (7 S , 7 a S , 13 a S ) -9,10- Dimethoxy -3,3-dimethyl-7,7a, 13,13a- Tetrahydro -3 H -Big Romeno [3,4 - b ] Pyrano [2,3, h ] Chromen -7-yl acetate ((7 S , 7a S , 13a S ) -9,10- Dimethoxy -3,3- dimethyl -7,7a, 13,13a- tetrahydro -3 H -chromeno [3,4- b ] pyrano [2,3, h ] chromen-7-yl acetate Manufacture of 20

Et ₃ N (0.012 mL, 0.086 mmol) and acetic anhydride (0.06) in a solution of CH ₂ Cl ₂ (1.0 mL) in which compound 14 (30 mg, 0.076 mmol) and DMAP (catalyst amount) prepared in Example 7 were dissolved mL, 0.64 mmol) was added under argon atmosphere at 0 ° C. Next, the reaction mixture was stirred at room temperature for 10 minutes and cooled with saturated aqueous NH ₄ Cl solution. The mixture was extracted with CH ₂ Cl ₂ , the organic layer was washed with brine, dried over MgSO ₄ and concentrated to obtain a residue obtained by flash column chromatography (EtOAc: n-hexane = 1: 5). Compound 20 of Example 13 was obtained as a white solid (yield 82%, 27 mg).

¹ H-NMR (CDCl ₃ , 500 MHz) δ 7.01 (d, 1H, J = 8.3 Hz), 6.63 (s, 1H), 6.63 (d, 1H, J = 9.9 Hz), 6.38 (s, 1H) , 6.38 (d, 1H, J = 7.5 Hz), 6.24 (d, 1H, J = 4.4 Hz), 5.56 (d, 1H, J = 9.9 Hz), 4.86 (m, 1H), 4.43 (t, 1H, J = 10.2 Hz), 4.24 (m, 1H), 3.81 (s, 6H), 3.49 (m, 1H), 1.71 (s, 3H), 1.4 (s, 6H); ¹³ C-NMR (CDCl ₃ , 125 MHz) δ 170.0, 154.6, 149.3, 148.6, 148.5, 143.4, 130.5, 129.1, 116.2, 111.7, 110.9, 109.7, 109.6, 108.6, 100.1, 76.1, 69.0, 66.7, 64.5 , 56.4, 55.8, 36.4, 27.9, 27.8, 20.8; HRMS (FAB) Calcd for C ₂₅ H ₂₆ O ₇ (M + H ⁺ ): 438.1679, Found: 438.1681.

< Example  14> (7 S , 7 a S , 13 a S ) -9,10- Dimethoxy -3,3-dimethyl-7,7a, 13,13a- Tetrahydro -3 H -Chromeno [ 3,4-b] pyrano [2,3- h ] Chromen -7 days Carbamate  ((7 S , 7a S , 13a S ) -9,10- Dimethoxy -3,3- dimethyl -7,7a, 13,13a- tetrahydro -3 H - chromeno [3,4-b] pyrano [2,3- h ] chromen-7-yl carbamate Manufacture of 21

To anhydrous CH ₂ Cl ₂ (0.5 mL) solution in which Compound 14 (30 mg, 0.076 mmol) was prepared in Example 7, trichloroacetyl isocyanate (0.014 mL, 0.11 mmol) was added under an argon atmosphere at 0 ° C. It stirred at 0 degreeC for 30 minutes. The solvent was removed under reduced pressure and the remaining residue was dissolved in methyl alcohol (1.0 mL) and water (0.2 mL). The mixture was cooled to 0 ° C. and then potassium carbonate (313 mg, 2.26 mmol) was added. The reaction mixture was stirred at 0 ° C. for 30 minutes, then left to room temperature, and further stirred for 1 hour. The reaction mixture was cooled with brine and extracted with EtOAc. The organic layer of the extract was dried over MgSO ₄ , filtered, and concentrated under reduced pressure. The residue obtained was purified by flash column chromatography (EtOAc: n-hexane = 1: 2) to give compound 21 of Example 14 as a white solid. Obtained (yield 67%, 21 mg).

_{^{1 H-NMR (CDCl 3,}} 500 MHz) δ6.87 (d, 1H, J = 8.2 Hz), 6.62 (d, 1H, J = 10.0 Hz), 6.53 (s, 1H), 6.33 (s, 1H) , 6.27 (d, 1H, J = 8.2 Hz), 5.46 (d, 1H, J = 10.0 Hz), 4.74 (m, 1H), 4.56 (dd, 1H, J = 11.7, 2.7 Hz), 4.49 (d, 1H, J = 2.7 Hz), 4.18 (d, 1H, J = 11.7 Hz), 3.73 (s, 3H), 3.72 (s, 3H), 3.14 (s, 6H); ¹³ C-NMR (CDCl ₃ , 125 MHz) δ 154.2, 149.6, 148.9, 148.3, 143.3, 130.6, 128.4, 116.6, 110.2, 110.1, 109.6, 108.6, 108.2, 100.9, 75.9, 75.1, 67.5, 65.9, 56.7 , 55.8, 55.6, 35.5, 28.1, 27.6.

< Example  15> (13 a S ) -9,10- Dimethoxy -3,3-dimethyl-13,13a- Dihydro -3 H -Chromeno [3,4- b ] Pyrano [2,3- h ] Chromen  ((13 a S ) -9,10- Dimethoxy -3,3- dimethyl -13,13a-dihydro-3 H -chromeno [3,4- b ] pyrano [2,3- h ] chromene) (22) Preparation

An acetic acid (1.0 mL) solution containing Compound 14 (3 mg, 7.6 μmol) prepared in Example 7 was stirred at 100 ° C. for 2 hours and treated with water (2.0 mL). The mixture was extracted with diethyl ether and the aqueous layer was extracted again with diethyl ether. The organic layer was washed with brine, dried over MgSO ₄ , filtered and concentrated under reduced pressure to purify the residue by flash column chromatography (EtOAc: n-hexane = 1: 7) to give compound 22 of Example 15. Obtained as a colorless oil (yield 70%, 2 mg).

¹ H-NMR (CDCl ₃ , 400 MHz) δ 6.98 (s, 1H), 6.81 (d, 1H, J = 8.2 Hz), 6.60 (d, 1H, J = 10.0 Hz), 6.55 (s, 1H) , 6.40 (s, 1H), 6.36 (d, 1H, J = 8.2 Hz), 5.59 (d, 1H, J = 10.0 Hz), 5.27 (m, 2H), 4.57 (dd, 1H, J = 10.0, 5.4 Hz), 4.13 (t, 1H, J = 10.0 Hz), 3.88 (s, 3H), 3.83 (s, 3H), 1.42 (s, 3H), 1.38 (s, 3H); ¹³ C-NMR (CDCl ₃ , 100 MHz) δ 153.3, 150.3, 149.2, 148.2, 144.7, 129.7, 126.4, 123.7, 116.6, 116.2, 111.8, 110.6, 109.8, 109.6, 105.2, 100.9, 76.1, 71.1, 67.9 , 56.3, 55.9, 28.0, 27.6; HRMS (FAB) Calcd for C ₂₃ H ₂₂ O ₅ (M + H ⁺ ): 378.1467, Found: 378.1474.

< Example  16> (7 a R , 13 a S ) -9,10- Dimethoxy -3,3-dimethyl-13,13a- Dihydro -3 H -Chromeno [3,4- b ] Pyrano [2,3- h ] Chromen -7 (7 a H )-On Oxime  ((7 a R , 13 a S ) -9,10- Dimethoxy -3,3-dimethyl-13,13a-dihydro-3 H -chromeno [3,4- b ] pyrano [2,3- h ] chromen-7 (7a H ) -one oxime Manufacture of 23

Hydroxylamine hydrochloride (14 mg, 0.19 mmol) was added to anhydrous pyridine (1.0 mL) in which deguanelin (25 mg, 0.063 mmol) prepared in Comparative Example 1 was dissolved, the reaction temperature was raised to 70 ° C, And stirred until the reaction was completed. The mixture was cooled with water (0.5 mL) and extracted with CH ₂ Cl _2. The organic layer of the extract was washed with 2N-HCl aqueous solution, water and brine. The solvent was removed under reduced pressure, and the remaining residue was dried over MgSO ₄ , filtered and concentrated to obtain a residue obtained by flash column chromatography (EtOAc: n-hexane = 1: 2) to obtain Compound 23 of Example 16. Obtained as a white solid (26 mg).

¹ H-NMR (CDCl ₃ , 500 MHz) δ 8.26 (br, 1H), 7.59 (d, 1H, J = 8.7 Hz), 6.62 (m, 2H), 6.41 (s, 1H), 6.37 (d, 1H, J = 8.7 Hz), 5.49 (d, 1H, J = 10.0 Hz), 4.84 (d, 1H, J = 3.2 Hz), 4.61 (dd, 1H, J = 12.0, 2.4 Hz), 4.48 (m, 1H), 4.24 (d, 1H, J = 12.0 Hz), 3.79 (s, 3H), 3.72 (s, 3H), 1.39 (s, 3H), 1.34 (s, 3H); ¹³ C-NMR (CDCl ₃ , 125 MHz) δ 155.7, 151.6, 151.3, 149.3, 147.7, 143.6, 128.6, 124.5, 116.2, 112.2, 110.7, 109.8, 108.2, 106.2, 100.6, 76.5, 69.6, 66.8, 60.4 , 56.4, 55.8, 31.6, 28.1, 27.8; HRMS (FAB) Calcd for C ₂₄ H ₂₅ N ₅ O ₇ (M + H ⁺ ): 409.1525, Found: 409.1513.

< Example  17> (7 a R , 13 a S ) -9,10- Dimethoxy -3,3-dimethyl-13,13a- Dihydro -3 H -Chromeno [3,4- b ] Pyrano [2,3- h ] Chromen -7 (7 a H )-On O - Methyloxime  ((7 a R , 13 a S ) -9,10- Dimethoxy -3,3-dimethyl-13,13a-dihydro-3 H -chromeno [3,4- b ] pyrano [2,3- h chro men-7 (7a H ) -one O - methyloxime Manufacture of 24

Iodomethane (1.5 equivalents) was added to anhydrous THF solution in which Compound 23 (1 equivalent) prepared in Example 16 was dissolved at 0 ° C., followed by t-BuOK solution (1 M in THF, 1 equivalent) ) Was added dropwise. The reaction mixture was monitored by TLC at 0 ° C. and stirred until the reaction was complete, then cooled with saturated aqueous NH ₄ Cl solution and extracted with EtOAc. The organic layer in the extract was dried over MgSO ₄ , filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography (EtOAc: n-hexane = 1: 4) to give compound 24 of Example 17 as a white solid. (Yield 57%, 12 mg).

¹ H-NMR (CDCl ₃ , 500 MHz) δ7.68 (d, 1H, J = 8.7 Hz), 6.61 (d, 1H, J = 10.0 Hz), 6.51 (s, 1H), 6.38 (m, 2H) , 5.48 (d, 1H, J = 10.0 Hz), 4.71 (d, 1H, J = 3.3 Hz), 4.59 (dd, 1H, J = 12.0, 2.4 Hz), 4.45 (m, 1H), 4.21 (d, 1H, J = 12.0 Hz), 4.03 (s, 3H), 3.77 (s, 3H), 3.73 (s, 3H), 1.39 (s, 3H), 1.33 (s, 3H); ¹³ C-NMR (CDCl ₃ , 125 MHz) δ 155.6, 151.2, 150.0, 149.2, 147.6, 143.5, 128.5, 124.7, 116.3, 111.9, 110.6, 109.7, 108.4, 106.3, 100.5, 76.5, 69.6, 66.9, 61.9 , 56.3, 55.8, 32.3, 28.1, 27.8; HRMS (FAB) Calcd for C ₂₄ H ₂₅ NO ₆ (M + H ⁺ ): 423.1682, Found: 423.1677.

< Example  18> (7 a R , 13 a S ) -9,10- Dimethoxy -3,3-dimethyl-13,13a- Dihydro -3 H -Chromeno [3,4- b ] Pyrano [2,3- h ] Chromen -7 (7 a H )-On O - Benzyl oxime  ((7 a R , 13 a S ) -9,10- Dimethoxy -3,3-dimethyl-13,13a-dihydro-3 H -chromeno [3,4- b ] pyrano [2,3- h ] chro men -7 (7 a H ) - one O - benzyloxime Manufacture of 25

Benzyl bromide (1.5 equivalents) was added to anhydrous THF solution in which Compound 23 (1 equivalent) prepared in Example 16 was dissolved at 0 ° C., followed by t-BuOK solution (1 M in THF, 1 equivalent). Was added dropwise. The reaction mixture was monitored by TLC at 0 ° C. and stirred until the reaction was complete, then cooled with saturated aqueous NH ₄ Cl solution and extracted with EtOAc. The organic layer in the extract was dried over MgSO ₄ , filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography (EtOAc: n-hexane = 1: 5) to give compound 24 of Example 17 as a white solid. (Yield 33%, 11 mg).

¹ H-NMR (CDCl ₃ , 500 MHz) δ7.71 (d, 1H, J = 8.7 Hz), 7.46 (d, 2H, J = 7.1 Hz), 7.31 (m, 3H), 7.24 (s, 1H) , 6.62 (d, 1H, J = 10.0 Hz), 6.46 (s, 1H), 6.37 (m, 2H), 5.48 (d, 1H, J = 10. Hz), 5.27 (AB quartet, 2H, J = 50.7 , 12.0 Hz), 4.76 (d, 1H, J = 3.0 Hz), 4.58 (dd, 1H, J = 12.0, 2.2 Hz), 4.44 (m, 1H), 4.20 (d, 1H, J = 12.0 Hz), 3.78 (s, 3H), 3.48 (s, 3H), 1.40 (s, 3H), 1.33 (s, 3H); ¹³ C-NMR (CDCl ₃ , 125 MHz) δ 155.6, 151.2, 150.1, 149.1, 147.5, 143.5, 137.5, 128.7, 128.5, 128.4, 128.1, 124.6, 116.3, 111.7, 110.6, 109.7, 108.5, 106.4, 100.5 , 76.5, 69.6, 66.8, 56.0, 55.7, 32.3, 29.6, 28.1, 27.8; HRMS (FAB) Calcd for C ₃₀ H ₂₉ NO ₆ (M + H ⁺ ): 499.1995, Found: 499.1999.

< Example  19> (7 a S , 13 a S ) -9,10- Dimethoxy -3,3-dimethyl-2,3,13,13a- Tetrahydro -One H - Chromeno [3,4- b ] Pyrano [2,3- h ] Chromen -7 (7 a H ) -On ((7a S , 13a S ) -9,10- Dimethoxy -3,3- dimethyl -2,3,13,13a- tetrahydro -One H - chromeno [3,4- b ] pyrano [2,3- h ] chromen -7 (7 a H ) - one Manufacture of 26

A solution of benzene (1.0 mL) containing Compound 8 (4 mg, 10 μmol) and p -toluenesulfonic acid (0.5 mg, 2.5 μmol) prepared in Example 1 was stirred at 80 ° C. for 1 hour, and a saturated aqueous NaHCO ₃ solution ( 1.0 mL), and extracted with diethyl ether. The organic layer was dried over MgSO ₄ , filtered, and concentrated. The residue obtained was purified by flash column chromatography (EtOAc: n-hexane: CH ₂ Cl ₂ = 1: 3). 1: 1 to 1: 2: 1) to give the compound 26 of Example 19 as a white solid (yield 99%, 3.5 mg).

¹ H-NMR (CDCl ₃ , 300 MHz) δ7.61 (d, 1H, J = 8.6 Hz), 6.79 (s, 1H), 6.43 (s, 1H), 6.43 (d, 1H, J = 8.7 Hz) , 4.90 (m, 1H), 4.62 (dd, 1H, J = 12.0, 3.0 Hz), 4.17 (d, 1H, J = 12.0 Hz), 3.81 (m, 1H), 3.79 (s, 3H), 3.75 ( s, 3H), 2.65 (m, 2H), 1.74 (t, 2H, J = 6.6 Hz), 1.33 (s, 3H), 1.27 (s, 3H); ¹³ C-NMR (CDCl ₃ , 125 MHz) δ 189.4, 161.0, 159.9, 149.2, 147.3, 143.7, 126.3, 112.2, 111.6, 110.2, 108.8, 104.9, 100.7, 75.5, 72.2, 66.3, 56.2, 55.7, 44.1 , 31.5, 26.9, 26.3, 16.5; HRMS (FAB) Calcd for C ₂₃ H ₂₅ O ₆ (M + H ⁺ ): 397.1651, Found: 397.1642.

