New benzopyrane derivative and its application

Abstract

FIELD: pharmaceutical; organic chemistry.SUBSTANCE: benzopyran derivative of formula 1, its pharmaceutically acceptable salt, stereoisomer and a pharmaceutical composition based on it. In Formula 1, X1, X2, X3, X4 and X5 each independently represent -CH=, =CH-, -N= or =N-; or -C= or =C- when substituted by R4 or R5 ; R1 is halogen, hydroxy, nitro, amino, cyano, C3-C8 cycloalkyl, C1-C7 alkylamino, di(C1-C7 alkyl)amino, C1-C7 alkylcarbonyl, halo-C1-C7 alkoxy, hydroxy-C1-C7 alkyl, hydroxy-C1-C7 alkoxy, C1-C7 alkylsulfonyl, C1-C7 alkylsulfonylamino, aminosulfonyloxy, 4-6-membered heterocycloalkyl, 5- or 6-membered heteroaryl, 4-6-membered heterocycloalkyl-oxy, 4-6-membered heterocyclyl-C1-C7 alkoxy or any one of the moieties of formulas (i)– (vii) presented in the claims; R2 and R3 each independently represent C1-C7 alkyl or halo-C1-C7 alkyl; R4 represents hydrogen, halogen, C1-C7 alkyl, C1-C7 alkylcarbonyl, halo-C1-C7 alkyl, carboxy, hydroxy-C1-C7 alkyl, 4- to 6-membered heterocycloalkylcarbonyl, or 4- to 6-membered heterocycloalkylcarbonyl substituted with C1-C7 alkyl or C1-C7 alkoxycarbonyl; R5 represents hydrogen; n represents an integer from 1 to 3; r and p represent an integer from 0 to 3; and q represents an integer from 1 to 4; wherein the 4- to 6-membered heterocycloalkyl has 1 or 2 heteroatoms selected from the group consisting of N and O; and the 5- or 6-membered heteroaryl has 1 or 2 heteroatoms selected from the group consisting of N, O and S; the remaining substituents are as defined in the claims. Provided that when R1 is hydroxy and n is 1, then i) R2 and R3 are not simultaneously C1-C7 alkyl, ii) at least one of X1, X2, X3, X4 and X5 is nitrogen, or iii) R4 is hydroxy-C1-C7 alkyl, 4-6-membered heterocycloalkylcarbonyl or 4-6-membered heterocycloalkylcarbonyl substituted with C1-C7 alkyl or C1-C7 alkoxycarbonyl; and when R1 is halogen or C1-C7 alkylamino, R4 and R5 are not simultaneously hydrogen.EFFECT: low-molecular derivatives of benzopyran of formula 1, which suppress cancer growth by blocking the polarization of M2-like tumor-associated macrophages (TAM).9 cl, 5 tbl, 149 ex

Description

[0001] FIELD OF TECHNOLOGY TO WHICH THE INVENTION RELATES

[0002] The present invention relates to a novel benzopyran derivative that can be used in the production of a drug for the treatment of cancer. More specifically, the present invention relates to a novel benzopyran derivative, which is a low-molecular compound with an inhibitory effect on macrophages and can be used in the production of a drug for the treatment of cancer.

[0003] The above-mentioned drug can be particularly used in the treatment of immune-related cancers by stimulating the immune system through inhibiting the differentiation of immune system macrophages.

[0004] STATE OF THE ART

[0005] Unlike traditional anticancer drugs, which directly target cancer cells, immunotherapeutic agents are therapeutic agents that stimulate the body's immune system to selectively attack cancer cells. Among the various immune functions of the human body, tumor immune surveillance is a system in which T cells recognize cancer cells among host immune cells during the developmental and growth stages of cancer cells. Various cytokines secreted by T cells mobilize immune cells around the tumor and destroy the cancer cells.Accordingly, cancer cells undergo a process of tumor immunoediting to evade T-cell targeting, and cancer cells themselves are known to have the ability to acquire immune tolerance in order to evade the immune surveillance of the human immune system, thereby allowing cancer cell growth and metastasis (References: Nature Reviews Clinical Oncology 16 (2019) 151–167; Cancer Immunotherapy, Immune Suppression and Tumor Growth, 2013, Chapter 7).

[0006] Therefore, it can be said that anticancer immunotherapeutic drugs are drugs designed to trigger the mechanism of restoration or enhance the immune system's ability to recognize or destroy tumors in order to overcome the immunosuppression or immune evasion mechanism acquired by cancer cells. Recently, typical cancer immunotherapy drugs include immune checkpoint inhibitors (CTLA4 inhibitors, PD-1 inhibitors, PD-L1 inhibitors), immune cell therapy drugs, cancer vaccines, immunoviral therapy drugs, and other similar drugs.

[0007] The tumor microenvironment (TME) is a complex environment that co-exists with cancer cells and enables their growth during tumor transformation into malignancy. Recent studies of the tumor microenvironment have shown that among various immune cells, some function actively to support or promote cancer growth, as opposed to the classic function of the host's defense mechanism. Therefore, research is actively underway to develop treatments that suppress cancer cell growth by regulating the activity of these cells. Immune cells present in the tumor microenvironment are primarily divided into myeloid cells and lymphocytes. These immune cells are derived from hematopoietic stem cells. The largest number of hematopoietic stem cells in the human body is found primarily in the bone marrow and lymphoid tissue.Myeloid cells undergo several stages of differentiation and ultimately differentiate into mast cells, macrophages, dendritic cells, and granulocytes (neutrophils, eosinophils, and basophils). Lymphocytes differentiate into B cells, T cells, NK cells, and other similar cells. Depending on their function, these cells exert tumor-promoting (pro-tumor), tumor-killing, or tumor-suppressing (antitumor) effects on cancer cells, respectively.

[0008] Tumor-associated macrophages (TAMs) are cells that terminally differentiate from myeloid cells and migrate to the tumor microenvironment via the bloodstream. Under various physiological and pathological conditions, these macrophages are clearly divided into M1 and M2 macrophages. M1 macrophages are activated by stimuli such as external pathogens and interferon gamma, secrete IL-12, inducing an inflammatory response, and are known to suppress cancer in the tumor microenvironment. M2 macrophages are known to exert anti-inflammatory effects when activated by IL-4, IL-10, IL-13, and other similar interleukins, and also promote cancer growth by secreting IL-10, TGF-β, VGEF, and other similar factors. In addition, M2 macrophages attenuate T cell cytotoxicity through immune function, promote the proliferation of Th2 cells instead of Th1 cells, and activate regulatory T cells (Treg), inducing immune tolerance.Regarding non-immune actions, they directly promote angiogenesis, support the invasion and metastatic ability of tumor cells, and induce tumor growth by suppressing cell death induced by anticancer drugs. Furthermore, for these reasons, the presence of tumor-associated macrophages (TAMs) has been reported to be clinically associated with poor prognosis in various types of cancer (References: European Jounal of Cancer 42 (2006) 717–727; Clinics 66 (2011) 1879–1886; Cancer Immunotherapy, Immune Suppression and Tumor Growth, 2013, Chapter 27; Med Biol Sci Eng 2 (2019) 1–5).

[0009] Recently, various attempts have been made to induce selective repolarization from M2 macrophages to M1 macrophages to achieve therapeutic effects in cancer by controlling macrophage polarization, but relatively few studies have been published on small molecule drugs that regulate polarization to develop into M2 macrophages (References: Korean Patent Application Publication No. 10-2020-0120624, Method and Composition for Macrophage Polarization; ACS Cent. Sci. 6 (2020) 1208-1222; International Journal of Oncology 50 (2017) 545-554; Inflammation, 43 (2020), 95-108; Cells 9 (2020) 1-24)).

[0010] Therefore, an object of the present invention is to develop a therapeutic agent that suppresses cancer growth by blocking the polarization of M2-like tumor-associated macrophages (TAMs) using low-molecular compounds of a benzopyran derivative.

[0011] Cited prior art documents

[0012] Patent documents

[0013] Korean Patent Application Publication No. 10-2020-0120624

[0014] Korean Patent Publication No. 10-0799246

[0015] Korean Patent Application Publication No. 10-2012-0060957

[0016] Korean Patent Application Publication No. 10-2016-0017934.

[0017] Non-patent documents

[0018] Nature Reviews Clinical Oncology 16 (2019) 151-167

[0019] Cancer Immunotherapy, Immune Suppression and Tumor Growth, 2013, Chapter 7

[0020] European Journal of Cancer 42 (2006) 717-727

[0021] Clinics 66 (2011) 1879-1886

[0022] Cancer Immunotherapy, Immune Suppression and Tumor Growth, 2013, Chapter 27

[0023] Med Biol Sci Eng 2 (2019) 1-5

[0024] ACS Cent. Sci. 6 (2020) 1208-1222

[0025] International Journal of Oncology 50 (2017) 545-554

[0026] Inflammation, 43 (2020), 95-108

[0027] Cells 9 (2020) 1-24

[0028] Chem. Commun., 2011, 47, 12754-12761

[0029] ACS Comb. Sci. 2012, 14, 124-134

[0030] J. Am. Chem. Soc. 2014, 136, 14629-14638.

[0031] DISCLOSURE OF THE INVENTION

[0032] TECHNICAL TASK

[0033] The technical problem to be solved in the present invention is to create a new benzopyran derivative or its pharmaceutically acceptable salt or isomer capable of enhancing immune activity in a tumor by suppressing the polarization of tumor-associated macrophages (TAM) in the tumor microenvironment (TME).

[0034] Furthermore, another technical problem to be solved in the present invention is to create a pharmaceutical composition comprising a benzopyran derivative or its pharmaceutically acceptable salt or isomer as an active ingredient together with a pharmaceutically acceptable carrier.

[0035] SOLUTION TO THE TECHNICAL PROBLEM

[0036] According to one aspect of the present invention, there is provided a compound of the following formula 1 or a pharmaceutically acceptable salt or isomer thereof:

[0037] [Formula 1]

[0038]

[0039] where

[0040] X1, X2, X3, X4, and X5 each independently represent carbon or nitrogen;

[0041] R1 is halogen, hydroxy, nitro, amino, cyano, alkyl, cycloalkyl, alkylamino, dialkylamino, alkylcarbonyl, haloalkyl, haloalkoxy, hydroxyalkyl, hydroxyalkoxy, alkylsulfonyl, alkylsulfonylamino, aminosulfonyloxy, 3-10-membered heterocycloalkyl, 5-10-membered heteroaryl, 3-10-membered heterocycloalkyl-oxy, 3-10-membered heterocyclyl-alkoxy, or any one of the moieties of the following formulas (i) to (vii), wherein the heterocycloalkyl or heteroaryl may be substituted with one or more substituents selected from the group consisting of hydroxy, carboxy, alkyl, alkylsulfonyl, alkylcarbonyl, oxo, hydroxyalkyl and halophenyl;

[0042]

[0043] Ra and Rb each independently represent hydroxy or alkoxy;

[0044] Rc represents hydrogen or alkyl;

[0045] Rd represents a direct chemical bond, carbonyl or sulfonyl;

[0046] Re is hydrogen, alkyl, haloalkyl, alkoxy, amino or 3- to 10-membered heterocycloalkyl;

[0047] Rf represents O or S;

[0048] Rg is hydrogen, alkyl, aminocarbonylalkyl or guanidinoalkyl;

[0049] Rh is hydrogen, alkyl, dialkylaminoalkyl, or may be condensed with Ri to form a 3- to 12-membered heterocycloalkyl, wherein the heterocycloalkyl may be substituted with one or more substituents selected from the group consisting of alkyl, oxo, aminoalkyl, dialkylaminoalkylcarbonyl, alkoxycarbonyl, acetylcarbonyl, 3- to 10-membered heterocycloalkyl, 5- to 10-membered heteroaryl, 3- to 10-membered heterocycloalkylcarbonyl, 3- to 10-membered heterocycloalkylalkyl, 5- to 10-membered heteroarylalkyl, acetylcarbonylheterocycloalkyl, alkoxyalkoxyalkoxyalkylcarbonyl, and alkylcarbonyl substituted with amino;

[0050] Ri is hydrogen, alkyl, aminoalkyl, carboxyalkyl, alkylaminoalkyl, dialkylaminoalkyl, alkylsulfonyl, alkylcarbonyl, 3- to 10-membered heterocycloalkyl, alkyl substituted with alkoxycarbonyl, guanidinoalkyl substituted with carboxy, acetylamino, or alkoxycarbonylalkyl;

[0051] Rj represents a direct chemical bond, alkylene, arylene-alkyleneoxy, or alkylene substituted by alkylcarbonylamino;

[0052] Rk is alkyl, alkoxycarbonylalkyl, alkoxy, trialkylamino, nitro, alkyl substituted with amino, aminocarbonylalkyl, 3- to 10-membered heterocycloalkyl, or 5- to 10-membered heteroaryl;

[0053] RL represents amino or dialkylamino;

[0054] Rm represents hydrogen or alkyl;

[0055] RN represents hydrogen or carboxyalkylcarbonyl;

[0056] R2 and R3 each independently represent alkyl or haloalkyl;

[0057] R4 is hydrogen, halogen, alkyl, alkylcarbonyl, haloalkyl, carboxy, hydroxyalkyl, 3- to 10-membered heterocycloalkylcarbonyl, or 3- to 10-membered heterocycloalkylcarbonyl substituted by alkyl or alkoxycarbonyl;

[0058] R5 represents hydrogen, halogen or alkyl;

[0059] n represents an integer between 1 and 3;

[0060] r and p represent an integer from 0 to 3; and

[0061] q represents an integer from 1 to 4;

[0062] provided that when R1 is hydroxy and n is 1, then i) R2 and R3 are not simultaneously alkyl, ii) at least one of X1, X2, X3, X4 and X5 is nitrogen, or iii) R4 is hydroxyalkyl, 3- to 10-membered heterocycloalkylcarbonyl, or 3- to 10-membered heterocycloalkylcarbonyl substituted with alkyl or alkoxycarbonyl; and

[0063] when R1 is halogen or alkylamino, then R4 and R5 are not both hydrogen; and

[0064] wherein heterocycloalkyl and heteroaryl have one or more heteroatoms selected from the group consisting of N, O and S.

[0065] Next, the present invention is described in more detail.

[0066] Unless otherwise defined, the following terms in the present invention have the meanings described below. Any terms not defined in the invention have the meanings generally accepted in the art.

[0067] In the present invention, the term "halogen", either alone or in combination with additional terms (e.g., haloalkyl), refers to fluorine (F), chlorine (Cl), bromine (Br), or iodine (I).

[0068] In the present invention, the term "hydroxyl" group refers to -OH.

[0069] In the present invention, the term "nitro group" refers to -NO2.

[0070] In the present invention, the term "amino", used alone or in combination, may refer to a primary, secondary or tertiary amino group attached via a nitrogen atom.

[0071] In the present invention, the term "cyano group" refers to -CN.

[0072] In the present invention, the term "carboxyl" group refers to -COOH.

[0073] In the present invention, the term "carbonyl" group refers to -C(=O)-.

[0074] In the present invention, the term "sulfonyl" group refers to -S(=O)2-.

[0075] In the present invention, the term "oxo group" refers to =O (that is, oxygen with a double bond).

[0076] In the present invention, the term "guanidino" group refers to -NH-C(=NH)-NH2.

[0077] In the present invention, the term "acetyl" group refers to -C(=O)-CH3.

[0078] In the present invention, the term "alkyl", either used alone or in combination with additional terms (e.g., haloalkyl), refers to a radical of a linear or branched saturated aliphatic hydrocarbon group having, for example, from 1 to 7 carbon atoms or from 1 to 5 carbon atoms. For example, alkyl may include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, tert-pentyl, 1-methylbutyl, 2-methylbutyl, 1-ethylpropyl, 1,2-dimethylpropyl and other similar alkyls, but not limited thereto.

[0079] In the present invention, the term "alkoxy" refers to an alkyloxy (-O-alkyl group) having, for example, 1 to 7 carbon atoms or 1 to 5 carbon atoms.

[0080] In the present invention, the term "alkylene" refers to a divalent linear or branched radical of a saturated aliphatic hydrocarbon group having, for example, from 1 to 7 carbon atoms or from 1 to 5 carbon atoms.

[0081] In the present invention, the term "cycloalkyl" refers to a radical of a cyclic saturated aliphatic hydrocarbon group having, for example, 3 to 10 carbon atoms or 3 to 8 carbon atoms. Typical examples of the cycloalkyl group may include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.

[0082] In the present invention, the term "aryl" refers to an aromatic hydrocarbon group having, for example, 6 to 10 carbon atoms. For example, aryl may include phenyl and naphthyl, but is not limited to.

[0083] In the present invention, the term "arylene" refers to a divalent aromatic hydrocarbon group having, for example, 6 to 10 carbon atoms.

[0084] In the present invention, the term "heterocycloalkyl" refers to a cyclic, for example, 3- to 10-membered or 4- to 8-membered saturated aliphatic hydrocarbon, including one or more heteroatoms selected from N, O and S as ring atoms.

[0085] In the present invention, the term "heteroaryl" refers to, for example, 5- to 10-membered or 5- to 8-membered aromatic hydrocarbons that form a single or fused ring that can be fused with benzo- or cycloalkyl, including one or more heteroatoms selected from N, O and S as ring atoms. Examples of heteroaryl include, but are not limited to, pyridyl, imidazolyl, pyrimidinyl, pyrazolyl, triazolyl, pyrazinyl, tetrazolyl, furyl, thienyl, isoxazolyl, thiazolyl, oxazolyl, isothiazolyl, pyrrolyl, quinolinyl, isoquinolinyl, indolyl, benzimidazolyl, benzofuranyl, cinnolinyl, indazolyl, indolizinyl, phthalazinyl, pyridazinyl, triazinyl, isoindolyl, pteridinyl, purinyl, oxadiazolyl, triazolyl, thiadiazolyl, furazanyl, benzofurazanyl, benzothiophenyl, benzothiazolyl, benzoxazolyl, quinazolinyl, quinoxalinyl, naphthyridinyl, or furopyridyl.

[0086] According to one embodiment of the present invention, in the above formula 1,

[0087] X1, X2, X3, X4 and X5 each independently represent -CH=, =CH-, -N= or =N-; or -C= or =C-, when substituted by R4 or R5;

[0088] R1 is halogen, hydroxy, nitro, amino, cyano, C1-C7 alkyl, C3-C 10 cycloalkyl, C1-C7 alkylamino, di(C1-C7 alkyl)amino, C1-C7 alkylcarbonyl, halo-C1-C7 alkyl, halo-C1-C7 alkoxy, hydroxy-C1-C7 alkyl, hydroxy-C1-C7 alkoxy, C1-C7 alkylsulfonyl, C1-C7 alkylsulfonylamino, aminosulfonyloxy, 3-10-membered heterocycloalkyl, 5-10-membered heteroaryl, 3-10-membered heterocycloalkyl-oxy, 3-10-membered heterocyclyl-alkoxy, or any one moiety described by general formulae (i) to (vii), wherein the heterocycloalkyl or heteroaryl may be substituted with from 1 to 4 substituents selected from the group consisting of hydroxy, carboxy, C1-C7 alkyl, C1-C7 alkylsulfonyl, C1-C7 alkylcarbonyl, oxo, hydroxy-C1-C7 alkyl and halophenyl;

[0089]

[0090] Ra and Rb each independently represent hydroxy or C1-C7alkoxy;

[0091] Rc represents hydrogen or C1-C7 alkyl;

[0092] Rd represents a direct chemical bond, carbonyl or sulfonyl;

[0093] Re is hydrogen, C1-C7 alkyl, halo-C1-C7 alkyl, C1-C7 alkoxy, amino or 3-10-membered heterocycloalkyl;

[0094] Rf represents O or S;

[0095] Rg represents hydrogen, C1-C7 alkyl, aminocarbonyl-C1-C7 alkyl or guanidino-C1-C7 alkyl;

[0096] Rh is hydrogen, C1-C7 alkyl, di(C1-C7 alkyl)amino-C1-C7 alkyl, or may be condensed with Ri to form a 3-12-membered heterocycloalkyl, wherein the heterocycloalkyl may be substituted with 1 to 4 substituents selected from the group consisting of C1-C7 alkyl, oxo, amino-C1-C7 alkyl, di(C1-C7 alkyl)amino-C1-C7 alkylcarbonyl, C1-C7 alkoxycarbonyl, acetylcarbonyl, 3-10-membered heterocycloalkyl, 5-10-membered heteroaryl, 3-10-membered heterocycloalkylcarbonyl, 3-10-membered heterocycloalkyl-C1-C7 alkyl, 5-10-membered heteroaryl-C1-C7alkyl, acetylcarbonyl-3-10-membered heterocycloalkyl, C1-C7alkoxy-C1-C7alkoxy-C1-C7alkoxy-C1-C7alkylcarbonyl and C1-C7alkylcarbonyl substituted with amino;

[0097] Ri is hydrogen, C1-C7 alkyl, amino-C1-C7 alkyl, carboxy-C1-C7 alkyl, C1-C7 alkylamino-C1-C7 alkyl, di(C1-C7 alkyl)amino-C1-C7 alkyl, C1-C7 alkylsulfonyl, C1-C7 alkylcarbonyl, 3- to 10-membered heterocycloalkyl, C1-C7 alkyl substituted with C1-C7 alkoxycarbonyl, guanidino-C1-C7 alkyl substituted with carboxy, acetylamino, or C1-C7 alkoxycarbonyl-C1-C7 alkyl;

[0098] Rj is a direct chemical bond, C1-C7 alkylene, C6-C 10 arylene-C1-C7alkyleneoxy or C1-C7alkylene substituted with C1-C7alkylcarbonylamino;

[0099] Rk is C1-C7 alkyl, C1-C7 alkoxycarbonyl-C1-C7 alkyl, C1-C7 alkoxy, tri(C1-C7 alkyl)amino, nitro, C1-C7 alkyl substituted with amino, aminocarbonyl-C1-C7 alkyl, 3- to 10-membered heterocycloalkyl, or 5- to 10-membered heteroaryl;

[0100] RL represents amino or di(C1-C7alkyl)amino;

[0101] Rm represents hydrogen or C1-C7 alkyl;

[0102] RN represents hydrogen or carboxy-C1-C7 alkylcarbonyl;

[0103] R2 and R3 each independently represent C1-C7 alkyl or halo-C1-C7 alkyl;

[0104] R4 represents hydrogen, halogen, C1-C7 alkyl, C1-C7 alkylcarbonyl, halo-C1-C7 alkyl, carboxy, hydroxy-C1-C7 alkyl, 3- to 10-membered heterocycloalkylcarbonyl, or 3- to 10-membered heterocycloalkylcarbonyl substituted with C1-C7 alkyl, or C1-C7 alkoxycarbonyl;

[0105] R5 represents hydrogen, halogen or C1-C7 alkyl;

[0106] n represents an integer between 1 and 3;

[0107] r and p represent an integer from 0 to 3; and

[0108] q represents an integer from 1 to 4;

[0109] provided that when R1 is hydroxy and n is 1, then i) R2 and R3 are not simultaneously C1-C7 alkyl, ii) at least one of X1, X2, X3, X4 and X5 is -N= or =N-, or iii) R4 is hydroxy-C1-C7 alkyl, 3-10-membered heterocycloalkylcarbonyl or 3-10-membered heterocycloalkylcarbonyl substituted with C1-C7 alkyl or C1-C7 alkoxycarbonyl; and

[0110] when R1 is halogen or C1-C7 alkylamino, R4 and R5 are not both hydrogen; and

[0111] wherein heterocycloalkyl and heteroaryl have from 1 to 4 heteroatoms selected from the group consisting of N, O and S.

[0112] According to one embodiment of the present invention, the compound of formula 1 is a compound of the following formula 2:

[0113] [Formula 2]

[0114]

[0115] where X1, X2, X4, X5, R1, R2, R3, R4, R5 and n are defined in formula 1.

[0116] According to one embodiment of the present invention, the compound of formula 1 is a compound of the following formula 3:

[0117] [Formula 3]

[0118]

[0119] where R1, R2, R3, R4, R5 and n are defined in formula 1.

[0120] According to one embodiment of the present invention, in the above formula 1,

[0121] R1 is halogen, hydroxy, nitro, amino, cyano, C1-C5 alkyl, C3-C8 cycloalkyl, C1-C5 alkylamino, di(C1-C5 alkyl)amino, C1-C5 alkylcarbonyl, halo-C1-C5 alkyl, halo-C1-C5 alkoxy, hydroxy-C1-C5 alkyl, hydroxy-C1-C5 alkoxy, C1-C5 alkylsulfonyl, C1-C5 alkylsulfonylamino, aminosulfonyloxy, 4- to 8-membered heterocycloalkyl, 5- to 8-membered heteroaryl, 4- to 8-membered heterocycloalkyloxy, 4- to 8-membered heterocyclylalkoxy, or any one moiety of the following formulae (i) to (vii); wherein heterocycloalkyl may be substituted with 1 to 4 substituents selected from the group consisting of hydroxy, carboxy, C1-C5 alkyl, C1-C5 alkylsulfonyl, C1-C5 alkylcarbonyl, oxo, hydroxy-C1-C5 alkyl and halophenyl; and heteroaryl may be substituted with 1 to 3 substituents selected from the group consisting of hydroxy, C1-C5 alkyl, C1-C5 alkylsulfonyl, C1-C5 alkylcarbonyl and hydroxy-C1-C5 alkyl;

[0122]

[0123] Ra and Rb each independently represent hydroxy or C1-C5alkoxy;

[0124] Rc represents hydrogen or C1-C5 alkyl;

[0125] Rd represents a direct chemical bond, carbonyl or sulfonyl;

[0126] Re is hydrogen, C1-C5 alkyl, halo-C1-C5 alkyl, C1-C5 alkoxy, amino or 3-10-membered heterocycloalkyl;

[0127] Rf represents O or S;

[0128] Rg represents hydrogen, C1-C5 alkyl, aminocarbonyl-C1-C5 alkyl or guanidino-C1-C5 alkyl;

[0129] Rh is hydrogen, C1-C5 alkyl, di(C1-C5 alkyl)amino-C1-C5 alkyl, or may be condensed with Ri to form a 4- to 8-membered heterocycloalkyl, wherein the heterocycloalkyl may be substituted with one or more substituents selected from the group consisting of C1-C5 alkyl, oxo, amino-C1-C5 alkyl, di(C1-C5 alkyl)amino-C1-C5 alkylcarbonyl, C1-C5 alkoxycarbonyl, acetylcarbonyl, 4- to 8-membered heterocycloalkyl, 5- to 8-membered heteroaryl, 4- to 8-membered heterocycloalkylcarbonyl, 4- to 8-membered heterocycloalkyl-C1-C5 alkyl, 5- to 8-membered heteroaryl-C1-C5 alkyl, acetylcarbonyl-4-8-membered heterocycloalkyl, C1-C5alkoxy-C1-C5alkoxy-C1-C5alkoxy-C1-C5alkylcarbonyl and C1-C5alkylcarbonyl substituted with amino;

[0130] Ri is hydrogen, C1-C5 alkyl, amino-C1-C5 alkyl, carboxy-C1-C5 alkyl, C1-C5 alkylamino-C1-C5 alkyl, di(C1-C5 alkyl)amino-C1-C5 alkyl, C1-C5 alkylsulfonyl, C1-C5 alkylcarbonyl, 3- to 10-membered heterocycloalkyl, C1-C5 alkyl substituted with C1-C5 alkoxycarbonyl, guanidino-C1-C5 alkyl substituted with carboxy, acetylamino, or C1-C5 alkoxycarbonyl-C1-C5 alkyl;

[0131] Rj is a direct chemical bond, C1-C5 alkylene, C6-C 10 arylene-C1-C5alkyleneoxy, C1-C5alkylene substituted with C1-C5alkylcarbonylamino;

[0132] Rk is C1-C5 alkyl, C1-C5 alkoxycarbonyl-Ci-C5 alkyl, C1-C5 alkoxy, tri(C1-C5 alkyl)amino, nitro, C1-C5 alkyl substituted with amino, aminocarbonyl-C1-C5 alkyl, 4- to 8-membered heterocycloalkyl, or 5- to 8-membered heteroaryl;

[0133] Rl represents amino or di(C1-C5alkyl)amino;

[0134] Rm represents hydrogen or C1-C5 alkyl; and

[0135] Rn represents hydrogen or carboxy-C1-C5alkylcarbonyl.

[0136] According to one embodiment of the present invention, in the above-mentioned formula 1, R2 and R3 each independently represent C1-C5 alkyl or halogen-C1-C5 alkyl.

[0137] According to one embodiment of the present invention, in the above formula 1,

[0138] R4 is hydrogen, halogen, C1-C5 alkyl, C1-C5 alkylcarbonyl, halo-C1-C5 alkyl, carboxy, hydroxy-C1-C5 alkyl, 4- to 8-membered heterocycloalkylcarbonyl, or 4- to 8-membered heterocycloalkylcarbonyl substituted with C1-C5 alkyl or C1-C5 alkoxycarbonyl; and

[0139] R5 represents hydrogen, halogen or C1-C5 alkyl.

[0140] Typical examples of the compound of formula 1 of the present invention may include, but are not limited to, the following compounds:

[0141] 1) 7,7-bis(fluoromethyl)-10-hydroxy-2-phenyl-5,12b-dihydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazine-1,3(2H)-dione;

[0142] 2) 2-(4-acetylphenyl)-7,7-bis(fluoromethyl)-10-hydroxy-5,12b-dihydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]-pyridazine-1,3(2H)-dione;

[0143] 3) N-(2-(4-acetylphenyl)-7,7-dimethyl-1,3-dioxo-2,3,5,12b-tetrahydroxy-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]-pyridazin-10-yl)acetamide;

[0144] 4) 2-(4-acetylphenyl)-7,7-dimethyl-10-(methylsulfonyl)-5,12b-dihydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]-pyridazine-1,3(2H)-dione;

[0145] 5) N-(2-(4-acetylphenyl)-7,7-dimethyl-1,3-dioxo-2,3,5,12b-tetrahydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazin-10-yl)methanesulfonamide;

[0146] 6) tert-butyl (2-(4-acetylphenyl)-7,7-dimethyl-1,3-dioxo-2,3,5,12b-tetrahydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]-pyridazin-10-yl)carbamate;

[0147] 7) 2-(4-acetylphenyl)-10-amino-7,7-dimethyl-5,12b-dihydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazine-1,3(2H)-dione;

[0148] 8) 2-(4-acetylphenyl)-7,7-dimethyl-10-morpholino-5,12b-dihydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazine-1,3(2H)-dione;

[0149] 9) N-(2-(4-acetylphenyl)-7,7-dimethyl-1,3-dioxo-2,3,5,12b-tetrahydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazin-10-yl)sulfate diamide;

[0150] 10) 2-(4-acetylphenyl)-9,11-dibromo-10-hydroxy-7,7-dimethyl-5,12b-dihydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]-pyridazine-1,3(2H)-dione;

[0151] 11) 2-(4-acetylphenyl)-9,11-dichloro-10-hydroxy-7,7-dimethyl-5,12b-dihydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]-pyridazine-1,3(2H)-dione;

[0152] 12) 2-(b-fluoropyridin-2-yl)-10-hydroxy-7,7-dimethyl-5,12b-dihydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazin-1,3(2H)-dione;

[0153] 13) 2-(4-acetylphenyl)-7,7-dimethyl-10-nitro-5,12b-dihydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo [1,2-a]pyridazine-1,3(2H)-dione;

[0154] 14) 2-(4-acetylphenyl)-10-(hydroxymethyl)-7,7-dimethyl-5,12b-dihydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazine-1,3(2H)-dione;

[0155] 15) 1-(2-(4-acetylphenyl)-7,7-dimethyl-1,3-dioxo-2,3,5,12b-tetrahydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazin-10-yl)urea;

[0156] 16) 2-(4-acetylphenyl)-10-(ethylamino)-7,7-dimethyl-5,12b-dihydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazine-1,3(2H)-dione;

[0157] 17) 2-(4-acetylphenyl)-7,7-dimethyl-10-((2,2,2-trifluoroethyl)-amino)-5,12b-dihydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo-[1,2-a]pyridazine-1,3(2H)-dione;

[0158] 18) 2-(4-acetylphenyl)-7,7-dimethyl-10-(piperazin-1-yl)-5,12b-dihydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]-pyridazine-1,3(2H)-dione hydrochloride;

[0159] 19) 2-(4-acetylphenyl)-10-(4-acetylpiperazin-1-yl)-7,7-di-methyl-5,12b-dihydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]-pyridazine-1,3(2H)-dione;

[0160] 20) 2-(5-acetylpyridin-2-yl)-10-hydroxy-7,7-dimethyl-5,12b-dihydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazine-1,3(2H)-dione;

[0161] 21) 10-acetyl-2-(4-acetylphenyl)-7,7-dimethyl-5,12b-dihydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazine-1,3(2H)-dione;

[0162] 22) 11-acetyl-2-(4-acetylphenyl)-10-hydroxy-7,7-dimethyl-5,12b-dihydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]-pyridazine-1,3(2H)-dione;

[0163] 23) 2-(6-acetylpyridin-3-yl)-10-hydroxy-7,7-dimethyl-5,12b-dihydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazine-1,3(2H)-dione;

[0164] 24) 2-(4-acetylphenyl)-7,7-dimethyl-1,3-dioxo-2,3,5,12b-tetrahydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazine-10-carbonitrile;

[0165] 25) 2-(4-acetylphenyl)-10-hydroxy-7,7-dimethyl-11-(trifluoromethoxy)-5,12b-dihydro-1H,7 H-chromeno[4,3-c][1,2,4]-triazolo-[1,2-a]pyridazine-1,3(2H)-dione;

[0166] 26) 2-(4-acetylphenyl)-11-cyclopropyl-10-hydroxy-7,7-dimethyl-5,12b-dihydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazine-1,3(2H)-dione;

[0167] 27) 2-(4-acetylphenyl)-9,11-difluoro-10-hydroxy-7,7-dimethyl-5,12b-dihydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]-pyridazine-1,3(2H)-dione;

[0168] 28) 2-(4-acetylphenyl)-10-amino-9,11-dibromo-7,7-dimethyl-5,12b-dihydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]-pyridazine-1,3(2H)-dione;

[0169] 29) 2-(4-acetylphenyl)-10-(isopropylamino)-7,7-dimethyl-5,12b-dihydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]-pyridazine-1,3(2H)-dione;

[0170] 30) 2-(4-acetylphenyl)-10-(tert-butylamino)-7,7-dimethyl-5,12b-dihydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]-pyridazine-1,3(2H)-dione;

[0171] 31) 2-(4-acetylphenyl)-10-amino-9,11-dichloro-7,7-dimethyl-5,12b-dihydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-azin]-pyrida,3,3(2)-dione;

[0172] 32) 2-(4-acetylphenyl)-7,7-dimethyl-10-(methylamino)-5,12b-dihydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazine-1,3(2H)dione;

[0173] 33) 2-(4-acetylphenyl)-10-(diethylamino)-7,7-dimethyl-5,12b-dihydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazine-1,3(2H)dione;

[0174] 34) 2-(4-acetylphenyl)-7,7-dimethyl-10-(pyrrolidin-1-yl)-5,12b-dihydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-azin]-pyrida,3-dione(2);

[0175] 35) 2-(4-fluorophenyl)-7,7-dimethyl-10-(oxetane-3-ylamino)-5,12b-dihydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]-pyrida-1),-3H(2H);

[0176] 36) 2-(4-acetylphenyl)-9,11-dichloro-7,7-dimethyl-10-(methyl-amino)-5,12b-dihydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a],3-pyrindazine-(2-H;

[0177] 37) 2-(4-acetylphenyl)-9,11-dichloro-10-(isopropylamino)-7,7-dimethyl-5,12b-dihydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazin-1,3(2H)-dione;

[0178] 38) 2-(4-acetylphenyl)-10-(1,3-dimethyl-1H-pyrazol-5-yl)-7,7-dimethyl-5,12b-dihydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazine-1,3(2H)-dione;

[0179] 39) 2-(4-acetylphenyl)-10-(2,5-dimethylthiazol-4-yl)-7,7-dimethyl-5,12b-dihydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazine-1,3(2H)-dione;

[0180] 40) 2-(4-acetylphenyl)-10-(1-ethyl-3,5-dimethyl-1H-pyrazol-4-yl)-7,7-dimethyl-5,12b-dihydro-1H,7H-chromeno[4,3-c][1,2,4]-triazolo[1,2-a]pyridazine-1,3(2H)-dione;

[0181] 41) 2-(4-acetylphenyl)-7,7-dimethyl-10-(3-methylisoxazol-4-yl)-5,12b-dihydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]-pyridazine-1,3(2H)-dione;

[0182] 42) 2-(4-acetylphenyl)-7,7-dimethyl-10-(pyridin-3-yl)-5,12b-dihydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazine-1,3(2H)-dione;

[0183] 43) 2-(4-acetylphenyl)-7,7-dimethyl-10-(pyridin-4-yl)-5,12b-dihydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazine-1,3(2H)-dione;

[0184] 44) 4-(7,7-dimethyl-1,3-dioxo-10-(pyrrolidin-1-yl)-5,12b-dihydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazin-2(3H)-yl)benzoic acid;

[0185] 45) 2-(4-acetylphenyl)-10-(isopropyl(methyl)amino)-7,7-di-methyl-5,12b-dihydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]-pyridazine-1,3(2H)-dione;

[0186] 46) 2-(4-acetylphenyl)-10-(ethyl(isopropyl)amino)-7,7-di-methyl-5,12b-dihydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]-pyridazine-1,3(2H)-dione;

[0187] 47) 2-(4-acetylphenyl)-10-(diisopropylamino)-7,7-dimethyl-5,12b-dihydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]-pyridazine-1,3(2H)-dione;

[0188] 48) 2-(4-(tert-butyl)phenyl)-7,7-dimethyl-10-(4-methyl-piperazin-1-yl)-5,12b-dihydro-1H,7H-chromeno[4,3-c][1,2,4]-triazolo[1,2-a]pyridazine-1,3(2H)-dione;

[0189] 49) 7,7-dimethyl-10-(4-methylpyrerazin-1-yl)-2-(4-(trifluoromethyl)phenyl)-5,12b-dihydro-1H,7 H-chromeno[4,3-c][1,2,4]-triazolo[1,2-a]pyridazine-1,3(2H)-dione;

[0190] 50) 2-(4-fluorophenyl)-7,7-dimethyl-10-(4-methylpiperazin-1-yl)-5,12b-dihydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]-pyridazine-1,3(2H)-dione;

[0191] 51) 2-(4-acetylphenyl)-7,7-dimethyl-10-(4-methyl-piperazin-1-yl)-5,12b-dihydro-1H,7 H-chromeno[4,3-c][1,2,4]-triazolo[1,2-a]-pyridazine-1,3(2H)-dione;

[0192] 52) 2-(4-acetylphenyl)-7,7-dimethyl-10-(4-(methylsulfonyl)-piperazin-1-yl)-5,12b-dihydro-1H,7H-chromeno[4,3-c][1,2,4]-triazolo[1,2-a]pyridazine-1,3(2H)-dione;

[0193] 53) 10-hydroxy-7,7-dimethyl-2-(4-(morpholine-4-carbonyl)-phenyl)-5,12b-dihydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazine-1,3(2H)-dione;

[0194] 54) tert-butyl 4-(4-(10-hydroxy-7,7-dimethyl-1,3-dioxo-5,12b-dihydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]-pyridazin-2(3H)-yl)benzoyl)piperazine-1-carboxylate;

[0195] 55) 10-hydroxy-7,7-dimethyl-2-(4-(piperazine-1-carbonyl)-phenyl)-5,12b-dihydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazine-1,3(2H)-dione;

[0196] 56) 10-hydroxy-7,7-dimethyl-2-(4-(4-methylpiperazine-1-carbonyl)phenyl)-5,12b-dihydro-1H,7H-chromeno[4,3-c][1,2,4]-triazolo[1,2-a]pyridazine-1,3(2H)-dione;

[0197] 57) 7,7-dimethyl-2-(4-(morpholine-4-carbonyl)phenyl)-10-(pyrrolidin-1-yl)-5,12b-dihydro-1H,7H-chromeno[4,3-c][1,2,4]-triazolo[1,2-a]pyridazine-1,3(2H)-dione;

[0198] 58) 2-(4-acetylphenyl)-7,7-dimethyl-1,3-dioxo-2,3,5,12b-tetrahydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazin-10-yl pivalate;

[0199] 59) 2-(4-acetylphenyl)-7,7-dimethyl-1,3-dioxo-2,3,5,12b-tetrahydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazin-10-yl 3-methylbutanoate;

[0200] 60) 2-(4-acetylphenyl)-7,7-dimethyl-1,3-dioxo-2,3,5,12b-tetrahydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazin-10-yl acetate;

[0201] 61) 2-(4-acetylphenyl)-7,7-dimethyl-1,3-dioxo-2,3,5,12b-tetrahydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazin-10-yl ethyl carbonate;

[0202] 62) 2-(4-acetylphenyl)-7,7-dimethyl-1,3-dioxo-2,3,5,12b-tetrahydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazin-10-yl dimethylcarbamate;

[0203] 63) 2-(4-acetylphenyl)-7,7-dimethyl-1,3-dioxo-2,3,5,12b-tetrahydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazin-10-yl morpholine-4-carboxylate;

[0204] 64) (2S,3S,4S,5R,6S)-6-((2-(4-acetylphenyl)-7,7-dimethyl-1,3-dioxo-2,3,5,12b-tetrahydro-1H,7H-chromeno[4,3-c][1,2,4]-triazolo[1,2-a]pyridazin-10-yl)oxy)-3,4,5-trihydroxytetra-hydro-2H-pyran-2-carboxylic acid;

[0205] 65) sodium (2S,3S,4S,5R,6S)-6-((2-(4-acetylphenyl)-7,7-dimethyl-1,3-dioxo-2,3,5,12b-tetrahydro-1H,7H-chromeno[4,3-c]-[1,2,4]triazolo[1,2-a]pyridazin-10-yl)oxy)-3,4,5-trihydroxy tetrahydro-2H-pyran-2-carboxylate;

[0206] 66) 2-(4-acetylphenyl)-7,7-dimethyl-1,3-dioxo-2,3,5,12b-tetrahydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-yldazine-a10-pyri 4-methylpiperazine-1-carboxylate hydrochloride;

[0207] 67) 2-(4-acetylphenyl)-7,7-dimethyl-1,3-dioxo-2,3,5,12b-tetrahydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-yldaxy-pia10la-pyri hydrochloride;

[0208] 68) 2-(4-acetylphenyl)-7,7-dimethyl-1,3-dioxo-2,3,5,12b-tetrahydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-yldazine-a10-pyri 4-(2-oxopropanoyl)piperazine-1-carboxylate;

[0209] 69) 2-(4-acetylphenyl)-7,7-dimethyl-1,3-dioxo-2,3,5,12b-tetrahydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-yldazine;droflosphry-pyri-

[0210] 70) disodium 2-(4-acetylphenyl)-7,7-dimethyl-1,3-dioxo-2,3,5,12b-tetrahydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[4,3-c][1,2,4]triazolo1];pyrida phyrida-a

[0211] 71) 1,3-dihydroxy-2-(hydroxymethyl)propane-2-amine 2-(4-acetylphenyl)-7,7-dimethyl-1,3-dioxo-2,3,5,12b-tetrahydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazine-10-yl phosphate;

[0212] 72) 2-(4-acetylphenyl)-7,7-dimethyl-1,3-dioxo-2,3,5,12b-tetrahydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,inadazine-yl10pycry- hydrochloride;

[0213] 73) 2-(4-acetylphenyl)-7,7-dimethyl-1,3-dioxo-2,3,5,12b-tetrahydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,ethyl2-yldazine (methyldazine)10-pyri carbonate;

[0214] 74) 2-(4-acetylphenyl)-7,7-dimethyl-1,3-dioxo-2,3,5,12b-tetrahydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,xyldazine-carolidine-pyridine-

[0215] 75) 2-(4-acetylphenyl)-7,7-dimethyl-1,3-dioxo-2,3,5,12b-tetrahydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-yldazine-a10-pyri (2,5,8,11-tetraoxatridecane-13-yl)carbonate;

[0216] 76) 2-(4-acetylphenyl)-7,7-dimethyl-1,3-dioxo-2,3,5,12b-tetrahydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazine-10-diethylcarbamate;

[0217] 77) 2-(4-acetylphenyl)-7,7-dimethyl-1,3-dioxo-2,3,5,12b-tetrahydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazine-10-glutaminate L- 2,2,2-trifluoroacetic acid;

[0218] 78) (((2-(4-acetylphenyl)-7,7-dimethyl-1,3-dioxo-2,3,5,12b-tetrahydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridyloxy-carbonyl-L))) 2,2,2-trifluoroacetic acid;

[0219] 79) 1-(2-(4-acetylphenyl)-7,7-dimethyl-1,3-dioxo-2,3,5,12b-tetrahydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazine-10-methyl) (2S)-pyrrolidine-1,2-dicarboxylate;

[0220] 80) methyl (((2-(4-acetylphenyl)-7,7-dimethyl-1,3-dioxo-2,3,5,12b-tetrahydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]-pyridazin-10-yl)oxy)-L-leucinate);

[0221] 81) 2-(4-acetylphenyl)-7,7-dimethyl-1,3-dioxo-2,3,5,12b-tetrahydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazin-10-yl L-leucinate 2,2,2-trifluoroacetic acid;

[0222] 82) 2-(4-acetylphenyl)-7,7-dimethyl-1,3-dioxo-2,3,5,12b-tetrahydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazin-10-yl 4-(L-prolyl)piperazine-1-carboxylate hydrochloride;

[0223] 83) 2-(4-acetylphenyl)-7,7-dimethyl-1,3-dioxo-2,3,5,12b-tetrahydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazin-10-yl methyl (2-(methylamino)ethyl)carbamate 2,2,2-trifluoroacetic acid;

[0224] 84) 2-(4-acetylphenyl)-7,7-dimethyl-1,3-dioxo-2,3,5,12b-tetrahydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazin-10-yl (2-aminoethyl)(ethyl)carbamate hydrochloride;

[0225] 85) 2-(4-acetylphenyl)-7,7-dimethyl-1,3-dioxo-2,3,5,12b-tetrahydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazin-10-yl methyl(pyrrolidin-3-yl)carbamate hydrochloride;

[0226] 86) 2-(4-acetylphenyl)-7,7-dimethyl-1,3-dioxo-2,3,5,12b-tetrahydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazin-10-yl bis(3-(dimethylamino)propyl)carbamate dihydrochloride;

[0227] 87) N-(((2-(4-acetylphenyl)-7,7-dimethyl-1,3-dioxo-2,3,5,12b-tetrahydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazin-10-yl)oxy)carbonyl)-N-methyl-L-alanine;

[0228] 88) sodium N-(((2-(4-acetylphenyl)-7,7-dimethyl-1,3-dioxo-2,3,5,12b-tetrahydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazin-10-yl)oxy)carbonyl)-N-methyl-L-alaninate;

[0229] 89) N-(((2-(4-acetylphenyl)-7,7-dimethyl-1,3-dioxo-2,3,5,12b-tetrahydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazin-10-yl)oxy)carbonyl)-N-methylglycine;

[0230] 90) sodium N-(((2-(4-acetylphenyl)-7,7-dimethyl-1,3-dioxo-2,3,5,12b-tetrahydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazin-10-yl)oxy)carbonyl)-N-methylglycinate;

[0231] 91) 3-((((2-(4-acetylphenyl)-7,7-dimethyl-1,3-dioxo-2,3,5,12b-tetrahydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-apromethylnoxyl)(10carboyl)amyl) acid;

[0232] 92) sodium 3-((((2-(4-acetylphenyl)-7,7-dimethyl-1,3-dioxo-2,3,5,12b-tetrahydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-apromethylnoxy)(10pamethyl)amyl)yl);

[0233] 93) 2-(4-acetylphenyl)-7,7-dimethyl-1,3-dioxo-2,3,5,12b-tetrahydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-yldazine-a10-pyri 4-(aminomethyl)piperidine-1-carboxylate trifluoroacetate;

[0234] 94) 2-(4-acetylphenyl)-7,7-dimethyl-1,3-dioxo-2,3,5,12b-tetrahydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-yldazine-a10-pyri 4-(piperidine-4-yl)piperazine-1-carboxylate dihydrochloride;

[0235] 95) 2-(4-acetylphenyl)-7,7-dimethyl-1,3-dioxo-2,3,5,12b-tetrahydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-yldazine-a10-pyri 4-(pyridine-2-ylmethyl)piperazine-1-carboxylate dihydrochloride;

[0236] 96) 2-(4-acetylphenyl)-7,7-dimethyl-1,3-dioxo-2,3,5,12b-tetrahydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-yldazine-a10-pyri 4-(2-(2-(2-methoxyethoxy)ethoxy)acetyl)piperazine-1-carboxylate;

[0237] 97) 2-(4-acetylphenyl)-7,7-dimethyl-1,3-dioxo-2,3,5,12b-tetrahydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-yldazine-a10-pyri 4-(L-valyl)piperazine-1-carboxylate formate;

[0238] 98) 2-(4-acetylphenyl)-7,7-dimethyl-1,3-dioxo-2,3,5,12b-tetrahydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a10-pyri 4-(L-leucyl)piperazine-1-carboxylate hydrochloride;

[0239] 99) 2-(4-acetylphenyl)-7,7-dimethyl-1,3-dioxo-2,3,5,12b-tetrahydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-yldazine-a10-pyri 4-(dimethylglycyl)piperazine-1-carboxylate hydrochloride;

[0240] 100) 2-(4-acetylphenyl)-7,7-dimethyl-1,3-dioxo-2,3,5,12b-tetrahydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyri 2,6-dimethylpiperazine-1-carboxylate hydrochloride;

[0241] 101) 2-(4-acetylphenyl)-7,7-dimethyl-1,3-dioxo-2,3,5,12b-tetrahydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazin-10-yl 2,6-dimethyl-4-prolylpiperazine-1-carboxylate hydrochloride;

[0242] 102) 2-(4-acetylphenyl)-7,7-dimethyl-1,3-dioxo-2,3,5,12b-tetrahydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazin-10-ylheptanoate;

[0243] 103) 2-(4-acetylphenyl)-7,7-dimethyl-1,3-dioxo-2,3,5,12b-tetrahydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazin-10-yl 2,2-dimethylbutanoate;

[0244] 104) 2-(4-acetylphenyl)-7,7-dimethyl-1,3-dioxo-2,3,5,12b-tetrahydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazin-10-yl ethyl succinate;

[0245] 105) 2-(4-acetylphenyl)-7,7-dimethyl-1,3-dioxo-2,3,5,12b-tetrahydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazin-10-yl diisopropylcarbamate;

[0246] 106) 2-(4-acetylphenyl)-7,7-dimethyl-1,3-dioxo-2,3,5,12b-tetrahydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazin-10-yl isopropyl carbonate;

[0247] 107) 2-(4-acetylphenyl)-7,7-dimethyl-1,3-dioxo-2,3,5,12b-tetrahydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazin-10-yl (2-((2-hydroxyethyl)disulfanyl)ethyl)carbonate;

[0248] 108) 4-(2-((2-((((2-(4-acetylphenyl)-7,7-dimethyl-1,3-dioxo-2,3,5,12b-tetrahydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazin-10-yl)oxy)carbonyl)oxy)ethyl)disulfanyl)ethoxy)-4-oxobutanoic acid;

[0249] 109) sodium 4-(2-((2-((((2-(4-acetylphenyl)-7,7-dimethyl-1,3-dioxo-2,3,5,12b-tetrahydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo-[1,2-a]pyridazin-10-yl)oxy)carbonyl)oxy)ethyl)disulfanyl)ethoxy)-4-oxobutanoate;

[0250] 110) 2-(4-acetylphenyl)-10-(2-hydroxyethoxy)-7,7-dimethyl-5,12b-dihydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]-pyridazine-1,3(2H)-dione;

[0251] 111) 2-((2-(4-acetylphenyl)-7,7-dimethyl-1,3-dioxo-2,3,5,12b-tetrahydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazin-10-yl)oxy)ethyl L-leucinate hydrochloride;

[0252] 112) 2-(4-acetylphenyl)-7,7-dimethyl-10-(2-(piperidin-1-yl)-ethoxy)-5,12b-dihydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo-[1,2-a]pyridazine-1,3(2H)-dione hydrochloride;

[0253] 113) 2-(4-acetylphenyl)-7,7-dimethyl-10-(2-morpholino-ethoxy)-5,12b-dihydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]-pyridazine-1,3(2H)-dione formate;

[0254] 114) (((2-(4-acetylphenyl)-7,7-dimethyl-1,3-dioxo-2,3,5,12b-tetrahydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazin-10-yl)oxy)methyl)phosphonic acid;

[0255] 115) disodium (((2-(4-acetylphenyl)-7,7-dimethyl-1,3-dioxo-2,3,5,12b-tetrahydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]-pyridazin-10-yl)oxy)methyl)phosphonate;

[0256] 116) 2-((2-(4-acetylphenyl)-7,7-dimethyl-1,3-dioxo-2,3,5,12b-tetrahydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]-pyridazin-10-yl)oxy)ethyl dimethylglycine hydrochloride;

[0257] 117) 2-(4-acetylphenyl)-7,7-dimethyl-1,3-dioxo-2,3,5,12b-tetrahydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazin-10-yl 4-(1-(2-oxopropanoyl)piperidin-4-yl)piperazine-1-carboxylate hydrochloride;

[0258] 118) 2-(4-acetylphenyl)-7,7-dimethyl-1,3-dioxo-2,3,5,12b-tetrahydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazin-10-yl 2,2-dimethylpiperazine-1-carboxylate hydrochloride;

[0259] 119) 2-(4-acetylphenyl)-7,7-dimethyl-1,3-dioxo-2,3,5,12b-tetrahydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazin-10-yl 4-(dimethylglycyl)-2,2-dimethylpiperazine-1-carboxylate hydrochloride;

[0260] 120) 2-(4-acetylphenyl)-10-(3-(4-(3-chlorophenyl)piperazin-1-yl)rgoroxy)-7,7-dimethyl-5,12b-dihydro-1H,7H-chromeno[4,3-c]-[1,2,4]triazolo[1,2-a]pyridazin-1,3(2H)-dione dihydrochloride;

[0261] 121) 2-(4-acetylphenyl)-7,7-dimethyl-10-(((2S,3R,4S,5S,6R)-3,4,5-trihydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-2-yl)-oxy)-5,12b-dihydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]-pyridazine-1,3(2H)-dione;

[0262] 122) 2-(4-acetylphenyl)-7,7-dimethyl-10-(((2S,3R,4S,5R,6R)-3,4,5-trihydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-2-yl)-oxy)-5,12b-dihydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]-pyridazine-1,3(2H)-dione;

[0263] 123) 2-((2-(4-acetylphenyl)-7,7-dimethyl-1,3-dioxo-2,3,5,12b-tetrahydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]-pyridazin-10-yl)oxy)-N,N,N-trimethyl-2-oxoethane-1-aminium iodide;

[0264] 124) 2-(4-acetylphenyl)-7,7-dimethyl-1,3-dioxo-2,3,5,12b-tetrahydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazin-10-yl (4-nitrobenzyl)carbonate;

[0265] 125) 2-(4-acetylphenyl)-7,7-dimethyl-1,3-dioxo-2,3,5,12b-tetrahydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazin-10-yl piperidin-1-carboxylate;

[0266] 126) O-(2-(4-acetylphenyl)-7,7-dimethyl-1,3-dioxo-2,3,5,12b-tetrahydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[-barymyl,2-zinoethyl-a]

[0267] 127) 2-(4-acetylphenyl)-7,7-dimethyl-1,3-dioxo-2,3,5,12b-tetrahydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyri 2-oxoimidazolidine-1-carboxylate;

[0268] 128) 2-(4-acetylphenyl)-7,7-dimethyl-1,3-dioxo-2,3,5,12b-tetrahydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyri (3-(dimethylamino)-2,2-dimethylpropyl)carbamate formate;

[0269] 129) 2-(4-acetylphenyl)-7,7-dimethyl-1,3-dioxo-2,3,5,12b-tetrahydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyri (2-(dimethylamino)ethyl)(methyl)carbamate formate;

[0270] 130) 2-(4-acetylphenyl)-7,7-dimethyl-1,3-dioxo-2,3,5,12b-tetrahydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyri methyl(piperidine-3-yl)carbamate hydrochloride;

[0271] 131) 2-(4-acetylphenyl)-7,7-dimethyl-1,3-dioxo-2,3,5,12b-tetrahydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazin-10-yl methyl(methylsulfonyl)carbamate;

[0272] 132) 2-(4-acetylphenyl)-7,7-dimethyl-1,3-dioxo-2,3,5,12b-tetrahydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazin-10-yl L-valinate 2,2,2-trifluoroacetic acid;

[0273] 133) 2-(4-acetylphenyl)-7,7-dimethyl-1,3-dioxo-2,3,5,12b-tetrahydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazin-10-yl L-prolinate 2,2,2-trifluoroacetic acid;

[0274] 134) 2-(4-acetylphenyl)-7,7-dimethyl-1,3-dioxo-2,3,5,12b-tetrahydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazin-10-yl acetyl-L-glutamate;

[0275] 135) 2-(4-acetylphenyl)-7,7-dimethyl-1,3-dioxo-2,3,5,12b-tetrahydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazin-10-yl L-argininate 2,2,2-trifluoroacetic acid;

[0276] 136) methyl (((2-(4-acetylphenyl)-7,7-dimethyl-1,3-dioxo-2,3,5,12b-tetrahydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]-pyridazin-10-yl)oxy)-L-carbonylate);

[0277] 137) 2-(4-acetylphenyl)-7,7-dimethyl-1,3-dioxo-2,3,5,12b-tetrahydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazine-10-sulfamate;

[0278] 138) 2-(4-acetylphenyl)-7,7-dimethyl-1,3-dioxo-2,3,5,12b-tetrahydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazinyl-10-picloride hydrochloride;

[0279] 139) 2-(4-acetylphenyl)-7,7-dimethyl-1,3-dioxo-2,3,5,12b-tetrahydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazine-10-isochloride hydrochloride;

[0280] 140) 10-hydroxy-2-(4 -(1-hydroxyethyl)phenyl)-7,7-dimethyl-5,12b-dihydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]-pyrida-1,3H(2H)-dione;

[0281] 141) 2-(4-acetylphenyl)-10-(azetidin-1-yl)-7,7-dimethyl-5,12b-dihydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]-pyrida-1),-3H(2H);

[0282] 142) 7,7-dimethyl-1,3-dioxo-2-(4-(trifluoromethyl)phenyl)-2,3,5,12b-tetrahydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]-pyridazin-10-yl dihydrogen phosphate;

[0283] 143) 2-(4-fluorophenyl)-7,7-dimethyl-1,3-dioxo-2,3,5,12b-tetrahydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazin-10-yl dihydrogen phosphate;

[0284] 144) 2-(4-(tert-butyl)phenyl)-7,7-dimethyl-1,3-dioxo-2,3,5,12b-tetrahydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]-pyridazin-10-yl dihydrogen phosphate;

[0285] 145) 7,7-dimethyl-1,3-dioxo-2-(4-(trifluoromethyl)phenyl)-2,3,5,12b-tetrahydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]-pyridazin-10-yl dimethylcarbamate;

[0286] 146) 2-(4-fluorophenyl)-7,7-dimethyl-1,3-dioxo-2,3,5,12b-tetrahydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazin-10-yl dimethylcarbamate and

[0287] 147) 2-(4-(tert-butyl)phenyl)-7,7-dimethyl-1,3-dioxo-2,3,5,12b-tetrahydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]-pyridazin-10-yl dimethylcarbamate.

