US 11,667,631 B2
FGFR4 inhibitor, preparation method therefor, and applications thereof
Peng Gao, Jiangsu (CN); Wenhua Xiu, Jiangsu (CN); Shaobao Wang, Jiangsu (CN); Lei Liu, Jiangsu (CN); and Rudi Bao, Jiangsu (CN)
Assigned to Jiangsu Hansoh Pharmaceutical Group Co., Ltd., Jiangsu (CN); and Shanghai Hansoh Biomedical Co., Ltd., Shanghai (CN)
Appl. No. 16/302,374
Filed by Jiangsu Hansoh Pharmaceutical Group Co., Ltd., Jiangsu (CN); and Shanghai Hansoh Biomedical Co., Ltd., Shanghai (CN)
PCT Filed May 16, 2017, PCT No. PCT/CN2017/084564
§ 371(c)(1), (2) Date Nov. 16, 2018,
PCT Pub. No. WO2017/198149, PCT Pub. Date Nov. 23, 2017.
Claims priority of application No. 201610339009.4 (CN), filed on May 20, 2016; and application No. 201611166598.7 (CN), filed on Dec. 16, 2016.
Prior Publication US 2019/0276451 A1, Sep. 12, 2019
Int. Cl. C07D 471/04 (2006.01); A61K 35/00 (2006.01); A61K 31/551 (2006.01); A61K 31/5386 (2006.01); A61K 31/5355 (2006.01); A61K 31/444 (2006.01); A61K 31/553 (2006.01)
CPC C07D 471/04 (2013.01) [A61K 31/444 (2013.01); A61K 31/5355 (2013.01); A61K 31/5386 (2013.01); A61K 31/551 (2013.01); A61K 31/553 (2013.01); A61K 35/00 (2013.01); Y02P 20/55 (2015.11)] 16 Claims
 
1. A compound of formula (III):

OG Complex Work Unit Chemistry
or a stereoisomer or a pharmaceutically acceptable salt thereof,
wherein:
X1 is —(CR3R4)m1—; X2 is —(CR5R6)m2—; X3 is —(CR7R8)m3—;
R3, R4, R5, R6, R7 and R8 are each independently selected from the group consisting of hydrogen, deuterium, halogen, C2-8 alkenyl, C2-8 alkynyl, haloC1-8 alkyl, C3-8 cycloalkyl, 3-8 membered heterocyclyl, C1-8 alkoxy, haloC1-8 alkoxy, C3-8 cycloalkoxy and 3-8 membered heterocyclyloxy,
or, R3 and R4, R5 and R6, or R7 and R8 together with the carbon atom to which they are directly attached form a 3-5 membered cycloalkyl or 3-5 membered heterocyclyl;
Y is selected from the group consisting of oxygen and sulfur;
Z is selected from the group consisting of NX4, oxygen and sulfur;
X4 is selected from the group consisting of hydrogen, deuterium, C3-8 cycloalkyl and haloC1-8 alkyl;
A2 is selected from the group consisting of a bond, NX4, oxygen and sulfur;
B2 is selected from the group consisting of methyl, n-propyl, isopropyl, n-butyl, isobutyl, t -butyl, sec-butyl, n-pentyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2-methylpropyl, 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1,3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2,3-dimethylbutyl, n-heptyl, 2-methylhexyl, 3-methylhexyl, 4-methylhexyl, 5-methylhexyl, 2,3-dimethylpentyl, 2,4-dimethylpentyl, 2,2-dimethylpentyl, 3,3-dimethylpentyl, 2-ethylpentyl, 3-ethylpentyl, n-octyl, 2,3-dimethylhexyl, 2,4-dimethylhexyl, 2,5-dimethylhexyl, 2,2-dimethylhexyl, 3,3-dimethylhexyl, 4,4-dimethylhexyl, 2-ethylhexyl, 3-ethylhexyl, 4-ethylhexyl, 2-methyl ethylpentyl, 2-methyl-3-ethylpentyl, C1-8 alkoxy and C1-8 alkoxysubstituted C1-8 alkyl;
R is selected from the group consisting of hydrogen, deuterium, halogen, hydroxy, thiol, cyano, nitro, azido, C1-8 alkyl, haloC1-8 alkyl, C3-8 cycloalkyl and 3-8 membered heterocyclyl;
