Antitumor agent for thyroid cancer

Abstract

The objective of the present invention is to provide a pharmaceutical composition and a therapeutic method that are specifically effective against at least one disease selected from multiple endocrine neoplasia, type IIA, multiple endocrine neoplasia, type IIB, familial medullary thyroid carcinoma, thyroid carcinoma, papillary thyroid carcinoma, sporadic medullary thyroid carcinoma, Hirschsprung disease, pheochromocytoma, parathyroid hyperplasia and mucosal neuromas of the gastrointestinal tract. 4-(3-chloro-4-(cyclopropylaminocarbonyl)aminophenoxy)-7-methoxy-6-quinolinecarboxamide and analogs thereof are specifically effective against at least one disease selected from multiple endocrine neoplasia, type IIA, multiple endocrine neoplasia, type IIB, familial medullary thyroid carcinoma, thyroid carcinoma, papillary thyroid carcinoma, sporadic medullary thyroid carcinoma, Hirschsprung disease, pheochromocytoma, parathyroid hyperplasia and mucosal neuromas of the gastrointestinal tract.

1 . A therapeutic agent comprising an RET kinase inhibiting substance for treating at least one disease selected from the group consisting of multiple endocrine neoplasia, type IIA, multiple endocrine neoplasia, type IIB, familial medullary thyroid carcinoma, papillary thyroid carcinoma, sporadic medullary thyroid carcinoma, Hirschsprung disease, pheochromocytoma, parathyroid hyperplasia and mucosal neuromas of the gastrointestinal tract, wherein said RET kinase inhibiting substance is a compound represented by General Formula (I) 
       
         
           
           
               
               
           
         
       
       wherein, R 1  represents a group represented by Formula —V 1 —V 2 —V 3  (wherein, V 1  represents C 1-6  alkylene group that may have a substituent; V 2  represents a single bond, an oxygen atom, a sulfur atom, carbonyl group, sulfinyl group, sulfonyl group, group represented by Formula —CONR 6 —, group represented by Formula —SO 2 NR 6 —, group represented by Formula —NR 6 SO 2 —, group represented by Formula —NR 6 CO— or group represented by Formula —NR 6 — (wherein, R 6  represents a hydrogen atom, C 1-6  alkyl group that may have a substituent or C 3-8  cycloalkyl group that may have a substituent); V 3  represents a hydrogen atom, C 1-6  alkyl group that may have a substituent, C 2-6  alkenyl group that may have a substituent, C 2-6  alkynyl group that may have a substituent, C 3-8  cycloalkyl group that may have a substituent, C 6-10  aryl group that may have a substituent, 5-10-membered heteroaryl group that may have a substituent or 3-10-membered non-aromatic heterocyclic group that may have a substituent);
 R 2  represents cyano group, C 1-6  alkoxy group that may have a substituent, carboxyl group, C 2-7  alkoxycarbonyl group that may have a substituent or group represented by Formula —CONV a11 V a12  (wherein, V a11  represents a hydrogen atom, C 1-6  alkyl group that may have a substituent, C 2-6  alkenyl group that may have a substituent, C 2-6  alkynyl group that may have a substituent, C 3-8  cycloalkyl group that may have a substituent, C 6-10  aryl group that may have a substituent, 5-10-membered heteroaryl group that may have a substituent or 3-10-membered non-aromatic heterocyclic group that may have a substituent; V a12  represents a hydrogen atom, C 1-6  alkyl group that may have a substituent, C 2-6  alkenyl group that may have a substituent, C 2-6  alkynyl group that may have a substituent, C 3-8  cycloalkyl group that may have a substituent, C 6-10  aryl group that may have a substituent, 5-10-membered heteroaryl group that may have a substituent, 3-10-membered non-aromatic heterocyclic group that may have a substituent, hydroxyl group, C 1-6  alkoxy group that may have a substituent or C 3-8  cycloalkoxy group that may have a substituent); 
 Y 1  represents a group represented by Formula 
 
       
         
           
           
               
               
           
         
       
       (wherein, R 7  and R 8  each independently represent a hydrogen atom, a halogen atom, cyano group, nitro group, amino group, C 1-6  alkyl group that may have a substituent, C 3-8  cycloalkyl group that may have a substituent, C 1-6  alkoxy group that may have a substituent, C 1-6  alkylthio group that may have a substituent, formyl group, C 2-7  acyl group that may have a substituent, C 2-7  alkoxycarbonyl group that may have a substituent or group represented by Formula —CONV d1 V d2  (wherein, V d1  and V d2  each independently represent a hydrogen atom or C 1-6  alkyl group that may have a substituent);
 W 1  and W 2  each independently represent a carbon atom or a nitrogen atom that may have a substituent); 
 R 3  and R 4  each independently represent a hydrogen atom, C 1-6  alkyl group that may have a substituent, C 2-6  alkenyl group that may have a substituent, C 2-6  alkynyl group that may have a substituent, C 3-8  cycloalkyl group that may have a substituent, C 2-7  acyl group that may have a substituent or C 2-7  alkoxycarbonyl group that may have a substituent; and 
 R 5  represents a hydrogen atom, C 1-6  alkyl group that may have a substituent, C 2-6  alkenyl group that may have a substituent, C 2-6  alkynyl group that may have a substituent, C 3-8  cycloalkyl group that may have a substituent, C 6-10  aryl group that may have a substituent, 5-10-membered heteroaryl group that may have a substituent or 3-10-membered non-aromatic heterocyclic group that may have a substituent, 
 
       a pharmacologically acceptable salt thereof or a solvate thereof. 
     
     
         2 . The therapeutic agent according to  claim 1 , wherein R 1  is C 1-6  alkyl group (where, R 1  may have at least one substituent selected from the group consisting of 3-10-membered non-aromatic heterocyclic group that may have C 1-6  alkyl group, hydroxyl group, C 1-6  alkoxy group, amino group, mono-C 1-6  alkylamino group and di-C 1-6  alkylamino group). 
     
     
         3 . The therapeutic agent according to  claim 1 , wherein R 1  is methyl group or group represented by any one of the following Formulae 
       
         
           
           
               
               
           
         
       
       (wherein, R a3  represents methyl group; R a1  represents a hydrogen atom or hydroxyl group; R a2  represents methoxy group, ethoxy group, 1-pyrrolidinyl group, 1-piperidinyl group, 4-morpholinyl group, dimethylamino group or diethylamino group). 
     
     
         4 . The therapeutic agent according to  claim 1 , wherein R 1  is methyl group or 2-methoxyethyl group. 
     
     
         5 . The therapeutic agent according to  claim 1 , wherein R 2  represents cyano group or group represented by Formula —CONV a11 V a12  (wherein, V a11  represents a hydrogen atom, C 1-6  alkyl group that may have a substituent, C 2-6  alkenyl group that may have a substituent, C 2-6  alkynyl group that may have a substituent, C 3-8  cycloalkyl group that may have a substituent, C 6-10  aryl group that may have a substituent, 5-10-membered heteroaryl group that may have a substituent or 3-10-membered non-aromatic heterocyclic group that may have a substituent; V a12  represents a hydrogen atom, C 1-6  alkyl group that may have a substituent, C 2-6  alkenyl group that may have a substituent, C 2-6  alkynyl group that may have a substituent, C 3-8  cycloalkyl group that may have a substituent, C 6-10  aryl group that may have a substituent, 5-10-membered heteroaryl group that may have a substituent, 3-10-membered non-aromatic heterocyclic group that may have a substituent, hydroxyl group, C 1-6  alkoxy group that may have a substituent or C 3-8  cycloalkoxy group that may have a substituent). 
     
     
         6 . The therapeutic agent according to  claim 1 , wherein R 2  is cyano group or group represented by Formula —CONHV a16  (wherein, V a16  represents a hydrogen atom, C 1-6  alkyl group, C 3-8  cycloalkyl group, C 1-6  alkoxy group or C 3-8  cycloalkoxy group, where V a16  may have at least one substituent selected from the group consisting of a halogen atom, cyano group, hydroxyl group and C 1-6  alkoxy group). 
     
     
         7 . The therapeutic agent according to  claim 1 , wherein R 2  is a group represented by Formula —CONHV a17  (wherein, V a17  represents a hydrogen atom, C 1-6  alkyl group or C 1-6  alkoxy group). 
     
     
         8 . The therapeutic agent according to  claim 1 , wherein R 2  is a group represented by Formula —CONHV a18  (wherein, V a18  represents a hydrogen atom, methyl group or methoxy group). 
     
     
         9 . The therapeutic agent according to  claim 1 , wherein Y 1  is a group represented by Formula 
       
         
           
           
               
               
           
         
       
       (wherein, R 71  represents a hydrogen atom or a halogen atom). 
     
     
         10 . The therapeutic agent according to  claim 1 , wherein R 3  and R 4  is a hydrogen atom. 
     
     
         11 . The therapeutic agent according to  claim 1 , wherein R 5  is a hydrogen atom, C 1-6  alkyl group, C 3-8  cycloalkyl group or C 6-10  aryl group (where, R 5  may have at least one substituent selected from the group consisting of a halogen atom and methanesulfonyl group). 
     
     
         12 . The therapeutic agent according to  claim 1 , wherein R 5  is methyl group, ethyl group or cyclopropyl group. 
     
     
         13 . The therapeutic agent according to  claim 1 , wherein the RET kinase inhibiting substance is at least one compound selected from the group consisting of: 
       N-(4-(6-cyano-7-(2-methoxyethoxy)-4-quinolyl)oxy-2-fluorophenyl)-N′-(4-fluorophenyl)urea; 
       N-(2-chloro-4-((6-cyano-7-((1-methyl-4-piperidyl)methoxy)-4-quinolyl)oxy)phenyl)-N′-cyclopropylurea; 
       N-(4-((6-cyano-7-(((2R)-3-(diethylamino)-2-hydroxypropyl)oxy)-4-quinolyl)oxy)phenyl)-N′-(4-fluorophenyl)urea; 
       N-(4-((6-cyano-7-(((2R)-2-hydroxy-3-(1-pyrrolidino)propyl)oxy)-4-quinolyl)oxy)phenyl)-N′-(4-fluorophenyl)urea; 
       4-(3-chloro-4-(cyclopropylaminocarbonyl)aminophenoxy)-7-methoxy-6-quinolinecarboxamide; 
       4-(3-chloro-4-(cyclopropylaminocarbonyl)aminophenoxy)-7-(2-methoxyethoxy)-6-quinolinecarboxamide; 
       N6-cyclopropyl-4-(3-chloro-4-(((cyclopropylamino)carbonyl)amino)phenoxy)-7-methoxy-6-quinolinecarboxamide; 
       N6-(2-methoxyethyl)-4-(3-chloro-4-(((cyclopropylamino)carbonyl)amino)phenoxy)-7-methoxy-6-quinolinecarboxamide; 
       N6-(2-fluoroethyl)-4-(3-chloro-4-(((cyclopropylamino)carbonyl)amino)phenoxy)-7-methoxy-6-quinolinecarboxamide; 
       N6-methoxy-4-(3-chloro-4-(((cyclopropylamino)carbonyl)amino)phenoxy)-7-methoxy-6-quinolinecarboxamide; 
       N6-methyl-4-(3-chloro-4-(((cyclopropylamino)carbonyl)amino)phenoxy)-7-methoxy-6-quinolinecarboxamide; 
       N6-ethyl-4-(3-chloro-4-(((cyclopropylamino)carbonyl)amino)phenoxy)-7-methoxy-6-quinolinecarboxamide; 
       4-(3-fluoro-4-(cyclopropylaminocarbonyl)aminophenoxy)-7-(2-methoxyethoxy)-6-quinolinecarboxamide; 
       4-(3-chloro-4-(cyclopropylaminocarbonyl)aminophenoxy)-7-(2-hydroxyethoxy)-6-quinolinecarboxamide; 
       4-(3-chloro-4-(cyclopropylaminocarbonyl)aminophenoxy)-7-((2S)-2,3-dihydroxypropyl)oxy-6-quinolinecarboxamide; 
       4-(3-chloro-4-(methylaminocarbonyl)aminophenoxy)-7-methoxy-6-quinolinecarboxamide; 
       4-(3-chloro-4-(ethylaminocarbonyl)aminophenoxy)-7-methoxy-6-quinolinecarboxamide; 
       N6-methoxy-4-(3-chloro-4-(((ethylamino)carbonyl)amino)phenoxy)-7-methoxy-6-quinolinecarboxamide; 
       4-(3-chloro-4-(cyclopropylaminocarbonyl)aminophenoxy)-7-(2-ethoxyethoxy)-6-quinolinecarboxamide; 
       4-(4-((cyclopropylamino)carbonyl)aminophenoxy)-7-(2-methoxyethoxy)-6-quinolinecarboxamide; 
       N-(2-fluoro-4-((6-carbamoyl-7-methoxy-4-quinolyl)oxy)phenyl)-N′-cyclopropylurea; 
       N6-(2-hydroxyethyl)-4-(3-chloro-4-(((cyclopropylamino)carbonyl)amino)phenoxy)-7-methoxy-6-quinolinecarboxamide; 
       4-(3-chloro-4-(1-propylaminocarbonyl)aminophenoxy)-7-methoxy-6-quinolinecarboxamide; 
       4-(3-chloro-4-(cis-2-fluoro-cyclopropylaminocarbonyl)aminophenoxy)-7-methoxy-6-quinolinecarboxamide; 
       N6-methyl-4-(3-chloro-4-(((cyclopropylamino)carbonyl)amino)phenoxy)-7-(2-methoxyethoxy)-6-quinolinecarboxamide; 
       N6-methyl-4-(3-chloro-4-(((ethylamino)carbonyl)amino)phenoxy)-7-methoxy-6-quinolinecarboxamide; 
       4-(3-chloro-4-(cyclopropylaminocarbonyl)aminophenoxy)-7-(2-(4-morpholino) ethoxy)-6-quinolinecarboxamide; 
       4-(3-chloro-4-(2-fluoroethylaminocarbonyl)aminophenoxy)-7-methoxy-6-quinolinecarboxamide; 
       N6-((2R)tetrahydro-2-furanylmethyl)-4-(3-chloro-4-(((methylamino)carbonyl)amino)phenoxy)-7-methoxy-6-quinolinecarboxamide; 
       4-(3-fluoro-4-(ethylaminocarbonyl)aminophenoxy)-7-methoxy-6-quinolinecarboxamide; 
       4-(3-chloro-4-(((cyclopropylamino)carbonyl)amino)phenoxy)-7-((2R)-2-hydroxy-3-(1-pyrrolidino)propoxy)-6-quinolinecarboxamide; 
       N6-methyl-4-(3-chloro-4-(((methylamino)carbonyl)amino)phenoxy)-7-((2R)-3-diethylamino-2-hydroxypropoxy)-6-quinolinecarboxamide; 
       N6-methyl-4-(3-chloro-4-(((ethylamino)carbonyl)amino)phenoxy)-7-((2R)-3-diethylamino-2-hydroxypropoxy)-6-quinolinecarboxamide; 
       N6-methyl-4-(3-chloro-4-(((methylamino)carbonyl)amino)phenoxy)-7-((2R)-2-hydroxy-3-(1-pyrrolidino)propoxy)-6-quinolinecarboxamide; 
       N6-methyl-4-(3-chloro-4-(((ethylamino)carbonyl)amino)phenoxy)-7-((2R)-2-hydroxy-3-(1-pyrrolidino)propoxy)-6-quinolinecarboxamide; 
       N6-methyl-4-(3-chloro-4-(((methylamino)carbonyl)amino)phenoxy)-7-((1-methyl-4-piperidyl)methoxy)-6-quinolinecarboxamide; 
       N6-methyl-4-(3-chloro-4-(((ethylamino)carbonyl)amino)phenoxy)-7-((1-methyl-4-piperidyl)methoxy)-6-quinolinecarboxamide; 
       N-(4-(6-cyano-7-(2-methoxyethoxy)-4-quinolyl)oxy-2-fluorophenyl)-N′-cyclopropylurea; 
       N-(4-(6-cyano-7-(3-(4-morpholino)propoxy)-4-quinolyl)oxyphenyl)-N′-(3-(methylsulfonyl)phenyl)urea; 
       4-(4-((cyclopropylamino)carbonyl)aminophenoxy)-7-methoxy-6-quinolinecarboxamide; 
       4-(3-fluoro-4-((2-fluoroethylamino)carbonyl)aminophenoxy)-7-methoxy-6-quinolinecarboxamide; 
       N6-(2-ethoxyethyl)-4-(3-chloro-4-(((methylamino)carbonyl)amino)phenoxy)-7-methoxy-6-quinolinecarboxamide; 
       4-(4-(3-ethylureido)-3-fluoro-phenoxy)-7-methoxyquinoline-6-carboxylic acid (2-cyanoethyl)amide; and 
       N-(4-(6-(2-cyanoethyl)carbamoyl-7-methoxy-4-quinolyl)oxy-2-fluorophenyl)-N′-cyclopropylurea, 
       a pharmacologically acceptable salt thereof or a solvate thereof. 
     
