Use of ring-fused bicyclic pyridyl derivatives as fgfr4 inhibitors

Abstract

The present invention relates to therapeutic uses of compounds of formula (I) or a pharmaceutically acceptable salt thereof

1 . A method of treating solid malignancies characterized by positive FGFR4 and FGF19 expression or by positive FGFR4 and KLB expression with a compound of formula (I) or a pharmaceutically acceptable salt thereof 
       
         
           
           
               
               
           
         
         wherein 
         V is selected from CH 2 , O, CH(OH); 
         W is selected from CH 2 , CH 2 CH 2 , bond; 
         X is C(R X ) or N; 
         Y is C(R Y ) or N; 
         Z is CH or N; 
         wherein when X is N, Y and Z are not N; 
         wherein when Y is N, X and Z are not N; 
         wherein when Z is N, X and Y are not N; 
         R X  is selected from hydrogen, halogen, haloC 1 -C 3 alkyl, cyano, C 1 -C 6 alkyl, hydroxyC 1 -C 6 alkyl; 
         R Y  is selected from hydrogen, halogen, C 1 -C 3 alkyl, C 1 -C 6 alkoxy, hydroxyC 1 -C 3 alkoxy, NR Y1 R Y2 , cyano, C 1 -C 3 alkoxyC 1 -C 3 alkoxy, C 1 -C 3 alkoxy-haloC 1 -C 3 alkoxy, di(C 1 -C 3 alkyl)aminoC 1 -C 6 alkoxy, O—(CH 2 ) 0-1 —R Y3 , CR Y6 R Y7 , S—C 1 -C 3 alkyl, haloC 1 -C 6 alkoxy optionally substituted with hydroxy; 
         or 
         R X  and R Y  together with the ring to which they are attached form a bicyclic aromatic ring system optionally further comprising one or two heteroatoms selected from N, O, or S, which ring system is optionally substituted with C 1 -C 3 alkyl; 
         R Y1  is hydrogen and 
         R Y2  is C 1 -C 6 alkyl; hydroxyC 1 -C 6 alkyl; haloC 1 -C 6 alkyl optionally substituted with hydroxy; C 1 -C 4 alkoxyC 1 -C 6 alkyl; haloC 1 -C 3 alkoxyC 1 -C 6 alkyl; (CH 2 ) 0-1 —R Y4 ; di(C 1 -C 3 alkyl)aminoC 1 -C 6 alkyl substituted with hydroxy; bicyclo[2.2.1]heptanyl substituted with hydroxyC 1 -C 3 alkyl; phenyl substituted with S(O) 2 —CH(CH 3 ) 2 ; bicycloC 5 -C 8 alkyl; C 2 -C 3 alkylsulfonic acid; 
         or 
         R Y1  and R Y2  together with the N atom to which they are attached form a saturated or unsaturated non-aromatic 6-membered heterocyclic ring which may contain an O atom, which ring may be substituted once or twice by R Y5 ; 
         R Y3  is selected from quinuclidinyl, a 4-, 5- or 6-membered saturated heterocyclic ring comprising at least one heteroatom selected from N, O or S, or a 5- or 6-membered aromatic heterocyclic ring, which saturated or aromatic heterocyclic ring is optionally substituted with C 1 -C 3 alkyl and/or oxo; 
         R Y4  is a 4-, 5- or 6-membered saturated heterocyclic ring comprising at least one heteroatom selected from N, O, or S, which ring is optionally substituted with C 1 -C 3 alkyl; 
         R Y5  is independently selected from C 1 -C 3 alkyl, hydroxy, di(C 1 -C 3 alkyl)aminoC 1 -C 3 alkyl, 
         or 
         two R Y5  attached at the same carbon atom form together with the carbon atom to which they are attached a 5-membered saturated heterocyclic ring comprising at least one heteroatom selected from N, O or S, which ring is substituted once or more than once with C 1 -C 3 alkyl; 
         R Y6  and R Y7  together with the carbon atom to which they are attached form a 6-membered saturated or unsaturated non-aromatic heterocyclic ring comprising one heteroatom selected from N, O or S; 
         R 1  is selected from hydrogen; halogen; C 1 -C 3 alkyl; haloC 1 -C 3 alkyl; hydroxyC 1 -C 3 alkyl; C 3 -C 6 cycloalkyl; CH 2 NR 2 R 3 ; CH(CH 3 )NR 2 R 3 ; C 1 -C 3 alkoxyC 1 -C 3 alkyl; CH 2 CO 2 H; C(O)H; C 1 -C 3 alkoxy; a 5- or 6-membered saturated heterocyclic or aromatic heterocyclic ring comprising at least one heteroatom selected from N, O or S, which ring is optionally substituted once or more than once with a group independently selected from C 1 -C 3 alkyl, haloC 1 -C 3 alkyl, oxetanyl or oxo; 
         R 2  is selected from C 1 -C 3 alkyl, di(C 1 -C 3 alkyl)aminoC 1 -C 3 alkyl; 
         R 3  is selected from C 1 -C 3 alkyl, C(O)C 1 -C 3 alkyl, C(O)—CH 2 —OH, C(O)—CH 2 —O—CH 3 , C(O)—CH 2 —N(CH 3 ) 2 , S(O) 2 CH 3 ; 
         or 
         R 2  and R 3  together with the N atom to which they are attached form a saturated 5- or 6-membered ring optionally comprising one additional heteroatom selected from N, N-oxide, O or S, which ring may be substituted once or more than once with R 4 ; 
         R 4  is independently selected from C 1 -C 3 alkyl, di(C 1 -C 3 alkyl)amino, C(O)CH 3 , hydroxy; 
         or 
         two R 4  attached at the same carbon atom form together with the carbon atom to which they are attached a 4-, 5- or 6-membered non-aromatic heterocyclic ring comprising at least one heteroatom selected from N, O or S; 
         or 
         two R 4  attached at the same ring atom form an oxo group; and 
         R 5  is selected from hydrogen or C 1 -C 3 alkyl. 
       