[0288] The names of the compounds above are given according to the nomenclature used in the computer program CS ChemDraw Ultra (version: 19.0.1.28) from CambridgeSoft.

[0289] The compound of formula 1 according to the present invention may have a center with an asymmetric carbon atom and an asymmetric axis or an asymmetric plane, whereby the compound may exist in the form of stereoisomers such as E or Z isomers, R or S isomers, and racemates, and all of these isomers and mixtures are included in the scope of the present invention. The compound of formula 1 according to the present invention may be a racemate, and this racemate can be separated by a conventional separation method, for example, by chiral column chromatography with a normal phase or a reversed phase, using an appropriate developing solvent, preferably a mixture of hexane, ethyl acetate, dichloromethane and methanol in the case of a normal phase, and a mixed solution of water and acetonitrile in the case of a reversed phase.

[0290] Furthermore, the compound of formula 1 of the present invention can form pharmaceutically acceptable salts. Typical acids that can be used to prepare such pharmaceutically acceptable salts include, but are not limited to, the following acids. Examples include acids that form non-toxic acid addition salts containing anions, for example, inorganic acids such as hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid, hydrobromic acid, hydroiodic acid; organic carboxylic acids such as tartaric acid, formic acid, citric acid, acetic acid, trichloroacetic acid or trifluoroacetic acid, gluconic acid, benzoic acid, lactic acid, fumaric acid, maleic acid, and sulfonic acids such as methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid or naphthalenesulfonic acid.Pharmaceutically acceptable salts also include alkali metal salts, such as sodium and potassium. Furthermore, pharmaceutically acceptable salts may include salts of other acids or bases, such as aromatic amidine derivatives or lactam derivatives, which are known and used in the art. These can be prepared by conventional methods.

[0291] The compounds of the present invention having the structure of formula 1 can be obtained by the method described in the examples below, but this method is not limiting the use of other methods.

[0292] According to another aspect of the present invention, there is provided a pharmaceutical composition comprising a therapeutically effective amount of a compound of formula 1 or a pharmaceutically acceptable salt or isomer thereof as an active ingredient together with a pharmaceutically acceptable carrier.

[0293] The compound of formula 1 according to the present invention has anticancer activity in the treatment of cancer diseases. The compound of formula 1 according to the present invention is a therapeutic agent for the treatment of cancer diseases and can be used in the treatment of cancer diseases, in particular, cancer diseases selected from the group consisting of colon cancer, skin cancer, melanoma, glioblastoma, bone cancer, liver cancer, stomach cancer, pancreatic cancer, colon cancer, rectal cancer, blood cancer, bladder cancer, kidney cancer, biliary tract cancer, cervical cancer, uterine cancer, ovarian cancer, breast cancer, lung cancer, non-small cell lung cancer, esophageal cancer, small intestine cancer, endocrine cancer, thyroid cancer and parathyroid cancer.

[0294] The pharmaceutical composition of the present invention can be prepared by mixing a therapeutically effective amount of a compound of formula 1 or a pharmaceutically acceptable salt or isomer thereof as an active ingredient with a pharmaceutically acceptable carrier, binder, stabilizer and / or diluent. Furthermore, when the pharmaceutical composition of the present invention is prepared in a liquid form for injection, the compound of formula 1 or a pharmaceutically acceptable salt or isomer thereof can be mixed with a pharmaceutically acceptable buffer, a dissolution promoting agent and / or an isotonic agent.

[0295] The pharmaceutical composition of the present invention can be prepared in a dosage form comprising one or more single doses of the drug using a preparation method known or available to a skilled person and a suitable pharmaceutical excipient. In the method of the present invention, the composition can be administered by an appropriate route of administration, for example, orally or parenterally, transdermally, rectally, topically or intraocularly, or by inhalation. The pharmaceutical composition can be prepared in the form of a tablet, capsule, sachet, sugar-coated tablet, powder, granules, lozenges, powder for solution, liquid preparation, or suppository. For example, the composition can be prepared in the form of an intravenous injection, spray, topical, or oral use.

[0296] When preparing the composition in an oral dosage form, any generally accepted pharmaceutical carriers can be used. For example, water, glycols, oils, alcohols, and other similar substances can be used as a carrier in the case of liquid oral forms such as suspensions, syrups, elixirs, and solutions; and starch, sugar, kaolin, lubricants, binders, disintegrants, and other similar substances can be used as a carrier in the case of solid forms such as powders, pills, capsules, and tablets. Due to the ease of administration, tablets and capsules are the most convenient dosage forms, and it is preferable when tablets and pills are prepared in an enteric-coated form.

[0297] For parenteral dosage forms, sterilized water is generally used, but other ingredients, such as a dissolution aid, may also be included. Injectable forms, such as sterilized aqueous or oily injection suspensions, can be prepared by known methods using an appropriate dispersing agent, wetting agent, or suspending agent. Solvents used for this purpose include water, Ringer's solution, and isotonic NaCl solution, and sterilized immobilized oils are generally used as a solvent or suspending medium. Any non-irritating immobilized oils, including mono- and diglycerides, can be used for this purpose, and fatty acids such as oleic acid can be used to prepare the injectable dosage form.

[0298] For transdermal dosage forms, the carrier may be a penetration enhancer and / or a suitable wetting agent, optionally in combination with a suitable non-irritating skin additive(s). Such additives may be selected to facilitate more effective transdermal administration and / or facilitate the preparation of the desired dosage form. The transdermal dosage form may be administered by various routes, such as a transdermal patch, spot treatment, or ointment.

[0299] The administration time and dosage of the pharmaceutical composition of the present invention can be appropriately determined based on the patient's disease, condition, age, body weight, and administration route. For adult patients, the pharmaceutical composition can be administered in an amount of 0.1 to 2000 mg, preferably 1 to 200 mg per day, in a single dose or in multiple doses, but these regimens are not limited to other options.

[0300] EFFECTS OF INVENTION

[0301] The compound of Formula 1 or a pharmaceutically acceptable salt or isomer thereof according to the present invention has an inhibitory effect on the polarization of M2 macrophages. In particular, the compound of Formula 1 or a pharmaceutically acceptable salt or isomer thereof according to the present invention exhibits an effective anti-cancer effect in a syngeneic tumor model in mice in which B16F10 melanoma cells are transplanted into C57BL / 6 mice, and enables effective treatment of cancers such as skin cancer, various solid cancers and blood cancer, in the form of monotherapy or combination therapy with traditional immunosuppressants.

[0302] EMBODIMENT OF THE INVENTION

[0303] The present invention is further explained in more detail using the following examples and experimental examples. However, it should be noted that these examples and experimental examples do not limit the scope of legal protection of the present invention.

[0304] The meanings of the abbreviated symbols used in the following examples are given below.

[0305]

[0306] Intermediate 1. Synthesis of 4-(4-acetylphenyl)-1,2,4-triazolidine-3,5-dione

[0307] (a) Synthesis of methyl 2-((4-acetylphenyl)carbamoyl)-hydrazine-1-carboxylate

[0308] N-aminocarbamate (5.59 g, 62.05 mmol) was dissolved in tetrahydrofuran (400 mL), and 1-(4-isocyanatophenyl)ethan-1-one (10 g, 62.05 mmol) was added and stirred at room temperature for 15 hours. After completion of the reaction, the resulting solid was filtered, washed with hexane (200 mL), and dried to give methyl 2-((4-acetylphenyl)carbamoyl)hydrazine-1-carboxylate (15.4 g, 98%).

[0309] (b) Synthesis of 4-(4-acetylphenyl)-1,2,4-triazolidine-3,5-dione

[0310] Methyl 2-((4-acetylphenyl)carbamoyl)hydrazine-1-carboxylate (15 g, 59.7 mmol) and potassium carbonate (37.13 g, 268.67 mmol) were added to water (600 mL) and stirred under reflux for 15 hours. After completion of the reaction, the reaction mixture was cooled to room temperature, insoluble impurities were removed by filtration, and concentrated hydrochloric acid (pH < 2) was added dropwise to the filtrate to precipitate a solid. The resulting solid was filtered, triturated with a mixed solvent of ethyl acetate / hexane, filtered and dried to give 4-(4-acetylphenyl)-1,2,4-triazolidine-3,5-dione (11 g, 84%).

[0311] Intermediate 2. Synthesis of 4-(4-(trifluoromethyl)-phenyl)-1,2,4-triazolidine-3,5-dione

[0312] (a) Synthesis of methyl 2-((4-(trifluoromethyl)phenyl)-carbamoyl)-hydrazine-1-carboxylate

[0313] To obtain methyl 2-((4-(trifluoromethyl)phenyl)carbamoyl)hydrazine-1-carboxylate (96%), the same synthesis as the above synthesis of intermediate 1(a) was carried out, except that 1-isocyanato-4-(trifluoromethyl)benzene was used instead of 1-(4-isocyanatophenyl)ethan-1-one.

[0314] (b) Synthesis of 4-(4-(trifluoromethyl)phenyl)-1,2,4-triazolidine-3,5-dione

[0315] To obtain 4-(4-(trifluoromethyl)phenyl)-1,2,4-triazolidine-3,5-dione (94%), the same synthesis as the above synthesis of intermediate 1(b) was carried out, except that methyl 2-((4-(trifluoromethyl)phenyl)carbamoyl)hydrazine-1-carboxylate was used instead of methyl 2-((4-(trifluoromethyl)phenyl)carbamoyl)hydrazine-1-carboxylate.

[0316] Intermediate 3. Synthesis of 4-(4-fluorophenyl)-1,2,4-triazolidine-3,5-dione

[0317] (a) Synthesis of methyl 2-((4-fluorophenyl)carbamoyl)-hydrazine-1-carboxylate

[0318] To obtain methyl 2-((4-fluorophenyl)carbamoyl)hydrazine-1-carboxylate (98%), the same synthesis as the above synthesis of intermediate 1(a) was carried out, except that 1-fluoro-4-isocyanatobenzene was used instead of 1-(4-isocyanatophenyl)ethan-1-one.

[0319] (b) Synthesis of 4-(4-fluorophenyl)-1,2,4-triazolidine-3,5-dione

[0320] To obtain 4-(4-fluorophenyl)-1,2,4-triazolidine-3,5-dione (93%), the same synthesis as the above synthesis of intermediate 1(b) was carried out, except that 2-((4-fluorophenyl)carbamoyl)hydrazine-1-carboxylate was used instead of methyl 2-((4-acetylphenyl)carbamoyl)hydrazine-1-carboxylate.

[0321] Intermediate 4. Synthesis of 4-(4-(tert-butyl)phenyl)-1,2,4-triazolidine-3,5-dione

[0322] (a) Synthesis of methyl 2-((4-(tert-butyl)phenyl)carbamoyl)-hydrazine-1-carboxylate

[0323] To obtain methyl 2-((4-(tert-butyl)phenyl)carbamoyl)-hydrazine-1-carboxylate (98%), the same synthesis as the above synthesis of intermediate 1(a) was carried out, except that 1-(tert-butyl)-4-isocyanatobenzene was used instead of 1-(4-isocyanato)ethan-1-one.

[0324] (b) Synthesis of 4-(4-(tert-butyl)phenyl)-1,2,4-triazolidine-3,5-dione

[0325] To obtain 4-(4-(tert-butyl)phenyl)-1,2,4-triazolidine-3,5-dione (95%), the same synthesis as the above synthesis of intermediate 1(b) was carried out, except that 2-((4-(tert-butyl)phenyl)carbamoyl)hydrazine-1-carboxylate was used instead of methyl 2-((4-acetylphenyl)carbamoyl)hydrazine-1-carboxylate.

[0326] Intermediate 5. Synthesis of 4-(4-bromophenyl)-1,2,4-triazolidine-3,5-dione

[0327] (a) Synthesis of methyl 2-((4-bromophenyl)carbamoyl)-hydrazine-1-carboxylate

[0328] To obtain 2-((4-bromophenyl)carbamoyl)hydrazine-1-carboxylate (55%), the same synthesis as the above synthesis of intermediate 1(a) was carried out, except that 1-bromo-4-isocyanatobenzene was used instead of 1-(4-isocyanato)ethan-1-one.

[0329] (b) Synthesis of 4-(4-bromophenyl)-1,2,4-triazolidine-3,5-dione

[0330] To obtain 4-(4-bromophenyl)-1,2,4-triazolidine-3,5-dione (42%), the same synthesis as the above synthesis of intermediate 1(b) was carried out, except that methyl 2-((4-acetylphenyl)carbamoyl)hydrazine-1-carboxylate was used instead of methyl 2-((4-bromophenyl)carbamoyl)hydrazine-1-carboxylate.

[0331] Intermediate 6. Synthesis of 4-(3,5-dioxo-1,2,4-triazolidin-4-yl)benzoic acid

[0332] (a) Synthesis of 4-(2-(methoxycarbonyl)hydrazine-1-carboxamido)benzoic acid

[0333] To obtain 4-(2-(methoxycarbonyl)hydrazine-1-carboxamido)benzoic acid (77%), the same synthesis as the above synthesis of intermediate 1(a) was carried out, except that 4-isocyanatobenzoic acid was used instead of 1-(4-isocyanato)ethan-1-one.

[0334] (b) Synthesis of 4-(3,5-dioxo-1,2,4-triazolidin-4-yl)benzoic acid

[0335] To obtain 4-(3,5-dioxo-1,2,4-triazolidin-4-yl)benzoic acid (57%), the same synthesis as the above synthesis of intermediate 1(b) was carried out, except that 4-(2-(methoxycarbonyl)hydrazine-1-carboxamido)benzoic acid was used instead of methyl 2-((4-acetylphenyl)carbamoyl)hydrazine-1-carboxylate.

[0336] Intermediate 7. Synthesis of ((2,2-dimethyl-3-vinyl-2H-chromen-7-yl)oxy)triisopropylsilane

[0337] (a) Synthesis of 7-hydroxy-2,2-dimethylchroman-4-one

[0338] 1-(2,4-Dihydroxyphenyl)ethanone (500 mg, 3.29 mmol) was dissolved in ethanol (32.9 ml), and pyrrolidine (0.54 9 ml, 6.57 mmol) and acetone (2.413 ml, 32.9 mmol) were added. The reaction mixture was stirred under reflux for 3 days. After completion of the reaction, the solvent was removed by distillation under reduced pressure, and the residue was diluted with dichloromethane and washed with 1N aqueous hydrochloric acid and aqueous sodium chloride. The separated organic layer was dried over sodium sulfate, filtered, concentrated by distillation under reduced pressure, and separated by MPLC (ethyl acetate:hexane = 1:5, by volume) to give 7-hydroxy-2,2-dimethylchroman-4-one (516 mg, 82%).

[0339] (b) Synthesis of 3-bromo-7-hydroxy-2,2-dimethylchroman-4-one

[0340] 7-Hydroxy-2,2-dimethylchroman-4-one (515 mg, 2.68 mmol) obtained in the above synthesis of intermediate 7(a) was dissolved in dichloromethane (5 ml), and copper(II) bromide (1.26 g, 5.63 mmol) was added thereto and stirred under reflux for 4 hours. After completion of the reaction, the reaction mixture was diluted with ethyl acetate and washed with aqueous sodium chloride solution. The separated organic layer was dried over sodium sulfate, filtered, concentrated by distillation under reduced pressure, and separated by MPLC (ethyl acetate:hexane = 1:7, by volume) to give 3-bromo-7-hydroxy-2,2-dimethylchroman-4-one (655 mg, 90%).

[0341] (c) Synthesis of 3-bromo-2,2-dimethyl-7-((triisopropyl-silyl)oxy)-chroman-4-one

[0342] 3-Bromo-7-hydroxy-2,2-dimethylchroman-4-one (650 mg, 2.4 mmol) obtained in the above synthesis of intermediate 7(b) and imidazole (245 mg, 3.6 mmol) were added to dichloromethane (10 mL) and cooled to 0°C, and triisopropylsilyl chloride (616 μL, 2.88 mmol) was added dropwise, and stirred at room temperature for 12 hours. After completion of the reaction, the reaction mixture was diluted with dichloromethane and washed with an aqueous ammonium chloride solution and an aqueous sodium chloride solution. The separated organic layer was dried over sodium sulfate, filtered, concentrated by distillation under reduced pressure, and separated by MPLC (ethyl acetate:hexane = 1:30, by volume) to give 3-bromo-2,2-dimethyl-7-((triisopropylsilyl)-oxy)chroman-4-one (931 mg, 91%).

[0343] (d) Synthesis of ((3-bromo-2,2-dimethyl-2H-chromen-7-yl)-oxy)triisopropylsilane

[0344] 3-Bromo-2,2-dimethyl-7-((triisopropylsilyl)oxy)chroman-4-one (500 mg, 1.17 mmol), obtained in the above synthesis of intermediate 7(c), was dissolved in ethanol (6 mL), and sodium borohydride (44 mg, 1.17 mmol) was added, and the mixture was heated with stirring at 40°C for 1 hour. After completion of the reaction, the reaction mixture was diluted with water, neutralized with aqueous ammonium chloride solution, and extracted with ethyl acetate. The separated organic layer was washed with aqueous sodium chloride solution, dried over sodium sulfate, filtered, and concentrated by distillation under reduced pressure. The residue was dissolved in toluene (6 ml), p-toluenesulfonic acid (20 mg, 0.117 mmol) was added, and the mixture was heated with stirring at 80°C for 4 hours. After completion of the reaction, the reaction mixture was diluted with ethyl acetate and washed with an aqueous solution of sodium chloride.The separated organic layer was dried over sodium sulfate, filtered, concentrated by distillation under reduced pressure, and separated by MPLC (ethyl acetate:hexane = 1:30, by volume) to give ((3-bromo-2,2-dimethyl-2H-chromen-7-yl)oxy)-triisopropylsilane (320 mg, 66.5%).

[0345] (e) Synthesis of ((2,2-dimethyl-3-vinyl-2H-chromen-7-yl)oxy)-triisopropylsilane

[0346] ((3-Bromo-2,2-dimethyl-2H-chromen-7-yl)oxy)triisopropylsilane (17.5 mg, 0.43 mmol) obtained in the above synthesis of intermediate 7(d), tetrakis(triphenylphosphine)palladium(0) (24 mg, 0.022 mmol) and sodium carbonate (113 mg, 1.06 mmol) were suspended in a mixed solvent of ethanol / toluene / water (1:2:2.5 mL), and vinyl boronic acid dibutyl ester (113 μL, 0.51 mmol) were added thereto, and heated with stirring at 70°C for 12 hours. After completion of the reaction, the reaction mixture was diluted with ethyl acetate and washed with aqueous sodium chloride solution. The separated organic layer was dried over sodium sulfate, filtered and distilled under reduced pressure to obtain quantitatively ((2,2-dimethyl-3-vinyl-2H-chromen-7-yl)oxy)triisopropylsilane, which was used in the next step without purification.

[0347] Intermediate 8. Synthesis of 1-(2,2-dimethyl-7-((triisopropylsilyl)oxy)-3-vinyl-2H-chromen-6-yl)ethan-1-one

[0348] (a) Synthesis of 1-(3-bromo-7-hydroxy-2,2-dimethyl-2H-chromen-6-yl)ethan-1-one

[0349] ((3-Bromo-2,2-dimethyl-2H-chromen-7-yl)oxy)triisopropylsilane (47 mg, 1.0 mmol), obtained in the above synthesis of intermediate 7(c!), was added to dichloromethane (10 mL) and cooled to 0°C. Aluminum chloride (290 mg, 2.17 mmol) and acetyl chloride (1.16 mL, 16.3 mmol) were added, and stirred at 0°C for 15 min. After completion of the reaction, the reaction mixture was diluted with dichloromethane and washed with water and aqueous sodium chloride solution. The separated organic layer was dried over sodium sulfate, filtered, and distilled under reduced pressure. The resulting residue was dissolved in MeOH (10 mL) and 1N aqueous sodium hydroxide solution (2.17 mL, 2.17 mmol) was added, stirred at room temperature for 15 min, diluted with ethyl acetate and washed with 1N aqueous hydrochloric acid, water and aqueous sodium chloride solution.The separated organic layer was dried over sodium sulfate, filtered, concentrated by distillation under reduced pressure, and separated by MPLC (ethyl acetate:hexane = 1:5, by volume) to give 1-(3-bromo-7-hydroxy-2,2-dimethyl-2H-chromen-6-yl)ethan-1-one (162 mg, 50%).

[0350] (b) Synthesis of 1-(3-bromo-2,2-dimethyl-7-((triisopropylsilyl)-oxy)-2H-chromen-6-yl)ethan-1-one

[0351] To obtain 1-(3-bromo-2,2-dimethyl-7-((triisopropylsilyl)-oxy)-2H-chromen-6-yl)ethan-1-one (80 mg, 60%), the same synthesis as the above synthesis of intermediate 7(c) was carried out, except that 1-(3-bromo-7-hydroxy-2,2-dimethyl-2H-chromen-6-ylethan-1-one was used instead of 3-bromo-7-hydroxy-2,2-dimethylchroman-4-one.

[0352] (c) Synthesis of 1-(2,2-dimethyl-7-((triisopropylsilyl)oxy)-3-vinyl-2H-chromen-6-yl)ethan-1-one

[0353] To obtain 1-(2,2-dimethyl-7-((triisopropylsilyl)oxy)-3-vinyl-2H-chromen-6-yl)ethan-1-one in quantitative yield, the same synthesis as the above synthesis of intermediate 7(e) was carried out, except that 1-(3-bromo-2,2-dimethyl-2H-chromen-7-yl)oxy)triisopropylsilane was used instead of ((3-bromo-2,2-dimethyl-7-((triisopropylsilyl)oxy)-2H-chromen-6-yl)ethan-1-one. The obtained compound was used in the next reaction without purification.

[0354] Intermediate 9. Synthesis of N-(2,2-dimethyl-3-vinyl-2H-chromen-7-yl)acetamide

[0355] (a) Synthesis of 7-bromo-2,2-dimethylchroman-4-one

[0356] To obtain 7-bromo-2,2-dimethylchroman-4-one (950 mg, 85%), the same synthesis was carried out as in the case of compound 7(a), except that 1-(4-bromo-2-hydroxyphenyl)ethan-1-one was used instead of 1-(2, 4-dihydroxyphenyl)ethenone.

[0357] (b) Synthesis of tert-butyl (2,2-dimethyl-4-oxochroman-7-yl)-carbamate

[0358] 7-Bromo-2,2-dimethylchroman-4-one (500 mg, 1.96 mmol) obtained in the above synthesis of intermediate 9(a) was dissolved in 1,4-dioxane (10 ml), and O-tert-butyl carbamate (34 mg, 2.94 mmol), palladium(II) acetate (44 mg, 0.196 mmol), Xphos (187 mg, 0.392 mmol) and cesium carbonate (958 mg, 2.94 mmol) were added thereto, and stirred under reflux for 1 hour. After completion of the reaction, the reaction mixture was diluted with ethyl acetate and washed with aqueous sodium chloride solution. The separated organic layer was dried over sodium sulfate, filtered, concentrated by distillation under reduced pressure, and separated by MPLC (ethyl acetate:hexane = 1:5, by volume) to give tert-butyl (2,2-dimethyl-4-oxochroman-7-yl)carbamate (560 mg, 98%).

[0359] (c) Synthesis of 7-amino-3-bromo-2,2-dimethylchroman-4-one

[0360] To obtain 7-amino-3-bromo-2,2-dimethylchroman-4-one (320 mg, 54%), the same synthesis as the above synthesis of intermediate 7(b) was carried out, except that tert-butyl (2,2-dimethyl-4-oxochroman-7-yl)carbamate was used instead of 7-hydroxy-2,2-dimethylchroman-4-one.

[0361] (d) Synthesis of N-(3-bromo-2,2-dimethyl-4-oxochroman-7-yl)-acetamide

[0362] 7-Amino-3-bromo-2,2-dimethylchroman-4-one (120 mg, 0.44 mmol), obtained in the above synthesis of intermediate 9(c), and 1-(3-dimethylaminopropyl)-ethylcarbodiimide hydrochloride (128 mg, 0.67 mmol) were added to pyridine (2 mL), and acetic acid (25 μL, 0.44 mmol) was added. The reaction mixture was then stirred at room temperature for 12 h, additional acetic acid (25 μL, 0.44 mmol) was added, and the mixture was stirred for another 4 h. After completion of the reaction, the reaction mixture was concentrated by distillation under reduced pressure, and the residue was separated by reverse phase chromatography (acetonitrile containing 0.1% formic acid: water containing 0.1% formic acid = 5:95-100:0) to obtain N-(3-bromo-2,2-dimethyl-4-oxochroman-7-yl)acetamide (126 mg, 91%).

[0363] (e) Synthesis of N-(3-bromo-2,2-dimethyl-2H-chromen-7-yl)-acetamide

[0364] To obtain N-(3-bromo-2,2-dimethyl-2H-chromen-7-yl)-acetamide (78 mg, 72%), the same synthesis as the above synthesis of intermediate 7(d) was carried out, except that N-(3-bromo-2,2-dimethyl-7-((triisopropylsilyl)oxy)chroman-4-one) was used instead of 3-bromo-2,2-dimethyl-7-((triisopropylsilyl)oxy)chroman-4-one.

[0365] (f) Synthesis of N-(2,2-dimethyl-3-vinyl-2H-chromen-7-yl)-acetamide

[0366] To obtain N-(2,2-dimethyl-3-vinyl-2H-chromen-7-yl)-acetamide, the same synthesis as the above synthesis of intermediate 7(e) was carried out, except that N-(3-bromo-2,2-dimethyl-2H-chromen-7-yl)oxy)triisopropylsilane was used instead of ((3-bromo-2,2-dimethyl-2H-chromen-7-yl)-acetamide.

[0367] Intermediate 10. Synthesis of 2,2-dimethyl-7-(methylsulfonyl)-3-vinyl-2H-chromene

[0368] (a) Synthesis of 2,2-dimethyl-7-(methylsulfonyl)chroman-4-one

[0369] 7-Bromo-2,2-dimethylchroman-4-one (500 mg, 1.96 mmol) obtained in the above synthesis of intermediate 9(a) was dissolved in dimethyl sulfoxide (10 mL), and methanesulfonic acid (400 mg, 3.92 mmol, Na salt), L-proline (45 mg, 0.39 mmol), copper(I) iodide (37 mg, 0.2 mmol) and potassium carbonate (542 mg, 3.92 mmol) were added thereto, and heated with stirring at 130°C for 2 hours. After completion of the reaction, the reaction mixture was added to water and extracted with ethyl acetate. The separated organic layer was washed with an aqueous solution of sodium chloride, dried over sodium sulfate, filtered, concentrated by distillation under reduced pressure, and subjected to separation by column chromatography (ethyl acetate:hexane = 1:10, by volume) to obtain 2,2-dimethyl-7-(methylsulfonyl)chroman-4-one (160 mg, 32%).

[0370] (b) Synthesis of 3-bromo-2,2-dimethyl-7-(methylsulfonyl)-chroman-4-one

[0371] To obtain 3-bromo-2,2-dimethyl-7-(methylsulfonyl)-chroman-4-one (84 mg, 67%), the same synthesis as the above synthesis of intermediate 7(b) was carried out, except that 2,2-di-methyl-7-(methylsulfonyl)chroman-4-one was used instead of 7-hydroxy-2,2-dimethylchroman-4-one.

[0372] (c) Synthesis of 3-bromo-2,2-dimethyl-7-(methylsulfonyl)-2H-chromene

[0373] To obtain 3-bromo-2,2-dimethyl-7-(methylsulfonyl)-2H-chromene (53 mg, 65%), the same synthesis as the above synthesis of intermediate 7(d) was carried out, except that 3-bromo-2,2-dimethyl-7-((triisopropylsilyl)oxy)-chroman-4-one was used instead of 3-bromo-2,2-dimethyl-7-(methylsulfonyl)-chroman-4-one.

[0374] (d) Synthesis of 2,2-dimethyl-7-(methylsulfonyl)-3-vinyl-2H-chromene

[0375] To obtain 2,2-dimethyl-7-(methylsulfonyl)-3-vinyl-2H-chromene in quantitative yield, the same synthesis as the above synthesis of intermediate 7(e) was carried out, except that 3-bromo-2,2-di-methyl-7-(methylsulfonyl)-2H-chromene was used instead of ((3-bromo-2,2-dimethyl-2H-chromen-7-yl)oxy)triisopropylsilane. The obtained compound was used in the next reaction without purification.

[0376] Intermediate 11. Synthesis of N-(2,2-dimethyl-3-vinyl-2H-chromen-7-yl)methanesulfonamide

[0377] (a) Synthesis of N-(3-bromo-2,2-dimethyl-4-oxochroman-7-yl)methanesulfonamide

[0378] 7-Amino-3-bromo-2,2-dimethylchroman-4-one (200 mg, 0.74 mmol), obtained in the above synthesis of intermediate 9(c), was dissolved in dichloromethane (10 mL) and cooled to 0°C. Pyridine (299 μL, 3.7 mmol) and methanesulfonyl chloride (288 μL, 3.7 mmol) were added dropwise to the reaction mixture, the temperature was raised to room temperature, and the mixture was stirred for 12 hours. After completion of the reaction, the solvent was removed by distillation under reduced pressure, and the residue was subjected to MPLC separation (ethyl acetate:hexane = 1:5, by volume) to obtain N-(3-bromo-2,2-dimethyl-4-oxochroman-7-yl)methanesulfonamide (230 mg, 89%).

[0379] (b) Synthesis of N-(3-bromo-2,2-dimethyl-2H-chromen-7-yl)-methanesulfonamide

[0380] To obtain N-(3-bromo-2,2-dimethyl-2H-chromen-7-yl)methanesulfonamide (170 mg, 70%), the same synthesis as the above synthesis of intermediate 7(b) was carried out, except that N-(3-bromo-2,2-dimethyl-4-oxo-chroman-7-yl)methanesulfonamide was used instead of 7-hydroxy-2,2-dimethylchroman-4-one.

[0381] (c) Synthesis of N-(2,2-dimethyl-3-vinyl-2H-chromen-7-yl)methanesulfonamide

[0382] To obtain N-(2,2-dimethyl-3-vinyl-2H-chromen-7-yl)methanesulfonamide in quantitative yield, the same synthesis as the above synthesis of intermediate 7(e) was carried out, except that N-(3-bromo-2,2-dimethyl-2H-chromen-7-yl)oxy)triisopropylsilane was used instead of ((3-bromo-2,2-dimethyl-2H-chromen-7-yl)methanesulfonamide.

[0383] Intermediate 12. Synthesis of tert-butyl (2,2-dimethyl-3-vinyl-2H-chromen-7-yl)carbamate

[0384] (a) Synthesis of tert-butyl (2,2-dimethyl-2H-chromen-7-yl)-carbamate

[0385] To obtain tert-butyl (2,2-dimethyl-2H-chromen-7-yl)carbamate (240 mg, 67%), the same synthesis as the above synthesis of intermediate 7(d) was carried out, except that tert-butyl (2,2-dimethyl-4-oxochroman-7-yl)carbamate was used instead of 3-bromo-2,2-dimethyl-7-((triisopropylsilyl)oxy)chroman-4-one.

[0386] (b) Synthesis of tert-butyl (3-bromo-2,2-dimethyl-2H-chromen-7-yl)-carbamate

[0387] To obtain tert-butyl (3-bromo-2,2-dimethyl-2H-chromen-7-yl)carbamate (100 mg, 78%), the same synthesis as the above synthesis of intermediate 7(b) was carried out, except that tert-butyl (2,2-dimethyl-2H-chromen-7-yl)carbamate was used instead of 7-hydroxy-2,2-dimethyl-chroman-4-one.

[0388] (c) Synthesis of tert-butyl (2,2-dimethyl-3-vinyl-2H-chromen-7-yl)-carbamate

[0389] To obtain tert-butyl (2,2-dimethyl-3-vinyl-2H-chromen-7-yl)carbamate in quantitative yield, the same synthesis as the above synthesis of intermediate 7(e) was carried out, except that (3-bromo-2,2-dimethyl-2H-chromen-7-yl)oxy)triisopropylsilane was used instead of ((3-bromo-2,2-dimethyl-2H-chromen-7-yl)carbamate.

[0390] Intermediate 13. Synthesis of 4-(2,2-dimethyl-3-vinyl-2H-chromen-7-yl)morpholine

[0391] (a) Synthesis of 1-(2-hydroxy-4-morpholinophenyl)-3-methyl-but-2-en-1-one

[0392] To obtain 1-(2-hydroxy-4-morpholinophenyl)-3-methylbut-2-en-1-one (200 mg, 56%), the same synthesis as the above synthesis of intermediate 9(b) was carried out, except that morpholine was used instead of O-tert-butyl carbamate.

[0393] (b) Synthesis of 2,2-dimethyl-7-morpholinochroman-4-one

[0394] 1-(2-Hydroxy-4-morpholinophenyl)-3-methylbut-2-en-1-one (150 mg, 0.57 mmol), obtained in the above synthesis of intermediate 13(a), and triethylamine (173 mg, 1.71 mmol) were dissolved in 1,2-dichloroethane, and sodium tert-butoxide (55 mg, 0.57 mmol) was added, and the mixture was heated with stirring at 70°C for 12 hours. After completion of the reaction, the reaction mixture was diluted with ethyl acetate and washed with aqueous sodium chloride solution. The separated organic layer was dried over sodium sulfate, filtered, concentrated by distillation under reduced pressure, and separated by MPLC (ethyl acetate:hexane = 1:3, by volume) to give 2,2-dimethyl-7-morpholinochroman-4-one (149 mg, 99%).

[0395] (c) Synthesis of 3-bromo-2,2-dimethyl-7-morpholinochroman-4-one

[0396] To ​​obtain 3-bromo-2,2-dimethyl-7-morpholinochroman-4-one (105 mg, 87%), the same synthesis as the above synthesis of intermediate 7(b) was carried out, except that 2,2-dimethyl-7-morpholinochroman-4-one was used instead of 7-hydroxy-2,2-dimethylchroman-4-one.

[0397] (d) Synthesis of 4-(3-bromo-2,2-dimethyl-2H-chromen-7-yl)morpholine

[0398] To obtain 4-(3-bromo-2,2-dimethyl-2H-chromen-7-yl)morpholine (55 mg, 58%), the same synthesis as the above synthesis of intermediate 7(d) was carried out, except that 3-bromo-2,2-dimethyl-7-((triisopropylsilyl)oxy)-chroman-4-one was used instead of 3-bromo-2,2-dimethyl-7-morpholino-chroman-4-one.

[0399] (e) Synthesis of 4-(2,2-dimethyl-3-vinyl-2H-chromen-7-yl)-morpholine

[0400] To obtain 4-(2,2-dimethyl-3-vinyl-2H-chromen-7-yl)-morpholine in quantitative yield, the same synthesis as the above synthesis of intermediate 7(c) was carried out, except that 4-(3-bromo-2,2-dimethyl-2H-chromen-7-yl)oxy)triisopropylsilane was used instead of ((3-bromo-2,2-dimethyl-2H-chromen-7-yl)-morpholine.

[0401] Intermediate 14. Synthesis of 7-(methoxymethyl)-2,2-dimethyl-3-vinyl-2H-chromene

[0402] (a) Synthesis of 2,2,7-trimethylchroman-4-one

[0403] To obtain 2,2,7-trimethylchroman-4-one (340 mg, 95%), the same synthesis as the above synthesis of intermediate 7(a) was carried out, except that 1-(2-hydroxy-4-methylphenyl)ethan-1-one was used instead of 1-(2,4-dihydroxyphenyl)ethenone.

[0404] (b) Synthesis of 3-bromo-2,2,7-trimethylchroman-4-one

[0405] To obtain 3-bromo-2,2,7-trimethylchroman-4-one (220 mg, 75%), the same synthesis as the above synthesis of intermediate 7(b) was carried out, except that 2,2,7-trimethylchroman-4-one was used instead of 7-hydroxy-2,2-dimethylchroman-4-one.

[0406] (c) Synthesis of 3-bromo-2,2,7-trimethyl-2H-chromene

[0407] To obtain 3-bromo-2,2,7-trimethyl-2H-chromene (100 mg, 58%), the same synthesis as the above synthesis of intermediate 7(c!) was carried out, except that 3-bromo-2,2-dimethyl-7-((triisopropylsilyl)oxy)-chroman-4-one was used instead of 3-bromo-2,2,7-trimethylchroman-4-one.

[0408] (d) Synthesis of 3-bromo-7-(bromomethyl)-2,2-dimethyl-2H-chromene

[0409] 3-Bromo-2,2,7-trimethyl-2H-chromene (50 mg, 0.2 mmol) obtained in the above synthesis of intermediate 14(c) was dissolved in dichloromethane (2 ml), and N-bromosuccinimide (35 mg, 0.2 mmol) and benzoyl peroxide (4.8 mg, 0.02 mmol) were added thereto, and the mixture was stirred under reflux for 1 hour. After completion of the reaction, the reaction mixture was concentrated by distillation under reduced pressure and separated by MPLC (ethyl acetate:hexane = 1:4, by volume) to quantitatively obtain 3-bromo-7-(bromomethyl)-2,2-dimethyl-2H-chromene.

[0410] (e) Synthesis of 3-bromo-7-(methoxymethyl)-2,2-dimethyl-2H-chromene

[0411] 3-Bromo-7-(bromomethyl)-2,2-dimethyl-2H-chromene (45 mg, 0.14 mmol), obtained in the above synthesis of intermediate 14(d), was dissolved in methanol (5 mL), and 1N aqueous sodium hydroxide solution (0.68 mL, 0.68 mmol) was added, and the mixture was stirred at room temperature for 2 hours. Then, sodium methoxide (7.3 mg, 0.14 mmol) was added, and the mixture was stirred for another 1 hour at room temperature. After completion of the reaction, the reaction mixture was diluted with ethyl acetate and washed with aqueous sodium chloride solution. The separated organic layer was dried over sodium sulfate, filtered, concentrated by distillation under reduced pressure, and separated by MPLC (ethyl acetate:hexane = 1:5, by volume) to give 3-bromo-7-(methoxymethyl)-2,2-dimethyl-2H-chromene (22 mg, 57%).

[0412] (f) Synthesis of 7-(methoxymethyl)-2,2-dimethyl-3-vinyl-2H-chromene

[0413] To obtain 7-(methoxymethyl)-2,2-dimethyl-3-vinyl-2H-chromene in quantitative yield, the same synthesis as the above synthesis of intermediate 7(e) was carried out, except that 3-bromo-7-(methoxymethyl)-2,2-dimethyl-2H-chromene was used instead of ((3-bromo-2,2-dimethyl-2H-chromen-7-yl)oxy)triisopropylsilane. The obtained compound was used in the next reaction without purification.

[0414] Intermediate 15. Synthesis of 7-(((4-methoxyphenyl)-diphenylmethoxy)methyl)-2,2-dimethyl-3-vinyl-2H-chromene

[0415] (a) Synthesis of (3-bromo-2,2-dimethyl-2H-chromen-7-yl)-methanol

[0416] 3-Bromo-7-(bromomethyl)-2,2-dimethyl-2H-chromene (120 mg, 0.36 mmol), obtained in the above synthesis of intermediate 14(d), was suspended in 1,4-dioxane (4 ml), N-methylmorpholine-N-oxide (169 mg, 1.45 mmol) was added, and heated with stirring at 50°C for 30 minutes. After completion of the reaction, the reaction mixture was added to water and extracted with ethyl acetate. The separated organic layer was washed with aqueous sodium chloride solution, dried over sodium sulfate, filtered, and distilled under reduced pressure. The resulting residue was dissolved in ethanol (4 ml), and sodium borohydride (21 mg, 0.54 mmol) was added, and stirred at room temperature for 1 hour.After completion of the reaction, the reaction mixture was concentrated by distillation under reduced pressure and subjected to separation by reverse phase chromatography (acetonitrile containing 0.1% formic acid: water containing 0.1% formic acid = 5:95-100:0) to obtain (3-bromo-2,2-dimethyl-2H-chromen-7-yl)-methanol (69 mg, 71%).

[0417] (b) Synthesis of 3-bromo-7-(((4-methoxyphenyl)diphenylmethoxy)-methyl)-2,2-dimethyl-2H-chromene

[0418] (3-Bromo-2,2-dimethyl-2H-chromen-7-yl)methanol (72 mg, 0.27 mmol), obtained in the above synthesis of intermediate 15(a), was dissolved in pyridine (1.5 ml), 4-methoxytrityl chloride (165 mg, 0.54 mmol) was added, and the mixture was heated with stirring at 70°C for 1 hour. After completion of the reaction, the reaction mixture was added to water and extracted with ethyl acetate. The separated organic layer was washed with an aqueous solution of sodium chloride, dried over sodium sulfate, filtered, concentrated by distillation under reduced pressure, and subjected to separation by reverse phase chromatography (acetonitrile containing 0.1% formic acid: water containing 0.1% formic acid = 5:95-100:0) to give 3-bromo-7-(((4-methoxyphenyl)diphenylmethoxy)methyl)-2,2-dimethyl-2H-chromene (115 mg, 79%).

[0419] (c) Synthesis of 7-(((4-methoxyphenyl)diphenylmethoxy)methyl)-2,2-dimethyl-3-vinyl-2H-chromene

[0420] To obtain 7-(((4-methoxyphenyl)diphenylmethoxy)methyl)-2,2-dimethyl-3-vinyl-2H-chromene in quantitative yield, the same synthesis as the above synthesis of intermediate 7(e) was carried out, except that 3-bromo-7-(((4-methoxyphenyl)diphenylmethoxy)methyl)-2,2-dimethyl-2H-chromene was used instead of ((3-bromo-2,2-dimethyl-2H-chromen-7-yl)oxy)triisopropylsilane. The obtained compound was used in the next reaction without purification.

[0421] Intermediate 16. Synthesis of tert-butyl 4-(2,2-dimethyl-3-vinyl-2H-chromen-7-yl)piperazine-1-carboxylate

[0422] (a) Synthesis of 7-bromo-2,2-dimethyl-2H-chromene

[0423] To obtain 7-bromo-2,2-dimethyl-2H-chromene (300 mg, 67%), the same synthesis as the above synthesis of intermediate 7(d) was carried out, except that 7-bromo-2,2-dimethyl-7-((triisopropylsilyl)oxy)chroman-4-one was used instead of 3-bromo-2,2-dimethylchroman-4-one.

[0424] (b) Synthesis of tert-butyl 4-(2,2-dimethyl-2H-chromen-7-yl)-piperazine-1-carboxylate

[0425] To obtain tert-butyl 4-(2,2-dimethyl-2H-chromen-7-yl)-piperazine-1-carboxylate (210 mg, 74%), the same synthesis as the above synthesis of intermediate 9(b) was carried out, except that 7-bromo-2,2-dimethyl-2H-chromene was used instead of 7-bromo-2,2-dimethylchroman-4-one.

[0426] (c) Synthesis of tert-butyl 4-(3-bromo-2,2-dimethyl-2H-chromen-7-yl)-piperazine-1-carboxylate

[0427] To obtain 4-(3-bromo-2,2-dimethyl-2H-chromen-7-yl)-piperazine-1-carboxylate (82 mg, 78%), the same synthesis as the above synthesis of intermediate 7(b) was carried out, except that 4-(2,2-dimethyl-2H-chromen-7-yl)-piperazine-1-carboxylate was used instead of 7-hydroxy-2,2-dimethylchroman-4-one.

[0428] (d) Synthesis of tert-butyl 4-(2,2-dimethyl-3-vinyl-2H-chromen-7-yl)piperazin-1-carboxylate

[0429] To obtain tert-butyl 4-(2,2-dimethyl-3-vinyl-2H-chromen-7-yl)piperazine-1-carboxylate in quantitative yield, the same synthesis as the above synthesis of intermediate 7(e) was carried out, except that 4-(3-bromo-2,2-dimethyl-2H-chromen-7-yl)piperazine-1-carboxylate was used instead of ((3-bromo-2,2-dimethyl-2H-chromen-7-yl)oxy)triisopropylsilane. The obtained compound was used in the next reaction without purification.

[0430] Intermediate 17. Synthesis of tert-butyl (2,2-dimethyl-3-vinylchromen-7-yl)(ethyl)carbamate

[0431] (a) Synthesis of tert-butyl ethyl (3-formyl-2,2-dimethyl-chromen-7-yl)carbamate

[0432] To obtain tert-butyl (2,2-dimethyl-3-vinylchromen-7-yl)(ethyl)carbamate (900 mg, 85%), the same synthesis as the above synthesis of intermediate 9(b) was carried out, except that 7-bromo-2,2-dimethylchroman-4-one and O-tert-butyl carbamate were replaced by 7-bromo-2,2-dimethyl-2H-chromene-3-carbaldehyde and tert-butyl ethyl carbamate, respectively.

[0433] (b) Synthesis of tert-butyl (2,2-dimethyl-3-vinylchromen-7-yl)(ethyl)carbamate

[0434] Methyl triphenylphosphonium bromide (2.14 g, 6.00 mmol) was dissolved in tetrahydrofuran and cooled to 0 °C. Potassium tert-butoxide (673 mg, 6.00 mmol) was added to the reaction mixture, and it was stirred for 1 hour at 0 °C under a nitrogen atmosphere. Then, tert-butyl ethyl (3-formyl-2,2-dimethylchromen-7-yl)carbamate (800 mg, 2.4 mmol) dissolved in tetrahydrofuran (5 ml) was added dropwise at 0 °C. The reaction mixture was warmed to room temperature and stirred for 2 hours. After completion of the reaction, the reaction mixture was placed in ice water and extracted with ethyl acetate. The separated organic layer was dried over sodium sulfate, filtered, and concentrated by distillation under reduced pressure. The resulting residue was used in the next reaction without purification.

[0435] Intermediate 18. Synthesis of ((6,8-difluoro-2,2-dimethyl-3-vinyl-2H-chromen-7-yl)oxy)triisopropylsilane

[0436] (a) Synthesis of 2,4-difluorobenzene-1,3-diol

[0437] 1,3-Difluoro-2,4-dimethoxybenzene (645 mg, 3.7 mmol) was dissolved in dichloromethane (5 ml), and boron tribromide (11.11 ml, 11.11 mmol, 1 M / hexane) was added dropwise, and stirred at room temperature for 19 hours. After completion of the reaction, water was added and extracted with diethyl ether. The separated organic layer was washed with aqueous sodium chloride solution, dried over sodium sulfate, filtered, concentrated by distillation under reduced pressure, and separated by MPLC (ethyl acetate:hexane = 1:3, by volume) to give 2,4-difluorobenzene-1,3-diol (463 mg, 86%).

[0438] (b) Synthesis of 6,8-difluoro-7-hydroxy-2,2-dimethylchroman-4-one

[0439] 2,4-Difluorobenzene-1,3-diol (463 mg, 3.17 mmol), obtained in the synthesis of the above intermediate 18(a), zinc chloride (432 mg, 3.17 mmol) and 3,3-dimethylacrylic acid (317 mg, 3.17 mmol) were added to phosphoryl chloride (2.6 mL), and heated with stirring at 50°C for 4 hours. After completion of the reaction, the reaction mixture was cooled to room temperature, placed in ice water, and extracted with ethyl acetate. The separated organic layer was washed with aqueous sodium chloride solution, dried over sodium sulfate, filtered, concentrated by distillation under reduced pressure, and separated by MPLC (ethyl acetate:hexane = 1:3, by volume) to give 6,8-difluoro-7-hydroxy-2,2-dimethylchroman-4-one (234 mg, 32.4%).

[0440] (c) Synthesis of 3-bromo-6,8-difluoro-7-hydroxy-2,2-dimethylchroman-4-one

[0441] To obtain 3-bromo-6,8-difluoro-7-hydroxy-2,2-dimethyl-chroman-4-one (299 mg, 90%), the same synthesis as the above synthesis of intermediate 7(b) was carried out, except that 6,8-difluoro-7-hydroxy-2,2-dimethylchroman-4-one was used instead of 7-hydroxy-2,2-dimethylchroman-4-one.

[0442] (d) Synthesis of 3-bromo-6,8-difluoro-2,2-dimethyl-7-((triisopropylsilyl)oxy)chroman-4-one

[0443] To obtain 3-bromo-6,8-difluoro-2,2-dimethyl-7-((triisopropylsilyl)oxy)chroman-4-one (245 mg, 61%), the same synthesis as the above synthesis of intermediate 7(c) was carried out, except that 3-bromo-6,8-difluoro-7-hydroxy-2,2-dimethylchroman-4-one was used instead of 3-bromo-7-hydroxy-2,2-dimethylchroman-4-one.

[0444] (e) Synthesis of ((6,8-difluoro-2,2-dimethyl-2H-chromen-7-yl)oxy)-triisopropylsilane

[0445] To obtain ((6,8-difluoro-2,2-dimethyl-2H-chromen-7-yl)oxy)-triisopropylsilane (127 mg, 51%), the same synthesis as the above synthesis of intermediate 7(d) was carried out, except that 3-bromo-6,8-difluoro-2,2-dimethyl-7-((triisopropylsilyl)oxy)chroman-4-one was used instead of 3-bromo-2,2-dimethyl-7-((triisopropylsilyl)oxy)chroman-4-one.

[0446] (f) Synthesis of 3-bromo-6,8-difluoro-2,2-dimethyl-7-((triisopropylsilyl)oxy)chroman-4-ol

[0447] ((6,8-Difluoro-2,2-dimethyl-2H-chromen-7-yl)oxy)triisopropylsilane (125 mg, 0.34 mmol) obtained in the above synthesis of intermediate 18(e) was dissolved in a mixed solvent of dimethyl sulfoxide / water (5:1, 3 ml), and N-bromosuccinimide (154 mg, 0.86 mmol) was added thereto, and stirred at room temperature for 4 hours. After completion of the reaction, the reaction mixture was separated by reverse phase chromatography (acetonitrile containing 0.1% formic acid:water containing 0.1% formic acid = 5:95-100:0) to obtain 3-bromo-6,8-difluoro-2,2-dimethyl-7-((triisopropylsilyl)oxy)chroman-4-ol (158 mg).

[0448] (g) Synthesis of ((3-bromo-6,8-difluoro-2,2-dimethyl-2H-chromen-7-yl)-oxy)triisopropylsilane

[0449] 3-Bromo-6,8-difluoro-2,2-dimethyl-7-((triisopropylsilyl)oxy)-chroman-4-ol (135 mg, 0.29 mmol), obtained in the above synthesis of intermediate 18(f), was dissolved in toluene (3 mL), and p-toluenesulfonic acid (8.6 mg, 0.05 mmol) was added, and the mixture was heated with stirring at 80°C for 2 hours. After completion of the reaction, the reaction mixture was diluted with ethyl acetate and then washed with an aqueous sodium bicarbonate solution and an aqueous sodium chloride solution. The separated organic layer was dried over sodium sulfate, filtered, concentrated by distillation under reduced pressure, and separated by MPLC (hexane:dichloromethane = 3:1, by volume) to give ((3-bromo-6,8-difluoro-2,2-dimethyl-2H-chromen-7-yl)-oxy)triisopropylsilane (105 mg, 81%).

