KR101350006B1 - Protein kinase inhibitors comprising pyridone derivatives - Google Patents

Abstract

The present invention relates to a novel compound which, by inhibiting protein kinase activity, can be used for the prevention and treatment of relevant diseases and a pharmaceutical composition including same. A compound made by protein kinase inhibitors comprising pyridine derivatives according to an embodiment of the present invention and pharmaceutically acceptable salts thereof inhibit protein kinase activity, and therefore, they can be used for the prevention and treatment of relevant diseases. [Reference numerals] (AA) Comparative example, 5mg/kg; (BB) Comparative example, 20mg/kg; (CC) Example 1, 5mg/kg; (DD) Example 1, 20mg/kg

Description

Protein kinase inhibitors comprising pyridone derivatives}

The present invention relates to novel compounds that can be usefully used for the prevention or treatment of diseases related thereto by inhibiting protein kinase activity and pharmaceutical compositions comprising the same.

Protein kinases are enzymes that phosphorylate other proteins to regulate the activity, location and function of proteins to control various intracellular processes. The dysregulation of these protein kinases is closely linked to disease mechanisms such as cancer, immune disease, neurological disease, metabolic disease and infection. The protein kinase includes Abl, ACK, ALK, Arg, ARK5, Aurora, Axl, Bmx, BTK, CDK, CHK, c-Kit, c-MET, c-RAF, c-SRC, EGFR, FAK, Fes, FGFR, Flt3, GSK3, IGF, IKK, JAK, Lck, LIMK, Lyn, MEK, Mer, MK-2, P38alpha, PDGFR, PDK, Pim, PKA, PKB, PKCR, Plk-1 / 3, Ret, Ron, Ros, Rse, Tie, Trk, Tyro3, VEGFR, YES and the like.

c-MET is a membrane receptor that plays an essential role in embryo development and wound healing. Hepatocyte growth factor (HGF) is a ligand of the c-MET receptor and promotes tumor growth, angiogenesis, invasion and metastasis (Bottaro DP, Rubin JS, Faletto DL, Chan AM, Kmiecik TE, Vande Woude GF, Aaronson SA). Identification of the hepatocyte growth factor receptor as the Met proto-oncogene product.Science 1991, 251 (4995), 802-804).

Abnormal c-MET activation in cancer cells is closely related to worsening the prognosis of chemotherapy, and overexpression and mutation of c-MET has been observed in several cancers such as non-small cell lung cancer. Tumor invasion and metastasis are the leading cause of death in cancer patients, and therefore, inhibition of c-MET signaling is expected to be effective in treating cancer.

Recepteur d'Origine receptor (RON) is a protein receptor belonging to the c-MET family and is a receptor of the serum protein macrophage-stimulating protein (MSP), which is secreted by the liver and regulates the action of macrophages (Zhou YQ, He C, Chen). YQ, Wang D, Wang MH: Altered expression of the RON receptor tyrosine kinase in primary human colorectal adenocarcinomas: generation of different splicing RON variants and their oncogenic potential.Oncogene 2003, 22 (2): 186-197). The expression of RON is abnormally regulated in breast cancer and colorectal cancer, and in particular closely related to metastasis of colorectal cancer. For example, as the monoclonal antibody IMC-41A10 that binds to RON has been reported to inhibit cell metastasis and tumorigenesis, RON inhibitors may show excellent efficacy in anticancer and cancer metastasis.

Lck protein kinase is expressed in T cells and NK cells, and Lck carries signals from T cell receptors (TCRs), such as CD4 receptors on helper T cells and CD8 receptors on cytotoxic T cells (Straus DB , Weiss A. Genetic evidence for the involvement of the lck tyrosine kinase in signal transduction through the T cell antigen receptor. Cell 1992, 70, 585-593). Lck protein kinases also play an essential role in the activation, development of T cells and initiation of T cell antigen receptor mediated signaling pathways. Autophosphorylation of Lck phosphorylates ZAP-70 in T cell antigen receptors, which initiates downstream signaling resulting in activation and proliferation of T cells. Therefore, inhibitors of Lck protein kinase are expected to be useful in the treatment of T cell-mediated autoimmune diseases and inflammatory diseases such as organ transplant rejection, multiple sclerosis, rheumatoid arthritis and the like by inhibiting T cell activation. In addition, it has been reported that abnormal expression of Lck is associated with T-cell leukemia, B-cell leukemia, colon cancer and the like.

Vascular endothelial growth factor (VEGF) is a signaling protein that promotes angiogenesis secreted by cells. VEGF plays a role in the formation of new blood vessels during embryonic development or after injury. VEGF is divided into VEGF-A, VEGF-B, VEGF-C, VEGF-D and Placenta growth factor (PlGF). VEGFR receptors are subtypes of VEGFR-1, VEGFR-2, and VEGFR-3 as receptors for VEGFs. VEGFR-1 receptors are known to bind VEGF-A and VEGF-B and to regulate VEGFR-2 signaling. VEGFR-2 receptor binds to VEGF-A and VEGF-C and mediates the cellular response in which VEGF is involved. VEGFR-3 receptors bind VEGF-C and VEGF-D and mediate neolymph node formation. Bevacizumab, an anti-vascular endothelial growth factor (anti-VEGF) treatment, is used in combination with chemotherapy for metastatic colorectal cancer.

Therefore, while the present inventors are studying a compound that can be used as a protein kinase inhibitor, the pyridone derivative described in the present invention effectively inhibits the activity of the protein kinase, thereby inhibiting cancer, psoriasis, rheumatoid arthritis, inflammatory bowel disease, or chronic obstructive pulmonary disease. The present invention was completed by confirming that the present invention can be usefully used for the prevention or treatment of cancer.

The present invention is to provide a novel pyridone derivative that can be usefully used in the treatment of a disease associated with it by inhibiting protein kinase activity and a pharmaceutical composition comprising the same.

In order to solve the above-mentioned problems, the present invention provides a compound represented by the following formula (1), or a pharmaceutically acceptable salt thereof.

A compound represented by Formula 1, or a pharmaceutically acceptable salt thereof:

[Formula 1]

Where

R ₁ is hydrogen; Or halogen,

R ₂ is hydrogen; Or a C _{1 -4} alkoxy,

R ₃ is C _{1 -6} alkyl; Phenyl; benzyl; Or pyridinyl, wherein the phenyl, benzyl or pyridinyl is unsubstituted or substituted with halogen,

이고, 여기서 상기 이미다졸릴, 페닐, 피라졸릴, 피리디닐 또는 싸이아졸릴은 비치환되거나 또는 C_{1 -4} 알킬로 치환되고, 여기서 상기 C_{1 -4} 알킬은 비치환되거나 또는 하이드록시, C_{1 -4} 알콕시, 디(C_1-4 알킬)아미노 또는 아세톡시로 치환되고,R ₄ is imidazolyl; Phenyl; Pyrazolyl; Pyridinyl; Thiazolyl; or

, Wherein said imidazolyl, phenyl, pyrazolyl, pyridinyl or pyridazinyl Sy O is substituted with unsubstituted or C _{1 -4} alkyl Beach, wherein the C _{1 -4} alkyl are unsubstituted or substituted by hydroxy, C _{1 -4} substituted with alkoxy, di (C _1-4 alkyl) amino or acetoxy,

R ₅ is hydrogen, C _{1 -4} alkyl, C _{1 -4} alkyl sulfonyl or tert-butyl-oxy-carbonyl.

Preferably, R ₁ is hydrogen or fluoro.

Preferably, R ₂ is hydrogen, methoxy or ethoxy.

Preferably, R ₃ is C _{1 -6} alkyl; Phenyl unsubstituted or substituted with halogen; Benzyl substituted with halogen; Or pyridinyl. More preferably, R ₃ is methyl, isopentyl, phenyl, phenyl substituted with fluoro, fluoro substituted benzyl, or pyridinyl.

이고, 여기서 R₅는 수소, 메틸, 메틸설포닐 또는 터트-부틸옥시카보닐이다.Preferably, R ₄ is imidazolyl substituted with C _{1 -4} alkyl, wherein the C _{1 -4} alkyl are unsubstituted or substituted by C _{1 -4} alkoxy, or di-substituted by (C _1-4 alkyl) amino ; Phenyl; C _{1 -4} the pyrazole is substituted by an alkyl group, the C _{1 -4} wherein the alkyl is unsubstituted or hydroxy or is substituted by acetoxy; Pyridinyl; Thiazolyl; or

Wherein R ₅ is hydrogen, methyl, methylsulfonyl or tert-butyloxycarbonyl.

Preferably, R ₄ is imidazolyl substituted with any one selected from the group consisting of methyl, ethyl, methoxymethyl and 2- (dimethylamino) ethyl; Phenyl; Pyrazolyl substituted with any one selected from the group consisting of methyl, ethyl, 2- (hydroxy) ethyl and 2- (acetoxy) ethyl; Pyridinyl; Thiazolyl; Piperazin-1-ylmethyl; (4-methylpiperazin-1-yl) methyl; (4-tert-butyloxycarbonylpiperazin-1-yl) methyl; Or (4-methanesulfonylpiperazin-1-yl) methyl.

Representative examples of the compound represented by Formula 1 or a pharmaceutically acceptable salt thereof are as follows:

1) 4-ethoxy-N- (3-fluoro-4- (2- (1-methyl-1H-imidazol-4-yl) thieno [3,2-b] pyridin-7-yloxy ) Phenyl) -1- (4-fluorophenyl) -2-oxo-1,2-dihydropyridine-3-carboxamide,

2) 4-ethoxy-N- (3-fluoro-4- (2- (1-methyl-1H-imidazol-4-yl) thieno [3,2-b] pyridin-7-yloxy ) Phenyl) -1-methyl-2-oxo-1,2-dihydropyridine-3-carboxamide,

3) 4-ethoxy-N- (3-fluoro-4- (2- (1-methyl-1H-imidazol-2-yl) thieno [3,2-b] pyridin-7-yloxy ) Phenyl) -1- (4-fluorophenyl) -2-oxo-1,2-dihydropyridine-3-carboxamide,

4) 4-ethoxy-N- (3-fluoro-4- (2- (1-methyl-1H-imidazol-2-yl) thieno [3,2-b] pyridin-7-yloxy ) Phenyl) -1-methyl-2-oxo-1,2-dihydropyridine-3-carboxamide,

5) 4-ethoxy-N- (3-fluoro-4- (2- (1-methyl-1H-pyrazol-4-yl) thieno [3,2-b] pyridin-7-yloxy ) Phenyl) -1- (4-fluorophenyl) -2-oxo-1,2-dihydropyridine-3-carboxamide,

6) 4-ethoxy-N- (4- (2- (1-ethyl-1H-imidazol-4-yl) thieno [3,2-b] pyridin-7-yloxy) -3-fluoro Rophenyl) -1- (4-fluorophenyl) -2-oxo-1,2-dihydropyridine-3-carboxamide,

7) 2- (4- (7- (4- (4-ethoxy-1- (4-fluorophenyl) -2-oxo-1,2-dihydropyridine-3-carboxamido) -2 -Fluorophenoxy) thieno [3,2-b] pyridin-2-yl) -1H-pyrazol-1-yl) ethyl acetate,

8) 4-ethoxy-N- (3-fluoro-4- (2- (pyridin-2-yl) thieno [3,2-b] pyridin-7-yloxy) phenyl) -1- ( 4-fluorophenyl) -2-oxo-1,2-dihydropyridine-3-carboxamide,

9) 4-ethoxy-N- (3-fluoro-4- (2- (pyridin-3-yl) thieno [3,2-b] pyridin-7-yloxy) phenyl) -1- ( 4-fluorophenyl) -2-oxo-1,2-dihydropyridine-3-carboxamide,

10) 4-ethoxy-N- (3-fluoro-4- (2- (thiazol-2-yl) thieno [3,2-b] pyridin-7-yloxy) phenyl) -1- (4-fluorophenyl) -2-oxo-1,2-dihydropyridine-3-carboxamide,

11) N- (4- (2- (1- (2- (dimethylamino) ethyl) -1H-imidazol-4-yl) thieno [3,2-b] pyridin-7-yloxy)- 3-fluorophenyl) -4-ethoxy-1- (4-fluorophenyl) -2-oxo-1,2-dihydropyridine-3-carboxamide,

12) 4-ethoxy-N- (3-fluoro-4- (2-phenylthieno [3,2-b] pyridin-7-yloxy) phenyl) -1- (4-fluorophenyl) -2-oxo-1,2-dihydropyridine-3-carboxamide,

13) 4-ethoxy-N- (3-fluoro-4- (2- (1- (2-hydroxyethyl) -1H-pyrazol-4-yl) thieno [3,2-b] Pyridin-7-yloxy) phenyl) -1- (4-fluorophenyl) -2-oxo-1,2-dihydropyridine-3-carboxamide,

14) 4-ethoxy-N- (4- (2- (1-ethyl-1H-imidazol-4-yl) thieno [3,2-b] pyridin-7-yloxy) -3-fluoro Lophenyl) -1- (4-fluorobenzyl) -2-oxo-1,2-dihydropyridine-3-carboxamide,

