KR101269097B1 - A novel Deguelin derivatives or its pharmaceutically acceptable salts and pharmaceutical composition containing the same as an active ingredient - Google Patents

Abstract

The present invention relates to a compound inhibiting HIF-1 activity and a pharmaceutical composition containing the same as an active ingredient. The compound according to the present invention does not exhibit anticancer activity by non-selective cytotoxicity, but selectively inhibits the accumulation of HIF-1α protein and effectively inhibits the activity of a neovascularization factor (VEGF), and thus the anticancer agent, diabetic retinopathy And arthritis therapeutic agents.

Description

[0001] The present invention relates to a novel degenerative derivative or a pharmaceutically acceptable salt thereof and a pharmaceutical composition containing the same as an active ingredient,

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

Molecular chaperones, such as heat-shock protein families (HSPs), modulate the folding of the client protein through ATP-dependent structural changes, thereby activating nascent proteins and helping to refold or break down damaged proteins It is a protein. In addition, the client protein avoids aggregation through association with molecular chaperons, and their binding facilitates intracellular deposition through membrane translocation of the client protein.

The molecular chaperone function of Hsp90, one of the heat shock protein families, is known to be required for stability and activation of various client proteins involved in the signal transduction pathway of the cell. Under normal conditions without external stimulation, the amount of Hsp90 is 1-2% of the intracellular protein, but the amount of Hsp90 is doubled under the condition of external stimulation. Cancer-induced mutations in the client protein require higher levels of Hsp90 function and lead to overexpression of Hsp90, and Hsp90 over-expressed 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, mitogen-activated protein kinase kinase, Akt, Raf-1, cyclin-dependent serine kinases, steroid hormone receptor, telomerase, The Hsp90 client proteins, including metalloprotein-2 (MMP-2) and HIF-1α (hypoxia-inducible factor-1α), are involved in a variety of signaling pathways including cell survival, proliferation, invasion, metastasis, And contribute to malignant phenotype [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 is a subunit that constitutes HIF (hypoxia-inducible factor) together with HIF-1β, and is an oxygen-unstable transcription factor and the expression of VEGF (vascular endothelial growth factor), a neovascularization- Induces angiogenesis in terms of vascular disruption and vascular dysfunction. Neovascularization is the process of creating new blood vessels and is necessary for the repair, regeneration, and development of blood vessels or metabolically activated tissues.

However, pathological neovascularization not only plays an important role in the growth and spread of cancer through metastasis, but also induces bleeding, vascular leakage and tissue destruction due to abnormally high rates of neovascularization. As a result, pathological neovascularization is known to be associated with not only cancer but also various neovascularization-dependent diseases including diabetic retinopathy and senile AMD, and chronic infectious diseases such as psoriasis and rheumatoid arthritis.

Thus, inhibition of Hsp90 can be considered as a new and effective treatment for neovascularization-related diseases, and Hsp90 inhibitors are potential chemotherapeutic agents for neovascularization-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 against 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, including a unique structural motif, also known as the Bergerat fold, which allows Hsp90 to be different from Hsp70 or other kinases ATP-binding region. This structural specificity suggests the possibility of developing highly selective Hsp90 inhibitors, and several Hsp90 inhibitors as shown below are known.

( 3 ), a more stable oxime derivative, and a synthetic derivative, PU3 ( 4 ), which is a less toxic derivative of geldanamycin ( 2 ) and 17-AAG (17-arylamino-17-dimethoxy geldanamycin) ), Are known to interact with the ATP-binding pocket of the N-terminal region of Hsp90, while nobiobiosin ( 5 ), an antibiotic natural product known as an inhibitor of DNA gyrase, Interacts with the ATP-binding pocket of the C-terminal region and thus exhibits an effective Hsp90 inhibitory effect. These Hsp90 inhibitors have shown a significant chemoprevention effect in preclinical models of various cancer cell lines by promoting the degradation of various cancer-causing Hsp90 client proteins. In addition, some Hsp90 inhibitors, including 17-AAG, entered the clinical phase.

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

Although the potential for denguellin as an anticancer drug or angiogenesis inhibitor has been identified in an efficacious manner, toxicity, low solubility, and chemical instability show limitations as a drug of degueline.

Thus, the present inventors synthesized derivatives having low toxicity and improved physicochemical properties while maintaining the activity of deguanelin based on the three-dimensional structure of deguelin, and confirmed the Hsp90 inhibitory effect of these novel degulanin derivatives And completed the present invention.

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

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

Still another object of the present invention is to provide a pharmaceutical composition for treating diabetic retinopathy comprising the novel compound as an active ingredient.

Another object of the present invention is to provide a pharmaceutical composition for the treatment of 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]

(Wherein 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]

(Wherein R & lt ^{; a} & gt ^; and R < ^b & gt ^; 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 the prevention or treatment of diabetic retinopathy comprising the compounds of Formulas (1) and (2) or a pharmaceutically acceptable salt thereof as an active ingredient.

Further, the present invention provides a pharmaceutical composition for preventing or treating rheumatoid arthritis, which comprises the compound of Chemical Formulas 1 and 2 or a pharmaceutically acceptable salt thereof as an active ingredient.

The compounds of formulas (1) and (2) according to the present invention inhibit Hsp90 expression and inhibit the accumulation of HSP90 protein, HSP90, and effectively inhibit the activity of angiogenic factor (VEGF) And arthritis therapeutic agents.

1 is a Western blot diagram showing the degree to which compounds according to one embodiment of the present invention inhibit HIF-1 alpha accumulation.
FIG. 2 is a photograph showing the effect of Compound 53 according to an embodiment of the present invention on the angiogenesis.
FIG. 3 is a photograph showing the effect of Compound 69 according to an embodiment of the present invention on angiogenesis.
FIG. 4 is a photograph showing the effect of Compound 72 according to an embodiment of the present invention on angiogenesis.

Hereinafter, the present invention will be described in detail.

The present invention provides a novel degulerine derivative represented by the following general formula (I) 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,

Wherein R ¹ and R ² are 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} The alkyl group may be substituted by 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 wherein said 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- dihydro-chroman Agate [3,4- b] chromen -12 ( 6H ) -one,

(7a S, 13a S) -9- hydroxy -13,13a--dihydro-10-methoxy-3,3-dimethyl -3 H - chroman Agate [3,4- b] pyrano [2,3- h] chromene -7 (7a H) - one,

(7a S, 13a S) -10- hydroxy -13,13a--dihydro-9-methoxy-3,3-dimethyl -3 H - chroman Agate [3,4- b] pyrano [2,3- h] chromene -7 (7a H) - one,

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

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 - chroman Agate [3,4- b] pyrano [2,3- - h ] chromene,

(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 ] chromene,

(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-ilrok City) -7,7a, 13,13a- tetrahydro Hydro- 3H -chromeno [3,4- b ] pyrano [2,3- h ]

(7 S, 7a S, 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-yl acetate,

(7 S, 7a S, 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-yl carbamate,

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

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

(7a R, 13a S) -9,10- dimethoxy-3,3-dimethyl-dihydro -13,13a- -3 H - chroman Agate [3,4- b] pyrano [2,3- h] chroman (7aH) -one < / RTI > O -methyloxime,

(7a R, 13a S) -9,10- dimethoxy-3,3-dimethyl-dihydro -13,13a- -3 H - chroman Agate [3,4- b] pyrano [2,3- h] chroman (7aH) -one < / RTI > O -benzyloxime,

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

(7a S, 13a S) -1,2- dihydroxy-9,10-dimethoxy-3,3-dimethyl-tetrahydro--2,3,13,13a- -1 H - chroman Agate [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,

(3-methyl-but-2-enyl) -12-oxo-6,6a, 12,12a-tetrahydrochromeno [3,4- b ] chromen-9- Yl 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 Methano [3,4- b ] pyrano [2,3- h ] chromene.

The present invention also provides a compound represented by the following general 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 a -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,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,

, -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 a -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,Wherein R ^a is

,

,

,

,

,

,

,

,

Or R < ^b & gt ^; and a heterocyclic ring containing one O in the ring, each of which may be substituted with one or two oxo and dimethoxyphenyl groups,

R ^b forms a 6-membered heterocyclic ring containing one O in the ring to each other with -H, -OH, methoxy or R ^a , in which one oxo and one 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)

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

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

Methoxy-2,2-dimethyl- 2H -chromen-6-yl) -2-methylpropan-1-

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

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

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

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

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-

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

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

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

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

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

( E ) -3- (3,4-dimethoxyphenyl) -1- (5-hydroxy-2,2-dimethyl- 2H -chromen-

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

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

( E ) -3- (3,4-dimethoxyphenyl) -1- (5-methoxy-2,2-dimethyl- 2H -chromen-

( E ) -1- (5-methoxy-2,2-dimethyl-2H-chromen-6-yl) -3- (2,4,5-trimethoxyphenyl) 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 -chromene-6-carboxamide,

N- (3,4-dimethoxyphenyl) -2,2-dimethyl- 2H -chromene-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-

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

Specific examples of the novel degenerate derivatives of formulas (1) and (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 as salts, acid addition salts formed by pharmaceutically acceptable free acids are useful . 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 salt according to the present invention can be obtained by a conventional method, for example, by dissolving the novel compound represented by the general formula (1) and the general formula (2) in an excess amount of an aqueous acid solution and then dissolving the salt in a water-miscible organic solvent such as methanol, , ≪ / RTI > acetone or acetonitrile. It is also possible to prepare the same by heating an acid or an alcohol in water and a novel compound represented by the general formula (1) and (2), followed by evaporating and drying the mixture, or by suction filtration of the precipitated salt.

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 preferable for the metal salt to produce sodium, potassium or calcium 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 degulanin 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], but the present invention is not limited thereto. In addition to the known method, a known method can be used as long as it can synthesize the novel degulanin derivative .

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

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

The compounds of formulas (1) and (2) or pharmaceutically acceptable salts thereof according to the present invention inhibit the expression of Hsp90 and inhibit the accumulation of Hsp90 protein, the Hsp90 client protein, and effectively inhibit the activity of the angiogenic factor (VEGF) . The HIF-1 alpha activity inhibition includes all of a series of phenomena that inhibit HIF-1 alpha protein accumulation inhibition or expression of HIF-1 alpha target gene protein.

As a result of the inhibition of HIF-1α accumulation by the compounds of the formulas (1) and (2) according to the present invention, the compounds according to the present invention can inhibit the formation of Tublin, a hypoxic condition, -1α accumulation. In particular, compound 14 of Example 6 according to the invention show that the HIF-1α accumulation inhibitory IC ₅₀ values than the conventional material degu Elin (Deguelin) outstanding at least about 10-fold (see Table 2 and Figure 1).

In addition, the compounds of formula (I) and (II) according to the present invention are useful for the growth and cancer of cancer, which are known to contribute to the proliferation and metastasis of cancer among HIF-1α target genes Dependent inhibition of the expression of VEGF (Vascular Endothelial Growth Factor A), a neovascularization factor (see FIGS. 2 to 4).

Therefore, the compounds of formula (I) and (II) of the present invention inhibit Hsp90 expression and inhibit the accumulation of HSP90 protein, which is a Hsp90 client protein, and effectively inhibit the activity of angiogenic factor (VEGF) Cancer of the stomach, cancer of the stomach, cancer of the stomach, cancer of the stomach, cancer of the stomach, cancer of the stomach, breast cancer, colon cancer, bone cancer, pancreatic cancer, head or neck cancer, uterine cancer, ovarian cancer, rectum cancer, Can be used as various cancer treatment agents such as Hodgkin's disease, prostate cancer, bladder cancer, kidney cancer, ureter cancer, kidney cell carcinoma, kidney pelvic carcinoma and central nervous system tumor.

Further, the present invention provides a pharmaceutical composition which shows a therapeutic effect on diabetic retinopathy or arthritis through inhibition of Hsp90 containing the compounds of the above-mentioned formulas (1) and (2) or a pharmaceutically acceptable salt thereof as an active ingredient.

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

The compounds of formula (I) and formula (II) of the present invention showed excellent inhibitory effects on angiogenesis of Zebrafish embryos (see FIGS. 2 to 4).

Therefore, it is possible to selectively inhibit the expression of VEGF (Vascular endothelial growth factor A), which is an angiogenic factor, so that the expression of VEGF by HIF-1α is increased in a hypoxic state and the active ingredient of a therapeutic agent for diabetic retinopathy or arthritis .

