KR101869534B1 - Novel Triazolo Pyridazine Derivatives and Use Thereof - Google Patents

Abstract

The present invention relates to a novel triazolo pyridazine derivative or a pharmaceutically acceptable salt thereof, a pharmaceutical composition for inhibiting c-Met tyrosine kinase activity and an agent for preventing or treating hyperproliferative disorder, ≪ / RTI >
The present invention relates to a therapeutic agent for a variety of abnormal proliferative diseases associated with excessive cell proliferation and growth due to abnormal kinase activity, for example, cancer, psoriasis, rheumatoid arthritis, diabetic retinopathy, etc. by efficiently inhibiting the activity of c-Met tyrosine kinase Can be usefully used.

Description

Novel Triazolopyridazine Derivatives and Their Use {Novel Triazolo Pyridazine Derivatives and Use Thereof}

The present invention relates to a novel triazolo pyridazine derivative having tyrosine kinase inhibitory activity and a pharmaceutical composition comprising the compound as an active ingredient.

The ligand of the hepatocyte growth factor receptor (c-MET or HGFR) tyrosine kinase (RTK) is HGF or a scatter factor [L. Naldini, KM Weidner, E. Vigna, G. Gaudino, A. Bardelli, C. Ponzetto, G. Michalopoulos , Eur . Mol . Biol . Org . J. 10: 2867-2878 (1991); DP Bottaro, JS Rubin, DL Faletto, AM Chan, TE Kmiecik, GF Vande Woude, SA Aaronson, Science 251: 802-804 (1991)], and is a disulfide-linked heterodimeric protein mainly produced by mesenchymal cells. Hepatocyte growth factor (HGF) binds to c-Met with strong binding and is automatically phosphorylated to a specific tyrosine kinase in the cell. When activated, cell growth, survival, neovascularization, wound healing, tissue regeneration, motility, invasion, and morphogenesis. Although c-Met and HGF are expressed in many tissues, their expression normally occurs in tissues composed mainly of epithelium and mesenchymal cells and is required for normal mammalian development and is involved in cell migration, cell proliferation and survival, differentiation, . In addition, HGF / SF is a neovascularization factor, and c-Met signaling in epithelial cells can induce many things such as cell proliferation, motility, and invasiveness essential for neovascularization.

The c-Met receptor has been shown to be expressed in many human cancers. In addition, c-Met gene amplification, mutation and rearrangement were observed in various human cancers. Overexpression of c-Met and its ligand, HGF, has also been reported in a variety of human cancers such as brain tumors, lung cancer, stomach cancer, pancreatic cancer, colon cancer, ovarian cancer, renal cell cancer, prostate cancer and the like (Oncology Reports, 5: 1013 (1998)). Classes with mutations that activate c-Met kinase are susceptible to multiple renal tumors and tumors of other tissues. Overexpression of c-Met or HGF has also been shown to correlate with poor prognosis and disease outcome in many major human cancers, including lung, liver, stomach and breast, and c-Met has also been associated with pancreatic cancer (RM Thomas, K Toney, Fenoglio-Preiser, MP Revelo-Penafiel, SR Hingorani, DA Tuveson, SE Waltz, AM Lowy, Cancer Res 2007, 67, 6075; ER Camp, A. Yang, MJ Gray, F. Fan, SR Hamilton, Hewlett, E. Pereira, DJ Hicklin, LM Ellis, CANCER , 109: 1031 (2007)) and glioma (B. Wullich, HP Sattler, U. Fischer, E. Meese, T, Anticancer Res . 14: 577-579 (1994)). In particular, c-Met overexpression and elevated levels of HGF in serum have been reported in gastric cancer ( Int . J. Cancer , 55: 72 (1993)).

Therefore, inhibition of hepatocyte growth factor receptor (c-Met or HGFR) tyrosine kinase (RTK), which is involved in various cancer growth and cell migration, cell proliferation and survival, differentiation, and tissue arrangement, leads to termination and degeneration of tumor formation.

Compounds that inhibit the signaling of HGF developed so far have been developed in clinical and preclinical studies, and inhibitors under development include c-Met, depending on the type of binding to the hinge binding domain of c-Met kinase And a selective inhibitor that inhibits c-Met alone. Currently c-Met selective inhibitors have been reported in ARQ-197, Pf-02341066, PF-04217903 and Johnson-Johnson's JNJ-38877605, as well as SGX, Sanofi-Aventis, Vertex and Amgen, It is in progress.

However, none of the literatures reported to date disclose effective synthesis of pyridoxazine derivatives as a compound characterized by the present invention.

The present inventors have sought to elucidate a compound having an inhibitory activity against tyrosine kinase to develop a composition for effectively preventing or treating various hyperproliferative disorders caused by the activity of abnormal tyrosine kinases. As a result, the novel triazolopyridazine derivative of the above formula (1), which has not been known until now, binds hepatocyte growth factor (HGF) and activates phosphorylation, thereby inducing cell proliferation, migration, infiltration and formation of new blood vessels Lt; RTI ID = 0.0 > c-Met < / RTI > kinase.

It is therefore an object of the present invention to provide a novel triazolo pyridazine derivative or a pharmaceutically acceptable salt thereof.

Another object of the present invention is to provide a pharmaceutical composition for inhibiting c-Met tyrosine kinase activity comprising the novel triazolo pyridazine derivative, a pharmaceutically acceptable salt thereof or a solvate thereof as an active ingredient.

Another object of the present invention is to provide a pharmaceutical composition for the prevention or treatment of a hyperproliferative disorder comprising the novel triazolopyridazine derivative, a pharmaceutically acceptable salt thereof or a solvate thereof as an active ingredient I have to.

Other objects and advantages of the present invention will become more apparent from the following detailed description of the invention, claims and drawings.

According to one aspect of the present invention, there is provided a triazolo pyridazine derivative represented by the following formula (I) or a pharmaceutically acceptable salt thereof.

Formula 1

In the above formulas, A is aryl or heteroaryl of five-to-ten each ring; R ₁ To R ₅ are each independently hydrogen or C ₁ -C ₅ alkyl; R ₆ is hydrogen, hydroxy, cyano, halogen, C ₁ -C ₄ alcohol, 5 each -6 heterocycloalkyl of each ring, each unsubstituted or substituted 5 -6 substituted with heterocycloalkyl, each of the ring C ₁ - C ₅ alkyl, unsubstituted or substituted 5 each -6 substituted with heterocycloalkyl rings, each of C ₁ -C ₃ alkoxy, C ₁ -C ₅ alkyl ester, an unsubstituted or substituted by C ₁ -C ₅ alkylamine, - C (= O) NR ₇ R ₈ , wherein R ₇ and R ₈ are each independently hydrogen or C ₁ -C ₅ alkyl, or R ₇ and R ₈ are heterocycloalkyl of a five- ≪ / RTI > n is an integer of 0-5.

The present inventors have sought to elucidate a compound having an inhibitory activity against tyrosine kinase to develop a composition for effectively preventing or treating various hyperproliferative disorders caused by the activity of abnormal tyrosine kinases. As a result, it has been found that the novel triazolopyridazine derivatives of the above formula (1), which have not been known so far, significantly inhibit the activity of c-Met kinase.

According to the present invention, the compound of formula (I) of the present invention is a compound of the formula (I) of the present invention which binds to hepatocyte growth factor (HGF) and activates phosphorylation to induce cell proliferation, migration, invasion and formation of neovascularization Significantly inhibits the activity. Accordingly, the compounds of the present invention can be usefully used for treating or preventing various abnormal proliferative diseases mediated by abnormal proliferation of cells and excessive angiogenesis.

As used herein, the term " aryl " means a substituted or unsubstituted monocyclic or polycyclic carbon ring that is totally or partially unsaturated and has aromaticity.

As used herein, the term " heteroaryl " means a heterocyclic aromatic group containing a hetero atom, oxygen, sulfur or nitrogen, in the ring. Preferably, the heteroatom is nitrogen or oxygen. The number of heteroatoms is 1-4, preferably 1-2. In heteroaryl, aryl is preferably monoaryl or biaryl.

As used herein, the term " alkyl " means a straight or branched saturated hydrocarbon group, including, for example, methyl, ethyl, propyl, isobutyl, pentyl or hexyl. C ₁ -C ₅ Alkyl means an alkyl group having an alkyl unit having 1 to 5 carbon atoms, and when C ₁ -C ₅ alkyl is substituted, the number of carbon atoms of the substituent is not included. In formula (1), R ₁ R ₅ to the position of C ₁ -C ₅ Alkyl is preferably C ₁ -C ₃ Alkyl, more preferably C ₁ -C ₂ Alkyl.

As used herein, the term " halogen " refers to a halogen group element and includes, for example, fluoro, chloro, bromo and iodo.

As used herein, the term " heterocycloalkyl " refers to a saturated carbon ring that contains a heteroatom containing oxygen, sulfur, or nitrogen in the ring. Preferably, the heteroatom is nitrogen or oxygen. The number of heteroatoms is 1-4, preferably 1-2. "Heterocycloalkyl of 5-membered to 6-membered rings" means that the sum of the numbers of carbon and heteroatoms forming the ring is 5-6.

As used herein, the term " alkoxy " means a radical formed by removing hydrogen from an alcohol, and when C ₁ -C ₃ alkoxy is substituted, the number of carbon atoms of the substituent is not included.

The term " C ₁ -C ₅ alkyl ester " as used herein means an ester in which a C ₁ -C ₅ alkoxy group is bonded to an acyl group (-C (O) -).

According to a preferred embodiment of the present invention, A of the present invention is phenyl, pyrazole, pyridine, indole or indazole; R ₁ To R < ₅ > are hydrogen; R ₆ is selected from the group consisting of hydrogen, hydroxy, cyano, halogen, C ₁ -C ₂ alcohol, piperidine, piperazine, morpholine, C ₁ -C ₃ unsubstituted or substituted by piperidine, piperazine or morpholine amine, -C (= O) substituted alkyl, unsubstituted or substituted piperidine, piperazine or morpholine substituted C ₁ -C ₂ alkoxy, C ₁ -C ₃ alkyl esters, C ₁ -C ₃ alkyl, NR ₇ R _{8 wherein} R ₇ and R ₈ are each independently hydrogen or C ₁ -C ₃ alkyl or R ₇ And R < ₈ > are cyclic linked piperazines; n is an integer of 1-3.

According to a more preferred embodiment of the present invention, the triazolopyridazine derivative represented by the formula (1) of the present invention is selected from the group consisting of the compounds represented by the following formulas (2) to (26)

      (2)

(4)

(6)

(8)

(10)

(12)

(14)

   (16)

    (18)

    (20)

(22)

     (24)

     26

Most preferably, the triazolopyridazine derivative of the present invention is selected from the group consisting of the compounds represented by the above formulas 2 to 5, 14 to 16, 18, 20, 22 and 26.

According to the present invention, the 11 compounds listed above have very low IC ₅₀ < RTI ID = 0.0 > Value. They can therefore be used as highly effective therapeutic compositions for a variety of atherogenic disorders.

The triazolopyridazine derivative of the present invention can be used in the form of a pharmaceutically acceptable salt, and as the salt, an acid addition salt formed by a pharmaceutically acceptable free acid is useful. As the free acid, inorganic acid and organic acid can be used. Preferably, the pharmaceutically acceptable salts of the triazolopyridazine derivatives of the present invention are those derived from the hydrochloride, bromate, sulfate, phosphate, citrate, acetate, trifluoroacetate, lactate, tartrate, maleate, fumarate, But are not limited to, gluconate, methanesulfonate, glycolate, succinate, 4-toluenesulfonate, gluturonate, ebonate, glutamate, or aspartate salts, And salts formed using various inorganic and organic acids commonly used in the art.

The triazolopyridazine derivative of the present invention may also exist in the form of a solvate (for example, a hydrate).

According to another aspect of the present invention, there is provided a pharmaceutical composition for inhibiting c-Met tyrosine kinase activity comprising the above-mentioned triazolo pyridazine derivative of the present invention, a pharmaceutically acceptable salt thereof or a solvate thereof as an active ingredient .

According to another aspect of the present invention, there is provided a method of preventing or treating a hyperproliferative disorder comprising the above-mentioned triazolo pyridazine derivative of the present invention, a pharmaceutically acceptable salt thereof or a solvate thereof as an active ingredient, There is provided a therapeutic pharmaceutical composition.

Since the novel triazolo pyridazine derivatives used in the present invention have already been described above, they are omitted in order to avoid excessive overlapping.

As used herein, the term " hyperproliferative disorder " refers to a pathological state caused by excessive cell growth, division, and migration that is not normally regulated by the general restriction means in the growing animal. The diarrheal diseases to be prevented or treated with the composition of the present invention include, for example, cancer, diabetic retinopathy, retinopathy of prematurity, corneal transplant rejection, neovascular glaucoma, hypoxia, proliferative retinopathy, psoriasis, rheumatoid arthritis, osteoarthritis, Including, but not limited to, Crohn's disease, recurrent stenosis, atherosclerosis, intestinal adhesion, ulceration, hepatopathy, glomerulonephritis, diabetic nephropathy, malignant neuropathy, thrombotic microangiopathy, All of which are caused by abnormal proliferation of blood vessels and excessive production of new blood vessels.

More preferably, the cancer, which is one of the abnormal hyperproliferative diseases that can be prevented and treated with the composition of the present invention, is lung cancer, gastric cancer, pancreatic cancer, colon cancer, ovarian cancer, renal cell cancer, prostate cancer or brain tumor.

When the composition of the present invention is manufactured from a pharmaceutical composition, the pharmaceutical composition of the present invention includes a pharmaceutically acceptable carrier. The pharmaceutically acceptable carriers to be contained in the pharmaceutical composition of the present invention are those conventionally used in the present invention and include lactose, dextrose, sucrose, sorbitol, mannitol, starch, acacia rubber, calcium phosphate, alginate, gelatin, But are not limited to, calcium silicate, microcrystalline cellulose, polyvinylpyrrolidone, cellulose, water, syrups, methylcellulose, methylhydroxybenzoate, propylhydroxybenzoate, talc, magnesium stearate and mineral oil. It is not. The pharmaceutical composition of the present invention may further contain a lubricant, a wetting agent, a sweetening agent, a flavoring agent, an emulsifying agent, a suspending agent, a preservative, etc. in addition to the above components. Suitable pharmaceutically acceptable carriers and formulations are described in detail in Remington ' s Pharmaceutical Sciences (19th ed., 1995).

The pharmaceutical composition of the present invention can be administered orally or parenterally, and in the case of parenteral administration, it can be administered by intravenous injection, subcutaneous injection, muscle injection, intraperitoneal injection, transdermal administration or the like.

The appropriate dosage of the pharmaceutical composition of the present invention may vary depending on factors such as the formulation method, administration method, age, body weight, sex, pathological condition, food, administration time, administration route, excretion rate, . The daily dosage of the pharmaceutical composition of the present invention is, for example, 0.001-100 mg / kg.

