Azole derivatives and pharmaceutical compositions containing them
View Patent ↗The invention provides substituted pyrazolidinone compounds, and methods of treatment and pharmaceutical compositions that utilize or comprise one or more such compounds. Compounds of the invention are useful for a variety of therapies, including treating or preventing various cancers, inflammation, septic shock, preterm labor, infertility, pain, and ischemia, and other diseases and disorders associated with MEK-1 and/or ERK-2 activation.
1. A method for treating a mammal suffering from or susceptible to a cancer selected from the group consisting of breast cancer, ovarian cancer, and colon cancer, comprising administering to the mammal in need of said treating an effective of amount of a compound of the following Formula I:
wherein each of A 1 , A 2 , and A 4 are carbon and A 3 is nitrogen;
each R is independently halo, nitro, optionally substituted alkyl; optionally substituted alkenyl; optionally substituted alkynyl; optionally substituted heteroalkyl; optionally substituted heteroalkenyl; optionally substituted heteroalkynyl; optionally substituted alkanol; optionally substituted aryl, optionally substituted heteroalicyclic, optionally substituted heteroaromatic, optionally substituted aralkyl; optionally substituted heteroarylalkyl; and optionally substituted heteroalicyclicalkyl;
or two R groups on adjacent ring atoms are taken together with the ring atoms to which they are bonded to form a fused alicyclic, heteroalicylic, aryl or heteraromatic group having from 4 to about 8 ring members;
k is an integer;
Y is selected from the group consisting of CH 2 CH, CH 2 CH(CH 2 ) q , CH 2 CR 7 CH 2 , and a branched alkyl having the formula CH 2 CH(CH 2 ) p (CH 2 ) s , wherein R 7 is H or C 1 -C 6 alkyl, s and p are the same or different and are zero or a positive integer, and q is a positive integer;
W and W′ are each independently a heteroatom; optionally substituted heteroalkyl; optionally substituted heteroalkenyl; and optionally substituted heteroalkynyl;
Z and Z′ are each independently a chemical bond or alkanoyl; R 1 and R 2 are each independently optionally substituted aryl or optionally substituted heteroaromatic; and a pharmaceutically acceptable salt or enantiomer thereof, with the caveat that the compound of Formula I is not a racemate of 4-methoxy benzoic acid 1-imidazol-1-yl methyl-2-phenoxy ethyl ester, 4-chloro benzoic acid 1-imidazol-1-yl methyl-2-phenoxy-ethyl ester, or benzoic acid 1-imidazol-1-yl methyl-2-phenoxy-ethyl ester.
2. The method of claim 1 , wherein when R 2 is aryl and said aryl is phenyl, said phenyl optionally is substituted.
3. The method of claim 1 , wherein the compound of Formula (I) is a compound of the following Formula (II):
wherein each of A 1 , A 2 , and A 4 are carbon and A 3 is nitrogen;
each R is independently halo, nitro, optionally substituted alkyl; optionally substituted alkenyl; optionally substituted alkynyl; optionally substituted heteroalkyl; optionally substituted heteroalkenyl; optionally substituted heteroalkynyl; optionally substituted alkanol; optionally substituted aryl, optionally substituted heteroalicyclic, optionally substituted heteroaromatic, optionally substituted aralkyl; optionally substituted heteroarylalkyl; and optionally substituted heteroalicyclicalkyl;
or two R groups on adjacent ring atoms are taken together with the ring atoms to which they are bonded to form a fused alicyclic, heteroalicyclic, aryl or heteraromatic group having from 4 to about 8 ring members;
k is an integer;
s and p are the same or different and are zero or a positive integer;
W and W′ are each independently a hetero atom; optionally substituted heteroalkyl; optionally substituted heteroalkenyl; and optionally substituted heteroalkynyl;
Z and Z′ are each independently a chemical bond or alkanoyl;
R 1 and R 2 are each independently optionally substituted aryl or optionally substituted heteroaromatic, wherein when R 2 is aryl and said aryl is phenyl, said phenyl optionally is substituted; or a pharmaceutically acceptable salt or enantiomer thereof.
4. The method of claim 3 , wherein q is 1.
5. The method of claim 3 , wherein said compound is N-[1-(4-Cyano-phenoxymethyl)-2-imidazol-1-yl-ethyl]-4-iodo-benzamide.
