Pyridone derivative having tetrahydropyranylmethyl group

Abstract

It is intended to provide a novel compound or a salt thereof, or crystals of the compound or the salt, which inhibit Axl and are useful in the treatment of a disease caused by hyperfunction of Axl, the treatment of a disease associated with hyperfunction of Axl, and/or the treatment of a disease involving hyperfunction of Axl.[Solution]The present invention provides a pyridone derivative having a tetrahydropyranylmethyl group represented by the following formula (I) having various substituents, or a salt thereof, or crystals of the compound or the salt (wherein R1, R2, R3, R4, R5, W, X, Y, and Z are each as defined in the specification).

1 . A combination, comprising:
 (1) a compound selected from the group consisting of a compound of formula (I)   
       
         
           
           
               
               
           
         
       
       a pharmaceutically acceptable salt thereof, and a solvate of the compound of formula (I) or a pharmaceutically acceptable salt thereof, and
 (2) a tyrosine kinase inhibitor, 
 
       wherein
 W, X, and Y are each independently C—H, C—F, or C—Cl, 
 Z is C—H, C—F, C—Cl, C—C 1 -C 6  alkyl group, or C—C 1 -C 6  alkoxy group, 
 R 1  is formula (II-1) 
 
       
         
           
           
               
               
           
         
         Q is C—H, or C—F, 
         T is C—H, 
         U is a nitrogen atom, 
         R 6  is a halogen atom, a C 1 -C 6  alkyl group, a C 3 -C 6  cycloalkyl group, a cyano group, or a trifluoromethoxy group, 
         R 2  is a hydrogen atom, a halogen atom, a C 1 -C 6  alkyl group, a C 1 -C 6  alkoxy group, or a cyano group, 
         R 3  is a hydrogen atom or a C 1 -C 6  alkyl group, 
         R 4  is a hydrogen atom, a halogen atom, or a C 1 -C 6  alkyl group, 
         R 5  is a group of formula (III-1) 
       
       
         
           
           
               
               
           
         
         R 8  and R 12  are each independently a hydrogen atom or a deuterium atom, 
         R 9  is a hydrogen atom, a halogen atom, or a C 1 -C 6  alkoxy group, 
         R 10  is 1,4-dioxan-2-ylmethoxy, and 
         R 11  is a hydrogen atom, a C 1 -C 6  alkoxy group, or a deuterium-substituted C 1 -C 6  alkoxy group. 
       
     
     
         2 . The combination of  claim 1 , wherein the compound and the tyrosine kinase inhibitor are separately contained in different formulations. 
     
     
         3 . The combination of  claim 1 , wherein the compound and the tyrosine kinase inhibitor are contained in a single formulation. 
     
     
         4 . The combination of  claim 1 , wherein the compound of formula (I) is N-[4-(2-Amino-5-{4-[(2R)-1,4-dioxan-2-ylmethoxy]-3-methoxyphenyl}pyridin-3-yl)-3-fluorophenyl]-5-methyl-4′-oxo-1′-(tetrahydro-2H-pyran-4-ylmethyl)-1′,4′-dihydro-2,3′-bipyridine-5′-carboxamide of the following formula: 
       
         
           
           
               
               
           
         
       
     
     
         5 . The combination of  claim 1 , wherein the compound of formula (I) is N-[4-(2-Amino-5-{4-[(2S)-1,4-dioxan-2-ylmethoxy]-3-methoxyphenyl}pyridin-3-yl)-3-fluorophenyl]-5-methyl-4′-oxo-1′-(tetrahydro-2H-pyran-4-ylmethyl)-1′,4′-dihydro-2,3′-bipyridine-5′-carboxamide of the following formula: 
       
         
           
           
               
               
           
         
       
     
     
         6 . The combination of  claim 4 , wherein the compound is a methanesulfonate, phosphate, naphthalene-1,5-disulfonate, or sulfate salt of N-[4-(2-Amino-5-{4-[(2R)-1,4-dioxan-2-ylmethoxy]-3-methoxyphenyl}pyridin-3-yl)-3-fluorophenyl]-5-methyl-4′-oxo-1′-(tetrahydro-2H-pyran-4-ylmethyl)-1′,4′-dihydro-2,3′-bipyridine-5′-carboxamide or a solvate thereof. 
     
