KR101505783B1 - Novel pyrrolopyridinyloxyphenylamide derivatives and use thereof - Google Patents

Abstract

The present invention relates to novel pyrrolopyridinyloxyphenylamide derivatives, or a pharmaceutically acceptable salt thereof; A composition for inhibiting c-MET activity comprising the same as an active ingredient, and a pharmaceutical composition for preventing or treating hyperproliferative disorder.

Description

Novel pyrrolopyridinyloxyphenylamide derivatives and uses thereof <br> <br> <br> Patents - stay tuned to the technology Novel pyrrolopyridinyloxyphenylamide derivatives and use thereof

The present invention relates to novel pyrrolopyridinyloxyphenylamide derivatives, or a pharmaceutically acceptable salt thereof; A composition for inhibiting c-MET activity comprising the same as an active ingredient, and a pharmaceutical composition for preventing or treating hyperproliferative disorder.

Protein kinases are enzymes that regulate the activity, location, and function of the protein by controlling phosphorylation of other proteins to control its various intracellular processes. The protein kinases include Abl, ACK, ALK, Arg, ARK5, Aurora, Ax1, Bmx, BTK, CDK, CHK, c-Kit, c-MET, c- RAF, c-SRC, EGFR, FAK, , Flt3, GSK3, IGF, IKK, JAK, Lck, LIMK, Lyn, MEK, Mer, MK-2, P38alpha, PDGFR, PDK, PIM, PKA, PKB, PKCR, Plk-1 / , Rse, Tie, Trk, Tyro3, VEGFR, YES. Such protein kinase control dysfunction is closely related to disease mechanisms such as cancer, immune diseases, neurological diseases, metabolic diseases and infections.

c-MET is a cell membrane receptor essential for embryonic development and wound healing. HGF (hepatocyte growth factor) promotes tumor growth, angiogenesis, invasion and metastasis as the c-MET receptor ligand (Bottaro DP et al . , &Lt; / RTI &gt; Science , 1991, 251 (4995): 802-804).

Abnormal c-MET activation in cancer cells is closely related to aggravation of the prognosis of chemotherapy, and c-MET overexpression and mutation were observed in various cancer diseases such as non-small cell lung cancer. Because tumor invasion and metastasis are the leading cause of death in cancer patients, inhibiting c-MET signaling may be effective in cancer treatment.

Receptor d'Origine Receptor (RON) is a receptor for the corticosterone receptor protein (c-MET), a receptor for macrophage-stimulating protein (MSP) secreted by the liver and controlling the action of macrophages (Zhou YQ et al . , Oncogene , 2003, 22 (2): 186-197). Expression of RON is abnormally regulated in breast cancer and colorectal cancer, and is closely related to metastasis of colorectal cancer. For example, the monoclonal antibody IMC-41A10, which binds to RON, has been reported to inhibit cell metastasis and tumorigenesis, and thus RON inhibitors may exert excellent efficacy in the inhibition of anti-cancer and metastasis.

In this regard, Korean Patent Registration No. 10-0979439 discloses a pyridine derivative substituted with pyrazole and benzoxazole, which has an effect of inhibiting protein kinase such as c-MET, and its use for the prophylaxis and treatment of abnormal cell growth diseases Korean Patent No. 10-0869393 discloses pyrazole-substituted aminoheteroaryl compounds having c-MET protein kinase inhibitory activity and anticancer uses thereof.

As a result of efforts to discover novel protein kinase inhibitors, the present inventors have found that a series of pyrrolopyridinyloxyphenylamide derivatives exhibit an excellent inhibitory effect on c-MET, a tyrosine kinase, and thus can be used for the treatment of cancer, psoriasis, rheumatoid arthritis, Inflammatory bowel disease or chronic obstructive pulmonary disease. The present invention has been completed based on this finding.

In one aspect, the present invention provides a compound represented by the following formula 1, a tautomer thereof, or a pharmaceutically acceptable salt thereof:

[Chemical Formula 1]

In this formula,

R ₁ is hydrogen or halogen;

R ₂ is aryl or heteroaryl selected from the group consisting of phenyl, pyrazolyl, pyridinyl, pyrimidinyl, thiazolyl and thienyl,

,

,

, C_{1 -4} 알킬, C_{1 -4} 알콕시, 할로겐, 니트로, 시아노, 아미노, NH(C_{1 -4} 알킬), NH-아세틸, CO-H, CO-(C_{1 -4} 알킬), CO-몰포리노, CO-NH₂, CO-NH(C_{1 -4} 알킬), CO-N(C_{1 -4} 알킬)₂, 피라졸릴, 몰포리노, 피페라지닐, 피페리디닐, SO₂-(C_{1 -4} 알킬), SO₂-NH₂, SO₂-NH(C_{1 -4} 알킬), SO₂-N(C_{1 -4} 알킬)₂로 구성된 군으로부터 선택되는 하나 이상의 치환기로 치환되고,The aryl or heteroaryl is unsubstituted or substituted with

,

,

, C _{1 -4} alkyl, C _{1 -4} alkoxy, halogen, nitro, cyano, amino, NH (C _{1 -4} alkyl), NH- acetyl, CO-H, CO- (C 1 -4 alkyl), CO - Dimorpholino _{Reno, CO-NH 2, CO-} NH (C 1 -4 _{alkyl), CO-N (C 1} -4 alkyl) _2, pyrazolyl, Dimorpholino Reno, piperazinyl, piperidinyl, SO ₂ - ( C _{1 -4} alkyl), SO ₂ -NH ₂ , SO ₂ -NH (C _{1 -4} alkyl), SO ₂ -N (C _{1 -4} alkyl) ₂ ,

R _i to R _iii is hydroxy, cyano, C _{1 -4 alkoxy, O- (CH 2) 2 -O} -CH 3, OCO-NH 2, Dimorpholino Reno, amino, NH (C _{1 -4} alkyl) or N (C _{1 -4} alkyl) _2;

또는

로서,R ₃ is

or

as,

R _3a, R _3b, R _3c and R _3d are each independently hydrogen, halogen, hydroxy, C _{1 -4} alkyl or C _{1 -4} alkoxy.

Preferably, in the above formula, R &lt; ₁ &gt; may be hydrogen or F. [

,

,

, C_1-4 알킬, C_{1 -4} 알콕시, 할로겐, 니트로, 시아노, 아미노, NH(C_{1 -4} 알킬) 또는 SO₂-(C_1-4 알킬)로 구성된 군으로부터 선택되는 하나 이상의 치환기로 치환된 페닐 또는 피라졸릴일 수 있다.Preferably, R &lt; ₂ &gt; in the above formula is unsubstituted,

,

,

, C _1-4 alkyl, C _{1 -4} alkoxy, halogen, nitro, cyano, amino, NH (C _{1 -4} alkyl), or SO ₂ - one or more substituents selected from the group consisting of (C _1-4 alkyl) &Lt; / RTI &gt; or pyrazolyl.

Preferably, the R _i is hydroxy, _{cyano, O- (CH 2) 2 -O} -CH 3 , or C _1-4 alkoxy in the formula, R _ii is an alkoxy or hydroxy-C _{1 -4,} R _iii Lt; / RTI &gt; may be hydroxy.

More preferably, in the above formula, R ₂ is unsubstituted or substituted with at least one substituent selected from the group consisting of methyl, ethyl, amino, F, Cl, lH-pyrazol-1-yl, cyanomethyl, nitro, methoxy, hydroxymethyl, Phenyl substituted with one or more substituents selected from the group consisting of amino, 1-hydroxyethyl, 2-hydroxypropan-2-yl, 1-methoxyethyl, (2-methoxyethoxy) methyl and ethylsulfonyl Lt; / RTI &gt;

More preferably, R ₂ in the above formula may be unsubstituted or 1-H-pyrazol-4-yl substituted on the nitrogen atom with methyl, ethyl, cyanomethyl or methoxymethyl.

Preferably, in the formula R _3a is an alkoxy C _{1 -4,} R _3b may be a hydrogen, R _3c and R _3d are each independently hydrogen or halogen.

More preferably, in the above formula, R _3a is methoxy or ethoxy, R _3b is hydrogen, and R _3c and R _3d are each independently hydrogen or F.

Preferably,

로서, R_3a는 메톡시 또는 에톡시, R_3b는 수소, R_3c는 F이거나,Wherein R &lt; ₁ &gt; is F; R ₂ is unsubstituted or substituted with at least one substituent selected from the group consisting of methyl, ethyl, amino, F, Cl, lH-pyrazol-1-yl, cyanomethyl, nitro, methoxy, hydroxymethyl, Phenyl substituted with one or two substituents selected from the group consisting of 2-hydroxypropan-2-yl, 1-methoxyethyl, (2-methoxyethoxy) methyl and ethylsulfonyl; Or 1-H-pyrazol-4-yl unsubstituted or substituted on the nitrogen atom with methyl, ethyl, cyanomethyl or methoxymethyl, and R ₃ is

Wherein R _3a is methoxy or ethoxy, R _3b is hydrogen, R _3c is F,

로서, R_3d는 F일 수 있다.
R ₁ is F; R ₂ is phenyl which is unsubstituted or substituted by F, methoxy or hydroxymethyl, and R ₃ is

, R _3d may be F.

More preferably, the compound is

1) N- (4- (3- (3-amino-4-fluorophenyl) -lH-pyrrolo [2,3- b] pyridin- Ethoxy-1- (4-fluorophenyl) -2-oxo-1,2-dihydropyridine-3- carboxamide,

2) N- (4- (3- (3-aminophenyl) -lH-pyrrolo [2,3- b] pyridin- 4- yloxy) -3-fluorophenyl) -4- (4-fluorophenyl) -2-oxo-1,2-dihydropyridine-3-carboxamide,

3) N- (4- (3- (3-Amino-2-methylphenyl) -lH- pyrrolo [2,3- b] pyridin- 4-yloxy) -3-fluorophenyl) -4- -1- (4-fluorophenyl) -2-oxo-1,2-dihydropyridine-3-carboxamide,

4) Preparation of N- (4- (3- (3-amino-4-chlorophenyl) -lH- pyrrolo [2,3- b] pyridin- 4- yloxy) -3-fluorophenyl) -4- (4-fluorophenyl) -2-oxo-1,2-dihydropyridine-3-carboxamide,

5) N- (4- (3- (lH-pyrazol-l-yl) phenyl) -lH- pyrrolo [2,3- b] pyridin- 4- yloxy) -3-fluorophenyl ) -4-ethoxy-1- (4-fluorophenyl) -2-oxo-1,2-dihydropyridine-

6) N- (4- (3- (3-Amino-4-methylphenyl) -lH- pyrrolo [2,3- b] pyridin- 4- yloxy) -3-fluorophenyl) -4- -1- (4-fluorophenyl) -2-oxo-1,2-dihydropyridine-3-carboxamide,

7) N- (4- (3- (3- (Cyanomethyl) phenyl) -lH- pyrrolo [2,3- b] pyridin- 4-yloxy) -3-fluorophenyl) -4- (4-fluorophenyl) -2-oxo-1,2-dihydropyridine-3-carboxamide,

2,3-b] pyridin-4-yloxy) -lH-pyrrolo [2,3-d] pyrimidin- Phenyl) -1- (4-fluorophenyl) -2-oxo-1,2-dihydropyridine-3- carboxamide,

9) 4-ethoxy-N- (3-fluoro-4- (3- Phenyl) -1- (4-fluorophenyl) -2-oxo-1,2-dihydropyridine-3- carboxamide,

10) N- (4- (3- (5-Amino-2-fluorophenyl) -lH-pyrrolo [2,3- b] pyridin- Ethoxy-1- (4-fluorophenyl) -2-oxo-1,2-dihydropyridine-3- carboxamide,

11) 4-ethoxy-N- (3-fluoro-4- (3- (3- ) -1- (4-fluorophenyl) -2-oxo-1,2-dihydropyridine-3-carboxamide,

Pyrrolo [2,3-b] pyridin-4-yloxy) phenyl) -1H-pyrrolo [2,3- -1- (4-fluorophenyl) -2-oxo-1,2-dihydropyridine-3-carboxamide,

2,3-b] pyridin-4-yloxy) -3-fluorophenyl) -1H-pyrrolo [2,3- -1- (4-fluorophenyl) -2-oxo-1,2-dihydropyridine-3-carboxamide,

14) 4-Ethoxy-N- (3-fluoro-4- (3- ) Phenyl) -1- (4-fluorophenyl) -2-oxo-1,2-dihydropyridine-3-carboxamide,

LH-pyrrolo [2,3-b] pyridin-3-yl) -lH- pyrrolo [2,3- Yloxy) phenyl) -1- (4-fluorophenyl) -2-oxo-1,2-dihydropyridine-3-carboxamide,

LH-pyrrolo [2,3-b] pyridin-4-yl) - lH-pyrrolo [2,3- Yloxy) phenyl) -1- (4-fluorophenyl) -2-oxo-1,2-dihydropyridine-3-carboxamide,

17) 4-ethoxy-N- (3-fluoro-4- (3- (3- (1- methoxyethyl) phenyl) -lH- pyrrolo [2,3- b] pyridin- ) Phenyl) -1- (4-fluorophenyl) -2-oxo-1,2-dihydropyridine-3-carboxamide,