The pharmaceutical composition of the present invention may be formulated into a conventional preparation using pharmaceutically acceptable carrier and / or excipient according to a method which can be easily carried out by a person having ordinary skill in the art to which the present invention belongs May be prepared in unit dosage form or may be manufactured by intrusion into a multi-dose container. Typical formulations are, for example, oral (tablets, capsules, powders), intraoral, sublingual, rectal, vaginal, intranasal, topical or parenteral (intravenous, intracameral, intramuscular, subcutaneous And intravenous) administration formulations. For example, a compound according to the present invention may be in the form of tablets containing starch or lactose, in the form of capsules containing the active ingredient alone or in an excipient, or in the form of an elixir or suspension containing a chemical that tastes or colors For example, orally, buccally or sublingually. Liquid preparations may contain suspending agents (e. G., A mixture of a semisynthetic glyceride such as methylcellulose, witepsol or apricot kernel oil and a PEG-6 ester or a mixture of PEG-8 and caprylic / Such as a glyceride mixture, such as a mixture of glycerides (e.g., a mixture of glycerides). It is also most preferred to use it as a sterile aqueous solution form when injected parenterally, for example, intravenously, intraperitoneally, intramuscularly, subcutaneously, and intratracheally, wherein the solution is administered in order to have isotonicity with the blood It may contain other substances (for example, salts or monosaccharides such as mannitol, glucose).

The features and advantages of the present invention are summarized as follows:

(a) The present invention relates to a novel triazolopyridazine derivative or a pharmaceutically acceptable salt thereof, a pharmaceutical composition for inhibiting c-Met tyrosine kinase activity comprising these as an active ingredient and a prophylactic or therapeutic agent for hyperproliferative disorder, There is provided a therapeutic pharmaceutical composition.

(b) The present invention relates to a method for effectively inhibiting the activity of c-Met tyrosine kinase, thereby inhibiting a variety of abnormal proliferative diseases associated with excessive cell growth and growth due to abnormal kinase activity, such as cancer, psoriasis, rheumatoid arthritis, And the like.

Hereinafter, the present invention will be described in more detail with reference to Examples. It is to be understood by those skilled in the art that these embodiments are only for describing the present invention in more detail and that the scope of the present invention is not limited by these embodiments in accordance with the gist of the present invention .

Example

Triazolo Pyridazine  The synthesis route of the derivative

The triazolepyridazine derivative of formula (1) of the present invention can be obtained by proceeding as shown in the following reaction formula (1).

<Reaction Scheme 1>

The synthesis of important intermediates represented by the above formulas (2) and (6) used in Reaction Scheme 1 was first disclosed by the present inventors. 3-Chloro-6-hydrazinylpyridazine represented by the formula (3) is commercially available or can be prepared according to J. Med . Chem . 30, 239-249 (1987). The preparation of the compound of formula (4) can be carried out by first coupling the compound of formula (2) and the compound of formula (3) by coupling with EDCI (1-Ethyl- 3- (3-dimethylaminopropyl) carbodiimide) , The triazolepyridazine derivative 5 in which the chloro group (Cl) is substituted can be obtained. (5) can be prepared by reacting a boronic acid or a boronic acid pinacol ester substituted with an aryl or heteroaryl group of a substituted pentagonal or hexagonal ring, . When trifluoroacetic acid (CF ₃ COOH) is added and heated, the aimed compound (1) in which the para-methoxybenzyl (PMB) protecting group of the pyridooxazole group is removed can be obtained.

In addition, the formula and then by hydrazine (NH ₂ NH ₂₎ and reaction with, and to obtain the same compound (9), well known in the ester method from the ester compound (6) of formula (2) obtained Hydra Zaid 7 (8) and butanol (n-BuOH) to obtain the target compound (9). At this time, the substituted chloropyridazine can be obtained by reacting 2,6-dichloropyridazine with various substituents such as boronic acid or boronic acid pinacol ester and palladium catalyst.

In the above Reaction Scheme 1, the formula (2) can be prepared in the same manner as in Reaction Scheme 2 below.

<Reaction Scheme 2>

Synthesis of pyridoxazine ethyl ester represented by formula (10) was prepared by the method disclosed in Tetrahedron 58 (2008) and 8145-8152 or US6465467 (2002). That is, 2-amino-3-hydroxypyridine and diethyl chloromalonate were heated and refluxed in the presence of an organic base to obtain the compound of formula (10). Amide was obtained by introducing a p-methoxybenzyl protecting group and reducing the amide and ester groups with borane (BH ₃ ) to obtain pyridoxime methanol (12) as an intermediate. In order to expand one methyl group, p-toluenesulfonyl is introduced into alcohol and then sodium cyanide (NaCN) is added thereto to obtain chemical formula (13). -CN group was reduced with DIBAL-H (Diisopropylaluminium hydride) to obtain aldehyde, and then carboxylic acid (2) was obtained by oxidation reaction using NaCl ₂ O ₂ .

The triazolepyridazine derivatives synthesized through the above synthetic schemes (Reaction Schemes 1 and 2) are as follows:

(1, 2, 4] triazolo [4,3-b] pyridazin-3- yl) methyl) - 3,4-dihydro-2H-pyrido [3,2-b] [1,4] oxazine;

(2) Synthesis of 2- (4- (3 - ((3,4-dihydro-2H-pyrido [3,2- b] [1,4] oxazin- , 4] triazolo [4,3-b] pyridazin-6-yl) -1H-pyrazol-1-yl) ethanol;

(3) Synthesis of 2 - ((6- (1- (piperidin-4-yl) -1H-pyrazol-4-yl) - [1,2,4] triazolo [ Yl) methyl) -3,4-dihydro-2H-pyrido [3,2-b] [1,4] oxazine;

(4) Synthesis of 4- (3 - ((3,4-dihydro-2H-pyrido [3,2- Triazolo [4,3-b] pyridazin-6-yl) -2-fluorophenol

(5) Synthesis of 2 - ((6- (3-fluoro-4- (2- (4- methylpiperazin- 1 -yl) ethoxy) phenyl) - [1,2,4] triazolo [ -b] pyridazin-3-yl) methyl) -3,4-dihydro-2H-pyrido [3,2- b] [1,4]

(6) Synthesis of 2 - ((6- (1 -methyl-1 H-indol-3-yl) - [1,2,4] triazolo [4,3- b] pyridazin- , 4-dihydro-2H-pyrido [3,2-b] [1,4] oxazine;

(7) Synthesis of 2 - ((6-phenyl- [1,2,4] triazolo [4,3- b] pyridazin-3-yl) methyl) -3,4-dihydro-2H- , 2-b] [l, 4] oxazine;

(8) Synthesis of 2 - ((6- (4-fluorophenyl) - [1,2,4] triazolo [4,3- b] pyridazin- 2H-pyrido [3,2-b] [1,4] oxazine;

(9) Synthesis of 2 - ((6- (3-fluorophenyl) - [1,2,4] triazolo [4,3- b] pyridazin- 2H-pyrido [3,2-b] [1,4] oxazine;

(10) Synthesis of 2 - ((6- (3,5-difluorophenyl) - [1,2,4] triazolo [4,3- b] pyridazin- Dihydro-2H-pyrido [3,2-b] [1,4] oxazine;

(11) Synthesis of 2 - ((6- (3-fluoro-4-methylphenyl) - [1,2,4] triazolo [4,3- b] pyridazin- Dihydro-2H-pyrido [3,2-b] [1,4] oxazine;

(12) 3- (3 - ((3,4-Dihydro-2H-pyrido [3,2- b] [1,4] oxazin- Triazolo [4,3-b] pyridazin-6-yl) benzonitrile;

(13) Synthesis of 2 - ((6- (pyridin-4-yl) - [1,2,4] triazolo [4,3- b] pyridazin- 2H-pyrido [3,2-b] [1,4] oxazine;

(14) Synthesis of 2 - ((6- (pyridin-3-yl) - [1,2,4] triazolo [4,3- b] pyridazin- 2H-pyrido [3,2-b] [1,4] oxazine;

(15) Synthesis of 2 - ((6- (4-methoxyphenyl) - [1,2,4] triazolo [4,3- b] pyridazin- 2H-pyrido [3,2-b] [1,4] oxazine;

(16) Synthesis of 4- (3 - ((3,4-dihydro-2H-pyrido [3,2- b] [1,4] oxazin- Triazolo [4,3-b] pyridazin-6-yl) -N, N-dimethylbenzeneamine;

(17) Synthesis of methyl 4- (3 - ((3,4-dihydro-2H-pyrido [3,2-b] [1,4] oxazin- ] Triazolo [4,3-b] pyridazin-6-yl) benzoate;

(18) Synthesis of methyl 3- (3 - ((3,4-dihydro-2H-pyrido [3,2- b] [1,4] oxazin- ] Triazolo [4,3-b] pyridazin-6-yl) benzoate

(19) (4- (3 - ((3,4-Dihydro-2H-pyrido [3,2- b] [1,4] oxazin- ] Triazolo [4,3-b] pyridazin-6-yl) phenyl) methanol;

(20) 2- ((6- (4- (morpholinomethyl) phenyl) - [1,2,4] triazolo [4,3- b] pyridazin- - dihydro-2H-pyrido [3,2-b] [1,4] oxazine;

(21) (3- (3 - ((3,4-dihydro- 2H -pyrido [3,2- b ] [1,4] oxazin- 4] triazolo [4,3- b ] pyridazin-6-yl) phenyl) (4-methylpiperazin-

(22) (4- (3 - ((3,4-Dihydro-2H-pyrido [3,2- b] [1,4] oxazin- ] Triazolo [4,3-b] pyridazin-6-yl) phenyl) (4-methyl-1-yl) methanone;

(23) 3- (3 - ((3,4-Dihydro-2H-pyrido [3,2-b] [1,4] oxazin- Triazolo [4,3-b] pyridazin-6-yl) -N-ethylbenzamide;

(24) (3- (3 - ((3,4-Dihydro-2H-pyrido [3,2- b] [1,4] oxazin-2-yl) methyl) - [ ] Triazolo [4,3-b] pyridazin-6-yl) phenyl) (4-methylpiperazin-1-yl) methanone;

(25) 2 - ((6- (1 -methyl-1 H-indazol-3-yl) - [1,2,4] triazolo [4,3- b] pyridazin- 3,4-dihydro-2H-pyrido [3,2-b] [1,4] oxazine;

Each Triazolo Pyridazine  Specific synthesis method of derivatives

Example  1. Ethyl 3-oxo-3,4- Dihydro -2H- Pyrido [3,2-b] [1,4] oxazine -2- Carboxylester

After dissolving 2-amino-3-hydroxypyridine (5 g, 45.4 mmol) in ethanol (90 mL), triethylamine (6.3 mL, 45.4 mmol) and diethyl 2- chloromalonate ), And the mixture was heated under reflux for 16 hours. The resulting solid was filtered and washed with cold ethanol to give ethyl 3-oxo-3,4-dihydro-2H-pyrido [3,2- b] [1,4] (6.41 g, 64%).

^{1 H-NMR (300 MHz,} CDCl 3) δ 11.65 (brs, 1H), 8.12 (d, J = 6.0 Hz, 1H), 7.41 (d, J = 8.0 Hz, 1H), 7.02 (dd, J = 9.0 , 6.0 Hz, 1H), 4.27 (q, J = 7.5 Hz, 2H) 3.83 (s, 1H), 1.26 (t, J = 7.5 Hz, 3H)

Example  2. (4- (4-Methoxybenzyl) -3,4- Dihydro -2H- Pyrido [3,2-b] [1,4] oxazine Yl) methanol

Oxo-3,4-dihydro-2H-pyrido [3,2-b] [1,4] oxazine-2- carboxylic ester (9.1 g, 40.95 mmol) After dissolving, potassium carbonate (17 g, 122.8 mmol) and 4-methoxybenzyl chloride (PMBCl, 5.8 mL, 43 mmol) were added and stirred at 50 ° C for 2 hours. After the reaction, ethyl acetate was added, and the organic layer was washed with brine several times, dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure. The residue was purified by column chromatography (20% EtOAc / hexane) to obtain ethyl 4- (4-methoxybenzyl) -3-oxo-3,4-dihydro-2H-pyrido [ b] [1,4] oxazine-2-carboxylate (12.2 g, 87%).

^{1 H-NMR (300 MHz,} CDCl 3) δ 8.06 (d, J = 6.0 Hz, 1H), 7.39 (d, J = 8.8 Hz, 2H), 7.33 (d, J = 8.0 Hz, 1H), 6.96 ( dd, J = 8.0, 6.0 Hz , 1H), 6.80 (d, J = 8.8 Hz, 2H), 5.27 (ABq, J = 14.0 Hz, 2H), 5.26 (s, 1H), 4.21 (q, J = 7.0 Hz, 2H), 3.76 (s, 3H), 1.24 (t, J = 7.0 Hz, 3H).

3-oxo-3,4-dihydro-2H-pyrido [3,2-b] [1,4] oxazine-2- carboxylate (27 g, 78.9 mmol) was dissolved in dry tetrahydrofuran (250 mL), BH ₃ SMe ₂ (2.0 M in THF, 178 mL, 355 mmol) was added slowly and the mixture was refluxed for 48 hours. After the reaction, the reaction mixture was cooled to 0 ° C, and 2N-calcium carbonate aqueous solution was carefully added to decompose excess BH ₃ SMe _2. Then, ethyl acetate was added and the organic layer was washed with brine several times. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography (30% EtOAC / hexane) to obtain the title compound (4- (4-methoxybenzyl) -3,4-dihydro- [3,2-b] [1,4] oxazine-2-yl) methanol (16.5 g, 73%) was obtained as a colorless oil.

^{1 H-NMR (300 MHz,} CDCl 3) δ 7.79 (dd, J = 4.9, 0.8 Hz, 1H), 7.22 (d, J = 8.5 Hz, 2H), 6.98 (d, J = 7.6 Hz, 1H), 6.84 (d, J = 8.5 Hz , 2H), 6.55 (dd, J = 7.5, 5.0 Hz, 1H), 4.79 (ABq, J = 14.0 Hz, 2H), 4.19 (m, 1H), 3.79 (s, 3H ), 3.75 (m, 2H), 3.26 (m, 2H).

Example  3. 2- (4- (4-Methoxybenzyl) -3,4- Dihydro -2H- Pyrido [3,2-b] [1,4] oxazine -2 days) Acetonitrile

(4-methoxybenzyl) -3,4-dihydro-2H-pyrido [3,2- b] [1,4] oxazin-2-yl) methanol (16.5 g, 57.5 mmol) dichloromethane chloride (TsCl, 14.3 g, 74.8 mmol ), DMAP (702 mg, 5.75 mmol) and triethylamine (12.03 mL, 86.3 mmol) at 0 ^o C 4- Tolo yen was dissolved in (170 mL) to Followed by stirring at room temperature for 3 hours. After the reaction, the reaction solution was washed with water and brine, and the organic layer was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by column chromatography (20% EtOAC / hexane) to obtain the desired compound, 4- (4-methoxybenzyl) -3 , 4-dihydro -2 H - pyrido [3,2- b] [1,4] oxazin-2-yl) methyl 4-methylbenzenesulfonate seulpo carbonate (25 g, yield 93%) as a solid yeonnoran .

^{1 H-NMR (300 MHz,} CDCl 3) δ 7.78 (m, 3H), 7.75 (d, J = 9.0 Hz, 2H), 7.18 (d, J = 9.0 Hz, 1H), 6.86 (m, 3H), 6.53 (dd, J = 7.6, 5.0 Hz, 1H), 4.79 (ABq, J = 14.0 Hz, 2H), 4.27 (m, 1H), 4.17-4.00 (m, 2H), 3.79 (s, 3H), 3.27 (dd, J = 12.2, 2.7 Hz, 1H), 3.14 (dd, J = 12.2, 7.0 Hz, 1H), 2.45 (s, 3H).

