3-arylamino pyridine derivatives
The invention provides novel, substituted 3-arylamino pyridine compounds pharmaceutically acceptable salts, solvates and prodrug compounds thereof, wherein W, R1, R2, R9, R10, R11, R12, R13, R14 are as defined in the specification. Such compounds are MEK inhibitors and useful in the treatment of hyperproliferative diseases, such as cancer, restenosis and inflammation. Also disclosed is the use of such compounds in the treatment of hyperproliferative diseases in mammals, especially humans, and pharmaceutical compositions containing such compounds.
1. A method of treating a subject with a hyperproliferative disease comprising administering to the subject an effective amount of a MEK inhibitor, wherein the hyperproliferative disease is related to the hyperactivity of MEK and diseases modulated by the MEK cascade in mammals, and wherein the MEK inhibitor is a compound according to Formula (II):
or a pharmaceutically acceptable salt thereof,
wherein:
R 1 , R 2 , R 9 , R 10 , R 11 , R 12 , R 13 and R 14 are independently selected from: hydrogen, halogen, cyano, nitro, azido, —OR 3 , —NR 4 C(O)OR 6 , —OC(O)R 3 , —NR 4 S(O) j R 6 , —S(O) j NR 3 R 4 —S(O) j NR 4 C(O)R 3 , —C(O)NR 4 S(O) j R 6 , —S(O) j R 6 , —NR 4 C(O)R 3 , —C(O)NR 3 R 4 , —NR 5 C(O)NR 3 R 4 , —NR 5 C(NCN)NR 3 R 4 , —NR 3 R 4 , C 1 -C 10 alkyl, C 2 -C 10 alkenyl, C 2 -C 10 alkynyl, C 3 -C 10 cycloalkyl, C 3 -C 10 cycloalkylalkyl, or —S(O) j (C 1 -C 6 alkyl);
provided that R 12 is not OH, and R 13 , R 14 are not C 1 -C 10 alkyl;
R 3 is selected from hydrogen, trifluoromethyl, C 1 -C 10 alkyl, C 2 -C 10 alkenyl, C 2 -C 10 alkynyl, C 3 -C 10 cycloalkyl or C 3 -C 10 cycloalkylalkyl, where each alkyl, alkenyl, alkynyl and cycloalkyl is unsubstituted or substituted with primary amino, aminocarbonyl, carboxyl, cyano, halogen, hydroxy, nitro or trihalomethyl;
R 4 is selected from hydrogen or C 1 -C 6 alkyl, whereby alkyl may be unsubstituted or substituted with primary amino, aminocarbonyl, carboxyl, cyano, halogen, hydroxy, nitro or trihalomethyl;
R 5 is selected from hydrogen or C 1 -C 6 alkyl, whereby alkyl may be unsubstituted or substituted with primary amino, aminocarbonyl, carboxyl, cyano, halogen, hydroxy, nitro or trihalomethyl;
R 6 is selected from trifluoromethyl, C 1 -C 10 alkyl or C 3 -C 10 cycloalkyl;
W is selected from —C(O)OR 15 , —C(O)NR 4 R 15 , —C(O)NR 4 OR 15 , —C(O)NR 4 S(O) j R 6 , —C(O)NR 4 NR 4 R 15 , —NR′C(O)R′, —NR′S(O) j R′,—NRC(O)NR′R″, NR′S(O) j NR′R″, or —C(O)NR 4 NR 4 C(O)R 15 ;
provided that W is not —C(O)OH;
R 15 is independently selected from: hydrogen, trifluoromethyl, C 1 -C 10 alkyl, C 2 -C 10 alkenyl, C 2 -C 10 alkynyl, C 3 -C 10 cycloalkyl, C 3 -C 10 cycloalkylalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocyclyl, and heterocyclylalkyl; wherein each alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl and heterocyclyl is unsubstituted or substituted with primary amino, aminocarbonyl, carboxyl, cyano, halogen, hydroxy, nitro, trihalomethyl, O—C 1 -C 4 alkyl or NR′R″;
R′ and R″ are independently selected from hydrogen, C 1 -C 4 alkyl, C 2 -C 4 alkenyl, aryl and arylalkyl;
X is N or N + O − ; and
j is 1 or 2, with the proviso that 3-Phenylamino-isonicotinic acid methyl ester and 3-Oxo-3-(3-phenylamino-pyridin-4-yl)-propionic acid ethyl ester are not included.