The pharmaceutical composition of the present invention can be formulated into various oral or parenteral dosage forms. Examples of the formulations for oral administration include tablets, pills, light / soft capsules, liquids, suspensions, emulsions, syrups, granules and elixirs. These formulations may contain, in addition to the active ingredient, a diluent (e.g., lactose, dextrose, (E.g., silica, talc, stearic acid and magnesium or calcium salts thereof and / or polyethylene glycols), such as, for example, water, rosin, sucrose, mannitol, sorbitol, cellulose and / or glycine. 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.

The pharmaceutical composition comprising the compounds of formulas (1) and (2) according to the present invention as an active ingredient can be administered parenterally, and parenteral administration is by subcutaneous injection, intravenous injection, intramuscular injection, . In order to formulate the composition for parenteral administration, the compound of Chemical Formulas 1 and 2 or a pharmaceutically acceptable salt thereof may be mixed with water or a stabilizer or a buffer to prepare a solution or suspension, which is then administered in an ampule or vial Can be manufactured. 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 the active ingredient, the compounds of the formulas (1) and (2) are administered once or divided once a day in an amount of 0.1 to 500 mg / kg (body weight), preferably 0.5 to 100 mg / Oral or parenteral route.

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 eq) and anhydrous DMF (catalytic) were dissolved in anhydrous CH ₂ Cl ₂ (0.1 M), cooled to 0 ° C and oxalic acid (3 eq.) Was added dropwise. After stirring at room temperature for 30 minutes, methanol (50 eq.) Was added dropwise and stirred for 10 minutes. Next, the mixture was treated with water, the aqueous layer was extracted with CH ₂ Cl ₂ , the organic layer was dried with MgSO ₄ , filtered, and concentrated under reduced pressure. The resulting residue was purified by flash column chromatography (EtOAc: n-hexane = 3) to obtain Compound (32).

(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 a 2N aqueous hydrochloric acid solution while stirring, poured into water and extracted with EtOAc (x3). The organic layer was washed with a saturated brine solution once, dried with MgSO _4, filtered, and the residue obtained by concentration under reduced pressure, silica gel eluted chromatography (EtOAc: n - hexane = 1: 1) to give a pale aldol product Obtained as a yellow solid (yield: 58%, 331 mg).

¹ H NMR (CDCl _3, 3H), 3.79 (s, 3H), 3.73 (m, 2H), 3.65 (s, 3H)

The aldol product (36 mg, 0.15 mmol) in dry CH ₂ Cl ₂ (1.0 mL) solution of the p obtained in-acetamido-dating-methoxybenzyl 2,2,2-trichloroethane (84 mg, 0.30 mmol) and The catalytic amount of CSA was added at room temperature. The reaction mixture was stirred under an argon atmosphere overnight and filtered, and the remaining filter cake was washed with CH ₂ Cl ₂ . The liquid filtered above was extracted with saturated NaHCO ₃ solution and brine. The organic layer is dried over MgSO _4, filtered, and the residue obtained by evaporation was purified by flash column chromatography (EtOAc: n- hexane = 1: 3) to obtain the compound 33 in Preparation Example 2 as a white solid (yield: 100 %, 54 mg).

¹ H NMR (CDCl _3, 500MHz) δ7.19 (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), 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

The compound 33 (20 mg, 0.055 mmol) obtained in Preparative Example 2 was dissolved in anhydrous THF (1.0 mL), treated with methanol (0.06 mmol, 1.1 eq.) And then cooled to -78 ° C. DIBAL- 0.16 mmol) was added slowly. The reaction mixture was monitored by TLC and stirred at -78 [deg.] C until the reaction was complete. An aqueous solution of Rochelle was carefully added for 15 minutes and the mixture of both layers was stirred vigorously at 0 &lt; 0 &gt; C for 1 hour and then poured into water. Give the aqueous layer was extracted with EtOAc (× 2), and extract the organic layer with anhydrous NaSO _4, filtered and the residue obtained by concentration under reduced pressure was purified by flash column chromatography (1 EtOAc: n- hexane = 1: 4 1) To obtain a primary alcohol. (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 ferriydan (2.0 eq.) Was added to a CH ₂ Cl ₂ (0.03 M) solution containing the above-obtained primary alcohol (1.0 eq.), Stirred for 1 hour, The mixture was diluted with CH ₂ Cl ₂ and sodium thiosulfate (10%) was added. The mixture was stirred at room temperature for 10 minutes until separated into two layers. The organic layer obtained above was washed with saturated aqueous NaHCO ₃ solution, dried over MgSO ₄ , filtered and concentrated under reduced pressure to give a residue which was purified by flash column chromatography (EtOAc: n-hexane = 1: 3) Compound 34 of Example 3 was obtained (Yield 71%, 11 mg).

¹ H NMR (CDCl _3, 300MHz) 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 - Kromen -6-yl) -3- (4-meth Oxybenzyl jade Propane-1-one (( S ) -2- (3,4- Dimethoxyphenyl ) -1- (5- 메틸oxy -2,2-dimethyl-2 H -chromen-6-yl) -3- (4-methoxybenzyl oxy ) propane -One- one Manufacture of 35

N- BuLi (1.4 eq.) Was added dropwise at -78 [deg.] C to an anhydrous THF solution containing aryl bromide (1.5 eq.) And stirred at -78 [deg.] C to generate the aryl anion. After stirring at -78 占 폚 for 20 minutes, aldehyde (1.0 eq.) Was added and stirring was continued for 30 minutes at room temperature. The reaction mixture was treated with a saturated aqueous NH ₄ Cl solution and extracted with EtOAc. The extract was washed with brine, dried over MgSO4 and the solvent was evaporated. 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 & lt ^; + & gt ^; ): 543.2359, Found: 543.2365.

Dess-Martin ferriydan (3.0 eq.) Was added to a CH ₂ Cl ₂ (0.03 M) solution containing the above-obtained secondary alcohol (1.0 eq.), Stirred for 1 hour, The mixture was diluted with CH ₂ Cl ₂ and sodium thiosulfate (10%) was added. The mixture was stirred at room temperature for 10 minutes until separated into two layers. The organic layer obtained above was washed with saturated aqueous NaHCO ₃ solution, dried over MgSO ₄ , filtered and concentrated under reduced pressure to give a residue which was purified by flash column chromatography (EtOAc: n-hexane = 1: 3) 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, 6H); HRMS (FAB) Calcd for C ₃₁ H ₃₄ O 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)

Compound 35 (23 mg, 0.044 mmol) obtained in Preparative Example 4 and CH ₂ Cl ₂ (1.0 mL) were added to a 10 mL round-bottomed flask, followed by heating and drying. The solution was cooled to -78 ℃, was added boron trichloride (0.16 mL, 0.16 mmol, 1.0 M solution in CH ₂ Cl _2). After stirring for an hour, cool the reaction with saturated NH ₄ Cl aqueous solution and extracted with CH Wh Cl _2, dried with MgSO _4, the residue obtained by concentration under reduced pressure was purified by flash column chromatography (EtOAc: n- hexane = 1 : 2) to obtain Compound 36 of Production Example 5 as a pale yellow solid (yield: 75%, 12 mg).

HRMS (FAB) Calcd for C ₂₂ H ₂₄ O ₆ (M + H & lt ^; + & gt ^; ): 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 a solution of anhydrous THF (12.0 mL) 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 concentrated under reduced pressure. The resulting residue was purified by flash column chromatography (EtOAc: n-hexane = 1: 3) Compound 38 of Example 6 was obtained as a pale yellow solid (96% yield, 660 mg).

_{^{1 H NMR (CDCl 3, 300MHz}} ) δ6.96 (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 Preparative Example 6 was dissolved in anhydrous 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 and stirred for 1 hour and warmed to -40 &lt; 0 &gt; C. The mixture was treated with a saturated aqueous NH ₄ Cl solution (5.0 mL) and poured into water (5.0 mL). The aqueous layer was extracted with EtOAc (2 x 15 mL) and the organic layer was dried over MgSO ₄ , filtered and concentrated under reduced pressure to give a residue which was purified 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 Preparative Example 7 was dissolved in anhydrous THF (2.0 mL) and cooled to 0 占 폚. 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 the two phases was stirred vigorously at 0 &lt; 0 &gt; C for 1 hour and then poured into water. The aqueous layer was extracted with EtOAc (× 2), and the organic layer was dried with NaSO _4, filtered, and the residue obtained by concentration under reduced pressure was purified by flash column chromatography (EtOAc: n- hexane = 1: 6) to give the primary alcohol (Yield: 88%).

^{_{1 H NMR (CDCl 3, 500zMHz}} ) 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).

Sodium hydride (64 mg, 1.59 mmol, 60% in mineral oil) was added to a solution of the primary alcohol (400 mg, 1.33 mmol) in anhydrous THF (7.0 mL) at 0 ° C and the mixture was stirred at room temperature for 30 minutes. Tetrabutylammonium 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), extracted with EtOAc (10 mL x 2), washed with brine, dried over MgSO ₄ , filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography Purification by chromatography (EtOAc: n-hexane = 1: 8) afforded the 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 the compound 40 (252 mg, 0.64 mmol) obtained in Preparation Example 8 and dissolved in a solution of acetone: water (4: 1, 25 mL) at 0 ° C. To this mixture was added OsO ₄ (0.32 mL, 0.032 mmol, 0.1 M solution in toluene) and stirred at ambient temperature for 6 h, then extracted with EtOAc (3 x 15 mL), washed with saturated sodium sulfate solution, The crude product obtained by drying with MgSO ₄ and removing the solvent under reduced pressure was dissolved in a solution of acetone: water (4: 1, 25 mL), stirred at room temperature and then NaIO ₄ (413 mg, 1.93 mmol) . The mixture was stirred at room temperature for 30 minutes, extracted with EtOAc (3 x 15 mL), washed with saturated sodium thiosulfate solution, and solvent removed under reduced pressure to give the crude aldehyde. The crude aldehyde was used in the next step without further purification.

Sodium borohydride (49 mg, 1.29 mmol) was added to methanol (6.0 mL) containing the crude aldehyde (0.64 mmol) obtained above at -100 ° C and the temperature was maintained for 1 hour. The mixture was cooled with a saturated aqueous NH ₄ Cl solution, extracted with EtOAc, dried over MgSO ₄ , concentrated under reduced pressure and the resulting residue was purified by flash column chromatography (EtOAc: n-hexane = 1: 1) 9 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

Pd ₂ (dba) ₃ (13 mg, 0.0143 mmol) and 2- (di-tert-butyloxycarbonylmethyl) piperazine (41 mg, 0.96 mmol) obtained in Preparation Example 9 and sodium t- t -butylphosphino) biphenyl (7.0 mg, 0.024 mmol) in toluene (10 mL). The reaction was heated to 50-55 ° C overnight, cooled to room temperature, diluted with EtOAc (10 mL), filtered through celite, and the solvent removed under reduced pressure to give a crude yellow crude product which was purified by flash column chromatography Purification by flash chromatography (EtOAc: n-hexane = 1: 6) afforded the 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)

A mixture of the compound 42 (191 mg, 0.61 mmol) obtained in Preparation 10 and methanol (5 mL) containing 20% Pd (OH) ₂ / C (38 mg) was stirred under a hydrogen atmosphere at room temperature for 5 hours. The mixture was filtered through celite, washed with methanol (10 mL) and evaporated under reduced pressure to give a residue which was purified by flash column chromatography (EtOAc: n-hexane = 1: 1) (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 , &Lt; / RTI &gt; 1H), 1.98 (m, 2H); LRMS (FAB) m / z 225 (M + H ^& lt ^{; +} & gt ^; ).

Dess-Martin ferriydan (3.0 eq.) Was added to a CH ₂ Cl ₂ (0.03 M) solution containing the above primary alcohol (1.0 eq) obtained above and stirred for 1 hour, Was diluted with CH ₂ Cl ₂ and sodium thiosulfate (10%) was added. The mixture was stirred at room temperature for 10 minutes until separated into two layers. The organic layer obtained above was washed with saturated aqueous NaHCO ₃ solution, dried over MgSO ₄ , filtered and concentrated under reduced pressure to give a residue which was purified by flash column chromatography (EtOAc: n-hexane = 1: 2) 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 - Kromen -6-yl) methanol ((6,7-Dimethoxychroman-4-yl) (2,2-dimethyl-2 H Preparation of -chromen-6-yl) methanol (44)

To a solution of 6-bromo-2,2-dimethyl- 2H -chromene (1.5 eq.) In anhydrous THF was added n- BuLi (1.4 eq.) Dropwise at -78 ° C and stirred at -78 ° C Aryl anion. After stirring at -78 占 폚 for 20 minutes, Compound 43 (1.0 equivalent) obtained in Preparative Example 11 was added and stirring was continued for 30 minutes so that the reaction temperature became room temperature. The reaction mixture was treated with a saturated aqueous NH ₄ Cl solution and extracted with EtOAc. Washing the extract with brine, dried over MgSO ₄ and the residue obtained by evaporating the solvent was purified by flash column chromatography (EtOAc: n- hexane = 1: 4) to obtain the compound 44 in Preparation Example 12 (yield: 75 %, 18 mg).