     
         7 . The combination of  claim 1 , wherein the compound is a solvate of N-[4-(2-amino-5-{4-[(2R)-1,4-dioxan-2-ylmethoxy]-3-methoxyphenyl}pyridin-3-yl)-3-fluorophenyl]-5-methyl-4′-oxo-1′-(tetrahydro-2H-pyran-4-ylmethyl)-1′,4′-dihydro-2,3′-bipyridine-5′-carboxamide of the following formula: 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof. 
     
     
         8 . The combination of  claim 7 , wherein the compound is a hydrate of N-[4-(2-amino-5-{4-[(2R)-1,4-dioxan-2-ylmethoxy]-3-methoxyphenyl}pyridin-3-yl)-3-fluorophenyl]-5-methyl-4′-oxo-1′-(tetrahydro-2H-pyran-4-ylmethyl)-1′,4′-dihydro-2,3′-bipyridine-5′-carboxamide or a pharmaceutically acceptable salt thereof. 
     
     
         9 . The combination of  claim 8 , wherein the compound is a hydrate of a sulfate, phosphate, or naphthalene-1,5-disulfonate of N-[4-(2-amino-5-{4-[(2R)-1,4-dioxan-2-ylmethoxy]-3-methoxyphenyl}pyridin-3-yl)-3-fluorophenyl]-5-methyl-4′-oxo-1′-(tetrahydro-2H-pyran-4-ylmethyl)-1′,4′-dihydro-2,3′-bipyridine-5′-carboxamide. 
     
     
         10 . The combination of  claim 9 , wherein the compound is N-[4-(2-amino-5-{4-[(2R)-1,4-dioxan-2-ylmethoxy]-3-methoxyphenyl}pyridin-3-yl)-3-fluorophenyl]-5-methyl-4′-oxo-1′-(tetrahydro-2H-pyran-4-ylmethyl)-1′,4′-dihydro-2,3′-bipyridine-5′-carboxamide sulfate hydrate. 
     
     
         11 . The combination of  claim 10 , wherein the compound is C 41 H 42 FN 5 O 7 .1.80H 2 SO 4 .3.0H 2 O. 
     
     
         12 . The combination of  claim 11 , wherein the compound exhibits characteristic peaks at diffraction angles 2θ=3.64, 6.40, 7.30, 9.76, 17.34, 18.38, 19.34, 20.56, 21.52, and 22.94 in a powder X-ray diffraction pattern obtained by irradiation with copper Kα radiation (wavelength λ=1.54 angstroms). 
     
     
         13 . The combination of  claim 1 , wherein the tyrosine kinase inhibitor is erlotinib or gefitinib. 
     
     
         14 . A method of treating cancer comprising administering, in combination:
 (1) a compound selected from the group consisting of a compound of formula (I):   
       
         
           
           
               
               
           
         
       
       a pharmaceutically acceptable salt thereof, or a solvate of the compound of formula (I) or a pharmaceutically acceptable salt thereof, and
 (2) a tyrosine kinase inhibitor, 
 
       wherein
 W, X, and Y are each independently C—H, C—F, or C—Cl, 
 Z is C—H, C—F, C—Cl, C—C 1 -C 6  alkyl group, or C—C 1 -C 6  alkoxy group, 
 R 1  is formula (II-1) 
 
       
         
           
           
               
               
           
         