Pyrrolo [2,3-b] pyridin-4-yloxy) -3, 4-dihydro-2H-pyrrolo [ -Fluorophenyl) -1- (4-fluorophenyl) -2-oxo-1,2-dihydropyridine-3- carboxamide,

Pyrrolo [2,3-b] pyridin-4-yloxy) phenyl) - l- (3-fluoro- - (4-fluorophenyl) -2-oxo-1,2-dihydropyridine-3-carboxamide,

LH-pyrrolo [2,3-b] pyridin-3-yl) -lH-pyrrolo [2,3- Yloxy) phenyl) -1- (4-fluorophenyl) -2-oxo-1,2-dihydropyridine-3-carboxamide,

21) N- (4- (3- (3,4-dimethoxyphenyl) -lH-pyrrolo [2,3- b] pyridin- 4-yloxy) -3-fluorophenyl) -4- -1- (4-fluorophenyl) -2-oxo-1,2-dihydropyridine-3-carboxamide,

2,3-b] pyridin-4-yloxy) -3-fluorophenyl) -1H-pyrrolo [2,3- ) -1- (4-fluorophenyl) -2-oxo-1,2-dihydropyridine-3-carboxamide,

2,3-b] pyridin-4-yloxy) -3- (4-fluorophenyl) Fluorophenyl) -4-ethoxy-1- (4-fluorophenyl) -2-oxo-1,2-dihydropyridine-

2,3-b] pyridin-2-ylmethyl) -lH-pyrrolo [2,3- b] Yloxy) phenyl) -1- (4-fluorophenyl) -2-oxo-1,2-dihydropyridine-3-carboxamide,

25) N- (4- (3- (4-chlorophenyl) -lH-pyrrolo [2,3- b] pyridin- 4- yloxy) -3-fluorophenyl) -4- (4-fluorophenyl) -2-oxo-1,2-dihydropyridine-3-carboxamide,

26) 4-ethoxy-N- (3-fluoro-4- (3- ) -1- (4-fluorophenyl) -2-oxo-1,2-dihydropyridine-3-carboxamide,

27) 4-ethoxy-N- (3-fluoro-4- (3- ) Phenyl) -1- (4-fluorophenyl) -2-oxo-1,2-dihydropyridine-3-carboxamide,

28) N- (4- (3- (3-chloro-4-fluorophenyl) -lH-pyrrolo [2,3- b] pyridin- Ethoxy-1- (4-fluorophenyl) -2-oxo-1,2-dihydropyridine-3- carboxamide,

29) N- (4- (3- (3,4-difluorophenyl) -lH-pyrrolo [2,3- b] pyridin- 4-yloxy) -3-fluorophenyl) -4- (4-fluorophenyl) -2-oxo-1,2-dihydropyridine-3-carboxamide,

30) N- (3-Fluoro-4- (3-phenyl-lH-pyrrolo [2,3- b] pyridin- 1,1-dicarboxyamide,

31) N- (3-Fluoro-4- (3- (4-fluorophenyl) -lH- pyrrolo [2,3- b] pyridin- Phenyl) cyclopropane-1,1-dicarboxamide,

32) N- (3-fluoro-4- (3- (4-methoxyphenyl) -lH- pyrrolo [2,3- b] pyridin- Phenyl) cyclopropane-1,1-dicarboxamide, or

33) N- (3-Fluoro-4- (3- (3- (hydroxymethyl) phenyl) -lH- pyrrolo [2,3- b] pyridin- 4-fluorophenyl) cyclopropane-l, l-dicarboxamide.

The compounds of the present invention may exist in the form of pharmaceutically acceptable salts. As the salts, acid addition salts formed by pharmaceutically acceptable free acids are useful. The term "pharmaceutically acceptable salt" of the present invention means a concentration that has a relatively non-toxic and harmless effective action in a patient, wherein the adverse effect due to the salt is an adverse effect of the compound &Quot; means all organic or inorganic addition salts.

The acid addition salt can be prepared by a conventional method, for example, by dissolving the compound in an excess amount of an acid aqueous solution and precipitating the salt using a water-miscible organic solvent such as methanol, ethanol, acetone or acetonitrile. The same molar amount of the compound and the acid or alcohol (e.g., glycol monomethyl ether) in water may be heated and then the mixture may be evaporated to dryness, or the precipitated salt may be subjected to suction filtration.

As the free acid, organic acids and inorganic acids can be used. As the inorganic acids, hydrochloric acid, phosphoric acid, sulfuric acid, nitric acid, tartaric acid and the like can be used. Examples of the organic acids include methanesulfonic acid, p- toluenesulfonic acid, acetic acid, trifluoroacetic acid, maleic acid, succinic acid, oxalic acid, benzoic acid, tartaric acid, fumaric acid, mandelic acid, propionic acid, citric acid, lactic acid, glycollic acid, gluconic acid, galacturonic acid, glutamic acid, glutaric acid, glucuronic acid, aspartic acid, ascorbic acid, carbonic acid, vanillic acid, hydroiodic acid and the like can be used , But are not limited to these.

In addition, bases can be used to make pharmaceutically acceptable metal salts. The alkali metal salt or alkaline earth metal salt is obtained, for example, by dissolving the compound in an excess amount of an alkali metal hydroxide or alkaline earth metal hydroxide solution, filtering the non-soluble salt salt, and evaporating and drying the filtrate. At this time, it is pharmaceutically acceptable to produce sodium, potassium, or calcium salt, but not limited thereto. The corresponding silver salt can also be obtained by reacting an alkali metal or alkaline earth metal salt with a suitable silver salt (e.g., silver nitrate).

Pharmaceutically acceptable salts of the compounds of this invention include, unless otherwise indicated, salts of acidic or basic groups that may be present in the compounds of formula (I). For example, pharmaceutically acceptable salts may include sodium, calcium and potassium salts of hydroxy groups, and the other pharmaceutically acceptable salts of amino groups include hydrobromides, sulphates, sulphates, phosphates, hydrogen phosphates (Hydrogen phosphate, acetate, succinate, citrate, tartrate, lactate, mandelate, methanesulfonate (mesylate) and p-toluenesulfonate (tosylate) salts and the like, &Lt; / RTI &gt;

As the salt of the pyrrolopyridinyloxyphenylamide derivative of the present invention, there may be mentioned a pharmacologically acceptable salt of a pyrrolopyridinyloxyphenylamide derivative having the equivalent c-MET inhibitory activity as the pyrrolopyridinyloxyphenylamide derivative compound Any salt can be used without limitation.

The present invention also encompasses compounds of formula (I) and pharmaceutically acceptable salts thereof as well as possible solvates which may be prepared therefrom.

In addition, the compounds of the present invention may exist as tautomers, i.e. constitutional isomers, and all these isomers and mixtures thereof are included in the scope of the present invention.

Furthermore, the compounds of the present invention may exist as R or S isomers, racemates, diastereomer mixtures and individual diastereoisomers since they have asymmetric carbon centers in their substituents, and all these isomers and mixtures thereof Category.

For example, the compounds of the present invention can be synthesized from 4-chloro-lH-pyrrolo [2,3-b] pyridine and nitrophenol derivatives through a series of reactions represented by the following Reaction Scheme 1. However, the following reaction formula is only an exemplary method for preparing the compound of the present invention, and the method for preparing the compound of the present invention is not limited thereto, and can be carried out by using methods known in the art or by appropriately changing it.

[Reaction Scheme 1]

In the above reaction formula, the substituent is as defined above.

Specifically, Step 1 is a step of reacting 4-chloro-1H-pyrrolo [2,3-b] pyridine represented by Formula 2 with a nitrophenol derivative represented by Formula 3 to prepare a compound represented by Formula 4 Preferably, the reaction of step 1 is carried out in the presence of diisopropyl adenine, and the solvent may be diphenyl ether, but is not limited thereto.

Step 2 is a step for preparing a compound represented by the formula (5) containing a highly reactive iodo substituent by reacting the compound represented by the formula (4) obtained from the step 1 with N-iodosuccinimide for the later introduction of an additional substituent . Preferably, dichloromethane is used as a solvent for the reaction, but it is not limited thereto.

Step 3 is a step for producing a compound represented by the formula (6) by reacting a compound represented by the formula (5) with NH ₄ Cl to reduce the nitro group to an amine group. Preferably, the reaction of Step 3 may be carried out in the presence of Fe, and a mixed solvent of ethanol and water may be used as the solvent. However, it is not limited thereto.

Step 4 is a step of reacting a compound represented by the general formula (6) obtained from the above step 3 with a compound represented by the general formula (7) containing a carboxylic acid group to produce a compound represented by the general formula (8) by condensation reaction of an amino group and a carboxyl group. Preferably, the reaction of Step 4 is carried out in the presence of Et ₃ N and SOCl ₂ , and dichloromethane can be used as a solvent, but is not limited thereto.

Step 5 is a step of introducing a protecting group to the nitrogen atom of pyrrole in order to block the side reaction prior to the substitution reaction at the iodo position, and the compound represented by the formula (8) obtained in the above step 4 is reacted with Boc ₂ O To prepare a compound represented by the formula (9). Preferably, the reaction of Step 5 is carried out in the presence of Et ₃ N, and tetrahydrofuran may be used as a solvent, but is not limited thereto.

Step 6 is a step of reacting a compound represented by the formula (9) obtained from the step 5 with a boronic acid derivative (formula 10) to introduce a substituent to the iodo position and to remove Boc. Preferably, Pd (PPh _{3) 4} and K ₂ CO ₃ may be carried out in the presence, as a solvent, but to use toluene, ethanol and water mixed solvent is not limited thereto.

In another aspect, the present invention provides a composition for inhibiting c-MET activity comprising a compound represented by the formula (1) or a pharmaceutically acceptable salt thereof as an active ingredient.

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

Preferably, the compounds of the invention, their tautomers, or their pharmaceutically acceptable salts can effectively inhibit the activity of tyrosine kinase c-MET. The "c-MET" is one of the membrane receptors necessary for embryonic development and wound healing. The only known ligand of the MET receptor is hepatocyte growth factor (HGF). MET is normally expressed in epithelial lineage cells, but the expression of HGF may be restricted to the midplane tpvhdptj. Abnormal MET activation in cancer is associated with poor prognosis and abnormal activity MET is known to cause tumor growth, nutrient-induced angiogenesis and metastasis to other organs. MET is known to be uncontrolled in many human malignant tumors, including kidney, liver, stomach, breast and brain cancers.

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 usual restriction means in the developing animal. For example, the abnormal proliferative disease may be caused by an abnormal activity or an activity disorder of c-MET. Non-limiting examples of hyperproliferative diseases that can be prevented or treated with the pharmaceutical compositions of the present invention include but are not limited to cancer, diabetic retinopathy, retinopathy of prematurity, corneal transplant rejection, neovascular glaucoma, hypersensitivity, proliferative retinopathy, psoriasis, rheumatoid arthritis, Atherosclerosis, glomerulonephritis, glomerulonephritis, glomerulonephritis, diabetic nephropathy, malignant neuropathies, thrombotic microangiopathy, organ transplant rejection, and gonococcal disease. Preferably, the cancer may be lung cancer, gastric cancer, pancreatic cancer, colorectal cancer, ovarian cancer, renal cell cancer, prostate cancer or brain tumor. The cancer may be a hereditary papillary renal cell carcinoma (PRCC) The present invention relates to a pharmaceutical composition for the treatment and prophylactic treatment of PRCC of sporadic forms, head and neck cancer, squamous cell carcinoma, gastric carcinoma, pancreatic carcinoma, lung cancer, bladder cancer Solid tumors, such as breast cancer, leiomyosarcoma, glioblastoma, melanoma or alveolar soft part sarcoma, or metastases derived therefrom, .

As used herein, the term "prevention" means any action that inhibits or delays the development, spread and recurrence of an abnormal pheochromocytotic disease upon administration of the pharmaceutical composition, and "treatment" Means any act in which the symptoms of the disease are improved or beneficially altered.

Preferably, the pharmaceutical composition according to the present invention contains 0.1 to 75% by weight, more preferably 1 to 50% by weight, based on the total weight of the composition, of a compound represented by the formula (I) or a pharmaceutically acceptable salt thereof as an active ingredient By weight.

The composition of the present invention may further comprise a pharmaceutically acceptable carrier, diluent or excipient, and may be formulated into powders, granules, tablets, capsules, suspensions, emulsions, syrups, Aerosol and the like, injections of sterile injectable solutions, and the like, and they can be administered by various routes including oral administration or intravenous, intraperitoneal, subcutaneous, rectal, topical administration and the like. Examples of suitable carriers, excipients or diluents that may be included in such compositions include lactose, dextrose, sucrose, sorbitol, mannitol, xylitol, erythritol, maltitol, starch, acacia rubber, alginate, gelatin, calcium phosphate, calcium silicate, Cellulose, methylcellulose, microcrystalline cellulose, polyvinylpyrrolidone, water, methylhydroxybenzoate, propylhydroxybenzoate, talc, magnesium stearate and mineral oil. The composition of the present invention may further include a filler, an anti-coagulant, a lubricant, a wetting agent, a flavoring agent, an emulsifying agent, an antiseptic, and the like.