R2 is selected from the group consisting of halogen, hydroxy, thiol, cyano, thiocyano, nitro, azido, C1-8 alkyl, C2-8 alkenyl, C2-8 alkynyl, C3-8 cycloalkyl, 3-8 membered heterocyclyl, C1-8 alkyloxy, C3-8 cycloalkoxy and 3-8 membered heterocyclyloxy, wherein the hydroxy, thiol, C1-8 alkyl, C2-8 alkenyl, C2-8 alkynyl, C3-8 cycloalkyl, 3-8 membered heterocyclyl, C1-8 alkyloxy, C3-8 cycloalkoxy and 3-8 membered heterocyclyloxy is optionally substituted by one or more groups selected from the group consisting of halogen, hydroxy, thiol, cyano, nitro, azido, C1-8 alkyl, C2-8 alkenyl, C2-8 alkynyl, haloC1-8 alkyl, C3-8 cycloalkyl, 3-8 membered heterocyclyl, 3-8 membered heterocyclyloxy, 3-8 membered heterocyclylthio, C5-10 aryl, C5-10 aryloxy, C5-10 arylthio, 5-10 membered heteroaryl, 5-10 membered heteroaryloxy, 5-10 membered heteroarylthio, —C0-8—S(O)rR9, —C0-8—O—R10, —C0-8—C(O)OR10, —C0-8—C(O)R11, —C0-8—O—C(O)R11, —C0-8—NR12R13, —C0-8—C(O)NR12R13, —N(R12)—C(O)R11 and —N(R12)—C(O)OR10;
R9 is selected from the group consisting of hydrogen, deuterium, C1-8 alkyl, C2-8 alkenyl, C3-8 cycloalkyl, 3-8 membered heterocyclyl, haloC1-8 alkyl, phenyl, p-methylphenyl, amino, mono C1-8 alkylamino, di C1-8 alkylamino and C1-8 alkanoylamino;
R10 is selected from the group consisting of hydrogen, deuterium, C1-8 alkyl, C3-8 cycloalkyl, C5-10 aryl, 3-8 membered heterocyclyl, haloC1-8 alkyl and hydroxyC1-8 alkyl;
R11 is selected from the group consisting of hydrogen, deuterium, C1-8 alkyl, C1-8 alkoxy, C3-8 cycloalkyl, C3-8 cycloalkoxy, haloC1-8 alkyl, haloC1-8 alkoxy, hydroxyC1-8 alkyl and hydroxyC1-8 alkoxy;
R12 and R13 are each independently selected from the group consisting of hydrogen, deuterium, C1-8 alkyl, C1-8 alkoxy-substituted C1-8 alkyl, C3-8 cycloalkyl-substituted C1-8 alkyl, C2-8 alkenyl, C2-8 alkynyl, C3-8 cycloalkyl, 3-8 membered heterocyclyl, C5-10 aryl, 5-10 membered heteroaryl and C1-8 alkanoyl;
R17 is selected from the group consisting of C1-8 alkyl, halogen, haloC1-8 alkyl, C3-8 cycloalkyl, 3-8 membered heterocyclyl, 3-8 membered heterocyclyloxy, 3-8 membered heterocyclylthio, —C0-8—S(O)rR9, —C0-8—O—R10, —C0-8—C(O)OR10, —C0-8—C(O)R11, —C0-8—O—C(O)R11, —C0-8—NR12R13, —C0-8—C(O)NR12R13, —N(R12)—C(O)R11 and —N(R12)—C(O)OR10;
R18 and R19 are each independently selected from the group consisting of halogen, hydroxy, alkyl, haloC1-8 alkyl, C3-8 cycloalkyl, 3-8 membered heterocyclyl, 3-8 membered heterocyclyloxy, 3-8 membered heterocyclylthio, —C0-8—S(O)rR9, —C0-8—O—R10, —C0-8—C(O)OR10, —C0-8—C(O)R11, —C0-8—O—C(O)R11, —C0-8—NR12R13, —C0-8—C(O)NR12R13, —N(R12)—C(O)R11 and —N(R12)—C(O)OR10;
or R18 and R19 together with the carbon atom to which they are directly attached form a cycloalkyl or heterocyclyl, wherein the cycloalkyl or heterocyclyl is optionally substituted by one or more groups selected from the group consisting of C1-8 alkyl, haloC1-8 alkyl, halogen, hydroxy, C1-8 alkoxy and hydroxyC1-8 alkyl;
n is selected from the group consisting of 0, 1, 2, 3 and 4;
m1 is 2, m2 is 2 and m3 is 0, or m1 is 2, m2 is 1 and m3 is 1; and
r is 0, 1 or 2.