< Example  20> (7 a S , 13 a S ) -1,2-dihydroxy-9,10- Dimethoxy -3,3-dimethyl-2,3,13,13a-tetrahydro-1 H - Chromeno [3,4- b ] Pyrano [2,3- h ] Chromen -7 (7 a H ) -On ((7 a S , 13 a S ) -1,2-Dihydroxy-9,10-dimethoxy-3,3-dimethyl-2,3,13,13a-tetrahydro-1 H -chromeno [3,4- b pyrano [2,3- h ] chromen-7 (7a H ) -one) Preparation of (27)

In acetone: water (4.0 mL, 4: 1) solution containing deguelin (20 mg, 0.051 mmol) prepared in Comparative Example 1, N -methylmorpholine N -oxide (NMO, 18 mg, 0.15 mmol) and OsO ₄ (0.1 M in toluene, 0.020 mL, 0.002 mmol) was added and stirred at 0 ° C for 10 min. The mixture was warmed to room temperature and stirred for 3 more days. After cooling to 0 ° C. with saturated aqueous sodium sulfite solution, the reaction mixture was filtered through a pad of celite and washed with EtOAc. The organic layer was extracted with EtOAc, dried over MgSO ₄ , filtered, and concentrated under reduced pressure. The residue obtained was purified by flash column chromatography (EtOAc: n-hexane = 2: 1 at 100% EtOAc) to obtain the residue of Example 20. Compound 27 was obtained as a light yellow solid (yield 47%, diastereomeric mixture, 10 mg).

(1) isomer A: ¹ H-NMR (CDCl ₃ , 400 MHz) δ7.76 (d, 1H, J = 8.8 Hz), 6.48 (m, 3H), 4.98 (d, 1H, J = 4.7 Hz), 4.46 (m, 3H), 4.42 (s, 1H), 3.80 (s, 3H), 3.76 (t, 1H, J = 4.7 Hz), 3.71 (s, 3H), 3.45 (br, 1H), 3.34 (d , 1H, J = 4.5 Hz), 1.40 (s, 3H), 1.31 (s, 3H); ¹³ C-NMR (CDCl ₃ , 100 MHz) δ 190.7, 160.6, 160.4, 151.2, 148.2, 144.3, 128.7, 113.0, 110.5, 110.0, 109.1, 108.6, 101.1, 79.1, 76.3, 70.4, 67.3, 63.7, 61.9 , 56.3, 55.9, 24.3, 22.5;

^{(2) isomer B: 1 H} -NMR (CDCl 3, 400 MHz) δ7.77 (d, 1H, J = 8.8 Hz), 6.47 (m, 3H), 4.97 (d, 1H, J = 4.7 Hz), 1H), 3.30 (d, IH, J = 8.3 Hz, 2H), 4.51 (s, 3H) 4.5 Hz), 1.43 (s, 3H), 1.27 (s, 3H); ¹³ C-NMR (CDCl ₃ , 100 MHz) δ 190.8, 160.8, 160.6, 151.2, 148.2, 144.1, 128.8, 113.2, 110.8, 109.7, 109.2, 108.4, 101.0, 79.0, 76.7, 70.3, 67.2, 63.8, 62.0 , 56.3, 55.8, 24.5, 22.5.

< Example  21> 2,3,9- Trimethoxy -8- (3- methyl - Boot -2- Enil ) -6a, 12a- Dihydro -6 H - Chromeno [3,4- b ] Chrome -12-on (2,3,9- Trimethoxy -8- (3- methyl - but -2- enyl ) -6a, 12a- dihydro -6 H -chromeno [3,4- b ] chromen-12-one) (28) Preparation

Cesium carbonate (1.5 equiv) was added to an anhydrous acetonitrile solution containing compound 8 (1 equiv) and iodomethane (2 equiv) prepared in Example 1, monitored by TLC at 0 ° C., and the reaction was completed. Stir until. The mixture was cooled with water, extracted with EtOAc, the organic layer was washed with brine, dried over MgSO ₄ , and concentrated under reduced pressure. The residue obtained was purified by flash column chromatography (EtOAc: n-hexane = 1: 4). Compound 28 of Example 21 was obtained as a white solid (yield 41%, 16 mg).

¹ H-NMR (CDCl ₃ , 500 MHz) δ 7.80 (d, 1H, J = 8.8 Hz), 6.74 (s, 1H), 6.56 (d, 1H, J = 8.9 Hz), 6.41 (s, 1H) , 5.11 (m, 1H), 4.87 (m, 1H), 4.58 (dd, 1H, J = 11.9, 3.3 Hz), 4.15 (d, 1H, J = 11.9 Hz), 3.83 (s, 3H), 3.81 ( d, 1H, J = 4.1 Hz), 3.77 (s, 3H), 3.74 (s, 3H), 3.28 (m, 2H), 1.74 (s, 3H), 1.61 (s, 3H); ¹³ C-NMR (CDCl ₃ , 125 MHz) δ 190.0, 163.6, 159.2, 149.3, 147.4, 143.6, 131.8, 126.9, 121.6, 117.4, 113.1, 110.3, 105.1, 104.6, 100.7, 71.8, 66.2, 56.2, 55.8 , 55.8, 44.3, 25.7, 21.9, 17.6; HRMS (FAB) Calcd for C ₂₄ H ₂₆ O ₆ (M + H ⁺ ): 410.1732, Found: 410.1735.

< Example  22> 9- Aryloxy -2,3- Dimethoxy -8- (3- methyl - Boot -2- Enil ) -6a, 12a- Dihydro -6H- size Romeno [3,4-b] chrome Men-12-on (9- Allyloxy -2,3- dimethoxy -8- (3- methyl - but -2-enyl) -6a, 12a-dihydro-6H-chromeno [3,4-b] chromen-12-one) (29)

To anhydrous acetonitrile solution containing compound 8 (1 equiv) and aryl iodide (2 equiv) prepared in Example 1, cesium carbonate (1.5 equiv) was added and monitored by TLC at 0 ° C. to complete the reaction. Stir until. The mixture was cooled with water, and then the organic layer obtained by extraction with EtOAc was washed with brine, dried over MgSO ₄ and concentrated under reduced pressure. The residue obtained was purified by flash column chromatography (EtOAc: n-hexane = 1: 6). Compound 29 of Example 22 was obtained as a pale yellow solid (yield 39%, 12 mg).

¹ H-NMR (CDCl ₃ , 400 MHz) δ7.78 (d, 1H, J = 8.9 Hz), 6.75 (s, 1H), 6.53 (d, 1H, J = 8.9 Hz), 6.42 (s, 1H) , 5.98 (m, 1H), 5.30 (m, 2H), 5.15 (m, 1H), 4.88 (m, 1H), 4.58 (m, 2H), 4.16 (d, 1H, J = 11.8 Hz), 3.81 ( d, 1H, J = 2.0 Hz), 3.78 (s, 3H), 3.74 (s, 3H), 3.33 (m, 2H), 1.74 (s, 3H), 1.62 (s, 3H); ¹³ C-NMR (CDCl ₃ , 100 MHz) δ 190.0, 162.6, 159.4, 149.4, 147.5, 143.7, 132.5, 131.7, 126.8, 121.6, 117.8, 117.6, 113.2, 110.5, 106.2, 104.7, 100.8, 72.0, 69.0 , 66.3, 56.3, 55.8, 44.4, 25.7, 22.1, 17.8; HRMS (FAB) Calcd for C ₂₆ H ₂₈ O ₆ (M + H ⁺ ): 436.1886, Found: 436.1883.

< Example  23> 9- Benzyloxy -2,3- Dimethoxy -8- (3- methyl - Boot -2- Enil ) -6a, 12a- Dihydro -6 H -Chromeno [ 3,4-b] chromen -12-on (9- Benzyloxy -2,3- dimethoxy -8- (3- methyl - but -2- enyl ) -6a, 12a-dihydro-6 H -chromeno [3,4-b] chromen-12-one) 30

To anhydrous acetonitrile solution containing compound 8 (1 equiv) and benzylbromide (2 equiv) prepared in Example 1 was added cesium carbonate (1.5 equiv), monitored by TLC at 0 ° C. until the reaction was complete Stirred. The mixture was cooled with water, and then the organic layer obtained by extraction with EtOAc was washed with brine, dried over MgSO ₄ and concentrated under reduced pressure. The residue obtained was purified by flash column chromatography (EtOAc: n-hexane = 1: 6). Compound 30 of Example 23 was obtained as a white solid (yield 25%, 12 mg).

¹ H-NMR (CDCl ₃ , 400 MHz) δ7.78 (d, 1H, J = 8.8 Hz), 7.31 (m, 5H), 6.74 (s, 1H), 6.60 (d, 1H, J = 8.8 Hz) , 6.41 (s, 1H), 5.15 (m, 3H), 4.48 (m, 1H), 4.61 (dd, 1H, J = 11.9, 3.0 Hz), 4.16 (d, 1H, J = 11.9 Hz), 3.81 ( d, 1H, J = 4.1 Hz), 3.78 (s, 3H), 3.73 (s, 3H), 3.35 (m, 2H), 1.66 (s, 3H), 1.61 (s, 3H); ¹³ C-NMR (CDCl ₃ , 75 MHz) δ 190.0, 162.7, 159.3, 149.4, 147.5, 143.6, 136.3, 131.8, 129.7, 128.6, 128.0, 127.1, 126.9, 122.8, 121.7, 117.9, 113.4, 110.5, 106.3 , 104.7, 100.8, 72.0, 70.3, 66.3, 56.3, 55.8, 44.4, 25.7, 22.2, 17.7; HRMS (FAB) Calcd for C ₃₀ H ₃₀ O ₆ (M + H ⁺ ): 487.2121, Found: 487.2113.

< Example  24> acetic acid 2,3- Dimethoxy -8- (3- methyl - Boot -2- Enil ) -12-oxo-6,6a, 12,12a-te Trahydrochromeno [ 3,4-b] chromen-9-yl ester ( Acetic acid  2,3- dimethoxy -8- (3- methyl - but -2- enyl ) -12- oxo -6,6a, 12,12a-tetrahydrochromeno [3,4-b] chromen -9- yl ester Manufacture of 31

Triethylamine (0.01 mL, 0.07 mmol) and acetic anhydride (0.05 mL) in a solution of CH ₂ Cl ₂ (1.0 mL) containing Compound 8 (25 mg, 0.063 mmol) and DMAP (catalyst amount) prepared in Example 1 , 0.53 mmol) was added under argon atmosphere at 0 ° C. The mixture was stirred at room temperature for 10 minutes, cooled with saturated aqueous NH ₄ Cl solution, extracted with CH ₂ Cl ₂ , the organic layer was washed with brine, dried over MgSO ₄ and concentrated under reduced pressure. Purification with EtOAc: n-hexane = 1: 4) afforded compound 31 of example 24 as pale yellow oil (yield 44%, 14 mg).

¹ H-NMR (CDCl ₃ , 400 MHz) δ 7.80 (d, 1H, J = 8.6 Hz), 6.70 (d, 1H, J = 8.6 Hz), 6.68 (s, 1H), 6.42 (s, 1H) , 5.02 (m, 1H), 4.93 (m, 1H), 4.60 (dd, 1H, J = 12.0, 3.2 Hz), 4.17 (d, 1H, J = 12.0 Hz), 3.87 (d, 1H, J = 4.0 Hz), 3.78 (s, 3H), 3.74 (s, 3H), 3.24 (m, 2H), 2.27 (s, 3H), 1.72 (s, 3H), 1.62 (s, 3H); ¹³ C-NMR (CDCl ₃ , 75 MHz) δ 190.1, 168.6, 159.8, 154.9, 149.7, 147.6, 143.9, 132.5, 125.9, 123.0, 120.7, 116.4, 110.5, 104.0, 100.9, 72.3, 66.1, 56.3, 55.8 , 44.4, 29.6, 25.6, 23.0, 20.8, 17.7; HRMS (FAB) Calcd for C ₂₅ H ₂₆ O ₇ (M + H ⁺ ): 438.1679, Found: 438.1681.

< Example  25> (3 S ) -3- (3,4- Dimethoxyphenyl ) -8,8-dimethyl-2,3- Dihydro -4 H ,8 H - Pyrano [2,3- f ] Chrome -4-one ((3 S ) -3- (3,4- Dimethoxyphenyl ) -8,8- dimethyl -2,3-dihydro-4 H ,8 H -pyrano [2,3- f ] chromen-4-one) (37) Preparation

Compound 36 obtained in Preparation Example 5 (10 mg, 0.026 Anhydrous THF (1.0 mL) solution containing 1 mmol) contained anhydrous THF (0.5 mL) containing triphenylphosphine (65 mg, 0.25 mmol) and diisopropylazodicarboxylate (0.024 mL, 0.12 mmol) under nitrogen atmosphere. ) Solution was added, monitored by TLC and stirred until the reaction was complete. After concentration of the reaction mixture under reduced pressure, the residue was purified by flash column chromatography (EtOAc: n-hexane = 1: 4) to give compound 37 of Example 25 as a white solid (yield 58%, 5.5 mg). .

¹ H NMR (CDCl _{3 ,} 500 MHz) δ7.74 (d, 1H, J = 8.7 Hz), 6.82 (s, 2H), 6.77 (s, 1H), 6.61 (d, 1H, J = 10.0 Hz), 6.47 (d, 1H, J = 8.7 Hz), 5.58 (d, 1H, J = 10.0 Hz), 4.63 (m, 2H), 3.83 (s, 3H), 3.83 (s, 3H), 1.44 (s, 6H ); ¹³ C NMR (CDCl ₃ , 125 MHz) δ 190.9, 159.5, 157.6, 149.1, 148.5, 128.9, 128.6, 127.8, 120.6, 115.6, 114.7, 111.8, 111.4, 111.2, 109.1, 77.5, 55.8, 51.3, 29.6, 28.2, 28.2, 21.7; HRMS (FAB) Calcd for C ₂₂ H ₂₂ NO ₅ (M + H ⁺ ): 367.1545, Found: 367.1552.

< Example  26> (6,7- Dimethoxy Chroma -4-yl) (2,2-dimethyl-2 H - Chromen -6- days) Metanon  ((6,7-Dimethoxychroman-4-yl) (2,2-dimethyl-2 H -chromen-6-yl) methanone) (45)

Dess-Martin periodinan (3.0 equiv) was added to a solution of CH ₂ Cl ₂ (0.03 M) containing Compound 44 (1.0 equiv) obtained in Preparation Example 12, followed by stirring for 1 hour. The reaction mixture was diluted with CH ₂ Cl ₂ and sodium thiosulfate (10%) was added. The mixture was stirred for 10 minutes until it was separated into two layers at room temperature. The organic layer obtained above was washed with saturated NaHCO ₃ aqueous solution, dried over MgSO ₄ , filtered, and concentrated under reduced pressure. The residue obtained was purified by flash column chromatography (EtOAc: n-hexane = 1: 6), followed by Compound 45 of Example 26 was obtained (yield 55%, 9.9 mg).

¹ H NMR (CDCl _{3 ,} 500 MHz) δ 7.79 (dd, 1H, J = 8.5, 2.1 Hz), 7.66 (d, 1H, J = 1.9 Hz), 6.81 (d, 1H, J = 8.4 Hz), 6.42 (s, 1H), 6.34 (m, 2H), 5.66 (d, 1H, J = 9.9 Hz), 4.61 (t, 1H, J = 5.8 Hz), 4.17 (m, 2H), 3.81 (s, 3H ), 3.65 (s, 3H), 2.21 (m, 2H), 1.45 (s, 6H); ¹³ C NMR (CDCl ₃ , 125 MHz) δ 199.6, 157.7, 149.4, 149.2, 143.3, 131.3, 130.5, 129.0, 127.4, 121.5, 120.9, 116.3, 112.4, 110.6, 101.1, 77.7, 63.4, 56.4, 55.8, 41.6, 28.4, 28.4, 26.57; HRMS (FAB) Calcd for C ₂₃ H ₂₄ NO ₅ (M + H ⁺ ): 380.1624, Found: 380.1621.