Solid formulations for oral administration include tablets, pills, powders, granules, capsules and the like, which may contain at least one excipient such as starch, calcium carbonate, sucrose, lactose, gelatin, Are mixed and formulated. In addition to simple excipients, lubricants such as magnesium stearate and talc may also be used.

Examples of the oral liquid preparation include suspensions, solutions, emulsions and syrups. In addition to water and liquid paraffin which are commonly used simple diluents, various excipients such as wetting agents, sweeteners, fragrances, preservatives and the like are included .

Formulations for parenteral administration include sterilized aqueous solutions, non-aqueous solutions, suspensions, emulsions, freeze-dried preparations, and suppositories. Examples of the suspending agent include propylene glycol, polyethylene glycol, vegetable oil such as olive oil, injectable ester such as ethyl oleate, and the like. The supplements of suppositories are etwesol, macrogol, tween 61. Cacao butter, laurin, glycerogelatin and the like can be used. On the other hand, injecting agents may include conventional additives such as solubilizers, isotonic agents, suspending agents, emulsifiers, stabilizers, preservatives and the like.

The composition of the present invention is administered in a pharmaceutically effective amount. The term "pharmaceutically effective amount " of the present invention means an amount sufficient to treat a disease at a reasonable benefit / risk ratio applicable to medical treatment and not causing side effects, The type of disease, the severity, the activity of the drug, the sensitivity to the drug, the method of administration, the time of administration, the route of administration and the rate of release, the duration of the treatment, the factors including the drugs used concurrently or concurrently and other factors well known in the medical arts . The composition of the present invention may be administered as an individual therapeutic agent or in combination with other therapeutic agents, and may be administered sequentially or simultaneously with conventional therapeutic agents, and may be administered singly or multiply. It is important to take into account all of the above factors and to administer the amount in which the maximum effect can be obtained in a minimal amount without side effects, which can be easily determined by those skilled in the art.

Specifically, the effective amount of the compound in the composition of the present invention may vary depending on the age, sex, and body weight of the patient, and is generally 1 to 1000 mg, preferably 5 to 200 mg per kg of body weight, It may be administered one to three times a day. However, the dosage may not be limited in any way because it may be increased or decreased depending on route of administration, severity of disease, sex, weight, age, and the like.

Preferably, the pharmaceutical composition of the present invention is administered for tumor therapy in combination with chemotherapy, radiation therapy, immunotherapy, hormone therapy, bone marrow transplantation, stem cell replacement therapy, other biological therapy, surgical intervention, . For example, they may be used as adjunctive therapies with other long-term treatment strategies, or may be used to maintain the patient's condition after tumor regression or chemoprevention therapy in severe patients.

Preferably, the pharmaceutical composition of the present invention may further comprise at least one active ingredient, wherein the active ingredient is an anti-proliferative compound such as an aromatase inhibitor, an anti-estrogen, a topoisomerase I inhibitor, a topoisomerase inhibitor, Microtubule active compounds, alkylated compounds, histone deacetylase inhibitors, compounds that induce cell differentiation processes, cyclooxygenase inhibitors, MMP inhibitors, mTOR inhibitors, anti-neoplastic anti-metabolites, Compounds targeting, decreasing or inhibiting the activity of a compound, protein or lipid kinase activity, anti-angiogenic compounds, protein or lipoprotein activity, gonadorelin agonists, anti-androgens, methionine aminopeptidase Antiproliferative antibodies, heparanase inhibitors, Ras tumorigenic isoforms, bisphosphonates, biological response modifiers, anti-proliferative antibodies, Inhibitors of telomerase, proteasome inhibitors, compounds used in the treatment of hematologic malignancies, compounds targeting, decreasing or inhibiting the activity of Flt-3, Hsp90 inhibitors, kinesin spindle protein inhibitors, MEK inhibitors, But are not limited to, leucovorin, EDG binding agents, anti-leukemia compounds, ribonucleotide reductase inhibitors, S-adenosyl methionine decarboxylase inhibitors, hemostatic steroids, corticosteroids, other chemotherapeutic compounds, .

Preferably, the active ingredient may be a known anti-cancer agent. Non-limiting examples of such anticancer agents include DNA alkylating agents such as mechloethamine, chlorambucil, phenylalanine, mustard, cyclophosphamide, But are not limited to, ifosfamide, carmustine (BCNU), lomustine (CCNU), streptozotocin, busulfan, thiotepa, cisplatin, (carboplatin); The anticancer antibiotics include dactinomycin (actinomycin D), doxorubicin (adriamycin), daunorubicin, idarubicin, mitoxantrone, Plicamycin, mitomycin C, and bleomycin; And plant alkaloids such as vincristine, vinblastine, paclitaxel, docetaxel, etoposide, teniposide, topotecan, And iridotecan and the like.

The present invention also provides a method for preventing or treating an abnormal pheochromocytosis in a subject, comprising administering the compound represented by the above-mentioned formula (1) or a pharmaceutically acceptable salt thereof to a subject in need thereof.

The term "individual" of the present invention means a monkey, a cow, a horse, a sheep, a pig, a chicken, a turkey, a quail, a cat, a dog, a mouse, a rat, a rabbit or a guinea Refers to all animals including pigs, and the pharmaceutical composition of the present invention can be administered to an individual to effectively prevent or treat the disease. The pharmaceutical composition of the present invention can be administered in parallel with existing therapeutic agents.

The term "administering" of the present invention means providing the patient with the desired substance in any suitable manner, and the administration route of the composition of the present invention may be administered through any conventional route so long as it can reach the target tissue have. But are not limited to, intraperitoneal, intravenous, intramuscular, subcutaneous, intradermal, oral, topical, intranasal, intrathecal, rectal. In addition, the pharmaceutical composition of the present invention may be administered by any device capable of moving the active substance to the target cell. The preferred modes of administration and formulations are intravenous, subcutaneous, intradermal, intramuscular, and drip injections. The injectable solution may be a non-aqueous solvent such as an aqueous solvent such as a physiological saline solution or a ring gel solution, a vegetable oil, a higher fatty acid ester (e.g., oleic acid), an alcohol (e.g., ethanol, benzyl alcohol, propylene glycol, glycerin, etc.) (For example, ascorbic acid, sodium hydrogen sulfite, sodium pyrophosphate, BHA, tocopherol, EDTA and the like), an emulsifier, a buffer for pH control, a microbial growth inhibitor And a pharmaceutical carrier such as a preservative (e.g., mercury nitrate, thimerosal, benzalkonium chloride, phenol, cresol, benzyl alcohol, etc.).

The term "therapeutically effective amount " used in combination with the active ingredient in the present invention means the amount of the pyrrolopyridinyloxyphenylamide derivative compound or a pharmaceutically acceptable salt thereof, which is effective in preventing or treating the target disease.

The pharmaceutical composition of the present invention may be used in the prevention or treatment of various diseases other than pyrrolopyridinyloxyphenylamide derivative compound or its pharmaceutically acceptable salt as an active ingredient depending on the kind of disease to be prevented or treated Lt; RTI ID = 0.0 &gt; of: &lt; / RTI &gt;

The novel pyrrolopyridinyloxyphenylamide derivative compounds of the present invention can effectively inhibit c-MET activity, and thus are useful for the prophylactic or therapeutic treatment of an abnormal pheochromocytosis caused by an abnormal activity of c-MET or an active disorder .

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.

Various methods for synthesizing the starting materials for synthesizing the compounds of the present invention are known. When the starting materials are commercially available, they can be purchased from a supplier. The reagent supply sources include, but are not limited to, Sigma-Aldrich, TCI, Wako, Kanto, Fluorchem, Acros, Alfa, Fluka, and Dae-Jung. In addition, all commercially available materials were used without further purification, except as otherwise provided.

First, in the following Examples, the compounds used in the synthesis were prepared according to the following Production Examples. The following preparation examples are examples of the compound represented by the general formula (7) in the above-mentioned Reaction formula 1 and can be appropriately changed in accordance with the structure of the example to be produced.

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

Step 1) Ethyl 4- Ethoxy -2-oxo-1,2- Dihydropyridine -3- Carboxylate  Produce

249.6 ml (1.32 mol) 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 and the mixture was stirred at 120 ° C for 12 hours or longer. After the reaction mixture solution was concentrated, 141 ml (0.55 mol) of DMF-DEA (N, N-dimethylformamide diethyl acetal) was added and the mixture was stirred at 70 ° C for 2 hours or longer. To the reaction mixture were added 500 ml of acetic acid and 60 ml of distilled water and refluxed for at least 12 hours. The reaction mixture was cooled to room temperature, and a saturated aqueous sodium hydrogencarbonate solution and water were added. And extracted with a 9: 1 mixed solvent of dichloromethane and methanol. The organic layer was dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. 100 ml of ethyl acetate was added and the mixture was concentrated. The resulting solid was filtered to give 37 g (26%) of the title 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) , &Lt; / RTI &gt; 1.22 (m, 6H).

Step 2) Ethyl 4- Ethoxy -1- (4- Fluorophenyl ) -2-oxo-1,2- Dihydropyridine -3-carboxylate

To 114 g (0.35 mol) of cesium carbonate was added 100 ml of N, N-dimethylformamide, and the flask was filled with nitrogen gas. The mixture was stirred for 10 minutes at room temperature, and 10.2 g (0.07 mol) of 8-hydroxyquinoline was dissolved in 200 ml of N, N-dimethylformamide. (0.05 mol) of copper iodide, 58.3 g (0.26 mol) of 4-fluoro-iodobenzene and 37 g (0.17 mol) of the compound obtained from the above step 1, and the mixture was stirred at 110 DEG C for 24 hours. After completion of the reaction, the reaction mixture was cooled to room temperature, ethyl acetate was added, and the mixture was 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 and used in the next step 3 without further purification.

Step 3) 4- Ethoxy -1- (4- Fluorophenyl ) -2-oxo-1,2- Dihydropyridine -3-carboxylic acid of  Produce

The compound obtained in the above step 2 was dissolved in 200 ml of ethanol, 400 ml of a 3N hydrochloric acid aqueous solution was added, and the mixture was stirred at 60 ° C for 24 hours. The resulting solid was filtered to obtain 21 g of the title compound 4-ethoxy-1- (4-fluorophenyl) -2-oxo-1,2-dihydropyridine-3-carboxylic acid (2-step yield: 43% .

^{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).

Example  1: N- (4- (3- (3-Amino-4- Fluorophenyl ) -1H- Pyrrolo [2,3-b] pyridine -4- Sake ) -3- Fluorophenyl )-4- Ethoxy -1- (4- Fluorophenyl ) -2-oxo-1,2- Dihydropyridine -3- Car Manufacture of amoxycillin

Step 1) 4- (2- Fluoro -4- Nitrophenoxy ) -1H- Pyrrolo [2,3-b] pyridine  Produce

5.7 g (36.05 mmol) of 2-fluoro-4-nitrophenol was added to 50 ml of diphenyl ether, 9 ml (49.16 mmol) of diisopropylethylamine was added thereto, and the mixture was stirred at room temperature for 30 minutes. 5 g (32.77 mmol) of 4-chloro-lH-pyrrolo [2,3-b] pyridine was added and stirred at 160 占 폚 for 18 hours. After cooling to room temperature, it was filtered through a celite pad, and washed with ethyl acetate. The filtrate was washed with a saturated aqueous sodium hydrogen carbonate solution, dried over anhydrous magnesium sulfate, filtered and concentrated. The residue was purified by silica gel column chromatography (30% ethyl acetate in n-hexane) to give 1.5 g (17%) of the title compound.

^{1 H NMR (400 MHz, DMSO} -d 6) δ 11.95 (s, 1H), 8.40 (dd, J = 2.8 and 8.0 Hz, 1H), 8.15-8.11 (m, 1H), 7.46-7.40 (m, 2H ), 6.72 (d, J = 5.2 Hz, 1 H), 6.25 - 6.24 (m, 1 H).

Step 2) 4- (2- Fluoro -4- Nitrophenoxy ) -3- Iodo -1H- Pyrrolo [2,3-b] pyridine  Produce

1.5 g (5.49 mmol) of 4- (2-fluoro-4-nitrophenoxy) -lH-pyrrolo [2,3-b] pyridine obtained in the above step 1 was added to 15 ml of dichloromethane, 1.24 g (5.49 mmol) of osadosimine imide was added thereto, followed by stirring at room temperature for 1 hour. The resulting solid was filtered to give 1.3 g (59%) of the title compound.

^{1 H NMR (400 MHz, DMSO} -d 6) δ 12.38 (s, 1H), 8.40 (dd, J = 2.8 and 10.4 Hz, 1H), 8.27 (d, J = 5.2 Hz, 1H), 8.12-8.08 ( 1H), 7.72 (d, J = 2.8 Hz, 1H), 7.19 (t, J = 8.8 Hz, 1H), 6.80 (d, J = 5.2 Hz, 1H).