[0450] (h) Synthesis of ((6,8-difluoro-2,2-dimethyl-3-vinyl-2H-chromen-7-yl)oxy)triisopropylsilane

[0451] To obtain ((6,8-difluoro-2,2-dimethyl-3-vinyl-2H-chromen-7-yl)oxy)triisopropylsilane in quantitative yield, the same synthesis as the above synthesis of intermediate 7(e) was carried out, except that ((3-bromo-6,8-difluoro-2,2-dimethyl-2H-chromen-7-yl)oxy)triisopropylsilane was used instead of ((3-bromo-2,2-dimethyl-2H-chromen-7-yl)oxy)triisopropylsilane. The obtained compound was used in the next reaction without purification.

[0452] Intermediate 19. Synthesis of 2,2-dimethyl-N-(2,2,2-trifluoroethyl)-3-vinyl-2H-chromen-7-amine

[0453] (a) Synthesis of 2,2-dimethyl-N-(2,2,2-trifluoroethyl)-2H-chromen-7-amine

[0454] 7-Bromo-2,2-dimethyl-2H-chromene (500 mg, 2.09 mmol) obtained in the above synthesis of intermediate 16(a), allyl palladium chloride dimer (153 mg, 0.42 mmol), [3,6-dimethoxy-2',4',6'-tris(1-methylethyl)[1,1'-biphenyl]-2-yl]bis(1,1-dimethylethyl)phosphine (51 mg, 0.105 mmol) and phenol (0.2 ml, 2.3 mmol) were dissolved in 1,4-dioxane (21 ml), and potassium tert-butoxide (2.2 ml, 2.2 mmol, 1 M / tetrahydrofuran) and 2,2,2 trifluoroethylamine (0.33 ml, 4.18 mmol) and stirred under reflux under nitrogen atmosphere for 1 hour. After completion of the reaction, the reaction mixture was diluted with ethyl acetate and washed with water and aqueous sodium chloride solution. The separated organic layer was dried over sodium sulfate, filtered, concentrated by distillation under reduced pressure and separated by MPLC (dichloromethane:hexane = 2:3, by volume) to give 2,2-dimethyl-N-(2,2,2-trifluoroethyl)-2H-chromen-7-amine (423 mg, 79%).

[0455] (b) Synthesis of 3-bromo-2,2-dimethyl-N-(2,2,2-trifluoroethyl)-2H-chromen-7-amine

[0456] To obtain 3-bromo-2,2-dimethyl-N-(2,2,2-trifluoroethyl)-2H-chromen-7-amine (200 mg, 86%), the same synthesis as the above synthesis of intermediate 1(a) was carried out, except that 2,2-dimethyl-N-(2,2,2-trifluoroethyl)-2H-chromen-7-amine was used instead of 7-hydroxy-2,2-dimethylchroman-4-one.

[0457] (c) Synthesis of 2,2-dimethyl-N-(2,2,2-trifluoroethyl)-3-vinyl-2H-chromen-7-amine

[0458] To obtain 2,2-dimethyl-N-(2,2,2-trifluoroethyl)-3-vinyl-2H-chromen-7-amine in quantitative yield, the same synthesis as the above synthesis of intermediate 7(e) was carried out, except that 3-bromo-2,2-dimethyl-N-(2,2,2-trifluoroethyl)-2H-chromen-7-amine was used instead of ((3-bromo-2,2-dimethyl-2H-chromen-7-yl)oxy)triisopropylsilane.

[0459] Intermediate 20. Synthesis of 1-(2,2-dimethyl-3-vinyl-2H-chromen-7-yl)ethan-1-one

[0460] (a) Synthesis of 2,2-dimethyl-4-oxochroman-7-carbonitrile

[0461] 7-Bromo-2,2-dimethylchroman-4-one (170 mg, 0.64 mmol) obtained in the above synthesis of intermediate 9(a), zinc cyanide (149 mg, 1.27 mmol), tris(dibenzylideneacetone)dipalladium(0) (29 mg, 0.032 mmol) and 2-dicyclohexylphosphino-2',6'-dimethoxy-1,1'-biphenyl (26 mg, 0.064 mmol) were added to a mixed solvent of N,N-dimethylformamide / water (10:1.7 mL), and the reaction was performed using microwave irradiation (150 watts, 120°C, 20 minutes) under a nitrogen atmosphere. After completion of the reaction, the reaction mixture was diluted with ethyl acetate and washed with aqueous sodium chloride solution. The separated organic layer was dried over sodium sulfate, filtered, concentrated by distillation under reduced pressure, and separated by MPLC (hexane:ethyl acetate = 3:1, by volume) to give 2,2-dimethyl-4-oxochroman-7-carbonitrile (105 mg, 72%).

[0462] (b) Synthesis of 2,2-dimethyl-2H-chromene-7-carbonitrile

[0463] To obtain 2,2-dimethyl-2H-chromene-7-carbonitrile (54 mg, 66%), the same synthesis as the above synthesis of intermediate 7(d) was carried out, except that 2,2-dimethyl-4-oxochroman-7-carbonitrile was used instead of 3-bromo-2,2-dimethyl-7-((triisopropylsilyl)-oxy)chroman-4-one.

[0464] (c) Synthesis of 1-(2,2-dimethyl-2H-chromen-7-yl)ethan-1-one

[0465] 2,2-Dimethyl-2H-chromene-7-carbonitrile (200 mg, 1.08 mmol), obtained in the above synthesis of intermediate 20(b), was dissolved in tetrahydrofuran (1 ml) and then cooled to 0°C. Methylmagnesium bromide (1.8 ml, 5.4 mmol, 3 M / diethyl ether) was added dropwise under a nitrogen atmosphere and stirred at room temperature for 30 min. After completion of the reaction, the reaction mixture was cooled to 0°C, aqueous ammonium chloride solution was added dropwise, stirred for 1 hour, and extracted with ethyl acetate. The separated organic layer was dried over sodium sulfate, filtered, concentrated by distillation under reduced pressure and separated by MPLC (100% dichloromethane) to give 1-(2,2-dimethyl-2H-chromen-7-yl)ethan-1-one (110 mg, 50%).

[0466] (d) Synthesis of 1-(3-bromo-4-hydroxy-2,2-dimethylchroman-7-yl)-ethan-1-one

[0467] To obtain 1-(3-bromo-4-hydroxy-2,2-dimethylchroman-7-yl)ethan-1-one (58 mg, 58%), the same synthesis as the above synthesis of intermediate 18(f) was carried out, except that 1-(2,2-dimethyl-2H-chromen-7-yl)oxy)triisopropylsilane was used instead of ((6,8-difluoro-2,2-dimethyl-2H-chromen-7-yl)ethan-1-one.

[0468] (e) Synthesis of 1-(3-bromo-2,2-dimethyl-2H-chromen-7-yl)ethan-1-one

[0469] To obtain 1-(3-bromo-2,2-dimethyl-2H-chromen-7-yl)ethan-1-one (35 mg, 85%), the same synthesis as the above synthesis of intermediate 18(d) was carried out, except that 1-(3-bromo-6,8-difluoro-2,2-dimethyl-7-((triisopropylsilyl)oxy)chroman-4-ol was used instead of 1-(3-bromo-4-hydroxy-2,2-dimethylchroman-7-yl)ethan-1-one.

[0470] (f) Synthesis of 1-(2,2-dimethyl-3-vinyl-2H-chromen-7-yl)ethan-1-one

[0471] To obtain 1-(2,2-dimethyl-3-vinyl-2H-chromen-7-yl)ethan-1-one in quantitative yield, the same synthesis as the above synthesis of intermediate 7(e) was carried out, except that 1-(3-bromo-2,2-dimethyl-2H-chromen-7-yl)oxy)triisopropylsilane was used instead of ((3-bromo-2,2-dimethyl-2H-chromen-7-yl)ethan-1-one. The obtained compound was used in the next reaction without purification.

[0472] Intermediate 21. Synthesis of tert-butyl (2,2-dimethyl-3-vinyl-2H-chromen-7-yl)(methyl)carbamate

[0473] (a) Synthesis of tert-butyl (3-formyl-2,2-dimethyl-2H-chromen-7-yl)-(methyl)carbamate

[0474] To obtain tert-butyl (3-formyl-2,2-dimethyl-2H-chromen-7-yl)(methyl)carbamate (500 mg, 88%), the same synthesis as the above synthesis of intermediate 9(b) was carried out, except that 7-bromo-2,2-dimethylchroman-4-one and O-tert-butylcarbamate were replaced by 7-bromo-2,2-dimethyl-2H-chromen-3-carbaldehyde and tert-butyl methylcarbamate, respectively.

[0475] (b) Synthesis of tert-butyl (2,2-dimethyl-3-vinyl-2H-chromen-7-yl)(methyl)carbamate

[0476] The same synthesis as the above synthesis of intermediate 17(b) was carried out to obtain tert-butyl (2,2-dimethyl-3-vinyl-2H-chromen-7-yl)(methyl)carbamate in quantitative yield, except that tert-butyl (3-formyl-2,2-dimethylchromen-7-yl)carbamate was used instead of tert-butyl ethyl (3-formyl-2,2-dimethylchromen-7-yl)carbamate. The resulting compound was used in the next reaction without purification.

[0477] Intermediate 22. Synthesis of N,N-diethyl-2,2-dimethyl-3-vinyl-2H-chromen-7-amine

[0478] (a) Synthesis of 7-(diethylamino)-2,2-dimethyl-2H-chromene-3-carbaldehyde

[0479] To obtain 7-(diethylamino)-2,2-dimethyl-2H-chromene-3-carbaldehyde (500 mg, 88%), the same synthesis as the above synthesis of intermediate 9(b) was carried out, except that 7-bromo-2,2-dimethylchroman-4-one and O-tert-butylcarbamate were replaced by 7-bromo-2,2-dimethyl-2H-chromene-3-carbaldehyde and diethylamine, respectively.

[0480] (b) Synthesis of N,N-diethyl-2,2-dimethyl-3-vinyl-2H-chromene-7-amine

[0481] To obtain N,1H-diethyl-2,2-dimethyl-3-vinyl-2H-chromen-7-amine in quantitative yield, the same synthesis as the above synthesis of intermediate 17(b) was carried out, except that 7-(diethylamino)-2,2-dimethyl-2H-chromen-3-carbaldehyde was used instead of tert-butyl ethyl (3-formyl-2,2-dimethylchromen-7-yl)carbamate. The obtained compound was used in the next reaction without purification.

[0482] Intermediate 23. Synthesis of 1-(2,2-dimethyl-3-vinyl-2H-chromen-7-yl)azetidine

[0483] (a) Synthesis of 1-(2,2-dimethyl-2H-chromen-7-yl)azetidine

[0484] To obtain 1-(2, 2-dimethyl-2H-chromen-7-yl)azetidine (520 mg, 84%), the same synthesis as the above synthesis of intermediate 9(b) was carried out, except that 7-bromo-2,2-dimethylchroman-4-one and O-tert-butylcarbamate were replaced by 7-bromo-2,2-dimethyl-2H-chromene and azetidine hydrochloride, respectively.

[0485] (b) Synthesis of 1-(3-bromo-2,2-dimethyl-2H-chromen-7-yl)azetidine

[0486] To obtain 1-(3-bromo-2,2-dimethyl-2H-chromen-7-yl)azetidine (580 mg, 90%), the same synthesis as the above synthesis of intermediate 7(b) was carried out, except that 1-(2,2-dimethyl-2H-chromen-7-yl)azetidine was used instead of 7-hydroxy-2,2-dimethylchroman-4-one.

[0487] (c) Synthesis of 1-(2,2-dimethyl-3-vinyl-2H-chromen-7-yl)azetidine

[0488] To obtain 1-(2,2-dimethyl-3-vinyl-2H-chromen-7-yl)-azetidine in quantitative yield, the same synthesis as the above synthesis of intermediate 7(e) was carried out, except that 1-(3-bromo-2,2-dimethyl-2H-chromen-7-yl)oxy)triisopropylsilane was used instead of ((3-bromo-2,2-dimethyl-2H-chromen-7-yl)azetidine. The obtained compound was used in the next reaction without purification.

[0489] Intermediate 24. Synthesis of 1-(2,2-dimethyl-3-vinyl-2H-chromen-7-yl)pyrrolidine

[0490] (a) Synthesis of 2,2-dimethyl-7-(pyrrolidin-1-yl)-2H-chromene-3-carbaldehyde

[0491] To obtain 2,2-dimethyl-7-(pyrrolidin-1-yl)-2H-chromene-3-carbaldehyde (550 mg, 94%), the same synthesis as the above synthesis of intermediate 9(b) was carried out, except that 7-bromo-2,2-dimethylchroman-4-one and O-tert-butylcarbamate were replaced by 7-bromo-2,2-dimethyl-2H-chromene-3-carbaldehyde and piperidine, respectively.

[0492] (b) Synthesis of 1-(2,2-dimethyl-3-vinyl-2H-chromen-7-yl)-pyrrolidine

[0493] To obtain 1-(2,2-dimethyl-3-vinyl-2H-chromen-7-yl)-pyrrolidine in quantitative yield, the same synthesis as the above synthesis of intermediate 17(b) was carried out, except that 2,2-dimethyl-7-(pyrrolidin-1-yl)-2H-chromen-3-carbaldehyde was used instead of tert-butyl ethyl (3-formyl-2,2-dimethylchromen-7-yl)carbamate. The obtained compound was used in the next reaction without purification.

[0494] Intermediate 25. Synthesis of ((2,2-dimethyl-6-(trifluoromethoxy)-3-vinyl-2H-chromen-7-yl)oxy)triisopropylsilane

[0495] (a) Synthesis of 7-hydroxy-2,2-dimethyl-6-(trifluoromethoxy)chroman-4-one

[0496] To ​​obtain 7-hydroxy-2,2-dimethyl-6-(trifluoromethoxy)-chroman-4-one (700 mg, 84%), the same synthesis as the above synthesis of intermediate 18(d) was carried out, except that 4-(trifluoromethoxy)benzene-1,3-diol was used instead of 2,4-difluorobenzene-1,3-diol.

[0497] (b) Synthesis of 3-bromo-7-hydroxy-2,2-dimethyl-6-(trifluoromethoxy)chroman-4-one

[0498] To obtain 3-bromo-7-hydroxy-2,2-dimethyl-6-(trifluoromethoxy)chroman-4-one (720 mg, 92%), the same synthesis as the above synthesis of intermediate 7(b) was carried out, except that 7-hydroxy-2,2-dimethyl-6-(trifluoromethoxy)chroman-4-one was used instead of 7-hydroxy-2,2-dimethylchroman-4-one.

[0499] (c) Synthesis of 3-bromo-2,2-dimethyl-6-(trifluoromethoxy)-7-((triisopropylsilyl)oxy)chroman-4-one

[0500] To obtain 3-bromo-2,2-dimethyl-6-(trifluoromethoxy)-7-((triisopropylsilyl)oxy)chroman-4-one (500 mg, 75%), the same synthesis as the above synthesis of intermediate 7(c) was carried out, except that 3-bromo-7-hydroxy-2,2-dimethylchroman-4-one was used instead of 3-bromo-7-hydroxy-2,2-dimethyl-6-(trifluoromethoxy)chroman-4-one.

[0501] (d) Synthesis of ((3-bromo-2,2-dimethyl-6-(trifluoromethoxy)-2H-chromen-7-yl)oxy)triisopropylsilane

[0502] To obtain ((3-bromo-2,2-dimethyl-6-(trifluoromethoxy)-2H-chromen-7-yl)oxy)triisopropylsilane (210 mg, 54%), the same synthesis as the above synthesis of intermediate 7(d) was carried out, except that 3-bromo-2,2-dimethyl-7-((triisopropylsilyl)oxy)chroman-4-one was used instead of 3-bromo-2,2-dimethyl-6-(trifluoromethoxy)-7-((triisopropylsilyl)oxy)-chroman-4-one.

[0503] (e) Synthesis of ((2,2-dimethyl-6-(trifluoromethoxy)-3-vinyl-2H-chromen-7-yl)oxy)triisopropylsilane

[0504] To obtain ((2,2-dimethyl-6-(trifluoromethoxy)-3-vinyl-2H-chromen-7-yl)oxy)triisopropylsilane in quantitative yield, the same synthesis as the above synthesis of intermediate 7(e) was carried out, except that ((3-bromo-2,2-dimethyl-2H-chromen-7-yl)oxy)triisopropylsilane was used instead of ((3-bromo-2,2-dimethyl-6-(trifluoromethoxy)-2H-chromen-7-yl)oxy)triisopropylsilane. The obtained compound was used in the next reaction without purification.

[0505] Intermediate 26. Synthesis of 2,2-dimethyl-3-vinyl-2H-chromene-7-carbonitrile

[0506] (a) Synthesis of 3-formyl-2,2-dimethyl-2H-chromene-7-carbonitrile

[0507] To obtain 3-formyl-2,2-dimethyl-2H-chromene-7-carbonitrile (320 mg, 65%), the same synthesis as the above synthesis of intermediate 20(a) was carried out, except that 7-bromo-2,2-dimethyl-2H-chromene-3-carbaldehyde was used instead of 7-bromo-2,2-dimethylchroman-4-one.

[0508] (b) Synthesis of 2,2-dimethyl-3-vinyl-2H-chromene-7-carbonitrile

[0509] To obtain 2,2-dimethyl-3-vinyl-2H-chromene-7-carbonitrile in quantitative yield, the same synthesis as the above synthesis of intermediate 17(b) was carried out, except that 3-formyl-2,2-dimethyl-2H-chromene-7-carbonitrile was used instead of tert-butyl ethyl (3-formyl-2,2-dimethylchromen-7-yl)carbamate.

[0510] Intermediate 27. Synthesis of 2,2-dimethyl-7-nitro-3-vinyl-2H-chromene

[0511] (a) Synthesis of (E)-2-(3-hydroxy-3-methylbut-1-en-1-yl)-5-nitrophenol

[0512] 2-Bromo-5-nitrophenol (500 mg, 2.3 mmol) was dissolved in N,N-dimethylacetamide (11 mL), and 2-methylbut-3-en-2-ol (395 mg, 4.6 mmol), triphenylphosphine (241 mg, 0.92 mmol), palladium(II) acetate (103 mg, 0.4 6 mmol) and triethylamine (696 mg, 6.88 mmol) were added thereto, and stirred under reflux at 130 °C for 4 hours. After completion of the reaction, the reaction mixture was diluted with ethyl acetate and washed with aqueous sodium chloride solution. The separated organic layer was dried over sodium sulfate, filtered, concentrated by distillation under reduced pressure, and subjected to separation by reverse phase chromatography (acetonitrile containing 0.1% formic acid: water containing 0.1% formic acid = 5:95-90:10) to give (E)-2-(3-hydroxy-3-methylbut-1-en-1-yl)-5-nitrophenol (288 mg, 56%).

[0513] (b) Synthesis of 2,2-dimethyl-7-nitro-2H-chromene

[0514] (E)-2-(3-hydroxy-3-methylbut-1-en-1-yl)-5-nitrophenol (288 mg, 1.29 mmol), obtained in the above synthesis of intermediate 27(a), was dissolved in N,N-dimethylformamide (2.4 ml), and silica gel (1.550 mg, 25.8 mmol) was added, and the mixture was heated with stirring at 140°C for 18 hours. After completion of the reaction, the reaction mixture was concentrated by distillation under reduced pressure, and the residue was filtered and washed with ethyl acetate. The filtrate was separated into ethyl acetate and water, and the aqueous layer was extracted with ethyl acetate. The separated organic layer was washed with aqueous sodium chloride solution, dried over sodium sulfate, filtered, concentrated by distillation under reduced pressure, and separated by MPLC (ethyl acetate:hexane = 10:90, by volume) to give 2,2-dimethyl-7-nitro-2H-chromene (190 mg, 72%).

[0515] (c) Synthesis of 3-bromo-2,2-dimethyl-7-nitrochroman-4-ol

[0516] To obtain 3-bromo-2,2-dimethyl-7-nitrochroman-4-ol (120 mg, 69%), the same synthesis as the above synthesis of intermediate 18(f) was carried out, except that 2,2-dimethyl-7-nitro-2H-chromene was used instead of ((6,8-difluoro-2,2-dimethyl-2H-chromen-7-yl)oxy)triisopropylsilane.

[0517] (d) Synthesis of 3-bromo-2,2-dimethyl-7-nitro-2H-chromene

[0518] To obtain 3-bromo-2,2-dimethyl-7-nitro-2H-chromene (60 mg, 58%), the same synthesis as the above synthesis of intermediate 18(d) was carried out, except that 3-bromo-2,2-dimethyl-7-((triisopropylsilyl)-oxy)-chroman-4-ol was used instead of 3-bromo-6,8-difluoro-2,2-dimethyl-7-nitro-chroman-4-ol.

[0519] (e) Synthesis of 2,2-dimethyl-7-nitro-3-vinyl-2H-chromene

[0520] To obtain 2,2-dimethyl-7-nitro-3-vinyl-2H-chromene in quantitative yield, the same synthesis as the above synthesis of intermediate 7(e) was carried out, except that 3-bromo-2,2-dimethyl-7-nitro-2H-chromene was used instead of ((3-bromo-2,2-dimethyl-2H-chromen-7-yl)oxy)triisopropylsilane. The obtained compound was used in the next reaction without purification.

[0521] Intermediate 28. Synthesis of 1-(2,2-dimethyl-3-vinyl-2H-chromen-7-yl)-4-methylpiperazine

[0522] (a) Synthesis of 2,2-dimethyl-7-(4-methylpiperazin-1-yl)-2H-chromene-3-carbaldehyde

[0523] To obtain 2,2-dimethyl-7-(4-methylpiperazin-1-yl)-2H-chromene-3-carbaldehyde (520 mg, 84%), the same synthesis as the above synthesis of intermediate 9(b) was carried out, except that 7-bromo-2,2-dimethylchroman-4-one and O-tert-butylcarbamate were replaced by 7-bromo-2,2-dimethyl-2H-chromene-3-carbaldehyde and N-methylpiperazine, respectively.

[0524] (b) Synthesis of 1-(2,2-dimethyl-3-vinyl-2H-chromen-7-yl)-4-methylpiperazine

[0525] To obtain 1-(2,2-dimethyl-3-vinyl-2H-chromen-7-yl)-4-methylpiperazine in quantitative yield, the same synthesis as the above synthesis of intermediate 17(b) was carried out, except that 2,2-dimethyl-7-(4-methylpiperazin-1-yl)-2H-chromen-3-carbaldehyde was used instead of tert-butyl ethyl (3-formyl-2,2-dimethylchromen-7-yl)carbamate. The obtained compound was used in the next reaction without purification.

[0526] Intermediate 29. Synthesis of tert-butyl 4-(2,2-dimethyl-3-vinyl-2H-chromen-7-yl)piperazine-1-carboxylate

[0527] (a) Synthesis of tert-butyl 4-(3-formyl-2,2-dimethyl-2H-chromen-7-yl)piperazine-1-carboxylate

[0528] To obtain tert-butyl 4-(3-formyl-2,2-dimethyl-2H-chromen-7-yl)piperazine-1-carboxylate (500 mg, 90%), the same synthesis as the above synthesis of intermediate 9(b) was carried out, except that 7-bromo-2,2-dimethylchroman-4-one and O-tert-butylcarbamate were replaced by 7-bromo-2,2-dimethyl-2H-chromen-3-carbaldehyde and N-tert-butoxycarbonylpiperazine, respectively.

[0529] (b) Synthesis of tert-butyl 4-(2,2-dimethyl-3-vinyl-2H-chromen-7-yl)piperazine-1-carboxylate

[0530] To obtain 4-(2,2-dimethyl-3-vinyl-2H-chromen-7-yl)-piperazine-1-carboxylate in quantitative yield, the same synthesis as the above synthesis of intermediate 17(b) was carried out, except that tert-butyl 4-(3-formyl-2,2-dimethylchromen-7-yl)carbamate was used instead of tert-butyl 4-(3-formyl-2,2-dimethyl-2H-chromen-7-yl)piperazine-1-carboxylate. The obtained compound was used in the next reaction without purification.

[0531] Intermediate 30. Synthesis of ((6-cyclopropyl-2,2-dimethyl-3-vinyl-2H-chromen-7-yl)oxy)triisopropylsilane

[0532] (a) Synthesis of 6-bromo-7-hydroxy-2,2-dimethylchroman-4-one

[0533] To obtain 6-bromo-7-hydroxy-2,2-dimethylchroman-4-one (800 mg, 80%), the same synthesis as the above synthesis of intermediate 18(d) was carried out, except that 4-bromobenzene-1,3-diol was used instead of 2,4-difluorobenzene-1,3-diol.

[0534] (b) Synthesis of 6-bromo-7-((4-methoxybenzyl)oxy)-2,2-dimethylchroman-4-one

[0535] 6-Bromo-7-hydroxy-2,2-dimethylchroman-4-one (180 mg, 0.66 mmol), obtained in the above synthesis of intermediate 30(a), and potassium carbonate (184 mg, 1.33 mmol) were dissolved in N,N-dimethylformamide (7 mL), and p-methoxybenzyl chloride (90 μL, 0.66 mmol) was added dropwise, and the mixture was stirred at room temperature for 12 hours. To the reaction mixture were added p-methoxybenzyl chloride (90 μL, 0.66 mmol) and potassium carbonate. Then, the reaction temperature was raised to 40°C and stirred for another 4 hours. After completion of the reaction, the reaction mixture was diluted with ethyl acetate and washed with water and an aqueous sodium chloride solution.The separated organic layer was dried over sodium sulfate, filtered, concentrated by distillation under reduced pressure, and subjected to separation by reverse phase chromatography (acetonitrile containing 0.1% formic acid: water containing 0.1% formic acid = 5:95-100:0) to give 6-bromo-7-((4-methoxybenzyl)oxy)-2,2-dimethylchroman-4-one (240 mg, 92%).

[0536] (c) Synthesis of 6-cyclopropyl-7-((4-methoxybenzyl)oxy)-2,2-dimethylchroman-4-one

[0537] To obtain 6-cyclopropyl-7-((4-methoxybenzyl)oxy)-2,2-dimethylchroman-4-one (200 mg, 85%), the same synthesis as the above synthesis of intermediate 7(e) was carried out, except that 6-bromo-7-((4-methoxybenzyl)oxy)-2,2-dimethyl-chroman-4-one was used instead of ((3-bromo-2,2-dimethyl-2H-chromen-7-yl)oxy)triisopropylsilane.

[0538] (d) Synthesis of 3-bromo-6-cyclopropyl-7-hydroxy-2,2-dimethyl-chroman-4-one

[0539] To obtain 3-bromo-6-cyclopropyl-7-hydroxy-2,2-dimethyl-chroman-4-one (160 mg, 78%), the same synthesis as the above synthesis of intermediate 7(b) was carried out, except that 6-cyclopropyl-7-((4-methoxybenzyl)oxy)-2,2-dimethylchroman-4-one was used instead of 7-hydroxy-2,2-dimethylchroman-4-one.

[0540] (e) Synthesis of 3-bromo-6-cyclopropyl-2,2-dimethyl-7-((triisopropylsilyl)oxy)chroman-4-one

[0541] To obtain 3-bromo-6-cyclopropyl-2,2-dimethyl-7-((triisopropylsilyl)oxy)chroman-4-one (140 mg, 80%), the same synthesis as the above synthesis of intermediate 7(c) was carried out, except that 3-bromo-6-cyclopropyl-7-hydroxy-2,2-dimethyl-chroman-4-one was used instead of 3-bromo-7-hydroxy-2,2-dimethyl-chroman-4-one.

[0542] (f) Synthesis of ((3-bromo-6-cyclopropyl-2,2-dimethyl-2H-chromen-7-yl)oxy)triisopropylsilane

[0543] To obtain ((3-bromo-6-cyclopropyl-2,2-dimethyl-2H-chromen-7-yl)oxy)triisopropylsilane (55 mg, 52%), the same synthesis as the above synthesis of intermediate 7(d) was carried out, except that 3-bromo-6-cyclopropyl-2,2-dimethyl-7-((triisopropylsilyl)oxy)chroman-4-one was used instead of 3-bromo-2,2-dimethyl-7-((triisopropylsilyl)oxy)chroman-4-one.

[0544] (g) Synthesis of ((6-cyclopropyl-2,2-dimethyl-3-vinyl-2H-chromen-7-yl)oxy)triisopropylsilane

[0545] To obtain ((6-cyclopropyl-2,2-dimethyl-3-vinyl-2H-chromen-7-yl)oxy)triisopropylsilane in quantitative yield, the same synthesis as the above synthesis of intermediate 7(e) was carried out, except that ((3-bromo-2,2-dimethyl-2H-chromen-7-yl)oxy)triisopropylsilane was used instead of ((3-bromo-2,2-dimethyl-2H-chromen-7-yl)oxy)triisopropylsilane. The obtained compound was used in the next reaction without purification.

[0546] Intermediate 31. Synthesis of ((2,2-bis(fluoromethyl)-3-vinyl-2H-chromen-7-yl)oxy)triisopropylsilane

[0547] (a) Synthesis of 1-(2-hydroxy-4-((tetrahydro-2H-pyran-2-yl)-oxy)phenyl)ethan-1-one

[0548] 1-(2,4-Dihydroxyphenyl)ethanone (2.51 g, 16.47 mmol) and pyridinium p-toluenesulfonic acid (170 mg, 0.68 mmol) were dissolved in dichloromethane (25 ml), and 3,4-dihydro-2H-pyran (3.46 g, 41.18 mmol) was added, and the mixture was stirred at room temperature for 3 hours. After completion of the reaction, the reaction mixture was diluted with dichloromethane and washed with aqueous sodium chloride solution. The separated organic layer was dried over sodium sulfate, filtered, concentrated by distillation under reduced pressure, and separated by MPLC (hexane:ethyl acetate = 10:1, by volume) to give 1-(2-hydroxy-4-((tetrahydro-2H-pyran-2-yl)oxy)phenyl)ethan-1-one (3.65 g, 94%).

[0549] (b) Synthesis of 4-fluoro-3-(fluoromethyl)-3-hydroxy-1-(2-hydroxy-4 -((tetrahydro-2H-pyran-2-yl)oxy)phenyl)butan-1-one

[0550] After cooling anhydrous tetrahydrofuran (15 mL) to 0 °C, lithium diisopropylamide (15 mL, 30 mmol, 2 M / tetrahydrofuran) was added thereto under a nitrogen atmosphere, and 1-(2-hydroxy-4-((tetrahydro-2H-pyran-2-yl)oxy)phenyl)ethan-1-one (3.02 g, 12.78 mmol) dissolved in anhydrous tetrahydrofuran (7 mL) was added dropwise thereto over 30 minutes. The reaction mixture was cooled to -40 °C, and difluoroacetone (1.57 g, 16.71 mmol) diluted with anhydrous tetrahydrofuran (7 mL) was added dropwise thereto over 1 hour, and stirred at -40 °C for another 40 minutes. After completion of the reaction, the temperature of the reaction mixture was brought to 0°C and an aqueous solution of ammonium chloride was added dropwise.The reaction mixture was diluted with ethyl acetate, washed with aqueous ammonium chloride and aqueous sodium chloride, dried over sodium sulfate, filtered, and concentrated by distillation under reduced pressure to quantitatively obtain 4-fluoro-3-(fluoromethyl)-3-hydroxy-1-(2-hydroxy-4-((tetrahydro-2H-pyran-2-yl)oxy)phenyl)butan-1-one. The resulting compound was used in the next reaction without purification.

[0551] (c) Synthesis of 2,2-bis(fluoromethyl)-7-((tetrahydro-2H-pyran-2-yl)oxy)chroman-4-one

[0552] 4-Fluoro-3-(fluoromethyl)-3-hydroxy-1-(2-hydroxy-4-((tetra-hydro-2H-pyran-2-yl)oxy)phenyl)butan-1-one (4.22 g, 12.78 mmol), obtained in the above synthesis of intermediate 31(b), was added to pyridine (30 ml) and cooled to 0°C. While maintaining the reaction temperature at 0°C, trifluoroacetic anhydride (5.55 g, 26.42 mmol) was added dropwise over 2 hours, and then ethanol (20 ml) and 1,8-diazabicyclo[5.4.0]undec-7-ene (12.24 g, 80.4 mmol) were added successively. The reaction mixture temperature was raised to 50°C and heated with stirring for 1 hour. After completion of the reaction, the reaction mixture was diluted with ethyl acetate and washed with an aqueous solution of ammonium chloride, an aqueous solution of sodium bicarbonate, and an aqueous solution of sodium chloride.The separated organic layer was dried over sodium sulfate, filtered, concentrated by distillation under reduced pressure, and separated by MPLC (hexane:ethyl acetate = 10:1, by volume) to give 2,2-bis(fluoromethyl)-7-((tetrahydro-2H-pyran-2-yl)-oxy)chroman-4-one (1.08 g, 27%).

[0553] (d) Synthesis of 2,2-bis(fluoromethyl)-7-hydroxychroman-4-one

[0554] 2,2-Bis(fluoromethyl)-7-((tetrahydro-2H-pyran-2-yl)oxy)-chroman-4-one (1.08 g, 3.45 mmol) obtained in the above synthesis of intermediate 31(c) was dissolved in tetrahydrofuran (10 ml), and p-toluenesulfonic acid (134 mg, 0.7 mmol) and methanol (10 ml) were added thereto, and heated with stirring at 50°C for 2 hours. After completion of the reaction, the reaction mixture was concentrated by distillation under reduced pressure and separated by MPLC (hexane:ethyl acetate = 2:1, by volume) to give 2,2-bis(fluoromethyl)-7-hydroxychroman-4-one (626 mg, 80%).

[0555] (e) Synthesis of 3-bromo-2,2-bis(fluoromethyl)-7-hydroxy-chroman-4-one

[0556] To obtain 3-bromo-2,2-bis(fluoromethyl)-7-hydroxy-chroman-4-one in quantitative yield, the same synthesis as the above synthesis of intermediate 7(b) was carried out, except that 2,2-bis(fluoromethyl)-7-hydroxychroman-4-one was used instead of 7-hydroxy-2,2-dimethylchroman-4-one. The obtained compound was used in the next reaction without purification.

[0557] (f) Synthesis of 3-bromo-2,2-bis(fluoromethyl)-7-((triisopropyl-silyl)oxy)chroman-4-one

[0558] To obtain 3-bromo-2,2-bis(fluoromethyl)-7-((triisopropylsilyl)oxy)chroman-4-one (1.17 g, 92%), the same synthesis as the above synthesis of intermediate 7(c) was carried out, except that 3-bromo-2,2-bis(fluoromethyl)-7-hydroxy-chroman-4-one was used instead of 3-bromo-7-hydroxy-2,2-dimethyl-chroman-4-one.

[0559] (g) Synthesis of 3-bromo-2,2-bis(fluoromethyl)-7-((triisopropyl-silyl)oxy)chroman-4-ol

[0560] 3-Bromo-2,2-bis(fluoromethyl)-7-((triisopropylsilyl)oxy)-chroman-4-one (1.17 g, 2.52 mmol), obtained in the above synthesis of intermediate 31(f), was dissolved in ethanol (12 ml) and cooled to 0°C, and then sodium borohydride (48 mg, 1.28 mmol) was added. Then, the reaction mixture was stirred at 0°C for 15 min, sodium borohydride (46 mg, 1.22 mmol) was added in three portions, and stirred at 0°C for another 5 min. After completion of the reaction, the reaction mixture was brought to 0°C, aqueous ammonium chloride solution was added dropwise, and extraction was performed several times with ethyl acetate. The separated organic layer was washed with aqueous sodium chloride solution, dried over sodium sulfate, filtered, and concentrated by distillation under reduced pressure to quantitatively obtain 3-bromo-2,2-bis(fluoromethyl)-7-((triisopropylsilyl)oxy)chroman-4-ol. The resulting compound was used in the next reaction without purification.

[0561] (h) Synthesis of ((3-bromo-2,2-bis(fluoromethyl)-2H-chromen-7-yl)-oxy)triisopropylsilane

[0562] To obtain ((3-bromo-2,2-bis(fluoromethyl)-2H-chromen-7-yl)-oxy)triisopropylsilane (506 mg, 1.1345%), the same synthesis as the above synthesis of intermediate 18(g) was carried out, except that 3-bromo-2,2-bis(fluoromethyl)-7-((triisopropylsilyl)oxy)chroman-4-ol was used instead of 3-bromo-6,8-difluoro-2,2-dimethyl-7-((triisopropylsilyl)oxy)chroman-4-ol.

[0563] (i) Synthesis of ((2,2-bis(fluoromethyl)-3-vinyl-2H-chromen-7-yl)-oxy)triisopropylsilane

[0564] To obtain ((2,2-bis(fluoromethyl)-3-vinyl-2H-chromen-7-yl)-oxy)triisopropylsilane in quantitative yield, the same synthesis as the above synthesis of intermediate 7(e) was carried out, except that ((3-bromo-2,2-dimethyl-2H-chromen-7-yl)oxy)triisopropylsilane was used instead of ((3-bromo-2,2-bis(fluoromethyl)-2H-chromen-7-yl)oxy)triisopropylsilane. The obtained compound was used in the next reaction without purification.

[0565] Intermediate 32. Synthesis of N,N-diisopropyl-2,2-dimethyl-3-vinyl-2H-chromen-7-amine

[0566] (a) Synthesis of 7-(diisopropylamino)-2,2-dimethyl-2H-chromene-3-carbaldehyde

[0567] To obtain 7-(diisopropylamino)-2,2-dimethyl-2H-chromene-3-carbaldehyde (620 mg, 93%), the same synthesis as the above synthesis of intermediate 9(b) was carried out, except that 7-bromo-2,2-dimethylchroman-4-one and O-tert-butylcarbamate were replaced by 7-bromo-2,2-dimethyl-2H-chromene-3-carbaldehyde and diisopropylamine, respectively.

[0568] (b) Synthesis of N,N-diisopropyl-2,2-dimethyl-3-vinyl-2H-chromen-7-amine

[0569] To obtain N,N-diisopropyl-2,2-dimethyl-3-vinyl-2H-chromen-7-amine in quantitative yield, the same synthesis as the above synthesis of intermediate 17(b) was carried out, except that 7-(diisopropylamino)-2,2-dimethyl-2H-chromen-3-carbaldehyde was used instead of tert-butyl ethyl (3-formyl-2,2-dimethylchromen-7-yl)carbamate. The obtained compound was used in the next reaction without purification.

[0570] Intermediate 33. Synthesis of N-isopropyl-N,2,2-trimethyl-3-vinyl-2H-chromen-7-amine

[0571] (a) Synthesis of 7-(isopropyl(methyl)amino)-2,2-dimethyl-2H-chromene-3-carbaldehyde

[0572] To obtain 7-(isopropyl(methyl)amino)-2,2-dimethyl-2H-chromene-3-carbaldehyde (430 mg, 85%), the same synthesis as the above synthesis of intermediate 9(b) was carried out, except that 7-bromo-2,2-dimethylchroman-4-one and O-tert-butylcarbamate were replaced by 7-bromo-2,2-dimethyl-2H-chromene-3-carbaldehyde and N-methylisopropylamine, respectively.

[0573] (b) Synthesis of N-isopropyl-N,2,2-trimethyl-3-vinyl-2H-chromene-7-amine

[0574] To obtain N-isopropyl-N,2,2-trimethyl-3-vinyl-2H-chromen-7-amine in quantitative yield, the same synthesis as the above synthesis of intermediate 17(b) was carried out, except that 7-(isopropyl(methyl)-amino)-2,2-dimethyl-2H-chromen-3-carbaldehyde was used instead of tert-butyl ethyl (3-formyl-2,2-dimethylchromen-7-yl)carbamate. The obtained compound was used in the next reaction without purification.

[0575] Intermediate 34. Synthesis of tert-butyl (2,2-dimethyl-3-vinyl-2H-chromen-7-yl)(ethyl)carbamate

[0576] (a) Synthesis of tert-butyl ethyl(3-formyl-2,2-dimethyl-2H-chromen-7-yl)carbamate

[0577] To obtain tert-butyl ethyl (3-formyl-2,2-dimethyl-2H-chromen-7-yl)carbamate (520 mg, 88%), the same synthesis as the above synthesis of intermediate 9(b) was carried out, except that 7-bromo-2,2-dimethylchroman-4-one and O-tert-butylcarbamate were replaced by 7-bromo-2,2-dimethyl-2H-chromen-3-carbaldehyde and tert-butyl ethyl carbamate, respectively.

[0578] (b) Synthesis of tert-butyl (2,2-dimethyl-3-vinyl-2H-chromen-7-yl)-(ethyl)carbamate

[0579] To obtain tert-butyl (2,2-dimethyl-3-vinyl-2H-chromen-7-yl)(ethyl)carbamate in quantitative yield, the same synthesis as the above synthesis of intermediate 17(b) was carried out, except that ethyl (3-formyl-2,2-dimethyl-2H-chromen-7-yl)carbamate was used instead of tert-butyl ethyl (3-formyl-2,2-dimethylchromen-7-yl)carbamate. The obtained compound was used in the next reaction without purification.

[0580] Intermediate 35. Synthesis of 5-(2,2-dimethyl-3-vinyl-2H-chromen-7-yl)-1,3-dimethyl-1H-pyrazole

[0581] (a) Synthesis of 7-(1,3-dimethyl-1H-pyrazol-5-yl)-2,2-dimethyl-2H-chromene-3-carbaldehyde

[0582] To obtain 7-(1,3-dimethyl-1H-pyrazol-5-yl)-2,2-dimethyl-2H-chromene-3-carbaldehyde (300 mg, 85%), the same synthesis as the above synthesis of intermediate 7(e) was carried out, except that 7-bromo-2,2-dimethyl-2H-chromen-7-yl)oxy)triisopropylsilane and vinyl boronic acid dibutyl ester were used, respectively.

[0583] (b) Synthesis of 5-(2,2-dimethyl-3-vinyl-2H-chromen-7-yl)-1,3-dimethyl-1H-pyrazole

[0584] To obtain 5-(2,2-dimethyl-3-vinyl-2H-chromen-7-yl)-1,3-dimethyl-1H-pyrazole in quantitative yield, the same synthesis as the above synthesis of intermediate 17(b) was carried out, except that 7-(1,3-dimethyl-1H-pyrazol-5-yl)-2,2-dimethyl-2H-chromen-3-carbaldehyde was used instead of tert-butyl ethyl (3-formyl-2,2-dimethylchromen-7-yl)carbamate.

[0585] Intermediate 36. Synthesis of 4-(2,2-dimethyl-3-vinyl-2H-chromen-7-yl)-2,5-dimethylthiazole

[0586] (a) Synthesis of 7-(2,5-dimethylthiazol-4-yl)-2,2-dimethyl-2H-chromene-3-carbaldehyde

[0587] To obtain 7-(2,5-dimethylthiazol-4-yl)-2,2-dimethyl-2H-chromene-3-carbaldehyde (300 mg, 85%), the same synthesis as the above synthesis of intermediate 7(e) was carried out, except that 7-bromo-2,2-dimethyl-2H-chromen-7-yl)oxy)triisopropylsilane and vinyl boronic acid dibutyl ester were used, respectively.

[0588] (b) Synthesis of 4-(2,2-dimethyl-3-vinyl-2H-chromen-7-yl)-2,5-dimethylthiazole

[0589] To obtain 4-(2,2-dimethyl-3-vinyl-2H-chromen-7-yl)-2,5-dimethylthiazole in quantitative yield, the same synthesis as the above synthesis of intermediate 17(b) was carried out, except that 7-(2,5-dimethylthiazol-4-yl)-2,2-dimethyl-2H-chromen-3-carbaldehyde was used instead of tert-butyl ethyl (3-formyl-2,2-dimethylchromen-7-yl)carbamate. The obtained compound was used in the next reaction without purification.

[0590] Intermediate 37. Synthesis of 4-(2,2-dimethyl-3-vinyl-2H-chromen-7-yl)-1-ethyl-3,5-dimethyl-1H-pyrazole

[0591] (a) Synthesis of 7-(1-ethyl-3,5-dimethyl-1H-pyrazol-4-yl)-2,2-dimethyl-2H-chromene-3-carbaldehyde

[0592] To obtain 7-(1-ethyl-3,5-dimethyl-1H-pyrazol-4-yl)-2,2-dimethyl-2H-chromene-3-carbaldehyde (442 mg, 80%), the same synthesis as the above synthesis of intermediate 7(e) was carried out, except that 7-bromo-2,2-dimethyl-2H-chromen-7-yl)oxy)triisopropylsilane and vinyl boronic acid dibutyl ester were used, respectively.

[0593] (b) Synthesis of 4-(2,2-dimethyl-3-vinyl-2H-chromen-7-yl)-1-ethyl-3,5-dimethyl-1H-pyrazole

[0594] To obtain 4-(2,2-dimethyl-3-vinyl-2H-chromen-7-yl)-1-ethyl-3,5-dimethyl-1H-pyrazole in quantitative yield, the same synthesis as the above synthesis of intermediate 17(b) was carried out, except that 7-(1-ethyl-3,5-dimethyl-1H-pyrazol-4-yl)-2,2-dimethyl-2H-chromen-3-carbaldehyde was used instead of tert-butyl ethyl (3-formyl-2,2-dimethylchromen-7-yl)carbamate. The obtained compound was used in the next reaction without purification.

[0595] Intermediate 38. Synthesis of 3-(2,2-dimethyl-3-vinyl-2H-chromen-7-yl)pyridine

[0596] (a) Synthesis of 2,2-dimethyl-7-(pyridin-3-yl)-2H-chromene-3-carbaldehyde

[0597] To obtain 2,2-dimethyl-7-(pyridin-3-yl)-2H-chromene-3-carbaldehyde (300 mg, 85%), the same synthesis as the above synthesis of intermediate 7(e) was carried out, except that 7-bromo-2,2-dimethyl-2H-chromen-3-carbaldehyde and 3-pyridylboronic acid were used instead of ((3-bromo-2,2-dimethyl-2H-chromen-7-yl)oxy)triisopropylsilane and vinyl boronic acid dibutyl ester, respectively.

[0598] (b) Synthesis of 3-(2,2-dimethyl-3-vinyl-2H-chromen-7-yl)pyridine

[0599] To obtain 3-(2,2-dimethyl-3-vinyl-2H-chromen-7-yl)pyridine in quantitative yield, the same synthesis as the above synthesis of intermediate 17(b) was carried out, except that 2,2-dimethyl-7-(pyridin-3-yl)-2H-chromen-3-carbaldehyde was used instead of tert-butyl ethyl (3-formyl-2,2-dimethylchromen-7-yl)carbamate. The obtained compound was used in the next reaction without purification.

[0600] Intermediate 39. Synthesis of 3-(2,2-dimethyl-3-vinyl-2H-chromen-7-yl)pyridine

[0601] (a) Synthesis of 2,2-dimethyl-7-(pyridin-4-yl)-2H-chromene-3-carbaldehyde

[0602] To obtain 2,2-dimethyl-7-(pyridin-4-yl)-2H-chromene-3-carbaldehyde (270 mg, 78%), the same synthesis as the above synthesis of intermediate 7(e) was carried out, except that 7-bromo-2,2-dimethyl-2H-chromen-3-carbaldehyde and 4-pyridylboronic acid were used instead of ((3-bromo-2,2-dimethyl-2H-chromen-7-yl)oxy)triisopropylsilane and vinyl boronic acid dibutyl ester, respectively.

[0603] (b) Synthesis of 3-(2,2-dimethyl-3-vinyl-2H-chromen-7-yl)pyridine

[0604] To obtain 3-(2,2-dimethyl-3-vinyl-2H-chromen-7-yl)pyridine in quantitative yield, the same synthesis as the above synthesis of intermediate 17(b) was carried out, except that 2,2-dimethyl-7-(pyridin-4-yl)-2H-chromen-3-carbaldehyde was used instead of tert-butyl ethyl (3-formyl-2,2-dimethylchromen-7-yl)carbamate. The obtained compound was used in the next reaction without purification.

[0605] Intermediate 40. Synthesis of 4-(2,2-dimethyl-3-vinyl-2H-chromen-7-yl)-3-methylisoxazole

[0606] (a) Synthesis of 2,2-dimethyl-7-(3-methylisoxazol-4-yl)-2H-chromene-3-carbaldehyde

[0607] To obtain 2,2-dimethyl-7-(3-methylisoxazol-4-yl)-2H-chromene-3-carbaldehyde (335 mg, 83%), the same synthesis as the above synthesis of intermediate 7(e) was carried out, except that 7-bromo-2,2-dimethyl-2H-chromen-7-yl)oxy)triisopropylsilane and vinyl boronic acid dibutyl ester were used, respectively.

[0608] (b) Synthesis of 4-(2,2-dimethyl-3-vinyl-2H-chromen-7-yl)-3-methylisoxazole

[0609] To obtain 4-(2,2-dimethyl-3-vinyl-2H-chromen-7-yl)-3-methylisoxazole in quantitative yield, the same synthesis as the above synthesis of intermediate 17(b) was carried out, except that 2,2-dimethyl-7-(3-methylisoxazol-4-yl)-2H-chromen-3-carbaldehyde was used instead of tert-butyl ethyl (3-formyl-2,2-dimethylchromen-7-yl)carbamate. The obtained compound was used in the next reaction without purification.

[0610] Intermediate 41. Synthesis of 2,2-dimethyl-7-((tetrahydro-2H-pyran-2-yl)oxy)-3-vinyl-2H-chromene

[0611] (a) Synthesis of 2,2-dimethyl-7-((tetrahydro-2H-pyran-2-yl)oxy)-2H-chromene-3-carbaldehyde

[0612] 1-(2-Hydroxy-4-((tetrahydro-2H-pyran-2-yl)oxy)phenyl)ethan-1-one (0.64 g, 2.9 mmol) obtained in the above synthesis of intermediate 31(a) and potassium carbonate (0.6 g, 4.3 mmol) were dissolved in a mixed solvent of 1,4-dioxane / water (3:1, 8 ml), and 3-methylbut-2-enal (0.49 g, 5.8 mmol) were added dropwise, and heated with stirring at 80°C for 72 hours. After completion of the reaction, the reaction mixture was diluted with ethyl acetate and washed with aqueous sodium chloride solution. The separated organic layer was dried over sodium sulfate, filtered, and concentrated by distillation under reduced pressure to quantitatively yield 2,2-dimethyl-7-((tetrahydro-2H-pyran-2-yl)oxy)-2H-chromene-3-carbaldehyde. The resulting compound was used in the next reaction without purification.

[0613] (b) Synthesis of 2,2-dimethyl-7-((tetrahydro-2H-pyran-2-yl)oxy)-3-vinyl-2H-chromene

[0614] To obtain 2,2-dimethyl-7-((tetrahydro-2H-pyran-2-yl)oxy)-3-vinyl-2H-chromene in quantitative yield, the same synthesis as the above synthesis of intermediate 17(b) was carried out, except that 2,2-dimethyl-7-((tetrahydro-2H-pyran-2-yl)oxy)-2H-chromene-3-carbaldehyde was used instead of tert-butyl ethyl (3-formyl-2,2-dimethylchromen-7-yl)carbamate. The obtained compound was used in the next reaction without purification.

[0615] Example 1. Synthesis of 7,7-bis(fluoromethyl)-10-hydroxy-2-phenyl-5,12b-dihydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]-pyridazine-1,3(2H)-dione

[0616] (a) Synthesis of 7,7-bis(fluoromethyl)-2-phenyl-10-((triisopropylsilyl)oxy)-5,12b-dihydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo-[1,2-a]pyridazine-1,3(2H)-dione

[0617] 4-Phenyl-1,2,4-triazolidine-3,5-dione (0.3 g, 1.7 mmol) was suspended in tetrahydrofuran (3 ml), and iodobenzene diacetate (0.55 g, 1.7 mmol) was added thereto, and stirred for 30 minutes under light-protected conditions. ((2,2-bis(fluoromethyl)-3-vinyl-2H-chromen-7-yl)oxy)triisopropylsilane (0.67 g, 1.7 mmol) dissolved in tetrahydrofuran (3 ml) was added to the reaction mixture, and stirred for another 30 minutes. After completion of the reaction, the reaction mixture was diluted with ethyl acetate and washed with water. The separated organic layer was dried over sodium sulfate, filtered, concentrated by distillation under reduced pressure, and separated by MPLC (hexane:ethyl acetate = 5:1, by volume) to give 7,7-bis(fluoromethyl)-2-phenyl-10-((triisopropylsilyl)oxy)-5,12b-dihydro-1H,7H-chromeno[4,3-c][1,2,4]-triazolo[1,2-a]pyridazine-1,3(2H)-dione (0.61 g, 67%).

[0618] (b) Synthesis of 7,7-bis(fluoromethyl)-10-hydroxy-2-phenyl-5,12b-dihydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazine-1,3(2H)-dione

[0619] After 7,7-bis(fluoromethyl)-2-phenyl-10-((triisopropylsilyl)oxy)-5,12b-dihydro-1H,7H-chromeno[4,3-c][1,2,4]-triazolo[1,2-a]pyridazine-1,3(2H)-dione (0.41 g, 0.72 mmol) obtained in Example 1(a) above was dissolved in tetrahydrofuran (5 ml), it was added to a conical centrifuge tube containing a 7:3 by volume mixture of hydrogen fluoride and pyridine (3.85 mmol, 5 ml), and stirred for 20 hours. After completion of the reaction, 2-(trimethylsilyl)ethanol (5 ml) was added dropwise to the reaction mixture, which was concentrated by distillation under reduced pressure. The resulting residue was separated by MPLC (hexane:ethyl acetate = 5:1, by volume) to give 7,7-bis(fluoromethyl)-10-hydroxy-2-phenyl-5,12b-dihydro-1H,7H-chromeno[4,3-c][1,2,4]-triazolo[1,2-a]pyridazine-1,3(2H)-dione (296 mg, 54%).

