FTO INHIBITORS

Abstract

Provided are a compound of Formula (I) as an FTO inhibitor with improved and selective FTO inhibition, a pharmaceutical composition comprising the same, and a method of inhibiting weight gain, promoting weight loss, reducing serum LDL, cholesterol, LDL-c, or triglycerides, or treating obesity or an obesity-related disease (esp. obesity-related diabetes, hyperglycemia, diabetic nephropathy, hyperlipemia, coronary heart disease, atherosclerosis, hypertension, cardiovascular or cerebrovascular disease) or Alzheimer's disease by inhibiting FTO by using the compound disclosed herein.

Claims

1. A compound of Formula (I) ##STR00719## or a pharmaceutically acceptable salt thereof, a stereoisomer thereof, or a deuterated analog thereof, L.sub.1 is NR.sub.a or a single bond, wherein R.sub.a is C.sub.1-6alkyl or C.sub.1-6alkoxy, each of said C.sub.1-6alkyl or C.sub.1-6alkoxy is unsubstituted or substituted with halogen, hydroxy, C.sub.1-6alkoxy or C.sub.1-6alkyl-S; L.sub.2 is C.sub.1-6alkylene, C.sub.2-6alkenylene, C.sub.2-6alkynylene, or a single bond, wherein each of said C.sub.1-6alkylene, C.sub.2-6alkenylene, or C.sub.2-6alkynylene is unsubstituted or substituted with halogen, or hydroxy; L.sub.3 is a single bond, O, S, SO, SO.sub.2, NR.sub.c, C(O), C(O)O, C(O)NR.sub.c, OC(O)NR.sub.c, C(O)ONR.sub.c, C(O)N(R.sub.c)O, OC(O)NR.sub.c, or NR.sub.cC(O); wherein R.sub.c is hydrogen, C.sub.1-6alkyl, C.sub.2-6alkenyl, C.sub.2-6alkynyl, haloC.sub.1-6alkyl, hydroxyC.sub.1-6alkyl, C.sub.1-6alkoxy-C.sub.1-6alkyl, phenyl, phenylalkyl-, heterocyclyl, heterocyclylalkyl, heteroaryl, or heteroarylalkyl; R.sub.1 is hydrogen, C.sub.1-6alkyl, C.sub.2-6alkenyl, C.sub.2-6alkynyl, C.sub.3-8cycloalkyl, aryl, heteroaryl, heterocyclyl, wherein each of said C.sub.1-6alkyl, C.sub.2-6alkenyl, or C.sub.2-6alkynyl is unsubstituted or substituted with R.sub.b, and each of said C.sub.3-8cycloalkyl, aryl, heteroaryl or heterocyclyl is unsubstituted or substituted with R.sub.d; wherein R.sub.b is halogen, cyano, hydroxy, C.sub.1-6alkoxy, NR.sub.mC(O)NR.sub.nR.sub.p, NR.sub.mC(O)R.sub.n, C(O)NR.sub.mR.sub.n, NR.sub.mR.sub.n, C(O)R.sub.m, C(O)OR.sub.m, C.sub.3-6cycloalkyl, phenyl, heteroaryl or heterocyclyl, wherein each of said C.sub.3-6cycloalkyl, phenyl, heteroaryl or heterocyclyl is unsubstituted or substituted with one to three substituents selected from the group consisting of cyano, halogen, C.sub.1-6alkyl, haloC.sub.1-6alkyl, hydroxy, C.sub.1-6alkoxy, haloC.sub.1-6alkoxy, C.sub.1-6alkyl-S, C.sub.3-6cycloalkyl, phenyl, heteroaryl or heterocyclyl; R.sub.d is selected from cyano, halogen, oxo, C.sub.1-6alkyl, C.sub.1-6alkoxy, hydroxy, C.sub.2-6alkenyl, C.sub.2-6alkynyl, C.sub.1-6alkyl-S, SF.sub.5, NR.sub.mC(O)NR.sub.nR.sub.p, NR.sub.mC(O)R.sub.n, C(O)NR.sub.mR.sub.n, NR.sub.mR.sub.n, C(O)R.sub.m, C(O)OR.sub.m, C.sub.3-8cycloalkyl, phenyl, heteroaryl or heterocyclyl, wherein said C.sub.1-6alkyl or C.sub.1-6alkoxy is unsubstituted or substituted with R.sub.e, and each of said phenyl, heteroaryl or heterocyclyl is unsubstituted or substituted with R.sub.f, wherein R.sub.m, R.sub.n and R.sub.p are each independently hydrogen, hydroxy, C.sub.1-6alkyl, haloC.sub.1-6alkyl, C.sub.1-6alkoxyC.sub.1-6alkyl-, phenyl-C.sub.1-6alkyl-, heteroaryl-C.sub.1-6alkyl-, heterocyclyl-C.sub.1-6alkyl-, heterocyclyl, heteroaryl, phenyl or naphthyl, each of said heterocyclyl, heteroaryl, phenyl or naphthyl is unsubstituted or substituted with halogen, hydroxy, oxo, C.sub.1-6alkyl, C.sub.1-6alkoxy, haloC.sub.1-6alkyl or haloC.sub.1-6alkoxy; R.sub.e is halogen, C.sub.1-6alkyl, C.sub.1-6alkoxy, haloalkoxy, hydroxy, C(O)NR.sub.e1R.sub.e2, NR.sub.e1C(O)R.sub.e2, C(O)R.sub.e1, OR.sub.e1, SR.sub.e1, NR.sub.e1R.sub.e2, heterocyclyl, heteroaryl or phenyl, each of said heterocyclyl, heteroaryl or phenyl is unsubstituted or substituted with halogen, hydroxy, C.sub.1-6alkyl, C.sub.1-6alkoxy, haloC.sub.1-6alkyl or haloC.sub.1-6alkoxy; wherein R.sub.e1 and R.sub.e2 are each independently hydrogen, C.sub.1-6alkyl or haloC.sub.1-6alkyl; R.sub.f is halogen, C.sub.1-6alkyl, haloC.sub.1-6alkyl, C.sub.2-6alkenyl, C.sub.2-6alkynyl, hydroxy, hydroxyC.sub.1-6alkyl-, C.sub.1-6alkoxy-C.sub.1-6alkyl-, C.sub.1-6alkoxy, haloC.sub.1-6alkoxy, C.sub.1-6alkyl-S, heterocyclyl, heteroaryl or phenyl, each of said heterocyclyl, heteroaryl or phenyl is unsubstituted or substituted with halogen, hydroxy, C.sub.1-6alkyl, C.sub.1-6alkoxy, haloC.sub.1-6alkyl or haloC.sub.1-6alkoxy; R.sub.2 is hydrogen, halogen, cyano, C.sub.1-6alkyl, hydroxy, or C.sub.1-6alkoxy; R.sub.3 is hydrogen, halogen, cyano, C.sub.1-6alkyl, hydroxy, or C.sub.1-6alkoxy; R.sub.4 is cyano; hydrogen; halogen; hydroxy; C.sub.1-6alkoxy; C.sub.1-6alkyl-S; nitro (NO.sub.2); or SF.sub.5, each of said C.sub.1-6alkoxy or C.sub.1-6alkyl-S is unsubstituted or substituted with halogen, hydroxy or C.sub.1-6alkoxy; or C.sub.1-6alkyl, C.sub.2-6alkenyl or C.sub.2-6alkynyl, each of said C.sub.1-6alkyl, C.sub.2-6alkenyl or C.sub.2-6alkynyl is unsubstituted or substituted with halogen, hydroxy, C.sub.1-6alkoxy or C.sub.1-6alkyl-S; R.sub.5 is hydrogen, nitro (NO.sub.2), cyano, halogen, C.sub.1-6alkyl, haloC.sub.1-6alkyl, C.sub.2-6alkenyl, C.sub.2-6alkynyl, C.sub.1-6alkoxy, haloC.sub.1-6alkoxy, C(O)OR.sub.5a, SO.sub.2R.sub.5a, or SF.sub.5, wherein R.sub.5a is hydrogen, C.sub.1-6alkyl or haloC.sub.1-6alkyl; provided that if L.sub.1, L.sub.2, and L.sub.3 are each a single bond, then R.sub.1 is not hydrogen; further provided that the compound is not (Z)-2-cyano-3-(3,4-dihydroxy-5-nitrophenyl)-N,N-diethyl-3-hydroxyacrylamide.

2. The compound of claim 1, wherein R.sub.4 is hydrogen; cyano; nitro; SF.sub.5; halogen; hydroxy; C.sub.1-6alkoxy; haloC.sub.1-6alkoxy or C.sub.1-6alkyl.

3. The compound of claim 2, wherein R.sub.4 is cyano, nitro, hydrogen, methyl, ethyl, hydroxymethyl, methoxymethyl, methylthiomethyl, hydroxy, methoxy, ethoxy, difluoromethoxy, trifluoromethoxy, methylthio, trifluoromethylthio, vinyl, ethynyl, fluoro, chloro, bromo or iodo.

4. The compound of claim 3, wherein R.sub.5 is nitro, cyano, fluoro, chloro, bromo, trifluoromethyl, ethynyl, vinyl, methoxycarbonyl, carboxyl, SF.sub.5, or methylsulfonyl.

5. The compound of claim 1, wherein R.sub.4 is halogen; methoxy; difluoromethoxy; trifluoromethoxy or methyl; and R.sub.5 is nitro, cyano, or halogen.

6. The compound of claim 1, wherein R.sub.4 is hydrogen, halogen, nitro, CN, C.sub.1-6alkyl, or C.sub.1-6alkoxy which is unsubstituted or substituted with halogen, hydroxy, or C.sub.1-6alkoxy, R.sub.5 is nitro, CN or halogen; L.sub.1 is NR.sub.a, wherein R.sub.a is C.sub.1-6alkyl, haloC.sub.1-6alkyl, C.sub.1-6alkoxy, or hydroxyC.sub.1-6alkyl; L.sub.2 is C.sub.1-6alkylene, C.sub.2-6alkenylene, or C.sub.2-6alkynylene, wherein each of said C.sub.1-6alkylene, C.sub.2-6alkenylene, or C.sub.2-6alkynylene is unsubstituted or substituted with halogen, or hydroxy; L.sub.3 is a single bond or O; R.sub.1 is aryl, heteroaryl, heterocyclyl, C.sub.3-8cycloalkyl, wherein each of said C.sub.3-8cycloalkyl, aryl, heteroaryl, or heterocyclyl is unsubstituted or substituted with R.sub.d; wherein R.sub.d is selected from cyano, halogen, oxo, C.sub.1-6alkyl, C.sub.1-6alkoxy, hydroxy, C.sub.2-6alkenyl, C.sub.2-6alkynyl, C.sub.1-6alkyl-S, SF.sub.5, NR.sub.mC(O)NR.sub.nR.sub.p, NR.sub.mC(O)R.sub.n, C(O)NR.sub.mR.sub.n, NR.sub.mR.sub.n, C(O)R.sub.m, C(O)OR.sub.m, C.sub.3-8cycloalkyl, phenyl, heteroaryl or heterocyclyl, wherein said C.sub.1-6alkyl or C.sub.1-6alkoxy is unsubstituted or substituted with R.sub.e, and each of said phenyl, heteroaryl or heterocyclyl is unsubstituted or substituted with R.sub.f, wherein R.sub.m, R.sub.n and R.sub.p are each independently hydrogen, hydroxy, C.sub.1-6alkyl, haloC.sub.1-6alkyl, C.sub.1-6alkoxyC.sub.1-6alkyl-, phenyl-C.sub.1-6alkyl-, heteroaryl-C.sub.1-6alkyl-, heterocyclyl-C.sub.1-6alkyl-, heterocyclyl, heteroaryl, phenyl or naphthyl, each of said heterocyclyl, heteroaryl, phenyl or naphthyl is unsubstituted or substituted with halogen, hydroxy, oxo, C.sub.1-6alkyl, C.sub.1-6alkoxy, haloC.sub.1-6alkyl or haloC.sub.1-6alkoxy; R.sub.e is halogen, C.sub.1-6alkyl, C.sub.1-6alkoxy, haloalkoxy, hydroxy, C(O)NR.sub.e1R.sub.e2, NR.sub.e1C(O)R.sub.e2, C(O)R.sub.e1, OR.sub.e1, SR.sub.e1, NR.sub.e1R.sub.e2, heterocyclyl, heteroaryl or phenyl, each of said heterocyclyl, heteroaryl or phenyl is unsubstituted or substituted with halogen, hydroxy, C.sub.1-6alkyl, C.sub.1-6alkoxy, haloC.sub.1-6alkyl or haloC.sub.1-6alkoxy; wherein R.sub.e1 and R.sub.e2 are each independently hydrogen, C.sub.1-6alkyl or haloC.sub.1-6alkyl; R.sub.f is halogen, C.sub.1-6alkyl, haloC.sub.1-6alkyl, C.sub.2-6alkenyl, C.sub.2-6alkynyl, hydroxy, hydroxyC.sub.1-6alkyl-, C.sub.1-6alkoxy-C.sub.1-6alkyl-, C.sub.1-6alkoxy, haloC.sub.1-6alkoxy, C.sub.1-6alkyl-S, heterocyclyl, heteroaryl or phenyl, each of said heterocyclyl, heteroaryl or phenyl is unsubstituted or substituted with halogen, hydroxy, C.sub.1-6alkyl, C.sub.1-6alkoxy, haloC.sub.1-6alkyl or haloC.sub.1-6alkoxy.

7. The compound of claim 6, wherein R.sub.4 is halogen, methoxy, difluoromethoxy, trifluoromethoxy or ethoxy.

8. The compound of claim 1, wherein R.sub.4 is hydroxy or halogen, R.sub.5 is haloC.sub.1-6alkyl or SO.sub.2R.sub.5a, wherein R.sub.5a is hydrogen, C.sub.1-6alkyl or haloC.sub.1-6alkyl; L.sub.1 is NR.sub.a, wherein R.sub.a is C.sub.1-6alkyl, haloC.sub.1-6alkyl, C.sub.1-6alkoxy, or hydroxyC.sub.1-6alkyl; L.sub.2 is C.sub.1-6alkylene, C.sub.2-6alkenylene, or C.sub.2-6alkynylene, wherein each of said C.sub.1-6alkylene, C.sub.2-6alkenylene, or C.sub.2-6alkynylene is unsubstituted or substituted with halogen, or hydroxy; L.sub.3 is a single bond or O; R.sub.1 is aryl, heteroaryl as defined in claim 1; or R.sub.4 is hydrogen, halogen, nitro, CN, C.sub.1-6alkyl, or C.sub.1-6alkoxy which is unsubstituted or substituted with halogen, hydroxy, or C.sub.1-6alkoxy, R.sub.5 is nitro, CN or halogen; L.sub.1 is NR.sub.a, wherein R.sub.a is C.sub.1-6alkyl, haloC.sub.1-6alkyl, C.sub.1-6alkoxy, or hydroxyC.sub.1-6alkyl; L.sub.2 is C.sub.1-6alkylene, C.sub.2-6alkenylene, or C.sub.2-6alkynylene, wherein each of said C.sub.1-6alkylene, C.sub.2-6alkenylene, or C.sub.2-6alkynylene is unsubstituted or substituted with halogen, or hydroxy; R.sub.1 is aryl, heteroaryl as defined in claim 1.

9. The compound of claim 1, wherein L.sub.1 is a single bond, L.sub.2 is a single bond, L.sub.3 is a single bond, O or S, and R.sub.1 is C.sub.1-6alkyl, C.sub.2-6alkenyl, C.sub.2-6alkynyl, or C.sub.3-8cycloalkyl; each of which is unsubstituted or substituted with halogen, hydroxy, C.sub.1-6alkoxy, or phenyl which is unsubstituted or substituted with halogen, C.sub.1-6alkyl, haloC.sub.1-6alkyl, hydroxy, C.sub.1-6alkoxy, haloC.sub.1-6alkoxy, C.sub.1-6alkyl-S or cyano.

10. The compound of claim 1, wherein L.sub.1 is NR.sub.a, wherein R.sub.a is C.sub.1-6alkyl, haloC.sub.1-6alkyl, C.sub.1-6alkoxy or hydroxyC.sub.1-6alkyl; preferably C.sub.1-4alkyl; more preferably methyl or ethyl; (a) L.sub.2 is C.sub.1-6alkylene, C.sub.2-6alkynyl, or C.sub.2-6alkynyl, each of which is unsubstituted or substituted with halogen, and L.sub.3 is a single bond, R.sub.1 is aryl, heteroaryl, heterocyclyl or C.sub.3-8cycloalkyl, wherein said aryl, heteroaryl, heterocyclyl or C.sub.3-8cycloalkyl is unsubstituted or substituted with R.sub.d, wherein R.sub.d is selected from cyano, halogen, C.sub.1-6alkyl, C.sub.1-6alkoxy, hydroxy, C.sub.2-6alkenyl, C.sub.2-6alkynyl, C.sub.1-6alkyl-S, SF.sub.5, C.sub.3-8cycloalkyl, NR.sub.mC(O)NR.sub.nR.sub.p, NR.sub.mC(O)R.sub.n, NR.sub.mR.sub.n, C(O)NR.sub.mR.sub.n, C(O)R.sub.m, C(O)OR.sub.m, phenyl, heteroaryl or heterocyclyl, wherein said C.sub.1-6alkyl or C.sub.1-6alkoxy is unsubstituted or substituted with R.sub.e, and each of said phenyl, heteroaryl or heterocyclyl is unsubstituted or substituted with R.sub.f, R.sub.m, R.sub.n and R.sub.p are each independently hydrogen, C.sub.1-6alkyl, haloC.sub.1-6alkyl, heterocyclyl, heteroaryl, or phenyl, each of said heterocyclyl, heteroaryl or phenyl is unsubstituted or substituted with halogen, hydroxy, C.sub.1-6alkyl, C.sub.1-6alkoxy, haloC.sub.1-6alkyl or haloC.sub.1-6alkoxy, wherein R.sub.e is halogen, C(O)NR.sub.e1R.sub.e2, NR.sub.e1C(O)R.sub.e2, C(O)R.sub.e1, OR.sub.e1, SR.sub.e1, NR.sub.e1R.sub.e2, heterocyclyl, heteroaryl or phenyl, each of said heterocyclyl, heteroaryl or phenyl is unsubstituted or substituted with halogen, hydroxy, C.sub.1-6alkyl, C.sub.1-6alkoxy, haloC.sub.1-6alkyl or haloC.sub.1-6alkoxy; wherein R.sub.e1 and R.sub.e2 are each independently hydrogen, C.sub.1-6alkyl or haloC.sub.1-6alkyl; R.sub.f is halogen, C.sub.1-6alkyl, C.sub.2-6alkenyl, C.sub.2-6alkynyl, hydroxy, hydroxyC.sub.1-6alkyl-, C.sub.1-6alkoxy-C.sub.1-6alkyl-, C.sub.1-6alkoxy, heterocyclyl, heteroaryl or phenyl, each of said heterocyclyl, heteroaryl or phenyl is unsubstituted or substituted with halogen, hydroxy, C.sub.1-6alkyl, C.sub.1-6alkoxy, haloC.sub.1-6alkyl or haloC.sub.1-6alkoxy; (b) L.sub.2 is C.sub.1-6alkylene, C.sub.2-6alkenyl, or C.sub.2-6alkynyl, each of which is unsubstituted or substituted with halogen: L.sub.3 is O, S, SO, SO.sub.2, NR.sub.c, C(O), C(O)O, C(O)NR.sub.c, OC(O)NR.sub.c, C(O)ONR.sub.c or NR.sub.cC(O) and R.sub.1 is hydrogen, C.sub.1-6alkyl, phenyl or naphthyl, heteroaryl or heterocyclyl; wherein said C.sub.1-6alkyl is unsubstituted or substituted with R.sub.b, and said phenyl or heteroaryl or heterocyclyl is unsubstituted or substituted with R.sub.d, wherein R.sub.b is halogen, cyano, hydroxy, C.sub.1-6alkoxy, phenyl, heteroaryl, or heterocyclyl; and R.sub.d is cyano, halogen, C.sub.1-6alkyl, oxo, C.sub.1-6alkoxyC.sub.1-6alkyl-, hydroxyC.sub.1-6alkyl, haloC.sub.1-6alkyl, haloC.sub.1-6alkoxy, phenyl, heterocyclyl, heteroaryl, SF.sub.5, NR.sub.mC(O)NR.sub.nR.sub.p, C(O)R.sub.m, C(O)OR.sub.m, NR.sub.mR.sub.n, C(O)NR.sub.nR.sub.n, NR.sub.mC(O)R.sub.n, C(O)R.sub.m, or C(O)OR.sub.m, wherein each of said heterocyclyl, heteroaryl or phenyl is unsubstituted or substituted with halogen, hydroxy, C.sub.1-6alkyl, C.sub.1-6alkoxy, haloC.sub.1-6alkyl or haloC.sub.1-6alkoxy, wherein R.sub.m and R.sub.n are each independently is hydrogen, C.sub.1-6alkyl or haloC.sub.1-6alkyl; or (c) L.sub.2 is a single bond, L.sub.3 is a single bond or O, S, NR.sub.c, C(O)NR.sub.c or SO.sub.2 and R.sub.1 is C.sub.1-6alkyl, C.sub.3-8cycloalkyl, heteroaryl, heterocyclyl, or aryl, wherein said C.sub.1-6alkyl is unsubstituted or substituted with R.sub.b, and each of heteroaryl, heterocyclyl, aryl, or C.sub.3-8cycloalkyl is unsubstituted or substituted with R.sub.d, wherein R.sub.d is cyano, C.sub.1-6alkyl, halogen, heteroaryl, heterocyclyl, oxo, C(O)R.sub.m, C(O)OR.sub.m, C(O)NR.sub.mR.sub.n, NR.sub.mR.sub.n, OR.sub.m or NR.sub.mC(O)NR.sub.nR.sub.p, wherein R.sub.m, R.sub.n and R.sub.p are each independently hydrogen, C.sub.1-6alkyl, haloC.sub.1-6alkyl, heterocyclyl, heteroaryl or phenyl, each of said heterocyclyl, heteroaryl or phenyl is unsubstituted or substituted with halogen, hydroxy, C.sub.1-6alkyl, C.sub.1-6alkoxy, haloC.sub.1-6alkyl or haloC.sub.1-6alkoxy; and R.sub.b is cyano, halogen, hydroxy, C.sub.3-6cycloalkyl, or phenyl.

11. The compound of claim 10, wherein L.sub.2 is C.sub.1-6alkylene; L.sub.3 is a single bond or O; R.sub.1 is a phenyl group, wherein said phenyl is unsubstituted or substituted with R.sub.d, wherein R.sub.d is selected from cyano, halogen, C.sub.1-6alkyl, C.sub.1-6alkoxy, hydroxy, C.sub.2-6alkenyl, C.sub.2-6alkynyl, C.sub.1-6alkyl-S, NR.sub.mC(O)NR.sub.nR.sub.p, NR.sub.mC(O)R.sub.n, NR.sub.mR.sub.n, C(O)R.sub.m, C(O)OR.sub.m, or phenyl, pyridinyl, piperidinyl, piperazinyl, azetidinyl, pyrazinyl, pyrimidinyl or morpholino, wherein said C.sub.1-6alkyl or C.sub.1-6alkoxy is unsubstituted or substituted with R.sub.e, and each of said phenyl, pyridinyl, piperidinyl, piperazinyl, azetidinyl, pyrazinyl, pyrimidinyl or morpholino is unsubstituted or substituted with R.sub.f, wherein R.sub.m, R.sub.n and R.sub.p are each independently hydrogen or C.sub.1-6alkyl, wherein R.sub.e is halogen, C(O)NR.sub.e1R.sub.e2, NR.sub.e1C(O)R.sub.e2, C(O)R.sub.e1, OR.sub.e1, SR.sub.e1, NR.sub.e1R.sub.e2, phenyl, pyridinyl, piperidinyl, piperazinyl, azetidinyl, pyrazinyl, pyrimidinyl, pyazolyl or morpholino, each of said phenyl, pyridinyl, piperidinyl, piperazinyl, azetidinyl, pyrazinyl, pyrimidinyl, pyazolyl or morpholino is unsubstituted or substituted with halogen, hydroxy, C.sub.1-6alkyl or C.sub.1-6alkoxy; R.sub.f is halogen, C.sub.1-6alkyl or hydroxyC.sub.1-6alkyl-; and R.sub.e1 and R.sub.e2 are each independently hydrogen or C.sub.1-6alkyl.

12. The compound of claim 11, wherein R.sub.1 is a phenyl group, which is unsubstituted or substituted with one or two or three substituents selected from chloro, fluoro, bromo, phenyl, methyl, ethyl, isopropyl, propyl, butyl, isobutyl, tert-butyl, cyano, methylureido, hydroxymethyl, hydroxy, methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, tert-butoxy, methoxymethyl, methylthio, ethynyl, vinyl, thiazol-2-ylamino, 1-methyl-1H-pyrazol-4-ylamino, dimethylamino, 3-(hydroxymethyl)pyridin-2-yl, 4-(4-methylpiperazin-1-yl)piperidin-1-yl, 4-methylpiperazin-1-yl, pyridin-3-yl, azetidin-1-yl, pyrazin-2-yl, 1-methylpiperidin-4-yl, pyrimidin-4-yl, morpholino, 2,2,2-trifluoroethoxy, trifluoromethoxy, difluoromethoxy, trifluoromethyl, trifluoromethoxymethyl, (1-methylpiperidin-4-yl)methoxy, (1-methyl-1H-pyrazol-4-yl)methyl, aminocarbonylmethyl, methylaminocarbonylmethyl or acetamido.

13. The compound of claim 10, wherein L.sub.2 is C.sub.1-6alkylene, L.sub.3 is a single bond and R.sub.1 is heteroaryl or heterocyclyl, wherein each of said heteroaryl or heterocyclyl is unsubstituted or substituted with R.sub.d, R.sub.d is cyano, halogen, oxo, C.sub.1-6alkyl, C.sub.1-6alkoxy, hydroxy, NR.sub.mR.sub.n, phenyl, heteroaryl, or heterocyclyl, wherein said phenyl, heteroaryl, or heterocyclyl is unsubstituted or substituted with R.sub.f, wherein R.sub.m and R.sub.n are each independently hydrogen, C.sub.1-6alkyl, haloC.sub.1-6alkyl, heterocyclyl, heteroaryl or phenyl, each of said heterocyclyl, heteroaryl or phenyl is unsubstituted or substituted with halogen, hydroxy, C.sub.1-6alkyl, C.sub.1-6alkoxy, haloC.sub.1-6alkyl or haloC.sub.1-6alkoxy; wherein R.sub.f is halogen, C.sub.1-6alkyl, C.sub.2-6alkenyl, C.sub.2-6alkynyl, hydroxy, hydroxyC.sub.1-6alkyl-, C.sub.1-6alkoxy-C.sub.1-6alkyl-, C.sub.1-6alkoxy, heterocyclyl, heteroaryl or phenyl, each of said heterocyclyl, heteroaryl or phenyl is unsubstituted or substituted with halogen, hydroxy, C.sub.1-6alkyl, C.sub.1-6alkoxy, haloC.sub.1-6alkyl or haloC.sub.1-6alkoxy.

14. The compound of claim 13, wherein R.sub.1 is heteroaryl or heterocyclyl, wherein said heteroaryl or heterocyclyl is pyridinyl, pyrazinyl, dihydrobenzofuranyl, indazolyl, benzodioxinyl, dihydrobenzodioxinyl, isoquinoliny, triazol-4-yl, imidazolyl, isoxazolyl, oxazolyl, thiazolyl or triazolyl, each of which is unsubstituted or substituted with R.sub.d as defined above. In some further embodiments, R.sub.d is cyano, halogen, oxo, C.sub.1-6alkyl, C.sub.1-6alkoxy, hydroxy, NR.sub.mR.sub.n; phenyl, heteroaryl, heterocyclyl; halogen or C.sub.1-6alkyl-substituted phenyl; halogen or C.sub.1-6alkyl-substituted heteroaryl; or halogen or C.sub.1-6alkyl-substituted heterocyclyl, wherein R.sub.m and R.sub.n are each independently hydrogen, C.sub.1-6alkyl, haloC.sub.1-6alkyl or heterocyclyl.

15. The compound of claim 13, wherein R.sub.1 is heteroaryl or heterocyclyl, wherein said heteroaryl or heterocyclyl is pyridinyl, pyrazinyl, dihydrobenzofuranyl, indazolyl, benzodioxinyl, dihydrobenzodioxinyl, isoquinoliny, triazol-4-yl, imidazolyl, isoxazolyl, oxazolyl, thiazolyl or triazolyl, each of which is unsubstituted or substituted with chloro, fluoro, hydroxy, methyl, cyano, oxo, methoxy, tetrahydropyranyl, pyridin-4-yl, phenyl or NR.sub.mR.sub.n, wherein R.sub.m and R.sub.n are each independently hydrogen, C.sub.1-6alkyl or triazolyl.

16. The compound of claim 10, wherein L.sub.2 is C.sub.1-6alkylene which is unsubstituted or substituted with halogen, and L.sub.3 is O, S, SO, or SO.sub.2, wherein R.sub.1 is hydrogen, C.sub.1-6alkyl, phenyl or naphthyl or heteroaryl selected from pyridinyl; pyrimidinyl; benzo[d]imidazolyl; indazolyl; or heterocyclyl, wherein said C.sub.1-6alkyl is unsubstituted or substituted with R.sub.b, and said phenyl is unsubstituted or substituted with R.sub.d, wherein R.sub.b is halogen, cyano, hydroxy or C.sub.1-6alkoxy; R.sub.d is halogen, C.sub.1-6alkyl, oxo, C.sub.1-6alkoxyC.sub.1-6alkyl-, hydroxyC.sub.1-6alkyl, haloC.sub.1-6alkyl, haloC.sub.1-6alkoxy, phenyl, heterocyclyl, heteroaryl, NR.sub.mR.sub.n, C(O)NR.sub.mR.sub.n or NR.sub.mC(O)R.sub.n, wherein each of said heterocyclyl, heteroaryl or phenyl is unsubstituted or substituted with halogen, hydroxy, C.sub.1-4alkyl, C.sub.1-4alkoxy, haloC.sub.1-4alkyl or haloC.sub.1-4alkoxy, wherein R.sub.m and R.sub.n are each independently is hydrogen or C.sub.1-4alkyl.

17. The compound of claim 10, wherein L.sub.2 is a single bond; L.sub.3 is a single bond or O, S, NR.sub.c, C(O)NR.sub.c or SO.sub.2; R.sub.1 is pyridinyl, triazolyl, oxazolyl, isoxazolyl, pyrimidinyl, pyrazolyl, benzoisoxazol-3-yl, triazolopyridin-3-yl, triazolooxazinyl, tetratriazolopyridin-3-yl, dihydrotriazolooxazinyl, each which is unsubstituted or substituted with one or two or three substituents selected from the group consisting of C.sub.1-6alkyl, halogen, heteroaryl, oxo, C(O)NR.sub.mR.sub.n, NR.sub.mR.sub.n, OR.sub.m or NR.sub.mC(O)NR.sub.nR.sub.p, preferably fluoro, chloro, bromo, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, pentyl, phenyl, pyridinyl, methylureido, acetylamino, amino, oxo, and phenoxy; or R.sub.1 is C.sub.1-6alkyl or phenyl, wherein said C.sub.1-6alkyl is unsubstituted or substituted with R.sub.b, and said phenyl is unsubstituted or substituted with R.sub.d, wherein R.sub.b is halogen or hydroxy, and R.sub.d is halogen, hydroxy and C.sub.1-6alkyl.