Step 3) 3- Fluoro -4- (3- Iodo -1H- Pyrrolo [2,3-b] pyridine -4- Sake ) Preparation of aniline

1.3 g (3.26 mmol) of 4- (2-fluoro-4-nitrophenoxy) -3-iodo-lH-pyrrolo [2,3-b] pyridine obtained in the above Step 2 was dissolved in 10 ml of ethanol, 0.54 g (9.77 mmol) of iron (Fe) and 1.74 g (32.57 mmol) of ammonium chloride were added to the mixed solvent, and the mixture was heated to 100 DEG C and stirred for 1 hour. After completion of the reaction, the solution was filtered through a celite pad and washed with ethanol. The residue was concentrated and then re-suspended in distilled water and filtered to give 1.05 g (88%) of the title compound.

^{1 H NMR (400 MHz, DMSO} -d 6) δ 8.04 (d, J = 5.6 Hz, 1H), 7.57 (d, J = 2.8 Hz, 1H), 7.01 (t, J = 8.8 Hz, 1H), 6.53 (dd, J = 2.8 and 12.8 Hz, 1H), 6.45-6.42 (m, 2H), 6.18 (d, J = 5.6 Hz, 1H), 5.45 (bs, 2H).

Step 4) 4- Ethoxy -N- (3- Fluoro -4- (3- Iodo -1H- Pyrrolo [2,3-b] pyridine 4-yloxy) Phenyl ) -1- (4- Fluorophenyl ) -2-oxo-1,2- Dihydropyridine -3- Carboxamide  Produce

0.63 g (2.28 mmol) of 4-ethoxy-1- (4-fluorophenyl) -2-oxo-1,2-dihydropyridine-3-carboxylic acid obtained in Preparation Example 1, , 0.54 g (4.55 mmol) of thionyl chloride was added, and the mixture was stirred at room temperature for 1 hour. When all the mixture dissolved, the mixture was concentrated under reduced pressure (reaction vessel A). To another reaction vessel were added 10 ml of dichloromethane as solvent and 3-fluoro-4- (3-iodo-lH-pyrrolo [2,3-b] pyridin-4-yloxy) aniline 0.56 g (1.52 mmol) of triethylamine and 0.30 g (3.03 mmol) of triethylamine, and the mixture was stirred for 0.5 hour (reaction vessel B). 10 ml of dichloromethane was added to the concentrated mixture of the reaction vessel A and stirred, and this was slowly added dropwise to the reaction vessel B. After further stirring at room temperature for 1.5 hours, it was washed with distilled water and a saturated aqueous solution of sodium hydrogencarbonate. Dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure to give a residue. The product obtained was used in the subsequent reaction without further purification.

Step 5) tert -Butyl 4- (4- (4- Ethoxy -1- (4- Fluorophenyl ) -2-oxo-1,2- Dihydropyridine -3- Carboxamido )-2- Fluorophenoxy ) -3- Iodo -1H- Pyrrolo [2,3-b] pyridine -1-car Decylate Manufacturing

Pyrrolo [2,3-b] pyridin-4-yloxy) phenyl) -1- (3-fluoro- (4-fluorophenyl) -2-oxo-1,2-dihydropyridine-3-carboxamide was dissolved in 10 ml of THF and 0.36 g (1.66 mmol) of di-tert-butyl dicarbonate and 0.17 g (1.66 mmol) of 4-dimethylaminopyridine and 2 g (0.02 mmol) of 4-dimethylaminopyridine were added, followed by stirring at room temperature for 20 hours. After completion of the reaction, the reaction mixture was extracted with dichloromethane and distilled water, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The filtrate was purified by silica gel column chromatography (60% ethyl acetate in n-hexane) to give 0.43 g (39%, step 4 and 5 overall yield) of the title compound.

^{1 H NMR (400 MHz, DMSO} -d 6) δ 11.63 (s, 1H), 8.30 (d, J = 5.6 Hz, 1H), 7.93 (dd, J = 2.8 and 12.4 Hz, 1H), 7.71 (s, 1H), 7.53 (d, J = 4.8 Hz, 1H), 7.37-7.29 (m, 3H), 7.26-7.21 (m, 2H), 7.14 (t, J = 8.8 Hz, 1H), 6.45-6.43 (m , 1H), 6.36 (d, J = 8.0 Hz, 1H), 4.36 (q, J = 6.8 Hz, 2H), 1.65 (s, 9H), 1.60 (t, J = 6.8 Hz, 3H).

Step 6) N- (4- (3- (3-Amino-4- Fluorophenyl ) -1H- Pyrrolo [2,3-b] pyridine -4- Sake ) -3- Fluorophenyl )-4- Ethoxy -1- (4- Fluorophenyl ) -2-oxo-1,2- Dihydropyridine -3-car Hexamid Manufacturing

(4-ethoxy-1- (4-fluorophenyl) -2-oxo-1,2-dihydropyridine-3-carboxamido) -2 (4-fluorophenoxy) -3-iodo-lH-pyrrolo [2,3-b] pyridine- 1-carboxylate was dissolved in a mixed solvent of toluene / ethanol / distilled water dissolved in 2.5 ml and phenylboronic acid to 3-amino-4-fluoro-16 mg (0.10 mmol), Pd (PPh 3) 2 Cl 2 5 mg (0.007 mmol), sodium carbonate 22 mg (0.21 mmol), lithium chloride 9 mg (0.21 mmol), and the mixture was stirred at 85 ° C for 2 hours. It was cooled to room temperature and extracted with dichloromethane and water. Dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. Prepare the residue. Separated by TLC _{(CH 2 Cl 2 / MeOH =} 30/1) to give the title compound N- (4- (3- (3- amino-4-fluoro-phenyl) -1H- pyrrolo [2,3-b] pyridine (36%) of 4-ethoxy-1- (4-fluorophenyl) -2-oxo-1,2-dihydropyridine- ).

^{1 H NMR (400 MHz, CDCl} 3) δ 11.54 (s, 1H), 10.77 (s, 1H), 8.11 (d, J = 5.6 Hz, 1H), 7.90 (dd, J = 2.4 and 12.8 Hz, 1H) , 7.46 (d, J = 8.0 Hz 1H), 7.34-7.31 (m, 2H), 7.27 (s, 1H), 7.23-7.19 (m, 3H), 7.16 (dd, J = 2.0 and 8.4 Hz, , 7.05-7.14 (m, 3H), 6.36 (d, J = 5.6 Hz, 1H), 6.32 (d, J = 8.0 Hz 1H), 4.32 (q, J = 7.2 Hz, 2H), 1.55 (t, J = 7.2 Hz, 3 H).

Example  2: N- (4- (3- (3- Aminophenyl ) -1H- Pyrrolo [2,3-b] pyridine -4- Sake ) -3- Fluorophenyl )-4- Ethoxy -1- (4- Fluorophenyl ) -2-oxo-1,2- Dihydropyridine -3- Carboxyamide  Produce

The title compound was synthesized by a method similar to that of Example 1, except that 3-aminophenylboronic acid was used instead of 3-amino-4-fluorophenylboronic acid.

^{1 H NMR (400 MHz, CDCl} 3) δ 11.52 (s, 1H), 10.62 (s, 1H), 8.10 (d, J = 5.6 Hz, 1H), 7.89 (dd, = 2.4 and 12.4 Hz, 1H), 7.12 (d, J = 8.0 Hz , 1H), 7.34-7.31 (m, 3H), 7.26-7.19 (m, 3H), 7.15-7.08 (m, 3H), 7.03 (t, J = 8.8 Hz, 1H) , 6.58 (m, 1H), 6.36 (d, J = 5.6 Hz, 1H), 6.31 (J = 8.0 Hz, 1H), 4.32 (q, J = 6.8 Hz, 2H), 1.55 (t, J = 6.8 Hz , 3H).

Example  3: N- (4- (3- (3-Amino-2- Methylphenyl ) -1H- Pyrrolo [2,3-b] pyridine -4- Sake ) -3- Fluorophenyl )-4- Ethoxy -1- (4- Fluorophenyl ) -2-oxo-1,2- Dihydropyridine -3- Carboxy Preparation of amide

The title compound was synthesized by a method similar to that of Example 1, except that 3-amino-2-methylphenylboronic acid was used instead of 3-amino-4-fluorophenylboronic acid.

^{1 H NMR (400 MHz, DMSO} -d 6) δ 11.80 (s, 1H), 10.50 (s, 1H), 8.03 (d, J = 5.6 Hz, 1H), 7.84 (d, J = 8.0 Hz, 1H) , 7.81 (dd, J = 2.4 and 13.2 Hz, 1H), 7.47-7.44 (m, 2H), 7.38-7.34 (m, 2H), 7.36 (t, J = 8.8 Hz, 1H), 7.23 (d, J = 2.4 Hz, 1H), 7.18 (t, J = 8.8 Hz, 1H), 6.83 (t, J = 7.6 Hz, 1H), 6.56 (d, J = 7.6 Hz, 1H), 6.50 (d, J = 7.6 Hz, 1H), 6.18 (d , J = 4.8 Hz, 1H), 4.75 (bs, 2H), 4.24 (q. J = 7.2 Hz, 2H), 2.00 (s, 3H), 1.29 (t, J = 7.2 Hz, 3H).

Example  4: N- (4- (3- (3-Amino-4- Chlorophenyl ) -1H- Pyrrolo [2,3-b] pyridine -4- Sake ) -3- Fluorophenyl )-4- Ethoxy -1- (4- Fluorophenyl ) -2-oxo-1,2- Dihydropyridine -3- Carbop Preparation of cyamide

The title compound was synthesized by a method similar to that of Example 1, except that 3-amino-4-chlorophenylboronic acid was used instead of 3-amino-4-fluorophenylboronic acid.

^{1 H NMR (400 MHz, CDCl} 3) δ 11.55 (s, 1H), 10.09 (s, 1H), 8.13 (d, J = 5.6 Hz, 1H), 7.92 (dd, J = 2.4 and 12.8 Hz, 1H) , 7.49 (d, J = 8.0 Hz, 1H), 7.37-7.32 (m, 3H), 7.30 (m, 1H), 7.25-7.20 (m, 4H), 7.17 (d, J = 2.0 Hz, 1H), 7.05 (t, J = 8.8 Hz , 1H), 7.02 (dd, J = 2.4 and 8.4 Hz, 1H), 6.38 (d, J = 5.2 Hz, 1H), 6.34 (d, J = 7.6 Hz, 1H), 4.35 (q, J = 7.2 Hz, 2H), 4.00 (br s, 2H), 1.58 (t, J = 7.2 Hz, 3H).

Example  5: N- (4- (3- (3- (1H- Pyrazole -1 day) Phenyl ) -1H- Pyrrolo [2,3-b] pyridine -4- Sake ) -3- Fluorophenyl )-4- Ethoxy -1- (4- Fluorophenyl ) -2-oxo-1,2- Dihydropyridine -3- Carbop Preparation of cyamide

The title compound was synthesized by a method similar to that of Example 1, except for using 3- (1H-pyrazol-1-yl) phenylboronic acid instead of 3-amino-4-fluorophenylboronic acid.

^{1 H NMR (400 MHz, CDCl} 3) δ 11.57 (s, 1H), 10.77 (s, 1H), 8.15 (d, J = 5.6 Hz, 1H), 8.06 (t, J = 1.6 Hz, 1H), 7.95 (M, 2H), 7.69 (d, J = 1.6 Hz, 1H), 7.65-7.63 (m, 2H), 7.48-7.41 (m, 3H), 7.08 ( t, J = 8.8 Hz, 1H), 6.41 (t, J = 2.0 Hz, 1H), 6.38 (d, J = 5.6 Hz, 1H), 6.33 (d, J = 7.6 Hz , 1H), 4.33 (q, J = 7.2 Hz, 1H), 1.56 (t, J = 7.2 Hz, 3H).

Example  6: N- (4- (3- (3-Amino-4- Methylphenyl ) -1H- Pyrrolo [2,3-b] pyridine -4- Sake ) -3- Fluorophenyl )-4- Ethoxy -1- (4- Fluorophenyl ) -2-oxo-1,2- Dihydropyridine -3- Carboxy Preparation of amide

The title compound was synthesized by a method similar to that of Example 1, except that 3-amino-4-methylphenylboronic acid was used instead of 3-amino-4-fluorophenylboronic acid.

^{1 H NMR (400 MHz, CDCl} 3) δ 11.51 (s, 1H), 9.85 (s, 1H), 8.10 (d, J = 5.6 Hz, 1H), 7.90 (dd, J = 2.4 and 12.8 Hz, 1H) , 7.48 (d, J = 8.0 Hz, 1H), 7.36-7.32 (m, 2H), 7.28-7.20 (m, 4H), 7.09-7.03 (m, 4H), 6.35 (t, J = 6.4 Hz, 1H ), 4.34 (q, J = 7.2 Hz, 1H), 2.17 (s, 3H), 1.57 (t, J = 7.2 Hz, 3H).

Example  7: N- (4- (3- (3- ( Cyanomethyl ) Phenyl ) -1H- Pyrrolo [2,3-b] pyridine -4- Sake ) -3- Fluorophenyl )-4- Ethoxy -1- (4- Fluorophenyl ) -2-oxo-1,2- Dihydropyridine -3- Carboxy Manufacture of Mead

The title compound was synthesized by a method similar to that of Example 1, except that 3- (cyanomethyl) phenylboronic acid was used instead of 3-amino-4-fluorophenylboronic acid.