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

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

A solution of anhydrous diethyl ether containing methyl 3 ', 4'-dimethoxyphenylacetate (1.94 g, 9.24 mmol) was stirred and DIBAL-H (11.1 mL, 1 M solution in THF) Was added dropwise and stirred at the same temperature for 1 hour. An aqueous Rochelle solution was carefully added for 15 minutes and the mixture was stirred vigorously at 0 &lt; 0 &gt; C for 1 hour and then poured into water. The aqueous layer was extracted with EtOAc (× 2), dried the organic layer with MgSO _4, filtered, and the residue obtained by concentration under reduced pressure was purified by flash column chromatography (EtOAc: n- hexane = 1: 2) to give Preparation 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 a solution of methyl 3 ', 4'-dimethoxyphenylacetate (4.76 g, 22.63 mmol) in anhydrous THF (5 mL) was added LDA (18.1 mL, 36.21 mmol, 2 M solution in THF) Was added dropwise and the mixture was stirred at the same temperature for 30 minutes. Methyl iodide (2.82 mL, 45.26 mmol) was then added and the mixture was stirred for 1 h. The reaction mixture was acidified by the addition of 2 N HCl aqueous solution and extracted with EtOAc. The organic layer was washed with brine, dried with MgSO _4, the residue obtained by concentration under reduced pressure, silica gel column chromatography (EtOAc: n - hexane = 1: 4) to give a colorless compound 55 in Preparation 14 five days (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, 1 H, J = 7.1 Hz); ¹³ C NMR (CDCl ₃ , 125 MHz)? 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 (x2) and the organic layer was basified with aqueous 2N-NaOH solution. The aqueous layer was acidified with aqueous 2N-HCl and extracted with EtOAc (x2) and the organic layer was washed with brine. The organic layer was dried over MgSO ₄ and concentrated under reduced pressure to give the product of Preparation 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- 피닐 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). Finally, (230 mg, 1.47 mmol). Finally, diisopropylethylamine (0.26 mL, 1.47 mmol) was added dropwise at 0 &lt; 0 &gt; C. The reaction mixture was stirred at room temperature overnight, the reaction was quenched with a 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 to give a residue which was purified by flash column chromatography (EtOAc: CH ₂ Cl ₂ : n - hexane = 3: 2: 1) (Yield 42%, 187 mg) and compound 66 (yield 42%, 186 mg) of Preparation 16 were obtained as a pale yellow solid.

( S ) -diastereomer (65) : ^{_{1 H NMR (CDCl 3, 300}} MHz) δ7.26 (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), 1H, J = 7.1 Hz), 1.46 (d, 3H, J = 5.0 Hz), 3.96 (s, 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

A solution of sulfonic acid (5.0 mL, 4.0 M in water) was slowly added to a solution of compound 65 (186 mg, 0.56 mmol) obtained in Preparation 16 in 1,4-dioxane (5.0 mL) at 0 ° C. The reaction mixture was refluxed for 2 hours, cooled to room temperature and diluted with EtOAc, the organic layer was washed with water, dried with 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) containing the compound 67 (115 mg, 0.55 mmol) obtained in Preparation 17 was cooled to 0 ° C and a solution of BH ₃ · SMe ₂ complex (1.5 mL, 3.00 mmol) . The solution was stirred at 0 &lt; 0 &gt; C for 1 hour and then at room temperature for 3 hours. Water was added dropwise to the reaction mixture at 0 ° C to terminate the reaction. When hydrogen gas bubbles were no longer observed, a 2N-NaOH aqueous solution was added dropwise. The aqueous layer was extracted with ether (× 2), washed the ether layer with brine, dried with MgSO _4, filtered, and the residue obtained by concentration under reduced pressure was purified by flash column chromatography (EtOAc: n- hexane = 1: 2) To give 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 ferriydan (3.0 eq.) Was added to a CH ₂ Cl ₂ (0.03 M) solution containing the above primary alcohol (1.0 eq.) Obtained above. After stirring for 1 hour, The mixture was diluted with CH ₂ Cl ₂ and sodium thiosulfate (10%) was added. The mixture was stirred at room temperature for 10 minutes until separated into two layers. The organic layer obtained above was washed with saturated aqueous NaHCO ₃ solution, dried over MgSO ₄ , filtered and concentrated under reduced pressure to give a residue which was purified by flash column chromatography (EtOAc: n-hexane = 1: 3) (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

Sulfonic acid aqueous solution (5.6 mL, 4.0 M in water) was slowly added to a solution of compound 66 (217 mg, 0.66 mmol) obtained in Preparation 17 in 1,4-dioxane (5.6 mL) at 0 ° C. The reaction mixture was refluxed for 2 hours, cooled to room temperature and diluted with EtOAc, the organic layer was washed with water, dried with 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) containing Compound 70 (115 mg, 0.55 mmol) obtained in Preparation Example 20 was cooled to 0 ° C and a solution of BH ₃ · SMe ₂ complex (1.8 mL, 3.61 mmol) . The solution was stirred at 0 &lt; 0 &gt; C for 1 hour and then at room temperature for 3 hours. Water was added dropwise to the reaction mixture at 0 ° C to terminate the reaction. When hydrogen gas bubbles were no longer observed, a 2N-NaOH aqueous solution was added dropwise. The aqueous layer was extracted with ether (× 2), washed the ether layer with brine, dried with MgSO _4, filtered, and the residue obtained by concentration under reduced pressure was purified by flash column chromatography (EtOAc: n- hexane = 1: 2) To obtain a 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 ferriydan (3.0 eq.) Was added to a CH ₂ Cl ₂ (0.03 M) solution containing the above primary alcohol (1.0 eq.) Obtained above. After stirring for 1 hour, The mixture was diluted with CH ₂ Cl ₂ and sodium thiosulfate (10%) was added. The mixture was stirred at room temperature for 10 minutes until separated into two layers. The organic layer obtained above was washed with saturated aqueous NaHCO ₃ solution, dried over MgSO ₄ , filtered and concentrated under reduced pressure to give a residue which was purified by flash column chromatography (EtOAc: n-hexane = 1: 3) 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 ) 46 Preparation of

Resorcinol (5.0 g, 44.96 mmol) was dissolved in a mixture of chloroform: acetic acid (2: 1, 270 mL) and acetic acid (70 mL) containing nitric acid (3.6 mL) Lt; / RTI &gt; 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 purified by flash column chromatography (EtOAc: n- The residue was purified by silica gel column chromatography (eluent: hexane = 1: 4, EtOAc: n -hexane: CH ₂ Cl ₂ = 1: 4: 2) to obtain 46 as a yellow solid (yield 52%, 3.6 g).

¹ H NMR (CD ₃ OD, 300 MHz) [delta] 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

DBU (0.63 mL, 4.19 mmol) was added to a solution of 2-methyl-3-butyn-2-ol (0.36 mL, 3.70 mmol) in acetonitrile (18 mL) at 0 ° C, and then trifluoroacetic anhydride (0.58 mL, 4.19 mmol) was added dropwise over 30 minutes, and the resulting yellow solution was stirred for 40 minutes at 0 ° C. To the other flask was added acetonitrile (500 mg, 3.22 mmol) containing the compound 46 (18 mL) solution was treated at 0 ℃ with DBU (0.63 mL, 4.19 mmol) and then, ₂ CuC1 a yellow solution prepared above to a mixture obtained by the addition of (8.65 mg, 0.064 mmol) ( 2- methyl-3 Butyn-2-yl trifluoroacetate) was added dropwise over 40 minutes at 0 DEG C. The reaction mixture was stirred overnight at 0 <0> C, concentrated under reduced pressure and the residue obtained was poured into water. Was extracted with ethyl acetate, and the organic layer was washed with 1N - HCl, 1N - KOH And brine in this order. The organic layer was dried over MgSO ₄ and concentrated under reduced pressure to give 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, 6H); _{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 - Kromen -5-ol (2,2- Dimethyl -6- nitro -2 H -chromen-5-ol) (48)

N , N -diethylaniline (28 mL) solution 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 ice 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 yielded the 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, 6H); _{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 - Kromen  (5- Methoxy -2,2- dimethyl -6-nitro-2 H -chromene) (49) Preparation

Acetone anhydride (7.0 mL) containing the compound 48 (130 mg, 0.59 mmol), potassium carbonate (244 mg, 1.76 mmol) and iodomethane (0.11 mL, 1.76 mmol) obtained in Preparation 24 was heated at 55 ° C overnight Respectively. The mixture was concentrated, treated with water and extracted with EtOAc (x3). Washing the extract layer with water, MgSO ₄ dried and concentrated under reduced pressure to give the 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 - Kromen -6-amine (5- Methoxy -2,2- dimethyl -2 H -chromen-6-amine) (50)

Boiling ethanol (2.0 mL) containing the compound 49 (136 mg, 0.663 mmol) obtained in Preparation 25 and tin (II) chloride dihydrate (740 mg, 3.21 mmol) was stirred under nitrogen atmosphere for 1 hour. The ethanol was removed by vacuum evaporation and the resulting residue was extracted with ethyl acetate (x3) and the organic layer was treated with 2N NaOH solution (10 mL) and then treated with water (2x10 mL). The organic layer was washed with brine, dried over MgSO ₄ and concentrated under reduced pressure. The resulting residue was purified by flash column chromatography (EtOAc: n-hexane = 1: 15) to obtain the compound 50 of Preparation 26 as a yellow solid (Yield 79%, 100 mg).

¹ H NMR (CDCl _3, 2H), 6.43 (d, 1H, J = 8.4 Hz), 5.63 (d, 1H, J = 9.9 Hz), 3.78 (s, 3H) 1.37 (s, 6H); 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 - Kromen  (6- Bromo -5- 메틸oxy -2,2-dimethyl-2 H -chromene (51)

Water (5.0 mL) containing the compound 50 (260 mg, 1.27 mmol) obtained in Preparation 26 was cooled to 0 ° C, and then HBr (1.6 mL, 48% in water) was added slowly. The reaction solid was stirred vigorously at 0 ° C for 10 minutes. A slurry containing NaNO ₂ and HBr was slowly added to a solution of sodium nitrite in water (1.0 mL), allowing the temperature of the reaction mixture to be below 5 ° C. Water (5.0 mL) containing copper (I) bromine (190 mg, 1.30 mmol) was placed in a separatory funnel, heated to 60 ° C, and the aniline solution was added dropwise to maintain the temperature at 60 ° C. After the reaction was completed, the reaction mixture was cooled to room temperature and extracted with EtOAc (x2). The organic layer was washed with brine, dried with MgSO _4, chromatography of the residue obtained by concentration under reduced pressure, flash column Photography (EtOAc: n- hexane = 1: 12) to give the soft compound 51 in Preparation 27 yellow five days (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, 1 H, J = 10.0 Hz), 3.74 (s, 3H), 1.35 (s, 6H); _{^{13 C NMR (CDCl 3, 125}} MHz) δ153.3, 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)

Was added to a solution of 4- (bromoethyl) -1,2-dimethoxybenzene (100 mg, 0.43 mmol) and benzenesulfonic acid sodium salt dihydrate (87 mg, 0.52 mmol) in anhydrous DMF (1.5 mL) Was stirred at 80 &lt; 0 &gt; C for 12 hours and cooled to room temperature. After a general synthetic procedure using 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) (Yield 93%, 118 mg) as a colorless oil.

_{^{1 H NMR (CDCl 3, 300}} MHz) δ7.56 (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 - Kromen -6- Carbaaldehyde  (5- Hydroxy -2,2-dimethyl-2 H -chromene-6-carbaldehyde) (110)

(0.01 M) solution of 3-methyl-but-2-enal (2.0 equivalents) in anhydrous acetone (0.01 M) containing 2,4-dihydroxy aldehyde One drop was added over a period of time and heated for a further 18 hours. After cooling to room temperature, the solvent was removed by rotary evaporation under reduced pressure, and the crude product obtained by azeotropic distillation with toluene was purified by flash column chromatography (EtOAc: n-hexane = 1: 8) (Yield 32%, 1.12 g) as a colorless solid.