18. The compound of claim 1, which is a compound of Formula (II) ##STR00720## R.sub.2 and R.sub.3 are both hydrogen; R.sub.4 is hydrogen, hydroxy, halogen, nitro, CN, C.sub.1-6alkyl, or C.sub.1-6alkoxy, said C.sub.1-6alkyl or C.sub.1-6alkoxy is unsubstituted or substituted with halogen, hydroxy, or C.sub.1-6alkoxy, R.sub.5 is nitro, CN or halogen; R.sub.a is C.sub.1-6alkyl, haloC.sub.1-6alkyl, or hydroxyC.sub.1-6alkyl; L.sub.2 is C.sub.1-6alkylene, C.sub.2-6alkenylene, or C.sub.2-6alkynylene, wherein each of said C.sub.1-6alkylene, C.sub.2-6alkenylene, or C.sub.2-6alkynylene is unsubstituted or substituted with halogen, or hydroxy; L.sub.3 is a single bond, O, S, NR.sub.c, or C(O); wherein R.sub.c is hydrogen or C.sub.1-6alkyl; R.sub.1 is aryl, heteroaryl, heterocyclyl, wherein each of said C.sub.3-8cycloalkyl, aryl, heteroaryl, or heterocyclyl is unsubstituted or substituted with R.sub.d; wherein R.sub.d is selected from cyano, halogen, oxo, C.sub.1-6alkyl, C.sub.1-6alkoxy, hydroxy, C.sub.2-6alkenyl, C.sub.2-6alkynyl, C.sub.1-6alkyl-S, NR.sub.mC(O)NR.sub.nR.sub.p, NR.sub.mC(O)R.sub.n, C(O)NR.sub.mR.sub.n, NR.sub.mR.sub.n, C.sub.3-8cycloalkyl, phenyl, heteroaryl or heterocyclyl, wherein said C.sub.1-6alkyl or C.sub.1-6alkoxy is unsubstituted or substituted with R.sub.e, and each of said phenyl, heteroaryl or heterocyclyl is unsubstituted or substituted with R.sub.f, wherein R.sub.m, R.sub.n and R.sub.p are each independently hydrogen, hydroxy, C.sub.1-6alkyl, haloC.sub.1-6alkyl, C.sub.1-6alkoxyC.sub.1-6alkyl-, phenyl-C.sub.1-6alkyl-, heteroaryl-C.sub.1-6alkyl-, heterocyclyl-C.sub.1-6alkyl-, heterocyclyl, heteroaryl, phenyl or naphthyl, each of said heterocyclyl, heteroaryl, phenyl or naphthyl is unsubstituted or substituted with halogen, hydroxy, oxo, C.sub.1-6alkyl, C.sub.1-6alkoxy, haloC.sub.1-6alkyl or haloC.sub.1-6alkoxy; R.sub.e is halogen, C.sub.1-6alkyl, C.sub.1-6alkoxy, haloalkoxy, hydroxy, C(O)NR.sub.e1R.sub.e2, NR.sub.e1C(O)R.sub.e2, C(O)R.sub.e1, OR.sub.e1, SR.sub.e1, NR.sub.e1R.sub.e2, heterocyclyl, heteroaryl or phenyl, each of said heterocyclyl, heteroaryl or phenyl is unsubstituted or substituted with halogen, hydroxy, C.sub.1-6alkyl, C.sub.1-6alkoxy, haloC.sub.1-6alkyl or haloC.sub.1-6alkoxy; wherein R.sub.e1 and R.sub.e2 are each independently hydrogen, C.sub.1-6alkyl or haloC.sub.1-6alkyl; R.sub.f is halogen, C.sub.1-6alkyl, haloC.sub.1-6alkyl, C.sub.2-6alkenyl, C.sub.2-6alkynyl, hydroxy, hydroxyC.sub.1-6alkyl-, C.sub.1-6alkoxy-C.sub.1-6alkyl-, C.sub.1-6alkoxy, haloC.sub.1-6alkoxy, C.sub.1-6alkyl-S, heterocyclyl, heteroaryl or phenyl, each of said heterocyclyl, heteroaryl or phenyl is unsubstituted or substituted with halogen, hydroxy, C.sub.1-6alkyl, C.sub.1-6alkoxy, haloC.sub.1-6alkyl or haloC.sub.1-6alkoxy.

19. The compound of claim 1, wherein the compounds are selected from the group consisting of Examples 1 to 672.

20. A pharmaceutical composition comprising the compounds of claim 1 and a pharmaceutically-acceptable excipient.

21. A method of inhibiting weight gain; or promoting weight loss; or reducing serum LDL, cholesterol, LDL-c, or triglycerides; or treating obesity or an obesity-related disease (especially, obesity-related diabetes, hyperglycemia, diabetic nephropathy, hyperlipemia, coronary heart disease, atherosclerosis, hypertension, cardiovascular or cerebrovascular disease), macular degeneration or Alzheimer's disease; or treating injury or promoting wound healing or tissue regeneration in a subject, comprising administering the subject in need thereof an effective amount of the compounds of claim 1.

22. The method of claim 21, wherein the method is characterized by FTO inhibition.

Description

DETAILED DESCRIPTION OF THE INVENTION

Definitions

[0151] The following terms have the indicated meanings throughout the specification:

[0152] As used herein, including the appended claims, the singular forms of words such as a, an, and the, include their corresponding plural references unless the context clearly dictates otherwise.

[0153] The term or is used to mean, and is used interchangeably with, the term and/or unless the context clearly dictates otherwise.

[0154] The term alkyl refers to a hydrocarbon group selected from linear and branched saturated hydrocarbon groups comprising from 1 to 18, such as from 1 to 12, further such as from 1 to 10, more further such as from 1 to 8, or from 1 to 6, or from 1 to 4, carbon atoms. Examples of alkyl groups comprising from 1 to 6 carbon atoms (i.e., C.sub.1-6alkyl) include, but not limited to, methyl, ethyl, 1-propyl or n-propyl, 2-propyl or isopropyl, 1-butyl or n-butyl, 2-methyl-1-propyl or isobutyl, 1-methylpropyl or s-butyl (s-Bu), 1,1-dimethylethyl or t-butyl (t-Bu), 1-pentyl, 2-pentyl, 3-pentyl, 2-methyl-2-butyl, 3-methyl-2-butyl, 3-methyl-1-butyl, 2-methyl-1-butyl, 1-hexyl, 2-hexyl, 3-hexyl, 2-methyl-2-pentyl, 3-methyl-2-pentyl, 4-methyl-2-pentyl, 3-methyl-3-pentyl, 2-methyl-3-pentyl, 2,3-dimethyl-2-butyl and 3,3-dimethyl-2-butyl groups. The alkyl group can be optionally substituted or enriched in deuterium, e.g., CD.sub.3 (methyl-d3), CD.sub.2CD.sub.3 (ethyl-d5) and the like.

[0155] The term alkylene refers to a divalent alkyl group as defined herein. For example, methylene refers to CH.sub.2.

[0156] The term halogen refers to fluoro (F), chloro (Cl), bromo (Br) and iodo (I).

[0157] The term haloalkyl refers to an alkyl group in which one or more hydrogen is/are replaced by one or more halogen atoms such as fluoro, chloro, bromo, and iodo. Examples of haloalkyl include haloC.sub.1-8alkyl, haloC.sub.1-6alkyl or halo C.sub.1-4alkyl, but not limited to CF.sub.3, CH.sub.2Cl, CH.sub.2CF.sub.3, CCl.sub.2, CF.sub.3, and the like.

[0158] The term alkyloxy or alkoxy refers to an alkyl group as defined above attached to the parent molecular moiety through an oxygen atom. Examples of an alkyloxy, e.g., C.sub.1-6alkyloxy or C.sub.1-4 alkyloxy include, but not limited to, methoxy, ethoxy, isopropoxy, propoxy, n-butoxy, tert-butoxy, pentoxy and hexoxy and the like.

[0159] The term alkoxy-alkyl- refers to an alkyl group as defined above further substituted with an alkoxy as defined above. Examples of an alkoxy-alkyl-, e.g., C.sub.1-6alkoxy-C.sub.1-6alkyl- include, but not limited to, methoxymethyl, ethoxymethyl, ethoxyethyl, isopropoxymethyl, or propoxymethyl and the like.

[0160] The term amino refers to NH.sub.2. The term alkylamino refers to NH(alkyl). The term dialkylamino refers to N(alkyl).sub.2.

[0161] The term alkenyl herein refers to a hydrocarbon group selected from linear and branched hydrocarbon groups comprising at least one CC double bond and from 2 to 18, such as from 2 to 8, further such as from 2 to 6, carbon atoms. Examples of the alkenyl group, e.g., C.sub.2-6alkenyl, include, but not limited to ethenyl or vinyl, prop-1-enyl, prop-2-enyl, 2-methylprop-1-enyl, but-1-enyl, but-2-enyl, but-3-enyl, buta-1,3-dienyl, 2-methylbuta-1,3-dienyl, hex-1-enyl, hex-2-enyl, hex-3-enyl, hex-4-enyl, and hexa-1,3-dienyl groups.

[0162] The term alkenylene refers to a divalent alkenyl group as defined herein.

[0163] The term alkynyl herein refers to a hydrocarbon group selected from linear and branched hydrocarbon group, comprising at least one CC triple bond and from 2 to 18, such as 2 to 8, further such as from 2 to 6, carbon atoms. Examples of the alkynyl group, e.g., C2-6 alkynyl, include, but not limited to ethynyl, 1-propynyl, 2-propynyl (propargyl), 1-butynyl, 2-butynyl, and 3-butynyl groups.

[0164] The term alkynylene refers to a divalent alkynyl group as defined herein.

[0165] The term cycloalkyl refers to a hydrocarbon group selected from saturated cyclic hydrocarbon groups, comprising monocyclic and polycyclic (e.g., bicyclic and tricyclic) groups including fused, bridged or spiro cycloalkyl.

[0166] For example, the cycloalkyl group may comprise from 3 to 12, such as from 3 to 10, further such as 3 to 8, further such as 3 to 6, 3 to 5, or 3 to 4 carbon atoms. Even further for example, the cycloalkyl group may be selected from monocyclic group comprising from 3 to 12, such as from 3 to 10, further such as 3 to 8, 3 to 6 carbon atoms. Examples of the monocyclic cycloalkyl group include cyclopropyl, cyclobutyl, cyclopentyl, 1-cyclopent-1-enyl, 1-cyclopent-2-enyl, 1-cyclopent-3-enyl, cyclohexyl, 1-cyclohex-1-enyl, 1-cyclohex-2-enyl, 1-cyclohex-3-enyl, cyclohexadienyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl, cycloundecyl, and cyclododecyl groups. In particular, Examples of the saturated monocyclic cycloalkyl group, e.g., C.sub.3-6cycloalkyl, include, but not limited to cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl groups. In a preferred embedment, the cycloalkyl is a monocyclic ring comprising 3 to 6 carbon atoms (abbreviated as C.sub.3-6 cycloalkyl), including but not limited to, cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl. Examples of the bicyclic cycloalkyl groups include those having from 7 to 12 ring atoms arranged as a fused bicyclic ring selected from [4,4], [4,5], [5,5], [5,6] and [6,6] ring systems, or as a bridged bicyclic ring selected from bicyclo[2.2.1]heptane, bicyclo[2.2.2]octane, and bicyclo[3.2.2]nonane. Further Examples of the bicyclic cycloalkyl groups include those arranged as a bicyclic ring selected from [5,6] and [6,6] ring systems. In some embodiments, a cycloalkyl group also comprises at least one double bond or at least one triple bond.

[0167] The term deuterated in a deuterated analog is used herein to modify a chemical structure or an organic group or radical, wherein one or more carbon-bound hydrogen(s) are replaced by one or more deuterium(s), e.g., deuterated-alkyl, deuterated-cycloalkyl, deuterated-heterocycloalkyl, deuterated-aryl, deuterated-morpholinyl, and the like. For example, the term deuterated-alkyl defined above refers to an alkyl group as defined herein, wherein at least one hydrogen atom bound to carbon is replaced by a deuterium. In a deuterated alkyl group, at least one carbon atom is bound to a deuterium; and it is possible for a carbon atom to be bound to more than one deuterium; it is also possible that more than one carbon atom in the alkyl group is bound to a deuterium.

[0168] The term aryl used alone or in combination with other terms refers to a group selected from: [0169] 5- and 6-membered carbocyclic aromatic rings, e.g., phenyl; [0170] bicyclic ring systems such as 7 to 12 membered bicyclic ring systems, wherein at least one ring is carbocyclic and aromatic, e.g., naphthyl and indanyl; and, [0171] tricyclic ring systems such as 10 to 15 membered tricyclic ring systems wherein at least one ring is carbocyclic and aromatic, e.g., fluorenyl.

[0172] The terms aromatic hydrocarbon ring and aryl are used interchangeable throughout the disclosure herein. In some embodiments, a monocyclic or bicyclic aromatic hydrocarbon ring has 5 to 10 ring-forming carbon atoms (i.e., C.sub.5-10 aryl). Examples of a monocyclic or bicyclic aromatic hydrocarbon ring include, but not limited to, phenyl, naphth-1-yl, naphth-2-yl, anthracenyl, phenanthrenyl, and the like.

[0173] In some embodiments, the aromatic hydrocarbon ring is a naphthalene ring (naphth-1-yl or naphth-2-yl) or phenyl ring. In some embodiments, the aromatic hydrocarbon ring is a phenyl ring.

[0174] The term heteroaryl herein refers to a group selected from: [0175] 5-, 6- or 7-membered aromatic, monocyclic rings comprising at least one heteroatom, for example, from 1 to 4, or, in some embodiments, from 1 to 3, in some embodiments, from 1 to 2, heteroatoms, selected from nitrogen (N), sulfur (S) and oxygen (O), with the remaining ring atoms being carbon; [0176] 7- to 12-membered bicyclic rings comprising at least one heteroatom, for example, from 1 to 4, or, in some embodiments, from 1 to 3, or, in other embodiments, 1 or 2, heteroatoms, selected from nitrogen, oxygen or optionally oxidized sulfur as ring member(s), with the remaining ring atoms being carbon and wherein at least one ring is aromatic and at least one heteroatom is present in the aromatic ring; and [0177] 11- to 14-membered tricyclic rings comprising at least one heteroatom, for example, from 1 to 4, or in some embodiments, from 1 to 3, or, in other embodiments, 1 or 2, heteroatoms, selected from nitrogen, oxygen or optionally oxidized sulfur as ring member(s), with the remaining ring atoms being carbon and wherein at least one ring is aromatic and at least one heteroatom is present in an aromatic ring.

[0178] When the total number of S and O atoms in the heteroaryl group exceeds 1, those heteroatoms are not adjacent to one another. In some embodiments, the total number of S and O atoms in the heteroaryl group is not more than 2. In some embodiments, the total number of S and O atoms in the aromatic heterocycle is not more than 1. When the heteroaryl group contains more than one heteroatom ring member, the heteroatoms may be the same or different. The nitrogen atoms in the ring(s) of the heteroaryl group can be oxidized to form N-oxides.

[0179] The term optionally oxidized sulfur used herein refers to S, SO or SO.sub.2.

[0180] The terms aromatic heterocyclic ring and heteroaryl are used interchangeably throughout the disclosure herein. In some embodiments, a monocyclic or bicyclic aromatic heterocyclic ring has 5-, 6-, 7-, 8-, 9- or 10-ring forming members with 1, 2, 3, or 4 heteroatom ring members independently selected from nitrogen (N), sulfur (S) and oxygen (O) and the remaining ring members being carbon. In some embodiments, the monocyclic or bicyclic aromatic heterocyclic ring is a monocyclic or bicyclic ring comprising 1 or 2 heteroatom ring members independently selected from nitrogen (N), sulfur (S) and oxygen (O). In some embodiments, the monocyclic or bicyclic aromatic heterocyclic ring is a 5- to 6-membered heteroaryl ring, which is monocyclic and which has 1 or 2 heteroatom ring members independently selected from nitrogen (N), sulfur (S) and oxygen (O). In some embodiments, the monocyclic or bicyclic aromatic heterocyclic ring is a 8- to 10-membered heteroaryl ring, which is bicyclic and which has 1 or 2 heteroatom ring members independently selected from nitrogen, sulfur and oxygen.

[0181] Examples of the heteroaryl group or the monocyclic or bicyclic aromatic heterocyclic ring include, but are not limited to, (as numbered from the linkage position assigned priority 1) pyridyl (such as 2-pyridyl, 3-pyridyl, or 4-pyridyl), cinnolinyl, pyrazinyl, 2,4-pyrimidinyl, 3,5-pyrimidinyl, 2,4-imidazolyl, imidazopyridinyl, isoxazolyl, oxazolyl, thiazolyl, isothiazolyl, thiadiazolyl (such as 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, or 1,3,4-thiadiazolyl), tetrazolyl, thienyl (such as thien-2-yl, thien-3-yl), triazinyl, benzothienyl, furyl or furanyl, benzofuryl, benzoimidazolyl, indolyl, isoindolyl, indolinyl, oxadiazolyl (such as 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, or 1,3,4-oxadiazolyl), phthalazinyl, pyrazinyl, pyridazinyl, pyrrolyl, triazolyl (such as 1,2,3-triazolyl, 1,2,4-triazolyl, or 1,3,4-triazolyl), quinolinyl, isoquinolinyl, pyrazolyl, pyrrolopyridinyl (such as 1H-pyrrolo[2,3-b]pyridin-5-yl), pyrazolopyridinyl (such as 1H-pyrazolo[3,4-b]pyridin-5-yl), benzoxazolyl (such as benzo[d]oxazol-6-yl), pteridinyl, purinyl, 1-oxa-2,3-diazolyl, 1-oxa-2,4-diazolyl, 1-oxa-2,5-diazolyl, 1-oxa-3,4-diazolyl, 1-thia-2,3-diazolyl, 1-thia-2,4-diazolyl, 1-thia-2,5-diazolyl, I-thia-3,4-diazolyl, furazanyl (such as furazan-2-yl, furazan-3-yl), benzofurazanyl, benzothiophenyl, benzothiazolyl, benzoxazolyl, quinazolinyl, quinoxalinyl, naphthyridinyl, furopyridinyl, benzothiazolyl (such as benzo[d]thiazol-6-yl), indazolyl (such as 1H-indazol-5-yl) and 5,6,7,8-tetrahydroisoquinoline.

[0182] Heterocyclyl, heterocycle or heterocyclic are interchangeable and refer to a non-aromatic heterocyclyl group comprising one or more heteroatoms selected from nitrogen, oxygen or optionally oxidized sulfur as ring members, with the remaining ring members being carbon, including monocyclic, fused, bridged, and spiro ring, i.e., containing monocyclic heterocyclyl, bridged heterocyclyl, spiro heterocyclyl, and fused heterocyclic groups.

[0183] Exemplary monocyclic 4 to 9-membered heterocyclyl groups include, but not limited to, (as numbered from the linkage position assigned priority 1) pyrrolidin-1-yl, pyrrolidin-2-yl, pyrrolidin-3-yl, imidazolidin-2-yl, imidazolidin-4-yl, pyrazolidin-2-yl, pyrazolidin-3-yl, piperidin-1-yl, piperidin-2-yl, piperidin-3-yl, piperidin-4-yl, 2,5-piperazinyl, pyranyl, morpholinyl, morpholino, morpholin-2-yl, morpholin-3-yl, oxiranyl, aziridin-1-yl, aziridin-2-yl, azocan-1-yl, azocan-2-yl, azocan-3-yl, azocan-4-yl, azocan-5-yl, thiiranyl, azetidin-1-yl, azetidin-2-yl, azetidin-3-yl, oxetanyl, thietanyl, 1,2-dithietanyl, 1,3-dithietanyl, dihydropyridinyl, tetrahydropyridinyl, thiomorpholinyl, thioxanyl, piperazinyl, homopiperazinyl, homopiperidinyl, azepan-1-yl, azepan-2-yl, azepan-3-yl, azepan-4-yl, oxepanyl, thiepanyl, 1,4-oxathianyl, 1,4-dioxepanyl, 1,4-oxathiepanyl, 1,4-oxaazepanyl, 1,4-dithiepanyl, 1,4-thiazepanyl and 1,4-diazepanyl, 1,4-dithianyl, 1,4-azathianyl, oxazepinyl, diazepinyl, thiazepinyl, dihydrothienyl, dihydropyranyl, dihydrofuranyl, tetrahydrofuranyl, tetrahydrothienyl, tetrahydropyranyl, tetrahydrothiopyranyl, 1-pyrrolinyl, 2-pyrrolinyl, 3-pyrrolinyl, indolinyl, 2H-pyranyl, 4H-pyranyl, 1,4-dioxanyl, 1,3-dioxolanyl, pyrazolinyl, pyrazolidinyl, dithianyl, dithiolanyl, pyrazolidinyl, imidazolinyl, pyrimidinonyl, or 1,1-dioxo-thiomorpholinyl.

[0184] Compounds disclosed herein may contain an asymmetric center and may thus exist as enantiomers. Enantiomers refer to two stereoisomers of a compound which are non-superimposable mirror images of one another. Where the compounds disclosed herein possess two or more asymmetric centers, they may additionally exist as diastereomers. Enantiomers and diastereomers fall within the broader class of stereoisomers. All such possible stereoisomers as substantially pure resolved enantiomers, racemic mixtures thereof, as well as mixtures of diastereomers are intended to be included. All stereoisomers of the compounds disclosed herein and/or pharmaceutically acceptable salts thereof are intended to be included. Unless specifically mentioned otherwise, reference to one isomer applies to any of the possible isomers. Whenever the isomeric composition is unspecified, all possible isomers are included.

[0185] When compounds disclosed herein contain olefinic double bonds, unless specified otherwise, such double bonds are meant to include both E and Z geometric isomers.

[0186] When compounds disclosed herein contain a di-substituted cyclohexyl or cyclobutyl group, substituents found on cyclohexyl or cyclobutyl ring may adopt cis and trans formations. Cis formation means that both substituents are found on the upper side of the 2 substituent placements on the carbon, while trans would mean that they were on opposing sides.

[0187] It may be advantageous to separate reaction products from one another and/or from starting materials. The desired products of each step or series of steps is separated and/or purified (hereinafter separated) to the desired degree of homogeneity by the techniques common in the art. Typically such separations involve multiphase extraction, crystallization from a solvent or solvent mixture, distillation, sublimation, or chromatography. Chromatography can involve any number of methods including, for example: reverse-phase and normal phase; size exclusion; ion exchange; high, medium and low pressure liquid chromatography methods and apparatus; small scale analytical; simulated moving bed (SMB) and preparative thin or thick layer chromatography, as well as techniques of small scale thin layer and flash chromatography. One skilled in the art will apply techniques most likely to achieve the desired separation.

[0188] Diastereomers refers to stereoisomers of a compound with two or more chiral centers but which are not mirror images of one another. Diastereomeric mixtures can be separated into their individual diastereomers on the basis of their physical chemical differences by methods well known to those skilled in the art, such as by chromatography and/or fractional crystallization. Enantiomers can be separated by converting the enantiomeric mixture into a diastereomeric mixture by reaction with an appropriate optically active compound (e.g., chiral auxiliary such as a chiral alcohol or Mosher's acid chloride), separating the diastereomers and converting (e.g., hydrolyzing) the individual diastereoisomers to the corresponding pure enantiomers. Enantiomers can also be separated by use of a chiral HPLC column.

[0189] A single stereoisomer, e.g., a substantially pure enantiomer, may be obtained by resolution of the racemic mixture using a method such as formation of diastereomers using optically active resolving agents [Eliel, E. and Wilen, S. Stereochemistry of Organic Compounds. New York: John Wiley & Sons, Inc. 1994; Lochmuller, C. H, et al. Chromatographic resolution of enantiomers: Selective review. J. Chromatogr., 113(3) (1975): pp. 283-302]. Racemic mixtures of chiral compounds of the invention can be separated and isolated by any suitable method, including: (1) formation of ionic, diastereomeric salts with chiral compounds and separation by fractional crystallization or other methods, (2) formation of diastereomeric compounds with chiral derivatizing reagents, separation of the diastereomers, and conversion to the pure stereoisomers, and (3) separation of the substantially pure or enriched stereoisomers directly under chiral conditions. See: Wainer, Irving W, Ed. Drug Stereochemistry: Analytical Methods and Pharmacology. New York: Marcel Dekker, Inc., 1993.

[0190] Pharmaceutically acceptable salts refers to those salts which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response and the like, and are commensurate with a reasonable benefit/risk ratio. A pharmaceutically acceptable salt may be prepared in situ during the final isolation and purification of the compounds disclosed herein, or separately by reacting the free base function with a suitable organic acid or by reacting the acidic group with a suitable base.

[0191] In addition, if a compound disclosed herein is obtained as an acid addition salt, the free base can be obtained by basifying a solution of the acid salt. Conversely, if the product is a free base, an addition salt, such as a pharmaceutically acceptable addition salt, may be produced by dissolving the free base in a suitable organic solvent and treating the solution with an acid, in accordance with conventional procedures for preparing acid addition salts from base compounds. Those skilled in the art will recognize various synthetic methodologies that may be used without undue experimentation to prepare non-toxic pharmaceutically acceptable addition salts.

[0192] As defined herein, a pharmaceutically acceptable salt thereof includes salts of at least one compound of Formula (I), and salts of the stereoisomers of the compound of Formula (I), such as salts of enantiomers, and/or salts of diastereomers.

[0193] The terms administration, administering, treating and treatment herein, when applied to an animal, human, experimental subject, cell, tissue, organ, or biological fluid, mean contact of an exogenous pharmaceutical, therapeutic, diagnostic agent, or composition to the animal, human, subject, cell, tissue, organ, or biological fluid. Treatment of a cell encompasses contact of a reagent to the cell, as well as the contact of a reagent to a fluid, where the fluid is in contact with the cell. The term administration and treatment also means in vitro and ex vivo treatments, e.g., of a cell, by a reagent, diagnostic, binding compound, or by another cell. The term subject herein includes any organism, preferably an animal, more preferably a mammal (e.g., rat, mouse, dog, cat, rabbit) and most preferably a human.

[0194] The term effective amount or therapeutically effective amount refers to an amount of the active ingredient, such as a compound that, when administered to a subject for treating a disease, or at least one of the clinical symptoms of a disease or disorder, is sufficient to affect such treatment for the disease, disorder, or symptom. The therapeutically effective amount can vary with the compound, the disease, disorder, and/or symptoms of the disease or disorder, severity of the disease, disorder, and/or symptoms of the disease or disorder, the age of the subject to be treated, and/or the weight of the subject to be treated. An appropriate amount in any given instance can be apparent to those skilled in the art or can be determined by routine experiments. In some embodiments, therapeutically effective amount is an amount of at least one compound and/or at least one stereoisomer thereof, and/or at least one pharmaceutically acceptable salt thereof disclosed herein effective to treat as defined above, a disease or disorder in a subject. In the case of combination therapy, the therapeutically effective amount refers to the total amount of the combination objects for the effective treatment of a disease, a disorder or a condition.

[0195] Throughout this specification and the claims which follow, unless the context requires otherwise, the term comprise, and variations such as comprises and comprising are intended to specify the presence of the features thereafter, but do not exclude the presence or addition of one or more other features. When used herein the term comprising can be substituted with the term containing, including or sometimes having.

[0196] Throughout this specification and the claims which follow, the term Cn-m indicates a range which includes the endpoints, wherein n and m are integers and indicate the number of carbons. Examples include C.sub.1-8, C.sub.1-6, and the like.

[0197] The expression unsubstituted or substituted with, e.g., unsubstituted or substituted with R.sub.d refers to that such a group is unsubstituted or substituted with at least one substituents, e.g., R.sub.d. With reference to substituted with . . . , e.g., substituted with R.sub.d, if without designating the number of substituents, it usually refers to a group substituted with at least one substituents, e.g., selected from R.sub.d, for example, 1 to 4, 1 to 3, 1 or 2, or 1 substituent, provided that the valency theory is met.

[0198] The expression selectivity of FTO inhibition over COMT inhibition refers to the extent of inhibition of a compound against FTO over ag COMT. Therefore, improved selectivity of FTO inhibition over COMT inhibition refers to a compound which shows a stronger FTO inhibitory activity than COMT inhibitory activity. It is desirable for a compound of the instant invention to show a comparable or improved FTO inhibition and show no observable COMT inhibition.

EXAMPLES

[0199] Reagents and solvents were obtained from commercial sources such as Sigma-Aldrich, Alfa, Sinopharm Chemical Reagent Co. (SCRC) or other, unless explicitly indicated otherwise.

[0200] As used herein, the symbols and conventions used in these processes, schemes, and examples, regardless of whether a particular abbreviation is specifically defined, are consistent with those used in the contemporary scientific literature, for example, the Journal of the American Chemical Society or the Journal of Biological Chemistry.

[0201] Specifically, but without limitation, the following abbreviations may be used in the Examples and throughout the specification:

TABLE-US-00001 aq. aqueous (Boc).sub.2O Di-tert-butyl dicarbonate calcd calculated CD3OD Methanol-d CO Carbon monoxide Conc. concentrated DCE Dichloroethane DCM Dichloromethane DIAD Diisopropyl azodicarboxylate DIEA N,N-Diisopropylethylamine DMF N,N-Dimethylformamide DMSO Dimethyl sulfoxide Et3N Triethylamine EtOAc Ethyl acetate or EA EtOH Ethanol h hour HATU 2-(7-Azabenzotriazol-1-yl)-N,N,N,N-tetramethyluronium hexafluorophosphate KOAc Potassium acetate LiHMDS Lithium bis(trimethylsilyl)amide MeCN Acetonitrile MeNH.sub.2 Methylamine min minute NBS N-Bromosuccinimide Pd(dppf)Cl.sub.2 [1,1- Bis(diphenylphosphino)ferrocene]dichloropalladium(II) Pd(PPh.sub.3).sub.4 Tetrakis(triphenylphosphine)palladium Pd/C Palladium on Carbon PE Petroleum ether PPh3 Triphenylphosphine rt room temperature T3P Propylphosphonic anhydride TFA Trifluoroacetic acid THF Tetrahydrofuran TsOH P-toluenesulfonic acid HOAc Acetic acid HNO3 Nitric acid

[0202] The following example, either for intermediates or for the final compounds, are for illustration only.

[0203] However, the invention shall not be construed thereto.

Intermediate B-1: 3-chloro-4-hydroxy-5-nitrobenzoic acid

##STR00003##

[0204] To a solution of 3-chloro-4-hydroxybenzoic acid (20 g, 116.28 mmol) in HOAc (100 mL), HNO.sub.3 (10 mL) was added dropwise at 0 C. for 30 min. The mixture was stirred at rt for 1 h. The reaction was quenched with ice water (200 mL) The precipitation was filtered, the cake was washed with water, The yellow solid was collected and dried to afford the desired product (16 g, yield: 64%). MS [MH].sup. calcd for C7H4ClNO5 216.6, found 216.6

Intermediate B-2: 3-fluoro-4-hydroxy-5-nitrobenzoic acid

##STR00004##

[0205] HNO.sub.3 (10 mL) was added to a solution of 1-ethyl-1H-imidazole (1 g, 6.41 mmol) in of HOAc (10 ml) at 0 C. for 15 min in a 250 ml flask. Then the solution was warmed to rt and stirred for 5 h. The reaction quenched with ice-water. The precipitation was filtered and dried to afford 3-fluoro-4-hydroxy-5-nitrobenzoic acid (720 mg, yield: 56%) as a yellow solid. MS [MH].sup. calcd for C7H4FNO5 200 found 200.