     
     
         2 . A method according to  claim 1 , wherein the solid malignancies are characterized by positive FGFR4, FGF19 and KLB expression. 
     
     
         3 . A method according to  claim 1 , wherein the solid malignancies are from a cancer selected from liver cancer, breast cancer, glioblastoma, prostate cancer, rhabdomyosarcoma, gastric cancer, ovarian cancer, lung cancer, colon cancer. 
     
     
         4 . A method of treating a patient having solid malignancies, characterized in that the compound of formula (I) or a pharmaceutically acceptable salt thereof is to be administered to the patient on the basis of said patient having positive FGFR4 and KLB expression, or positive FGFR4 and FGF19 expression, or positive FGFR4, KLB and FGF19 expression with a compound of formula (I) or a pharmaceutically acceptable salt thereof 
       
         
           
           
               
               
           
         
         wherein 
         V is selected from CH 2 , O, CH(OH); 
         W is selected from CH 2 , CH 2 CH 2 , bond; 
         X is C(R X ) or N; 
         Y is C(R Y ) or N; 
         Z is CH or N; 
         wherein when X is N, Y and Z are not N; 
         wherein when Y is N, X and Z are not N; 
         wherein when Z is N, X and Y are not N; 
         R X  is selected from hydrogen, halogen, haloC 1 -C 3 alkyl, cyano, C 1 -C 6 alkyl, hydroxyC 1 -C 6 alkyl; 
         R Y  is selected from hydrogen, halogen, C 1 -C 3 alkyl, C 1 -C 6 alkoxy, hydroxyC 1 -C 3 alkoxy, NR Y1 R Y2 , cyano, C 1 -C 3 alkoxyC 1 -C 3 alkoxy, C 1 -C 3 alkoxy-haloC 1 -C 3 alkoxy, di(C 1 -C 3 alkyl)aminoC 1 -C 6 alkoxy, O—(CH 2 ) 0-1 —R Y3 , CR Y6 R Y7 , S—C 1 -C 3 alkyl, haloC 1 -C 6 alkoxy optionally substituted with hydroxy; 
         or 
         R X  and R Y  together with the ring to which they are attached form a bicyclic aromatic ring system optionally further comprising one or two heteroatoms selected from N, O, or S, which ring system is optionally substituted with C 1 -C 3 alkyl; 
         R Y1  is hydrogen and 
         R Y2  is C 1 -C 6 alkyl; hydroxyC 1 -C 6 alkyl; haloC 1 -C 6 alkyl optionally substituted with hydroxy; C 1 -C 4 alkoxyC 1 -C 6 alkyl; haloC 1 -C 3 alkoxyC 1 -C 6 alkyl; (CH 2 ) 0-1 —R Y4 ; di(C 1 -C 3 alkyl)aminoC 1 -C 6 alkyl substituted with hydroxy; bicyclo[2.2.1]heptanyl substituted with hydroxyC 1 -C 3 alkyl; phenyl substituted with S(O) 2 —CH(CH 3 ) 2 ; bicycloC 5 -C 8 alkyl; C 2 -C 3 alkylsulfonic acid; 
         or 
         R Y1  and R Y2  together with the N atom to which they are attached form a saturated or unsaturated non-aromatic 6-membered heterocyclic ring which may contain an O atom, which ring may be substituted once or twice by R Y5 ; 
         R Y3  is selected from quinuclidinyl, a 4-, 5- or 6-membered saturated heterocyclic ring comprising at least one heteroatom selected from N, O or S, or a 5- or 6-membered aromatic heterocyclic ring, which saturated or aromatic heterocyclic ring is optionally substituted with C 1 -C 3 alkyl and/or oxo; 
         R Y4  is a 4-, 5- or 6-membered saturated heterocyclic ring comprising at least one heteroatom selected from N, O, or S, which ring is optionally substituted with C 1 -C 3 alkyl; 
         R Y5  is independently selected from C 1 -C 3 alkyl, hydroxy, di(C 1 -C 3 alkyl)aminoC 1 -C 3 alkyl, 
         or 
         two R Y5  attached at the same carbon atom form together with the carbon atom to which they are attached a 5-membered saturated heterocyclic ring comprising at least one heteroatom selected from N, O or S, which ring is substituted once or more than once with C 1 -C 3 alkyl; 
         R Y6  and R Y7  together with the carbon atom to which they are attached form a 6-membered saturated or unsaturated non-aromatic heterocyclic ring comprising one heteroatom selected from N, O or S; 
         R 1  is selected from hydrogen; halogen; C 1 -C 3 alkyl; haloC 1 -C 3 alkyl; hydroxyC 1 -C 3 alkyl; C 3 -C 6 cycloalkyl; CH 2 NR 2 R 3 ; CH(CH 3 )NR 2 R 3 ; C 1 -C 3 alkoxyC 1 -C 3 alkyl; CH 2 CO 2 H; C(O)H; C 1 -C 3 alkoxy; a 5- or 6-membered saturated heterocyclic or aromatic heterocyclic ring comprising at least one heteroatom selected from N, O or S, which ring is optionally substituted once or more than once with a group independently selected from C 1 -C 3 alkyl, haloC 1 -C 3 alkyl, oxetanyl or oxo; 
         R 2  is selected from C 1 -C 3 alkyl, di(C 1 -C 3 alkyl)aminoC 1 -C 3 alkyl; 
         R 3  is selected from C 1 -C 3 alkyl, C(O)C 1 -C 3 alkyl, C(O)—CH 2 —OH, C(O)—CH 2 —O—CH 3 , C(O)—CH 2 —N(CH 3 ) 2 , S(O) 2 CH 3 ; 
         or 
         R 2  and R 3  together with the N atom to which they are attached form a saturated 5- or 6-membered ring optionally comprising one additional heteroatom selected from N, N-oxide, O or S, which ring may be substituted once or more than once with R 4 ; 
         R 4  is independently selected from C 1 -C 3 alkyl, di(C 1 -C 3 alkyl)amino, C(O)CH 3 , hydroxy; 
         or 
         two R 4  attached at the same carbon atom form together with the carbon atom to which they are attached a 4-, 5- or 6-membered non-aromatic heterocyclic ring comprising at least one heteroatom selected from N, O or S; 
         or 
         two R 4  attached at the same ring atom form an oxo group; and 
         R 5  is selected from hydrogen or C 1 -C 3 alkyl. 
       