     
         14 . The therapeutic agent according to  claim 1 , wherein the RET kinase inhibiting substance is at least one compound selected from the group consisting of: 
       4-(3-chloro-4-(cyclopropylaminocarbonyl)aminophenoxy)-7-methoxy-6-quinolinecarboxamide; 
       4-(3-chloro-4-(ethylaminocarbonyl)aminophenoxy)-7-methoxy-6-quinolinecarboxamide; 
       N6-methoxy-4-(3-chloro-4-(((cyclopropylamino)carbonyl)amino)phenoxy)-7-methoxy-6-quinolinecarboxamide; 
       4-(3-chloro-4-(methylaminocarbonyl)aminophenoxy)-7-methoxy-6-quinolinecarboxamide; and 
       N6-methoxy-4-(3-chloro-4-(((ethylamino)carbonyl)amino)phenoxy)-7-methoxy-6-quinolinecarboxamide, 
       a pharmacologically acceptable salt thereof or a solvate thereof. 
     
     
         15 . The therapeutic agent according to  claim 1 , wherein the RET kinase inhibiting substance is 4-(3-chloro-4-(cyclopropylaminocarbonyl)aminophenoxy)-7-methoxy-6-quinolinecarboxamide, a pharmacologically acceptable salt thereof or a solvate thereof. 
     
     
         16 . The therapeutic agent according to  claim 1 , wherein the RET kinase inhibiting substance is methanesulfonate of 4-(3-chloro-4-(cyclopropylaminocarbonyl)aminophenoxy)-7-methoxy-6-quinolinecarboxamide. 
     
     
         17 . A therapeutic agent comprising an RET kinase inhibiting substance for treating at least one disease selected from the group consisting of multiple endocrine neoplasia, type IIA, multiple endocrine neoplasia, type IIB, familial medullary thyroid carcinoma, papillary thyroid carcinoma, sporadic medullary thyroid carcinoma, Hirschsprung disease, pheochromocytoma, parathyroid hyperplasia and mucosal neuromas of the gastrointestinal tract, wherein said RET kinase inhibiting substance is at least one compound selected from the group consisting of: 
       5-(5-fluoro-2-oxo-1,2-dihydroindole-3-ylidenemethyl)-2,4-dimethyl-1H-pyrrole-3-carboxylic acid(2-diethylaminoethyl)amide; 
       N-{2-chloro-4-[(6,7-dimethoxy-4-quinolyl)oxy]phenyl}-N′-(5-methyl-3-isoxazolyl)urea; and 
       4-[(4-fluoro-2-methylindole-5-yl)oxy]-6-methoxy-7-[3-(pyrrolidine-1-yl)propoxy]quinazoline, 
       a pharmacologically acceptable salt thereof or a solvate thereof. 
     
     
         18 . The therapeutic agent according to  claim 1 , wherein the disease comprises a cell expressing mutant RET. 
     
     
         19 . The therapeutic agent according to  claim 18 , wherein the mutant RET comprises a mutation site where at least one amino acid selected from the group consisting of amino acids at codons 321, 533, 609, 611, 618, 620, 630, 631, 634, 691, 768, 790, 791, 804, 806, 844, 883, 891 and 918 in the amino acid sequence represented by SEQ ID NO: 2 or 4 is substituted with other amino acid. 
     
     
         20 . The therapeutic agent according to  claim 18 , wherein the mutant RET is a polypeptide encoded by RET gene rearranged with at least one gene selected from the group consisting of H4 gene, RIα gene, ELE1 gene, RFG5 gene, hTIF gene, RFG7 gene, ELKS gene, kinectin gene, PCM-1 gene and RFP gene. 
     
     
         21 . A therapeutic agent comprising an RET kinase inhibiting substance for treating thyroid carcinoma, wherein said RET kinase inhibiting substance is a compound represented by General Formula (I) 
       
         
           
           
               
               
           
         
       
       wherein, R 1  represents a group represented by Formula —V 1 —V 2 —V 3  (wherein, V 1  represents C 1-6  alkylene group that may have a substituent; V 2  represents a single bond, an oxygen atom, a sulfur atom, carbonyl group, sulfinyl group, sulfonyl group, group represented by Formula —CONR 6 —, group represented by Formula —SO 2 NR 6 —, group represented by Formula —NR 6 SO 2 —, group represented by Formula —NR 6 CO— or group represented by Formula —NR 6 — (wherein, R 6  represents a hydrogen atom, C 1-6  alkyl group that may have a substituent or C 3-8  cycloalkyl group that may have a substituent); V 3  represents a hydrogen atom, C 1-6  alkyl group that may have a substituent, C 2-6  alkenyl group that may have a substituent, C 2-6  alkynyl group that may have a substituent, C 3-8  cycloalkyl group that may have a substituent, C 6-10  aryl group that may have a substituent, 5-10-membered heteroaryl group that may have a substituent or 3-10-membered non-aromatic heterocyclic group that may have a substituent);
 R 2  represents cyano group, C 1-6  alkoxy group that may have a substituent, carboxyl group, C 2-7  alkoxycarbonyl group that may have a substituent or group represented by Formula —CONV a11 V a12  (wherein, V a11  represents a hydrogen atom, C 1-6  alkyl group that may have a substituent, C 2-6  alkenyl group that may have a substituent, C 2-6  alkynyl group that may have a substituent, C 3-8  cycloalkyl group that may have a substituent, C 6-10  aryl group that may have a substituent, 5-10-membered heteroaryl group that may have a substituent or 3-10-membered non-aromatic heterocyclic group that may have a substituent; V a12  represents a hydrogen atom, C 1-6  alkyl group that may have a substituent, C 2-6  alkenyl group that may have a substituent, C 2-6  alkynyl group that may have a substituent, C 3-8  cycloalkyl group that may have a substituent, C 6-10  aryl group that may have a substituent, 5-10-membered heteroaryl group that may have a substituent, 3-10-membered non-aromatic heterocyclic group that may have a substituent, hydroxyl group, C 1-6  alkoxy group that may have a substituent or C 3-8  cycloalkoxy group that may have a substituent); 
 Y 1  represents a group represented by Formula 
 
       
         
           
           
               
               
           
         
       
       (wherein, R 7  and R 8  each independently represent a hydrogen atom, a halogen atom, cyano group, nitro group, amino group, C 1-6  alkyl group that may have a substituent, C 3-8  cycloalkyl group that may have a substituent, C 1-6  alkoxy group that may have a substituent, C 1-6  alkylthio group that may have a substituent, formyl group, C 2-7  acyl group that may have a substituent, C 2-7  alkoxycarbonyl group that may have a substituent or group represented by Formula —CONV d1 V d2  (wherein, V d1  and V d2  each independently represent a hydrogen atom or C 1-6  alkyl group that may have a substituent);
 W 1  and W 2  each independently represent a carbon atom or a nitrogen atom that may have a substituent); 
 R 3  and R 4  each independently represent a hydrogen atom, C 1-6  alkyl group that may have a substituent, C 2-6  alkenyl group that may have a substituent, C 2-6  alkynyl group that may have a substituent, C 3-8  cycloalkyl group that may have a substituent, C 2-7  acyl group that may have a substituent or C 2-7  alkoxycarbonyl group that may have a substituent; and 
 R 5  represents a hydrogen atom, C 1-6  alkyl group that may have a substituent, C 2-6  alkenyl group that may have a substituent, C 2-6  alkynyl group that may have a substituent, C 3-8  cycloalkyl group that may have a substituent, C 6-10  aryl group that may have a substituent, 5-10-membered heteroaryl group that may have a substituent or 3-10-membered non-aromatic heterocyclic group that may have a substituent, 
 
       a pharmacologically acceptable salt thereof or a solvate thereof. 
     
     
         22 . The therapeutic agent according to  claim 21 , wherein R 1  is C 1-6  alkyl group (where, R 1  may have at least one substituent selected from the group consisting of 3-10-membered non-aromatic heterocyclic group that may have C 1-6  alkyl group, hydroxyl group, C 1-6  alkoxy group, amino group, mono-C 1-6  alkylamino group and di-C 1-6  alkylamino group). 
     
     
         23 . The therapeutic agent according to  claim 21 , wherein R 1  is methyl group or group represented by any one of the following Formulae 
       
         
           
           
               
               
           
         
       
       (wherein, R a3  represents methyl group; R a1  represents a hydrogen atom or hydroxyl group; R a2  represents methoxy group, ethoxy group, 1-pyrrolidinyl group, 1-piperidinyl group, 4-morpholinyl group, dimethylamino group or diethylamino group). 
     
     
         24 . The therapeutic agent according to  claim 21 , wherein R 1  is methyl group or 2-methoxyethyl group. 
     
     
         25 . The therapeutic agent according to  claim 21 , wherein R 2  represents cyano group or group represented by Formula —CONV a11 V a12  (wherein, V a11  represents a hydrogen atom, C 1-6  alkyl group that may have a substituent, C 2-6  alkenyl group that may have a substituent, C 2-6  alkynyl group that may have a substituent, C 3-8  cycloalkyl group that may have a substituent, C 6-10  aryl group that may have a substituent, 5-10-membered heteroaryl group that may have a substituent or 3-10-membered non-aromatic heterocyclic group that may have a substituent; V a12  represents a hydrogen atom, C 1-6  alkyl group that may have a substituent, C 2-6  alkenyl group that may have a substituent, C 2-6  alkynyl group that may have a substituent, C 3-8  cycloalkyl group that may have a substituent, C 6-10  aryl group that may have a substituent, 5-10-membered heteroaryl group that may have a substituent, 3-10-membered non-aromatic heterocyclic group that may have a substituent, hydroxyl group, C 1-6  alkoxy group that may have a substituent or C 3-8  cycloalkoxy group that may have a substituent). 
     
     
         26 . The therapeutic agent according to  claim 21 , wherein R 2  is cyano group or group represented by Formula —CONHV a16  (wherein, V a16  represents a hydrogen atom, C 1-6  alkyl group, C 3-8  cycloalkyl group, C 1-6  alkoxy group or C 3-8  cycloalkoxy group, where V a16  may have at least one substituent selected from the group consisting of a halogen atom, cyano group, hydroxyl group and C 1-6  alkoxy group). 
     
     
         27 . The therapeutic agent according to  claim 21 , wherein R 2  is a group represented by Formula —CONHV a17  (wherein, V a17  represents a hydrogen atom, C 1-6  alkyl group or C 1-6  alkoxy group). 
     
     
         28 . The therapeutic agent according to  claim 21 , wherein R 2  is a group represented by Formula —CONHV a18  (wherein, V a18  represents a hydrogen atom, methyl group or methoxy group). 
     
     
         29 . The therapeutic agent according to  claim 21 , wherein Y 1  is a group represented by Formula 
       
         
           
           
               
               
           
         
       
       (wherein, R 71  represents a hydrogen atom or a halogen atom). 
     
     
         30 . The therapeutic agent according to  claim 21 , wherein R 3  and R 4  is a hydrogen atom. 
     
     
         31 . The therapeutic agent according to  claim 21 , wherein R 5  is a hydrogen atom, C 1-6  alkyl group, C 3-8  cycloalkyl group or C 6-10  aryl group (where, R 5  may have at least one substituent selected from the group consisting of a halogen atom and methanesulfonyl group). 
     
     
         32 . The therapeutic agent according to  claim 21 , wherein R 5  is methyl group, ethyl group or cyclopropyl group. 
     