Intermediate B-3: 4-hydroxy-2-methoxy-5-nitrobenzoic acid

##STR00005##

[0206] To a solution of 4-hydroxy-2-methoxybenzoic acid (1 g, 6.0 mmol) in HOAc (20 mL), HNO.sub.3 (0.5 mL) was added dropwise at 0 T for 30 min. The mixture was stirred at rt for 1 h. The reaction was quenched with ice water (20 mL). The precipitation was filtered, and the cake was washed with water. The yellow solid was collected and dried to afford the desired product (1.0 g, yield: 81.2%) MS [MH].sup. calcd for C.sub.8H.sub.7NO.sub.6 211.9, found 211.9

Intermediate B-4: 4-hydroxy-3-methoxy-5-nitrobenzoic acid

##STR00006##

Step1: Synthesis of methyl 4-hydroxy-3-methoxy-5-nitrobenzoate (2)

[0207] To a solution of methyl 4-hydroxy-3-methoxybenzoate (1.0 g, 5.49 mmol) in HOAc (10 mL), HNO.sub.3 (0.5 mL) was added dropwise at 0 C. for 30 min. The mixture was stirred at rt for 1 h. The reaction was quenched with ice water (10 mL). The precipitation was filtered, and the cake was washed with water. The yellow solid was collected and dried to afford the desired product (900 mg, 72.3%) MS [MH].sup. calcd for C.sub.9H.sub.9NO.sub.6 225.9, found 225.9.

Step2: Synthesis of 4-hydroxy-3-methoxy-5-nitrobenzoic acid (B-4)

[0208] To a mixture of methyl 4-hydroxy-3-methoxy-5-nitrobenzoate (900 mg, 3.96 mmol) in MeOH/H.sub.2O (10 mL/5 mL) was added NaOH (633 mg, 15.84 mmol). The reaction was stirred at 70 C. overnight. The mixture was cooled to rt and subsequently acidified to pH 3-4 with HCl aqueous. The precipitation was filtered. The cake was collected and dried to obtain the desired product (700 mg, 83.0%). MS [MH].sup. calcd for C.sub.8H.sub.7NO.sub.6 211.9, found 211.9.

Intermediate B-5: 4-hydroxy-3-methyl-5-nitrobenzoic acid

##STR00007##

[0209] To a solution of 4-hydroxy-3-methylbenzoic acid (3 g, 19.7 mmol) in HOAc (30 mL), HNO.sub.3 (1.6 g) was added dropwise at 0 C. for 30 min. The mixture was stirred at rt for 1 h. The reaction was quenched with ice water (30 mL). The precipitation was filtered, and the cake was washed with water. The yellow solid was collected and dried to afford the desired product (2 g, 51.5%) MS [MH].sup. calcd for C8H.sub.7NO5 196.1, found 196.1.

Intermediate B-6: 3-bromo-4-hydroxy-5-methoxybenzoic acid

##STR00008##

Step1: 4-hydroxy-3-methoxybenzoic acid (2)

[0210] To a mixture of methyl 4-hydroxy-3-methoxybenzoate (900 mg, 4.94 mmol) in MeOH/H.sub.2O (20 mL/10 mL) was added NaOH (989 mg, 24.72 mmol). The reaction was stirred at 70 C. overnight. The mixture was cooled to rt and subsequently acidified to pH 3-4 with HCl aqueous. The precipitation was filtered. The cake was collected and dried to obtain the desired product (750 mg, 90.4%). MS [MH].sup. calcd for C8H8O4 167.1, found 167.1.

Step2: Synthesis of 3-bromo-4-hydroxy-5-methoxybenzoic acid (B-6)

[0211] To a solution of 4-hydroxy-3-methoxybenzoic acid (650 mg, 3.87 mmol) in DMF (10 mL) NBS (1.38 g, 7.74 mmol) was added at 0 C. The mixture was stirred at rt for 60 min. The mixture was quenched with ice, extracted with EA (50 mL*3). The organic phase was combined and dried over anhydrous Na.sub.2SO.sub.4, concentrated in vacuo. The residue was purified by silica gel chromatography (PE/EA=1/7) to obtain the product (450 mg, 47.1%). MS [MH].sup. calcd for C8H7BrO4 246.5, found 246.5

Intermediate B-7: 3-cyano-4-hydroxy-5-methoxybenzoic acid

##STR00009##

[0212] To a solution of 3-bromo-4-hydroxy-5-methoxybenzoic acid (400 mg, 1.62 mmol) in DMF (10 mL) CuCN (173.0 mg, 1.94 mmol) was added at 0 C. The mixture was heated to 150 C. and stirred overnight at the temperature. The mixture was quenched by ice, extracted with EA (50 mL*3). The organic phases were combined and dried over anhydrous Na.sub.2SO.sub.4, concentrated in vacuo. The residue was purified by silica gel chromatography (PE/EA=1/7) to obtain the product (300 mg, 96.1%). MS [MH].sup. calcd for C9H7NO4 192.1, found 192.1.

Intermediate B-8: 3,5-dicyano-4-hydroxybenzoic acid

##STR00010##

Step1: Synthesis of methyl 3,5-dicyano-4-hydroxybenzoate (2)

[0213] A solution of methyl 4-hydroxy-3,5-diiodobenzoate (800.0 mg, 1.98 mmol), CuCN (193.8 mg, 2.18 mmol) in DMF (10 mL) was stirred at 150 C. for 8 h. Then the reaction was quenched with water (20 mL). The mixture was extracted with ethyl acetate (100 mL3) The extraction was dried over anhydrous Na.sub.2SO.sub.4 and filtered. The filtrate was concentrated in vacuo to afford the crude product. Further purification by column chromatography (silica gel, PE/EA=3/2) afforded the desired product (350.0 mg, 87.5%). MS [M+H].sup.+ calcd for C10H6N203 203.2, found 203.2.

Step2: Synthesis of 3,5-dicyano-4-hydroxybenzoic acid (B-8)

[0214] A solution of methyl 3,5-dicyano-4-hydroxybenzoat (350.0 mg, 1.73 mmol), LiOH (207.6 mg, 8.65 mmol) in THF/H.sub.2O (10 ml/2 mL) was stirred at room temperature for 5 h. 1 N HCl (5 mL) and water (20 mL) were added to the mixture. The mixture was extracted with ethyl acetate (100 mL3). and the extraction was dried over anhydrous Na.sub.2SO.sub.4, filtered. The filtrate was concentrated in vacuo to afford the crude product. Further purification by column chromatography (silica gel, PE/EA=3/2) afforded the desired product (120.0 mg, 36.9%). MS [MH].sup. calcd for C9H4N203 187.1, found 187.1.

Intermediate B-9: 3-cyano-4-hydroxybenzoic acid

##STR00011##

Step1: Synthesis of methyl 3-cyano-4-hydroxybenzoate (2)

[0215] CuCN (360 mg, 4.0 mmol) was added to a solution of methyl 4-hydroxy-3-iodobenzoate (556 mg, 2.0 mmol) in DMF (10 mL). The mixture was stirred at 150 C. overnight. The mixture was cooled to room temperature. The reaction was quenched with water, and extracted with EA. The extraction was dried over anhydrous Na.sub.2SO.sub.4, filtered. The filtrate was concentrated in vacuo Further purification by prep-TLC to afford solid as the desired product. (305 mg, crude). MS [MH].sup. calcd for C.sub.9H.sub.7NO.sub.3 176.0, found 176.0.

Step2: Synthesis of 3-cyano-4-hydroxybenzoic acid (B-9)

[0216] To a solution of methyl 3-cyano-4-hydroxybenzoate (177 mg, 1.0 mmol) in THF/H.sub.2O (10 mL/10 mL) was added NaOH (160 mg, 4.0 mmol). The reaction was stirred at RT for 6 h. The mixture was acidified to pH 5-6 with conc. HCl, extracted with DCM (150 mL*3) The extractions were dried over anhydrous Na.sub.2SO.sub.4, and concentrated in vacuo. The residue was purified by silica gel chromatography (DCM/McOH=20/1) to obtain the product (155 mg, 95.0%). MS [MH].sup. calcd for C.sub.8H.sub.5NO.sub.3 161.9, found 161.9

Intermediate B-10:3-cyano-4-hydroxy-5-methylbenzoic acid

##STR00012##

Step1: Synthesis of methyl 3-bromo-4-hydroxy-5-methylbenzoate (2)

[0217] NBS (1.9 g, 10.84 mmol) was added to a solution of methyl 4-hydroxy-3-methylbenzoate (900 mg, 5.42 mmol) in DMF (10 mL). The mixture was stirred at rt for 2 h. The reaction was quenched with water (20 mL). The mixture was extracted with ethyl acetate (100 mL3) The extractions were combined, dried over anhydrous Na.sub.2SO.sub.4, filtered. The filtrate was concentrated in vacuo to afford the crude product. Further purification by column chromatography (silica gel, PE/EA=1/1) afforded the desired product (1 g, 75.7%). MS [M+H].sup.+ calcd for C9H9BrO3 246.1, found 246.1.

Step2: Synthesis of methyl 3-cyano-4-hydr-oxy-5-methylbenzoate (3)

[0218] CuCN (399.6 mg, 4.49 mmol) was added to a solution of methyl 3-bromo-4-hydroxy-5-methylbenzoate (1 g, 4.08 mmol) in DMF (20 mL). The mixture was heated to 150 C. and stirred overnight. The mixture was cooled to room temperature. Water and EA were added to the mixture extracted with EA, removed in vacuo Further purification by prep-TLC to afford solid as the desired product. (300.0 mg, crude). MS [M+H].sup.+ calcd for C10H9NO3 192.1, found 192.1.

Step3: Synthesis of 3-cyano-4-hydroxy-5-methylbenzoic acid (B-10)

[0219] To a solution of methyl 3-cyano-4-hydroxy-5-methylbenzoate (300 mg, 1.57 mol) in THF/H.sub.2O (10 mL/2 mL) was added NaOH (314.1 mg, 7.85 mol). The reaction was stirred at 70 C. overnight. 1 N HCl (15 mL) and water (30 mL) were added. The mixture was extracted with ethyl acetate (20 mL3) The extractions were combined, dried over anhydrous Na.sub.2SO.sub.4, filtered. The filtrate was concentrated in vacuo to afford the crude product. Further purification by column chromatography (silica gel, PE/EA=1/5) afforded the desired product (200 mg, 71.9%). MS [MH].sup. calcd for C9H7NO3 176.4, found 176.4.

Intermediate B-11:3-chloro-5-fluoro-4-hydroxybenzoic acid

##STR00013##

[0220] To a of 3-fluoro-4-hydroxybenzoic acid (500 mg, 3.2 mmol) in chloroform (50 mL), sulfuryl chloride (1.1 g, 8.0 mmol) was added. The reactor was degassed with nitrogen. The mixture was stirred at 70 C. overnight under nitrogen atmosphere. The reaction was quenched with water (20 ML), extracted with DCM (150 mL*3), The extractions were combined, dried over anhydrous Na.sub.2SO.sub.4 and filtrated. The filtrate was concentrated in vacuo. The residue was purified by silica get chromatography (PE/EA=2/3) to obtain the product (413 mg, 68%). MS [MH].sup. calcd for C.sub.7H.sub.4ClFO.sub.3 189.0, found 189.0

Intermediate B-12: 3-chloro-5-cyano-4-hydroxybenzoic acid

##STR00014##

Step1: Synthesis of methyl 3-chloro-5-cyano-4-hydroxybenzoate (2)

[0221] N-chlorosuccinimide (2.26 g, 16.9 mmol) was added to a mixture of 3-cyano-4-hydroxybenzoate (3.0 g, 16.9 mmol) in DMF (30 mL) was stirred at 0 C. Then the solution was stirred at rt for 60 min. The mixture was quenched with ice, extracted with EA (50 mL*3). The combined extraction was dried over anhydrous Na.sub.2SO.sub.4, then filtered. The filtrate was concentrated in vacuo to dryness. The residue was purified by silica gel chromatography (PE/EA=1/6) to obtain the product (2.9 g, 81.0%). MS [M+H].sup.+ calcd for C9H6ClNO3 212.6, found 212.6.

Step2: Synthesis of 3-chloro-5-cyano-4-hydroxybenzoic acid (B-12)

[0222] To a mixture of 3-chloro-5-cyano-4-hydroxybenzoate (2.9 g, 13.74 mmol) in MeOH/H.sub.2O (20 mL/10 mL) was added NaOH (550 mg, 13.74 mmol) at room temperature. The reaction was stirred at 70T overnight. The mixture was cooled to rt and acidified to pH 3-4 with conc. HCl, the precipitation was filtered and dried to obtain the desired product (2.3 g, 84.9%). MS [MH].sup. calcd for C8H4ClNO3 196.6, found 196.6

Intermediate B-13: 3-bromo-4-hydroxy-5-nitrobenzoic acid

##STR00015##

[0223] NBS (486 mg, 2.73 mmol) was added to a solution of 4-hydroxy-3-nitrobenzoic acid (500 mg, 2.73 mmol) in DCM (4 mL)/HOAc (4 mL)/sulfuric acid (0.08 mL). The mixture was stirred at room temperature overnight, then warmed to 60 C. and stirred for 4 h. The solution was concentrated in vacuo, diluted with water (15 mL). The precipitation was filtered and dried to afford the desired product (450 mg, 63%). MS [MH].sup.+ calcd for C7H4BrNO5 262, found 262

Intermediate B-14:3-fluoro-4-methoxy-5-(trifluoromethyl) benzoic acid

##STR00016##

Step1: Synthesis of methyl 3-fluoro-4-methoxy-5-(trifluoromethyl) benzoate (2)

[0224] A solution of 5-bromo-1-fluoro-2-methoxy-3-(trifluoromethyl) benzene (5 g, 18.3 mmol), Pd(dppf)Cl.sub.2 (1.5 g, 1.8 mmol) and Et.sub.3N (5.5 g, 54.9 mmol) in MeOH (60 mL) was stirred under CO at 120 C. for 16 h.

[0225] The solvent was removed in vacuo to afford crude product. Further purification by column chromatography (silica gel, PE/EA=5/1) afforded the desired product (3.2 g, 69%). MS [MH].sup.+ calcd for C.sub.10H.sub.8F.sub.4O.sub.3 253.0, found 253.0.

Step2: Synthesis of 3-fluoro-4-methoxy-5-(trifluoromethyl) benzoic acid (B-14)

[0226] NaOH (1.5 g, 13.53 mmol) was added to a solution of methyl 3-fluoro-4-methoxy-5-(trifluoromethyl) benzoate (3.2 g, 12.7 mmol) in water (20 mL) and THF (20 mL). The mixture was stirred at room temperature overnight. The reaction was diluted with 1 N HCl (15 mL). The mixture was filtered, and the cake was dried to afford the crude product (1.4 g, 46%). MS [MH].sup. calcd for C.sub.9H.sub.6F.sub.4O.sub.3 237.0, found 237.0

Intermediate B-15: Synthesis of 3-cyano-5-fluoro-4-hydroxybenzoic acid

##STR00017##

Step1: Synthesis of 5-bromo-3-fluoro-2-hydroxybenzonitrile (2)

[0227] NBS (1.33 g, 7.45 mmol) was added to a solution of 3-fluoro-2-hydroxybenzonitrile (1.021 g, 7.45 mmol) in anhydrous MeCN (20 mL). The mixture was stirred at room temperature for 2 h. The solvent was removed in vacuo. NaHCO.sub.3 aq., and ether were added to the residue. Aqueous phase was adjusted pH to 2, extracted with ether, The extraction was concentrated in vacuo afforded the desired product (1.67 g, crude). MS [MH].sup. calcd for C.sub.7H.sub.3BrFNO 214.0, found 214.0.

Step2: Synthesis of methyl 3-cyano-5-fluoro-4-hydroxybenzoate (3)

[0228] A solution of 5-bromo-3-fluoro-2-hydroxybenzonitrile (1.586 g, 7.34 mmol), Pd(dppt)Cl.sub.2 (600 mg, 0.73 mmol) and Et.sub.3N (2.303 g, 22.76 mmol) in MeOH (20 mL) was stirred under CO at 120 C. for 16 h. The solvent was removed in vacuo to afford crude product. Further purification by column chromatography (silica gel, PE/EA=5/1) afforded the desired product (880 mg, 61%). MS [MH].sup. calcd for C.sub.9H.sub.6FNO.sub.3 194.0, found 194.0.

Step3: Synthesis of 3-cyano-5-fluoro-4-hydroxybenzoic acid (B-15)

[0229] NaOH (541 mg, 13.53 mmol) was added to a solution of methyl 3-cyano-5-fluoro-4-hydroxybenzoate (880 mg, 4.51 mmol) in water (10 mL) and THF (10 mL). The mixture was stirred at room temperature overnight. The reaction was diluted by 1 N HCl (15 mL). The mixture was filtered. The solid was dried to afford solid as the crude product (750 mg, crude). MS [MH].sup. calcd for C.sub.8H.sub.4FNO.sub.3 180.0, found 180.0

Intermediate B-16: 3,4-dimethoxy-5-nitrobenzoic acid

##STR00018##

Step1: Synthesis of methyl 3,4-dimethoxy-5-nitrobenzoate (2)

[0230] To a mixture of methyl 4-hydroxy-3-methoxy-5-nitrobenzoate (10.0 g, 44.1 mmol) in acetone (150 mL) was added dimethyl sulfate (8.3 g, 66.1 mmol) and K.sub.2CO.sub.3 (9.1 g, 66.1 mmol). The mixture was warmed to 65 C., stirred at this temperature overnight. The reaction was cooled and quenched with ice water (50 mL), extracted by EA (200 mL*3). The combined extraction was dried over anhydrous Na.sub.2SO.sub.4, filtered. The filtrate was concentrated in vacuo to dryness. The residue was purified by silica gel chromatography (PE/EA=2/1) to obtain the product (5.0 g, 47%). MS [MH].sup.+ calcd for C.sub.10H.sub.11NO.sub.6 242.1, found 242.1.

Step2: Synthesis of 3,4-dimethoxy-5-nitrobenzoic acid (B-16)

[0231] A mixture of methyl 3,4-dimethoxy-5-nitrobenzoate (5.0 g, 20.7 mmol) in THF/H.sub.2O (30 mL/30 mL) was added LiOH (2.6 g, 62.2 mmol). The reaction was stirred at RT for 6 h. The mixture was acidified to pH about 5-6 by HCl extracted by DCM (150 mL*3), dried by Na.sub.2SO.sub.4 to obtain the product (3.0 g, 65.0%). MS [MH].sup. calcd for C9H9NO6 226.0, found 226.0

Intermediate B-17: 4-hydroxy-3-methoxy-5-(trifluoromethyl)benzoic acid

##STR00019##

Step1: Synthesis of 2-methoxy-6-(trifluoromethyl)phenol (2)

[0232] N-butyllithium (102 mL, 255.5 mmol) and N,N,N,N-Tetramethylethylenediamine (45 mL, 298 mmol) were added to anhydrous THF (250 mL) at 78 C. 1-Methoxy-3-(trifluoromethyl)benzene (50 g, 285 mmol) was added dropwise. The reaction mixture was stirred at 78C for 15 min then allowed to warm to RT and stirred for 10 min. The reaction mixture was cooled to 78 C. and trimethyl borate (80.5 mL, 710 mmol) was added dropwise slowly, the reaction mixture was stirred at 78 C. for 15 min then allowed to warm to RT and stirred for 20 h. 7N NH.sub.3/MeOH (100 mL) was added and the solvent was removed in vacuo. The residue was dissolved in formic acid (100 mL) and the mixture cooled to 0C before hydrogen peroxide (30 mL, 342.5 mmol) was added. The solution was allowed to warm to RT and stirred for 2 h. The product was extracted with EtOAc (3250 mL), and then the combined organics were shaken with NaOH (2250 mL). The aqueous phase was acidified with 1 M HCl and the product was extracted with DCM (2150 mL). The organic layer was washed with brine (2150 mL), dried over MgSO.sub.4 and filtered. The solvent was removed in vacuo and the residue was purified by silica gel chromatography (silica gel, PE/EA=2/1) to afford 2-methoxy-6-(trifluoromethyl)phenol (2) (38 g, 70%) as a colorless oil. MS [MH].sup. calcd for C8H7F3O2 191.0, found 191.0.

Step2: Synthesis of 4-hydroxy-3-methoxy-5-(trifluoromethyl)benzaldehyde (3)

[0233] A mixture of 2-methoxy-6-(trifluoromethyl)phenol (36 g, 187.2 mmol) and hexamethylenetetramine (25.92 g, 43.2 mmol) in TFA (300 mL) was stirred under reflux for 3 h. The solvent was removed in vacuo and the residue was dissolved in 1 M HCl (280 mL). The product was extracted with DCM (3250 mL), the combined organic phase was washed with brine (2250 mL) Then the solvent was removed in vacuo. The residue was purified by silica gel chromatography (silica gel, PE/EA=1/1) to afford 4-hydroxy-3-methoxy-5-(trifluoromethyl)benzaldehyde (3) (18 g, 43%) as a white solid. MS [M+H].sup.+ calcd for C9H7F3O3 221.1, found 221.1.

Step3: Synthesis of 4-hydroxy-3-methoxy-5-(trifluoromethyl)benzoic acid (B-17)

[0234] A suspension of 4-hydroxy-3-methoxy-5-(trifluoromethyl)benzaldehyde (18 g, 81.76 mmol) and Oxone (60 g, 98.11 mmol) in DMF (300 mL) was stirred at RT for 2 h. The reaction mixture was diluted with EtOAc (600 mL) and the solution was washed sequentially with 1 M HCl (600 mL) and brine (4600 mL). The solvent was removed in vacuo and the residue was purified by silica gel chromatography (silica gel, MeOH/DCM=1/15) to afford 4-hydroxy-3-methoxy-5-(trifluoromethyl)benzoic acid (8 g, 41%) as a white solid. MS [MH].sup.+ calcd for C9H7F3O4 235.0, found 235.0.

Intermediate B-18:5-chloro-2-fluoro-4-hydroxybenzoic acid

##STR00020##

[0235] NaOH (294.1 mg, 7.35 mmol) was added to a solution of methyl 5-chloro-2-fluoro-4-hydroxybenzoate (300.0 mg, 1.47 mmol) in water (10 mL) and THF (10 mL). The mixture was stirred at 70 C. overnight. The reaction mixture was acidified with 1 N HCl (15 mL). The mixture was extracted with DCM (100 mL3) The combined extraction was dried over anhydrous Na.sub.2SO.sub.4, filtered. The filtrate was concentrated in vacuo to afford the crude product. Further purification by column chromatography (silica gel, PE/EA=1/5) afforded the desired product (250.0 mg, 89.6%). MS [MH].sup.+ calcd for C7H4ClFO3 189.2, found 189.2.

Intermediate B-19: 4-hydroxy-3-methoxy-5-(methylsulfonyl)benzoic acid

##STR00021##

Step1: Synthesis of methyl 3-bromo-4-hydroxy-5-methoxybenzoate (2)

[0236] To a mixture of methyl 4-hydroxy-3-methoxybenzoate (3 g, 16.5 mmol) and TsOH (2.8 g, 16.5 mmol) in MeCN (100 mL). NBS (2.9 g, 16.5 mmol) was added. The mixture was stirred at room temperature for 8 h. The reaction mixture was concentrated in vacuo. The residue was purified by silica gel chromatography (DCM/MeOH=30/1) to obtain the product (2.6 g, 60%). MS [MH].sup.+ calcd for C.sub.9H.sub.9BrO.sub.4 258.9, found 258.9.

Step2: Synthesis of methyl 4-hydroxy-3-methoxy-5-(methylsulfonyl) benzoate (3)

[0237] L-Valine (540 mg, 4.6 mmol) and CuI (440 mg, 2.3 mmol) were added to a mixture of methyl 3-bromo-4-hydroxy-5-methoxybenzoate (2 g, 7.7 mmol) and methane sulfinic acid sodium (6.3 g, 61.3 mmol) in DMSO (60 mL). The solution was stirred at 110 C. for 16 h. The reaction was quenched with ice water (100 mL). The mixture was extracted with DCM (200 mL*3). The combined extraction was dried over anhydrous Na.sub.2SO.sub.4, filtered. The filtrate was concentrated in vacuo to dryness. The residue was purified by silica gel chromatography (DCM/MeOH=30/1) to obtain the product (700 mg, 35%). MS [MH].sup. calcd for C.sub.10H.sub.12O.sub.6S 258.9, found 258.9.

Step3: Synthesis of 4-hydroxy-3-methoxy-5-(methylsulfonyl)benzoic acid (B-19)

[0238] To a mixture of 4-hydroxy-3-methoxy-5-(methylsulfonyl) benzoate (700 mg, 2.7 mmol) in MeOH/H.sub.2O (20 mL/10 mL) was added NaOH (430.5 mg, 10.8 mmol). The reaction was stirred at 70 C. overnight. The mixture was cooled to rt and acidified to pH 5-6 with 1N HCl. The precipitation was filtered and dried to obtain the desired product (569.6 mg, 86%). MS [MH].sup. calcd for C.sub.9H.sub.10O.sub.6S 245.0, found 245.0

Intermediate B-20: 4-methoxy-3-(methylsulfonyl) benzoic acid

##STR00022##

Step1: Synthesis of (2-methoxy-5-(methoxycarbonyl) phenyl) boronic acid (2)

[0239] A mixture of methyl 3-bromo-4-methoxybenzoate (3 g, 12.2 mmol), boric acid (911 mg, 14.7 mmol), Pd(dppf)Cl.sub.2 (993 mg, 1.2 mmol) and KOAc (2.4 g, 24.4 mmol) in dioxane (100 mL) was stirred for 8 h at 100 C. under nitrogen. The reaction was quenched with water (20 ML), extracted by DCM (150 mL*3). The combined extraction was dried over anhydrous Na.sub.2SO.sub.4, evaporated in vacuo. The residue was purified by silica gel chromatography (DCM/MeOH=30/1) to obtain the product (1.7 g, 68%). MS [MH].sup. calcd for C.sub.9H.sub.11BO.sub.5 208.9, found 208.9.

Step2: Synthesis of methyl 4-methoxy-3-(methylsulfonyl) benzoate (3)

[0240] K.sub.2CO.sub.3 (1.1 g, 8.1 mmol) and Cu(OAc).sub.2 (486 mg, 2.4 mmol) were added to a mixture of (2-methoxy-5-(methoxycarbonyl) phenyl) boronic acid (1.7 g, 8.1 mmol) and methane sulfinic acid sodium (6.6 g, 64.8 mmol) in DMSO (60 mL). The mixture was stirred at 110 C. for 16 h. The reaction was quenched with ice water (100 mL), extracted with DCM (200 mL*3). The combined extraction was dried over anhydrous Na.sub.2SO.sub.4, filtered. The filtrate was concentrated in vacuo to dryness. The residue was purified by silica gel chromatography (DCM/MeOH=50/1) to obtain the product (691 mg, 35%). MS [MH].sup.+ calcd for C.sub.10H.sub.12O.sub.5S 242.9, found 242.9.

Step3: Synthesis of 4-methoxy-3-(methylsulfonyl) benzoic acid (B-20)

[0241] A mixture of methyl 4-methoxy-3-(methylsulfonyl) benzoate (690 mg, 2.8 mmol) in MeOH/H.sub.2O (20 mL/10 mL) was added NaOH (452 mg, 11.3 mmol). The reaction was stirred at 70C overnight. The mixture was cooled to rt and acidified to pH 5-6 with 1N HCl. The precipitation was filtered and dried to obtain the desired product (559 mg, 86%). MS [MH].sup. calcd for C.sub.9H.sub.10O.sub.5S 229.0, found 229.0

Intermediate B-21: 3,4-dimethoxy-5-(methylsulfonyl) benzoic acid

##STR00023##

Step1: Synthesis of 3-bromo-4,5-dimethoxybenzoic acid (2)

[0242] Methyl 3-bromo-4,5-dimethoxybenzaldehyde (10 g, 40.8 mmol) was added into 6% KMnO.sub.4 aq (20 mL) at 0 C. The mixture was stirred for 8 h at 0 C. Additional water (20 mL) was added. The mixture was extracted with DCM (150 mL*3). The combined extraction was dried over anhydrous Na.sub.2SO.sub.4, filtered. The filtrate was evaporated in vacuo. The residue was purified by silica gel chromatography (DCM/MeOH=30/1) to obtain the product (10.1 g, 95%). MS [MH].sup. calcd for C.sub.9H.sub.9BrO.sub.4 258.9, found 258.9.

Step2: Synthesis of methyl 3-bromo-4,5-dimethoxybenzoate (3)

[0243] A mixture of methyl 3-bromo-4,5-dimethoxybenzoic acid (10 g, 40.8 mmol) and sulfuric acid (one drop) in MeOH (20 mL) was stirred for 8 h at 70 C. The reaction was evaporated. The residue was washed with water (20 mL), extracted with DCM (150 mL*3). The combined extraction was dried over anhydrous Na.sub.2SO.sub.4, evaporated in vacuo. The residue was purified by silica gel chromatography (DCM/MeOH=30/1) to obtain the product (8.4 g, 80%). MS [MH].sup.+ calcd for C.sub.10H.sub.11BrO.sub.4 274.9, found 274.9.

Step3: Synthesis of methyl 3,4-dimethoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) benzoate (4)

[0244] A mixture of methyl 3-bromo-4-methoxybenzoate (8 g, 29.1 mmol), Bis(pinacolato)diboron (8.9 mg, 34.9 mmol), Pd(dppf)Cl.sub.2 (2.3 mg, 2.9 mmol) and KOAc (5.7 g, 58.2 mmol) in dioxane (200 mL) was stirred for 8 h at 100 C. The reaction mixture was washed with water (20 ML), extracted with DCM (150 mL*3).

[0245] The combined extraction was dried over anhydrous Na.sub.2SO.sub.4, evaporated in vacuo. The residue was purified by silica gel chromatography (DCM/MeOH=30/1) to obtain the product (4.5 g, 48%). MS [MH].sup.+ calcd for C.sub.16H.sub.23BO.sub.6 323.1, found 323.1.

Step4: Synthesis of methyl 3,4-dimethoxy-5-(methylsulfonyl) benzoate (5)

[0246] K.sub.2CO.sub.3 (642 mg, 4.7 mmol) and Cu(OAc).sub.2 (280 mg, 1.4 mmol) were added to a mixture of methyl 3,4-dimethoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) benzoate (1.5 g, 4.7 mmol) and methane sulfinic acid sodium (3.8 g, 37.3 mmol) in DMSO (60 mL). The mixture was stirred at 110 C. for 16 h. The reaction mixture was cooled to room temperature, washed with ice water (100 mL), and extracted with DCM (200 mL*3). The combined extraction was dried over anhydrous Na.sub.2SO.sub.4, filtered. The filtrate was concentrated in vacuo to dryness. The residue was purified by silica gel chromatography (DCM/MeOH=50/1) to obtain the product (213 mg, 25%). MS [MH].sup.+ calcd for C.sub.11H.sub.44OS 274.9, found 274.9.

Step5: Synthesis of 3,4-dimethoxy-5-(methylsulfonyl) benzoic acid (B-21)

[0247] A mixture of methyl 3,4-dimethoxy-5-(methylsulfonyl) benzoate (200 mg, 0.7 mmol) in MeOH/H.sub.2O (20 mL/10 mL) was added NaOH (117 mg, 2.9 mmol). The reaction was stirred at 70C overnight. The mixture was cooled to rt and acidified to pH 5-6 with 1N HCl. The precipitation was filtered and dried to obtain the desired product (152 mg, 80%). MS [MH].sup. calcd for C.sub.10H.sub.12O.sub.6S 259.0, found 259.0

Intermediate B-22: 4-hydroxy-3-nitro-5-(trifluoromethoxy)benzoic acid

##STR00024##

Step1: Synthesis of 4-hydroxy-3-(trifluoromethoxy)benzoic acid (2)

[0248] A mixture of 4-hydroxy-3-(trifluoromethoxy)benzaldehyde (1.0 g, 4.85 mmol) in acetone (10 mL) was stirred at 0 C. Jones reagent (0.25 mL, 2.5M/L) was added to the mixture and stirred at 0C for 10 mins. The reaction was stirred at rt for 1 h. The reaction was quenched by isopropanol, extracted with EA (20 mL*3), dried by Na2SO4, concentrated in vacuo. The residue was purified by Prep-HPLC (H2O/MeCN=20/80, 0.1% TFA, 2 times) to obtain the crude product (900 mg, 83.6%). MS [MH].sup. calcd for C8H5F3O4 221.1, found 221.1.