     
     
         5 . A method of treating a patient having solid malignancies, characterized in that
 The patient is selected for treatment on the basis of the patient having positive FGFR4 and KLB expression, or positive FGFR4 and FGF19 expression, or positive FGFR4, KLB and FGF19 expression; and then treated with   a compound of formula (I) or a pharmaceutically acceptable salt thereof   
       
         
           
           
               
               
           
         
       
       wherein 
       V is selected from CH 2 , O, CH(OH); 
       W is selected from CH 2 , CH 2 CH 2 , bond; 
       X is C(R X ) or N; 
       Y is C(R Y ) or N; 
       Z is CH or N; 
       wherein when X is N, Y and Z are not N; 
       wherein when Y is N, X and Z are not N; 
       wherein when Z is N, X and Y are not N; 
       R X  is selected from hydrogen, halogen, haloC 1 -C 3 alkyl, cyano, C 1 -C 6 alkyl, hydroxyC 1 -C 6 alkyl; 
       R Y  is selected from hydrogen, halogen, C 1 -C 3 alkyl, C 1 -C 6 alkoxy, hydroxyC 1 -C 3 alkoxy, NR Y1 R Y2 , cyano, C 1 -C 3 alkoxyC 1 -C 3 alkoxy, C 1 -C 3 alkoxy-haloC 1 -C 3 alkoxy, di(C 1 -C 3 alkyl)aminoC 1 -C 6 alkoxy, O—(CH 2 ) 0-1 —R Y3 , CR Y6 R Y7 , S—C 1 -C 3 alkyl, haloC 1 -C 6 alkoxy optionally substituted with hydroxy; 
       or 
       R X  and R Y  together with the ring to which they are attached form a bicyclic aromatic ring system optionally further comprising one or two heteroatoms selected from N, O, or S, which ring system is optionally substituted with C 1 -C 3 alkyl; 
       R Y1  is hydrogen and 
       R Y2  is C 1 -C 6 alkyl; hydroxyC 1 -C 6 alkyl; haloC 1 -C 6 alkyl optionally substituted with hydroxy; C 1 -C 4 alkoxyC 1 -C 6 alkyl; haloC 1 -C 3 alkoxyC 1 -C 6 alkyl; (CH 2 ) 0-1 —R Y4 ; di(C 1 -C 3 alkyl)aminoC 1 -C 6 alkyl substituted with hydroxy; bicyclo[2.2.1]heptanyl substituted with hydroxyC 1 -C 3 alkyl; phenyl substituted with S(O) 2 —CH(CH 3 ) 2 ; bicycloC 5 -C 8 alkyl; C 2 -C 3 alkylsulfonic acid; 
       or 
       R Y1  and R Y2  together with the N atom to which they are attached form a saturated or unsaturated non-aromatic 6-membered heterocyclic ring which may contain an O atom, which ring may be substituted once or twice by R Y5 ; 
       R Y3  is selected from quinuclidinyl, a 4-, 5- or 6-membered saturated heterocyclic ring comprising at least one heteroatom selected from N, O or S, or a 5- or 6-membered aromatic heterocyclic ring, which saturated or aromatic heterocyclic ring is optionally substituted with C 1 -C 3 alkyl and/or oxo; 
       R Y4  is a 4-, 5- or 6-membered saturated heterocyclic ring comprising at least one heteroatom selected from N, O, or S, which ring is optionally substituted with C 1 -C 3 alkyl; 
       R Y5  is independently selected from C 1 -C 3 alkyl, hydroxy, di(C 1 -C 3 alkyl)aminoC 1 -C 3 alkyl, 