(4-methoxybenzyl) -3,4-dihydro- 2H -pyrido [3,2- b ] [1,4] oxazin-2-yl) methyl-4-methylbenzenesulfonate (3 g, 6.81 mmol) was dissolved in DMSO (30 mL), sodium cyanide (NaCN, 1.74 g, 35.41 mmol) was added, and the mixture was stirred at 50 ° C for 2 hours. The reaction mixture was diluted with ethyl acetate, washed several times with saturated sodium bicarbonate (NaHCO ₃ ) aqueous solution and brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by column chromatography (20% EtOAc / hexane) to give 2- (4- (4-methoxybenzyl desired compound as a) 3,4-dihydro -2 H - pyrido [3,2- b] [1,4] oxazin-2-yl) acetonitrile (1.52 g, 75%) as a yellow oil.

^{1 H-NMR (300 MHz,} CDCl 3) δ 7.85 (dd, J = 4.9, 1.4 Hz, 1H), 7.22 (d, J = 8.6 Hz, 2H), 7.01 (dd, J = 7.7, 1.4 Hz, 1H ), 6.84 (d, J = 8.6 Hz, 2H), 6.59 (dd, J = 7.7, 4.9 Hz, 1H), 4.79 (s, 2H), 4.38 (dd, J = 12.2, 2.7 Hz, 1H), 3.22 (dd, J = 12.2, 7.0 Hz, 1H), 2.68 (t, J = 6.5 Hz, 2H).

Example  4. 2- (4- (4-Methoxybenzyl) -3,4- Dihydro -2H- Pyrido [3,2-b] [1,4] oxazine Yl) acetic acid

2, 4-dihydro- 2H -pyrido [3,2- b ] [1,4] oxazin-2-yl) acetonitrile (2.85 g, , 9.66 mmol) was dissolved in anhydrous dichloromethane (100 mL), and then di-val (DIBAL-H, 3.4 mL, 19.33 mmol) was added dropwise at -78 ^° C. After stirring for 1 hour, isopropyl alcohol . Add distilled water (2 mL) and stir at room temperature for one hour. Add silica gel (5 g) and anhydrous magnesium sulfate (MgSO _{4 ,} 5 g) and stir at room temperature for an additional hour. The reaction solution was filtered through celite, and the filtrate was concentrated under reduced pressure and then purified by column chromatography (5% EtOAc / hexane) to obtain the desired compound 2- (4- (4-methoxybenzyl) - dihydro- 2H -pyrido [3,2- b ] [1,4] oxazin-2-yl) acetaldehyde (2.3 g, 80%).

2, 4-dihydro- 2H -pyrido [3,2- b ] [1,4] oxazin-2-yl) acetaldehyde (1.3 g, 4.36 mmol) was added t -butanol (11 mL) and. It was added to 2-methyl-2-butyne (11 mL) NaClO ₂ eseo 0 ^o C (1.97 g, 21.79 mmol) was added thereto, followed by stirring for 10 minutes. Then, KH ₂ PO ₄ (2.96 g, 21.79 mmol) was dissolved in distilled water (11 mL), added dropwise to the reaction solution, and stirred at room temperature for 2 hours. After the reaction, the solution was concentrated under reduced pressure, and water was added a little. The mixture was adjusted to pH 3 to 4 with a 5N aqueous hydrochloric acid solution. Dichloromethane was added thereto and washed several times with brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain yellow 2- (4- -3,4-dihydro- 2H -pyrido [3,2- b ] [1,4] oxazin-2-yl) acetic acid (0.73 g, 53%).

^{1 H-NMR (300 MHz,} DMSO-d 6) δ 7.67 (dd, J = 4.9, 1.5 Hz, 1H), 7.18 (d, J = 8.6 Hz, 2H), 6.93 (dd, J = 7.7, 1.4 Hz , 1H), 6.85 (d, J = 8.6 Hz, 2H), 6.51 (dd, J = 7.7, 4.9 Hz, 1H), 4.83 (d, A of ABq, J = 15.0 Hz, 1H), 4.70 (d, B of ABq, J = 15.0 Hz , 1H), 4.39 (m, 1H), 3.68 (s, 3H), 3.41 (dd, J = 12.2, 2.7 Hz, 2H), 3.22 (dd, J = 12.2, 7.0 Hz , 2H).

Example  5. 2 - ((6- Chloro - [1,2,4] Triazolo [4,3-b] Pyridazine -3 days) methyl ) -4- (4-methoxybenzyl) -3,4- Dihydro -2H-pyrrolo [ Lt; / RTI &gt; [3,2-b] [1,4] oxazole camp

2, 4-dihydro- 2H -pyrido [3,2- b ] [1,4] oxazine-2-yl) acetic acid (0.5 g, 1.59 mmol) was dissolved in DMF (15 mL), and then hydroxybenzotriazole (HOBT, 0.33 g, 2.387 mmol) and 1-ethyl-3- (3- dimethylaminopropyl) carbodiimide ), 3-chloro-6-hydrazinylpyridazine (0.28 g, 1.91 mmol) and triethylamine (0.45 mL, 3.18 mmol) were added thereto and stirred for 12 hours at room temperature. The reaction mixture was diluted with ethyl acetate and washed with brine subeon after the cleaning was dried over anhydrous sodium sulfate N '- (6- chloropyridazin-3-yl) -2- (4 (4-methoxybenzyl) -3,4-dihydro -2 H - pyrido [ B ] [l, 4] oxazin-2-yl) acetohydrazide (650 mg) was obtained and the following reaction was carried out without purification: After dissolving in acetic acid (15 mL) After neutralization with a 2M aqueous sodium carbonate solution, the mixture was extracted with ethyl acetate. The organic layer was washed with anhydrous sulfur Dried with sodium is concentrated under reduced pressure and purified by column chromatography _{(3% MeOH / CH 2 Cl} 2) the desired compound 2 - ((6-chloro [1,2,4] triazolo [4,3-b] Yl) methyl) -4- (4-methoxybenzyl) -3,4-dihydro- 2H -pyrido [3,2- b ] [1,4] oxazine (285 mg, 46%).

^{1 H-NMR (300 MHz,} CDCl 3) δ 8.58 (d, J = 6.0 Hz, 1H), 8.25 (d, J = 6.0 Hz, 1H), 7.80 (dd, J = 4.8, 1.4 Hz, 1H), 7.21 (d, J = 8.6 Hz , 2H), 6.99 (dd, J = 7.7, 1.4 Hz, 1H), 6.83 (d, J = 8.6 Hz, 2H), 6.54 (dd, J = 7.7, 4.8 Hz, 1H ), 4.73 (ABq, J = 14.9 Hz, 2H), 4.53 (m, 1H), 3.79 (s, 3H), 3.35 (dd, J = 12.2, 2.7 Hz, 1H), 3.18 (dd, J = 12.2, 7.0 Hz, 1 H), 2.53 (m, 2 H).

Example  6. 4- (4-Methoxybenzyl) -2 - ((6- (1- methyl -1H- Pyrazole Yl) - [l, 2,4] Triazolo [4,3-b] Pyridazine -3 days) methyl ) -3,4- Dihydro -2H- Pyrido [3,2-b] [1,4] oxazine

Yl) methyl) -4- (4-methoxybenzyl) -3,4-dihydro-2H-pyrrolo [2,3- -2 H - pyrido [3,2- b] [1,4] oxazine (0.5, 1.18 mmol) were placed in a pressure tube was dissolved subjected to dimethoxyethane (DME, 20 mL) and distilled water (5 mL) and then After adding 4-pyrazoleboronic acid pinacol ester (390 mg, 1.77 mmol), sodium carbonate (0.38 g, 3.54 mmol) and PdCl ₂ (Ph ₃ ) ₂ (42 mg, 0.057 mmol) Oxygen was blown into the flask, and the flask was sealed, followed by stirring at 80 DEG C for 8 hours. After the reaction, ethyl acetate was added and the mixture was washed with brine. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. Of the residue was purified by column chromatography _{(3% MeOH / CH 2 Cl} 2) The desired compound 4- (4-methoxybenzyl) -2 - ((6- (1-methyl -1 H-pyrazole-4 yl) - [1,2,4] triazolo [4,3- b] pyridazin-3-yl) methyl) -3,4-dihydro -2 H-pyrido [3,2- b] [1 , 4] oxazine (200 mg, 36%).

^{1 H-NMR (300 MHz,} CDCl 3) δ 8.05 (d, J = 9.6 Hz, 1H), 7.97 (s, 1H), 7.89 (s, 1H), 7.80 (dd, J = 4.8, 1.4 Hz, 1H ), 7.30 (d, J = 9.6 Hz, 1H), 7.18 (d, J = 8.6 Hz, 2H), 6.89 (d, J = 7.7 Hz, 1H), 6.74 (d, J = 8.6 Hz, 2H), 6.52 (dd, J = 7.7, 4.8 Hz, 1H), 4.89 (d, A of ABq, J = 14.7 Hz, 1H), 4.82 (m, 1H), 4.66 (d, B of ABq, J = 14.7 Hz, 1H), 4.01 (s, 3H), 3.76 (s, 3H), 3.63 (m, 1H), 3.48-3.36 (m, 3H).

Example  7. 2 - ((6- (1- methyl -1H- Pyrazole Yl) - [l, 2,4] Triazolo [4,3-b] Pyridazine -3 days) methyl ) -3,4- Dihydro -2H-pyrrolo [ Lt; / RTI &gt; [3,2-b] [1,4] oxazole camp

4- (4-methoxybenzyl) -2 - ((6- (1-methyl -1 H-pyrazol-4-yl) - [1,2,4] triazolo [4,3- b] pyridazine 3-yl) methyl) -3,4-dihydro -2 H - pyrido [3,2- b] [1,4] oxazine (200 mg, 0.43 mmol) acetic acid (CF ₃ COOH trifluoroacetate , 10 mL), and the mixture was stirred at 60 ^° C for 12 hours. The mixture was concentrated under reduced pressure, and ethyl ether was added thereto. The resulting solid was filtered and dried to obtain the target compound 2 - ((6- (1-methyl-1H- Yl) methyl] -3,4-dihydro-2H-pyrido [3,2-b] [1, 2,4] triazolo [4,3-b] pyridazin- , 4] oxazine trifluoroacetate (150 mg, 75%).

^{1 H-NMR (300 MHz,} DMSO-d 6) δ 8.49 (s, 1H), 8.32 (d, J = 9.7 Hz, 1H), 8.12 (s, 1H), 7.68 (d, J = 9.7 Hz, 1H ), 7.59 (dd, J = 6.0,1.2 Hz, 1H), 7.24 (d, J = 6.7 Hz, 1H), 6.59 (dd, J = 7.7, 6.0 Hz, 1H) (s, 3H), 3.79-3.50 (m, 4H).

Example  8. tert - Butyl 4 - (4- (3 - ((4- (4-methoxybenzyl) -3,4- Dihydro -2H- Pyrido [3,2-b] [1,4] oxazine -2 days) methyl ) - [l, 2,4] triazolo [4,3-b] Pyridazine -6-yl) -1H- Pyrazole Yl) piperidin-l- Carboxylate

The procedure of Example 6 was repeated to obtain tert-butyl 4- (4- (3 - ((4- (4-methoxybenzyl) -3,4-dihydro- b] [1,4] oxazin-2-yl) methyl) - [1,2,4] triazolo [4,3- b] pyridazin- Piperidine-1-carboxylate.

^{1 H-NMR (300 MHz,} CDCl 3) δ 8.12 (s, 1H), 8.07 (s, 1H), 8.03 (d, J = 9.7 Hz, 1H), 7.78 (dd, J = 4.8, 1.4 Hz, 1H ), 7.29 (d, J = 9.7 Hz, 1H), 7.18 (d, J = 8.6 Hz, 2H), 6.87 (d, J = 7.7, 1.4 Hz, 1H), 6.73 (d, J = 8.6 Hz, 2H ), 6.52 (dd, J = 7.7, 4.8 Hz, 1H), 4.86 (d, A of ABq, J = 14.7 Hz, 1H), 4.81 (m, 1H), 4.65 (d, B of ABq, J = 14.7 2H), 2.20 (m, 2H), 2.01 (m, 3H) (m, 2 H), 1.29 (s, 9 H).

Example  9. 2 - ((6- (1- (Piperidin-4-yl) -1H- Pyrazole Yl) - [l, 2,4] Triazolo [4,3-b] Pyridazine -3 days) methyl ) -3,4- Dihydro -2H- Pyrido [3,2-b] [1,4] oxazine

The title compound was obtained from 2 - ((6- (1- (piperidin-4-yl) -1H-pyrazol-4-yl) - [1,2,4] triazolo [ Yl) methyl) -3,4-dihydro-2H-pyrido [3,2-b] [1,4] oxazine trifluoroacetic acid salt.

^{1 H-NMR (300 MHz,} DMSO-d 6) δ 8.80 (s, 1H), 8.39 (s, 1H), 8.31 (d, J = 9.7 Hz, 1H), 7.67 (d, J = 9.7 Hz, 1H ), 7.58 (dd, J = 6.0,1.2 Hz, 1H), 7.24 (d, J = 7.7 Hz, 1H), 7.59 (dd, J = 7.7, 6.0 Hz, 1H) (m, 1H), 3.80-3.51 (m, 4H), 3.32 (m, 2H), 3.02 (m, 2H), 2.30-2.02 (m, 4H).

Example  10. 4- (4-Methoxybenzyl) -2 - ((6- (1- (2- ( Tetrahydro -2H-pyran-2- Sake ) Ethyl) -1H- Pyrazole Yl) - [l, 2,4] triazolo [4,3-b] pyridin- Pyridazine -3 days) methyl ) -3,4- Dihydro -2H- Pyrido [3,2-b] [1,4] oxazine

2-yloxy) ethyl) -1 H (4-methoxybenzyl) -2 - ((6- Yl) - [l, 2,4] triazolo [4,3-b] pyridazin-3- yl) methyl) -3,4- dihydro-2H-pyrido [ -b] [l, 4] oxazine.

^{1 H-NMR (300 MHz,} CDCl 3) δ 8.17 (s, 1H), 8.12 (s, 1H), 8.03 (d, J = 9.5 Hz, 1H), 7.78 (dd, J = 4.8, 1.4 Hz, 1H ), 7.28 (d, J = 9.5 Hz, 1H), 7.19 (d, J = 8.6 Hz, 2H), 6.88 (dd, J = 7.7, 1.4 Hz, 1H), 6.74 (d, J = 8.6 Hz, 2H ), 6.54 (dd, J = 7.7, 4.8 Hz, 1H), 4.85 (d, A of ABq, J = 14.7 Hz, 1H), 4.82 (m, 1H), 4.66 (d, B of ABq, J = 14.7 1H), 4.72 (m, 1H), 4.57 (m, 1H), 4.32 (m, 2H), 4.12 1H), 3.48 (m, 1H), 3.43 (m, 1H), 3.47-3.36 (m, 3H), 1.79-1.45 (m, 6H).

Example  11. 2- (4- (3 - ((3,4- Dihydro -2H- Pyrido [3,2-b] [1,4] oxazine -2 days) methyl ) - [l, 2,4] Triazolo [4,3-b] Pyridazine -6-yl) -1H- Pyrazole -1-yl) ethanol

The title compound was prepared in the same manner as in Example 7 to obtain the desired compound 2- (4- (3 - ((3,4-dihydro-2H-pyrido [3,2- ) Methyl) - [1,2,4] triazolo [4,3-b] pyridazin-6-yl) -1H-pyrazol-1-yl) ethanol trifluoroacetate.

^{1 H-NMR (300 MHz,} DMSO-d 6) δ 8.59 (s, 1H), 8.32 (d, J = 9.6 Hz, 1H), 8.31 (s, 1H), 7.66 (d, J = 9.6 Hz, 1H ), 7.59 (dd, J = 6.0,1.2 Hz, 1H), 7.25 (d, J = 7.7 Hz, 1H), 7.60 (dd, J = 7.7, 6.0 Hz, 1H) (m, 2 H), 3.77 (m, 2 H), 3.80 - 3.51 (m, 4 H).