_{^{1 H-NMR (CDCl 3,}} 300 MHz) δ11.61 (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 - Kromen -6- Carbaaldehyde  (5- (Methoxymethoxy) -2,2-dimethyl-2 H -chromene-6-carbaldehyde) (108)

Chloromethyl methyl ether (0.11 mL, 1.47 mmol) was added at room temperature to a solution of the compound 110 (200 mg, 0.98 mmol) obtained in Preparation 29 and potassium carbonate (406 mg, 2.94 mmol) in acetone . 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. The crude residue was purified by flash column chromatography (EtOAc: n-hexane = 1: 10) to give the compound 108 of Preparation Example 30 as a pale yellow solid Yield 100%, 231 mg).

_{^{1 H NMR (CDCl 3, 300}} MHz) δ10.07 (s, 1H), 7.59 (d, J = 8.6 Hz, 1H), 6.61 (d, J = 8.6 Hz, 1H), 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 - Kromen -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)

N- BuLi (0.26 mL, 0.444 mmol, 1.6 M in hexane) was added at -78 ° C to a solution of compound 105 (119 mg, 0.407 mmol) from preparation 28 in anhydrous THF (5.0 mL) And stirred for 1 hour. To the reaction mixture was slowly added anhydrous THF (3.0 mL) containing the compound 108 of Preparation Example 30 (121 mg, 0.448 mmol) at -78 ° C. After 1 hour of addition, water was added to the reaction mixture to complete the reaction and extracted with EtOAc (x3). The extract was washed with brine, dried over anhydrous MgSO ₄ and concentrated under reduced pressure to give the intermediate residue (secondary alcohol) which was used in the next step without further purification.

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

^{_{1 H NMR (CDCl 3, 300}} MHz) δ7.95 (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 - Kromen Yl) Ethanone  (2- (3,4- Dimethoxyphenyl ) -1- (5- hydroxy -2,2- dimethyl -2 H - chromen -6-yl) ethanone) (107) Preparation

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

^{_{1 H NMR (CDCl 3, 300}} MHz) δ12.88 (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- Enyloxy ) Benzene (1,2- Dimethoxy -4-( prop -2-ynyloxy) benzene) 115

(225 mg, 1.51 mmol) and potassium carbonate (211 mg, 1.51 mmol) were added to DMF (0.2 M) solution containing 3,4-dimethoxyphenol and the mixture was stirred at room temperature for 12 hours. The reaction mixture was quenched with saturated aqueous ammonium chloride solution and extracted with diethyl ether. Purification of the organic layer was washed with water (× 2), brine, and the residue obtained by concentration under the following reduced pressure and dried with anhydrous MgSO ₄ was purified by flash column chromatography (n- hexane _{1:: CH 2 Cl 2 = 1} ) Compound 115 of Preparation 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- Enyloxy ) -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 - Kromen  (4- Bromo -6,7- dimethoxy -2 H -chromene) Preparation of 118

Compound 116 (130 mg, 0.48 mmol) obtained in Preparative Example 34 was placed in N , N -diethylaniline (7.0 mL) and monitored by TLC and heated to 210 DEG C under nitrogen atmosphere until completion of the reaction. The reaction mixture was poured into ice water and extracted with EtOAc (10 mL). The organic layer was washed with 2N HCl aqueous solution, 2N NaOH aqueous solution and water, and the organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The resulting residue was purified by flash column chromatography (EtOAc: n-hexane = 1: 8) To give Compound 118 of Preparation 35 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, 3H), 3.86 (s, 3H).

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

A solution of 2,2-dimethylchromanone (100 mg, 0.41 mmol) in anhydrous trichlorethylene (1.5 mL) containing anhydrous DMF (0.05 mL, 0.62 mmol) and phosphorus oxybromide (188 mg, 0.62 mmol) A solution of anhydrous trichlorethylene (1.5 mL) was added at 0 &lt; 0 &gt; C. The reaction mixture was monitored by TLC, heated to 60 &lt; 0 &gt; 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 (x 5) and the extract was washed with brine. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The obtained residue was purified by flash column chromatography (EtOAc: n-hexane = 1: 5) to obtain 119 as a yellow solid in a yield of 91% 9 mg).

_{^{1 H NMR (CDCl 3, 300}} MHz) δ6.95 (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- Kromen -6- Carbaaldehyde  (2,2- dimethyl -2H- chromene -6-carbaldehyde) Preparation of 120

A DMF (1.0 M) suspension containing phenol (1 eq), potassium carbonate (2 eq), potassium iodine (1.7 eq) and copper (I) iodine (0.02 eq.) Was prepared at room temperature. To the mixture was added 3-chloro-3-methyl-1-butyne (1.8 eq) and the reaction mixture was heated to 65 [deg.] C for 2 hours, then cooled to room temperature, poured into diethyl ether, 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 eq.) was monitored by TLC at 190 &lt; 0 &gt; C under nitrogen atmosphere and heated until completion of the reaction. The reaction mixture was poured into ice water and extracted with EtOAc. The organic layer was washed with 2 N aqueous HCl solution, 2 N NaOH aqueous solution and water. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure, and the resulting crude residue was purified by flash column chromatography (EtOAc: n-hexane) to give 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 C12H13rO2 (M + H ^& lt ^{; +} & gt ^; ): 189.0916, Found: 189.0916.

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

Iodomethane (0.11 mL, 1.47 mmol) was added at room temperature to a solution of the compound 110 (200 mg, 0.98 mmol) obtained in Preparation 29 and potassium carbonate (406 mg, 2.94 mmol) in acetone (5 mL). 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 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) δ10.07 (s, 1H), 7.59 (d, J = 8.6 Hz, 1H), 6.61 (d, J = 8.6 Hz, 1H), 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 - Kromen  (6- Bromo -2,2- dimethyl -2 H - chromene 131)

To a solution of acetonitrile (0.02 M) containing 2-methyl-3-butyn-2-ol (1.15 eq) at 0 ° C was added DBU (1.3 eq.) Via syringe for 30 min. The resulting yellow solution was stirred at 0 &lt; 0 &gt; C for 40 minutes. In another flask, 4-bromo-phenol (1 eq) in acetonitrile at 0 ℃ into a (0.03 M) was treated with DBU (1.3 eq) was added and _{then, CuC1 2 · H 2 0 (} 0.02 eq.). The mixture was added at 0 &lt; 0 &gt; C to the yellow solution prepared above (2-methyl-3-butyn-2-yl trifluoroacetate) via cannula for 40 min. The reaction mixture was stirred at 0 &lt; 0 &gt; C for 5 hours, and the residue obtained by concentration under reduced pressure was poured into water. The aqueous layer was extracted with hexane; The organic layer was washed with 1N- HCl, 1N- KOH (x2) and brine. The organic layer was dried over anhydrous MgSO ₄ and concentrated under reduced pressure to give o -alkylated phenol (1.0 eq.). The product was used immediately in the next step.

The N , N -diethylaniline (0.05 M) solution containing the o -alkylated phenol (1.0 eq) was monitored by TLC and heated to 190 &lt; 0 &gt; C under nitrogen atmosphere until the reaction was complete. The reaction mixture was poured into ice water and extracted with EtOAc. The organic layer was washed with 2 N aqueous HCl, 2 N aqueous NaOH, 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 131 as a pale yellow oil (yield 68%, 464 mg).

¹ H NMR (CDCl _3, 300 MHz) δ7.15 (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 - Kromen -6-yl) methanol ((3,4-Dimethoxyphenyl) (2,2-dimethyl-2 H -chromen-6-yl) methanol) (132)

N- BuLi (0.17 mL, 0.28 mmol, 1.6 M solution in n-hexane) was added at -78 째 C to a solution of compound 131 (60 mg, 0.25 mmol) obtained in Preparation 39 in anhydrous THF Then, the mixture was 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, and the mixture was stirred for 30 minutes, and maintained at -78 ° C. The reaction mixture was quenched by the addition of a saturated aqueous solution of ammonium chloride, extracted with EtOAc (x2), and washed with brine. The organic layer was dried over anhydrous MgSO ₄ , filtered, and concentrated under reduced pressure. The obtained residue was purified by flash column chromatography (EtOAc: n-hexane = 1: 4) to give 132 as a white solid (Yield 66% , 108 mg).

^{_{1 H NMR (CDCl 3, 300}} MHz) δ7.06 (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 - Kromen Yl) Ethanone  (1- (5- hydroxy -2,2- dimethyl -2 H - chromen -6-yl) ethanone) (112) Preparation

N-BuLi (1.4 eq.) Was added dropwise at -78 [deg.] C to an anhydrous THF solution containing aryl bromide (1.5 eq.) And stirred at -78 [deg.] C to generate the aryl anion. After stirring at -78 ° C for 20 minutes, 2 ', 4'-dihydroxyacetophenone (1.0 eq.) Was added and stirring continued for 30 minutes to allow the reaction temperature to rise to room temperature. The reaction mixture was treated with a saturated aqueous NH ₄ Cl solution and extracted with EtOAc. Washing the extract with brine, dried over MgSO ₄ and the residue obtained by evaporating the solvent was purified by flash column chromatography (EtOAc:: n- hexane = 1: 15 in 1: 10), the compound 112 as a light yellow solid (Yield: 32%, 460 mg).

_{^{1 H-NMR (CDCl 3,}} 300 MHz) δ12.94 (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- Kromen Yl) Ethanone  (1- (2,2- Dimethyl -2H-chromen-6-yl) ethanone) (134)

A DMF (1.0 M) suspension containing 133 (1 equivalent), potassium carbonate (2 equivalents), potassium iodine (1.7 equivalents) and copper (I) iodine (0.02 equivalents) was prepared at room temperature. To the mixture was added 3-chloro-3-methyl-1-butyne (1.8 eq) and the reaction mixture was heated to 65 [deg.] C for 2 hours, then cooled to room temperature, poured into diethyl ether, 3) and brine. The extract was dried over anhydrous MgSO ₄ and concentrated. 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 eq) was monitored by TLC at 190 &lt; 0 &gt; C under nitrogen atmosphere and heated until completion of the reaction. The reaction mixture was poured into ice water and extracted with EtOAc. The organic layer was washed with 2 N aqueous HCl solution, 2 N 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 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 ^& lt ^{; +} & gt ^; ).

< 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

Rectonon (Sigma-Aldrich, BBr ₃ (0.53 mL, 0.53 mmol, 1.0 M solution in CH ₂ Cl ₂ ) was added to a solution of anhydrous CH ₂ Cl ₂ (5.0 mL) in an 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 solution of hexamethylphosphoramide (HMPA), heated to 70 ° C, stirred for 3 hours, and poured into water. The extract was washed with brine, the mixture was concentrated under reduced pressure and then dried in MgSO _4. Next, the product 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 _{^{13 H-NMR (CDCl 3,}} 125 MHz) δ190.4, 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 ] Kromen -7 (7 a H ) -On ((7a S , 13a S ) -9-Hydroxy-13,13a- dihydro -10- 메틸oxy -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- 메틸oxy -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

BBr ₃ (0.25 mL, 0.25 mmol, 1.0 in CH ₂ Cl ₂ ) was added to anhydrous CH ₂ Cl ₂ (7.0 mL) in which deguanelin (100 mg, 0.25 mmol) M solution) was added and stirred for 1 hour and then allowed to stand at 0 &lt; 0 &gt; C. After stirring for an additional 30 min, the reaction mixture was quenched with water, extracted with CH ₂ Cl ₂ and washed with brine. The organic layer obtained was dried over MgSO ₄ , filtered and concentrated. The resulting residue was purified by flash column chromatography (EtOAc: n -hexane: CH ₂ Cl ₂ = 1: 3: 1 to 1: 2: 1) , And Compound 9 of Example 2 as a pale yellow solid (16% yield, 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, IH, J = 12.2 Hz), 3.85 (d, IH, J = 4.0 Hz), 3.62 (s, 1.30 (s, 3 H); ¹³ C-NMR (acetone-d ₆ , 100 MHz)? 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 (14% yield, 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, IH, J = 12.2 Hz), 3.82 (d, IH, J = 4.0 Hz), 3.71 (s, 3H), 2.00 1.30 (s, 3 H); ¹³ C-NMR (acetone-d ₆ , 75 MHz)? 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.

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

¹ H-NMR (acetone-d ₆ , 400 MHz)? 7.75 (s, 1H), 7.63 (d, 1H, J = 8.7 Hz), 7.38 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) δ190.1, 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 ] Kromen -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 diclobin (50 mg, 0.13 mmol) of Comparative Example 1 in ethyl alcohol (2.0 mL). The mixture was refluxed for 12 hours, then cooled to room temperature and extracted with EtOAc. The organic layer was washed the extract with brine, dried with MgSO _4, the residue obtained by concentration under reduced pressure, EtOAc: n - hexane = 1: 1 was crystallized from the first solution, to give the compound 12 of Example 5 as a light yellow solid ( Yield 35%, 17 mg).