     
         33 . The therapeutic agent according to  claim 21 , wherein the RET kinase inhibiting substance is at least one compound selected from the group consisting of: 
       N-(4-(6-cyano-7-(2-methoxyethoxy)-4-quinolyl)oxy-2-fluorophenyl)-N′-(4-fluorophenyl)urea; 
       N-(2-chloro-4-((6-cyano-7-((1-methyl-4-piperidyl)methoxy)-4-quinolyl)oxy)phenyl)-N′-cyclopropylurea; 
       N-(4-((6-cyano-7-(((2R)-3-(diethylamino)-2-hydroxypropyl)oxy)-4-quinolyl)oxy)phenyl)-N′-(4-fluorophenyl)urea; 
       N-(4-((6-cyano-7-(((2R)-2-hydroxy-3-(1-pyrrolidino)propyl)oxy)-4-quinolyl)oxy)phenyl)-N′-(4-fluorophenyl)urea; 
       4-(3-chloro-4-(cyclopropylaminocarbonyl)aminophenoxy)-7-methoxy-6-quinolinecarboxamide; 
       4-(3-chloro-4-(cyclopropylaminocarbonyl)aminophenoxy)-7-(2-methoxyethoxy)-6-quinolinecarboxamide; 
       N6-cyclopropyl-4-(3-chloro-4-(((cyclopropylamino)carbonyl)amino)phenoxy)-7-methoxy-6-quinolinecarboxamide; 
       N6-(2-methoxyethyl)-4-(3-chloro-4-(((cyclopropylamino)carbonyl)amino)phenoxy)-7-methoxy-6-quinolinecarboxamide; 
       N6-(2-fluoroethyl)-4-(3-chloro-4-(((cyclopropylamino)carbonyl)amino)phenoxy)-7-methoxy-6-quinolinecarboxamide; 
       N6-methoxy-4-(3-chloro-4-(((cyclopropylamino)carbonyl)amino)phenoxy)-7-methoxy-6-quinolinecarboxamide; 
       N6-methyl-4-(3-chloro-4-(((cyclopropylamino)carbonyl)amino)phenoxy)-7-methoxy-6-quinolinecarboxamide; 
       N6-ethyl-4-(3-chloro-4-(((cyclopropylamino)carbonyl)amino)phenoxy)-7-methoxy-6-quinolinecarboxamide; 
       4-(3-fluoro-4-(cyclopropylaminocarbonyl)aminophenoxy)-7-(2-methoxyethoxy)-6-quinolinecarboxamide; 
       4-(3-chloro-4-(cyclopropylaminocarbonyl)aminophenoxy)-7-(2-hydroxyethoxy)-6-quinolinecarboxamide; 
       4-(3-chloro-4-(cyclopropylaminocarbonyl)aminophenoxy)-7-((2S)-2,3-dihydroxypropyl)oxy-6-quinolinecarboxamide; 
       4-(3-chloro-4-(methylaminocarbonyl)aminophenoxy)-7-methoxy-6-quinolinecarboxamide; 
       4-(3-chloro-4-(ethylaminocarbonyl)aminophenoxy)-7-methoxy-6-quinolinecarboxamide; 
       N6-methoxy-4-(3-chloro-4-(((ethylamino)carbonyl)amino)phenoxy)-7-methoxy-6-quinolinecarboxamide; 
       4-(3-chloro-4-(cyclopropylaminocarbonyl)aminophenoxy)-7-(2-ethoxyethoxy)-6-quinolinecarboxamide; 
       4-(4-((cyclopropylamino)carbonyl)aminophenoxy)-7-(2-methoxyethoxy)-6-quinolinecarboxamide; 
       N-(2-fluoro-4-((6-carbamoyl-7-methoxy-4-quinolyl)oxy)phenyl)-N′-cyclopropylurea; 
       N6-(2-hydroxyethyl)-4-(3-chloro-4-(((cyclopropylamino)carbonyl)amino)phenoxy)-7-methoxy-6-quinolinecarboxamide; 
       4-(3-chloro-4-(1-propylaminocarbonyl)aminophenoxy)-7-methoxy-6-quinolinecarboxamide; 
       4-(3-chloro-4-(cis-2-fluoro-cyclopropylaminocarbonyl)aminophenoxy)-7-methoxy-6-quinolinecarboxamide; 
       N6-methyl-4-(3-chloro-4-(((cyclopropylamino)carbonyl)amino)phenoxy)-7-(2-methoxyethoxy)-6-quinolinecarboxamide; 
       N6-methyl-4-(3-chloro-4-(((ethylamino)carbonyl)amino)phenoxy)-7-methoxy-6-quinolinecarboxamide; 
       4-(3-chloro-4-(cyclopropylaminocarbonyl)aminophenoxy)-7-(2-(4-morpholino) ethoxy)-6-quinolinecarboxamide; 
       4-(3-chloro-4-(2-fluoroethylaminocarbonyl)aminophenoxy)-7-methoxy-6-quinolinecarboxamide; 
       N6-((2R)tetrahydro-2-furanylmethyl)-4-(3-chloro-4-(((methylamino)carbonyl)amino) phenoxy)-7-methoxy-6-quinolinecarboxamide; 
       4-(3-fluoro-4-(ethylaminocarbonyl)aminophenoxy)-7-methoxy-6-quinolinecarboxamide; 
       4-(3-chloro-4-(((cyclopropylamino)carbonyl)amino)phenoxy)-7-((2R)-2-hydroxy-3-(1-pyrrolidino)propoxy)-6-quinolinecarboxamide; 
       N6-methyl-4-(3-chloro-4-(((methylamino)carbonyl)amino)phenoxy)-7-((2R)-3-diethylamino-2-hydroxypropoxy)-6-quinolinecarboxamide; 
       N6-methyl-4-(3-chloro-4-(((ethylamino)carbonyl)amino)phenoxy)-7-((2R)-3-diethylamino-2-hydroxypropoxy)-6-quinolinecarboxamide; 
       N6-methyl-4-(3-chloro-4-(((methylamino)carbonyl)amino)phenoxy)-7-((2R)-2-hydroxy-3-(1-pyrrolidino)propoxy)-6-quinolinecarboxamide; 
       N6-methyl-4-(3-chloro-4-(((ethylamino)carbonyl)amino)phenoxy)-7-((2R)-2-hydroxy-3-(1-pyrrolidino)propoxy)-6-quinolinecarboxamide; 
       N6-methyl-4-(3-chloro-4-(((methylamino)carbonyl)amino)phenoxy)-7-((1-methyl-4-piperidyl)methoxy)-6-quinolinecarboxamide; 
       N6-methyl-4-(3-chloro-4-(((ethylamino)carbonyl)amino)phenoxy)-7-((1-methyl-4-piperidyl)methoxy)-6-quinolinecarboxamide; 
       N-(4-(6-cyano-7-(2-methoxyethoxy)-4-quinolyl)oxy-2-fluorophenyl)-N′-cyclopropylurea; 
       N-(4-(6-cyano-7-(3-(4-morpholino)propoxy)-4-quinolyl)oxyphenyl)-N′-(3-(methylsulfonyl)phenyl)urea; 
       4-(4-((cyclopropylamino)carbonyl)aminophenoxy)-7-methoxy-6-quinolinecarboxamide; 
       4-(3-fluoro-4-((2-fluoroethylamino)carbonyl)aminophenoxy)-7-methoxy-6-quinolinecarboxamide; 
       N6-(2-ethoxyethyl)-4-(3-chloro-4-(((methylamino)carbonyl)amino)phenoxy)-7-methoxy-6-quinolinecarboxamide; 
       4-(4-(3-ethylureido)-3-fluoro-phenoxy)-7-methoxyquinoline-6-carboxylic acid (2-cyanoethyl)amide; and 
       N-(4-(6-(2-cyanoethyl)carbamoyl-7-methoxy-4-quinolyl)oxy-2-fluorophenyl)-N′-cyclopropylurea, 
       a pharmacologically acceptable salt thereof or a solvate thereof. 
     
     
         34 . The therapeutic agent according to  claim 21 , wherein the RET kinase inhibiting substance is at least one compound selected from the group consisting of: 
       4-(3-chloro-4-(cyclopropylaminocarbonyl)aminophenoxy)-7-methoxy-6-quinolinecarboxamide; 
       4-(3-chloro-4-(ethylaminocarbonyl)aminophenoxy)-7-methoxy-6-quinolinecarboxamide; 
       N6-methoxy-4-(3-chloro-4-(((cyclopropylamino)carbonyl)amino)phenoxy)-7-methoxy-6-quinolinecarboxamide; 
       4-(3-chloro-4-(methylaminocarbonyl)aminophenoxy)-7-methoxy-6-quinolinecarboxamide; and 
       N6-methoxy-4-(3-chloro-4-(((ethylamino)carbonyl)amino)phenoxy)-7-methoxy-6-quinolinecarboxamide, 
       a pharmacologically acceptable salt thereof or a solvate thereof. 
     
     
         35 . The therapeutic agent according to  claim 21 , wherein the RET kinase inhibiting substance is 4-(3-chloro-4-(cyclopropylaminocarbonyl)aminophenoxy)-7-methoxy-6-quinolinecarboxamide, a pharmacologically acceptable salt thereof or a solvate thereof. 
     
     
         36 . The therapeutic agent according to  claim 21 , wherein the RET kinase inhibiting substance is methanesulfonate of 4-(3-chloro-4-(cyclopropylaminocarbonyl)aminophenoxy)-7-methoxy-6-quinolinecarboxamide. 
     
     
         37 . A therapeutic agent comprising an RET kinase inhibiting substance for treating thyroid carcinoma, wherein said RET kinase inhibiting substance is at least one compound selected from the group consisting of: 
       5-(5-fluoro-2-oxo-1,2-dihydroindole-3-ylidenemethyl)-2,4-dimethyl-1H-pyrrole-3-carboxylic acid(2-diethylaminoethyl)amide; 
       N-{2-chloro-4-[(6,7-dimethoxy-4-quinolyl)oxy]phenyl}-N′-(5-methyl-3-isoxazolyl)urea; and 
       4-[(4-fluoro-2-methylindole-5-yl)oxy]-6-methoxy-7-[3-(pyrrolidine-1-yl)propoxy]quinazoline, 
       a pharmacologically acceptable salt thereof or a solvate thereof. 
     
     
         38 . The therapeutic agent according to  claim 21 , wherein the thyroid carcinoma comprises a cell expressing mutant RET. 
     
     
         39 . The therapeutic agent according to  claim 38 , wherein the mutant RET comprises a mutation site where at least one amino acid selected from the group consisting of amino acids at codons 321, 533, 609, 611, 618, 620, 630, 631, 634, 691, 768, 790, 791, 804, 806, 844, 883, 891 and 918 in the amino acid sequence represented by SEQ ID NO: 2 or 4 is substituted with other amino acid. 
     
     
         40 . The therapeutic agent according to  claim 38 , wherein the mutant RET is a polypeptide encoded by RET gene rearranged with at least one gene selected from the group consisting of H4 gene, RIα gene, ELE1 gene, RFG5 gene, hTIF gene, RFG7 gene, ELKS gene, kinectin gene, PCM-1 gene and RFP gene. 
     
     
         41 . A pharmaceutical composition comprising an RET kinase inhibiting substance for administering to an organism comprising a cell expressing mutant RET, wherein said RET kinase inhibiting substance is a compound represented by General Formula (I) 
       
         
           
           
               
               
           
         
       
       wherein, R 1  represents a group represented by Formula —V 1 —V 2 —V 3  (wherein, V 1  represents C 1-6  alkylene group that may have a substituent; V 2  represents a single bond, an oxygen atom, a sulfur atom, carbonyl group, sulfinyl group, sulfonyl group, group represented by Formula —CONR 6 —, group represented by Formula —SO 2 NR 6 —, group represented by Formula —NR 6 SO 2 —, group represented by Formula —NR 6 CO— or group represented by Formula —NR 6 — (wherein, R 6  represents a hydrogen atom, C 1-6  alkyl group that may have a substituent or C 3-8  cycloalkyl group that may have a substituent); V 3  represents a hydrogen atom, C 1-6  alkyl group that may have a substituent, C 2-6  alkenyl group that may have a substituent, C 2-6  alkynyl group that may have a substituent, C 3-8  cycloalkyl group that may have a substituent, C 6-10  aryl group that may have a substituent, 5-10-membered heteroaryl group that may have a substituent or 3-10-membered non-aromatic heterocyclic group that may have a substituent);
 R 2  represents cyano group, C 1-6  alkoxy group that may have a substituent, carboxyl group, C 2-7  alkoxycarbonyl group that may have a substituent or group represented by Formula —CONV a11 V a12  (wherein, V a11  represents a hydrogen atom, C 1-6  alkyl group that may have a substituent, C 2-6  alkenyl group that may have a substituent, C 2-6  alkynyl group that may have a substituent, C 3-8  cycloalkyl group that may have a substituent, C 6-10  aryl group that may have a substituent, 5-10-membered heteroaryl group that may have a substituent or 3-10-membered non-aromatic heterocyclic group that may have a substituent; V a12  represents a hydrogen atom, C 1-6  alkyl group that may have a substituent, C 2-6  alkenyl group that may have a substituent, C 2-6  alkynyl group that may have a substituent, C 3-8  cycloalkyl group that may have a substituent, C 6-10  aryl group that may have a substituent, 5-10-membered heteroaryl group that may have a substituent, 3-10-membered non-aromatic heterocyclic group that may have a substituent, hydroxyl group, C 1-6  alkoxy group that may have a substituent or C 3-8  cycloalkoxy group that may have a substituent); 
 Y 1  represents a group represented by Formula 
 
       
         
           
           
               
               
           
         
       
       (wherein, R 7  and R 8  each independently represent a hydrogen atom, a halogen atom, cyano group, nitro group, amino group, C 1-6  alkyl group that may have a substituent, C 3-8  cycloalkyl group that may have a substituent, C 1-6  alkoxy group that may have a substituent, C 1-6  alkylthio group that may have a substituent, formyl group, C 2-7  acyl group that may have a substituent, C 2-7  alkoxycarbonyl group that may have a substituent or group represented by Formula —CONV d1 V d2  (wherein, V d1  and V d2  each independently represent a hydrogen atom or C 1-6  alkyl group that may have a substituent);
 W 1  and W 2  each independently represent a carbon atom or a nitrogen atom that may have a substituent); 
 R 3  and R 4  each independently represent a hydrogen atom, C 1-6  alkyl group that may have a substituent, C 2-6  alkenyl group that may have a substituent, C 2-6  alkynyl group that may have a substituent, C 3-8  cycloalkyl group that may have a substituent, C 2-7  acyl group that may have a substituent or C 2-7  alkoxycarbonyl group that may have a substituent; and 
 R 5  represents a hydrogen atom, C 1-6  alkyl group that may have a substituent, C 2-6  alkenyl group that may have a substituent, C 2-6  alkynyl group that may have a substituent, C 3-8  cycloalkyl group that may have a substituent, C 6-10  aryl group that may have a substituent, 5-10-membered heteroaryl group that may have a substituent or 3-10-membered non-aromatic heterocyclic group that may have a substituent, 
 
       a pharmacologically acceptable salt thereof or a solvate thereof. 
     