2. The method according to claim 1 , wherein the disease is selected from the group consisting of cancer, inflammation, pancreatitis or kidney disease, pain, benign hyperplasia of the skin, restenosis, prostate, diseases related to vasculogenesis or angiogenesis, tumor angiogenesis, skin diseases selected from psoriasis, eczema, and sclerodema, diabetes, diabetic retinopathy, retinopathy of prematurity, age-related macular degeneration, hemangioma, glioma, melanoma and Kaposi's sarcoma.
3. The method according to claim 2 , wherein the disease is cancer or inflammation.
4. The method according to claim 2 , wherein the cancer is selected from the group consisting of ovarian, breast, lung, pancreatic, prostate, colon, melanoma and epidermoid cancer.
5. The method according to claim 3 , wherein the inflammation is selected from the group consisting of rheumatoid arthritis, inflammatory bowel disease and atherosclerosis.
6. A method of treating a subject with a hyperproliferative disease comprising administering to the subject an effective amount of a pharmaceutical composition comprising an MEK inhibitor and a pharmaceutically acceptable excipient, wherein the hyperproliferative disease is related to the hyperactivity of MEK and diseases modulated by the MEK cascade in mammals, and wherein the MEK inhibitor is a compound of Formula (II):
or a pharmaceutically acceptable salt thereof,
wherein:
R 1 , R 2 , R 9 , R 10 , R 11 , R 12 , R 13 and R 14 are independently selected from: hydrogen, halogen, cyano, nitro, azido, —OR 3 , —NR 4 C(O)OR 6 , —OC(O)R 3 , —NR 4 S(O) j R 6 , —S(O) j NR 3 R 4 —S(O) j NR 4 C(O)R 3 , —C(O)NR 4 S(O) j R 6 ,—S(O) j R 6 , —NR 4 C(O)R 3 , —C(O)NR 3 R 4 , —NR 5 C(O)NR 3 R 4 , —NR 5 C(NCN)NR 3 R 4 , —NR 3 R 4 , C 1 -C 10 alkyl, C 2 -C 10 alkenyl, C 2 -C 10 alkynyl, C 3 -C 10 cycloalkyl, C 3 -C 10 cycloalkylalkyl, or —S(O) j (C 1 -C 6 alkyl);
provided that R 12 is not OH, and R 13 , R 14 are not C 1 -C 10 alkyl;
R 3 is selected from hydrogen, trifluoromethyl, C 1 -C 10 alkyl, C 2 -C 10 alkenyl, C 2 -C 10 alkynyl, C 3 -C 10 cycloalkyl or C 3 -C 10 cycloalkylalkyl, where each alkyl, alkenyl, alkynyl and cycloalkyl is unsubstituted or substituted with primary amino, aminocarbonyl, carboxyl, cyano, halogen, hydroxy, nitro or trihalomethyl;
R 4 is selected from hydrogen or C 1 -C 6 alkyl, whereby alkyl may be unsubstituted or substituted with primary amino, aminocarbonyl, carboxyl, cyano, halogen, hydroxy, nitro or trihalomethyl;
R 5 is selected from hydrogen or C 1 -C 6 alkyl, whereby alkyl may be unsubstituted or substituted with primary amino, aminocarbonyl, carboxyl, cyano, halogen, hydroxy, nitro or trihalomethyl;
R 6 is selected from trifluoromethyl, C 1 -C 10 alkyl or C 3 -C 10 cycloalkyl;
W is selected from —C(O)OR 15 , —C(O)NR 4 R 15 , —C(O)NR 4 OR 15 , —C(O)NR 4 S(O) j R 6 , —C(O)NR 4 NR 4 R 15 , —NR′C(O)R′, —NR′S(O) j R′, —NRC(O)NR′R″, NR′S(O) j NR′R″, or —C(O)NR 4 NR 4 C(O)R 15 ;
provided that W is not —C(O)OH;
R 15 is independently selected from: hydrogen, trifluoromethyl, C 1 -C 10 alkyl, C 2 -C 10 alkenyl, C 2 -C 10 alkynyl, C 3 -C 10 cycloalkyl, C 3 -C 10 cycloalkylalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocyclyl, and heterocyclylalkyl; wherein each alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl and heterocyclyl is unsubstituted or substituted with primary amino, aminocarbonyl, carboxyl, cyano, halogen, hydroxy, nitro, trihalomethyl, O—C 1 -C 4 alkyl or NR′R″;
R′ and R″ are independently selected from hydrogen, C 1 -C 4 alkyl, C 2 -C 4 alkenyl, aryl and arylalkyl;
X is N or N + O − ; and
j is 1 or 2, with the proviso that 3-Phenylamino-isonicotinic acid methyl ester and 3-Oxo-3-(3-phenylamino-pyridin-4-yl)-propionic acid ethyl ester are not included.