Example  12. 2- Fluoro -4- (3 - ((4- (4-methoxybenzyl) -3,4- Dihydro -2H- Pyrido [3,2-b] [1,4] oxazine -2 days) methyl ) - [l, 2,4] triazolo [4,3-b] Pyridazine -6-yl) phenol

Yl) methyl) -4- (4-methoxybenzyl) -3 (1 H-pyrrolo [ , 4-dihydro- 2H -pyrido [3,2- b ] [1,4] oxazine and 2-fluoro-4- (4,4,5,5-tetramethyl- -Dioxaborolan-2-yl) phenol was subjected to Suzuki coupling in the same manner as in Example 6 to obtain the target compound 2-fluoro-4- (3 - ((4- (4-methoxybenzyl) -3 , 4-dihydro-2H-pyrido [3,2-b] [1,4] oxazin-2- yl) methyl) - [1,2,4] triazolo [ -6-yl) phenol.

^{1 H-NMR (300 MHz,} CDCl 3) δ 8.10 (d, J = 9.7 Hz, 1H), 7.95 (m, 2H), 7.88 (d, J = 8.0 Hz, 1H), 7.64 (d, J = 7.8 Hz, 1H), 7.48 (d , J = 7.8 Hz, 1H), 7.12 (d, J = 8.6 Hz, 2H), 6.89 (d, J = 7.8 Hz, 1H), 6.86 (d, J = 8.6 Hz, 2H), 6.48 (dd, J = 6.8, 5.0 Hz, 1H), 4.85 (d, A of ABq, J = 14.7 Hz, 1H), 4.79 (m, 1H), 4.84 (d, B of ABq, J = 14.7 Hz, 1H), 3.74 (s, 3H), 3.62 (m, 1H), 3.47-3.33 (m, 3H).

Example  13. 4- (3 - ((3,4- Dihydro -2H- Pyrido [3,2-b] [1,4] oxazine -2 days) methyl ) - [l, 2,4] Triazolo [4,3-b] Pyridazine -6-yl) -2- Fluorophenol

2,3,4-tetrahydro-2H-pyrido [3,2-b] [1,4] oxazin-2-yl) methyl) - [1,2,4] triazolo [4,3-b] pyridazin-6-yl) -2-fluorophenol.

^{1 H-NMR (300 MHz,} CDCl 3) δ 8.10 (d, J = 9.7 Hz, 1H), 7.95 (m, 2H), 7.88 (d, J = 8.0 Hz, 1H), 7.48 (m, 2H), 6.86 (d, J = 7.8 Hz, 1H), 6.48 (dd, J = 5.0,6.8 Hz, 1H), 4.79 (m, 1H), 3.81-3.52 (m, 4H).

Example  14. 2 - ((6- (3- Fluoro -4- (2- (4- Methylpiperazine -1 day) Ethoxy ) Phenyl ) - [l, 2,4] Triazolo [4,3-b] Pyridazine -3 days) methyl ) -4- (4-methoxybenzyl) -3,4- Dihydro -2H- Pyrido [3,2-b] [1,4] oxazine

Yl) methyl) -4- (4-methoxybenzyl) -3 (1 H-pyrrolo [ , 4-dihydro- 2H -pyrido [3,2- b ] [1,4] oxazine and l- (2- (2-fluoro- Methyl-1,3,2-dioxabororan-2-yl) phenoxy) ethyl) -4-methylpiperazine was subjected to Suzuki coupling in the same manner as in Example 6 to obtain the objective compound 2 - ((6- (4-methylpiperazin-1-yl) ethoxy) phenyl) - [l, 2,4] triazolo [4,3- b] pyridazin- ) Methyl) -4- (4-methoxybenzyl) -3,4-dihydro-2H-pyrido [3,2-b] [1,4] oxazine.

^{1 H-NMR (300 MHz,} CDCl 3) δ 8.10 (d, J = 9.7 Hz, 1H), 7.81 (m, 2H), 7.74 (d, J = 9.7 Hz, 1H), 7.66 (d, J = 7.8 Hz, 1H), 7.53 (m , 2H), 7.27 (d, J = 8.6 Hz, 2H), 6.90 (d, J = 7.8 Hz, 1H), 6.74 (d, J = 8.6 Hz, 2H), 6.49 ( dd, J = 7.7, 4.8 Hz , 1H), 4.87 (d, A of ABq, J = 14.7 Hz, 1H), 4.83 (m, 1H), 4.65 (d, B of ABq, J = 14.7 Hz, 1H) , 3.74 (s, 3H), 3.63 (m, 1H), 3.59 (t, J = 14.8 Hz, 2H), 3.48-3.36 (m, 3H), 2.67 (t, J = 14.8 Hz, 2H), 2.39- 2.52 (m, 8 H), 2.21 (s, 3 H).

Example  15. 2 - ((6- (3- Fluoro -4- (2- (4- Methylpiperazine -1 day) Ethoxy ) Phenyl ) - [l, 2,4] Triazolo [4,3-b] Pyridazine -3 days) methyl ) -3,4- Dihydro -2H- Pyrido [3,2-b] [1,4] oxazine

Ethoxy) phenyl] - [1, &lt; RTI ID = 0.0 &gt; 4] triazolo [4,3-b] pyridazin-3-yl) methyl) -3,4-dihydro-2H-pyrido [3,2-b] [1,4] oxazine.

^{1 H-NMR (300 MHz,} CDCl 3) δ 8.00 (d, J = 9.7 Hz, 1H), 7.80 (m, 2H), 7.66 (d, J = 9.7 Hz, 1H), 7.27 (m, 2H), 6.88 (d, J = 7.8 Hz , 1H), 6.48 (dd, J = 7.7, 4.8 Hz, 1H), 4.87 (m, 1H), 3.59 (t, J = 14.8 Hz, 2H), 3.81-3.52 (m , 4H), 2.67 (t, J = 14.8 Hz, 2H), 2.39-2.52 (m, 8H), 2.21 (s, 3H).

Example  16. Preparation of 4- (4-methoxybenzyl) -2 - ((6- (1- methyl -LH-indol-3-yl) - [l, 2,4] Triazolo [4,3-b] Pyridazine -3 days) methyl ) -3,4- Dihydro -2H- Pyrido [3,2-b] [1,4] oxazine

(4-methoxybenzyl) -2 - ((6- (1-methyl-1H-indol-3-yl) - [ [4,3-b] pyridazin-3-yl) methyl) -3,4-dihydro-2H-pyrido [3,2- b] [1,4] oxazine.

^{1 H-NMR (300 MHz,} CDCl 3) δ 8.34 (d, J = 9.7 Hz, 1H), 7.97 (s, 1H), 7.89 (s, 1H), 7.80 (dd, J = 4.8, 1.4 Hz, 1H ), 7.30 (d, J = 9.7 Hz, 1H), 7.18 (d, J = 8.6 Hz, 2H), 6.89 (dd, J = 7.7, 1.4 Hz, 1H), 6.74 (d, J = 8.6 Hz, 2H ), 6.52 (dd, J = 7.7, 4.8 Hz, 1H), 4.89 (d, A of ABq, J = 14.7 Hz, 1H), 4.82 (m, 1H), 4.66 (d, B of ABq, J = 14.7 (S, 3H), 3.63 (m, 1H), 3.48-3.66 (m, 2H).

Example  17. 2 - ((6- (1- methyl -LH-indol-3-yl) - [l, 2,4] Triazolo [4,3-b] Pyridazine -3 days) methyl ) -3,4- Dihydro -2H-pyrido [ 3,2-b] [1,4] oxazine

The title compound was prepared by the same procedure as in Example 7 to give the desired compound 2 - ((6- (1 -methyl-1 H-indol-3-yl) - [1,2,4] triazolo [4,3- b] pyridazine- Yl) methyl) -3,4-dihydro-2H-pyrido [3,2-b] [1,4] oxazine trifluoroacetic acid salt.

¹ H-NMR (300 MHz, CDCl ₃ ) ? 8.47 (d, J = 7.9 Hz, 1 H), 8.01 (d, J = 9.7 Hz, 7.48-7.34 (m, 4H), 6.98 (d, J = 7.7, 1.4 Hz, 1H), 6.53 (dd, J = 7.7, 4.8 Hz, 1H), 4.87 (m, 1H), 3.93 (s, 3H) , 3.91-3.53 (m, 4H).

Example  18. 2- (4- (4-Methoxybenzyl) -3,4- Dihydro -2H- Pyrido [3,2-b] [1,4] oxazine -2 days) Acetohydrazide

2- (4- (4-methoxybenzyl) -3,4-dihydro -2 H - pyrido [3,2- b] [1,4] oxazin-2-yl) acetate (1.08 g, 3.44 mmol) was dissolved in benzene / methanol (2/1; 12 mL), and then trimethylsalildiazomethane (TMSCHN ₂ in 2M in diethyl ether, 4.6 mL, 12.02 mmol) was added dropwise thereto and stirred at room temperature for 1 hour. Concentration under reduced pressure and then the reaction solvent was purified by column chromatography (20% EtOAc / Hexane) Methyl 2- (4- (4-methoxybenzyl) -3,4-dihydro -2 H - pyrido [3,2 - b ] [1,4] oxazin-2-yl) acetate (530 mg, 47%).

^{1 H-NMR (300 MHz,} CDCl 3) δ 7.79 (m, 1H), 7.23 (d, J = 8.5 Hz, 2H), 6.94 (m, 1H), 6.84 (d, J = 8.5 Hz, 2H), 6.53 (m, 1H), 4.79 (ABq, J = 15.1 Hz, 2H), 4.54 (m, 1H), 3.78 (s, 3H), 3.69 (s, 3H), 3.34 (m, 1H), 3.11 (m , 2.69 (dd, J = 15.7, 7.4 Hz, 1H), 2.52 (dd, J = 15.7, 5.5 Hz, 1H).

Methyl 2- (4- (4-methoxybenzyl) -3,4-dihydro -2 H - pyrido [3,2- b] [1,4] oxazin-2-yl) acetate (300 mg, 0.91 mmol) was dissolved in methanol (6 mL), followed by addition of 80% hydrazine hydrate (NH ₂ NH ₂ .H ₂ O; 0.28 mL, 4.57 mmol), and the mixture was stirred at 50 ° C for 1 hour. After the reaction, the solvent was concentrated under reduced pressure to obtain 290 mg (96%) of a yellow solid, which was further purified without further purification.

^{1 H-NMR (300 MHz,} CDCl 3) δ 7.80 (d, J = 4.8 Hz, 1H), 7.20 (d, J = 8.6 Hz, 2H), 7.08 (brs, 1H), 6.95 (d, J = 7.6 Hz, 1H), 6.83 (d , J = 8.6 Hz, 2H), 6.53 (dd, J = 7.6, 4.8 Hz, 1H), 4.75 (ABq, J = 14.8 Hz, 2H), 4.51 (m, 1H), (Dd, J = 12.1, 2.6 Hz, 1H), 3.12 (dd, J = 12.1, 7.1 Hz, 1H), 2.51-2.40 (m, 2H).

Example  19. 3- Chloro -6- (4- Fluorophenyl ) Pyridazine

4-Fluorophenylboronic acid (0.15 g, 1.074 mmol) and potassium carbonate (0.25 g, 1.34 mmol) were dissolved in dioxane / distilled water (3/1; 0.46 g, 3.36 mmol) and PdCl ₂ (dppf) ₂ (55 mg, 0.067 mmol) were added and stirred at 90 ° C. After the reaction, ethyl acetate was added and the mixture was washed with brine. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography (20% EtOAc / hexane) to obtain 3-chloro-6- (4-fluorophenyl) pyridazine (123 mg, 55%) as a target compound.

^{1 H-NMR (300 MHz,} DMSO-d 6) δ 8.33 (d, J = 9.1 Hz, 1H), 8.21 (dd, J = 8.9, 5.5 Hz, 2H), 8.01 (d, J = 9.1 Hz, 1H ), 7.41 (t, J = 11.4 Hz, 2H).

Example  20. 3- Chloro -6- Phenylpyridazine

By proceeding in the same manner as in Example 19, the desired compound 3-chloro-6-phenylpyridazine was obtained.

¹ H-NMR (300 MHz, CDCl ₃ ) ? 8.04 (m, 2H), 7.81 (d, J = 9.1 Hz, 1H), 7.57 (m, 4H), 7.55 (d, J = 9.1 Hz, 1H).

Example  21. 3- Chloro -6- (3- Fluorophenyl ) Pyridazine

Proceeding as in Example 19, the objective compound 3-chloro-6- (3-fluorophenyl) pyridazine was obtained.

^{1 H-NMR (300 MHz,} CDCl 3) δ 7.93 (m, 1H), 7.82 (d, J = 9.0 Hz, 1H), 7.80 (m, 1H), 7.59 (d, J = 9.0 Hz, 1H), 7.54-7.49 (m, 1 H), 7.25-7.19 (m, 1 H).

Example  22. 3- Chloro -6- (3,5- Difluorophenyl ) Pyridazine

Proceeding in the same manner as in Example 19, the target compound 3-chloro-6- (3,5-difluorophenyl) pyridazine was obtained.

^{1 H-NMR (300 MHz,} CDCl 3) δ 7.79 (d, J = 9.0 Hz, 1H), 7.63 (d, J = 9.0 Hz, 1H), 7.63-7.60 (m, 2H), 7.01-6.93 (m , 1H).

Example  23. 3- Chloro -6- (3- Fluoro -4- Methylphenyl ) Pyridazine

Proceeding in the same manner as in Example 19, the objective compound 3-chloro-6- (3-fluoro-4-methylphenyl) pyridazine was obtained.

^{1 H-NMR (300 MHz,} CDCl 3) δ 7.79 (d, J = 9.0 Hz, 1H), 7.78-7.70 (m, 2H), 7.56 (d, J = 9.0 Hz, 1H), 7.34 (t, J = 7.7 Hz, 1 H), 2.36 (s, 3 H).

Example  24. 3- (6- Chloropyridazine -3 days) Benzonitrile

Proceeding as in Example 19, the objective compound 3- (6-chloropyridazin-3-yl) benzonitrile was obtained.

^{1 H-NMR (300 MHz,} CDCl 3) δ 8.37 (s, 1H), 8.35 (d, J = 5.4 Hz, 1H), 7.88 (d, J = 5.4 Hz, 1H), 7.83 (d, J = 4.6 Hz, 1 H), 7.65 (m, 2H).

Example  25. 3- Chloro -6- (pyridin-4-yl) Pyridazine

Proceeding as in Example 19, the objective compound 3-chloro-6- (pyridin-4-yl) pyridazine was obtained.

^{1 H-NMR (300 MHz,} CDCl 3) δ 8.85 (m, 2H), 7.94 (m, 2H), 7.90 (d, J = 9.0 Hz, 1H), 7.67 (d, J = 9.0 Hz, 1H).

Example  26. 3- Chloro -6- (pyridin-3-yl) Pyridazine

Proceeding as in Example 19, the objective compound 3-chloro-6- (pyridin-3-yl) pyridazine was obtained.

^{1 H-NMR (300 MHz,} CDCl 3) δ 9.15 (d, J = 2.3 Hz, 1H), 8.71 (dd, J = 4.8, 1.2 Hz, 1H), 8.40 (dt, J = 1.9, 8.0 Hz, 1H ), 7.83 (d, J = 9.0 Hz, 1H), 7.58 (d, J = 9.0 Hz, 1H), 7.44 (dd, J = 8.0, 4.8 Hz, 1H).