^{1 H NMR (400 MHz, CDCl} 3) δ 11.54 (s, 1H), 10.69 (s, 1H), 8.15 (d, J = 5.6 Hz, 1H), 7.90 (dd, J = 2.4 and 12.4 Hz, 1H) , 7.67-7.65 (m, 2H), 7.49 (d, J = 8.0 Hz, 1H), 7.38-7.32 (m, 4H), 7.24-7.20 (m, 4H), 7.05 (t, J = 8.8 Hz, 1H ), 6.40 (d, J = 5.6 Hz, 1H), 6.34 (d, J = 8.0 Hz, 1H), 4.34 (q, J = 7.2 Hz, 1H), 3.75 (s, 2H), 1.57 (t, J = 7.2 Hz, 3 H).

Example  8: 4- Ethoxy -N- (3- Fluoro -4- (3- (2- Fluoro -5- Nitrophenyl ) -1H- Pyrrolo [2,3-b] pyridine -4- Sake ) Phenyl ) -1- (4- Fluorophenyl ) -2-oxo-1,2- Dihydropyridine -3- Carbop Preparation of cyamide

The title compound was synthesized by a method similar to that of Example 1, except that 2-fluoro-5-nitrophenylboronic acid was used instead of 3-amino-4-fluorophenylboronic acid.

^{1 H NMR (400 MHz, CDCl} 3) δ 11.65 (s, 1H), 11.54 (s, 1H), 8.68 (m, 1H), 8.19 (d, J = 5.6 Hz, 1H), 8.13-8.09 (m, (M, 2H), 7.32-7.18 (m, 1H), 7.89 (dd, J = 2.4 and 12.4 Hz, , 4H), 7.12 (t, J = 8.8 Hz, 1H), 6.39 (d, J = 5.6 Hz, 1H), 6.34 (d, J = 8.0 Hz, 1H), 4.34 (q, J = 7.2 Hz, 1H ), 1.56 (t, J = 7.2 Hz, 3 H).

Example  9: 4- Ethoxy -N- (3- Fluoro -4- (3- (4- Methoxy -3- Nitrophenyl ) -1H- Pyrrolo [2,3-b] pyridine -4- Sake ) Phenyl ) -1- (4- Fluorophenyl ) -2-oxo-1,2- Dihydropyridine -3- Carboxy Preparation of amide

The title compound was synthesized by a method similar to that of Example 1, except that 4-methoxy-3-nitrophenylboronic acid was used instead of 3-amino-4-fluorophenylboronic acid.

^{1 H NMR (400 MHz, CDCl} 3) δ 11.56 (s, 1H), 10.95 (s, 1H), 8.20 (d, J = 2.4 Hz, 1H), 8.15 (d, J = 5.6 Hz, 1H), 7.94 (M, 2H), 7.49 (d, J = 8.0 Hz, 1 H), 7.36-7.33 (m, 3H), 7.27-7. (m, 2H), 4.34 (q, J = 7.2 Hz, 1H), 3.96 (s, 3H), 1.56 (t, J = 7.2 Hz, 3H).

Example  10: N- (4- (3- (5-Amino-2- Fluorophenyl ) -1H- Pyrrolo [2,3-b] pyridine Yloxy) -3- Fluorophenyl )-4- Ethoxy -1- (4- Fluorophenyl ) -2-oxo-1,2- Dihydropyridine -3- Car Manufacture of amoxycillin

The title compound was synthesized by a method similar to that of Example 1, except that 5-amino-2-fluorophenylboronic acid was used instead of 3-amino-4-fluorophenylboronic acid.

^{1 H NMR (400 MHz, CDCl} 3) δ 11.51 (s, 1H), 7.89 (dd, J = 2.4 and 12.4 Hz, 1H), 7.16 (d, J = 8.0 Hz, 1H), 7.38-7.34 (m, J = 8.8 Hz, 1 H), 6.98 (dd, J = 2.8 and 6.4 Hz, 1H), 6.88 (t, J = 9.2 Hz, 1H), 7.25-7.21 6.55-6.51 (m, 1H), 6.42 (m, 1H), 6.35 (d, J = 7.2 Hz, 1H), 4.35 (q, J = 7.2 Hz, 1H), 1.57 (t, J = 7.2 Hz, 3H ).

Example  11: 4- Ethoxy -N- (3- Fluoro -4- (3- (3- ( Hydroxymethyl ) Phenyl ) -1H- Pyrrolo [2,3-b] pyridine -4- Sake ) Phenyl ) -1- (4- Fluorophenyl ) -2-oxo-1,2- Dihydropyridine -3- Carboxy Preparation of amide

The title compound was synthesized by a method similar to that of Example 1, except that 3- (hydroxymethyl) phenylboronic acid was used instead of 3-amino-4-fluorophenylboronic acid.

^{1 H NMR (400 MHz, CDCl} 3) δ 8.00 (d, J = 5.6 Hz, 1H), 7.79 (dd, J = 2.4 and 12.8 Hz, 1H), 7.60-7.55 (m, 2H), 7.47 (d, J = 8.0 Hz, 1H), 7.32-7.28 (m, 4H), 7.21-7.16 (m, 4H), 6.98 (t, J = 8.8 Hz, 1H), 6.32 (d, J = 8.0 Hz, 1H), 6.31 (d, J = 5.2 Hz , 1H), 4.61 (s, 2H), 4.29 (q, J = 7.2 Hz, 2H), 1.50 (t, J = 7.2 Hz, 3H).

Example  12: 4- Ethoxy -N- (3- Fluoro -4- (3- (3- ( Methyl amino ) Phenyl ) -1H- Pyrrolo [2,3-b] pyridine -4- Sake ) Phenyl ) -1- (4- Fluorophenyl ) -2-oxo-1,2- Dihydropyridine -3- Carboxy Manufacture of Mead

The title compound was synthesized by a method similar to that of Example 1, except that 3- (methylamino) phenylboronic acid was used instead of 3-amino-4-fluorophenylboronic acid.

^{1 H NMR (400 MHz, CDCl} 3) δ 11.53 (s, 1H), 10.10 (s, 1H), 8.11 (d, J = 5.6 Hz, 1H), 7.90 (dd, J = 2.4 and 12.8 Hz, 1H) , 7.48 (d, J = 8.0 Hz 1H), 7.36-7.31 (m, 3H), 7.247-7.10 (m, 4H), 7.07-7.00 (m, 3H), 6.52 (dd, J = 1.6 and 8.0 Hz, 1H), 6.52 (d, J = 1.6 Hz, 1H), 6.34-6.32 (m, 2H), 4.34 (q, J = 7.2 Hz, 2H), 2.80 (s, 3H), 1.56 (t, J = 7.2 Hz, 3H).

Example  13: 4- Ethoxy -N- (4- (3- (3- ( Ethylamino ) Phenyl ) -1H- Pyrrolo [2,3-b] pyridine Yloxy) -3- Fluorophenyl ) -1- (4- Fluorophenyl ) -2-oxo-1,2- Dihydropyridine -3- Carboxy Manufacture of Mead

The title compound was synthesized by a method similar to that of Example 1, except that 3- (ethylamino) phenylboronic acid was used instead of 3-amino-4-fluorophenylboronic acid.

^{1 H NMR (400 MHz, CDCl} 3) δ 11.56 (s, 1H), 10.03 (s, 1H), 8.13 (d, J = 5.6 Hz, 1H), 7.91 (dd, J = 2.4 and 12.8 Hz, 1H) , 7.49 (d, J = 8.0 Hz 1H), 7.36-7.34 (m, 3H), 7.26-7.20 (m, 3H), 7.15 (t, J = 7.6 Hz, 3H), 7.07-7.01 , 6.53-6.50 (m, 1H), 6.34-6.33 (m, 2H), 4.34 (q, J = 7.2 Hz, 2H), 3.14 (q, J = 7.2 Hz, 2H), 1.55 (t, J = 7.2 Hz, 3H), 1.19 (t, J = 7.2 Hz, 3H).

Example  14: 4- Ethoxy -N- (3- Fluoro -4- (3- (3- (1- Hydroxyethyl ) Phenyl ) -1H- &lt; / RTI & &Lt; RTI ID = 0.0 &gt; [2,3-b] &Lt; RTI ID = Sake ) Phenyl ) -1- (4- Fluorophenyl ) -2-oxo-1,2- Dihydropyridine -3- Carbop Preparation of cyamide

The title compound was synthesized by a method similar to that of Example 1, except for using 3- (1-hydroxyethyl) phenylboronic acid instead of 3-amino-4-fluorophenylboronic acid.

^{1 H NMR (400 MHz, CDCl} 3) δ 11.50 (s, 1H), 10.30 (s, 1H), 8.11 (d, J = 5.6 Hz, 1H), 7.86 (dd, J = 2.4 and 12.8 Hz, 1H) , 7.72 (s, 1H), 7.58 (d, J = 8.0 Hz, 1H), 7.47 (d, J = 7.6 Hz, 1H), 7.35-7.31 (m, 4H), 7.28-7.19 7.01 (t, J = 8.8 Hz , 1H), 6.36 (d, 5.6 Hz, 1H), 6.33 (d, J = 8.0 Hz, 1H), 4.89 (q, J = 6.4 Hz, 1H), 4.33 (q, J = 7.2 Hz, 2H), 1.56 (t, J = 7.2 Hz, 3H), 1.46 (d, J = 6.4 Hz, 3H).

Example  15: 4- Ethoxy -N- (3- Fluoro -4- (3- (3- (2-hydroxypropan-2-yl) Phenyl ) -1H- &lt; / RTI & &Lt; RTI ID = 0.0 &gt; [2,3-b] &Lt; RTI ID = Sake ) Phenyl ) -1- (4- Fluorophenyl ) -2-oxo-1,2- Dihydropyridine -3-car Hexamid Manufacturing

The title compound was synthesized by a method similar to that of Example 1, except for using 3- (2-hydroxypropane-2-yl) phenylboronic acid instead of 3-amino-4-fluorophenylboronic acid.

^{1 H NMR (400 MHz, CDCl} 3) δ 11.52 (s, 1H), 10.05 (s, 1H), 8.12 (d, J = 5.2 Hz, 1H), 7.91-7.87 (m, 2H), 7.56-7.53 ( J = 8.0 Hz, 1H), 7.43-7.40 (m, 1H), 7.36-7.32 (m, 4H), 7.24-7.20 (m, 3H), 7.03 (t, J = 8.8 Hz, 1H), 6.36-6.33 (m, 2H), 4.35 (q, J = 7.2 Hz, 2H), 1.59-1.54 (m, 9H);

MS: 637 [M + H] &lt; ⁺ &gt;.

Example  16: 4- Ethoxy -N- (3- Fluoro -4- (3- (1- methyl -1H- Pyrazole -4-yl) -1H- Pyrrolo [2,3-b] pyridine -4- Sake ) Phenyl ) -1- (4- Fluorophenyl ) -2-oxo-1,2- Dihydropyridine -3- Carbop Preparation of cyamide

The title compound was synthesized by a method similar to that of Example 1, except that 1-methyl-1H-pyrazol-4-ylboronic acid was used instead of 3-amino-4-fluorophenylboronic acid.

^{1 H NMR (400 MHz, CDCl} 3) δ 11.59 (s, 1H), 9.92 (s, 1H), 8.10 (d, J = 5.6 Hz, 1H), 7.94 (dd, J = 2.4 and 12.8 Hz, 1H) , 7.77 (s, 1H), 7.73 (s, 1H), 7.50 (d, J = 8.0 Hz, 1H), 7.37-7.29 (m, 4H), 7.27-7.21 (m, 2H), 7.11 (t, J = 8.8 Hz, 1H), 6.37-6.33 (m, 2H), 4.34 (q, J = 7.2 Hz, 2H), 3.90 (s, 3H), 1.58 (t, J = 7.2 Hz, 3H).

Example  17: 4- Ethoxy -N- (3- Fluoro -4- (3- (3- (1- Methoxyethyl ) Phenyl ) -1H- Pyrrolo [2,3-b] pyridine -4- Sake ) Phenyl ) -1- (4- Fluorophenyl ) -2-oxo-1,2- Dihydropyridine -3- Carboxy Preparation of amide

The title compound was synthesized by a method similar to that of Example 1, except for using 3- (1-methoxyethyl) phenylboronic acid instead of 3-amino-4-fluorophenylboronic acid.

^{1 H NMR (400 MHz, CDCl} 3) δ 11.54 (s, 1H), 9.42 (s, 1H), 8.12 (d, J = 5.6 Hz, 1H), 7.90 (dd, J = 2.4 and 12.8 Hz, 1H) , 7.70 (m, 1H), 7.60-7.58 (m, 1H), 7.50 (d, J = 8.0 Hz, 1H), 7.37-7.33 (m, 4H), 7.26-7.20 , J = 8.8 Hz, 1H) , 6.43-6.35 (m, 2H), 4.36 (q, J = 7.2 Hz, 2H), 4.28 (q, J = 6.4 Hz, 2H), 3.14 (s, 3H), 1.58 (t, J = 7.2 Hz, 3H), 1.40 (d, J = 6.4 Hz, 1H).