     
         42 . The pharmaceutical composition according to  claim 41 , wherein R 1  is C 1-6  alkyl group (where, R 1  may have at least one substituent selected from the group consisting of 3-10-membered non-aromatic heterocyclic group that may have C 1-6  alkyl group, hydroxyl group, C 1-6  alkoxy group, amino group, mono-C 1-6  alkylamino group and di-C 1-6  alkylamino group). 
     
     
         43 . The pharmaceutical composition according to  claim 41 , wherein R 1  is methyl group or group represented by any one of the following Formulae 
       
         
           
           
               
               
           
         
       
       (wherein, R a3  represents methyl group; R a1  represents a hydrogen atom or hydroxyl group; R a2  represents methoxy group, ethoxy group, 1-pyrrolidinyl group, 1-piperidinyl group, 4-morpholinyl group, dimethylamino group or diethylamino group). 
     
     
         44 . The pharmaceutical composition according to  claim 41 , wherein R 1  is methyl group or 2-methoxyethyl group. 
     
     
         45 . The pharmaceutical composition according to  claim 41 , wherein R 2  represents cyano group or group represented by Formula —CONV a11 V a12  (wherein, V a11  represents a hydrogen atom, C 1-6  alkyl group that may have a substituent, C 2-6  alkenyl group that may have a substituent, C 2-6  alkynyl group that may have a substituent, C 3-8  cycloalkyl group that may have a substituent, C 6-10  aryl group that may have a substituent, 5-10-membered heteroaryl group that may have a substituent or 3-10-membered non-aromatic heterocyclic group that may have a substituent; V a12  represents a hydrogen atom, C 1-6  alkyl group that may have a substituent, C 2-6  alkenyl group that may have a substituent, C 2-6  alkynyl group that may have a substituent, C 3-8  cycloalkyl group that may have a substituent, C 6-10  aryl group that may have a substituent, 5-10-membered heteroaryl group that may have a substituent, 3-10-membered non-aromatic heterocyclic group that may have a substituent, hydroxyl group, C 1-6  alkoxy group that may have a substituent or C 3-8  cycloalkoxy group that may have a substituent). 
     
     
         46 . The pharmaceutical composition according to  claim 41 , wherein R 2  is cyano group or group represented by Formula —CONHV a16  (wherein, V a16  represents a hydrogen atom, C 1-6  alkyl group, C 3-8  cycloalkyl group, C 1-6  alkoxy group or C 3-8  cycloalkoxy group, where V a16  may have at least one substituent selected from the group consisting of a halogen atom, cyano group, hydroxyl group and C 1-6  alkoxy group). 
     
     
         47 . The pharmaceutical composition according to  claim 41 , wherein R 2  is a group represented by Formula —CONHV a17  (wherein, V a17  represents a hydrogen atom, C 1-6  alkyl group or C 1-6  alkoxy group). 
     
     
         48 . The pharmaceutical composition according to  claim 41 , wherein R 2  is a group represented by Formula —CONHV a18  (wherein, V a18  represents a hydrogen atom, methyl group or methoxy group). 
     
     
         49 . The pharmaceutical composition according to  claim 41 , wherein Y 1  is a group represented by Formula 
       
         
           
           
               
               
           
         
       
       (wherein, R 71  represents a hydrogen atom or a halogen atom). 
     
     
         50 . The pharmaceutical composition according to  claim 41 , wherein R 3  and R 4  is a hydrogen atom. 
     
     
         51 . The pharmaceutical composition according to  claim 41 , wherein R 5  is a hydrogen atom, C 1-6  alkyl group, C 3-8  cycloalkyl group or C 6-10  aryl group (where, R 5  may have at least one substituent selected from the group consisting of a halogen atom and methanesulfonyl group). 
     
     
         52 . The pharmaceutical composition according to  claim 41 , wherein R 5  is methyl group, ethyl group or cyclopropyl group. 
     
     
         53 . The pharmaceutical composition according to  claim 41 , wherein the RET kinase inhibiting substance is at least one compound selected from the group consisting of: 
       N-(4-(6-cyano-7-(2-methoxyethoxy)-4-quinolyl)oxy-2-fluorophenyl)-N′-(4-fluorophenyl)urea; 
       N-(2-chloro-4-((6-cyano-7-((1-methyl-4-piperidyl)methoxy)-4-quinolyl)oxy)phenyl)-N′-cyclopropylurea; 
       N-(4-((6-cyano-7-(((2R)-3-(diethylamino)-2-hydroxypropyl)oxy)-4-quinolyl)oxy)phenyl)-N′-(4-fluorophenyl)urea; 
       N-(4-((6-cyano-7-(((2R)-2-hydroxy-3-(1-pyrrolidino)propyl)oxy)-4-quinolyl)oxy)phenyl)-N′-(4-fluorophenyl)urea; 
       4-(3-chloro-4-(cyclopropylaminocarbonyl)aminophenoxy)-7-methoxy-6-quinolinecarboxamide; 
       4-(3-chloro-4-(cyclopropylaminocarbonyl)aminophenoxy)-7-(2-methoxyethoxy)-6-quinolinecarboxamide; 
       N6-cyclopropyl-4-(3-chloro-4-(((cyclopropylamino)carbonyl)amino)phenoxy)-7-methoxy-6-quinolinecarboxamide; 
       N6-(2-methoxyethyl)-4-(3-chloro-4-(((cyclopropylamino)carbonyl)amino)phenoxy)-7-methoxy-6-quinolinecarboxamide; 
       N6-(2-fluoroethyl)-4-(3-chloro-4-(((cyclopropylamino)carbonyl)amino)phenoxy)-7-methoxy-6-quinolinecarboxamide; 
       N6-methoxy-4-(3-chloro-4-(((cyclopropylamino)carbonyl)amino)phenoxy)-7-methoxy-6-quinolinecarboxamide; 
       N6-methyl-4-(3-chloro-4-(((cyclopropylamino)carbonyl)amino)phenoxy)-7-methoxy-6-quinolinecarboxamide; 
       N6-ethyl-4-(3-chloro-4-(((cyclopropylamino)carbonyl)amino)phenoxy)-7-methoxy-6-quinolinecarboxamide; 
       4-(3-fluoro-4-(cyclopropylaminocarbonyl)aminophenoxy)-7-(2-methoxyethoxy)-6-quinolinecarboxamide; 
       4-(3-chloro-4-(cyclopropylaminocarbonyl)aminophenoxy)-7-(2-hydroxyethoxy)-6-quinolinecarboxamide; 
       4-(3-chloro-4-(cyclopropylaminocarbonyl)aminophenoxy)-7-((2S)-2,3-dihydroxypropyl)oxy-6-quinolinecarboxamide; 
       4-(3-chloro-4-(methylaminocarbonyl)aminophenoxy)-7-methoxy-6-quinolinecarboxamide; 
       4-(3-chloro-4-(ethylaminocarbonyl)aminophenoxy)-7-methoxy-6-quinolinecarboxamide; 
       N6-methoxy-4-(3-chloro-4-(((ethylamino)carbonyl)amino)phenoxy)-7-methoxy-6-quinolinecarboxamide; 
       4-(3-chloro-4-(cyclopropylaminocarbonyl)aminophenoxy)-7-(2-ethoxyethoxy)-6-quinolinecarboxamide; 
       4-(4-((cyclopropylamino)carbonyl)aminophenoxy)-7-(2-methoxyethoxy)-6-quinolinecarboxamide; 
       N-(2-fluoro-4-((6-carbamoyl-7-methoxy-4-quinolyl)oxy)phenyl)-N′-cyclopropylurea; 
       N6-(2-hydroxyethyl)-4-(3-chloro-4-(((cyclopropylamino)carbonyl)amino)phenoxy)-7-methoxy-6-quinolinecarboxamide; 
       4-(3-chloro-4-(1-propylaminocarbonyl)aminophenoxy)-7-methoxy-6-quinolinecarboxamide; 
       4-(3-chloro-4-(cis-2-fluoro-cyclopropylaminocarbonyl)aminophenoxy)-7-methoxy-6-quinolinecarboxamide; 
       N6-methyl-4-(3-chloro-4-(((cyclopropylamino)carbonyl)amino)phenoxy)-7-(2-methoxyethoxy)-6-quinolinecarboxamide; 
       N6-methyl-4-(3-chloro-4-(((ethylamino)carbonyl)amino)phenoxy)-7-methoxy-6-quinolinecarboxamide; 
       4-(3-chloro-4-(cyclopropylaminocarbonyl)aminophenoxy)-7-(2-(4-morpholino) ethoxy)-6-quinolinecarboxamide; 
       4-(3-chloro-4-(2-fluoroethylaminocarbonyl)aminophenoxy)-7-methoxy-6-quinolinecarboxamide; 
       N6-((2R)tetrahydro-2-furanylmethyl)-4-(3-chloro-4-(((methylamino)carbonyl)amino) phenoxy)-7-methoxy-6-quinolinecarboxamide; 
       4-(3-fluoro-4-(ethylaminocarbonyl)aminophenoxy)-7-methoxy-6-quinolinecarboxamide; 
       4-(3-chloro-4-(((cyclopropylamino)carbonyl)amino)phenoxy)-7-((2R)-2-hydroxy-3-(1-pyrrolidino)propoxy)-6-quinolinecarboxamide; 
       N6-methyl-4-(3-chloro-4-(((methylamino)carbonyl)amino)phenoxy)-7-((2R)-3-diethylamino-2-hydroxypropoxy)-6-quinolinecarboxamide; 
       N6-methyl-4-(3-chloro-4-(((ethylamino)carbonyl)amino)phenoxy)-7-((2R)-3-diethylamino-2-hydroxypropoxy)-6-quinolinecarboxamide; 
       N6-methyl-4-(3-chloro-4-(((methylamino)carbonyl)amino)phenoxy)-7-((2R)-2-hydroxy-3-(1-pyrrolidino)propoxy)-6-quinolinecarboxamide; 
       N6-methyl-4-(3-chloro-4-(((ethylamino)carbonyl)amino)phenoxy)-7-((2R)-2-hydroxy-3-(1-pyrrolidino)propoxy)-6-quinolinecarboxamide; 
       N6-methyl-4-(3-chloro-4-(((methylamino)carbonyl)amino)phenoxy)-7-((1-methyl-4-piperidyl)methoxy)-6-quinolinecarboxamide; 
       N6-methyl-4-(3-chloro-4-(((ethylamino)carbonyl)amino)phenoxy)-7-((1-methyl-4-piperidyl)methoxy)-6-quinolinecarboxamide; 
       N-(4-(6-cyano-7-(2-methoxyethoxy)-4-quinolyl)oxy-2-fluorophenyl)-N′-cyclopropylurea; 
       N-(4-(6-cyano-7-(3-(4-morpholino)propoxy)-4-quinolyl)oxyphenyl)-N′-(3-(methylsulfonyl)phenyl)urea; 
       4-(4-((cyclopropylamino)carbonyl)aminophenoxy)-7-methoxy-6-quinolinecarboxamide; 
       4-(3-fluoro-4-((2-fluoroethylamino)carbonyl)aminophenoxy)-7-methoxy-6-quinolinecarboxamide; 
       N6-(2-ethoxyethyl)-4-(3-chloro-4-(((methylamino)carbonyl)amino)phenoxy)-7-methoxy-6-quinolinecarboxamide; 
       4-(4-(3-ethylureido)-3-fluoro-phenoxy)-7-methoxyquinoline-6-carboxylic acid (2-cyanoethyl)amide; and 
       N-(4-(6-(2-cyanoethyl)carbamoyl-7-methoxy-4-quinolyl)oxy-2-fluorophenyl)-N′-cyclopropylurea, 
       a pharmacologically acceptable salt thereof or a solvate thereof. 
     
     
         54 . The pharmaceutical composition according to  claim 41 , wherein the RET kinase inhibiting substance is at least one compound selected from the group consisting of: 
       4-(3-chloro-4-(cyclopropylaminocarbonyl)aminophenoxy)-7-methoxy-6-quinolinecarboxamide; 
       4-(3-chloro-4-(ethylaminocarbonyl)aminophenoxy)-7-methoxy-6-quinolinecarboxamide; 
       N6-methoxy-4-(3-chloro-4-(((cyclopropylamino)carbonyl)amino)phenoxy)-7-methoxy-6-quinolinecarboxamide; 
       4-(3-chloro-4-(methylaminocarbonyl)aminophenoxy)-7-methoxy-6-quinolinecarboxamide; and 
       N6-methoxy-4-(3-chloro-4-(((ethylamino)carbonyl)amino)phenoxy)-7-methoxy-6-quinolinecarboxamide, 
       a pharmacologically acceptable salt thereof or a solvate thereof. 
     
     
         55 . The pharmaceutical composition according to  claim 41 , wherein the RET kinase inhibiting substance is 4-(3-chloro-4-(cyclopropylaminocarbonyl)aminophenoxy)-7-methoxy-6-quinolinecarboxamide, a pharmacologically acceptable salt thereof or a solvate thereof. 
     
     
         56 . The pharmaceutical composition according to  claim 41 , wherein the RET kinase inhibiting substance is methanesulfonate of 4-(3-chloro-4-(cyclopropylaminocarbonyl)aminophenoxy)-7-methoxy-6-quinolinecarboxamide. 
     
     
         57 . A pharmaceutical composition comprising an RET kinase inhibiting substance for administering to an organism comprising a cell expressing mutant RET, wherein said RET kinase inhibiting substance is at least one compound selected from the group consisting of: 
       5-(5-fluoro-2-oxo-1,2-dihydroindole-3-ylidenemethyl)-2,4-dimethyl-1H-pyrrole-3-carboxylic acid(2-diethylaminoethyl)amide; 
       N-{2-chloro-4-[(6,7-dimethoxy-4-quinolyl)oxy]phenyl}-N′-(5-methyl-3-isoxazolyl)urea; and 
       4-[(4-fluoro-2-methylindole-5-yl)oxy]-6-methoxy-7-[3-(pyrrolidine-1-yl)propoxy]quinazoline, 
       a pharmacologically acceptable salt thereof or a solvate thereof. 
     
     
         58 . The pharmaceutical composition according to  claim 41 , wherein the mutant RET comprises a mutation site where at least one amino acid selected from the group consisting of amino acids at codons 321, 533, 609, 611, 618, 620, 630, 631, 634, 691, 768, 790, 791, 804, 806, 844, 883, 891 and 918 in the amino acid sequence represented by SEQ ID NO: 2 or 4 is substituted with other amino acid. 
     