6. The method of claim 1 , wherein the compound of Formula (I) is a compound of the following Formula (III):
wherein each of A 1 , A 2 , and A 4 is carbon and A 3 is nitrogen;
each R is independently halo, nitro, optionally substituted alkyl; optionally substituted alkenyl; optionally substituted alkynyl; optionally substituted heteroalkyl; optionally substituted heteroalkenyl; optionally substituted heteroalkynyl; optionally substituted alkanol; optionally substituted aryl, optionally substituted heteroalicyclic, optionally substituted heteroaromatic, optionally substituted aralkyl; optionally substituted heteroarylalkyl; and optionally substituted heteroalicyclicalkyl;
or two R groups on adjacent ring atoms are taken together with the ring atoms to which they are bonded to form a fused alicyclic, heteroalicylic, aryl or heteraromatic group having from 4 to about 8 ring members;
k is an integer;
q is a positive integer,
R 3 and R 4 are each optionally substituted aryl or optionally substituted heteroaromatic, wherein when R 4 is aryl and said aryl is phenyl, said phenyl optionally is substituted; or a pharmaceutically acceptable salt or enantiomer thereof.
7. The method of claim 6 , wherein q is 1.
8. The method of claim 1 , wherein the compound of Formula (I) is a compound of the following Formula (IV):
wherein each of A 1 , A 2 , and A 4 is carbon and A 3 is nitrogen;
each R is independently halo, nitro, optionally substituted alkyl; optionally substituted alkenyl; optionally substituted alkynyl; optionally substituted heteroalkyl; optionally substituted heteroalkenyl; optionally substituted heteroalkynyl; optionally substituted alkanol; optionally substituted aryl, optionally substituted heteroalicyclic, optionally substituted heteroaromatic, optionally substituted aralkyl; optionally substituted heteroarylalkyl; and optionally substituted heteroalicyclicalkyl;
or two R groups on adjacent ring atoms are taken together with the ring atoms to which they are bonded to form a fused alicyclic, heteroalicyclic, aryl or heteraromatic group having from 4 to about 8 ring members;
k is an integer;
q is a positive integer;
R 3 and R 4 are each optionally substituted aryl or optionally substituted heteroaromatic, wherein when R 4 is aryl and said aryl is phenyl, said phenyl optionally is substituted;
R 5 is hydrogen, optionally substituted alkyl; optionally substituted alkenyl; optionally substituted alkynyl; optionally substituted heteroalkyl; optionally substituted heteroalkenyl; or optionally substituted heteroalkynyl; optionally substituted aryl or optionally substituted heteroaromatic; or a pharmaceutically acceptable salt or enantiomer thereof.
9. The method of claim 1 , wherein the compound of Formula (I) is a compound of the following Formula (V):
wherein A 1 is CR 9 where R 9 is H, C 1 -C 6 alkyl, aryl or halogen;
B is —C(O)—;
R 6 is C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl C 1 -C 6 alkyl, C 3 -C 6 heterocycloalkyl, aryl or heteroaryl;
R 7 is H or C 1 -C 6 alkyl;
R 8 is C 1 -C 6 alkyl, C 1 -C 6 alkoxy or halogen;
n is 0 or 1;
m is 1 or 2; or a pharmaceutically acceptable salt or enantiomer thereof.
10. The method of claim 9 , wherein A 1 is CR 9 ; R 9 is H, C 1 -C 6 alkyl or halogen; R 6 is aryl or heteroaryl; R 7 is H or C 1 -C 6 alkyl; R 8 is substituted C 1 -C 6 alkyl, C 1 -C 6 alkoxy or halogen; n is 0; m is 1 or 2.
11. The method of claim 10 , wherein A 1 is CR 9 ; R 9 is H, C 1 -C 6 alkyl or halogen; R 6 is aryl or heteroaryl; R 7 is H; R 8 is C 1 -C 6 alkyl, C 1 -C 6 alkoxy or halogen; n is 0; m is 1 or 2.
12. The method of claim 1 , wherein the compound of Formula (I) is a compound of the following Formula (VI):
wherein A 1 is CR 9 R 9 is H, C 1 -C 6 alkyl, C 1 -C 6 alkyl, aryl or halogen; B is —C(O)—;
R 6 is C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl-C 1 -C 6 alkyl, C 3 -C 6 heterocycloalkyl, aryl or heteroaryl;
R 7 is H or C 1 -C 6 alkyl;
R 8 is C 1 -C 6 alkyl, C 1 -C 6 alkoxy or halogen;
n is 0 or 1;
m is 1 or 2; or a pharmaceutically acceptable salt or enantiomer thereof.
13. The method of claim 12 , wherein A 1 is CR 9 ; R 9 is H, C 1 -C 6 alkyl or halogen; R 6 is aryl or heteroaryl; R 7 is H or C 1 -C 6 alkyl; R 8 is substituted C 1 -C 6 alkyl, C 1 -C 6 alkoxy or halogen; n is 0; m is 1 or 2.