< Example  27> 2- (3,4- Dimethoxyphenyl ) -1- (2,2-dimethyl-2 H - Chromen -6- days) Ethanone  (2- (3,4-Dimethoxyphenyl) -1- (2,2-dimethyl-2 H -chromen-6-yl) ethanone) (53)

To anhydrous THF solution containing aryl bromide 6-bromo-2,2-dimethyl-2 H -chromen (1.5 equiv), n- BuLi (1.4 equiv) was added dropwise at -78 ° C and at -78 ° C Stirring produced an aryl anion. After stirring at −78 ° C. for 20 minutes, Compound 52 (1.0 equivalent) obtained in Preparation Example 13 was added and stirring was continued for 30 minutes, so that the reaction temperature was brought to room temperature. The reaction mixture was treated with saturated aqueous NH ₄ Cl solution and extracted with EtOAc. The extract was washed with brine, dried over MgSO 4 and the solvent was evaporated and the residue was purified by flash column chromatography (EtOAc: n-hexane = 1: 2) to give a secondary alcohol.

Dess-Martin periodinan (3.0 equiv) was added to a solution of CH ₂ Cl ₂ (0.03 M) containing the secondary alcohol (1.0 equiv) obtained above, followed by stirring for 1 hour. The mixture was diluted with CH ₂ Cl ₂ and sodium thiosulfate (10%) was added. The mixture was stirred for 10 minutes until it was separated into two layers at room temperature. The organic layer obtained above was washed with saturated NaHCO ₃ aqueous solution, dried over MgSO ₄ , filtered, and concentrated under reduced pressure. The residue obtained was purified by flash column chromatography (EtOAc: n-hexane = 1: 3), followed by Compound 53 of Example 27 was obtained as a light yellow solid (yield 46%, 37 mg).

¹ H NMR (CDCl ₃ , 400 MHz) δ7.76 (dd, 1H, J = 8.4, 2.2 Hz), 7.62 (d, 1H, J = 2.2 Hz), 6.76 (m, 4H), 6.29 (d, 1H, J = 9.8 Hz), 5.61 (d, 1H, J = 9.8 Hz), 4.10 (s, 2H), 3.80 (s, 3H), 3.79 (s, 3H), 1.40 (s, 6H); ¹³ C NMR (CDCl ₃ , 100 MHz) δ 196.3, 157.3, 148.8, 147.7, 131.0, 130.4, 129.4, 127.3, 127.1, 121.5, 121.4, 120.6, 116.0, 112.3, 111.2, 77.4, 55.7, 55.7, 44.5, 28.2 28.2; HRMS (FAB) Calcd for C ₂₁ H ₂₃ O ₄ (M + H ⁺ ): 339.1596, Found: 339.1595.

< Example  28> 2- (3,4- Dimethoxyphenyl ) -1- (5- Methoxy -2,2-dimethyl-2 H - Chromen -6- days) Ethanone  (2- (3,4- Dimethoxyphenyl ) -1- (5- methoxy -2,2- dimethyl -2 H - chromen -6-yl) ethanone) (54)

To the anhydrous THF solution containing Compound 51 (1.5 equivalents) obtained in Preparation Example 27, n- BuLi (1.4 equivalents) was added dropwise at -78 ° C and stirred at -78 ° C to generate an aryl anion. After stirring at −78 ° C. for 20 minutes, Compound 52 (1.0 equivalent) obtained in Preparation Example 13 was added and stirring was continued for 30 minutes, so that the reaction temperature was brought to room temperature. The reaction mixture was treated with saturated aqueous NH ₄ Cl solution and extracted with EtOAc. The extract was washed with brine, dried over MgSO ₄ and the solvent was evaporated and the residue obtained was purified by flash column chromatography (EtOAc: n-hexane = 1: 2) to give a secondary alcohol.

Dess-Martin periodinan (3.0 equiv) was added to a solution of CH ₂ Cl ₂ (0.03 M) containing the secondary alcohol (1.0 equiv) obtained above, followed by stirring for 1 hour. The mixture was diluted with CH ₂ Cl ₂ and sodium thiosulfate (10%) was added. The mixture was stirred for 10 minutes until it was separated into two layers at room temperature. The organic layer obtained above was washed with saturated NaHCO ₃ aqueous solution, dried over MgSO ₄ , filtered, and concentrated under reduced pressure. The residue obtained was purified by flash column chromatography (EtOAc: n-hexane = 1: 4), followed by Compound 54 of Example 28 was obtained as a light yellow solid (yield 48%, 80 mg).

¹ H NMR (CDCl _{3 ,} 300 MHz) δ 7.43 (d, 1H, J = 8.4 Hz), 6.72 (s, 3H), 6.54 (d, 1H, J = 9.9 Hz), 6.52 (d, 1H, J = 8.4 Hz), 5.62 (d, 1H, J = 9.9 Hz), 4.12 (s, 2H), 3.77 (s, 6H), 3.69 (s, 3H), 1.37 (s, 6H); ¹³ C NMR (CDCl ₃ , 75 MHz) δ 198.7, 157.7, 156.3, 148.8, 147.8, 131.1, 130.5, 127.6, 124.8, 121.7, 116.5, 114.8, 112.8, 112.6, 111.2, 63.2, 55.8, 55.8, 50.3, 50.2, 28.1, 28.0; HRMS (FAB) Calcd for C ₂₂ H ₂₅ O ₅ (M + H ⁺ ): 369.1702, Found: 369.1705.

< Example  29> 2- (3,4- Dimethoxyphenyl -1- (5- Methoxy -2,2-dimethyl-2 H - Chromen -6-yl) propan-1-one (2- (3,4- Dimethoxyphenyl ) -1- (5- methoxy -2,2- dimethyl -2 H - chromen -6- yl ) propan Preparation of -1-one (56)

To the anhydrous THF solution containing Compound 51 (1.5 equivalents) obtained in Preparation Example 27, n- BuLi (1.4 equivalents) was added dropwise at -78 ° C and stirred at -78 ° C to generate an aryl anion. After stirring at −78 ° C. for 20 minutes, Compound 55 (1.0 equiv.) Obtained in Preparation Example 14 was added and stirring was continued for 30 minutes, thereby allowing the reaction temperature to reach room temperature. The reaction mixture was treated with saturated aqueous NH ₄ Cl solution and extracted with EtOAc. The extract was washed with brine, dried over MgSO ₄ and the solvent was evaporated and the residue obtained was purified by flash column chromatography (EtOAc: n-hexane = 1: 2) to give a secondary alcohol.

Dess-Martin periodinan (3.0 equiv) was added to a solution of CH ₂ Cl ₂ (0.03 M) containing the secondary alcohol (1.0 equiv) obtained above, followed by stirring for 1 hour. The mixture was diluted with CH ₂ Cl ₂ and sodium thiosulfate (10%) was added. The mixture was stirred for 10 minutes until it was separated into two layers at room temperature. The organic layer obtained above was washed with saturated NaHCO ₃ aqueous solution, dried over MgSO ₄ , filtered, and concentrated under reduced pressure. The residue obtained was purified by flash column chromatography (EtOAc: n-hexane = 1: 4), followed by Compound 56 of Example 29 was obtained as a pale yellow solid (yield 64%, 11 mg).

¹ H NMR (CDCl _{3 ,} 500 MHz) δ 7.27 (d, 1H, J = 8.5 Hz), 6.76 (m, 3H), 6.55 (d, 1H, J = 10.0 Hz), 6.48 (d, 1H, J = 8.5 Hz), 5.62 (d, 1H, J = 10.0 Hz), 4.60 (q, 1H, J = 6.9 Hz), 3.81 (s, 3H), 3.80 (s, 3H), 3.65 (s, 3H), 1.48 (d, 3H, J = 6.9 Hz), 1.39 (s, 6H); ¹³ C NMR (CDCl ₃ , 75 MHz) δ 202.5, 157.1, 155.7, 149.0, 147.9, 133.8, 130.7, 130.5, 125.5, 120.2, 116.5, 112.3, 111.2, 77.2, 76.7, 63.3, 55.8, 55.7, 50.0, 43.1, 28.0, 28.0, 19.0; HRMS (FAB) Calcd for C ₂₃ H ₂₇ O ₅ (M + H ⁺ ): 383.1858, Found: 383.1853.

< Example  30> 2- (3,4- Dimethoxyphenyl ) -1- (5- Methoxy -2,2-dimethyl-2 H - Chromen -6-day) -2- methyl Propane-1-one (2- (3,4- Dimethoxyphenyl ) -1- (5- methoxy -2,2- dimethyl -2 H - chromen -6-yl) -2-methylpropan-1-one) (57)

Anhydrous THF (1.0 mL) solution containing compound 54 (15 mg, 0.041 mmol) of Example 28 was stirred, sodium hydride (5.0 mg, 0.12 mmol, 60% in mineral oil) and iodine methane (0.02 mL, 0.16 mmol) was added under an argon atmosphere at room temperature. After completion of the reaction, the mixture was extracted with EtOAc (2.0 mL × 3), and the organic layer of the extract was washed with brine, dried over MgSO ₄ , and concentrated under reduced pressure. The residue obtained by flash column chromatography (EtOAc: n- Hexane = 1: 4) to give the compound 57 of Example 30 as a pale yellow solid (yield 88%, 14 mg).

¹ H NMR (CDCl _{3 ,} 400 MHz) δ6.87 (m, 3H), 6.52 (d, J = 9.9 Hz, 1H), 6.21 (q, 1H, J = 5.4 Hz), 5.61 (d, 1H, J = 9.9 Hz), 3.88 (s, 3H), 3.83 (s, 3H), 3.70 (s, 3H), 1.50 (s, 3H), 1.37 (s, 3H); ¹³ C NMR (CDCl ₃ , 100 MHz) δ 206.6, 155.1, 154.1, 148.9, 147.9, 136.2, 130.5, 127.8, 126.7, 118.2, 116.6, 115.0, 111.1, 111.0, 109.8, 77.2, 76.2, 63.6, 55.8, 55.8, 51.6, 27.9, 27.8, 26.3; HRMS (FAB) Calcd for C ₂₄ H ₂₉ O ₅ (M + H ⁺ ): 397.2015, Found: 397.2015.

< Example  31> 2- (3,4- Dimethoxyphenyl ) -1- (5- Methoxy -2,2-dimethyl-2 H - Chromen -6- days) Prop 2-en-1-one (2- (3,4- Dimethoxyphenyl ) -1- (5- methoxy -2,2- dimethyl -2 H - chromen Preparation of -6-yl) prop-2-en-1-one (58)

To anhydrous DMF (1 mL) solution containing compound 54 (20 mg, 0.054 mmol) of Example 28, potassium carbonate (15 mg, 0.11 mmol) was added under a nitrogen atmosphere at room temperature, and stirred at room temperature for 40 minutes with paraformaldehyde. (3 mg, 0.082 mmol) was added. The mixture was stirred for 4 hours and then extracted with EtOAc (2.0 mL × 2). The organic extract was washed with saturated aqueous NH ₄ Cl solution and brine, dried over MgSO ₄ , and concentrated under reduced pressure. The residue obtained was purified by flash column chromatography (EtOAc: n-hexane = 1: 4), and Example 31 Compound 58 was obtained as a colorless oil (yield 87%, 18 mg).

¹ H NMR (CDCl ₃ , 300 MHz) δ7.30 (d, 1H, J = 8.6 Hz), 6.95 (m, 2H), 6.78 (d, 1H, J = 8.0 Hz), 6.51 (m, 2H), 5.90 (s, 1H), 5.60 (d, 1H, J = 10.0 Hz), 5.55 (s, 1H), 3.81 (s, 3H), 3.80 (s, 3H), 3.70 (s, 3H), 1.38 (s, 6H); ¹³ C NMR (CDCl ₃ , 100 MHz) δ 196.5, 157.3, 156.2, 149.4, 149.1, 148.6, 131.7, 130.4, 129.7, 125.0, 121.7, 120.2, 116.5, 114.8, 111.8, 110.9, 110.7, 77.2, 76.8, 63.1, 55.8, 28.0, 27.9; HRMS (FAB) Calcd for C ₂₃ H ₂₅ O ₅ (M + H ⁺ ): 381.1702, Found: 381.1709.

< Example  32> 1- (3,4- Dimethoxyphenyl ) Cyclopropyl ) (5- Methoxy -2,2-dimethyl-2 H - Chromen -6- days) Metanon  (1- (3,4- Dimethoxyphenyl ) cyclopropyl ) (5- methoxy -2,2- dimethyl -2 H -chromen-6-yl) methanone) (59)

To anhydrous DMSO (0.5 mL) was added sodium hydride (1.2 mg, 0.029 mmol, 60% in mineral oil) and trimethylsulfonium iodide (6.5 mg, 0.029 mmol) under a nitrogen atmosphere at room temperature. The mixture was stirred for 40 minutes and then anhydrous DMSO (0.5 mL) solution containing compound 58 (10 mg, 0.026 mmol) of Example 31 was added. The reaction mixture was stirred for 1 h, cooled with saturated aqueous NH ₄ Cl solution and extracted with EtOAc (× 3). The organic layer was washed with saturated aqueous NH ₄ Cl solution and brine, dried over MgSO ₄ , and concentrated under reduced pressure. The residue obtained was purified by flash column chromatography (EtOAc: n-hexane = 1: 4) to obtain Example 32. Compound 59 was obtained as a light yellow solid (yield 91%, 9 mg).

¹ H NMR (CDCl _{3 ,} 500 MHz) δ 6.98 (d, 1H, J = 8.4 Hz), 6.78 (m, 2H), 6.67 (d, 1H, J = 8.4 Hz), 6.48 (d, 1H, J = 10.0 Hz), 6.35 (d, 1H, J = 8.4 Hz), 5.58 (d, 1H, J = 10.0 Hz), 3.78 (s, 3H), 3.75 (s, 3H), 3.73 (s, 3H), 1.67 (q, 2H, J = 4.0 Hz), 1.35 (s, 6H), 1.28 (q, 2H, J = 4.0 Hz); ¹³ C NMR (CDCl ₃ , 125 MHz) δ 203.6, 155.4, 153.9, 148.4, 147.8, 133.0, 130.4, 128.7, 126.3, 121.4, 116.5, 114.7, 113.6, 111.4, 110.6, 76.2, 63.1, 55.7, 55.7, 37.1, 27.8, 17.7; HRMS (FAB) Calcd for C ₂₄ H ₂₆ O ₅ (M + H ⁺ ): 394.1780, Found: 394.1774.