     
         59 . The pharmaceutical composition according to  claim 41 , wherein the mutant RET is a polypeptide encoded by RET gene rearranged with at least one gene selected from the group consisting of H4 gene, RIα gene, ELE1 gene, RFG5 gene, hTIF gene, RFG7 gene, ELKS gene, kinectin gene, PCM-1 gene and RFP gene. 
     
     
         60 . The pharmaceutical composition according to  claim 41 , wherein the organism is a patient suffering from at least one disease selected from the group consisting of multiple endocrine neoplasia, type IIA, multiple endocrine neoplasia, type IIB, familial medullary thyroid carcinoma, thyroid carcinoma, papillary thyroid carcinoma, sporadic medullary thyroid carcinoma, Hirschsprung disease, pheochromocytoma, parathyroid hyperplasia and mucosal neuromas of the gastrointestinal tract. 
     
     
         61 . A method for treating at least one disease selected from the group consisting of multiple endocrine neoplasia, type IIA, multiple endocrine neoplasia, type IIB, familial medullary thyroid carcinoma, papillary thyroid carcinoma, sporadic medullary thyroid carcinoma, Hirschsprung disease, pheochromocytoma, parathyroid hyperplasia and mucosal neuromas of the gastrointestinal tract, the method comprising the step of administering an effective amount of an RET kinase inhibiting substance to a patient, wherein said RET kinase inhibiting substance is a compound represented by General Formula (I) 
       
         
           
           
               
               
           
         
       
       wherein, R 1  represents a group represented by Formula —V 1 —V 2 —V 3  (wherein, V 1  represents C 1-6  alkylene group that may have a substituent; V 2  represents a single bond, an oxygen atom, a sulfur atom, carbonyl group, sulfinyl group, sulfonyl group, group represented by Formula —CONR 6 —, group represented by Formula —SO 2 NR 6 —, group represented by Formula —NR 6 SO 2 —, group represented by Formula —NR 6 CO— or group represented by Formula —NR 6 — (wherein, R 6  represents a hydrogen atom, C 1-6  alkyl group that may have a substituent or C 3-8  cycloalkyl group that may have a substituent); V 3  represents a hydrogen atom, C 1-6  alkyl group that may have a substituent, C 2-6  alkenyl group that may have a substituent, C 2-6  alkynyl group that may have a substituent, C 3-8  cycloalkyl group that may have a substituent, C 6-10  aryl group that may have a substituent, 5-10-membered heteroaryl group that may have a substituent or 3-10-membered non-aromatic heterocyclic group that may have a substituent);
 R 2  represents cyano group, C 1-6  alkoxy group that may have a substituent, carboxyl group, C 2-7  alkoxycarbonyl group that may have a substituent or group represented by Formula —CONV a11 V a12  (wherein, V a11  represents a hydrogen atom, C 1-6  alkyl group that may have a substituent, C 2-6  alkenyl group that may have a substituent, C 2-6  alkynyl group that may have a substituent, C 3-8  cycloalkyl group that may have a substituent, C 6-10  aryl group that may have a substituent, 5-10-membered heteroaryl group that may have a substituent or 3-10-membered non-aromatic heterocyclic group that may have a substituent; V a12  represents a hydrogen atom, C 1-6  alkyl group that may have a substituent, C 2-6  alkenyl group that may have a substituent, C 2-6  alkynyl group that may have a substituent, C 3-8  cycloalkyl group that may have a substituent, C 6-10  aryl group that may have a substituent, 5-10-membered heteroaryl group that may have a substituent, 3-10-membered non-aromatic heterocyclic group that may have a substituent, hydroxyl group, C 1-6  alkoxy group that may have a substituent or C 3-8  cycloalkoxy group that may have a substituent); 
 Y 1  represents a group represented by Formula 
 
       
         
           
           
               
               
           
         
       
       (wherein, R 7  and R 8  each independently represent a hydrogen atom, a halogen atom, cyano group, nitro group, amino group, C 1-6  alkyl group that may have a substituent, C 3-8  cycloalkyl group that may have a substituent, C 1-6  alkoxy group that may have a substituent, C 1-6  alkylthio group that may have a substituent, formyl group, C 2-7  acyl group that may have a substituent, C 2-7  alkoxycarbonyl group that may have a substituent or group represented by Formula —CONV d1 V d2  (wherein, V d1  and V d2  each independently represent a hydrogen atom or C 1-6  alkyl group that may have a substituent);
 W 1  and W 2  each independently represent a carbon atom or a nitrogen atom that may have a substituent); 
 R 3  and R 4  each independently represent a hydrogen atom, C 1-6  alkyl group that may have a substituent, C 2-6  alkenyl group that may have a substituent, C 2-6  alkynyl group that may have a substituent, C 3-8  cycloalkyl group that may have a substituent, C 2-7  acyl group that may have a substituent or C 2-7  alkoxycarbonyl group that may have a substituent; and 
 R 5  represents a hydrogen atom, C 1-6  alkyl group that may have a substituent, C 2-6  alkenyl group that may have a substituent, C 2-6  alkynyl group that may have a substituent, C 3-8  cycloalkyl group that may have a substituent, C 6-10  aryl group that may have a substituent, 5-10-membered heteroaryl group that may have a substituent or 3-10-membered non-aromatic heterocyclic group that may have a substituent, 
 
       a pharmacologically acceptable salt thereof or a solvate thereof. 
     
     
         62 . A method for treating at least one disease selected from the group consisting of multiple endocrine neoplasia, type IIA, multiple endocrine neoplasia, type IIB, familial medullary thyroid carcinoma, papillary thyroid carcinoma, sporadic medullary thyroid carcinoma, Hirschsprung disease, pheochromocytoma, parathyroid hyperplasia and mucosal neuromas of the gastrointestinal tract, the method comprising the step of administering an effective amount of an RET kinase inhibiting substance to a patient, wherein said RET kinase inhibiting substance is at least one compound selected from the group consisting of: 
       5-(5-fluoro-2-oxo-1,2-dihydroindole-3-ylidenemethyl)-2,4-dimethyl-1H-pyrrole-3-carboxylic acid(2-diethylaminoethyl)amide; 
       N-{2-chloro-4-[(6,7-dimethoxy-4-quinolyl)oxy]phenyl}-N′-(5-methyl-3-isoxazolyl)urea; and 
       4-[(4-fluoro-2-methylindole-5-yl)oxy]-6-methoxy-7-[3-(pyrrolidine-1-yl)propoxy]quinazoline, 
       a pharmacologically acceptable salt thereof or a solvate thereof. 
     
     
         63 . A method for treating thyroid carcinoma, comprising the step of administering an effective amount of an RET kinase inhibiting substance to a patient, wherein said RET kinase inhibiting substance is a compound represented by General Formula (I) 
       
         
           
           
               
               
           
         
       
       wherein, R 1  represents a group represented by Formula —V 1 —V 2 —V 3  (wherein, V 1  represents C 1-6  alkylene group that may have a substituent; V 2  represents a single bond, an oxygen atom, a sulfur atom, carbonyl group, sulfinyl group, sulfonyl group, group represented by Formula —CONR 6 —, group represented by Formula —SO 2 NR 6 —, group represented by Formula —NR 6 SO 2 —, group represented by Formula —NR 6 CO— or group represented by Formula —NR 6 — (wherein, R 6  represents a hydrogen atom, C 1-6  alkyl group that may have a substituent or C 3-8  cycloalkyl group that may have a substituent); V 3  represents a hydrogen atom, C 1-6  alkyl group that may have a substituent, C 2-6  alkenyl group that may have a substituent, C 2-6  alkynyl group that may have a substituent, C 3-8  cycloalkyl group that may have a substituent, C 6-10  aryl group that may have a substituent, 5-10-membered heteroaryl group that may have a substituent or 3-10-membered non-aromatic heterocyclic group that may have a substituent);
 R 2  represents cyano group, C 1-6  alkoxy group that may have a substituent, carboxyl group, C 2-7  alkoxycarbonyl group that may have a substituent or group represented by Formula —CONV a11 V a12  (wherein, V a11  represents a hydrogen atom, C 1-6  alkyl group that may have a substituent, C 2-6  alkenyl group that may have a substituent, C 2-6  alkynyl group that may have a substituent, C 3-8  cycloalkyl group that may have a substituent, C 6-10  aryl group that may have a substituent, 5-10-membered heteroaryl group that may have a substituent or 3-10-membered non-aromatic heterocyclic group that may have a substituent; V a12  represents a hydrogen atom, C 1-6  alkyl group that may have a substituent, C 2-6  alkenyl group that may have a substituent, C 2-6  alkynyl group that may have a substituent, C 3-8  cycloalkyl group that may have a substituent, C 6-10  aryl group that may have a substituent, 5-10-membered heteroaryl group that may have a substituent, 3-10-membered non-aromatic heterocyclic group that may have a substituent, hydroxyl group, C 1-6  alkoxy group that may have a substituent or C 3-8  cycloalkoxy group that may have a substituent); 
 Y 1  represents a group represented by Formula 
 
       
         
           
           
               
               
           
         
       
       (wherein, R 7  and R 8  each independently represent a hydrogen atom, a halogen atom, cyano group, nitro group, amino group, C 1-6  alkyl group that may have a substituent, C 3-8  cycloalkyl group that may have a substituent, C 1-6  alkoxy group that may have a substituent, C 1-6  alkylthio group that may have a substituent, formyl group, C 2-7  acyl group that may have a substituent, C 2-7  alkoxycarbonyl group that may have a substituent or group represented by Formula —CONV d1 V d2  (wherein, V d1  and V d2  each independently represent a hydrogen atom or C 1-6  alkyl group that may have a substituent);
 W 1  and W 2  each independently represent a carbon atom or a nitrogen atom that may have a substituent); 
 R 3  and R 4  each independently represent a hydrogen atom, C 1-6  alkyl group that may have a substituent, C 2-6  alkenyl group that may have a substituent, C 2-6  alkynyl group that may have a substituent, C 3-8  cycloalkyl group that may have a substituent, C 2-7  acyl group that may have a substituent or C 2-7  alkoxycarbonyl group that may have a substituent; and 
 R 5  represents a hydrogen atom, C 1-6  alkyl group that may have a substituent, C 2-6  alkenyl group that may have a substituent, C 2-6  alkynyl group that may have a substituent, C 3-8  cycloalkyl group that may have a substituent, C 6-10  aryl group that may have a substituent, 5-10-membered heteroaryl group that may have a substituent or 3-10-membered non-aromatic heterocyclic group that may have a substituent, 
 
       a pharmacologically acceptable salt thereof or a solvate thereof. 
     
     
         64 . A method for treating thyroid carcinoma, comprising the step of administering an effective amount of an RET kinase inhibiting substance to a patient, wherein said RET kinase inhibiting substance is at least one compound selected from the group consisting of: 
       5-(5-fluoro-2-oxo-1,2-dihydroindole-3-ylidenemethyl)-2,4-dimethyl-1H-pyrrole-3-carboxylic acid(2-diethylaminoethyl)amide; 
       N-{2-chloro-4-[(6,7-dimethoxy-4-quinolyl)oxy]phenyl}-N′-(5-methyl-3-isoxazolyl)urea; and 
       4-[(4-fluoro-2-methylindole-5-yl)oxy]-6-methoxy-7-[3-(pyrrolidine-1-yl)propoxy]quinazoline, 
       a pharmacologically acceptable salt thereof or a solvate thereof. 
     
     
         65 . A method for treating a disease, comprising the step of administering an effective amount of an RET kinase inhibiting substance to an organism comprising a cell expressing mutant RET, wherein said RET kinase inhibiting substance is a compound represented by General Formula (I) 
       
         
           
           
               
               
           
         
       
       wherein, R 1  represents a group represented by Formula —V 1 —V 2 —V 3  (wherein, V 1  represents C 1-6  alkylene group that may have a substituent; V 2  represents a single bond, an oxygen atom, a sulfur atom, carbonyl group, sulfinyl group, sulfonyl group, group represented by Formula —CONR 6 —, group represented by Formula —SO 2 NR 6 —, group represented by Formula —NR 6 SO 2 —, group represented by Formula —NR 6 CO— or group represented by Formula —NR 6 — (wherein, R 6  represents a hydrogen atom, C 1-6  alkyl group that may have a substituent or C 3-8  cycloalkyl group that may have a substituent); V 3  represents a hydrogen atom, C 1-6  alkyl group that may have a substituent, C 2-6  alkenyl group that may have a substituent, C 2-6  alkynyl group that may have a substituent, C 3-8  cycloalkyl group that may have a substituent, C 6-10  aryl group that may have a substituent, 5-10-membered heteroaryl group that may have a substituent or 3-10-membered non-aromatic heterocyclic group that may have a substituent);
 R 2  represents cyano group, C 1-6  alkoxy group that may have a substituent, carboxyl group, C 2-7  alkoxycarbonyl group that may have a substituent or group represented by Formula —CONV a11 V a12  (wherein, V a11  represents a hydrogen atom, C 1-6  alkyl group that may have a substituent, C 2-6  alkenyl group that may have a substituent, C 2-6  alkynyl group that may have a substituent, C 3-8  cycloalkyl group that may have a substituent, C 6-10  aryl group that may have a substituent, 5-10-membered heteroaryl group that may have a substituent or 3-10-membered non-aromatic heterocyclic group that may have a substituent; V a12  represents a hydrogen atom, C 1-6  alkyl group that may have a substituent, C 2-6  alkenyl group that may have a substituent, C 2-6  alkynyl group that may have a substituent, C 3-8  cycloalkyl group that may have a substituent, C 6-10  aryl group that may have a substituent, 5-10-membered heteroaryl group that may have a substituent, 3-10-membered non-aromatic heterocyclic group that may have a substituent, hydroxyl group, C 1-6  alkoxy group that may have a substituent or C 3-8  cycloalkoxy group that may have a substituent); 
 Y 1  represents a group represented by Formula 
 
       
         
           
           
               
               
           
         
       
       (wherein, R 7  and R 8  each independently represent a hydrogen atom, a halogen atom, cyano group, nitro group, amino group, C 1-6  alkyl group that may have a substituent, C 3-8  cycloalkyl group that may have a substituent, C 1-6  alkoxy group that may have a substituent, C 1-6  alkylthio group that may have a substituent, formyl group, C 2-7  acyl group that may have a substituent, C 2-7  alkoxycarbonyl group that may have a substituent or group represented by Formula —CONV d1 V d2  (wherein, V d1  and V d2  each independently represent a hydrogen atom or C 1-6  alkyl group that may have a substituent);
 W 1  and W 2  each independently represent a carbon atom or a nitrogen atom that may have a substituent); 
 R 3  and R 4  each independently represent a hydrogen atom, C 1-6  alkyl group that may have a substituent, C 2-6  alkenyl group that may have a substituent, C 2-6  alkynyl group that may have a substituent, C 3-8  cycloalkyl group that may have a substituent, C 2-7  acyl group that may have a substituent or C 2-7  alkoxycarbonyl group that may have a substituent; and 
 R 5  represents a hydrogen atom, C 1-6  alkyl group that may have a substituent, C 2-6  alkenyl group that may have a substituent, C 2-6  alkynyl group that may have a substituent, C 3-8  cycloalkyl group that may have a substituent, C 6-10  aryl group that may have a substituent, 5-10-membered heteroaryl group that may have a substituent or 3-10-membered non-aromatic heterocyclic group that may have a substituent, 
 
       a pharmacologically acceptable salt thereof or a solvate thereof. 
     