[0620] 1H NMR (400 MHz, acetone) δ 8.56 (s, 1H), 7.69-7.62 (m, 2H), 7.54 (dd, J=8.5, 7.1 Hz, 2H), 7.48-7.39 (m, 1H), 6.95-6.9 m, (6.59-6.1H), (m, 2H), 6.21-6.14 (m, 1H), 5.61 (d, J=1.4 Hz, 1H), 4.93 (t, J=2.1 Hz, 1H), 4.90-4.75 (m, 2H), 4.75-4.64 (m, 1H, 46, 2H), J = 17.3, dd Hz, 1H), 4.34-4.18 (m, 2H), 2.91-2.84 (m, 1H)

[0621] Example 2. Synthesis of 2-(4-acetylphenyl)-7,7-bis(fluoromethyl)-10-hydroxy-5,12b-dihydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]-pyrione,3(2H)

[0622] (a) Synthesis 2-(4-acetylphenyl)-7,7-bis(fluoromethyl)-10-((triisopropylsilyl)oxy)-5,12b-dihydro-1H,7H-chromeno[4,3-c]-[1,2,4]-triazolo[1,2-a]pyridazine-1,3(2H)-dione

[0623] 4-(4-Acetylphenyl)-1,2,4-triazolidine-3,5-dione (0.3 g, 1.37 mmol) was suspended in tetrahydrofuran (3 ml), and iodobenzenediacetate (0.45 g, 1.37 mmol) was added and stirred for 30 minutes under light-protected conditions. ((2,2-bis(fluoromethyl)-3-vinyl-2H-chromen-7-yl)oxy)-triisopropylsilane (0.54 g, 1.37 mmol) dissolved in tetrahydrofuran (3 ml) was added to the reaction mixture, and stirred for another 30 minutes. After completion of the reaction, the reaction mixture was diluted with ethyl acetate and washed with water. The separated organic layer was dried over sodium sulfate, filtered, concentrated by distillation under reduced pressure, and separated by MPLC (hexane:ethyl acetate = 5:1, by volume) to give 2-(4-acetylphenyl)-7,7-bis(fluoromethyl)-10-((triisopropylsilyl)oxy)-5,12b-dihydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]-pyridazine-1,3(2H)-dione (0.42 g, 53%).

[0624] (b) Synthesis of 2-(4-acetylphenyl)-7,7-bis(fluoromethyl)-10-hydroxy-5,12b-dihydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo-[1,2-a]pyridazine-1,3(2H)-dione

[0625] To obtain 2-(4-acetylphenyl)-7,7-bis(fluoromethyl)-10-hydroxy-5,12b-dihydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazine-1,3(2H)-dione (132 mg, 60%), the same synthesis as the above synthesis in Example 1(b) was carried out, except that 7,7-bis(fluoromethyl)-2-phenyl-10-((triisopropylsilyl)oxy)-5,12b-dihydro-1H,7H-chromeno[4,3-c]-[1,2,4]triazolo-[1,2-a]pyridazine-1,3(2H)-dione was used 2-(4-acetylphenyl)-7,7-bis(fluoromethyl)-10-((triisopropylsilyl)oxy)-5,12b-dihydro-1H,7H-chromeno[4,3-c]-[1,2,4]triazolo[1,2-a]-pyridazine-1,3(2H)-dione.

[0626] 1 H NMR (400 MHz, acetone) δ 9.62 (s, 1H), 8.14-8.12 (m, 1H), 7.80-7.78 (m, 1H), 6.81-6.79 (m, 1H), 6.45-6.11 (m, 1H), 5.63 (s, 1H), 4.88-4.53 (m, 4H), 4.24 (s, 1H), 2.63 (s, 3H), 2.07 (s, 1H)

[0627] Example 3. Synthesis of N-(2-(4-acetylphenyl)-7,7-dimethyl-1,3-dioxo-2,3,5,12b-tetrahydroxy-1H,7H-chromeno[4,3-c][1,2,4]-triazolo[1,2-a]pyridazin-10-yl)acetamide

[0628] To obtain N-(2-(4-acetylphenyl)-7,7-dimethyl-1,3-dioxo-2,3,5,12b-tetrahydroxy-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazin-10-yl)acetamide (28 mg, 36%), the same synthesis as the above synthesis in Example 2(a) was carried out except that N-(2,2-dimethyl-3-vinyl-2H-chromen-7-yl)acetamide was used instead of ((2,2-bis(fluoromethyl)-3-vinyl-2H-chromen-7-yl)oxy)triisopropylsilane.

[0629] 1 H NMR (400 MHz, DMSO-D6) δ 9.95 (s, 1H), 8.17-8.10 (m, J=8.6 Hz, 2H), 7.85-7.78 (m, J=8.6 Hz, 1H), 7.33 (s, 1H), 7.06-6.97 (m, 2H), 5.97 (br.s, 1H), 5.66 (s, 1H), 4.20 (br.s, 2H), 2.64 (s, 3H), 2.02 (s, 3H), 1.57 (s, 3H), 1.52 (s, 3H)

[0630] Example 4. Synthesis of 2-(4-acetylphenyl)-7,7-dimethyl-10-(methylsulfonyl)-5,12b-dihydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo-[1,2-a]pyridazine-1,3(2H)-dione

[0631] To obtain 2-(4-acetylphenyl)-7,7-dimethyl-10-(methylsulfonyl)-5,12b-dihydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo-[1,2-a]pyridazine-1,3(2H)-dione (58 mg, 39%), the same synthesis as the above synthesis in Example 2(a) was carried out except that 2,2-dimethyl-7-(methylsulfonyl)-3-vinyl-2H-chromen was used instead of ((2,2-bis(fluoromethyl)-3-vinyl-2H-chromen-7-yl)-oxy)triisopropylsilane.

[0632] 1 H NMR (400 MHz, DMSO-D6) δ 8.17-8.12 (m, J=8.4 Hz, 2H), 7.84-7.80 (m, J=8.4 Hz, 2H), 7.54 (d, J=7.81 Hz, 1H), 7.39 (s, 1H), 7.38 (d, J=8.1 Hz, 1H), 6.07 (br.s, 1H), 5.84 (s, 1H), 4.24 (br.s, 2H), 3.21 (s, 3H), 2.67-2.63 (s, 3H), 1.65 (s, 3H), 1.55 (s, 3H)

[0633] Example 5. Synthesis of N-(2-(4-acetylphenyl)-7,7-dimethyl-1,3-dioxo-2,3,5,12b-tetrahydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo-[1,2-a]pyridazin-10-yl)methanesulfonamide

[0634] To obtain N-(2-(4-acetylphenyl)-7,7-dimethyl-1,3-dioxo-2,3,5,12b-tetrahydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]-pyridazin-10-yl)methanesulfonamide (78 mg, 46%), the same synthesis as the above synthesis in Example 2(a) was carried out except that N-(2,2-dimethyl-3-vinyl-2H-chromen-7-yl)oxy)triisopropylsilane was used instead of ((2,2-bis(fluoromethyl)-3-vinyl-2H-chromen-7-yl)methanesulfonamide.

[0635] 1 H NMR (400 MHz, DMSO-D6) δ 9.88-9.71 (m, 1H), 8.14 (d, J=8.6 Hz, 2H), 7.81 (d, J=8.4 Hz, 2H), 7.06 (d, J=8.3 Hz, 1H), 6.82 (br d, J=8.3 Hz, 1H), 6.72 (d, J=1.6 Hz, 1H), 6.01 (br s, 1H), 5.69 (s, 1H), 4.21 (br s, 2H), 2.98 (s, 3H), 2.65 (s, 3H), 1.56 (d, J=15.8 Hz, 6h)

[0636] Example 6. Synthesis of tert-butyl (2-(4-acetylphenyl)-7,7-dimethyl-1,3-dioxo-2,3,5,12b-tetrahydro-1H,7H-chromeno[4,3-c][1,2,4]-triazolo[1,2-a]pyridazin-10-yl)carbamate

[0637] To obtain tert-butyl (2-(4-acetylphenyl)-7,7-dimethyl-1,3-dioxo-2,3,5,12b-tetrahydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo-[1,2-a]pyridazin-10-yl)carbamate (67 mg, 36%), the same synthesis as the above synthesis in Example 2(a) was carried out except that tert-butyl (2,2-dimethyl-3-vinyl-2H-chromen-7-yl)oxy)triisopropylsilane was used instead of ((2,2-bis(fluoromethyl)-3-vinyl-2H-chromen-7-yl)carbamate.

[0638] 1 H NMR (400 MHz, DMSO-D6) δ 9.36 (s, 1H), 8.16-8.11 (m, J=8.6 Hz, 2H), 7.82-7.78 (m, J=8.6 Hz, 2H), 7.10 (s, 1H), 7.01-6.94 (m, 2H), 5.97 (br.s, 1H), 5.65 (s, 1H), 4.20 (br.s, 2H), 2.64 (s, 3H), 1.56 (s, 3H), 1.52 (s, 3H), 1.46 (s, 9h)

[0639] Example 7. Synthesis of 2-(4-acetylphenyl)-10-amino-7,7-dimethyl-5,12b-dihydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]-pyridazine-1,3(2H)-dione

[0640] Tertiary butyl (2-(4-acetylphenyl)-7,7-dimethyl-1,3-dioxo-2,3,5,12b-tetrahydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]-pyridazin-10-yl)carbamate (40 mg, 0.077 mmol) obtained in Example 6 above was dissolved in dichloromethane (1.5 ml), and trifluoroacetic acid (8.8 mg, 0.077 mmol) was added dropwise, and stirred at room temperature for 30 minutes. After completion of the reaction, the reaction mixture was concentrated by distillation under reduced pressure, and the resulting residue was separated by reverse phase chromatography (acetonitrile containing 0.1% formic acid: water containing 0.1% formic acid = 5:95-100:0) to obtain 2-(4-acetylphenyl)-10-amino-7,7-dimethyl-5,12b-dihydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]-pyridazine-1,3(2H)-dione (22 mg, 68%).

[0641] 1H NMR (400 MHz, DMSO-D6) δ 8.16-8.11 (m, J=8.6 Hz, 2H), 7.82-7.76 (m, J=8.6 Hz, 2H), 6.72 (d, J=8.3 Hz, 1H), 6.16 (dd, J=1.8, 8.3 Hz, 1H), 6.08-6.04 (m, 1H), 5.92 (br.s, 1H), 5.56 (s, 1H), 5.09 (br.s, 2H), 4.24-4.12 (m, 2H), 2.64 (s, 3H), 1.51 (d, J=7.8 Hz, 6h)

[0642] Example 8. Synthesis of 2-(4-acetylphenyl)-7,7-dimethyl-10-morpholino-5,12b-dihydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo-[1,2-a]pyridazine-1,3(2H)-dione

[0643] To obtain 2-(4-acetylphenyl)-7,7-dimethyl-10-morpholino-5,12b-dihydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]-pyridazine-1,3(2H)-dione (80 mg, 46%), the same synthesis as the above synthesis in Example 2(a) was carried out except that 4-(2,2-dimethyl-3-vinyl-2H-chromen-7-yl)morpholine was used instead of ((2,2-bis(fluoromethyl)-3-vinyl-2H-chromen-7-yl)oxy)-triisopropylsilane.

[0644] 1H NMR (400 MHz, DMSO-D6) δ 8.09-8.03 (m, J=8.4 Hz, 2H), 7.74-7.69 (m, J=8.4 Hz, 2H), 6.87 (d, J=8.6 Hz, 1H), 6.48 (dd, J=2.0, 8.6 Hz, 1H), 6.33 (d, J=2.0 Hz, 1H), 5.91 (br.s, 1H), 5.59 (s, 1H), 4.12 (br.s, 2H), 3.62 (br.t, J=4.5 Hz, 4H), 3.02-2.93 (m, 4H), 2.57 (s, 3H), 1.47 (d, J=6.8 Hz, 6H)

[0645] Example 9. Synthesis of N-(2-(4-acetylphenyl)-7,7-dimethyl-1,3-dioxo-2,3,5,12b-tetrahydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo-[1,2-a]pyridazin-10-yl)diamide sulfate

[0646] 2-(4-Acetylphenyl)-10-amino-7,7-dimethyl-5,12b-dihydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazine-1,3(2H)-dione (18 mg, 0.043 mmol) obtained in Example 7 above was dissolved in N,N-dimethylacetamide (0.5 ml), and sulfamoyl chloride (9.9 mg, 0.086 mmol) was added dropwise, and stirred at room temperature for 18 hours. After completion of the reaction, the reaction mixture was concentrated by distillation under reduced pressure, and the resulting residue was separated by reverse phase chromatography (acetonitrile containing 0.1% formic acid: water containing 0.1% formic acid = 5:95-100:0) to obtain N-(2-(4-acetylphenyl)-7,7-dimethyl-1,3-dioxo-2,3,5,12b-tetrahydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazin-10-yl)diamide sulfate (4 mg, 19%).

[0647] 1H NMR (400 MHz, DMSO-D6) δ 9.44 (ear s, 1H), 8.09-8.03 (m, J=8.6 Hz, 2H), 7.76-7.70 (m, J=8.6 Hz, 2H), 7.03 (s, 2Hz, 6.98 Hz), J 1H), 6.67 (d, J=8.7 Hz, 1H), 6.64 (d, J=1.8 Hz, 1H), 5.92 (ear s, 1H), 5.59 (s, 1H) 4.13 (ear s, 2H), 2.57 (s, 3H), 1, 3H, (s, 1, 36). 3H)

[0648] Example 10. Synthesis 2-(4-acetylphenyl)-9,11-dibromo-10-hydroxy-7,7-dimethyl-5,12b-dihydro-1H,7H-chromeno[4,3-c][1,2,4]-triazolo[1,2-a]pyridazine-1,3(2H)-dione

[0649] (a) Synthesis of 2-(4-acetylphenyl)-7,7-dimethyl-10-((triisopropylsilyl)oxy)-5,12b-dihydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo-[1,2-a-1-H,3-H)-diiona

[0650] To obtain 2-(4-acetylphenyl)-7,7-dimethyl-10-((triisopropylsilyl)oxy)-5,12b-dihydro-1H,7H-chromeno[4,3-c][1,2,4]-triazolo[1,2-a]pyridazine-1,3(2H)-dione (120 mg, 42%), the same synthesis as the above synthesis in Example 2(a) was carried out except that ((3-bromo-2,2-dimethyl-2H-chromen-7-yl)oxy)triisopropylsilane was used instead of ((2,2-bis(fluoromethyl)-3-vinyl-2H-chromen-7-yl)oxy)triisopropylsilane.

[0651] (b) Synthesis of 2-(4-acetylphenyl)-10-hydroxy-7,7-dimethyl-5,12b-dihydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazine-1,3(2H)-dione

[0652] To obtain 2-(4-acetylphenyl)-10-hydroxy-7,7-dimethyl-5,12b-dihydro-1H,7H-chromeno[4,3-c][1,2,4]-triazolo[1,2-a]pyridazine-1,3(2H)-dione (57 mg, 62%), the same synthesis as the above synthesis in Example 1(b) was carried out, except that 7,7-bis(fluoromethyl)-2-phenyl-10-((triisopropylsilyl)oxy)-5,12b-dihydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo-[1,2-a]pyridazine-1,3(2H)-dione was used 2-(4-acetylphenyl)-7,7-dimethyl-10-((triisopropylsilyl)oxy)-5,12b-dihydro-1H,7H-chromeno[4,3-c]-[1,2,4]triazolo[1,2-a]pyridazin-1,3(2H)-dione.

[0653] (c) Synthesis of 2-(4-acetylphenyl)-9,11-dibromo-10-hydroxy-7,7-dimethyl-5,12b-dihydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazine-1,3(2H)-dione

[0654] 2-(4-acetylphenyl)-10-hydroxy-7,7-dimethyl-5,12b-dihydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazine-1,3(2H)-dione(30 mg, 0.072 mmol) obtained in Example 10(b) above was suspended in acetonitrile (2 ml), N-bromosuccinimide (15 mg, 0.086 mmol) was added thereto, and stirred at room temperature for 2 hours. 1-Bromopyrrolidine-2,5-dione (3.82 mg, 0.021 mmol) was added thereto, and stirred for another 2 hours. After completion of the reaction, the reaction mixture was diluted with dichloromethane and washed with water. The separated organic layer was dried over sodium sulfate, filtered, concentrated by distillation under reduced pressure, and subjected to separation by reverse phase chromatography (acetonitrile containing 0.1% formic acid: water containing 0.1% formic acid = 5:95-100:0) to give 2-(4-acetylphenyl)-9,11-dibromo-10-hydroxy-7,7-dimethyl-5,12b-dihydro-1H,7H-chromeno[4,3-c][1,2,4]-triazolo[1,2-a]pyridazine-1,3(2H)-dione (17 mg, 41%).

[0655] 1 H NMR (400 MHz, DMSO-D6) δ 9.97 (s, 1H), 8.15-8.13 (m, 2H), 7.78-7.76 (m, 2H), 7.23 (s, 1H), 6.02-6.01 (m, 1H), 5.66 (s, 1H), 4.26-4.15 (m, 2H), 2.63 (s, 3H), 1.61 (s, 3H), 1.52 (s, 3H)

[0656] Example 11. Synthesis of 2-(4-acetylphenyl)-9,11-dichloro-10-hydroxy-7,7-dimethyl-5,12b-dihydro-1H,7H-chromeno[4,3-c]-[1,2,4]-triazolo[1,2-a]pyridazin-1,3(2H)-dione

[0657] 2-(4-acetylphenyl)-10-hydroxy-7,7-dimethyl-5,12b-dihydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazine-1,3(2H)-dione (71 mg, 0.17 mmol) obtained in Example 10(b) above was suspended in acetonitrile (2 ml), and N-chlorosuccinimide (27 mg, 0.203 mmol) was added thereto, and heated with stirring at 70°C for 3 hours. 1-Chloropyrrolidine-2,5-dione (18 mg, 0.136 mmol) was added thereto, and heated with stirring at 70°C for another 4 hours. After completion of the reaction, the reaction mixture was diluted with dichloromethane and washed with water. The separated organic layer was dried over sodium sulfate, filtered, concentrated by distillation under reduced pressure and subjected to separation by reverse phase chromatography (acetonitrile containing 0.1% formic acid: water containing 0.1% formic acid = 5:95-100:0) to give 2-(4-acetylphenyl)-9,11-dichloro-10-hydroxy-7,7-dimethyl-5,12b-dihydro-1H,7H-chromeno[4,3-c][1,2,4]-triazolo[1,2-a]pyridazine-1,3(2H)-dione (9 mg, 11%).

[0658] 1 H NMR (400 MHz, DMSO-D6) δ 10.20 (s, 1H), 8.15-8.12 (m, 2H), 7.79-7.76 (m, 2H), 7.09 (s, 1H), 6.04-6.02 (m, 1H), 5.64 (s, 1H), 4.26-4.18 (m, 2H), 2.63 (s, 3H), 1.61 (s, 3H), 1.53 (s, 3H)

[0659] Example 12. Synthesis of 2-(6-fluoropyridin-2-yl)-10-hydroxy-7,7-dimethyl-5,12b-dihydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazine-1,3(2H)-dione

[0660] (a) Synthesis of 7,7-dimethyl-10-((triisopropylsilyl)oxy)-5,12b-dihydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazine-1,3(2H)-dione

[0661] To obtain 7,7-dimethyl-10-((triisopropylsilyl)oxy)-5,12b-dihydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo-[1,2-a]-pyridazine-1,3(2H)-dione (50 mg, 48%), the same synthesis as the above synthesis in Example 2(a) was carried out except that ((2,2-bis(fluoromethyl)-3-vinyl-2H-chromen-7-yl)oxy)-triisopropylsilane and 4-(4-acetylphenyl)-1,2,4-triazolidine-3,5-dione were used, respectively, for 7,7-dimethyl-10-((triisopropylsilyl)oxy)-5,12b-dihydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo-[1,2-a]-pyridazine-1,3(2H)-dione (50 mg, 48%). 1,2,4-triazolidine-3,5-dione.

[0662] (b) Synthesis of 2-(6-fluoropyridin-2-yl)-10-hydroxy-7,7-dimethyl-5,12b-dihydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]-pyridazine-1,3(2H)-dione

[0663] 7,7-Dimethyl-10-((triisopropylsilyl)oxy)-5,12b-dihydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazine-1,3(2H)-dione (35 mg, 0.076 mmol) obtained in Example 12(a) above was dissolved in N,N-dimethylformamide (3 ml), and 2,6-difluoropyridine (14 mg, 0.12 mmol) and cesium carbonate (50 mg, 0.15 mmol) were added thereto, and heated with stirring at 80°C for 2 hours. After completion of the reaction, the reaction mixture was diluted with dichloromethane and washed with water and an aqueous sodium chloride solution. The separated organic layer was dried over sodium sulfate, filtered, concentrated by distillation under reduced pressure, and subjected to separation by reverse phase chromatography (acetonitrile containing 0.1% formic acid: water containing 0.1% formic acid = 5:95-80:20) to give 2-(6-fluoropyridin-2-yl)-10-hydroxy-7,7-dimethyl-5,12b-dihydro-1H,7H-chromeno[4,3-c]-[1,2,4]triazolo[1,2-a]pyridazine-1,3(2H)-dione (7 mg, 23%).

[0664] 1H NMR (400 MHz, DMSO-D6) δ 11.71-11.57 (m, 1H), 8.09-7.78 (m, 1H), 7.01-6.97 (m, 1H), 6.90 (ddd, J=2.0, 8.1, 11.2 Hz, 2H), 6.77 (dd, J=2.4, 8.4 Hz, 1H), 6.68 (d, J=2.3 Hz, 1H), 6.08-5.86 (m, 1H), 5.59 (s, 1H), 4.16-4.05 (m, 1H), 4.05-3.94 (m, 1H), 1.55 (d, J=19.6 Hz, 6H)

[0665] Example 13. Synthesis of 2-(4-acetylphenyl)-7,7-dimethyl-10-nitro-5,12b-dihydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]-pyridazine-1,3(2H)-dione

[0666] To obtain 2-(4-acetylphenyl)-7,7-dimethyl-10-nitro-5,12b-dihydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazine-1,3(2H)-dione (54 mg, 68%), the same synthesis as the above synthesis in Example 2(a) was carried out except that 2,2-dimethyl-7-nitro-3-vinyl-2H-chromen-7-yl)oxy)-triisopropylsilane was used instead of ((2,2-bis(fluoromethyl)-3-vinyl-2H-chromen-7-yl)oxy)-triisopropylsilane.

[0667] 1H NMR (400 MHz, DMSO-D6) δ 8.16-8.13 (m, 2H), 7.88-7.82 (m, 3H), 7.68-7.67 (m, 1H), 7.41-7.38 (m, 1H), 6.08-6.08 (m, 1H), 5.87 (m, 1H), 4.24 (s, 2H), 2.64 (s, 3H), 1.65 (s, 3H), 1.55 (s, 3H)

[0668] Example 14. Synthesis of 2-(4-acetylphenyl)-10-(hydroxymethyl)-7,7-dimethyl-5,12b-dihydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazine-1,3(2H)-dione

[0669] (a) Synthesis of 2-(4-acetylphenyl)-10-(((4-methoxyphenyl)-diphenyl-methoxy)methyl)-7,7-dimethyl-5,12b-dihydro-1H,7H-chromeno[4,3-c]-[1,2,4]triazolo[1,2-a]pyridazin-1,3(2H)-dione

[0670] To obtain 2-(4-acetylphenyl)-10-(((4-methoxyphenyl)-diphenylmethoxy)methyl)-7,7-dimethyl-5,12b-dihydro-1H,7H-chromeno-[4,3-c][1,2,4]triazolo[1,2-a]pyridazine-1,3(2H)-dione (142 mg, 62%), the same synthesis as the above synthesis in Example 2(a) was carried out except that 7-(((4-methoxyphenyl)diphenylmethoxy)methyl)-2,2-dimethyl-3-vinyl-2H-chromen was used instead of ((2,2-bis(fluoromethyl)-3-vinyl-2H-chromen-7-yl)oxy)triisopropylsilane.

[0671] (b) Synthesis of 2-(4-acetylphenyl)-10-(hydroxymethyl)-7,7-dimethyl-5,12b-dihydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazine-1,3(2H)-dione

[0672] 2-(4-Acetylphenyl)-10-(((4-methoxyphenyl)diphenylmethoxy)-methyl)-7,7-dimethyl-5,12b-dihydro-1H,7H-chromeno[4,3-c][1,2,4]-triazolo[1,2-a]pyridazine-1,3(2H)-dione (100 mg, 0.14 mmol) obtained in Example 14(a) above was dissolved in dichloromethane (2 ml), and trifluoroacetic acid (16 mg, 0.14 mmol) was added dropwise thereto, and stirred at room temperature for 20 minutes. After completion of the reaction, the reaction mixture was concentrated by distillation under reduced pressure, and the resulting residue was separated by reverse phase chromatography (acetonitrile containing 0.1% formic acid: water containing 0.1% formic acid = 5:95-100:0) to obtain 2-(4-acetylphenyl)-10-(hydroxymethyl)-7,7-dimethyl-5,12b-dihydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]-pyridazine-1,3(2H)-dione (43 mg, 70%).

[0673] 1 H NMR (400 MHz, DMSO-D6) δ 8.07 (e.g., J=8.2 Hz, 2H), 7.73 (e.g., J=7.8 Hz, 2H), 6.94 (e.g., J=7.7 Hz, 1H), 6.84 (e.g., J=7.6 Hz, 1H), 6.84 (e.g., J=7.6 Hz, 16.6Hz). (ush. s, 1H), 5.90 (ush. s, 1H), 5.61 (ush. s, 1H), 5.13-5.09 (m, 1H), 4.39-4.32 (m, 2H), 4.13 (ush. s, 2H), 2.59-2.55 (ush. s, 1H), 2.59-2.55 (ush. s, 1, 3H), s. 1.43 (s, 3H)

[0674] Example 15. Synthesis of 1-(2-(4-acetylphenyl)-7,7-dimethyl-1,3-dioxo-2,3,5,12b-tetrahydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo-[1,2-pyrizinyl)

[0675] 2-(4-Acetylphenyl)-10-amino-7,7-dimethyl-5,12b-dihydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazine-1,3(2H)-dione (18 mg, 0.043 mmol) obtained in Example 7 above was dissolved in a mixed solvent of acetic acid / water (2:1, 1 mL), and sodium cyanate (5.6 mg, 0.086 mmol) was added thereto, and stirred at room temperature for 30 minutes. After completion of the reaction, the reaction mixture was concentrated by distillation under reduced pressure, and the resulting residue was separated by reverse phase chromatography (acetonitrile containing 0.1% formic acid: water containing 0.1% formic acid = 5:95-100:0) to obtain 1-(2-(4-acetylphenyl)-7,7-dimethyl-1,3-dioxo-2,3,5,12b-tetrahydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo-[1,2-a]pyridazin-10-yl)urea (11 mg, 55%).

[0676] 1H NMR (400 MHz, DMSO-D6) δ 8.07 (e.g., J=8.2 Hz, 2H), 7.73 (e.g., J=7.8 Hz, 2H), 6.94 (e.g., J=7.7 Hz, 1H), 6.84 (e.g., J=7.6 Hz, 1H), 6.84 (e.g., J=7.6 Hz, 16.6Hz). (ush. s, 1H), 5.90 (ush. s, 1H), 5.61 (ush. s, 1H), 5.13-5.09 (m, 1H), 4.39-4.32 (m, 2H), 4.13 (ush. s, 2H), 2.59-2.55 (ush. s, 1H), 2.59-2.55 (ush. s, 1, 3H), s. 1.43 (s, 3H)

[0677] Example 16: Synthesis of 2-(4-acetylphenyl)-10-(ethylamino)-7,7-dimethyl-5,12b-dihydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyrione(1,2-a]1,3-H)

[0678] (a) Synthesis of tertbutyl (2-(4-acetylphenyl)-7,7-dimethyl-1,3-dioxo-2,3,5,12b-tetrahydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo-[1,2-a]pyridazin-10-yl)(ethyl)carbamate

[0679] To obtain tert-butyl (2-(4-acetylphenyl)-7,7-dimethyl-1,3-dioxo-2,3,5,12b-tetrahydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo-[1,2-a]pyridazin-10-yl)(ethyl)carbamate (54 mg, 52%), the same synthesis as the above synthesis in Example 2(a) was carried out except that tert-butyl (2,2-dimethyl-3-vinyl-2H-chromen-7-yl)oxy)triisopropylsilane was used.

[0680] (b) Synthesis of 2-(4-acetylphenyl)-10-(ethylamino)-7,7-dimethyl-5,12b-dihydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]-pyridazine-1,3(2H)-dione

[0681] To prepare 2-(4-acetylphenyl)-10-(ethylamino)-7,7-dimethyl-5,12b-dihydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]-pyridazine-1,(26) m(26) m carried out the same synthesis as the above synthesis in Example 7 except that instead of tertbutyl (2-(4-acetylphenyl)-7,7-dimethyl-1,3-dioxo-2,3,5,12b-tetrahydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]-pyridazin-10-yl)carbamate used tretbutyl (2-(4-acetylphenyl)-7,7-dimethyl-1,3-dioxo-2,3,5,12b-tetrahydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazin-10-yl)(ethyl)-carbamate.

[0682] 1 H NMR (400 MHz, CDCl3) δ 8.14-8.07 (m, J=8.7 Hz, 2H), 7.88-7. 80 (m, J=8.6 Hz, 2H), 6.91 (d, J=8.4 Hz, 1H), 6.19 (dd, J=2.2 Hz, 8.4 Hz, 1H), 6.11 (d, J=2.2 Hz, 1H), 5.87-5.80 (m, 1H), 7.7H), 4.31 (dd, J=4.8, 16.0 Hz, 1H), 4.09 (td, J=2.3, 16.4 Hz, 1H), 3.60 (ear c, 1H), 3.09 (quartet, J=7.1 Hz, 2H), 2.65 (c, 3.0 Hz), (d, 16.9 Hz, J 6H), 1.30-1.14 (m, 3H)

[0683] Example 17. Synthesis of 2-(4-acetylphenyl)-7,7-dimethyl-10-((2,2,2-trifluoroethyl)amino)-5,12b-dihydro-1H,7H-chromeno[4,3-c][1,2,4]-triazolo[1,2-a]pyridazin-1,3(2H)-dione

[0684] To obtain 2-(4-acetylphenyl)-7,7-dimethyl-10-((2,2,2-trifluoroethyl)amino)-5,12b-dihydro-1H,7H-chromeno[4,3-c][1,2,4]-triazolo[1,2-a]pyridazine-1,3(2H)-dione (58 mg, 60%), the same synthesis as the above synthesis in Example 2(a) was carried out except that 2,2-dimethyl-1-(2,2,2-trifluoroethyl)-3-vinyl-2H-chromen-7-amine was used instead of ((2,2-bis(fluoromethyl)-3-vinyl-2H-chromen-7-yl)oxy)triisopropylsilane.

[0685] 1 H NMR (400 MHz, CDCl3) δ 8.14-8.08 (m, J=8.7 Hz, 2H), 7.86-7. 81 (m, J=8.1 Hz, 2H), 6.91 (d, J=8.4 Hz, 1H), 6.19 (br. d, J=8.6 Hz, 1H), 6.21 (s, 1H), 5.86 (br. s, 1H), 5.73 (br. s, 1H), 4.36-4.27 (m, 1H), 4.11 (br.d, J=17.4 Hz, 1H), 4.01-3.92 (m, 1H), 3.77-3.66 (m, 2H), 2.65 (s, 3H), 1.60 (br.d, J=9.7 Hz, 6H)

[0686] Example 18. Synthesis of 2-(4-acetylphenyl)-7,7-dimethyl-10-(piperazin-1-yl)-5,12b-dihydro-1H,7H-chromeno[4,3-c][1,2,4]-triazolo[1,2-a]pyridazin-1,3(2H)-dione hydrochloride

[0687] (a) Synthesis of tert-butyl 4-(2-(4-acetylphenyl)-7,7-dimethyl-1,3-dioxo-2,3,5,12b-tetrahydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo-[1,2-a]pyridazin-10-yl)piperazine-1-carboxylate

[0688] To obtain tert-butyl 4-(2-(4-acetylphenyl)-7,7-dimethyl-1,3-dioxo-2,3,5,12b-tetrahydro-1H,7H-chromeno[4,3-c][1,2,4]-triazolo[1,2-a]pyridazin-10-yl)piperazine-1-carboxylate (100 mg, 50%), the same synthesis as the above synthesis in Example 2(a) was carried out except that tert-butyl 4-(2,2-dimethyl-3-vinyl-2H-chromen-7-yl)oxy)triisopropylsilane was used instead of ((2,2-bis(fluoromethyl)-3-vinyl-2H-chromen-7-yl)-piperazine-1-carboxylate.

[0689] (b) Synthesis of 2-(4-acetylphenyl)-7,7-dimethyl-10-(piperazin-1-yl)-5,12b-dihydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]-pyridazin-1,3(2H)-dione hydrochloride

[0690] Tertiary butyl 4-(2-(4-acetylphenyl)-7,7-dimethyl-1,3-dioxo-2,3,5,12b-tetrahydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazin-10-yl)piperazine-1-carboxylate (55 mg, 0.09 mmol) obtained in Example 18(a) above was dissolved in dichloromethane (1 ml), and 4 M hydrogen chloride solution (94 μl, 0.374 mmol, 4 M HCl / dioxane) was added dropwise thereto, and stirred at room temperature for 1 hour. After completion of the reaction, the reaction mixture was concentrated by distillation under reduced pressure, triturated with ethyl acetate, and the resulting solid was filtered to obtain 2-(4-acetylphenyl)-7,7-dimethyl-10-(piperazin-1-yl)-5,12b-dihydro-1H,7H-chromeno[4,3-c]-[1,2,4]triazolo[1,2-a]pyridazine-1,3(2H)-dione hydrochloride (31 mg, 63%).

[0691] 1H NMR (400 MHz, DMSO-D6) δ 8.07 (br. s, 2H), 8.15-8.13 (m, 2H), 7.78-7.77 (m, 2H), 6.98-6.96 (m, 1H), 6.61-6.60 (m, 1H), 6.58 (s, 1H), 6.49 (s, 1H), 5.67 (s, 1H), 4.20 (s, 1H), 3.30 (s, 4H) 3.18 (s, 4H), 2.59 (s, 3H), 1.56 (br.s, 3H), 1.53 (br.s, 3H)

[0692] Example 19. Synthesis of 2-(4-acetylphenyl)-10-(4-acetyl-piperazin-1-yl)-7,7-dimethyl-5,12b-dihydro-1H,7H-chromeno[4,3-c][1,2,4]-triazolo[1,2-a]pyridazin-1,3(2H)-dione

[0693] 2-(4-Acetylphenyl)-7,7-dimethyl-10-(piperazin-1-yl)-5,12b-dihydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazine-1,3(2H)-dione hydrochloride (20 mg, 0.038 mmol) obtained in Example 18(b) above was dissolved in dimethyl sulfoxide (0.5 ml), acetic anhydride (4.32 μl, 0.046 mmol) and triethylamine (5.32 μl, 0.038 mmol) were added thereto, and stirred at room temperature for 1 hour. After completion of the reaction, the reaction mixture was concentrated by distillation under reduced pressure, and the resulting residue was separated by reverse phase chromatography (acetonitrile containing 0.1% formic acid: water containing 0.1% formic acid = 5:95-100:0) to obtain 2-(4-acetylphenyl)-10-(4-acetylpiperazin-1-yl)-7,7-dimethyl-5,12b-dihydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazine-1,3(2H)-dione (18 mg, 89%).

[0694] 1H NMR (400 MHz, DMSO-D6) δ 8.14-8.12 (m, 2H), 7.79-7.77 (m, 2H), 6.98-6.96 (m, 1H), 6.61-6.60 (m, 1H), 6.58 (s, 1H), 6.49 (s, 1H), 5.67 (s, 1H), 4.20 (s, 1H), 3.04 (s, 4H) 3.03 (s, 4H), 2.66 (s, 1H), 2.01 (s, 3H), 1.54 (br.s, 3H), 1.53 (br.s, 3H)

[0695] Example 20. Synthesis of 2-(5-acetylpyridin-2-yl)-10-hydroxy-7,7-dimethyl-5,12b-dihydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazine-1,3(2H)-dione

[0696] To ​​obtain 2-(5-acetylpyridin-2-yl)-10-hydroxy-7,7-dimethyl-5,12b-dihydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazine-1,3(2H)-dione (46 mg, 34%), the same synthesis as the above synthesis in Example 12(b) was carried out except that 1-(6-fluoropyridin-3-yl)ethan-1-one was used instead of 2,6-difluoropyridine.

[0697] 1H NMR (400 MHz, DMSO-D6) δ 11.65 (br s, 1H), 8.75 (d, J=2.3 Hz, 1H), 8.30 (dd, J=2.4, 8.7 Hz, 1H), 7.12 (d, J=8.6 Hz), 6.99 (d, J=8.3 Hz, 1H), 6.77 (dd, J=2.3, 8.4 Hz, 1H), 6.69 (d, J=2.3 Hz 1H), 6.05-5.91 (m, 1H), 4.14-4.06 (m, 1H), 2.55 (s, 1H), 2.56-2.54 (m, 1H), 2.56-2.54 (m, 1H), 2.61-2.53 (m, 1H), 2.61-2.53 (m, 1H), 1.57 (s, 3H)

[0698] Example 21. Synthesis of 10-acetyl-2-(4-acetylphenyl)-7,7-dimethyl-5,12b-dihydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]-pyridazine-1,3(2H)-dione

[0699] To obtain 10-acetyl-2-(4-acetylphenyl)-7,7-dimethyl-5,12b-dihydro-1H,7H-chromeno[4,3-c]-[1,2,4]triazolo[1,2-a]pyridazine-1,3(2H)-dione (37 mg, 46%), the same synthesis as the above synthesis in Example 2(a) was carried out except that 1-(2,2-dimethyl-3-vinyl-2H-chromen-7-yl)oxy)-triisopropylsilane was used instead of ((2,2-bis(fluoromethyl)-3-vinyl-2H-chromen-7-yl)-ethan-1-one.

[0700] 1H NMR (400 MHz, CDCl3) δ=8.12 (d, J=8.8 Hz, 2H), 7.85 (d, J=8.7 Hz, 2H), 7.57 (dd, J=1.5, 8.1 Hz, 1H), 7.49 (d, J=1.5 Hz, 1.7 Hz), J=7.9 Hz, 1H), 5.88-5.84 (m, 1H), 5.72 (s, 1H), 4.31 (dd, J=3.7, 16.7 Hz, 1H),. 4.17 (td, J=2.6, 16.6 Hz, 1H), 2.66 (s, 3H), 2.56 (s, 3H), 1.65 (s, 3H), 1.60-1.58 (m, 3H)

[0701] Example 22. Synthesis of 11-acetyl-2-(4-acetylphenyl)-10-hydroxy-7,7-dimethyl-5,12b-dihydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo-[1,2-a]-pyriodine(2,3H)

[0702] (a) Synthesis 11-acetyl-2-(4-acetylphenyl)-7,7-dimethyl-10-((triisopropylsilyl)oxy)-5,12b-dihydro-1H,7H-chromeno[4,3-c]-[1,2,4]triazolo[1,2-a]pyridazine-1,3(2H)-dione

[0703] To obtain 11-acetyl-2-(4-acetylphenyl)-7,7-dimethyl-10-((triisopropylsilyl)oxy)-5,12b-dihydro-1H,7H-chromeno[4,3-c]-[1,2,4]triazolo[1,2-a]pyridazine-1,3(2H)-dione (45 mg, 50%), the same synthesis as the above synthesis in Example 2(a) was carried out except that 1-(3-bromo-2,2-dimethyl-7-((triisopropylsilyl)oxy)-2H-chromen-6-yl)-ethan-1-one was used instead of ((2,2-bis(fluoromethyl)-3-vinyl-2H-chromen-7-yl)oxy)triisopropylsilane.

[0704] (b) Synthesis of 11-acetyl-2-(4-acetylphenyl)-10-hydroxy-7,7-dimethyl-5,12b-dihydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazine-1,3(2H)-dione

[0705] To obtain 11-acetyl-2-(4-acetylphenyl)-10-hydroxy-7,7-dimethyl-5,12b-dihydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazine-1,3(2H)-dione (20 mg, 57%), the same synthesis as the above synthesis in Example 1(b) was carried out except that 1- was used instead of 7,7-bis(fluoromethyl)-2-phenyl-10-((triisopropylsilyl)oxy)-5,12b-dihydro-1H,7H-chromeno[4,3-c]-[1,2,4]triazolo[1,2-a]pyridazine-1,3(2H)-dione. (3-bromo-2,2-dimethyl-7-((triisopropylsilyl)-oxy)-2H-chromen-6-yl)-ethan-1-one.

[0706] 1 H NMR (400 MHz, DMSO-D6) δ 12.20 (s, 1H), 8.17-8.13 (m, J=8.6 Hz, 2H), 7.81-7.76 (m, J=8.6 Hz, 2H), 7.69 (s, 1H), 6.36 (s, 1H), 6.13 (br. s, 1H), 5.80 (s, 1H), 4.25 (br. s, 2H), 2.64 (s, 1H), 2.49-2.48 (m, 3H), 1.61 (d, J=5.6 Hz, 6H)

[0707] Example 23. Synthesis of 2-(6-acetylpyridin-3-yl)-10-hydroxy-7,7-dimethyl-5,12b-dihydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazine-1,3(2H)-dione

[0708] To obtain 2-(6-acetylpyridin-3-yl)-10-hydroxy-7,7-dimethyl-5,12b-dihydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazine-1,3(2H)-dione (32 mg, 38%), the same synthesis as the above synthesis in Example 12(b) was carried out except that 1-(5-fluoropyridin-2-yl)ethan-1-one was used instead of 2,6-difluoropyridine.

[0709] 1 H NMR (400 MHz, DMSO-D6) δ=8.48-8.48 (m, 1H), 7.97-7.95 (m, 1H), 7.46-7.44 (m, 1H), 7.05-7.03 (m, 1H), 6.76 -6.73 (m, 1H), 6.64 (s, 1H), 5.95-5.94 (m, 1H), 5.49-5.49 (m, 1H), 4.04-4.00 (m, 1H), 3.85-3.81 (m, 1H), 2.60 (s, 3H), 1.55-1.51 (m, 6H)

[0710] Example 24. Synthesis of 2-(4-acetylphenyl)-7,7-dimethyl-1,3-dioxo-2,3,5,12b-tetrahydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]-pyridazine-10-carbonitrile

[0711] To obtain 2-(4-acetylphenyl)-7,7-dimethyl-1,3-dioxo-2,3,5,12b-tetrahydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazine-10-carbonitrile (34 mg, 46%), the same synthesis as the above synthesis in Example 2(a) was carried out except that 2,2-dimethyl-3-vinyl-2H-chromen-7-yl)oxy)triisopropylsilane was used instead of ((2,2-bis(fluoromethyl)-3-vinyl-2H-chromen-7-yl)oxy)triisopropylsilane.

[0712] 1 H NMR (400 MHz, DMSO-D6) δ 8.14-8.13 (m, 2H), 7.81-7.79 (m, 2H), 7.46-7.40 (m, 2H), 7.31-7.29 (m, 1H), 6.06-6.05 (m, 1H), 5.81 (s, 1H), 4.22 (s, 1H), 2.64 (s, 3H), 1.63 (s, 3H), 1.52 (s, 3H)

[0713] Example 25. Synthesis of 2-(4-acetylphenyl)-10-hydroxy-7,7-dimethyl-11-(trifluoromethoxy)-5,12b-dihydro-1H,7H-chromeno[4,3-c]-[1,2,4]triazolo[1,2-a]pyridazin-1,3(2H)-dione

[0714] (a) Synthesis 2-(4-acetylphenyl)-7,7-dimethyl-11-(trifluoromethoxy)-10-((triisopropylsilyl)oxy)-5,12b-dihydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazine-1,3(2H)-dione

[0715] To obtain 2-(4-acetylphenyl)-7,7-dimethyl-11-(trifluoromethoxy)-10-((triisopropylsilyl)oxy)-5,12b-dihydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazine-1,3(2H)-dione (50 mg, 42%), the same synthesis as the above synthesis in Example 2(a) was carried out except that ((2,2-bis(fluoromethyl)-3-vinyl-2H-chromen-7-yl)oxy)triisopropylsilane was used instead of ((2,2-dimethyl-6-(trifluoromethoxy)-3-vinyl-2H-chromen-7-yl)oxy)triisopropylsilane.

[0716] (b) Synthesis of 2-(4-acetylphenyl)-10-hydroxy-7,7-dimethyl-11-(trifluoromethoxy)-5,12b-dihydro-1H,7H-chromeno[4,3-c][1,2,4]-triazolo[1,2-a]pyridazine-1,3(2H)-dione

[0717] To obtain 2-(4-acetylphenyl)-10-hydroxy-7,7-dimethyl-11-(trifluoromethoxy)-5,12b-dihydro-1H,7H-chromeno[4,3-c][1,2,4]-triazolo[1,2-a]pyridazine-1,3(2H)-dione (20 mg, 60%), the same synthesis as the above synthesis in Example 1(b) was carried out, except that 7,7-bis(fluoromethyl)-2-phenyl-10-((triisopropylsilyl)oxy)-5,12b-dihydro-1H,7H-chromeno[4,3-c]-[1,2,4]triazolo[1,2-a]pyridazine-1,3(2H)-dione was used 2-(4-acetylphenyl)-7,7-dimethyl-11-(trifluoromethoxy)-10-((triisopropylsilyl)oxy)-5,12b-dihydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo-[1,2-a]pyridazine-1,3(2H)-dione.

[0718] 1 H NMR (400 MHz, DMSO-D6) δ=10.30 (s, 1H), 8.17-8.11 (m, J=8.6 Hz, 2H), 7.76-7.70 (m, J=8.4 Hz, 2H), 7.02 (s, 1H), 6.47 (s, 1H), 6.07 (m, 1H), 5.69 (s, 1H), 4.21 (br. s, 2H), 2.63 (s, 3H), 1.54 (d, J=3.1 Hz, 6H)

[0719] Example 26. Synthesis of 2-(4-acetylphenyl)-11-cyclopropyl-10-hydroxy-7,7-dimethyl-5,12b-dihydro-1H,7H-chromeno[4,3-c][1,2,4]-triazolo[1,2-a]pyridazine-1,3(2H)-dione

[0720] (a) Synthesis of 2-(4-acetylphenyl)-11-cyclopropyl-7,7-dimethyl-10-((triisopropylsilyl)oxy)-5,12b-dihydro-1H,7H-chromeno[4,3-c]-[1,2,4]triazolo[1,2-a]pyridazine-1,3(2H)-dione

[0721] To obtain 2-(4-acetylphenyl)-11-cyclopropyl-7,7-dimethyl-10-((triisopropylsilyl)oxy)-5,12b-dihydro-1H,7H-chromeno[4,3-c]-[1,2,4]triazolo[1,2-a]pyridazine-1,3(2H)-dione (54 mg, 50%), the same synthesis as the above synthesis in Example 2(a) was carried out except that ((6-cyclopropyl-2,2-dimethyl-3-vinyl-2H-chromen-7-yl)oxy)triisopropylsilane was used instead of ((2,2-bis(fluoromethyl)-3-vinyl-2H-chromen-7-yl)oxy)triisopropylsilane.

[0722] (b) Synthesis of 2-(4-acetylphenyl)-11-cyclopropyl-10-hydroxy-7,7-dimethyl-5,12b-dihydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo-[1,2-a]pyridazine-1,3(2H)-dione

[0723] To obtain 2-(4-acetylphenyl)-11-cyclopropyl-10-hydroxy-7,7-dimethyl-5,12b-dihydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo-[1,2-a]pyridazine-1,3(2H)-dione (18 mg, 48%), the same synthesis as the above synthesis in Example 1(b) was carried out, except that 7,7-bis(fluoromethyl)-2-phenyl-10-((triisopropylsilyl)oxy)-5,12b-dihydro-1H,7H-chromeno[4,3-c]-[1,2,4]triazolo-[1,2-a]pyridazine-1,3(2H)-dione was used 2-(4-acetylphenyl)-11-cyclopropyl-7,7-dimethyl-10-((triisopropylsilyl)oxy)-5,12b-dihydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo-[1,2-a]pyridazine-1,3(2H)-dione.

[0724] 1 H NMR (400 MHz, DMSO-D6) δ 9.37 (s, 1H), 8.12-8.06 (m, J=8.6 Hz, 2H), 7.70-7.65 (m, J=8.6 Hz, 2H), 6.38 (s, 1H), 6.22 (s, 1H), 5.88 (br. s, 1H), 5.51 (s, 1H), 4.17-4.06 (m, 2H), 2.57 (s, 3H), 1.87-1.79 (m, 1H), 1.44 (d, J=2.2, 8.3 Hz, 2H), 0.28 (br. t, J=5.9 Hz, 2H)

[0725] Example 27. Synthesis of 2-(4-acetylphenyl)-9,11-difluoro-10-hydroxy-7,7-dimethyl-5,12b-dihydro-1H,7H-chromeno[4,3-c][1,2,4]-triazolo[1,2-a]pyridazine-1,3(2H)-dione

[0726] (a) Synthesis of 2-(4-acetylphenyl)-9,11-difluoro-7,7-dimethyl-10-((triisopropylsilyl)oxy)-5,12b-dihydro-1H,7H-chromeno[4,3-c]-[1,2,4]triazolo[1,2-a]pyridazin-1,3(2H)-dione

[0727] To obtain 2-(4-acetylphenyl)-9,11-difluoro-7,7-dimethyl-10-((triisopropylsilyl)oxy)-5,12b-dihydro-1H,7H-chromeno[4,3-c]-[1,2,4]triazolo[1,2-a]pyridazine-1,3(2H)-dione (54 mg, 52%), the same synthesis as the above synthesis in Example 2(a) was carried out except that ((6,8-difluoro-2,2-dimethyl-3-vinyl-2H-chromen-7-yl)oxy)triisopropylsilane was used instead of ((2,2-bis(fluoromethyl)-3-vinyl-2H-chromen-7-yl)oxy)triisopropylsilane.

[0728] (b) Synthesis of 2-(4-acetylphenyl)-9,11-difluoro-10-hydroxy-7,7-dimethyl-5,12b-dihydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazine-1,3(2H)-dione

[0729] To obtain 2-(4-acetylphenyl)-9,11-difluoro-10-hydroxy-7,7-dimethyl-5,12b-dihydro-1H,7H-chromeno-[4,3-c][1,2,4]triazolo[1,2-a]pyridazine-1,3(2H)-dione, the same synthesis as the above synthesis in Example 1(b) was carried out, except that 7,7-bis(fluoromethyl)-2-phenyl-10-((triisopropylsilyl)oxy)-5,12b-dihydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazine-1,3(2H)-dione was used 2-(4-acetylphenyl)-9,11-difluoro-7,7-dimethyl-10-((triisopropylsilyl)oxy)-5,12b-dihydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazin-1,3(2H)-dione.

[0730] 1 H NMR (400 MHz, DMSO-D6) δ 10.31 (s, 1H), 8.13 (d, J=8.6 Hz, 2H), 7.79 (d, J=8.6 Hz, 2H), 6.83-6.80 (m, 2H), 6.02 (s, 1H), 5.67 (s, 1H), 4.25-4.15 (m, 2H), 2.63 (s, 3H), 1.59 (s, 3H), 1.53 (s, 3H)

[0731] Example 28. Synthesis of 2-(4-acetylphenyl)-10-amino-9,11-dibromo-7,7-dimethyl-5,12b-dihydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo-[1,2-a]pyridazine-1,3(2H)-dione

[0732] To obtain 2-(4-acetylphenyl)-10-amino-9,11-dibromo-7,7-dimethyl-5,12b-dihydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazine-1,3(2H)-dione (20 mg, 32%), the same synthesis as the above synthesis in Example 10(c) was carried out, except that 2-(4-acetylphenyl)-10-hydroxy-7,7-dimethyl-5,12b-dihydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazine-1,3(2H)-dione was used 2-(4-acetylamine)-7,7-dimethyl-10-morpholino-5,12b-dihydro-1H,7H-chromeno[4,3-c][1,2,4]-triazolo[1,2-a]pyridazine-1,3(2H)-dione.

[0733] 1 H NMR (400 MHz, DMSO-D6) δ 8.17-8.11 (m, 2H), 7.80-7.75 (m, 2H), 7.15 (d, J=1.1 Hz, 1H), 6.01 (br. s, 1H), 5.64 (s, 1H), 5.39 (s, 2H), 4.26-4.12 (m, 2H), 2.64 (s, 3H), 1.60 (s, 3H), 1.53 (s, 3H)

[0734] Example 29. Synthesis of 2-(4-acetylphenyl)-10-(isopropylamino)-7,7-dimethyl-5,12b-dihydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo-[1,2-a]pyridazine-1,3(2H)-dione

[0735] 2-(4-Acetylphenyl)-10-amino-7,7-dimethyl-5,12b-dihydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazine-1,3(2H)-dione (713 mg, 1.7 mmol) obtained in Example 7 above was dissolved in 1,2-dichloroethane (7 ml), and 2-methoxyprop-1-ene (253 mg, 3.41 mmol), sodium triacetoxyborohydride (533 mg, 3.41 mmol), and acetic acid (368 mg, 5.94 mmol) were added thereto, and stirred at room temperature for 2 hours. After completion of the reaction, the reaction mixture was diluted with dichloromethane and washed with an aqueous sodium bicarbonate solution. The separated organic layer was dried over sodium sulfate, filtered, concentrated by distillation under reduced pressure, and subjected to separation by reverse phase chromatography (acetonitrile containing 0.1% formic acid: water containing 0.1% formic acid = 5:95-100:0) to give 2-(4-acetylphenyl)-10-(isopropylamino)-7,7-dimethyl-5,12b-dihydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo-[1,2-a]pyridazine-1,3(2H)-dione (526 mg, 66%).

[0736] 1 H NMR (400 MHz, DMSO-D6) δ 8.16-8.11 (m, 2H), 7.81-7.77 (m, J=8.7 Hz, 2H), 6.77 (d, J=8.4 Hz, 1H), 6.16 (dd, J=2.2, 8.4 Hz, 1H), J=2.1 Hz, 1H), 5.94 (ear, J=1.8 Hz, 1H), 5.58 (s, 1H), 5.43 (d, J=8.1 Hz, 1H), 4.25-4.13 (m, 2H), 3.50-3.36 (m, 2.6H), (d, J=3.3 Hz, 5H), 1.48-1.47 (m, 1H), 1.08 (d, J=6.4 Hz, 6H)

[0737] Example 30. Synthesis of 2-(4-acetylphenyl)-10-(tertbutylamino)-7,7-dimethyl-5,12b-dihydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo-[1,2-a],3-pyrionadazine(2H)-7,7-H

[0738] 2-(4-Acetylphenyl)-10-amino-7,7-dimethyl-5,12b-dihydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazine-1,3(2H)-dione (100 mg, 0.24 mmol) obtained in Example 7 above was dissolved in nitromethane (1 mL), and copper(II) trifluoromethanesulfonate (4.3 mg, 0.012 mmol) and tert-butyl trichloroacetimidate (107 μL, 0.6 mmol) were added thereto, and stirred at room temperature for 12 hours. After completion of the reaction, the reaction mixture was diluted with ethyl acetate and washed with an aqueous sodium chloride solution. The separated organic layer was dried over sodium sulfate, filtered, concentrated by distillation under reduced pressure, and separated by MPLC (ethyl acetate:hexane = 1:1, by volume) to give 2-(4-acetylphenyl)-10-(tert-butylamino)-7,7-dimethyl-5,12b-dihydro-1H,7H-chromeno[4,3-c]-[1,2,4]triazolo[1,2-a]pyridazine-1,3(2H)-dione (5 mg, 4.4%).