Example  27. 3- Chloro -6- (4- Methoxyphenyl ) Pyridazine

Proceeding as in Example 19, the objective compound 3-chloro-6- (4-methoxyphenyl) pyridazine was obtained.

^{1 H-NMR (300 MHz,} CDCl 3) δ 8.01 (d, J = 6.9 Hz, 2H), 7.77 (d, J = 9.0 Hz, 1H), 7.51 (d, J = 9.0 Hz, 1H), 7.04 ( d, J = 6.9 Hz, 2H), 3.89 (s, 3H).

Example  28. 4- (6- Chloropyridazine Yl) -N, N- Dimethylbenzene amine

The procedure of Example 15 was followed except that 4- (6-chloropyridazin-3-yl) -N, N-dimethylbenzeneamine was obtained.

^{1 H-NMR (300 MHz,} CDCl 3) δ 7.97 (d, J = 8.9 Hz, 2H), 7.72 (d, J = 9.0 Hz, 1H), 7.43 (d, J = 9.0 Hz, 1H), 6.80 ( d, J = 8.9 Hz, 2H), 3.05 (s, 6H).

Example  29. methyl  4- (6- Chloropyridazine -3 days) Benzoate

Proceeding as in Example 19, the objective compound methyl 4- (6-chloropyridazin-3-yl) benzoate was obtained.

^{1 H-NMR (300 MHz,} CDCl 3) δ 8.20 (d, J = 8.3 Hz, 2H), 8.13 (d, J = 8.3 Hz, 2H), 7.89 (d, J = 9.0 Hz, 1H), 7.62 ( d, J = 9.0 Hz, 1H), 3.97 (s, 3H).

Example  30. (4- (6- Chloropyridazine -3 days) Phenyl ) Methanol

3-Dichloropyridazine (400 mg, 2.69 mmol) was dissolved in dioxane (6 mL) and distilled water (2 mL), and then 4-formylphenylboronic acid (321 mg, 2.15 mmol) and potassium carbonate , 6.71 mmol) and PdCl ₂ (dppf) ₂ (110 mg, 0.13 mmol) were added and stirred at 90 ^° C. The reaction mixture was diluted with dichloromethane, washed with brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. Purification by column chromatography (40% EtOAc / Hexane) provided 4- (6-chloropyridazin-3-yl) benzaldehyde (148 mg, 25%) as a white solid.

^{1 H-NMR (300 MHz,} CDCl 3) δ 10.12 (s, 1H), 8.24 (d, J = 8.1 ㎐, 2H), 8.07 (d, J = 8.1 ㎐, 2H), 7.91 (d, J = 9.0 ㎐, 1H), 7.65 (d, J = 9.0 Hz, 1H).

(40 mg, 0.18 mmol) was dissolved in methanol / dichloromethane (4: 1, 2 mL) and sodium borohydride (NaBH ₄ , 10 mg , 0.26 mmol) was slowly added, and the mixture was stirred at room temperature for 2 hours. After the reaction, ethyl acetate was added, and the mixture was washed with brine. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain 39 mg (98%) of 4- .

^{1 H-NMR (300 MHz,} CDCl 3) δ 8.06 (d, J = 8.4 ㎐, 2H), 7.83 (d, J = 9.0 ㎐, 1H), 7.55 (d, J = 8.4 ㎐, 2H), 7.54 ( d, J = 9.0 Hz, 1H), 4.80 (d, J = 4.2 Hz, 2H).

Example  31. 4- (4- (6- Chloropyridazine Yl) benzyl) Morpholine

To a solution of 4- (6-chloropyridazin-3-yl) benzaldehyde (100 mg, 0.46 mmol) and morpholine (80 mg) obtained in Example 30 in dichloromethane (5 mL) The mixture was stirred at room temperature for 30 minutes and then NaB (OAc) ₃ H (0.15 g, 0.69 mmol) was added. After stirring at room temperature for 3 hours, 5% K ₂ CO ₃ aqueous solution was added to adjust the pH to 8, followed by extraction with dichloromethane. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography (4% MeOH / CH ₂ Cl ₂ ) to obtain 4- (4- (6-chloropyridazin-3-yl) benzyl) morpholine (92 mg, 69%).

^{1 H-NMR (300 MHz,} CDCl 3) δ 8.00 (d, J = 8.3 ㎐, 2H), 7.82 (d, J = 8.9 ㎐, 1H), 7.56 (d, J = 8.9 ㎐, 1H), 7.49 ( d, J = 8.3 Hz, 2H), 3.71 (m, 4H), 3.57 (s, 2H), 2.47 (m, 4H).

Example  32. methyl  3- (6- Chloropyridazine -3 days) Benzoate

By proceeding in the same manner as in Example 19, the objective compound methyl 3- (6-chloropyridazin-3-yl) benzoate was obtained.

^{1 H-NMR (300 MHz,} CDCl 3) δ 8.65 (s, 1H), 8.37 (d, J = 7.7 Hz, 1H), 8.20 (d, J = 7.7 Hz, 1H), 7.92 (d, J = 9.0 Hz, 1 H), 7.64 (m, 2 H), 3.99 (s, 3 H).

Example  33. 3- (6- Chloropyridazine Yl) -N- Ethylbenzamide

Methyl embodiment obtained in Example 32 3- (6-chloro-3-yl) benzoate (100 mg, 0.4 mmol) in tetrahydrofuran (0.6 mL) and distilled water 0 ℃ was dissolved in (0.1 mL), 1 N - aqueous sodium hydroxide solution (0.4 mL) was added, followed by stirring at room temperature for 3 hours. After the reaction, a 1N aqueous hydrochloric acid solution was added at 0 ° C to adjust the pH to 3-4, thereby producing a white solid. After filtration and washing with distilled water, benzene was added and the mixture was concentrated under reduced pressure to obtain 3- (6-chloropyridazin-3-yl) benzoic acid (141 mg, 68%) as a white solid.

^{1 H-NMR (300 MHz,} CDCl 3) δ 8.71 (s, 1H), 8.44 (d, J = 9.0 ㎐, 1H), 8.38 (d, J = 7.8 ㎐, 1H), 8.12 (d, J = 7.8 Hz, 1H), 8.06 (d, J = 9.0 Hz, 1H), 7.72 (t, J = 7.8 Hz, 1H).

3- (6-Chloropyridazin-3-yl) benzoic acid (141 mg, 0.601 mmol) was added to thionyl chloride (SOCl ₂ , 5 mL) and the mixture was refluxed for 12 hours. The reaction mixture was concentrated under reduced pressure to give 3- (6-chloropyridazin-3-yl) benzoyl chloride (126 mg, 86%) as an ocher-colored solid. The following reaction was carried out without purification.

3- (6-chloro-3-yl) benzoyl chloride (60 mg, 0.24 mmol) to dry dichloromethane (3 mL) of triethylamine at 0 ^o C were dissolved in (0.06 mL, 0.48 mmol) and ethyl Amine hydrochloride (21 mg, 0.25 mmol) was added thereto, followed by stirring at room temperature for 12 hours. After the reaction, the solvent was concentrated under reduced pressure, and ethyl acetate was added thereto. After washing with brine, the organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. Purified by column chromatography (80% EtOAc / Hexane) to 3- (6-chloropyridazin-3-yl) acetate was obtained Provenza polyimide (31 mg, 50%) as a white solid-N.

^{1 H-NMR (300 MHz,} CDCl 3) δ 8.48 (s, 1H), 8.18 (d, J = 7.8 ㎐, 1H), 7.95 (d, J = 7.4 ㎐, 1H), 7.92 (d, J = 9.0 ㎐, 1H), 7.62 (d , J = 9.0 ㎐, 1H), 7.59 (d, J = 7.8 ㎐, 1H), 6.32 (brs, 1H), 3.54 (m, 2H), 1.29 (d, J = 7.7 Hz, 3H).

Example  34. 4- (4-Methoxybenzyl) -2 - ((6- Phenyl - [1,2,4] Triazolo [4,3-b] Pyridazine -3 days) methyl ) -3,4- Dihydro -2H-pyrrolo [ Lt; / RTI &gt; [3,2-b] [1,4] oxazole camp

Embodiment 2 obtained in Example 18 (4- (4-methoxybenzyl) -3,4-dihydro -2 H - pyrido [3,2- b] [1,4] oxazin-2-yl) acetonitrile (20 mg, 0.061 mmol) and 3-chloro-6-phenylpyridazine (11 mg, 0.055 mmol) obtained in Example 20 were dissolved in n-butanol (2 mL), and the mixture was stirred at 130 ^° C for 48 hours Lt; / RTI &gt; After the reaction, ethyl acetate was added and the mixture was washed with a saturated aqueous sodium hydrogen carbonate solution. The organic layer was dried over anhydrous sodium sulfate and then purified by column chromatography (3% MeOH / CH ₂ Cl ₂ ) to obtain the desired compound 4- (4-methoxybenzyl) Yl) methyl) -3,4-dihydro-2H-pyrido [3,2- -b] [1,4] oxazine (10 mg, 40%).

^{1 H-NMR (300 MHz,} CDCl 3) δ 8.13 (d, J = 9.7 Hz, 1H), 7.81 (dd, J = 4.9, 1.4 Hz, 1H), 7.62-7.55 (m, 5H), 7.55 (d , J = 9.7 Hz, 1H) , 7.18 (d, J = 8.6 Hz, 2H), 6.90 (dd, J = 7.6, 1.1 Hz, 1H), 6.73 (d, J = 8.6 Hz, 2H), 6.50 (dd , J = 7.6, 4.8 Hz, 1H), 4.90 (d, A of AB q, J = 14.7 Hz, 1H), 4.87 (m, 1H), 4.67 (d, B of AB q, J = 14.7 Hz, 1H ), 3.72 (s, 3H), 3.52-3.39 (m, 4H).

Example  35. 2 - ((6- Phenyl - [1,2,4] Triazolo [4,3-b] Pyridazine -3 days) methyl ) -3,4- Dihydro -2H- Pyrido [3,2-b] [1,4] oxazine

The title compound was prepared by the same procedure as in Example 7 to give the target compound 2 - ((6-phenyl- [1,2,4] triazolo [4,3- b] pyridazin- Hydo-2H-pyrido [3,2-b] [1,4] oxazine trifluoroacetic acid salt.

^{1 H-NMR (300 MHz,} DMSO-d 6) δ 10.8 (brs, 1H), 8.39 (d, J = 9.6 Hz, 1H), 7.68 (d, J = 9.6 Hz, 1H), 7.41 (d, J = 6.2 Hz, 1H), 7.21 (d, J = 7.5 Hz, 1H), 6.64 (dd, J = 7.5, 4.8 Hz, 1H), 4.90 (m, 1H), 3.92-3.62 (m, 4H).

Example  36. 2 - ((6- (4- Fluorophenyl ) - [l, 2,4] Triazolo [4,3-b] Pyridazine -3 days) methyl ) -4- (4-methoxybenzyl) -3,4-dihydro-2H- Pyrido [3,2-b] [1,4] oxazine

(4,3-b] pyridazin-3-yl) methyl) propanoic acid was obtained in the same manner as in Example 34, (4-methoxybenzyl) -3,4-dihydro-2H-pyrido [3,2-b] [1,4] oxazine.

^{1 H-NMR (300 MHz,} CDCl 3) δ 8.15 (d, J = 9.7 Hz, 1H), 7.92 (dd, J = 8.8, 5.2 Hz, 2H), 7.80 (d, J = 4.8 Hz, 1H), 7.54 (d, J = 9.7 Hz , 1H), 7.20 (d, J = 8.6 Hz, 2H), 7.18 (d, J = 8.8 Hz, 2H), 6.88 (d, J = 7.6 Hz, 1H), 6.73 ( d, J = 8.6 Hz, 2H ), 6.51 (dd, J = 7.6, 4.8 Hz, 1H), 4.90 (d, A of AB q, J = 14.7 Hz, 1H), 4.87 (m, 1H), 4.67 ( d, B of AB q, J = 14.7 Hz, 1H), 3.73 (s, 3H), 3.69 (m, 1H), 3.54-3.35 (m, 3H).

Example  37. 2 - ((6- (4- Fluorophenyl ) - [l, 2,4] Triazolo [4,3-b] Pyridazine -3 days) methyl ) -3,4- Dihydro -2H- Pyrido [3,2-b] [1,4] oxazine

4,3-b] pyridazin-3-yl) methyl) propanoic acid was obtained by proceeding in the same manner as in Example 7 to obtain the target compound 2 - ((6- (4- fluorophenyl) - [ -3,4-dihydro-2H-pyrido [3,2-b] [1,4] oxazine trifluoroacetic acid salt.

^{1 H-NMR (300 MHz,} CDCl 3) δ 10.91 (brs, 1H), 8.26 (d, J = 9.7 Hz, 1H), 7.96 (dd, J = 8.8, 5.2 Hz, 2H), 7.62 (d, J = 9.7 Hz, 1H), 7.39 (d, J = 6.2 Hz, 1H), 7.26 (m, 2H), 7.22 (d, J = 7.6 Hz, 1H), 6.63 (dd, J = 7.6, 4.8 Hz, 1H ), 4.87 (m, 1H), 3.89-3.78 (m, 2H), 3.70-3.61 (m, 2H).

Example  38. 2 - ((6- (3- Fluorophenyl ) - [l, 2,4] Triazolo [4,3-b] Pyridazine -3 days) methyl ) -4- (4-methoxybenzyl) -3,4-di Hi Doro-2H- Pyrido [3,2-b] [1,4] oxazine

(4,3-b] pyridazin-3-yl) methyl) propanoic acid was obtained by proceeding in the same manner as in Example 34 to obtain the target compound 2 - ((6- (3- fluorophenyl) - [ (4-methoxybenzyl) -3,4-dihydro-2H-pyrido [3,2-b] [1,4] oxazine.

^{1 H-NMR (300 MHz,} CDCl 3) δ 8.17 (d, J = 9.7 Hz, 1H), 7.80 (dd, J = 5.0, 1.4 Hz, 1H), 7.69 (d, J = 8.0 Hz, 1H), 7.65 (dt, J = 9.4, 1.9 Hz, 1H), 7.54 (d, J = 9.7 Hz, 1H), 7.50 (m, 1H), 7.26 (m, 1H), 7.18 (d, J = 8.6 Hz, 2H ), 6.88 (dd, J = 7.7,1.4 Hz, 1H), 6.74 (d, J = 8.6 Hz, 2H), 6.51 (dd, J = 7.6, 4.8 Hz, 1H) J = 14.8 Hz, 1H), 4.84 (m, 1H), 4.66 (d, B of ABq, J = 14.8 Hz, 1H), 3.70 (s, 3H), 3.69 (m, 1H), 3.53-3.35 (m , 3H).

Example  39. 2 - ((6- (3- Fluorophenyl ) - [l, 2,4] Triazolo [4,3-b] Pyridazine -3 days) methyl ) -3,4- Dihydro -2H- Pyrido [3,2-b] [1,4] oxazine

(4,3-b] pyridazin-3-yl) methyl) -2,3-dimethyl-lH-pyrrolo [2,3- -3,4-dihydro-2H-pyrido [3,2-b] [1,4] oxazine trifluoroacetic acid salt.

^{1 H-NMR (300 MHz,} CDCl 3) δ 10.81 (brs, 1H), 8.32 (d, J = 9.7 Hz, 1H), 7.80-7.52 (m, 3H), 7.40 (d, J = 6.0 Hz, 2H ), 7.31 (m, 1H) , 7.20 (d, J = 8.2 Hz, 1H), 6.64 (dd, J = 7.6, 4.8 Hz, 1H), 4.88 (m, 1H), 3.92-3.80 (m, 2H) , 3.72-3.62 (m, 2H).

