N1- and N2-carbamoyl-1,2,3-triazole serine hydrolase inhibitors and methods
The present invention provides inhibitors of a wide variety of serine hydrolase enzymes. The inhibitors of the present invention are N1- and N2-carbamoyl-1,2,3-triazole compounds such as those of Formula (I): in which N1, N2, and N3 are the nitrogen atoms at positions 1, 2, and 3, respectively, of the triazole ring, and R 4 , R 5 , R 6 and R 7 in Formula (I) are as described herein. Methods of inhibiting serine hydrolase enzymes and methods of preparing carbamoyl-1,2,3-triazole compounds also are described.
1. A compound represented by:
pharmaceutically acceptable salts thereof;
wherein:
X 2 is CH 2 ;
R 8 is benzyl;
R 4 is selected from the group consisting of H, phenyl (optionally substituted by a member of the group consisting of cyano, hydroxyl, nitro, C 1-6 alkyl (optionally substituted by one, two, or three halogens, cyano, or hydroxyl), C 2-6 alkenyl (optionally substituted by one, two, or three halogens), C 3-6 alkynyl (optionally substituted by one, two, or three halogens), C 3-6 cycloalkyl, C 1-6 alkoxy (optionally substituted by one, two, or three halogens), —COOH, —C(O)—O—C 1-6 alkyl, R a R b N—, R a R b N—SO 2 —, R a R b N—C(O)—, C 1-6 alkyl-C(O)NR a —, R a —S(O) v —NR b — (wherein v is 0, 1 or 2), or R a —S(O) v — (wherein v is 0, 1 or 2), biphenyl (optionally substituted by R c ), phenyloxyphenyl (optionally substituted by R c ), naphthyl (optionally substituted by R c ), or C 1-6 alkyl (optionally substituted by one, two, or three substituents each independently selected from hydroxyl, halo, and phenyl (optionally substituted by R c ));
R 5 is selected from the group consisting of H, phenyl (optionally substituted by R c ), biphenyl (optionally substituted by R c ), phenyloxyphenyl (optionally substituted by R c ), naphthyl (optionally substituted by R c ), or C 1-6 alkyl (optionally substituted by one, two, or three substituents each independently selected from hydroxyl, cyano, halo, and phenyl (optionally substituted by R c );
R a and R b may be independently selected, for each occurrence, from the group consisting of hydrogen and C 1-3 alkyl; wherein C 1-3 alkyl may optionally be substituted by one or more substituents selected from fluorine, cyano, oxo and hydroxyl;
or R a and R b , when they occur together with the nitrogen to which they are attached, may form a 4-6 membered heterocyclic ring, which may have an additional heteroatom selected from O, S, or N; wherein the 4-6 membered heterocyclic ring may optionally be substituted by one or more substituents selected from the group consisting of fluorine, cyano, oxo or hydroxyl;
R c is selected from the group consisting of halogen, cyano, hydroxyl, nitro, C 1-6 alkyl (optionally substituted by one, two, or three halogens, cyano, or hydroxyl), C 2-6 alkenyl (optionally substituted by one, two, or three halogens), C 3-6 alkynyl (optionally substituted by one, two, or three halogens), C 3-6 cycloalkyl, C 1-6 alkoxy (optionally substituted by one, two, or three halogens), —COOH, —C(O)—O—C 1-6 alkyl, R a R b N—, R a R b N—SO 2 —, R a R b N—C(O)—, C 1-6 alkyl-C(O)NR a —, R a —S(O) v —NR b — (wherein v is 0, 1 or 2), or R a —S(O) v — (wherein v is 0, 1 or 2).
2. The triazole compound of claim 1 , wherein R 4 or R 5 is 4-phenyloxyphenyl.
3. The triazole compound of claim 1 , wherein R 4 is phenyl or naphthyl optionally substituted by a moiety selected from the group consisting of halo, hydroxyl, NO 2 , C 1-6 alkyl (optionally substituted by one, two, or three substituents each independently selected from hydroxyl, cyano, or halo), and C 1-6 alkoxy (optionally substituted by one, two, or three halo groups, R 5 is phenyl optionally substituted by a moiety selected from the group consisting of hydroxyl, NO 2 , C 1-6 alkyl (optionally substituted by one, two, or three substituents each independently selected from hydroxyl, cyano, or halo), and C 1-6 alkoxy (optionally substituted by one, two, or three halo groups), or R 5 is naphthyl optionally substituted by a moiety selected from the group consisting of halo, hydroxyl, NO 2 , C 1-6 alkyl (optionally substituted by one, two, or three substituents each independently selected from hydroxyl, cyano, or halo), and C 1-6 alkoxy (optionally substituted by one, two, or three halo groups).