15) 4-ethoxy-N- (4- (2- (1-ethyl-1H-imidazol-4-yl) thieno [3,2-b] pyridin-7-yloxy) -3-fluoro Lophenyl) -1-isopentyl-2-oxo-1,2-dihydropyridine-3-carboxamide,

16) 4-ethoxy-N- (4- (2- (1-ethyl-1H-imidazol-4-yl) thieno [3,2-b] pyridin-7-yloxy) -3-fluoro Lophenyl) -2-oxo-1-phenyl-1,2-dihydropyridine-3-carboxamide,

17) 4-ethoxy-N- (4- (2- (1-ethyl-1H-imidazol-4-yl) thieno [3,2-b] pyridin-7-yloxy) -3-fluoro Lophenyl) -2-oxo-1- (pyridin-2-yl) -1,2-dihydropyridine-3-carboxamide,

18) 4-ethoxy-N- (4- (2- (1-ethyl-1H-imidazol-4-yl) thieno [3,2-b] pyridin-7-yloxy) -3-fluoro Rophenyl) -1- (2-fluorophenyl) -2-oxo-1,2-dihydropyridine-3-carboxamide,

19) 4-ethoxy-N- (4- (2- (1-ethyl-1H-imidazol-4-yl) thieno [3,2-b] pyridin-7-yloxy) phenyl) -1 -(4-fluorophenyl) -2-oxo-1,2-dihydropyridine-3-carboxamide,

20) N- (4- (2- (1-ethyl-1H-imidazol-4-yl) thieno [3,2-b] pyridin-7-yloxy) -3-fluorophenyl) -1 -(4-fluorophenyl) -4-methoxy-2-oxo-1,2-dihydropyridine-3-carboxamide,

21) N- (4- (2- (1-ethyl-1H-imidazol-4-yl) thieno [3,2-b] pyridin-7-yloxy) -3-fluorophenyl) -1 -(4-fluorophenyl) -2-oxo-1,2-dihydropyridine-3-carboxamide,

22) 4-methoxy-N- (3-fluoro-4- (2- (1-methyl-1H-pyrazol-4-yl) thieno [3,2-b] pyridin-7-yloxy ) Phenyl) -1-phenyl-2-oxo-1,2-dihydropyridine-3-carboxamide,

23) 4-ethoxy-N- (3-fluoro-4- (2- (1-methyl-1H-pyrazol-4-yl) thieno [3,2-b] pyridin-7-yloxy ) Phenyl) -1-phenyl-2-oxo-1,2-dihydropyridine-3-carboxamide,

24) 4-ethoxy-N- (3-fluoro-4- (2- (1-methyl-1H-imidazol-4-yl) thieno [3,2-b] pyridin-7-yloxy ) Phenyl) -1-phenyl-2-oxo-1,2-dihydropyridine-3-carboxamide,

25) 4-methoxy-N- (3-fluoro-4- (2- (1-methyl-1H-imidazol-4-yl) thieno [3,2-b] pyridin-7-yloxy ) Phenyl) -1-phenyl-2-oxo-1,2-dihydropyridine-3-carboxamide,

26) 4-methoxy-N- (3-fluoro-4- (2- (1-ethyl-1H-imidazol-4-yl) thieno [3,2-b] pyridin-7-yloxy ) Phenyl) -1-phenyl-2-oxo-1,2-dihydropyridine-3-carboxamide,

27) 4-methoxy-N- (3-fluoro-4- (2- (1-ethyl-1H-pyrazol-4-yl) thieno [3,2-b] pyridin-7-yloxy ) Phenyl) -1-phenyl-2-oxo-1,2-dihydropyridine-3-carboxamide,

28) 4-methoxy-N- (3-fluoro-4- (2- (1- (methoxymethyl) -1H-imidazol-4-yl) thieno [3,2-b] pyridine- 7-yloxy) phenyl) -1-phenyl-2-oxo-1,2-dihydropyridine-3-carboxamide,

29) 4-ethoxy-N- (3-fluoro-4- (2- (piperazin-1-ylmethyl) thieno [3,2-b] pyridin-7-yloxy) phenyl) -1 -(4-fluorophenyl) -2-oxo-1,2-dihydropyridine-3-carboxamide hydrochloride,

30) 4-ethoxy-N- (3-fluoro-4- (2-((4-methylpiperazin-1-yl) methyl) thieno [3,2-b] pyridin-7-yloxy ) Phenyl) -1- (4-fluorophenyl) -2-oxo-1,2-dihydropyridine-3-carboxamide,

31) tert-butyl 4-((7- (4- (4-ethoxy-1- (4-fluorophenyl) -2-oxo-1,2-dihydropyridine-3-carboxamido)- 2-fluorophenoxy) thieno [3,2-b] pyridin-2-yl) methyl) piperazin-1-carboxylate, and

32) 4-ethoxy-N- (3-fluoro-4- (2-((4- (methylsulfonyl) piperazin-1-yl) methyl) thieno [3,2-b] pyridine- 7-yloxy) phenyl) -1- (4-fluorophenyl) -2-oxo-1,2-dihydropyridine-3-carboxamide.

In addition, the compound represented by Formula 1 may form a pharmaceutically acceptable salt. Such pharmaceutically acceptable salts include acids that form non-toxic acid addition salts containing pharmaceutically acceptable anions such as inorganic acids, such as hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid, hydrobromic acid, hydroiodic acid, tartaric acid, formic acid, Organic carbon acids such as citric acid, acetic acid, adipic acid, trichloroacetic acid, trifluoroacetic acid, gluconic acid, benzoic acid, lactic acid, fumaric acid, maleic acid, etc., methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid or naphthalenesulfonic acid Acid addition salts formed by the same sulfonic acid and the like. The compound of formula 1 according to the present invention can be converted to its salts by conventional methods.

In addition, the compounds according to the invention may have an asymmetric carbon center and therefore exist as R or S isomers, racemates, diastereomeric mixtures and individual diastereomers, all of these isomers and mixtures being included within the scope of the invention. do.

In addition, the present invention provides a method for preparing a compound represented by Formula 1 represented by the following Scheme 1.

[Reaction Scheme 1]

In the above scheme, the definitions of R ₁ , R ₂ , R ₃ and R ₄ are as defined above. Specific reaction of Scheme 1 is as follows.

Step 1 is a step of preparing a compound represented by Chemical Formula 3 by reacting the compound represented by Chemical Formula 2 with POCl ₃ . It is preferred to react under heating reflux.

Step 2 is a step of preparing a compound represented by Chemical Formula 5 by reacting the compound represented by Chemical Formula 3 with the compound represented by Chemical Formula 4. It is preferable to react in the presence of n-BuLi, ZnCl ₂ and Pd (PPh ₃ ) ₄ , and the solvent is preferably THF.

Step 3 is a step of preparing a compound represented by Chemical Formula 7 by reacting the compound represented by Chemical Formula 5 with the compound represented by Chemical Formula 6. It is preferable to react in the presence of K ₂ CO ₃ , and the solvent is preferably Ph ₂ O.

Step 4 is a step of preparing a compound represented by Chemical Formula 8 by reacting the compound represented by Chemical Formula 7 with NH 4 Cl. It is preferred to react in the presence of Fe, preferably using ethanol / water as the solvent.

Step 5 is a step of preparing a compound represented by Chemical Formula 1 by reacting the compound represented by Chemical Formula 8 with the compound represented by Chemical Formula 9. It is preferable to react in the presence of Et ₃ N and SOCl _2, and it is preferable to use CH ₂ Cl ₂ as a solvent.

The present invention also provides a pharmaceutical composition for preventing or treating a protein kinase related disease comprising the compound represented by Formula 1, or a pharmaceutically acceptable salt thereof as an active ingredient.

The term 'protein kinase-related disease' means a disease that can be prevented or treated by inhibiting the activity of protein kinase, and specifically means cancer, psoriasis, rheumatoid arthritis, inflammatory bowel disease or chronic obstructive pulmonary disease.

As used herein, the term "prevention" means any action that inhibits or delays the disease by administration of the pharmaceutical composition. In addition, the term "treatment" used in the present invention means all the actions that improve or cure the symptoms of the disease by administration of the pharmaceutical composition.

The pharmaceutical composition may additionally include a pharmaceutically acceptable carrier, diluent or excipient. As used herein, the term 'pharmaceutically acceptable carrier' refers to a carrier or diluent that does not cause significant irritation to the organism and does not discard the biological activity and properties of the compound being administered. In addition, the term 'pharmaceutically acceptable excipient' as used herein means an inert substance added to the pharmaceutical composition to further facilitate administration of the compound of formula 1 of the present invention. Examples of such excipients include, but are not limited to, calcium carbonate, calcium phosphate, various types of sugars and starches, cellulose derivatives, gelatin, vegetable oils and polyethylene glycols.

The pharmaceutical compositions of the present invention can be administered orally or parenterally (eg, applied intravenously, subcutaneously, intraperitoneally or topically) according to the desired method, and the dosage is determined by the condition and weight of the patient, Depending on the extent, drug form, route of administration, and time, it may be appropriately selected by those skilled in the art. The daily dosage of the compound represented by Formula 1 or a pharmaceutically acceptable salt thereof is preferably 1 mg / kg to 1000 mg / kg, and may be administered once to several times daily if necessary.

The compounds according to the invention and their pharmaceutically acceptable salts can be usefully used for the prevention or treatment of diseases associated with them by inhibiting protein kinase activity.

Figure 1 shows the effect on the growth of MKN45 tumor of the compound according to an embodiment of the present invention with a comparative example.
Figure 2 shows the effect on the growth of U87MG tumor of the compound according to an embodiment of the present invention.

Hereinafter, preferred embodiments of the present invention will be described in order to facilitate understanding of the present invention. However, the following examples are provided to further understand the present invention, and the present invention is not limited by the examples.

In the case of starting materials for synthesizing the compounds of the present invention, various synthesis methods are known, and if the starting materials are commercially available, they can be purchased from a supplier. Reagent suppliers include, but are not limited to, companies such as Sigma-Aldrich, TCI, Wako, Kanto, Fluorchem, Acros, Alfa, Fluka, Dae-Jung, and the like. In addition, all commercially available materials were used without further purification except as otherwise defined.

First, the compounds used for synthesis in the following Examples were prepared as in the following Preparation Examples. The preparation examples below are examples of the compound represented by the formula (9) in Scheme 1, and may be appropriately changed in accordance with the structure of the embodiment to be prepared.

Manufacturing example  1: 4- Ethoxy -1- (4- Fluorophenyl ) -2-oxo-1,2- Dihydropyridine Preparation of 3-carboxylic acid

Step 1) Preparation of ethyl 4-ethoxy-2-oxo-1,2-dihydropyridine-3-carboxylate

249.6 mL (1.32 mmol) of triethyl orthoacetate and 19.6 mL (0.33 mol) of acetic acid were added to 70.5 mL (0.66 mol) of ethyl cyanoacetate, followed by stirring at 120 DEG C for 12 hours or longer. The solvent of the reaction mixture was concentrated and 141 mL (0.55 mol) of DMFDEA (N, N-dimethylformamide diethylacetal) was added. It stirred at 70 degreeC for 2 hours or more. 500 mL of acetic acid and 60 mL of distilled water were added to the reaction mixture, and the mixture was refluxed for at least 12 hours. The reaction mixture was cooled to room temperature, and saturated aqueous sodium hydrogen carbonate solution and water were added thereto. It was extracted with dichloromethane and methanol 9: 1 mixed solvent. The organic layer was dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. 100 mL of ethyl acetate was added and concentrated. The resulting solid was filtered to afford 37 g (26%) of compound ethyl 4-ethoxy-2-oxo-1,2-dihydropyridine-3-carboxylate.

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 11.61 (bs, 1H), 7.46 (d, J = 7.6 Hz, 1H), 6.21 (d, J = 7.6 Hz, 1H), 4.14 (m, 4H) , 1.22 (m, 6H)

MS (ESI) m / z 212.12 (M + H) ⁺

Step 2) Preparation of ethyl 4-ethoxy-1- (4-fluorophenyl) -2-oxo-1,2-dihydropyridine-3-carboxylate

100 mL of N, N-dimethylformamide was added to 114 g (0.35 mol) of cesium carbonate and charged with nitrogen gas. After stirring for 10 minutes at room temperature, 10.2 g (0.07 mol) of 8-hydroxyquinolinol was dissolved in 200 mL of N, N-dimethylformamide in the mixture, 10 g (0.05 mol) of copper iodide, and 4-fluoro- 58.3 g (0.26 mol) of iodobenzene and 37 g (0.17 mol) of the compound obtained above were added. Stir at 110 ° C. for 24 h. After the reaction was completed, the reaction mixture was cooled to room temperature, ethyl acetate was added and stirred for 10 minutes. The reaction mixture was filtered through a pad of celite and extracted with water and ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, filtered and the solvent was removed under reduced pressure.