Step2: Synthesis of 4-hydroxy-3-nitro-5-(trifluoromethoxy)benzoic acid (B-22)

[0249] A mixture of 4-hydroxy-3-(trifluoromethoxy)benzaldehyde (400 mg, 1.80 mmol) in AcOH (10 mL) was stirred at 10 C. HNO3 (0.2 mL) was added to the mixture and stirred at 10C for 10 mins. The reaction was stirred at rt for 16 h. The reaction was quenched by ice water (20 ML), extracted with EA (20 mL*3), dried by Na2SO4, concentrated in vacuo. The residue was purified by Prep-HPLC (H2O/MeCN=40/60, 0.1% TFA, 2 times) to obtain the crude product (150 mg, 30.9%). MS [MH].sup. calcd for C8H4F3NO6 266.0, found 266.0

Intermediate B-23: 3-(difluoromethoxy)-4-hydroxy-5-nitrobenzoic acid

##STR00025##

Step1: Synthesis of methyl 4-(benzyloxy)-3-(difluoromethoxy) benzoate (2)

[0250] To a solution of methyl 4-(benzyloxy)-3-hydroxybenzoate (2 g, 7.75 mmol) and sodium 2-bromo-2,2-difluoroacetate (2.9 g, 19.38 mmol) in DMF (20 mL) was added K2CO3 (1.3 g, 9.3 mmol). After stirring at 70 C. for 16 h. The reaction mixture was diluted with water (50 mL), extracted with EA (50 mL3). The combined organic phases were washed with brine (30 mL3), dried by anhydrous Na2SO4, and concentrated in vacuo to give a residue which was purified by silica gel chromatography (PE/EA=2/1) to obtain the product (1 g, 42%). MS [MH].sup.+ calcd for C16H14F2O4 309.2, found 309.2.

Step2: Synthesis of methyl 3-(difluoromethoxy)-4-hydroxybenzoate (3)

[0251] A solution of methyl 4-(benzyloxy)-3-(difluoromethoxy) benzoate (1 g, 3.25 mmol) and Pd/C (300 mg) in MeOH (30 mL) was stirred under H2 at rt for 3 h. The reaction solution is removed Pd/C by filtration and removed in vacuo to afford crude product. Further purification by column chromatography (silica gel, PE/EA 1/1) afforded the desired product (650 mg, 92%). MS [MH].sup.+ calcd for C9H8F2O4 219.2, found 219.2.

Step3: Synthesis of methyl 3-(difluoromethoxy)-4-hydroxy-5-nitrobenzoate (4)

[0252] To a solution of compound 3 (650 mg, 2.98 mmol) in AcOH (8 mL) was added HNO3 (282 mg, 4.47 mmol) at 0 C. After stirring at room temperature for 1 h. The reaction mixture was diluted with water (20 mL) and extracted by EA (100 mL3), dried by Na2SO4, concentrated in vacuo to dryness to afford the desired product (600 mg, 77%). MS [MH].sup.+ calcd for C9H7F2NO6 264.2, found 264.2.

Step4: Synthesis of 3-(difluoromethoxy)-4-hydroxy-5-nitrobenzoic acid (5)

[0253] To a solution of methyl 3-(difluoromethoxy)-4-hydroxy-5-nitrobenzoate (600 mg, 2.28 mmol) in THF/H2O (10/10 mL) was added LiOH (239.54 mg, 5.70 mmol) at 0 C. After addition, the reaction was warmed to RT and stirred for 2 h. The mixture was neutralized with hydrochloric acid, extracted by EA (100 mL3), dried by Na2SO4, concentrated in vacuo to dryness to afford the desired product (550 mg, 97%). MS [MH].sup.+ calcd for C8H5F2NO6 250.2, found 250.2.

[0254] Intermediate A serie amides were prepared by the general operations of synthesis of intermediates A-1 and A-2

##STR00026##

Intermediate A-1: 2-cyano-N,N-diethylacetamide (A-1)

##STR00027##

[0255] The mixture of diethylamine (1.0 g, 13.70 mmol) in DCM (20 mL) was added 2-cyanoacetic acid (1.28 g, 15.07 mmol), T.sub.3P (13.07 g, 20.55 mmol) and DIEA (5.3 g, 41.1 mmol). The reaction was stirred at rt for 16 h. The reaction mixture was washed with ice water (50 ML), extracted with EA (50 mL*3). The combined extraction was dried over anhydrous Na2SO4, concentrated in vacuo to dryness. The residue was purified by silica gel chromatography (PE/EA=3/1) to obtain the product (900 mg, 46.9%). MS [M+H].sup.+ calcd for C7H12N20 141.2, found 141.2.

Intermediate A-2: 2-cyano-N-methy-N-(2-phenoxyethyl)acetamide

##STR00028##

[0256] A solution of N-methyl-2-phenoxyethan-1-amine (1.51 g, 10.03 mmol), 2-cyanoacetic acid (853 mg, 10.03 mmol), HATU (2.59 g, 20.05 mmol) and DIEA (7.62 g, 20.05 mmol) in DCM (30 mL) was stirred at room temperature for 5 h, then the solution was washed with water (30 mL). The mixture was extracted with ethyl acetate (25 mL3). The combined extraction was dried over anhydrous Na2SO4, then filtered and concentrated in vacuo to afford the crude product. Further purification by column chromatography (silica gel, PE/EA=10/1) afforded the desired product (1.5 g, 68%). MS [MH].sup.+ calcd for C12H14N2O2 219, found 219.

[0257] By using the same procedures as in scheme 1 for preparing intermediate A-1 and A-2, substituting the appropriate amines, it may be obtained the corresponding intermediate A amides. Among of the amines those commercially unavailable need to be synthesized in the lab.

Synthesis of N-ethyl-3-(2-methoxyl)enyl)propan-1-amine

##STR00029##

Step1: Synthesis of N-ethyl-3-(2-methoxyphenyl)propanamide

[0258] The mixture of 3-(2-methoxyphenyl)propanoic acid (1.0 g, 5.56 mmol) in DCM (20 mL) was added ethamine (250 mg, 5.56 mmol), T.sub.3P (5.3 g, 8.34 mmol) and DIEA (2.15 g, 16.68 mmol). The reaction was stirred at rt for 16 ht. The reaction mixture was washed with ice water (50 ML), extracted with EA (50 mL*3). The combined extraction was dried over anhydrous Na2SO4, filtered and concentrated in vacuo to dryness. The residue was purified by silica gel chromatography (PE/EA=1/2) to obtain the product (1.0 g, 87.0%). MS [M+H].sup.+ calcd for C12H17NO2 208.2, found 208.2.

Step2: Synthesis of N-ethyl-3-(2-methoxyphenyl)propan-1-amine

[0259] The mixture of N-ethyl-3-(2-methoxyphenyl)propanamide (1.0 g, 4.83 mmol) in THF (30 mL) was added BH3-THF (9.66 mL) at 78 C. The reaction was stirred at rt for 2 h. The reaction was quenched with ice water (50 ML). The mixture was extracted with DCM (50 mL*3). The combined extraction was dried over anhydrous Na2SO4, filtered and concentrated in vacuo to dryness. The residue was purified by silica gel chromatography (PE/EA=1/5) to obtain the product (720 mg, 77.3%). MS [M+H].sup.+ calcd for C12H-19NO 194.3, found 194.3

Synthesis of 2-(3-(methylamino)propyl)benzonitrile

##STR00030##

[0260] Prepared as described for N-ethyl-3-(2-methoxyphenyl)propan-1-amine using 3-(2-cyanophenyl)propanoic acid in place of 3-(2-methoxyphenyl)propanoic acid. MS [M+H].sup.+ calcd for C11H14N2 175.2, found 175.2

Synthesis of 3-(2-chlorophenyl)-N-ethylpropan-1-amine

##STR00031##

[0261] Prepared as described for N-ethyl-3-(2-methoxyphenyl)propan-1-amine using 3-(2-chlorophenyl)propanoic acid in place of 3-(2-methoxyphenyl)propanoic acid. MS [MH].sup.+ calcd for C11H16ClN 198, found 198

Synthesis of 1-(3-fluoro-[1,1-biphenyl]-4-yl)-N-methylmethanamine

##STR00032##

Step1: Synthesis of 3-fluoro-[1,1-biphenyl]-4-carbaldehyde

[0262] A solution of (3-fluoro-4-formylphenyl)boronic acid (1 g, 5.95 mmol), bromobenzene (928 mg, 5.95 mmol), Na.sub.2CO.sub.3 (946 mg, 8.93 mmol) and Pd(PPh.sub.3).sub.4 (347 mg, 0.30 mmol) in water (5 mL), THF (5 mL) and 1,2-Dimethoxyethane (10 mL) was stirred at 90 C. for 16 h, The solution was washed with water (20 mL). The mixture was extracted with ethyl acetate (20 mL3). The combined extraction was dried over anhydrous Na.sub.2SO.sub.4, then filtered and concentrated in vacuo to afford the crude product. Further purification by column chromatography (silica gel, PE/EA=10/1) afforded the desired product (900 mg, 75.6%). MS [M+H].sup.+ calcd for C13H9FO 201.2, found 201.2.

Step2: Synthesis of 1-(3-fluoro-[1,1-biphenyl]-4-yl)-N-methylmethanamine

[0263] NaBH(OAc).sub.3 (1.07 g, 5.03 mmol) was added to a solution of 3-fluoro-[1,1-biphenyl]-4-carbaldehyde (900 mg, 4.19 mmol) and Methylamine (4.19 mL, 8.38 mmol) in DCE (10 mL). The mixture was stirred at room temperature for 5 h, then the solution was quenched with 1N NaOH (10 mL). The mixture was extracted with DCM (30 mL3) The combined extraction was dried over anhydrous Na.sub.2SO.sub.4, then filtered and concentrated in vacuo to afford the crude product. Further purification by column chromatography (silica gel, PE/EA=5/1) afforded the desired product (800 mg, 88.9%). MS [M+H].sup.+ calcd for C14H14FN 216.3, found 216.3

Synthesis of 1-(4-fluoro-[1,1-biphenyl]-3-yl)-N-methylmethanamine

##STR00033##

[0264] Prepared as described for 1-(3-fluoro-[1,1-biphenyl]-4-yl)-N-methylmethanamine using (4-fluoro-3-formylphenyl)boronic acid in place of (3-fluoro-4-formylphenyl)boronic acid MS [MH].sup.+ calcd for C14H14FN 216, found 216

Synthesis of 1-(2-fluoro-4-(pyridin-3-yl)phenyl)-N-methylmethanamine

##STR00034##

[0265] Prepared as described for 1-(3-fluoro-[1,1-biphenyl]-4-yl)-N-methylmethanamine using 3-bromopyridine in place of bromobenzene. MS [MH].sup.+ calcd for C14H14FN 216, found 216MS [M+H].sup.+ calcd for C13H13FN2 217.3, found 217.3

Synthesis of 1-(2-fluoro-5-(pyrimidin-4-yl) phenyl)-N-methylmethanamine

##STR00035##

[0266] Prepared as described for 1-(4-fluoro-[1,1-biphenyl]-3-yl)-N-methylmethanamine using 4-chloropyrimidine in place of bromobenzene. MS [MH].sup.+ calcd for C.sub.12H.sub.12FN.sub.3 217.9, found 217.9.

Synthesis of 2-methyl-6-((methylamino)methyl)phenol

##STR00036##

[0267] NaBH(OAc).sub.3 (1.87 g, 8.82 mmol) was added to a solution of 2-hydroxy-3-methylbenzaldehyde (g, 7.35 mmol) and Methylamine (7.35 mL, 14.7 mmol) in DCE (20 mL) was stirred at room temperature for 5 h, then the solution was washed with 1N NaOH (20 mL). The mixture was extracted with DCM (20 mL3) The combined extraction was dried over anhydrous Na.sub.2SO.sub.4, then filtered and concentrated in vacuo to afford the crude product. Further purification by column chromatography (silica gel, PE/EA=6/1) afforded the desired product (1.0 g, 90.1%). MS [M+H].sup.+ calcd for C9H13NO 152.2, found 152.2.

[0268] The following analogous amines were synthesized in a similar manner starting from corresponding aldehydes or ketones, characterized.

TABLE-US-00002 Aldehyde(or ketone) Amine Analysis 2-methoxybenzaldehyde 1-(2-methoxyphenyl)-N- MS [MH].sup.+ calcd for C9H13NO methylmethanamine 152, found 152 2-fluoro-5-methylbenzaldehyde 1-(2-fluoro-5-methylphenyl)-N- MS [M + H].sup.+ calcd for C9H12FN methylmethanamine 154.1, found 154.1 2-fluoro-3-methylbenzaldehyde 1-(2-fluoro-5-methylphenyl)-N- [MH].sup.+ calcd for C9H12FN 154, methylmethanamine found 154 2-fluoro-4-methylbenzaldehyde 1-(2-fluoro-4-methylphenyl)-N- MS [MH].sup.+ calcd for C9H12FN methylmethanamine 154, found 154 2-fluoro-5- 1-(2-fluoro-5-(trifluoromethyl)phenyl)- MS [M + H].sup.+ calcd for C9H9F4N (trifluoromethyl)benzaldehyde N-methylmethanamine 208.2, found 208.2 5-chloro-2-fluorobenzaldehyde 1-(5-chloro-2-fluorophenyl)-N- MS [M + H].sup.+ calcd for C.sub.8H.sub.9ClFN methylmethanamine 174.1, found 174.1 5-chloro-2-fluorobenzaldehyde N-(5-chloro-2-fluorobenzyl)ethanamine MS [M + H].sup.+ calcd for C.sub.9H.sub.11ClFN 188.1, found 188.1 2,6-difluorobenzaldehyde 1-(2,6-difluorophenyl)-N- MS [M + H].sup.+ calcd for C7H4F2O methylmethanamine 158.1, found 158.1 2,4-difluorobenzaldehyde 1-(3-chloro-2-fluorophenyl)-N- MS [M + H].sup.+ calcd for C8H9ClFN methylmethanamine 174.4, found 174.4 2,5-difluorobenzaldehyde 1-(2,5-difluorophenyl)-N- MS [M + H].sup.+ calcd for C8H9F2N methylmethanamine 158.3, found 158.3. 2-fluoro-4-methoxybenzaldehyde 1-(2-fluoro-4-methoxyphenyl)-N- MS [M + H].sup.+ calcd for methylmethanamine C9H12FNO 170.2, found 170.2 1-(5-chloro-2-fluorophenyl)ethan- 1-(5-chloro-2-fluorophenyl)-N- MS [M + H].sup.+ calcd for 1-one methylethan-1-amine C9H11ClFN 188.2, found 188.2 2-fluoro-5-methoxybenzaldehyde 1-(2-fluoro-5-methoxyphenyl)-N- MS [M + H].sup.+ calcd for methylmethanamine C9H12FNO 170.4, found 170.4 2,4,5-trifluorobenzaldehyde N-methyl-1-(2,4,5-trifluorophenyl) MS [M + H].sup.+ calcd for C8H8F3N methanamine 176.1, found 176.1 2,4-difluorobenzaldehyde 1-(2,4-difluorophenyl)-N- MS [M + H].sup.+ calcd for C8H9F2N methylmethanamine 158.1, found 158.1. 4-fluoro-3-formylbenzonitrile 4-fluoro-3-((methylamino)methyl) MS [M + H].sup.+ calcd for C.sub.9H.sub.9FN.sub.2 benzonitrile 165.1, found 165.1

Synthesis of 1-(7-fluoroisoquinolin-6-yl)-N-methylmethanamine

##STR00037##

Step1: Synthesis of 7-fluoroisoquinoline-6-carbonitrile

[0269] CuCN (6.0 g, 66.4 mmol) was added to a solution of 6-bromo-7-fluoroisoquinoline (10 g, 44.2 mmol) in DMF (100 mL). The mixture was stirred at 150 C. overnight. The reaction mixture was washed with water, extracted with EA. The solvent of the combined extraction was removed in vacuo Further purification by prep-TLC to afford solid as the desired product. (7.4 g, 97%). MS [MH].sup.+ calcd for C.sub.10H.sub.5FN.sub.3 173.0, found 173.0.

Step2: Synthesis of tert-butyl ((7-fluoroisoquinolin-6-yl) methyl) carbamate

[0270] A mixture of 7-fluoroisoquinoline-6-carbonitrile (7.4 g, 43.0 mmol), (Boc).sub.20 (18.7 g, 86.0 mmol), NiCl.Math.6H.sub.2O (1.0 g, 4.3 mmol), NaBH.sub.4 (11.4 g, 301.0 mmol) in MeOH (100 mL) was stirred overnight at 25 C. The reaction was quenched with water (20 mL), The mixture was extracted with DCM (150 mL*3). The combined extraction was dried over anhydrous Na.sub.2SO.sub.4, filtered and evaporated in vacuo. The residue was purified by silica gel chromatography (DCM/MeOH=30/1) to obtain the product (1.9 g, 16%). MS [MH].sup.+ calcd for C.sub.15H.sub.17FN.sub.2O.sub.2 276.9, found 276.9.

Step3: Synthesis of tert-butyl ((7-fluoroisoquinolin-6-yl) methyl) (methyl)carbamate

[0271] NaH (0.3 g, 13.0 mmol) was added to a mixture of tert-butyl ((7-fluoroisoquinolin-6-yl) methyl) carbamate (1.8 g, 6.5 mmol) in THF (50 mL) at 20 C. The mixture was stirred at 20 C. for 30 min under nitrogen atmosphere. Subsequently iodomethane (0.4 mL, 6.5 mmol) was added, the mixture was stirred overnight. The mixture was acidified to pH 5-6 with 1N HCl, extracted with DCM (200 mL*3). The combined extraction was dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated in vacuo The residue was purified by silica gel chromatography (DCM/MeOH=50/1) to obtain the product (1.8 g, 96%). MS [MH].sup.+ calcd for C.sub.16H.sub.19FN.sub.2O.sub.2 290.9, found 290.9.

Step4: Synthesis of 1-(7-fluoroisoquinolin-6-yl)-N-methylmethanamine

[0272] A mixture of tert-butyl ((7-fluoroisoquinolin-6-yl) methyl) (methyl)carbamate (1.8 g, 6.2 mmol) in dioxane (60 mL) was stirred at 0 C. Conc. HCl (a drop) was added. The mixture stirred for 16 h. The reaction was quenched with ice water (50 mL), The mixture was extracted with DCM (200 mL*3). The combined extraction was dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated in vacuo to dryness. The residue was purified by silica gel chromatography (DCM/MeOH=30/1) to obtain the product (500 mg, 45%). MS [MH].sup.+ calcd for C.sub.11H.sub.11FN.sub.2 190.9, found 190.9

Synthesis of 1-(2-fluoro-3,5-dimethylphenyl)-N-methylmethanamine

##STR00038##

Step1: Synthesis of 2-fluoro-3,5-dimethylbenzaldehyde

[0273] A solution of 1-bromo-2-fluoro-3,5-dimethylbenzene (2 g, 9.9 mmol) in THF (20 mL) was cooled to 78 C., then n-butyllithium (9.9 mL, 9.9 mmol) was added to the above solution. The mixture was stirred at 78 C. for 1 h. DMF (73 mg, 9.9 mmol) was added to the above solution. The mixture was stirred at 25 C. for 1 h. The reaction was quenched with 1 N HCl (2 mL) and water (15 mL). The mixture was extracted with ethyl acetate (30 mL3) The combined extraction was dried over anhydrous Na.sub.2SO.sub.4, then filtered and concentrated in vacuo to afford the crude product (1.2 g, 80%). MS [M+H].sup.+ calcd for C9H9FO 153.2, found 153.2.

Step2: Synthesis of 1-(2-fluoro-3,5-dimethylphenyl)-N-methylmethanamine

[0274] NaBH.sub.4(OAc).sub.3 (2.0 g, 9.47 mmol) was added to a solution of 2-fluoro-3,5-dimethylbenzaldehyde (1.2 g, 7.89 mmol) and Methylamine (7.89 mL, 15.78 mmol) in DCE (40 mL). The mixture was stirred at room temperature for 5 h, then the reaction was quenched with 1N NaOH (10 mL). The mixture was extracted with DCM (30 mL3) The combined extraction was dried over anhydrous Na.sub.2SO.sub.4, then filtered and concentrated in vacuo to afford the crude product. Further purification by column chromatography (silica gel, PE/EA=3/1) afforded the desired product (1.0 g, 75.8%). MS [M+H].sup.+ calcd for C10H14FN 168.2, found 168.2

Synthesis of 1-(2,4-difluoro-5-methylphenyl)-N-methylmethanamine

##STR00039##

[0275] Prepared as described for 1-(2-fluoro-3,5-dimethylphenyl)-N-methylmethanamine above using 1-bromo-2,4-difluoro-5-methylbenzene in place of 1-bromo-2-fluoro-3,5-dimethylbenzene. MS [M+H].sup.+ calcd for C9H11F2N 172.2, found 172.2

Synthesis of 1-(3-fluoro-6-methylpyridin-2-yl)-N-methylmethanamine

##STR00040##

[0276] Prepared as described for 1-(2-fluoro-3,5-dimethylphenyl)-N-methylmethanamine above using 2-bromo-3-fluoro-6-methylpyridine in place of 1-bromo-2-fluoro-3,5-dimethylbenzene. MS [M+H].sup.+ calcd for C8H11FN2 155.1, found 155.1.

Synthesis of 2-(2-chlorophenoxy)-N-ethylethan-1-amine

##STR00041##

Step1: Synthesis of tert-butyl (2-(2-chlorophenoxy) ethyl) carbamate

[0277] NaH (187.5 mg, 7.8 mmol) was added to a solution of 2-chlorophenol (1.0 g, 7.8 mmol) in anhydrous THF (25 mL) at 0 C. The mixture was stirred at 0 C. for 30 min. Tert-butyl (2-bromoethyl) carbamate (1.7 g, 7.8 mmol) was added dropwise. The reaction mixture was stirred at 0 C. for 15 min then allowed to warm to RT and stirred overnight. The reaction was quenched with water (30 mL) The mixture was extracted with EtOAc (200 mL3), The combined extraction was dried over Na.sub.2SO.sub.4, and filtered. The solvent was removed in vacuo to tert-butyl (2-(2-chlorophenoxy) ethyl) carbamate (1.1 g, 52%). MS [MH].sup.+ calcd for C.sub.13H.sub.18ClNO.sub.3 272.1, found 272.1.

Step2: Synthesis of tert-butyl (2-(2-chlorophenoxy) ethyl) (ethyl)carbamate

[0278] NaH (0.2 g, 8.1 mmol) was added to a mixture of tert-butyl (2-(2-chlorophenoxy) ethyl) carbamate (1.1 g, 4.1 mmol) in THF (50 mL) at 20 C. The solution was stirred at 20T for 30 min under N.sub.2 atmosphere. Subsequently iodoethane (0.6 g, 4.1 mmol) was added. The mixture was stirred at room temperature overnight. The mixture was acidified to pH 5-6 with 1N HCl, extracted with DCM (200 mL*3). The combined extraction was dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated in vacuo The residue was purified by silica gel chromatography (DCM/MeOH=50/1) to obtain the product (1.0 g, 83%). MS [MH].sup.+ calcd for C.sub.15H.sub.22ClNO.sub.3 299.9, found 299.9.

Step3: Synthesis of 2-(2-chlorophenoxy)-N-ethylethan-1-amine

[0279] A mixture of tert-butyl (2-(2-chlorophenoxy) ethyl) (ethyl)carbamate (900 mg, 3.0 mmol), and TFA (0.5 mL) in DCM (20 mL) was stirred overnight at 25 C. The reaction was evaporated to obtain the product (500 mg, 83%). MS [MH].sup. calcd for C.sub.10H.sub.14ClNO 199.9, found 199.9.

Synthesis of N-ethyl-2-(pyrimidin-2-yloxy)ethan-1-amine

##STR00042##

Step1: Synthesis of tert-butyl ethyl(2-(pyrimidin-2-yloxy)ethyl)carbamate (2)

[0280] NaH (194 mg, 4.86 mmol) was added to a solution of tert-butyl ethyl(2-hydroxyethyl)carbamate (1.1 g, 5.81 mmol) in anhydrous THF (15 mL) at 0 C. The mixture was stirred at 0 C. for 30 min. 2-chloropyrimidine (497 mg, 4.34 mmol) was added dropwise. The reaction mixture was stirred at 0 C. for 15 min then allowed to warm to RT and stirred overnight. The reaction was quenched with water (30 mL). The mixture was extracted with EtOAc (20 mL3). The combined extraction was dried over Na.sub.2SO.sub.4, and filtered. The solvent of the filtrate was removed in vacuo to afford tert-butyl ethyl(2-(pyrimidin-2-yloxy)ethyl)carbamate (1.6 g, crude). MS [MH].sup.+ calcd for C13H21N3O3 268, found 268.

Step2: Synthesis of N-ethyl-2-(pyrimidin-2-yloxy)ethan-1-amine (3)

[0281] A solution of tert-butyl ethyl(2-(pyrimidin-2-yloxy)ethyl)carbamate (1.6 g, 5.98 mmol) in HCl/dioxane (15 mL) was stirred at r.t for 3 h. The mixture was evaporated in vacuo to afford N-ethyl-2-(pyrimidin-2-yloxy)ethan-1-amine (1.1 g, crude) as a yellow solid. MS [MH].sup.+ calcd for C8H13N3O 168, found 168.

Synthesis of 3-(2-chlorophenyl)-N-methylprop-2-yn-1-amine

##STR00043##

[0282] To a mixture of N-methylprop-2-yn-1-amine (1 g, 14.5 mmol) in dioxane (40 mL) were added 1-chloro-2-iodobenzene (3.4 g, 14.5 mmol), PdCl.sub.2(PPh.sub.3).sub.2 (0.2 g, 0.3 mmol) and CuI (28 mg, 0.14 mmol). The reaction was stirred at 0 C. for 22 h. The reaction mixture was washed with ice water (30 ML), extracted with DCM (200 mL*3). The combined extraction was dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated in vacuo to dryness. The residue was purified by silica gel chromatography (PE/EA=1/3) to obtain the product (2.1 g, 80.6%). MS [M+H].sup. calcd for C.sub.10H.sub.10ClNO 180.1, found 180.1.

Synthesis of N-methylbut-2-yn-1-amine

##STR00044##

[0283] To a mixture of 1-bromobut-2-yne (1.0 g, 7.5 mmol) in MeOH (20 mL) was added Methylamine methanol (2.86 g, 15.0 mmol). The mixture was stirred for 16 h at 25 C. The reaction was quenched with ice water (30 ML). The mixture was acidified to pH 7-8 with Na.sub.2CO.sub.3 aqueous, extracted with EA (20 mL*3). The combined extraction was dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated in vacuo to dryness. The residue was purified by silica gel chromatography (DCM/MeOH=20/1) to obtain the product (500 mg, 80%). MS [M+H].sup.+ calcd for C.sub.5H9N 84.1, found 84.1.

Synthesis of N-methyl-2-phenylethan-1-amine

##STR00045##

[0284] A solution of (2-bromoethyl) benzene (2.5 g, 13.5 mmol) and MeNH.sub.2 (30 mL, 135.1 mmol) in EtOH (50 mL) was stirred at 80 C. for 16 h, then the solution was concentrated in vacuo The residue was dissolved in DCM (3 mL) and PE (30 mL). The mixture was filtered. The cake was collected and dried to afford the desired product (875 mg, 48%). MS [MH].sup.+ calcd for C.sub.9H.sub.13N 136.1, found 136.1

Synthesis of 2-(methylamino)-N-phenylacetamide

##STR00046##

[0285] Prepared as described for N-methyl-2-phenylethan-1-amine using 2-bromo-N-phenylacetamide above in place of (2-bromoethyl) benzene. MS [MH].sup.+ calcd for C.sub.9H.sub.12N20 165.1, found 165.1 Synthesis of N-methyl-1-(1-(pyridin-4-yl)-1H-1,2,3-triazol-4-yl)methanamine

##STR00047##

Step1: Synthesis of 4-azidopyridine

[0286] NaOH (1 M) was added to a solution of 4-bromopyridine (5.0 g, 25.71 mmol) in H.sub.2O (40 mL) to adjust pH to 6-7. EtOH (20 mL) and sodium azide (2.5 g, 38.57 mmol) were added. The mixture was stirred at 100 T overnight. The mixture was cooled to rt and acidified to pH 3-4 with 1N HCl The mixture was washed water, extracted with EA. The combined extraction was dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated in vacuo to dryness. The residue was purified by silica gel chromatography (PE/EA=2/1) to obtain the product (2.56 g, 82.9%). MS [M+H].sup.+ calcd for C5H4N4 121.1, found 121.1.

Step2: Synthesis of 1-(pyridin-4-yl)-1H-1,2,3-triazole-4-carbaldehyde

[0287] To a mixture of 4-azidopyridine (2.0 g, 16.65 mmol) in THF/H2O (20 mL/20 mL) were added 3,3-diethoxyprop-1-yne (2.1 mg, 16.65 mmol), CuSO4.Math.5H2O (4.2 g, 16.65 mmol) and sodium ascorbate (3.3 g, 16.65 mmol). Then the mixture was warmed to 55 C., stirred overnight. The reaction was quenched with ice water (20 mL). The mixture was extracted with DCM (20 mL*3). The combined extraction was dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated in vacuo to dryness. The residue was purified by silica gel chromatography (DCM/MeOH=20/1) to obtain the product (1.27 g, 43.9%). MS [M+H].sup.+ calcd for C8H6N40 175.1, found 175.1.

Step3: Synthesis of N-methyl-1-(1-(pyridin-4-yl)-1H-1,2,3-triazol-4-yl)methanamine

[0288] To a mixture of 1-(pyridin-4-yl)-1H-1,2,3-triazole-4-carbaldehyde (300 mg, 1.72 mmol) in MeOH (10 mL) were added Methylamine hydrochloride (116.1 mg, 1.72 mmol), NaBH.sub.3CN (108 mg, 1.72 mmol) and ZnCl.sub.2 (234 mg, 1.72 mmol), then the mixture was warmed to 50 C., stirred for 6 hours. The reaction was quenched with ice water (20 mL), The mixture was adjusted to pH 7-8 with Na.sub.2CO.sub.3 aqueous, extracted with EA (20 mL*3). The combined extraction was dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated in vacuo to dryness. The residue was purified by silica gel chromatography (DCM/MeOH=20/1) to obtain the product (250 mg, 76.9%). MS [M+H].sup.+ calcd for C9H11N5 190.1, found 190.1.

Synthesis of N-methyl-1-(1-methyl-1H-1,2,3-triazol-4-yl) methanamine

##STR00048##

[0289] Prepared as described for N-methyl-1-(1-methyl-1H-1,2,3-triazol-4-yl) methanamine using iodomethane in place of 4-bromopyridine. MS [MH].sup.+ calcd for C.sub.5H.sub.10N.sub.4 127.1, found 127.1.

[0290] Experimental procedures for compounds of the invention are provided below.