14. The method of claim 1 , wherein the compound, or a pharmaceutically acceptable salt or enantiomer thereof, is selected from the group consisting of:
4-methoxy-benzoic acid 1-imidazol-1-yl methyl-2-(4-fluorophenoxy)-ethyl ester;
3-methoxy-benzoic acid 1-imidazol-1-yl methyl-2-phenoxy-ethyl ester;
4-methoxy-benzoic acid 1-imidazol-1-yl methyl-2-(4-methoxy phenoxy)-ethyl ester;
4-methoxy-benzoic acid 1-imidazol-1-yl methyl-2-(4-iodophenoxy)-ethyl ester;
4-iodo-benzoic acid 1-imidazol-1-yl methyl-2-(4-iodo phenoxy)-ethyl ester;
4-bromo-2-chloro-benzoic acid 1-imidazol-1-yl methyl-2-phenoxy)-ethyl ester;
4-bromo-2-chloro-benzoic acid 1-imidazol-1-yl methyl-2-(4-iodophenoxy)-ethyl ester;
4-bromo-benzoic acid 1-imidazol-1-yl methyl-2-phenoxy-ethyl ester;
4-trifluoromethyl-benzoic acid 1-imidazol-1-yl methyl-2-phenoxy-ethyl ester;
N-(1-imidazol-1-yl methyl-2-phenoxy-ethyl)-4-methoxy-benzamide;
4-iodo-benzoic acid 1-imidazol-1-yl methyl-2-(4-fluorophenoxy)-ethyl ester;
4-fluoro-benzoic acid 1-imidazol-1-yl methyl-2-phenoxy-ethyl ester;
N-[(1-imidazol-1-yl methyl)-2-phenoxy-ethyl]-N-methyl-4-iodo-benzamide;
N-[(1-imidazol-1-yl methyl)-2-(4-fluorophenoxy-ethyl)]-N-methyl-4-iodobenzamide;
4-Iodo-benzoic acid 2-(4-acetylamino-phenoxy)-1-imidazol-1-ylmethyl-ethyl ester (R-isomer);
N-[2-(4-Fluoro-phenoxy)-1-imidazol-1-ylmethyl-ethyl]-4-iodo-benzamide (R-isomer);
N-[2-(4-tert-Butyl-phenoxy)-1-imidazol-1-ylmethyl-ethyl]-4-iodo-benzamide;
4-Iodo-benzoic acid 2-imidazol-1-yl-1-(3-nitro-phenoxymethyl)-ethyl ester (R-isomer);
4-Iodo-benzoic acid 2-imidazol-1-yl-1-(2-nitro-phenoxymethyl)-ethyl ester (R-isomer);
4-Iodo-benzoic acid 1-(4-nitrobenzoyloxymethyl)-2-imidazol-1-yl-1-methyl-ethyl ester (R-isomer);
4-Iodo-benzoic acid 2-imidazol-1yl-1-(4-nitro-phenoxymethyl)-ethyl ester (R-isomer);
4-Iodo-benzoic acid 1-imidazol-1-ylmethyl-2-methoxy-ethyl ester (R-isomer);
4-Iodo-benzoic acid 1-(2-methyl-imidazol-1-ylmethyl)-2-(tetrahydro-pyran-2-yloxy)-ethyl ester;
4-Iodo-benzoic acid 1-imidazol-1-yl methyl-2-(pyridin-3-yloxy)-ethyl ester (R-isomer);
2,4-Dichloro-benzoic acid 2-(4-fluoro-phenoxy)-1-imidazol-1-ylmethyl-ethyl ester (R-isomer);
4-Iodo-benzoic acid 1-(4-cyano-phenoxymethyl)-2-imidazol-1-yl-ethyl ester;
4-Iodo-benzoic acid 1-(4-cyano-phenoxymethyl)-2-(2-methyl-imidazol-1-yl)-ethyl ester (R-isomer);
2-Chloro-N-[2-(4-fluoro-phenoxy)-1-imidazol-1-ylmethyl-ethyl]-4-iodo-benzamide (R-isomer);
N-[2-(4-Fluoro-phenoxy)-1-(2-methyl-imidazol-1-ylmethyl)-ethyl]-4-iodo-benzamide (R-isomer);
2-Chloro-4-iodo-benzoic acid 1-cyclopropylmethoxymethyl-2-(2-methyl-imidazol-1-yl)-ethyl ester (R-isomer);
N-[1-(2-Chloro-imidazol-1-ylmethyl)-2-(4-fluoro-phenoxy)-ethyl]-4-iodo-benzamide (R-isomer);
N-[2-(4-Fluoro-phenoxy)-1-imidazol-1-ylmethyl-ethyl]-3-iodo-benzamide;
2-Chloro-N-[2-imidazol-1-yl-1-(pyridin-3-yloxymethyl)-ethyl]-4-iodo-benzamide;
N-[2-Imidazol-1-yl-1-(pyridin-3-yloxymethyl)-ethyl]-4-iodo-benzamide;
N-[2-(4-Fluoro-phenoxy)-1-(2-phenyl-imidazol-1-ylmethyl)-ethyl]-4-iodo-benzamide;