Step 3) Preparation of 4-ethoxy-1- (4-fluorophenyl) -2-oxo-1,2-dihydropyridine-3-carboxylic acid

The compound from which the solvent was completely removed in step 2 was dissolved in 200 mL of ethanol, and 400 mL of 3N hydrogen chloride aqueous solution was added. Stir at 60 ° C. for 24 hours. The resulting solid was filtered to give 21 g (2 step yield: 43%) of 4-ethoxy-1- (4-fluorophenyl) -2-oxo-1,2-dihydropyridine-3-carboxylic acid.

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 7.95 (d, J = 7.6 Hz, 1H), 7.48 (m, 2H), 7.35 (m, 2H), 6.58 (d, J = 8 Hz, 1H) , 4.28 (q, J = 6.8 Hz, 2H), 1.32 (t, J = 6.8 Hz, 3H)

MS (ESI) m / z 276.09 (M-H) ^-

Manufacturing example  2: 4- Ethoxy -2-oxo-1- Phenyl -1,2- Dihydropyridine -3-carboxylic acid Produce

Prepared in the same manner as in Preparation Example 1, the following compound was prepared in the step 2 of Preparation Example 1 using iodobenzene instead of 4-fluoro- iodobenzene.

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 7.98 (d, J = 8 Hz, 1H), 7.56-7.41 (m, 5H), 6.60 (d, J = 7.6 Hz, 1H), 4.30 (q, J = 7.2 Hz, 2H), 1.34 (t, J = 7.2 Hz, 3H)

MS (ESI) m / z 260.05 (M + H) ⁺

Manufacturing example  3: 4- Ethoxy -1- (2- Fluorophenyl ) -2-oxo-1,2- Dihydropyridine Preparation of 3-carboxylic acid

Prepared in the same manner as in Preparation Example 1, the following compound was prepared in the step 2 of Preparation Example 1 using 2-fluoro-iodobenzene instead of 4-fluoro-iodobenzene.

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 13.27 (bs, 1H), 7.99 (d, J = 6 Hz, 1H), 7.35-7.19 (m, 4H), 6.95 (d, J = 6 Hz, 1H), 4.21 (q, J = 6.8 Hz, 2H), 1.32 (t, J = 7.2 Hz, 3H)

MS (ESI) m / z 278.02 (M + H) ⁺

Manufacturing example  4: 4- Ethoxy -2-oxo-2H- [1,2'- Bipyridine ] -3-carboxylic acid

Prepared in the same manner as in Preparation Example 1, the following compound was prepared in the step 2 of Preparation Example 1 using 2-iodopyridine instead of 4-fluoro-iodobenzene.

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.61 (dt, J = 4.8 Hz, 0.8 Hz, 1H), 8.12 (d, J = 8 Hz, 1H), 8.01 (td, J = 7.6 Hz, 1.6 Hz, 1H), 7.75 (d, J = 8 Hz, 1H), 7.54-7.51 (m, 1H), 6.63 (d, J = 8 Hz, 1H), 4.30 (q, J = 7.2 Hz, 2H), 1.34 (t, J = 7.2 Hz, 3H)

MS (ESI) m / z 261.11 (M + H) ⁺

Manufacturing example  5: 1- (4- Fluorophenyl )-4- Methoxy -2-oxo-1,2- Dihydropyridine Preparation of 3-carboxylic acid

Step 1) Preparation of Methyl 4-methoxy-1- (4-fluorophenyl) -2-oxo-1,2-dihydropyridine-3-carboxylate

0.37 g (1.20 mmol) of ethyl 4-ethoxy-1- (4-fluorophenyl) -2-oxo-1,2-dihydropyridine-3-carboxylate was treated with 28% NaOMe solution and then cooled to 10 at room temperature. Stirred for a minute. After removing the solvent by concentration under reduced pressure, 0.26 g (77% yield) of the following compound was obtained.

Step 2) Preparation of 4-methoxy-1- (4-fluorophenyl) -2-oxo-1,2-dihydropyridine-3-carboxylic acid

2.75 N hydrochloric acid solution after 0.33 g (1.18 mmol) of methyl 4-methoxy-1- (4-fluorophenyl) -2-oxo-1,2-dihydropyridine-3-carboxylate was treated with 5 mL of ethanol. 10 mL was added dropwise at room temperature. After stirring at 60 ° C. for 4 hours, the resulting solid was filtered to yield 0.16 g (52%) of the following compound.

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 13.89 (bs, 1H), 8.02 (d, J = 7.6 Hz, 1H), 7.53-7.48 (m, 2H), 7.40-7.34 (m, 2H), 6.63 (d, J = 8 Hz, 1H), 4.02 (s, 3H)

MS (ESI) m / z 264.06 (M + H) ⁺

Manufacturing example  6: 4- Methoxy -2-oxo-1- Phenyl -1,2- Dihydropyridine -3-carboxylic acid Produce

Prepared in the same manner as in Preparation Example 5, except that in Step 1 of Preparation Example 5, ethyl 4-ethoxy-1- (4-fluorophenyl) -2-oxo-1,2-dihydropyridine-3-carboxylate Instead, the following compound was prepared using ethyl 4-ethoxy-1-phenyl-2-oxo-1,2-dihydropyridine-3-carboxylate used in Preparation Example 2.

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 7.96 (d, J = 7.8 Hz, 1H), 7.55-7.45 (m, 5H), 6.58 (d, J = 7.8 Hz, 1H), 3.99 (s, 3H)

MS (ESI) m / z 246.06 (M + H) ⁺

Manufacturing example  7: 4- Ethoxy -One- methyl -2-oxo-1,2- Dihydropyridine -3-carboxylic acid Produce

30 g of N, N-dimethylformamide in 5 g (23.7 mmol) of the compound obtained in Step 1 of Preparation Example 1 (ethyl 4-ethoxy-2-oxo-1,2-dihydropyridine-3-carboxylate), 15.4 g (0.05 mol) of cesium carbonate was added and stirred at room temperature for 10 minutes. 6.7 g (47.3 mmol) of iodomethane were added and stirred at room temperature for 5 hours. After the reaction, the mixture was concentrated and 50 mL of ethyl acetate was added and concentrated again. 50 mL of isopropyl ether was added to the concentrated mixture and stirred to obtain a solid in the form of a slurry by filtration. 20 mL of tetrahydrofuran and 10 mL of 3N hydrogen chloride aqueous solution were added to the obtained solid, stirred at 80 ° C. for 5 hours, and concentrated. 180 mL of dichloromethane and 10 mL of methanol were added thereto, and the organic layer was separated. Anhydrous magnesium sulfate was added to the separated organic layer, and the filtrate obtained by filtration was concentrated and the resulting solid was filtered to obtain 3 g (64%) of the following compound.

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.04 (d, J = 8 Hz, 1H), 6.56 (d, J = 7.6 Hz, 1H), 4.24 (q, J = 6.8 Hz, 1H), 1.32 (t, J = 7.2 Hz, 1H)

MS (ESI) m / z 198.17 (M + H) ⁺

Manufacturing example  8: 4- Ethoxy -One- Isopentyl -2-oxo-1,2- Dihydropyridine Preparation of 3-carboxylic acid

Prepared in the same manner as in Preparation Example 7, using 1-iodo-2-methoxybutane, sodium hydride instead of iodomethane, cesium carbonate to obtain the following compound.

¹ H NMR (400 MHz, CDCl ₃ ) δ 7.48 (d, J = 7.6 Hz, 1H), 6.28 (J = 7.6 Hz, 1H), 4.29 (q, J = 7.2 Hz, 2H), 4.02-3.96 (m, 2H), 1.66-1.61 (m, 3H), 1.54 (t, J = 7.2 Hz, 3H), 0.99 (s, 3H), 0.97 (s, 3H)

MS (ESI) m / z 252.02 (M-H) ^-

Manufacturing example  9: 4- Ethoxy -1- (4- Fluorobenzyl ) -2-oxo-1,2- Dihydropyridine Preparation of 3-carboxylic acid

Prepared in the same manner as in Preparation Example 7, using 4-fluorobenzyl bromide, sodium hydride instead of iodomethane, cesium carbonate to obtain the following compound.

¹ H NMR (400 MHz, CDCl ₃ ) δ 7.50 (d, J = 7.6 Hz, 1H), 7.31 (d, J = 5.2 Hz, 1H), 7.29 (d, J = 5.2 Hz, 1H), 6.29 (d, J = 7.6 Hz, 1H), 5.15 (s, 2H), 4.28 (q, J = 7.2 Hz, 2H), 1.52 (t, J = 7.2 Hz, 3H)

MS (ESI) m / z 289.98 (M−H) ⁻

Manufacturing example  10: 1- (4- Fluorophenyl ) -2-oxo-1,2- Dihydropyridine Preparation of 3-carboxylic acid

Step 1) Preparation of Methyl 1- (4-fluorophenyl) -2-oxo-1,2-dihydropyridine-3-carboxylate

5 g (32.4 mmol) of methyl 2-oxo-2H-pyran-3-carboxylate are dissolved in 100 mL of tetrahydrofuran, 3.6 g (32.4 mmol) of 4-fluoroaniline are added and stirred at room temperature for 3 hours. It was. 8.1 g (42.2 mmol) of 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride and 0.4 g (3.2 mmol) of 4- (dimethylamino) pyridine were added and stirred at room temperature for 16 hours. Ethyl acetate and water were added, followed by extraction with 10% aqueous hydrogen chloride solution. The organic layer was separated, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to obtain a residue. The residue was purified by silica gel column chromatography (20% n-hexane in ethyl acetate) to give a white, white solid, methyl 1- (4-fluorophenyl) -2-oxo-1,2-dihydropyridine-3-carboxyl. Yield 1.8 g (22%).

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.12 (dd, J = 6.8 and 2.0 Hz, 1H), 7.95 (dd, J = 6.8 and 2.0 Hz, 1H), 7.50 (d, J = 4.8 Hz, 1H ), 7.48 (J = 5.2 Hz, 1H), 7.36 (t, J = 8.8 Hz, 2H), 6.41 (t, J = 6.8 Hz, 2H), 3.75 (s, 1H)

MS (ESI) m / z 248.09 (M + H) ⁺ , 270.07 (M + Na) ⁺

Step 2) Preparation of 1- (4-fluorophenyl) -2-oxo-1,2-dihydropyridine-3-carboxylic acid

1.8 g (7.29 mmol) of methyl 1- (4-fluorophenyl) -2-oxo-1,2-dihydropyridine-3-carboxylate are dissolved in 25 mL of methanol, and 11 mL of 1N aqueous sodium hydroxide solution is added. And stirred at room temperature for 15 hours. The reaction mixture was concentrated under reduced pressure, acidified with 1N aqueous hydrogen chloride solution and filtered to yield 1.6 g (94%) of 1- (4-fluorophenyl) -2-oxo-1,2-dihydropyridine-3-carboxylic acid as a white solid. It was.

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 14.23 (s, 1H), 8.49 (dd, J = 6.8 and 2.0 Hz), 8.21 (dd, J = 6.8 and 2.0 Hz), 7.63 (d, J = 4.8 Hz, 1H), 7.61 (J = 5.2 Hz, 1H), 7.42 (t, J = 8.8 Hz, 2H), 6.79 (t, J = 7.2 Hz, 2H)

MS (ESI) m / z 234.09 (M + H) ⁺ , 256.06 (M + Na) ⁺

Example  1: 4- Ethoxy -N- (3- Fluoro -4- (2- (1- methyl -1H- Imidazole Yl) Cyeno [ 3,2-b] pyridine -7- Sake ) Phenyl ) -1- (4- Fluorophenyl ) -2-oxo-1,2- Dihydropyridine -3-car Levoxamide Manufacturing

Step 1) Preparation of 7-chlorothieno [3,2-b] pyridine

25 mL of phosphoryl chloride was heated to 60 ° C. and 15 g (99.2 mmol) of thieno [3,2-b] pyridin-7-ol were added. After stirring for 1 hour at the same temperature, it was cooled to room temperature. The reaction mixture was concentrated under reduced pressure, and 100 mL of ice water was added for dissolution. Ammonia water was added to basify and the resulting solid was filtered. The filtered solid was dissolved in ethyl acetate and filtered. The filtrate was dried over anhydrous magnesium sulfate and concentrated under reduced pressure to obtain 15 g (89%) of 7-chlorocyeno [3,2-b] pyridine as a white solid.