##STR00049##

Example 1: (Z)-3-(3-chloro-4-hydroxy-5-nitrophenyl)-2-cyano-N,N-diethyl-3-hydroxyacrylamide

##STR00050##

[0291] The mixture of 3-chloro-4-hydroxy-5-nitrobenzoic acid (100 mg, 0.46 mmol) in SOCl.sub.2 (10 mL) was heated to 80 C. for 2 hours. Then it was concentrated in vacuo to obtain an acyl chloride. A solution of 2-cyano-N,N-diethylacetamide (64.4 mg, 0.46 mmol) in THF (10 mL) was stirred at 0 C. for 10 min under N.sub.2 atmosphere, subsequently NaH (27.6 mg, 0.69 mmol) was added. The mixture was stirred for 1 hour. The acyl chloride was added to the reaction mixture. The solution was warmed to RT, and stirred overnight. The mixture was acidified to pH 3-4 with 1N HCl, extracted with DCM (30 mL*3). The combined extraction was dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated in vacuo. The residue was purified by Prep-HPLC (H2O/MeCN=1/1, 0.1% TFA) to obtain the product (20 mg, 12.8%). MS [M+H].sup.+ calcd for C14H14C1N3O5 338.1, found 337.8. .sup.1H NMR (400 MHz, DMSO-d.sub.6) 8.353 (s, 1H), 8.210 (s, 1H), 3.574 (s, 4H), 1.208 (s, 6H) Examples 2-4 were synthesized in a manner similar to those of Example 1 generally following Scheme 2 starting from the appropriate intermediates A.

TABLE-US-00003 Structure Name Analysis Ex. 2 [00051] (Z)-3-(3-chloro-4-hydroxy- 5-nitrophenyl)-2-cyano-3- hydroxy-N-methyl-N-(2- phenoxyethyl) acrylamide MS [M H].sup. calcd for C.sub.19H.sub.16ClN.sub.3O.sub.6 415.6, found 415.6..sup.1H NMR (400 MHz, DMSO-d.sub.6) 8.314 (s, 1H), 8.179(t, J = 2.4 Hz, 1H), 7.29 (t, J = 8.0 Hz, 2H), 6.944 (t, J = 8.0 Hz, 3H), 4.225(s, 2H), 3.925(s, 2H), 3.262(s, 3H) Ex. 3 [00052] (Z)-3-(3-chloro-4-hydroxy- 5-nitrophenyl)-2-cyano-3- hydroxy-N-methyl-N-(3- phenylpropyl)acrylamide MS [M H].sup.+ caled for C.sub.20H.sub.18ClN.sub.3O.sub.5 413.6, found 413.6. .sup.1H NMR (400 MHz, DMSO-d.sub.6) 8.33 (s, 1H), 8.18 (s, 1H), 7.16-7.28 (m, 5H), 3.55 (s, 2H), 3.16 (s, 3H), 2.51(s, 2H), 1.93(s, 2H) Ex. 4 [00053] (Z)-3-(3-chloro-4-hydroxy- 5-nitrophenyl)-2-cyano-N- (2-fluoro-4-(pyridin-3- yl)benzyl)-3-hydroxy-N- methylacrylamide [M H].sup. calcd for C.sub.23H.sub.16ClFN.sub.4O.sub.5 482.8, found 482.8..sup.1H NMR (400 MHz, DMSO-d.sub.6) 9.05 (s, 1H), 8.69 (s, 1H), 8.37 (s, 2H), 8.13 (s, 1H), 7.67-7.75 (m, 3H), 7.49 (s, 1H), 4.83 (s, 2H), 3.17 (s, 3H)

Example 5: (Z)-2-cyano-3-(3,4-dihydroxy-5-nitrophenyl)-3-hydroxy-N-methyl-N-(2-phenoxyethyl)acrylamide

##STR00054##

[0292] A solution of 3,4-dihydroxy-5-nitrobenzoic acid (155 mg, 0.78 mmol) in SOCl.sub.2 (10 mL) was stirred at 80 C. for 2 h, then it was concentrated in vacuo to get an acyl chloride. NaH (78 mg, 1.95 mmol) was added to a solution of 2-cyano-N-methyl-N-(2-phenoxyethyl)acetamide (170 mg, 0.78 mmol) in THF (15 mL) at 0 C. The solution was stirred for 1 h, then the acyl chloride was added. The mixture was stirred at 0 C. for 1 h, then at room temperature overnight. The reaction mixture was washed with 1 N HCl (5 mL) and water (15 mL). The mixture was extracted with ethyl acetate (20 mL3). The combined extraction was dried over anhydrous Na.sub.2SO.sub.4, then filtered and concentrated in vacuo to afford the crude. Further purification was performed by Prep-HPLC (0.05% TFA; ACNH2O) to afford (Z)-2-cyano-3-(3,4-dihydroxy-5-nitrophenyl)-3-hydroxy-N-methyl-N-(2-phenoxyethyl)acrylamide (25 mg, 8). 11 NMR (400 MHz, DMSO-d6) 10.84 (s, 1H), 7.83 (s, 1H), 7.47 (s, 1H), 7.29 (t, J=7.8 Hz, 2H), 6.95 (dd, J=13.2, 6.2 Hz, 3H), 4.22 (s, 2H), 3.92 (s, 2H), 3.25 (s, 311). MS [MH].sup. calcd for C19H17N3O7 397.7, found 397.7.

[0293] Examples 6-9 were synthesized in a manner similar to those of Example 5 generally following Scheme 2 starting from the appropriate intermediates B.

TABLE-US-00004 No. Structure Name Analysis Ex. 6 [00055] (Z)-2-cyano-3-(3-cyano-4- hydroxyphenyl)-3-hydroxy- N-methyl-N-(2- phenoxyethyl)acrylamide MS [M H] calcd for C20H17N3O4 362.1, found 361.7.1HNMR (400 MHz, DMSO- d.sub.6) 12.09(s, 1H), 8.08(s, 1H), 7.90 (d, J = 8.0 Hz,1H), 7.31-7.27 (m, 2H), 7.14 (s, 1H), 6.96-6.93 (m,3H), 4.22 (s, 2H), 3.92 (s, 2H), 3.25 (s, 3H). Ex. 7 [00056] (Z)-2-cyano-3-hydroxy-3-(4- hydroxy-3-methoxy-5- nitrophenyl)-N-methyl-N-(2- phenoxyethyl)acrylamide MS [M H] calcd for C20H19N3O7 412.1, found 411.6.1HNMR (400 MHz, DMSO- d.sub.6) 7.93(s, 1H), 7.63(s, 1H), 7.27(s, 2H), 6.97-6.92(m, 3H),4.23(s, 2H), 3.93(s, 5H),3.27(s, 3H) Ex. 8 [00057] (Z)-3-(3-chloro-5-cyano-4- hydroxyphenyl)-2-cyano-3- hydroxy-N-methyl-N-(2- phenoxyethyl)acrylamide MS [M H] calcd for C20H16ClN3O4 396.1, found 396.1. 1H NMR (400 MHz, DMSO-d.sub.6) 8.03 (s, 2H), 7.26 (s, 2H), 6.93-6.90 (m, 3H), 4.18 (s, 2H), 3.88 (s, 2H), 3.21 (s, 3H). Ex. 9 [00058] (Z)-2-cyano-3-(3-cyano-5- fluoro-4-hydroxyphenyl)-3- hydroxy-N-methyl-N-(2- phenoxyethyl)acrylamide MS [M H] calcd for C20H16FN3O4 379.7, found 379.7. 1HNMR (400 MHz, DMSO-d.sub.6) 7.88 (d, J = 12.0 Hz, 2H), 7.26-7.23 (m,2H), 6.93-6.89 (m, 3H), 4.18 (s, 2H), 3.87 (s, 2H), 3.21 (s, 3H).

[0294] The following compounds were synthesized in a manner similar to those of Examples 1 and 5 generally following Scheme 2 starting from the appropriate intermediates A or B.