[0739] 1H NMR (400 MHz, DMSO-D6) δ 8.09-8.03 (m, 2H), 7.75-7.69 (m, 2H), 6.72-6.65 (m, 1H), 6.28-6.21 (m, 1H), 6.12-6.7m, (5.8.90-H), (m, 1H), 5.54-5.48 (m, 1H), 5.18-5.12 (m, 1H), 4.19-4.03 (m, 2H), 2.58-2.56 (m, 3H), 1.47-1.43 (m, 6H), 1.19-1.17 (m, 9H)

[0740] Example 31. Synthesis of 2-(4-acetylphenyl)-10-amino-9,11-dichloro-7,7-dimethyl-5,12b-dihydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo-[1,2-a]-pyrionada(2,2,2)

[0741] To prepare 2-(4-acetylphenyl)-10-amino-9,11-dichloro-7,7-dimethyl-5,12b-dihydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyrione (H 38%) carried out the same synthesis as the above synthesis in Example 11, except that instead of used 2-(4-acetylphenyl)-10-hydroxy-7,7-dimethyl-5,12b-dihydro-1H,7H-chromeno[4,3-c]-[1,2,4]triazolo[1,2-a]-pyridazine-1,3(2H)-dione 2-(4-acetylamine)-7,7-dimethyl-10-morpholino-5,12b-dihydro-1H,7H-chromeno[4,3-c][1,2,4]-triazolo[1,2-a]pyridazine-1,3(2H)-dione.

[0742] 1H NMR (400 MHz, CDCl3) δ=8.16-8.09 (m, J=8.4 Hz, 2H), 7.86-7.82 (m, J=8.6 Hz, 2H), 6.94 (s, 1H), 5.85 (s, 1H), 5.85 (s, 1H), 5.5, (5.5). (s, 2H), 4.29 (dd, J=4,4,16.6 Hz, 1H), 4.16 (ear d, J=16.5 Hz, 1H), 2.66 (s, 3H), 2.03-2.00 (m, 1H), 1.64 (d, J=6.5 Hz, 6H)

[0743] Example 32. Synthesis of 2-(4-acetylphenyl)-7,7-dimethyl-10-(methyl-amino)-5,12b-dihydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]-1,3-diionadazine)-(2H)

[0744] (a) Synthesis of tertbutyl (2-(4-acetylphenyl)-7,7-dimethyl-1,3-dioxo-2,3,5,12b-tetrahydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo-[1,2-a]pyridazin-10-yl)(methyl)carbamate

[0745] To obtain tert-butyl (2-(4-acetylphenyl)-7,7-dimethyl-1,3-dioxo-2,3,5,12b-tetrahydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo-[1,2-a]pyridazin-10-yl)(methyl)carbamate (54 mg, 36%), the same synthesis as the above synthesis in Example 2(a) was carried out except that tert-butyl (2,2-dimethyl-3-vinyl-2H-chromen-7-yl)oxy)triisopropylsilane was used.

[0746] (b) Synthesis of 2-(4-acetylphenyl)-7,7-dimethyl-10-(methyl-amino)-5,12b-dihydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]-pyridazine-1,3(2H)-dione

[0747] To prepare 2-(4-acetylphenyl)-7,7-dimethyl-10-(methylamino)-5,12b-dihydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]-pyridazine-1,3(28%)-dione (28%) carried out the same synthesis as the above synthesis in Example 7 except that instead of tertbutyl (2-(4-acetylphenyl)-7,7-dimethyl-1,3-dioxo-2,3,5,12b-tetrahydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]-pyridazin-10-yl)carbamate used tretbutyl (2-(4-acetylphenyl)-7,7-dimethyl-1,3-dioxo-2,3,5,12b-tetrahydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazin-10-yl)(methyl)-carbamate.

[0748] 1 H NMR (400 MHz, CDCl3) δ=8.15-8.10 (m, J=8.4 Hz, 2H), 7.89-7.83 (m, J=8.4 Hz, 2H), 6.95 (d, J=8.3 Hz, 1H), 6.22 (dd, J=8.3 Hz, 1H), 6.22 (dd, J=8.4 Hz, 2H), 6.14 (s, 1H), 5.89-5.54 (m, 1H), 5.76 (ear, 1H), 4.33 (dd, J=4.9,16.5 Hz, 1H), 4.12 (ear, J=16.4 Hz, 1H), 3.76 (ear, 1H), 3.76 (s, 1H), 2.67 (s, 3H), 2.03 (s, 1H), 1.65-1.60 (m, 6H)

[0749] Example 33. Synthesis of 2-(4-acetylphenyl)-10-(diethylamino)-7,7-dimethyl-5,12b-dihydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazine-1,3(2H)-dione

[0750] To obtain 2-(4-acetylphenyl)-10-(diethylamino)-7,7-dimethyl-5,12b-dihydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazine-1,3(2H)-dione (30 mg, 51%), the same synthesis as the above synthesis in Example 2(a) was carried out except that N,N-diethyl-2,2-dimethyl-3-vinyl-2H-chromen-7-amine was used instead of ((2,2-bis(fluoromethyl)-3-vinyl-2H-chromen-7-yl)-oxy)triisopropylsilane.

[0751] 1 H NMR (400 MHz, DMSO-D6) δ=8.14-8.12 (m, 2H) 7.79-7.78 (m, 2H), 6.87-6.85 (m, 1H), 6.27-6.24 (m, 1H), 6.07 (s, 1H), 5.98 (s, 1H), 5.62 (s, 1H), 4.24-4.14 (m, 2H), 3.29-3.23 (m, 4H), 2.64 (s, 3H), 1.53 (s, 6H), 1.05-1.02 (m, 6H)

[0752] Example 34. Synthesis of 2-(4-acetylphenyl)-7,7-dimethyl-10-(pyrrolidin-1-yl)-5,12b-dihydro-1H,7H-chromeno[4,3-c][1,2,4]-triazolo[1,2-a]pyridazin-1,3(2H)-dione

[0753] To obtain 2-(4-acetylphenyl)-7,7-dimethyl-10-(pyrrolidin-1-yl)-5,12b-dihydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]-pyridazine-1,3(2H)-dione (100 mg, 42%), the same synthesis as the above synthesis in Example 2(a) was carried out except that ((2,2-bis(fluoromethyl)-3-vinyl-2H-chromen-7-yl)oxy)triisopropylsilane was used instead of ((2,2-bis(fluoromethyl)-3-vinyl-2H-chromen-7-yl)oxy)triisopropylsilane.

[0754] 1 H NMR (400 MHz, DMSO-D6) δ=8.14-8.12 (m, 2H) 7.79-7.77 (m, 2H), 6.88-6.86 (m, 1H), 6.16 (m, 1H), 5.98 (s, 1H), 5.95-5.95 (m, 1H), 5.63 (s, 1H), 4.24-4.14 (m, 2H), 3.14 (s, 4H), 2.64 (s, 3H), 1.91 (s, 4H), 1.53 (s, 6H)

[0755] Example 35. Synthesis of 2-(4-fluorophenyl)-7,7-dimethyl-10-(oxetan-3-ylamino)-5,12b-dihydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo-[1,2-a]pyridazin-1,3(2H)-dione

[0756] (a) Synthesis of tert-butyl (2-(4-fluorophenyl)-7,7-dimethyl-1,3-dioxo-2,3,5,12b-tetrahydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo-[1,2-a]pyridazin-10-yl)carbamate

[0757] To obtain tert-butyl (2-(4-fluorophenyl)-7,7-dimethyl-1,3-dioxo-2,3,5,12b-tetrahydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo-[1,2-a]pyridazin-10-yl)carbamate (82 mg, 43%), the same synthesis as the above synthesis in Example 6 was carried out except that 4-(4-fluorophenyl)-1,2,4-triazolidine-3,5-dione was used instead of 4-(4-acetylphenyl)-1,2,4-triazolidine-3,5-dione.

[0758] (b) Synthesis of 10-amino-2-(4-fluorophenyl)-7,7-dimethyl-5,12b-dihydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazine-1,3(2H)-dione

[0759] To obtain 10-amino-2-(4-fluorophenyl)-7,7-dimethyl-5,12b-dihydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazine-1,3(2H)-dione (56 mg, 78%), the same synthesis as the above synthesis in Example 7 was carried out except that tert-butyl (2-(4-acetylphenyl)-7,7-dimethyl-1,3-dioxo-2,3,5,12b-tetrahydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazin-10-yl)-carbamate was used (2-(4-fluorophenyl)-7,7-dimethyl-1,3-dioxo-2,3,5,12b-tetrahydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazin-10-yl)carbamate.

[0760] (c) Synthesis of 2-(4-fluorophenyl)-7,7-dimethyl-10-(oxetan-3-yl-amino)-5,12b-dihydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]-pyridazin-1,3(2H)-dione

[0761] 10-Amino-2-(4-fluorophenyl)-7,7-dimethyl-5,12b-dihydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazine-1,3(2H)-dione (17 mg, 0.043 mmol) obtained in Example 35(b) above was dissolved in dichloromethane (1 mL) and cooled to 0°C, and 3-oxetanone (4.15 μL, 0.065 mmol), acetic acid (2.468 μL, 0.043 mmol), sodium triacetoxyborohydride (73 mg, 0.35 mmol) and titanium(IV) propane-2-oleate (12.8 μL, 0.043 mmol) were added and stirred at room temperature for 15 hours. After completion of the reaction, the reaction mixture was diluted with dichloromethane and washed with aqueous sodium bicarbonate solution. The separated organic layer was dried over sodium sulfate, filtered, concentrated by distillation under reduced pressure and separated by MPLC (ethyl acetate:hexane = 1:1, by volume) to give 2-(4-fluorophenyl)-7,7-dimethyl-10-(oxetan-3-ylamino)-5,12b-dihydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo-[1,2-a]pyridazine-1,3(2H)-dione (8 mg, 41%).

[0762] 1H NMR (400 MHz, CDCl3) δ=7.63 (e.g. dd, J=4.6, 8.8 Hz, 2H), 7.23 (e.g. t, J=8.5 Hz, 2H), 6.96 (e, J=8.3 Hz, 1H), 6.17-6.1 m, (1.98 Hz), (s 1H), 5.90-5.84 (m, 1H), 5.73 (ear c, 1H), 4.99 (ear t, J=6.4 Hz, 2H), 4.58 (ear d, J=5.6 Hz, 1H), 4.55-4.48 (m, 2H), 4.55-4.48 (m, 2H, 4.4, 4.6 Gdd). 1H), 4.10 (ear, J=16.3 Hz, 1H), 1.60 (s, 6H)

[0763] Example 36. Synthesis 2-(4-acetylphenyl)-9,11-dichloro-7,7-dimethyl-10-(methylamino)-5,12b-dihydro-1H,7H-chromeno[4,3-c]-[1,2,4]triazolo[1,2-a]pyridazine-1,3(2H)-dione

[0764] To prepare 2-(4-acetylphenyl)-9,11-dichloro-7,7-dimethyl-10-(methylamino)-5,12b-dihydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo-[1,2-a-1-H,2-H)-diiona (32 mg, 28%) carried out the same synthesis as the above synthesis in Example 11, except that instead of used 2-(4-acetylphenyl)-10-hydroxy-7,7-dimethyl-5,12b-dihydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]-pyridazine-1,3(2H)-dione 2-(4-acetylphenyl)-7,7-dimethyl-10-(methyl-amino)-5,12b-dihydro-1H,7H-chromeno[4,3-c]-[1,2,4]triazolo[1,2-a]pyridazine-1,3(2H)-dione.

[0765] 1 H NMR (400 MHz, CDCl3) δ 8.15-8.08 (m, 2H), 7.87-7.80 (m, 2H), 6.97-6.92 (m, 1H), 5.83 (t, J=3.5 Hz, 1H), 5.61 (s, 3.4, 4.2H), 1H), 4.17 (dt, J=16.5, 2.8 Hz, 1H), 4.00 (p, J=6.4 Hz, 1H), 2.65 (d, J=0.6 Hz, 3H), 1.65 (s, 3H), 1.60 (s, 3H), 6H)

[0766] Example 37. Synthesis of 2-(4-acetylphenyl)-9,11-dichloro-10-(iso-propylamino)-7,7-dimethyl-5,12b-dihydro-1H,7H-chromeno[4,3-c]-[1,2,4]triazolo[1,2-a]pyridazin-1,3(2H)-dione

[0767] To obtain 2-(4-acetylphenyl)-9,11-dichloro-10-(isopropylamino)-7,7-dimethyl-5,12b-dihydro-1H,7H-chromeno[4,3-c][1,2,4]-triazolo[1,2-a]pyridazine-1,3(2H)-dione (22 mg, 30%), the same synthesis as the above synthesis in Example 11 was carried out, except that 2-(4-acetylphenyl)-10-hydroxy-7,7-dimethyl-5,12b-dihydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazine-1,3(2H)-dione was used 2-(4-acetylphenyl)-10-(isopropylamino)-7,7-dimethyl-5,12b-dihydro-1H,7H-chromeno[4,3-c]-[1,2,4]triazolo[1,2-a]pyridazine-1,3(2H)-dione.

[0768] 1H NMR (400 MHz, CDCl3) δ 8.16-8.08 (m, 2H), 7.87-7.79 (m, 2H), 6.95 (d, J=1.2 Hz, 1H), 5.88-5.81 (m, 1H), 5.61 (d, J=2.7 Hz, 1H), 4.28 (ddd, J=16.6, 4.5, 1.4 Hz, 1H), 4.17 (dt, J=16.5, 2.8 Hz, 1H), 3.01 (s, 3H), 2.65 (s, 3H), 1.63 (d, J=15.3 Hz, 7H)

[0769] Example 38. Synthesis 2-(4-acetylphenyl)-10-(1,3-dimethyl-1H-pyrazol-5-yl)-7,7-dimethyl-5,12b-dihydro-1H,7H-chromeno[4,3-c]-[1,2,4]triazolo[1,2-a]pyridazin-1,3(2H)-dione

[0770] To obtain 2-(4-acetylphenyl)-10-(1,3-dimethyl-1H-pyrazol-5-yl)-7,7-dimethyl-5,12b-dihydro-1H,7H-chromeno[4,3-c][1,2,4]-triazolo[1,2-a]pyridazine-1,3(2H)-dione (42 mg, 50%), the same synthesis as the above synthesis in Example 2(a) was carried out except that 5-(2,2-dimethyl-3-vinyl-2H-chromen-7-yl)oxy)triisopropylsilane was used instead of ((2,2-bis(fluoromethyl)-3-vinyl-2H-chromen-7-yl)oxy)triisopropylsilane.

[0771] 1H NMR (400 MHz, DMSO-D6) δ 8.18-8.10 (m, 2H), 7.85-7.77 (m, 2H), 7.18 (dd, J=8.0, 1.0 Hz, 1H), 7.10 (dd, J=7.9, 1.7 Hz, 1H), 6.99 (d, J=1.7 Hz, 1H), 6.15 (s, 1H), 6.03 (td, J=3.7, 1.8 Hz, 1H), 5.77 (d, J=1.7 Hz, 1H), 4.23 (dd, J=4.0, 2.0 Hz, 2H), 3.74 (s, 3H), 2.64 (s, 3H), 2.14 (s, 3H), 1.62 (s, 3H), 1.55 (s, 3H)

[0772] Example 39. Synthesis of 2-(4-acetylphenyl)-10-(2,5-dimethylthiazol-4-yl)-7,7-dimethyl-5,12b-dihydro-1H,7H-chromeno-[4,3-c][1,2,4]-triazolo[1,2-a]pyridazin-1,3(2H)-dione

[0773] To obtain 2-(4-acetylphenyl)-10-(2,5-dimethylthiazol-4-yl)-7,7-dimethyl-5,12b-dihydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo-[1,2-a]pyridazine-1,3(2H)-dione (28 mg, 48%), the same synthesis as the above synthesis in Example 2(a) was carried out except that 4-(2,2-dimethyl-3-vinyl-2H-chromen-7-yl)-oxy)triisopropylsilane was used instead of ((2,2-bis(fluoromethyl)-3-vinyl-2H-chromen-7-yl)-2,5-dimethylthiazole.

[0774] 1H NMR (400 MHz, DMSO-D6) δ 8.18-8.10 (m, 2H), 7.85-7.78 (m, 2H), 7.26 (dd, J=8.0, 1.7 Hz, 1H), 7.18-7.11 (m, 2H), 6.00 (td, J=3.7, 1.8 Hz, 1H), 5.75 (d, J=2.3 Hz, 1H), 4.23 (quartet, J=2.0 Hz, 2H), 2.64 (s, 3H), 2.60 (s, 3H), 2.48 (s, 3H), 1.62 (s, 3H), 1.53 (s, 3H)

[0775] Example 40. Synthesis 2-(4-acetylphenyl)-10-(1-ethyl-3,5-dimethyl-1H-pyrazol-4-yl)-7,7-dimethyl-5,12b-dihydro-1H,7H-chromeno[4,3-c]-[1,2,4]triazolo[1,2-a]pyridazin-1,3(2H)-dione

[0776] To obtain 2-(4-acetylphenyl)-10-(1-ethyl-3,5-dimethyl-1H-pyrazol-4-yl)-7,7-dimethyl-5,12b-dihydro-1H,7H-chromeno[4,3-c]-[1,2,4]triazolo[1,2-a]pyridazine-1,3(2H)-dione (38 mg, 51%), the same synthesis as the above synthesis in Example 2(a) was carried out except that 4-(2,2-dimethyl-3-vinyl-2H-chromen-7-yl)oxy)triisopropylsilane was used instead of ((2,2-bis(fluoromethyl)-3-vinyl-2H-chromen-7-yl)-1-ethyl-3,5-dimethyl-1H-pyrazole.

[0777] 1H NMR (400 MHz, DMSO-D6) δ 8.18-8.10 (m, 2H), 7.85-7.77 (m, 2H), 7.09 (dd, J=7.9, 1.1 Hz, 1H), 6.87 (dd, J=7.9, 1.7 Hz, 17.6, H J=1.6 Hz, 1H), 6.00 (h, J=1.8 Hz, 1H), 5.73 (s, 1H), 4.23 (quartet, J=2.6 Hz, 2H), 4.00 (quartet, J=7.2 Hz, 2H), 2.64 (s, 3H), (s, 2.2, 1H), (s, 2.1H), (s, 3H), 1.61 (s, 3H), 1.53 (s, 3H), 1.29 (t, J=7.2 Hz, 3H)

[0778] Example 41. Synthesis 2-(4-acetylphenyl)-7,7-dimethyl-10-(3-methylisoxazol-4-yl)-5,12b-dihydro-1H,7H-chromeno[4,3-c][1,2,4]-triazolo[1,2-a]pyridazine-1,3(2H)-dione

[0779] To prepare 2-(4-acetylphenyl)-7,7-dimethyl-10-(3-methylisoxazol-4-yl)-5,12b-dihydro-1H,7H-chromeno[4,3-c][1,2,4]-triazolo[1,2-a]-pyrionade(3-H),3H (33 mg, 54%) carried out the same synthesis as the above synthesis in Example 2 (a), except that instead of ((2,2-bis(fluoromethyl)-3-vinyl-2H-chromen-7-yl)oxy)triisopropylsilane was used 4-(2,2-dimethyl-3-vinyl-2H-chromen-7-yl)-3-methylisoxazole.

[0780] 1H NMR (499 MHz, CDCl3) δ 8.41 (s, 1H), 8.12 (d, J=8.7 Hz, 2H), 7.88-7.84 (m, 2H), 7.15-7.11 (m, 1H), 6.98 (dd, J=8.0, 1.7 Hz, 1H), 6.92 (d, J=1.7 Hz, 1H), 5.91-5.86 (m, 1H), 5.77 (s, 1H), 4.33 (dd, J=16.5, 4.8 Hz, 1H), 4.16 (dt, J=16.5, 2.6 Hz, 1H), 2.65 (s, 3H), 2.40 (s, 3H), 1.64 (d, J=11.2 Hz, 6N)

[0781] Example 42. Synthesis of 2-(4-acetylphenyl)-7,7-dimethyl-10-(pyridin-3-yl)-5,12b-dihydro-1H,7H-chromeno[4,3-c][1,2,4]-triazolo[1,2-a]pyridazin-1,3(2H)-dione

[0782] To obtain 2-(4-acetylphenyl)-7,7-dimethyl-10-(pyridin-3-yl)-5,12b-dihydro-1H,7H-chromeno[4,3-c]-[1,2,4]triazolo[1,2-a]-pyridazine-1,3(2H)-dione (25 mg, 60%), the same synthesis as the above synthesis in Example 2(a) was carried out except that 3-(2,2-dimethyl-3-vinyl-2H-chromen-7-yl)pyridine was used instead of ((2,2-bis(fluoromethyl)-3-vinyl-2H-chromen-7-yl)oxy)triisopropylsilane.

[0783] 1H NMR (400 MHz, CDCl3) δ 8.80 (dd, J=2.2, 0.8 Hz, 1H), 8.59 (dd, J=4.8, 1.6 Hz, 1H), 8.15-8.10 (m, 2H), 7.89-7.84 (m, 2H), 7.82 (dt, J=8.0, 2.1 Hz, 1H), 7.37-7.32 (m, 1H), 7.19 (d, J=1.3 Hz, 2H), 7.15-7.11 (m, 1H), 5.91-5.86 (m, 1H), 5.79 (s, 1H), 4.37-4.29 (m, 1H), 4.17 (dt, J=16.4, 2.6 Hz, 1H), 2.65 (s, 3H), 1.65 (d, J=10.6 Hz, 7H)

[0784] Example 43. Synthesis of 2-(4-acetylphenyl)-7,7-dimethyl-10-(pyridin-4-yl)-5,12b-dihydro-1H,7H-chromeno[4,3-c][1,2,4]-triazolo[1,2-a]pyridazin-1,3(2H)-dione

[0785] To obtain 2-(4-acetylphenyl)-7,7-dimethyl-10-(pyridin-4-yl)-5,12b-dihydro-1H,7H-chromeno[4,3-c]-[1,2,4]triazolo[1,2-a]-pyridazine-1,3(2H)-dione (42 mg, 50%), the same synthesis as the above synthesis in Example 2(a) was carried out except that 3-(2,2-dimethyl-3-vinyl-2H-chromen-7-yl)pyridine was used instead of ((2,2-bis(fluoromethyl)-3-vinyl-2H-chromen-7-yl)oxy)triisopropylsilane.

[0786] 1H NMR (400 MHz) δ 8.66-8.61 (m, 2H), 8.15-8.09 (m, 2H), 7.89-7.83 (m, 2H), 7.47-7.42 (m, 2H), 7.24 (dd, J=8.1, 1.7 Hz, 1H), 7.22-7.16 (m, 2H), 5.89 (dt, J=4.7, 2.3 Hz, 1H), 5.78 (quartet, J=1.6 Hz, 1H), 4.33 (ddd, J=16.5, 4.8, 1.4 Hz, 1H), 4.17 (dt, J=16.5, 2.7 Hz, 1H), 2.65 (s, 3H), 1.65 (d, J=12.1 Hz, 6N)

[0787] Example 44. Synthesis of 4-(7,7-dimethyl-1,3-dioxo-10-(pyrrolidin-1-yl)-5,12b-dihydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]-pyridazin-2(3H)-yl)benzoic acid

[0788] To obtain 4-(7,7-dimethyl-1,3-dioxo-10-(pyrrolidin-1-yl)-5,12b-dihydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]-pyridazin-2(3H)-yl)benzoic acid (34 mg, 45%), the same synthesis as the above synthesis in Example 2(a) was carried out except that 1-(2,2-dimethyl-3-vinyl-2H-chromen-7-yl)pyrrolidine was used instead of ((2,2-bis(fluoromethyl)-3-vinyl-2H-chromen-7-yl)oxy)triisopropylsilane.

[0789] 1H NMR (500 MHz) δ 8.24 (d, J=8.4 Hz, 2H), 7.85 (d, J=8.6 Hz, 2H), 6.99 (dd, J=8.6, 1.0 Hz, 1H), 6.17 (dd, J=8.6, 2.4 Hz, 1H), 6.06 (d, J=2.3 Hz, 1H), 5.84 (dd, J=4.9, 2.2 Hz, 1H), 5.77 (s, 1H), 4.35-4.27 (m, 1H), 4.10 (dt, J=16.3, 2.5 Hz, 1H), 3.25-3.17 (m, 4H), 2.03-1.91 (m, 4H), 1.61 (d, J=12.6 Hz, 6N)

[0790] Example 45. Synthesis of 2-(4-acetylphenyl)-10-(isopropyl(methyl)-amino)-7,7-dimethyl-5,12b-dihydro-1H,7H-chromeno[4,3-c][1,2,4]-triazolo[1,2-a]pyridazin-1,3(2H)-dione

[0791] To obtain 2-(4-acetylphenyl)-10-(isopropyl(methyl)amino)-7,7-dimethyl-5,12b-dihydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo-[1,2-a]pyridazine-1,3(2H)-dione (20 mg, 38%), the same synthesis as the above synthesis in Example 2(a) was carried out except that N-isopropyl-N,2,2-trimethyl-3-vinyl-2H-chromen-7-amine was used instead of ((2,2-bis(fluoromethyl)-3-vinyl-2H-chromen-7-yl)oxy)triisopropylsilane.

[0792] 1H NMR (400 MHz, CDCl3) δ 8.14-8.06 (m, 2H), 7.87-7.82 (m, 2H), 6.98 (d, J=8.7 Hz, 1H), 6.37 (dd, J=8.8, 2.6 Hz, 1H), J, 26.5 Hz (26.5 Hz). 1H), 5.87-5.81 (m, 1H), 5.75 (s, 1H), 4.34-4.27 (m, 1H), 4.09 (d, J=16.4 Hz, 1H), 4.02 (p, J=6.6 Hz, 1H), 2.68 (s, 3H), 1.60 (d, J=11.9 Hz, 6H), 1.12 (dd, J=6.6, 1.2 Hz, 6H)

[0793] Example 46. Synthesis 2-(4-acetylphenyl)-10-(ethyl-(isopropyl)-amino)-7,7-dimethyl-5,12b-dihydro-1H,7H-chromeno[4,3-c][1,2,4]-triazolo[1,2-a]pyridazine-1,3(2H)-dione

[0794] To obtain 2-(4-acetylphenyl)-10-(ethyl(isopropyl)amino)-7,7-dimethyl-5,12b-dihydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo-[1,2-a]pyridazine-1,3(2H)-dione (15 mg, 39%), the same synthesis as the above synthesis in Example 29 was carried out, except that 2-(4-acetylphenyl)-10-amino-7,7-dimethyl-5,12b-dihydro-1H,7H-chromeno[4,3-c]-[1,2,4]triazolo[1,2-a]pyridazine-1,3(2H)-dione was used 2-(4-acetylphenyl)-10-(ethylamino)-7,7-dimethyl-5,12b-dihydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazine-1,3(2H)-dione.

[0795] 1 H NMR (400 MHz, DMSO-D6) δ 8.17-8.09 (m, 2H), 7.82-7.74 (m, 2H), 6.87 (dd, J=8.7, 1.0 Hz, 1H), 6.32 (dd, J=8.8, 2.5 Hz, 1H), 6.13 (d, J=2.5 Hz, 1H), 5.96 (quartet, J=2.5 Hz, 1H), 5.62 (s, 1H), 4.25-4.13 (m, 2H), 3.95 (p, J=6.7 Hz, 1H), 3.16 (quartet, J=6.9 Hz, 2H), 2.64 (s, 3H), 1.53 (s, 6H), 1.09 (d, J=6.6 Hz, 6H), 1.05 (t, J=6.9 Hz, 3H)

[0796] Example 47. Synthesis of 2-(4-acetylphenyl)-10-(diisopropylamino)-7,7-dimethyl-5,12b-dihydro-1H,7H-chromeno-[4,3-c][1,2,4]triazolo-[1,2-a]pyridazine-1,3(2H)-dione

[0797] To obtain 2-(4-acetylphenyl)-10-(diisopropylamino)-7,7-dimethyl-5,12b-dihydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazine-1,3(2H)-dione (30 mg, 40%), the same synthesis as the above synthesis in Example 2(a) was carried out except that N,N-diiso-propyl-2,2-dimethyl-3-vinyl-2H-chromen-7-yl)oxy)triisopropylsilane was used instead of ((2,2-bis(fluoromethyl)-3-vinyl-2H-chromen-7-yl)oxy)triisopropylsilane.

[0798] 1 H NMR (400 MHz, DMSO-D6) δ 8.17-8.09 (m, 2H), 7.83-7.75 (m, 2H), 6.85 (dd, J=8.7, 1.0 Hz, 1H), 6.43 (dd, J=8.7, 2.5 Hz, 1H), 6.21 (d, J=2.4 Hz, 1H), 5.96 (dt, J=4.7, 2.3 Hz, 1H), 5.62 (s, 1H), 4.27-4.12 (m, 2H), 3.74 (hept, J=6.6 Hz, 2H), 2.64 (s, 3H), 1.53 (d, J=3.5 Hz, 6H), 1.15 (dd, J=6.7, 1.4 Hz, 12N)

[0799] Example 48. Synthesis of 2-(4-(tert-butyl)phenyl)-7,7-dimethyl-10-(4-methylpiperazin-1-yl)-5,12b-dihydro-1H,7H-chromeno[4,3-c][1,2,4]-triazolo[1,2-a]pyridazin-1,3(2H)-dione

[0800] To obtain 2-(4-(tert-butyl)phenyl)-7,7-dimethyl-10-(4-methylpiperazin-1-yl)-5,12b-dihydro-1H,7H-chromeno[4,3-c][1,2,4]-triazolo[1,2-a]-pyridazine-1,3(2H)-dione (22 mg, 47%), the same synthesis as the above synthesis in Example 2(a) was carried out except that 1-(2,2-dimethyl-3-vinyl-2H-chromen-7-yl)oxy)triisopropylsilane was used instead of ((2,2-bis(fluoromethyl)-3-vinyl-2H-chromen-7-yl)oxy)triisopropylsilane.

[0801] 1 H NMR (400 MHz, CDCl3) δ 7.52 (s, 3H), 7.03 (d, J=8.7 Hz, 1H), 6.50 (dd, J=8.7, 2.5 Hz, 1H), 6.41 (d, J=2.4 Hz, 1H), 5.86-5.82 (m, 1H), 5.73 (s, 1H), 4.29 (dd, J=16.3, 5.0 Hz, 1H), 4.07 (d, J=16.2 Hz, 1H), 3.21-3.13 (m, 4H), 2.54 (s, 4H), 2.33 (s, 3H), 1.61 (s, 3H), 1.59 (s, 3H), 1.35 (s, 9H)

[0802] Example 49. Synthesis of 7,7-dimethyl-10-(4-methylpyrezin-1-yl)-2-(4-(trifluoromethyl)phenyl)-5,12b-dihydro-1H,7H-chromeno[4,3-c]-[1,2,4]triazolo[1,2-a]pyridazin-1,3(2H)-dione

[0803] To obtain 7,7-dimethyl-10-(4-methylpyrerazin-1-yl)-2-(4-(trifluoromethyl)phenyl)-5,12b-dihydro-1H,7H-chromeno[4,3-c][1,2,4]-triazolo[1,2-a]pyridazine-1,3(2H)-dione (30 mg, 60%), the same synthesis as the above synthesis in Example 48 was carried out except that 4-(4-(trifluoromethyl)phenyl)-1,2,4-triazolidine-3,5-dione was used instead of 4-(4-(tert-butyl)phenyl)-1,2,4-triazolidine-3,5-dione.

[0804] 1 H NMR (400 MHz, CDCl3) δ 7.86 (d, J=8.4 Hz, 2H), 7.78 (d, J=8.6 Hz, 2H), 7.00 (d, J=8.5 Hz, 1H), 6.51 (dd, J=8.6, 2.5 Hz, 1H), 6.42 (d, J=2.4 Hz, 1H), 5.87-5.83 (m, 1H), 5.73 (s, 1H), 4.31 (dd, J=16.3, 5.0 Hz, 1H), 4.15-4.07 (m, 1H), 3.19 (t, J=4.8 Hz, 4H), 2.58 (s, 4H), 2.36 (s, 3H), 1.60 (d, J=6.8 Hz, 6N)

[0805] Example 50. Synthesis of 2-(4-fluorophenyl)-7,7-dimethyl-10-(4-methylpiperazin-1-yl)-5,12b-dihydro-1H,7H-chromeno[4,3-c][1,2,4]-triazolo[1,2-a]pyridazin-1,3(2H)-dione

[0806] To obtain 2-(4-fluorophenyl)-7,7-dimethyl-10-(4-methyl-piperazin-1-yl)-5,12b-dihydro-1H,7H-chromeno[4,3-c][1,2,4]-triazolo[1,2-a]pyridazine-1,3(2H)-dione (30 mg, 60%), the same synthesis as the above synthesis in Example 48 was carried out except that 4-(4-(tert-butyl)phenyl)-1,2,4-triazolidine-3,5-dione was used instead of 4-(4-(tert-butyl)phenyl)-1,2,4-triazolidine-3,5-dione.

[0807] 1 H NMR (400 MHz, CDCl3) δ 7.63-7.58 (m, 2H), 7.20 (dd, J=9.0, 8.2 Hz, 2H), 7.01 (dd, J=8.8, 1.1 Hz, 1H), 6.50 (dd, J=8.7, 2.5 Hz, 1H), 6.41 (d, J=2.4 Hz, 1H), 5.88-5.82 (m, 1H), 5.72 (s, 1H), 4.29 (dd, J=16.6, 5.2 Hz, 1H), 4.13-4.05 (m, 1H), 3.26-3.16 (m, 4H), 2.66 (t, J=4.9 Hz, 4H), 2.40 (s, 3H), 1.59 (d, J=6.9 Hz, 6H)

[0808] Example 51. Synthesis 2-(4-acetylphenyl)-7,7-dimethyl-10-(4-methylpiperazin-1-yl)-5,12b-dihydro-1H,7H-chromeno[4,3-c][1,2,4]-triazolo[1,2-a]pyridazine-1,3(2H)-dione

[0809] To prepare 2-(4-acetylphenyl)-7,7-dimethyl-10-(4-methyl-piperazin-1-yl)-5,12b-dihydro-1H,7H-chromeno[4,3-c][1,2,4]-triazolo[1,2-a]pyriona(2,2-H]-pyrione (32 mg, 48%) carried out the same synthesis as the above synthesis in Example 48, except that instead of 4-(4-(tertbutyl)phenyl)-1,2,4-triazolidin-3,5-dione, 4-(4-acetylphenyl)-1,4-triaz,2,5-olidione was used.

[0810] 1 H NMR (400 MHz, CDCl3) δ 8.10 (d, J=8.7 Hz, 2H), 7.84 (d, J=8.6 Hz, 2H), 7.01 (dd, J=8.4, 0.9 Hz, 1H), 6.50 (dd, J=8.7, 2.7 Hz, 1H), (e, J=2.4 Hz, 1H), 5.88-5.82 (m, 1H), 5.73 (s, 1H), 4.30 (dd, J=16.5, 5.0 Hz, 1H), 4.15-4.07 (m, 1H), 3.24 (t, J=2.4 Hz, 1H), 4H), 2.64 (s, 3H), 2.43 (s, 3H), 1.60 (d, J=5.9 Hz, 6H)

[0811] Example 52. Synthesis 2-(4-acetylphenyl)-7,7-dimethyl-10-(4-(methylsulfonyl)piperazin-1-yl)-5,12b-dihydro-1H,7H-chromeno-[4,3-c][1,2,4]triazolo[1,2-a]pyridazin-1,3(2H)-dione

[0812] To obtain 2-(4-acetylphenyl)-7,7-dimethyl-10-(4-(methylsulfonyl)piperazin-1-yl)-5,12b-dihydro-1H,7H-chromeno[4,3-c]-[1,2,4]triazolo[1,2-a]-pyridazine-1,3(2H)-dione (34 mg, 70%), the same synthesis as the above synthesis of intermediate 11(a) was carried out, except that 7-amino-3-bromo-2,2-dimethylchroman-4-one was used instead of 2-(4-acetylphenyl)-7,7-dimethyl-10-(piperazin-1-yl)-5,12b-dihydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazin-1,3(2H)-dione hydrochloride.

[0813] 1H NMR (400 MHz, CDCl3) δ 8.11 (d, J=8.7 Hz, 2H), 7.84 (d, J=8.6 Hz, 2H), 7.03 (d, J=8.5 Hz, 1H), 6.51 (dd, J=8.6, 2.5 Hz, 1,42 Hz), J=2.4 Hz, 1H), 4.31 (dd, J=16.4, 4.9 Hz, 1H), 4.14-4.09 (m, 1H), 3.36-3.31 (m, 4H), 3.27-3.23 (m, 4H), 2.81 (s, 3.6H), (d, J=4.0 Hz, 6H)

[0814] Example 53. Synthesis 10-hydroxy-7,7-dimethyl-2-(4-(morpholin-4-carbonyl)phenyl)-5,12b-dihydro-1H,7H-chromeno[4,3-c][1,2,4]-triazolo[1,2-a]pyridazine-1,3(2H)-dione

[0815] (a) Synthesis 4-(7,7-dimethyl-1,3-dioxo-10-((tetrahydro-2H-pyran-2-yl)oxy)-5,12b-dihydro-1H,7H-chromeno[4,3-c][1,2,4]-triazolo[1,2-a]pyridazin-2(3H-yl)benzoic acid)

[0816] To obtain 4-(7,7-dimethyl-1,3-dioxo-10-((tetrahydro-2H-pyran-2-yl)oxy)-5,12b-dihydro-1H,7H-chromeno[4,3-c][1,2,4]-triazolo[1,2-a]pyridazin-2(3H)-yl)benzoic acid (100 mg, 30%), the same synthesis as the above synthesis in Example 2(a) was carried out except that ((2,2-bis(fluoromethyl)-3-vinyl-2H-chromen-7-yl)oxy)triisopropylsilane and 4-(4-acetylphenyl)-1,2,4-triazolidine-3,5-dione were used, respectively, 2,2-dimethyl-7-((tetrahydro-2H-pyran-2-yl)oxy)-3-vinyl-2H-chromene and 4-(3,5-dioxo-1,2,4-triazolidin-4-yl)benzoic acid.

[0817] (b) Synthesis 7,7-dimethyl-2-(4-(morpholine-4-carbonyl)-phenyl)-10-((tetrahydro-2H-pyran-2-yl)oxy)-5,12b-dihydro-1H,7H-chromeno-[4,3-c][1,2,4]triazolo[1,2-a]pyridazin-1,3(2H)-dione

[0818] 4-(7,7-Dimethyl-1,3-dioxo-10-((tetrahydro-2H-pyran-2-yl)-oxy)-5,12b-dihydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]-pyridazin-2(3H)-yl)benzoic acid (230 mg, 0.46 mmol) obtained in Example 53(a) above was dissolved in N,N-dimethylformamide (3 ml), and triethylamine (92 mg, 0.91 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (131 mg, 0.68 mmol), and 1-hydroxybenzotriazole (92 mg, 0.68 mmol) were added thereto, and stirred at room temperature temperature for 10 minutes. Morpholine (51.4 mg, 0.59 mmol) was added and the mixture was stirred for another 3 hours at room temperature. After completion of the reaction, the reaction mixture was diluted with ethyl acetate and washed with an aqueous solution of sodium chloride.The separated organic layer was dried over sodium sulfate, filtered, concentrated by distillation under reduced pressure, and separated by MPLC (dichloromethane:methanol = 30:1, by volume) to give 7,7-dimethyl-2-(4-(morpholine-4-carbonyl)phenyl)-10-((tetrahydro-2H-pyran-2-yl)oxy)-5,12b-dihydro-1H,7H-chromeno[4,3-c][1,2,4]-triazolo[1,2-a]pyridazine-1,3(2H)-dione (140 mg, 54%).

[0819] (c) Synthesis of 10-hydroxy-7,7-dimethyl-2-(4-(morpholine-4-carbonyl)phenyl)-5,12b-dihydro-1H,7H-chromeno[4,3-c][1,2,4]-triazolo[1,2-a]pyridazin-1,3(2H)-dione

[0820] To obtain 10-hydroxy-7,7-dimethyl-2-(4-(morpholine-4-carbonyl)phenyl)-5,12b-dihydro-1H,7H-chromeno-[4,3-c][1,2,4]-triazolo[1,2-a]pyridazine-1,3(2H)-dione (50 mg, 70%), the same synthesis as the above synthesis of intermediate 31(d) was carried out, except that 2,2-bis(fluoromethyl)-7-((tetrahydro-2H-pyran-2-yl)oxy)chroman-4-one was used instead of 7,7-dimethyl-2-(4-(morpholine-4-carbonyl)phenyl)-10-((tetrahydro-2H-pyran-2-yl)oxy)-5,12b-dihydro-1H,7H-chromeno-[4,3-c][1,2,4]triazolo[1,2-a]pyridazine-1,3(2H)-dione.

[0821] 1 H NMR (400 MHz, DMSO-D6) δ 9.47 (s, 1H), 7.68 (d, J=8.5 Hz, 2H), 7.59 (d, J=8.5 Hz, 2H), 6.85 (dd, J=8.3, 1.1 Hz, 1H), 6.40-6.36 (m, 1H), 6.25 (d, J=2.3 Hz, 1H), 5.95 (dt, J=4.8, 2.3 Hz, 1H), 5.60 (s, 1H), 4.25-4.18 (m, 1H), 4.18-4.11 (m, 1H), 3.63 (s, 8H), 1.54 (s, 3H), 1.51 (s, 3H)

[0822] Example 54. Synthesis of tert-butyl 4-(4-(10-hydroxy-7,7-dimethyl-1,3-dioxo-5,12b-dihydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo-[1,2-a]pyridazin-2(3H)-yl)benzoyl)piperazine-1-carboxylate

[0823] (a) Synthesis of tert-butyl 4-(4-(7,7-dimethyl-1,3-dioxo-10-((tetrahydro-2H-pyran-2-yl)oxy)-5,12b-dihydro-1H,7H-chromeno-[4,3-c][1,2,4]triazolo[1,2-a]pyridazin-2(3H)-yl)benzoyl)-piperazine-1-carboxylate

[0824] To obtain tert-butyl 4-(4-(7,7-dimethyl-1,3-dioxo-10-((tetrahydro-2H-pyran-2-yl)oxy)-5,12b-dihydro-1H,7H-chromeno-[4,3-c][1,2,4]triazolo[1,2-a]pyridazin-2(3H)-yl)benzoyl)piperazine-1-carboxylate (100 mg, 70%), the same synthesis as the above synthesis in Example 53(b) was carried out except that 1-(tert-butoxycarbonyl)piperazine was used instead of morpholine.

[0825] (b) Synthesis of tert-butyl 4-(4-(10-hydroxy-7,7-dimethyl-1,3-dioxo-5,12b-dihydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]-pyridazin-2(3H)-yl)benzoyl)piperazine-1-carboxylate

[0826] To obtain tert-butyl 4-(4-(10-hydroxy-7,7-dimethyl-1,3-dioxo-5,12b-dihydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]-pyridazin-2(3H)-yl)benzoyl)piperazine-1-carboxylate (38 mg, 51%), the same synthesis as the above synthesis of intermediate 31(d) was carried out, except that tert-butyl was used instead of 2,2-bis(fluoromethyl)-7-((tetrahydro-2H-pyran-2-yl)oxy)-chroman-4-one. 4-(4-(7,7-dimethyl-1,3-dioxo-10-((tetrahydro-2H-pyran-2-yl)oxy)-5,12b-dihydro-1H,7H-chromeno-[4,3-c][1,2,4]triazolo[1,2-a]pyridazin-2(3H)-yl)-benzoyl)piperazine-1-carboxylate.

[0827] 1 H NMR (400 MHz, CDCl3) δ 7.76 (d, J=8.5 Hz, 2H), 7.56 (d, J=8.4 Hz, 2H), 7.29 (s, 1H), 6.95 (d, J=8.4 Hz, 1H), 6.41 (dd, J=8.4, 2.5 Hz, 1H), 6.38 (d, J=2.4 Hz, 1H), 5.84 (d, J=3.0 Hz, 1H), 5.70 (s, 1H), 4.92 (s, 1H), 4.36-4.21 (m, 1H), 4.11 (d, J=16.4 Hz, 1H), 3.49 (s, 8H), 1.60 (s, 6H), 1.48 (s, 9H)

[0828] Example 55. Synthesis of 10-hydroxy-7,7-dimethyl-2-(4-(piperazine-1-carbonyl)phenyl)-5,12b-dihydro-1H,7H-chromeno[4,3-c][1,2,4]-triazolo[1,2-a]pyridazin-1,3(2H)-dione

[0829] To obtain 10-hydroxy-7,7-dimethyl-2-(4-(piperazine-1-carbonyl)phenyl)-5,12b-dihydro-1H,7H-chromeno[4,3-c][1,2,4]-triazolo[1,2-a]pyridazine-1,3(2H)-dione (12 mg, 70%), the same synthesis as the above synthesis in Example 7 was carried out except that tert-butyl (2-(4-acetylphenyl)-7,7-dimethyl-1,3-dioxo-2,3,5,12b-tetrahydro-1H,7H-chromeno[4,3-c]-[1,2,4]triazolo[1,2-a]pyridazin-10-yl)carbamate was used 4-(4-(10-hydroxy-7,7-dimethyl-1,3-dioxo-5,12b-dihydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazin-2(3H)-yl)benzoyl)piperazine-1-carboxylate.

[0830] 1H NMR (400 MHz, cd3od) δ 8.31 (s, 1H), 7.79 (e, J=8.5 Hz, 2H), 7.66 (d, J=8.5 Hz, 2H), 6.92-6.84 (m, 1H), 6.39 (dd, 5.8 Hz, 2.5 Hz), 6.31 (d, J=2.4 Hz, 1H), 5.96 (d, J=2.1 Hz, 1H), 5.67 (s, 1H), 4.31-4.22 (m, 1H), 4.20-4.12 (m, 1H), 3.83 (s, 4H, 3H), (, , 4.58), J=10.7 Hz, 6H)

[0831] Example 56. Synthesis 10-hydroxy-7,7-dimethyl-2-(4-(4-methyl-piperazine-1-carbonyl)phenyl)-5,12b-dihydro-1H,7H-chromeno[4,3-c]-[1,2,4]triazolo[1,2-a]pyridazine-1,3(2H)-dione

[0832] (a) Synthesis 7,7-dimethyl-2-(4-(4-methylpiperazine-1-carbonyl)-phenyl)-10-((tetrahydro-2H-pyran-2-yl)oxy)-5,12b-dihydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-pyriona]-1,3-H

[0833] To obtain 7,7-dimethyl-2-(4-(4-methylpiperazine-1-carbonyl)phenyl)-10-((tetrahydro-2H-pyran-2-yl)oxy)-5,12b-dihydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazine-1,3(2H)-dione (80 mg, 56%), the same synthesis as the above synthesis in Example 53(b) was carried out except that N-methylpiperazine was used instead of morpholine.

[0834] (b) Synthesis of 10-hydroxy-7,7-dimethyl-2-(4-(4-methylpiperazine-1-carbonyl)phenyl)-5,12b-dihydro-1H,7H-chromeno[4,3-c][1,2,4]-triazolo[1,2-a]pyridazin-1,3(2H)-dione

[0835] To obtain 10-hydroxy-7,7-dimethyl-2-(4-(4-methyl-piperazine-1-carbonyl)phenyl)-5,12b-dihydro-1H,7H-chromeno[4,3-c]-[1,2,4]triazolo[1,2-a]pyridazine-1,3(2H)-dione (42 mg, 72%), the same synthesis as the above synthesis of intermediate 31(d) was carried out, except that 2,2-bis(fluoromethyl)-7-((tetrahydro-2H-pyran-2-yl)oxy)-chroman-4-one was used 7,7-dimethyl-2-(4-(4-methylpiperazine-1-carbonyl)phenyl)-10-((tetrahydro-2H-pyran-2-yl)oxy)-5,12b-dihydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazine-1,3(2H)-dione.

[0836] 1 H NMR (400 MHz, CDCl3) δ 8.14 (s, 1H), 7.75 (d, J=8.5 Hz, 2H), 7.55 (d, J=8.6 Hz, 2H), 6.94 (d, J=8.1 Hz, 1H), 6.43-6.36 (m, 2H), 5.87-5.81 (m, 1H), 5.70 (s, 1H), 4.30 (dd, J=16.3, 4.9 Hz, 1H), 4.15-4.06 (m, 1H), 3.89 (s, 2H), 3.59 (s, 2H), 2.62 (d, J=39.6 Hz, 4H), 2.43 (s, 3H), 1.59 (s, 6H)

[0837] Example 57. Synthesis 7,7-dimethyl-2-(4-(morpholine-4-carbonyl)-phenyl)-10-(pyrrolidin-1-yl)-5,12b-dihydro-1H,7H-chromeno[4,3-c]-[1,2,4]triazolo[1,2-a]pyridazin-1,3(2H)-dione

[0838] To obtain 7,7-dimethyl-2-(4-(morpholine-4-carbonyl)phenyl)-10-(pyrrolidin-1-yl)-5,12b-dihydro-1H,7H-chromeno[4,3-c][1,2,4]-triazolo[1,2-a]pyridazine-1,3(2H)-dione (40 mg, 62%), the same synthesis as the above synthesis in Example 53(b) was carried out, except that instead of 4-(7,7-dimethyl-1,3-dioxo-10-((tetrahydro-2H-pyran-2-yl)oxy)-5,12b-dihydro-1H,7H-chromeno-[4,3-c][1,2,4]triazolo[1,2-a]pyridazin-2(3H)-yl)benzoic acid was used 4-(7,7-dimethyl-1,3-dioxo-10-(pyrrolidin-1-yl)-5,12b-dihydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazin-2(3H)-yl)benzoic acid.

[0839] 1H NMR (400 MHz, CDCl3) δ 7.76 (d, J=8.4 Hz, 2H), 7.56 (d, J=8.4 Hz, 2H), 6.97 (d, J=8.6 Hz, 1H), 6.19-6.12 (m, 1H), 6.06 (d, J=2.3 Hz, 1H), 5.83 (d, J=5.1 Hz, 1H), 5.75 (s, 1H), 4.30 (dd, J=16.3, 5.0 Hz, 1H), 4.08 (d, J=16.4 Hz, 1H), 3.73 (s, 7H), 3.51 (s, 1H), 3.21 (d, J=6.6 Hz, 4H), 1.99-1.92 (m, 4H), 1.60 (d, J=10.3 Hz, 6H)

[0840] Example 58. Synthesis of 2-(4-acetylphenyl)-7,7-dimethyl-1,3-dioxo-2,3,5,12b-tetrahydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]-pyridazin-10-yl pivalate

[0841] 2-(4-Acetylphenyl)-10-hydroxy-7,7-dimethyl-5,12b-dihydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazine-1,3(2H)-dione (300 mg, 0.72 mmol) obtained in Example 10(b) above was dissolved in dichloromethane (7 ml), and triethylamine (220 mg, 2.15 mmol) was added thereto, and stirred at room temperature for 10 minutes. Trimethylacetyl chloride (136 mg, 1.12 mmol) was added dropwise to the reaction mixture, which was stirred at room temperature for 15 hours. After completion of the reaction, the reaction mixture was diluted with dichloromethane and washed with water. The separated organic layer was dried over sodium sulfate, filtered, concentrated by distillation under reduced pressure, and separated by MPLC (ethyl acetate:hexane = 1:1, by volume) to give 2-(4-acetylphenyl)-7,7-dimethyl-1,3-dioxo-2,3,5,12b-tetrahydro-1H,7H-chromeno[4,3-c]-[1,2,4]triazolo[1,2-a]pyridazin-10-yl pivalate (331 mg, 91%).

[0842] 1H NMR (400 MHz, DMSO-D6) δ 8.17-8.09 (m, 2H), 7.84-7.76 (m, 2H), 7.12 (dd, J=8.4, 1.1 Hz, 1H), 6.70 (dd, J=8.4, 2.3 Hz, 1H), 6.66 (d, J=2.3 Hz, 1H), 6.02 (g, J=1.8 Hz, 1H), 5.75-5.70 (m, 1H), 4.22 (dd, J=3.7, 2.0 Hz, 2H), 2.64 (s, 3H), 1.60 (s, 3H), 1.53 (s, 3H), 1.27 (s, 9H).

[0843] Example 59. Synthesis of 2-(4-acetylphenyl)-7,7-dimethyl-1,3-dioxo-2,3,5,12b-tetrahydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]-pyridazin-10-yl 3-methylbutanoate

[0844] To obtain 2-(4-acetylphenyl)-7,7-dimethyl-1,3-dioxo-2,3,5,12b-tetrahydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazin-10-yl 3-methylbutanoate (100 mg, 90%), the same synthesis as the above synthesis in Example 58 was carried out except that 3-methylbutanoyl chloride was used instead of trimethylacetyl chloride.

[0845] 1H NMR (400 MHz, DMSO-D6) δ 8.17-8.09 (m, 2H), 7.84-7.76 (m, 2H), 7.12 (dd, J=8.4, 1.1 Hz, 1H), 6.71 (dd, J=8.4, 2.3 Hz, 16.5H), J=2.3 Hz, 1H), 6.02 (quartet, J=3.1 Hz, 1H), 5.73 (d, J=2.3 Hz, 1H), 4.22 (dd, J=3.7, 2.0 Hz, 2H), 2.64 (s, 3H), 2.43 (d, J=7, 2.1H), G 2.14-2.02 (m, 1H), 1.60 (s, 3H), 1.53 (s, 3H), 0.98 (d, J=6.7 Hz, 6H).

[0846] Example 60. Synthesis of 2-(4-acetylphenyl)-7,7-dimethyl-1,3-dioxo-2,3,5,12b-tetrahydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-azineta-10

[0847] To prepare 2-(4-acetylphenyl)-7,7-dimethyl-1,3-dioxo-2,3,5,12b-tetrahydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-azin]-pyridyl-acetate (102-m 98%) carried out the same synthesis as the above synthesis in Example 58 except that acetyl chloride was used instead of trimethylacetyl chloride.

[0848] 1H NMR (400 MHz, DMSO-D6) δ 8.17-8.10 (m, 2H), 7.84-7.77 (m, 2H), 7.11 (dd, J=8.4, 1.1 Hz, 1H), 6.73 (dd, J=8.4, 2.3 Hz, 1H), 6.68 (d, J=2.3 Hz, 1H), 6.02 (d, J=1.9 Hz, 1H), 5.72 (d, J=2.4 Hz, 1H), 4.22 (dd, J=3.9, 2.0 Hz, 2H), 2.64 (s, 3H), 2.23 (s, 3H), 1.60 (s, 3H), 1.53 (s, 3H).

[0849] Example 61. Synthesis of 2-(4-acetylphenyl)-7,7-dimethyl-1,3-dioxo-2,3,5,12b-tetrahydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]-pyridazin-10-yl ethyl carbonate

[0850] To obtain 2-(4-acetylphenyl)-7,7-dimethyl-1,3-dioxo-2,3,5,12b-tetrahydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazin-10-yl ethyl carbonate (120 mg, 94%), the same synthesis as the above synthesis in Example 58 was carried out except that ethyl chloroformate was used instead of trimethylacetyl chloride.