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.66 (d, J = 4.8 Hz, 1H), 8.26 (d, J = 5.6 Hz, 1H), 7.67 (d, J = 5.6 Hz, 1H), 7.58 ( d, J = 4.8 Hz, 1H)

MS (ESI) m / z 169.92 (M + H) ⁺

Step 2) Preparation of 7-chloro-2- (1-methyl-1H-imidazol-4-yl) thieno [3,2-b] pyridine

50 g (294.8 mmol) of 7-chlorothieno [3,2-b] pyridine was dissolved in 500 mL of tetrahydrofuran, and then cooled to -78 ° C. At the same temperature, 118 mL (294.8 mmol) of normal butyllithium (2.5 M hexane solution) was slowly added and stirred for 10 minutes. 295 mL (294.8 mmol) of zinc chloride (1M diethyl ether solution) was added slowly and stirred for 10 minutes. After gradually raising the temperature to room temperature and stirring for 1 hour, 28 g (29.5 mmol) of tetrakistriphenylphosphine palladium (0) and 51 g (245.6 mmol) of 4-iodo-1-methyl-1H-imidazole were added thereto. It was stirred at reflux for 4 hours. The reaction mixture was cooled to room temperature and concentrated under reduced pressure. 500 mL of ethyl acetate and 20 mL of water were added thereto, stirred, and filtered through a pad of celite. The filtrate was concentrated under reduced pressure, dichloromethane was added, and acidified with 1N aqueous hydrogen chloride solution. The filtered solid was washed with ammonia water and water to obtain 29 g (39%) of an off-white solid 7-chloro-2- (1-methyl-1H-imidazol-4-yl) thieno [3,2-b] pyridine. Got it.

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.55 (d, J = 4.8 Hz, 1H), 7.90 (S, 1H), 7.75 (s, 1H), 7.74 (s, 1H), 7.45 (d, J = 4.8 Hz, 1H), 3.73 (s, 3H)

MS (ESI) m / z 249.98 (M + H) < + >, 252.02 (M + Na) ⁺

Step 3) Preparation of 7- (2-fluoro-4-nitrophenoxy) -2- (1-methyl-1H-imidazol-4-yl) thieno [3,2-b] pyridine

64 g of anhydrous potassium carbonate in a mixture of 200 mL of diphenylether and 29 g (116.1 mmol) of 7-chloro-2- (1-methyl-1H-imidazol-4-yl) thieno [3,2-b] pyridine (464.5 mmol) and 36 g (232.2 mmol) of 2-fluoro-4-nitrophenol were added. The reaction mixture was heated to 200 ° C. and stirred for 3 hours. After cooling to room temperature, water was added and stirred, and the resulting solid was filtered to give 7- (2-fluoro-4-nitrophenoxy) -2- (1-methyl-1H-imidazol-4-yl) cyp. 16.6 g (39%) of eno [3,2-b] pyridine was obtained.

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.53 (d, J = 5.6 Hz, 1H), 8.46 (dd, J = 10.4 and 2.8 Hz, 1H), 8.21-8.18 (m, 1H), 7.88 (d , J = 1.2 Hz, 1H), 7.73 (s, 1H), 7.72 (d, J = 1.2 Hz, 1H), 7.68 (t, J = 8.4 Hz, 1H), 6.87 (d, J = 5.6 Hz, 1H ), 3.73 (s, 3 H)

MS (ESI) m / z 370.91 (M + H) ⁺

Step 4) Preparation of 3-fluoro-4-((2- (1-methyl-1H-imidazol-4-yl) thieno [3,2-b] pyridin-7-yl) oxy) aniline

7- (2-fluoro-4-nitrophenoxy) -2- (1-methyl-1H-imidazol-4-yl) thieno [3,2-b] in 400 mL of ethanol and 200 mL of water 16.2 g (43.7 mmol) of pyridine, 7 g (131.2 mmol) of iron and 23.4 g (437.4 mmol) of ammonium chloride were added. The mixture was raised to 100 ° C. and stirred for 1 hour. After cooling to room temperature, the mixture was filtered through a pad of celite and concentrated under reduced pressure. Water was added and stirred, followed by filtration to 3-fluoro-4-((2- (1-methyl-1H-imidazol-4-yl) thieno [3,2-b] pyridin-7-yl ) Oxy) aniline 8.3 g (56%) was obtained.

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.40 (d, J = 5.2 Hz, 1H), 7.84 (S, 1H), 7.71 (s, 1H), 7.64 (s, 1H), 7.10 (t, J = 8.8 Hz, 1H), 6.55-6.43 (m, 3H), 5.52 (s, 2H), 3.72 (s, 3H)

MS (ESI) m / z 341.11 (M + H) ⁺

Step 5) 4-Ethoxy-N- (3-fluoro-4- (2- (1-methyl-1H-imidazol-4-yl) thieno [3,2-b] pyridin-7-yljade Phenyl) -1- (4-fluorophenyl) -2-oxo-1,2-dihydropyridine-3-carboxamide

11.6 g of thionyl chloride in a mixture of 100 mL of dichloromethane and 10 g (36.6 mmol) of 4-ethoxy-1- (4-fluorophenyl) -2-oxo-1,2-dihydropyridine-3-carboxylic acid ( 97.5 mmol) was added. After stirring for 2 hours at room temperature, the mixture was concentrated under reduced pressure to synthesize 4-ethoxy-1- (4-fluorophenyl) -2-oxo-1,2-dihydropyridine-3-carbonyl chloride. 8.3 g (24.4 mmol) of 3-fluoro-4-((2- (1-methyl-1H-imidazol-4-yl) thieno [3,2-b] pyridin-7-yl) oxy) aniline Was dissolved in 100 mL of dichloromethane, and 4.93 g (48.8 mmol) of triethylamine were added thereto, followed by stirring at room temperature for 2 hours. 4-ethoxy-1- (4-fluorophenyl) -2-oxo-1,2-dihydropyridine-3-carbonyl chloride, which was concentrated under reduced pressure, was added to the reaction mixture, which was then stirred for 2 hours. The resulting solid was filtered and washed with water to give the off white solid 4-ethoxy-N- (3-fluoro-4- (2- (1-methyl-1H-imidazol-4-yl) thieno [3, 2-b] pyridin-7-yloxy) phenyl) -1- (4-fluorophenyl) -2-oxo-1,2-dihydropyridine-3-carboxamide 10.4 g (71%) was obtained.

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 10.61 (s, 1H), 8.42 (d, J = 5.2 Hz, 1H), 7.92 (dd, J = 2.0 and 13.6 Hz, 1H), 7.86 (d, J = 7.6 Hz, 1H), 7.86 (s, 1H), 7.72 (s, 1H), 7.68 (s, 1H), 7.50-7.43 (m, 4H), 7.37 (t, J = 8.8 Hz, 1H), 6.59 (d, J = 5.2 Hz, 1H), 6.52 (d, J = 7.6 Hz, 1H), 4.26 (q, J = 7.2 Hz, 2H), 3.73 (s, 1H), 1.31 (t, J = 7.2 Hz , 3H)

MS (ESI) m / z 600.16 (M + H) ⁺

Example  2: 4- Ethoxy -N- (3- Fluoro -4- (2- (1- methyl -1H- Imidazole Yl) Cyeno [ 3,2-b] pyridine -7- Sake ) Phenyl )-One- methyl -2-oxo-1,2- Dihydropyridine -3- Carboxamide  Produce

The following compound was prepared in a similar manner as in Example 1.

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 10.58 (s, 1H), 8.43 (d, J = 5.6 Hz, 1H), 7.94 (d, J = 13.2 Hz, 1H), 7.87 (t, J = 4.0 Hz, 2H), 7.73 (s, 1H), 7.69 (s, 1H), 7.46 (m, 2H), 6.60 (d, J = 5.2 Hz, 1H), 6.39 (d, J = 8.0 Hz, 1H) , 4.19 (q, J = 7.2 Hz, 2H), 3.74 (s, 3H), 3.44 (s, 3H), 1.28 (t, J = 7.2 Hz, 3H)

MS (ESI) m / z 520.15 (M + H) ⁺

Example  3: 4- Ethoxy -N- (3- Fluoro -4- (2- (1- methyl -1H- Imidazole -2 days) Cyeno [ 3,2-b] pyridine -7- Sake ) Phenyl ) -1- (4- Fluorophenyl ) -2-oxo-1,2- Dihydropyridine -3-car Levoxamide Manufacturing

The following compound was prepared in a similar manner as in Example 1.

¹ H NMR (400 MHz, CDCl ₃ ) δ 11.65 (s, 1H), 8.47 (d, J = 5.6 Hz, 1H), 7.97 (dd, J = 12.8 Hz, 2.4 Hz, 1H), 7.72-7.68 (m , 3H), 7.54-7.50 (m, 3H), 7.38-7.35 (m, 2H), 7.34-7.31 (m, 1H), 7.24-7.12 (m, 3H), 7.03 (d, J = 0.8 Hz, 1H ), 6.53 (d, J = 5.6 Hz, 1H), 6.37 (d, J = 8 Hz, 1H), 4.37 (q, J = 7.2 Hz, 2H), 3.96 (s, 3H), 1.63 (t, J = 7.2 Hz, 3H)

MS (ESI) m / z 599.99 (M + H) ⁺

Example  4: 4- Ethoxy -N- (3- Fluoro -4- (2- (1- methyl -1H- Imidazole -2 days) Cyeno [ 3,2-b] pyridine -7- Sake ) Phenyl )-One- methyl -2-oxo-1,2- Dihydropyridine -3- Carboxamide  Produce

The following compound was prepared in a similar manner as in Example 1.

¹ H NMR (400 MHz, CDCl ₃ ) δ 11.95 (s, 1H), 8.48 (d, J = 5.6 Hz, 1H), 7.97 (dd, J = 12.8 Hz, 2.4 Hz, 1H), 7.52 (m, 1H ), 7.47 (d, J = 8 Hz, 1H), 7.37 (m, 1H), 7.20 (t, J = 8.8 Hz, 1H), 7.17 (d, J = 1.2 Hz, 1H), 7.02 (d, J = 0.8 Hz, 1H), 6.54 (dd, J = 5.2 Hz, 0.8 Hz, 1H), 6.24 (d, J = 8 Hz, 1H), 4.29 (q, J = 7.2 Hz, 2H), 3.96 (s, 3H), 3.61 (s, 3H), 0.92 (t, J = 7.6 Hz, 3H)

MS (ESI) m / z 519.95 (M + H) ⁺

Example  5: 4- Ethoxy -N- (3- Fluoro -4- (2- (1- methyl -1H- Pyrazole Yl) Cyeno [ 3,2-b] pyridine -7- Sake ) Phenyl ) -1- (4- Fluorophenyl ) -2-oxo-1,2- Dihydropyridine -3-car Levoxamide Manufacturing

The following compound was prepared in a similar manner as in Example 1.

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 10.60 (s, 1H), 8.44 (d, 1H, J = 5.6 Hz, 1H), 8.31 (s, 1H), 7.80 (s, 1H), 7.93 ( dd, J = 2.8 Hz, J = 12.8 Hz, 1H), 7.86 (d, J = 8.0 Hz, 1H), 7.69 (s, 1H), 7.47 (m, 5H), 7.37 (t, J = 8.8 Hz, 1H), 6.60 (d, J = 5.6 Hz, 1H), 6.52 (d, J = 8.0 Hz, 1H), 4.27 (q, J = 7.2 Hz, 2H), 3.90 (s, 3H), 1.31 (t, J = 7.2 Hz, 3H)

MS (ESI) m / z 600.10 (M + H) ⁺

Example  6: 4- Ethoxy -N- (4- (2- (1-ethyl-1H-) Imidazole Yl) Cyeno [3,2-b] pyridine-7- Sake ) -3- Fluorophenyl ) -1- (4- Fluorophenyl ) -2-oxo-1,2- Dihydropyridine -3-car Levoxamide Manufacturing

The following compound was prepared in a similar manner as in Example 1.

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 10.60 (s, 1H), 8.42 (d, J = 5.6 Hz, 1H), 7.95 (d, J = 1.2 Hz, 1H), 7.94-7.89 (m, 1H), 7.86 (d, J = 7.6 Hz, 1H), 7.78 (d, J = 1.2 Hz, 1H), 7.66 (s, 1H), 7.48-7.33 (m, 6H), 6.59 (d, J = 5.6 Hz, 1H), 6.52 (d, J = 8 Hz, 1H), 4.26 (q, J = 6.8 Hz, 2H), 4.06 (q, J = 7.2 Hz, 2H), 1.40 (t, J = 7.6 Hz, 3H), 1.30 (t, J = 6.8 Hz, 3H)

MS (ESI) m / z 614.25 (M + H) ⁺

Example  7: 2- (4- (7- (4- (4- Ethoxy -1- (4- Fluorophenyl ) -2-oxo-1,2- Dihydropyridine -3- Carboxamido )-2- Fluorophenoxy ) Cyeno [3,2-b] pyridin-2-yl) -1H- Pyrazole Preparation of -1-yl) ethyl acetate

The following compound was prepared in a similar manner as in Example 1.