4. The triazole compound of claim 1 , wherein the compounds are represented by:
5. The triazole compound of claim 1 , wherein R 4 is H.
6. The triazole compound of claim 1 , wherein R 5 is H.
7. A compound represented by the following formula where w is 1, and R 11 is H:
R 4 is selected from the group consisting of H, halo, cyano, carboxyl, —C(O)—O—C 1-6 alkyl, R a R b N—, R a R b N—SO 2 —, R a R b N—C(O)—, C 1-6 alkyl-C(O)NR a —, R a —S(O) v —NR b — (wherein v is 0, 1 or 2), R a —S(O) v — (wherein v is 0, 1 or 2), C 1-6 alkyl (optionally substituted by one, two, or three substituents each independently selected from group consisting of halogen, hydroxyl, C 1-6 alkoxy, carboxyl, cyano, and phenyl (optionally substituted by one, two or three moieties independently selected from R c )), C 3-6 cycloalkyl (optionally substituted by one, two or three substituents independently selected from the group consisting of halogen, cyano, hydroxyl, and C 1-6 alkyl), phenyl (optionally substituted by one, two or three moieties independently selected from R d ), naphthyl (optionally substituted by one, two or three moieties independently selected from R d ), C 2-6 alkenyl, and C 2-6 alkynyl;
R a and R b may be independently selected, for each occurrence, from the group consisting of hydrogen and C 1-3 alkyl; wherein C 1-3 alkyl may optionally be substituted by one or more substituents selected from fluorine, cyano, oxo and hydroxyl;
or R a and R b , when they occur together with the nitrogen to which they are attached, may form a 4-6 membered heterocyclic ring, which may have an additional heteroatom selected from O, S, or N; wherein the 4-6 membered heterocyclic ring may optionally be substituted by one or more substituents selected from the group consisting of fluorine, cyano, oxo, and hydroxyl;
R c is selected from the group consisting of halogen, cyano, hydroxyl, nitro, C 1-6 alkyl (optionally substituted by one, two, or three halogens, cyano, or hydroxyl), C 2-6 alkenyl (optionally substituted by one, two, or three halogens), C 3-6 alkynyl (optionally substituted by one, two, or three halogens), C 3-6 cycloalkyl, C 1-6 alkoxy (optionally substituted by one, two, or three halogens), —COOH, —C(O)—O—C 1-6 alkyl, R a R b N—, R a R b N—SO 2 —, R a R b N—C(O)—, C 1-6 alkyl-C(O)NR a —, R a —S(O) v —NR b — (wherein v is 0, 1 or 2), or R a —S(O) v — (wherein v is 0, 1 or 2); and
R d is selected from the group consisting of phenyl (optionally substituted by R c ), phenyloxy (optionally substituted by R c ), halo en cyano, hydroxyl, nitro, C 1-6 alkyl (optionally substituted by one, two, or three halogens, cyano, or hydroxyl), C 2-6 alkenyl (optionally substituted by one, two, or three halogens), C 3-6 alkynyl (optionally substituted by one, two, or three halogens), C 3-6 cycloalkyl, C 1-6 alkoxy (optionally substituted by one, two, or three halogens), —COOH, —C(O)—O—C 1-6 alkyl, R a R b N—, R a R b N—SO 2 —, R a R b N—C(O)—, C 1-6 alkyl-C(O)NR a —, R a —S(O) v —NR b — (wherein v is 0, 1 or 2), or R a —S(O) v — (wherein v is 0, 1 or 2).
8. The triazole compound of claim 7 wherein R 4 is phenyl, optionally substituted with one, two, or three substituents each independently selected from the group consisting of: C 1-6 alkyl, C 1-6 hydroxyalkyl, C 1-6 alkoxy, halogen, and hydroxyl.
9. A compound selected from the group consisting of compounds represented by:
pharmaceutically acceptable salts thereof.
10. A pharmaceutical composition comprising a compound of claim 1 and a pharmaceutically acceptable carrier.
11. The compound of claim 1 , wherein the compound is
or a pharmaceutically acceptable salt thereof.