Use of ring-fused bicyclic pyridyl derivatives as FGFR4 inhibitors

Patent metadata

Field	Value
Publication number	US-10507201-B2
Application number	US-201916289612-A
Country	US
Kind code	B2
Filing date	Feb 28, 2019
Priority date	Oct 3, 2014
Publication date	Dec 17, 2019
Grant date	Dec 17, 2019

Abstract

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

First claim

The invention claimed is:

1. A method of treating a solid malignancy comprising a cancer characterized by positive FGFR4 and FGF19 expression or by positive FGFR4 and KLB expression or positive FGFR4, FGF19 and KLB expression, comprising administering a compound of formula (I), or a pharmaceutically acceptable salt thereof:

wherein
V is selected from CH 2 , O, and CH(OH);
W is selected from CH 2 , CH 2 CH 2 , and 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, and 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, and 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, and 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; or 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 and S, and 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, and S, which ring is optionally substituted with C 1 -C 3 alkyl;
R Y5 is independently selected from C 1 -C 3 alkyl, hydroxy, and 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 and 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 and 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; and a 5- or 6-membered saturated heterocyclic or aromatic heterocyclic ring comprising at least one heteroatom selected from N, O and 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 and oxo;
R 2 is selected from C 1 -C 3 alkyl, and 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 , and 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 and 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 , and 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 and S;
or
two R 4 attached at the same ring atom form an oxo group; and
R 5 is selected from hydrogen and C 1 -C 3 alkyl,
for use in the treatment of the cancer, wherein the cancer is selected from breast cancer, glioblastoma, prostate cancer, rhabdomyosarcoma, gastric cancer, ovarian cancer, lung cancer, colon cancer characterized by positive FGFR4 and KLB expression, or by positive FGFR4 and FGF19 expression, or by positive FGFR4, KLB and FGF19 expression.

2. The method according to claim 1 , wherein the cancer is characterized by positive FGFR4, FGF19 and KLB expression.

3. A method of treating a patient having solid malignancies, comprising administering to the patient a compound of formula (I) or a pharmaceutically acceptable salt thereof 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, wherein the compound of formula (I), or a pharmaceutically acceptable salt thereof is:

wherein
V is selected from CH 2 , O, and CH(OH);
W is selected from CH 2 , CH 2 CH 2 , and 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, and 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, and 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, and 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; or 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 and S, and a 5- or 6-membered aromatic heterocyclic ring, which saturated or aromatic heterocyclic

Assignees

• Novartis Ag

Inventors

• Buschmann Nicole
• Fairhurst Robin Alec
• Furet Pascal
• Graus Porta Diana
• Haefliger Carolina
• Han Bo
• Knöpfel Thomas
• Leblanc Catherine
• Liao Lv
• Mah Robert
• Murakami Masato
• Nimsgern Pierre
• Palmer Michael
• Porter Dale
• Ripoche Sebastien
• Wang Can
• Wang Youzhen
• Weiss Andreas
• Xiong Jing
• Zhao Xianglin

Classifications

• A61P35/00

  Antineoplastic agents · CPC title

• A61K31/496

  Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin · CPC title

• A61K31/4545

  containing a six-membered ring with nitrogen as a ring hetero atom, e.g. pipamperone, anabasine · CPC title

• A61K31/55

  having seven-membered rings, e.g. azelastine, pentylenetetrazole · CPC title

• A61K31/4375 Primary

  the heterocyclic ring system containing a six-membered ring having nitrogen as a ring heteroatom, e.g. quinolizines, naphthyridines, berberine, vincamine · CPC title