< Example  33> ( S ) -2- (3,4- Dimethoxyphenyl ) -1- (5- Methoxy -2,2-dimethyl-2H- Chromen -6-yl) propan-1-one (( S ) -2- (3,4- Dimethoxyphenyl ) -1- (5- methoxy -2,2- dimethyl -2H- chromen -6-yl) propan-1-one) (69)

_{CeCl 3? 7H 2 O (189} mg, 0.52 mmol) placed in a 1-neck flask and heated gradually under reduced pressure to 135-140 ℃ under (0.1 Torr), and the mixture was stirred for 2 hours. When the flask was hot, argon gas was injected and the flask was cooled in an ice bath. The reaction mixture was stirred vigorously and THF (1.0 mL) was added all at once, then the ice bath was removed and the suspension was stirred overnight at room temperature under argon atmosphere. Next, the flask was cooled to -78 ° C again and n -BuLi (0.13 mL, 0.13 mmol) was added to anhydrous THF (1.0 mL) solution containing Compound 51 (61 mg, 0.23 mmol) obtained in Preparation Example 27. After addition at 78 ° C., the resulting aryl anions were added by stirring for 20 minutes. After stirring at −78 ° C. for 1.5 hours, Compound 68 (20 mg, 0.10 mmol) obtained in Preparation Example 19 was added and stirred for 30 minutes. The reaction mixture was treated with saturated aqueous NH ₄ Cl solution and the product was extracted with EtOAc, washed with brine, NaHCO ₃ , brine and dried over anhydrous MgSO ₄ . The solvent was evaporated and the residue obtained was purified by flash column chromatography (EtOAc: n-hexane = 1: 3) to give a secondary alcohol as a diastereomeric mixture (yield 80%, 32 mg).

isomer A : ¹ H-NMR (Acetone-d ₆ , 300 MHz) δ7.22 (d, 1H, J = 8.4 Hz), 6.73 (m, 3H), 6.50 (m, 2H), 5.69 (d, 1H, J = 9.9 Hz), 4.95 (m, 1H), 3.70 (s, 6H), 3.61 (s, 3H), 3.07 (quin, 1H, J = 6.8 Hz), 1,35 (s, 6H), 1.28 ( d, 3H, J = 6.9 Hz);

isomer B : ¹ H-NMR (Acetone-d ₆ , 500 MHz) δ 7.02 (d, 1H, J = 8.4 Hz), 6.75 (m, 3H), 6.55 (d, 1H, J = 10.0 Hz), 6.43 (d, 1H, J = 8.5 Hz), 5.70 (d, 1H, J = 9.9 Hz), 4.93 (dd, 1H, J = 7.5, 4.0 Hz), 3.72 (s, 3H), 3.72 (s, 3H) , 3.71 (s, 3H), 2.95 (quin, 1H, J = 7.2 Hz), 1,34 (d, 6H, J = 11.8 Hz), 1.06 (d, 3H, J = 7.2 Hz).

The secondary alcohol (32 mg, 0.083 mmol) obtained above was dissolved in CH ₂ C1 ₂ (2.0 mL), followed by molecular sieve (41 mg) and N -methyl morpholine- N -oxide (NMO, 15 mg, 0.13). mmol) was added. After stirring the mixture for 10 minutes, tetrapropylammonium perunateate (TPAP, 3 mg, 0.0083 mmol) is added and when the reaction is complete, the mixture is diluted with CH ₂ C1 ₂ and 10% sodium sulfite It was washed with aqueous solution, brine and finally saturated copper (II) sulfate solution. The organic layer was dried over MgSO ₄ , filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography (EtOAc: n-hexane = 1: 4) to give compound 69 of Example 33 (yield 84%) , 27 mg).

¹ H NMR (CDCl _{3 ,} 500 MHz) δ 7.27 (d, 1H, J = 8.5 Hz), 6.76 (m, 3H), 6.55 (d, 1H, J = 10.0 Hz), 6.48 (d, 1H, J = 8.5 Hz), 5.62 (d, 1H, J = 10.0 Hz), 4.60 (q, 1H, J = 6.9 Hz), 3.81 (s, 3H), 3.80 (s, 3H), 3.65 (s, 3H), 1.48 (d, 3H, J = 6.9 Hz), 1.39 (s, 6H); ¹³ C NMR (CDCl ₃ , 75 MHz) δ 202.5, 157.1, 155.7, 149.0, 147.9, 133.8, 130.7, 130.5, 125.5, 120.2, 116.5, 112.3, 111.2, 77.2, 76.7, 63.3, 55.8, 55.7, 50.0, 43.1, 28.0, 28.0, 19.0; HRMS (FAB) Calcd for C ₂₃ H ₂₇ O ₅ (M + H ⁺ ): 383.1858, Found: 383.1853.

< Example  34> ( R ) -2- (3,4- Dimethoxyphenyl ) -1- (5- Methoxy -2,2-dimethyl-2H- Chromen -6-yl) propan-1-one (( R ) -2- (3,4- Dimethoxyphenyl ) -1- (5- methoxy -2,2- dimethyl -2H- chromen -6-yl) propan-1-one) Preparation of 72

_{CeCl 3? 7H 2 O (125} mg, 0.34 mmol) placed in a 1-neck flask and heated gradually under reduced pressure to 135-140 ℃ under (0.1 Torr), and the mixture was stirred for 2 hours. When the flask was hot, argon gas was injected and the flask was cooled in an ice bath. The reaction mixture was stirred vigorously and THF (1.0 mL) was added all at once, then the ice bath was removed and the suspension was stirred overnight at room temperature under argon atmosphere. Next, the flask was cooled to -78 ° C and n -BuLi (0.084 mL, 0.13 mmol) was added to anhydrous THF (1.0 mL) solution containing Compound 51 (36 mg, 0.14 mmol) obtained in Preparation Example 27. After addition at 78 ° C., the resulting aryl anions were added by stirring for 20 minutes. After stirring at −78 ° C. for 1.5 hours, Compound 71 (13 mg, 0.067 mmol) obtained in Preparation Example 21 was added and stirred for 30 minutes. The reaction mixture was treated with saturated aqueous NH ₄ Cl solution and the product was extracted with EtOAc, washed with brine, NaHCO ₃ , brine and dried over anhydrous MgSO ₄ . The solvent was evaporated and the residue obtained was purified by flash column chromatography (EtOAc: n-hexane = 1: 3) to give a secondary alcohol as a diastereomeric mixture (yield 48%, 12 mg).

isomer A : ¹ H-NMR (Acetone-d ₆ , 300 MHz) δ7.22 (d, 1H, J = 8.4 Hz), 6.73 (m, 3H), 6.50 (m, 2H), 5.69 (d, 1H, J = 9.9 Hz), 4.95 (m, 1H), 3.70 (s, 6H), 3.61 (s, 3H), 3.07 (quin, 1H, J = 6.8 Hz), 1,35 (s, 6H), 1.28 ( d, 3H, J = 6.9 Hz);

isomer B : ¹ H-NMR (Acetone-d ₆ , 500 MHz) δ 7.02 (d, 1H, J = 8.4 Hz), 6.75 (m, 3H), 6.55 (d, 1H, J = 10.0 Hz), 6.43 (d, 1H, J = 8.5 Hz), 5.70 (d, 1H, J = 9.9 Hz), 4.93 (dd, 1H, J = 7.5, 4.0 Hz), 3.72 (s, 3H), 3.72 (s, 3H) , 3.71 (s, 3H), 2.95 (quin, 1H, J = 7.2 Hz), 1,34 (d, 6H, J = 11.8 Hz), 1.06 (d, 3H, J = 7.2 Hz).

The secondary alcohol (14 mg, 0.036 mmol) obtained above was dissolved in CH ₂ C1 ₂ (1.0 mL), followed by molecular sieve (18 mg) and N -methyl morpholine- N -oxide (NMO, 7.0 mg, 0.055). mmol) was added. After stirring the mixture for 10 minutes, tetrapropylammonium perunateate (TPAP, 1.3 mg, 0.0036 mmol) is added and when the reaction is complete, the mixture is diluted with CH ₂ C1 ₂ and 10% sodium sulfite It was washed with aqueous solution, brine and finally saturated copper (II) sulfate solution. The organic layer was dried over MgSO ₄ , filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography (EtOAc: n-hexane = 1: 4) to give compound 72 of Example 34 (yield 71%). , 10 mg).

¹ H NMR (CDCl _{3 ,} 500 MHz) δ 7.27 (d, 1H, J = 8.5 Hz), 6.76 (m, 3H), 6.55 (d, 1H, J = 10.0 Hz), 6.48 (d, 1H, J = 8.5 Hz), 5.62 (d, 1H, J = 10.0 Hz), 4.60 (q, 1H, J = 6.9 Hz), 3.81 (s, 3H), 3.80 (s, 3H), 3.65 (s, 3H), 1.48 (d, 3H, J = 6.9 Hz), 1.39 (s, 6H); ¹³ C NMR (CDCl ₃ , 75 MHz) δ 202.5, 157.1, 155.7, 149.0, 147.9, 133.8, 130.7, 130.5, 125.5, 120.2, 116.5, 112.3, 111.2, 77.2, 76.7, 63.3, 55.8, 55.7, 50.0, 43.1, 28.0, 28.0, 19.0; HRMS (FAB) Calcd for C ₂₃ H ₂₇ O ₅ (M + H ⁺ ): 383.1858, Found: 383.1849.

< Example  35> 3- (3,4- Dimethoxyphenyl ) -8,8-dimethyl-4 H ,8 H - Pyrano [2,3- f ] Chrome 4-one (3- (3,4-Dimethoxyphenyl) -8,8-dimethyl-4 H ,8 H -pyrano [2,3- f ] chromen-4-one) 80

To anhydrous toluene (1.0 mL) solution containing compound 107 (15 mg, 0.042 mmol) of Preparation Example 32, dimethylaminodimethoxymethane (6.7 μl, 0.051 mmol) was added at room temperature and refluxed for 2 hours, followed by solvent under reduced pressure. The residue obtained by removal was purified by flash column chromatography (EtOAc: n-hexane = 1: 3) to give compound 80 of Example 35 (yield 100%, 20 mg).

¹ H-NMR (CDCl ₃ , 300 MHz) δ8.00 (d, 1H, J = 8.8 Hz), 7.90 (s, 1H), 7.14 (d, 1H, J = 2.0 Hz), 6.98 (dd, 1H , J = 8.3, 2.0 Hz), 6.86 (d, 1H, J = 8.3 Hz), 6.80 (d, 1H, J = 9.0 Hz), 6.75 (d, 1H, J = 10.0 Hz), 5.66 (d, 1H, J = 10.0 Hz), 3.86 (s, 3H), 3.84 (s, 3H), 1.43 (s, 6H); ¹³ C-NMR (CDCl ₃ , 100 MHz) δ 175.8, 157.2, 152.2, 151.8, 149.0, 148.7, 130.8, 126.6, 124.6, 124.6, 120.9, 118.2, 115.2, 114.8, 112.5, 111.1, 109.1, 77.6, 55.9 , 55.8, 28.0, 28.0; HRMS (FAB) Calcd for C ₂₂ H ₂₁ O ₅ (M + H ⁺ ): 365.1389, Found: 365.1394.

< Example  36> 6,7- Dimethoxy -2 H - Chromen -4- Day (2,2-dimethyl-2 H -Chromen-6-yl) methanone  (6,7-Dimethoxy-2 H -chromen-4-yl (2,2-dimethyl-2 H -chromen-6-yl) methanone) (81)

Compound 118 (49 mg, 0.179 mmol) obtained in Preparation Example 35 was added to anhydrous THF (2.0 mL) solution under nitrogen atmosphere, and n- BuLi (0.12 mL, 0.20 mmol, 1.6 M in hexane) was added dropwise at -78 ° C. Was added. After the reaction mixture was stirred at −78 ° C. for 20 minutes, anhydrous THF (1.0 mL) solution containing Compound 120 (78 mg, 0.357 mmol) obtained in Preparation Example 37 was added dropwise via cannula. The pale yellow solution obtained through the above procedure was stirred at −78 ° C. for 20 minutes, and then extracted with EtOAc (× 2). The organic layer was washed with brine, dried over anhydrous sodium sulfate, and concentrated on a rotary evaporator under reduced pressure to purify the crude residue by flash column chromatography (EtOAc: n-hexane = 1: 10) to give an intermediate of a pale yellow solid. Secondary alcohol was obtained (yield 61%, 45 mg).

¹ H NMR (CDCl3 , 300 MHz) δ7.15 (dd, 1H, J = 8.3, 2.2 Hz), 7.03 (d, 1H, J = 2.2 Hz), 6.75 (d, 1H, J = 8.3 Hz), 6.62 (s, 1H), 6.41 (s, 1H), 6.26 (d, 1H, J = 9.9 Hz), 5.83 (t, 1H, J = 4.1 Hz), 5.59 (d, 1H, J = 9.9 Hz), 5.52 (br, 1H), 4.77 (m, 2H), 3.79 (s, 3H), 3.62 (s, 3H), 1.39 (s, 6H).

Dess-Martin periodinan (3.0 equiv) was added to a solution of CH ₂ Cl ₂ (0.03 M) containing the secondary alcohol (1.0 equiv) obtained above, followed by stirring for 1 hour. The mixture was diluted with CH ₂ Cl ₂ and sodium thiosulfate (10%) was added. The mixture was stirred for 10 minutes until it was separated into two layers at room temperature. The organic layer obtained above was washed with saturated NaHCO ₃ aqueous solution, dried over MgSO ₄ , filtered, and concentrated under reduced pressure. The residue obtained was purified by flash column chromatography (EtOAc: n-hexane = 1: 5) to obtain a compound. 81 was obtained (yield 87%, 39 mg).

¹ H NMR (CDCl ₃ , 300 MHz) δ7.70 (dd, 1H, J = 8.4, 2.2 Hz), 7.59 (d, 1H, J = 2.2 Hz), 6.91 (s, 1H), 6.77 (d, 1H, J = 8.4 Hz), 6.48 (s, 1H), 6.32 (d, 1H, J = 9.9 Hz), 5.96 (t, 1H, J = 4.0 Hz), 5.65 (d, 1H, J = 9.9 Hz), 4.77 (d, 2H, J = 4.0 Hz), 3.84 (s, 3H), 3.72 (s, 3H), 1.44 (s, 6H): ¹³ C NMR (CDCl ₃ , 100 MHz) δ 193.7, 157.8, 160.0, 148.4, 143.4, 134.7, 132.1, 131.2, 129.7, 128.5, 124.1, 121.4, 120, 6, 116.1, 112.0, 108.3, 100.4, 77.7, 64.6, 56.1, 55.9, 28.3, 28.3; HRMS (FAB) Calcd for C ₂₃ H ₂₂ O ₅ (M + H ⁺ ): 378.1467, Found: 378.1475.

< Example  37> 6,7- Dimethoxy -2,2-dimethyl-2 H - Chromen -4- days) (4- Methoxy -2,2-dimethyl-2 H - Chromen -6- days) Metanon  (6,7- Dimethoxy -2,2- dimethyl -2 H - chromen -4- yl )(4- methoxy -2,2-dimethyl-2 H -chromen-6-yl) methanone) (82)

Compounds were prepared in the same manner as in Example 36, except that Compound 119 was used instead of Compound 118, Compound 121 was used instead of Compound 120, and flash column chromatography (EtOAc: n-hexane = 1: 4) was used. 82 was obtained as a colorless solid (yield 44%, 29 mg).

Secondary alcohol : ¹ H NMR (CDCl _{3 ,} 300 MHz): δ 7.01 (d, 1H, J = 8.2 Hz), 6.59 (s, 1H), 6.56 (d, 1H, J = 10.0 Hz), 6.50 (d, 1H, J = 8.2 Hz), 6.38 (s, 1H), 5.91 (br, 1H), 5.74 (s, 1H), 5.63 (d, 1H, J = 10.0 Hz), 3.88 (s, 3H), 3.77 (s, 3H), 3.62 (s, 3H), 1.45 (s, 3H), 1.43 (s, 3H), 1.39 (s, 6H);

Compound 82 : ¹ H NMR (CDCl _{3 ,} 300 MHz) δ 7.31 (d, J = 8.4 Hz, 1H), 7.21 (s, 1H), 6.60 (d, J = 9.5 Hz, 1H), 6.57 (d, J = 7.9 Hz, 1H), 6.45 ( s, 1H), 5.88 (s, 1H), 5.65 (d, J = 10 Hz, 1H), 3.83 (s, 3H), 3.75 (s, 3H), 3.72 (s, 3H), 1.43 (s, 6H ), 1.42 (s, 6 H); ¹³ C NMR (CDCl ₃ , 75 MHz) δ 194.3, 157.4, 156.3, 150.1, 147.3, 143.1, 136.1, 133.2, 131.8, 130.4, 124.7, 116.5, 114.8, 111.8, 110.7, 108.8, 108.7, 101.1, 77.4, 76.8, 75.4, 63.1, 56.3, 56.8, 28.0, 26.6; HRMS (FAB) Calcd for C ₂₆ H ₂₉ O ₆ (M + H ⁺ ): 437.1964, Found: 437.1973.