¹ H NMR (400 MHz, CDCl ₃ ) δ 11.66 (s, 1H), 8.43 (d, J = 5.6 Hz, 1H), 7.95 (dd, J = 12.8 Hz, 2.4 Hz, 1H), 7.85 (s, 1H ), 7.76 (s, 1H), 7.50 (d, J = 5.6 Hz, 1H), 7.38-7.34 (m, 2H), 7.34-7.30 (m, 1H), 7.24 (d, J = 9.2 Hz, 1H) , 7.16 (t, J = 8.4 Hz, 1H), 6.49 (d, J = 5.6 Hz, 1H), 6.37 (d, J = 8 Hz, 1H), 4.5-4.40 (m, 4H), 4.36 (q, J = 7.2 Hz, 2H), 2.07 (s, 3H), 1.58 (t, J = 7.2 Hz, 3H)

MS (ESI) m / z 672.24 (M + H) ⁺

Example  8: 4- Ethoxy -N- (3- Fluoro -4- (2- (pyridin-2-yl) Cyeno [3,2-b] pyridine-7- Sake ) Phenyl ) -1- (4- Fluorophenyl ) -2-oxo-1,2- Dihydropyridine -3- Carboxamide  Produce

The following compound was prepared in a similar manner as in Example 1.

¹ H NMR (400 MHz, MeOH-d ₄ ) δ 8.61 (dd, J = 4.8 Hz, 0.4 Hz, 1H), 8.47 (d, J = 5.6 Hz, 1H), 8.1 (s, 1H), 8.08 (s , 1H), 7.95-7.91 (m, 2H), 7.77 (d, J = 8 Hz, 1H), 7.46-7.37 (m, 5H), 7.27 (t, J = 8.4 Hz, 2H), 6.65 (dd, J = 0.8, 5.6 Hz, 1H), 6.58 (d, J = 7.6 Hz, 1H), 4.32 (q, J = 6.8 Hz, 2H), 1.46 (t, J = 7.2 Hz, 3H)

MS (ESI) m / z 597.16 (M + H) ⁺

Example  9: 4- Ethoxy -N- (3- Fluoro -4- (2- (pyridin-3-yl) Cyeno [3,2-b] pyridine-7- Sake ) Phenyl ) -1- (4- Fluorophenyl ) -2-oxo-1,2- Dihydropyridine -3- Carboxamide  Produce

The following compound was prepared in a similar manner as in Example 1.

¹ H NMR (400 MHz, CDCl ₃ ) δ 11.68 (s, 1H), 9.02 (d, J = 1.6 Hz, 1H), 8.63 (dd, J = 4.8 Hz, 1.2 Hz, 1H), 8.49 (d, J = 5.6 Hz, 1H), 8.02 (dt, J = 8, 1.6 Hz, 1H), 7.96 (dd, J = 12.4 Hz, 2.4 Hz, 1H), 7.80 (s, 1H), 7.51 (d, J = 7.6 Hz, 1H), 7.41-7.31 (m, 4H), 7.25-7.15 (m, 3H), 6.53 (dd, J = 5.2 Hz, 0.8 Hz 1H), 6.36 (d, J = 8 Hz, 1H), 4.36 (q, J = 6.8 Hz, 2H), 1.58 (t, J = 7.2 Hz, 3H)

MS (ESI) m / z 597.13 (M + H) ⁺

Example  10: 4- Ethoxy -N- (3- Fluoro -4- (2- ( Thiazole -2 days) Cyeno [3,2-b] pyridine-7- Sake ) Phenyl ) -1- (4- Fluorophenyl ) -2-oxo-1,2- Dihydropyridine -3- Carboxamide  Produce

The following compound was prepared in a similar manner as in Example 1.

¹ H NMR (400 MHz, CDCl ₃ ) δ 11.65 (s, 1H), 8.49 (d, 1H, J = 5.6 Hz, 1H), 7.96 (dd, J = 2.8 Hz, J = 12.8 Hz, 1H), 7.93 (s, 1H), 7.88 (d, J = 3.6 Hz, 1H), 7.51 (d, J = 7.6 Hz, 1H), 7.42 (d, J = 3.2 Hz, 1H), 7.22-7.38 (m, 6H) , 7.18 (t, J = 8.8 Hz, 1H), 6.54 (dd, J = 1.2 Hz, J = 5.6 Hz, 1H), 6.37 (d, J = 8.0 Hz, 1H), 4.37 (q, J = 7.2 Hz , 2H), 1.59 (t, J = 7.2 Hz, 3H)

MS (ESI) m / z 603.15 (M + H) ⁺

Example  11: N- (4- (2- (1- (2- (dimethylamino) ethyl) -1H- Imidazole Yl) Cyeno [ 3,2-b] pyridine -7- Sake ) -3- Fluorophenyl )-4- Ethoxy -1- (4- Fluorophenyl ) -2-oxo-1,2-di Hydrophy Lidin-3- Carboxamide  Produce

The following compound was prepared in a similar manner as in Example 1.

¹ H NMR (400 MHz, CDCl ₃ ) δ 11.61 (s, 1H), 8.42 (d, J = 5.6 Hz, 1H), 7.94 (dd, J = 12.4 and 2.4 Hz, 1H), 7.66 (s, 1H) , 7.60 (d, J = 1.2 Hz, 1H), 7.51 (d, J = 7.6 Hz, 1H), 7.39 (d, J = 1.2 Hz, 1H), 7.22-7.38 (m, 5H), 7.16 (t, J = 8.8 Hz, 1H), 6.45 (d, J = 5.6 Hz, 1H), 6.37 (d, J = 8.0 Hz, 1H), 4.37 (q, J = 7.2 Hz, 2H), 4.07 (t, J = 6.8 Hz, 2H), 2.71 (t, J = 6.8 Hz, 2H), 2.31 (s, 3H), 1.59 (t, J = 7.2 Hz, 3H)

MS (ESI) m / z 657.34 (M + H) ⁺

Example  12: 4- Ethoxy -N- (3- Fluoro -4- (2- Phenylthieno [3,2-b] pyridine -7- Sake ) Phenyl ) -1- (4- Fluorophenyl ) -2-oxo-1,2- Dihydropyridine -3- Carboxamide  Produce

The following compound was prepared in a similar manner as in Example 1.

¹ H NMR (400 MHz, CDCl ₃ ) δ 11.65 (s, 1H), 8.47 (d, J = 5.6 Hz, 1H), 7.96 (dd, J = 12.4 and 2.4 Hz, 1H), 7.80 (s, 1H) , 7.76 (d, J = 7.2 Hz, 2H), 7.16-7.51 (m, 10H), 6.52 (d, J = 5.6 Hz, 1H), 6.35 (d, J = 7.6 Hz, 1H), 4.34 (q, J = 7.2 Hz, 2H), 1.57 (t, J = 7.2 Hz, 3H)

MS (ESI) m / z 596.11 (M + H) ⁺

Example  13: 4- Ethoxy -N- (3- Fluoro -4- (2- (1- (2-hydroxyethyl) -1H- Pyrazole Yl) Cyeno [3,2-b] pyridine-7- Sake ) Phenyl ) -1- (4- Fluorophenyl ) -2-oxo-1,2- Dihydropyridine -3- Carboxamide  Produce

The following compound was prepared in a similar manner as in Example 1.

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 10.60 (s, 1H), 8.43 (d, J = 5.6 Hz, 1H), 8.31 (s, 1H), 8.01 (s, 1H), 7.93 (dd, J = 12.4 Hz, 2.4 Hz, 1H), 7.86 (d, J = 8 Hz, 1H), 7.69 (s, 1H), 7.50-7.43 (m, 4H), 7.39-7.34 (m, 2H), 6.59 ( d, J = 5.6 Hz, 1H), 6.52 (d, J = 8 Hz, 1H), 4.95 (t, J = 5.6 Hz, 1H), 4.26 (q, J = 6.8 Hz, 2H), 4.19 (t, J = 5.2 Hz, 2H), 3.77 (q, J = 5.2 Hz, 2H), 1.30 (t, J = 6.8 Hz, 3H)

MS (ESI) m / z 630.30 (M + H) ⁺

Example  14: 4- Ethoxy -N- (4- (2- (1-ethyl-1H-) Imidazole Yl) Cyeno [3,2-b] pyridine-7- Sake ) -3- Fluorophenyl ) -1- (4- Fluorobenzyl ) -2-oxo-1,2- Dihydropyridine -3- Carboxamide  Produce

The following compound was prepared in a similar manner as in Example 1.

¹ H NMR (400 MHz, CDCl ₃ ) δ 11.76 (s, 1H), 8.43 (d, J = 5.6 Hz, 1H), 7.95 (dd, J = 12.8 and 2.0 Hz, 1H), 7.66 (s, 1H) , 7.55 (s, 1H), 7.44 (d, J = 8.0 Hz, 1H), 7.28-7.37 (m, 4H), 7.19 (t, J = 8.8 Hz, 1H), 7.00 (t, J = 8.8 Hz, 1H), 6.47 (d, J = 5.6 Hz, 1H), 6.24 (d, J = 8.0 Hz, 1H), 5.15 (s, 1H), 4.27 (q, J = 7.2 Hz, 2H), 4.05 (q, J = 7.2 Hz, 2H), 1.53 (t, J = 7.2 Hz, 3H)

MS (ESI) m / z 628.24 (M + H) ⁺

Example  15: 4- Ethoxy -N- (4- (2- (1-ethyl-1H-) Imidazole Yl) Cyeno [3,2-b] pyridine-7- Sake ) -3- Fluorophenyl )-One- Isopentyl -2-oxo-1,2- Dihydropyridine -3- Carboxamide  Produce

The following compound was prepared in a similar manner as in Example 1.

¹ H NMR (400 MHz, CDCl ₃ ) δ 11.91 (s, 1H), 8.42 (d, J = 5.6 Hz, 1H), 7.96 (dd, J = 12.8 and 2.0 Hz, 1H), 7.66 (s, 1H) , 7.55 (s, 1H), 7.43 (d, J = 7.6 Hz, 1H), 7.35-7.39 (m, 2H), 7.19 (t, J = 8.8 Hz, 1H), 6.47 (d, J = 5.6 Hz, 1H), 6.22 (d, J = 7.6 Hz, 1H), 4.28 (q, J = 7.2 Hz, 2H), 4.05 (q, J = 7.2 Hz, 2H), 3.99 (m, 2H), 2.04 (m, 3H), 1.53 (m, 6H), 1.00 (d, J = 6.0 Hz, 6H)

MS (ESI) m / z 590.29 (M + H) ⁺

Example  16: 4- Ethoxy -N- (4- (2- (1-ethyl-1H-) Imidazole Yl) Cyeno [3,2-b] pyridine-7- Sake ) -3- Fluorophenyl ) -2-oxo-1- Phenyl -1,2- Dihydropyridine -3- Carboxamide  Produce

The following compound was prepared in a similar manner as in Example 1.

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 10.61 (s, 1H), 8.42 (d, J = 5.6 Hz, 1H), 7.95 (d, J = 1.2 Hz, 1H), 7.92 (dd, J = 13.2 Hz, 2 Hz, 1H), 7.85 (d, J = 8 Hz, 1H), 7.78 (d, J = 1.2 Hz, 1H), 7.66 (s, 1H), 7.55-7.52 (m, 2H), 7.48 -7.40 (m, 5H), 6.59 (d, J = 5.2 Hz, 1H), 6.51 (d, J = 8 Hz, 1H), 4.26 (q, J = 6.8 Hz, 2H), 4.06 (q, J = 7.2 Hz, 2H), 1.40 (t, J = 7.2 Hz, 3H), 1.31 (t, J = 7.2 Hz, 3H)

MS (ESI) m / z 596.21 (M + H) ⁺

Example  17: 4- Ethoxy -N- (4- (2- (1-ethyl-1H-) Imidazole Yl) Cyeno [3,2-b] pyridine-7- Sake ) -3- Fluorophenyl ) -2-oxo-1- (pyridin-2-yl) -1,2- Dihydropyridine -3-car Levoxamide Manufacturing

The following compound was prepared in a similar manner as in Example 1.

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 10.59 (s, 1H), 8.61 (m, 1H), 8.42 (d, J = 5.2 Hz, 1H), 8.08 (d, J = 8 Hz, 1H) , 8.00 (td, J = 0.8 Hz, 2.0 Hz, 1H), 7.95 (d, J = 1.2 Hz, 1H), 7.92 (d, J = 2 Hz, 1H), 7.79 (d, J = 1.2 Hz , 1H), 7.78 (d, J = 8.4 Hz, 1H), 7.67 (s, 1H), 7.52-7.43 (m, 3H), 6.60 (s, 1H), 6.58 (d, J = 2.8 Hz, 1H) , 4.28 (q, J = 7.2 Hz, 2H), 4.06 (q, J = 7.2 Hz, 2H), 1.40 (t, J = 7.2 Hz, 3H), 1.31 (t, J = 7.2 Hz, 3H)

MS (ESI) m / z 597.24 (M + H) ⁺

Example  18: 4- Ethoxy -N- (4- (2- (1-ethyl-1H-) Imidazole Yl) Cyeno [3,2-b] pyridine-7- Sake ) -3- Fluorophenyl ) -1- (2- Fluorophenyl ) -2-oxo-1,2- Dihydropyridine -3- Carboxamide  Produce

The following compound was prepared in a similar manner as in Example 1.