     
         66 . A method for treating a disease, comprising the step of administering an effective amount of an RET kinase inhibiting substance to an organism comprising a cell expressing mutant RET, wherein said RET kinase inhibiting substance is at least one compound selected from the group consisting of: 
       5-(5-fluoro-2-oxo-1,2-dihydroindole-3-ylidenemethyl)-2,4-dimethyl-1H-pyrrole-3-carboxylic acid(2-diethylaminoethyl)amide; 
       N-{2-chloro-4-[(6,7-dimethoxy-4-quinolyl)oxy]phenyl}-N′-(5-methyl-3-isoxazolyl)urea; and 
       4-[(4-fluoro-2-methylindole-5-yl)oxy]-6-methoxy-7-[3-(pyrrolidine-1-yl)propoxy]quinazoline, 
       a pharmacologically acceptable salt thereof or a solvate thereof. 
     
     
         67 - 72 . (canceled) 
     
     
         73 . An RET kinase inhibiting substance for a therapeutic agent for treating at least one disease selected from the group consisting of multiple endocrine neoplasia, type IIA, multiple endocrine neoplasia, type IIB, familial medullary thyroid carcinoma, papillary thyroid carcinoma, sporadic medullary thyroid carcinoma, Hirschsprung disease, pheochromocytoma, parathyroid hyperplasia and mucosal neuromas of the gastrointestinal tract, wherein said RET kinase inhibiting substance is a compound represented by General Formula (I) 
       
         
           
           
               
               
           
         
       
       wherein, R 1  represents a group represented by Formula —V 1 —V 2 —V 3  (wherein, V 1  represents C 1-6  alkylene group that may have a substituent; V 2  represents a single bond, an oxygen atom, a sulfur atom, carbonyl group, sulfinyl group, sulfonyl group, group represented by Formula —CONR 6 —, group represented by Formula —SO 2 NR 6 —, group represented by Formula —NR 6 SO 2 —, group represented by Formula —NR 6 CO— or group represented by Formula —NR 6 — (wherein, R 6  represents a hydrogen atom, C 1-6  alkyl group that may have a substituent or C 3-8  cycloalkyl group that may have a substituent); V 3  represents a hydrogen atom, C 1-6  alkyl group that may have a substituent, C 2-6  alkenyl group that may have a substituent, C 2-6  alkynyl group that may have a substituent, C 3-8  cycloalkyl group that may have a substituent, C 6-10  aryl group that may have a substituent, 5-10-membered heteroaryl group that may have a substituent or 3-10-membered non-aromatic heterocyclic group that may have a substituent);
 R 2  represents cyano group, C 1-6  alkoxy group that may have a substituent, carboxyl group, C 2-7  alkoxycarbonyl group that may have a substituent or group represented by Formula —CONV a11 V a12  (wherein, V a11  represents a hydrogen atom, C 1-6  alkyl group that may have a substituent, C 2-6  alkenyl group that may have a substituent, C 2-6  alkynyl group that may have a substituent, C 3-8  cycloalkyl group that may have a substituent, C 6-10  aryl group that may have a substituent, 5-10-membered heteroaryl group that may have a substituent or 3-10-membered non-aromatic heterocyclic group that may have a substituent; V a12  represents a hydrogen atom, C 1-6  alkyl group that may have a substituent, C 2-6  alkenyl group that may have a substituent, C 2-6  alkynyl group that may have a substituent, C 3-8  cycloalkyl group that may have a substituent, C 6-10  aryl group that may have a substituent, 5-10-membered heteroaryl group that may have a substituent, 3-10-membered non-aromatic heterocyclic group that may have a substituent, hydroxyl group, C 1-6  alkoxy group that may have a substituent or C 3-8  cycloalkoxy group that may have a substituent); 
 Y 1  represents a group represented by Formula 
 
       
         
           
           
               
               
           
         
       
       (wherein, R 7  and R 8  each independently represent a hydrogen atom, a halogen atom, cyano group, nitro group, amino group, C 1-6  alkyl group that may have a substituent, C 3-8  cycloalkyl group that may have a substituent, C 1-6  alkoxy group that may have a substituent, C 1-6  alkylthio group that may have a substituent, formyl group, C 2-7  acyl group that may have a substituent, C 2-7  alkoxycarbonyl group that may have a substituent or group represented by Formula —CONV d1 V d2  (wherein, V d1  and V d2  each independently represent a hydrogen atom or C 1-6  alkyl group that may have a substituent);
 W 1  and W 2  each independently represent a carbon atom or a nitrogen atom that may have a substituent); 
 R 3  and R 4  each independently represent a hydrogen atom, C 1-6  alkyl group that may have a substituent, C 2-6  alkenyl group that may have a substituent, C 2-6  alkynyl group that may have a substituent, C 3-8  cycloalkyl group that may have a substituent, C 2-7  acyl group that may have a substituent or C 2-7  alkoxycarbonyl group that may have a substituent; and 
 R 5  represents a hydrogen atom, C 1-6  alkyl group that may have a substituent, C 2-6  alkenyl group that may have a substituent, C 2-6  alkynyl group that may have a substituent, C 3-8  cycloalkyl group that may have a substituent, C 6-10  aryl group that may have a substituent, 5-10-membered heteroaryl group that may have a substituent or 3-10-membered non-aromatic heterocyclic group that may have a substituent, 
 
       a pharmacologically acceptable salt thereof or a solvate thereof. 
     
     
         74 . An RET kinase inhibiting substance for a therapeutic agent for treating at least one disease selected from the group consisting of multiple endocrine neoplasia, type IIA, multiple endocrine neoplasia, type IIB, familial medullary thyroid carcinoma, papillary thyroid carcinoma, sporadic medullary thyroid carcinoma, Hirschsprung disease, pheochromocytoma, parathyroid hyperplasia and mucosal neuromas of the gastrointestinal tract, wherein said RET kinase inhibiting substance is at least one compound selected from the group consisting of: 
       5-(5-fluoro-2-oxo-1,2-dihydroindole-3-ylidenemethyl)-2,4-dimethyl-1H-pyrrole-3-carboxylic acid(2-diethylaminoethyl)amide; 
       N-{2-chloro-4-[(6,7-dimethoxy-4-quinolyl)oxy]phenyl}-N′-(5-methyl-3-isoxazolyl)urea; and 
       4-[(4-fluoro-2-methylindole-5-yl)oxy]-6-methoxy-7-[3-(pyrrolidine-1-yl)propoxy]quinazoline, 
       a pharmacologically acceptable salt thereof or a solvate thereof. 
     
     
         75 . An RET kinase inhibiting substance for a therapeutic agent for treating thyroid carcinoma, wherein said RET kinase inhibiting substance is a compound represented by General Formula (I) 
       
         
           
           
               
               
           
         
       
       wherein, R 1  represents a group represented by Formula —V 1 —V 2 —V 3  (wherein, V 1  represents C 1-6  alkylene group that may have a substituent; V 2  represents a single bond, an oxygen atom, a sulfur atom, carbonyl group, sulfinyl group, sulfonyl group, group represented by Formula —CONR 6 —, group represented by Formula —SO 2 NR 6 —, group represented by Formula —NR 6 SO 2 —, group represented by Formula —NR 6 CO— or group represented by Formula —NR 6 — (wherein, R 6  represents a hydrogen atom, C 1-6  alkyl group that may have a substituent or C 3-8  cycloalkyl group that may have a substituent); V 3  represents a hydrogen atom, C 1-6  alkyl group that may have a substituent, C 2-6  alkenyl group that may have a substituent, C 2-6  alkynyl group that may have a substituent, C 3-8  cycloalkyl group that may have a substituent, C 6-10  aryl group that may have a substituent, 5-10-membered heteroaryl group that may have a substituent or 3-10-membered non-aromatic heterocyclic group that may have a substituent);
 R 2  represents cyano group, C 1-6  alkoxy group that may have a substituent, carboxyl group, C 2-7  alkoxycarbonyl group that may have a substituent or group represented by Formula —CONV a11 V a12  (wherein, V a11  represents a hydrogen atom, C 1-6  alkyl group that may have a substituent, C 2-6  alkenyl group that may have a substituent, C 2-6  alkynyl group that may have a substituent, C 3-8  cycloalkyl group that may have a substituent, C 6-10  aryl group that may have a substituent, 5-10-membered heteroaryl group that may have a substituent or 3-10-membered non-aromatic heterocyclic group that may have a substituent; V a12  represents a hydrogen atom, C 1-6  alkyl group that may have a substituent, C 2-6  alkenyl group that may have a substituent, C 2-6  alkynyl group that may have a substituent, C 3-8  cycloalkyl group that may have a substituent, C 6-10  aryl group that may have a substituent, 5-10-membered heteroaryl group that may have a substituent, 3-10-membered non-aromatic heterocyclic group that may have a substituent, hydroxyl group, C 1-6  alkoxy group that may have a substituent or C 3-8  cycloalkoxy group that may have a substituent); 
 Y 1  represents a group represented by Formula 
 
       
         
           
           
               
               
           
         
       
       (wherein, R 7  and R 8  each independently represent a hydrogen atom, a halogen atom, cyano group, nitro group, amino group, C 1-6  alkyl group that may have a substituent, C 3-8  cycloalkyl group that may have a substituent, C 1-6  alkoxy group that may have a substituent, C 1-6  alkylthio group that may have a substituent, formyl group, C 2-7  acyl group that may have a substituent, C 2-7  alkoxycarbonyl group that may have a substituent or group represented by Formula —CONV d1 V d2  (wherein, V d1  and V d2  each independently represent a hydrogen atom or C 1-6  alkyl group that may have a substituent);
 W 1  and W 2  each independently represent a carbon atom or a nitrogen atom that may have a substituent); 
 R 3  and R 4  each independently represent a hydrogen atom, C 1-6  alkyl group that may have a substituent, C 2-6  alkenyl group that may have a substituent, C 2-6  alkynyl group that may have a substituent, C 3-8  cycloalkyl group that may have a substituent, C 2-7  acyl group that may have a substituent or C 2-7  alkoxycarbonyl group that may have a substituent; and 
 R 5  represents a hydrogen atom, C 1-6  alkyl group that may have a substituent, C 2-6  alkenyl group that may have a substituent, C 2-6  alkynyl group that may have a substituent, C 3-8  cycloalkyl group that may have a substituent, C 6-10  aryl group that may have a substituent, 5-10-membered heteroaryl group that may have a substituent or 3-10-membered non-aromatic heterocyclic group that may have a substituent, 
 
       a pharmacologically acceptable salt thereof or a solvate thereof. 
     
     
         76 . An RET kinase inhibiting substance for a therapeutic agent for treating thyroid carcinoma, wherein said RET kinase inhibiting substance is at least one compound selected from the group consisting of: 
       5-(5-fluoro-2-oxo-1,2-dihydroindole-3-ylidenemethyl)-2,4-dimethyl-1H-pyrrole-3-carboxylic acid(2-diethylaminoethyl)amide; 
       N-{2-chloro-4-[(6,7-dimethoxy-4-quinolyl)oxy]phenyl}-N′-(5-methyl-3-isoxazolyl)urea; and 
       4-[(4-fluoro-2-methylindole-5-yl)oxy]-6-methoxy-7-[3-(pyrrolidine-1-yl)propoxy]quinazoline, 
       a pharmacologically acceptable salt thereof or a solvate thereof. 
     
     
         77 . An RET kinase inhibiting substance for a pharmaceutical composition comprising the RET kinase inhibiting substance for administering to an organism comprising a cell expressing mutant RET, wherein said RET kinase inhibiting substance is a compound represented by General Formula (I) 
       
         
           
           
               
               
           
         
       
       wherein, R 1  represents a group represented by Formula —V 1 —V 2 —V 3  (wherein, V 1  represents C 1-6  alkylene group that may have a substituent; V 2  represents a single bond, an oxygen atom, a sulfur atom, carbonyl group, sulfinyl group, sulfonyl group, group represented by Formula —CONR 6 —, group represented by Formula —SO 2 NR 6 —, group represented by Formula —NR 6 SO 2 —, group represented by Formula —NR 6 CO— or group represented by Formula —NR 6 — (wherein, R 6  represents a hydrogen atom, C 1-6  alkyl group that may have a substituent or C 3-8  cycloalkyl group that may have a substituent); V 3  represents a hydrogen atom, C 1-6  alkyl group that may have a substituent, C 2-6  alkenyl group that may have a substituent, C 2-6  alkynyl group that may have a substituent, C 3-8  cycloalkyl group that may have a substituent, C 6-10  aryl group that may have a substituent, 5-10-membered heteroaryl group that may have a substituent or 3-10-membered non-aromatic heterocyclic group that may have a substituent);
 R 2  represents cyano group, C 1-6  alkoxy group that may have a substituent, carboxyl group, C 2-7  alkoxycarbonyl group that may have a substituent or group represented by Formula —CONV a11 V a12  (wherein, V a11  represents a hydrogen atom, C 1-6  alkyl group that may have a substituent, C 2-6  alkenyl group that may have a substituent, C 2-6  alkynyl group that may have a substituent, C 3-8  cycloalkyl group that may have a substituent, C 6-10  aryl group that may have a substituent, 5-10-membered heteroaryl group that may have a substituent or 3-10-membered non-aromatic heterocyclic group that may have a substituent; V a12  represents a hydrogen atom, C 1-6  alkyl group that may have a substituent, C 2-6  alkenyl group that may have a substituent, C 2-6  alkynyl group that may have a substituent, C 3-8  cycloalkyl group that may have a substituent, C 6-10  aryl group that may have a substituent, 5-10-membered heteroaryl group that may have a substituent, 3-10-membered non-aromatic heterocyclic group that may have a substituent, hydroxyl group, C 1-6  alkoxy group that may have a substituent or C 3-8  cycloalkoxy group that may have a substituent); 
 Y 1  represents a group represented by Formula 
 
       
         
           
           
               
               
           
         
       
       (wherein, R 7  and R 8  each independently represent a hydrogen atom, a halogen atom, cyano group, nitro group, amino group, C 1-6  alkyl group that may have a substituent, C 3-8  cycloalkyl group that may have a substituent, C 1-6  alkoxy group that may have a substituent, C 1-6  alkylthio group that may have a substituent, formyl group, C 2-7  acyl group that may have a substituent, C 2-7  alkoxycarbonyl group that may have a substituent or group represented by Formula —CONV d1 V d2  (wherein, V d1  and V d2  each independently represent a hydrogen atom or C 1-6  alkyl group that may have a substituent);
 W 1  and W 2  each independently represent a carbon atom or a nitrogen atom that may have a substituent); 
 R 3  and R 4  each independently represent a hydrogen atom, C 1-6  alkyl group that may have a substituent, C 2-6  alkenyl group that may have a substituent, C 2-6  alkynyl group that may have a substituent, C 3-8  cycloalkyl group that may have a substituent, C 2-7  acyl group that may have a substituent or C 2-7  alkoxycarbonyl group that may have a substituent; and 
 R 5  represents a hydrogen atom, C 1-6  alkyl group that may have a substituent, C 2-6  alkenyl group that may have a substituent, C 2-6  alkynyl group that may have a substituent, C 3-8  cycloalkyl group that may have a substituent, C 6-10  aryl group that may have a substituent, 5-10-membered heteroaryl group that may have a substituent or 3-10-membered non-aromatic heterocyclic group that may have a substituent, 
 
       a pharmacologically acceptable salt thereof or a solvate thereof. 
     