< Example  38> 6,7- Dimethoxy -2,2-dimethyl-2 H - Chromen -4-yl) (2,2-dimethyl-2 H - Chromen -6-yl) methanone (6,7- Dimethoxy -2,2- dimethyl -2 H - chromen -4- yl ) (2,2- dimethyl -2 H - chromen -6-yl) methanone) (83)

Compound 83 was obtained as a colorless solid by the same method as Example 36, except that Compound 119 was used instead of Compound 118, and flash column chromatography (EtOAc: n-hexane = 1: 4) was used (Yield 51). %, 35 mg).

Secondary alcohol : ¹ H NMR (CDCl ₃ , 300 MHz) δ 7.09 (dd, 1H, J = 8.3 Hz), 6.98 (d, 1H, J = 2.0 Hz), 6.50 (s, 1H), 6.35 (s, 1H), 6.21 (d, 1H, 0 J = 9.9 Hz), 5.65 (s, 1H), 5.54 (d, 1H, J = 9.9 Hz), 5.46 (br, 1H), 3.73 (s, 3H), 3.54 (s, 3H), 1.39 (s, 6H), 1.34 (s, 6H);

Compound 83 : ¹ H NMR (CDCl ₃ , 300 MHz) δ7.68 (dd, 1H, J = 8.4, 2.2 Hz), 7.57 (d, 1H, J = 2.2 Hz), 6.86 (s, 1H), 6.76 (d, 1H, J = 8.4 Hz), 6.46 (s, 1H), 6.32 (d, 1H, J = 9.9 Hz), 5.74 (s, 1H), 5.65 (d, 1H, J = 9.9 Hz), 3.84 (s, 3H), 3.71 (s, 3H ), 1.47 (s, 6H), 1.44 (s, 6H); ¹³ C NMR (CDCl ₃ , 75 MHz) δ 194.0, 157.8, 150.4, 147.3, 143.2, 132.5, 132.3, 132.1, 131.2, 130.1, 128.5, 121.6, 120.7, 116.1, 108.7, 101.2, 77.7, 77.2, 75.5, 56.4, 55.9, 50.3, 50.3, 28.4, 27.0; HRMS (FAB) Calcd for C ₂₅ H ₂₆ O ₅ (M + H ⁺ ): 406.1780, Found: 406.1775.

< Example  39> 6,7- Dimethoxy -2 H - Chromen -4- days) (4- Methoxy -2,2-dimethyl-2 H - Chromen -6-yl) methanone (6,7- Dimethoxy -2 H - chromen -4- yl )(4- methoxy -2,2- dimethyl -2 H - chromen -6-yl) methanone) (84)

Compound 84 was obtained as a colorless solid by the same method as Example 36 except for using Compound 121 instead of Compound 120 and using flash column chromatography (EtOAc: n-hexane = 1: 5) (yield 41 %, 22 mg).

Secondary alcohol : ¹ H NMR (CDCl ₃ , 300 MHz) δ 7.01 (d, 1H, J = 8.3 Hz), 6.60 (s, 1H), 6.48 (s, 1H), 6.34 (s, 1H), 5.83 (m, 2H), 5.59 (d, 1H, J = 9.9 Hz), 4.73 (d, 1H, J = 3.8 Hz), 3.81 (s, 3H), 3.73 (s, 3H), 3.60 (s, 3H) , 1.34 (s, 6 H);

Compound 84 : ¹ H NMR (CDCl _{3 ,} 300 MHz): δ 7.31 (d, J = 8.6 Hz, 1H), 7.27 (s, 1H), 6.59 (d, J = 10.1 Hz, 1H), 6.56 (d, J = 8.0 Hz, 1H), 6.47 (s, 1H), 6.11 (t, J = 4.0 Hz, 1H), 5.65 (d, J = 10 Hz, 1H), 4.78 (d, J = 4.2 Hz, 2H), 3.84 (s, 3H), 3.77 (s, 3H), 3.72 (s, 3H), 1.43 (s, 6H): ¹³ C NMR (CDCl ₃ , 100 MHz) δ 193.3, 157.3, 156.1, 149.8, 148.6, 143.3 , 135.4, 131.6, 130.5, 128.2, 124.3, 116.4, 114.8, 111.8, 111.7, 108.5, 100.3, 77.2, 64.7, 63.1, 56.1, 55.8, 27.9, 27.9; LRMS (FAB) m / z 409 (M + H ⁺ ).

< Example  40> 2- (3,4- Dimethoxyphenyl ) -1- (5-hydroxy-2,2-dimethyl-2 H - Chromen -6-day) -2- (pe Nilsulfo Neil) Ethanone  (2- (3,4- Dimethoxyphenyl ) -1- (5- hydroxy -2,2- dimethyl -2 H - chromen Preparation of -6-yl) -2- (phenylsulfonyl) ethanone) (86)

To anhydrous THF (5.0 mL) solution containing Compound 105 (0.407 mmol) obtained in Preparation Example 28, n- BuLi (0.26 mL, 0.444 mmol, 1.6 M in hexane) was added dropwise at -78 ° C, and the mixture was It stirred at the temperature for 1 hour. Anhydrous THF (3.0 mL) containing Compound 121 (0.448 mmol) obtained in Preparation Example 38 was slowly added to the reaction mixture at -78 ° C. After 1 hour of addition, the reaction mixture was quenched with water and extracted with EtOAc (× 3). The extract was washed with brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to afford the crude residue (Compound 126) which was used for the next step without further purification.

To anhydrous CH ₂ Cl ₂ (5.0 mL) solution containing Compound 126 (183 mg, 0.339 mmol) was added Dess-Martin periodinan (286 mg, 0.660 mmol) at room temperature, After stirring for 1 hour, the reaction mixture was treated with saturated aqueous sodium carbonate: saturated aqueous sodium thiosulfate solution (1: 1, 4.0 mL), stirred for 30 minutes, and then the mixture was poured into water and poured into CH ₂ Cl ₂ (× 3). The residue obtained by extraction, filtration and concentration under reduced pressure was purified by flash column chromatography (EtOAc: n-hexane = 1: 2) to give compound 86 (yield 63%, 137 mg).

¹ H NMR (CDCl _{3 ,} 300 MHz) δ 7.53 (m, 3H), 7.35 (m, 3H), 6.80 (m, 2H), 6.68 (d, J = 8.2 Hz, 1H), 6.50 (d, J = 8.6 Hz, 1H), 6.45 (d, J = 10.1 Hz, 1H), 6.35 (s, 1H), 5.61 (d, J = 10.1 Hz, 1H), 3.79 (s, 3H), 3.61 (s, 3H ), 3.53 (s, 3H), 1.38 (s, 3H), 1.35 (s, 3H); ¹³ C NMR (CDCl ₃ , 100 MHz) δ 206.6, 155.1, 154.1, 148.9, 147.9, 136.2, 130.5, 127.8, 126.7, 118.2, 116.6, 115.0, 111.1, 111.0, 109.8, 77.2, 76.2, 63.6, 55.8, 55.8, 51.6, 27.9, 27.8, 26.3; HRMS (FAB) Calcd for C ₂₄ H ₂₉ O ₅ (M + H ⁺ ): 397.2015, Found: 397.2015.

< Example  41> (3,4- Dimethoxyphenyl ) (2,2-dimethyl-2 H - Chromen -6- days) Metanon  ((3,4-Dimethoxyphenyl) (2,2-dimethyl-2 H -chromen-6-yl) methanone) (87)

Dess-Martin periodinan (3.0 equiv) was added to a solution of CH ₂ Cl ₂ (0.03 M) containing Compound 132 (1.0 equiv) obtained in Preparation Example 40, followed by stirring for 1 hour. The reaction mixture was diluted with CH ₂ Cl ₂ and sodium thiosulfate (10%) was added. The mixture was stirred for 10 minutes until it was separated into two layers at room temperature. The organic layer obtained above was washed with saturated NaHCO ₃ aqueous solution, dried over MgSO ₄ , filtered, and concentrated under reduced pressure. The residue obtained was purified by flash column chromatography (EtOAc: n-hexane = 1: 8) to obtain a compound. 87 was obtained as a colorless solid (yield 81%, 86 mg).

¹ H NMR (CDCl ₃ , 300 MHz) δ 7.56 (d, 1H, J = 8.4, 2.2 Hz), 7.47 (d, 1H, J = 2.2 Hz), 7.41 (d, 1H, J = 1.8 Hz), 7.34 (d, 1H, J = 8.2, 2.0 Hz), 6.88 (d, 1H, J = 8.4 Hz), 6.79 (d, 1H, J = 8.4 Hz), 6.34 (d, 1H, J = 9.9 Hz), 5.65 (d, 1H, J = 9.9 Hz), 3.94 (s, 3H), 3.92 (s, 3H), 1.45 (s, 6H); ¹³ C NMR (CDCl ₃ , 100 MHz) δ 194.3, 156.7, 152.5, 148.8, 131.8, 131.1, 130.7, 130.7, 128.5, 124.7, 121.6, 120.5, 115.7, 112.1, 109.7, 77.4, 56.0, 28.3, 28.2. ; LRMS (FAB) m / z 325 (M + H ⁺ ).

< Example  42> ( E ) -1- (3,4- Dimethoxyphenyl ) -3- (2,2-dimethyl-2 H - Chromen -6- days) Prop 2-en-1-one (( E ) -1- (3,4- Dimethoxyphenyl ) -3- (2,2- dimethyl -2 H - chromen -6- yl ) prop -2- en -1-one) Preparation of (88)

Aqueous potassium hydroxide solution (1.5 equiv) was added to a pure ethyl alcohol (0.1 M) solution containing 3 ', 4'-dimethoxyphenylacetophenone (1.0 equiv) and compound 120 (2.0 equiv) obtained in Preparation Example 37 at room temperature It was then refluxed for 5 hours. After cooling to room temperature, the solvent was removed by rotary evaporator under reduced pressure and the crude residue obtained was extracted with EtOAc (× 2). The organic layer was washed with brine, dried over anhydrous MgSO ₄ and concentrated under a rotary evaporator under reduced pressure to purify the residue by flash column chromatography (EtOAc: n-hexane = 1: 5) to give compound 88 as a pale yellow solid. (Yield 59%, 29 mg).

¹ H NMR (CDCl ₃ , 300 MHz) δ7.62 (m, 3H), 7.35 (m, 2H), 7.21 (d, 1H, J = 2.0 Hz), 6.86 (d, 1H, J = 8.4 Hz), 6.74 (d, 1H, J = 8.4 Hz), 6.29 (d, 1H, J = 9.9 Hz), 5.61 (d, 1H, J = 9.7 Hz), 3.90 (s, 3H), 3.90 (s, 3H), 1.39 (s, 6H); ¹³ C NMR (CDCl ₃ , 100 MHz) δ 188.6, 155.3, 153.0, 149.1, 143.9, 131.6, 131.3, 129.7, 127.7, 123.2, 121.6, 121.3, 119.1, 116.8, 116.0, 110.7, 109.9, 77.1, 56.1, 56.0, 28.2, 28.1.

< Example  43> ( E ) -3- (3,4- Dimethoxyphenyl ) -1- (5-hydroxy-2,2-dimethyl-2 H - Chromen -6-yl) prop-2-en-1-one (( E ) -3- (3,4- Dimethoxyphenyl ) -1- (5- hydroxy -2,2- dimethyl -2 H -chromen-6-yl) prop-2-en-1-one) (89)

Aqueous solution of carium hydroxide (1.0 mL, 0.5 mM) in pure ethyl alcohol (4.0 mL) containing compound 112 (100 mg, 0.46 mmol) and 3,4-dimethoxybenzaldehyde (154 mg, 0.92 mmol) obtained in Preparation Example 41. Was added at room temperature and refluxed for 5 hours. After cooling to room temperature, the crude residue obtained by concentration under pressure was extracted with EtOAc (10 mL) and water (5.0 mL). The organic layer was washed with brine, dried over anhydrous MgSO ₄ and the residue obtained under reduced pressure was purified by flash column chromatography (EtOAc: n-hexane = 1: 4) to give compound 89 as a white solid (yield 57%, 95 mg).

¹ H-NMR (CDCl ₃ , 400 MHz) δ 13.77 (s, 1H), 7.78 (d, 1H, J = 15.3 Hz), 7.68 (d, 1H, J = 8.8 Hz), 7.37 (d, 1H, J = 15.3 Hz), 7.18 (d, 1H, J = 8.1 Hz), 7.10 (s, 1H), 6.84 (d, 1H, J = 8.3 Hz), 6.71 (d, 1H, J = 10.0 Hz), 6.33 (d, 1H, J = 8.8 Hz), 5.54 (d, 1H, J = 10.0 Hz), 3.90 (s, 3H), 3.88 (s, 3H), 1.42 (s, 6H); ¹³ C-NMR (CDCl ₃ , 100 MHz) δ 191.7, 160.8, 159.5, 151.4, 149.1, 144.3, 130.4, 127.9, 127.6, 123.2, 117.8, 115.8, 113.9, 111.0, 110.2, 110.0, 109.3, 108.8, 108.0 , 77.6, 55.8, 28.2.

< Example  44> ( E ) -3- (3,4- Dimethoxyphenyl ) -1- (2,2-dimethyl-2 H - Chromen -6- days) Prop 2-en-1-one (( E ) -3- (3,4- Dimethoxyphenyl ) -1- (2,2- dimethyl -2 H - chromen -6- yl ) prop -2- en -1-one) Preparation of (90)

An aqueous potassium hydroxide solution (1.5 equiv) was added to a pure ethyl alcohol (0.1 M) solution containing 3,4-dimethoxybenzaldehyde (1.0 equiv) and compound 134 (2.0 equiv) obtained in Preparation Example 42, followed by 5 It was refluxed for hours. After cooling to room temperature, the solvent was removed by rotary evaporator under reduced pressure and the crude residue obtained was extracted with EtOAc (× 2). The organic layer was washed with brine, dried over anhydrous MgSO ₄ and concentrated on a rotary evaporator under reduced pressure to purify the residue by flash column chromatography (EtOAc: n-hexane = 1: 4) to afford compound 90 as a pale yellow solid. Obtained (yield 57%, 23 mg).

¹ H NMR (CDCl _{3 ,} 300 MHz) δ 7.87 (dd, 1H, J = 8.4, 2.0 Hz), 7.77 (m, 2H), 7.41 (d, 1H, J = 15.5 Hz), 7.24 (m, 2H ), 6.92 (d, 1H, J = 8.4 Hz), 6.87 (d, 1H, J = 8.4 Hz), 6.43 (d, 1H, J = 9.9 Hz), 5.71 (d, 1H, J = 9.9 Hz), 3.98 (s, 3 H), 3.95 (s, 3 H), 1.49 (s, 6 H); ¹³ C NMR (CDCl ₃ , 100 MHz) δ 190.7, 188.5, 157.1, 151.1, 149.1, 143.9, 131.2, 131.0, 130.1, 127.9, 127.0, 122.8, 121.6, 120.7, 119.6, 116.0, 111.0, 110.0, 77.4, 55.8, 28.2, 28.1; HRMS (FAB) Calcd for C ₂₂ H ₂₃ O ₄ (M + H ⁺ ): 351.1596, Found: 351.1590.

< Example  45> (E) -1- (5-hydroxy-2,2-dimethyl-2H- Chromen -6-yl) -3- (2,4,5- Trimethoxyphenyl ) Prop 2-en-1-one ((E) -1- (5- hydroxy -2,2- dimethyl -2H- chromen -6- yl ) -3- (2,4,5-trimethoxyphenyl) prop-2-en-1-one) 91

Compound 91 was obtained by the same method as Example 43 except for using 2,4,5-trimethoxybenzaldehyde instead of 3,4-dimethoxybenzaldehyde (yield 61%, 29 mg).

¹ HNMR (CDCl _{3 ,} 300 MHz) δ 7.87 (dd, 1H, J = 8.4, 2.0 Hz), 7.77 (m, 2H), 7.41 (d, 1H, J = 15.5 Hz), 7.24 (m, 2H), 6.92 (d, 1H, J = 8.4 Hz), 6.87 (d, 1H, J = 8.4 Hz), 6.43 (d, 1H, J = 9.9 Hz), 5.71 (d, 1H, J = 9.9 Hz), 3.98 ( s, 3H), 3.95 (s, 3H), 1.49 (s, 6H); ¹³ CNMR (CDCl ₃ , 100 MHz) δ 190.7, 188.5, 157.1, 151.1, 149.1, 143.9, 131.2, 131.0, 130.1, 127.9, 127.0, 122.8, 121.6, 120.7, 119.6, 116.0, 111.0, 110.0, 77.4, 55.8, 28.2, 28.1; HRMS (FAB) Calcd for C ₂₂ H ₂₃ O ₄ (M + H ⁺ ): 351.1596, Found: 351.1590.