       or 
       two R Y5  attached at the same carbon atom form together with the carbon atom to which they are attached a 5-membered saturated heterocyclic ring comprising at least one heteroatom selected from N, O or S, which ring is substituted once or more than once with C 1 -C 3 alkyl; 
       R Y6  and R Y7  together with the carbon atom to which they are attached form a 6-membered saturated or unsaturated non-aromatic heterocyclic ring comprising one heteroatom selected from N, O or S; 
       R 1  is selected from hydrogen; halogen; C 1 -C 3 alkyl; haloC 1 -C 3 alkyl; hydroxyC 1 -C 3 alkyl; C 3 -C 6 cycloalkyl; CH 2 NR 2 R 3 ; CH(CH 3 )NR 2 R 3 ; C 1 -C 3 alkoxyC 1 -C 3 alkyl; CH 2 CO 2 H; C(O)H; C 1 -C 3 alkoxy; a 5- or 6-membered saturated heterocyclic or aromatic heterocyclic ring comprising at least one heteroatom selected from N, O or S, which ring is optionally substituted once or more than once with a group independently selected from C 1 -C 3 alkyl, haloC 1 -C 3 alkyl, oxetanyl or oxo; 
       R 2  is selected from C 1 -C 3 alkyl, di(C 1 -C 3 alkyl)aminoC 1 -C 3 alkyl; 
       R 3  is selected from C 1 -C 3 alkyl, C(O)C 1 -C 3 alkyl, C(O)—CH 2 —OH, C(O)—CH 2 —O—CH 3 , C(O)—CH 2 —N(CH 3 ) 2 , S(O) 2 CH 3 ; 
       or 
       R 2  and R 3  together with the N atom to which they are attached form a saturated 5- or 6-membered ring optionally comprising one additional heteroatom selected from N, N-oxide, O or S, which ring may be substituted once or more than once with R 4 ; 
       R 4  is independently selected from C 1 -C 3 alkyl, di(C 1 -C 3 alkyl)amino, C(O)CH 3 , hydroxy; 
       or 
       two R 4  attached at the same carbon atom form together with the carbon atom to which they are attached a 4-, 5- or 6-membered non-aromatic heterocyclic ring comprising at least one heteroatom selected from N, O or S; 
       or 
       two R 4  attached at the same ring atom form an oxo group; and 
       R 5  is selected from hydrogen or C 1 -C 3 alkyl. 
     
     
         6 . A method of treating a patient having solid malignancies, characterized in that
 a biological sample from the patient is assayed for positive FGFR4 and KLB expression, or positive FGFR4 and FGF19 expression, or positive FGFR4, KLB and FGF19 expression; and   a compound of formula (I) or a pharmaceutically acceptable salt thereof is administered to the patient on the basis of the biological sample from the patient having positive FGFR4 and KLB expression, or positive FGFR4 and FGF19 expression, or positive FGFR4, KLB and FGF19 expression with the treatment of a   compound of formula (I) or a pharmaceutically acceptable salt thereof   
       
         
           
           
               
               
           
         
       