         Q is C—H, or C—F, 
         T is C—H, 
         U is a nitrogen atom, 
         R 6  is a halogen atom, a C 1 -C 6  alkyl group, a C 3 -C 6  cycloalkyl group, a cyano group, or a trifluoromethoxy group, 
         R 2  is a hydrogen atom, a halogen atom, a C 1 -C 6  alkyl group, a C 1 -C 6  alkoxy group, or a cyano group, 
         R 3  is a hydrogen atom or a C 1 -C 6  alkyl group, 
         R 4  is a hydrogen atom, a halogen atom, or a C 1 -C 6  alkyl group, 
         R 5  is a group of formula (III-1) 
       
       
         
           
           
               
               
           
         
         R 8  and R 12  are each independently a hydrogen atom or a deuterium atom, 
         R 9  is a hydrogen atom, a halogen atom, or a C 1 -C 6  alkoxy group, 
         R 10  is 1,4-dioxan-2-ylmethoxy, 
         R 11  is a hydrogen atom, a C 1 -C 6  alkoxy group, or a deuterium-substituted C 1 -C 6  alkoxy group, and 
         the cancer is lung cancer. 
       
     
     
         15 . The method of  claim 14 , wherein the compound and the tyrosine kinase inhibitor are administered at the same time. 
     
     
         16 . The method of  claim 14 , wherein the compound and the tyrosine kinase inhibitor are administered at different times. 
     
     
         17 . The method of  claim 14 , wherein the cancer is non-small cell lung cancer, lung cancer in which Axl is overexpressed, or lung cancer having an EGFR mutation. 
     
     
         18 . The method of  claim 14 , wherein the compound is a solvate of N-[4-(2-amino-5-{4-[(2R)-1,4-dioxan-2-ylmethoxy]-3-methoxyphenyl}pyridin-3-yl)-3-fluorophenyl]-5-methyl-4′-oxo-1v-(tetrahydro-2H-pyran-4-ylmethyl)-1′,4′-dihydro-2,3′-bipyridine-5′-carboxamide represented by the following formula: 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof. 
     
     
         19 . The method of  claim 18 , wherein the compound is a hydrate of N-[4-(2-amino-5-{4-[(2R)-1,4-dioxan-2-ylmethoxy]-3-methoxyphenyl}pyridin-3-yl)-3-fluorophenyl]-5-methyl-4′-oxo-1′-(tetrahydro-2H-pyran-4-ylmethyl)-1′,4′-dihydro-2,3′-bipyridine-5′-carboxamide or a pharmaceutically acceptable salt thereof. 
     
     
         20 . The method of  claim 19 , wherein the compound is a hydrate of a sulfate, phosphate, or naphthalene-1,5-disulfonate of N-[4-(2-amino-5-{4-[(2R)-1,4-dioxan-2-ylmethoxy]-3-methoxyphenyl}pyridin-3-yl)-3-fluorophenyl]-5-methyl-4′-oxo-1′-(tetrahydro-2H-pyran-4-ylmethyl)-1′,4′-dihydro-2,3′-bipyridine-5′-carboxamide. 
     
     
         21 . The method of  claim 20 , wherein the compound is N-[4-(2-amino-5-{4-[(2R)-1,4-dioxan-2-ylmethoxy]-3-methoxyphenyl}pyridin-3-yl)-3-fluorophenyl]-5-methyl-4′-oxo-1′-(tetrahydro-2H-pyran-4-ylmethyl)-1′,4′-dihydro-2,3′-bipyridine-5′-carboxamide sulfate hydrate. 
     
     
         22 . The method of  claim 21 , wherein the compound is C 41 H 42 FN 5 O 7 .1.80H 2 SO 4 .3.0H 2 O. 
     
     
         23 . The method of  claim 22 , wherein the compound exhibits characteristic peaks at diffraction angles 2θ=3.64, 6.40, 7.30, 9.76, 17.34, 18.38, 19.34, 20.56, 21.52, and 22.94 in a powder X-ray diffraction pattern obtained by irradiation with copper Kα radiation (wavelength λ=1.54 angstroms). 
     
     
         24 . The method of  claim 14 , wherein the tyrosine kinase inhibitor is erlotinib or gefitinib.