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 10.91 (s, 1H), 8.41 (d, J = 5.6 Hz, 1H), 8.06 (d, J = 6 Hz, 1H), 7.96 (dd, J = 12.8 Hz, 2.4 Hz, 1H), 7.95 (d, J = 1.2 Hz, 1H), 7.78 (d, J = 1.2 Hz, 1H), 7.67 (s, 1H), 7.55-7.49 (m, 2H), 7.34- 7.23 (m, 4H), 7.04 (d, J = 6 Hz 1H), 6.59 (d, J = 5.2 Hz, 1H), 4.26 (q, J = 7.2 Hz, 2H), 4.06 (q, J = 7.2 Hz , 2H), 1.40 (t, J = 7.2 Hz, 3H), 1.31 (t, J = 7.2 Hz, 3H)

MS (ESI) m / z 614.22 (M + H) ⁺

Example  19: 4- Ethoxy -N- (4- (2- (1-ethyl-1H-) Imidazole Yl) Cyeno [3,2-b] pyridine-7- Sake ) Phenyl ) -1- (4- Fluorophenyl ) -2-oxo-1,2- Dihydropyridine -3- Carboxamide  Produce

The following compound was prepared in a similar manner as in Example 1.

¹ H NMR (400 MHz, CDCl ₃ ) δ 11.37 (s, 1H), 8.40 (d, J = 5.6 Hz, 1H), 7.76 (d, J = 8.8 Hz, 2H), 7.66 (s, 1H), 7.55 (s, 1H), 7.49 (d, J = 8.0 Hz, 1H), 7.34-7.39 (m, 3H), 7.23 (t, J = 8.0 Hz, 2H), 7.12 (d, J = 8.8 Hz, 2H) , 6.50 (d, J = 5.6 Hz, 1H), 6.35 (d, J = 7.6 Hz, 1H), 4.35 (q, J = 7.2 Hz, 2H), 4.05 (q, J = 7.2 Hz, 2H), 1.58 (t, J = 7.2 Hz, 3H), 1.53 (t, J = 7.2 Hz, 3H)

MS (ESI) m / z 596.22 (M + H) ⁺

Example  20: N- (4- (2- (1-ethyl-1 H-) Imidazole Yl) Cyeno [3,2-b] pyridin-7-yloxy) -3- Fluorophenyl ) -1- (4- Fluorophenyl )-4- Methoxy -2-oxo-1,2- Dihydropyridine -3- Carboxamide  Produce

The following compound was prepared in a similar manner as in Example 1.

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 10.64 (s, 1H), 8.42 (d, J = 5.6 Hz, 1H), 7.95 (d, J = 0.8 Hz, 1H), 7.91 (s, 1H) , 7.89 (s, 1H), 7.78 (d, J = 0.8 Hz, 1H), 7.66 (s, 1H), 7.48-7.45 (m, 4H), 7.37 (t, J = 8.8 Hz, 1H), 6.59 ( d, J = 5.6 Hz, 1H), 6.54 (d, J = 7.6 Hz, 1H), 4.06 (q, J = 7.2 Hz, 2H), 3.93 (s, 3H), 1.40 (t, J = 7.2 Hz, 3H)

MS (ESI) m / z 600.25 (M + H) ⁺

Example  21: N- (4- (2- (1-ethyl-1 H-) Imidazole Yl) Cyeno [3,2-b] pyridin-7-yloxy) -3- Fluorophenyl ) -1- (4- Fluorophenyl ) -2-oxo-1,2- Dihydropyridine -3- Carboxamide  Produce

The following compound was prepared in a similar manner as in Example 1.

¹ H NMR (400 MHz, CDCl ₃ ) δ 12.00 (s, 1H), 8.75 (dd, J = 7.2 and 2.0 Hz, 1H), 8.43 (d, J = 5.2 Hz, 1H), 7.95 (dd, J = 12.4 and 2.4 Hz, 1H), 7.66 (s, 1H), 7.63 (dd, J = 6.8 and 2.0 Hz, 1H), 7.55 (s, 1H), 7.35-7.73 (m, 4H), 7.27 (m, 2H ), 7.21 (t, J = 8.8 Hz, 1H), 6.63 (t, J = 6.8 Hz, 1H), 6.47 (d, J = 5.2 Hz, 1H), 4.05 (q, J = 7.2 Hz, 2H), 1.53 (t, J = 7.2 Hz, 3H)

MS (ESI) m / z 570.19 (M + H) ⁺

Example  22: 4- Methoxy -N- (3- Fluoro -4- (2- (1- methyl -1H- Pyrazole Yl) Cyeno [ 3,2-b] pyridine -7- Sake ) Phenyl )-One- Phenyl -2-oxo-1,2- Dihydropyridine -3- Carboxamide  Produce

The following compound was prepared in a similar manner as in Example 1.

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 10.66 (s, 1H), 8.43 (d, J = 5.6 Hz, 1H), 8.30 (s, 1H), 7.99 (d, J = 0.4 Hz, 1H) , 7.93 (dd, J = 12.8 Hz, 2Hz, 1H), 7.89 (d, J = 7.6 Hz, 1H), 7.68 (s, 1H), 7.54-7.52 (m, 2H), 7.49-7.42 (m, 3H ), 7.42-7.39 (m, 2H), 6.59 (d, J = 5.2 Hz, 1H), 6.53 (d, J = 8 Hz, 1H), 3.93 (s, 3H), 3.89 (s, 3H).

MS (ESI) m / z 568.12 (M + H) ⁺

Example  23: 4- Ethoxy -N- (3- Fluoro -4- (2- (1- methyl -1H- Pyrazole Yl) Cyeno [ 3,2-b] pyridine -7- Sake ) Phenyl )-One- Phenyl -2-oxo-1,2- Dihydropyridine -3- Carboxamide  Produce

The following compound was prepared in a similar manner as in Example 1.

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 10.66 (s, 1H), 8.58 (d, J = 6 Hz, 1H), 8.43 (s, 1H), 8.09 (s, 1H), 7.97 (d, J = 12 Hz, 1H), 7.86 (d, J = 7.6 Hz, 1H), 7.75 (s, 1H), 7.56-7.42 (m, 5H), 7.41-7.39 (m, 2H), 6.85 (d, J = 6 Hz, 1H), 6.51 (d, J = 8 Hz, 1H), 4.26 (q, J = 7.2 Hz, 2H), 3.91 (s, 3H), 1.30 (t, J = 7.2 Hz, 3H)

MS (ESI) m / z 582.16 (M + H) ⁺

Example  24: 4- Ethoxy -N- (3- Fluoro -4- (2- (1- methyl -1H- Imidazole Yl) Cyeno [ 3,2-b] pyridine -7- Sake ) Phenyl )-One- Phenyl -2-oxo-1,2- Dihydropyridine -3- Carboxamide  Produce

The following compound was prepared in a similar manner as in Example 1.

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 10.67 (s, 1H), 8.60 (d, J = 6.0 Hz, 1H), 8.11 (s, 1H), 8.08 (s, 1H), 7.87 (d, J = 8.0 Hz, 1H), 7.83 (s, 1H), 7.56-7.40 (m, 7H), 6.89 (d, J = 6.0 Hz, 1H), 6.52 (d, J = 7.6 Hz, 1H), 4.27 ( q, J = 7.2 Hz, 2H), 3.78 (s, 3H), 1.31 (t, J = 7.2 Hz, 3H).

MS (ESI) m / z 582.16 (M + H) ⁺

Example  25: 4- Methoxy -N- (3- Fluoro -4- (2- (1- methyl -1H- Imidazole Yl) Cyeno [ 3,2-b] pyridine -7- Sake ) Phenyl )-One- Phenyl -2-oxo-1,2- Dihydropyridine -3- Carboxamide  Produce

The following compound was prepared in a similar manner as in Example 1.

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 10.66 (s, 1H), 8.42 (d, J = 5.6 Hz, 1H), 7.93 (dd, J = 12.8 Hz, 1.6 Hz, 1H), 7.90 (d , J = 8 Hz, 1H), 7.85 (s, 1H), 7.72 (s, 1H), 7.67 (s, 1H), 7.56-7.40 (m, 7H), 6.59 (d, J = 5.6 Hz, 1H) , 6.53 (d, J = 7.6 Hz, 1H), 3.93 (s, 3H), 3.72 (s, 3H)

MS (ESI) m / z 568.17 (M + H) ⁺

Example  26: 4- Methoxy -N- (3- Fluoro -4- (2- (1-ethyl-1H-) Imidazole Yl) Cyeno [ 3,2-b] pyridine -7- Sake ) Phenyl )-One- Phenyl -2-oxo-1,2- Dihydropyridine -3- Carboxamide  Produce

The following compound was prepared in a similar manner as in Example 1.

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 10.66 (s, 1H), 8.42 (d, J = 5.6 Hz, 1H), 7.96-7.89 (m, 3H), 7.29 (m, 1H), 7.67 ( s, 1H), 7.56-7.40 (m, 7H), 1.41 (t, J = 7.2 Hz, 3H), 3.94 (s, 3H), 4.06 (q, J = 7.2 Hz, 2H), 6.54 (d, J = 8.0 Hz, 1H), 6.59 (d, J = 6.8 Hz, 1H),

MS (ESI) m / z 582.12 (M + H) ⁺

Example  27: 4- Methoxy -N- (3- Fluoro -4- (2- (1-ethyl-1H-) Pyrazole Yl) Cyeno [ 3,2-b] pyridine -7- Sake ) Phenyl )-One- Phenyl -2-oxo-1,2- Dihydropyridine -3- Carboxamide  Produce

The following compound was prepared in a similar manner as in Example 1.

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 10.66 (s, 1H), 8.43 (d, J = 5.6 Hz, 1H), 8.36 (s, 1H), 8.00 (s, 1H), 7.96-7.89 ( m, 2H), 7.69 (s, 1H), 7.56-7.40 (m, 7H), 6.59 (d, J = 5.6 Hz, 1H), 6.53 (d, J = 7.6 Hz, 1H), 4.19 (q, J = 7.2 Hz, 2H), 3.93 (s, 3H), 1.42 (t, J = 7.2 Hz, 3H)

MS (ESI) m / z 568.12 (M + H) ⁺

Example  28: 4- Methoxy -N- (3- Fluoro -4- (2- (1- ( Methoxymethyl ) -1H- Imidazole Yl) Cyeno [3,2-b] pyridine-7- Sake ) Phenyl )-One- Phenyl -2-oxo-1,2- Dihydropyridine Preparation of 3-Carboxamide

The following compound was prepared in a similar manner as in Example 1.

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 10.66 (s, 1H), 8.44 (d, J = 5.6 Hz, 1H), 8.04 (s, 1H), 7.95-7.89 (m, 3H), 7.77 ( s, 1H), 7.56-7.40 (m, 7H), 6.61 (d, J = 5.6 Hz, 1H), 6.53 (d, J = 7.6 Hz, 1H), 5.37 (s, 2H), 3.94 (s, 1H ), 3.27 (s, 3 H)

MS (ESI) m / z 568.12 (M + H) ⁺

Example  29: 4- Ethoxy -N- (3- Fluoro -4- (2- (piperazin-1- Yl methyl ) Cyeno [ 3,2-b] pyridine -7- Sake ) Phenyl ) -1- (4- Fluorophenyl ) -2-oxo-1,2- Dihydropyridine -3-car Le Bois Ami De Of hydrochloride  Produce

Step 1) Preparation of 7-chlorothieno [3,2-b] pyridine-2-carbaldehyde

1 g (5.89 mmol) of 7-chlorothieno [3,2-b] pyridine was dissolved in 20 mL of tetrahydrofuran, and then cooled to -70 ° C. 3.06 mL (7.66 mmol) of normal butyllithium (2.5M hexane solution) was added, followed by stirring for 1 hour. At the same temperature, 0.68 mL (8.84 mmol) of anhydrous N, N-dimethylformamide was added and then stirred for 1 hour. After cooling to room temperature, 40 mL of water was added, extracted with 40 mL of ethyl acetate, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure, 7-chlorocyeno [3,2-b] pyridine-2-carbaldehyde 1.17 g (98%) was obtained.

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 10.24 (s, 1H), 8.82 (d, J = 4.8 Hz, 1H), 8.64 (s, 1H), 7.81 (d, J = 4.8 Hz, 1H)

MS (ESI) m / z 197.99 (M + H) ⁺

Step 2) Preparation of 7- (2-fluoro-4-nitrophenoxy) thieno [3,2-b] pyridine-2-carbaldehyde

To 20 mL of diphenyl ether, 1.17 g (5.91 mmol) of the compound obtained in Step 1, 1.39 g (8.87 mmol) of 2-fluoro-4-nitrophenol, and 2.45 g (17.73 mmol) of potassium carbonate were added thereto, followed by heating to 170 ° C. Reflux for hours. After completion of the reaction, the mixture was cooled to room temperature. 40 mL of water was added and extracted with 40 mL of ethyl acetate. After drying over anhydrous magnesium sulfate, filtration and concentration under reduced pressure, 1.05 g of 7- (2-fluoro-4-nitrophenoxy) thieno [3,2-b] pyridine-2-carbaldehyde with silica gel column chromatography 54%) was purified separately.