       wherein 
       V is selected from CH 2 , O, CH(OH); 
       W is selected from CH 2 , CH 2 CH 2 , bond; 
       X is C(R X ) or N; 
       Y is C(R Y ) or N; 
       Z is CH or N; 
       wherein when X is N, Y and Z are not N; 
       wherein when Y is N, X and Z are not N; 
       wherein when Z is N, X and Y are not N; 
       R X  is selected from hydrogen, halogen, haloC 1 -C 3 alkyl, cyano, C 1 -C 6 alkyl, hydroxyC 1 -C 6 alkyl; 
       R Y  is selected from hydrogen, halogen, C 1 -C 3 alkyl, C 1 -C 6 alkoxy, hydroxyC 1 -C 3 alkoxy, NR Y1 R Y2 , cyano, C 1 -C 3 alkoxyC 1 -C 3 alkoxy, C 1 -C 3 alkoxy-haloC 1 -C 3 alkoxy, di(C 1 -C 3 alkyl)aminoC 1 -C 6 alkoxy, O—(CH 2 ) 0-1 —R Y3 , CR Y6 R Y7 , S—C 1 -C 3 alkyl, haloC 1 -C 6 alkoxy optionally substituted with hydroxy; 
       or 
       R X  and R Y  together with the ring to which they are attached form a bicyclic aromatic ring system optionally further comprising one or two heteroatoms selected from N, O, or S, which ring system is optionally substituted with C 1 -C 3 alkyl; 
       R Y1  is hydrogen and 
       R Y2  is C 1 -C 6 alkyl; hydroxyC 1 -C 6 alkyl; haloC 1 -C 6 alkyl optionally substituted with hydroxy; C 1 -C 4 alkoxyC 1 -C 6 alkyl; haloC 1 -C 3 alkoxyC 1 -C 6 alkyl; (CH 2 ) 0-1 —R Y4 ; di(C 1 -C 3 alkyl)aminoC 1 -C 6 alkyl substituted with hydroxy; bicyclo[2.2.1]heptanyl substituted with hydroxyC 1 -C 3 alkyl; phenyl substituted with S(O) 2 —CH(CH 3 ) 2 ; bicycloC 5 -C 8 alkyl; C 2 -C 3 alkylsulfonic acid; 
       or 
       R Y1  and R Y2  together with the N atom to which they are attached form a saturated or unsaturated non-aromatic 6-membered heterocyclic ring which may contain an O atom, which ring may be substituted once or twice by R Y5 ; 
       R Y3  is selected from quinuclidinyl, a 4-, 5- or 6-membered saturated heterocyclic ring comprising at least one heteroatom selected from N, O or S, or a 5- or 6-membered aromatic heterocyclic ring, which saturated or aromatic heterocyclic ring is optionally substituted with C 1 -C 3 alkyl and/or oxo; 
       R Y4  is a 4-, 5- or 6-membered saturated heterocyclic ring comprising at least one heteroatom selected from N, O, or S, which ring is optionally substituted with C 1 -C 3 alkyl; 
       R Y5  is independently selected from C 1 -C 3 alkyl, hydroxy, di(C 1 -C 3 alkyl)aminoC 1 -C 3 alkyl, 
       or 
       two R Y5  attached at the same carbon atom form together with the carbon atom to which they are attached a 5-membered saturated heterocyclic ring comprising at least one heteroatom selected from N, O or S, which ring is substituted once or more than once with C 1 -C 3 alkyl; 
       R Y6  and R Y7  together with the carbon atom to which they are attached form a 6-membered saturated or unsaturated non-aromatic heterocyclic ring comprising one heteroatom selected from N, O or S; 
       R 1  is selected from hydrogen; halogen; C 1 -C 3 alkyl; haloC 1 -C 3 alkyl; hydroxyC 1 -C 3 alkyl; C 3 -C 6 cycloalkyl; CH 2 NR 2 R 3 ; CH(CH 3 )NR 2 R 3 ; C 1 -C 3 alkoxyC 1 -C 3 alkyl; CH 2 CO 2 H; C(O)H; C 1 -C 3 alkoxy; a 5- or 6-membered saturated heterocyclic or aromatic heterocyclic ring comprising at least one heteroatom selected from N, O or S, which ring is optionally substituted once or more than once with a group independently selected from C 1 -C 3 alkyl, haloC 1 -C 3 alkyl, oxetanyl or oxo; 
       R 2  is selected from C 1 -C 3 alkyl, di(C 1 -C 3 alkyl)aminoC 1 -C 3 alkyl; 
       R 3  is selected from C 1 -C 3 alkyl, C(O)C 1 -C 3 alkyl, C(O)—CH 2 —OH, C(O)—CH 2 —O—CH 3 , C(O)—CH 2 —N(CH 3 ) 2 , S(O) 2 CH 3 ; 
       or 
       R 2  and R 3  together with the N atom to which they are attached form a saturated 5- or 6-membered ring optionally comprising one additional heteroatom selected from N, N-oxide, O or S, which ring may be substituted once or more than once with R 4 ; 
       R 4  is independently selected from C 1 -C 3 alkyl, di(C 1 -C 3 alkyl)amino, C(O)CH 3 , hydroxy; 
       or 
       two R 4  attached at the same carbon atom form together with the carbon atom to which they are attached a 4-, 5- or 6-membered non-aromatic heterocyclic ring comprising at least one heteroatom selected from N, O or S; 
       or 
       two R 4  attached at the same ring atom form an oxo group; 
       R 5  is selected from hydrogen or C 1 -C 3 alkyl. 
     
