1,4-disubstituted imidazole derivative
The present invention provides a 1,4-disubstituted imidazole derivative of formula (1′) wherein ring Q 1 is optionally-substituted C 6-10 aryl group, etc.; R 1 and R 2 are independently hydrogen atom, etc.; W 1 is optionally-substituted C 1-4 alkylene group; W 2 is —NR 3a C(O)— wherein R 3a is hydrogen atom or C 1-6 alkyl group, etc.; ring Q 2 is 5- to 10-membered heteroaryl group, etc.; W 3 is optionally-substituted C 1-4 alkylene group, etc.; n is 1, 2, 3, 4, or 5; R 4 is independently halogen atom, optionally-substituted C 1-6 alkyl group, etc.; R 5 is hydroxy group, etc.; and a pharmacologically acceptable salt thereof, which have a potent inhibitory effect on the sphere-forming capacity of cancer cells and are useful as an orally-available anti-tumor agent.
1. A process of preparing a compound of formula (1-7):
or a pharmaceutically acceptable salt thereof, wherein ring Q 1 is optionally-substituted C 6-10 aryl, optionally-substituted C 3-10 cycloalkyl, or optionally-substituted 5- to 10-membered heteroaryl;
R 1 and R 2 are each independently hydrogen, halogen, or C 1-6 alkyl, wherein said C 1-6 alkyl is optionally substituted with 1 to 3 halogen atoms;
W 1 is optionally-substituted C 1-4 alkylene;
ring Q 2 is 5- to 10-membered heteroaryl;
W 3 is optionally-substituted C 1-4 alkylene, optionally-substituted C 3-4 alkenylene, or optionally-substituted C 3-4 alkynylene;
n is 1, 2, 3, 4, or 5;
each R 4 is independently hydrogen, halogen, optionally-substituted C 1-6 alkyl, optionally-substituted C 1-6 alkoxy, optionally-substituted C 3-10 cycloalkyl, optionally-substituted C 2-6 alkenyl, optionally-substituted C 2-6 alkynyl, cyano, or optionally-substituted amino;
or, any R 4 and W 3 attached to adjacent carbon atoms on ring Q 2 , together with the carbon atoms to which they are attached, form a 5- to 8-membered cycloalkane ring; and
R 5 is
(1) hydroxy,
(2) C 1-6 alkoxy optionally substituted with 1 to 3 substituents each independently halogen, hydroxy, C 1-6 alkoxy, or C 6-10 aryl, wherein said C 6-10 aryl is optionally substituted with 1 to 4 substituents each independently halogen, C 1-6 alkyl, or C 1-6 alkoxy,
(3) amino, which is optionally substituted with 1 or 2 C 1-6 alkyl, or
(4) C 1-6 alkyl-carbonylamino, wherein the alkyl moiety thereof is optionally substituted with 1 to 3 halogen;
the process comprising:
reacting compound (1-6):
with compound (1-2):
in an inert solvent in the presence of a condensation agent, wherein the compound (1-2) is prepared according to a process comprising hydrolyzing compound (1-1):
wherein R 101 is C 1-6 alkyl.
2. The process according to claim 1 , wherein the compound (1-6) is prepared according to a process comprising reacting compound (1-3):
with compound (1-4):
wherein L is a leaving group, to give compound (1-5):
and reducing the nitro group of compound (1-5) to give compound (1-6).
3. The process according to claim 1 , wherein the compound (1-1) is compound (2-5), (2-8), (2-11), (2-13) or (13-2):
wherein R 102 is optionally-substituted C 1-6 alkyl, R 103 is optionally-substituted phenyl, and R a and R b are each independently hydrogen or methyl.
4. The process according to claim 1 , wherein the compound (1-1) is compound (4-3):
5. The process according to claim 1 , wherein the compound (1-1) is compound (5-1):
6. The process according to claim 1 , wherein the compound (1-1) is compound (6-2):
7. The process according to claim 1 , wherein the compound (1-1) is compound (7-2):