N-[1-(2-Chloro-imidazol-1-ylmethyl)-2-(4-cyano-phenoxy)-ethyl]-4-iodo-benzamide;
N-[2-Imidazol-1-yl-1-(3-nitro-pyridin-2-yloxymethyl)-ethyl]-4-iodo-benzamide;
N-[2-Imidazol-1-yl-1-(4-nitro-phenoxymethyl)-ethyl]-4-iodo-benzamide;
N-[1-(3-Cyano-pyridin-2-yloxymethyl)-2-imidazol-1-yl-ethyl]-4-iodo-benzamide;
N-[1-(5-Cyano-pyridin-2-yloxymethyl)-2-imidazol-1-yl-ethyl]-4-iodo-benzamide;
N-[1-(4-Cyano-phenoxymethyl)-2-imidazol-1-yl-ethyl]-4-iodo-benzamide;
N-[1-(4-Cyano-phenoxymethyl)-2-(2-methyl-imidazol-1-yl)-ethyl]-4-iodo-benzamide; and
N-[1-(2-Difluoromethyl-imidazol-1-ylmethyl)-2-(4-fluoro-phenoxy)-ethyl]-4-iodo-benzamide.
15. The method of claim 1 , wherein the compound is 4-iodo-benzoic acid 1-imidazol-1-yl methyl-2-phenoxy-ethyl ester, or a pharmaceutically acceptable salt or enantiomer thereof.
16. The method of claim 1 , wherein the compound is N-[(1-imidazol-1-yl methyl)-2-phenoxy-ethyl]-4-iodo-benzamide, or a pharmaceutically acceptable salt or enantiomer thereof.
17. The method of claim 1 , wherein the compound is present in an enantiomeric excess.
18. The method of claim 1 , wherein the compound of Formula (I) is a compound of the following Formula (VII):
wherein A 4 is CR 9 ;
R 9 is H, C 1 -C 6 alkyl, C 1 -C 6 alkyl, aryl or halogen;
B is —C(O)—
R 6 is C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl C 1 -C 6 alkyl, C 3 -C 6 heterocycloalkyl, aryl or heteroaryl;
R 7 is H or C 1 -C 6 alkyl;
R 8 is C 1 -C 6 alkyl, C 1 -C 6 alkoxy or halogen;
n is 0 or 1;
m is 1 or 2; or a pharmaceutically acceptable salt or enantiomer thereof.
19. The method of claim 18 , wherein A 4 is CR 9 ; R 9 is H, C 1 -C 6 alkyl or halogen; R 6 is aryl or heteroaryl; R 7 is H or C 1 -C 6 alkyl; R 8 is C 1 -C 6 alkyl, C 1 -C 6 alkoxy or halogen; n is 0 or 1; m is 1 or 2.
20. The method of claim 19 , wherein A 4 is CR 9 ; R 9 is H, C 1 -C 6 alkyl or halogen; R 6 is aryl or heteroaryl; R 7 is H; R 8 is C 1 -C 6 alkyl, C 1 -C 6 alkoxy or halogen; n is 0; m is 1 or 2.
21. The method of claim 1 , wherein the compound of Formula (I) is a compound of the following Formula (VIII):
wherein A 4 is CR 9 ;
R 9 is H, C 1 -C 6 alkyl, C 1 -C 6 alkyl, aryl or halogen;
B is —C(O)—;
R 6 is C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl C 1 -C 6 alkyl, C 3 -C 6 heterocycloalkyl, aryl or heteroaryl;
R 7 is H or C 1 -C 6 alkyl;
R 8 is C 1 -C 6 alkyl, C 1 -C 6 alkoxy or halogen;
n is 0 or 1;
m is 1 or 2; or a pharmaceutically acceptable salt or enantiomer thereof.
22. The method of claim 21 , wherein A 4 is CR 9 ; R 9 is H, C 1 -C 6 alkyl or halogen; R 6 is aryl or heteroaryl; R 7 is H or C 1 -C 6 alkyl; R 8 is C 1 -C 6 alkyl, C 1 -C 6 alkoxy or halogen; n is 0 or 1; m is 1 or 2.
23. The method of claim 1 , wherein said mammal is a human.
24. The method of claim 1 , wherein said form of cancer is breast cancer.
25. The method of claim 1 , wherein said form of cancer is ovarian cancer.
26. The method of claim 1 , wherein said form of cancer is colon cancer.