< Example  46> ( E ) -3- (3,4- Dimethoxyphenyl ) -1- (5- Methoxy -2,2-dimethyl-2 H - Chromen -6- days) F Rob-2-en-1-one (( E ) -3- (3,4- Dimethoxyphenyl ) -1- (5- methoxy -2,2- dimethyl -2 H -chromen-6-yl) prop-2-en-1-one) (92)

An acetone (0.25 M) mixture containing phenol (1 equiv), potassium carbonate (3 equiv) and iodine methane (1.5 equiv) was refluxed for 4 hours and stirred overnight at room temperature. The mixture was concentrated, treated with water and extracted with CH ₂ Cl ₂ (× 3). The extract was washed with water, dried over anhydrous MgSO ₄ , the solvent was removed under reduced pressure and the crude residue obtained was purified by flash column chromatography (EtOAc: n-hexane = 1: 5) to give compound 92 as a pale yellow solid. Obtained (yield 81%, 18 mg).

¹ H NMR (CDCl _{3 ,} 300 MHz) δ7.60 (d, 1H, J = 14.5 Hz), 7.46 (d, 1H, J = 8.4 Hz), 7.30 (d, 1H, J = 14.5 Hz), 7.12 ( m, 2H), 6.82 (d, 1H, J = 8.4 Hz), 6.58 (m, 2H), 6.63 (d, 1H, J = 10.0 Hz), 3.86 (s, 3H), 3.85 (s, 3H), 1.39 (s, 6 H); HRMS (FAB) Calcd for C ₂₃ H ₂₅ O ₅ (M + H ⁺ ): 381.1702, Found: 381.1698.

< Example  47> (E) -1- (5- Methoxy -2,2-dimethyl-2H- Chromen -6-yl) -3- (2,4,5- Trimethoxyphenyl Prop-2-en-1-one ((E) -1- (5- methoxy -2,2- dimethyl -2H- chromen -6- yl ) -3- (2,4,5-trimethoxyphenyl) prop-2-en-1-one) (93)

Compound 93 was obtained by the same method as Example 46 except for using compound 91 instead of compound 89 (yield 75%, 20 mg).

¹ H NMR (CDCl _{3 ,} 300 MHz) δ 7.96 (d, 1H, J = 15.9 Hz), 7.44 (d, 1H, J = 8.4 Hz), 7.32 (d, 1H, J = 15.9 Hz), 7.05 (s , 1H), 6.57 (m, 1H), 6.44 (s, 1H), 5.62 (d, 1H, J = 9.8 Hz), 3.87 (s, 3H), 3.81 (s, 3H), 3.81 (s, 3H) , 3.69 (s, 3 H), 1.39 (s, 6 H); ¹³ CNMR (CDCl ₃ , 100 MHz) δ 191.5, 156.9, 156.0, 154.4, 152.3, 143.2, 138.6, 131.1, 130.4, 126.0, 124.1, 116.6, 115.7, 114.7, 112.4, 110.9, 96.9, 76.7, 63.2, 56.5, 56.4, 56.3, 28.0, 28.0; HRMS (FAB) Calcd for C ₂₄ H ₂₇ O ₆ (M + H ⁺ ): 411.1808, Found: 411.1813.

< Example  48> 2- (3,4- Dimethoxyphenyl ) -8,8-dimethyl-4 H ,8 H - Pyrano [2,3- f ] Chrome 4-one (2- (3,4-Dimethoxyphenyl) -8,8-dimethyl-4 H ,8 H -pyrano [2,3- f ] chromen-4-one) (94)

To anhydrous DMSO (5.0 mL) solution containing compound 89 (50 mg, 0.14 mmol) prepared in Example 43 was added a catalytic amount of iodine at room temperature and monitored by TLC and refluxed until the reaction was complete. After cooling to room temperature, the mixture was poured into 20% aqueous sodium thiosulfate solution (10 mL) and extracted with EtOAc (10 mL). The organic layer was washed with water and brine, dried over anhydrous sodium sulfate and concentrated on a rotary evaporator under reduced pressure to purify the residue by flash column chromatography (CH ₂ Cl ₂ : MeOH = 1: 10) to give compound 94 as a white solid. Obtained (yield 28%, 14 mg).

¹ H-NMR (CDCl ₃ , 300 MHz) δ7.92 (d, 1H, J = 8.6 Hz), 7.48 (dd, 1H, J = 8.4, 2.0 Hz), 7.29 (d, 1H, J = 2.0 Hz) , 6.93 (d, 1H, J = 8.4 Hz), 6.81 (m, 2H), 6.66 (s, 1H), 5.70 (d, 1H, J = 9.8 Hz), 3.91 (s, 3H), 3.90 (s, 3H), 1.45 (s, 6H); HRMS (FAB) Calcd for C ₂₂ H ₂₁ O ₅ (M + H ⁺ ): 365.1389, Found: 365.1387.

< Example  49> 2- (3,4- Dimethoxyphenyl ) - N -(5- Methoxy -2,2-dimethyl-2 H - Chromen -6- days) Acetate -Amide (2- (3,4- Dimethoxyphenyl ) - N -(5- methoxy -2,2- dimethyl -2 H - chromen -6-yl) acetamide) (95)

N , N -diiso in anhydrous dichloromethane (0.3 M) mixture containing 3 ', 4'-dimethoxyphenylacetic acid (1.0 equiv), PyBOP (1.0 equiv) and compound 50 (1.2 equiv) obtained in Preparation 26 Propylethylamine (2.2 equiv) was added. The mixture was stirred overnight under nitrogen atmosphere and the residue obtained by evaporation of the solvent was dissolved in EtOAc. The solution was extracted with 5% aqueous hydrochloric acid solution, washed with brine, extracted with saturated aqueous sodium hydrogen carbonate solution, dried over anhydrous MgSO ₄ , filtered, and the solvent was evaporated to obtain a brown oil residue obtained by flash column chromatography ( Purification with EtOAc: n-hexane = 1: 2) gave compound 95 as a yellow solid (yield 91%, 31 mg).

¹ H NMR (CDCl _{3 ,} 400 MHz) δ7.93 (d, 1H, J = 8.8 Hz), 7.52 (br, 1H), 6.82 (m, 3H), 6.49 (d, 1H, J = 8.8 Hz), 6.37 (d, 1H, J = 9.9 Hz), 5.57 (d, 1H, J = 9.9 Hz), 3.82 (s, 3H), 3.81 (s, 3H), 3.62 (s, 2H), 3.35 (s, 3H ), 1.31 (s, 6 H); ¹³ C NMR (CDCl ₃ , 100 MHz) δ 168.8, 149.5, 149.3, 148.3, 144.8, 131.2, 127.0, 124.2, 121.5, 120.3, 116.2, 114.1, 112.3, 112.0, 111.5, 75.4, 61.4, 55.7, 55.7, 44.3, 27.3, 27.2; HRMS (FAB) Calcd for C ₂₂ H ₂₅ NO ₅ (M + H ⁺ ): 384.1811, Found: 384.1806.

< Example  50> N- (3,4- Dimethoxybenzyl ) -2,2-dimethyl-2 H - Chromen -6- Carboxamide  ( N- (3,4-Dimethoxybenzyl) -2,2-dimethyl-2 H -chromene-6-carboxamide) (96)

N , N -diisopropylethyl in anhydrous dichloromethane (0.3 M) mixture containing 3,4-dimethoxybenzylamine (1.0 equiv), PyBOP (1.0 equiv) and compound 121 (1.2 equiv) obtained in Preparation 38 Compound 96 was obtained as a yellow solid (yield 79%, 41 mg) in the same manner as in Example 49, except for adding amine (2.2 equivalents).

¹ H NMR (CDCl _{3 ,} 400 MHz) δ 7.51 (dd, 1H, J = 8.3, 2.0 Hz), 7.43 (d, 1H, J = 2.0 Hz), 6.80 (m, 3H), 6.71 (d, 1H , J = 8.3 Hz), 6.46 (m, 2H), 5.60 (d, 1H, J = 9.8 Hz), 4.49 (d, 1H, J = 5.5 Hz), 3.81 (s, 3H), 3.80 (s, 3H ), 1.39 (s, 6 H); ¹³ C NMR (CDCl ₃ , 100 MHz) δ 166.7, 155.8, 149.0, 148.3, 131.2, 130.9, 127.8, 126.6, 125.5, 121.6, 120.8, 120.1, 116.0, 111.2, 111.1, 77.6, 55.8, 55.7, 43.8, 28.1, 28.1; HRMS (FAB) Calcd for C ₂₁ H ₂₃ NO ₄ (M + H ⁺ ): 354.1705, Found: 354.1703.

< Example  51> N- (3,4- Dimethoxyphenyl ) -2,2-dimethyl-2 H - Chromen -6- Carboxamide  ( N- (3,4-Dimethoxyphenyl) -2,2-dimethyl-2 H -chromene-6-carboxamide) (97)

N , N -diisopropylethylamine in anhydrous dichloromethane (0.3 M) mixture containing 3,4-dimethoxyaniline (1.0 equiv), PyBOP (1.0 equiv) and compound 121 (1.2 equiv) obtained in Preparation 38 Compound 97 was obtained as a yellow solid by the same method as Example 49 except for the addition of (2.2 equivalents) and the purification by flash column chromatography (EtOAc: n-hexane = 1: 3). %, 29 mg).

¹ H NMR (CDCl _{3 ,} 400 MHz) δ 7.89 (s, 1 H), 7.53 (dd, 1 H, J = 8.8, 2.2 Hz), 7.50 (d, 1H, J = 2.3 Hz), 7.42 (d, 1H , J = 2.2 Hz), 6.96 (dd, 1H, J = 8.6, 2.3 Hz), 6.76 (m, 2H), 6.28 (d, 1H, J = 9.8 Hz), 5.63 (d, 1H, J = 9.8 Hz ), 3.82 (s, 6 H), 1.42 (s, 6 H); ¹³ C NMR (CDCl ₃ , 100 MHz) δ 184.5, 165.2, 156.0, 148.9, 145.7, 131.7, 131.4, 127.9, 127.0, 125.6, 121.5, 121.0, 116.2, 112.1, 111.2, 105.9, 77.2, 56.0, 56.0, 55.7, 28.1, 28.1; HRMS (FAB) Calcd for C ₂₀ H ₂₁ NO ₄ (M + H ⁺ ): 340.1549, Found: 340.1542.

< Example  52> N- (2,2-dimethyl-2 H - Chromen -6-day) -3,4- Dimethoxybenzamide  ( N- (2,2-Dimethyl-2 H -chromen-6-yl) -3,4-dimethoxybenzamide) (98)

N , N -diisopropylethylamine in anhydrous dichloromethane (0.3 M) mixture containing 3,4-dimethoxybenzoic acid (1.0 equiv), PyBOP (1.0 equiv) and compound 50 (1.2 equiv) obtained in Preparation 26 (2.2 equiv) was added. The mixture was stirred overnight under nitrogen atmosphere and the residue obtained by evaporation of the solvent was dissolved in EtOAc. The solution was extracted with 5% aqueous hydrochloric acid solution, washed with brine, extracted with saturated aqueous sodium hydrogen carbonate solution, dried over anhydrous MgSO ₄ , filtered, and the solvent was evaporated to obtain a brown oil residue obtained by flash column chromatography ( Purification with EtOAc: n-hexane = 1: 2) gave compound 98 as a yellow solid (yield 60%, 17 mg).

¹ H NMR (CDCl _{3 ,} 500 MHz) δ 8.16 (s, 1H), 8.08 (d, 1H, J = 8.8 Hz), 7.49 (s, 1H), 7.36 (dd, 1H, J = 7.8.1.8 Hz ), 6.89 (d, 1H, J = 7.8 Hz), 6.61 (d, 1H, J = 8.8 Hz), 6.53 (d, 1H, J = 9.9 Hz), 6.57 (d, 1H, J = 9.9 Hz), 3.93 (s, 3 H), 3.91 (s, 3 H), 3.78 (s, 1 H), 1.40 (s, 6 H); ¹³ C NMR (CDCl ₃ , 125 MHz) δ 164.7, 151.9, 149.8, 149.1, 145.4, 131.4, 127.7, 124.6, 121.2, 119.1, 116.5, 114.3, 112.4, 110.7, 110.3, 75.6, 62.0, 56.0, 27.5, 27.5; LRMS (FAB) m / z 370 (M + H ⁺ ).

< Example  53> ( R ) -2- (3,4- Dimethoxyphenyl ) -1- (2,2-dimethyl-2 H - Chromen -6-yl) propan-1-one (( R ) -2- (3,4-Dimethoxyphenyl) -1- (2,2-dimethyl-2 H -chromen-6-yl) propan-1-one) (99)

To the anhydrous THF solution containing the aryl bromide compound 131 (1.5 equivalents), n- BuLi (1.4 equivalents) was added dropwise at -78 ° C, and stirred at -78 ° C to generate an aryl anion. After stirring at −78 ° C. for 20 minutes, Compound 71 (1.0 equiv) obtained in Preparation 21 was added and stirring continued for 30 minutes, after which the reaction mixture was treated with saturated aqueous NH ₄ Cl solution and extracted with EtOAc. The extract was washed with brine, dried over MgSO ₄ and the solvent was evaporated and the residue was purified by flash column chromatography (EtOAc: n-hexane = 1: 4) to give a secondary alcohol (yield 48%, 19 mg).

Dess-Martin periodinan (3.0 equiv) was added to a solution of CH ₂ Cl ₂ (0.03 M) containing the secondary alcohol (1.0 equiv) obtained above, followed by stirring for 1 hour. The mixture was diluted with CH ₂ Cl ₂ and sodium thiosulfate (10%) was added. The mixture was stirred for 10 minutes until it was separated into two layers at room temperature. The organic layer obtained above was washed with saturated NaHCO ₃ aqueous solution, dried over MgSO ₄ , filtered, and concentrated under reduced pressure. The residue obtained was purified by flash column chromatography (EtOAc: n-hexane = 1: 5) to obtain a compound. 99 was obtained (yield 85%, 16 mg).

¹ H NMR (CDCl _{3 ,} 500 MHz) δ7.73 (dd, 1H, J = 8.4, 1.7 Hz), 7.60 (d, 1H, J = 1.6 Hz), 6.78 (m, 3H), 6.68 (d, 1H , J = 8.5 Hz), 6.27 (d, 1H, J = 9.9 Hz), 5.59 (d, 1H, J = 9.9 Hz), 4.54 (q, 1H, J = 6.8 Hz), 3.82 (s, 3H), 3.80 (s, 3 H), 1.46 (d, 3 H, J = 6.8 Hz), 1.39 (s, 6H); ¹³ C NMR (CDCl ₃ , 125 MHz) δ 198.9, 157.1, 149.2, 147.8, 134.3, 130.9, 130.5, 129.4, 127.3, 121.6, 120.5, 119.9, 115.9, 111.4, 110.5, 77.4, 55.8, 55.7, 46.8, 28.3, 28.3, 19.5; HRMS (FAB) Calcd for C ₂₂ H ₂₄ O ₄ (M + H ⁺ ): 353.1753, Found: 353.1760.

< Example  54> ( S ) -2- (3,4- Dimethoxyphenyl ) -1- (2,2-dimethyl-2 H - Chromen -6-yl) propan-1-one (( S ) -2- (3,4-Dimethoxyphenyl) -1- (2,2-dimethyl-2 H -chromen-6-yl) propan-1-one) (100)

To the anhydrous THF solution containing aryl bromide compound 131 (1.5 equiv), n-BuLi (1.4 equiv) was added dropwise at −78 ° C. and stirred at −78 ° C. to generate an aryl anion. After stirring at −78 ° C. for 20 minutes, Compound 68 (1.0 equiv) obtained in Preparation 19 was added and stirring continued for 30 minutes, after which the reaction mixture was treated with saturated aqueous NH ₄ Cl solution and extracted with EtOAc. The extract was washed with brine, dried over MgSO ₄ and the solvent was evaporated and the residue was purified by flash column chromatography (EtOAc: n-hexane = 1: 4) to give a secondary alcohol (yield 59%, 13 mg).