Example  40. 2 - ((6- (3,5- Difluorophenyl ) - [l, 2,4] Triazolo [4,3-b] Pyridazine -3 days) methyl ) -4- (4-methoxybenzyl) -3,4-di Hi Doro-2H- Pyrido [3,2-b] [1,4] oxazine

The title compound 2 - ((6- (3,5-difluorophenyl) - [1,2,4] triazolo [4,3- b] pyridazin- ) Methyl) -4- (4-methoxybenzyl) -3,4-dihydro-2H-pyrido [3,2-b] [1,4] oxazine.

^{1 H-NMR (300 MHz,} CDCl 3) δ 8.18 (d, J = 9.7 Hz, 1H), 7.80 (d, J = 5.0 Hz, 1H), 7.49 (d, J = 9.7 Hz, 1H), 7.46 ( m, 1H), 7.19 (d , J = 8.6 Hz, 2H), 7.02 (m, 1H), 6.87 (d, J = 7.6 Hz, 1H), 6.75 (d, J = 8.6 Hz, 2H), 6.51 ( dd, J = 7.6, 4.8 Hz , 1H), 4.86 (d, A of ABq, J = 14.8 Hz, 1H), 4.84 (m, 1H), 4.66 (d, B of ABq, J = 14.8 Hz, 1H) , 3.70 (s, 3H), 3.66 (m, IH), 3.53 - 3.36 (m, 3H).

Example  41. 2 - ((6- (3,5- Difluorophenyl ) - [l, 2,4] Triazolo [4,3-b] Pyridazine -3 days) methyl ) -3,4- Dihydro -2H-pyrido [ 3,2-b] [1,4] oxazine

The procedure of Example 7 was repeated to obtain the target compound 2 - ((6- (3,5-difluorophenyl) - [1,2,4] triazolo [4,3- b] pyridazin- ) Methyl) -3,4-dihydro-2H-pyrido [3,2-b] [1,4] oxazine trifluoroacetic acid salt.

^{1 H-NMR (300 MHz,} CDCl 3) δ 10.90 (brs, 1H), 8.27 (d, J = 9.7 Hz, 1H), 7.57-7.44 (m, 3H), 7.38 (m, 1H), 7.18 (m 2H), 7.03 (m, 1H), 6.64 (dd, J = 7.6, 4.8 Hz, 1H), 4.84 (m, 1H), 3.93-3.81 (m, 2H), 3.71-3.63 (m, 2H).

Example  42. 2 - ((6- (3- Fluoro -4- Methylphenyl ) - [l, 2,4] Triazolo [4,3-b] Pyridazine -3 days) methyl ) -4- (4-methoxybenzyl) -3,4- Dihydro -2H- Pyrido [3,2-b] [1,4] oxazine

The title compound 2 - ((6- (3-fluoro-4-methylphenyl) - [1,2,4] triazolo [4,3- b] pyridazin- ) Methyl) -4- (4-methoxybenzyl) -3,4-dihydro-2H-pyrido [3,2-b] [1,4] oxazine.

^{1 H-NMR (300 MHz,} CDCl 3) δ 8.15 (d, J = 9.7 Hz, 1H), 7.62 (dd, J = 4.5, 1.4 Hz, 1H), 7.64-7.62 (m, 1H), 7.60 (s , 1H), 7.54 (d, J = 9.7 Hz, 1H), 7.35 (m, 1H), 7.18 (d, J = 8.6 Hz, 2H), 6.88 (dd, J = 7.7, 1.4 Hz, 1H), 6.74 (d, J = 8.6 Hz, 2H), 6.51 (dd, J = 7.6, 4.8 Hz, 1H), 4.88 (d, A of ABq, J = 14.7 Hz, 1H), 4.84 (m, 1H), 4.66 ( (d, B of ABq, J = 14.7 Hz, 1H), 3.70 (s, 3H), 3.68 (m, 1H), 3.50-3.39 (m, 3H), 2.38

Example  43. 2 - ((6- (3- Fluoro -4- Methylphenyl ) - [l, 2,4] Triazolo [4,3-b] Pyridazine -3 days) methyl ) -3,4- Dihydro -2H-pyrrolo [ Lt; / RTI &gt; [3,2-b] [1,4] oxazole camp

The title compound 2 - ((6- (3-fluoro-4-methylphenyl) - [1,2,4] triazolo [4,3- b] pyridazin- ) Methyl) -3,4-dihydro-2H-pyrido [3,2-b] [1,4] oxazine trifluoroacetic acid salt.

^{1 H-NMR (300 MHz,} CDCl 3) δ 10.90 (brs, 1H), 8.26 (d, J = 9.7 Hz, 1H), 7.66-7.42 (m, 4H), 7.54 (d, J = 9.7 Hz, 1H ), 7.22 (m, IH), 6.64 (dd, J = 7.6, 4.8 Hz, IH), 4.88 (m, IH), 3.92-3.80 (m, 2H), 3.72-3.62 s, 3H).

Example  44. 3- (3 - ((4- (4-methoxybenzyl) -3,4- Dihydro -2H- Pyrido [3,2-b] [1,4] oxazine -2 days) methyl ) - [l, 2,4] Triazolo [ 4,3-b] pyridazine Yl) Benzonitrile

The title compound 3- (3 - ((4- (4-methoxybenzyl) -3,4-dihydro-2H-pyrido [3,2-b] [1,4 Yl] methyl) - [1,2,4] triazolo [4,3-b] pyridazin-6-yl) benzonitrile.

^{1 H-NMR (300 MHz,} CDCl 3) δ 8.23 (d, J = 9.7 Hz, 1H), 8.22 (m, 1H), 8.15 (dd, J = 8.0, 1.0 Hz, 1H), 7.87-7.80 (m , 2H), 7.68 (t, J = 7.8 Hz, 1H), 7.55 (d, J = 9.7 Hz, 1H), 7.19 (d, J = 8.6 Hz, 2H), 6.85 (dd, J = 7.7, 1.4 Hz , 1H), 6.75 (d, J = 8.6 Hz, 2H), 6.51 (dd, J = 7.6, 4.8 Hz, 1H), 4.88 (d, A of ABq, J = 14.7 Hz, 1H), 4.85 (m, 1H), 4.68 (d, B of ABq, J = 14.7Hz, 1H), 3.75 (s, 3H), 3.69 (m, 1H), 3.50-3.39 (m, 3H).

Example  45. 3- (3 - ((3,4- Dihydro -2H- Pyrido [3,2-b] [1,4] oxazine -2 days) methyl ) - [l, 2,4] Triazolo [4,3-b] Pyridazine Yl) Benzonitrile

2,3,4-tetrahydro-2H-pyrido [3,2-b] [1,4] oxazin-2-yl) methyl) - [1,2,4] triazolo [4,3-b] pyridazin-6-yl) benzonitrile trifluoroacetic acid salt.

^{1 H-NMR (300 MHz,} CDCl 3) δ 10.78 (brs, 1H), 8.34 (d, J = 9.7 Hz, 1H), 8.33 (m, 1H), 8.20 (d, J = 7.8 Hz, 1H), 7.88 (d, J = 7.8 Hz , 1H), 7.74 (t, J = 7.8 Hz, 1H), 7.63 (d, J = 9.7 Hz, 1H), 7.40 (d, J = 6.2 Hz, 1H), 6.66 ( dd, J = 7.6, 4.8 Hz, 1H), 4.89 (m, 1H), 3.92-3.62 (m, 4H).

Example  46. 4- (4-Methoxybenzyl) -2 - ((6- (pyridin-4-yl) - [ Triazolo [4,3-b] Pyridazine -3 days) methyl ) -3,4- Dihydro -2H- Pyrido [3,2-b] [1,4] oxazine

(4-methoxybenzyl) -2 - ((6- (pyridin-4-yl) - [1,2,4] triazolo [4,3-b ] Pyridazin-3-yl) methyl) -3,4-dihydro-2H-pyrido [3,2-b] [1,4] oxazine.

^{1 H-NMR (300 MHz,} CDCl 3) δ 8.83 (d, J = 6.0 Hz, 2H), 8.24 (d, J = 9.7 Hz, 1H), 7.80 (m, 3H), 7.58 (d, J = 9.7 Hz, 1H), 7.19 (d , J = 8.6 Hz, 2H), 6.86 (dd, J = 7.6, 1.2 Hz, 1H), 6.75 (d, J = 8.6 Hz, 2H), 6.50 (dd, J = 7.6 , 4.8 Hz, 1H), 4.90 (d, A of ABq, J = 14.7 Hz, 1H), 4.86 (m, 1H), 4.68 (d, B of ABq, J = 14.7 Hz, 1H), 3.75 (s, 3H), 3.69 (m, 1H), 3.51-3.40 (m, 3H).

Example  47. 2 - ((6- (Pyridin-4-yl) - [l, 2,4] Triazolo [4,3-b] Pyridazine -3 days) methyl ) -3,4- Dihydro -2H- Pyrido [3,2-b] [1,4] oxazine

PMB protecting group elimination reaction proceeded in the same manner as in Example 7 to obtain 2 - ((6- (pyridin-4-yl) - [1,2,4] triazolo [4,3- b] pyridazin- ) Methyl) -3,4-dihydro-2H-pyrido [3,2-b] [1,4] oxazine trifluoroacetic acid salt.

^{1 H-NMR (300 MHz,} CDCl 3) δ 10.82 (brs, 1H), 8.93 (d, J = 6.0 Hz, 2H), 8.40 (d, J = 9.7 Hz, 1H), 8.07 (d, J = 6.0 Hz, 2H), 7.69 (d , J = 9.7 Hz, 1H), 7.41 (d, J = 6.0 Hz, 1H), 7.21 (d, J = 7.5 Hz, 1H), 6.66 (dd, J = 7.6, 4.8 Hz, &lt; / RTI &gt; 1H), 4.91 (m, 1H), 3.90-3.66 (m, 4H).

Example  48. 4- (4-Methoxybenzyl) -2 - ((6- (pyridin-3-yl) - [ Triazolo [4,3-b] Pyridazine -3 days) methyl ) -3,4- Dihydro -2H- Pyrido [3,2-b] [1,4] oxazine

(4-methoxybenzyl) -2 - ((6- (pyridin-3-yl) - [1,2,4] triazolo [4,3-b ] Pyridazin-3-yl) methyl) -3,4-dihydro-2H-pyrido [3,2-b] [1,4] oxazine.

^{1 H-NMR (300 MHz,} CDCl 3) δ 9.27 (s, 1H), 8.72 (s, 1H), 8.54 (d, J = 6.7 Hz, 1H), 8.25 (d, J = 9.7 Hz, 1H), 7.81 (m, 1H), 7.61 (m, 1H), 7.58 (d, J = 9.7 Hz, 1H), 7.19 (d, J = 8.6 Hz, 2H), 6.87 (d, J = 7.6 Hz, 1H), 6.73 (d, J = 8.6 Hz , 2H), 6.52 (dd, J = 7.6, 4.8 Hz, 1H), 4.91 (d, A of ABq, J = 14.7 Hz, 1H), 4.87 (m, 1H), 4.68 (d, B of ABq, J = 14.7Hz, 1H), 3.75 (s, 3H), 3.68 (m, 1H), 3.52-3.41 (m, 3H).

Example  49. 2 - ((6- (Pyridin-3-yl) - [1, 2,4] Triazolo [4,3-b] Pyridazine -3 days) methyl ) -3,4- Dihydro -2H- Pyrido [3,2-b] [1,4] oxazine

PMB protecting group elimination reaction proceeded in the same manner as in Example 7 to obtain 2 - ((6- (pyridin-3-yl) - [1,2,4] triazolo [4,3- b] pyridazin- ) Methyl) -3,4-dihydro-2H-pyrido [3,2-b] [1,4] oxazine trifluoroacetic acid salt.

^{1 H-NMR (300 MHz,} CDCl 3) δ 10.63 (brs, 1H), 9.40 (s, 1H), 8.90 (s, 1H), 8.56 (d, J = 6.6 Hz, 1H), 8.42 (d, J = 9.7 Hz, 1H), 7.78 (m, 1H), 7.72 (d, J = 9.7 Hz, 1H), 7.4 (d, J = 6.4 Hz, 1H), 7.21 (d, J = 7.8 Hz, 1H), 6.67 (dd, J = 7.6, 4.8 Hz, 1H), 4.90 (m, 1H), 3.89-3.62 (m, 4H).

Example  50. 4- (4-Methoxybenzyl) -2 - ((6- (4- Methoxyphenyl ) - [l, 2,4] Triazolo [4,3-b] Pyridazine -3 days) methyl ) -3,4- Dihydro -2H- Pyrido [3,2-b] [1,4] oxazine

(4-methoxybenzyl) -2 - ((6- (4-methoxyphenyl) - [1,2,4] triazolo [4,3-b ] Pyridazin-3-yl) methyl) -3,4-dihydro-2H-pyrido [3,2-b] [1,4] oxazine.

^{1 H-NMR (300 MHz,} CDCl 3) δ 8.10 (d, J = 9.7 Hz, 1H), 7.89 (d, J = 6.8 Hz, 2H), 7.80 (dd, J = 4.9, 1.4 Hz, 1H), 7.55 (d, J = 9.7 Hz , 1H), 7.18 (d, J = 8.6 Hz, 2H), 7.04 (d, J = 6.8 Hz, 2H), 6.91 (d, J = 7.6 Hz, 1H), 6.74 ( d, J = 8.6 Hz, 2H ), 6.50 (dd, J = 7.6, 4.8 Hz, 1H), 4.90 (d, A of ABq, J = 14.7 Hz, 1H), 4.87 (m, 1H), 4.67 (d , B of ABq, J = 14.7 Hz, 1H), 3.90 (s, 3H), 3.74 (s, 3H), 3.69 (m, 1H), 3.52-3.39 (m, 3H).

Example  51. 2 - ((6- (4- Methoxyphenyl ) - [l, 2,4] Triazolo [4,3-b] Pyridazine -3 days) methyl ) -3,4- Dihydro -2H- Pyrido [3,2-b] [1,4] oxazine

PMB protecting group elimination reaction proceeded in the same manner as in Example 7 to obtain 2 - ((6- (4-methoxyphenyl) - [1,2,4] triazolo [4,3- b] pyridazin- ) Methyl) -3,4-dihydro-2H-pyrido [3,2-b] [1,4] oxazine trifluoroacetic acid salt.

^{1 H-NMR (300 MHz,} CDCl 3) δ 10.75 (brs, 1H), 8.28 (d, J = 9.7 Hz, 1H), 7.92 (d, J = 8.7 Hz, 2H), 7.68 (d, J = 9.7 Hz, 1H), 7.39 (d , J = 6.4 Hz, 1H), 7.19 (d, J = 7.6 Hz, 1H), 7.06 (d, J = 8.7 Hz, 2H), 6.74 (d, J = 8.6 Hz, 2H), 6.63 (dd, J = 7.6,4.8Hz, 1H), 4.80 (m, 1H), 3.91 (s, 3H), 3.79-3.61 (m, 4H).

Example  52. 4- (3 - ((4- (4-methoxybenzyl) -3,4- Dihydro -2H- Pyrido [3,2-b] [1,4] oxazine -2 days) methyl ) - [l, 2,4] Triazolo [ 4,3-b] pyridazine -6-yl) -N, N- Dimethylbenzene amine

The title compound was obtained from 4- (3 - ((4- (4-methoxybenzyl) -3,4-dihydro-2H-pyrido [3,2- Yl] methyl] - [1,2,4] triazolo [4,3-b] pyridazin-6-yl) -N, N-dimethylbenzenamine.

