Azole derivatives and pharmaceutical compositions containing them
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.