Dess-Martin periodinan (3.0 equiv) was added to a solution of CH ₂ Cl ₂ (0.03 M) containing the secondary alcohol (1.0 equiv) obtained above, followed by stirring for 1 hour. The mixture was diluted with CH ₂ Cl ₂ and sodium thiosulfate (10%) was added. The mixture was stirred for 10 minutes until it was separated into two layers at room temperature. The organic layer obtained above was washed with saturated NaHCO ₃ aqueous solution, dried over MgSO ₄ , filtered, and concentrated under reduced pressure. The residue obtained was purified by flash column chromatography (EtOAc: n-hexane = 1: 5) to obtain a compound. 100 was obtained (yield 79%, 9.8 mg, 76% ee).

¹ H NMR (CDCl _{3 ,} 500 MHz) δ7.74 (dd, 1H, J = 8.4, 1.7 Hz), 7.60 (d, 1H, J = 1.6 Hz), 6.78 (m, 3H), 6.68 (d, 1H , J = 8.5 Hz), 6.28 (d, 1H, J = 9.9 Hz), 5.59 (d, 1H, J = 9.9 Hz), 4.54 (q, 1H, J = 6.8 Hz), 3.82 (s, 3H), 3.80 (s, 3H), 1.46 (d, 3H, J = 6.8 Hz), 1.40 (s, 32H), 1.39 (s, H); ¹³ C NMR (CDCl ₃ , 125 MHz) δ 198.9, 157.1, 149.2, 147.8, 134.3, 130.9, 130.5, 129.4, 127.4, 121.7, 120.5, 119.9, 116.0, 111.4, 110.5, 77.5, 55.8, 55.7, 46.8, 28.3, 28.3, 19.6; HRMS (FAB) Calcd for C ₂₂ H ₂₄ O ₄ (M + H ⁺ ): 353.1753, Found: 353.1759.

< Example  55> (7 S , 7 a R , 3 a S ) -9,10- Dimethoxy -3,3-dimethyl-7- ( Prop 2-yen Oxy ) -7,7a, 13,13a-tetrahydro-3H- Chromeno [3,4- b ] Pyrano [2,3- h ] Chromen  ((7 S , 7a R , 3a S ) -9,10- Dimethoxy -3,3- dimethyl -7- ( prop -2- en - oxy ) -7,7a, 13,13a- tetrahydro -3H-chromeno [3,4- b ] pyrano [2,3- h ] chromene) Preparation of 17

The compound 14 (1 equivalent) prepared in Example 7 was dissolved in anhydrous THF solution at 0 ° C. 3 - Iodopropene (1.5 equiv) was added and then at 0 ° C. t- BuOK solution (1 M in THF, 1 equiv) was added dropwise. The reaction mixture is monitored by TLC at 0 ° C. until the reaction is complete After stirring, it was cooled with saturated aqueous NH ₄ Cl solution and extracted with EtOAc. The organic layer in the extract was dried over MgSO ₄ , filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography (EtOAc: n-hexane = 1: 5) to give compound 101 as a colorless solid (yield 68%). , 15 mg).

¹ H NMR (CDCl _{3 ,} 500 MHz) δ7.93 (d, 1H, J = 8.2 Hz), 6.79 (s, 1H), 6.64 (d, 1H, J = 9.9 Hz), 6.41 (s, 1H), 6.36 (d, 1H, J = 8.2 Hz), 5.66 (m, 1H), 5.54 (d, 1H, J = 9.9 Hz), 5.56 (m, 2H), 4.78 (quin, 1H, J = 5.3 Hz), 4.57 (m, 2H), 4.23 (dd, 1H, J = 9.4, 3.8 Hz) 3.90 (m, 1H), 3.81 (s, 3H), 1.39 (s, 3H); ¹³ C NMR (CDCl ₃ , 125 MHz) δ 154.1, 149.1, 149.0, 148.5, 143.4, 134.7, 129.0, 128.9, 116.5, 116.4, 113.9, 111.6, 109.9, 109.9, 108.5, 100.3, 75.9, 73.8, 70.0, 69.6, 65.8, 56.5, 55.7, 37.0, 27.9, 27.8.

< Comparative example  1> (7 a S , 13 a S ) -9,10- Dimethoxy -3,3-dimethyl-13,13a- Dihydro -3 H -Chromeno [3,4- b ] Pyrano [2,3- h ] Chromen -7 (7 a H ) -On ((7 a S , 13 a S ) -9,10- Dimethoxy -3,3-dimethyl-13,13a-dihydro-3 H -chromeno [3,4- b ] pyrano [2,3- h ] chromen-7 (7a H ) -one) (Deguelin) Preparation

To anhydrous CH ₂ Cl ₂ (4.0 mL) solution in which compound 8 (128 mg, 0.32 mmol) of Example 1 was dissolved, phenylselenyl chloride (68 mg, 0.35 mmol) was added under argon atmosphere at -30 ° C, and- The mixture was stirred for 10 minutes while maintaining at 30 ° C., then stirred for 2 hours until the temperature reached room temperature, and further stirred for 1 hour. The reaction mixture was then depressurized to remove the solvent and the resulting residue was dissolved in THF (4.0 mL) and then hydrogen peroxide (30% in water, 0.06 mL) was added at 0 ° C. The reaction mixture was stirred until room temperature and monitored by TLC, EtOAc (8.0 mL) and water (4.0 mL) were added. The organic layer was separated, washed with 5% aqueous NaHCO ₃ solution and brine, dried over MgSO ₄ , filtered and concentrated to obtain crude residue by flash column chromatography (EtOAc: n -hexane = 1: 2). Thus, deguelin was obtained as a pale yellow solid (yield 61%, 78 mg).

¹ H-NMR (CDCl ₃ , 400 MHz) δ7.72 (d, 1H, J = 8.7 Hz), 6.77 (s, 1H), 6.62 (d, 1H, J = 10.0 Hz), 6.43 (s, 1H) , 6.43 (d, 1H, J = 8.7 Hz), 5.53 (d, 1H, J = 10.0 Hz), 4.89 (m, 1H), 4.17 (d, 1H, J = 12.0 Hz), 3.82 (d, 1H, J = 4.1 Hz), 3.78 (s, 3H), 3.75 (s, 3H), 1.43 (s, 3H), 1.36 (s, 3H); ¹³ C-NMR (CDCl ₃ , 100 MHz) δ 189.2, 160.0, 156.9, 149.4, 147.4, 143.8, 128.6, 128.5, 115.7, 112.7, 111.4, 110.4, 109.1, 104.7, 100.9, 77.6, 72.4, 66.2, 56.3 , 55.8, 44.3, 28.4, 28.1; HRMS (FAB) Calcd for C ₂₃ H ₂₃ O ₆ (M + H ⁺ ): 395.1495, Found: 395.1495.

< Experimental Example  1> Evaluation of Cancer Cell Growth Inhibition

In order to determine the extent to which the compounds of the embodiment of the present invention inhibit the growth of cancer cells, experiments were performed as follows. Specifically, H1299 non-small cell lung cancer (NSCLC) cells are dispensed in 96-well plates at a concentration of 5 × 10 ³ cells / well and incubated at 37 ^° C., 5% CO ₂ for 24 hours. The compounds of each example were dissolved in DMSO (10 nM, 100 nM, 1 uM, 10 uM) and treated in each well, and after 48 hours the MTS reagent (3- (4,5-dimethylthiazol-2-yl)- Cell growth was measured using 5- (3-carboxymethoxyphenyl) -2- (4-sulfophenyl) -2 H -tetrazolium). The same experiment was performed three times to correct the standard deviation of each analysis result, and the results are shown in Table 2 below.

compound IC ₅₀ ([mu] M) Comparative Example 1
(Deguelin) 0.11 Example 1
(Compound 8) NA Example 2
(Compound 9) 9.8 Example 3
(Compound 10) 0.87 Example 4
(Compound 11) 0.97 Example 5
(Compound 12) 10.1 Example 7
(Compound 13) 4.2 Example 6
(Compound 14) 0.01 Example 8
(Compound 15) 4.1 Example 9
(Compound 16) 9.8 Example 10
(Compound 17) 10.5 Example 11
(Compound 18) NA Example 12
(Compound 19) NA Example 13
(Compound 20) 0.68 Example 14
(Compound 21) 0.11 Example 15
(Compound 22) NA Example 16
(Compound 23) 0.3 Example 17
(Compound 24) 4.3 Example 18
(Compound 25) NA Example 19
(Compound 26) 0.14 Example 20
(Compound 27) NA Example 21
(Compound 28) 5.2 Example 22
(Compound 29) NA Example 23
(Compound 30) NA Example 24
(Compound 31) NA Example 25
(Compound 37) 4.5 Example 26
(Compound 45) 3.8 Example 27
(Compound 53) 1.0 Example 28
(Compound (54) 0.14 Example 29
(Compound 56) 0.73 Example 30
(Compound 57) 3.2 Example 32
(Compound 59) 102 Example 33
(Compound 69) 0.49 Example 34
(Compound 72) 1.3

As shown in Table 2, when the new deguelin derivatives according to the present invention were treated with H1299 NSCLC cells, the average cell growth IC ₅₀ was about 3-5 μM. Particularly, Compound 14 of Example 6 exhibited an IC ₅₀ value of 0.01 μM, which showed about 10 times more cancer cell growth inhibition effect than deguelin of Comparative Example 1.

Therefore, the novel deguelin derivative according to the present invention is excellent in inhibiting the growth of cancer cells, and thus may be usefully used as an anticancer agent.

< Experimental Example  2> HIF -1α Inhibitory Activity Assessment

Experimental Example 1 measured the inhibition of HIF-1α accumulation (accumulation) in the lung cancer cell line H1299 NSCLC cells for the deguelin derivative showing a strong cell growth inhibition. Specifically, in order to confirm the effect of the compounds prepared in Examples of the present invention concentration-dependently inhibit the production of HIF-1α protein induced by hypoxia conditions, deguelin derivatives prepared in Examples And when the concentration of deguelin prepared in Comparative Example 1 was treated differently, the degree of production of HIF-1α protein was compared using Western blot analysis.

First, H1299 non-small cell lung cancer (NSCLC) cells were dispensed in 96-well plates at a concentration of 5 x 10 ³ cells / well, followed by incubation for 24 hours, followed by hypoxic conditions (oxygen 1%, nitrogen 94%, After pretreatment for 12 hours in 5% of carbon dioxide to induce the accumulation of HIF-1α, the compound of Formula 1 was dissolved in DMSO solvent and treated with H1299 NSCLC cells at a concentration of 0-10 μM, and then 16 hours under the hypoxic conditions After incubation, nuclear extracts were prepared using RIPA buffer. At this time, the experiment was performed with a control containing 20% oxygen in order to compare the expression of HIF-1 target gene according to hypoxic conditions. About 30 μg of each sample of the nuclear extract was separated by SDS PAGE (sodium dodecyl sulfate-polyacrylamide gel electrophoresis) and transferred to a polyvinylidene fluoride membrane, followed by HIF-1α antibody (BD Pharmingen) and HRP ( The amount of HIF-1α protein was detected using a secondary antibody labeled with horseradish peroxidase, and tubulin was used as an internal control gene. The measurement results are shown in FIG. 1.

1 is a Western blot diagram showing the extent to which the compounds inhibit HIF-1α accumulation according to an embodiment of the present invention.

As shown in Figure 1, the deguelin derivatives prepared in one embodiment of the present invention concentration-dependently inhibit the production of HIF-1α protein without affecting the production of tubulin (Tublin) in hypoxic conditions You can check it.

Therefore, since the deguelin derivatives according to the present invention inhibit the accumulation of HIF-1α that causes cancer, it can be usefully used as an active ingredient of an anticancer agent.

< Experimental Example  3> assessment of neovascularization inhibition

In order to determine the degree to which the deguelin derivatives according to the present invention inhibit VEGF (Vascular endothelial growth factor A), an experiment was performed to determine neovascularization using a transgenic striped fish (zebrafish).

Specifically, streaked fish embryos (Albino; Tg ( fli1 : EGFP ) ^{b4; y1} , Zebrafish International Resource Center, University of Oregon, Eugene) produced after paired stray fish were crossed at 28.5 ° C. (artificial sea salt 0.2 g / L in distilled water dissolved at a concentration of 6 hours. Ten embryonic striped fish embryos were cultured in groups of 1 to 500 μl in 24-well plates, and the deguelin derivatives of each example were treated at 50 nM, 250 nM and 1.25 μM. Amniotic fluid (including deguelin derivatives in each example) was replaced at 48 hours during the experiment. After 72 hours of incubation, angiogenesis was measured and photographed in subintestinal vessel plexus (SIV) of each embryo using a Leica DM5000B fluorescence microscope (Leica Microsystems, Wetzlar GmbH, Germany).

Figure 2 is a photograph showing the effect of compound 53 on neovascularization according to an embodiment of the present invention.

Figure 3 is a photograph showing the effect of compound 69 on neovascularization according to an embodiment of the present invention.

Figure 4 is a photograph showing the effect of compound 72 on neovascularization according to an embodiment of the present invention.

As shown in FIG. 2, FIG. 3 and FIG. 4, when the deguelin derivatives according to the present invention were treated, it was confirmed that the number of neovascularization was reduced in a concentration-dependent manner as compared with no treatment.

Therefore, since the deguelin derivatives according to the present invention have angiogenesis inhibitory activity, that is, inhibit the activity of VEGF, an angiogenesis factor, it can be used as an active ingredient of an anticancer agent.

Hereinafter, the preparation example using the composition of this invention is illustrated.

< Formulation example  1> Sanje  Produce

2 g of a compound of Formula 1 or Formula 2

1 g lactose

The above components were mixed and packed in airtight bags to prepare powders.

< Formulation example  2> Preparation of tablets

100 mg of compound of Formula 1 or Formula 2

Corn starch 100 mg

Lactose 100 mg

2 mg magnesium stearate

After mixing the above components, tablets were prepared by tableting according to a conventional tablet production method.

< Formulation example  3> Preparation of capsules

100 mg of compound of Formula 1 or Formula 2

Corn starch 100 mg

Lactose 100 mg

2 mg magnesium stearate

After mixing the above components, the capsule was prepared by filling in gelatin capsules according to the conventional method for producing a capsule.

< Formulation example  4> Preparation of injection solution

10 μg / ml of the compound of Formula 1 or Formula 2

Dilute hydrochloric acid BP until pH 3.5

Injectable sodium chloride BP up to 1 ml

Dissolve the compound of formula 1 or formula 2 according to the invention in an appropriate volume of sodium chloride BP for injection, adjust the pH of the resulting solution to pH 3.5 with dilute hydrochloric acid BP, and adjust the volume with sodium chloride BP for injection. Adjusted and mixed well. The solution was filled into a 5 ml Type I ampoule made of clear glass, encapsulated under an upper grid of air by dissolving the glass, and sterilized by autoclaving at 120 ° C. for at least 15 minutes to prepare an injection solution.