Example  18: 4- Ethoxy -N- (4- (3- (1-ethyl-1H- Pyrazole -4-yl) -1H- Pyrrolo [2,3-b] pyridine -4- Sake ) -3- Fluorophenyl ) -1- (4- Fluorophenyl ) -2-oxo-1,2- Dihydropyridine -3- Carbop Preparation of cyamide

The title compound was synthesized by a method similar to that of Example 1, except that 1-ethyl-1H-pyrazol-4-ylboronic acid was used instead of 3-amino-4-fluorophenylboronic acid.

¹ H NMR (400 MHz, CDCl ₃ )? 11.59 (s, IH), 10.07 (s, IH), 8.11 (d, J = 5.6 Hz, 1H), 7.95 dd, J = 2.4 and 12.8 Hz, 7.79 (m, 2H), 7.50 (d, J = 8.0 Hz, 1H), 7.37-7.33 (m, 3H), 7.29-7.21 (m, 4H), 7.12 (t, J = 8.8 Hz, 1H), 6.37 -6.35 (m, 2H), 4.36 (q, J = 7.2 Hz, 2H), 4.16 (q, J = 7.2 Hz, 2H), 1.58 (t, J = 7.2 Hz, 3H), 1.48 (t, J = 7.2 Hz, 3 H).

Example  19: 4- Ethoxy -N- (3- Fluoro -4- (3- (4- Methoxyphenyl ) -1H- Pyrrolo [2,3-b] pyridine -4- Sake ) Phenyl ) -1- (4- Fluorophenyl ) -2-oxo-1,2- Dihydropyridine -3- Carboxyamide Manufacturing

The title compound was synthesized by a method similar to that of Example 1, except that 4-methoxyphenylboronic acid was used instead of 3-amino-4-fluorophenylboronic acid.

^{1 H NMR (400 MHz, CDCl} 3) δ 11.56 (s, 1H), 10.72 (s, 1H), 8.10 (d, J = 5.6 Hz, 1H), 7.89 (dd, J = 2.4 and 12.8 Hz, 1H) , 7.65-7.61 (m, 2H), 7.46 (d, J = 8.0 Hz, 1H), 7.34-7.18 (m, 6H), 7.05 (t, J = 8.8 Hz, 1H), 6.92-6.89 ), 6.33-6.29 (m, 2H), 4.31 (q, J = 7.2 Hz, 2H), 3.81 (s, 1H), 1.54 (t, J = 7.2 Hz, 3H).

Example  20: 4- Ethoxy -N- (3- Fluoro -4- (3- (3 - ((2- Methoxyethoxy ) methyl ) Phenyl ) -1H- &lt; / RTI & &Lt; RTI ID = 0.0 &gt; [2,3-b] &Lt; RTI ID = Sake ) Phenyl ) -1- (4- Fluorophenyl ) -2-oxo-1,2- Dihydropyridine -3-car Hexamid Manufacturing

The title compound was synthesized by a method similar to that of Example 1, except that 3 - ((2-methoxyethoxy) methyl) phenylboronic acid was used instead of 3-amino-4-fluorophenylboronic acid.

^{1 H NMR (400 MHz, CDCl} 3) δ 11.58 (s, 1H), 10.87 (s, 1H), 8.14 (d, J = 5.6 Hz, 1H), 7.92 (dd, J = 2.4 and 12.8 Hz, 1H) , 7.72 (s, IH), 7.64 (d, J = 8.0 Hz, IH), 7.49 (d, J = 8.0 Hz, IH), 7.37-7.32 (m, 4H), 7.28-7.20 7.07 (t, J = 8.8 Hz , 1H), 6.37-6.33 (m, 2H), 4.59 (s, 2H), 4.35 (q, J = 7.2 Hz, 2H), 3.58-3.47 (m, 4H), 3.35 (s, 2H), 1.57 (t, J = 7.2 Hz, 3H).

Example  21: N- (4- (3- (3,4- Dimethoxyphenyl ) -1H- Pyrrolo [2,3-b] pyridine -4- Sake ) -3- Luo Lope Yl) -4- Ethoxy -1- (4- Fluorophenyl ) -2-oxo-1,2- Dihydropyridine -3-car Fuxia Manufacture of Mead

The title compound was synthesized by a method similar to that of Example 1, except that 3,4-dimethoxyphenylboronic acid was used instead of 3-amino-4-fluorophenylboronic acid.

^{1 H NMR (400 MHz, CDCl} 3) δ 11.56 (s, 1H), 10.56 (s, 1H), 8.11 (d, J = 5.6 Hz, 1H), 7.92 (dd, J = 2.4 and 12.8 Hz, 1H) , 7.48 (d, J = 8.0 Hz, 1H), 7.37 (d, J = 2.0 Hz, 1H), 7.36-7.32 (m, 3H), 7.26-7.18 (m, 4H), 7.05 (t, J = 8.8 Hz, 1H), 6.88 (d , J = 8.8 Hz, 1H), 6.34-6.32 (m, 2H), 4.34 (q, J = 7.2 Hz, 2H), 3.88 (s, 3H), 3.83 (s, 3H ), 1.56 (t, J = 7.2 Hz, 3 H).

Example  22: 4- Ethoxy -N- (4- (3- (3- ( Ethylsulfonyl ) Phenyl ) -1H- Pyrrolo [2,3-b] pyridine Yloxy) -3- Fluorophenyl ) -1- (4- Fluorophenyl ) -2-oxo-1,2- Dihydropyridine -3- Carboxy Manufacture of Mead

The title compound was synthesized by a method similar to that of Example 1, except that 3- (ethylsulfonyl) phenylboronic acid was used instead of 3-amino-4-fluorophenylboronic acid.

^{1 H NMR (400 MHz, CDCl} 3) δ 11.58 (s, 1H), 10.87 (s, 1H), 8.14 (d, J = 5.6 Hz, 1H), 7.92 (dd, J = 2.4 and 12.8 Hz, 1H) , 7.72 (s, IH), 7.64 (d, J = 8.0 Hz, IH), 7.49 (d, J = 8.0 Hz, IH), 7.37-7.32 (m, 4H), 7.28-7.20 7.07 (t, J = 8.8 Hz , 1H), 6.37-6.33 (m, 2H), 4.59 (s, 2H), 4.35 (q, J = 7.2 Hz, 2H), 3.58-3.47 (m, 4H), 3.35 (s, 2H), 1.57 (t, J = 7.2 Hz, 3H).

Example  23: N- (4- (3- (1- ( Cyanomethyl ) -1H- Pyrazole -4-yl) -1H- Pyrrolo [2,3-b] pyridine -4- Sake ) -3- Fluorophenyl )-4- Ethoxy -1- (4- Fluorophenyl ) -2-oxo-1,2- Dihydropyridine -3-car Hexamid Manufacturing

The title compound was synthesized by a method similar to that of Example 1, except that 1- (cyanomethyl) -1H-pyrazol-4-ylboronic acid was used instead of 3-amino-4-fluorophenylboronic acid .

^{1 H NMR (400 MHz, CDCl} 3) δ 11.64 (s, 1H), 9.93 (s, 1H), 8.10 (d, J = 5.2 Hz, 1H), 7.97-7.93 (m, 1H), 7.88-7.85 ( m, 2H), 7.52 (d , J = 8.0 Hz, 1H), 7.38-7.35 (m, 3H), 7.30 (s, 1H), 7.24-7.22 (m, 2H), 7.12 (t, J = 8.8 Hz J = 7.2 Hz, 2H), 1.59 (t, J = 6.8 Hz, 3H).

Example  24: 4- Ethoxy -N- (3- Fluoro -4- (3- (1- ( Methoxymethyl ) -1H- Pyrazole -4-yl) -1H- &Lt; RTI ID = 0.0 &gt; [2,3-b] &Lt; RTI ID = Sake ) Phenyl ) -1- (4- Fluorophenyl ) -2-oxo-1,2- Dihydropyridine -3-car Hexamid Manufacturing

The title compound was synthesized by a method similar to that of Example 1, except that 1- (methoxymethyl) -1H-pyrazol-4-ylboronic acid was used instead of 3-amino-4-fluorophenylboronic acid .

^{1 H NMR (400 MHz, CDCl} 3) δ 11.62 (s, 1H), 10.29 (s, 1H), 8.11 (d, J = 5.6 Hz, 1H), 7.96-7.92 (m, 2H), 7.87 (s, 1H), 7.51 (d, J = 8.0 Hz, 1H), 7.37-7.33 (m, 3H), 7.30 (s, 1H), 7.27-7.21 (m, 2H), 7.11 (t, J = 8.4 Hz, 1H ), 6.37-6.35 (m, 2H), 5.38 (s, 2H), 4.36 (q, J = 6.8 Hz, 2H), 3.31 (s, 3H), 1.58 (t, J = 7.2 Hz, 3H).

Example  25: N- (4- (3- (4- Chlorophenyl ) -1H- Pyrrolo [2,3-b] pyridine -4- Sake ) -3- Fluorophenyl )-4- Ethoxy -1- (4- Fluorophenyl ) -2-oxo-1,2- Dihydropyridine -3- Carboxyamide Manufacturing

The title compound was synthesized by a method similar to that of Example 1, except that 4-chlorophenylboronic acid was used instead of 3-amino-4-fluorophenylboronic acid.

^{1 H NMR (400 MHz, CDCl} 3) δ 11.60 (s, 1H), 11.21 (s, 1H), 8.11 (d, J = 5.6 Hz, 1H), 7.93-7.90 (m, 1H), 7.65-7.62 ( m, 2H), 7.50 (d , J = 7.6 Hz, 1H), 7.37-7.31 (m, 5H), 7.25-7.19 (m, 3H), 7.06 (t, J = 8.8 Hz, 1H), 6.36-6.33 (m, 2H), 4.35 (q, J = 7.2 Hz, 2H), 1.58 (t, J = 7.2 Hz, 3H).

Example  26: 4- Ethoxy -N- (3- Fluoro -4- (3- (4- Fluoro -3- Methylphenyl ) -1H- Pyrrolo [2,3-b] pyridine -4- Sake ) Phenyl ) -1- (4- Fluorophenyl ) -2-oxo-1,2- Dihydropyridine -3- Carbop Preparation of cyamide

The title compound was synthesized by a method similar to that of Example 1, except that 4-fluoro-3-methylphenylboronic acid was used instead of 3-amino-4-fluorophenylboronic acid.

^{1 H NMR (400 MHz, CDCl} 3) δ 11.58 (s, 1H), 10.20 (s, 1H), 8.11 (d, J = 6.0 Hz, 1H), 7.93-7.89 (m, 1H), 7.53-7.49 ( m, 2H), 7.47-7.45 (m , 1H), 7.37-7.34 (m, 2H), 7.27 (s, 1H), 7.25-7.21 (m, 3H), 7.05 (t, J = 8.8 Hz, 1H) , 6.98 (t, J = 8.4 Hz, 1H), 6.37-6.35 (m, 2H), 4.35 (q, J = 7.2 Hz, 2H), 2.27 (s, 3H), 1.58 (t, J = 6.8 Hz, 3H).

Example  27: 4- Ethoxy -N- (3- Fluoro -4- (3- (4- Fluoro -3- Methoxyphenyl ) -1H- Pyrrolo [2,3-b] pyridine -4- Sake ) Phenyl ) -1- (4- Fluorophenyl ) -2-oxo-1,2- Dihydropyridine -3-car Hexamid Manufacturing

The title compound was synthesized by a method similar to that of Example 1, except that 4-fluoro-3-methoxyphenylboronic acid was used instead of 3-amino-4-fluorophenylboronic acid.

^{1 H NMR (400 MHz, CDCl} 3) δ 11.62 (s, 1H), 10.51 (s, 1H), 8.12 (d, J = 5.6 Hz, 1H), 7.96-7.93 (m, 1H), 7.50 (d, J = 7.6 Hz, 1H), 7.46-7.43 (m, 1H), 7.37-7.33 (m, 3H), 7.25-7.21 (m, 3H), 7.16-7.12 (m, 1H), 7.08-7.03 (m, 2H), 6.37-6.33 (m, 2H), 4.35 (q, J = 7.2 Hz, 2H), 3.83 (s, 3H), 1.58 (t, J = 7.2 Hz, 3H).

Example  28: N- (4- (3- (3- Chloro -4- Fluorophenyl ) -1H- Pyrrolo [2,3-b] pyridine Yloxy) -3- Fluorophenyl )-4- Ethoxy -1- (4- Fluorophenyl ) -2-oxo-1,2- Dihydropyridine -3- Car Manufacture of amoxycillin

The title compound was synthesized by a method similar to that of Example 1, except that 3-chloro-4-fluorophenylboronic acid was used instead of 3-amino-4-fluorophenylboronic acid.