[0851] 1H NMR (400 MHz, CDCl3) δ 8.11 (d, J=8.7 Hz, 2H), 7.84 (d, J=8.7 Hz, 2H), 7.09 (dd, J=8.4, 1.1 Hz, 1H), 6.80-6.72 (m, 2H), 5.87 (dt, J=4.7, 2.3 Hz, 1H), 5.72 (quartet, J=1.6 Hz, 1H), 4.33-4.25 (m, 3H), 4.13 (dt, J=16.5, 2.7 Hz, 1H), 2.64 (s, 3H), 1.61 (d, J=4.5 Hz, 6H), 1.37 (t, J=7.1 Hz, 3H)

[0852] Example 62. Synthesis of 2-(4-acetylphenyl)-7,7-dimethyl-1,3-dioxo-2,3,5,12b-tetrahydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]-pyridazin-10-yl dimethylcarbamate

[0853] To obtain 2-(4-acetylphenyl)-7,7-dimethyl-1,3-dioxo-2,3,5,12b-tetrahydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazin-10-yl dimethylcarbamate (400 mg, 99%), the same synthesis as the above synthesis in Example 58 was carried out except that dimethylcarbamoyl chloride was used instead of trimethylacetyl chloride.

[0854] 1H NMR (400 MHz, DMSO-D6) δ 8.13 (d, J=8.6 Hz, 2H), 7.80 (d, J=8.6 Hz, 2H), 7.08 (dd, J=8.4, 1.1 Hz, 1H), 6.72 (dd, J=8.4, 2.3 Hz, 1H), 6.65 (d, J=2.3 Hz, 1H), 6.01 (td, J=3.7, 1.8 Hz, 1H), 5.74-5.66 (m, 1H), 4.21 (dd, J=3.8, 2.0 Hz, 2H), 3.01 (s, 3H), 2.88 (s, 3H), 2.64 (s, 3H), 1.59 (s, 3H), 1.53 (s, 3H).

[0855] Example 63. Synthesis of 2-(4-acetylphenyl)-7,7-dimethyl-1,3-dioxo-2,3,5,12b-tetrahydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]-pyridazin-10-yl morpholin-4-carboxylate

[0856] To obtain 2-(4-acetylphenyl)-7,7-dimethyl-1,3-dioxo-2,3,5,12b-tetrahydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazin-10-yl morpholine-4-carboxylate (210 mg, 96%), the same synthesis as the above synthesis in Example 58 was carried out except that 4-morpholinecarbonyl chloride was used instead of trimethylacetyl chloride.

[0857] 1H NMR (400 MHz, DMSO-D6) δ 8.17-8.09 (m, 2H), 7.84-7.76 (m, 2H), 7.09 (dd, J=8.4, 1.1 Hz, 1H), 6.75 (dd, J=8.4, 2.3 Hz, 6.9H), d J=2.3 Hz, 1H), 6.01 (quartet, J=3.1 Hz, 1H), 5.71 (s, 1H), 4.21 (dd, J=3.8, 2.0 Hz, 2H), 3.62 (dd, J=5.7, 4.0 Hz, 4H, 47), (d, 3.8), J=3.8, G 2.64 (s, 3H), 1.59 (s, 3H), 1.52 (s, 3H).

[0858] Example 64. Synthesis (2S,3S,4S,5R,6S)-6-((2-(4-acetylphenyl)-7,7-dimethyl-1,3-dioxo-2,3,5,12b-tetrahydro-1H,7H-chromeno[4 ,3-c][1,2,4]triazolo[1,2-a]pyridazine-10-yl)oxy)-3,4,5-trihydroxy-tetrahydro-2H-pyran-2-carboxylic acids

[0859] (a) Synthesis (2S,3R,4S,5S,6S)-2-((2-(4-acetylphenyl)-7,7-dimethyl-1,3-dioxo-2,3,5,12b-tetrahydro-1H,7H-chromeno[4, 3-c]-[1,2,4]triazolo[1,2-a]pyridazin-10-yl)oxy)-6-(methoxycarbonyl)-tetrahydro-2H-pyran-3,4,5-triyl triacetate

[0860] 2-(4-Acetylphenyl)-10-hydroxy-7,7-dimethyl-5,12b-dihydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazine-1,3(2H)-dione (1 g, 2.38 mmol) obtained in Example 10(b) above, methyl (2S,3S,4S,5R,6R)-3,4,5-triacetoxy-6-bromo-tetrahydropyran-2-carboxylate (1.42 g, 3.58 mmol) and 4A molecular sieve (3 g) were suspended in dichloromethane (10 ml) and stirred for 1 hour under a nitrogen atmosphere. Silver carbonate (1.31 g, 4.77 mmol) was added to the reaction mixture, stirred for 5 minutes, and then cooled to 0°C. Trifluoromethanesulfonic acid (358 mg, 2.38 mmol) was added, and the mixture was stirred for another 15 hours at room temperature. After completion of the reaction, a few drops of triethylamine were added to the reaction mixture, and the insoluble solid was filtered through celite and washed with dichloromethane. The filtrate was washed with water, dried over sodium sulfate, filtered, and concentrated by distillation under reduced pressure.The resulting residue was separated by reverse phase chromatography (acetonitrile containing 0.1% formic acid: water containing 0.1% formic acid = 5:95-100:0) to give (2S,3R,4S,5S,6S)-2-((2-(4-acetylphenyl)-7,7-dimethyl-1,3-dioxo-2,3,5,12b-tetrahydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazin-10-yl)oxy)-6-(methoxycarbonyl)tetrahydro-2H-pyran-3,4,5-triyl triacetate (178 mg, 10%).

[0861] (b) Synthesis (2S,3S,4S,5R,6S)-6-((2-(4-acetylphenyl)-7,7-di-methyl-1,3-dioxo-2,3,5,12b-tetrahydro-1H,7H-chromeno[4 ,3-c]-[1,2,4]triazolo[1,2-a]pyridazin-10-yl)oxy)-3,4,5-trihydroxy-tetrahydro-2H-pyran-2-carboxylic acid acids

[0862] (2S,3R,4S,5S,6S)-2-((2-(4-acetylphenyl)-7,7-dimethyl-1,3-dioxo-2,3,5,12b-tetrahydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo-[1,2-a]pyridazin-10-yl)oxy)-6-(methoxycarbonyl)tetrahydro-2H-pyran-3,4,5-triyl triacetate (178 mg, 0.24 mmol) obtained in Example 64(a) above was dissolved in a mixed solvent of methanol / triethylamine (1:1, 10 ml), and water (9 ml) was added dropwise, and stirred at room temperature for 2 hours. After completion of the reaction, the reaction mixture was concentrated by distillation under reduced pressure, and the resulting residue was separated by reverse phase chromatography (acetonitrile containing 0.1% formic acid: water containing 0.1% formic acid = 5:95-100:0) to give (2S,3S,4S,5R,6S)-6-((2-(4-acetylphenyl)-7,7-dimethyl-1,3-dioxo-2,3,5,12b-tetrahydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazin-10-yl)oxy)-3,4,5-trihydroxytetrahydro-2H-pyran-2-carboxylic acid (90 mg, 62%).

[0863] 1H NMR (500 MHz, MeOD) δ 8.18-8.13 (m, 2H), 7.86-7.81 (m, 2H), 7.03 (dd, J=8.6, 1.1 Hz, 1H), 6.71 (ddd, J=8.6, 4.2, 2.4 Hz, 6.6 Hz), J=4.8, 2.4 Hz, 1H), 6.01-5.94 (m, 1H), 5.71 (t, J=2.0 Hz, 1H), 4.97-4.91 (m, 1H), 4.31-4.22 (m, 1H), 4.23-4.13 (m, 1H), 4.23-4.13 (d, 196H), d Hz, 1H), 3.59 (ddt, J=9.5, 7.4, 1.8 Hz, 1H), 3.48-3.44 (m, 2H), 2.66 (s, 3H), 1.61 (s, 3H), 1.57 (d, J=4.3 Hz, 3H).

[0864] Example 65. Sodium Synthesis (2S,3S,4S,5R,6S)-6-((2-(4-acetylphenyl)-7,7-dimethyl-1,3-dioxo-2,3,5,12b-tetrahydro -1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazine-10-yl)oxy)-3,4,5-trihydroxy tetrahydro-2H-pyran-2-carboxylate

[0865] (2S,3S,4S,5R,6S)-6-((2-(4-acetylphenyl)-7,7-dimethyl-1,3-dioxo-2,3,5,12b-tetrahydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo-[1,2-a]pyridazin-10-yl)oxy)-3,4,5-trihydroxytetrahydro-2H-pyran-2-carboxylic acid (100 mg, 0.17 mmol) obtained in Example 64(b) above was suspended in water (1 ml), and sodium bicarbonate (14.11 mg, 0.17 mmol) was added thereto, and stirred at room temperature for 2 hours. After completion of the reaction, the reaction mixture was concentrated by distillation under reduced pressure, and the resulting residue was triturated with ethyl acetate to obtain sodium (2S,3S,4S,5R,6S)-6-((2-(4-acetylphenyl)-7,7-dimethyl-1,3-dioxo-2,3,5,12b-tetrahydro-1H,7H-chromeno[4,3-c]-[1,2,4]triazolo[1,2-a]pyridazin-10-yl)oxy)-3,4,5-trihydroxytetrahydro-2H-pyran-2-carboxylate (97 mg, 94%).

[0866] 1H NMR (500 MHz, D2O) δ 7.98-7.90 (m, 2H), 7.59-7.50 (m, 2H), 6.94 (ddd, J=24.0, 8.7, 1.0 Hz, 1H), 6.73 (ddd, J=9.4, 2.5 Hz, 1H), 6.66 (dd, J=4.1, 2.4 Hz, 1H), 5.94 (dd, J=3.9, 1.9 Hz, 1H), 5.64 (d, J=7.8 Hz, 1H), 5.08-4.97 (m, 1H), 4.20-4.09 (m, 3.8), 3.8 Hz, 1H), 3.64-3.55 (m, 3H), 2.62 (s, 3H), 1.57-1.50 (m, 6H).

[0867] Example 66. Synthesis of 2-(4-acetylphenyl)-7,7-dimethyl-1,3-dioxo-2,3,5,12b-tetrahydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a-pyridazine]-10-1 4-methylpiperazine-1-carboxylate hydrochloride

[0868] To prepare 2-(4-acetylphenyl)-7,7-dimethyl-1,3-dioxo-2,3,5,12b-tetrahydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]-pyridyl-10- 4-methylpiperazine-1-carboxylate hydrochloride (400 mg, 87%) was synthesized in the same manner as the above synthesis in Example 58 except that 4-methylpiperazine-1-carbonyl chloride was used instead of trimethylacetyl chloride.

[0869] 1H NMR (400 MHz, D2O) δ 8, 13 (d, J=8.3 Hz, 2H), 7.70 (d, J=8.2 Hz, 2H), 7.15 (d, J=8.3 Hz, 1H), 6.84 (d, J=11.9 Hz, 2H), (s 5.79 (s, 1H), 4.28 (s, 3H), 3.63 (d, J=12.5 Hz, 2H), 3.53 (s, 1H), 3.37 (s, 1H), 3.24 (s, 2H), 3.00 (s, 3H), 2.71 (s, 3H), (d, 1,62) J=20.3 Hz, 6H)

[0870] Example 67. Synthesis of 2-(4-acetylphenyl)-7,7-dimethyl-1,3-dioxo-2,3,5,12b-tetrahydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a-pyridazine]-10-1 piperazine-1-carboxylate hydrochloride

[0871] (a) Synthesis 1-(2-(4-acetylphenyl)-7,7-dimethyl-1,3-dioxo-2,3,5,12b-tetrahydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]-pyridazin-10-yl)4-(tretibutyl-1,4-hyperboxyladicardi

[0872] 2-(4-Acetylphenyl)-10-hydroxy-7,7-dimethyl-5,12b-dihydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazine-1,3(2H)-dione (4 g, 9.54 mmol) obtained in Example 10(b) above was dissolved in dichloromethane (40 ml), and triethylamine (2.9 g, 11.44 mmol) was added thereto, and stirred for 10 minutes. tert-butyl 4-chlorocarbonylpiperazine-1-carboxylate (2.85 g, 11.44 mmol) and 4-dimethylaminopyridine (350 mg, 2.86 mmol) were added thereto, and stirred for 15 hours. After completion of the reaction, the reaction mixture was diluted with dichloromethane and washed with water and aqueous ammonium chloride solution. The separated organic layer was dried over sodium sulfate, filtered, concentrated by distillation under reduced pressure and separated by MPLC (ethyl acetate:hexane = 1:1, by volume) to give 1-(2-(4-acetylphenyl)-7,7-dimethyl-1,3-dioxo-2,3,5,12b-tetrahydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazin-10-yl)4-(tert-butyl)piperazine-1,4-dicarboxylate (6 g, 99%).

[0873] (b) Synthesis of 2-(4-acetylphenyl)-7,7-dimethyl-1,3-dioxo-2,3,5,12b-tetrahydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]-pyridazin-10-yl piperazin-1-carboxylate hydrochloride

[0874] 1-(2-(4-Acetylphenyl)-7,7-dimethyl-1,3-dioxo-2,3,5,12b-tetrahydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazin-10-yl)4-(tert-butyl)piperazine-1,4-dicarboxylate (6 g, 9.5 mmol) obtained in Example 67(a) above was dissolved in 1,4-dioxane (30 ml), and 4 M hydrochloric acid solution (10 ml, 4 M / dioxane) was added dropwise, and stirred at room temperature for 15 hours. After completion of the reaction, the resulting solid was filtered and washed with ethyl acetate to obtain 2-(4-acetylphenyl)-7,7-dimethyl-1,3-dioxo-2,3,5,12b-tetrahydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazin-10-yl piperazine-1-carboxylate hydrochloride (5.2 g, 96%).

[0875] 1H NMR (400 MHz, DMSO-D6) δ 8.13 (d, J=8.2 Hz, 2H), 7.80 (d, J=8.6 Hz, 2H), 7.10 (d, J=8.3 Hz, 1H), 6.79-6.72 (m, 2H), 6.02 (s, 1H), 5.71 (s, 1H), 4.22 (s, 2H), 3.75 (s, 2H), 3.63 (s, 2H), 3.18 (s, 4H), 2.64 (s, 3H), 1.60 (s, 3H), 1.52 (s, 3H).

[0876] Example 68. Synthesis of 2-(4-acetylphenyl)-7,7-dimethyl-1,3-dioxo-2,3,5,12b-tetrahydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]-pyridazin-10-yl 4-(2-oxopropanoyl)piperazine-1-carboxylate.

[0877] To obtain 2-(4-acetylphenyl)-7,7-dimethyl-1,3-dioxo-2,3,5,12b-tetrahydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]-pyridazin-10-yl 4-(2-oxopropanoyl)piperazine-1-carboxylate (100 mg, 53%), the same synthesis as the above synthesis in Example 53(b) was carried out, except that instead of 4-(7,7-dimethyl-1,3-dioxo-10-((tetrahydro-2H-pyran-2-yl)oxy)-5,12b-di-hydro-1H,7H-chromeno-[4,3-c][1,2,4]triazolo[1,2-a]pyridazin-2(3H)-yl)benzoic acid and morpholine were used, respectively, pyruvic acid and 2-(4-acetylphenyl)-7,7-dimethyl-1,3-dioxo-2,3,5,12b-tetrahydro-1H,7H-chromeno[4,3-c]-[1,2,4]triazolo[1,2-a]pyridazin-10-yl piperazine-1-carboxylate hydrochloride.

[0878] 1H NMR (400 MHz, CDCl3) δ 8.11 (d, J=8.7 Hz, 2H), 7.83 (d, J=8.7 Hz, 2H), 7.08 (dd, J=8.4, 1.2 Hz, 1H), 6.73-6.65 (m, 2.8.8-m), 1H), 5.72 (s, 1H), 4.30 (dd, J=16.4, 4.8 Hz, 1H), 4.16-4.10 (m, 1H), 3.70 (s, 4H), 3.61 (d, J=17.3 Hz, 4H), 2.64 (s, 3H), (s, 3H), 3H 1.60 (d, J=5.7 Hz, 6H).

[0879] Example 69. Synthesis of 2-(4-acetylphenyl)-7,7-dimethyl-1,3-dioxo-2,3,5,12b-tetrahydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a-pyrida-dihydrophosphazine]-10

[0880] (a) Synthesis of 2-(4-acetylphenyl)-7,7-dimethyl-1,3-dioxo-2,3,5,12b-tetrahydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]-pyridazine-10-diethylphosphata

[0881] To prepare 2-(4-acetylphenyl)-7,7-dimethyl-1,3-dioxo-2,3,5,12b-tetrahydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]-pyridazine-diethylphosphata (3,3 95%) carried out the same synthesis as the above synthesis in Example 58 except that diethyl chlorophosphate was used instead of trimethylacetyl chloride.

[0882] (b) Synthesis of 2-(4-acetylphenyl)-7,7-dimethyl-1,3-dioxo-2,3,5,12b-tetrahydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]-pyridazin-10-yl dihydrogen phosphate

[0883] 2-(4-Acetylphenyl)-7,7-dimethyl-1,3-dioxo-2,3,5,12b-tetra-hydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazin-10-yl diethyl phosphate (1.5 g, 2.7 mmol) obtained in Example 69(a) above was dissolved in dichloromethane (15 ml), and bromotrimethylsilane (1.65 g, 10.8 mmol) was added thereto, and stirred at room temperature for 15 hours. After completion of the reaction, the reaction mixture was concentrated by distillation under reduced pressure, and methanol (30 ml) was added to the resulting residue, and stirred at room temperature for 1 hour. The reaction mixture was concentrated by distillation under reduced pressure and recrystallized from ethanol to give 2-(4-acetylphenyl)-7,7-dimethyl-1,3-dioxo-2,3,5,12b-tetrahydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazin-10-yl dihydrogen phosphate (1.3 g, 96%).

[0884] 1 H NMR (500 MHz, D2O) δ 8.22 (dt, J=8.4, 0.5 Hz, 2H), 7.80-7.74 (m, 2H), 7.09-7.05 (m, 1H), 6.93 (ddd, J=8.5, 2.3, 1.0, Gdd, 8.6H), J=2.3, 1.0 Hz, 1H), 6.02 (td, J=4.2, 3.8, 1.9 Hz, 1H), 5.81 (s, 1H), 4, 36-4, 28 (m, 2H), 2.76 (s, 3H), 1.67 (s, 3H), (s, 3H).

[0885] Example 70. Synthesis of disodium 2-(4-acetylphenyl)-7,7-dimethyl-1,3-dioxo-2,3,5,12b-tetrahydro-1H,7H-chromeno[4,3-c][1,2,4]-triazolo[1,2-pyrosphate-1-0

[0886] 2-(4-Acetylphenyl)-7,7-dimethyl-1,3-dioxo-2,3,5,12b-tetra-hydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazin-10-yl dihydrogen phosphate (100 mg, 0.2 mmol) obtained in Example 69(b) above was suspended in water (3 ml), and sodium bicarbonate (33.78 mg, 0.4 mmol) was added thereto, and stirred at room temperature for 1 hour. After completion of the reaction, the reaction mixture was added dropwise into acetone (10 ml), and the precipitated solid was filtered and washed with acetone to obtain disodium 2-(4-acetylphenyl)-7,7-dimethyl-1,3-dioxo-2,3,5,12b-tetrahydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazin-10-yl phosphate (80 mg, 80%).

[0887] 1 H NMR (400 MHz, D2O) δ 8.30-8.22 (m, 2H), 7.89-7.78 (m, 2H), 7.13 (d, J=8.5 Hz, 1H), 7.05-6.96 (m, 1H), 6.93 (d, J=2.3 Hz, 1H), 6.08 (d, J=3.5 Hz, 1H), 5.87 (s, 1H), 4.36 (t, J=3.1 Hz, 2H), 2.82 (s, 3H), 1.71 (d, J=19.9 Hz, 6H).

[0888] Example 71. Synthesis of 1,3-dihydroxy-2-(hydroxymethyl)propane-2-aminium 2-(4-acetylphenyl)-7,7-dimethyl-1,3-dioxo-2,3,5,12b-tetra-hydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazin-10-yl phosphate

[0889] 2-(4-Acetylphenyl)-7,7-dimethyl-1,3-dioxo-2,3,5,12b-tetra-hydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazin-10-yl dihydrogen phosphate (100 mg, 0.2 mmol) obtained in Example 69(b) above was suspended in water (3 ml), and tromethamine (24 mg, 0.4 mmol) was added thereto, and stirred at room temperature for 1 hour. After completion of the reaction, the reaction mixture was added dropwise into acetone (10 ml), and the precipitated solid was filtered and washed with acetone to obtain 1,3-dihydroxy-2-(hydroxymethyl)propan-2-aminium 2-(4-acetylphenyl)-7,7-dimethyl-1,3-dioxo-2,3,5,12b-tetrahydro-1H,7H-chromeno[4,3-c][1,2,4]-triazolo[1,2-a]pyridazin-10-yl phosphate (78 mg, 53%).

[0890] 1H NMR (400 MHz, D2O) δ 8.22 (d, J=8.7 Hz, 2H), 7.86-7.73 (m, 2H), 7.16 (d, J=8.5 Hz, 1H), 7.00-6.95 (m, 1H), 6.92 (dd, J=8.2, Hz, 1H). 1H), 6.07 (d, J=2.2 Hz, 1H), 5.84 (s, 1H), 4.35 (d, J=2.9 Hz, 2H), 3.83 (s, 12H), 2.80 (s, 3H), 2.32 (s, 2H), 1.70 (d, J=2.8 Hz, 6H).

[0891] Example 72. Synthesis of 2-(4-acetylphenyl)-7,7-dimethyl-1,3-dioxo-2,3,5,12b-tetrahydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a-pyridyl-glycine-10 hydrochloride

[0892] 2-(4-Acetylphenyl)-10-hydroxy-7,7-dimethyl-5,12b-dihydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazine-1,3(2H)-dione (2 g, 4.77 mmol) obtained in Example 10(b) above was dissolved in dichloromethane (10 ml), and triethylamine (1.45 g, 14.31 mmol) and 2-(dimethylamino)acetyl chloride (0.87 g, 7.15 mmol) were added thereto, and stirred at room temperature for 15 hours. After completion of the reaction, the reaction mixture was diluted with dichloromethane and washed with water. The separated organic layer was dried over sodium sulfate, filtered, and concentrated by distillation under reduced pressure. The resulting residue was dissolved in acetone (20 ml) and 4 M hydrochloric acid solution (10 ml, 4 M / dioxane) was added dropwise, and stirred at room temperature for 30 minutes.The resulting solid precipitate was filtered off and washed with acetone to give 2-(4-acetylphenyl)-7,7-dimethyl-1,3-dioxo-2,3,5,12b-tetrahydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazin-10-yl dimethylglycinate hydrochloride (900 mg, 35%).

[0893] 1 H NMR (500 MHz, D2O) δ 8.00-7.89 (m, 2H), 7.60-7.52 (m, 2H), 7.07 (dd, J=8.6, 1.2 Hz, 1H), 6.84-6.77 (m, 2H), 5.96-5.91 (m, 1H), 5.65 (s, 1H), 4.42 (s, 2H), 4.16 (dt, J=3.9, 2.3 Hz, 2H), 3.03 (d, J=0.8 Hz, 6H), 2.61 (s, 3H), 1.53 (d, J=9.7 Hz, 6H).

[0894] Example 73: Synthesis of 2-(4-acetylphenyl)-7,7-dimethyl-1,3-dioxo-2,3,5,12b-tetrahydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]-pyridazin-10-yl (2-methoxyethyl)carbonate

[0895] To obtain 2-(4-acetylphenyl)-7,7-dimethyl-1,3-dioxo-2,3,5,12b-tetrahydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]-pyridazin-10-yl (2-methoxyethyl) carbonate (120 mg, 95%), the same synthesis as the above synthesis in Example 58 was carried out except that methoxyethyl chloroformate was used instead of trimethylacetyl chloride.

[0896] 1 H NMR (400 MHz, DMSO-D6) δ 8.17-8.07 (m, 2H), 7.85-7.74 (m, 2H), 7.14 (dd, J=8.4, 1.2 Hz, 1H), 6.84 (dd, J=8.4, 2.4 Hz, 1H), 6.80 (d, J=2.3 Hz, 1H), 6.03 (td, J=3.8, 1.8 Hz, 1H), 5.76-5.68 (m, 1H), 4.34-4.26 (m, 2H), 4.22 (dd, J=3.9, 2.0 Hz, 2H), 3.62-3.55 (m, 2H), 3.28 (s, 3H), 2.64 (s, 3H), 1.60 (s, 3H), 1.54 (s, 3H).

[0897] Example 74. Synthesis of 2-(4-acetylphenyl)-7,7-dimethyl-1,3-dioxo-2,3,5,12b-tetrahydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]-pyridazin-10-yl pyrrolidin-1-carboxylate

[0898] To prepare 2-(4-acetylphenyl)-7,7-dimethyl-1,3-dioxo-2,3,5,12b-tetrahydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]-pyridyl-10-pyrrolidine-carboxyla-1 (98 mg, 96%) carried out the same synthesis as the above synthesis in Example 58 except that pyrrolidine-1-carbonyl chloride was used instead of trimethylacetyl chloride.

[0899] 1 H NMR (400 MHz, CDCl3) δ 8.10 (d, J=8.7 Hz, 2H), 7.84 (d, J=8.7 Hz, 2H), 7.04 (dd, J=8.3, 1.1 Hz, 1H), 6.75-6.69 (m, 2.5, 4.4, J=4, 4H), (dt 2.3 Hz, 1H), 5.75-5.68 (m, 1H), 4.29 (ddd, J=16.5, 4.8, 1.4 Hz, 1H), 4.12 (dt, J=16.4, 2.6 Hz, 1H), 3.49 (dt, J=16.4, 2.6 Hz, 2.64H), (s, 3H), 1.99-1.85 (m, 4H), 1.59 (d, J=6.6 Hz, 6H).

[0900] Example 75. Synthesis of 2-(4-acetylphenyl)-7,7-dimethyl-1,3-dioxo-2,3,5,12b-tetrahydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a-pyridazine]-10-1 (2,5,8,11-tetraoxatridecan-13-yl)carbonate

[0901] To obtain 2-(4-acetylphenyl)-7,7-dimethyl-1,3-dioxo-2,3,5,12b-tetrahydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]-pyridazin-10-yl (2,5,8,11-tetraoxatridecan-13-yl) carbonate (60 mg, 90%), the same synthesis as the above synthesis in Example 58 was carried out except that 2-[2-[2-(2-methoxyethoxy)ethoxy]ethoxy]ethyl chloroformate was used instead of trimethylacetyl chloride.

[0902] 1 H NMR (400 MHz, CDCl3) δ 8.13-8.04 (m, 2H), 7.89-7.78 (m, 2H), 7.08 (d, J=8.4 Hz, 1H), 6.81-6.71 (m, 2H), 5.86 (dt, J=4.7, 2.2 Hz, 1H), 5.72 (s, 1H), 4.40-4.34 (m, 2H), 4.30 (dd, J=16.5, 4.8 Hz, 1H), 4.13 (dt, J=16.5, 2.6 Hz, 1H), 3.80-3.75 (m, 2H), 3.65 (dd, J=13.9, 5.4 Hz, 10H), 3.54 (dd, J=5.9, 3.4 Hz, 2H), 3.37 (s, 3H), 2.64 (s, 3H), 1.60 (d, J=3.9 Hz, 6H).

[0903] Example 76. Synthesis of 2-(4-acetylphenyl)-7,7-dimethyl-1,3-dioxo-2,3,5,12b-tetrahydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]-pyridazin-10-yl diethylcarbamate

[0904] To obtain 2-(4-acetylphenyl)-7,7-dimethyl-1,3-dioxo-2,3,5,12b-tetrahydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazin-10-yl diethylcarbamate (120 mg, 94%), the same synthesis as the above synthesis in Example 58 was carried out except that diethylcarbamyl chloride was used instead of trimethylacetyl chloride.

[0905] 1 H NMR (400 MHz, CDCl3) δ 8.11 (d, J=8.7 Hz, 2H), 7.83 (d, J=8.7 Hz, 2H), 7.05 (d, J=8.2 Hz, 1H), 6.74-6.68 (m, 2H), 5.84 (dt, J=4.7, 2.2 Hz, 1H), 5.73 (s, 1H), 4.29 (ddd, J=16.6, 4.8, 1.3 Hz, 1H), 4.12 (dt, J=16.4, 2.6 Hz, 1H), 3.38 (s, 4H), 2.64 (s, 3H), 1.60 (d, J=4.1 Hz, 6H), 1.26-1.15 (m, 6H).

[0906] Example 77. Synthesis of 2-(4-acetylphenyl)-7,7-dimethyl-1,3-dioxo-2,3,5,12b-tetrahydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]-pyridazin-10-yl L-glutamate 2,2,2-trifluoroacetic acid

[0907] (a) Synthesis of 2-(4-acetylphenyl)-7,7-dimethyl-1,3-dioxo-2,3,5,12b-tetrahydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]-pyridazine-10-yl (tertbutoxycarbonyl)-L-glutaminate

[0908] 2-(4-Acetylphenyl)-10-hydroxy-7,7-dimethyl-5,12b-dihydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazine-1,3(2H)-dione (350 mg, 0.84 mmol) obtained in Example 10(b) above, (2S)-5-amino-2-(tert-butoxycarbonylamino)-5-oxo-pentanoic acid (247 mg, 1.0 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (320 mg, 1.67 mmol) and 4-dimethylaminopyridine (20 mg, 0.17 mmol) were dissolved in dichloromethane (5 ml) and stirred at room temperature for 15 hours. After completion of the reaction, the reaction mixture was diluted with dichloromethane and washed with water and aqueous sodium chloride solution. The separated organic layer was dried over sodium sulfate, filtered, concentrated by distillation under reduced pressure and separated by MPLC (dichloromethane:methanol = 95:5, by volume) to give 2-(4-acetylphenyl)-7,7-dimethyl-1,3-dioxo-2,3,5,12b-tetrahydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazin-10-yl (tert-butoxycarbonyl)-L-glutaminate (250 mg, 46%).

[0909] (b) Synthesis of 2-(4-acetylphenyl)-7,7-dimethyl-1,3-dioxo-2,3,5,12b-tetrahydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]-pyridazin-10-yl L-glutamate

[0910] 2-(4-Acetylphenyl)-7,7-dimethyl-1,3-dioxo-2,3,5,12b-tetra-hydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazin-10-yl (tert-butoxycarbonyl)-L-glutaminate (300 mg, 0.46 mmol) obtained in Example 77(a) above was dissolved in dichloromethane (2 ml), and trifluoroacetic acid (2 ml) was added dropwise thereto, and stirred at room temperature for 5 hours. After completion of the reaction, the reaction mixture was diluted with water and washed with ethyl acetate. The separated aqueous layer was lyophilized to give 2-(4-acetylphenyl)-7,7-dimethyl-1,3-dioxo-2,3,5,12b-tetrahydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazin-10-yl L-glutaminate (80 mg, 24%).

[0911] 1H NMR (400 MHz, D2O) δ 8.10 (e, J=8.3 Hz, 2H), 7.68 (e, J=8.3 Hz, 2H), 7.18 (e, J=8.5 Hz, 1H), 6.89 (d, J=8.4 Hz, 2H), 6.89 (e, J=8.4 Hz, 2H), (s, 1H), 4.50 (t, J=6.6 Hz, 1H), 4.28 (s, 2H), 2.71 (s, 3H), 2.66 (s, 2H), 2.42 (dd, J=17.8, 7.3 Hz, 2H), 1.93 (s, 1H), (d, 16.3 Hz, J=6.6) 6H), 1.32 (s, 3H).

[0912] Example 78. Synthesis (((2-(4-acetylphenyl)-7,7-dimethyl-1,3-dioxo-2,3,5,12b-tetrahydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo-[1,2-a]pyridazin-10-yl)oxy-L-arginyl) 2,2,2-trifluoro-acetic acid

[0913] (a) Synthesis of tertbutyl (((2-(4-acetylphenyl)-7,7-dimethyl-1,3-dioxo-2,3,5,12b-tetrahydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo-[1,2-a]pyridazin-10-yl)oxy)-L-argininate)

[0914] Tertiary butyl (2S)-2-amino-5-guanidinopentanoate (790 mg, 2.48 mmol, 2HCl) and 4-dimethylaminopyridine (611 mg, 4.95 mmol) were dissolved in dichloromethane (10 mL), and a solution of bis(4-nitrophenyl)carbonate (768 mg, 2.48 mmol) dissolved in 10 mL of dichloromethane was added dropwise to the reaction mixture. The reaction mixture was cooled to -10°C and stirred for 5 hours, and a solution of 2-(4-acetylphenyl)-10-hydroxy-7,7-dimethyl-5,12b-dihydro-1H,7H-chromeno[4,3-c]-[1,2,4]triazolo[1,2-a]pyridazine-1,3(2H)-dione (1.25 g, 2.97 mmol) and 4-dimethylaminopyridine (305 mg, 2.48 mmol) dissolved in dichloromethane (10 ml) was added dropwise to the reaction mixture, stirred at -10°C for 2 hours, warmed to room temperature and stirred for another 72 hours. After completion of the reaction, the reaction mixture was diluted with dichloromethane and washed with 1N aqueous hydrochloric acid solution.The separated organic layer was dried over sodium sulfate, filtered, concentrated by distillation under reduced pressure, and separated by MPLC (dichloromethane:methanol = 9:1, by volume) to give tert-butyl (((2-(4-acetylphenyl)-7,7-dimethyl-1,3-dioxo-2,3,5,12b-tetrahydro-1H,7H-chromeno[4,3-c][1,2,4]-triazolo[1,2-a]pyridazin-10-yl)oxy)carbonyl)-L-argininate (800 mg, 47%).

[0915] (b) Synthesis of (((2-(4-acetylphenyl)-7,7-dimethyl-1,3-dioxo-2,3,5,12b-tetrahydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]-pyridazin-10-yl)oxy)carbonyl)-L-arginine 2,2,2-trifluoroacetic acid

[0916] Tertiary (((2-(4-acetylphenyl)-7,7-dimethyl-1,3-dioxo-2,3,5,12b-tetrahydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazin-10-yl)oxy)carbonyl)-L-argininate (600 mg, 0.89 mmol) obtained in Example 78(a) above was dissolved in dichloromethane (3 ml), and the reaction mixture was cooled to 0°C. Trifluoroacetic acid (2.96 g, 26 mmol) was added dropwise, and stirred at 0°C for 3 hours. After completion of the reaction, the reaction mixture was concentrated by distillation under reduced pressure, and the resulting residue was triturated with diethyl ether to obtain (((2-(4-acetylphenyl)-7,7-dimethyl-1,3-dioxo-2,3,5,12b-tetra-hydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo-[1,2-a]pyridazin-10-yl)oxy)carbonyl)-L-arginine 2,2,2-trifluoroacetic acid (611 mg, 91%).

[0917] 1H NMR (400 MHz, DMSO-D6) δ 8.17-8.09 (m, 3H), 7.84-7.76 (m, 2H), 7.53 (s, 1H), 7.09 (d, J=8.4 Hz, 1H), 6.71 (dt, J=8.5, 2.0 Hz, 1H), 6.62 (t, J=2.0 Hz, 1H), 6.02 (quartet, J=3.2 Hz, 1H), 5.71 (s, 1H), 4.25-4.19 (m, 2H), 3.99 (td, J=8.1, 4.4 Hz, 1H), 3.11 (quartet, J=6.5 Hz, 2H), 2.64 (s, 3H), 1.86-1.72 (m, 1H), 1.72-1.40 (m, 10H).

[0918] Example 79. Synthesis of 1-(2-(4-acetylphenyl)-7,7-dimethyl-1,3-dioxo-2,3,5,12b-tetrahydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo-[1,2-a]pyridazin-10-yl) 2-methyl (2S)-pyrrolidine-1,2-dicarboxylate

[0919] To obtain 1-(2-(4-acetylphenyl)-7,7-dimethyl-1,3-dioxo-2,3,5,12b-tetrahydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]-pyridazin-10-yl) 2-methyl (2S)-pyrrolidine-1,2-dicarboxylate (100 mg, 85%), the same synthesis as the above synthesis in Example 58 was carried out except that 1-(chlorocarbonyl)proline methyl ester was used instead of trimethylacetyl chloride.

[0920] 1H NMR (400 MHz, CDCl3) δ 8.11 (d, J=8.6 Hz, 2H), 7.83 (d, J=8.6 Hz, 2H), 7.04 (d, J=8.4 Hz, 1H), 6.77-6.72 (m, 1H, 6.6.6H), 5.84 (s, 1H), 5.71 (s, 1H), 4.29 (d, J=16.5 Hz, 1H), 4.12 (d, J=16.2 Hz, 1H), 3.73 (s, 3H), 3.70-3.53 (m, 2H), 2.70-3.37 (s, 2.3H), (m, 1H), 2.14-1.89 (m, 4H), 1.59 (d, J=4.4 Hz, 6H).

[0921] Example 80. Synthesis of methyl (((2-(4-acetylphenyl)-7,7-dimethyl-1,3-dioxo-2,3,5,12b-tetrahydro-1H,7H-chromeno[4,3-c][1,2,4]-triazolo[1,2-a]pyridazin-10-yl)oxy-L-leucinate)

[0922] 2-(4-Acetylphenyl)-10-hydroxy-7,7-dimethyl-5,12b-dihydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazine-1,3(2H)-dione (189 mg, 0.45 mmol) obtained in Example 10(b) above and triethylamine (69 mg, 0.68 mmol) were dissolved in tetrahydrofuran (2 ml), and a solution of methyl 2-isocyanato-4-methylpentanoate (100 mg, 0.58 mmol) dissolved in tetrahydrofuran (1 ml) and 4-dimethylaminopyridine (56 mg, 0.45 mmol) were added thereto, and stirred at 100°C for 20 hours. After completion of the reaction, the reaction mixture was diluted with dichloromethane and washed with water and aqueous sodium chloride solution.The separated organic layer was dried over sodium sulfate, filtered, concentrated by distillation under reduced pressure, and subjected to separation by reverse phase chromatography (acetonitrile containing 0.1% formic acid: water containing 0.1% formic acid = 5:95-100:0) to give methyl (((2-(4-acetylphenyl)-7,7-dimethyl-1,3-dioxo-2,3,5,12b-tetrahydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazin-10-yl)oxy)-carbonyl)-L-leucinate (141 mg, 53%).

[0923] 1 H NMR (400 MHz, DMSO-D6) δ 8.24 (d, J=7.9 Hz, 1H), 8.17-8.09 (m, 2H), 7.83-7.76 (m, 2H), 7.09 (d, J=8.4 Hz, 1H), 6.74-6.67 (m, 1H), 6.62 (dd, J=2.4, 1.0 Hz, 1H), 6.04-5.99 (m, 1H), 5.71 (s, 1H), 4.21 (t, J=2.7 Hz, 2H), 4.09 (dq, J=5.0, 2.9 Hz, 1H), 3.65 (s, 3H), 2.64 (s, 3H), 1.66 (dd, J=14.8, 7.1 Hz, 1H), 1.63-1.45 (m, 8H), 0.89 (dd, J=12.4, 6.5 Hz, 6H).

[0924] Example 81. Synthesis of 2-(4-acetylphenyl)-7,7-dimethyl-1,3-dioxo-2,3,5,12b-tetrahydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]-pyridazin-10-yl L-leucinate 2,2,2-trifluoroacetic acid

[0925] (a) Synthesis of 2-(4-acetylphenyl)-7,7-dimethyl-1,3-dioxo-2,3,5,12b-tetrahydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazin-10-yl (tert-butoxycarbonyl)-L-leucinate

[0926] To obtain 2-(4-acetylphenyl)-7,7-dimethyl-1,3-dioxo-2,3,5,12b-tetrahydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazin-10-yl (tert-butoxycarbonyl)-L-leucinate (200 mg, 78%), the same synthesis as the above synthesis in Example 77 was carried out except that (2S)-2-(tert-butoxycarbonylamino)-4-methylpentanoic acid was used instead of (2S)-5-amino-2-(tert-butoxycarbonylamino)-5-oxopentanoic acid.

[0927] (b) Synthesis of 2-(4-acetylphenyl)-7,7-dimethyl-1,3-dioxo-2,3,5,12b-tetrahydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]-pyridazin-10-yl L-leucinate 2,2,2-trifluoroacetic acid

[0928] To obtain 2-(4-acetylphenyl)-7,7-dimethyl-1,3-dioxo-2,3,5,12b-tetrahydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazin-10-yl 2,2,2-trifluoroacetic acid L-leucine (39 mg, 35%), the same synthesis as the above synthesis in Example 77(b) was carried out, except that instead of 2-(4-acetylphenyl)-7,7-dimethyl-1,3-dioxo-2,3,5,12b-tetrahydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazin-10-yl (tert-butoxycarbonyl) -L-glutamate was used 2-(4-acetylphenyl)-7,7-dimethyl-1,3-dioxo-2,3,5,12b-tetrahydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazin-10-yl (tert-butoxycarbonyl)-L-leucinate.

[0929] 1H NMR (400 MHz,) δ 8.64-8.33 (m, 3H), 8.17-8.09 (m, 2H), 7.85-7.74 (m, 2H), 7.19 (ddd, J=8.4, 3.4, 1.1 Hz, 1H, 8.4, J=8.4), J Hz, 1H), 6.77 (dd, J=2.4, 1.3 Hz, 1H), 6.04 (dt, J=5.9, 3.5 Hz, 1H), 5.75 (t, J=2.7 Hz, 1H), 4.27 (s, 1H), 4.25-4.1 (s, 1H), 1.83 (td, J=13.0, 12.0, 6.4 Hz, 2H), 1.74 (quartet, J=7.3, 6.7 Hz, 1H), 1.57 (d, J=28.9 Hz, 6H), 0.96 (dd, J=6.1 Hz, 3.3H).

[0930] Example 82. Synthesis of 2-(4-acetylphenyl)-7,7-dimethyl-1,3-dioxo-2,3,5,12b-tetrahydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a-pyridazine]-10-1 4-(L-prolyl)piperazine-1-carboxylate hydrochloride

[0931] (a) Synthesis of 2-(4-acetylphenyl)-7,7-dimethyl-1,3-dioxo-2,3,5,12b-tetrahydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]-pyridazine-10-yl 4-((tertbutoxycarbonyl)-L-prolyl)piperazine-1-carboxylate

[0932] 2-(4-Acetylphenyl)-7,7-dimethyl-1,3-dioxo-2,3,5,12b-tetra-hydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazin-10-yl piperazine-1-carboxylate hydrochloride (200 mg, 0.35 mmol) obtained in Example 67(b) above, N-(tert-butoxycarbonyl)-L-proline (91 mg, 0.42 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (135 mg, 0.7 mmol) and 4-dimethylaminopyridine (8.6 mg, 0.07 mmol) were dissolved in dichloromethane (4 ml), and the reaction mixture was stirred at room temperature for 3 hours. After completion of the reaction, the reaction mixture was diluted with dichloromethane and washed with water. The separated organic layer was dried over sodium sulfate, filtered, concentrated by distillation under reduced pressure, and separated by MPLC (ethyl acetate:hexane = 1:1, by volume) to give 2-(4-acetylphenyl)-7,7-dimethyl-1,3-dioxo-2,3,5,12b-tetrahydro-1H,7H-chromeno[4,3-c]-[1,2,4]triazolo[1,2-a]pyridazin-10-yl 4-((tertbutoxycarbonyl)-L-prolyl)piperazine-1-carboxylate (160 mg, 62%).

[0933] (b) Synthesis of 2-(4-acetylphenyl)-7,7-dimethyl-1,3-dioxo-2,3,5,12b-tetrahydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]-pyridazin-10-yl 4-(L-prolyl)piperazine-1-carboxylate hydrochloride

[0934] To obtain 2-(4-acetylphenyl)-7,7-dimethyl-1,3-dioxo-2,3,5,12b-tetrahydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazin-10-yl 4-(L-prolyl)piperazine-1-carboxylate hydrochloride (50 mg, 78%), the same synthesis as the above synthesis in Example 67(b) was carried out, except that instead of 1-(2-(4-acetylphenyl)-7,7-dimethyl-1,3-dioxo-2,3,5,12b-tetrahydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazin-10-yl) 4-(tert-butyl)piperazine-1,4-dicarboxylate was used 2-(4-acetylphenyl)-7,7-dimethyl-1,3-dioxo-2,3,5,12b-tetrahydro-1H,7H-chromeno[4,3-c]-[1,2,4]triazolo[1,2-a]pyridazin-10-yl 4-((tert-butoxycarbonyl)-L-prolyl)piperazine-1-carboxylate.

[0935] 1H NMR (400 MHz, D2O) δ 7.86 (d, J=8.2 Hz, 2H), 7.51(d, J=8.2 Hz, 2H), 7.01 (d, J=8.4 Hz, 1H), 6.73-6.60(m, 2Hz, 87Hz), 5.58 (s), (s 1H), 4.73 (s, 1H), 4.03 (quartet, J=16.4 Hz, 2H), 3.58 (d, J=20.7 Hz, 8H), 3.49-3.38 (m, 3H), 2.58 (s, 3H), 2.49 (s, 1H), (d, 2.0, J=0.0, J 13.5,6.9 Hz, 4H), 1.50 (e, J=6.b Hz, 7H).

[0936] Example 83. Synthesis of 2-(4-acetylphenyl)-7,7-dimethyl-1,3-dioxo-2,3,5,12b-tetrahydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a-pyridazine]-10-1 methyl(2-(methylamino)ethyl)carbamate of 2,2,2-trifluoroacetic acid

[0937] (a) Synthesis of 2-(4-acetylphenyl)-7,7-dimethyl-1,3-dioxo-2,3,5,12b-tetrahydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]-pyridazine tert-butyl-1 ethane-1,2-diylbis(methylcarbamate)

[0938] Trifosgene (611 mg, 2.02 mmol) was dissolved in dichloromethane (20 mL) and cooled to 0 °C. Tert-butyl N-methyl-N-[2-(methylamino)ethyl]carbamate (400 mg, 2.02 mmol) was added dropwise, and then triethylamine (619 mg, 6.06 mmol) was added dropwise. The reaction mixture was stirred at 0 °C for 5 min, warmed to room temperature, and stirred for 1 hour. After adding water, the layers were separated to obtain an organic layer. The separated organic layer was dried over sodium sulfate, filtered, and concentrated by distillation under reduced pressure. The resulting residue was dissolved in dichloromethane (10 ml), and triethylamine (1.86 g, 18.17 mmol) and a solution of 2-(4-acetylphenyl)-10-hydroxy-7,7-dimethyl-5,12b-dihydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazine-1,3(2H)-dione (847 mg, 2.02 mmol) dissolved in dichloromethane (10 ml) were added dropwise to the reaction mixture, which was stirred at room temperature for 30 minutes.After completion of the reaction, the reaction mixture was diluted with dichloromethane and washed with water. The separated organic layer was dried over sodium sulfate, filtered, and concentrated by distillation under reduced pressure. The resulting residue was subjected to MPLC separation (ethyl acetate:hexane = 1:9, by volume) to give 2-(4-acetylphenyl)-7,7-dimethyl-1,3-dioxo-2,3,5,12b-tetrahydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo-[1,2-a]pyridazin-10-yl tert-butyl ethane-1,2-diylbis(methylcarbamate) (1.01 g, 79%).

[0939] (b) Synthesis of 2-(4-acetylphenyl)-7,7-dimethyl-1,3-dioxo-2,3,5,12b-tetrahydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]-pyridazin-10-yl methyl(2-(methylamino)ethyl)carbamate 2,2,2-trifluoroacetic acid

[0940] To obtain 2-(4-acetylphenyl)-7,7-dimethyl-1,3-dioxo-2,3,5,12b-tetrahydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazin-10-yl methyl (2-(methylamino)ethyl)carbamate 2,2,2-trifluoroacetic acid (230 mg, 42%), the same synthesis as the above synthesis in Example 77(b) was carried out, except that instead of 2-(4-acetylphenyl)-7,7-dimethyl-1,3-dioxo-2,3,5,12b-tetrahydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazin-10-yl (tert-butoxycarbonyl)-L-glutaminate was used 2-(4-acetylphenyl)-7,7-dimethyl-1,3-dioxo-2,3,5,12b-tetrahydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazin-10-yl tert-butyl ethane-1,2-diylbis(methylcarbamate).

[0941] 1H NMR (400 MHz, DMSO-D6) δ 8.54 (d, J=34.8 Hz, 1H), 8.18-8.10 (m, 2H), 7.84-7.76 (m, 2H), 7.09 (dd, J=9.0, 1.1 Hz, 1.6 Hz, 7.6.6 m 2H), 6.02 (td, J=3.7, 1.8 Hz, 1H), 5.71 (quartet, J=1.9 Hz, 1H), 4.22 (dd, J=4.1, 2.0 Hz, 2H), 3.71-3.60 (m, 1H), 3.5-3.50, (1H), 3.21-3.11 (m, 2H), 2.96 (d, J=42.0 Hz, 3H), 2.64 (s, 3H), 2.63-2.56 (m, 3H), 1.59 (s, 3H), 1.52 (s, 3H).

[0942] Example 84. Synthesis of 2-(4-acetylphenyl)-7,7-dimethyl-1,3-dioxo-2,3,5,12b-tetrahydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a-pyridazine]-10-1 (2-aminoethyl)(ethyl)carbamate hydrochloride

[0943] (a) Synthesis of 2-(4-acetylphenyl)-7,7-dimethyl-1,3-dioxo-2,3,5,12b-tetrahydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]-pyridazine-10-yl (2-((tertbutoxycarbonyl)amino)ethyl)(ethyl)-carbamate

[0944] To prepare 2-(4-acetylphenyl)-7,7-dimethyl-1,3-dioxo-2,3,5,12b-tetrahydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-azin-10-pyridyl (2-((tertbutoxycarbonyl)amino)ethyl)(ethyl)- The same synthesis as the above synthesis in Example 58 was carried out to obtain

[0945] carbamate in quantitative yield, except that tert-butyl N-[2-[chlorocarbonyl(ethyl)amino]ethyl]carbamate was used instead of trimethylacetyl chloride. The obtained compound was used in the next reaction without purification.

[0946] (b) Synthesis of 2-(4-acetylphenyl)-7,7-dimethyl-1,3-dioxo-2,3,5,12b-tetrahydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazin-10-yl (2-aminoethyl)(ethyl)carbamate hydrochloride

[0947] To obtain 2-(4-acetylphenyl)-7,7-dimethyl-1,3-dioxo-2,3,5,12b-tetrahydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazin-10-yl (2-aminoethyl)(ethyl)carbamate hydrochloride (80 mg, 54%), the same synthesis as the above synthesis in Example 67(b) was carried out, except that instead of 1-(2-(4-acetylphenyl)-7,7-dimethyl-1,3-dioxo-2,3,5,12b-tetrahydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazin-10-yl) 4-(tert-butyl)piperazine-1,4-dicarboxylate was used 2-(4-acetylphenyl)-7,7-dimethyl-1,3-dioxo-2,3,5,12b-tetrahydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazin-10-yl (2-((tert-butoxycarbonyl)amino)ethyl)(ethyl)carbamate.

[0948] 1H NMR (500 MHz, D2O) δ 8.09 (dd, J=13.4, 8.3 Hz, 2H), 7.71-7.61 (m, 2H), 7.11 (dd, J=16.6, 8.5 Hz, 1H), 6.87-6.75, (6.6H), (s 5.76 (s, 1H), 4.26 (s, 2H), 3.80 (s, 1H), 3.66 (s, 1H), 3.51 (d, J=7.3 Hz, 1H), 3.39 (d, J=7.2 Hz, 1H), 3.28 (dt, J=7.2 Hz, 1H), 2.69 (d, J=2.7 Hz, 3H), 1.62 (d, J=2.3 Hz, 3H), 1.57 (s, 3H), 1.22 (dt, J=37.3, 7.1 Hz, 3H).

[0949] Example 85. Synthesis of 2-(4-acetylphenyl)-7,7-dimethyl-1,3-dioxo-2,3,5,12b-tetrahydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a-pyridazine]-10-1 methyl(pyrrolidin-3-yl)carbamate hydrochloride

[0950] (a) Synthesis of tertbutyl 3-((((2-(4-acetylphenyl)-7,7-dimethyl-1,3-dioxo-2,3,5,12b-tetrahydro-1H,7H-chromeno[4,3-c][1 ,2,4]-triazolo[1,2-a]pyridazin-10-yl)oxy)carbonyl)(methyl)amino)-pyrrolidine-1-carboxylate

[0951] To obtain tert-butyl 3-((((2-(4-acetylphenyl)-7,7-dimethyl-1,3-dioxo-2,3,5,12b-tetra-hydro-1H,7H-chromeno[4,3-c][1,2,4]-triazolo[1,2-a]pyridazin-10-yl)oxy)carbonyl)(methyl)amino)pyrrolidine-1-carboxylate (220 mg, 86%), the same synthesis as the above synthesis in Example 58 was carried out except that N-methyl-N-pyrrolidin-3-ylcarbamoyl chloride was used instead of trimethylacetyl chloride.

[0952] (b) Synthesis of 2-(4-acetylphenyl)-7,7-dimethyl-1,3-dioxo-2,3,5,12b-tetrahydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]-pyridazin-10-yl methyl(pyrrolidin-3-yl)carbamate hydrochloride

[0953] To obtain 2-(4-acetylphenyl)-7,7-dimethyl-1,3-dioxo-2,3,5,12b-tetrahydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazin-10-yl methyl (pyrrolidin-3-yl)carbamate hydrochloride (80 mg, 54%), the same synthesis as the above synthesis in Example 67(b) was carried out, except that instead of 1-(2-(4-acetylphenyl)-7,7-dimethyl-1,3-dioxo-2,3,5,12b-tetrahydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazin-10-yl) 4-(tert-butyl) piperazine-1,4-dicarboxylate was used 3-((((2-(4-acetyl-phenyl)-7,7-dimethyl-1,3-dioxo-2,3,5,12b-tetrahydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazin-10-yl)oxy)-carbonyl)(methyl)amino)pyrrolidine-1-carboxylate.

[0954] 1H NMR (500 MHz, D2O) δ 7, 94 (d, J=8.6 Hz, 2H), 7.56 (d, J=8.5 Hz, 2H), 7.03 (d, J=8.4 Hz, 1H), 6.74 (s, 1H), 6.69 (s, 1H), 5.64 (s, 1H), 4, 67-4, 57 (m, 1H), 4.16-4.10 (m, 2H), 3, 60-3.50 (m, 2H), 3.43 (s, 1H), 3.32 (d, J=21.5 Hz, 1, 1H), 3.32 (d, J=21.5 Hz, 3, 20H), (s, 1H), 2.62 (s, 3H), 2.38 (dtd, J=12.8, 7.9, 4.5 Hz, 1H), 2.22 (s, 1H), 1.54 (d, J=4.l Hz, 6H).