     
         7 . A method of treating a patient having solid malignancies comprising
 Assaying a biological sample from the patient;   Determining if the biological sample from the patient is characterized by positive FGFR4 and KLB expression, or by positive FGFR4 and FGF19 expression, or by positive FGFR4, KLB and FGF19 expression; and   If the biological sample is characterized by positive FGFR4 and KLB expression, or by positive FGFR4 and FGF19 expression, or by positive FGFR4, KLB and FGF19 expression, administering a compound of formula (I) or a pharmaceutically acceptable salt thereof to the patient with a   compound of formula (I) or a pharmaceutically acceptable salt thereof   
       
         
           
           
               
               
           
         
       
       wherein 
       V is selected from CH 2 , O, CH(OH); 
       W is selected from CH 2 , CH 2 CH 2 , bond; 
       X is C(R X ) or N; 
       Y is C(R Y ) or N; 
       Z is CH or N; 
       wherein when X is N, Y and Z are not N; 
       wherein when Y is N, X and Z are not N; 
       wherein when Z is N, X and Y are not N; 
       R X  is selected from hydrogen, halogen, haloC 1 -C 3 alkyl, cyano, C 1 -C 6 alkyl, hydroxyC 1 -C 6 alkyl; 
       R Y  is selected from hydrogen, halogen, C 1 -C 3 alkyl, C 1 -C 6 alkoxy, hydroxyC 1 -C 3 alkoxy, NR Y1 R Y2 , cyano, C 1 -C 3 alkoxyC 1 -C 3 alkoxy, C 1 -C 3 alkoxy-haloC 1 -C 3 alkoxy, di(C 1 -C 3 alkyl)aminoC 1 -C 6 alkoxy, O—(CH 2 ) 0-1 —R Y3 , CR Y6 R Y7 , S—C 1 -C 3 alkyl, haloC 1 -C 6 alkoxy optionally substituted with hydroxy; 
       or 
       R X  and R Y  together with the ring to which they are attached form a bicyclic aromatic ring system optionally further comprising one or two heteroatoms selected from N, O, or S, which ring system is optionally substituted with C 1 -C 3 alkyl; 
       R Y1  is hydrogen and 
       R Y2  is C 1 -C 6 alkyl; hydroxyC 1 -C 6 alkyl; haloC 1 -C 6 alkyl optionally substituted with hydroxy; C 1 -C 4 alkoxyC 1 -C 6 alkyl; haloC 1 -C 3 alkoxyC 1 -C 6 alkyl; (CH 2 ) 0-1 —R Y4 ; di(C 1 -C 3 alkyl)aminoC 1 -C 6 alkyl substituted with hydroxy; bicyclo[2.2.1]heptanyl substituted with hydroxyC 1 -C 3 alkyl; phenyl substituted with S(O) 2 —CH(CH 3 ) 2 ; bicycloC 5 -C 8 alkyl; C 2 -C 3 alkylsulfonic acid; 
       or 
       R Y1  and R Y2  together with the N atom to which they are attached form a saturated or unsaturated non-aromatic 6-membered heterocyclic ring which may contain an O atom, which ring may be substituted once or twice by R Y5 ; 
       R Y3  is selected from quinuclidinyl, a 4-, 5- or 6-membered saturated heterocyclic ring comprising at least one heteroatom selected from N, O or S, or a 5- or 6-membered aromatic heterocyclic ring, which saturated or aromatic heterocyclic ring is optionally substituted with C 1 -C 3 alkyl and/or oxo; 
       R Y4  is a 4-, 5- or 6-membered saturated heterocyclic ring comprising at least one heteroatom selected from N, O, or S, which ring is optionally substituted with C 1 -C 3 alkyl; 
       R Y5  is independently selected from C 1 -C 3 alkyl, hydroxy, di(C 1 -C 3 alkyl)aminoC 1 -C 3 alkyl, 
       or 
       two R Y5  attached at the same carbon atom form together with the carbon atom to which they are attached a 5-membered saturated heterocyclic ring comprising at least one heteroatom selected from N, O or S, which ring is substituted once or more than once with C 1 -C 3 alkyl; 
       R Y6  and R Y7  together with the carbon atom to which they are attached form a 6-membered saturated or unsaturated non-aromatic heterocyclic ring comprising one heteroatom selected from N, O or S; 
       R 1  is selected from hydrogen; halogen; C 1 -C 3 alkyl; haloC 1 -C 3 alkyl; hydroxyC 1 -C 3 alkyl; C 3 -C 6 cycloalkyl; CH 2 NR 2 R 3 ; CH(CH 3 )NR 2 R 3 ; C 1 -C 3 alkoxyC 1 -C 3 alkyl; CH 2 CO 2 H; C(O)H; C 1 -C 3 alkoxy; a 5- or 6-membered saturated heterocyclic or aromatic heterocyclic ring comprising at least one heteroatom selected from N, O or S, which ring is optionally substituted once or more than once with a group independently selected from C 1 -C 3 alkyl, haloC 1 -C 3 alkyl, oxetanyl or oxo; 
       R 2  is selected from C 1 -C 3 alkyl, di(C 1 -C 3 alkyl)aminoC 1 -C 3 alkyl; 
       R 3  is selected from C 1 -C 3 alkyl, C(O)C 1 -C 3 alkyl, C(O)—CH 2 —OH, C(O)—CH 2 —O—CH 3 , C(O)—CH 2 —N(CH 3 ) 2 , S(O) 2 CH 3 ; 
       or 
       R 2  and R 3  together with the N atom to which they are attached form a saturated 5- or 6-membered ring optionally comprising one additional heteroatom selected from N, N-oxide, O or S, which ring may be substituted once or more than once with R 4 ; 
       R 4  is independently selected from C 1 -C 3 alkyl, di(C 1 -C 3 alkyl)amino, C(O)CH 3 , hydroxy; 
       or 
       two R 4  attached at the same carbon atom form together with the carbon atom to which they are attached a 4-, 5- or 6-membered non-aromatic heterocyclic ring comprising at least one heteroatom selected from N, O or S; 
       or 
       two R 4  attached at the same ring atom form an oxo group; 
       R 5  is selected from hydrogen or C 1 -C 3 alkyl, 
     