7. The method according to claim 6 , wherein the disease is selected from the group consisting of cancer, inflammation, pancreatitis or kidney disease, pain, benign hyperplasia of the skin, restenosis, prostate, diseases related to vasculogenesis or angiogenesis, tumor angiogenesis, skin diseases selected from psoriasis, eczema, and sclerodema, diabetes, diabetic retinopathy, retinopathy of prematurity, age-related macular degeneration, hemangioma, glioma, melanoma and Kaposi's sarcoma.
8. The method according to claim 7 , wherein the disease is cancer or inflammation.
9. The method according to claim 7 , wherein the cancer is selected from the group consisting of ovarian, breast, lung, pancreatic, prostate, colon, melanoma and epidermoid cancer.
10. The method according to claim 8 , wherein the inflammation is selected from the group consisting of rheumatoid arthritis, inflammatory bowel disease and atherosclerosis.
11. A method of treating a subject with a hyperproliferative disease comprising administering to the subject an effective amount of a MEK inhibitor, wherein the hyperproliferative disease is cancer, and wherein the MEK inhibitor is a compound according to Formula (II):
or a pharmaceutically acceptable salt thereof,
wherein:
R 1 , R 2 , R 9 , R 10 , R 11 , R 12 , R 13 and R 14 are independently selected from: hydrogen, halogen, cyano, nitro, azido, —OR 3 , —NR 4 C(O)OR 6 , —OC(O)R 3, —NR 4 S(O) j R 6 , —S(O) j NR 3 R 4 , —S(O) j NR 4 C(O)R 3 , —C(O)NR 4 S(O) j R 6 , —S(O) j R 6 , —NR 4 C(O)R 3 , —C(O)NR 3 R 4 , —NR 5 C(O)NR 3 R 4 , —NR 5 C(NCN)NR 3 R 4 , —NR 3 R 4 , C 1 -C 10 alkyl, C 2 -C 10 alkenyl, C 2 -C 10 alkynyl, C 3 -C 10 cycloalkyl, C 3 -C 10 cycloalkylalkyl, or —S(O) j (C 1 -C 6 alkyl);
provided that R 12 is not OH, and R 13 , R 14 are not C 1 -C 10 alkyl;
R 3 is selected from hydrogen, trifluoromethyl, C 1 -C 10 alkyl, C 2 -C 10 alkenyl, C 2 -C 10 alkynyl, C 3 -C 10 cycloalkyl or C 3 -C 10 cycloalkylalkyl, where each alkyl, alkenyl, alkynyl and cycloalkyl is unsubstituted or substituted with primary amino, aminocarbonyl, carboxyl, cyano, halogen, hydroxy, nitro or trihalomethyl;
R 4 is selected from hydrogen or C 1 -C 6 alkyl, whereby alkyl may be unsubstituted or substituted with primary amino, aminocarbonyl, carboxyl, cyano, halogen, hydroxy, nitro or trihalomethyl;
R 5 is selected from hydrogen or C 1 -C 6 alkyl, whereby alkyl may be unsubstituted or substituted with primary amino, aminocarbonyl, carboxyl, cyano, halogen, hydroxy, nitro or trihalomethyl;
R 6 is selected from trifluoromethyl, C 1 -C 10 alkyl or C 3 -C 10 cycloalkyl;
W is selected from —C(O)OR 15 , —C(O)NR 4 R 15 , —C(O)NR 4 OR 15 , —C(O)NR 4 S(O) j R 6 , —C(O)NR 4 NR 4 R 15 , —NR′C(O)R′, —NR′S(O) j R′, —NRC(O)NR′R″, NR′S(O) j NR′R″, or —C(O)NR 4 NR 4 C(O)R 15 ;
provided that W is not —C(O)OH;
R 15 is independently selected from: hydrogen, trifluoromethyl, C 1 -C 10 alkyl, C 2 -C 10 alkenyl, C 2 -C 10 alkynyl, C 3 -C 10 cycloalkyl, C 3 -C 10 cycloalkylalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocyclyl, and heterocyclylalkyl; wherein each alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl and heterocyclyl is unsubstituted or substituted with primary amino, aminocarbonyl, carboxyl, cyano, halogen, hydroxy, nitro, trihalomethyl, O—C 1 -C 4 alkyl or NR′R″;
R′ and R″ are independently selected from hydrogen, C 1 -C 4 alkyl, C 2 -C 4 alkenyl, aryl and arylalkyl;
X is N or N + O − ; and
j is 1 or 2, with the proviso that 3-Phenylamino-isonicotinic acid methyl ester and 3-Oxo-3-(3-phenylamino-pyridin-4-yl)-propionic acid ethyl ester are not included.