     
         78 . An RET kinase inhibiting substance for a pharmaceutical composition comprising the RET kinase inhibiting substance for administering to an organism comprising a cell expressing mutant RET, wherein said RET kinase inhibiting substance is at least one compound selected from the group consisting of: 
       5-(5-fluoro-2-oxo-1,2-dihydroindole-3-ylidenemethyl)-2,4-dimethyl-1H-pyrrole-3-carboxylic acid(2-diethylaminoethyl)amide; 
       N-{2-chloro-4-[(6,7-dimethoxy-4-quinolyl)oxy]phenyl}-N′-(5-methyl-3-isoxazolyl)urea; and 
       4-[(4-fluoro-2-methylindole-5-yl)oxy]-6-methoxy-7-[3-(pyrrolidine-1-yl)propoxy]quinazoline, 
       a pharmacologically acceptable salt thereof or a solvate thereof. 
     
     
         79 . An RET kinase inhibitor comprising a compound represented by General Formula (I) 
       
         
           
           
               
               
           
         
       
       wherein, R 1  represents a group represented by Formula —V 1 —V 2 —V 3  (wherein, V 1  represents C 1-6  alkylene group that may have a substituent; V 2  represents a single bond, an oxygen atom, a sulfur atom, carbonyl group, sulfinyl group, sulfonyl group, group represented by Formula —CONR 6 —, group represented by Formula —SO 2 NR 6 —, group represented by Formula —NR 6 SO 2 —, group represented by Formula —NR 6 CO— or group represented by Formula —NR 6 — (wherein, R 6  represents a hydrogen atom, C 1-6  alkyl group that may have a substituent or C 3-8  cycloalkyl group that may have a substituent); V 3  represents a hydrogen atom, C 1-6  alkyl group that may have a substituent, C 2-6  alkenyl group that may have a substituent, C 2-6  alkynyl group that may have a substituent, C 3-8  cycloalkyl group that may have a substituent, C 6-10  aryl group that may have a substituent, 5-10-membered heteroaryl group that may have a substituent or 3-10-membered non-aromatic heterocyclic group that may have a substituent);
 R 2  represents cyano group, C 1-6  alkoxy group that may have a substituent, carboxyl group, C 2-7  alkoxycarbonyl group that may have a substituent or group represented by Formula —CONV a11 V a12  (wherein, V a11  represents a hydrogen atom, C 1-6  alkyl group that may have a substituent, C 2-6  alkenyl group that may have a substituent, C 2-6  alkynyl group that may have a substituent, C 3-8  cycloalkyl group that may have a substituent, C 6-10  aryl group that may have a substituent, 5-10-membered heteroaryl group that may have a substituent or 3-10-membered non-aromatic heterocyclic group that may have a substituent; V a12  represents a hydrogen atom, C 1-6  alkyl group that may have a substituent, C 2-6  alkenyl group that may have a substituent, C 2-6  alkynyl group that may have a substituent, C 3-8  cycloalkyl group that may have a substituent, C 6-10  aryl group that may have a substituent, 5-10-membered heteroaryl group that may have a substituent, 3-10-membered non-aromatic heterocyclic group that may have a substituent, hydroxyl group, C 1-6  alkoxy group that may have a substituent or C 3-8  cycloalkoxy group that may have a substituent); 
 Y 1  represents a group represented by Formula 
 
       
         
           
           
               
               
           
         
       
       (wherein, R 7  and R 8  each independently represent a hydrogen atom, a halogen atom, cyano group, nitro group, amino group, C 1-6  alkyl group that may have a substituent, C 3-8  cycloalkyl group that may have a substituent, C 1-6  alkoxy group that may have a substituent, C 1-6  alkylthio group that may have a substituent, formyl group, C 2-7  acyl group that may have a substituent, C 2-7  alkoxycarbonyl group that may have a substituent or group represented by Formula —CONV d1 V d2  (wherein, V d1  and V d2  each independently represent a hydrogen atom or C 1-6  alkyl group that may have a substituent);
 W 1  and W 2  each independently represent a carbon atom or a nitrogen atom that may have a substituent); 
 R 3  and R 4  each independently represent a hydrogen atom, C 1-6  alkyl group that may have a substituent, C 2-6  alkenyl group that may have a substituent, C 2-6  alkynyl group that may have a substituent, C 3-8  cycloalkyl group that may have a substituent, C 2-7  acyl group that may have a substituent or C 2-7  alkoxycarbonyl group that may have a substituent; and 
 R 5  represents a hydrogen atom, C 1-6  alkyl group that may have a substituent, C 2-6  alkenyl group that may have a substituent, C 2-6  alkynyl group that may have a substituent, C 3-8  cycloalkyl group that may have a substituent, C 6-10  aryl group that may have a substituent, 5-10-membered heteroaryl group that may have a substituent or 3-10-membered non-aromatic heterocyclic group that may have a substituent, 
 
       a pharmacologically acceptable salt thereof or a solvate thereof. 
     
     
         80 . An RET kinase inhibitor comprising at least one compound selected from the group consisting of: 
       5-(5-fluoro-2-oxo-1,2-dihydroindole-3-ylidenemethyl)-2,4-dimethyl-1H-pyrrole-3-carboxylic acid(2-diethylaminoethyl)amide; 
       N-{2-chloro-4-[(6,7-dimethoxy-4-quinolyl)oxy]phenyl}-N′-(5-methyl-3-isoxazolyl)urea; and 
       4-[(4-fluoro-2-methylindole-5-yl)oxy]-6-methoxy-7-[3-(pyrrolidine-1-yl)propoxy]quinazoline, 
       a pharmacologically acceptable salt thereof or a solvate thereof. 
     
     
         81 . A method for predicting whether a patient is highly sensitive to an RET kinase inhibiting substance, comprising the step of using the presence or the absence of RET mutation in the cell as an indication, wherein said RET kinase inhibiting substance is a compound represented by General Formula (I) 
       
         
           
           
               
               
           
         
       
       wherein, R 1  represents a group represented by Formula —V 1 —V 2 —V 3  (wherein, V 1  represents C 1-6  alkylene group that may have a substituent; V 2  represents a single bond, an oxygen atom, a sulfur atom, carbonyl group, sulfinyl group, sulfonyl group, group represented by Formula —CONR 6 —, group represented by Formula —SO 2 NR 6 —, group represented by Formula —NR 6 SO 2 —, group represented by Formula —NR 6 CO— or group represented by Formula —NR 6 — (wherein, R 6  represents a hydrogen atom, C 1-6  alkyl group that may have a substituent or C 3-8  cycloalkyl group that may have a substituent); V 3  represents a hydrogen atom, C 1-6  alkyl group that may have a substituent, C 2-6  alkenyl group that may have a substituent, C 2-6  alkynyl group that may have a substituent, C 3-8  cycloalkyl group that may have a substituent, C 6-10  aryl group that may have a substituent, 5-10-membered heteroaryl group that may have a substituent or 3-10-membered non-aromatic heterocyclic group that may have a substituent);
 R 2  represents cyano group, C 1-6  alkoxy group that may have a substituent, carboxyl group, C 2-7  alkoxycarbonyl group that may have a substituent or group represented by Formula —CONV a11 V a12  (wherein, V a11  represents a hydrogen atom, C 1-6  alkyl group that may have a substituent, C 2-6  alkenyl group that may have a substituent, C 2-6  alkynyl group that may have a substituent, C 3-8  cycloalkyl group that may have a substituent, C 6-10  aryl group that may have a substituent, 5-10-membered heteroaryl group that may have a substituent or 3-10-membered non-aromatic heterocyclic group that may have a substituent; V a12  represents a hydrogen atom, C 1-6  alkyl group that may have a substituent, C 2-6  alkenyl group that may have a substituent, C 2-6  alkynyl group that may have a substituent, C 3-8  cycloalkyl group that may have a substituent, C 6-10  aryl group that may have a substituent, 5-10-membered heteroaryl group that may have a substituent, 3-10-membered non-aromatic heterocyclic group that may have a substituent, hydroxyl group, C 1-6  alkoxy group that may have a substituent or C 3-8  cycloalkoxy group that may have a substituent); 
 Y 1  represents a group represented by Formula 
 
       
         
           
           
               
               
           
         
       
       (wherein, R 7  and R 8  each independently represent a hydrogen atom, a halogen atom, cyano group, nitro group, amino group, C 1-6  alkyl group that may have a substituent, C 3-8  cycloalkyl group that may have a substituent, C 1-6  alkoxy group that may have a substituent, C 1-6  alkylthio group that may have a substituent, formyl group, C 2-7  acyl group that may have a substituent, C 2-7  alkoxycarbonyl group that may have a substituent or group represented by Formula —CONV d1 V d2  (wherein, V d1  and V d2  each independently represent a hydrogen atom or C 1-6  alkyl group that may have a substituent);
 W 1  and W 2  each independently represent a carbon atom or a nitrogen atom that may have a substituent); 
 R 3  and R 4  each independently represent a hydrogen atom, C 1-6  alkyl group that may have a substituent, C 2-6  alkenyl group that may have a substituent, C 2-6  alkynyl group that may have a substituent, C 3-8  cycloalkyl group that may have a substituent, C 2-7  acyl group that may have a substituent or C 2-7  alkoxycarbonyl group that may have a substituent; and 
 R 5  represents a hydrogen atom, C 1-6  alkyl group that may have a substituent, C 2-6  alkenyl group that may have a substituent, C 2-6  alkynyl group that may have a substituent, C 3-8  cycloalkyl group that may have a substituent, C 6-10  aryl group that may have a substituent, 5-10-membered heteroaryl group that may have a substituent or 3-10-membered non-aromatic heterocyclic group that may have a substituent, 
 
       a pharmacologically acceptable salt thereof or a solvate thereof. 
     
     
         82 . The method according to  claim 81 , wherein R 1  is C 1-6  alkyl group (where, R 1  may have at least one substituent selected from the group consisting of 3-10-membered non-aromatic heterocyclic group that may have C 1-6  alkyl group, hydroxyl group, C 1-6  alkoxy group, amino group, mono-C 1-6  alkylamino group and di-C 1-6  alkylamino group). 
     
     
         83 . The method according to  claim 81 , wherein R 1  is methyl group or group represented by any one of the following Formulae 
       
         
           
           
               
               
           
         
       
       (wherein, R a3  represents methyl group; R a1  represents a hydrogen atom or hydroxyl group; R a2  represents methoxy group, ethoxy group, 1-pyrrolidinyl group, 1-piperidinyl group, 4-morpholinyl group, dimethylamino group or diethylamino group). 
     
     
         84 . The method according to  claim 81 , wherein R 1  is methyl group or 2-methoxyethyl group. 
     
     
         85 . The method according to  claim 81 , wherein R 2  represents cyano group or group represented by Formula —CONV a11 V a12  (wherein, V a11  represents a hydrogen atom, C 1-6  alkyl group that may have a substituent, C 2-6  alkenyl group that may have a substituent, C 2-6  alkynyl group that may have a substituent, C 3-8  cycloalkyl group that may have a substituent, C 6-10  aryl group that may have a substituent, 5-10-membered heteroaryl group that may have a substituent or 3-10-membered non-aromatic heterocyclic group that may have a substituent; V a12  represents a hydrogen atom, C 1-6  alkyl group that may have a substituent, C 2-6  alkenyl group that may have a substituent, C 2-6  alkynyl group that may have a substituent, C 3-8  cycloalkyl group that may have a substituent, C 6-10  aryl group that may have a substituent, 5-10-membered heteroaryl group that may have a substituent, 3-10-membered non-aromatic heterocyclic group that may have a substituent, hydroxyl group, C 1-6  alkoxy group that may have a substituent or C 3-8  cycloalkoxy group that may have a substituent). 
     
     
         86 . The method according to  claim 81 , wherein R 2  is cyano group or group represented by Formula —CONHV a16  (wherein, V a16  represents a hydrogen atom, C 1-6  alkyl group, C 3-8  cycloalkyl group, C 1-6  alkoxy group or C 3-8  cycloalkoxy group, where V a16  may have at least one substituent selected from the group consisting of a halogen atom, cyano group, hydroxyl group and C 1-6  alkoxy group). 
     
     
         87 . The method according to  claim 81 , wherein R 2  is a group represented by Formula —CONHV a17  (wherein, V a17  represents a hydrogen atom, C 1-6  alkyl group or C 1-6  alkoxy group). 
     
     
         88 . The method according to  claim 81 , wherein R 2  is a group represented by Formula —CONHV a18  (wherein, V a18  represents a hydrogen atom, methyl group or methoxy group). 
     
     
         89 . The method according to  claim 81 , wherein Y 1  is a group represented by Formula 
       
         
           
           
               
               
           
         
       
       (wherein, R 71  represents a hydrogen atom or a halogen atom). 
     