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 10.26 (s, 1H), 8.75 (d, J = 5.6 Hz, 1H), 8.63 (s, 1H), 8.49 (dd, J = 10.4 Hz, 2.8 Hz, 1H), 8.24 (m, 1H), 7.79 (t, J = 8 Hz, 1H), 7.11 (dd, J = 5.2 Hz, 0.4 Hz, 1H)

MS (ESI) m / z 351.08 (M + H) ⁺

Step 3) Tert-Butyl 4-((7- (2-fluoro-4-nitrophenoxy) thieno [3,2-b] pyridin-2-yl) methyl) piperazin-1-carboxylate Manufacture

100 mg (0.31 mmol) of the compound obtained in step 2 were dissolved in 1 mL of anhydrous dichloromethane, and 64.3 mg (0.34 mmol) of tert-butyl piperazine-1-carboxylate were added. Stirred at room temperature for 1 hour. 95.8 mg (0.45 mmol) of sodium triacetoxyborohydride were added and stirred at room temperature for 2 hours. 2 mL of saturated aqueous sodium hydrogen carbonate solution was added and extracted with 1 mL of dichloromethane. Dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure, tert-butyl 4-((7- (2-fluoro-4-nitrophenoxy) thieno [3,2-b] pyridin-2-yl) methyl) 148.5 mg (97%) of piperazine-1-carboxylate were obtained.

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.54 (d, J = 5.6 Hz, 1H), 8.46 (dd, J = 10.4 Hz, 2.4 Hz, 1H), 8.20 (m, 1H) 7.68 (t, J = 5.2 Hz, 1H), 7.52 (s, 1H), 6.88 (d, J = 5.2 Hz, 1H), 3.33 (t, J = 4.8 Hz, 4H), 2.44 (t, J = 4.8 Hz, 4H), 1.39 (s, 9 H)

MS (ESI) m / z 489.27 (M + H) ⁺

Step 4) Tert-Butyl 4-((7- (4-amino-2-fluorophenoxy) thieno [3,2-b] pyridin-2-yl) methyl) piperazin-1-carboxylate Manufacture

140 mg (0.28 mmol) of the compound obtained in step 3 was dissolved in 10 mL of ethanol: water (2: 1), followed by addition of 48 mg (0.86 mmol) of iron and 152 mg (2.85 mmol) of ammonium chloride. Stir at 110 ° C. for 1 hour. After the reaction was completed, the reaction mixture was cooled to room temperature, ethyl acetate was added and stirred for 10 minutes. The reaction mixture was washed with ethyl acetate, distilled water was added to the solution passed through celite, and extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, filtered, and the solvent was removed under reduced pressure to give tert-butyl 4-((7- (4-amino-2-fluorophenoxy) thieno [3,2-b] pyridine. 120 mg (93%) of 2-yl) methyl) piperazine-1-carboxylate were obtained.

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.42 (d, J = 5.2 Hz, 1H), 7.43 (s, 1H), 7.08 (t, J = 9.2 Hz, 1H), 6.54-6.49 (m, 2H ), 6.44 (dd, J = 8.8 Hz, 2.4 Hz, 1H), 5.51 (bs, 2H), 3.86 (s, 1H), 3.33 (m, 4H), 2.43 (m, 4H), 1.39 (s, 9H )

MS (ESI) m / z 459.31 (M + H) ⁺

Step 5) Tert-Butyl 4-((7- (4- (4-ethoxy-1- (4-fluorophenyl) -2-oxo-1,2-dihydropyridine-3-carboxamido) Preparation of -2-fluorophenoxy) thieno [3,2-b] pyridin-2-yl) methyl) piperazine-1-carboxylate

90.6 mg (0.32 mmol) of 4-ethoxy-1- (4-fluorophenyl) -2-oxo-1,2-dihydropyridine-3-carboxylic acid are dissolved in 4 mL of dichloromethane and then 47.5 uL of thionyl chloride (0.65 mmol) was added slowly and stirred at room temperature for 1 hour. The solvent was removed under reduced pressure and dried under vacuum to synthesize 4-ethoxy-1- (4-fluorophenyl) -2-oxo-1,2-dihydropyridine-3-carbonyl chloride. 100 mg (0.21 mmol) of the compound obtained in step 4 were dissolved in 2 mL of dichloromethane. 45.6 uL (0.32 mmol) of triethylamine were added. Stirred at room temperature for 30 minutes. The acid chloride removed solvent under reduced pressure was again dissolved in 2 mL of dichloromethane and added to the reaction. Stirred at room temperature for 1 hour. Water and saturated aqueous sodium hydrogen carbonate were added, and the mixture was extracted with dichloromethane. The organic layer was dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure, and then purified by silica gel column chromatography with tert-butyl 4-((7- (4- (4-ethoxy-1- (4-fluorophenyl) -2-oxo- 1,2-dihydropyridine-3-carboxamido) -2-fluorophenoxy) thieno [3,2-b] pyridin-2-yl) methyl) piperazin-1-carboxylate 150 mg (99%) was purified separately. The compound is a compound corresponding to Example 24.

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 10.59 (s, 1H), 8.44 (d, J = 5.2 Hz, 1H), 7.92 (dd, J = 12.8 Hz, 2 Hz, 1H), 7.86 (d , J = 8 Hz, 1H), 7.49-7.41 (m, 5H), 7.39-7.34 (m, 2H), 6.60 (d, J = 5.2 Hz, 1H), 6.51 (d, J = 7.6 Hz, 1H) , 4.26 (q, J = 6.8 Hz, 2H), 3.87 (s, 1H), 3.35 (bs, 4H), 2.45 (bs, 1H), 1.39 (s, 9H), 1.30 (t, J = 14 Hz, 3H)

MS (ESI) m / z 718.44 (M + H) ⁺

Step 6) 4-Ethoxy-N- (3-fluoro-4- (2- (piperazin-1-ylmethyl) thieno [3,2-b] pyridin-7-yloxy) phenyl)- Preparation of 1- (4-fluorophenyl) -2-oxo-1,2-dihydropyridine-3-carboxamide hydrochloride

126 mg (0.17 mmol) of the compound obtained in step 5 were dissolved in dichloromethane, and then 4N aqueous hydrogen chloride solution dioxane was added. The mixture was stirred at room temperature for 12 hours. After concentration under reduced pressure, diethyl ether was added and the solid was filtered to afford 4-ethoxy-N- (3-fluoro-4-((2- (piperazin-1-ylmethyl) cyeno [3,2- b] 123 mg (95%) of pyridin-7-yl) oxy) phenyl) -1- (4-fluorophenyl) -2-oxo-1,2-dihydropyridine-3-carboxamide hydrochloride were obtained. .

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 10.66 (s, 1H), 8.63 (d, J = 6 Hz, 1H), 8.05 (m, 2H), 7.87 (d, J = 7.6 Hz, 1H) , 7.55-7.44 (m, 5H), 7.40-7.34 (m, 2H), 6.90 (d, J = 5.2 Hz, 1H), 6.53 (d, J = 8 Hz, 1H), 4.26 (q, J = 6.8 Hz, 2H), 3.23 (bs, 4H), 2.97 (bs, 4H), 1.30 (t, J = 7.2 Hz, 3H)

MS (ESI) m / z 652.02 (M + HCl) ^-

Example  30: 4- Ethoxy -N- (3- Fluoro -4- (2-((4- Methylpiperazine -1 day) methyl ) Cyeno [ 3,2-b] pyridine -7- Sake ) Phenyl ) -1- (4- Fluorophenyl ) -2-oxo-1,2- Dihydropyridine -3- Carboxamide  Produce

In the same manner as in Example 29, the following compound was prepared.

¹ H NMR (400 MHz, CDCl ₃ ) δ 11.65 (s, 1H), 8.45 (d, J = 5.6 Hz, 1H), 7.96 (dd, J = 12.4 and 2.0 Hz, 1H), 8.45 (d, J = 7.6 Hz, 1H), 7.40-7.24 (m, 6H), 7.15 (t, J = 8.8 Hz, 1H), 6.49 (d, J = 4.8 Hz, 1H), 6.39 (d, J = 7.6 Hz, 1H) , 4.39 (q, J = 7.2 Hz, 2H), 3.90 (s, 1H), 2.87-2.52 (m, 8H), 1.61 (t, J = 7.2 Hz, 3H), 1.27 (s, 3H)

MS (ESI) m / z 632.25 (M + H) ⁺

Example  31: Rat -Butyl 4-((7- (4- (4- Ethoxy -1- (4- Fluorophenyl ) -2-oxo-1,2-dihydropyridine-3- Carboxamido )-2- Fluorophenoxy ) Cyeno [3,2-b] pyridin-2-yl) methyl ) Piperazin-l- Carboxylate  Produce

The compound corresponds to step 5 in the synthesis of Example 29.

Example  32: 4- Ethoxy -N- (3- Fluoro -4- (2-((4- ( Methylsulfonyl ) Piperazin-1-yl) methyl) Cyeno [3,2-b] pyridine-7- Sake ) Phenyl ) -1- (4- Fluorophenyl ) -2-oxo-1,2- Dihydropyridine -3- Carboxamide  Produce

30 mg (0.045 mmol) of the compound obtained in Example 29 was dissolved in dichloromethane, and then 12.8 uL (0.091 mmol) of triethylamine was added and stirred at room temperature for 1 hour. 3.9 uL (0.05 mmol) of methanesulfonyl chloride was added to the reaction mixture, and the mixture was stirred at room temperature for 12 hours. Dichloromethane and water were added and the organic layer was separated, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure to give a residue. The residue is prep. Developing solvent using TLC Dichloromethane: Methyl alcohol = 30: 1 Separation under conditions of 4-ethoxy-N- (3-fluoro-4- (2-((4- (methylsulfonyl) piperazin-1) -Yl) methyl) thieno [3,2-b] pyridin-7-yloxy) phenyl) -1- (4-fluorophenyl) -2-oxo-1,2-dihydropyridine-3-car 14 mg (44%) of voxamide were obtained.

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 10.60 (s, 1H), 8.44 (d, J = 5.6 Hz, 1H), 7.86 (d, J = 8 Hz, 1H), 7.48-7.43 (m, 5H), 7.36 (t, J = 8.8 Hz, 2H), 6.61 (d, J = 5.6 Hz, 1H), 6.52 (d, J = 8 Hz, 1H), 4.26 (q, J = 7.2 Hz, 2H) , 3.93 (s, 1H), 3.15 (t, J = 4.4 Hz, 4H), 2.59 (t, J = 4.4 Hz, 4H), 1.30 (t, J = 7.2 Hz, 3H)

MS (ESI) m / z 696.10 (M + H) ⁺

Comparative Example

In the following experimental examples, the following compounds (Cas No. 877399-52-5, purchased from Shanghai Sun-shine Chemical Technology (China)) were used as comparative examples.

Experimental Example  1: c- MET  Activity inhibition assay ( ADP - Glo ™ kinase assay )

250 uM G4Y1 peptide serving as substrate for 2 ng / uL c-MET enzyme, 50 uM ATP in reaction buffer (40 mM Tris-HCl, pH 7.5), 20 mM MgCl ₂ , 0.1 mg / mL bovine serum albumin, 50 enzymatic reaction was carried out in uM DTT). After the compound prepared in Example and the comparative example were treated at various concentrations and reacted at room temperature for 1 hour, ADP-Glo ™ Reagent and Kinase detection reagent were sequentially added and reacted at room temperature for 40 minutes and 30 minutes, respectively.

Since luminescence was measured using Wallaac Victor 2TM (PerkinElmer life sciences, 1420-042). Data were analyzed with the measured RLU values to verify the activity of the c-MET inhibitor. The RLU value of the sample that was not treated with the compound was a 100% control group, and the activity of the c-MET inhibitor was evaluated as a percentage of the residual activity of the c-MET enzyme in the sample treated with the concentration of the compound to be tested. The concentration of the compound at which 50% c-MET enzyme activity inhibition occurs compared to the control was determined by the IC ₅₀ value (nM) of the c-MET inhibitor. The results are shown in Table 1 below.

Experimental Example  2: Cell growth inhibition assay

MTS analysis was performed to determine whether the compound according to the present invention has cancer cell proliferation inhibitory effect through inhibition of extracellular signal-regulated kinase activity.