TABLE-US-00005 No. Structure Name Analysis Ex. 10 [00059] (Z)-2-cyano-N,N-diethyl-3-hydroxy-3-(4- hydroxy-3-methoxy-5-nitrophenyl)acrylamide MS [M + H].sup.+ calcd for C.sub.15H.sub.17N.sub.3O.sub.6 336.1, found 335.9. .sup.1H NMR (400 MHz, DMSO-d6) 7.979 (s, 1H), 7.674 (s, 1H), 3.939 (s, 3H), 3.591 (d, J = 5.6 Hz, 4H), 1.216 (s, 6H) Ex. 11 [00060] (Z)-2-cyano-N-(2-fluoro-5- methylbenzyl)-3-hydroxy-3-(4-hydroxy- 3-methoxy-5-nitrophenyl)-N- methylacrylamide MS [M H].sup. calcd for C.sub.20H.sub.18FN.sub.3O.sub.6 414.1, Found 414.2. .sup.1HNMR (400 MHz, DMSO-d.sub.6) 7.87 (s, 1H), 7.23 (d, 1H), 7.07-6.97 (m, 3H), 4.50 (s, 2H), 3.66 (s, 3H), 2.83 (s, 3H), 2.27 (s, 3H) Ex. 12 [00061] (Z)-2-cyano-3-hydroxy-3-(4-hydroxy-3- methoxy-5-nitrophenyl)-N,N- dimethylacrylamide MS [M H].sup. calcd for C.sub.13H.sub.13N.sub.3O.sub.6 306.1, found 306.2. .sup.1HNMR (400 MHz, DMSO-d.sub.6) 7.96 (s, 1H), 7.64 (s, 1H), 3.90 (s, 3H), 3.13 (s, 6H) Ex. 13 [00062] (Z)-N-(5-chloro-2-fluorobenzyl)-2-cyano- 3-hydroxy-3-(4-hydroxy-3-methoxy-5- nitrophenyl)-N-methylacrylamide MS [M H].sup. calcd for C.sub.19H.sub.15ClFN.sub.3O.sub.6 434.0, found 433.7. .sup.1HNMR (400 MHz, DMSO-d.sub.6) 7.87 (s, 1H), 7.57 (s, 1H), 7.23 (t, J = 12.0 Hz, 1H), 7.19 (s, 1H), 6.94 (d, J = 4.0 Hz, 1H), 4.52 (s, 2H), 3.65 (s, 3H), 2.85 (s, 3H). Ex. 14 [00063] (Z)-2-cyano-N-(2,6-difluorobenzyl)-3- hydroxy-3-(4-hydroxy-3-methoxy-5- nitrophenyl)-N-methylacrylamide MS [M H].sup. calcd for C.sub.19H.sub.15F.sub.2N.sub.3O.sub.6 418.1, found 418.1. .sup.1HNMR (400 MHz, DMSO-d.sub.6) 7.96 (s, 1H), 7.40 (s, 1H), 7.38-6.97 (m, 3H), 4.70 (s, 2H), 3.84 (s, 3H), 2.96 (s, 3H). Ex. 15 [00064] (Z)-N-(3-chloro-2-fluorobenzyl)-2-cyano- 3-hydroxy-3-(4-hydroxy-3-methoxy-5- nitrophenyl)-N-methylacrylamide MS [M H].sup. calcd for C.sub.19H.sub.15ClFN.sub.3O.sub.6 434.1, found 434.1. .sup.1HNMR (400 MHz, DMSO-d.sub.6) 7.96 (s, 1H), 7.55 (m, 2H), 7.29 (m, 2H), 4.82 (s, 2H), 3.93 (s, 3H), 3.17 (s, 3H) Ex. 16 [00065] (Z)-2-cyano-N-(2,5-difluorobenzyl)-3- hydroxy-3-(4-hydroxy-3-methoxy-5- nitrophenyl)-N-methylacrylamide MS [M H].sup. calcd for C.sub.19H.sub.15F.sub.2N.sub.3O.sub.6 418.2, found 418.2. .sup.1HNMR (400 MHz, DMSO-d.sub.6) 8.00 (s, 1H), 7.64 (s, 1H), 7.30-7.10 (m, 3H), 4.75 (s, 2H), 3.93 (s, 3H), 3.16 (s, 3H) Ex. 17 [00066] (Z)-2-cyano-N-(2-fluoro-4- methoxybenzyl)-3-hydroxy-3-(4- hydroxy-3-methoxy-5-nitrophenyl)-N- methylacrylamide MS [M H].sup. calcd for C.sub.20H.sub.18FN.sub.3O.sub.7 430.6, found 430.6. .sup.1HNMR (400 MHz, DMSO-d.sub.6) 7.89 (s, 1H), 7.62 (s, 1H), 7.31 (s, 1H), 6.72-6.61 (m, 2H), 4.96 (s, 2H), 3.89 (s, 3H), 3.73 (s, 3H), 3.04 (s, 3H) Ex. 18 [00067] (Z)-N-(1-(5-chloro-2-fluorophenyl)ethyl)- 2-cyano-3-hydroxy-3-(4-hydroxy-3- methoxy-5-nitrophenyl)-N- methylacrylamide MS [M H].sup. calcd for C.sub.20H.sub.17ClFN.sub.3O.sub.6 448.5, found 448.5. .sup.1HNMR (400 MHz, DMSO-d.sub.6) 7.96 (s, 1H), 7.55-7.46 (m, 3H), 7.28 (s, 1H), 5.79 (s, 1H), 3.92 (s, 3H), 2.91 (s, 3H), 1.58 (s, 3H) Ex. 19 [00068] (Z)-2-cyano-N-(2-fluoro-5- methoxybenzyl)-3-hydroxy-3-(4- hydroxy-3-methoxy-5-nitrophenyl)-N- methylacrylamide MS [M H].sup. calcd for C.sub.20H.sub.18FN.sub.3O.sub.7 430.0, found 430.0. .sup.1HNMR (400 MHz, DMSO-d.sub.6) 7.92 (s, 1H), 7.62 (s, 1H), 7.11 (s, 1H), 6.85 (s, 2H), 4.70 (s, 2H), 3.90 (s, 3H), 3.69 (s, 3H), 3.11 (s, 3H) Ex. 20 [00069] (Z)-2-cyano-3-hydroxy-3-(4-hydroxy-3- methoxy-5-nitrophenyl)-N-methyl-N- (2,4,5-trifluorobenzyl)acrylamide MS [M H].sup. calcd for C.sub.19H.sub.14F.sub.3N.sub.3O.sub.6 436.1, found 436.1. .sup.1HNMR (400 MHz, DMSO-d.sub.6) 7.99 (s, 1H), 7.64 (s, 3H), 4.73 (s, 2H), 3.93 (s, 3H), 3.15 (s, 3H) Ex. 21 [00070] (Z)-2-cyano-N-(2,4-difluorobenzyl)-3- hydroxy-3-(4-hydroxy-3-methoxy-5- nitrophenyl)-N-methylacrylamide MS [M H].sup. calcd for C.sub.19H.sub.15F.sub.2N.sub.3O.sub.6 418.1, found 418.1. .sup.1HNMR (400 MHz, DMSO- d.sub.6) 7.95 (s, 1H), 7.42 (s, 2H), 7.29-7.09 (m, 2H), 4.74 (s, 2H), 3.99 (s, 3H), 3.14 (s, 3H) Ex. 22 [00071] (Z)-2-cyano-N-(2,4-difluoro-5- methylbenzyl)-3-hydroxy-3-(4-hydroxy- 3-methoxy-5-nitrophenyl)-N- methylacrylamide MS [M + H].sup.+ calcd for C.sub.20H.sub.17F.sub.2N.sub.3O.sub.6 434.1, found 434.1 .sup.1HNMR (400 MHz, CDCl3) 11.08 (s, 1H), 8.40 (d, J = 4.0 Hz, 1H), 7.72 (s, 1H), 7.17-7.15 (m, 1H), 6.87-6.85 (m, 1H), 4.92 (s, 2H), 4.01 (s, 3H), 3.25 (s, 3H), 2.26 (s, 3H) Ex. 23 [00072] (Z)-N-(2-(2-chlorophenoxy)ethyl)-2- cyano-3-hydroxy-3-(4-hydroxy-3- methoxy-5-nitrophenyl)-N- methylacrylamide MS [M H].sup. calcd for C.sub.20H.sub.18ClN.sub.3O.sub.7 446.1, found 446.1. .sup.1HNMR (400 MHz, DMSO-d.sub.6) 7.96 (s, 1H), 7.66 (s, 1H), 7.31 (s, 1H), 7.28 (s, 1H), 7.18 (s, 1H), 6.99-6.95 (m, 1H), 4.33 (s, 2H), 4.00 (s, 2H), 3.93 (s, 3H), 3.36 (s, 3H) Ex. 24 [00073] (Z)-2-cyano-3-hydroxy-3-(4-hydroxy-3- methoxy-5-nitrophenyl)-N-methyl-N-((1- methyl-2-oxo-1,2-dihydropyridin-3- yl)methyl)acrylamide MS [M H].sup. calcd for C19H18N4O7 413.1, found 413.1. .sup.1H NMR (400 MHz, DMSO-d.sub.6) 7.94 (d, J = 12.0 Hz, 1H), 7.64 (s, 2H), 7.28 (s, 1H), 6.21 (s, 1H), 4.69 (s, 2H), 3.89 (s, 3H), 3.45 (s, 3H), 3.13 (s, 3H) Ex. 25 [00074] (Z)-N-(5-chloro-2-fluorobenzyl)-2-cyano- N-ethyl-3-hydroxy-3-(4-hydroxy-3- methoxy-5-nitrophenyl)acrylamide MS [M H].sup. calcd for C.sub.20H.sub.17ClFN.sub.3O.sub.6 448.1, found 448.1. .sup.1HNMR (400 MHz, DMSO-d.sub.6) 7.93 (s, 1H), 7.62 (s, 1H), 7.42-7.30 (m, 3H), 4.76 (s, 2H), 3.93 (s, 3H), 3.59 (s, 2H), 1.23-1.17 (m, 3H) Ex. 26 [00075] (Z)-2-cyano-N-((3-fluoro-6- methylpyridin-2-yl)methyl)-3-hydroxy-3- (4-hydroxy-3-methoxy-5-nitrophenyl)-N- methylacrylamide MS [M H].sup. calcd for C.sub.19H.sub.17FN.sub.4O.sub.6 414.9, found 414.9. .sup.1HNMR (400 MHz, DMSO-d.sub.6) 7.92 (s, 1H), 7.54 (s, 1H), 7.24 (m, 1H), 7.23 (m, 1H), 4.89 (s, 2H), 3.93 (s, 3H), 3.24 (s, 3H), 2.44 (s, 3H). Ex. 27 [00076] (Z)-2-cyano-N-(2-fluoro-5- (methoxymethyl)benzyl)-3-hydroxy-3- (4-hydroxy-3-methoxy-5-nitrophenyl)-N- methylacrylamide MS [M H].sup. calcd for C.sub.21H.sub.20FN.sub.3O.sub.7 444.1, found 444.1. .sup.1HNMR (400 MHz, DMSO-d.sub.6) 7.93 (s, 1H), 7.62 (s, 1H), 7.27 (s, 1H), 7.18 (t, J = 8.0 Hz, 2H), 4.75 (s, 2H), 4.34 (s, 2H), 3.89 (s, 3H), 3.23 (s, 3H), 3.11 (s, 3H). Ex. 28 [00077] (Z)-2-cyano-N-cyclopropyl-3-hydroxy-3- (4-hydroxy-3-methoxy-5-nitrophenyl)-N- methylacrylamide MS [M H].sup. calcd for C.sub.15H.sub.15N.sub.3O.sub.6 332.1, found 332.1. .sup.1HNMR (400 MHz, DMSO-d.sub.6) 7.96 (d, J = 4.0 Hz, 1H), 7.62 (s, 1H), 3.91 (s, 3H), 3.00 (s, 3H), 2.46 (t, J = 4.0 Hz, 1H), 0.92 (s, 4H). Ex. 29 [00078] (Z)-N-(3-(2-chlorophenyl)prop-2-yn-1- yl)-2-cyano-3-hydroxy-3-(4-hydroxy-3- methoxy-5-nitrophenyl)-N- methylacrylamide MS [M H].sup. calcd for C.sub.21H.sub.16ClN.sub.3O.sub.6 440.1, found 440.1. .sup.1HNMR (400 MHz, DMSO-d.sub.6) 7.94 (s, 1H), 7.52 (d, J = 8.0 Hz, 3H), 7.31-7.41 (m, 2H), 4.62 (s, 2H), 3.89 (s, 3H), 3.25 (s, 3H) Ex. 30 [00079] (Z)-N-(but-2-yn-1-yl)-2-cyano-3- hydroxy-3-(4-hydroxy-3-methoxy-5- nitrophenyl)-N-methylacrylamide MS [M H].sup. calcd for C.sub.16H.sub.15N.sub.3O.sub.6 344.1, found 344.1. .sup.1HNMR (400 MHz, DMSO-d.sub.6) 7.98 (s, 1H), 7.67 (s, 1H), 4.29 (s, 2H), 3.94 (s, 3H), 3.20 (s, 3H), 1.82 (s, 3H) Ex. 31 [00080] (Z)-2-cyano-N,N-diethyl-3-(3-fluoro-4- hydroxy-5-nitrophenyl)-3- hydroxyacrylamide MS [MH].sup. calcd for C14H14F3N3O5 322, found 322. .sup.1H NMR (400 MHz, DMSO-d.sub.6) 8.234 (s, 1H), 8.045 (d, J = 10.4 Hz, 1H), 3.580 (s, 4H), 1.209 (s, 6H) Ex. 32 [00081] (Z)-2-cyano-3-(3-cyano-5-fluoro-4- hydroxyphenyl)-N,N-diethyl-3- hydroxyacrylamide MS [MH].sup.+ calcd for C15H14FN3O3 304.1, found 304.1. .sup.1H NMR (400 MHz, DMSO-d.sub.6) 7.99 (m, 2H), 3.58 (d, J = 5.8 Hz, 4H), 1.21 (s, 6H). Ex. 33 [00082] (Z)-2-cyano-N,N-diethyl-3-hydroxy-3-(4- hydroxy-3-nitrophenyl)acrylamide MS [MH].sup. calcd for C.sub.14H.sub.15N.sub.3O.sub.5 303.8, found 303.8. .sup.1HNMR (400 MHz, DMSO-d.sub.6) 11.97 (s, 1H), 8.37 (s, 1H), 8.00 (d, J = 8.0 Hz, 1H), 7.25 (d, J = 8.7 Hz, 1H), 3.58 (d, J = 6.7 Hz, 4H), 1.21 (t, J = 6.6 Hz, 6H) Ex. 34 [00083] (Z)-2-cyano-N,N-diethyl-3-hydroxy-3-(4- hydroxy-3-methyl-5- nitrophenyl)acrylamide MS [M + H]+ calcd for C.sub.15H.sub.17N.sub.3O.sub.5 320.1, found 319.8. .sup.1HNMR (400 MHz, DMSO-d.sub.6) 8.32 (s, 1H), 7.98 (s, 1H), 3.59 (s, 4H), 2.31 (s, 3H), 1.02-0.92 (m, 6H). Ex. 35 [00084] (Z)-2-cyano-N-ethyl-3-(3-fluoro-4- hydroxy-5-nitrophenyl)-3-hydroxy-N- methylacrylamide MS [MH] calcd for C.sub.13H.sub.12FN.sub.3O.sub.5 307.8, found 307.8. .sup.1H NMR (400 MHz, DMSO-d.sub.6) 8.24 (d, J = 7.8 Hz, 1H), 8.04 (d, J = 9.5 Hz, 1H), 3.57 (s, 2H), 3.15 (s, 3H), 1.21 (d, J = 17.9 Hz, 3H) Ex. 36 [00085] (Z)-3-(3-bromo-4-hydroxy-5- nitrophenyl)-2-cyano-N,N-diethyl-3- hydroxyacrylamide MS [MH] calcd for C.sub.14H.sub.14BrN.sub.3O.sub.5 381.5, 383.5, found 381.5. .sup.1HNMR (400 MHz, DMSO-d.sub.6) 8.38 (m, 2H), 3.57 (s, 4H), 1.21 (s, 6H) Ex. 37 [00086] (Z)-2-cyano-3-(3-cyano-4- hydroxyphenyl)-N,N-diethyl-3- hydroxyacrylamide MS [M H].sup.+ C.sub.15H.sub.15N.sub.3O.sub.3 285.8, found 285.8. .sup.1H NMR (400 MHz, DMSO-d.sub.6) 8.111 (s, 1H), 7.917 (s, 1H), 7.111 (s, 1H), 3.537 (s, 4H), 1.186 (s, 6H). Ex. 38 [00087] (Z)-3-(3-chloro-5-fluoro-4- hydroxyphenyl)-2-cyano-N,N-diethyl-3- hydroxyacrylamide MS [MH].sup. calcd for C.sub.14H.sub.14ClFN.sub.2O.sub.3 310.8, found 310.8. 1H NMR (400 MHz, DMSO-d.sub.6) 11.50 (s, 1H), 7.70 (m, 2H), 3.57 (d, J = 8.0 Hz, 4H), 1.20 (t, J = 8.0 Hz, 6H). Ex. 39 [00088] (Z)-2-cyano-3-(3-fluoro-4-hydroxy-5- nitrophenyl)-3-hydroxy-N-methyl-N-(3- phenylpropyl)acrylamide [M H].sup.+ calcd for C.sub.20H.sub.18FN.sub.3O.sub.5 397.7, found 397.7. .sup.1H NMR (400 MHz, DMSO-d.sub.6) 8.21 (s, 1H), 8.00 (d, J = 8.0 Hz, 1H), 7.16-7.28 (m, 5H), 3.55 (s, 2H), 3.16 (s, 3H), 2.51 (s, 2H), 1.93 (s, 2H) Ex. 40 [00089] (Z)-2-cyano-3-(3-cyano-5-fluoro-4- hydroxyphenyl)-N-ethyl-3-hydroxy-N- methylacrylamide MS [MH].sup. calcd for C.sub.14H.sub.12FN.sub.3O.sub.3 287.8, found 287.8. .sup.1H NMR (400 MHz, DMSO-d.sub.6) 8.037 (s, 1H), 7.984 (d, J = 4.4 Hz, 1H), 3.563 (s, 2H), 3.143 (s, 3H), 1.183 (s, 3H). Ex. 41 [00090] (Z)-3-(3-chloro-5-cyano-4- hydroxyphenyl)-2-cyano-N,N-diethyl-3- hydroxyacrylamide MS [MH].sup.+ calcd for C.sub.15H.sub.14ClN.sub.3O.sub.3 317.7, found. 317.7. .sup.1HNMR (400 MHz, DMSO-d.sub.6) 8.14 (s, 2H), 3.58 (d, J = 5.5 Hz, 4H), 1.21 (s, 6H). Ex. 42 [00091] (Z)-2-cyano-3-(3-cyano-4- hydroxyphenyl)-N-ethyl-3-hydroxy-N- methylacrylamide MS [M H].sup. calcd for C.sub.14H.sub.13N.sub.3O.sub.3 269.9, found 269.9. .sup.1H NMR (400 MHz, DMSO-d.sub.6) 12.101 (s, 1H), 8.172 (s, 1H), 7.955 (d, J = 4.0 Hz, 1H), 7.141 (d, J = 4.0 Hz, 1H), 3.571 (d, J = 3.2 Hz, 2H), 3.143 (s, 3H), 1.186 (t, J = 7.2 Hz, 3H) Ex. 45 [00092] (Z)-2-cyano-3-(3-cyano-5-fluoro-4- hydroxyphenyl)-3-hydroxy-N,N- dimethylacrylamide MS [MH].sup. calcd for C.sub.15H.sub.10FN.sub.3O.sub.3 273.8, found 273.8. .sup.1H NMR (400 MHz, DMSO-d.sub.6) 7.996 (s, 1H), 7.922 (s, 1H), 3.131 (s, 6H) Ex. 46 [00093] (Z)-2-cyano-3-(3-cyano-4- hydroxyphenyl)-3-hydroxy-N,N- dimethylacrylamide MS [M H].sup. calcd for C13H11N3O3 258.1, found 257.9. .sup.1H NMR (400 MHz, DMSO-d.sub.6) 12.15 (s, 1H), 8.17 (s, 1H), 7.97 (s, 1H), 7.13 (s, 1H), 3.15 (s, 6H) Ex. 47 [00094] (Z)-3-(3-chloro-5-cyano-4- hydroxyphenyl)-2-cyano-3-hydroxy-N,N- dimethylacrylamide MS [M + H].sup.+ calcd for C13H10ClN3O3 292.0, found 291.7. .sup.1H NMR (400 MHz, DMSO-d.sub.6) 8.14 (s, 2H), 3.14 (s, 6H). Ex. 48 [00095] (Z)-2-cyano-3-(3,5-dichloro-4- hydroxyphenyl)-3-hydroxy-N,N- dimethylacrylamide [M H].sup. calcd for C.sub.12H.sub.10Cl.sub.2N.sub.2O.sub.3 299.0, found 298.9. .sup.1HNMR (400 MHz, DMSO-d.sub.6) 7.84 (s, 2H), 3.14 (s, 6H). Ex. 49 [00096] (Z)-2-cyano-3-(3-cyano-4- hydroxyphenyl)-N-(2-fluoro-5- methylbenzyl)-3-hydroxy-N- methylacrylamide MS [M + H].sup.+ calcd for C20H16FN3O3 366.1, found 365.7. .sup.1H NMR (400 MHz, DMSO-d.sub.6) 12.11 (s, 1H), 8.23 (s, 1H), 7.91 (s, 1H), 7.21 (s, 4H), 4.73 (s, 2H), 3.12 (s, 3H), 2.28 (s, 3H) Ex. 50 [00097] (Z)-2-cyano-3-(3-cyano-5-fluoro-4- hydroxyphenyl)-N-(2-fluoro-5- methylbenzyl)-3-hydroxy-N- methylacrylamide MS [M + H].sup.+ calcd for C20H15F2N3O3 384.1, found 384.2 .sup.1H NMR (400 MHz, DMSO-d.sub.6) 8.14-7.95 (m, 2H), 7.15-7.08 (m, 3H), 4.73 (s, 2H), 3.12 (s, 3H), 2.27 (s, 3H). Ex. 51 [00098] (Z)-N-(5-chloro-2-fluorobenzyl)-2-cyano- 3-(3-cyano-4-hydroxy-5-methylphenyl)- N-ethyl-3-hydroxyacrylamide MS [M H].sup. calcd for C.sub.21H.sub.17ClFN.sub.3O.sub.3 412.1, found 412.1. .sup.1H NMR (400 MHz, DMSO-d.sub.6) 7.97 (s, 1H), 7.80 (s, 1H), 7.41 (d, J = 12.0 Hz, 2H), 7.30 (t, J = 8.0 Hz, 1H), 4.75 (s, 2H), 3.57 (s, 2H), 2.28 (s, 3H), 1.19 (s, 3H). Ex. 52 [00099] (Z)-2-cyano-3-(3-cyano-4- hydroxyphenyl)-N-(2-fluoro-3,5- dimethylbenzyl)-3-hydroxy-N- methylacrylamide MS [M H].sup. calcd for C.sub.21H.sub.18FN.sub.3O.sub.3 378.1, found 378.2. .sup.1H NMR (400 MHz, DMSO-d.sub.6) 12.02 (s, 1H), 8.11 (s, 1H), 7.91 (s, 1H), 7.12- 6.95 (m, 3H), 4.69 (s, 2H), 3.09 (s, 3H), 2.20 (s, 6H) Ex. 53 [00100] (Z)-2-cyano-3-(3-cyano-4-hydroxy-5- methoxyphenyl)-N-(2-fluoro-5- methylbenzyl)-3-hydroxy-N- methylacrylamide MS [M H].sup. calcd for C.sub.21H.sub.18FN.sub.3O.sub.4 394.1, found 394.2. .sup.1HNMR (400 MHz, DMSO-d.sub.6) 11.544 (s, 1H), 7.739 (s, 1H), 7.618 (s, 1H), 7.156 (s, 3H), 4.741 (s, 2H), 3.913 (s, 3H), 3.139 (s, 3H), 2.280 (s, 3H) Ex. 54 [00101] (Z)-2-cyano-3-(3-cyano-4-hydroxy-5- methylphenyl)-N-(2-fluoro-5- methylbenzyl)-3-hydroxy-N- methylacrylamide MS [M + H].sup.+ calcd for C21H18FN3O3 380.1, found 380.1. .sup.1H NMR (400 MHz, DMSO-d.sub.6) 8.00 (s, 1H), 7.83 (s, 1H), 7.14 (t, 3H), 4.73 (s, 2H), 3.12 (s, 3H), 2.28 (s, 6H) Ex. 55 [00102] (Z)-3-(3-chloro-5-cyano-4- hydroxyphenyl)-2-cyano-N-(2-fluoro-5- methylbenzyl)-3-hydroxy-N- methylacrylamide .MS [M H].sup. calcd for C20H15ClFN3O3 398.1, found 398.1. .sup.1H NMR (400 MHz, DMSO-d.sub.6) 8.14 (s, 2H), 7.15-7.10 (m, 3H), 4.73 (s, 2H), 3.11 (s, 3H), 2.28 (s, 3H) Ex. 56 [00103] (Z)-2-cyano-3-(3,5-dichloro-4- hydroxyphenyl)-N-(2-fluoro-5- methylbenzyl)-3-hydroxy-N- methylacrylamide MS [M H].sup. calcd for C.sub.19H.sub.15Cl.sub.2FN.sub.2O.sub.3 406.5, found 406.5. .sup.1H NMR (400 MHz, DMSO-d.sub.6) 11.14 (s, 1H), 7.84 (s, 1H), 7.15-7.08 (m, 3H), 4.72 (s, 2H), 3.12 (s, 3H), 2.28 (s, 3H). Ex. 57 [00104] (Z)-N-benzyl-2-cyano-3-(3-cyano-5- fluoro-4-hydroxyphenyl)-3-hydroxy-N- methylacrylamide MS [M H].sup. calcd for C19H14FN3O3 350.1, found 350.1 .sup.1H NMR (400 MHz, DMSO-d.sub.6) 8.0 (m, 2H), 7.38-7.31 (m, 5H), 4.73 (s, 2H), 3.10 (s, 3H). Ex. 58 [00105] (Z)-2-cyano-3-(3-cyano-5-fluoro-4- hydroxyphenyl)-3-hydroxy-N-methyl-N- (pyridin-2-ylmethyl)acrylamide MS [M + H].sup.+ calcd for C18H13FN4O3 353.1, found 353.1. .sup.1H NMR (400 MHz, DMSO-d.sub.6) 8.45 (d, J = 8.0 Hz, 1H), 7.72 (m, 1H), 7.19 (d, J = 4.0 Hz, 1H), 7.18 (d, J = 4.0 Hz, 1H), 7.17-7.15 (m, 1H), 7.11-7.11 (m, 1H), 4.51 (s, 2H), 2.81 (s, 3H). Ex. 59 [00106] (Z)-N-(5-chloro-2-fluorobenzyl)-2-cyano- 3-(3-cyano-5-fluoro-4-hydroxyphenyl)-3- hydroxy-N-methylacrylamide MS [M H].sup. calcd for C19H12ClF2N3O3 402.1, found 402.1. .sup.1H NMR (400 MHz, DMSO-d.sub.6) 7.99-7.96 (m, 2H), 7.43-7.28 (m, 3H), 4.74 (s, 2H), 3.16 (s, 3H) Ex. 60 [00107] (Z)-N-(2-(2-chlorophenoxy)ethyl)-2- cyano-3-(3-cyano-5-fluoro-4- hydroxyphenyl)-3-hydroxy-N- methylacrylamide MS [M H].sup. calcd for C20H15ClFN3O4 414.1, found 414.1. .sup.1H NMR (400 MHz, DMSO-d.sub.6) 7.96 (m, 2H), 7.42 (s, 1H), 7.20 (s, 1H), 7.18 (s, 1H), 6.99-6.96 (m, 1H), 4.31 (s, 2H), 3.97 (s, 2H), 3.25 (s, 3H) Ex. 61 [00108] (Z)-N-(5-chloro-2-fluorobenzyl)-2-cyano- 3-(3-cyano-4-hydroxy-5- methoxyphenyl)-3-hydroxy-N- methylacrylamide MS [M H].sup. calcd for C20H15ClFN3O4 414.1, found 414.1. .sup.1H NMR (400 MHz, DMSO-d.sub.6) 7.73-7.61 (m, 2H), 7.33-7.29 (m, 3H), 4.76 (s, 2H), 3.91 (s, 3H), 3.16 (s, 3H) Ex. 62 [00109] (Z)-N-(5-chloro-2-fluorobenzyl)-2-cyano- 3-(3-cyano-4-hydroxy-5-methylphenyl)- 3-hydroxy-N-methylacrylamide MS [M + H].sup.+ calcd for C20H15ClFN3O3 400.1, found 400.1. .sup.1H NMR (400 MHz, DMSO-d.sub.6) 11.13 (s, 1H), 7.99-7.83 (m, 2H), 7.42 (s, 2H), 7.33-7.28 (m, 1H), 4.75 (s, 2H), 3.14-3.11 (m, 3H), 2.27 (s, 3H) Ex. 63 [00110] (Z)-2-cyano-3-(3-cyano-5-fluoro-4- hydroxyphenyl)-3-hydroxy-N-methyl-N- (2-(o-tolyloxy)ethyl)acrylamide MS [M + H].sup.+ calcd for C21H18FN3O4 396.1, found 396.1. .sup.1H NMR (400 MHz, DMSO-d.sub.6) 7.99-7.92 (m, 2H), 7.16-7.12 (m, 2H), 6.97- 6.95 (m, 1H), 6.87-6.83 (m, 1H), 4.23 (s, 2H), 3.98 (s, 2H), 3.31 (s, 3H), 2.21 (s, 3H) Ex. 64 [00111] (Z)-N-(2-(2-chlorophenoxy)ethyl)-2- cyano-3-(3-cyano-4-hydroxy-5- methoxyphenyl)-3-hydroxy-N- methylacrylamide MS [M H].sup. calcd for C21H18ClN3O5 426.1, found 426.1. .sup.1H NMR (400 MHz, DMSO-d.sub.6) 7.71 (s, 1H), 7.61 (s, 1H), 7.43 (s, 1H), 7.36 (s, 1H), 7.18 (s, 1H), 6.99-6.96 (m, 1 H), 4.33 (s, 2H), 3.99 (s, 2H), 3.91 (s, 3H), 3.35 (s, 3H) Ex. 65 [00112] (Z)-N-(5-chloro-2-fluorobenzyl)-2-cyano- 3-(3,5-dichloro-4-hydroxyphenyl)-3- hydroxy-N-methylacrylamide MS [M H].sup. calcd for C18H12Cl3FN2O3 428.6, found. 428.6. .sup.1H NMR (400 MHz, DMSO-d.sub.6) 7.52-7.50 (m, 1H), 7.45 (s, 2H), 7.36-7.33 (m, 1H), 7.32-7.20 (m, 1H), 4.51 (s, 2H), 2.85 (s, 3H) Ex. 66 [00113] (S,Z)-N-(1-(5-chloro-2- fluorophenyl)ethyl)-2-cyano-3-hydroxy- 3-(4-hydroxy-3-methoxy-5-nitrophenyl)- N-methylacrylamide MS [M H].sup. calcd for C.sub.20H.sub.17ClFN.sub.3O.sub.6 448.5, found 448.5. .sup.1H NMR (400 MHz, DMSO-d.sub.6) 7.96 (s, 1H), 7.55-7.46 (m, 3H), 7.28 (s, 1H), 5.79 (s, 1H), 3.92 (s, 3H), 2.91 (s, 3H), 1.58 (s, 3H) Ex. 67 [00114] (R,Z)-N-(1-(5-chloro-2- fluorophenyl)ethyl)-2-cyano-3-hydroxy- 3-(4-hydroxy-3-methoxy-5-nitrophenyl)- N-methylacrylamide MS [M H].sup. calcd for C.sub.20H.sub.17ClFN.sub.3O.sub.6 448.5, found 448.5. .sup.1HNMR (400 MHz, DMSO-d.sub.6) 7.96 (s, 1H), 7.55-7.46 (m, 3H), 7.28 (s, 1H), 5.79 (s, 1H), 3.92 (s, 3H), 2.91 (s, 3H), 1.58 (s, 3H) Ex. 68 [00115] (Z)-2-cyano-3-(3,5-dicyano-4- hydroxyphenyl)-N-(2-fluoro-5- methylbenzyl)-3-hydroxy-N- methylacrylamide MS [M H].sup. calcd for C21H15FN4O3 388.6, found 388.6. .sup.1H NMR (400 MHz, DMSO-d.sub.6) 8.25-8.24 (m, 2H), 7.11-7.01 (m, 3H), 4.69 (s, 2H), 3.08 (s, 3H), 2.24 (s, 3H). Ex. 69 [00116] (Z)-3-(5-chloro-2-fluoro-4- hydroxyphenyl)-N-(5-chloro-2- fluorobenzyl)-2-cyano-3-hydroxy-N- methylacrylamide MS [M + H].sup.+ calcd for C18H12Cl2F2N2O3 413.1, found 413.1 .sup.1H NMR (400 MHz, CD3OD) 7.62 (s, 1H), 7.45-7.32 (m, 2H), 7.38- 7.35 (m, 1H), 6.78-6.75 (m, 1H), 4.80 (s, 2H), 3.21 (s, 3H). Ex. 70 [00117] (Z)-N-(5-chloro-2-fluorobenzyl)-3-(3- chloro-5-fluoro-4-hydroxyphenyl)-2- cyano-3-hydroxy-N-methylacrylamide MS [M H].sup. calcd for C18H12Cl2F2N2O3 411.1, found 411.1. .sup.1H NMR (400 MHz, DMSO-d.sub.6) 7.68-7.59 (m, 2H), 7.39-7.24 (m, 3H), 4.69 (s, 2H), 3.09 (s, 3H) Ex. 71 [00118] (Z)-N-(2-(2-chlorophenoxy)ethyl)-2- cyano-3-(3,5-dichloro-4-hydroxyphenyl)- N-ethyl-3-hydroxyacrylamide MS [M H].sup. calcd for C.sub.20H.sub.17Cl.sub.3N.sub.2O.sub.4 453.1, found 453.1. .sup.1H NMR (400 MHz, DMSO-d.sub.6) 7.77 (s, 2H), 7.40 (s, 1H), 7.25 (s, 1H), 7.13 (s, 1H), 6.91-6.95 (m, 1H), 4.28 (s, 2H), 3.93 (s, 2H), 3.74 (s, 2H), 1.20 (s, 3H) Ex. 72 [00119] (Z)-N-(5-chloro-2-fluorobenzyl)-2-cyano- 3-(3,5-difluoro-4-hydroxyphenyl)-3- hydroxy-N-methylacrylamide MS [M H].sup. calcd for C.sub.18H.sub.12ClF.sub.3N.sub.2O.sub.3 395.1, found 395.1. .sup.1H NMR (400 MHz, DMSO-d.sub.6) 11.24 (s, 1H), 7.25-7.53 (s, 5H), 4.77 (s, 2H), 3.10 (s, 3H). Ex. 73 [00120] (Z)-2-cyano-3-(3,5-dichloro-4- hydroxyphenyl)-N-(2-fluoro-5- methoxybenzyl)-3-hydoxy-N- methylacrylamide MS [M H].sup. calcd for C.sub.19H.sub.15Cl.sub.2FN.sub.2O.sub.4 423.0, found 423.0. .sup.1H NMR (400 MHz, DMSO-d.sub.6) 7.84 (s, 2H), 7.16 (t, J = 8.0 Hz, 1H), 6.90 (t, J = 4.0 Hz, 2H), 4.72 (s, 2H), 3.72 (s, 3H), 3.11 (s, 3H) Ex. 74 [00121] (Z)-2-cyano-N-(5-cyano-2-fluorobenzyl)- 3-(3,5-dichloro-4-hydroxyphenyl)-3- hydroxy-N-methylacrylamide MS [M H].sup. calcd for C.sub.19H.sub.12Cl.sub.2FN.sub.3O.sub.3 418.0, found 418.0. .sup.1H NMR (400 MHz, DMSO-d.sub.6) 7.79-7.92 (m, 4H), 7.46 (t, J = 12.0 Hz, 1H), 4.74 (s, 2H), 3.11 (s, 3H) Ex. 75 [00122] (Z)-2-cyano-N-(5-cyano-2-fluorobenzyl)- 3-hydroxy-3-(4-hydroxy-3-methoxy-5- nitrophenyl)-N-methylacrylamide MS [M H].sup. calcd for C.sub.20H.sub.15FN.sub.4O.sub.6 425.1, found 425.1 .sup.1H NMR (400 MHz, DMSO-d.sub.6) 7.93- 7.86 (m, 3H), 7.62 (s, 1H), 7.48-7.44 (m, 1H), 4.77 (s, 2H), 3.90 (s, 3H), 3.16 (s, 3H). Ex. 76 [00123] Synthesis of (Z)-N-(2-cyano-3-(3,5- dichloro-4-hydroxyphenyl)-3- hydroxyacryloyl)-N-methylglycine MS [M H].sup. calcd for C.sub.13H.sub.10Cl.sub.2N.sub.2O.sub.5 342.9, found 342.9. .sup.1H NMR (400 MHz, DMSO-d.sub.6) 7.86 (s, 2H), 4.25 (s, 2H), 3.19 (s, 3H) Ex. 77 [00124] (Z)-3-(5-chloro-2-fluoro-4- hydroxyphenyl)-2-cyano-3-hydroxy-N,N- dimethylacrylamide MS [M H].sup. calcd for C12H10ClFN2O3 283.0, found 283.0. .sup.1H NMR (400 MHz, DMSO-d.sub.6) 11.55 (s, 1H), 7.69 (d, J = 8 Hz, 1H), 6.88 (d, J = 12 Hz, 1H), 3.09 (s, 6H) Ex. 78 [00125] (Z)-2-cyano-3-(3,5-dichloro-4- hydroxyphenyl)-3-hydroxy-N-methyl-N- ((1-(pyridin-4-yl)-1H-1,2,3-triazol-4- yl)methyl)acrylamide MS [M H].sup. calcd for C19H14Cl2N6O3 442.8, found 442.8 .sup.1H NMR (400 MHz, DMSO-d.sub.6) 9.05 (s, 1H), 8.85 (s, 2H), 8.08 (s, 2H) 7.86 (s, 2H), 4.86 (s, 2H), 3.26 (s, 3H) Ex. 79 [00126] (Z)-N-(5-chloro-2-fluorobenzyl)-2-cyano- 3-hydroxy-3-(4-hydroxy-3-nitro-5- (trifluoromethoxy)phenyl)-N- methylacrylamide .sup.1H NMR (400 MHz, CD3CN) 8.71-8.71 (d, J = 4.0 Hz, 1H), 8.21 (s, 1H), 7.38-7.36 (m, 2H), 7.36-7.15 (m, 1H), 4.82 (s, 2H), 3.30 (s, 3H). MS [M H] calcd for C19H12ClF4N3O6 488.0, found 487.8 Ex. 80 [00127] (Z)-2-cyano-3-hydroxy-3-(4-hydroxy-3- methoxy-5-nitrophenyl)-N-methyl-N- (prop-2-ynyl)acrylamide MS [M H].sup. calcd for C15H13N3O6 330.1, found 330.1. Ex. 81 [00128] (Z)-2-cyano-N-(cyanomethyl)-3-hydroxy-3- (4-hydroxy-3-methoxy-5-nitrophenyl)- N-methylacrylamide MS [M H].sup. calcd for C14H12N406 331.1, found 331.1. Ex. 82 [00129] (Z)-N-(but-2-ynyl)-2-cyano-2-ethyl-3- hydroxy-3-(4-hydroxy-3-methoxy-5- nitrophenyl)acrylamide MS [M H].sup. calcd for C17H17N3O6 358.1, found 358.1. Ex. 83 [00130] (Z)-2-cyano-N-(3-cyclopropylprop-2- ynyl)-3-hydroxy-3-(4-hydroxy-3- methoxy-5-nitrophenyl)-N- methylacrylamide MS [M H].sup. calcd for C18H17N3O6 370.1, found 370.1. Ex. 84 [00131] (Z)-5-(2-cyano-3-hydroxy-3-(4-hydroxy- 3-methoxy-5-nitrophenyl)-N- methylacrylamido)-N,N-dimethylpent-3- ynamide MS [M H].sup. calcd for C19H20N4O7 415.1, found 415.1. Ex. 85 [00132] (Z)-5-(2-cyano-3-hydroxy-3-(4-hydroxy- 3-methoxy-5-nitrophenyl)-N- methylacrylamido)-N,N,2-trimethylpent- 3-ynamide MS [M H].sup. calcd for C20H22N407 429.1, found 429.1. Ex. 86 [00133] (Z)-2-cyano-3-hydroxy-3-(4-hydroxy-3- methoxy-5-nitrophenyl)-N-methyl-N-(3- (1-methyl-2-oxopiperidin-3-yl)prop-2- ynyl)acrylamide MS [M H].sup. calcd for C21H22N4O7 441.1, found 441.1. Ex. 87 [00134] (Z)-2-cyano-3-hydroxy-3-(4-hydroxy-3- methoxy-5-nitrophenyl)-N-methyl-N-(4- (1-methyl-2-oxopiperidin-3-yl)but-3-yn- 2-yl)acrylamide MS [M H].sup. calcd for C21H22N4O7 455.2, found 455.2. Ex. 88 [00135] (Z)-2-cyano-3-hydroxy-3-(4-hydroxy-3- methoxy-5-nitrophenyl)-N-(5- hydroxyhex-2-ynyl)-N-methylacrylamide MS [M H].sup. calcd for C18H19N3O7 388.1, found 388.1 Ex. 89 [00136] (Z)-2-cyano-N-(5,6-dihydroxyhex-2- ynyl)-3-hydroxy-3-(4-hydroxy-3- methoxy-5-nitrophenyl)-N- methylacrylamide