_{^{1 H-NMR (CDCl 3,}} 500 MHz) δ8.42 (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 ] Kromen -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

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

_{^{1 H-NMR (CDCl 3,}} 400 MHz) δ6.99 (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, IH, J = 4.9 Hz), 1.41 (s, 3H), 1.39 ¹³ C-NMR (CDCl ₃ , 100 MHz)? 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 ] Kromen  ((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

Sodium hydride (16 mg, 0.40 mmol) was added to a solution of compound 14 (40 mg, 0.10 mmol) prepared in Example 6 dissolved in anhydrous THF (2.0 mL) at 0 ° C and stirred for 30 minutes Then carbon disulfide (0.063 mL, 1.00 mmol) was added at 0 占 폚. Iodomethane (0.064 mL, 1.00 mmol) was added to the mixture at 0 &lt; 0 &gt; C and the reaction temperature was allowed to reach room temperature. After confirming that the reaction was completed by TLC, the mixture was cooled with methanol (1.0 mL), the solvent was removed under reduced pressure, and the obtained residue was extracted with EtOAc and washed with brine. The organic layer of the extract was dried over MgSO ₄ , filtered, and concentrated. The crude residue was purified by flash column chromatography (EtOAc: n-hexane = 1: 6) to give 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 (catalytic amount) were added. The reaction mixture was monitored by TLC, refluxed until the reaction was completed, and the solvent was removed under reduced pressure. The resulting residue was purified by flash column chromatography (EtOAc: n-hexane = 1: 6) to give the compound of Example 7 13 as a pale 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 _{^{13 C-NMR (CDCl 3,}} 75 MHz) δ152.2, 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- Tetrahydro Rho-3 H - Chromeno [3,4- b ] Pyrano [2,3- h ] Kromen  ((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)

To a solution of compound 14 (1 eq) prepared in Example 7 dissolved in anhydrous THF at 0 &lt; 0 &gt; C Iodomethane (1.5 eq.) Was added followed by a solution of t- BuOK solution (1 M in THF, 1 eq.) was added dropwise. The reaction mixture was monitored by TLC at &lt; RTI ID = 0.0 &gt; 0 C &lt; After stirring, it was quenched with saturated aqueous NH ₄ Cl solution and extracted with EtOAc. The organic layer was dried over MgSO ₄ , filtered, and concentrated under reduced pressure. The resulting residue was purified by flash column chromatography (EtOAc: n-hexane = 1: 3) to give 15 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, IH), 1.41 (s, 3H), 1.39 (s, 3H); _{^{13 C-NMR (CDCl 3,}} 100 MHz) δ154.2, 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 ] Kromen  ((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)

To a solution of compound 14 (1 eq) prepared in Example 7 dissolved in anhydrous THF at 0 &lt; 0 &gt; C Iodoethane (1.5 eq.) Was added followed by a solution of t- BuOK solution (1 M in THF, 1 eq.) was added dropwise. The reaction mixture was monitored by TLC at &lt; RTI ID = 0.0 &gt; 0 C &lt; After stirring, it was quenched 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 resulting residue was purified by flash column chromatography (EtOAc: n-hexane = 1: 3) to obtain the 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)? 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, , 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 ] Kromen  ((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

To a solution of compound 14 (1 eq) prepared in Example 7 dissolved in anhydrous THF at 0 &lt; 0 &gt; C Iodopropane (1.5 eq.) Was added followed by a solution of t- BuOK solution (1 M in THF, 1 eq.) was added dropwise. The reaction mixture was monitored by TLC at &lt; RTI ID = 0.0 &gt; 0 C &lt; After stirring, it was quenched 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 resulting residue was purified by flash column chromatography (EtOAc: n-hexane = 1: 5) to give the 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) δ153.9, 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 ] Kromen  ((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

To a solution of compound 14 (1 eq) prepared in Example 7 dissolved in anhydrous THF at 0 &lt; 0 &gt; C Benzyl bromide (1.5 eq.) Was added followed by a solution of t- BuOK solution (1 M in THF, 1 eq.) was added dropwise. The reaction mixture was monitored by TLC at &lt; RTI ID = 0.0 &gt; 0 C &lt; After stirring, it was quenched with saturated aqueous NH ₄ Cl solution and extracted with EtOAc. The organic layer was dried over MgSO ₄ , filtered, and concentrated under reduced pressure. The resulting 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) δ154.2, 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 O 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 ] Kromen  ((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

Examples of the compound 14 prepared in 7 (30 mg, 0.076 mmol) and DHP (13 mg, 0.15 mmol) are p in dissolved _{CH 2 Cl 2 (1.0 mL)} - toluene sulfonate (5.8 mg, 0.023 mmol) to And the mixture was stirred at room temperature for 1 hour. The reaction was then 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 resulting residue was purified by flash column chromatography (EtOAc: n-hexane = 1: 4) to give the compound 19 of Example 12 as a colorless oil (Yield 50%, diastereomeric mixture, 18 mg).

_{^{1 H-NMR (CDCl 3,}} 500 MHz) δ7.06 (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) 3H), 3.79 (s, 3H), 3.78 (s, 3H), 3.78 (s, 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, , 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 ] Kromen -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 mmol) were added to a solution of the compound 14 (30 mg, 0.076 mmol) prepared in Example 7 and DMAP (catalytic amount) dissolved in CH ₂ Cl ₂ mL, 0.64 mmol) was added at 0 &lt; 0 &gt; C under an argon atmosphere. 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 and the organic layer was washed with brine, dried over MgSO ₄ , concentrated and the residue was purified by flash column chromatography (EtOAc: n-hexane = 1: 5) Compound 13 of Example 13 was obtained as a white solid (yield 82%, 27 mg).

_{^{1 H-NMR (CDCl 3,}} 500 MHz) δ7.01 (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) δ170.0, 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 ] Kromen -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

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

Acetic acid (1.0 mL) in which Compound 14 (3 mg, 7.6 μmol) prepared in Example 7 was dissolved 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 the residue obtained by concentration under reduced pressure was purified by flash column chromatography (EtOAc: n- hexane = 1: 7) to yield compound 22 in Example 15 carried out in (Yield 70%, 2 mg) as a colorless oil.

_{^{1 H-NMR (CDCl 3,}} 400 MHz) δ6.98 (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 ¹³ C-NMR (CDCl ₃ , 100 MHz)? 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, , 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 ] Kromen -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 extracted with CH ₂ Cl ₂ with water (0.5 mL), and 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 residue was dried by MgSO _4, filtered, concentrated and the residue obtained is purified by flash column chromatography (EtOAc: n- hexane = 1: 2) to give the compound 23 of Example 16 Obtained as a white solid (26 mg).

_{^{1 H-NMR (CDCl 3,}} 500 MHz) δ8.26 (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 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, , 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 ] Kromen -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 eq.) Was added at 0 ° C to a solution of compound 23 (1 eq.) Prepared in Example 16 dissolved in anhydrous THF at 0 ° C followed by the addition of t-BuOK solution (1 M in THF, ) Was added dropwise. Monitoring the reaction mixture at 0 ℃ by TLC, and was stirred until the reaction is complete, it cooled to and then saturated NH ₄ Cl aqueous solution and extracted with EtOAc. The organic layer was dried over MgSO ₄ , filtered and concentrated under reduced pressure. The obtained residue was purified by flash column chromatography (EtOAc: n-hexane = 1: 4) to obtain the 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 _{^{13 C-NMR (CDCl 3,}} 125 MHz) δ155.6, 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 ] Kromen -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 eq.) Was added at 0 ° C to a solution of compound 23 (1 eq.) Prepared in Example 16 dissolved in anhydrous THF at 0 ° C and a solution of t-BuOK (1 M in THF, Was added dropwise. Monitoring the reaction mixture at 0 ℃ by TLC, and was stirred until the reaction is complete, it cooled to and then saturated NH ₄ Cl aqueous solution and extracted with EtOAc. The organic layer was dried over MgSO ₄ , filtered and concentrated under reduced pressure. The obtained residue was purified by flash column chromatography (EtOAc: n-hexane = 1: 5) to obtain the 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) δ155.6, 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 ] Kromen -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

Benzene (1.0 mL) containing the 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 solution of NaHCO ₃ 1.0 mL) and extracted with diethyl ether. The organic layer was dried over MgSO ₄ , filtered and concentrated. The resulting residue was purified by flash column chromatography (EtOAc: n-hexane: CH ₂ Cl ₂ = 1: 3 : 1 to 1: 2: 1) to obtain 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 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)? 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 ] Kromen -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)

N -methylmorpholine N -oxide (NMO, 18 mg, 0.15 mmol) and OsO (0.35 mmol) were added to a solution of acetone: water (4.0 mL, 4: 1) containing deguanelin ₄ (0.1 M in toluene, 0.020 mL, 0.002 mmol), and the mixture was stirred at 0 ° C for 10 minutes. The mixture was dewatered to room temperature and further stirred for 3 days. After cooling to 0 &lt; 0 &gt; C with a saturated sodium sulphite aqueous 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 to give a residue which was purified by flash column chromatography (EtOAc: n-hexane = 2: 1 to 100% EtOAc) Compound 27 was obtained as a pale yellow solid (47% yield, 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)? 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, , 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)? 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, , 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 eq.) Was added to anhydrous acetonitrile solution containing Compound 8 (1 eq) and iodomethane (2 eq) prepared in Example 1 and monitored by TLC at 0 ° C . The mixture was cooled with water and extracted with EtOAc. 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: 4) To give the compound 28 of Example 21 as a white solid (yield 41%, 16 mg).

_{^{1 H-NMR (CDCl 3,}} 500 MHz) δ7.80 (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, IH, J = 4.1 Hz), 3.77 (s, 3H), 3.74 (s, 3H), 3.28 (m, 2H), 1.74 (s, 3H), 1.61 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)

Cesium carbonate (1.5 eq.) Was added to anhydrous acetonitrile solution containing compound 8 (1 eq.) And aryl iodide (2 eq.) Prepared in Example 1 and monitored by TLC at 0 &Lt; / RTI &gt; The mixture was cooled with water and extracted with EtOAc. 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: 6) To obtain Compound 29 of Example 22 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 ¹³ C-NMR (CDCl ₃ , 100 MHz)? 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

Cesium carbonate (1.5 eq.) Was added to anhydrous acetonitrile solution containing compound 8 (1 eq) and benzyl bromide (2 eq) prepared in Example 1 and monitored by TLC at 0 &lt; 0 &Lt; / RTI &gt; The mixture was cooled with water and extracted with EtOAc. 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: 6) To give Compound 30 of Example 23 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 _{^{13 C-NMR (CDCl 3,}} 75 MHz) δ190.0, 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

(0.01 mL, 0.07 mmol) and acetic anhydride (0.05 mL) were added to a solution of compound 8 (25 mg, 0.063 mmol) prepared in Example 1 and CH ₂ Cl ₂ (1.0 mL) containing DMAP , 0.53 mmol) at 0 &lt; 0 &gt; C under an argon atmosphere. The mixture was stirred at room temperature for 10 minutes, cooled with saturated aqueous NH ₄ Cl, extracted with CH ₂ Cl ₂ , and 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: 4) to obtain the compound 31 of Example 24 as a pale yellow oil (yield: 44%, 14 mg).

_{^{1 H-NMR (CDCl 3,}} 400 MHz) δ7.80 (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 3H), 1.72 (s, 3H), 1.62 (s, 3H), 3.27 (s, 3H). ¹³ C-NMR (CDCl ₃ , 75 MHz)? 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 (10 mg, 0.026 &lt; RTI ID = 0.0 &gt; (0.5 mL) containing triphenylphosphine (65 mg, 0.25 mmol) and diisopropyl azodicarboxylate (0.024 mL, 0.12 mmol) in anhydrous THF (1.0 mL) containing diisopropyl azodicarboxylate ) Solution was added and 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 the 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) δ190.9, 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 - Kromen Yl) Metanon  ((6,7-Dimethoxychroman-4-yl) (2,2-dimethyl-2 H -chromen-6-yl) methanone) (45)

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

^{_{1 H NMR (CDCl 3, 500}} MHz) δ7.79 (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) δ199.6, 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 - Kromen Yl) Ethanone  (2- (3,4-Dimethoxyphenyl) -1- (2,2-dimethyl-2 H -chromen-6-yl) ethanone) (53)

To a solution of arylbromide 6-bromo-2,2-dimethyl- 2H -chromene (1.5 eq.) In anhydrous THF was added n- BuLi (1.4 eq.) Dropwise at -78 & Followed by stirring to produce an aryl anion. After stirring at -78 占 폚 for 20 minutes, the compound 52 (1.0 equivalent) obtained in Preparation Example 13 was added and stirring was continued for 30 minutes so that the reaction temperature became room temperature. The reaction mixture was treated with a saturated aqueous NH ₄ Cl solution and extracted with EtOAc. The extract was washed with brine, dried over MgSO4, and the solvent was evaporated. The resulting residue was purified by flash column chromatography (EtOAc: n-hexane = 1: 2) to give a secondary alcohol.