The following analysis was performed on the MKN45 cell line, a human gastric cancer cell line. MKN45 cell lines were dispensed at a concentration of 5,000 cells / well in 96-well plates each containing RPMI-1640 medium (GIBCO, Invitrogen) containing 10% FBS, followed by 24 hours at 5% CO ₂ and 37 ° C. Incubated. Each well was then subjected to sequential dilution of the compounds prepared in Examples above at a concentration of 10 μM each, and 0.1% (v / v) of the same solvent used to treat dimethylsulfoxide (DMSO) as a compound. Treated at a concentration of Each cell was then incubated for 48 hours. To confirm the viability of the cells, a mixture of MTS and PMS (phenazine methosulfate) provided in CellTiter 96® AQuous Non-Radioactive Cell Proliferation Assay Kit (Promega) was added to each cultured cell medium. Incubated for 2 h 30 min. Then, absorbance was measured at 490 nm. The degree of inhibition of cell proliferation according to the treatment concentration of each compound was calculated based on the absorbance of the solvent-controlled cells without treatment of the compounds, and the concentration of each compound that inhibits the proliferation of cancer cells by 50% was determined by the IC ₅₀ (nM) value. It was. The results are shown in Table 1 below.

Example No. ADP Glo assay c-Met, IC ₅₀ MKN45 cell growth inhibitory activity, IC ₅₀ Example No. ADP Glo assay c-Met, IC ₅₀ MKN45 cell growth inhibitory activity, IC ₅₀ One A A 18 A C 2 B C 19 A A 3 B B 20 A A 4 C C 21 A A 5 A B 22 A B 6 A A 23 A B 7 A B 24 A B 8 A B 25 A B 9 A B 26 A B 10 A C 27 A B 11 A A 28 A B 12 B C 29 B C 13 A B 30 B C 14 A C 31 C C 15 A C 32 B C 16 A A Comparative Example A B 17 A C

(In the above, A: <10 nM, B: 10-50 nM, C:> 50 nM.)

Experimental Example  3: Antitumor Effect Evaluation Using Human Glioblastoma and Gastric Cancer Cell Line Transplantation Tumor Model

Human glioblastoma cells U87MG and human gastric cancer cells MKN45 were grown in media and harvested and subcutaneously injected in the posterior right flank of athymic nude mice. The compound prepared in Example was prepared in 0.5% methyl cellulose solvent, and when the average tumor size was grown by about 80-90 mm 3 (after 10-14 days of transplantation), the compound was administered by oral gavage for 14 days. . Tumor volume was measured 2-3 times a week during the course of treatment, and the increase in tumor volume was calculated by subtracting the tumor volume of the last dose from the tumor volume of the first dose. Relative tumor volume was calculated by dividing the tumor volume increase of the test substance dose group by the tumor volume increase of the solvent control group. Tumor inhibition rate was calculated by subtracting the relative tumor volume from 1. Body weight was confirmed as a general measure of toxicity and weight loss by administration of the test substance was not observed during the administration.

As a result of the tumor growth inhibition test of the comparative example having a similar pharmacological mechanism and the usefulness as a medicament as the control compound of the present invention, the compounds prepared in the examples of the present invention showed superior tumor growth inhibition than the comparative example. Confirmed.

As shown in FIG. 1, the compound of Example 1 of the present invention demonstrated excellent dose dependent antitumor activity in this model. That is, when administered at 20 mg / kg (oral (PO), once daily (QD) x 14) induced 75% growth inhibition of MKN45 tumors, the comparative example when administered at 20 mg / kg (oral, 1 Once daily 14) induced 34% growth inhibition of MKN45 tumors.

In addition, as shown in Figure 2, the compound of Example 5 of the present invention induced 70% growth inhibition of U87MG tumors when administered at 20 mg / kg (oral, once a day x 14).

Experimental Example  4: Lck  And VEGFR1 , 2,3 Low performance  evaluation

Activity similar to that of Example 1 was obtained in Example 1 in a similar manner to Experimental Example 1.

ADP Glo assay, IC ₅₀ Lck B VEGFR1 B VEGFR2 B VEGFR3 B

(In the above, A: <10 nM, B: 10-50 nM, C:> 50 nM.)

Claims (10)

A compound represented by Formula 1, or a pharmaceutically acceptable salt thereof:
[Chemical Formula 1]

In this formula,
R ₁ is hydrogen; Or halogen,
R ₂ is C _1-4 alkoxy,
R ₃ is isopentyl; Phenyl; 4-fluorophenyl; benzyl; Or pyridinyl, wherein said benzyl or pyridinyl is unsubstituted or substituted with halogen,
R ₄ is imidazol- ₄ -yl; Phenyl; Pyrazolyl; Pyridinyl; Or O Im pyridazinyl, wherein the imidazol-4-yl, phenyl, pyrazolyl, pyridinyl or pyridazinyl Sy O is substituted with unsubstituted or C _1-4 alkyl Beach, wherein said C _1-4 alkyl is unsubstituted Or substituted with hydroxy, C _1-4 alkoxy, di (C _1-4 alkyl) amino or acetoxy.
The method of claim 1,
R ₁ is hydrogen or fluoro, or a pharmaceutically acceptable salt thereof.
The method of claim 1,
R ₂ is methoxy or ethoxy, or a pharmaceutically acceptable salt thereof.
The method of claim 1,
R ₃ is isopentyl; Phenyl; 4-fluorophenyl; Benzyl substituted with halogen; Or pyridinyl, or a pharmaceutically acceptable salt thereof.
5. The method of claim 4,
R ₃ is isopentyl; Phenyl; 4-fluorophenyl; Benzyl substituted with fluoro; Or pyridinyl, or a pharmaceutically acceptable salt thereof.
The method of claim 1,
R ₄ is imidazol-4-yl substituted with C _1-4 alkyl, wherein said C _1-4 alkyl is unsubstituted or substituted with C _1-4 alkoxy or di (C _1-4 alkyl) amino; Phenyl; Pyrazolyl substituted with C _1-4 alkyl, wherein said C _1-4 alkyl is unsubstituted or substituted with hydroxy or acetoxy; Pyridinyl; Or thiazolyl, or a pharmaceutically acceptable salt thereof.
The method according to claim 6,
R ₄ is imidazol-4-yl substituted with any one selected from the group consisting of methyl, ethyl, methoxymethyl, and 2- (dimethylamino) ethyl; Phenyl; Pyrazolyl substituted with any one selected from the group consisting of methyl, ethyl, 2- (hydroxy) ethyl and 2- (acetoxy) ethyl; Pyridinyl; Or thiazolyl, or a pharmaceutically acceptable salt thereof.
The method of claim 1, wherein the compound represented by Formula 1, or a pharmaceutically acceptable salt thereof
1) 4-ethoxy-N- (3-fluoro-4- (2- (1-methyl-1H-imidazol-4-yl) thieno [3,2-b] pyridin-7-yloxy ) Phenyl) -1- (4-fluorophenyl) -2-oxo-1,2-dihydropyridine-3-carboxamide,
5) 4-ethoxy-N- (3-fluoro-4- (2- (1-methyl-1H-pyrazol-4-yl) thieno [3,2-b] pyridin-7-yloxy ) Phenyl) -1- (4-fluorophenyl) -2-oxo-1,2-dihydropyridine-3-carboxamide,
6) 4-ethoxy-N- (4- (2- (1-ethyl-1H-imidazol-4-yl) thieno [3,2-b] pyridin-7-yloxy) -3-fluoro Rophenyl) -1- (4-fluorophenyl) -2-oxo-1,2-dihydropyridine-3-carboxamide,
7) 2- (4- (7- (4- (4-ethoxy-1- (4-fluorophenyl) -2-oxo-1,2-dihydropyridine-3-carboxamido) -2 -Fluorophenoxy) thieno [3,2-b] pyridin-2-yl) -1H-pyrazol-1-yl) ethyl acetate,
8) 4-ethoxy-N- (3-fluoro-4- (2- (pyridin-2-yl) thieno [3,2-b] pyridin-7-yloxy) phenyl) -1- ( 4-fluorophenyl) -2-oxo-1,2-dihydropyridine-3-carboxamide,
9) 4-ethoxy-N- (3-fluoro-4- (2- (pyridin-3-yl) thieno [3,2-b] pyridin-7-yloxy) phenyl) -1- ( 4-fluorophenyl) -2-oxo-1,2-dihydropyridine-3-carboxamide,
10) 4-ethoxy-N- (3-fluoro-4- (2- (thiazol-2-yl) thieno [3,2-b] pyridin-7-yloxy) phenyl) -1- (4-fluorophenyl) -2-oxo-1,2-dihydropyridine-3-carboxamide,
11) N- (4- (2- (1- (2- (dimethylamino) ethyl) -1H-imidazol-4-yl) thieno [3,2-b] pyridin-7-yloxy)- 3-fluorophenyl) -4-ethoxy-1- (4-fluorophenyl) -2-oxo-1,2-dihydropyridine-3-carboxamide,
12) 4-ethoxy-N- (3-fluoro-4- (2-phenylthieno [3,2-b] pyridin-7-yloxy) phenyl) -1- (4-fluorophenyl) -2-oxo-1,2-dihydropyridine-3-carboxamide,
13) 4-ethoxy-N- (3-fluoro-4- (2- (1- (2-hydroxyethyl) -1H-pyrazol-4-yl) thieno [3,2-b] Pyridin-7-yloxy) phenyl) -1- (4-fluorophenyl) -2-oxo-1,2-dihydropyridine-3-carboxamide,
14) 4-ethoxy-N- (4- (2- (1-ethyl-1H-imidazol-4-yl) thieno [3,2-b] pyridin-7-yloxy) -3-fluoro Lophenyl) -1- (4-fluorobenzyl) -2-oxo-1,2-dihydropyridine-3-carboxamide,
15) 4-ethoxy-N- (4- (2- (1-ethyl-1H-imidazol-4-yl) thieno [3,2-b] pyridin-7-yloxy) -3-fluoro Lophenyl) -1-isopentyl-2-oxo-1,2-dihydropyridine-3-carboxamide,
16) 4-ethoxy-N- (4- (2- (1-ethyl-1H-imidazol-4-yl) thieno [3,2-b] pyridin-7-yloxy) -3-fluoro Lophenyl) -2-oxo-1-phenyl-1,2-dihydropyridine-3-carboxamide,
17) 4-ethoxy-N- (4- (2- (1-ethyl-1H-imidazol-4-yl) thieno [3,2-b] pyridin-7-yloxy) -3-fluoro Lophenyl) -2-oxo-1- (pyridin-2-yl) -1,2-dihydropyridine-3-carboxamide,
19) 4-ethoxy-N- (4- (2- (1-ethyl-1H-imidazol-4-yl) thieno [3,2-b] pyridin-7-yloxy) phenyl) -1 -(4-fluorophenyl) -2-oxo-1,2-dihydropyridine-3-carboxamide,
20) N- (4- (2- (1-ethyl-1H-imidazol-4-yl) thieno [3,2-b] pyridin-7-yloxy) -3-fluorophenyl) -1 -(4-fluorophenyl) -4-methoxy-2-oxo-1,2-dihydropyridine-3-carboxamide,
22) 4-methoxy-N- (3-fluoro-4- (2- (1-methyl-1H-pyrazol-4-yl) thieno [3,2-b] pyridin-7-yloxy ) Phenyl) -1-phenyl-2-oxo-1,2-dihydropyridine-3-carboxamide,
23) 4-ethoxy-N- (3-fluoro-4- (2- (1-methyl-1H-pyrazol-4-yl) thieno [3,2-b] pyridin-7-yloxy ) Phenyl) -1-phenyl-2-oxo-1,2-dihydropyridine-3-carboxamide,
24) 4-ethoxy-N- (3-fluoro-4- (2- (1-methyl-1H-imidazol-4-yl) thieno [3,2-b] pyridin-7-yloxy ) Phenyl) -1-phenyl-2-oxo-1,2-dihydropyridine-3-carboxamide,
25) 4-methoxy-N- (3-fluoro-4- (2- (1-methyl-1H-imidazol-4-yl) thieno [3,2-b] pyridin-7-yloxy ) Phenyl) -1-phenyl-2-oxo-1,2-dihydropyridine-3-carboxamide,
26) 4-methoxy-N- (3-fluoro-4- (2- (1-ethyl-1H-imidazol-4-yl) thieno [3,2-b] pyridin-7-yloxy ) Phenyl) -1-phenyl-2-oxo-1,2-dihydropyridine-3-carboxamide,
27) 4-methoxy-N- (3-fluoro-4- (2- (1-ethyl-1H-pyrazol-4-yl) thieno [3,2-b] pyridin-7-yloxy ) Phenyl) -1-phenyl-2-oxo-1,2-dihydropyridine-3-carboxamide, and
28) 4-methoxy-N- (3-fluoro-4- (2- (1- (methoxymethyl) -1H-imidazol-4-yl) thieno [3,2-b] pyridine- 7-yloxy) phenyl) -1-phenyl-2-oxo-1,2-dihydropyridine-3-carboxamide
&Lt; / RTI &gt; or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable salt thereof.
A pharmaceutical for the prevention or treatment of cancer, psoriasis, rheumatoid arthritis, inflammatory bowel disease or chronic obstructive pulmonary disease comprising the compound of any one of claims 1 to 8, or a pharmaceutically acceptable salt thereof as an active ingredient Composition.
The pharmaceutical composition of claim 9, further comprising a pharmaceutically acceptable carrier, diluent or excipient.

Images