MS [M H].sup. calcd for C18H19N3O8 404.1, found 404.1 Ex. 90 [00137] (Z)-2-cyano-3-hydroxy-3-(4-hydroxy-3- methoxy-5-nitrophenyl)-N-(5-hydroxy-4- methylpent-2-ynyl)-N-methylacrylamide MS [M H].sup. calcd for C18H19N3O7 388.1, found 388.1 Ex. 91 [00138] (Z)-2-cyano-3-hydroxy-3-(4-hydroxy-3- methoxy-5-nitrophenyl)-N-methyl-N-(4- (pyridin-2-yl)but-2-ynyl)acrylamide MS [M H].sup. calcd for C21H18N4O6 421.1, found 421.1 Ex. 92 [00139] (Z)-2-cyano-3-hydroxy-3-(4-hydroxy-3- methoxy-5-nitrophenyl)-N-methyl-N-(4- (pyrazin-2-yl)but-2-ynyl)acrylamide MS [M H].sup. calcd for C20H17N5O6 422.1, found 422.1 Ex. 93 [00140] (Z)-2-cyano-3-hydroxy-3-(4-hydroxy-3- methoxy-5-nitrophenyl)-N-methyl-N-(4- (pyridin-2-yl)pent-2-ynyl)acrylamide MS [M H].sup. calcd for C22H20N4O6 435.1, found 435.1 Ex. 94 [00141] (Z)-methyl 2-(2-cyano-3-hydroxy-3-(4- hydroxy-3-methoxy-5-nitrophenyl)-N- methylacrylamido)acetate MS [M H].sup. calcd for C15H15N3O8 364.1, found 364.1 Ex. 95 [00142] (Z)-2-cyano-3-hydroxy-3-(4-hydroxy-3- methoxy-5-nitrophenyl)-N-methyl-N-(2- oxobutyl)acrylamide MS [M H].sup. calcd for C16H17N3O7 362.1, found 362.1 Ex. 96 [00143] (Z)-2-cyano-3-hydroxy-3-(4-hydroxy-3- methoxy-5-nitrophenyl)-N-methyl-N-(2- (methylamino)-2-oxoethyl)acrylamide MS [M H].sup. calcd for C15H16N4O7 363.1, found 363.1 Ex. 97 [00144] (Z)-2-cyano-3-hydroxy-3-(4-hydroxy-3- methoxy-5-nitrophenyl)-N-methyl-N-(1- oxo-1-(phenylamino)propan-2- yl)acrylamide MS [M H].sup. calcd for C21H20N4O7 439.1, found 439.1 Ex. 98 [00145] (Z)-2-cyano-3-hydroxy-3-(4-hydroxy-3- methoxy-5-nitrophenyl)-N-methyl-N-(2- oxo-2-(pyridin-4- ylamino)ethyl)acrylamide MS [M H].sup. calcd for C19H17N5O7 426.1, found 426.1 Ex. 99 [00146] (Z)-2-cyano-N-(2-(dimethylamino)-2- oxoethyl)-3-hydroxy-3-(4-hydroxy-3- methoxy-5-nitrophenyl)-N- methylacrylamide MS [M H].sup. calcd for C16H18N4O7 377.1, found 377.1 Ex. 100 [00147] (Z)-2-cyano-3-hydroxy-3-(4-hydroxy-3- methoxy-5-nitrophenyl)-N-(2- (methoxyamino)-2-oxoethyl)-N- methylacrylamide MS [M H].sup. calcd for C15H16N4O8 379.1, found 379.1 Ex. 101 [00148] (Z)-2-cyano-N-(3-(dimethylamino)-3- oxopropyl)-3-hydroxy-3-(4-hydroxy-3- methoxy-5-nitrophenyl)-N- methylacrylamide MS [M H].sup. calcd for C17H20N4O7 391.1, found 391.1 Ex. 102 [00149] (Z)-N-(3-(azetidin-1-yl)-3-oxopropyl)-2- cyano-3-hydroxy-3-(4-hydroxy-3- methoxy-5-nitrophenyl)-N- methylacrylamide MS [M H].sup. calcd for C18H20N4O7 403.1, found 403.1 Ex. 103 [00150] (Z)-2-cyano-3-hydroxy-3-(4-hydroxy-3- methoxy-5-nitrophenyl)-N-methyl-N-(3- oxo-3-phenylpropyl)acrylamide MS [M H].sup. calcd for C21H19N3O7 435.1, found Ex. 104 [00151] (Z)-N-(2-acetamidoethyl)-2-cyano-3- hydroxy-3-(4-hydroxy-3-methoxy-5- nitrophenyl)-N-methylacrylamide MS [M H].sup. calcd for C16H18N4O7 424.1, found 424.1 Ex. 105 [00152] (Z)-2-(2-cyano-3-hydroxy-3-(4-hydroxy- 3-methoxy-5-nitrophenyl)-N- methylacrylamido)ethyl dimethylcarbamate MS [M H].sup. calcd for C17H20N4O8 407.1, found 407.1 Ex. 106 [00153] (Z)-2-cyano-N-(5-fluoro-2- methylphenyl)-3-hydroxy-3-(4-hydroxy- 3-methoxy-5-nitrophenyl)-N- methylacrylamide MS [M H].sup. calcd for C19H16N3O6 400.1, found 400.1 Ex. 107 [00154] (Z)-N-(2-chloro-5-fluorophenyl)-2- cyano-3-hydroxy-3-(4-hydroxy-3- methoxy-5-nitrophenyl)-N- methylacrylamide MS [M H].sup. calcd for C18H13ClN3O6 420.0, found 420.0 Ex. 108 [00155] (Z)-2-cyano-N-(2-cyano-5-fluorophenyl)- 3-hydroxy-3-(4-hydroxy-3-methoxy-5- nitrophenyl)-N-methylacrylamide MS [M H].sup. calcd for C19H13FN4O6 411.1, found 411.1 Ex. 109 [00156] (Z)-2-cyano-N-ethyl-N-(5-fluoro-2- methylphenyl)-3-hydroxy-3-(4-hydroxy- 3-methoxy-5-nitrophenyl)acrylamide MS [M H].sup. calcd for C20H18FN3O6 414.1, found 414.1 Ex. 110 [00157] (Z)-2-cyano-3-hydroxy-3-(4-hydroxy-3- methoxy-5-nitrophenyl)-N-methyl-N- (pyridin-3-yl)acrylamide MS [M H].sup. calcd for C17H14N4O6 369.1, found 369.0 Ex. 111 [00158] (Z)-2-cyano-3-hydroxy-3-(4-hydroxy-3- methoxy-5-nitrophenyl)-N-methyl-N-(4- methylpyridin-3-yl)acrylamide MS [M H].sup. calcd for C18H16N4O6 383.1, found 383.1 Ex. 112 [00159] (Z)-2-cyano-3-hydroxy-3-(4-hydroxy-3- methoxy-5-nitrophenyl)-N-(4- methoxypyridin-3-yl)-N- methylacrylamide MS [M H].sup. calcd for C18H16N4O7 399.1, found 399.1 Ex. 113 [00160] (Z)-2-cyano-3-hydroxy-3-(4-hydroxy-3- methoxy-5-nitrophenyl)-N-methyl-N-(4- methylpyrimidin-5-yl)acrylamide MS [M H].sup. calcd for C17H15N5O6 384.1, found 384.1 Ex. 114 [00161] (Z)-2-cyano-N-ethyl-3-hydroxy-3-(4- hydroxy-3-methoxy-5-nitrophenyl)-N-(4- methylpyridin-3-yl)acrylamide MS [M H].sup. calcd for C19H18N4O6 397.1, found 397.1 Ex. 115 [00162] (Z)-N-(4-benzylpyridin-3-yl)-2-cyano-3- hydroxy-3-(4-hydroxy-3-methoxy-5- nitrophenyl)-N-methylacrylamide MS [M H].sup. calcd for C24H20N4O6 459.1, found 459.1 Ex. 116 [00163] (Z)-2-cyano-3-hydroxy-3-(4-hydroxy-3- methoxy-5-nitrophenyl)-N-methyl-N-(5- phenoxypyridin-3-yl)acrylamide MS [M H].sup. calcd for C23H18N4O7 461.1, found 461.1 Ex. 117 [00164] (Z)-2-cyano-3-hydroxy-3-(4-hydroxy-3- methoxy-5-nitrophenyl)-N-(5- methoxpyridin-3-yl)-N- methylacrylamide MS [M H].sup. calcd for C18H16N4O7 399.1, found 399.1 Ex. 118 [00165] (Z)-2-cyano-N-(5-fluoro-4- methylpyridin-3-yl)-3-hydroxy-3-(4- hydroxy-3-methoxy-5-nitrophenyl)-N- methylacrylamide MS [M H].sup. calcd for C19H18N4O6 401.1, found 401.1 Ex. 119 [00166] (Z)-2-cyano-N-(4,6-dimethylpyridin-3- yl)-3-hydroxy-3-(4-hydroxy-3-methoxy- 5-nitrophenyl)-N-methylacrylamide MS [M H].sup. calcd for C18H15FN4O6 397.1, found 397.1 Ex. 120 [00167] (Z)-N-(6-amino-4-methylpyridin-3-yl)-2- cyano-3-hydroxy-3-(4-hydroxy-3- methoxy-5-nitrophenyl)-N- methylacrylamide MS [M H].sup. calcd for C18H17N5O6 398.1, found 398.1 Ex. 121 [00168] (Z)-N-(6-acetamido-4-methylpyridin-3- yl)-2-cyano-3-hydroxy-3-(4-hydroxy-3- methoxy-5-nitrophenyl)-N- methylacrylamide MS [M H].sup. calcd for C20H19N5O7 440.1, found 440.1 Ex. 122 [00169] (Z)-2-cyano-3-hydroxy-3-(4-hydroxy-3- methoxy-5-nitrophenyl)-N-methyl-N-(4- methyl-6-(3-methylureido)pyridin-3- yl)acrylamide MS [M H].sup. calcd for C20H20N6O7 455.1, found 455.1 Ex. 123 [00170] (Z)-2-cyano-3-hydroxy-3-(4-hydroxy-3- methoxy-5-nitrophenyl)-N-(isoquinolin- 4-yl)-N-methylacrylamide MS [M H].sup. calcd for C21H16N4O6 419.1, found 419.1 Ex. 124 [00171] (Z)-2-cyano-3-hydroxy-3-(4-hydroxy-3- methoxy-5-nitrophenyl)-N-methyl-N-(5- methyl-2-oxo-1,2-dihydropyridin-4- yl)acrylamide MS [M H].sup. calcd for C18H16N4O7 399.1, found 399.1 Ex. 125 [00172] (Z)-2-cyano-3-hydroxy-3-(4-hydroxy-3- methoxy-5-nitrophenyl)-N-(isoxazol-5- yl)-N-methylacrylamide MS [M H].sup. calcd for C15H12N4O7 359.1, found 359.1 Ex. 126 [00173] (Z)-2-cyano-3-hydroxy-3-(4-hydroxy-3- methoxy-5-nitrophenyl)-N-methyl-N-(4- methylisoxazol-5-yl)acrylamide(Z)-2- cyano-3-hydroxy-3-(4-hydroxy-3- methoxy-5-nitrophenyl)-N-methyl-N-(4- methylisoxazol-5-yl)acrylamide MS [M H].sup. calcd for C16H14N4O7 373.1, found 373.1 Ex. 127 [00174] (Z)-2-cyano-3-hydroxy-3-(4-hydroxy-3- methoxy-5-nitrophenyl)-N-methyl-N-(4- methyl-4H-1,2,4-triazol-3-yl)acrylamide MS [M H].sup. calcd for C15H14N6O6 373.1, found 373.1 Ex. 128 [00175] (Z)-2-cyano-3-hydroxy-3-(4-hydroxy-3- methoxy-5-nitrophenyl)-N-methyl-N-(4- methylisoxazol-3-yl)acrylamide MS [M H].sup. calcd for C16H14N4O7 373.1, found 373.1 Ex. 129 [00176] (Z)-2-cyano-3-hydroxy-3-(4-hydroxy-3- methoxy-5-nitrophenyl)-N-methyl-N-(4- phenylisoxazol-5-yl)acrylamide MS [M H].sup. calcd for C21H16N4O7 435.1, found 435.1 Ex. 130 [00177] (Z)-2-cyano-N-(3,4-dimethylisoxazol-5- yl)-3-hydroxy-3-(4-hydroxy-3-methoxy- 5-nitrophenyl)-N-methylacrylamide MS [M H].sup. calcd for C17H16N4O7 387.1, found 387.1 Ex. 131 [00178] (Z)-2-cyano-3-hydroxy-3-(4-hydroxy-3- methoxy-5-nitrophenyl)-N-methyl-N-(3- methyl-4-phenylisoxazol-5-yl)acrylamide MS [M H].sup. calcd for C22H18N4O7 449.1, found 449.1 Ex. 132 [00179] (Z)-2-cyano-3-hydroxy-3-(4-hydroxy-3- methoxy-5-nitrophenyl)-N-methyl-N-(4- methyl-3-phenylisoxazol-5-yl)acrylamide MS [M H].sup. calcd for C22H18N4O7 449.1, found 449.1 Ex. 133 [00180] (Z)-2-cyano-3-hydroxy-3-(4-hydroxy-3- methoxy-5-nitrophenyl)-N-methyl-N-(4- methyl-3-(pyridin-2-yl)isoxazol-5- yl)acrylamide MS [M H].sup. calcd for C21H17N5O7 450.1, found 450.1 Ex. 134 [00181] (Z)-N-(benzo[c]isoxazol-3-yl)-2-cyano-3- hydroxy-3-(4-hydroxy-3-methoxy-5- nitrophenyl)-N-methylacrylamide MS [M H].sup. calcd for C19H14N4O7 409.1, found 409.1 Ex. 135 [00182] (Z)-2-cyano-N-(6,8-dihydro-5H- [1,2,4]triazolo[3,4-c][1,4]oxazin-3-yl)-3- hydroxy-3-(4-hydroxy-3-methoxy-5- nitrophenyl)-N-methylacrylamide MS [M H].sup. calcd for C16H16N6O7 415.1, found 415.1 Ex. 136 [00183] (Z)-2-cyano-3-hydroxy-3-(4-hydroxy-3- methoxy-5-nitrophenyl)-N-methyl-N- (5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3- a]pyridin-3-yl)acrylamide MS [M H].sup. calcd for C18H18N6O6 413.1, found 413.1 Ex. 137 [00184] (Z)-2-cyano-N-(6,7-dihydro-4H- [1,2,3]triazolo[5,1-c]oxazin-3-yl)-3- hydroxy-3-(4-hydroxy-3-methoxy-5- nitrophenyl)-N-methylacrylamide MS [M H].sup. calcd for C17H16N6O7 415.1, found 415.1 Ex. 138 [00185] (Z)-2-cyano-N-(cyclopropylmethyl)-3- hydroxy-3-(4-hydroxy-3-methoxy-5- nitrophenyl)-N-methylacrylamide MS [M H].sup. calcd for C16H17N3O6 346.1, found 346.1 Ex. 139 [00186] (Z)-N-benzyl-2-cyano-3-hydroxy-3-(4- hydroxy-3-methoxy-5-nitrophenyl)-N- methylacrylamide MS [M H].sup. calcd for C19H17N3O6 382.1, found 382.1 Ex. 140 [00187] (Z)-2-cyano-3-hydroxy-3-(4-hydroxy-3- methoxy-5-nitrophenyl)-N-methyl-N- (pyridin-2-ylmethyl)acrylamide MS [M H].sup. calcd for C18H16N4O6 383.1, found 383.1 Ex. 141 [00188] (Z)-2-cyano-3-hydroxy-3-(4-hydroxy-3- methoxy-5-nitrophenyl)-N-methyl-N- (pyridin-3-ylmethyl)acrylamide MS [M H].sup. calcd for C18H16N4O6 383.1, found 383.1 Ex. 142 [00189] (Z)-2-cyano-3-hydroxy-3-(4-hydroxy-3- methoxy-5-nitrophenyl)-N-methyl-N- (pyridin-4-ylmethyl)acrylamide MS [M H].sup. calcd for C18H16N4O6 383.1, found 383.1 Ex. 143 [00190] (Z)-2-cyano-3-hydroxy-3-(4-hydroxy-3- methoxy-5-nitrophenyl)-N-methyl-N- (pyrazin-2-ylmethyl)acrylamide MS [M H].sup. calcd for C17H15N5O6 384.1, found 384.1 Ex. 144 [00191] (Z)-2-cyano-3-hydroxy-3-(4-hydroxy-3- methoxy-5-nitrophenyl)-N-methyl-N-((4- methylpyridin-2-yl)methyl)acrylamide MS [M H].sup. calcd for C19H18N4O6 397.1, found 397.1 Ex. 145 [00192] (Z)-2-cyano-3-hydroxy-3-(4-hydroxy-3- methoxy-5-nitrophenyl)-N-((4- methoxypyridin-2-yl)methyl)-N- methylacrylamide MS [M H].sup. calcd for C19H18N4O7 413.1, found 413.1 Ex. 146 [00193] (Z)-2-cyano-3-hydroxy-3-(4-hydroxy-3- methoxy-5-nitrophenyl)-N-methyl-N-((4- methylpyridin-2-yl)methyl)acrylamide MS [M H].sup. calcd for C16H14N4O7 400.1, found 400.1 Ex. 147 [00194] (Z)-N-(2-chlorobenzyl)-2-cyano-3- hydroxy-3-(4-hydroxy-3-methoxy-5- nitrophenyl)-N-methylacrylamide MS [M H].sup. calcd for C19H16ClN3O6 416.1, found 416.1 Ex. 148 [00195] (Z)-2-cyano-N-(2-cyanobenzyl)-3- hydroxy-3-(4-hydroxy-3-methoxy-5- nitrophenyl)-N-methylacrylamide MS [M H].sup. calcd for C20H16N4O6 407.1, found 407.1 Ex. 149 [00196] (Z)-2-cyano-3-hydroxy-3-(4-hydroxy-3- methoxy-5-nitrophenyl)-N-(2- hydroxybenzyl)-N-methylacrylamide MS [M H].sup. calcd for C19H17N3O7 398.1, found 398.1 Ex. 150 [00197] (Z)-N-(5-chloro-2-hydroxybenzyl)-2- cyano-3-hydroxy-3-(4-hydroxy-3- methoxy-5-nitrophenyl)-N- methylacrylamide MS [M H].sup. calcd for C19H16ClN3O7 432.1, found 432.1 Ex. 151 [00198] (Z)-2-cyano-N-(5-cyano-2- hydroxybenzyl)-3-hydroxy-3-(4-hydroxy- 3-methoxy-5-nitrophenyl)-N- methylacrylamide MS [M H].sup. calcd for C20H16N4O7 423.1, found 423.1 Ex. 152 [00199] (Z)-2-cyano-N-(2-cyano-5- methylbenzyl)-3-hydroxy-3-(4-hydroxy- 3-methoxy-5-nitrophenyl)-N- methylacrylamide MS [M H].sup. calcd for C21H18N4O6 421.1, found 421.1 Ex. 153 [00200] (Z)-2-cyano-N-(2-fluoro-5- (trifluoromethyl)benzyl)-3-hydroxy-3-(4- hydroxy-3-methoxy-5-nitrophenyl)-N- methylacrylamide MS [M H].sup. calcd for C20H15F4N3O6 468.1, found 468.1 Ex. 154 [00201] (Z)-2-cyano-N-(2-fluoro-5- (trifluoromethoxy)benzyl)-3-hydroxy-3- (4-hydroxy-3-methoxy-5-nitrophenyl)-N- methylacrylamide MS [M H].sup. calcd for C20H15F4N3O7 484.1, found 484.0 Ex. 155 [00202] (Z)-2-cyano-N-(5-(difluoromethoxy)-2- fluorobenzyl)-3-hydroxy-3-(4-hydroxy-3- methoxy-5-nitrophenyl)-N- methylacrylamide MS [M H].sup. calcd for C20H16F3N3O7 466.1, found 466.0 Ex. 156 [00203] (Z)-2-cyano-N-(2-fluoro-5-(2,2,2- trifluoroethoxy)benzyl)-3-hydroxy-3-(4- hydroxy-3-methoxy-5-nitrophenyl)-N- methylacrylamide MS [M H].sup. calcd for C21H17F4N3O7 498.1, found 498.1 Ex. 157 [00204] (Z)-2-cyano-N-(5-(dimethylamino)-2- fluorobenzyl)-3-hydroxy-3-(4-hydroxy-3- methoxy-5-nitrophenyl)-N- methylacrylamide MS [M H].sup. calcd for C21H21FN406 443.1, found 443.1 Ex. 158 [00205] (Z)-2-cyano-N-(2-fluoro-5- (methylthio)benzyl)-3-hydroxy-3-(4- hydroxy-3-methoxy-5-nitrophenyl)-N- methylacrylamide MS [M H].sup. calcd for C20H18FN3O6S 446.1, found 446.1 Ex. 159 [00206] (Z)-2-cyano-N-(5-ethynyl-2- fluorobenzyl)-3-hydroxy-3-(4-hydroxy-3- methoxy-5-nitrophenyl)-N- methylacrylamide MS [M H].sup. calcd for C21H16FN3O6 424.1, found 424.1 Ex. 160 [00207] (Z)-2-cyano-N-(2-fluoro-5-vinylbenzyl)- 3-hydroxy-3-(4-hydroxy-3-methoxy-5- nitrophenyl)-N-methylacrylamide MS [M H].sup. calcd for C21H18FN3O6 426.1, found 426.1 Ex. 161 [00208] (Z)-2-cyano-N-(2-fluoro-5- ((trifluoromethoxy)methyl)benzyl)-3- hydroxy-3-(4-hydroxy-3-methoxy-5- nitrophenyl)-N-methylacrylamide MS [M H].sup. calcd for C21H17F4N3O7 498.1, found 498.1 Ex. 162 [00209] (Z)-2-cyano-N-(2-fluoro-5- (hydroxymethyl)benzyl)-3-hydroxy-3-(4- hydroxy-3-methoxy-5-nitrophenyl)-N- methylacrylamide MS [M H].sup. calcd for C20H18FN3O7 430.1, found 430.1 Ex. 163 [00210] (Z)-N-(5-(2-amino-2-oxoethyl)-2- fluorobenzyl)-2-cyano-3-hydroxy-3-(4- hydroxy-3-methoxy-5-nitrophenyl)-N- methylacrylamide MS [M H].sup. calcd for C21H19FN4O7 457.1, found 457.1 Ex. 164 [00211] (Z)-2-cyano-N-(2-fluoro-5-(2- (methylamino)-2-oxoethyl)benzyl)-3- hydroxy-3-(4-hydroxy-3-methoxy-5- nitrophenyl)-N-methylacrylamide MS [M H].sup. calcd for C22H21FN4O7 473.1, found 473.1 Ex. 165 [00212] (Z)-2-cyano-N-(2-fluoro-5-((1-methyl- 1H-pyrazol-4-yl)methyl)benzyl)-3- hydroxy-3-(4-hydroxy-3-methoxy-5- nitrophenyl)-N-methylacrylamide MS [M H].sup. calcd for C24H22FN5O6 494.2, found 494.2 Ex. 166 [00213] (Z)-N-(5-(azetidin-1-yl)-2-fluorobenzyl)- 2-cyano-3-hydroxy-3-(4-hydroxy-3- methoxy-5-nitrophenyl)-N- methylacrylamide MS [M H].sup. calcd for C22H21FN4O6 455.1, found 455.1 Ex. 167 [00214] (Z)-2-cyano-N-(5-cyclopropyl-2- fluorobenzyl)-3-hydoxy-3-(4-hydroxy-3- methoxy-5-nitrophenyl)-N- methylacrylamide MS [M H].sup. calcd for C22H20FN3O6 440.1, found 440.1 Ex. 168 [00215] (Z)-2-cyano-N-((4-fluorobiphenyl-3- yl)methyl)-3-hydroxy-3-(4-hydroxy-3- methoxy-5-nitrophenyl)-N- methylacrylamide MS [M H].sup. calcd for C25H20FN3O6 476.1, found 476.1 Ex. 169 [00216] (Z)-2-cyano-N-(2-fluoro-5-(pyrimidin-4- yl)benzyl)-3-hydroxy-3-(4-hydroxy-3- methoxy-5-nitrophenyl)-N- methylacrylamide MS [M H].sup. calcd for C23H18FN5O6 478.1, found 478.1 Ex. 170 [00217] (Z)-2-cyano-N-(2-fluoro-5- morpholinobenzyl)-3-hydroxy-3-(4- hydroxy-3-methoxy-5-nitrophenyl)-N- methylacrylamide MS [M H].sup. calcd for C23H23FN4O7 485.2, found 485.2 Ex. 171 [00218] (Z)-N-(2-(5-chloro-2- fluorophenyl)propan-2-yl)-2-cyano-3- hydroxy-3-(4-hydroxy-3-methoxy-5- nitrophenyl)-N-methylacrylamide MS [M H].sup. calcd for C21H19ClFN3O6 462.1, found 462.1 Ex. 172 [00219] (Z)-N-(1-(5-chloro-2- fluorophenyl)cyclopropyl)-2-cyano-3- hydroxy-3-(4-hydroxy-3-methoxy-5- nitrophenyl)-N-methylacrylamide MS [M H].sup. calcd for C21H17ClFN3O6 460.1, found 460.1 Ex. 173 [00220] (Z)-N-((5-chloro-2- fluorophenyl)fluoromethyl)-2-cyano-3- hydroxy-3-(4-hydroxy-3-methoxy-5- nitrophenyl)-N-methylacrylamide MS [M H].sup. calcd for C19H14ClF2N3O6 452.0, found 452.0 Ex. 174 [00221] (Z)-N-((5-chloro-2- fluorophenyl)difluoromethyl)-2-cyano-3- hydroxy-3-(4-hydroxy-3-methoxy-5- nitrophenyl)-N-methylacrylamide MS [M H].sup. calcd for C19H13ClF3N3O6 470.0, found 470.0 Ex. 175 [00222] (Z)-N-(1-(3-chlorophenyl)-2- hydroxyethyl)-2-cyano-3-hydroxy-3-(4- hydroxy-3-methoxy-5-nitrophenyl)-N- methylacrylamide MS [M H].sup. calcd for C20H18ClN3O7 446.1, found 446.1 Ex. 176 [00223] (Z)-N-(5-chloro-2-fluorobenzyl)-2-cyano- 3-hydroxy-3-(4-hydroxy-3-methoxy-5- nitrophenyl)-N- (trifluoromethyl)acrylamide MS [M H].sup. calcd for C19H12ClF4N3O6 488.0, found 488.0 Ex. 177 [00224] (Z)-N-(5-chloro-2-fluorobenzyl)-2-cyano- N-(difluoromethyl)-3-hydroxy-3-(4- hydroxy-3-methoxy-5- nitrophenyl)acrylamide MS [M H].sup. calcd for C19H13ClF3N3O6 470.0, found 470.0 Ex. 178 [00225] (Z)-N-(5-chloro-2-fluorobenzyl)-2-cyano- 3-hydroxy-3-(4-hydroxy-3-methoxy-5- nitrophenyl)-N-methoxyacrylamide MS [M H].sup. calcd for C19H15ClFN3O7 450.1, found 450.1 Ex. 179 [00226] (Z)-N-((2-chloro-5-methylpyridin-3- yl)methyl)-2-cyano-3-hydroxy-3-(4- hydroxy-3-methoxy-5-nitrophenyl)-N- methylacrylamide MS [M H].sup. calcd for C19H17ClN4O6 431.1, found 431.1 Ex. 180 [00227] (Z)-N-((2-chloro-5-fluoropyridin-4- yl)methyl)-2-cyano-3-hydroxy-3-(4- hydroxy-3-methoxy-5-nitrophenyl)-N- methylacrylamide MS [M H].sup. calcd for C18H14ClFN4O6 435.0, found 435.0 Ex. 181 [00228] (Z)-N-((2-chloro-5-hydroxypyridin-4- yl)methyl)-2-cyano-3-hydroxy-3-(4- hydroxy-3-methoxy-5-nitrophenyl)-N- methylacrylamide MS [M H].sup. calcd for C18H15ClN4O7 433.1, found 433.0 Ex. 182 [00229] (Z)-2-cyano-N-((5-fluoro-2- methylpyridin-4-yl)methyl)-3-hydroxy-3- (4-hydroxy-3-methoxy-5-nitrophenyl)-N- methylacrylamide MS [M H].sup. calcd for C19H17FN4O6 415.1, found 415.1 Ex. 183 [00230] (Z)-2-cyano-N-((5-fluoro-2- methoxypyridin-4-yl)methyl)-3-hydroxy- 3-(4-hydroxy-3-methoxy-5-nitrophenyl)- N-methylacrylamide MS [M H].sup. calcd for C19H17FN4O7 431.1, found 431.1 Ex. 184 [00231] (Z)-2-cyano-N-((2-cyano-5- hydroxypyridin-4-yl)methyl)-3-hydroxy- 3-(4-hydroxy-3-methoxy-5-nitrophenyl)- N-methylacrylamide MS [M H].sup. calcd for C19H15N5O7 424.1, found 424.1 Ex. 185 [00232] (Z)-2-cyano-N-((2-cyano-5- fluoropyridin-4-yl)methyl)-3-hydroxy-3- (4-hydroxy-3-methoxy-5-nitrophenyl)-N- methylacrylamide MS [M H].sup. calcd for C19H14FN5O6 426.1, found 426.1 Ex. 186 [00233] (Z)-2-cyano-N-((5-fluoro-2-(tetrahydro- 2H-pyran-4-yl)pyridin-4-yl)methyl)-3- hydroxy-3-(4-hydroxy-3-methoxy-5- nitrophenyl)-N-methylacrylamide MS [M H].sup. calcd for C23H23FN4O7 485.2, found 485.2 Ex. 187 [00234] (Z)-2-cyano-N-((5-fluoro-2-(1-methyl- 1H-1,2,3-triazol-4-ylamino)pyridin-4- yl)methyl)-3-hydroxy-3-(4-hydroxy-3- methoxy-5-nitrophenyl)-N- methylacrylamide MS [M H].sup. calcd for C21H19FN8O6 497.1, found 497.1 Ex. 188 [00235] (Z)-2-cyano-N-(2-fluoro-3- hydroxybenzyl)-3-hydroxy-3-(4-hydroxy- 3-methoxy-5-nitrophenyl)-N- methylacrylamide MS [M H].sup. calcd for C19H16FN3O7 416.1, found 416.1 Ex. 189 [00236] (Z)-2-cyano-N-(2-fluoro-3- (hydroxymethyl)benzyl)-3-hydroxy-3-(4- hydroxy-3-methoxy-5-nitrophenyl)-N- methylacrylamide MS [M H].sup. calcd for C20H18FN3O7 430.1, found 430.1 Ex. 190 [00237] (Z)-2-cyano-N-(2-fluoro-3-(3- methylureido)benzyl)-3-hydroxy-3-(4- hydroxy-3-methoxy-5-nitrophenyl)-N- methylacrylamide MS [M H].sup. calcd for C21H20FN5O7 472.1, found 472.1 Ex. 191 [00238] (Z)-2-cyano-N-(2-fluoro-3-(thiazol-2- ylamino)benzyl)-3-hydroxy-3-(4- hydroxy-3-methoxy-5-nitrophenyl)-N- methylacrylamide MS [M H].sup. calcd for C22H18FN5O6S 498.1, found 498.1 Ex. 192 [00239] (Z)-N-(4-chloro-2-fluorobenzyl)-2-cyano- 3-hydroxy-3-(4-hydroxy-3-methoxy-5- nitrophenyl)-N-methylacrylamide MS [M H].sup. calcd for C19H15ClFN3O6 434.0, found 434.0 Ex. 193 [00240] (Z)-2-cyano-N-(4-ethyl-2-fluorobenzyl)- 3-hydroxy-3-(4-hydroxy-3-methoxy-5- nitrophenyl)-N-methylacrylamide MS [M H].sup. calcd for C21H20FN3O6 428.1, found 428.1 Ex. 194 [00241] (Z)-2-cyano-N-(4-cyano-2-fluorobenzyl)- 3-hydroxy-3-(4-hydroxy-3-methoxy-5- nitrophenyl)-N-methylacrylamide MS [M H].sup. calcd for C20H15FN4O6 425.1, found 425.1 Ex. 195 [00242] (Z)-2-cyano-N-(2-fluoro-4-(2- (methylamino)-2-oxoethyl)benzyl)-3- hydroxy-3-(4-hydroxy-3-methoxy-5- nitrophenyl)-N-methylacrylamide MS [M H].sup. calcd for C22H21FN407 471.1, found 471.1 Ex. 196 [00243] (Z)-2-cyano-N-(2-fluoro-4-(1-methyl-1H- pyrazol-4-ylamino)benzyl)-3-hydroxy-3- (4-hydroxy-3-methoxy-5-nitrophenyl)-N- methylacrylamide MS [M H].sup. calcd for C23H21FN6O6 495.1, found 495.1 Ex. 197 [00244] (Z)-N-(4-(azetidin-1-yl)-2-fluorobenzyl)- 2-cyano-3-hydroxy-3-(4-hydroxy-3- methoxy-5-nitrophenyl)-N- methylacrylamide MS [M H].sup. calcd for C22H21FN4O6 455.1, found 455.1 Ex. 198 [00245] (Z)-2-cyano-N-(2-fluoro-4-(pyridin-3- yl)benzyl)-3-hydroxy-3-(4-hydroxy-3- methoxy-5-nitrophenyl)-N-methylacrylamide MS [M H].sup. calcd for C24H19FN4O6 477.1, found 477.1 Ex. 199 [00246] (Z)-N-(5-chloro-2-fluoro-4-(pyrazin-2- yl)benzyl)-2-cyano-3-hydroxy-3-(4- hydroxy-3-methoxy-5-nitrophenyl)-N- methylacrylamide MS [M H].sup. calcd for C23H17ClFN5O6 512.1, found 512.0 Ex. 200 [00247] (Z)-2-cyano-N-(2-fluoro-4-(3- (hydroxymethyl)pyridin-2-yl)benzyl)-3- hydroxy-3-(4-hydroxy-3-methoxy-5- nitrophenyl)-N-methylacrylamide MS [M H].sup. calcd for C25H21FN4O7 507.1, found 507.1 Ex. 201 [00248] (Z)-2-cyano-N-(2-fluoro-4-(4- methylpiperazin-1-yl)benzyl)-3-hydroxy- 3-(4-hydroxy-3-methoxy-5-nitrophenyl)- N-methylacrylamide MS [M H].sup. calcd for C24H26FN5O6 498.2, found 498.2 Ex. 202 [00249] (Z)-2-cyano-N-(2-fluoro-4-(4-(4- methylpiperazin-1-yl)piperidin-1- yl)benzyl)-3-hydroxy-3-(4-hydroxy-3- methoxy-5-nitrophenyl)-N- methylacrylamide MS [M H].sup. calcd for C29H35FN6O6 581.3, found 581.3 Ex. 203 [00250] (Z)-N-(5-chloro-2-fluoro-4-((1- methylpiperidin-4-yl)methoxy)benzyl)-2- cyano-3-hydroxy-3-(4-hydroxy-3- methoxy-5-nitrophenyl)-N- methylacrylamide MS [M H].sup. calcd for C26H28ClFN4O7 561.2, found 561.2 Ex. 204 [00251] (Z)-2-cyano-N-(2-fluoro-4-((1- methylpiperidin-4-yl)methoxy)benzyl)-3- hydroxy-3-(4-hydroxy-3-methoxy- 5-nitrophenyl)-N-methylacrylamide MS [M H].sup. calcd for C26H29FN4O7 527.2, found 527.2 Ex. 205 [00252] (Z)-N-(3-chloro-2,6-difluorobenzyl)-2- cyano-3-hydroxy-3-(4-hydroxy-3- methoxy-5-nitrophenyl)-N- methylacrylamide MS [M H].sup. calcd for C19H14ClF2N3O6 452.0, found 452.0 Ex. 206 [00253] (Z)-2-cyano-N-(2-fluoro-3,5- dimethylbenzyl)-3-hydroxy-3-(4- hydroxy-3-methoxy-5-nitrophenyl)-N- methylacrylamide MS [M H].sup. calcd for C21H20FN3O6 428.1, found 428.1 Ex. 207 [00254] (Z)-N-(5-chloro-2,4-difluorobenzyl)-2- cyano-3-hydroxy-3-(4-hydroxy-3- methoxy-5-nitrophenyl)-N- methylacrylamide MS [M H].sup. calcd for C19H14ClF2N3O6 452.0, found 452.0 Ex. 208 [00255] (Z)-N-(3-amino-5-chloro-2- fluorobenzyl)-2-cyano-3-hydroxy-3-(4- hydroxy-3-methoxy-5-nitrophenyl)-N- methylacrylamide MS [M H].sup. calcd for C19H16ClFN4O6 449.1, found 449.1 Ex. 209 [00256] (Z)-N-(3-acetamido-5-chloro-2- fluorobenzyl)-2-cyano-3-hydroxy-3-(4- hydroxy-3-methoxy-5-nitrophenyl)-N- methylacrylamide MS [M H].sup. calcd for C21H18ClFN4O7 491.1, found 491.1 Ex. 210 [00257] (Z)-N-((5-chloro-2-oxo-1,2- dihydropyridin-3-yl)methyl)-2-cyano-3- hydroxy-3-(4-hydroxy-3-methoxy-5- nitrophenyl)-N-methylacrylamide MS [M H].sup. calcd for C18H15ClN4O7 433.0, found 433.0 Ex. 211 [00258] (Z)-2-cyano-3-hydroxy-3-(4-hydroxy-3- methoxy-5-nitrophenyl)-N-methyl-N-((5- methyl-2-oxo-1,2-dihydropyridin-3- yl)methyl)acrylamide MS [M H].sup. calcd for C19H18N4O7 413.1, found 413.1 Ex. 212 [00259] (Z)-2-cyano-N-((4-fluoro-1-methyl-6- oxo-1,6-dihydropyridin-3-yl)methyl)-3- hydroxy-3-(4-hydroxy-3-methoxy-5- nitrophenyl)-N-methylacrylamide MS [M H].sup. calcd