     
         8 . A method according to  claim 1 , wherein the compound is of formula (Ia-1) or a pharmaceutically acceptable salt thereof 
       
         
           
           
               
               
           
         
       
     
     
         9 . A method according to  claim 1  wherein said compound is selected from
 N-(5-cyanopyridin-2-yl)-7-formyl-3,4-dihydro-1,8-naphthyridine-1 (2H)-carboxamide; 
 N-(5-cyanopyridin-2-yl)-7-formyl-6-(hydroxymethyl)-3,4-dihydro-1,8-naphthyridine-1 (2H)-carboxamide; 
 N-(5-cyano-4-(2-methoxyethoxy)pyridin-2-yl)-7-formyl-6-(hydroxymethyl)-3,4-dihydro-1,8-naphthyridine-1(2H)-carboxamide; 
 (R)—N-(5-cyano-4-((tetrahydrofuran-3-yl)oxy)pyridin-2-yl)-7-formyl-6-(hydroxymethyl)-3,4-dihydro-1,8-naphthyridine-1(2H)-carboxamide; 
 (S)—N-(5-cyano-4-((tetrahydrofuran-3-yl)oxy)pyridin-2-yl)-7-formyl-6-(hydroxymethyl)-3,4-dihydro-1,8-naphthyridine-1(2H)-carboxamide; 
 N-(5-cyano-4-(2-methoxyethoxy)pyridin-2-yl)-6-(difluoromethyl)-7-formyl-3,4-dihydro-1,8-naphthyridine-1(2H)-carboxamide; 
 N-(5-cyanopyridin-2-yl)-7-formyl-6-((N-methylacetamido)methyl)-3,4-dihydro-1,8-naphthyridine-1(2H)-carboxamide; 
 N-(5-cyano-4-((2-methoxyethyl)amino)pyridin-2-yl)-7-formyl-6-(hydroxymethyl)-3,4-dihydro-1,8-naphthyridine-1(2H)-carboxamide; 
 N-(5-cyano-4-((2-methoxyethyl)amino)pyridin-2-yl)-7-formyl-6-((4-methyl-2-oxopiperazin-1-yl)methyl)-3,4-dihydro-1,8-naphthyridine-1(2H)-carboxamide; 
 N-(5-cyano-4-isopropoxypyridin-2-yl)-7-formyl-6-((4-methyl-2-oxopiperazin-1-yl)methyl)-3,4-dihydro-1,8-naphthyridine-1(2H)-carboxamide; 
 N-(5-cyano-4-(2-methoxyethoxy)pyridin-2-yl)-7-formyl-6-((4-methyl-2-oxopiperazin-1-yl)methyl)-3,4-dihydro-1,8-naphthyridine-1(2H)-carboxamide; or 
 (R)—N-(5-cyano-4-((1-methoxypropan-2-yl)oxy)pyridin-2-yl)-7-formyl-6-((4-methyl-2-oxopiperazin-1-yl)methyl)-3,4-dihydro-1,8-naphthyridine-1(2H)-carboxamide. 
 
     
     
         10 . A method of treating solid malignancies characterized by positive FGFR4 and KLB expression, or by positive FGFR4 and FGF19 expression, or by positive FGFR4, KLB and FGF19 expression pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof and one or more pharmaceutically acceptable carriers 
       
         
           
           
               