Dess-Martin ferriydan (3.0 eq.) Was added to a CH ₂ Cl ₂ (0.03 M) solution containing the above-obtained secondary alcohol (1.0 eq.), Stirred for 1 hour, The mixture was diluted with CH ₂ Cl ₂ and sodium thiosulfate (10%) was added. The mixture was stirred at room temperature for 10 minutes until separated into two layers. The organic layer obtained above was washed with saturated aqueous NaHCO ₃ solution, dried over MgSO ₄ , filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography (EtOAc: n-hexane = 1: 3) Compound 53 of Example 27 was obtained as a pale 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) δ196.3, 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 - Kromen Yl) Ethanone  (2- (3,4- Dimethoxyphenyl ) -1- (5- 메틸oxy -2,2- dimethyl -2 H - chromen -6-yl) ethanone) (54)

N- BuLi (1.4 eq.) Was added dropwise at -78 째 C to an anhydrous THF solution containing the compound 51 (1.5 eq.) Obtained in Preparation 27, and stirred at -78 째 C to generate an aryl anion. After stirring at -78 占 폚 for 20 minutes, the compound 52 (1.0 equivalent) obtained in Preparation Example 13 was added and stirring was continued for 30 minutes so that the reaction temperature became room temperature. The reaction mixture was treated with a 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: 2) to give a secondary alcohol.

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

^{_{1 H NMR (CDCl 3, 300}} MHz) δ7.43 (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 _{^{13 C NMR (CDCl 3, 75}} MHz) δ198.7, 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 - Kromen -6-yl) propan-1-one (2- (3,4- Dimethoxyphenyl ) -1- (5- 메틸oxy -2,2- dimethyl -2 H - chromen -6- yl ) propane Preparation of -1-one (56)

N- BuLi (1.4 eq.) Was added dropwise at -78 째 C to an anhydrous THF solution containing the compound 51 (1.5 eq.) Obtained in Preparation 27, and stirred at -78 째 C to generate an aryl anion. After stirring at -78 占 폚 for 20 minutes, Compound 55 (1.0 equivalent) obtained in Preparative Example 14 was added and stirring was continued for 30 minutes so that the reaction temperature became room temperature. The reaction mixture was treated with a 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: 2) to give a secondary alcohol.

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

^{_{1 H NMR (CDCl 3, 500}} MHz) δ7.27 (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 1.48 (d, 3H, J = 6.9 Hz), 1.39 (s, 6H); _{^{13 C NMR (CDCl 3, 75}} MHz) δ202.5, 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 - Kromen -6-day) -2- methyl Propane-1-one (2- (3,4- Dimethoxyphenyl ) -1- (5- 메틸oxy -2,2- dimethyl -2 H - chromen -6-yl) -2-methylpropan-1-one) (57)

(5.0 mg, 0.12 mmol, 60% in mineral oil) and iodomethane (0.02 mL, 0.042 mmol) in anhydrous THF (1.0 mL) containing the compound 54 of Example 28 (15 mg, 0.041 mmol) 0.16 mmol) at room temperature under an argon atmosphere. After the reaction was completed, the mixture was extracted with EtOAc (2.0 mL x 3). The organic layer of the extract 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: 4) to obtain 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) δ206.6, 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 - Kromen Yl) Prop 2-en-1-one (2- (3,4- Dimethoxyphenyl ) -1- (5- 메틸oxy -2,2- dimethyl -2 H - chromen Preparation of -6-yl) prop-2-en-1-one (58)

Potassium carbonate (15 mg, 0.11 mmol) was added to a solution of compound 54 (20 mg, 0.054 mmol) in Example 28 in anhydrous DMF (1 mL) under nitrogen atmosphere at room temperature, stirred at room temperature for 40 minutes, (3 mg, 0.082 mmol). The mixture was stirred for 4 h and then extracted with EtOAc (2.0 mL x 2). The organic extracts were washed with saturated aqueous NH ₄ Cl and brine, dried over MgSO ₄ , concentrated under reduced pressure and the resulting residue was purified by flash column chromatography (EtOAc: n-hexane = 1: 4) Of compound 58 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), (D, 1H, J = 10.0 Hz), 5.55 (s, 1H), 3.81 (s, 3H), 3.80 (s, 3H), 3.70 (s, 3H), 1.38 _{^{13 C NMR (CDCl 3, 100}} MHz) δ196.5, 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 - Kromen Yl) Metanon  (1- (3,4- Dimethoxyphenyl ) cyclopropyl ) (5- 메틸oxy -2,2- dimethyl -2 H -chromen-6-yl) methanone) (59)

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

^{_{1 H NMR (CDCl 3, 500}} MHz) δ6.98 (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) δ203.6, 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- Kromen -6-yl) propan-1-one (( S ) -2- (3,4- Dimethoxyphenyl ) -1- (5- 메틸oxy -2,2- dimethyl -2H- chromen -6-yl) propan-1-one) (69)

CeCl ₃ .7H ₂ O (189 mg, 0.52 mmol) was placed in a one-necked flask and slowly heated to 135-140 ° C under reduced pressure (0.1 Torr) and stirred for 2 hours. When the flask was hot, argon gas was injected and the flask was cooled in an ice water 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 an argon atmosphere. Next, the flask was cooled again to -78 ° C, and n- BuLi (0.13 mL, 0.13 mmol) was added to a solution of compound 51 (61 mg, 0.23 mmol) obtained in Preparation Example 27 in anhydrous THF At 78 [deg.] C and then stirred for 20 minutes to add the resulting aryl anion. After stirring at -78 ° C for 1.5 hours, the compound 68 (20 mg, 0.10 mmol) obtained in Preparative Example 19 was added thereto, followed by stirring for 30 minutes. The reaction mixture was treated with a saturated aqueous NH ₄ Cl solution, the product was extracted with EtOAc, washed with brine, NaHCO ₃ , brine and dried over anhydrous MgSO ₄ . The solvent was evaporated and the obtained residue was purified by flash column chromatography (EtOAc: n-hexane = 1: 3) to give the 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) δ7.02 (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 Cl ₂ (2.0 mL) and then molecular sieves (41 mg) and N -methylmorpholine- N -oxide (NMO, 15 mg, 0.13 mmol). After the mixture was stirred for 10 minutes, tetrapropylammonium ferutenate (TPAP, 3 mg, 0.0083 mmol) was added and when the reaction was complete, the mixture was diluted with CH ₂ Cl ₂ and washed with 10% sodium sulfite Aqueous solution, brine, and finally with a saturated solution of copper (II) sulfate. The organic layer was dried over MgSO ₄ , filtered, and concentrated under reduced pressure. The resulting residue was purified by flash column chromatography (EtOAc: n-hexane = 1: 4) to obtain the compound 69 of Example 33 (Yield: 84% , 27 mg).

^{_{1 H NMR (CDCl 3, 500}} MHz) δ7.27 (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 1.48 (d, 3H, J = 6.9 Hz), 1.39 (s, 6H); _{^{13 C NMR (CDCl 3, 75}} MHz) δ202.5, 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- Kromen -6-yl) propan-1-one (( R ) -2- (3,4- Dimethoxyphenyl ) -1- (5- 메틸oxy -2,2- dimethyl -2H- chromen -6-yl) propan-1-one) Preparation of 72

CeCl ₃ .7H ₂ O (125 mg, 0.34 mmol) was placed in a one-necked flask and heated to 135-140 ° C under reduced pressure (0.1 Torr) and stirred for 2 hours. When the flask was hot, argon gas was injected and the flask was cooled in an ice water 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 an argon atmosphere. Next, the flask was cooled again to -78 ° C, and n- BuLi (0.084 mL, 0.13 mmol) was added to a solution of the compound 51 (36 mg, 0.14 mmol) obtained in Preparation Example 27 in anhydrous THF At 78 [deg.] C and then stirred for 20 minutes to add the resulting aryl anion. After stirring at -78 ° C for 1.5 hours, the compound 71 (13 mg, 0.067 mmol) obtained in Preparation 21 was added and stirred for 30 minutes. The reaction mixture was treated with a saturated aqueous NH ₄ Cl solution, the product was extracted with EtOAc, washed with brine, NaHCO ₃ , brine and dried over anhydrous MgSO ₄ . The solvent was evaporated and the obtained residue was purified by flash column chromatography (EtOAc: n-hexane = 1: 3) to give the 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) δ7.02 (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 Cl ₂ (1.0 mL) and then molecular sieves (18 mg) and N -methylmorpholine- N -oxide (NMO, 7.0 mg, 0.055 mmol). After the mixture was stirred for 10 minutes, tetrapropylammonium perruthenate (TPAP, 1.3 mg, 0.0036 mmol) was added and when the reaction was complete, the mixture was diluted with CH ₂ Cl ₂ and washed with 10% sodium sulfite Aqueous solution, brine, and finally with a saturated solution of copper (II) sulfate. The organic layer was dried over MgSO ₄ , filtered, and concentrated under reduced pressure. The resulting residue was purified by flash column chromatography (EtOAc: n-hexane = 1: 4) , 10 mg).

^{_{1 H NMR (CDCl 3, 500}} MHz) δ7.27 (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 1.48 (d, 3H, J = 6.9 Hz), 1.39 (s, 6H); _{^{13 C NMR (CDCl 3, 75}} MHz) δ202.5, 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

Dimethylamino dimethoxymethane (6.7 L, 0.051 mmol) was added at room temperature to a solution of compound 107 (15 mg, 0.042 mmol) of Preparation Example 32 in anhydrous toluene (1.0 mL), and the mixture was refluxed for 2 hours. And the residue was purified by flash column chromatography (EtOAc: n-hexane = 1: 3) to obtain 80 of the compound 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)? 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, , 55.8, 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 - Kromen -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)

N- BuLi (0.12 mL, 0.20 mmol, 1.6 M in hexane) was added dropwise at -78 ° C to a solution of compound 118 (49 mg, 0.179 mmol) obtained in Preparation 35 in anhydrous THF (2.0 mL) . The reaction mixture was stirred at -78 째 C for 20 minutes, and then an anhydrous THF (1.0 mL) solution containing the compound 120 (78 mg, 0.357 mmol) obtained in Preparation 37 was added dropwise via a cannula. The pale yellow solution obtained above was stirred at -78 &lt; 0 &gt; C for 20 min and extracted with EtOAc (x2). The organic layer was washed with brine, dried over anhydrous sodium sulfate and concentrated in a rotary evaporator under reduced pressure to give the crude residue which was purified by flash column chromatography (EtOAc: n-hexane = 1: 10) to give the intermediate as 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 = 2.2Hz), 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, IH), 4.77 (m, 2H), 3.79 (s, 3H), 3.62 (s, 3H), 1.39 (s, 6H).

Dess-Martin ferriydan (3.0 eq.) Was added to a CH ₂ Cl ₂ (0.03 M) solution containing the above-obtained secondary alcohol (1.0 eq.), Stirred for 1 hour, The mixture was diluted with CH ₂ Cl ₂ and sodium thiosulfate (10%) was added. The mixture was stirred at room temperature for 10 minutes until separated into two layers. The organic layer obtained above was washed with a saturated aqueous solution of NaHCO ₃ , dried over MgSO ₄ , filtered and concentrated under reduced pressure. The resulting residue was purified by flash column chromatography (EtOAc: n-hexane = 1: 5) 81 (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) δ193.7, 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 - Kromen -4- days) (4- Methoxy -2,2-dimethyl-2 H - Kromen Yl) Metanon  (6,7- Dimethoxy -2,2- dimethyl -2 H - chromen -4- yl )(4- 메틸oxy -2,2-dimethyl-2 H -chromen-6-yl) methanone) (82)

The procedure of Example 36 was repeated 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) 82 as a colorless solid (yield 44%, 29 mg).

Secondary alcohol : ¹ H NMR (CDCl _{3 ,} 300 MHz): δ7.01 (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) δ7.31 (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, 6H); _{^{13 C NMR (CDCl 3, 75}} MHz) δ194.3, 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 - Kromen -4-yl) (2,2-dimethyl-2 H - Kromen -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 following the procedure of Example 36 while using Compound 119 instead of Compound 118 and using flash column chromatography (EtOAc: n-hexane = 1: 4) %, 35 mg).