     
         90 . The method according to  claim 81 , wherein R 3  and R 4  is a hydrogen atom. 
     
     
         91 . The method according to  claim 81 , wherein R 5  is a hydrogen atom, C 1-6  alkyl group, C 3-8  cycloalkyl group or C 6-10  aryl group (where, R 5  may have at least one substituent selected from the group consisting of a halogen atom and methanesulfonyl group). 
     
     
         92 . The method according to  claim 81 , wherein R 5  is methyl group, ethyl group or cyclopropyl group. 
     
     
         93 . The method according to  claim 81 , wherein the RET kinase inhibiting substance is at least one compound selected from the group consisting of: 
       N-(4-(6-cyano-7-(2-methoxyethoxy)-4-quinolyl)oxy-2-fluorophenyl)-N′-(4-fluorophenyl)urea; 
       N-(2-chloro-4-((6-cyano-7-((1-methyl-4-piperidyl)methoxy)-4-quinolyl)oxy)phenyl)-N′-cyclopropylurea; 
       N-(4-((6-cyano-7-(((2R)-3-(diethylamino)-2-hydroxypropyl)oxy)-4-quinolyl)oxy)phenyl)-N′-(4-fluorophenyl)urea; 
       N-(4-((6-cyano-7-(((2R)-2-hydroxy-3-(1-pyrrolidino)propyl)oxy)-4-quinolyl)oxy)phenyl)-N′-(4-fluorophenyl)urea; 
       4-(3-chloro-4-(cyclopropylaminocarbonyl)aminophenoxy)-7-methoxy-6-quinolinecarboxamide; 
       4-(3-chloro-4-(cyclopropylaminocarbonyl)aminophenoxy)-7-(2-methoxyethoxy)-6-quinolinecarboxamide; 
       N6-cyclopropyl-4-(3-chloro-4-(((cyclopropylamino)carbonyl)amino)phenoxy)-7-methoxy-6-quinolinecarboxamide; 
       N6-(2-methoxyethyl)-4-(3-chloro-4-(((cyclopropylamino)carbonyl)amino)phenoxy)-7-methoxy-6-quinolinecarboxamide; 
       N6-(2-fluoroethyl)-4-(3-chloro-4-(((cyclopropylamino)carbonyl)amino)phenoxy)-7-methoxy-6-quinolinecarboxamide; 
       N6-methoxy-4-(3-chloro-4-(((cyclopropylamino)carbonyl)amino)phenoxy)-7-methoxy-6-quinolinecarboxamide; 
       N6-methyl-4-(3-chloro-4-(((cyclopropylamino)carbonyl)amino)phenoxy)-7-methoxy-6-quinolinecarboxamide; 
       N6-ethyl-4-(3-chloro-4-(((cyclopropylamino)carbonyl)amino)phenoxy)-7-methoxy-6-quinolinecarboxamide; 
       4-(3-fluoro-4-(cyclopropylaminocarbonyl)aminophenoxy)-7-(2-methoxyethoxy)-6-quinolinecarboxamide; 
       4-(3-chloro-4-(cyclopropylaminocarbonyl)aminophenoxy)-7-(2-hydroxyethoxy)-6-quinolinecarboxamide; 
       4-(3-chloro-4-(cyclopropylaminocarbonyl)aminophenoxy)-7-((2S)-2,3-dihydroxypropyl)oxy-6-quinolinecarboxamide; 
       4-(3-chloro-4-(methylaminocarbonyl)aminophenoxy)-7-methoxy-6-quinolinecarboxamide; 
       4-(3-chloro-4-(ethylaminocarbonyl)aminophenoxy)-7-methoxy-6-quinolinecarboxamide; 
       N6-methoxy-4-(3-chloro-4-(((ethylamino)carbonyl)amino)phenoxy)-7-methoxy-6-quinolinecarboxamide; 
       4-(3-chloro-4-(cyclopropylaminocarbonyl)aminophenoxy)-7-(2-ethoxyethoxy)-6-quinolinecarboxamide; 
       4-(4-((cyclopropylamino)carbonyl)aminophenoxy)-7-(2-methoxyethoxy)-6-quinolinecarboxamide; 
       N-(2-fluoro-4-((6-carbamoyl-7-methoxy-4-quinolyl)oxy)phenyl)-N′-cyclopropylurea; 
       N6-(2-hydroxyethyl)-4-(3-chloro-4-(((cyclopropylamino)carbonyl)amino)phenoxy)-7-methoxy-6-quinolinecarboxamide; 
       4-(3-chloro-4-(1-propylaminocarbonyl)aminophenoxy)-7-methoxy-6-quinolinecarboxamide; 
       4-(3-chloro-4-(cis-2-fluoro-cyclopropylaminocarbonyl)aminophenoxy)-7-methoxy-6-quinolinecarboxamide; 
       N6-methyl-4-(3-chloro-4-(((cyclopropylamino)carbonyl)amino)phenoxy)-7-(2-methoxyethoxy)-6-quinolinecarboxamide; 
       N6-methyl-4-(3-chloro-4-(((ethylamino)carbonyl)amino)phenoxy)-7-methoxy-6-quinolinecarboxamide; 
       4-(3-chloro-4-(cyclopropylaminocarbonyl)aminophenoxy)-7-(2-(4-morpholino) ethoxy)-6-quinolinecarboxamide; 
       4-(3-chloro-4-(2-fluoroethylaminocarbonyl)aminophenoxy)-7-methoxy-6-quinolinecarboxamide; 
       N6-((2R)tetrahydro-2-furanylmethyl)-4-(3-chloro-4-(((methylamino)carbonyl)amino) phenoxy)-7-methoxy-6-quinolinecarboxamide; 
       4-(3-fluoro-4-(ethylaminocarbonyl)aminophenoxy)-7-methoxy-6-quinolinecarboxamide; 
       4-(3-chloro-4-(((cyclopropylamino)carbonyl)amino)phenoxy)-7-((2R)-2-hydroxy-3-(1-pyrrolidino)propoxy)-6-quinolinecarboxamide; 
       N6-methyl-4-(3-chloro-4-(((methylamino)carbonyl)amino)phenoxy)-7-((2R)-3-diethylamino-2-hydroxypropoxy)-6-quinolinecarboxamide; 
       N6-methyl-4-(3-chloro-4-(((ethylamino)carbonyl)amino)phenoxy)-7-((2R)-3-diethylamino-2-hydroxypropoxy)-6-quinolinecarboxamide; 
       N6-methyl-4-(3-chloro-4-(((methylamino)carbonyl)amino)phenoxy)-7-((2R)-2-hydroxy-3-(1-pyrrolidino)propoxy)-6-quinolinecarboxamide; 
       N6-methyl-4-(3-chloro-4-(((ethylamino)carbonyl)amino)phenoxy)-7-((2R)-2-hydroxy-3-(1-pyrrolidino)propoxy)-6-quinolinecarboxamide; 
       N6-methyl-4-(3-chloro-4-(((methylamino)carbonyl)amino)phenoxy)-7-((1-methyl-4-piperidyl)methoxy)-6-quinolinecarboxamide; 
       N6-methyl-4-(3-chloro-4-(((ethylamino)carbonyl)amino)phenoxy)-7-((1-methyl-4-piperidyl)methoxy)-6-quinolinecarboxamide; 
       N-(4-(6-cyano-7-(2-methoxyethoxy)-4-quinolyl)oxy-2-fluorophenyl)-N′-cyclopropylurea; 
       N-(4-(6-cyano-7-(3-(4-morpholino)propoxy)-4-quinolyl)oxyphenyl)-N′-(3-(methylsulfonyl)phenyl)urea; 
       4-(4-((cyclopropylamino)carbonyl)aminophenoxy)-7-methoxy-6-quinolinecarboxamide; 
       4-(3-fluoro-4-((2-fluoroethylamino)carbonyl)aminophenoxy)-7-methoxy-6-quinolinecarboxamide; 
       N6-(2-ethoxyethyl)-4-(3-chloro-4-(((methylamino)carbonyl)amino)phenoxy)-7-methoxy-6-quinolinecarboxamide; 
       4-(4-(3-ethylureido)-3-fluoro-phenoxy)-7-methoxyquinoline-6-carboxylic acid (2-cyanoethyl)amide; and 
       N-(4-(6-(2-cyanoethyl)carbamoyl-7-methoxy-4-quinolyl)oxy-2-fluorophenyl)-N′-cyclopropylurea, 
       a pharmacologically acceptable salt thereof or a solvate thereof. 
     
     
         94 . The method according to  claim 81 , wherein the RET kinase inhibiting substance is at least one compound selected from the group consisting of: 
       4-(3-chloro-4-(cyclopropylaminocarbonyl)aminophenoxy)-7-methoxy-6-quinolinecarboxamide; 
       4-(3-chloro-4-(ethylaminocarbonyl)aminophenoxy)-7-methoxy-6-quinolinecarboxamide; 
       N6-methoxy-4-(3-chloro-4-(((cyclopropylamino)carbonyl)amino)phenoxy)-7-methoxy-6-quinolinecarboxamide; 
       4-(3-chloro-4-(methylaminocarbonyl)aminophenoxy)-7-methoxy-6-quinolinecarboxamide; and 
       N6-methoxy-4-(3-chloro-4-(((ethylamino)carbonyl)amino)phenoxy)-7-methoxy-6-quinolinecarboxamide, 
       a pharmacologically acceptable salt thereof or a solvate thereof. 
     
     
         95 . The method according to  claim 81 , wherein the RET kinase inhibiting substance is 4-(3-chloro-4-(cyclopropylaminocarbonyl)aminophenoxy)-7-methoxy-6-quinolinecarboxamide, a pharmacologically acceptable salt thereof or a solvate thereof. 
     
     
         96 . The method according to  claim 81 , wherein the RET kinase inhibiting substance is methanesulfonate of 4-(3-chloro-4-(cyclopropylaminocarbonyl)aminophenoxy)-7-methoxy-6-quinolinecarboxamide. 
     
     
         97 . A method for predicting whether a patient is highly sensitive to an RET kinase inhibiting substance, comprising the step of using the presence or the absence of RET mutation in the cell as an indication, wherein said RET kinase inhibiting substance is at least one compound selected from the group consisting of: 
       5-(5-fluoro-2-oxo-1,2-dihydroindole-3-ylidenemethyl)-2,4-dimethyl-1H-pyrrole-3-carboxylic acid(2-diethylaminoethyl)amide; 
       N-{2-chloro-4-[(6,7-dimethoxy-4-quinolyl)oxy]phenyl}-N′-(5-methyl-3-isoxazolyl)urea; and 
       4-[(4-fluoro-2-methylindole-5-yl)oxy]-6-methoxy-7-[3-(pyrrolidine-1-yl)propoxy]quinazoline, 
       a pharmacologically acceptable salt thereof or a solvate thereof. 
     
     
         98 . The method according to  claim 81 , wherein the RET mutation is substitution of at least one amino acid selected from the group consisting of amino acids at codons 321, 533, 609, 611, 618, 620, 630, 631, 634, 691, 768, 790, 791, 804, 806, 844, 883, 891 and 918 in the amino acid sequence represented by SEQ ID NO: 2 or 4 with other amino acid. 
     
     
         99 . The method according to  claim 81 , wherein the RET mutation owes to rearrangement of RET gene and at least one gene selected from the group consisting of H4 gene, RIα gene, ELE1 gene, RFG5 gene, hTIF gene, RFG7 gene, ELKS gene, kinectin gene, PCM-1 gene and RFP gene. 
     
     
         100 . The method according to  claim 81 , wherein the patient is suffering from at least one disease selected from the group consisting of multiple endocrine neoplasia, type IIA, multiple endocrine neoplasia, type IIB, familial medullary thyroid carcinoma, thyroid carcinoma, papillary thyroid carcinoma, sporadic medullary thyroid carcinoma, Hirschsprung disease, pheochromocytoma, parathyroid hyperplasia and mucosal neuromas of the gastrointestinal tract. 
     
     
         101 . The method according to  claim 81 , wherein the prediction comprises the steps of:
 determining the presence or the absence of RET mutation in the cell; and   predicting that the patient is highly sensitive to the RET kinase inhibiting substance when mutant RET is expressed in the cell.   
     
     
         102 . The method according to  claim 101 , wherein the determination of the presence or the absence of RET mutation in the cell is carried out by dideoxynucleotide chain termination technique. 
     
     
         103 . The method according to  claim 101 , wherein the determination of the presence or the absence of RET mutation in the cell is carried out by RT-PCR. 
     
     
         104 . The method according to  claim 101 , wherein the determination of the presence or the absence of RET mutation in the cell is carried out by immunochemical technique. 
     
     
         105 . The method according to  claim 97 , wherein the RET mutation is substitution of at least one amino acid selected from the group consisting of amino acids at codons 321, 533, 609, 611, 618, 620, 630, 631, 634, 691, 768, 790, 791, 804, 806, 844, 883, 891 and 918 in the amino acid sequence represented by SEQ ID NO: 2 or 4 with other amino acid. 
     
     
         106 . The method according to  claim 97 , wherein the RET mutation owes to rearrangement of RET gene and at least one gene selected from the group consisting of H4 gene, RIα gene, ELE1 gene, RFG5 gene, hTIF gene, RFG7 gene, ELKS gene, kinectin gene, PCM-1 gene and RFP gene. 
     
     
         107 . The method according to  claim 97 , wherein the patient is suffering from at least one disease selected from the group consisting of multiple endocrine neoplasia, type IIA, multiple endocrine neoplasia, type IIB, familial medullary thyroid carcinoma, thyroid carcinoma, papillary thyroid carcinoma, sporadic medullary thyroid carcinoma, Hirschsprung disease, pheochromocytoma, parathyroid hyperplasia and mucosal neuromas of the gastrointestinal tract. 
     
     
         108 . The method according to  claim 97 , wherein the prediction comprises the steps of:
 determining the presence or the absence of RET mutation in the cell; and   predicting that the patient is highly sensitive to the RET kinase inhibiting substance when mutant RET is expressed in the cell.   
     
     
         109 . The method according to  claim 108 , wherein the determination of the presence or the absence of RET mutation in the cell is carried out by dideoxynucleotide chain termination technique. 
     
     
         110 . The method according to  claim 108 , wherein the determination of the presence or the absence of RET mutation in the cell is carried out by RT-PCR. 
     
     
         111 . The method according to  claim 108 , wherein the determination of the presence or the absence of RET mutation in the cell is carried out by immunochemical technique.