               
           
         
         wherein 
         V is selected from CH 2 , O, CH(OH); 
         W is selected from CH 2 , CH 2 CH 2 , bond; 
         X is C(R X ) or N; 
         Y is C(R Y ) or N; 
         Z is CH or N; 
         wherein when X is N, Y and Z are not N; 
         wherein when Y is N, X and Z are not N; 
         wherein when Z is N, X and Y are not N; 
         R X  is selected from hydrogen, halogen, haloC 1 -C 3 alkyl, cyano, C 1 -C 6 alkyl, hydroxyC 1 -C 6 alkyl; 
         R Y  is selected from hydrogen, halogen, C 1 -C 3 alkyl, C 1 -C 6 alkoxy, hydroxyC 1 -C 3 alkoxy, NR Y1 R Y2 , cyano, C 1 -C 3 alkoxyC 1 -C 3 alkoxy, C 1 -C 3 alkoxy-haloC 1 -C 3 alkoxy, di(C 1 -C 3 alkyl)aminoC 1 -C 6 alkoxy, O—(CH 2 ) 0-1 —R Y3 , CR Y6 R Y7 , S—C 1 -C 3 alkyl, haloC 1 -C 6 alkoxy optionally substituted with hydroxy; 
         or 
         R X  and R Y  together with the ring to which they are attached form a bicyclic aromatic ring system optionally further comprising one or two heteroatoms selected from N, O, or S, which ring system is optionally substituted with C 1 -C 3 alkyl; 
         R Y1  is hydrogen and 
         R Y2  is C 1 -C 6 alkyl; hydroxyC 1 -C 6 alkyl; haloC 1 -C 6 alkyl optionally substituted with hydroxy; C 1 -C 4 alkoxyC 1 -C 6 alkyl; haloC 1 -C 3 alkoxyC 1 -C 6 alkyl; (CH 2 ) 0-1 —R Y4 ; di(C 1 -C 3 alkyl)aminoC 1 -C 6 alkyl substituted with hydroxy; bicyclo[2.2.1]heptanyl substituted with hydroxyC 1 -C 3 alkyl; phenyl substituted with S(O) 2 —CH(CH 3 ) 2 ; bicycloC 5 -C 8 alkyl; C 2 -C 3 alkylsulfonic acid; 
         or 
         R Y1  and R Y2  together with the N atom to which they are attached form a saturated or unsaturated non-aromatic 6-membered heterocyclic ring which may contain an O atom, which ring may be substituted once or twice by R Y5 ; 
         R Y3  is selected from quinuclidinyl, a 4-, 5- or 6-membered saturated heterocyclic ring comprising at least one heteroatom selected from N, O or S, or a 5- or 6-membered aromatic heterocyclic ring, which saturated or aromatic heterocyclic ring is optionally substituted with C 1 -C 3 alkyl and/or oxo; 
         R Y4  is a 4-, 5- or 6-membered saturated heterocyclic ring comprising at least one heteroatom selected from N, O, or S, which ring is optionally substituted with C 1 -C 3 alkyl; 
         R Y5  is independently selected from C 1 -C 3 alkyl, hydroxy, di(C 1 -C 3 alkyl)aminoC 1 -C 3 alkyl, 
         or 
         two R Y5  attached at the same carbon atom form together with the carbon atom to which they are attached a 5-membered saturated heterocyclic ring comprising at least one heteroatom selected from N, O or S, which ring is substituted once or more than once with C 1 -C 3 alkyl; 
         R Y6  and R Y7  together with the carbon atom to which they are attached form a 6-membered saturated or unsaturated non-aromatic heterocyclic ring comprising one heteroatom selected from N, O or S; 
         R 1  is selected from hydrogen; halogen; C 1 -C 3 alkyl; haloC 1 -C 3 alkyl; hydroxyC 1 -C 3 alkyl; C 3 -C 6 cycloalkyl; CH 2 NR 2 R 3 ; CH(CH 3 )NR 2 R 3 ; C 1 -C 3 alkoxyC 1 -C 3 alkyl; CH 2 CO 2 H; C(O)H; C 1 -C 3 alkoxy; a 5- or 6-membered saturated heterocyclic or aromatic heterocyclic ring comprising at least one heteroatom selected from N, O or S, which ring is optionally substituted once or more than once with a group independently selected from C 1 -C 3 alkyl, haloC 1 -C 3 alkyl, oxetanyl or oxo; 
         R 2  is selected from C 1 -C 3 alkyl, di(C 1 -C 3 alkyl)aminoC 1 -C 3 alkyl; 
         R 3  is selected from C 1 -C 3 alkyl, C(O)C 1 -C 3 alkyl, C(O)—CH 2 —OH, C(O)—CH 2 —O—CH 3 , C(O)—CH 2 —N(CH 3 ) 2 , S(O) 2 CH 3 ; 
         or 
         R 2  and R 3  together with the N atom to which they are attached form a saturated 5- or 6-membered ring optionally comprising one additional heteroatom selected from N, N-oxide, O or S, which ring may be substituted once or more than once with R 4 ; 
         R 4  is independently selected from C 1 -C 3 alkyl, di(C 1 -C 3 alkyl)amino, C(O)CH 3 , hydroxy; 
         or 
         two R 4  attached at the same carbon atom form together with the carbon atom to which they are attached a 4-, 5- or 6-membered non-aromatic heterocyclic ring comprising at least one heteroatom selected from N, O or S; 
         or 
         two R 4  attached at the same ring atom form an oxo group; 
         R 5  is selected from hydrogen or C 1 -C 3 alkyl.