^{1 H NMR (400 MHz, CDCl} 3) δ 11.60 (s, 1H), 10.18 (s, 1H), 8.13 (d, J = 5.6 Hz, 1H), 7.94-7.90 (m, 1H), 7.74-7.71 ( m, 1H), 7.51 (d , J = 8.0 Hz, 1H), 7.38-7.34 (m, 2H), 7.30-7.27 (m, 2H), 7.24-7.21 (m, 2H), 7.14-7.05 (m, 2H), 6.37-6.35 (m, 2H), 4.36 (q, J = 6.8 Hz, 2H), 1.58 (t, J = 7.2 Hz, 3H).

Example 29: N- (4- (3- (3,4-difluorophenyl) -lH-pyrrolo [2,3-b] pyridin- 4-yloxy) -3-fluorophenyl) -4- -Ethoxy-1- (4-fluorophenyl) -2-oxo-1,2-dihydropyridine-3-carboxamide

The title compound was synthesized by a method similar to that of Example 1, except that 3,4-difluorophenylboronic acid was used instead of 3-amino-4-fluorophenylboronic acid.

^{1 H NMR (400 MHz, CDCl} 3) δ 11.61 (s, 1H), 10.47 (s, 1H), 8.13 (d, J = 5.6 Hz, 1H), 7.94-7.90 (m, 1H), 7.56-7.49 ( (m, 2H), 7.42-7.34 (m, 3H), 7.31 (s, IH), 7.28 (s, IH), 7.24-7.22 m, 2H), 4.36 (q, J = 7.2 Hz, 2H), 1.58 (t, J = 7.2 Hz, 3H).

Example  30: N- (3- Fluoro -4- (3- Phenyl -1H- Pyrrolo [2,3-b] pyridine -4- Sake ) Phenyl ) -N- (4- Fluorophenyl ) Cyclopropane-l, l- Dicarboxamido  Produce

Step 1: N- (3- Fluoro -4- (3- Iodo -1H- Pyrrolo [2,3-b] pyridine -4- Sake ) Phenyl ) -N- (4- Fluorophenyl ) Cyclopropane-l, l- Dicarboxamido  Produce

0.95 g (3.42 mmol) of 1- (4-fluorophenyl) -2-oxo-1,2-dihydropyridine-3-carboxylic acid and 15 ml of dichloromethane were added, and thionyl chloride (0.81 g, 6.82 mmol) And the mixture was stirred at room temperature for 1 hour. When all the mixture dissolved, the mixture was concentrated under reduced pressure (reaction vessel A). Another reaction vessel was charged with 0.51 g (2.28 mmol, purchased from Fluorochem; CAS. #: 849217-48-7) of 1 - ((4- fluorophenyl) carbamoyl) cyclopropanecarboxylic acid, 15 ml of dichloromethane, 0.45 g (4.54 mmol) were added thereto and stirred for 0.5 hour (reaction vessel B). 15 ml of dichloromethane was added to the concentrated mixture of reaction vessel A, stirred, and slowly dropped into reaction vessel B. After stirring at room temperature for 1.5 hours, it was washed with distilled water and a saturated aqueous sodium hydrogen carbonate solution. Dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure to give a residue. The residue obtained was used in the next reaction without further purification.

Step 2: tert -Butyl 4- (2- Fluoro -4- (1- (4- Fluorophenylcarbamoyl ) Cyclopropanecarboxyamido ) Phenoxy ) -3- Iodo -1H- Pyrrolo [2,3-b] pyridine -One- Carboxylate  Produce

Pyrrolo [2,3-b] pyridin-4-yloxy) phenyl) -N- (4-fluoro Phenyl) cyclopropane-1,1-dicarboxamide was dissolved in 15 ml of THF, and then 0.54 mg (2.49 mmol) of di-tert-butyl dicarbonate, 0.25 g (2.49 mmol) of triethylamine and 4-dimethylaminopyridine 3 mg (0.03 mmol) of triethylamine were added thereto, and the mixture was stirred at room temperature for 24 hours. After completion of the reaction, the reaction mixture was extracted with dichloromethane and distilled water, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The filtrate was purified by silica gel column chromatography (50% ethyl acetate in n-hexane) to give tert-butyl 4- (2-fluoro-4- (1- (4-fluorophenylcarbamoyl) cyclopropanecarboxamido) (58%, overall yields in steps 1 and 2) of the title compound was obtained in analogy to example 1 from 3-iodo-lH-pyrrolo [2,3-b] pyridine- 1 -carboxylate.

^{1 H NMR (400 MHz, DMSO} -d 6) δ 8.38 (d, J = 5.8 Hz, 1H), 7.60-7.50 (m, 3H), 7.26-7.22 (m, 4H), 7.04 (d, J = 8.1 Hz), 6.91 (d, J = 8.3 Hz, 1H), 1.63 (s, 9H), 1.02 (d, J = 3.4 Hz, 2H), 0.78 (d, J = 3.4 Hz, 2H).

Step 3: N- (3- Fluoro -4- (3- Phenyl -1H- Pyrrolo [2,3-b] pyridine -4- Sake ) Phenyl ) -N- (4- Luo Luo Phenyl) cyclopropane-l, l- Dicarboxamido  Produce

To a solution of tert-butyl 4- (2-fluoro-4- (1- (4-fluorophenylcarbamoyl) cyclopropanecarboxamido) phenoxy) -3-iodo-lH-pyrrolo 33 mg (0.05 mmol) of [2,3-b] pyridine-1-carboxylate was dissolved in 1.7 ml of a mixed solvent of toluene / ethanol / distilled water (2: 2: 1), 10 mg (0.07 mmol) 3 mg (0.005 mmol) of Pd (PPh ₃ ) ₂ Cl ₂ , 15 mg (0.14 mmol) of sodium carbonate and 6 mg (0.14 mmol) of lithium chloride were added and stirred at 85 ° C for 4 hours. Dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The residue is prep. TLC (CH ₂ Cl ₂ / MeOH) = 20/1) to give 12 mg (51%) of the title compound.

^{1 H NMR (400 MHz, CDCl} 3) δ 10.06 (s, 1H), 9.73 (s, 1H), 8.40 (s, 1H), 8.12 (d, J = 5.6 Hz, 1H), 7.71-7.67 (m, 3H), 7.47-7.44 (m, 2H ), 7.44-7.34 (m, 3H), 7.28-7.03 (m, 5H), 6.35 (d, J = 5.6 Hz, 1H), 1.77-1.68 (m, 2H) , 1.63-1.60 (m, 2H).

Example  31: N- (3- Fluoro -4- (3- (4- Fluorophenyl ) -1H- Pyrrolo [2,3-b] pyridine -4-yl jade city) Phenyl ) -N- (4- Fluorophenyl ) Cyclopropane-l, l- Dicarboxamido  Produce

The title compound was synthesized by a method similar to that of Example 30, except that 4-fluorophenylboronic acid was used instead of phenylboronic acid.

^{1 H NMR (400 MHz, DMSO} -d 6) δ 10.31 (s, 1H), 9.87 (s, 1H), 8.43 (s, 1H), 8.12 (d, J = 5.6 Hz, 1H), 7.69 (dd, J = 2.4 and 12.4 Hz, 1H ), 7.65-7.46 (m, 2H), 7.45-7.43 (m, 2H), 7.30 (s, 1H), 7.17-7.16 (9m, 1H), 7.12-7.02 (m, 5H), 6.34 (d, J = 5.6 Hz, 1H), 1.77-1.60 (m, 4H).

Example  32: N- (3- Fluoro -4- (3- (4- Methoxyphenyl ) -1H- Pyrrolo [2,3-b] pyridine 4-yloxy) Phenyl ) -N- (4- Fluorophenyl ) Cyclopropane-l, l- Dicarboxamido  Produce

The title compound was synthesized by a method similar to that of Example 30, except that 4-methoxyphenylboronic acid was used instead of phenylboronic acid.

^{1 H NMR (400 MHz, CDCl} 3) δ 11.95 (s, 1H), 10.35 (s, 1H), 10.03 (s, 1H), 8.06 (d, J = 5.6 Hz, 1H), 8.84 (dd, = 2.4 J = 8.8 Hz, 1 H), 6.91 (d, J = 8.8 Hz, 1H), 7.65-7.58 (m, 4H), 7.51-7.43 (d, J = 8.4 Hz, 1H), 6.22 (d, J = 5.2 Hz, 1H), 3.74 (s, 3H), 1.45 (m, 4H).

Example  33: N- (3- Fluoro -4- (3- (3- ( Hydroxymethyl ) Phenyl ) -1H- Pyrrolo [2,3-b] pyridine -4- Sake ) Phenyl ) -N- (4- Fluorophenyl ) Cyclopropane-l, l- Dicarboxamido  Produce

The title compound was synthesized by a method similar to that of Example 30, except that (3-hydroxymethyl) phenylboronic acid was used in place of phenylboronic acid.

^{1 H NMR (400 MHz, CDCl} 3) δ 10.65 (s, 1H), 9.90 (s, 1H), 9.18 (s, 1H), 7.97 (d, J = 5.6 Hz, 1H), 7.62 (s, 1H) , 7.57-7.53 (m, 2H), 7.44-7.40 (m, 2H), 7.29 (t, J = 7.6 Hz, 1H), 7.21-7.19 1H), 7.05-6.92 (m, 3H), 6.27 (d, J = 5.6Hz, 1H), 4.64 (s, 2H), 1.65-1.56 (m, 4H).

Experimental Example  1: c- MET  Active inhibition assay

The c-MET inhibitory effect of the compounds according to the present invention was confirmed using the ADP-Glo ™ kinase assays. Specifically, 250 μM G4Y1 peptide serving as a c-MET enzyme substrate at a concentration of 2 ng / μl and 50 μM ATP were added to the reaction buffer (40 mM Tris-HCl, pH 7.5, 20 mM MgCl 2, 0.1 mg / 50 [mu] M DTT). The compounds prepared in Examples 1 to 33 and the comparative compounds were treated at various concentrations and reacted at room temperature for 1 hour. Then, ADP-Glo ™ reagent and kinase detection reagent were added in turn, And reacted for 30 minutes.

After the reaction was completed, luminescence was measured using Wallaac Victor 2 TM (PerkinElmer life sciences, 1420-042). Data were analyzed from the measured RLU values to verify the activity of c-MET inhibitors. The activity of the c-MET inhibitor was assessed by using the RLU value of the untreated sample as a 100% control and deriving the residual activity percentage of the c-MET enzyme in the sample treated with the compound to be tested. The IC ₅₀ value (nM) of the c-MET inhibitor was determined as the concentration causing the inhibition of 50% c-MET enzyme activity compared with the control.

Experimental Example  2: MKN45  Cell growth inhibition assay

MTS analysis was performed to confirm that the compounds prepared in Examples 1 to 33 can inhibit cancer cell proliferation through inhibition of extracellular signal-regulated kinase activity. For this purpose, analysis was carried out using MKN45 cells, a human gastric cancer cell line.

Specifically, MKN45 cells were plated at a concentration of 5,000 cells / well in a 96-well plate containing RPMI-1640 medium (GIBCO, Invitrogen) containing 10% FBS and cultured at 5% CO ₂ and 37 ° C And cultured for 24 hours. Then, the compounds obtained from the above-mentioned Examples were prepared at a high concentration of 10 μM in each well and sequentially diluted. The control group was treated with the same 0.1% (v / v) dimethylsulfoxide (DMSO) Respectively. Cells treated with the compound or dimethylsulfoxide were further cultured for 48 hours. To confirm the viability of the cells, a mixture of MTS and PMS (phenazine methosulfate) supplied by CellTiter 96 ^® Aquatic Non-Radioactive Cell Proliferation Assay Kit (Promega) was added to each of the cultured cell culture media. Lt; RTI ID = 0.0 &gt; 490 &lt; / RTI &gt; nm. Measured value was calculated according to the degree of cell growth inhibition for each compound concentration based on the absorbance of the control cells, wherein the concentration that inhibits the growth of cancer cells, 50% of each compound was determined as IC ₅₀ values (μM). The obtained results are shown in Table 1 below.