12. The method according to claim 11 , wherein the cancer is selected from the group consisting of ovarian, breast, lung, pancreatic, prostate, colon and epidermoid cancer.
13. The method according to claim 11 , wherein the MEK inhibitor is provided in a pharmaceutical composition comprising the MEK inhibitor and a pharmaceutically acceptable excipient.
14. A method of inhibiting hyperactivity of MEK in a cell, comprising administering to the cell an effective amount of a MEK inhibitor, wherein the MEK inhibitor is a compound according to Formula (II):
or a pharmaceutically acceptable salt thereof,
wherein:
R 1 , R 2 , R 9 , R 10 , R 11 , R 12 , R 13 and R 14 are independently selected from: hydrogen, halogen, cyano, nitro, azido, —OR 3 , —NR 4 C(O)OR 6 , —OC(O)R 3 , —NR 4 S(O) j R 6 , —S(O) j NR 3 R 4 , —S(O) j NR 4 C(O)R 3 , —C(O)NR 4 S(O) j R 6 , —S(O) j R 6 , —NR 4 C(O)R 3 , —C(O)NR 3 R 4 , —NR 5 C(O)NR 3 R 4 , —NR 5 C(NCN)NR 3 R 4 , —NR 3 R 4 , C 1 -C 10 alkyl, C 2 -C 10 alkenyl, C 2 -C 10 alkynyl, C 3 -C 10 cycloalkyl, C 3 -C 10 cycloalkylalkyl, or —S(O) j (C 1 -C 6 alkyl);
provided that R 12 is not OH, and R 13 , R 14 are not C 1 -C 10 alkyl;
R 3 is selected from hydrogen, trifluoromethyl, C 1 -C 10 alkyl, C 2 -C 10 alkenyl, C 2 -C 10 alkynyl, C 3 -C 10 cycloalkyl or C 3 -C 10 cycloalkylalkyl, where each alkyl, alkenyl, alkynyl and cycloalkyl is unsubstituted or substituted with primary amino, aminocarbonyl, carboxyl, cyano, halogen, hydroxy, nitro or trihalomethyl;
R 4 is selected from hydrogen or C 1 -C 6 alkyl, whereby alkyl may be unsubstituted or substituted with primary amino, aminocarbonyl, carboxyl, cyano, halogen, hydroxy, nitro or trihalomethyl;
R 5 is selected from hydrogen or C 1 -C 6 alkyl, whereby alkyl may be unsubstituted or substituted with primary amino, aminocarbonyl, carboxyl, cyano, halogen, hydroxy, nitro or trihalomethyl;
R 6 is selected from trifluoromethyl, C 1 -C 10 alkyl or C 3 -C 10 cycloalkyl;
W is selected from —C(O)OR 15 , —C(O)NR 4 R 15 , —C(O)NR 4 OR 15 , —C(O)NR 4 S(O) j R 6 , —C(O)NR 4 NR 4 R 15 , —NR′C(O)R′, —NR′S(O) j R′, —NRC(O)NR′R″, NR′S(O) j NR′R″, or —C(O)NR 4 NR 4 C(O)R 15 ;
provided that W is not —C(O)OH;
R 15 is independently selected from: hydrogen, trifluoromethyl, C 1 -C 10 alkyl, C 2 -C 10 alkenyl, C 2 -C 10 alkynyl, C 3 -C 10 cycloalkyl, C 3 -C 10 cycloalkylalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocyclyl, and heterocyclylalkyl; wherein each alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl and heterocyclyl is unsubstituted or substituted with primary amino, aminocarbonyl, carboxyl, cyano, halogen, hydroxy, nitro, trihalomethyl, O—C 1 -C 4 alkyl or NR′R″;
R′ and R″ are independently selected from hydrogen, C 1 -C 4 alkyl, C 2 -C 4 alkenyl, aryl and arylalkyl;
X is N or N +O − ; and
j is 1 or 2, with the proviso that 3-Phenylamino-isonicotinic acid methyl ester and 3-Oxo-3-(3-phenylamino-pyridin-4-yl)-propionic acid ethyl ester are not included.