[0955] Example 86. Synthesis of 2-(4-acetylphenyl)-7,7-dimethyl-1,3-dioxo-2,3,5,12b-tetrahydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a-pyridazine]-10-1 bis(3-(dimethylamino)propyl)carbamate dihydro-chloride

[0956] Trifosgene (772 mg, 2.6 mmol) was dissolved in dichloromethane (15 mL) and cooled to 0°C. Pyridine (3.1 g, 39 mmol) was added dropwise to the reaction mixture, which was stirred at 0°C for 15 minutes. While maintaining the reaction temperature at 0°C, N-[3-(dimethylamino)propyl]-N',N'-dimethyl-propane-1,3-diamine (974 mg, 5.2 mmol) was added dropwise, warmed to room temperature, and stirred for 6 hours. To the reaction mixture was added 4-dimethylaminopyridine (974 mg, 5.2 mmol), and a solution of 2-(4-acetylphenyl)-10-hydroxy-7,7-dimethyl-5,12b-dihydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazine-1,3(2H)-dione (545 mg, 1.3 mmol) dissolved in dichloromethane (10 ml) was added dropwise, and stirred at room temperature for 15 hours. After completion of the reaction, the reaction mixture was diluted with dichloromethane and washed with water.The separated organic layer was dried over sodium sulfate, filtered, concentrated by distillation under reduced pressure, subjected to column chromatography (dichloromethane:methanol=9:1, by volume), and concentrated under reduced pressure. The resulting residue was purified with ethyl acetate (0.5 ml), and the solid was precipitated by adding 4 M hydrochloric acid solution (1 ml, 4 M / diethyl ether). The precipitated solid was filtered to obtain 2-(4-acetylphenyl)-7,7-dimethyl-1,3-dioxo-2,3,5,12b-tetrahydro-1H,7H-chromeno[4,3-c]-[1,2,4]triazolo[1,2-a]pyridazin-10-yl bis(3-(dimethylamino)propyl)carbamate dihydrochloride (88 mg, 9.6%).

[0957] 1H NMR (400 MHz, DMSO-D6) δ 10.33 (d, J=40.8 Hz, 2H), 8.25-8.03 (m, 2H), 7, 93-7, 72 (m, 2H),7.10 (dd, J=8.4, 1.1 Hz, 6.8 Hz, 6.6 Hz). 2H), 6.04 (td, J=3.8, 1.8 Hz, 1H), 5.72 (d, J=2.5 Hz,1H), 4.23 (t, J=2.8 Hz, 2H), 3.35 (d, J=6.8 Hz, 4H), 3.15-3.00 (m, J=6.8 Hz, 4H), (m J=4.0 Hz, 12H),2.65 (s, 3H), 2.07-1.92 (m, 4H), 1.57 (d, J=24.2 Hz, 6H)

[0958] Example 87. Synthesis N-(((2-(4-acetylphenyl)-7,7-dimethyl-1,3-dioxo-2,3,5,12b-tetrahydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo-[1,2-a]pyridazin-10-yl)oxy)-L-carinamethyl-L)

[0959] (a) Synthesis of tertbutyl N-(((2-(4-acetylphenyl)-7,7-dimethyl-1,3-dioxo-2,3,5,12b-tetrahydro-1H,7H-chromeno[4,3-c][1,2,4]-triazolo[1,2-a]pyridazin-10-yl)oxy)-L-carinamethyl-)-L-alanethane

[0960] To obtain tert-butyl N-(((2-(4-acetylphenyl)-7,7-dimethyl-1,3-dioxo-2,3,5,12b-tetrahydro-1H,7H-chromeno[4,3-c][1,2,4]-triazolo[1,2-a]pyridazin-10-yl)oxy)carbonyl)-N-methyl-L-alaninate (120 mg, 40%), the same synthesis as the above synthesis in Example 83(a) was carried out except that tert-butyl (2S)-2-(methylamino)propanoate was used instead of tert-butyl N-methyl-N-[2-(methylamino)ethyl]carbamate.

[0961] (b) Synthesis N-(((2-(4-acetylphenyl)-7,7-dimethyl-1,3-dioxo-2,3,5,12b-tetrahydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazin-10-yl)oxy)carbonyl)-N-methyl-L-alanine

[0962] To obtain N-(((2-(4-acetylphenyl)-7,7-dimethyl-1,3-dioxo-2,3,5,12b-tetrahydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]-pyridazin-10-yl)oxy)carbonyl)-N-methyl-L-alanine (600 mg, 52%), the same synthesis as the above synthesis in Example 78(b) was carried out, except that tert-butyl (((2-(4-acetylphenyl)-7,7-dimethyl-1,3-dioxo-2,3,5,12b-tetrahydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazin-10-yl)oxy)-carbonyl)-L-argininate was used tert-butyl N-(((2-(4-acetylphenyl)-7,7-dimethyl-1,3-dioxo-2,3,5,12b-tetrahydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazin-10-yl)oxy)-carbonyl)-N-methyl-L-alaninate.

[0963] 1H NMR (500 MHz, DMSO-D6) δ 9.48 (s, 1H), 8.16-8.09 (m, 2H), 7.82-7.72 (m, 2H), 6.87 (dd, J=8.4, 1.1 Hz, 1H), 6.37 (dd, J=8.4, 2.4 Hz, 1H), 6.25 (d, J=2.4 Hz, 1H), 5.98-5.92 (m, 1H), 5.63-5.58 (m, 1H), 4.39 (quartet, J=7.1 Hz, 1H), 4.25-4.12 (m, 2H), 2.84 (s, 3H), 2.63 (s, 3H), 1.54 (s, 3H), 1.51 (s, 3H), 1.38 (d, J=7.1 Hz, 3H)

[0964] Example 88. Synthesis of sodium N-(((2-(4-acetylphenyl)-7,7-dimethyl-1,3-dioxo-2,3,5,12b-tetrahydro-1H,7H-chromeno[4,3-c]-[1,2,4]triazolo[1,2-a]pyridazin-10-yl)oxy)carbonyl)-N-methyl-L-alaninate

[0965] N-(((2-(4-acetylphenyl)-7,7-dimethyl-1,3-dioxo-2,3,5,12b-tetrahydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazin-10-yl)oxy)carbonyl)-N-methyl-L-alanine (530 mg, 0.97 mmol) obtained in Example 87(b) above was suspended in water (20 ml), and sodium bicarbonate (82 mg, 0.98 mmol) was added thereto, and stirred at room temperature for 3 hours. After completion of the reaction, the reaction mixture was diluted with water and washed with ethyl acetate. The separated aqueous layer was lyophilized to obtain sodium N-(((2-(4-acetylphenyl)-7,7-dimethyl-1,3-dioxo-2,3,5,12b-tetrahydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo-[1,2-a]pyridazin-10-yl)oxy)carbonyl)-N-methyl-L-alaninate (510 mg, 88%).

[0966] 1H NMR (500 MHz, D2O) δ 8.06 (d, J=8.3 Hz, 2H), 7.65 (d, J=8.3 Hz, 2H), 7.09 (t, J=9.4 Hz, 1H), 6.88-6.71 (m, 2Hz, 9.7Hz), (5, 72H), (s 1H), 4.28-4.15 (m, 2H), 3.45 (quartet, J=6.9 Hz, 1H), 2.99 (d, J=43.2 Hz, 3H), 2.67 (s, 3H), 2.58 (s, 2H), 1.61 (s, 3H), (s, 1.47), (s, 3H (d, J=7.0 Hz, 3H).

[0967] Example 89. Synthesis N-(((2-(4-acetylphenyl)-7,7-dimethyl-1,3-dioxo-2,3,5,12b-tetrahydro-1H,7H-chromeno[4,3-c][1,2,4]-triazolo[1,2-a]pyridazin-10-yl)oxy)-N-glycine-methyl-glycine

[0968] (a) Synthesis N-(((2-(4-acetylphenyl)-7,7-dimethyl-1,3-dioxo-2,3,5,12b-tetrahydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]-pyridazin-10-yl)oxy)-Nata-methyl-lycin

[0969] To obtain N-(((2-(4-acetylphenyl)-7,7-dimethyl-1,3-dioxo-2,3,5,12b-tetrahydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazin-10-yl)oxy)carbonyl)-N-methylglycinate (620 mg, 42%), the same synthesis as the above synthesis in Example 83(a) was carried out except that tert-butyl 2-(methylamino)acetate was used instead of tert-butyl N-methyl-N-[2-(methylamino)ethyl]carbamate.

[0970] (b) Synthesis N-(((2-(4-acetylphenyl)-7,7-dimethyl-1,3-dioxo-2,3,5,12b-tetrahydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]-pyridazin-10-yl)oxy)carbonyl)-N-methylglycine

[0971] To obtain N-(((2-(4-acetylphenyl)-7,7-dimethyl-1,3-dioxo-2,3,5,12b-tetrahydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazin-10-yl)oxy)carbonyl)-N-methylglycine (220 mg, 58%), the same synthesis as the above synthesis in Example 78(b) was carried out, except that tert-butyl (((2-(4-acetylphenyl)-7,7-dimethyl-1,3-dioxo-2,3,5,12b-tetrahydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo-[1,2-a]pyridazin-10-yl)oxy)carbonyl)-L-argininate was used N-(((2-(4-acetylphenyl)-7,7-dimethyl-1,3-dioxo-2,3,5,12b-tetrahydro-1H,7H-chromeno[4,3-c]-[1,2,4]triazolo[1,2-a]pyridazin-10-yl)oxy)carbonyl)-N-methyl-glycinate.

[0972] 1 H NMR (400 MHz, DMSO-D6) δ 12.83 (s, 1H), 8.13 (d, J=8.6 Hz, 2H), 7.84-7.77 (m, 2H), 7.13-7.05 (m, 1H), 6.78-6.66 (m, 1H), 6. 66-6, 54 (m, 1H), 6.01 (dt, J=3.8, 2.4 Hz, 1H), 5.71 (s, 1H), 4.21 (t, J=2.5 Hz, 2H), 4.10 (s, 1H), 3.98 (s, 1H), 3.05-2, 89 (amide tautomer, m, 3H), 2.64 (s, 3H), 1.59 (d, J=1.8 Hz, 3H), 1.53 (s, 3H)

[0973] Example 90. Synthesis of sodium N-(((2-(4-acetylphenyl)-7,7-dimethyl-1,3-dioxo-2,3,5,12b-tetrahydro-1H,7H-chromeno[4,3-c]-[1,2,4]triazolo[1,2-a]pyridazin-10-yl)oxy)carbonyl)-N-methyl-glycinate

[0974] N-(((2-(4-acetylphenyl)-7,7-dimethyl-1,3-dioxo-2,3,5,12b-tetrahydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazin-10-yl)oxy)carbonyl)-N-methylglycine (155 mg, 0.29 mmol) obtained in Example 89(b) above was suspended in water (4 ml), and sodium bicarbonate (25 mg, 0.29 mmol) was added thereto, and stirred at room temperature for 3 hours. After completion of the reaction, the reaction mixture was diluted with water and washed with ethyl acetate. The separated aqueous layer was lyophilized to obtain sodium N-(((2-(4-acetylphenyl)-7,7-dimethyl-1,3-dioxo-2,3,5,12b-tetra-hydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazin-10-yl)oxy)carbonyl)-N-methylglycinate (139 mg, 83%).

[0975] 1H NMR (500 MHz, D2O) δ 7, 95-7, 88 (m, 2H), 7, 58-7, 52 (m, 2H), 7.00 (ddd, J=23.8, 8.4, 1.1 Hz, 1H), 6, 83-6, 73, 6, 6, 73 H 66 (m, 1H), 5.91-5.87 (m, 1H), 5.64-5, 58 (m, 1H), 4.15-4.06 (m, 2H), 4.00 (s, 1H), 3.87 (d, J=2.7 Hz, 1H, 1H), 3.87 (d, J=2.7 Hz, 1H, 0.05), d, J=2.3 Hz, 2.61 (s, 3H), 1.57-1.50 (m, 6H).

[0976] Example 91. Synthesis 3-((((2-(4-acetylphenyl)-7,7-dimethyl-1,3-dioxo-2,3,5,12b-tetrahydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo-[1,2-a]pyridazin-10-yl)oxy)carbonyl)promethino)

[0977] (a) Synthesis of tertbutyl 3-((((2-(4-acetylphenyl)-7,7-dimethyl-1,3-dioxo-2,3,5,12b-tetrahydro-1H,7H-chromeno[4,3-c][1,2,4]-triazolo[1,2-a]pyridazin-10-yl)oxy)ylcarbonanol()-methyl amino)

[0978] To obtain tert-butyl 3-((((2-(4-acetylphenyl)-7,7-dimethyl-1,3-dioxo-2,3,5,12b-tetrahydro-1H,7H-chromeno[4,3-c][1,2,4]-triazolo[1,2-a]pyridazin-10-yl)oxy)carbonyl)(methyl)amino)propanoate (230 mg, 38%), the same synthesis as the above synthesis in Example 83(a) was carried out, except that tert-butyl 3-(methylamino)propanoate was used instead of tert-butyl N-methyl-N-[2-(methylamino)ethyl]carbamate.

[0979] (b) Synthesis 3-((((2-(4-acetylphenyl)-7,7-dimethyl-1,3-dioxo-2,3,5,12b-tetrahydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]-pyridazin-10-yl)oxy)carbonyl)(methyl)amino)propanoic acid

[0980] To obtain 3-((((2-(4-acetylphenyl)-7,7-dimethyl-1,3-dioxo-2,3,5,12b-tetrahydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo-[1,2-a]pyridazin-10-yl)oxy)carbonyl)(methyl)amino)propanoic acid (90 mg, 50%), the same synthesis as the above synthesis in Example 78(b) was carried out, except that tert-butyl (((2-(4-acetylphenyl)-7,7-dimethyl-1,3-dioxo-2,3,5,12b-tetrahydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazin-10-yl)oxy)carbonyl)-L-argininate was used tert-butyl 3-((((2-(4-acetylphenyl)-7,7-dimethyl-1,3-dioxo-2,3,5,12b-tetra-hydro-1H,7H-chromeno[4,3-c]-[1,2,4]triazolo[1,2-a]pyridazin-10-yl)oxy)carbonyl)(methyl)amino)propanoate.

[0981] 1H NMR (400 MHz, DMSO-D6) δ 12.28 (s, 1H), 8.13 (d, J=8.6 Hz, 2H), 7.84-7.77 (m, 2H), 7.08 (d, J=8.4 Hz, 1H), 6.72 (dd, J=8.4, 2.3 Hz, 1H), 6.67 (d, J=2.7 Hz, 1H), 6.01 (s, 1H), 5.71 (s, 1H), 4.24-4.19 (m, 2H), 3.59 (t, J=7.2 Hz, 1H), 3.47 (t, J=7.3 Hz, 1H), 3.02-2.87 (amide tautomer, m, 3H), 2.64 (s, 3H), 1.59 (s, 3H), 1.53 (s, 3H)

[0982] Example 92. Sodium synthesis 3-((((2-(4-acetylphenyl)-7,7-dimethyl-1,3-dioxo-2,3,5,12b-tetrahydro-1H,7H-chromeno[4,3-c]-[1,2,4]triazolo[1,2-a]pyridazin-10-yl)oxy)carbonyl)(methyl)-amino)propanoate

[0983] To obtain sodium 3-((((2-(4-acetylphenyl)-7,7-dimethyl-1,3-dioxo-2,3,5,12b-tetrahydro-1H,7H-chromeno[4,3-c][1,2,4]-triazolo[1,2-a]pyridazin-10-yl)oxy)carbonyl)(methyl)amino)propanoate (92 mg, 87%), the same synthesis as the above synthesis in Example 90 was carried out, except that instead of N-(((2-(4-acetylphenyl)-7,7-dimethyl-1,3-dioxo-2,3,5,12b-tetrahydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazin-10-yl)oxy)carbonyl)-N-methylglycine was used 3-((((2-(4-acetylphenyl)-7,7-dimethyl-1,3-dioxo-2,3,5,12b-tetrahydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazin-10-yl)oxy)-carbonyl)(methyl)amino)propanoic acid.

[0984] 1H NMR (500 MHz, D2O) δ 7.98 (dd, J=8.5, 4.1 Hz, 2H), 7.59 (dd, J=8.4f 4.5 Hz, 2H), 7.04 (d, J=8.3 Hz, 1H), 6, 78-6, 69, m, (s, 2H), (s 1H), 5.66 (s, 1H), 4.19-4.12 (m, 2H), 3.70 (t, J=7.2 Hz, 1H), 3.55 (t, J=7.3 Hz, 1H), 3.03 (d, J=59.9 Hz, 3H), J=7.l Hz, 1H), 2.45 (t, J=7.3 Hz, 1H), 1.58-1.53 ​​(m, 6H).

[0985] Example 93. Synthesis of 2-(4-acetylphenyl)-7,7-dimethyl-1,3-dioxo-2,3,5,12b-tetrahydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a-pyridazine]-10-1 4-(aminomethyl)piperidine-1-carboxylate trifluoro-acetate

[0986] (a) Synthesis of 2-(4-acetylphenyl)-7,7-dimethyl-1,3-dioxo-2,3,5,12b-tetrahydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]-pyridazine-10-yl 4-(((tertbutoxycarbonyl)amino)methyl)piperidine-1-carboxylate

[0987] To obtain 2-(4-acetylphenyl)-7,7-dimethyl-1,3-dioxo-2,3,5,12b-tetrahydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazin-10-yl 4-(((tert-butoxycarbonyl)amino)methyl)piperidine-1-carboxylate (250 mg, 50%), the same synthesis as the above synthesis in Example 83(a) was carried out except that tert-butyl N-methyl-N-[2-(methylamino)ethyl]carbamate was used instead of tert-butyl N-(4-piperidylmethyl)carbamate.

[0988] (b) Synthesis of 2-(4-acetylphenyl)-7,7-dimethyl-1,3-dioxo-2,3,5,12b-tetrahydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]-pyridazin-10-yl 4-(Aminomethyl)piperidine-1-carboxylate trifluoroacetate

[0989] To obtain 2-(4-acetylphenyl)-7,7-dimethyl-1,3-dioxo-2,3,5,12b-tetrahydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo-[1,2-a]pyridazin-10-yl 4-(aminomethyl)piperidine-1-carboxylate trifluoroacetate (50 mg, 31%), the same synthesis as the above synthesis in Example 77(b) was carried out, except that instead of 2-(4-acetylphenyl)-7,7-dimethyl-1,3-dioxo-2,3,5,12b-tetrahydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazin-10-yl (tert-butoxycarbonyl)-L-glutaminate was used 2-(4-acetylphenyl)-7,7-dimethyl-1,3-dioxo-2,3,5,12b-tetrahydro-1H, 7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazin-10-yl 4-(((tert-butoxycarbonyl)amino)methyl)piperidine-1-carboxylate.

[0990] 1H NMR (400 MHz, DMSO-D6) δ 8.17-8.10 (m, 2H), 7.86-7.76 (m, 4H), 7.08 (dt, J=8.4, 1.2 Hz, 1H), 6.73 (dd, J=8.5, 2.3 Hz, 1H), 6.67 (d, J=2.3 Hz, 1H), 6.02 (quartet, J=3.2 Hz, 1H), 5.73-5.68 (m, 1H), 4.22 (dd, J=4.0, 2.0 Hz, 2H), 4.13-3.95 (m, 2H), 2.94-2.81 (m, 1H), 2.80-2.71 (m, 2H), 2.64 (s, 3H), 1.88-1.76 (m, 2H), 1.74-1.67 (m, 1H), 1.59 (s, 3H), 1.52 (s, 3H), 1.47-1.37 (m, 1H), 1.25-1.19 (m, 1H).

[0991] Example 94. Synthesis of 2-(4-acetylphenyl)-7,7-dimethyl-1,3-dioxo-2,3,5,12b-tetrahydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]-pyridazin-10-yl 4-(piperidin-4-yl)piperazine-1-carboxylate dihydrochloride

[0992] (a) Synthesis of 2-(4-acetylphenyl)-7,7-dimethyl-1,3-dioxo-2,3,5,12b-tetrahydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]-pyridazin-10-yl 4-(1-(tert-butoxycarbonyl)piperidin-4-yl)-piperazine-1-carboxylate

[0993] To obtain 2-(4-acetylphenyl)-7,7-dimethyl-1,3-dioxo-2,3,5,12b-tetrahydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]-pyridazin-10-yl 4-(1-(tertbutoxycarbonyl)-piperidin-4-yl)-piperazine-1-carboxylate (200 mg, 40%), the same synthesis as the above synthesis in Example 29 was carried out, except that instead of 2-(4-acetylphenyl)-10-amino-7,7-dimethyl-5,12b-dihydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazine-1,3(2H)-dione and 2-methoxyprop-1-ene were used, respectively, 2-(4-acetylphenyl)-7,7-dimethyl-1,3-dioxo-2,3,5,12b-tetra-hydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazin-10-yl piperazine-1-carboxylate hydrochloride and tert-butyl 4-oxopiperidine-1-carboxylate.

[0994] (b) Synthesis of 2-(4-acetylphenyl)-7,7-dimethyl-1,3-dioxo-2,3,5,12b-tetrahydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]-pyridazin-10-yl 4-(piperidin-4-yl)piperazine-1-carboxylate dihydrochloride

[0995] To obtain 2-(4-acetylphenyl)-7,7-dimethyl-1,3-dioxo-2,3,5,12b-tetrahydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]-pyridazin-10-yl 4-(piperidin-4-yl)piperazine-1-carboxylate dihydrochloride (200 mg, 89%), the same synthesis as the above synthesis in Example 67(b) was carried out, except that instead of 1-(2-(4-acetylphenyl)-7,7-dimethyl-1,3-dioxo-2,3,5,12b-tetrahydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]-pyridazin-10-yl) 4-(tert-butyl)piperazine-1,4-dicarboxylate was used 2-(4-acetylphenyl)-7,7-dimethyl-1,3-dioxo-2,3,5,12b-tetrahydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazin-10-yl 4-(1-(tert-butoxycarbonyl)piperidin-4-yl)piperazine-1-carboxylate.

[0996] 1H NMR (400 MHz, DMSO-D6) δ 11.70 (s, 1H), 9.07 (s, 1H), 8.85 (s, 1H), 8.18-8.09 (m, 2H), 7.87-7.72 (m, 2H), 7.10 (d, J=8.2 Hz, 1H), 6.83-6.66 (m, 2H), 6.02 (quartet, J=3.l Hz, 1H), 5.71 (s, 1H), 4.27-4.10 (m, 3H), 3.69-3.42 (m, 7H), 3.22-3.11 (m, 2H), 2.95-2.85 (m, 2H), 2.64 (s, 3H), 2.34-2.23 (m, 2H), 2.04-1.85 (m, 2H), 1.60 (s, 3H), 1.53 (s, 3H).

[0997] Example 95. Synthesis of 2-(4-acetylphenyl)-7,7-dimethyl-1,3-dioxo-2,3,5,12b-tetrahydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]-pyridazin-10-yl 4-(pyridin-2-ylmethyl)piperazine-1-carboxylate dihydrochloride

[0998] 2-(4-Acetylphenyl)-7,7-dimethyl-1,3-dioxo-2,3,5,12b-tetra-hydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazin-10-yl piperazine-1-carboxylate hydrochloride (200 mg, 0.35 mmol) obtained in Example 67(b) above was dissolved in tetrahydrofuran, and sodium hydride (25 mg, 1.06 mmol, 60%) was added thereto, and stirred at room temperature for 30 minutes. 2-(Chloromethyl)pyridine (87 mg, 0.53 mmol, HCl) was added thereto, and stirred at room temperature for 12 hours. After completion of the reaction, the reaction mixture was quenched by adding water (5 ml) and extracted with dichloromethane. The separated organic layer was washed with aqueous sodium chloride solution, dried over sodium sulfate, filtered, and concentrated by distillation under reduced pressure. The resulting residue was subjected to MPLC separation (ethyl acetate:hexane = 3:7, by volume) and concentrated by distillation under reduced pressure.The resulting residue was dissolved in ethyl acetate, and 4M hydrochloric acid (1 ml, 4M / dioxane) was added and stirred for 1 hour. The resulting residue was filtered and washed with ethyl acetate to give 2-(4-acetylphenyl)-7,7-dimethyl-1,3-dioxo-2,3,5,12b-tetrahydro-1H,7H-chromeno[4,3-c]-[1,2,4]triazolo-[1,2-a]pyridazin-10-yl 4-(pyridin-2-ylmethyl)piperazine-1-carboxylate dihydrochloride (115 mg, 47%).

[0999] 1 H NMR (400 MHz, DMSO-D6) δ 8.72-8.68 (m, 1H), 8.16-8.11 (m, 2H), 7.96 (td, J=7.7, 1.9 Hz, 1H), 7.82-7.77 (m, 2H), 7.62 (d, J=7.7 Hz, 1H), 7.51 (dd, J=7.7, 5.0 Hz, 1H), 7.10 (d, J=8.4 Hz, 1H), 6.79-6.69 (m, 2H), 6.02 (quartet, J=2.5, 1.8 Hz, 1H), 5.71 (d, J=2.4 Hz, 1H), 4.52 (s, 2H), 4.21 (d, J=3.3 Hz, 2H), 3.80 (d, J=56.2 Hz, 8H), 2.64 (s, 3H), 1.59 (s, 3H), 1.52 (s, 3H).

[1000] Example 96. Synthesis of 2-(4-acetylphenyl)-7,7-dimethyl-1,3-dioxo-2,3,5,12b-tetrahydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]-pyridazin-10-yl 4-(2-(2-(2-methoxyethoxy)ethoxy)acetyl)-piperazine-1-carboxylate.

[1001] To obtain 2-(4-acetylphenyl)-7,7-dimethyl-1,3-dioxo-2,3,5,12b-tetrahydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazin-10-yl 4-(2-(2-(2-methoxyethoxy)ethoxy)acetyl)piperazine-1-carboxylate (200 mg, 78%), the same synthesis as the above synthesis in Example 77(a) was carried out except that instead of 2-(4-acetylphenyl)-10-hydroxy-7,7-dimethyl-5,12b-dihydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazine-1,3(2H)-dione and (2S)-5-amino-2-(tert-butoxycarbonylamino)-5-oxo-pentanoic acid, 2-(4-acetylphenyl)-7,7-dimethyl-1,3-dioxo-2,3,5,12b-tetrahydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]-pyridazin-10-yl piperazine-1-carboxylate hydrochloride and 2-[2-(2-methoxyethoxy)ethoxy]acetic acid were used, respectively.

[1002] 1 H NMR (400 MHz, CDCl3) δ 8.11 (d, J=8.6 Hz, 2H), 7.88-7.80 (m, 2H), 7.09-7.04 (m, 1H), 6.76-6.64 (m, 2H), 5.85(dt, 2.7, Hz), H 5.72 (d, J=2.6 Hz, 1H), 4.33-4.27(m, 1H), 4.23 (s, 2H), 4.13 (dt, J=16.7, 2.7 Hz, 1H), 3.72-3, 52 (m, 17H), 2.64, (d, 1,60H), (d, 1,60H). J=5.7 Hz, 6H).

[1003] Example 97. Synthesis of 2-(4-acetylphenyl)-7,7-dimethyl-1,3-dioxo-2,3,5,12b-tetrahydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a-pyridazine]-10-1 4-(L-valyl)piperazine-1-carboxylate formate

[1004] (a) Synthesis of 2-(4-acetylphenyl)-7,7-dimethyl-1,3-dioxo-2,3,5,12b-tetrahydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]-pyridazine-10-yl 4-((tertbutoxycarbonyl)-L-valyl)piperazine-1-carboxylate

[1005] 2-(4-Acetylphenyl)-7,7-dimethyl-1,3-dioxo-2,3,5,12b-tetra-hydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazin-10-yl piperazine-1-carboxylate hydrochloride (200 mg, 0.38 mmol) obtained in Example 67(b) above, (2S)-2-(tert-butoxycarbonylamino)-3-methylbutanoic acid (91 mg, 0.41 mmol) and 2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (189 mg, 0.49 mmol) were dissolved in acetonitrile (5 ml) and added dropwise triethylamine (156 mg, 1.52 mmol) and stirred at room temperature for 2 hours. After completion of the reaction, the reaction mixture was concentrated by distillation under reduced pressure, and the resulting residue was subjected to MPLC separation (ethyl acetate:hexane=3:7, by volume) to give 2-(4-acetylphenyl)-7,7-dimethyl-1,3-dioxo-2,3,5,12b-tetrahydro-1H,7H-chromeno[4,3-c][1,2,4]-triazolo[1,2-a]pyridazin-10-yl 4-((tert-butoxycarbonyl)-L-valyl)piperazine-1-carboxylate (200 mg, 73%).

[1006] (b) Synthesis of 2-(4-acetylphenyl)-7,7-dimethyl-1,3-dioxo-2,3,5,12b-tetrahydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]-pyridazin-10-yl 4-(L-valyl)piperazine-1-carboxylate formate

[1007] 2-(4-Acetylphenyl)-7,7-dimethyl-1,3-dioxo-2,3,5,12b-tetra-hydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazin-10-yl 4-((tertbutoxycarbonyl)-L-valyl)piperazine-1-carboxylate (200 mg, 0.27 mmol) obtained in Example 97(a) above was dissolved in dichloromethane (1 ml), and 4M hydrochloric acid solution (0.6 ml, 4M / dioxane) was added dropwise thereto, and stirred at room temperature for 3 hours. After completion of the reaction, the reaction mixture was concentrated by distillation under reduced pressure, and the resulting residue was separated by reverse phase chromatography (acetonitrile containing 0.1% formic acid: water containing 0.1% formic acid=5:95-100:0) and lyophilized to obtain 2-(4-acetylphenyl)-7,7-dimethyl-1,3-dioxo-2,3,5,12b-tetrahydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazin-10-yl 4-(L-valyl)piperazine-1-carboxylate formate (179 mg, 94%).

[1008] 1H NMR (400 MHz, DMSO-D6) δ 8.24 (amine, d, J=l.5 Hz, 2H), 8.17-8.09 (m, 2H), 7.84-7.76 (m, 2H), 7.10 (dd, 1.6 (d, 1.6), 1.3, 1H J=8.4, 2.3 Hz, 1H), 6.71 (d, J=2.3 Hz, 1H), 6.02 (td, J=3.7, 1.8 Hz, 1H), 5.71 (d, J=2.5 Hz, 1H), 4.22 (dd, 3, 2.3, J=3.8 J=5.2 Hz, 1H), 3, 69-3.36 (m, 8H), 2.69 (c, 1H), 2.54 (c, 1H), 1.81 (dt, J=13,l, 6.7 Hz, 1H), 1.59 (c, 3,3 (J=H), 1,5 Hz, 3H), 0.85 (d, J=6.7 Hz, 3H).

[1009] Example 98. Synthesis of 2-(4-acetylphenyl)-7,7-dimethyl-1,3-dioxo-2,3,5,12b-tetrahydro-1H,7H-chromeno[4,3-c][1,2-2,2-pyridazinalo][0,2,2-triazolo][1,2,2-triazolo-[1,2,4] 4-(L-leucyl)piperazine-1-carboxylate hydrochloride

[1010] (a) Synthesis of 2-(4-acetylphenyl)-7,7-dimethyl-1,3-dioxo-2,3,5,12b-tetrahydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1-pyridazine] 4-((tretbutoxycarbonyl)-L-leucyl)piperazine-1-carboxylate

[1011] To obtain 2-(4-acetylphenyl)-7,7-dimethyl-1,3-dioxo-2,3,5,12b-tetrahydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazin-10-yl 4-((tertbutoxycarbonyl)-L-leucyl)piperazine-1-carboxylate (200 mg, 76%), the same synthesis as the above synthesis in Example 97 was carried out except that (2S)-2-(tertbutoxycarbonylamino)-4-methylpentanoic acid was used instead of (2S)-2-(tertbutoxycarbonylamino)-3-methylbutanoic acid.

[1012] (b) Synthesis of 2-(4-acetylphenyl)-7,7-dimethyl-1,3-dioxo-2,3,5,12b-tetrahydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]-pyridazin-10-yl 4-(L-leucyl)piperazine-1-carboxylate hydrochloride

[1013] To obtain 2-(4-acetylphenyl)-7,7-dimethyl-1,3-dioxo-2,3,5,12b-tetrahydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazin-10-yl 4-(L-leucyl)piperazine-1-carboxylate hydrochloride (120 mg, 88%), the same synthesis as the above synthesis in Example 67(b) was carried out, except that instead of 1-(2-(4-acetylphenyl)-7,7-dimethyl-1,3-dioxo-2,3,5,12b-tetrahydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazin-10-yl) 4-(tert-butyl)piperazine-1,4-dicarboxylate was used 2-(4-acetylphenyl)-7,7-dimethyl-1,3-dioxo-2,3,5,12b-tetrahydro-1H,7H-chromeno[4,3-c]-[1,2,4]triazolo[1,2-a]pyridazin-10-yl 4-((tert-butoxycarbonyl)-L-leucyl)piperazine-1-carboxylate.

[1014] 1H NMR (400 MHz, DMSO-D6) δ 8.20 (s, 3H), 8.16-8.12 (m, 2H), 7, 84-7, 76 (m, 2H), 7.10 (dd, J=8.5, 1.1 Hz, 1H), 6.76 (dd, J=8.4, 2.4 Hz, 1H), 6.72 (d, J=2.3 Hz, 1H), 6.02 (quartet, J=3.4 Hz, 1H), 5.72 (d, J=2.3 Hz, 1H), 4.39 (s, 1H), 4, 25-4, 20 (m, 2H), 3.81-3.71 (m, 2H), 3, 65-3.58 (m, 2H), 3.43-3.24 (m, 4H), 2.64 (s, 3H), 1.77-1.71 (m, 1H), 1.60 (s, 3H), 1.53 (s, 3H), 1.50-1.42 (m, 2H), 0.94 (d, J=6.5 Hz, 3H), 0.90 (d, J=6.5 Hz, 3H).

[1015] Example 99. Synthesis of 2-(4-acetylphenyl)-7,7-dimethyl-1,3-dioxo-2,3,5,12b-tetrahydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]-pyridazin-10-yl 4-(dimethylglycyl)piperazine-1-carboxylate hydrochloride

[1016] To prepare 2-(4-acetylphenyl)-7,7-dimethyl-1,3-dioxo-2,3,5,12b-tetrahydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]-pyridyl-10- 4-(dimethylglycyl)piperazine-1-carboxylate hydro-chloride (320 mg, 67%) carried out the same synthesis as the above synthesis in Example 72 except that instead of used 2-(4-acetylphenyl)-10-hydroxy-7,7-dimethyl-5,12b-dihydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazine-1,3(2H)-dione 2-(4-acetylphenyl)-7,7-dimethyl-1,3-dioxo-2,3,5,12b-tetrahydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazin-10-yl piperazine-1-xcarboxylate hydroxylate.

[1017] 1 H NMR (400 MHz, D2O) δ 8, 19 (e, J=8.4 Hz, 2H), 7.77 (e, J=8.5 Hz, 2H), 7.21 (e, J=8.4 Hz, 1H), 6.89 (e, J=8.2 Hz, 2H), (s (s, 1H), 4.43 (s, 2H), 4.34 (s, 2H), 3.88-3.63 (m, 8H), 3.08 (s, 6H), 2.79 (s, 3H), 1.70 (d, J=18.4 Hz, 6H).

[1018] Example 100. Synthesis of 2-(4-acetylphenyl)-7,7-dimethyl-1,3-dioxo-2,3,5,12b-tetrahydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo-[1,2-a]pyridazin-10-yl 2,6-dimethylpiperazine-1-carboxylate hydrochloride

[1019] (a) Synthesis of 1-(2-(4-acetylphenyl)-7,7-dimethyl-1,3-dioxo-2,3,5,12b-tetrahydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]-pyridazin-10-yl) 4-(tert-butyl) 2,6-dimethylpiperazine-1,4-dicarboxylate

[1020] To obtain 1-(2-(4-acetylphenyl)-7,7-dimethyl-1,3-dioxo-2,3,5,12b-tetrahydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazin-10-yl) 4-(tert-butyl) 2,6-dimethylpiperazine-1,4-dicarboxylate (700 mg, 88%), the same synthesis as the above synthesis in Example 58 was carried out except that tert-butyl 4-chloro-carbonyl-3,5-dimethylpiperazine-1-carboxylate was used instead of trimethylacetyl chloride.

[1021] (b) Synthesis of 2-(4-acetylphenyl)-7,7-dimethyl-1,3-dioxo-2,3,5,12b-tetrahydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]-pyridazin-10-yl 2,6-Dimethylpiperazine-1-carboxylate hydrochloride

[1022] To obtain 2-(4-acetylphenyl)-7,7-dimethyl-1,3-dioxo-2,3,5,12b-tetrahydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazin-10-yl 2,6-dimethylpiperazine-1-carboxylate hydrochloride (180 mg, 88%), the same synthesis as the above synthesis in Example 67(b) was carried out, except that instead of 1-(2-(4-acetylphenyl)-7,7-dimethyl-1,3-dioxo-2,3,5,12b-tetrahydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazin-10-yl) 4-(tert-butyl) 1-(2-(4-acetylphenyl)-7,7-dimethyl-1,3-dioxo-2,3,5,12b-tetrahydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazin-10-yl) 4-(tert-butyl) 2,6-dimethylpiperazine-1,4-dicarboxylate was used for piperazine-1,4-dicarboxylate.

[1023] 1H NMR (500 MHz, DMSO-D6) δ 9.31 (s, 1H), 8.13 (d, J=8.6 Hz, 2H), 7.80 (d, J=8.7 Hz, 2H), 7.10 (dd, J=8.3, 1.1 Hz, 7.6, J=8.3 Hz, 2H), 2.3 Hz, 1H), 6.71 (d, J=2.3 Hz, 1H), 6.02 (td, J=3.7, 1.8 Hz, 1H), 5.75-5, 69 (m, 1H), 4, 53-4, 45 (m, 1H), t 4.22 (dd, J=3.9, 2.0 Hz, 2H), 3, 46-3, 42 (m, 2H), 3.04 (t, J=12.6 Hz, 2H), 2.63 (s, 3H), 1.59 (s, 3H), 1.53 (s, 3.3Hz), (d, 3.6 Hz, J 6H).

[1024] Example 101. Synthesis of 2-(4-acetylphenyl)-7,7-dimethyl-1,3-dioxo-2,3,5,12b-tetrahydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo-[1,2-a-pyrida-10] 2,6-dimethyl-4-prolylpiperazine-1-carboxylate hydrochloride

[1025] (a) Synthesis of 2-(4-acetylphenyl)-7,7-dimethyl-1,3-dioxo-2,3,5,12b-tetrahydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]-pyridazine-10-yl 4-((tertbutoxycarbonyl)prolyl)-2,6-dimethyl-piperazine-1-carboxylate

[1026] To obtain 2-(4-acetylphenyl)-7,7-dimethyl-1,3-dioxo-2,3,5,12b-tetrahydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]-pyridazin-10-yl 4-((tertbutoxycarbonyl)prolyl)-2,6-dimethylpiperazine-1-carboxylate (100 mg, 70%), the same synthesis as the above synthesis in Example 97(a) was carried out, except that instead of 2-(4-acetylphenyl)-7,7-dimethyl-1, 3-dioxo-2,3,5,12b-tetrahydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo-[1,2-a]pyridazin-10-yl piperazine-1-carboxylate hydrochloride and (2S)-2-(tert-butoxycarbonylamino)-3-methylbutanoic acid were used, respectively, 2-(4-acetylphenyl)-7,7-dimethyl-1,3-dioxo-2,3,5,12b-tetrahydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo-[1,2-a]pyridazin-10-yl 2,6-dimethylpiperazine-1-carboxylate hydrochloride and 1-tert-butoxycarbonylpyrrolidine-2-carboxylic acid.

[1027] (b) Synthesis of 2-(4-acetylphenyl)-7,7-dimethyl-1,3-dioxo-2,3,5,12b-tetrahydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]-pyridazin-10-yl 2,6-dimethyl-4-prolylpiperazine-1-carboxylate hydrochloride

[1028] To obtain 2-(4-acetylphenyl)-7,7-dimethyl-1,3-dioxo-2,3,5,12b-tetrahydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]-pyridazin-10-yl 2,6-dimethyl-4-prolylpiperazine-1-carboxylate hydrochloride (78 mg, 88%), the same synthesis as the above synthesis in Example 67(b) was carried out, except that instead of 1-(2-(4-acetylphenyl)-7,7-dimethyl-1,3-dioxo-2,3,5,12b-tetrahydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]-pyridazin-10-yl) 4-(tert-butyl) piperazine-1,4-dicarboxylate was used 2-(4-acetylphenyl)-7,7-dimethyl-1,3-dioxo-2,3,5,12b-tetrahydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazin-10-yl 4-((tert-butoxycarbonyl)prolyl)-2,6-dimethylpiperazine-1-carboxylate.

[1029] 1H NMR (500 MHz, D2O) δ 7, 99 (d, J=8.2 Hz, 2H), 7.59 (d,J=8.3 Hz, 2H), 7.06 (d, J=8.4 Hz, 1H), 6.75 (s, 1H), 6.71 (s, 1H), (s, 196), 5.69 (s, 1H), 4.22 (s, 1H), 4.17 (s, 2H), 3.76 (dd, J=24.6, 12.7 Hz, 1H), 3.53-3.37 (m, 4H), 3.09-3.01 (m, 16H), 3.09-3.01 (m, 1H), J=13.8, 7.0 Hz, 1H), 2.24-1.92 (m, 5H), 1.56 (d, J=9.4 Hz, 6H), 1.34 (s, 3H), 1.28-1.24 (m, 3H).

[1030] Example 102. Synthesis of 2-(4-acetylphenyl)-7,7-dimethyl-1,3-dioxo-2,3,5,12b-tetrahydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo-[1,2-apyridalazine-ata-10

[1031] To prepare 2-(4-acetylphenyl)-7,7-dimethyl-1,3-dioxo-2,3,5,12b-tetrahydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-azine]-pyridayl-heptanog (1000 92%) carried out the same synthesis as the above synthesis in Example 58 except that heptanoyl chloride was used instead of trimethylacetyl chloride.

[1032] 1H NMR (400 MHz, CDCl3) δ 8.15-8.07 (m, 2H), 7.88-7.80 (m, 2H),7.08 (dd, J=8.3, 1.1 Hz, 1H), 6.73-6.60 (m, 2Hz, 5.86, dt, J=8.3, 2Hz). 1H), 5.73 (d, J=2.5 Hz, 1H), 4.30 (ddd, J=16.5, 4.8, 1.3 Hz, 1H),4.13 (dt, J=16.6, 2.7 Hz, 1H), 2.64 (s, 3H), t 2.52 (J, 2.5 Hz), H 1.72(p, J=7, 4 Hz, 2H), 1.60 (d, J=4.5 Hz, 6H), 1.42-1.29 (m, 6H), 0.93-0.86 (m, 3H).

[1033] Example 103. Synthesis of 2-(4-acetylphenyl)-7,7-dimethyl-1, 3-dioxo-2,3,5,12b-tetrahydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo-[1,2-a]pyrizil-10-1 2,2-dimethylbutanoate

[1034] To prepare 2-(4-acetylphenyl)-7,7-dimethyl-1,3-dioxo-2,3,5,12b-tetrahydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]-pyridazine-2,20-atadimethyl-butano (115 mg, 95%) carried out the same synthesis as the above synthesis in Example 58 except that 2,2-dimethylbutanoyl chloride was used instead of trimethylacetyl chloride.

[1035] 1H NMR (400 MHz, CDCl3) δ 8.14-8.07 (m, 2H), 7.86-7.80 (m, 2H), 7.11-7.04 (m, 1H), 6.66-6.59 (m, 2H), 5.88-5.82 (m, 1H), 5.73 (s, 1H), 4.34-4.26 (m, 1H), 4.13 (dt, J=16.4, 2.6 Hz, 1H), 2.65 (d, J=0.6 Hz, 3H), 1.69 (quartet, J=7.5 Hz, 2H), 1.60 (d, J=3.6 Hz, 6H), 1.55 (s, 3Н), 1, 29-1, 25 (m, 6H), 0.98-0.90 (m, 3H).

[1036] Example 104. Synthesis of 2-(4-acetylphenyl)-7,7-dimethyl-1,3-dioxo-2,3,5,12b-tetrahydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo-[1,2-a]pyridazin-10-yl ethyl succinate

[1037] To obtain 2-(4-acetylphenyl)-7,7-dimethyl-1,3-dioxo-2,3,5,12b-tetrahydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazin-10-yl ethyl succinate (120 mg, 92%), the same synthesis as the above synthesis in Example 58 was carried out except that 4-chloro-4-oxobutanoate was used instead of trimethylacetyl chloride.

[1038] 1H NMR (400 MHz, DMSO-D6) δ 8.17-8.09 (m, 2H), 7.84-7.77 (m, 2H), 7.13 (dd, J=8.4, 1.1 Hz, 1H), 6.71 (dd, J=8.4, 2.3 Hz, 1H), 6.64 (d, J=2.2 Hz, 1H), 6.02 (td, J=3.7, 1.8 Hz, 1H), 5.75-5.69 (m, 1H), 4.22 (dd, J=3.8, 2.0 Hz, 2H), 4.08 (quartet, J=7.1 Hz, 2H), 2.80 (dd, J=7.6, 5.4 Hz, 2H), 2.67-2.62 (m, 5H), 1.60 (s, 3H), 1.53 (s, 3H), 1.18 (t, J=7.l Hz, 3H).

[1039] Example 105. Synthesis of 2-(4-acetylphenyl)-7,7-dimethyl-1,3-dioxo-2,3,5,12b-tetrahydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo-[1,2-a]pyridazin-10-yl diisopropylcarbamate

[1040] To obtain 2-(4-acetylphenyl)-7,7-dimethyl-1,3-dioxo-2,3,5,12b-tetrahydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazin-10-yl diisopropylcarbamate (80 mg, 95%), the same synthesis as the above synthesis in Example 58 was carried out except that N,N-diisopropylcarbamoyl chloride was used instead of trimethylacetyl chloride.

[1041] 1H NMR (400 MHz, DMSO-D6) δ 8.16-8.10 (m, 2H), 7.82-7.77 (m, 2H), 7.12-7.03 (m, 1H), 6.70 (dd, J=8.4, 2.3 Hz, 1H), 6.62 (d, J=2.3 Hz, 1H), 6.02 (quartet, J=3.2 Hz, 1H), 5.71 (s, 1H), 4.21 (t, J=2.8 Hz, 2H), 4.02-3, 89 (m, 2H), 2.63 (s, 3H), 1.56 (d, J=21.8 Hz, 6H), 1.20 (d, J=19.9 Hz, 14H).

[1042] Example 106. Synthesis of 2-(4-acetylphenyl)-7,7-dimethyl-1,3-dioxo-2,3,5,12b-tetrahydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo-[1,2-a]pyridazin-10-yl isopropyl carbonate

[1043] To obtain 2-(4-acetylphenyl)-7,7-dimethyl-1,3-dioxo-2,3,5,12b-tetrahydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazin-10-yl isopropyl carbonate (120 mg, 93%), the same synthesis as the above synthesis in Example 58 was carried out except that 1 M isopropyl chloroformate solution (1 M / toluene) was used instead of trimethylacetyl chloride.

[1044] 1H NMR (400 MHz, DMSO-D6) δ 8.17-8.09 (m, 2H), 7.83-7.76 (m, 2H), 7.12 (dd, J=8.4, 1.1 Hz, 1H), 6.91-6.72 (m, 2H), 6.02 (td, J=3.7, 1.8 Hz, 1H), 5.73 (d, J=1.9 Hz, 1H), 4.84 (p, O=6.2 Hz, 1H), 4.21 (dd, J=3.8, 2.0 Hz, 2H), 2.63 (s, 3H), 1.59 (s, 3H), 1.53 (s, 3H), 1.29 (d, J=6.2 Hz, 6H).

[1045] Example 107. Synthesis of 2-(4-acetylphenyl)-7,7-dimethyl-1, 3-dioxo-2,3,5,12b-tetrahydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo-[1,2-a]-pyridazin-10-yl (2-((2-hydroxyethyl)disulfanyl)ethyl)-carbonate

[1046] To obtain 2-(4-acetylphenyl)-7,7-dimethyl-1,3-dioxo-2,3,5,12b-tetra-hydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazin-10-yl (2-((2-hydroxyethyl)disulfanyl)ethyl)carbonate (830 mg, 58%), the same synthesis as the above synthesis in Example 83(a) was carried out except that 2-hydroxyethyl disulfide was used instead of tert-butyl N-methyl-N-[2-(methylamino)ethyl]carbamate.

[1047] 1H NMR (400 MHz, CDCl3) δ 8.14-7.99 (m, 2H), 7.94-7.70 (m, 2H), 7.09 (dd, J=8.5, 1.1 Hz, 1H), 6.88-6.66 (m, 2H), 5.87 (dt, J=4.9, 2.3 Hz, 1H), 5.73 (d, J=2.3 Hz, 1H), 4.48 (td, J=6.7, 1.1 Hz, 2H), 4.37 (t, J=6.5 Hz, 2H), 4.31 (ddd, J=16.1, 4.7, 1.2 Hz, 1H), 4.14 (dt, J=16.3, 2.7 Hz, 1H), 3.03-2.93 (m, 4H), 2.64 (d, J=2.7 Hz, 6H), 1.61 (d, J=6.3 Hz, 6H).

[1048] Example 108. Synthesis of 4-(2-((2-((((2-(4-acetylphenyl)-7,7-dimethyl-1,3-dioxo-2,3,5,12b-tetrahydro-1H,7H-chromeno[4,3-c]-[1,2,4]triazolo[1,2-a]pyridazin-10-yl)oxy)carbonyl)oxy)ethyl)-disulfanyl)ethoxy)-4-oxobutanoic acid

[1049] 2-(4-Acetylphenyl)-7,7-dimethyl-1,3-dioxo-2,3,5,12b-tetra-hydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazin-10-yl (2-((2-hydroxyethyl)disulfanyl)ethyl)carbonate (700 mg, 1.17 mmol) obtained above in Example 107 and 4-dimethylaminopyridine (71 mg, 0.58 mmol) were dissolved in dichloromethane (30 ml), and tetrahydrofuran-2, 5-dione (467 mg, 4.67 mmol) was added thereto, and heated with stirring at 35°C for 1 hour. After completion of the reaction, the reaction mixture was diluted with dichloromethane and washed with aqueous ammonium chloride solution. The separated organic layer was dried over sodium sulfate, filtered, concentrated by distillation under reduced pressure and separated by the MHC method (ethyl acetate : hexane = 3 : 1, by volume) to give 4-(2-((2-((((2-(4-acetylphenyl)-7,7-dimethyl-1,3-dioxo-2,3,5,12b-tetra-hydro-1H,7H-chromeno[4,3-c][1,2,4]-triazolo[1,2-a]pyridazin-10-yl)oxy)carbonyl)oxy)ethyl)disulfanyl)ethoxy)-4-oxobutanoic acid (0.81 g, 99%).

[1050] 1H NMR (400 MHz, DMSO-D6) δ 8.13 (d, J=8.6 Hz, 2H), 7.80 (d, J=8.1 Hz, 2H), 7.14 (d, J=8.4 Hz, 1H), 6.85 (dd, J=8.3, 2.4 Hz, 1H), 6.81 (d, J=2.4 Hz, 1H), 6.05-5.99 (m, 1H), 5.73 (s, 1H), 4.43 (t, J=6.2 Hz, 2H), 4.21 (d, J=6.7 Hz, 4H), 3.08 (t, J=6.2 Hz, 2H), 2.98 (t, J=6.5 Hz, 2H), 2.63 (s, 3H), 2.38 (d, J=6.4 Hz, 2H), 2.13 (t, J=7.8 Hz, 2H), 1.60 (s, 3H), 1.54 (s, 3H).

[1051] Example 109. Synthesis of sodium 4-(2-((2-((((2-(4-acetylphenyl)-7,7-dimethyl-1,3-dioxo-2,3,5,12b-tetrahydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazin-10-yl)oxy)carbonyl)oxy)-ethyl)disulfanyl)ethoxy)-4-oxobutanoate

[1052] To obtain sodium 4-(2-((2-((((2-(4-acetylphenyl)-7,7-dimethyl-1,3-dioxo-2,3,5,12b-tetrahydro-1H,7H-chromeno[4,3-c]-[1,2,4]triazolo[1,2-a]pyridazin-10-yl)oxy)-carbonyl)oxy)ethyl)disulfanyl)ethoxy)-4-oxobutanoate (100 mg, 90%), the same synthesis as the above synthesis in Example 90 was carried out, except that instead of N-(((2-(4-acetylphenyl)-7,7-dimethyl-1,3-dioxo-2,3,5,12b-tetrahydro-1H,7H-chromeno[4,3-c][1,2,4]-triazolo[1,2-a]pyridazin-10-yl)oxy)carbonyl)-N-methylglycine was used 4-(2-((2-(((2-(4-acetylphenyl)-7,7-dimethyl-1,3-dioxo-2,3,5,12b-tetrahydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo-[1,2-a]pyridazin-10-yl)oxy)carbonyl)oxy)ethyl)disulfanyl)ethoxy)-4-oxobutanoic acid.

[1053] 1H NMR (400 MHz, DMSO-D6) δ 8.13 (d, J=8.6 Hz, 2H), 7.80 (d, J=8.1 Hz, 2H), 7.14 (d, J=8.4 Hz, 1H), 6.85 (dd, J=8.3, 2.4 Hz, 1H), 6.81 (d, J=2.4 Hz, 1H), 6.05-5.99 (m, 1H), 5.73 (s, 1H), 4.43 (t, J=6.2 Hz, 2H), 4.21 (d, J=6.7 Hz, 4H), 3.08 (t, J=6.2 Hz, 2H), 2.98 (t, J=6.5 Hz, 2H), 2.63 (s, 3H), 2.38 (d, J=6.4 Hz, 2H), 2.13 (t, J=7.8 Hz, 2H), 1.60 (s, 3H), 1.54 (s, 3H)

[1054] Example 110. Synthesis of 2-(4-acetylphenyl)-10-(2-hydroxyethoxy)-7,7-dimethyl-5,12b-dihydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo-[1,2-a]pyridazine-1,3(2H)dione

[1055] 2-(4-Acetylphenyl)-10-hydroxy-7,7-dimethyl-5,12b-dihydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazine-1,3(2H)-dione (500 mg, 1.19 mmol) obtained in Example 10(b) above and potassium carbonate (752 mg, 3.58 mmol) were suspended in acetone, and 2-bromoethanol (298 mg, 2.38 mmol) was added to the reaction mixture, which was heated with stirring at 60°C for 24 hours. After completion of the reaction, acetone was removed by distillation under reduced pressure. The resulting residue was diluted with ethyl acetate and washed with water. The separated organic layer was dried over sodium sulfate, filtered, concentrated by distillation under reduced pressure, and separated by MPLC (ethyl acetate:hexane=1:1, by volume) to give 2-(4-acetylphenyl)-10-(2-hydroxyethoxy)-7,7-dimethyl-5,12b-dihydro-1H,7H-chromeno[4,3-c]-[1,2,4]triazolo[1,2-a]pyridazine-1,3(2H)-dione (478 mg, 87%).