Secondary alcohol : ¹ H NMR (CDCl ₃ , 300 MHz) δ7.09 (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, 6 H), 1.44 (s, 6 H); _{^{13 C NMR (CDCl 3, 75}} MHz) δ194.0, 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 - Kromen -4- days) (4- Methoxy -2,2-dimethyl-2 H - Kromen -6-yl) methanone (6,7- Dimethoxy -2 H - chromen -4- yl )(4- 메틸oxy -2,2- dimethyl -2 H - chromen -6-yl) methanone) (84)

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

Secondary _{^{alcohol: 1 H NMR (CDCl 3,}} 300 MHz) δ7.01 (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, IH, J = 9.9 Hz), 4.73 (d, IH, J = 3.8 Hz), 3.81 (s, 3H) , &Lt; / RTI &gt; 1.34 (s, 6H);

Compound 84 : ^{_{1 H NMR (CDCl 3, 300}} MHz): δ7.31 (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) δ193.3, 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 ^& lt ^{; +} & gt ^; ).

< Example  40> 2- (3,4- Dimethoxyphenyl ) -1- (5-hydroxy-2,2-dimethyl-2 H - Kromen -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)

N- BuLi (0.26 mL, 0.444 mmol, 1.6 M in hexane) was added dropwise at -78 째 C to a solution of compound 105 (0.407 mmol) obtained in Preparation 28 in 5.0 mL of anhydrous THF. And the mixture was stirred at a temperature for 1 hour. To the reaction mixture was slowly added anhydrous THF (3.0 mL) containing the compound 121 (0.448 mmol) obtained in Preparation 38 at -78 ° C. After 1 hour of addition, the reaction mixture was quenched with water and extracted with EtOAc (x3). The extract was washed with brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure to give the crude residue (Compound 126) which was used in the next step without further purification.

Dess-Martin ferriodin (286 mg, 0.660 mmol) was added to a solution of compound 126 (183 mg, 0.339 mmol) obtained above in anhydrous CH ₂ Cl ₂ (5.0 mL) After stirring for 1 hour, the reaction mixture was treated with a saturated aqueous solution of sodium carbonate: aqueous sodium thiosulfate (1: 1, 4.0 mL) and stirred for 30 minutes. The mixture was poured into water and extracted with CH ₂ Cl ₂ The residue was purified by flash column chromatography (EtOAc: n-hexane = 1: 2) to obtain 86 (yield 63%, 137 mg).

^{_{1 H NMR (CDCl 3, 300}} MHz) δ7.53 (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) δ206.6, 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 - Kromen Yl) Metanon  ((3,4-Dimethoxyphenyl) (2,2-dimethyl-2 H -chromen-6-yl) methanone) (87)

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

¹ H NMR (CDCl _3, 300 MHz) δ7.56 (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) δ194.3, 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 ^& lt ^{; +} & gt ^; ).

< Example  42> ( E ) -1- (3,4- Dimethoxyphenyl ) -3- (2,2-dimethyl-2 H - Kromen Yl) 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)

Potassium hydroxide aqueous solution (1.5 equivalents) was added at room temperature to a solution of pure ethyl alcohol (0.1 M) containing 3 ', 4'-dimethoxyphenylacetophenone (1.0 eq.) And compound 120 And then refluxed for 5 hours. After cooling to room temperature, the solvent was removed by rotary evaporation under reduced pressure, and the resulting crude residue was extracted with EtOAc (x2). The organic layer was washed with brine, dried over anhydrous MgSO ₄ and concentrated by rotary evaporation under reduced pressure. The residue was purified by flash column chromatography (EtOAc: n-hexane = 1: 5) to give 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, IH, J = 9.9 Hz), 5.61 (d, IH, J = 9.7 Hz), 3.90 (s, 3H), 3.90 (s, 3H), 1.39 _{^{13 C NMR (CDCl 3, 100}} MHz) δ188.6, 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 - Kromen -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)

(1.0 mL, 0.5 mM) was added to pure ethyl alcohol (4.0 mL) containing Compound 112 (100 mg, 0.46 mmol) obtained in Production Example 41 and 3,4-dimethoxybenzaldehyde (154 mg, Was added at room temperature and refluxed for 5 hours. After cooling to room temperature, the filtrate was concentrated under reduced pressure and the crude residue 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 obtain the compound 89 as a white solid (yield: 57%, 95 mg).

_{^{1 H-NMR (CDCl 3,}} 400 MHz) δ13.77 (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)? 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 - Kromen Yl) 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)

Potassium hydroxide aqueous solution (1.5 eq.) Was added at room temperature to a solution of 3,4-dimethoxybenzaldehyde (1.0 eq.) And the compound 134 (2.0 eq.) Obtained in Preparation 42 in pure ethyl alcohol Lt; / RTI &gt; After cooling to room temperature, the solvent was removed by rotary evaporation under reduced pressure, and the resulting crude residue was extracted with EtOAc (x2). The organic layer was washed with brine, dried over anhydrous MgSO ₄ and concentrated by rotary evaporation under reduced pressure. The residue was purified by flash column chromatography (EtOAc: n-hexane = 1: 4) to give 90 as a pale yellow solid (Yield 57%, 23 mg).

^{_{1 H NMR (CDCl 3, 300}} MHz) δ7.87 (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 C NMR (CDCl 3, 100}} MHz) δ190.7, 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- Kromen -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

The procedure of Example 43 was repeated, except that 2,4,5-trimethoxybenzaldehyde was used instead of 3,4-dimethoxybenzaldehyde to obtain 91 (yield: 61%, 29 mg).

^{_{1 HNMR (CDCl 3, 300MHz)}} δ7.87 (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 C} NMR (CDCl ₃ , 100 MHz)? 190.7, 188.5, 157.1, 151.1, 149.1, 143.9, 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 - Kromen Yl) The Rob-2-en-1-one (( E ) -3- (3,4- Dimethoxyphenyl ) -1- (5- 메틸oxy -2,2- dimethyl -2 H -chromen-6-yl) prop-2-en-1-one) (92)

A mixture of acetone (0.25 M) containing phenol (1 eq), potassium carbonate (3 eq) and iodomethane (1.5 eq) was refluxed for 4 hours and stirred at room temperature overnight. The mixture was concentrated, treated with water and extracted with CH ₂ Cl ₂ (x 3). The extract was washed with water, dried over anhydrous MgSO _4, the crude residue obtained by removing the solvent under reduced pressure was purified by flash column chromatography (EtOAc: n- hexane = 1: 5) to give pale yellow solid of Compound 92 (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- Kromen -6-yl) -3- (2,4,5- Trimethoxyphenyl Prop-2-en-1-one ((E) -1- (5- 메틸oxy -2,2- dimethyl -2H- chromen -6- yl ) -3- (2,4,5-trimethoxyphenyl) prop-2-en-1-one) (93)

Compound 93 was obtained in the same manner as in Example 46, except that Compound 91 was used instead of Compound 89 (yield: 75%, 20 mg).

^{_{1 H NMR (CDCl 3, 300MHz}} ) δ7.96 (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 C} NMR (CDCl ₃ , 100 MHz)? 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 the anhydrous DMSO (5.0 mL) solution containing the compound 89 (50 mg, 0.14 mmol) prepared in Example 43 was added at room temperature a catalytic amount of iodine, monitored by TLC, and refluxed until the reaction was completed. 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 by rotary evaporation under reduced pressure. The residue was purified by flash column chromatography (CH ₂ Cl ₂ : MeOH = 1: 10) to give 94 as a white solid (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 5} O (M + H ^+): 365.1389, Found: 365.1387.

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

3 ', 4'-dimethoxyphenyl acetic acid (1.0 eq.), PyBOP (1.0 eq.) And anhydrous dichloromethane (0.3 M) containing the compound 50 (1.2 eq.) Obtained in Preparation Example 26, the mixture in N, N - diisopropyl Propylethylamine (2.2 eq.) Was added. The mixture was stirred under nitrogen atmosphere overnight, the solvent was evaporated and the residue obtained was dissolved in EtOAc. The solution was extracted with a 5% aqueous hydrochloric acid solution, washed with brine, extracted with a saturated aqueous sodium hydrogen carbonate solution, dried over anhydrous MgSO ₄ , filtered and the solvent evaporated. The resulting brown oil residue was purified by flash column chromatography EtOAc: n-hexane = 1: 2) to obtain 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, 6H); _{^{13 C NMR (CDCl 3, 100}} MHz) δ168.8, 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 - Kromen -6- Carboxamide  ( N- (3,4-Dimethoxybenzyl) -2,2-dimethyl-2 H -chromene-6-carboxamide) (96)

To a mixture of anhydrous dichloromethane (0.3 M) containing 3,4-dimethoxybenzylamine (1.0 eq.), PyBOP (1.0 eq.) And Compound 121 (1.2 eq.) Obtained in Preparation 38 was added N , N -diisopropylethyl Amine (2.2 eq.), To give 96 as a yellow solid (yield 79%, 41 mg).

^{_{1 H NMR (CDCl 3, 400}} MHz) δ7.51 (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, 6H); _{^{13 C NMR (CDCl 3, 100}} MHz) δ166.7, 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 - Kromen -6- Carboxamide  ( N- (3,4-Dimethoxyphenyl) -2,2-dimethyl-2 H -chromene-6-carboxamide) (97)

To a mixture of anhydrous dichloromethane (0.3 M) containing 3,4-dimethoxy aniline (1.0 eq.), PyBOP (1.0 eq.) And compound 121 (1.2 eq.) Obtained in preparation 38 was added N , N -diisopropylethylamine (2.2 eq.) And purified by flash column chromatography (EtOAc: n-hexane = 1: 3) to give 97 as a yellow solid (Yield 87 %, 29 mg).

^{_{1 H NMR (CDCl 3, 400}} MHz) δ7.89 (s, 1H), 7.53 (dd, 1H, 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) δ184.5, 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 - Kromen -6-yl) -3,4- Dimethoxybenzamide  ( N- (2,2-Dimethyl-2 H -chromen-6-yl) -3,4-dimethoxybenzamide) (98)

To a mixture of anhydrous dichloromethane (0.3 M) containing 3,4-dimethoxybenzoic acid (1.0 eq.), PyBOP (1.0 eq.) And compound 50 (1.2 eq.) Obtained in preparation 26 was added N , N -diisopropylethylamine (2.2 eq). The mixture was stirred under nitrogen atmosphere overnight, the solvent was evaporated and the residue obtained was dissolved in EtOAc. The solution was extracted with a 5% aqueous hydrochloric acid solution, washed with brine, extracted with a saturated aqueous sodium hydrogen carbonate solution, dried over anhydrous MgSO ₄ , filtered and the solvent evaporated. The resulting brown oil residue was purified by flash column chromatography EtOAc: n-hexane = 1: 2) to obtain 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) δ164.7, 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 ^& lt ^{; +} & gt ^; ).

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

N- BuLi (1.4 eq.) Was added dropwise to a solution of aryl bromide compound 131 (1.5 eq.) In anhydrous THF at -78 &lt; 0 &gt; C and stirred at -78 [deg.] C to generate the aryl anion. After stirring at -78 ° C for 20 minutes, the compound 71 (1.0 eq.) Obtained in Preparation 21 was added and stirring was continued for 30 minutes. The reaction mixture was then treated with a saturated aqueous NH ₄ Cl solution and extracted with EtOAc. Washing the extract with brine, dried over MgSO ₄ and the residue obtained by evaporating the solvent was purified by flash column chromatography (EtOAc: n- hexane = 1: 4) to give the secondary alcohol (yield 48%, 19 mg).

Dess-Martin ferriydan (3.0 eq.) Was added to a CH ₂ Cl ₂ (0.03 M) solution containing the above-obtained secondary alcohol (1.0 eq.), Stirred for 1 hour, The mixture was diluted with CH ₂ Cl ₂ and sodium thiosulfate (10%) was added. The mixture was stirred at room temperature for 10 minutes until separated into two layers. The organic layer obtained above was washed with a saturated aqueous solution of NaHCO ₃ , dried over MgSO ₄ , filtered and concentrated under reduced pressure. The resulting residue was purified by flash column chromatography (EtOAc: n-hexane = 1: 5) 99 (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, 3H), 1.46 (d, 3H, J = 6.8 Hz), 1.39 (s, 6H); _{^{13 C NMR (CDCl 3, 125}} MHz) δ198.9, 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 - Kromen -6-yl) propan-1-one (( S ) -2- (3,4-Dimethoxyphenyl) -1- (2,2-dimethyl-2 H -chromen-6-yl) propan-1-one) (100)

N-BuLi (1.4 eq.) Was added dropwise to a solution of aryl bromide compound 131 (1.5 eq.) In anhydrous THF at -78 &lt; 0 &gt; C and stirred at -78 [deg.] C to generate the aryl anion. After stirring at -78 ° C for 20 minutes, 68 (1.0 eq.) Of the compound obtained in Preparation 19 was added and stirring was continued for 30 minutes. The reaction mixture was then treated with a saturated aqueous NH ₄ Cl solution and extracted with EtOAc. Washing the extract with brine, dried over MgSO ₄ and the residue obtained by evaporating the solvent was purified by flash column chromatography (EtOAc: n- hexane = 1: 4) to give the secondary alcohol (yield 59%, 13 mg).