15. The method according to claim 1 , wherein:
R 1 , R 2 , R 9 , R 10 , R 11 , R 12 , R 13 and R 14 are independently selected from hydrogen, halogen, cyano, nitro, azido, —OR 3 , —NR 4 C(O)OR 6 , —OC(O)R 3 , —NR 4 S(O) j R 6 , —S(O) j NR 3 R 4 , —S(O) j NR 4 C(O)R 3 , —C(O)NR 4 S(O) j R 6 , S(O) j R 6 , —NR 4 C(O)R 3 , —C(O)NR 3 R 4 , —NR 5 C(O)NR 3 R 4 , —NR 5 C(NCN)NR 3 R 4 , —NR 3 R 4 , C 1 -C 10 alkyl, C 2 -C 10 alkenyl, C 2 -C 10 alkynyl, C 3 -C 10 cycloalkyl, C 3 -C 10 cycloalkylalkyl or —S(O)j(C1-C6 alkyl);
provided that R 12 is not OH, and R 13 , R 14 are not C 1 -C 10 alkyl;
R 3 is selected from hydrogen, trifluoromethyl, C 1 -C 10 alkyl, C 2 -C 10 alkenyl, C 2 -C 10 alkynyl, C 3 -C 10 cycloalkyl or C 3 -C 10 cycloalkylalkyl, where each alkyl, alkenyl, alkynyl and cycloalkyl is unsubstituted or substituted with primary amino, aminocarbonyl, carboxyl, cyano, halogen, hydroxy, nitro or trihalomethyl;
R 4 is selected from hydrogen or C 1 -C 6 alkyl, whereby alkyl may be unsubstituted or substituted with primary amino, aminocarbonyl, carboxyl, cyano, halogen, hydroxy, nitro or trihalomethyl;
R 5 is selected from hydrogen or C 1 -C 6 alkyl, whereby alkyl may be unsubstituted or substituted with primary amino, aminocarbonyl, carboxyl, cyano, halogen, hydroxy, nitro or trihalomethyl;
R 6 is selected from trifluoromethyl, C 1 -C 10 alkyl or C 3 -C 10 cycloalkyl;
W is —C(O)OR 15 , —C(O)NR 4 R 15 , —C(O)NR 4 OR 15 or —C(O)NR 4 S(O) j R 6 ;
provided that W is not C(O)OH;
R 15 is independently selected from hydrogen, trifluoromethyl, C 1 -C 10 alkyl, C 2 -C 10 alkenyl, C 2 -C 10 alkynyl, C 3 -C 10 cycloalkyl, C 3 -C 10 cycloalkylalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocyclyl or heterocyclylalkyl, where each alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl and heterocyclyl is unsubstituted or substituted with primary amino, aminocarbonyl, carboxyl, cyano, halogen, hydroxy, nitro, trihalomethyl, O—C 1 -C 4 alkyl or NR′R″;
R′ and R″are independently selected from hydrogen, C 1 -C 4 alkyl, C 2 -C 4 alkenyl, aryl or arylalkyl;
X is N or N + O − ; and
j is 1 or 2.