[1056] 1H NMR (500 MHz, DMSO-D6) δ 8.13 (d, J=8.0 Hz, 2H), 7.79 (d, J=7.7 Hz, 2H), 6.99 (d, J=8.9 Hz, 1H), 6.54 (d, J=8.4 Hz, 1H), 6.44 (d, J=3.0 Hz, 1H), 5.99 (d, J=4.1 Hz, 1H), 5.66 (s, 1H), 4.20 (d, J=3.7 Hz, 2H), 3.92 (quartet, J=4.1 Hz, 2H), 3.67 (s, 2H), 2.64 (d, J=2.5 Hz, 3H), 1.55 (d, J=16.2 Hz, 6H)

[1057] Example 111. Synthesis of 2-((2-(4-acetylphenyl)-7,7-dimethyl-1, 3-dioxo-2,3,5,12b-tetrahydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo-[1,2-a]pyridazin-10-yl)oxy)ethyl L-leucinate hydrochloride

[1058] (a) Synthesis of 2-((2-(4-acetylphenyl)-7,7-dimethyl-1,3-dioxo-2,3,5,12b-tetrahydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]-pyridazin-10-yl)oxy)ethyl (tert-butoxycarbonyl)-L-leucinate

[1059] To obtain 2-((2-(4-acetylphenyl)-7,7-dimethyl-1,3-dioxo-2,3,5,12b-tetrahydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazin-10-yl)oxy)ethyl (tert-butoxycarbonyl)-L-leucinate (98 mg, 62%), the same synthesis as the above synthesis in Example 77 was carried out except that instead of 2-(4-acetylphenyl)-10-hydroxy-7,7-dimethyl-5,12b-dihydro-1H,7H-chromeno[4,3-c]-[1,2,4]triazolo[1,2-a]pyridazine-1,3(2H)-dione and (2S)-5-amino-2-(tert-butoxycarbonylamino)-5-oxo-pentanoic acid was used, respectively, 2-(4-acetylphenyl)-10-(2-hydroxy-ethoxy)-7,7-di-methyl-5,12b-dihydro-1H,7H-chromeno[4,3-c][1,2,4]-triazolo[1,2-a]pyridazine-1,3(2H)-dione and N-(tert-butoxycarbonyl)-L-leucine monohydrate.

[1060] (b) Synthesis of 2-((2-(4-acetylphenyl)-7,7-dimethyl-1,3-dioxo-2,3,5,12b-tetrahydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]-pyridazin-10-yl)oxy)ethyl L-leucinate hydrochloride

[1061] To obtain 2-((2-(4-acetylphenyl)-7,7-dimethyl-1,3-dioxo-2,3,5,12b-tetrahydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazin-10-yl)oxy)ethyl L-leucinate hydrochloride (70 mg, 80%), the same synthesis as the above synthesis in Example 67(b) was carried out, except that instead of 1-(2-(4-acetylphenyl)-7,7-dimethyl-1,3-dioxo-2,3,5,12b-tetrahydro-1H,7H-chromeno[4,3-c]-[1,2,4]triazolo[1,2-a]pyridazin-10-yl) 4-(tert-butyl)-piperazine-1,4-dicarboxylate was used 2-((2-(4-acetylphenyl)-7,7-di-methyl-1,3-dioxo-2,3,5,12b-tetrahydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazin-10-yl)oxy)ethyl (tert-butoxycarbonyl)-L-leucine

[1062] 1H NMR (500 MHz, DMSO-D6) δ 8.51 (s, 3H), 8.17-8.11 (m, 2H), 7.82-7.76 (m, 2H), 7.01 (d, J=8.5 Hz, 1H), 6.55 (dd, J=8.5 Hz, 1H), 6.55 (dd, J=8.8), H 6.47 (d, J=2.4 Hz, 1H), 6.00 (d, J=2.5 Hz, 1H), 5.67 (s, 1H), 4.54 (dqv, J=13.0, 4.5 Hz, 1H), 4.44-4.39 (m, 1H, 20, Jvar, 4.1Hz), (kvar, 4.l Hz). 4H), 3.98 (s, 1H), 2.64 (s, 3H), 1.75 (dt, 0=13.4, 6.8 Hz, 1H), 1.62 (td, J=7.2, 2.6 Hz, 2H), 1.57 (s, 3H), 1.57 (s, 3H), 6H).

[1063] Example 112. Synthesis 2-(4-acetylphenyl)-7,7-dimethyl-10-(2-(piperidin-1-yl)ethoxy)-5,12b-dihydro-1H,7H-chromeno[4,3-c]-[1,2,4]triazolo[1,2-a]pyridazine-1,3(2H)-dione hydrochloride

[1064] 2-(4-Acetylphenyl)-10-hydroxy-7,7-dimethyl-5,12b-dihydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazine-1,3(2H)-dione (300 mg, 0.72 mmol) obtained in Example 10(b) above and potassium carbonate (395 mg, 2.86 mmol) were suspended in acetone, and 1-(2-chloroethyl)piperidine (158 mg, 0.86 mmol, HCl) was added thereto, and stirred at 70°C for 5 hours. After completion of the reaction, acetone was removed by distillation under reduced pressure, and the resulting residue was diluted in dichloromethane and washed with water. The separated organic layer was dried over sodium sulfate, filtered, concentrated by distillation under reduced pressure, subjected to MPLC separation (ethyl acetate:hexane=1:1, by volume), and concentrated by distillation under reduced pressure. The resulting residue was dissolved in ethyl acetate (3 ml), and 4M hydrochloric acid solution (2 ml, 4M / dioxane) was added dropwise, and the mixture was stirred at room temperature for 30 minutes.The resulting solid precipitate was filtered and washed with ethyl acetate to give 2-(4-acetylphenyl)-7,7-dimethyl-10-(2-(piperidin-1-yl)ethoxy)-5,12b-dihydro-1H,7H-chromeno[4,3-c]-[1,2,4]triazolo[1,2-a]pyridazine-1,3(2H)-dione hydrochloride (120 mg, 30%).

[1065] 1 H NMR (500 MHz, DMSO-D6) δ 10.14 (s, 1H), 8.11 (d, J=8.6 Hz, 2H), 7.77 (d, J=8.6 Hz, 2H), 7.02 (d, J=8.5 Hz, 1H), 6.59 (dd, J=8.6, 2.5 Hz, 1H), 6.53 (d, J=2.5 Hz, 1H), 5.99 (d, J=2.0 Hz, 1H), 5.66 (s, 1H), 4.33 (t, 0=5.1 Hz, 2H), 4.19 (t, J=2.9 Hz, 2H), 3, 49-3, 38 (m, 6H), 3, 02-2, 85 (m, 2H), 2.62 (s, 3H), 1.82-1.62 (m, 5H), 1.54 (d, J=13.7 Hz, 6H).

[1066] Example 113. Synthesis of 2-(4-acetylphenyl)-7,7-dimethyl-10-(2-morpholinoethoxy)-5,12b-dihydro-1H,7H-chromeno[4,3-c][1,2,4]-triazolo[1,2-a]pyridazine-1,3(2H)-dione formate

[1067] 2-(4-Acetylphenyl)-10-hydroxy-7,7-dimethyl-5,12b-dihydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazine-1,3(2H)-dione (560 mg, 1.34 mmol) obtained in Example 10(b) above was dissolved in N,N-dimethylformamide (10 ml), and sodium hydride (64 mg, 2.67 mmol, 60%) was added thereto, and stirred at room temperature for 30 minutes. 4-(2-chloroethyl)-morpholine hydrochloride (298 mg, 1.6 mmol) was added to the reaction mixture, and stirred at room temperature for 15 hours. After completion of the reaction, the reaction mixture was quenched by adding water (5 ml) and extracted with dichloromethane. The separated organic layer was washed with aqueous sodium chloride solution, dried over sodium sulfate, filtered, and concentrated by distillation under reduced pressure.The resulting residue was separated by reverse phase chromatography (acetonitrile containing 0.1% formic acid: water containing 0.1% formic acid=5:95-100:0) and lyophilized to give 2-(4-acetylphenyl)-7,7-dimethyl-10-(2-morpholinoethoxy)-5,12b-dihydro-1H,7H-chromeno-[4,3-c][1,2,4]-triazolo[1,2-a]pyridazine-1,3(2H)-dione formate (60 mg, 70%).

[1068] 1 H NMR (500 MHz, CDCl3) δ 8.11 (d, J=8.7 Hz, 2H), 7.83 (d, J=8.7 Hz, 2H), 7.09-7.05 (m, 1H), 6.72-6.67 (m, 2H), 5.86 (dt, J=4.6, 2.3 Hz, 1H), 5.72 (s, 1H), 4, 34-4, 24 (m, 1H), 4.14 (dt, J=16.5, 2.6 Hz, 1H), 3.64 (d, J=60.0 Hz, 9H), 2.65 (s, 3H), 2.47 (s, 3H), 1.61 (s, 3H), 1.59 (s, 3H).

[1069] Example 114. Synthesis of (((2-(4-acetylphenyl)-7,7-dimethyl-1,3-dioxo-2,3,5,12b-tetrahydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo-[1,2-a]pyridazin-10-yl)oxy)methyl)phosphonic acid

[1070] (a) Synthesis of diethyl (((2-(4-acetylphenyl)-7,7-dimethyl-1,3-dioxo-2,3,5,12b-tetrahydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo-[1,2-a]pyridazin-10-yl)oxy)phosphonatamethyl)

[1071] 2-(4-Acetylphenyl)-10-hydroxy-7,7-dimethyl-5,12b-dihydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazine-1,3(2H)-dione (300 mg, 0.72 mmol) obtained in Example 10(b) above was dissolved in N,N-dimethylformamide (8 ml), and sodium hydride (17 mg, 0.72 mmol, 60%) was added thereto, and stirred at room temperature for 1 hour. Diethoxyphosphoryl methyl 4-methylbenzenesulfonate (346 mg, 1.07 mmol) was added to the reaction mixture, and stirred at room temperature under a nitrogen atmosphere for 15 hours. After completion of the reaction, the reaction mixture was diluted with ethyl acetate and washed with aqueous sodium chloride solution. The separated organic layer was dried over sodium sulfate, filtered, and concentrated by distillation under reduced pressure to quantitatively obtain diethyl (((2-(4-acetylphenyl)-7,7-dimethyl-1,3-dioxo-2,3,5,12b-tetrahydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazin-10-yl)oxy)methyl)phosphonate.The obtained compound was used in the next reaction without purification.

[1072] (b) Synthesis of (((2-(4-acetylphenyl)-7,7-dimethyl-1,3-dioxo-2,3,5,12b-tetrahydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]-pyridazin-10-yl)oxy)methyl)phosphonic acid

[1073] To obtain (((2-(4-acetylphenyl)-7,7-dimethyl-1,3-dioxo-2,3,5,12b-tetrahydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazin-10-yl)oxy)methyl)phosphonic acid (70 mg, 50%), the same synthesis as the above synthesis in Example 69(b) was carried out, except that diethyl phosphate was used instead of 2-(4-acetylphenyl)-7,7-dimethyl-1,3-dioxo-2,3,5,12b-tetrahydro-1H,7H-chromeno[4,3-c]-[1,2,4]triazolo[1,2-a]pyridazin-10-yl diethyl phosphate (((2-(4-acetylphenyl)-7,7-dimethyl-1,3-dioxo-2,3,5,12b-tetrahydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazin-10-yl)oxy)methyl)phosphonate.

[1074] 1H NMR (500 MHz, DMSO-D6) δ 8.09 (d, J=8.4 Hz, 2H), 7.71 (d, J=8.1 Hz, 2H), 7.23 (d, J=14.2 Hz, 1H), 7.03 (d, J=8.7 Hz, 1H), 6.61 (s, 1H), 6.51 (d, J=8.4 Hz, 1H), 6.42 (s, 1H), 5.87 (d, J=14.2 Hz, 1H), 4.05 (d, J=10.1 Hz, 2H), 2.62 (s, 3H), 1.43 (s, 6H)

[1075] Example 115. Synthesis of disodium (((2-(4-acetylphenyl)-7,7-dimethyl-1,3-dioxo-2,3,5,12b-tetrahydro-1H,7H-chromeno[4,3-c]-[1,2,4]triazolo[1,2-a]pyridazin-10-yl)oxy)methyl)phosphonate

[1076] To obtain disodium (((2-(4-acetylphenyl)-7,7-dimethyl-1,3-dioxo-2,3,5,12b-tetrahydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo-[1,2-a]pyridazin-10-yl)oxy)methyl)phosphonate, the same synthesis as the above synthesis in Example 70 was carried out, except that 2-(4-acetylphenyl)-7,7-dimethyl-1,3-dioxo-2,3,5,12b-tetrahydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazin-10-yl dihydrogen phosphate was used (((2-(4-acetylphenyl)-7,7-dimethyl-1,3-dioxo-2,3,5,12b-tetrahydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazin-10-yl)oxy)methyl)phosphonic acid.

[1077] 1 H NMR (500 MHz, D2O) δ 8, 17-8, 10 (m, 2H), 7, 60-7, 54 (m, 2H), 7.30 (d, J=14.0 Hz, 1H), 7.10 (d, J=8.4 Hz, 1H), 6.68 (dd, J=8.4, 2.5 Hz, 1H), 6.61 (s, 1H), 6.56 (d, J=2.5 Hz, 1H), 6.11 (dd, J=14.1, 1.0 Hz, 1H), 3.99 (d, J=9.8 Hz, 3H), 2.71 (s, 3H), 1.53 (s, 7H)

[1078] Example 116. Synthesis of 2-((2-(4-acetylphenyl)-7,7-dimethyl-1,3-dioxo-2,3,5,12b-tetrahydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo-[1,2-a]pyridazin-10-yl)oxy)ethyl dimethylglycinate hydrochloride

[1079] To obtain 2-((2-(4-acetylphenyl)-7,7-dimethyl-1,3-dioxo-2,3,5,12b-tetra-hydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazin-10-yl)oxy)ethyl dimethylglycinate hydrochloride (98 mg, 62%), the same synthesis as the above synthesis in Example 72 was carried out, except that 2-(4-acetylphenyl)-10-hydroxy-7,7-dimethyl-5,12b-dihydro-1H,7H-chromeno[4,3-c]-[1,2,4]triazolo[1,2-a]pyridazine-1,3(2H)-dione was used 2-(4-acetyl-phenyl)-10-(2-hydroxyethoxy)-7,7-dimethyl-5,12b-dihydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazine-1,3(2H)-dione.

[1080] 1H NMR (500 MHz, DMSO-D6) δ 10.35 (s, 1Hz), 8.14 (d, J=7.9Hz, 2H), 7.79 (quartet, 0=5.9, 4.5 Hz, 2H), 7.05-6.96 (m, 15.9 Hz), J, 58.9 Hz 1H), 6.49 (s, 1H), 6.00 (s, 1H), 5.67 (s,1H), 4.48 (s, 2H), 4.32-4.12 (m, 6H), 2.83 (t, 0=3.4 Hz,6H), 2.63 (d, 4.4Hz), 1.63Hz (m, 6H).

[1081] Example 117. Synthesis of 2-(4-acetylphenyl)-7,7-dimethyl-1,3-dioxo-2,3,5,12b-tetrahydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo-[1,2-a-pyrida-10] 4-(1-(2-oxopropanoyl)piperidin-4-yl)piperazine-1-carboxylate hydrochloride

[1082] 2-(4-Acetylphenyl)-7,7-dimethyl-1,3-dioxo-2,3,5,12b-tetra-hydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazin-10-yl 4-(piperidin-4-yl)piperazine-1-carboxylate dihydrochloride (201 mg, 0.29 mmol) obtained in Example 94(b) above, pyruvic acid (32 mg, 0.35 mmol) and 2-(1H-benzo-triazol-1-yl)-1,1,3,3-tetra-methyluronium hexafluorophosphate (225 mg, 0.58 mmol) were dissolved in dichloromethane (4 ml), and this reaction mixture was added dropwise to triethylamine (131 mg, 0.58 mmol) and stirred at room temperature for 19 hours. After completion of the reaction, the reaction mixture was concentrated by distillation under reduced pressure, separated by MPLC (ethyl acetate:hexane=3:7, b...

Claims

1. A compound of the following formula 1 or a pharmaceutically acceptable salt or stereoisomer thereof: [Formula 1] Where X1, X2, X3, X4 and X5 each independently represent -CH=, =CH-, -N= or =N-; or -C= or =C- when substituted by R4 or R5; R1 is halogen, hydroxy, nitro, amino, cyano, C3-C8cycloalkyl, C1-C7alkylamino, di(C1-C7alkyl)amino, C1-C7alkylcarbonyl, halo-C1-C7alkoxy, hydroxy-C1-C7alkyl, hydroxy-C1-C7alkoxy, C1-C7alkylsulfonyl, C1-C7alkylsulfonylamino, aminosulfonyloxy, 4- to 6-membered heterocycloalkyl, 5- or 6-membered heteroaryl, 4- to 6-membered heterocycloalkyl-oxy, 4- to 6-membered heterocyclyl-C1-C7alkoxy, or any one of the following formulae (i) to (vii), wherein the heterocycloalkyl or heteroaryl may be substituted with 1 to 4 substituents selected from the group consisting of hydroxy, carboxy, C1-C7 alkyl, C1-C7 alkylsulfonyl, C1-C7 alkylcarbonyl, hydroxy-C1-C7 alkyl and halophenyl; Ra and Rb each independently represent hydroxy or C1-C7alkoxy; Rc is hydrogen; Rd represents a direct chemical bond, carbonyl or sulfonyl; Re is C1-C7 alkyl, halo-C1-C7 alkyl, C1-C7 alkoxy, amino, or 4-6 membered heterocycloalkyl; Rf is O or S; Rg is hydrogen, C1-C7 alkyl, aminocarbonyl-C1-C7 alkyl, or guanidino-C1-C7 alkyl; Rh is hydrogen, C1-C7 alkyl, di(C1-C7 alkyl)aminoalkyl, or may be condensed with Ri to form a 4-6 membered heterocycloalkyl, wherein the heterocycloalkyl may be substituted with 1-3 substituents selected from the group consisting of C1-C7 alkyl, oxo, amino-C1-C7 alkyl, di(C1-C7 alkyl)amino-C1-C7 alkylcarbonyl, C1-C7 alkoxycarbonyl, 4-6 membered heterocycloalkyl, 4-6 membered heterocycloalkylcarbonyl, pyridyl-C1-C7 alkyl, C1-C7 alkoxy-C1-C7 alkoxy-C1-C7 alkylcarbonyl, and C1-C7 alkylcarbonyl substituted with amino; Ri is hydrogen, C1-C7 alkyl, amino-C1-C7 alkyl, carboxy-C1-C7 alkyl, C1-C7 alkylamino-C1-C7 alkyl, di(C1-C7 alkyl)amino-C1-C7 alkyl, C1-C7 alkylsulfonyl, C1-C7 alkylcarbonyl, 4-6-membered heterocycloalkyl, C1-C7 alkyl substituted with C1-C7 alkoxycarbonyl, guanidino-C1-C7 alkyl substituted with carboxy, or C1-C7 alkoxycarbonyl-C1-C7 alkyl; Rj is a direct chemical bond, C1-C7 alkylene, C6-C 10 arylene-C1-C7alkyleneoxy or C1-C7alkylene substituted with C1-C7alkylcarbonylamino; Rk is C1-C7 alkyl, C1-C7 alkoxycarbonyl-C1-C7 alkyl, C1-C7 alkoxy, tri(C1-C7 alkyl)amino, nitro, C1-C7 alkyl substituted with amino, aminocarbonyl-C1-C7 alkyl, 4-6-membered heterocycloalkyl, or pyridyl; RL is amino or di(C1-C7alkyl)amino; Rm is hydrogen or C1-C7 alkyl; RN is hydrogen or carboxy-C1-C7 alkylcarbonyl; R2 and R3 each independently represent C1-C7 alkyl or halo-C1-C7 alkyl; R4 is hydrogen, halogen, C1-C7 alkyl, C1-C7 alkylcarbonyl, halo-C1-C7 alkyl, carboxy, hydroxy-C1-C7 alkyl, 4-6-membered heterocycloalkylcarbonyl, or 4-6-membered heterocycloalkylcarbonyl substituted with C1-C7 alkyl or C1-C7 alkoxycarbonyl; R5 represents hydrogen; n is an integer from 1 to 3; r and p are integers between 0 and 3; and q represents an integer from 1 to 4; provided that when R1 is hydroxy and n is 1, then i) R2 and R3 are not simultaneously C1-C7 alkyl, ii) at least one of X1, X2, X3, X4 and X5 is nitrogen, or iii) R4 is hydroxy-C1-C7 alkyl, 4-6-membered heterocycloalkylcarbonyl, or 4-6-membered heterocycloalkylcarbonyl substituted with C1-C7 alkyl or C1-C7 alkoxycarbonyl; and when R1 is halogen or C1-C7 alkylamino, R4 and R5 are not both hydrogen; and wherein the 4- to 6-membered heterocycloalkyl has 1 or 2 heteroatoms selected from the group consisting of N and O; and the 5- or 6-membered heteroaryl has 1 or 2 heteroatoms selected from the group consisting of N, O and S.

2. A compound or a pharmaceutically acceptable salt or stereoisomer thereof according to claim 1, wherein the compound of formula 1 is a compound of the following formula 2: [Formula 2] where X1, X2, X4, X5, R1, R2, R3, R4, R5 and n are defined in paragraph 1.

3. A compound or a pharmaceutically acceptable salt or stereoisomer thereof according to claim 1, wherein the compound of formula 1 is a compound of the following formula 3: [Formula 3] where R1, R2, R3, R4, R5 and n are defined in paragraph 1.

4. The compound or its pharmaceutically acceptable salt or stereoisomer according to claim 1, wherein R1 is halogen, hydroxy, nitro, amino, cyano, C3-C8cycloalkyl, C1-C5alkylamino, di(C1-C5alkyl)amino, C1-C5alkylcarbonyl, halo-C1-C5alkoxy, hydroxy-C1-C5alkyl, hydroxy-C1-C5alkoxy, C1-C5alkylsulfonyl, C1-C5alkylsulfonylamino, aminosulfonyloxy, 4-6-membered heterocycloalkyl, 5- or 6-membered heteroaryl, 4-6-membered heterocycloalkyloxy, 4-6-membered heterocyclyl-C1-C5alkoxy, or any one of the following formulae (i) to (vii); wherein heterocycloalkyl may be substituted with 1 to 4 substituents selected from the group consisting of hydroxy, carboxy, C1-C5 alkyl, C1-C5 alkylsulfonyl, C1-C5 alkylcarbonyl, oxo, hydroxy-C1-C5 alkyl and halophenyl; and heteroaryl may be substituted with 1 to 3 substituents selected from the group consisting of hydroxy, C1-C5 alkyl, C1-C5 alkylsulfonyl, C1-C5 alkylcarbonyl and hydroxy-C1-C5 alkyl; Ra and Rb each independently represent hydroxy or C1-C5alkoxy; Rc is hydrogen; Rd represents a direct chemical bond, carbonyl or sulfonyl; Re is C1-C5 alkyl, halo-C1-C5 alkyl, C1-C5 alkoxy, amino, or 4-6 membered heterocycloalkyl; Rf is O or S; Rg is hydrogen, C1-C5 alkyl, aminocarbonyl-C1-C5 alkyl, or guanidino-C1-C5 alkyl; Rh is hydrogen, C1-C5 alkyl, di(C1-C5 alkyl)amino-C1-C5 alkyl, or may be condensed with Ri to form a 4-6 membered heterocycloalkyl, wherein the heterocycloalkyl may be substituted with 1-3 substituents selected from the group consisting of C1-C5 alkyl, oxo, amino-C1-C5 alkyl, di(C1-C5 alkyl)amino-C1-C5 alkylcarbonyl, C1-C5 alkoxycarbonyl, 4-6 membered heterocycloalkyl, 4-6 membered heterocycloalkylcarbonyl, pyridyl-C1-C5 alkyl, C1-C5 alkoxy-C1-C5 alkoxy-C1-C5 alkylcarbonyl, and C1-C5 alkylcarbonyl substituted with amino; Ri represents hydrogen, C1-C5alkyl, amino-C1-C5alkyl, carboxy-C1-C5alkyl, C1-C5alkylamino-C1-C5alkyl, di(C1-C5alkyl)amino-C1-C5alkyl, C1-C5alkylsulfonyl, C1-C5alkylcarbonyl, 4-6 membered heterocycloalkyl, C1-C5alkyl substituted with C1-C5alkoxycarbonyl, guanidino-C1-C5alkyl substituted with carboxy or C1-C5alkoxycarbonyl-C1-C5alkyl; Rj is a direct chemical bond, C1-C5 alkylene, C6-C 10 arylene-C1-C5alkyleneoxy, C1-C5alkylene substituted with C1-C5alkylcarbonylamino; Rk is C1-C5 alkyl, C1-C5 alkoxycarbonyl-C1-C5 alkyl, C1-C5 alkoxy, tri(C1-C5 alkyl)amino, nitro, C1-C5 alkyl substituted with amino, aminocarbonyl-C1-C5 alkyl, 4-6 membered heterocycloalkyl, or pyridyl; Rl is amino or di(C1-C5alkyl)amino; Rm is hydrogen or C1-C5 alkyl; and Rn is hydrogen or carboxy-C1-C5alkylcarbonyl.

5. The compound or pharmaceutically acceptable salt or stereoisomer thereof according to claim 1, wherein R2 and R3 each independently represent C1-C5 alkyl or halo-C1-C5 alkyl.

6. The compound or its pharmaceutically acceptable salt or stereoisomer according to claim 1, wherein R4 is hydrogen, halogen, C1-C5 alkyl, C1-C5 alkylcarbonyl, halo-C1-C5 alkyl, carboxy, hydroxy-C1-C5 alkyl, 4-6-membered heterocycloalkylcarbonyl, or 4-6-membered heterocycloalkylcarbonyl substituted with C1-C5 alkyl or C1-C5 alkoxycarbonyl; and R5 represents hydrogen.

7. A compound or a pharmaceutically acceptable salt or stereoisomer thereof according to claim 1, wherein the compound of formula 1 is selected from the group consisting of the following compounds: 1) 7,7-bis(fluoromethyl)-10-hydroxy-2-phenyl-5,12b-dihydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazine-1,3(2H)-dione; 2) 2-(4-acetylphenyl)-7,7-bis(fluoromethyl)-10-hydroxy-5,12b-dihydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazine-1,3(2H)-dione; 3) N-(2-(4-acetylphenyl)-7,7-dimethyl-1,3-dioxo-2,3,5,12b-tetrahydroxy-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazin-10-yl)acetamide; 4) 2-(4-acetylphenyl)-7,7-dimethyl-10-(methylsulfonyl)-5,12b-dihydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazine-1,3(2H)-dione; 5) N-(2-(4-acetylphenyl)-7,7-dimethyl-1,3-dioxo-2,3,5,12b-tetrahydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazin-10-yl)methanesulfonamide; 6) tert-butyl (2-(4-acetylphenyl)-7,7-dimethyl-1,3-dioxo-2,3,5,12b-tetrahydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2a]pyridazin-10-yl)carbamate; 7) 2-(4-acetylphenyl)-10-amino-7,7-dimethyl-5,12b-dihydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazine-1,3(2H)-dione; 8) 2-(4-acetylphenyl)-7,7-dimethyl-10-morpholino-5,12b-dihydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazine-1,3(2H)-dione; 9) N-(2-(4-acetylphenyl)-7,7-dimethyl-1,3-dioxo-2,3,5,12b-tetrahydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazin-10-yl)sulfate diamide; 10) 2-(4-acetylphenyl)-9,11-dibromo-10-hydroxy-7,7-dimethyl-5,12b-dihydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazine-1,3(2H)-dione; 11) 2-(4-acetylphenyl)-9,11-dichloro-10-hydroxy-7,7-dimethyl-5,12b-dihydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazine-1,3(2H)-dione; 12) 2-(6-fluoropyridin-2-yl)-10-hydroxy-7,7-dimethyl-5,12b-dihydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazine-1,3(2H)-dione; 13) 2-(4-acetylphenyl)-7,7-dimethyl-10-nitro-5,12b-dihydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazine-1,3(2H)-dione; 14) 2-(4-acetylphenyl)-10-(hydroxymethyl)-7,7-dimethyl-5,12b-dihydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazine-1,3(2H)-dione; 15) 1-(2-(4-acetylphenyl)-7,7-dimethyl-1,3-dioxo-2,3,5,12b-tetrahydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazin-10-yl)urea; 16) 2-(4-acetylphenyl)-10-(ethylamino)-7,7-dimethyl-5,12b-dihydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazine-1,3(2H)-dione; 17) 2-(4-acetylphenyl)-7,7-dimethyl-10-((2,2,2-trifluoroethyl)amino)-5,12b-dihydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo-[1,2a]pyridazine-1,3(2H)-dione; 18) 2-(4-acetylphenyl)-7,7-dimethyl-10-(piperazin-1-yl)-5,12b-dihydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazine-1,3(2H)-dione hydrochloride; 19) 2-(4-acetylphenyl)-10-(4-acetylpiperazin-1-yl)-7,7-dimethyl-5,12b-dihydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2a]pyridazine-1,3(2H)-dione; 20) 2-(5-acetylpyridin-2-yl)-10-hydroxy-7,7-dimethyl-5,12b-dihydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazine-1,3(2H)-dione; 21) 10-acetyl-2-(4-acetylphenyl)-7,7-dimethyl-5,12b-dihydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazine-1,3(2H)-dione; 22) 11-acetyl-2-(4-acetylphenyl)-10-hydroxy-7,7-dimethyl-5,12b-dihydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazine-1,3(2H)-dione; 23) 2-(6-acetylpyridin-3-yl)-10-hydroxy-7,7-dimethyl-5,12b-dihydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazine-1,3(2H)-dione; 24) 2-(4-acetylphenyl)-7,7-dimethyl-1,3-dioxo-2,3,5,12b-tetrahydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]-pyridazine-10-carbonitrile; 25) 2-(4-acetylphenyl)-10-hydroxy-7,7-dimethyl-11-(trifluoromethoxy)-5,12b-dihydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo-[1,2-a]pyridazine-1,3(2H)-dione; 26) 2-(4-acetylphenyl)-11-cyclopropyl-10-hydroxy-7,7-dimethyl-5,12b-dihydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2a]pyridazine-1,3(2H)-dione; 27) 2-(4-acetylphenyl)-9,11-difluoro-10-hydroxy-7,7-dimethyl-5,12b-dihydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazine-1,3(2H)-dione; 28) 2-(4-acetylphenyl)-10-amino-9,11-dibromo-7,7-dimethyl-5,12b-dihydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazine-1,3(2H)-dione; 29) 2-(4-acetylphenyl)-10-(isopropylamino)-7,7-dimethyl-5,12b-dihydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazine-1,3(2H)-dione; 30) 2-(4-acetylphenyl)-10-(tert-butylamino)-7,7-dimethyl-5,12b-dihydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazine-1,3(2H)-dione; 31) 2-(4-acetylphenyl)-10-amino-9,11-dichloro-7,7-dimethyl-5,12b-dihydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazine-1,3(2H)-dione; 32) 2-(4-acetylphenyl)-7,7-dimethyl-10-(methylamino)-5,12b-dihydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazine-1,3(2H)-dione; 33) 2-(4-acetylphenyl)-10-(diethylamino)-7,7-dimethyl-5,12b-dihydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazine-1,3(2H)-dione; 34) 2-(4-acetylphenyl)-7,7-dimethyl-10-(pyrrolidin-1-yl)5,12b-dihydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazine-1,3(2H)-dione; 35) 2-(4-fluorophenyl)-7,7-dimethyl-10-(oxetan-3-ylamino)-5,12b-dihydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazine-1,3(2H)-dione; 36) 2-(4-acetylphenyl)-9,11-dichloro-7,7-dimethyl-10-(methylamino)-5,12b-dihydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2a]pyridazine-1,3(2H)-dione; 37) 2-(4-acetylphenyl)-9,11-dichloro-10-(isopropylamino)-7,7-dimethyl-5,12b-dihydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2a]pyridazine-1,3(2H)-dione; 38) 2-(4-acetylphenyl)-10-(1,3-dimethyl-1H-pyrazol-5-yl)-7,7-dimethyl-5,12b-dihydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2a]pyridazine-1,3(2H)-dione; 39) 2-(4-acetylphenyl)-10-(2,5-dimethylthiazol-4-yl)-7,7-dimethyl-5,12b-dihydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2a]pyridazine-1,3(2H)-dione; 40) 2-(4-acetylphenyl)-10-(1-ethyl-3,5-dimethyl-1H-pyrazol-4yl)-7,7-dimethyl-5,12b-dihydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazine-1,3(2H)-dione; 41) 2-(4-acetylphenyl)-7,7-dimethyl-10-(3-methylisoxazol-4yl)-5,12b-dihydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazine-1,3(2H)-dione; 42) 2-(4-acetylphenyl)-7,7-dimethyl-10-(pyridin-3-yl)-5,12b-dihydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazine-1,3(2H)-dione; 43) 2-(4-acetylphenyl)-7,7-dimethyl-10-(pyridin-4-yl)-5,12b-dihydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazine-1,3(2H)-dione; 44) 4-(7,7-dimethyl-1,3-dioxo-10-(pyrrolidin-1-yl)-5,12b-dihydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazin2(3H)-yl)benzoic acid; 45) 2-(4-acetylphenyl)-10-(isopropyl(methyl)amino)-7,7-dimethyl-5,12b-dihydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2a]pyridazine-1,3(2H)-dione; 46) 2-(4-acetylphenyl)-10-(ethyl(isopropyl)amino)-7,7-dimethyl-5,12b-dihydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2a]pyridazine-1,3(2H)-dione; 47) 2-(4-acetylphenyl)-10-(diisopropylamino)-7,7-dimethyl-5,12b-dihydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazine-1,3(2H)-dione; 48) 2-(4-(tert-butyl)phenyl)-7,7-dimethyl-10-(4-methylpiperazin-1-yl)-5,12b-dihydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazine-1,3(2H)-dione; 49) 7,7-dimethyl-10-(4-methylpyrerazin-1-yl)-2-(4-(trifluoromethyl)phenyl)-5,12b-dihydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazine-1,3(2H)-dione; 50) 2-(4-fluorophenyl)-7,7-dimethyl-10-(4-methylpiperazin-1-yl)5,12b-dihydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazine-1,3(2H)-dione; 51) 2-(4-acetylphenyl)-7,7-dimethyl-10-(4-methylpiperazin-1yl)-5,12b-dihydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazine-1,3(2H)-dione; 52) 2-(4-acetylphenyl)-7,7-dimethyl-10-(4-(methylsulfonyl)piperazin-1-yl)-5,12b-dihydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazine-1,3(2H)-dione; 53) 10-hydroxy-7,7-dimethyl-2-(4-(morpholine-4-carbonyl)phenyl)-5,12b-dihydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2a]pyridazine-1,3(2H)-dione; 54) tert-butyl 4-(4-(10-hydroxy-7,7-dimethyl-1,3-dioxo-5,12b-dihydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazin-2(3H)-yl)benzoyl)piperazine-1-carboxylate; 55) 10-hydroxy-7,7-dimethyl-2-(4-(piperazine-1-carbonyl)phenyl)-5,12b-dihydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2a]pyridazine-1,3(2H)-dione; 56) 10-hydroxy-7,7-dimethyl-2-(4-(4-methylpiperazine-1carbonyl)phenyl)-5,12b-dihydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazine-1,3(2H)-dione; 57) 7,7-dimethyl-2-(4-(morpholine-4-carbonyl)phenyl)-10(pyrrolidin-1-yl)-5,12b-dihydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazine-1,3(2H)-dione; 58) 2-(4-acetylphenyl)-7,7-dimethyl-1,3-dioxo-2,3,5,12b-tetrahydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazin-10-yl pivalate; 59) 2-(4-acetylphenyl)-7,7-dimethyl-1,3-dioxo-2,3,5,12b-tetrahydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazin-10-yl 3-methylbutanoate; 60) 2-(4-acetylphenyl)-7,7-dimethyl-1,3-dioxo-2,3,5,12b-tetrahydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazin-10-yl acetate; 61) 2-(4-acetylphenyl)-7,7-dimethyl-1,3-dioxo-2,3,5,12b-tetrahydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazin-10-yl ethyl carbonate; 62) 2-(4-acetylphenyl)-7,7-dimethyl-1,3-dioxo-2,3,5,12b-tetrahydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazin-10-yl dimethylcarbamate; 63) 2-(4-acetylphenyl)-7,7-dimethyl-1,3-dioxo-2,3,5,12b-tetrahydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazin-10-yl morpholine-4-carboxylate; 64) (2S,3S,4S,5R,6S)-6-((2-(4-acetylphenyl)-7,7-dimethyl-1,3dioxo-2,3,5,12b-tetrahydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazin-10-yl)oxy)-3,4,5-trihydroxytetrahydro-2Hpyran-2-carboxylic acid; 65) sodium (2S,3S,4S,5R,6S)-6-((2-(4-acetylphenyl)-7,7dimethyl-1,3-dioxo-2,3,5,12b-tetrahydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazin-10-yl)oxy)-3,4,5-trihydroxy tetrahydro-2H-pyran-2-carboxylate; 66) 2-(4-acetylphenyl)-7,7-dimethyl-1,3-dioxo-2,3,5,12b-tetrahydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazin-10-yl 4-methylpiperazine-1-carboxylate hydrochloride; 67) 2-(4-acetylphenyl)-7,7-dimethyl-1,3-dioxo-2,3,5,12b-tetrahydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazin-10-yl piperazine-1-carboxylate hydrochloride; 68) 2-(4-acetylphenyl)-7,7-dimethyl-1,3-dioxo-2,3,5,12b-tetrahydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazin-10-yl 4-(2-oxopropanoyl)piperazine-1-carboxylate; 69) 2-(4-acetylphenyl)-7,7-dimethyl-1,3-dioxo-2,3,5,12b-tetrahydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazin-10-yl dihydrogen phosphate; 70) disodium 2-(4-acetylphenyl)-7,7-dimethyl-1,3-dioxo-2,3,5,12b-tetrahydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2a]pyridazin-10-yl phosphate; 71) 1,3-dihydroxy-2-(hydroxymethyl)propan-2-aminium 2-(4-acetylphenyl)-7,7-dimethyl-1,3-dioxo-2,3,5,12b-tetrahydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazin-10-yl phosphate; 72) 2-(4-acetylphenyl)-7,7-dimethyl-1,3-dioxo-2,3,5,12b-tetrahydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazin-10-yl dimethylglycinate hydrochloride; 73) 2-(4-acetylphenyl)-7,7-dimethyl-1,3-dioxo-2,3,5,12b-tetrahydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazin-10-yl (2-methoxyethyl)carbonate; 74) 2-(4-acetylphenyl)-7,7-dimethyl-1,3-dioxo-2,3,5,12b-tetrahydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazin-10-yl pyrrolidin-1-carboxylate; 75) 2-(4-acetylphenyl)-7,7-dimethyl-1,3-dioxo-2,3,5,12b-tetrahydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazin-10-yl (2,5,8,11-tetraoxatridecan-13-yl)carbonate; 76) 2-(4-acetylphenyl)-7,7-dimethyl-1,3-dioxo-2,3,5,12b-tetrahydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazin-10-yl diethylcarbamate; 77) 2-(4-acetylphenyl)-7,7-dimethyl-1,3-dioxo-2,3,5,12b-tetrahydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazin-10-yl L-glutamate 2,2,2-trifluoroacetic acid; 78) (((2-(4-acetylphenyl)-7,7-dimethyl-1,3-dioxo-2,3,5,12b-tetrahydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazin-10-yl)oxy)carbonyl)-L-arginine 2,2,2-trifluoroacetic acid; 79) 1-(2-(4-acetylphenyl)-7,7-dimethyl-1,3-dioxo-2,3,5,12b-tetrahydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazin-10-yl) 2-methyl-(2S)-pyrrolidine-1,2-dicarboxylate; 80) methyl (((2-(4-acetylphenyl)-7,7-dimethyl-1,3-dioxo-2,3,5,12b-tetrahydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2a]pyridazin-10-yl)oxy)carbonyl)-L-leucinate; 81) 2-(4-acetylphenyl)-7,7-dimethyl-1,3-dioxo-2,3,5,12b-tetrahydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazin-10-yl L-leucine 2,2,2-trifluoroacetic acid; 82) 2-(4-acetylphenyl)-7,7-dimethyl-1,3-dioxo-2,3,5,12b-tetrahydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazin-10-yl 4-(L-prolyl)piperazine-1-carboxylate hydrochloride; 83) 2-(4-acetylphenyl)-7,7-dimethyl-1,3-dioxo-2,3,5,12b-tetrahydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazin-10-yl methyl(2-(methylamino)ethyl)carbamate 2,2,2-trifluoroacetic acid; 84) 2-(4-acetylphenyl)-7,7-dimethyl-1,3-dioxo-2,3,5,12b-tetrahydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazin-10-yl (2-aminoethyl)(ethyl)carbamate hydrochloride; 85) 2-(4-acetylphenyl)-7,7-dimethyl-1,3-dioxo-2,3,5,12b-tetrahydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazin-10-yl methyl(pyrrolidin-3-yl)carbamate hydrochloride; 86) 2-(4-acetylphenyl)-7,7-dimethyl-1,3-dioxo-2,3,5,12b-tetrahydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazin-10-yl bis(3-(dimethylamino)propyl)carbamate dihydrochloride; 87) N-(((2-(4-acetylphenyl)-7,7-dimethyl-1,3-dioxo-2,3,5,12b-tetrahydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2a]pyridazin-10-yl)oxy)carbonyl)-N-methyl-L-alanine; 88) sodium N-(((2-(4-acetylphenyl)-7,7-dimethyl-1,3-dioxo-2,3,5,12b-tetrahydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2a]pyridazin-10-yl)oxy)carbonyl)-N-methyl-L-alaninate; 89) N-(((2-(4-acetylphenyl)-7,7-dimethyl-1,3-dioxo-2,3,5,12b-tetrahydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2a]pyridazin-10-yl)oxy)carbonyl)-N-methylglycine; 90) sodium N-(((2-(4-acetylphenyl)-7,7-dimethyl-1,3-dioxo-2,3,5,12b-tetrahydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2a]pyridazin-10-yl)oxy)carbonyl)-N-methylglycinate; 91) 3-((((2-(4-acetylphenyl)-7,7-dimethyl-1,3-dioxo-2,3,5,12b-tetrahydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2a]pyridazin-10-yl)oxy)carbonyl)(methyl)amino)propanoic acid; 92) sodium 3-((((2-(4-acetylphenyl)-7,7-dimethyl-1,3-dioxo-2,3,5,12b-tetrahydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2a]pyridazin-10-yl)oxy)carbonyl)(methyl)amino) propanoate; 93) 2-(4-acetylphenyl)-7,7-dimethyl-1,3-dioxo-2,3,5,12b-tetrahydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazin-10-yl 4-(aminomethyl)piperidine-1-carboxylate trifluoroacetate; 94) 2-(4-acetylphenyl)-7,7-dimethyl-1,3-dioxo-2,3,5,12b-tetrahydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazin-10-yl 4-(piperidin-4-yl)piperazine-1-carboxylate dihydrochloride; 95) 2-(4-acetylphenyl)-7,7-dimethyl-1,3-dioxo-2,3,5,12b-tetrahydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazin-10-yl 4-(pyridin-2-ylmethyl)piperazine-1-carboxylate dihydrochloride; 96) 2-(4-acetylphenyl)-7,7-dimethyl-1,3-dioxo-2,3,5,12b-tetrahydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazin-10-yl 4-(2-(2-(2-methoxyethoxy)ethoxy)acetyl)piperazine-1carboxylate; 97) 2-(4-acetylphenyl)-7,7-dimethyl-1,3-dioxo-2,3,5,12b-tetrahydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazin-10-yl 4-(L-valyl)piperazine-1-carboxylate formate; 98) 2-(4-acetylphenyl)-7,7-dimethyl-1,3-dioxo-2,3,5,12b-tetrahydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazin-10-yl 4-(L-leucyl)piperazine-1-carboxylate hydrochloride; 99) 2-(4-acetylphenyl)-7,7-dimethyl-1,3-dioxo-2,3,5,12b-tetrahydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazin-10-yl 4-(dimethylglycyl)piperazine-1-carboxylate hydrochloride; 100) 2-(4-acetylphenyl)-7,7-dimethyl-1,3-dioxo-2,3,5,12b-tetrahydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazin-10-yl 2,6-dimethylpiperazine-1-carboxylate hydrochloride; 101) 2-(4-acetylphenyl)-7,7-dimethyl-1,3-dioxo-2,3,5,12b-tetrahydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazin-10-yl 2,6-dimethyl-4-prolylpiperazine-1-carboxylate hydrochloride; 102) 2-(4-acetylphenyl)-7,7-dimethyl-1,3-dioxo-2,3,5,12b-tetrahydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazin-10-ylheptanoate; 103) 2-(4-acetylphenyl)-7,7-dimethyl-1,3-dioxo-2,3,5,12b-tetrahydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazin-10-yl 2,2-dimethylbutanoate; 104) 2-(4-acetylphenyl)-7,7-dimethyl-1,3-dioxo-2,3,5,12b-tetrahydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazin-10-yl ethylsuccinate; 105) 2-(4-acetylphenyl)-7,7-dimethyl-1,3-dioxo-2,3,5,12b-tetrahydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazin-10-yl diisopropylcarbamate; 106) 2-(4-acetylphenyl)-7,7-dimethyl-1,3-dioxo-2,3,5,12b-tetrahydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazin-10-yl isopropyl carbonate; 107) 2-(4-acetylphenyl)-7,7-dimethyl-1,3-dioxo-2,3,5,12b-tetrahydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazin-10-yl (2-((2-hydroxyethyl)disulfanyl)ethyl)carbonate; 108) 4-(2-((2-((((2-(4-acetylphenyl)-7,7-dimethyl-1,3-dioxo-2,3,5,12b-tetrahydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2a]pyridazin-10-yl)oxy)carbonyl)oxy)ethyl) disulfanyl)ethoxy)-4-oxobutanoic acid; 109) sodium 4-(2-((2-((((2-(4-acetylphenyl)-7,7-dimethyl-1,3dioxo-2,3,5,12b-tetrahydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazin-10-yl)oxy)carbonyl)oxy)ethyl)disulfanyl)ethoxy)-4-oxobutanoate; 110) 2-(4-acetylphenyl)-10-(2-hydroxyethoxy)-7,7-dimethyl-5,12b-dihydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazine-1,3(2H)-dione; 111) 2-((2-(4-acetylphenyl)-7,7-dimethyl-1,3-dioxo-2,3,5,12b-tetrahydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2a]pyridazin-10-yl)oxy)ethyl L-leucinate hydrochloride; 112) 2-(4-acetylphenyl)-7,7-dimethyl-10-(2-(piperidin-1yl)ethoxy)-5,12b-dihydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo-[1,2-a]pyridazine-1,3(2H)-dione hydrochloride; 113) 2-(4-acetylphenyl)-7,7-dimethyl-10-(2-morpholinoethoxy)-5,12b-dihydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2a]pyridazine-1,3(2H)-dione formate; 114) (((2-(4-acetylphenyl)-7,7-dimethyl-1,3-dioxo-2,3,5,12b-tetrahydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazin-10-yl)oxy)methyl)phosphonic acid; 115) disodium (((2-(4-acetylphenyl)-7,7-dimethyl-1,3-dioxo-2,3,5,12b-tetrahydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2a]pyridazin-10-yl)oxy)methyl)phosphonate; 116) 2-((2-(4-acetylphenyl)-7,7-dimethyl-1,3-dioxo-2,3,5,12b-tetrahydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2a]pyridazin-10-yl)oxy)ethyl dimethylglycinate hydrochloride; 117) 2-(4-acetylphenyl)-7,7-dimethyl-1,3-dioxo-2,3,5,12b-tetrahydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazin-10-yl 4-(1-(2-oxopropanoyl)piperidin-4-yl)piperazine-1carboxylate hydrochloride; 118) 2-(4-acetylphenyl)-7,7-dimethyl-1,3-dioxo-2,3,5,12b-tetrahydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazin-10-yl 2,2-dimethylpiperazine-1-carboxylate hydrochloride; 119) 2-(4-acetylphenyl)-7,7-dimethyl-1,3-dioxo-2,3,5,12b-tetrahydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazin-10-yl 4-(dimethylglycyl)-2,2-dimethylpiperazine-1-carboxylate hydrochloride; 120) 2-(4-acetylphenyl)-10-(3-(4-(3-chlorophenyl)piperazin-1yl)propoxy)-7,7-dimethyl-5,12b-dihydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazin-1,3(2H)-dione dihydrochloride; 121) 2-(4-acetylphenyl)-7,7-dimethyl-10-(((2S,3R,4S,5S,6R)3,4,5-trihydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-2yl)oxy)-5,12b-dihydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2a]pyridazine-1,3(2H)-dione; 122) 2-(4-acetylphenyl)-7,7-dimethyl-10-(((2S,3R,4S,5R,6R)3,4,5-trihydroxy-6-(hydroxymethyl)tetrahydro- 2H-pyran-2-yl)oxy)-5,12b-dihydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2a]pyridazine-1,3(2H)-dione; 123) 2-((2-(4-acetylphenyl)-7,7-dimethyl-1,3-dioxo-2,3,5,12b-tetrahydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2a]pyridazin-10-yl)oxy)-N,N,N-oxomethane-1-aminoe iodide; 124) 2-(4-acetylphenyl)-7,7-dimethyl-1,3-dioxo-2,3,5,12b-tetrahydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazin-10-yl (4-nitrobenzyl)carbonate; 125) 2-(4-acetylphenyl)-7,7-dimethyl-1,3-dioxo-2,3,5,12b-tetrahydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazin-10-yl piperidin-1-carboxylate; 126) O-(2-(4-acetylphenyl)-7,7-dimethyl-1,3-dioxo-2,3,5,12b-tetrahydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazin-10-yl) dimethyl mothionate; 127) 2-(4-acetylphenyl)-7,7-dimethyl-1,3-dioxo-2,3,5,12b-tetrahydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazin-10-yl 2-oxoimidazolidine-1-carboxylate; 128) 2-(4-acetylphenyl)-7,7-dimethyl-1,3-dioxo-2,3,5,12b-tetrahydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazin-10-yl (3-(dimethylamino)-2,2-dimethylpropyl)carbamate formate; 129) 2-(4-acetylphenyl)-7,7-dimethyl-1,3-dioxo-2,3,5,12b-tetrahydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazin-10-yl (2-(dimethylamino)ethyl)(methyl)carbamate formate; 130) 2-(4-acetylphenyl)-7,7-dimethyl-1,3-dioxo-2,3,5,12b-tetrahydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazin-10-yl methyl(piperidin-3-yl)carbamate hydrochloride; 131) 2-(4-acetylphenyl)-7,7-dimethyl-1,3-dioxo-2,3,5,12b-tetrahydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazin-10-yl methyl(methylsulfonyl)carbamate; 132) 2-(4-acetylphenyl)-7,7-dimethyl-1,3-dioxo-2,3,5,12b-tetrahydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazin-10-yl L-valinate 2,2,2-trifluoroacetic acid; 133) 2-(4-acetylphenyl)-7,7-dimethyl-1,3-dioxo-2,3,5,12b-tetrahydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazin-10-yl L-prolinate 2,2,2-trifluoroacetic acid; 134) 2-(4-acetylphenyl)-7,7-dimethyl-1,3-dioxo-2,3,5,12b-tetrahydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazin-10-yl acetyl-L-glutaminate; 135) 2-(4-acetylphenyl)-7,7-dimethyl-1,3-dioxo-2,3,5,12b-tetrahydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazin-10-yl L-argininate 2,2,2-trifluoroacetic acid; 136) methyl (((2-(4-acetylphenyl)-7,7-dimethyl-1,3-dioxo-2,3,5,12b-tetrahydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2a]pyridazin-10-yl)oxy)carbonyl)-L-valinate; 137) 2-(4-acetylphenyl)-7,7-dimethyl-1,3-dioxo-2,3,5,12b-tetrahydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazin-10-yl sulfamate; 138) 2-(4-acetylphenyl)-7,7-dimethyl-1,3-dioxo-2,3,5,12b-tetrahydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazin-10-yl picolinate hydrochloride; 139) 2-(4-acetylphenyl)-7,7-dimethyl-1,3-dioxo-2,3,5,12b-tetrahydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazin-10-yl isonicotinate hydrochloride; 140) 10-hydroxy-2-(4-(1-hydroxyethyl)phenyl)-7,7-dimethyl-5,12b-dihydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazine-1,3(2H)-dione; 141) 2-(4-acetylphenyl)-10-(azetidin-1-yl)-7,7-dimethyl-5,12b-dihydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazine-1,3(2H)-dione; 142) 7,7-dimethyl-1,3-dioxo-2-(4-(trifluoromethyl)phenyl)2,3,5,12b-tetrahydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2a]pyridazin-10-yl dihydrogen phosphate; 143) 2-(4-fluorophenyl)-7,7-dimethyl-1,3-dioxo-2,3,5,12b-tetrahydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazin-10-yl dihydrogen phosphate; 144) 2-(4-(tert-butyl)phenyl)-7,7-dimethyl-1,3-dioxo-2,3,5,12b-tetrahydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2a]pyridazin-10-yl dihydrogen phosphate; 145) 7,7-dimethyl-1,3-dioxo-2-(4-(trifluoromethyl)phenyl)2,3,5,12b-tetrahydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2a]pyridazin-10-yl dimethylcarbamate; 146) 2-(4-fluorophenyl)-7,7-dimethyl-1,3-dioxo-2,3,5,12b-tetrahydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazin-10-yl dimethylcarbamate and 147) 2-(4-(tert-butyl)phenyl)-7,7-dimethyl-1,3-dioxo-2,3,5,12b-tetrahydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2a]pyridazin-10-yl dimethylcarbamate.

8. A pharmaceutical composition having an inhibitory effect on macrophages, comprising a therapeutically effective amount of a compound or a pharmaceutically acceptable salt or stereoisomer according to any one of claims 1 to 7 as an active ingredient together with a pharmaceutically acceptable carrier.

9. The pharmaceutical composition according to claim 8, which is intended for the treatment of a cancer disease selected from the group consisting of colon cancer, skin cancer, melanoma, glioblastoma, bone cancer, liver cancer, stomach cancer, pancreatic cancer, colon cancer, rectal cancer, blood cancer, bladder cancer, kidney cancer, bile duct cancer, cervical cancer, uterine cancer, ovarian cancer, breast cancer, lung cancer, non-small cell lung cancer, esophageal cancer, small intestine cancer, endocrine cancer, thyroid and parathyroid cancer.

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