Claims (20)

A novel compound represented by formula (1) or a pharmaceutically acceptable salt thereof:
[Formula 1]

(In Formula 1,
R ¹ And R ² is independently -H, -OH, C ₁ to each other _{- 4} straight or branched chain alkyl, or C _{1 - 4} alkoxy;
R ³ is -H, -OH, = O, -OR ⁶ Or = NOR ⁷ ;
R ⁴ is -H, -OH, C _{1 - 4} alkoxy, phenyl acetate or methoxy;
R ⁵ is C _{1 - 6} straight or branched chain alkyl or alkenyl;
R ⁶ is C _{1 - 6} straight or branched chain alkyl or alkenyl, C _{5 - 8} aryl,

,

or

ego; And
R ⁷ is -H, C _{1 -4} straight or branched chain alkyl, or C _{5 - 8} is aryl.
In this case, R ⁴ and R ⁵ may be achieved for each heterocyclic ring containing 5-8 to each other in the O ring greater than or equal to 1, this ring is -OH or C _{1 - 2} alkyl group may be substituted with more than a 1.
Also,

Is a single bond or a double bond)
The compound of claim 1, wherein R ¹ and R ² are, independently from each other, -OH or -OMe;
R ³ is -H, -OH, = O, -OR ⁶ Or = NOR ⁷ ;
R ⁴ is -OH, C _{1 - 3} alkoxy, phenyl acetate or methoxy;
R ⁵ is C _{1 - 5} alkyl or linear or branched alkenyl;
R ⁶ is C _{1 - 3} linear or branched alkyl or alkenyl, C _{5 - 6} arylalkyl,

,

or

ego; And
R ⁷ is -H, C _{1 -3} straight or branched chain alkyl, or C _{5 - 6} is arylalkyl.
In this case, R ⁴ and R ⁵ may be achieved for each heterocyclic ring containing five or six to one another within the at least one O ring, the ring is -OH or C _{1 -,} characterized in that at least _two alkyl groups which may be substituted 1 Compound or a pharmaceutically acceptable salt thereof.
The compound of claim 1, wherein R ³ is —H, —OH, ═O, methoxy, ethoxy, propoxy, propenoxy, benzyloxy,

,

,

, = N-OH, = N-OMe or = N-OBn, or a pharmaceutically acceptable salt thereof.
2. The ring of claim 1, wherein R ^{4 together} with —OH, methoxy, propenoxy, benzyloxy, acetate or R ⁵ form a hexagonal heterocycle containing one O in the ring together; OH or C _{1 - 2} alkyl group is one or more compounds or pharmaceutically acceptable salts thereof, characterized in that which may be substituted.
The compound of claim 1, wherein R ⁵ is

Or R ⁴ together with R ⁴ to form a hexagonal heterocycle containing one O in the ring, wherein the ring may be substituted with one or more -OH or C _1-2 alkyl groups, or a pharmaceutically thereof Acceptable salts.
The method of claim 4, wherein the ring is

,

or

Compound or a pharmaceutically acceptable salt thereof.
The compound of claim 1, wherein
(6a S , 12a S ) -9-hydroxy-2,3-dimethoxy-8- (3-methyl-2-butenyl) -6a, 12a-dihydrochromeno [3,4- b ] chromen -12 ( 6H ) -on,
(7a S , 13a S ) -9-hydroxy-13,13a-dihydro-10-methoxy-3,3-dimethyl- 3H -chromeno [3,4- b ] pyrano [2,3- h ] chromen-7 (7a H ) -on,
(7a S , 13a S ) -10-hydroxy-13,13a-dihydro-9-methoxy-3,3-dimethyl- 3H -chromeno [3,4- b ] pyrano [2,3- h ] chromen-7 (7a H ) -on,
(7a S , 13a S ) -13,13a-dihydro-9,10-dihydroxy-3,3-dimethyl-3 H -chromeno [3,4- b ] pyrano [2,3- h ] Chromen-7 (7a H ) -on,
9,10-Dimethoxy-3,3-dimethyl -3 H - chroman Agate [3,4- b] pyrano [2,3- h] chromen -7- (13 H) - one,
(7 S, 7a R, 13a S) -9,10- dimethoxy-3,3-dimethyl -7,7a, 13,13a- tetrahydro -3 H - chroman Agate [3,4- b] pyrano [ 2,3- h ] chromen-7-ol,
(7a S , 13a S ) -9,10-dimethoxy-3,3-dimethyl-7,7a, 13,13a-tetrahydro-3 H -chromeno [3,4- b ] pyrano [2,3 h ] chromen,
(7 S, 7a R, 3a S) -7,9,10- -trimethoxy-3,3-dimethyl -7,7a, 13,13a- tetrahydro -3 H - chroman Agate [3,4- b] Pyrano [2,3- h ] chromen,
(7 S, 7a R, 3a S) to 9,10-dimethoxy-3,3-dimethyl-7-ethoxy -7,7a, 13,13a- tetrahydro -3 H - chroman Agate [3,4- b ] pyrano [2,3- h ] chromen,
(7 S, 7a R, 3a S) -9,10- dimethoxy-3,3-dimethyl-7-propoxy -7,7a, 13,13a- tetrahydro -3 H - chroman Agate [3,4- b ] pyrano [2,3- h ] chromen,
(7 S, 7a R, 3a S) -7- benzyloxy-9,10-dimethoxy-3,3-dimethyl -7,7a, 13,13a- tetrahydro -3 H - chroman Agate [3,4- b ] pyrano [2,3- h ] chromen,
(7 S , 7a S , 13a S ) -9,10-dimethoxy-3,3-dimethyl-7- (tetrahydro-2 H -pyran-2-yloxy) -7,7a, 13,13a-tetra Hydro- 3H -chromeno [3,4- b ] pyrano [2,3- h ] chromen,
(7 S , 7a S , 13a S ) -9,10-dimethoxy-3,3-dimethyl-7,7a, 13,13a-tetrahydro-3 H -chromeno [3,4- b ] pyrano [ 2,3, h ] chromen-7-yl acetate,
(7 S , 7a S , 13a S ) -9,10-dimethoxy-3,3-dimethyl-7,7a, 13,13a-tetrahydro-3 H -chromeno [3,4-b] pyrano [ 2,3- h ] chromen-7-yl carbamate,
(13a S ) -9,10-dimethoxy-3,3-dimethyl-13,13a-dihydro-3 H -chromeno [3,4- b ] pyrano [2,3- h ] chromen,
(7a R , 13a S ) -9,10-dimethoxy-3,3-dimethyl-13,13a-dihydro-3 H -chromeno [3,4- b ] pyrano [2,3- h ] chrome Men-7 (7a H ) -one oxime,
(7a R , 13a S ) -9,10-dimethoxy-3,3-dimethyl-13,13a-dihydro-3 H -chromeno [3,4- b ] pyrano [2,3- h ] chrome Mentioned -7 (7a H) - one O - methyl oxime,
(7a R , 13a S ) -9,10-dimethoxy-3,3-dimethyl-13,13a-dihydro-3 H -chromeno [3,4- b ] pyrano [2,3- h ] chrome Men-7 (7a H ) -on O -benzyloxime,
(7a S , 13a S ) -9,10-dimethoxy-3,3-dimethyl-2,3,13,13a-tetrahydro-1 H -chromeno [3,4- b ] pyrano [2,3 h ] chromen-7 (7a H ) -on,
(7a S , 13a S ) -1,2-dihydroxy-9,10-dimethoxy-3,3-dimethyl-2,3,13,13a-tetrahydro-1 H -chromeno [3,4- b ] pyrano [2,3- h ] chromen-7 (7a H ) -one,
2,3,9- trimethoxy-8- (3-methyl-boot-2-enyl) -6a, 12a- dihydro -6 H-chroman Agate [3,4- b] chromen -12- one,
9-aryloxy-2,3-dimethoxy-8- (3-methyl-boot-2-enyl) -6a, 12a- dihydro -6 H-chroman Agate [3,4- b] chromen -12- On,
9-benzyloxy-2,3-dimethoxy-8- (3-methyl-boot-2-enyl) -6a, 12a- dihydro -6 H-chroman Agate [3,4- b] chromen -12- On,
Acetic acid 2,3-dimethoxy-8- (3-methyl-but-2-enyl) -12-oxo-6,6a, 12,12a-tetrahydrochromeno [3,4- b ] chromen-9- One ester, and
(7 S, 7a R, 3a S) -9,10- dimethoxy-3,3-dimethyl-7- (prop-2-en-oxy) -7,7a, 13,13a- tetrahydro -3H- croissant A compound or a pharmaceutically acceptable salt thereof, wherein the compound is any one selected from the group consisting of meno [3,4- b ] pyrano [2,3- h ] chromen.
A novel compound represented by formula (2) or a pharmaceutically acceptable salt thereof:
(2)

(In the formula (2)
R ^a is

or

ego,
R ^b is -H, -OH or C _{1 - 3} alkoxy and,
R ^c and R ^d are each independently -H, C _{1 - 3} is straight or branched chain alkyl,
R ^e is independently -H or C ₁ to each other _- and the _3-alkoxy,
X is

, -NH-, or C _{1 - 3} alkyl or alkenyl, and
Y is -H, C _{1 - 3} alkyl or alkenyl,

,

,

,

,

,

, -NH-,

,

Or -SO ₂ Ph.
In this case, R ^a and R ^b may form a 5-8 hexaheterocycle containing one or more O in a ring, and at least one oxo or dimethoxyphenyl group may be substituted on the ring.
Also,

Is a single bond or a double bond)
The compound of claim 8, wherein R ^a is

or

ego,
R ^b is -H, -OH or C _{1 - 2} alkoxy and,
R ^c and R ^d are each independently -H, C _{1 -} a _divalent straight or branched chain alkyl,
R ^e is independently -H or C ₁ to each other _- and _two alkoxy,
X is

, -NH-, or C _{1 - 2} alkyl or alkenyl, and
Y is -H, C _{1 - 2} alkyl or alkenyl,

,

,

,

,

,

, -NH-,

,

Or -SO ₂ Ph.
Herein, R ^a and R ^b may form a 5-6 hexaheterocycle containing one or more O in a ring, and the ring may be substituted with one or more oxo or dimethoxyphenyl groups, or a compound thereof. Pharmaceutically acceptable salts.
The compound of claim 8, wherein R ^a is

,

,

,

,

,

,

,

,

Or R ^b and a six-membered heterocyclic ring containing one O in the ring, wherein each ring is substituted with one oxo and dimethoxyphenyl group, or a pharmaceutically acceptable salt thereof.
9. A compound according to claim 8, wherein R ^b forms a hexagonal heterocycle containing -H, -OH, methoxy or R ^a with one O in the ring, in which each oxo and dimethoxyphenyl group is substituted. Or a pharmaceutically acceptable salt thereof.
The method of claim 10, wherein the ring is

or

Compound or a pharmaceutically acceptable salt thereof.
The compound of claim 8, wherein
(3 S) -3- (3,4- dimethoxy-phenyl) -8,8- dimethyl-2,3-dihydro -4 H, 8 H - pyrano [2,3- f] chromene-4 On,
(6,7-dimethoxychroman-4-yl) (2,2-dimethyl- 2H -chromen-6-yl)
2- (3,4-dimethoxyphenyl) -1- (2,2-dimethyl- 2H -chromen-6-yl) ethanone,
2- (3,4-dimethoxyphenyl) -1- (5-methoxy-2,2-dimethyl- 2H -chromen-6-yl) ethanone,
2- (3,4-dimethoxyphenyl-1- (5-methoxy-2,2-dimethyl- 2H -chromen-6-yl) propan-1-one
2- (3,4-dimethoxyphenyl) -1- (5-methoxy-2,2-dimethyl- 2H -chromen-6-yl) -2-methylpropan-1-one,
2- (3,4-dimethoxyphenyl) -1- (5-methoxy-2,2-dimethyl- 2H -chromen-6-yl) prop-2-en-1-one,
1- (3,4-dimethoxyphenyl) cyclopropyl) (5-methoxy-2,2-dimethyl- 2H -chromen-6-yl) methanone,
( S ) -2- (3,4-dimethoxyphenyl) -1- (5-methoxy-2,2-dimethyl- 2H -chromen-6-yl) propan-1-one,
( R ) -2- (3,4-dimethoxyphenyl) -1- (5-methoxy-2,2-dimethyl- 2H -chromen-6-yl) propan-1-one,
3- (3,4-dimethoxyphenyl) -8,8- dimethyl -4 H, 8 H - pyrano [2,3- f] chromene-4-one,
6,7-dimethoxy- 2H -chromen-4-yl (2,2-dimethyl- 2H -chromen-6-yl) methanone,
6,7-dimethoxy-2,2-dimethyl- 2H -chromen-4-yl) (4-methoxy-2,2-dimethyl- 2H -chromen-6-yl) methanone,
6,7-dimethoxy-2,2-dimethyl- 2H -chromen-4-yl) (2,2-dimethyl- 2H -chromen-6-yl) methanone,
6,7-dimethoxy- 2H -chromen-4-yl) (4-methoxy-2,2-dimethyl- 2H -chromen-6-yl) methanone,
2- (3,4-dimethoxyphenyl) -1- (5-hydroxy-2,2-dimethyl- 2H -chromen-6-yl) -2- (phenylsulfonyl) ethanone,
(3,4-dimethoxyphenyl) (2,2-dimethyl- 2H -chromen-6-yl) methanone,
( E ) -1- (3,4-dimethoxyphenyl) -3- (2,2-dimethyl- 2H -chromen-6-yl) prop-2-en-1-one,
( E ) -3- (3,4-dimethoxyphenyl) -1- (5-hydroxy-2,2-dimethyl- 2H -chromen-6-yl) prop-2-en-1-one,
( E ) -3- (3,4-dimethoxyphenyl) -1- (2,2-dimethyl- 2H -chromen-6-yl) prop-2-en-1-one,
( E ) -1- (5-hydroxy-2,2-dimethyl- 2H -chromen-6-yl) -3- (2,4,5-trimethoxyphenyl) prop-2-ene-1 -On,
( E ) -3- (3,4-dimethoxyphenyl) -1- (5-methoxy-2,2-dimethyl- 2H -chromen-6-yl) prop-2-en-1-one,
( E ) -1- (5-methoxy-2,2-dimethyl-2H-chromen-6-yl) -3- (2,4,5-trimethoxyphenyl) prop-2-ene-1- On,
2- (3,4-dimethoxy-phenyl) -8,8- dimethyl -4 H, 8 H - pyrano [2,3- f] chromene-4-one,
2- (3,4-dimethoxyphenyl) - N - (5- methoxy-2,2-dimethyl -2 H-chromen-6-yl) acetamido-amide,
N- (3,4-dimethoxybenzyl) -2,2-dimethyl- 2H -chromen-6-carboxamide,
N- (3,4-dimethoxyphenyl) -2,2-dimethyl- 2H -chromen-6-carboxamide,
N- (2,2-dimethyl- 2H -chromen-6-yl) -3,4-dimethoxybenzamide,
( R ) -2- (3,4-dimethoxyphenyl) -1- (2,2-dimethyl- 2H -chromen-6-yl) propan-1-one,
( S ) -2- (3,4-dimethoxyphenyl) -1- (2,2-dimethyl- 2H -chromen-6-yl) propan-1-one which is any one selected from the group consisting of Characterized by a compound or a pharmaceutically acceptable salt thereof.
The pharmaceutical composition for preventing or treating cancer according to claim 1, which contains the compound as an active ingredient.
15. The method of claim 14, wherein the cancer is a solid cancer with a high accumulation of Hsp90 protein colon cancer, liver cancer, stomach cancer, breast cancer, colon cancer, bone cancer, pancreatic cancer, head or neck cancer, uterine cancer, ovarian cancer, rectal cancer, esophageal cancer, small intestine cancer, anal It consists of nearby cancer, colon cancer, fallopian tube carcinoma, endometrial carcinoma, cervical carcinoma, vaginal carcinoma, vulvar carcinoma, Hodgkin's disease, prostate cancer, bladder cancer, kidney cancer, ureter cancer, renal cell carcinoma, renal pelvic carcinoma and central nervous system tumor. A pharmaceutical composition for preventing or treating cancer, which is selected from the group.
The pharmaceutical composition for preventing or treating cancer of claim 14, wherein the composition exhibits anticancer activity by inhibiting Hsp90.
A pharmaceutical composition for preventing or treating diabetic retinopathy, comprising the compound of claim 1 as an active ingredient.
The pharmaceutical composition for preventing or treating diabetic retinopathy of claim 17, wherein the composition inhibits the accumulation of HIF-1α and the expression of VEGF protein to inhibit the generation of neovascularization.
A pharmaceutical composition for preventing or treating rheumatoid arthritis, comprising the compound of claim 1 as an active ingredient.
The pharmaceutical composition for preventing or treating rheumatoid arthritis according to claim 19, wherein the composition inhibits the accumulation of HIF-1α and the expression of VEGF protein to inhibit the generation of neovascularization.

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