Dess-Martin ferriydan (3.0 eq.) Was added to a CH ₂ Cl ₂ (0.03 M) solution containing the above-obtained secondary alcohol (1.0 eq.), Stirred for 1 hour, The mixture was diluted with CH ₂ Cl ₂ and sodium thiosulfate (10%) was added. The mixture was stirred at room temperature for 10 minutes until separated into two layers. The organic layer obtained above was washed with a saturated aqueous solution of NaHCO ₃ , dried over MgSO ₄ , filtered and concentrated under reduced pressure. The resulting residue was purified by flash column chromatography (EtOAc: n-hexane = 1: 5) 100 (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) δ198.9, 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 & lt ^; + & gt ^; ): 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 ] Kromen  ((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

To a solution of compound 14 (1 eq) prepared in Example 7 dissolved in anhydrous THF at 0 &lt; 0 &gt; C 3 - iodopropene (1.5 eq.) Was added followed by a solution of t- BuOK solution (1 M in THF, 1 eq.) was added dropwise. The reaction mixture was monitored by TLC at &lt; RTI ID = 0.0 &gt; 0 C &lt; After stirring, it was quenched with saturated aqueous NH ₄ Cl solution and extracted with EtOAc. Dry the organic layer of the extract was MgSO _4, filtered, and the residue obtained by concentration under reduced pressure was purified by flash column chromatography (EtOAc: n- hexane = 1: 5) to give the 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 = 5.3Hz), 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) δ154.1, 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 ] Kromen -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

Phenyl-selenyl chloride (68 mg, 0.35 mmol) was added to anhydrous CH ₂ Cl ₂ (4.0 mL) in which Compound 8 (128 mg, 0.32 mmol) The mixture was stirred for 10 minutes while maintaining the temperature at 30 DEG C, and then stirred for 2 hours until the temperature became normal, and further stirred for 1 hour. Next, the reaction mixture was reduced in pressure to remove the solvent, and the obtained 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 at room temperature and monitored by TLC, and EtOAc (8.0 mL) and water (4.0 mL) were added. The organic layer was separated and washed with 5% aqueous NaHCO ₃ and brine, then dried over MgSO ₄ , filtered and concentrated. The crude residue was purified by flash column chromatography (EtOAc: n -hexane = 1: 2) To give Deguelin 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)? 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, , 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> Cancer cell growth inhibition evaluation

In order to examine the degree of inhibition of growth of cancer cells by the compounds of the examples according to the present invention, the following experiment was conducted. Specifically, H1299 non-small cell lung cancer (NSCLC) cells were plated at a density of 5 × 10 ³ cells / well in a 96-well plate and cultured at 37 ^° C and 5% CO ₂ for 24 hours. The compound of each example was dissolved in DMSO (10 nM, 100 nM, 1 uM, 10 uM) and treated in each well. After 48 hours, the MTS reagent (3- (4,5-dimethylthiazol- 5- (3-carboxy-methoxyphenyl) -2- (4-sulfophenyl) -2 H - the tetrazolium), cell growth was measured using. 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 novel deguanelin derivatives according to the present invention were treated on H1299 NSCLC cells, the mean IC ₅₀ values of the cells were about 3 to 5 μM. In particular, Compound 14 of Example 6 exhibited an IC ₅₀ value of 0.01 μM, indicating that cancer cell growth inhibitory effect was about 10 times or more higher than that of conventionally known degueline of Comparative Example 1.

Therefore, the novel deguanelin derivatives according to the present invention are excellent in the effect of inhibiting the growth of cancer cells, and thus can be usefully used as anticancer agents and the like.

< Experimental Example  2> HIF -1α inhibition activity evaluation

The degree of inhibition of HIF-1α accumulation in H1299 NSCLC cells, a lung cancer cell line, was measured for deguline derivatives showing strong inhibition of cell growth through the above Experimental Example 1. Specifically, in order to confirm the effect of the compounds prepared in the examples of the present invention in the concentration-dependent inhibition of the production of HIF-1α protein induced by hypoxia conditions, the degenerate derivatives And the degree of production of HIF-1α protein by different treatment of the concentration of degulanin prepared in Comparative Example 1 were compared using Western blot analysis.

First, H1299 non-small cell lung cancer (NSCLC) cells were seeded at a density of 5 × 10 ³ cells / well on a 96-well plate and cultured for 24 hours. Then, hypoxic conditions (oxygen 1%, nitrogen 94% 5%) for 12 hours to induce accumulation of HIF-1.alpha., The compound of Formula 1 was dissolved in DMSO solvent and treated with H1299 NSCLC cells at a concentration of 0 to 10 .mu.M, And then the nuclear extract was prepared using RIPA buffer solution. 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. Approximately 30 μg of each of the nuclear extracts was separated by sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS PAGE), transferred to a polyvinylidene fluoride membrane, and incubated with 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 is a Western blot diagram showing the degree to which compounds according to one embodiment of the present invention inhibit HIF-1 alpha accumulation.

As shown in FIG. 1, the deguanelin derivatives prepared in one embodiment of the present invention inhibit the production of HIF-1α protein in a concentration-dependent manner without affecting the production of tubulin under hypoxic conditions Can be confirmed.

Therefore, the deguanelin derivatives according to the present invention inhibit the accumulation of HIF-1α, which is a malignant cancer, and thus can be effectively used as an active ingredient of an anticancer agent.

< Experimental Example  3> Assessment of inhibition of neovascularization

In order to confirm the degree of inhibition of VEGF (vascular endothelial growth factor A) by the deguanelin derivatives according to the present invention, experiments were carried out to examine the angiogenesis using transfected zebrafish.

Specifically, a striped fish embryo (Albino; Tg ( fli1 : EGFP ) ^{b4; y1} , Zebrafish International Resource Center, University of Oregon, Eugene) / L) for 6 hours. Ten groups of the striped fish embryos cultured in the above manner were divided into groups and were distributed to a 24-well plate together with 500 μL of positive water. The deguanelin derivatives of the respective examples were treated at concentrations of 50 nM, 250 nM and 1.25 μM. The amniotic fluid (including the degulline derivative of each of the examples) was replaced 48 hours after the experiment. Seventy-two hours after incubation, neovascularization was measured in a subintestinal vessel plexus (SIV) of each embryo using a Leica DM5000B fluorescence microscope (Leica Microsystems, Wetzlar GmbH, Germany).

FIG. 2 is a photograph showing the effect of Compound 53 according to an embodiment of the present invention on the angiogenesis.

FIG. 3 is a photograph showing the effect of Compound 69 according to an embodiment of the present invention on angiogenesis.

FIG. 4 is a photograph showing the effect of Compound 72 according to an embodiment of the present invention on angiogenesis.

As shown in FIG. 2, FIG. 3 and FIG. 4, when the deguaneline derivative according to the present invention was treated, it was confirmed that the number of angiogenesis was decreased in a concentration-dependent manner compared to no treatment.

Therefore, the deguanelin derivative according to the present invention has an activity of inhibiting angiogenesis, that is, it inhibits the activity of VEGF, a neovascularization factor, and thus 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 &lt; RTI ID = 0.0 &gt;

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 the compound of formula (1) or (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 the compound of formula (1) or (2)

Corn starch 100 mg

Lactose 100 mg

2 mg magnesium stearate

After mixing the above components, the capsules were filled in gelatin capsules according to the conventional preparation method of capsules.

< Formulation example  4> Preparation of injection solution

10 &lt; RTI ID = 0.0 &gt; pg / ml &lt; / RTI &

Dilute hydrochloric acid BP until pH 3.5

Injectable sodium chloride BP up to 1 ml

The pH of the resulting solution was adjusted to pH 3.5 with dilute hydrochloric acid BP and the volume was adjusted to pH 3.5 using injectable sodium chloride BP. Lt; / RTI &gt; The solution was filled in a 5 ml type I ampoule made of transparent glass, sealed in the upper lattice of the air by dissolving the glass, sterilized by autoclaving at 120 캜 for 15 minutes or longer, and an injection solution was prepared.

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 are, independently from each other, -H, -OH, C _1-4 straight or branched 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, acetate or phenylmethoxy;
R ⁵ is C _1-6 straight or branched alkyl or alkenyl;
R ⁶ is C _1-6 straight or branched alkyl or alkenyl, C _5-8 arylalkyl,

,

or

ego;
R ⁷ is —H, C _1-4 straight or branched alkyl, or C _5-8 arylalkyl,
In this case, R ⁴ and R ⁵ may form a 5-8 hexaheterocycle containing one or more O in the ring, and the ring may be substituted with one or more -OH or C _1-2 alkyl group,
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, acetate or phenylmethoxy;
R ⁵ is C _1-5 straight or branched alkyl or alkenyl;
R ⁶ is C _1-3 straight or branched alkyl or alkenyl, C _5-6 arylalkyl,

,

or

ego;
R ⁷ is —H, C _1-3 straight or branched alkyl, or C _5-6 arylalkyl,
In this case, R ⁴ and R ⁵ may form a 5-6 hexaheterocycle containing one or more O in the ring, and the ring may be substituted with one or more -OH or C _1-2 alkyl group. 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 or 5, 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- dihydro-chroman Agate [3,4- b] chromen -12 ( 6H ) -one,
(7a S, 13a S) -9- hydroxy -13,13a--dihydro-10-methoxy-3,3-dimethyl -3 H - chroman Agate [3,4- b] pyrano [2,3- h] chromene -7 (7a H) - one,
(7a S, 13a S) -10- hydroxy -13,13a--dihydro-9-methoxy-3,3-dimethyl -3 H - chroman Agate [3,4- b] pyrano [2,3- h] chromene -7 (7a H) - one,
(7a S, 13a S) -13,13a--dihydro-9,10-dihydroxy-3,3-dimethyl -3 H - chroman Agate [3,4- b] pyrano [2,3- h] chromen -7 (7a H) - one,
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 - chroman Agate [3,4- b] pyrano [2,3- - h ] chromene,
(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 ] chromene,
(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-ilrok City) -7,7a, 13,13a- tetrahydro Hydro- 3H -chromeno [3,4- b ] pyrano [2,3- h ]
(7 S, 7a S, 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-yl acetate,
(7 S, 7a S, 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-yl carbamate,
(13a S) -9,10- dimethoxy-3,3-dimethyl-dihydro -13,13a- -3 H - chroman Agate [3,4- b] pyrano [2,3- h] chromene,
(7a R, 13a S) -9,10- dimethoxy-3,3-dimethyl-dihydro -13,13a- -3 H - chroman Agate [3,4- b] pyrano [2,3- h] chroman Mentioned -7 (7a H) - one oxime,
(7a R, 13a S) -9,10- dimethoxy-3,3-dimethyl-dihydro -13,13a- -3 H - chroman Agate [3,4- b] pyrano [2,3- h] chroman (7aH) -one &lt; / RTI &gt; O -methyloxime,
(7a R, 13a S) -9,10- dimethoxy-3,3-dimethyl-dihydro -13,13a- -3 H - chroman Agate [3,4- b] pyrano [2,3- h] chroman (7aH) -one &lt; / RTI &gt; O -benzyloxime,
(7a S, 13a S) -9,10- dimethoxy-3,3-dimethyl-tetrahydro--2,3,13,13a- -1 H - chroman Agate [3,4- b] pyrano [2,3- - h] chromen -7 (7a H) - one,
(7a S, 13a S) -1,2- dihydroxy-9,10-dimethoxy-3,3-dimethyl-tetrahydro--2,3,13,13a- -1 H - chroman Agate [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,
(3-methyl-but-2-enyl) -12-oxo-6,6a, 12,12a-tetrahydrochromeno [3,4- b ] chromen-9- Yl 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.
delete delete delete delete delete delete A pharmaceutical composition for preventing or treating cancer containing the compound of claim 1 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 containing 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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