^{1 H-NMR (300 MHz,} CDCl 3) δ 8.02 (d, J = 9.7 Hz, 1H), 7.83 (d, J = 8.7 Hz, 2H), 7.80 (dd, J = 5.3, 1.2 Hz, 1H), 7.53 (d, J = 9.7 Hz , 1H), 7.17 (d, J = 8.6 Hz, 2H), 6.92 (dd, J = 7.7, 1.2 Hz, 1H), 6.77 (d, J = 8.7 Hz, 2H), 6.73 (d, J = 8.6 Hz , 2H), 6.52 (dd, J = 7.6, 4.8 Hz, 1H), 4.88 (d, A of ABq, J = 14.7 Hz, 1H), 4.86 (m, 1H), 4.66 (d, B of ABq, J = 14.7 Hz, 1H), 3.72 (s, 3H), 3.68 (m, 1H), 3.51-3.33 (m, 3H), 3.08 (s, 6H).

Example  53. 4- (3 - ((3,4- Dihydro -2H- Pyrido [3,2-b] [1,4] oxazine -2 days) methyl ) - [l, 2,4] Triazolo [4,3-b] Pyridazine -6-yl) -N, N- Dimethylbenzene amine

PMB protecting group elimination reaction proceeded in the same manner as in Example 7 to obtain 4- (3 - ((3,4-dihydro-2H-pyrido [3,2- b] [1,4] ) Methyl) - [1,2,4] triazolo [4,3-b] pyridazin-6-yl) -N, N-dimethylbenzenamine trifluoroacetate.

^{1 H-NMR (300 MHz,} CDCl 3) δ 10.87 (brs, 1H), 8.14 (d, J = 9.7 Hz, 1H), 7.85 (d, J = 8.9 Hz, 2H), 7.62 (d, J = 9.7 Hz, 1H), 7.37 (d , J = 6.2 Hz, 1H), 7.19 (d, J = 7.5 Hz, 1H), 6.79 (d, J = 8.9 Hz, 2H), 6.60 (dd, J = 7.5, 4.8 1H), 4.86 (m, 1H), 3.86-3.76 (m, 2H), 3.67-3.57 (m, 2H), 3.09 (s, 6H).

Example  54. methyl  4- (3 - ((4- (4-methoxybenzyl) -3,4- Dihydro -2H- Pyrido [3,2-b] [1,4] oxazine -2 days) methyl ) - [l, 2,4] triazolo [ 4,3-b] pyridazine Yl) Benzoate

The title compound was obtained from methyl 4- (3 - ((4- (4-methoxybenzyl) -3,4-dihydro-2H-pyrido [3,2- 4] oxazin-2-yl) methyl) - [1,2,4] triazolo [4,3- b] pyridazin-6-yl) benzoate.

^{1 H-NMR (300 MHz,} CDCl 3) δ 8.22 (d, J = 8.4 Hz, 2H), 8.16 (d, J = 9.7 Hz, 1H), 8.14 (d, J = 8.4 Hz, 2H), 7.79 ( dd, J = 4.9, 1.2 Hz , 1H), 7.61 (d, J = 9.7 Hz, 1H), 7.18 (d, J = 8.6 Hz, 2H), 6.89 (dd, J = 7.6, 1.2 Hz, 1H), 6.73 (d, J = 8.6 Hz , 2H), 6.51 (dd, J = 7.6, 4.8 Hz, 1H), 4.92 (d, A of ABq, J = 14.7 Hz, 1H), 4.91 (m, 1H), 4.67 (d, B of ABq, J = 14.7Hz, 1H), 3.98 (s, 3H), 3.71 (s, 3H), 3.72 (m, 1H), 3.53-3.34 (m, 3H).

Example  55. methyl  4- (3 - ((3,4- Dihydro -2H- Pyrido [3,2-b] [1,4] oxazine -2 days) methyl ) - [l, 2,4] Triazolo [4,3-b] pyridazin-6-yl) Benzoate

PMB protecting group elimination reaction proceeded in the same manner as in Example 7 to obtain methyl 4- (3 - ((3,4-dihydro-2H-pyrido [3,2- b] [1,4] Yl) methyl) - [1,2,4] triazolo [4,3-b] pyridazin-6-yl) benzoate trifluoroacetic acid salt.

^{1 H-NMR (300 MHz,} DMSO-d 6) δ 8.62 (d, J = 9.7 Hz, 1H), 8.54 (d, J = 8.4 Hz, 2H), 8.51 (d, J = 8.4 Hz, 2H), 8.05 (d, J = 9.7 Hz , 1H), 7.62 (d, J = 6.0 Hz, 1H), 7.33 (d, J = 7.6 Hz, 1H), 6.72 (dd, J = 7.6, 4.8 Hz, 1H), 4.88 (m, 1 H), 3.93 (s, 3 H), 3.72 - 3.50 (m, 4 H).

Example  56. methyl  3- (3 - ((4- (4-methoxybenzyl) -3,4- Dihydro -2H- Pyrido [3,2-b] [1,4] oxazine -2 days) methyl ) - [l, 2,4] triazolo [ 4,3-b] pyridazine Yl) Benzoate

The title compound was obtained from methyl 3- (3 - ((4- (4-methoxybenzyl) -3,4-dihydro-2H-pyrido [3,2- 4] oxazin-2-yl) methyl) - [1,2,4] triazolo [4,3- b] pyridazin-6-yl) benzoate.

^{1 H-NMR (300 MHz,} CDCl 3) δ 8.58 (s, 1H), 8.22 (m, 2H), 8.16 (d, J = 9.7 Hz, 1H), 7.78 (dd, J = 4.9, 1.2 Hz, 1H ), 7.64 (d, J = 9.7 Hz, 1H), 7.62 (d, J = 7.8 Hz, 1H), 7.18 (d, J = 8.6 Hz, 2H), 6.89 (dd, J = 7.6, 1.2 Hz, 1H ), 6.73 (d, J = 8.6 Hz, 2H), 6.50 (dd, J = 7.6, 4.8 Hz, 1H), 4.91 (d, A of ABq, J = 14.7 Hz, 1H), 4.90 (m, 1H) , 4.67 (d, B of ABq, J = 14.7 Hz, 1H), 3.99 (s, 3H), 3.73 (s, 3H), 3.74 (m, 1H), 3.52-3.37 (m, 3H).

Example  57. methyl  3- (3 - ((3,4- Dihydro -2H- Pyrido [3,2-b] [1,4] oxazine -2 days) methyl ) - [l, 2,4] Triazolo [4,3-b] pyridazin-6-yl) Benzoate

PMB protecting group elimination reaction proceeded in the same manner as in Example 7 to obtain methyl 3- (3 - ((3,4-dihydro-2H-pyrido [3,2- b] [1,4] Yl) methyl) - [1,2,4] triazolo [4,3-b] pyridazin-6-yl) benzoate trifluoroacetic acid salt.

^{1 H-NMR (300 MHz,} DMSO-d 6) δ 8.62 (s, 1H), 8.51 (d, J = 9.7 Hz, 1H), 8.40 (d, J = 7.8 Hz, 1H), 8.18 (d, J = 7.8 Hz, 1H), 8.05 (d, J = 9.7 Hz, 1H), 7.78 (t, J = 7.8 Hz, 1H), 7.62 (d, J = 6.0 Hz, 1H), 7.33 (dd, J = 7.6 (D, J = 7.6, 4.8 Hz, 1H), 4.88 (m, 1H), 3.93 (s, 3H), 3.72-3.50 (m, 4H).

Example  58. (4- (3 - ((4- (4-methoxybenzyl) -3,4- Dihydro -2H- Pyrido [3,2-b] [1,4] oxazine -2 days) methyl ) - [l, 2,4] Triazolo [ 4,3-b] pyridazine Yl) Phenyl ) Methanol

This compound was prepared in the same manner as in Example 34 to give the desired compound (4- (3 - ((4- (4-methoxybenzyl) -3,4-dihydro- Yl] methyl) - [1,2,4] triazolo [4,3-b] pyridazin-6-yl) phenyl) methanol (38%).

^{1 H-NMR (300 MHz,} CDCl 3) δ 8.15 (d, J = 9.7㎐, 1H), 7.92 (d, J = 8.4㎐, 2H), 7.80 (dd, J = 4.5, 1.2㎐, 1H), 7.58 (q, J = 9.7㎐, 1H), 7.53 (d, J = 8.4㎐, 2H), 7.17 (d, J = 8.6㎐, 2H), 6.90 (dd, J = 7.6, 1.4㎐, 1H), 6.72 (d, J = 8.6㎐, 2H), 6.51 (dd, J = 7.6, 4.8㎐, 1H), 4.91 (d, A of ABq, J = 14.7Hz, 1H), 4.88 (m, 1H), 4.83 (s, 3H), 3.74 (m, 1H), 3.51-3.39 (m, 3H), 4.65 (d, B of ABq, J = 14.7 Hz, 1H).

Example  59. (4- (3 - ((3,4- Dihydro -2H- Pyrido [3,2-b] [1,4] oxazine -2 days) methyl ) - [l, 2,4] Triazolo [4,3-b] Pyridazine Yl) Phenyl ) Methanol

PMB protecting group elimination reaction proceeded in the same manner as in Example 7 to obtain (4- (3 - ((3,4-dihydro-2H-pyrido [3,2- b] [1,4] Yl) methyl) - [1,2,4] triazolo [4,3-b] pyridazin-6-yl) phenyl) methanol trifluoroacetic acid salt.

^{1 H-NMR (300 MHz,} CDCl 3) δ 10.91 (brs, 1H), 8.25 (d, J = 9.7 Hz, 1H), 8.00 (d, J = 8.4 Hz, 2H), 7.63 (d, J = 9.7 Hz, 1H), 7.60 (d , J = 8.4 Hz, 2H), 7.38 (d, J = 6.0 Hz, 1H), 7.20 (d, J = 7.5 Hz, 2H), 6.62 (dd, J = 7.5, 4.8 1H), 5.46 (s, 2H), 4.85 (m, 1H), 3.86-3.79 (m, 2H), 3.70-3.63 (m, 2H).

Example  60. 4- (4-Methoxybenzyl) -2 - ((6- (4- ( Molopolymomethyl ) Phenyl ) - [l, 2,4] Triazolo [4,3-b] Pyridazine -3 days) methyl ) -3,4- Dihydro -2H- Pyrido [3,2-b] [1,4] oxazine

The title compound was obtained from methyl 4- (4-methoxybenzyl) -2 - ((6- (4- (morpholinomethyl) phenyl) - [l, 2,4] triazolo [ 4,3-b] pyridazin-3-yl) methyl) -3,4-dihydro-2H-pyrido [3,2-b] [1,4] oxazine.

^{1 H-NMR (300 MHz,} CDCl 3) δ 8.13 (d, J = 9.7 ㎐, 1H), 7.87 (d, J = 8.1 ㎐, 2H), 7.79 (dd, J = 4.5, 1.2 ㎐, 1H), 7.56 (q, J = 9.7 ㎐ , 1H), 7.50 (d, J = 8.1 ㎐, 2H), 7.17 (d, J = 8.6 ㎐, 2H), 6.88 (dd, J = 7.6, 1.4 ㎐, 1H), 6.73 (d, J = 8.6 ㎐ , 2H), 6.51 (dd, J = 7.6, 4.8 ㎐, 1H), 4.88 (d, A of ABq, J = 14.7 Hz, 1H), 4.86 (m, 1H), 4.66 (d, B of ABq, J = 14.7 Hz, 1H), 3.78 (s, 2H), 3.74 (m, 4H), 3.68 (m, 1H), 3.54-3.34 (m, 3H), 2.43 (m, 4H ).

Example  61. 2 - ((6- (4- ( Molopolymomethyl ) Phenyl ) - [l, 2,4] Triazolo [4,3-b] Pyridazine -3 days) methyl ) -3,4- Dihydro -2H-pyrrolo [ Lt; / RTI &gt; [3,2-b] [1,4] oxazole camp

PMB protecting group elimination reaction proceeded in the same manner as in Example 7 to obtain 2 - ((6- (4- (morpholinomethyl) phenyl) - [1,2,4] triazolo [4,3- b] pyridazine Yl) methyl) -3,4-dihydro-2H-pyrido [3,2-b] [1,4] oxazine trifluoroacetic acid salt.

^{1 H-NMR (300 MHz,} CDCl 3) δ 10.75 (brs, 1H), 8.27 (d, J = 9.7 Hz, 1H), 7.98 (d, J = 8.1 Hz, 2H), 7.65 (d, J = 8.1 Hz, 2H), 7.64 (d , J = 9.7 Hz, 1H), 7.38 (d, J = 6.0 Hz, 1H), 7.22 (d, J = 7.5 Hz, 1H), 6.64 (dd, J = 7.5, 4.8 (M, 2H), 2.85 (m, 4H), 4.22 (s, 2H), 3.86-3.79 (m, 2H), 3.70-3.63

Example  62. N-Ethyl-3- (3 - ((4- (4-methoxybenzyl) -3,4- Dihydro -2H- Pyrido [3,2-b] [1,4] oxazine -2 days) methyl ) - [l, 2,4] triazolo [4,3-b] Pyridazine Yl) Benzamide

3- (6-chloropyridazin-3-yl) -N -ethylbenzamide obtained in Example 33 and 2- (4- (4-methoxybenzyl) -3,4-dihydro- 2 H-pyrido [3,2- b] [1,4] oxazin-2-yl l) acetonitrile high in the same way as the reaction of hydrazide and example 34 N-ethyl-3- (3 - ((4 - (4-methoxybenzyl) -2 H -3,4-dihydro-pyrido [3,2- b] [1,4] oxazin-2-yl) methyl) - [1, 2,4] Triazolo [4,3- b ] pyridazin-6-yl) benzamide.

^{1 H-NMR (300 MHz,} CDCl 3) δ 8.32 (s, 1H), 8.17 (d, J = 9.7 ㎐, 1H), 8.05 (d, J = 7.9 ㎐, 1H), 7.91 (d, J = 7.7 J = 9.7 Hz, 1H), 7.61 (m, 1H), 7.19 (d, J = 8.5 Hz, 2H), 7.75 (dd, J = 6.83 (dd, J = 7.7, 1.3 ㎐, 1H), 6.74 (d, J = 8.5 ㎐, 2H), 6.46 (dd, J = 7.7 4.9 ㎐, 1H), 6.41 (brs, 1H), 4.91 (d, A of ABq, J = 14.7 ㎐ , 1H), 4.88 (m, 1H), 4.67 (d, B of ABq, J = 14.7 ㎐, 1H), 3.74 (s, 3H), 3.57-3.35 (m, 6H) , 1.29 (t, J = 7.2 Hz, 3H).

Example  63. 3- (3 - ((3,4- Dihydro -2H- Pyrido [3,2-b] [1,4] oxazine -2 days) methyl ) - [l, 2,4] Triazolo [4,3-b] pyridazin-6-yl) -N- Ethylbenzamide

N -ethyl-3- (3 - ((4- (4-methoxybenzyl) -3,4-dihydro- 2H -pyrido [3,2- b ] [1,4] yl) methyl) - [1,2,4] triazol twos [4,3- b] pyridazin-6-yl) the PMB protecting group removing reaction of Provenza polyimide is conducted in the same manner as in example 7 2 - ((6 Yl) methyl) -3,4-dihydropyrrolo [2,3-b] pyridin- Dihydro-2H-pyrido [3,2-b] [1,4] oxazine trifluoroacetic acid salt.