Example ADP Glo Assay c-MET, IC ₅₀ Inhibition of MKN45 cell growth, IC ₅₀ One A A 2 A B 3 B B 4 A B 5 A B 6 B B 7 A B 8 A B 9 B B 10 A B 11 B B 12 B B 13 B B 14 B B 15 B B 16 B B 17 B C 18 B C 19 B B 20 B B 21 B B 22 B C 23 B C 24 A C 25 B B 26 B C 27 A C 28 C C 29 B B 30 B B 31 B C 32 B B 33 B B

A: <10 nM, B: 10-50 nM, C:> 50 nM

Claims (17)

A compound represented by the following formula (1), a tautomer thereof or a pharmaceutically acceptable salt thereof:
[Chemical Formula 1]

In this formula,
R ₁ is hydrogen or halogen;
R &lt; ₂ &gt; is aryl or heteroaryl selected from the group consisting of phenyl and pyrazolyl,
The aryl or heteroaryl is unsubstituted or substituted with

,

,

, C _1-4 alkyl, C _1-4 alkoxy, halogen, nitro, cyano, amino, NH (C _1-4 alkyl), NH- acetyl, CO-H, CO- (C _1-4 alkyl), CO - Dimorpholino _{Reno, CO-NH 2, CO-} NH (C 1-4 alkyl), CO-N (C _1-4 alkyl) _2, pyrazolyl, Dimorpholino Reno, piperazinyl, piperidinyl, SO ₂ - ( C _1-4 alkyl), SO ₂ -NH ₂ , SO ₂ -NH (C _1-4 alkyl), SO ₂ -N (C _1-4 alkyl) ₂ ,
R _i to R _iii is hydroxy, cyano, C _{1-4 alkoxy, O- (CH 2) 2 -O} -CH 3, OCO-NH 2, Dimorpholino Reno, amino, NH (C _1-4 alkyl) or N (C _1-4 alkyl) ₂ ;
R ₃ is

or

as,
R _3a , R _3b , R _3c and R _3d are each independently hydrogen, halogen, hydroxy, C _1-4 alkyl or C _1-4 alkoxy.
The method according to claim 1,
Wherein R &lt; _{1 &gt;} is hydrogen or F, a tautomer thereof or a pharmaceutically acceptable salt thereof.
The method according to claim 1,
R &lt; _{2 &gt;} is unsubstituted,

,

,

, C _{1 -4} alkyl, C _{1 -4} alkoxy, halogen, nitro, cyano, amino, NH (C _{1 -4} alkyl), or SO ₂ - (C _{1 -4} alkyl) one or more substituents selected from the group consisting of &Lt; / RTI &gt; or a tautomer thereof, or a pharmaceutically acceptable salt thereof.
The method of claim 3,
R _i is hydroxy, cyano, and _{O- (CH 2) 2 -O-} CH 3 , or C _{1 -4} alkoxy,
R _ii is hydroxy and hydroxy or C _{1 -4} alkoxy,
And R &lt; _iii &gt; is hydroxy, a tautomer thereof or a pharmaceutically acceptable salt thereof.
The method of claim 3,
R ₂ is unsubstituted or substituted with at least one substituent selected from the group consisting of methyl, ethyl, amino, F, Cl, lH-pyrazol-1-yl, cyanomethyl, nitro, methoxy, hydroxymethyl, , 2-hydroxypropane-2-yl, 1-methoxyethyl, (2-methoxyethoxy) methyl and ethylsulfonyl, Or a pharmaceutically acceptable salt thereof.
The method of claim 3,
R ₂ is unsubstituted or 1-H-pyrazol-4-yl substituted on the nitrogen atom with methyl, ethyl, cyanomethyl or methoxymethyl, the tautomers thereof or a pharmaceutically acceptable salt thereof salt.
The method according to claim 1,
R _3a is an alkoxy C _{1 -4,}
R _3b is hydrogen,
R _3c and R _3d are each independently hydrogen or halogen, a tautomer thereof or a pharmaceutically acceptable salt thereof.
8. The method of claim 7,
R &lt; _3a &gt; is methoxy or ethoxy,
R _3b is hydrogen,
R _3c and R _3d are each independently hydrogen or F, a tautomer thereof or a pharmaceutically acceptable salt thereof.
The method according to claim 1,
R ₁ is F;
R ₂ is unsubstituted or substituted with at least one substituent selected from the group consisting of methyl, ethyl, amino, F, Cl, lH-pyrazol-1-yl, cyanomethyl, nitro, methoxy, hydroxymethyl, Phenyl substituted with one or two substituents selected from the group consisting of 2-hydroxypropan-2-yl, 1-methoxyethyl, (2-methoxyethoxy) methyl and ethylsulfonyl; Or 1-H-pyrazol-4-yl, unsubstituted or substituted on the nitrogen atom by methyl, ethyl, cyanomethyl or methoxymethyl,
R ₃ is

as,
R &lt; _3a &gt; is methoxy or ethoxy,
R _3b is hydrogen,
R _3c is F, its tautomers, or a pharmaceutically acceptable salt thereof.
The method according to claim 1,
R ₁ is F;
R ₂ is phenyl which is unsubstituted or substituted by F, methoxy or hydroxymethyl,
R ₃ is

as,
R _3d is F in a compound, its tautomeric or pharmaceutically acceptable salts thereof will.
The method according to claim 1,
The compound
1) N- (4- (3- (3-amino-4-fluorophenyl) -lH-pyrrolo [2,3- b] pyridin- Ethoxy-1- (4-fluorophenyl) -2-oxo-1,2-dihydropyridine-3- carboxamide,
2) N- (4- (3- (3-aminophenyl) -lH-pyrrolo [2,3- b] pyridin- 4- yloxy) -3-fluorophenyl) -4- (4-fluorophenyl) -2-oxo-1,2-dihydropyridine-3-carboxamide,
3) N- (4- (3- (3-Amino-2-methylphenyl) -lH- pyrrolo [2,3- b] pyridin- 4-yloxy) -3-fluorophenyl) -4- -1- (4-fluorophenyl) -2-oxo-1,2-dihydropyridine-3-carboxamide,
4) Preparation of N- (4- (3- (3-amino-4-chlorophenyl) -lH- pyrrolo [2,3- b] pyridin- 4- yloxy) -3-fluorophenyl) -4- (4-fluorophenyl) -2-oxo-1,2-dihydropyridine-3-carboxamide,
5) N- (4- (3- (lH-pyrazol-l-yl) phenyl) -lH- pyrrolo [2,3- b] pyridin- 4- yloxy) -3-fluorophenyl ) -4-ethoxy-1- (4-fluorophenyl) -2-oxo-1,2-dihydropyridine-
6) N- (4- (3- (3-Amino-4-methylphenyl) -lH- pyrrolo [2,3- b] pyridin- 4- yloxy) -3-fluorophenyl) -4- -1- (4-fluorophenyl) -2-oxo-1,2-dihydropyridine-3-carboxamide,
7) N- (4- (3- (3- (Cyanomethyl) phenyl) -lH- pyrrolo [2,3- b] pyridin- 4-yloxy) -3-fluorophenyl) -4- (4-fluorophenyl) -2-oxo-1,2-dihydropyridine-3-carboxamide,
2,3-b] pyridin-4-yloxy) -lH-pyrrolo [2,3-d] pyrimidin- Phenyl) -1- (4-fluorophenyl) -2-oxo-1,2-dihydropyridine-3- carboxamide,
9) 4-ethoxy-N- (3-fluoro-4- (3- Phenyl) -1- (4-fluorophenyl) -2-oxo-1,2-dihydropyridine-3- carboxamide,
10) N- (4- (3- (5-Amino-2-fluorophenyl) -lH-pyrrolo [2,3- b] pyridin- Ethoxy-1- (4-fluorophenyl) -2-oxo-1,2-dihydropyridine-3- carboxamide,
11) 4-ethoxy-N- (3-fluoro-4- (3- (3- ) -1- (4-fluorophenyl) -2-oxo-1,2-dihydropyridine-3-carboxamide,
Pyrrolo [2,3-b] pyridin-4-yloxy) phenyl) -1H-pyrrolo [2,3- -1- (4-fluorophenyl) -2-oxo-1,2-dihydropyridine-3-carboxamide,
2,3-b] pyridin-4-yloxy) -3-fluorophenyl) -1H-pyrrolo [2,3- -1- (4-fluorophenyl) -2-oxo-1,2-dihydropyridine-3-carboxamide,
14) 4-Ethoxy-N- (3-fluoro-4- (3- ) Phenyl) -1- (4-fluorophenyl) -2-oxo-1,2-dihydropyridine-3-carboxamide,
LH-pyrrolo [2,3-b] pyridin-3-yl) -lH- pyrrolo [2,3- Yloxy) phenyl) -1- (4-fluorophenyl) -2-oxo-1,2-dihydropyridine-3-carboxamide,
LH-pyrrolo [2,3-b] pyridin-4-yl) - lH-pyrrolo [2,3- Yloxy) phenyl) -1- (4-fluorophenyl) -2-oxo-1,2-dihydropyridine-3-carboxamide,
17) 4-ethoxy-N- (3-fluoro-4- (3- (3- (1- methoxyethyl) phenyl) -lH- pyrrolo [2,3- b] pyridin- ) Phenyl) -1- (4-fluorophenyl) -2-oxo-1,2-dihydropyridine-3-carboxamide,
Pyrrolo [2,3-b] pyridin-4-yloxy) -3, 4-dihydro-2H-pyrrolo [ -Fluorophenyl) -1- (4-fluorophenyl) -2-oxo-1,2-dihydropyridine-3- carboxamide,
Pyrrolo [2,3-b] pyridin-4-yloxy) phenyl) - l- (3-fluoro- - (4-fluorophenyl) -2-oxo-1,2-dihydropyridine-3-carboxamide,
LH-pyrrolo [2,3-b] pyridin-3-yl) -lH-pyrrolo [2,3- Yloxy) phenyl) -1- (4-fluorophenyl) -2-oxo-1,2-dihydropyridine-3-carboxamide,
21) N- (4- (3- (3,4-dimethoxyphenyl) -lH-pyrrolo [2,3- b] pyridin- 4-yloxy) -3-fluorophenyl) -4- -1- (4-fluorophenyl) -2-oxo-1,2-dihydropyridine-3-carboxamide,
2,3-b] pyridin-4-yloxy) -3-fluorophenyl) -1H-pyrrolo [2,3- ) -1- (4-fluorophenyl) -2-oxo-1,2-dihydropyridine-3-carboxamide,
2,3-b] pyridin-4-yloxy) -3- (4-fluorophenyl) Fluorophenyl) -4-ethoxy-1- (4-fluorophenyl) -2-oxo-1,2-dihydropyridine-
2,3-b] pyridin-2-ylmethyl) -lH-pyrrolo [2,3- b] Yloxy) phenyl) -1- (4-fluorophenyl) -2-oxo-1,2-dihydropyridine-3-carboxamide,
25) N- (4- (3- (4-chlorophenyl) -lH-pyrrolo [2,3- b] pyridin- 4- yloxy) -3-fluorophenyl) -4- (4-fluorophenyl) -2-oxo-1,2-dihydropyridine-3-carboxamide,
26) 4-ethoxy-N- (3-fluoro-4- (3- ) -1- (4-fluorophenyl) -2-oxo-1,2-dihydropyridine-3-carboxamide,
27) 4-ethoxy-N- (3-fluoro-4- (3- ) Phenyl) -1- (4-fluorophenyl) -2-oxo-1,2-dihydropyridine-3-carboxamide,
28) N- (4- (3- (3-chloro-4-fluorophenyl) -lH-pyrrolo [2,3- b] pyridin- Ethoxy-1- (4-fluorophenyl) -2-oxo-1,2-dihydropyridine-3- carboxamide,
29) N- (4- (3- (3,4-difluorophenyl) -lH-pyrrolo [2,3- b] pyridin- 4-yloxy) -3-fluorophenyl) -4- (4-fluorophenyl) -2-oxo-1,2-dihydropyridine-3-carboxamide,
30) N- (3-Fluoro-4- (3-phenyl-lH-pyrrolo [2,3- b] pyridin- 1,1-dicarboxyamide,
31) N- (3-Fluoro-4- (3- (4-fluorophenyl) -lH- pyrrolo [2,3- b] pyridin- Phenyl) cyclopropane-1,1-dicarboxamide,
32) N- (3-fluoro-4- (3- (4-methoxyphenyl) -lH- pyrrolo [2,3- b] pyridin- Phenyl) cyclopropane-1,1-dicarboxamide, and
33) N- (3-Fluoro-4- (3- (3- (hydroxymethyl) phenyl) -lH- pyrrolo [2,3- b] pyridin- 4-fluorophenyl) cyclopropane-1,1-dicarboxamide, the tautomers thereof, or a pharmaceutically acceptable salt thereof.
11. A composition for inhibiting c-MET activity comprising a compound according to any one of claims 1 to 11, a tautomer thereof or a pharmaceutically acceptable salt thereof as an active ingredient.
11. A pharmaceutical composition for preventing or treating a hyperproliferative disorder comprising the compound according to any one of claims 1 to 11, a tautomer thereof or a pharmaceutically acceptable salt thereof as an active ingredient.
14. The method of claim 13,
The present invention relates to a method for the treatment of diabetic retinopathy, retinopathy of prematurity, corneal transplant rejection, neovascular glaucoma, hypoxia, proliferative retinopathy, psoriasis, rheumatoid arthritis, osteoarthritis, autoimmune disease, Crohns disease, restenosis, Wherein the disease is selected from the group consisting of hypercholesterolemia, stenosis, ulceration, cirrhosis, glomerulonephritis, diabetic nephropathy, malignant neuropathies, thrombotic microangiopathy, organ transplant rejection and gonadal stricture.
15. The method of claim 14,
Wherein said cancer is lung cancer, gastric cancer, pancreatic cancer, colon cancer, ovarian cancer, renal cell cancer, prostate cancer or brain tumor.
16. The method of claim 15,
The cancer may be a hereditary papillary renal cell carcinoma (PRCC), sporadic forms of PRCC, head and neck cancer, squamous cell carcinoma, gastric cancer cancer, breast cancer, leiomyosarcoma, glioblastoma, melanoma, and soft tissue sarcoma (for example, pancreatic carcinoma, pancreatic carcinoma, lung cancer, bladder cancer, breast cancer, leiomyosarcoma, alveolar soft part sarcoma), or a derivative derived therefrom.
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