16. The method according to claim 1 , wherein:
R 1 , R 2 , R 9 and R 11 are independently selected from hydrogen, halo, C 1 -C 4 alkyl, C 3 -C 4 cycloalkyl, C 2 -C 4 alkenyl, C 2 -C 4 alkynyl, cyano, nitro, OR 3 or NR 3 R 4 , where each alkyl, alkenyl, alkynyl, cycloalkyl is optionally substituted with one to five halogens;
R 10 and R 12 are independently selected from hydrogen, halo, C 1 -C 10 alkyl, C 3 -C 10 cycloalkyl, C 2 -C 10 alkenyl, C 2 -C 10 alkynyl, cyano, nitro, azido, NR 4 SO 2 R 6 , SO 2 NR 3 R 4 , SO 2 R 6 , C(O)NR 3 R 4 , —S(O) j NR 4 C(O)R 3 , —C(O)NR 4 S(O) j R 6 , OR 3 , NR 3 R 4 or —S(C 1 -C 2 alkyl) substituted with 1 to 5 F;
R 13 and R 14 are independently selected from H, F, Cl, C 1 -C 4 alkyl, C 3 -C 4 cycloalkyl, C 2 -C 4 alkenyl or C 2 -C 4 alkynyl, where each alkyl, alkenyl, cycloalky, alkynyl is optionally substituted with one to five halogens;
W is —C(O)OR 15 , —C(O)NR 4 R 15 , —C(O)NR 4 OR 15 , —C(O)(C 2 -C 10 alkyl) or —C(O)NR 4 S(O) j R 6 ;
R 15 is selected from hydrogen, C 1 -C 4 alkyl, C 1 -C 4 alkenyl or C 4 -C 6 cycloalkylalkyl, where alkyl or alkenyl is optionally substituted by 1 or 2 of OH, O—C 1 -C 4 alkyl or NR′R″; and
R′ and R″ are each independently selected from hydrogen, C 1 -C 4 alkyl, C 2 -C 4 alkenyl, aryl or arylalkyl.
17. The method according to claim 1 , wherein:
R 1 is independently selected from H and F;
R 2 is independently selected from hydrogen, F, Cl or Me, where the methyl group is optionally substituted with one to three fluorines;
R 9 is independently selected from H, F or Cl;
R 10 is independently selected from H, F, Cl, Br, nitro, Me or OMe, where the methyl groups are optionally substituted with one to three fluorines, SO 2 NR 3 R 4 or C(O)NR 3 R 4 , wherein R 3 and R 4 are independently C 1 -C 6 alkyl, optionally substituted by 1 or 2 alkyl amino or O-alkyl, or R 3 and R 4 taken together form a cyclic ring with 1 or 2 N atoms and optionally an O atom, said ring being optionally substituted by 1 or 2 alkyl amino or O-alkyl;
R 11 is independently selected from H, F, Cl, Br, Me or OMe, where the methyl groups are optionally substituted with one to three fluorines;
R 12 is independently selected from H, F, Cl, Br, nitro, Me, SCF 3 , SCHF 2 , SCH 2 F, SO 2 NR 3 R 4 , C(O)NR 3 R 4 or OMe, where the methyl groups are optionally substituted with one to three fluorines, wherein R 3 and R 4 are independently C 1 -C 6 alkyl, optionally substituted by 1 or 2 alkyl amino or O-alkyl, or R 3 and R 4 taken together form a cyclic ring with 1 or 2 N atoms and optionally an O atom, said ring being optionally substituted by 1 or 2 alkyl amino or O-alkyl;
R 13 is independently selected from H and F;
R 14 is independently selected from H and F;
W is —C(O)NR 4 OR 15 ; and
R 15 is C 1 -C 4 alkyl or C 1 -C 4 alkenyl optionally substituted with 1 to 3 substituents OH, O-Me, NH 2 , N(methyl) 2 or N(ethyl) 2 .
18. The method according to claim 1 , wherein:
W is —C(O)NR 4 OR 15 ;
R 4 is hydrogen;
R 15 is selected from C 1 -C 4 alkyl or C 1 -C 4 alkenyl that may be further substituted by 1 or 2 of OH, O—C 1 -C 4 alkyl or NR′R″; and
R′ and R″ are independently hydrogen, methyl or ethyl.