^{1 H-NMR (300 MHz,} CDCl 3) δ 10.63 (s, 1H), 8.45 (s, 1H), 8.33 (d, J = 9.6 ㎐, 1H), 8.10 (d, J = 7.8 ㎐, 1H), J = 7.7 Hz, 1H), 7.74 (d, J = 9.6 Hz, 1H), 7.64 (t, J = 7.8 Hz, 1H), 7.38 (d, J = 6.2 Hz, 1H) d, J = 7.7 ㎐, 1H ), 6.63 (t, J = 6.8 ㎐, 1H), 6.36 (brs, 1H), 4.87 (m, 1H), 3.86-3.54 (m, 6H), 1.30 (t, J = 7.2 Hz, 3H).

Example  64. (3- (3 - ((4- (4-methoxybenzyl) -3,4- Dihydro -2H- Pyrido [3,2-b] [1,4] oxazine -2 days) methyl ) - [l, 2,4] Triazolo [ 4,3-b] pyridazine Yl) Phenyl )(4- Methylpiperazine -1 day) Methanone

The title compound (3- (3- ((4- (4-methoxybenzyl) -3,4-dihydro-2H-pyrido [3,2- Yl) methyl] - [1,2,4] triazolo [4,3-b] pyridazin-6-yl) phenyl) (4-methylpiperazin- (48%).

^{1 H NMR (300 ㎒, CDCl} 3) δ 8.17 (d, J = 9.7 ㎐, 1H), 7.99 (m, 2H), 7.79 (d, J = 4.9 ㎐, 1H), 7.59-7.56 (m, 3H) , 7.18 (d, J = 8.5 ㎐, 2H), 6.89 (d, J = 7.6 ㎐, 1H), 6.74 (d, J = 8.5 ㎐, 1H), 6.50 (dd, J = 7.6, 4.9 ㎐, 1H) , 4.89 (d, A of ABq , J = 14.7 Hz, 1H), 4.87 (m, 1H), 4.67 (d, B of ABq, J = 14.7 ㎐, 1H), 3.85 (m, 2H), 3.72 (s 3H), 3.70 (m, 1H), 3.56-3.35 (m, 5H), 2.53 (m, 2H), 2.38 (m, 2H), 2.33

Example  65. (3- (3 - ((3,4- Dihydro -2H- Pyrido [3,2-b] [1,4] oxazine -2 days) methyl ) - [l, 2,4] Triazolo [4,3-b] Pyridazine Yl) Phenyl )(4- Methylperazine -1 day) Methanone

Removal of the PMB protecting group proceeded in the same manner as in Example 7 to obtain (3- (3 - ((3,4-dihydro- 2H -pyrido [3,2- b ] [1,4] Yl) methyl) - [1,2,4] triazolo [4,3- b ] pyridazin-6-yl) phenyl) (4-methylpiperazin-1-yl) methanone.

^{1 H NMR (300 ㎒, CDCl} 3) δ 10.55 (brs, 1H), 8.36 (d, J = 9.7 ㎐, 1H), 8.06 (m, 2H), 7.66 (m, 3H), 7.41 (d, J = J = 7.5, 4.9 Hz, 1H), 4.89 (m, 1H), 3.86-3.53 (m, 12H), 2.88 (d, J = 7.8 Hz, s, 3H).

Example  66. (4- (3 - ((3,4- Dihydro -2H- Pyrido [3,2-b] [1,4] oxazine -2 days) methyl ) - [l, 2,4] Triazolo [4,3-b] Pyridazine Yl) Phenyl )(4- Methylpiperazine -1 day) Methanone

2,3,4-tetrahydro-2H-pyrido [3,2-b] [1,4] oxazin-2-yl) methyl ) - [1,2,4] triazolo [4,3-b] pyridazin-6-yl) phenyl) (4-methylpiperazin-1-yl) methanone trifluoroacetate.

^{1 H NMR (300 ㎒, CDCl} 3) δ 10.57 (brs, 1H), 8.60 (d, J = 9.7 ㎐, 1H), 8.51 (d, J = 8.3 Hz, 2H), 8.49 (d, J = 8.3 Hz , 2H), 8.04 (d, J = 9.7 Hz, 1H), 7.62 (d, J = 6.2 ㎐, 1H), 7.32 (d, J = 7.6 ㎐, 1H), 6.69 (dd, J = 7.6, 4.8 ㎐ , &Lt; / RTI &gt; 1H), 4.89 (m, 1H), 3.87-3.50 (m, 12H), 2.88 (s, 3H).

Example  67. 4- (4-Methoxybenzyl) -2 - ((6- (1- methyl -1H- Indazole Yl) - [l, 2,4] Triazolo [4,3-b] Pyridazine -3 days) methyl ) -3,4- Dihydro -2H- Pyrido [3,2-b] [1,4] oxazine

To a solution of 2-fluorophenylacetonitrile (80 mg, 0.54 mmol) in dimethylformamide (5 mL) was added potassium tert-butoxide ( t- BuOK, 30 mg, 1.1 mmol) Respectively. 2 embodiment obtained in Examples 6 - ((6-chloro [1,2,4] triazolo [4,3- b] pyridazin-3-yl) methyl) -4- (4-methoxybenzyl) -3 , 4-dihydro- 2H -pyrido [3,2- b ] [1,4] oxazine (0.23 g, 0.54 mmol) was dissolved in dimethylformamide (2 mL) and added dropwise to the reaction solution. After stirring at 0 ° C for 1 hour, the mixture was stirred at room temperature for 12 hours, cooled to 0 ° C, and hydrogen peroxide (H ₂ O ₂ , 5 mL) was added dropwise thereto, followed by stirring at room temperature for 12 hours. After the reaction, the reaction mixture was diluted with ethyl acetate and washed with brine. The organic layer was dried over anhydrous sodium sulfate, concentrated, and then purified by column chromatography (60% EtOAc / Hexane) Yl) methyl) - [1, 2,4] triazolo [4,2-b] [1,4] oxazin- 4,3-b] pyridazin-6-yl) methanone (70 mg, 25%).

^{1 H NMR (300 ㎒, CDCl} 3) δ 8.24 (d, J = 9.7 ㎐, 1H), 7.78 (m, 2H), 7.71 (t, J = 7.2 Hz, 1H), 7.58 (m, 1H), 7.28 (d, J = 7.6 Hz, 1H), 7.15 (d, J = 8.6 Hz, 2H), 7.01 (t, J = 9.4 ㎐, 1H), 7.81 (d, J = 7.4 ㎐, 1H), 6.77 (d , J = 8.6 Hz, 2H) , 6.49 (dd, J = 7.6, 4.8 ㎐, 1H), 4.83 (d, A of ABq, J = 14.8 ㎐, 1H), 4.74 (m, 1H), 4.66 (d, B of ABq, J = 14.8 Hz, 1H), 3.77 (s, 3H), 3.56-3.22 (m, 4H).

(2-fluorophenyl) (3 - ((4- (4-methoxybenzyl) -3,4-dihydro-2H-pyrido [3,2- b] [1,4] Yl) methanone (20 mg, 0.04 mmol) and methyl hydrazine (0.16 mL, 3.14 mmol) were added to a solution of 4-amino- Amide (1 mL) and reacted at 150 ^° C for 15 minutes using a microwave device. After the reaction, the reaction mixture was diluted with ethyl acetate and washed with brine. The organic layer was dried over anhydrous sodium sulfate, concentrated, and then purified by column chromatography (EtOAc) to give 4- (4-methoxybenzyl) -2- Yl) methyl] -3,4-dihydro-2H-pyrido [l, 2,4] triazolo [ 3,2-b] [1,4] oxazine (11 mg, 55%).

^{1 H NMR (300 ㎒, CDCl} 3) δ 8.34 (d, J = 9.7 ㎐, 1H), 8.09 (m, 2H), 7.73 (d, J = 4.8 Hz, 1H), 7.47 (m, 2H), 7.29 (m, 1H), 7.14 ( d, J = 8.6 Hz, 2H), 6.88 (d, J = 7.6 ㎐, 1H), 6.69 (d, J = 8.6 Hz, 2H), 6.45 (dd, J = 7.6, 4.8 ㎐, 1H), 4.88 ( m, 1H), 4.80 (d, A of ABq, J = 14.7 ㎐, 1H), 4.67 (d, B of ABq, J = 14.7 ㎐, 1H), 4.16 (s, 3H ), 3.72 (m, 1 H), 3.70 (s, 3 H), 3.54 (m 2H), 3.39 (m,

Example  68. 2 - ((6- (1- methyl -1H- Indazole Yl) - [l, 2,4] Triazolo [4,3-b] Pyridazine -3 days) methyl ) -3,4- Dihydro -2H-pyrrolo [ Lt; / RTI &gt; [3,2-b] [1,4] oxazole camp

PMB protecting group elimination reaction proceeded in the same manner as in Example 7 to obtain 2 - ((6- (1 -methyl-1 H-indazol-3-yl) - [1,2,4] triazolo [ ] Pyridazin-3-yl) methyl) -3,4-dihydro-2H-pyrido [3,2-b] [1,4] oxazine trifluoroacetic acid salt.

^{1 H-NMR (300 MHz,} CDCl 3) δ 10.72 (brs, 1H), 8.05 (d, J = 9.7 Hz, 1H), 7.99 (m, 2H), 7.69 (d, J = 9.7 Hz, 1H), 7.42 (d, J = 6.4 Hz , 1H), 7.42 (m 2H), 7.18 (d, J = 7.6 Hz, 1H), 6.60 (dd, J = 7.5, 4.8 Hz, 1H), 4.89 (m, 1H) , 4.17 (s, 3H), 3.60 (m, IH), 3.51 (m, 2H), 3.38 (m, IH).

Formulation example  1: Tablet (direct pressurization)

After 5.0 mg of the active ingredient was sieved, 14.1 mg of lactose, 0.8 mg of crospovidone USNF and 0.1 mg of magnesium stearate were mixed and pressurized to make tablets.

Formulation example  2: Tablet (wet assembly)

After 5.0 mg of the active ingredient was sieved, 16.0 mg of lactose and 4.0 mg of starch were mixed. 0.3 mg of Polysorbate 80 was dissolved in pure water, and an appropriate amount of this solution was added, followed by atomization. After drying, the granules were sieved and mixed with 2.7 mg of colloidal silicon dioxide and 2.0 mg of magnesium stearate. The granules were pressurized to make tablets.

Formulation example  3: Powder and Capsule

5.0 mg of the active ingredient was sieved and mixed with 14.8 mg of lactose, 10.0 mg of polyvinylpyrrolidone and 0.2 mg of magnesium stearate. The mixture was filtered through a hard No. 5 gelatin capsules.

Formulation example  4: Injection

100 mg as an active ingredient, 180 mg of mannitol, 26 mg of Na ₂ HPO _{4 12} H ₂ O and 2974 mg of distilled water were added to prepare an injection.

Experimental Example  1. c- Met Kinase  Inhibitory activity experiment

In order to measure the proliferation inhibitory activity of abnormal cells of the pyrazolopyridine derivative or its pharmaceutically acceptable salt according to the present invention in the cell stage, the following experiment was conducted.

The inhibitory activity against c-Met kinase was analyzed by using Dissociation Enhanced Lanthanide Fluoro Immuno Assay (DELFIA; Perkin Elmer), which is a kind of time-resolved fluorescence (TRF) Respectively.

10 mL of the compound prepared in Examples 4 to 6 and 8 to 12 was added as a test compound to a 96-well V-shaped bottom plate and added with tyrosine kinase buffer (20 mL) mixed with c-Met enzyme, The compounds were mixed and incubated for 15 minutes. ATP solution (10 mL) was added thereto, and the reaction was quenched at room temperature for 30 minutes. Then, 50 mM ethylenediaminetetraacetic acid solution (EDTA, 40 mL) was added to stop the reaction.

  The reaction was transferred to a plate coated with streptavidin, incubated under shaking, and washed three times with PBS-T buffer (PBS 0.05% Tween 20) for 2 hours.

The anti-phosphotyrosine antibody with europium was diluted 1: 2,500, added 100 mL per well, incubated under shaking, and washed 1 hour later with PBS-T buffer (PBS 0.05% Tween 20) 5 times.

An enhancement solution (100 mL) was added and incubated for 5 minutes with shaking, and then read in a wavelength range of 615/665 nm with a Wallac Envision 2103 instrument. The IC ₅₀ of the test compound subjected to the above experiment was determined by two sets of data and was determined using a prism (version 5.01, GraphPad) software.

IC ₅₀ &lt; / RTI &gt; of the compound reducing the c-Met kinase enzyme activity to 50% Or% inhibition at 1 uM concentration are shown in Table 1 below.

compound c-Met IC ₅₀ ([mu] M) compound c-Met IC ₅₀ ([mu] M) or
% Inhibition rate Example 7 0.05 Example 47 0.06 Example 9 0.07 Example 49 0.08 Example 11 0.04 Example 51 0.04 Example 13 0.04 Example 53 0.27 Example 15 0.15 Example 55 0.01 Example 17 0.18 Example 57 0.26 Example 35 0.28 Example 59 0.03 Example 37 0.22 Example 61 0.21 Example 39 0.29 Example 63 0.12 Example 41 0.24 Example 65 0.01 Example 43 0.44 Example 66 0.12 Example 45 1.2 Example 68 0.01

The compounds of Examples 7, 9, 11, 13, 47, 49, 51, 55, 59, 65 and 68 show excellent in vitro activity against c-Met.

Claims (9)

A triazolopyridazine derivative selected from the group consisting of compounds represented by the following formulas (2) to (26): or a pharmaceutically acceptable salt thereof:
(2)

(4)

(6)

(8)

(10)

(12)

(14)

(16)

(18)

(20)

(22)

(24)

26

delete delete The triazolo pyridazine derivative according to claim 1, wherein the triazolo pyridazine derivative is selected from the group consisting of the compounds represented by the above formulas 2 to 5, 14 to 16, 18, 20, 22 and 26 Or a pharmaceutically acceptable salt thereof.
The pharmaceutical composition according to claim 1 or 4, wherein the pharmaceutically acceptable salt of the triazolo pyridazine derivative is at least one selected from the group consisting of hydrochloride, bromate, sulfate, phosphate, citrate, acetate, trifluoroacetate, lactate, tartrate, Characterized in that it is selected from the group consisting of fumarate, fumarate, gluconate, methanesulfonate, glycinate, succinate, 4-toluenesulfonate, gluturonate, ebonate, glutamate or aspartate. A solopyridazine derivative or a pharmaceutically acceptable salt thereof.
delete A pharmaceutical composition for preventing or treating a hyperproliferative disorder comprising the triazolopyridazine derivative of claim 1 or 4, or a pharmaceutically acceptable salt thereof as an active ingredient.
8. The method of claim 7, wherein the hyperproliferative disorder is selected from the group consisting of cancer, diabetic retinopathy, retinopathy of prematurity, corneal transplant rejection, neovascular glaucoma, hypoxia, proliferative retinopathy, psoriasis, rheumatoid arthritis, osteoarthritis, , Crohn's disease, recurrent stenosis, atherosclerosis, intestinal adhesion, ulcer, hepatopathy, glomerulonephritis, diabetic nephropathy, malignant neuropathy, thrombotic microangiopathy, organ transplant rejection, .
The composition according to claim 8, wherein the cancer is lung cancer, stomach cancer, pancreatic cancer, colon cancer, ovarian cancer, renal cell cancer, prostate cancer or brain tumor.