Fatty acid cox inhibitor derivatives and their uses

A method of treating inflammation, swelling, stiffness, or joint pain associated with rheumatoid arthritis, osteoarthritis, juvenile arthritis, ankylosing spondylitis, tendinitis, bursitis, or acute gout, the method comprising administering to a patient in need thereof an effective amount of a compound of Formula I:

• or a pharmaceutically acceptable salt, enantiomer, or stereoisomer thereof;
• wherein
• Rn is
• W1 and W2 are each independently S, NH, or NR;
• each a, b, c and d is independently —H, -D, —CH3, —OCH3, —OCH2CH3, —C(O)OR, or benzyl, or two of a, b, c, and d can be taken together, along with the single carbon to which they are bound, to form a cycloalkyl or heterocycle;
• each n, o, p, and q is independently 0, 1 or 2;
• each L is independently null, —O—, —S—, —S(O)—, —S(O)2—, —S—S—, —(C1-C6alkyl)-, —(C3-C6 cycloalkyl)-, a heterocycle, a heteroaryl,
• wherein the representation of L is not limited directionally left to right as is depicted, rather either the left side or the right side of L can be bound to the W1 side of the compound of Formula I;
• R6 is independently —H, -D, —C1-C4 alkyl, -halogen, cyano, oxo, thiooxo, —OH, —C(O)C1-C4 alkyl, —O-aryl, —O-benzyl, —OC(O)C1-C4 alkyl, C2-C3 alkene, C2-C3 alkyne, —C(O)C1-C4 alkyl, —NH2, —NH(C1-C3 alkyl), —N(C1-C3 alkyl)2, —NH(C(O)C1-C3 alkyl), —N(C(O)C1-C3 alkyl)2, —SH, —S(C1-C3 alkyl), —S(O)C1-C3 alkyl, or —S(O)2C1-C3 alkyl;
• each g is independently 2, 3 or 4;
• each h is independently 1, 2, 3 or 4;
• m is 0, 1, 2, or 3;
• if m is more than 1, then L can be the same or different;
• m1 is 0, 1, 2 or 3;
• k is 0, 1, 2, or 3;
• z is 1, 2, or 3;
• each R3 is independently H or C1-C6 alkyl, or both R3 groups, when taken together with the nitrogen to which they are attached, can form a heterocycle;
• each R4 is independently e, H or straight or branched C1-C10 alkyl which can be optionally substituted with OH, NH2, CO2R, CONH2, phenyl, C6H4OH, imidazole or arginine;
• each e is independently H or any side chain of a naturally occurring amino acid;
• each Z is independently —H,
• each r is independently 2, 3, or 7;
• each s is independently 3, 5, or 6;
• each t is independently 0 or 1;
• each v is independently 1, 2, or 6;
• R1 and R2 are each independently hydrogen, deuterium, —C1-C4 alkyl, -halogen, —OH, —C(O)C1-C4 alkyl, —O-aryl, —O-benzyl, —OC(O)C1-C4 alkyl, C2-C3 alkene, C2-C3 alkyne, —C(O)C1-C4 alkyl, —NH2, —NH(C1-C3 alkyl), —N(C1-C3 alkyl)2, —NH(C(O)C1-C3 alkyl), —N(C(O)C1-C3 alkyl)2, —SH, —S(C1-C3 alkyl), —S(O)C1-C3 alkyl, —S(O)2C1-C3 alkyl;
• and
• each R is independently —H, —C1-C3 alkyl, or straight or branched C1-C4 alkyl optionally substituted with OH, or halogen.

A method of treating pain associated with a menstrual period, a migraine headache, or dental pain, the method comprising administering to a patient in need thereof an effective amount of a compound of Formula I:

• or a pharmaceutically acceptable salt, enantiomer, or stereoisomer thereof;
• wherein
• Rn is
• W1 and W2 are each independently S, NH, or NR;
• each a, b, c and d is independently —H, -D, —CH3, —OCH3, —OCH2CH3, —C(O)OR, or benzyl, or two of a, b, c, and d can be taken together, along with the single carbon to which they are bound, to form a cycloalkyl or heterocycle;
• each n, o, p, and q is independently 0, 1 or 2;
• each L is independently null, —O—, —S—, —S(O)—, —S(O)2—, —S—S—, —(C1-C6alkyl)-, —(C3-C6cycloalkyl)-, a heterocycle, a heteroaryl,
• wherein the representation of L is not limited directionally left to right as is depicted, rather either the left side or the right side of L can be bound to the W1 side of the compound of Formula I;
• R6 is independently —H, -D, —C1-C4 alkyl, -halogen, cyano, oxo, thiooxo, —OH, —C(O)C1-C4 alkyl, —O-aryl, —O-benzyl, —OC(O)C1-C4 alkyl, C2-C3 alkene, C2-C3 alkyne, —C(O)C1-C4 alkyl, —NH2, —NH(C1-C3 alkyl), —N(C1-C3 alkyl)2, —NH(C(O)C1-C3 alkyl), —N(C(O)C1-C3 alkyl)2, —SH, —S(C1-C3 alkyl), —S(O)C1-C3 alkyl, or —S(O)2C1-C3 alkyl;
• each g is independently 2, 3 or 4;
• each h is independently 1, 2, 3 or 4;
• m is 0, 1, 2, or 3;
• if m is more than 1, then L can be the same or different;
• m1 is 0, 1, 2 or 3;
• k is 0, 1, 2, or 3;
• z is 1, 2, or 3;
• each R3 is independently H or C1-C6 alkyl, or both R3 groups, when taken together with the nitrogen to which they are attached, can form a heterocycle;
• each R4 is independently e, H or straight or branched C1-C10 alkyl which can be optionally substituted with OH, NH2, CO2R, CONH2, phenyl, C6H4OH, imidazole or arginine;
• each e is independently H or any side chain of a naturally occurring amino acid;
• each Z is independently —H,
• each r is independently 2, 3, or 7;
• each s is independently 3, 5, or 6;
• each t is independently 0 or 1;
• each v is independently 1, 2, or 6;
• R1 and R2 are each independently hydrogen, deuterium, —C1-C4 alkyl, -halogen, —OH, —C(O)C1-C4 alkyl, —O-aryl, —O-benzyl, —OC(O)C1-C4 alkyl, C2-C3 alkene, C2-C3 alkyne, —C(O)C1-C4 alkyl, —NH2, —NH(C1-C3 alkyl), —N(C1-C3 alkyl)2, —NH(C(O)C1-C3 alkyl), —N(C(O)C1-C3 alkyl)2, —SH, —S(C1-C3 alkyl), —S(O)C1-C3 alkyl, —S(O)2C1-C3 alkyl;
• and
• each R is independently —H, —C1-C3 alkyl, or straight or branched C1-C4 alkyl optionally substituted with OH, or halogen.