for C19H17FN4O7 431.1, found 431.1 Ex. 213 [00260] (Z)-2-cyano-3-hydroxy-3-(4-hydroxy-3- methoxy-5-nitrophenyl)-N-methyl-N-((1- phenyl-1H-1,2,3-triazol-4- yl)methyl)acrylamide MS [M H].sup. calcd for C21H18N6O6 449.1, found 449.1 Ex. 214 [00261] (Z)-2-cyano-3-hydroxy-3-(4-hydroxy-3- methoxy-5-nitrophenyl)-N-methyl-N-((1- phenyl-1H-1,2,4-triazol-3- yl)methyl)acrylamide MS [M H].sup. calcd for C21H18N6O6 449.1, found 449.1 Ex. 215 [00262] (Z)-2-cyano-3-hydroxy-3-(4-hydroxy-3- methoxy-5-nitrophenyl)-N-methyl-N-((1- phenyl-1H-imidazol-4- yl)methyl)acrylamide MS [M H].sup. calcd for C22H19N5O6 448.1, found 448.1 Ex. 216 [00263] (Z)-2-cyano-3-hydroxy-3-(4-hydroxy-3- methoxy-5-nitrophenyl)-N-methyl-N-((1- (pyridin-4-yl)-1H-1,2,3-triazol-4- yl)methyl)acrylamide MS [M H].sup. calcd for C20H17N7O6 450.1, found 450.1 Ex. 217 [00264] (Z)-2-cyano-N-((3-fluoronaphthalen-2- yl)methyl)-3-hydroxy-3-(4-hydroxy-3- methoxy-5-nitrophenyl)-N- methylacrylamide MS [M H].sup. calcd for C23H18FN3O6 450.1, found 450.1 Ex. 218 [00265] (Z)-2-cyano-N-((7-fluoroisoquinolin-6- yl)methyl)-3-hydroxy-3-(4-hydroxy-3- methoxy-5-nitrophenyl)-N- methylacrylamide MS [M H].sup. calcd for C22H17FN4O6 451.1, found 451.1 Ex. 219 [00266] (Z)-2-cyano-N-((5-fluoro-2,3- dihydrobenzofuran-6-yl)methyl)-3- hydroxy-3-(4-hydroxy-3-methoxy-5- nitrophenyl)-N-methylacrylamide MS [M H].sup. calcd for C21H18FN3O7 442.1, found 442.1 Ex. 220 [00267] (Z)-2-cyano-N-((6-fluoro-2,3- dihydrobenzofuran-5-yl)methyl)-3- hydroxy-3-(4-hydroxy-3-methoxy-5- nitrophenyl)-N-methylacrylamide MS [M H].sup. calcd for C21H18FN3O7 442.1, found 442.1 Ex. 221 [00268] (Z)-2-cyano-N-((7-fluoro-2,3- dihydrobenzo[b][1,4]dioxin-6-yl)methyl)- 3-hydroxy-3-(4-hydroxy-3-methoxy-5- nitrophenyl)-N-methylacrylamide MS [M H].sup. calcd for C21H18FN3O8 458.1, found 458.1 Ex. 222 [00269] (Z)-2-cyano-N-((7-fluoro-1H-indazol-6- yl)methyl)-3-hydroxy-3-(4-hydroxy-3- methoxy-5-nitrophenyl)-N- methylacrylamide MS [M H].sup. calcd for C20H16FN5O6 440.1, found 440.1 Ex. 223 [00270] (Z)-2-cyano-3-hydroxy-3-(4-hydroxy-3- methoxy-5-nitrophenyl)-N-methyl-N- phenethylacrylamide MS [M H].sup. calcd for C20H19N3O6 396.1, found 396.1 Ex. 224 [00271] (Z)-2-cyano-3-hydroxy-3-(4-hydroxy-3- methoxy-5-nitrophenyl)-N-methyl-N-(3- phenylpropyl)acrylamide MS [M H].sup. calcd for C21H21N3O6 410.1, found 410.1 Ex. 225 [00272] (Z)-2-cyano-3-hydroxy-3-(4-hydroxy-3- methoxy-5-nitrophenyl)-N-methyl-N-(2- (pyridin-2-yloxy)ethyl)acrylamide MS [M H].sup. calcd for C19H18N4O7 413.1, found 413.1 Ex. 226 [00273] (Z)-2-cyano-3-hydroxy-3-(4-hydroxy-3- methoxy-5-nitrophenyl)-N-methyl-N-(2- (pyridin-3-yloxy)ethyl)acrylamide MS [M H].sup. calcd for C19H18N4O7 413.1, found 413.1 Ex. 227 [00274] (Z)-2-cyano-3-hydroxy-3-(4-hydroxy-3- methoxy-5-nitrophenyl)-N-methyl-N-(2- (pyridin-4-yloxy)ethyl)acrylamide MS [M H].sup. calcd for C19H18N4O7 413.1, found 413.1 Ex. 228 [00275] (Z)-2-cyano-3-hydroxy-3-(4-hydroxy-3- methoxy-5-nitrophenyl)-N-methyl-N-(2- (2-(trifluoromethyl)phenoxy)ethyl)acrylamide MS [M H].sup. calcd for C21H18F3N3O7 480.1, found 480.1 Ex. 229 [00276] (Z)-2-cyano-3-hydroxy-3-(4-hydroxy-3- methoxy-5-nitrophenyl)-N-(2-(2- (hydroxymethyl)phenoxy)ethyl)-N- methylacrylamide MS [M H].sup. calcd for C21H21N3O8 442.1, found 442.1 Ex. 230 [00277] (Z)-2-cyano-3-hydroxy-3-(4-hydroxy-3- methoxy-5-nitrophenyl)-N-(2-(2- (hydroxymethyl)-3- methylphenoxy)ethyl)-N- methylacrylamide MS [M H].sup. calcd for C22H23N3O8 456.2, found 456.2 Ex. 231 [00278] (Z)-N-(3-(2-(2-amino-2- oxoethyl)phenyl)propyl)-2-cyano-3- hydroxy-3-(4-hydroxy-3-methoxy-5- nitrophenyl)-N-methylacrylamide MS [M H].sup. calcd for C23H24N4O7 467.2, found 467.2 Ex. 232 [00279] (Z)-N-(2-(3-acetamidophenoxy)ethyl)-2- cyano-3-hydroxy-3-(4-hydroxy-3- methoxy-5-nitrophenyl)-N- methylacrylamide MS [M H].sup. calcd for C22H22N4O8 469.1, found 469.1 Ex. 233 [00280] (Z)-N-(2-(3-(azetidin-1- yl)phenoxy)ethyl)-2-cyano-3-hydroxy-3- (4-hydroxy-3-methoxy-5-nitrophenyl)-N- methylacrylamide MS [M H].sup. calcd for C23H24N4O7 467.2, found 467.2 Ex. 234 [00281] (Z)-N-(2-(4-(azetidin-1- yl)phenoxy)ethyl)-2-cyano-3-hydroxy-3- (4-hydroxy-3-methoxy-5-nitrophenyl)-N- methylacrylamide MS [M H].sup. calcd for C23H24N4O7 467.2, found 467.2 Ex. 235 [00282] (Z)-2-cyano-3-hydroxy-3-(4-hydroxy-3- methoxy-5-nitrophenyl)-N-methyl-N-(2- (4-(pyridin-2- yl)phenoxy)ethyl)acrylamide MS [M H].sup. calcd for C25H22N4O7 489.1, found 489.1 Ex. 236 [00283] (Z)-2-cyano-3-hydroxy-3-(4-hydroxy-3- methoxy-5-nitrophenyl)-N-methyl-N-(2- (3-(pyrazin-2- yl)phenoxy)ethyl)acrylamide MS [M H].sup. calcd for C24H21N5O7 490.1, found 490.1 Ex. 237 [00284] (Z)-2-cyano-3-hydroxy-3-(4-hydroxy-3- methoxy-5-nitrophenyl)-N-methyl-N-(2- (4-methyl-3-(1H-pyrazol-1- yl)phenoxy)ethyl)acrylamide MS [M H].sup. calcd for C24H23N5O7 492.2, found 492.2 Ex. 238 [00285] (Z)-3-(2-(2-cyano-3-hydroxy-3-(4- hydroxy-3-methoxy-5-nitrophenyl)-N- methylacrylamido)ethoxy)-N,N- dimethylbenzamide MS [M H].sup. calcd for C23H24N4O8 483.2, found 483.2 Ex. 239 [00286] (Z)-2-cyano-3-hydroxy-3-(4-hydroxy-3- methoxy-5-nitrophenyl)-N-methyl-N-(2- (2-(2-oxopyridin-1(2H)-yl)pyridin-4- yloxy)ethyl)acrylamide MS [M H].sup. calcd for C24H21N5O8 506.0, found 506.0 Ex. 240 [00287] (Z)-2-cyano-N-(2-(3-(2-(dimethylamino)- 2-oxoethyl)phenoxy)ethyl)-3-hydroxy-3- (4-hydroxy-3-methoxy-5-nitrophenyl)-N- methylacrylamide MS [M H].sup. calcd for C24H26N4O8 497.2, found 497.2 Ex. 241 [00288] (Z)-2-cyano-3-hydroxy-3-(4-hydroxy-3- methoxy-5-nitrophenyl)-N-(2-(3-(2- hydroxypropyl)phenoxy)ethyl)-N- methylacrylamide MS [M H].sup. calcd for C23H25N3O8 472.2, found 472.2 Ex. 242 [00289] (Z)-5-(2-(2-cyano-3-hydroxy-3-(4- hydroxy-3-methoxy-5-nitrophenyl)-N- methylacrylamido)ethoxy)-N,2- dimethylbenzamide MS [M H].sup. calcd for C23H24N4O8 483.2, found 483.2 Ex. 243 [00290] (Z)-2-cyano-3-hydroxy-3-(4-hydroxy-3- methoxy-5-nitrophenyl)-N-methyl-N-(2- (1-methyl-1H-indazol-4- yloxy)ethyl)acrylamide MS [M H].sup. calcd for C22H21N5O7 466.1, found 466.1 Ex. 244 [00291] (Z)-2-cyano-3-hydroxy-3-(4-hydroxy-3- methoxy-5-nitrophenyl)-N-methyl-N-(2- (1-methyl-1H-benzo[d]imidazol-4- yloxy)ethyl)acrylamide MS [M H].sup. calcd for C22H21N5O7 466.1, found 466.1 Ex. 245 [00292] (Z)-2-cyano-3-hydroxy-3-(4-hydroxy-3- methoxy-5-nitrophenyl)-N-methyl-N-(2- (1-methyl-2-oxo-1,2-dihydropyridin-3- yloxy)ethyl)acrylamide MS [M H].sup. calcd for C20H20N4O8 443.1, found 443.1 Ex. 246 [00293] (Z)-2-cyano-3-hydroxy-3-(4-hydroxy-3- methoxy-5-nitrophenyl)-N-methyl-N-(2- (1-methyl-2-oxo-1,2-dihydropyridin-3- ylamino)ethyl)acrylamide MS [M H].sup. calcd for C20H21N5O7 442.1, found 442.1 Ex. 247 [00294] (Z)-2-cyano-3-hydroxy-3-(4-hydroxy-3- methoxy-5-nitrophenyl)-N-methyl-N-(3- phenylprop-2-ynyl)acrylamide MS [M H].sup. calcd for C21H17N3O6 406.1, found 406.1 Ex. 248 [00295] (Z)-2-cyano-3-hydroxy-3-(4-hydroxy-3- methoxy-5-nitrophenyl)-N-methyl-N-(3- (pyridin-3-yl)prop-2-ynyl)acrylamide MS [M H].sup. calcd for C20H16N4O6 407.1, found 407.1 Ex. 249 [00296] (Z)-2-cyano-3-hydroxy-3-(4-hydroxy-3- methoxy-5-nitrophenyl)-N-methyl-N-(4- (pyridin-3-yl)but-3-yn-2-yl)acrylamide MS [M H].sup. calcd for C21H18N4O6 421.1, found 421.1 Ex. 250 [00297] (Z)-2-cyano-3-hydroxy-3-(4-hydroxy-3- methoxy-5-nitrophenyl)-N-methyl-N-(3- (pyridin-4-yl)prop-2-ynyl)acrylamide MS [M H].sup. calcd for C21H18N4O6 421.1, found 421.1 Ex. 251 [00298] (Z)-2-cyano-N-(3-(2-cyanophenyl)prop- 2-ynyl)-3-hydroxy-3-(4-hydroxy-3- methoxy-5-nitrophenyl)-N- methylacrylamide MS [M H].sup. calcd for C22H16N4O6 431.1, found 431.1 Ex. 252 [00299] (Z)-2-cyano-N-(3-(2-fluorophenyl)prop- 2-ynyl)-3-hydroxy-3-(4-hydroxy-3- methoxy-5-nitrophenyl)-N- methylacrylamide MS [M H].sup. calcd for C21H16FN3O6 424.1, found 424.1 Ex. 253 [00300] (Z)-2-cyano-N-(3-(3-fluorophenyl)prop- 2-ynyl)-3-hydroxy-3-(4-hydroxy-3- methoxy-5-nitrophenyl)-N- methylacrylamide MS [M H].sup. calcd for C21H16FN3O6 424.1, found 424.1 Ex. 254 [00301] (Z)-2-cyano-N-(3-(4-fluorophenyl)prop- 2-ynyl)-3-hydroxy-3-(4-hydroxy-3- methoxy-5-nitrophenyl)-N- methylacrylamide MS [M H].sup. calcd for C21H16FN3O6 424.1, found 424.1 Ex. 255 [00302] (Z)-2-cyano-3-hydroxy-3-(4-hydroxy-3- methoxy-5-nitrophenyl)-N-(3-(2- hydroxyphenyl)prop-2-ynyl)-N- methylacrylamide MS [M H].sup. calcd for C21H17N3O7 422.1, found 422.1 Ex. 256 [00303] (Z)-2-cyano-3-hydroxy-3-(4-hydroxy-3- methoxy-5-nitrophenyl)-N-methyl-N-(3- o-tolylprop-2-ynyl)acrylamide MS [M H].sup. calcd for C22H19N3O6 420.1, found 4201.1 Ex. 257 [00304] (Z)-2-cyano-3-hydroxy-3-(4-hydroxy-3- methoxy-5-nitrophenyl)-N-methyl-N-(3- (1-methyl-2-oxo-1,2-dihydropyridin-3- yl)prop-2-ynyl)acrylamide MS [M H].sup. calcd for C21H18N4O7 437.1, found 437.1 Ex. 258 [00305] (Z)-2-cyano-3-hydroxy-3-(4-hydroxy-3- methoxy-5-nitrophenyl)-N-methyl-N-(3- (1-methyl-1H-pyrazol-4-yl)prop-2- ynyl)acrylamide MS [M H].sup. calcd for C19H17N5O6 410.1, found 410.1 Ex. 259 [00306] (Z)-2-cyano-3-hydroxy-3-(4-hydroxy-3- methoxy-5-nitrophenyl)-N-(2-hydroxy-3- methylbenzyl)-N-methylacrylamide MS [M H].sup. calcd for C20H19N3O7 412.1, found 412.1 Ex. 260 [00307] (Z)-2-cyano-N-(2-fluoro-3- methylbenzyl)-3-hydroxy-3-(4-hydroxy- 3-methoxy-5-nitrophenyl)-N- methylacrylamide MS [M H].sup. calcd for C20H18FN3O6 414.1, found 414.1 Ex. 261 [00308] (Z)-2-cyano-N-(2-fluoro-4- methylbenzyl)-3-hydroxy-3-(4-hydroxy- 3-methoxy-5-nitrophenyl)-N- methylacrylamide MS [M H].sup. calcd for C20H18FN3O6 414.1, found 414.1 Ex. 262 [00309] (Z)-3-(3-chloro-4-hydroxy-5- nitrophenyl)-2-cyano-3-hydroxy-N,N- dimethylacrylamide MS [M H].sup. calcd for C12H10ClN3O5 310.1, found 310.1 Ex. 263 [00310] (Z)-2-cyano-3-hydroxy-3-(4-hydroxy-3- nitrophenyl)-N-methyl-N-(3-(1-methyl-2- oxopiperidin-3-yl)prop-2- ynyl)acrylamide MS [M H].sup. calcd for C20H20N4O6 411.1, found 411.1 Ex. 264 [00311] (Z)-2-cyano-3-hydroxy-3-(4-hydroxy-3- methyl-5-nitrophenyl)-N-methyl-N-(3-(1- methyl-2-oxopiperidin-3-yl)prop-2- ynyl)acrylamide MS [M H].sup. calcd for C21H22N4O6 425.2, found 425.2 Ex. 265 [00312] (Z)-2-cyano-3-(3-fluoro-4-hydroxy-5- nitrophenyl)-3-hydroxy-N-methyl-N-(3- (1-methyl-2-oxopiperidin-3-yl)prop-2- ynyl)acrylamide MS [M H].sup. calcd for C20H19FN4O6 429.1, found 429.1 Ex. 266 [00313] (Z)-3-(3-chloro-4-hydroxy-5- nitrophenyl)-2-cyano-3-hydroxy-N- methyl-N-(3-(1-methyl-2-oxopiperidin-3- yl)prop-2-ynyl)acrylamide MS [M H].sup. calcd for C20H19ClN4O6 445.1, found 445.1 Ex. 267 [00314] (Z)-3-(3-chloro-4-hydroxy-5- nitrophenyl)-2-cyano-3-hydroxy-N- methyl-N-(4-(pyridin-2-yl)but-2- ynyl)acrylamide MS [M H].sup. calcd for C20H15ClN4O5 425.0, found 425.0 Ex. 268 [00315] (Z)-2-cyano-3-(3-cyano-5-fluoro-4- hydroxyphenyl)-3-hydroxy-N-methyl-N- (prop-2-ynyl)acrylamide MS [M H].sup. calcd for C15H10FN3O3 298.0, found 298.0 Ex. 269 [00316] (Z)-2-cyano-3-(3-cyano-4-hydroxy-5- methylphenyl)-N-(cyanomethyl)-3- hydroxy-N-methylacrylamide MS [M H].sup. calcd for C15H12N4O3 295.1, found 295.1 Ex. 270 [00317] (Z)-N-(but-2-ynyl)-2-cyano-3-(3,5- dichloro-4-hydroxyphenyl)-3-hydroxy-N- methylacrylamide MS [M H].sup. calcd for C15H12Cl2N2O3 337.0, found 337.0 Ex. 271 [00318] (Z)-2-cyano-3-(3-cyano-5-fluoro-4- hydroxyphenyl)-N-(3-cyclopropylprop-2- ynyl)-3-hydroxy-N-methylacrylamide MS [M H].sup. calcd for C18H14FN3O3 338.1, found 338.1 Ex. 272 [00319] (Z)-5-(2-cyano-3-(3-cyano-4-hydroxy-5- methylphenyl)-3-hydroxy-N- methylacrylamido)-N,N-dimethylpent-3- ynamide MS [M H].sup. calcd for C20H20N4O4 379.1, found 379.1 Ex. 273 [00320] (Z)-5-(3-(3-chloro-5-cyano-4- hydroxyphenyl)-2-cyano-3-hydroxy-N- methylacrylamido)-N,N,2-trimethylpent- 3-ynamide MS [M H].sup. calcd for C20H19ClN4O4 413.1, found 413.1 Ex. 274 [00321] (Z)-2-cyano-3-(3,5-dichloro-4- hydroxyphenyl)-3-hydroxy-N-methyl-N- (3-(1-methyl-2-oxopiperidin-3-yl)prop-2- ynyl)acrylamide MS [M H].sup. calcd for C20H19Cl2N3O4 434.0, found 434.0 Ex. 275 [00322] (Z)-2-cyano-3-(3-cyano-5-fluoro-4- hydroxyphenyl)-3-hydroxy-N-methyl-N- (4-(1-methyl-2-oxopiperidin-3-yl)but-3- yn-2-yl)acrylamide MS [M H].sup. calcd for C22H21FN4O4 423.1, found 423.1 Ex. 276 [00323] (Z)-2-cyano-3-(3-cyano-4-hydroxy-5- methylphenyl)-3-hydroxy-N-(5- hydroxyhex-2-ynyl)-N-methylacrylamide MS [M H].sup. calcd for C19H19N3O4 352.1, found 352.1 Ex. 277 [00324] (Z)-2-cyano-3-(3,5-dichloro-4- hydroxyphenyl)-N-(5,6-dihydroxyhex-2- ynyl)-3-hydroxy-N-methylacrylamide MS [M H].sup. calcd for C17H16Cl2N2O5 397.0, found 397.0 Ex. 278 [00325] (Z)-3-(3-chloro-5-cyano-4- hydroxyphenyl)-2-cyano-3-hydroxy-N- (5-hydroxy-4-methylpent-2-ynyl)-N- methylacrylamide MS [M H].sup. calcd for C18H16ClN3O4 372.1, found 372.1 Ex. 279 [00326] (Z)-2-cyano-3-(3-cyano-5-fluoro-4- hydroxyphenyl)-3-hydroxy-N-methyl-N- (4-(pyridin-2-yl)but-2-ynyl)acrylamide MS [M H].sup. calcd for C21H15FN4O3 389.1, found 389.1 Ex. 280 [00327] (Z)-2-cyano-3-(3-cyano-4-hydroxy-5- methylphenyl)-3-hydroxy-N-methyl-N- (4-(pyrazin-2-yl)but-2-ynyl)acrylamide MS [M H].sup. calcd for C21H17N5O3 386.1, found 386.1 Ex. 281 [00328] (Z)-2-cyano-3-(3,5-dichloro-4- hydroxyphenyl)-3-hydroxy-N-methyl-N- (4-(pyridin-2-yl)pent-2-ynyl)acrylamide MS [M H].sup. calcd for C21H17Cl2N3O3 428.0, found 428.0 Ex. 282 [00329] (Z)-2-cyano-N-(2-fluoro-5- methylphenoxy)-3-hydroxy-3-(4- hydroxy-3-nitrophenyl)-N- methylacrylamide MS [M H].sup. calcd for C18H14FN3O6 386.1, found 386.1 Ex. 283 [00330] (Z)-2-cyano-N-(2-fluoro-5- methylphenoxy)-3-hydroxy-3-(4- hydroxy-3-methyl-5-nitrophenyl)-N- methylacrylamide MS [M H].sup. calcd for C19H16FN3O6 400.1, found 400.1 Ex. 284 [00331] (Z)-2-cyano-3-(3-fluoro-4-hydroxy-5- nitrophenyl)-N-(2-fluoro-5- methylphenoxy)-3-hydroxy-N- methylacrylamide MS [M H].sup. calcd for C18H13F2N3O6 404.1, found 404.1 Ex. 285 [00332] (Z)-3-(3-chloro-4-hydroxy-5- nitrophenyl)-2-cyano-N-(2-fluoro-5- methylphenoxy)-3-hydroxy-N- methylacrylamide MS [M H].sup. calcd for C18H13ClFN3O6 420.1, found 420.1 Ex. 286 [00333] (Z)-3-(3-chloro-4-hydroxy-5- nitrophenyl)-2-cyano-N-(2-fluoro-5- methylphenyl)-3-hydroxy-N,N- dimethylacrylohydrazide MS [M H].sup. calcd for C19H16ClFN4O5 433.1, found 433.1 Ex. 287 [00334] (Z)-3-(3-chloro-5-cyano-4- hydroxyphenyl)-2-cyano-N-(2-fluoro-5- methylphenoxy)-3-hydroxy-N- methylacrylamide MS [M H].sup. calcd for C19H13ClFN3O4 400.0, found 400.0 Ex. 288 [00335] (Z)-2-cyano-3-hydroxy-3-(4-hydroxy-3- nitrophenyl)-N-methyl-N-(2-oxo-2- (phenylamino)ethyl)acrylamide MS [M H].sup. calcd for C19H16N4O6 395.1, found 395.1 Ex. 289 [00336] (Z)-2-cyano-3-hydroxy-3-(4-hydroxy-3- methyl-5-nitrophenyl)-N-methyl-N-(2- oxo-2-(phenylamino)ethyl)acrylamide MS [M H].sup. calcd for C20H18N4O6 409.1, found 409.1 Ex. 290 [00337] (Z)-2-cyano-3-(3-fluoro-4-hydroxy-5- nitrophenyl)-3-hydroxy-N-methyl-N-(2- oxo-2-(phenylamino)ethyl)acrylamide MS [M H].sup. calcd for C19H15FN4O6 413.1, found 413.1 Ex. 291 [00338] (Z)-3-(3-chloro-4-hydroxy-5- nitrophenyl)-2-cyano-3-hydroxy-N- methyl-N-(2-oxo-2- (phenylamino)ethyl)acrylamide MS [M H].sup. calcd for C19H15ClN4O6 429.0, found 429.0 Ex. 292 [00339] (Z)-N-(2-acetamidoethyl)-3-(3-chloro-4- hydroxy-5-nitrophenyl)-2-cyano-3- hydroxy-N-methylacrylamide MS [M H].sup. calcd for C15H15ClN4O6 381.0, found 381.0 Ex. 293 [00340] (Z)-N-(3-(azetidin-1-yl)-3-oxopropyl)-3- (3-chloro-4-hydroxy-5-nitrophenyl)-2- cyano-3-hydroxy-N-methylacrylamide MS [M H].sup. calcd for C17H17ClN4O6 407.1, found 407.1 Ex. 294 [00341] (Z)-methyl 2-(3-(3-chloro-5-cyano-4- hydroxyphenyl)-2-cyano-3-hydroxy-N- methylacrylamido)acetate MS [M H].sup. calcd for C15H12ClN3O5 348.0, found 348.0 Ex. 295 [00342] (Z)-2-cyano-3-(3-cyano-5-fluoro-4- hydroxyphenyl)-3-hydroxy-N-methyl-N- (2-oxobutyl)acrylamide MS [M H].sup. calcd for C16H14FN3O4 330.0, found 330.0 Ex. 296 [00343] (Z)-2-cyano-3-(3-cyano-4-hydroxy-5- methylphenyl)-3-hydroxy-N-methyl-N- (2-(methylamino)-2-oxoethyl)acrylamide MS [M H].sup. calcd for C16H16N4O4 327.1, found 327.1 Ex. 297 [00344] (Z)-2-cyano-3-(3,5-dichloro-4- hydroxyphenyl)-3-hydroxy-N-methyl-N- (2-oxo-2-(phenylamino)ethyl)acrylamide MS [M H].sup. calcd for C19H15Cl2N3O4 418.0, found 418.0 Ex. 298 [00345] (Z)-2-cyano-3-(3,5-dichloro-4- hydroxyphenyl)-3-hydroxy-N-methyl-N- (2-oxo-2-(pyridin-4- ylamino)ethyl)acrylamide MS [M H].sup. calcd for C18H14Cl2N4O4 419.0, found 419.0 Ex. 299 [00346] (Z)-3-(3-chloro-5-cyano-4- hydroxyphenyl)-2-cyano-N-(2- (dimethylamino)-2-oxoethyl)-3-hydroxy- N-methylacrylamide MS [M H].sup. calcd for C16H15ClN4O4 361.1, found 361.1 Ex. 300 [00347] (Z)-2-cyano-3-(3-cyano-4-hydroxy-5- methylphenyl)-3-hydroxy-N-(2- (methoxyamino)-2-oxoethyl)-N- methylacrylamide MS [M H].sup. calcd for C16H16N4O5 343.1, found 343.1 Ex. 301 [00348] (Z)-3-(3-chloro-5-cyano-4- hydroxyphenyl)-2-cyano-N-(3- (dimethylamino)-3-oxopropyl)-3- hydroxy-N-methylacrylamide MS [M H].sup. calcd for C17H17ClN4O4 375.1, found 375.1 Ex. 302 [00349] (Z)-N-(3-(azetidin-1-yl)-3-oxopropyl)-2- cyano-3-(3,5-dichloro-4-hydroxyphenyl)- 3-hydroxy-N-methylacrylamide MS [M H].sup. calcd for C17H17Cl2N3O4 376.0, found 376.0 Ex. 303 [00350] (Z)-2-cyano-3-(3-cyano-4-hydroxy-5- methylphenyl)-3-hydroxy-N-methyl-N- (3-oxo-3-phenylpropyl)acrylamide MS [M H].sup. calcd for C22H19N3O4 388.1, found 388.1 Ex. 304 [00351] (Z)-N-(2-acetamidoethyl)-2-cyano-3-(3- cyano-4-hydroxy-5-methylphenyl)-3- hydroxy-N-methylacrylamide MS [M H].sup. calcd for C17H18N4O4 341.1, found 341.1 Ex. 305 [00352] (Z)-2-(2-cyano-3-(3-cyano-4-hydroxy-5- methylphenyl)-3-hydroxy-N- methylacrylamido)ethyl dimethylcarbamate MS [M H].sup. calcd for C18H20N4O5 371.1, found 371.1 Ex. 306 [00353] (Z)-2-cyano-3-hydroxy-3-(4-hydroxy-3- nitrophenyl)-N-methyl-N-(4- methylpyridin-3-yl)acrylamide MS [M H].sup. calcd for C17H14N4O5 353.1, found 353.1 Ex. 307 [00354] (Z)-2-cyano-3-hydroxy-3-(4-hydroxy-3- methyl-5-nitrophenyl)-N-methyl-N-(4- methylpyridin-3-yl)acrylamide MS [M H].sup. calcd for C18H16N4O5 367.1, found 367.1 Ex. 308 [00355] (Z)-2-cyano-3-(3-fluoro-4-hydroxy-5- nitrophenyl)-3-hydroxy-N-methyl-N-(4- methylpyridin-3-yl)acrylamide MS [M H].sup. calcd for, found Ex. 309 [00356] (Z)-3-(3-chloro-4-hydroxy-5- nitrophenyl)-2-cyano-3-hydroxy-N- methyl-N-(4-methylpyridin-3- yl)acrylamide MS [M H].sup. calcd for C17H13FNO5 371.1, found 371.1 Ex. 310 [00357] (Z)-N-(2-chloro-5-fluorophenyl)-2- cyano-3-(3-cyano-4-hydroxy-5- methylphenyl)-3-hydroxy-N- methylacrylamide MS [M H].sup. calcd for C19H13ClFN3O3 384.0, found 384.0 Ex. 311 [00358] (Z)-2-cyano-N-(2-cyano-5-fluorophenyl)- 3-(3,5-dichloro-4-hydroxyphenyl)-3- hydroxy-N-methylacrylamide MS [M H].sup. calcd for C18H10Cl2FN3O3 404.0, found 404.0 Ex. 312 [00359] (Z)-3-(3-chloro-5-cyano-4- hydroxyphenyl)-2-cyano-3-hydroxy-N- methyl-N-(4-methylpyridin-3- yl)acrylamide MS [M H].sup. calcd for C18H13ClN4O3 367.0, found 367.0 Ex. 313 [00360] (Z)-N-(6-amino-4-methylpyridin-3-yl)-2- cyano-3-(3-cyano-5-fluoro-4- hydroxyphenyl)-3-hydroxy-N- methylacrylamide MS [M H].sup. calcd for C18H14FN5O3 366.1, found 366.1 Ex. 314 [00361] (Z)-2-cyano-3-(3-cyano-5-fluoro-4- hydroxyphenyl)-3-hydroxy-N- (isoquinolin-4-yl)-N-methylacrylamide MS [M H].sup. calcd for C21H13FN4O3 387.1, found 387.1 Ex. 315 [00362] (Z)-2-cyano-3-(3,5-dichloro-4- hydroxyphenyl)-3-hydroxy-N-methyl-N- (5-methyl-2-oxo-1,2-dihydropyridin-4- yl)acrylamide MS [M H].sup. calcd for C17H13Cl2N3O4 392.0, found 392.0 Ex. 316 [00363] (Z)-2-cyano-3-(3-cyano-4-hydroxy-5- methylphenyl)-3-hydroxy-N-methyl-N- (4-methylisoxazol-5-yl)acrylamide MS [M H].sup. calcd for C17H14N4O4 337.1, found 337.1 Ex. 317 [00364] (Z)-3-(3-chloro-5-cyano-4- hydroxyphenyl)-2-cyano-3-hydroxy-N- methyl-N-(4-phenylisoxazol-5- yl)acrylamide MS [M H].sup. calcd for C21H13ClN4O4 419.0, found 419.0 Ex. 318 [00365] (Z)-3-(3-chloro-5-cyano-4- hydroxyphenyl)-2-cyano-3-hydroxy-N- methyl-N-(5,6,7,8-tetrahydro- [1,2,4]triazolo[4,3-a]pyridin-3- yl)acrylamide MS [M H].sup. calcd for C18H15ClN6O3 397.1, found 397.1 Ex. 319 [00366] (Z)-N-(benzo[c]isoxazol-3-yl)-2-cyano-3- (3,5-dichloro-4-hydroxyphenyl)-3- hydroxy-N-methylacrylamide MS [M H].sup. calcd for C18H11Cl2N3O4 402.0, found 402.0 Ex. 320 [00367] (Z)-2-cyano-N-(2-fluoro-5- methylbenzyl)-3-hydroxy-3-(4-hydroxy- 3-nitrophenyl)-N-methylacrylamide MS [M H].sup. calcd for C19H16FN3O5 384.1, found 384.1 Ex. 321 [00368] (Z)-2-cyano-N-(2-fluoro-5- methylbenzyl)-3-hydroxy-3-(4-hydroxy- 3-methyl-5-nitrophenyl)-N- methylacrylamide MS [M H].sup. calcd for C20H18FN3O5 398.1, found 398.1 Ex. 322 [00369] (Z)-2-cyano-N-(2-fluoro-5- methoxybenzyl)-3-hydroxy-3-(4- hydroxy-3-methyl-5-nitrophenyl)-N- methylacrylamide MS [M H].sup. calcd for C20H18FN3O6 414.1, found 414.1 Ex. 323 [00370] (Z)-N-(5-chloro-2-fluorobenzyl)-2-cyano- 3-(3-ethoxy-4-hydroxy-5-nitrophenyl)-3- hydroxy-N-methylacrylamide MS [M H].sup. calcd for C20H17ClFN3O6 448.1, found 448.1 Ex. 324 [00371] (Z)-N-(5-chloro-2-fluorobenzyl)-2-cyano- 3-hydroxy-3-(4-hydroxy-3- (methoxymethyl)-5-nitrophenyl)-N- methylacrylamide MS [M H].sup. calcd for C20H17ClFN3O6 448.1, found 448.1 Ex. 325 [00372] (Z)-N-(5-chloro-2-fluorobenzyl)-2-cyano- 3-(3-(difluoromethoxy)-4-hydroxy-5- nitrophenyl)-3-hydroxy-N- methylacrylamide MS [M H].sup. calcd for C19H13ClF3N3O6 470.1, found 470.1 .sup.1H NMR (400 MHz, DMSO-d.sub.6) 8.37-8.24 (m, 1H), 7.91 (d, J = 3.5 Hz, 1H), 7.43 (dd, J = 15.0, 11.7 Hz, 2H), 7.34-7.20 (m, 2H), 4.75 (s, 2H), 3.18 (d, J = 23.5 Hz, 3H) Ex. 326 [00373] (Z)-2-cyano-N-(5-cyano-2-fluorobenzyl)- 3-(3-(difluoromethoxy)-4-hydroxy-5- nitrophenyl)-3-hydroxy-N- methylacrylamide MS [M H].sup. calcd for C20H13F3N4O6 461.1, found 461.1. Ex. 327 [00374] (Z)-N-(5-chloro-2-fluorobenzyl)-2-cyano- 3-(2-fluoro-4-hydroxy-5-nitrophenyl)-3- hydroxy-N-methylacrylamide MS [M H].sup. calcd for C18H12ClF2N3O5 422.0, found 422.0 Ex. 328 [00375] (Z)-N-(5-chloro-2-fluorobenzyl)-2-cyano- 3-(2-fluoro-4-hydroxy-3-nitrophenyl)-3- hydroxy-N-methylacrylamide MS [M H].sup. calcd for C18H12ClF2N3O5 422.0, found 422.0 Ex. 329 [00376] (Z)-2-cyano-3-(2-fluoro-4-hydroxy-3- methoxy-5-nitrophenyl)-3-hydroxy-N- methyl-N-(3-(1-methyl-2-oxopiperidin-3- yl)prop-2-ynyl)acrylamide MS [M H].sup. calcd for C21H21FN407 459.1, found 459.1 Ex. 330 [00377] (Z)-2-cyano-3-(2-fluoro-4-hydroxy-5- methoxy-3-nitrophenyl)-3-hydroxy-N- methyl-N-(3-(1-methyl-2-oxopiperidin-3- yl)prop-2-ynyl)acrylamide MS [M H].sup. calcd for C21H21FN4O7 459.1, found 459.1 Ex. 331 [00378] (Z)-N-(5-chloro-2-fluorobenzyl)-2-cyano- 3-(2-fluoro-4-hydroxy-5-methoxy-3- nitrophenyl)-3-hydroxy-N- methylacrylamide MS [M H].sup. calcd for C19H14ClF2N3O6 452.0, found 452.0 Ex. 332 [00379] (Z)-N-(5-chloro-2-fluorobenzyl)-2-cyano- 3-(2-fluoro-4-hydroxy-3-methoxy-5- nitrophenyl)-3-hydroxy-N- methylacrylamide MS [M H].sup. calcd for C19H14ClF2N3O6 452.0, found 452.0 Ex. 333 [00380] (Z)-N-(5-chloro-2-fluorobenzyl)-3-(5- chloro-4-hydroxy-2-methylphenyl)-2- cyano-3-hydroxy-N-methylacrylamide MS [M H].sup. calcd for C19H15Cl2FN2O3 407.0, found 407.0 Ex. 334 [00381] (Z)-3-(5-chloro-2-fluoro-4- hydroxyphenyl)-2-cyano-N-(5-cyano-2- fluorobenzyl)-3-hydroxy-N- methylacrylamide MS [M H].sup. calcd for C19H12ClF2N3O3 402.0, found 402.0 Ex. 335 [00382] (Z)-2-cyano-N-(5-cyano-2-fluorobenzyl)- 3-(2,5-dichloro-4-hydroxyphenyl)-3- hydroxy-N-methylacrylamide MS [M H].sup. calcd for C19H12Cl2FN3O3 418.0, found 418.0 Ex. 336 [00383] (Z)-3-(3-chloro-2-fluoro-4- hydroxyphenyl)-2-cyano-N-(5-cyano-2- fluorobenzyl)-3-hydroxy-N- methylacrylamide MS [M H].sup. calcd for C19H12ClF2N3O3 402.0, found 402.0 Ex. 337 [00384] (Z)-N-(5-chloro-2-fluorobenzyl)-2-cyano- 3-(5-cyano-2-fluoro-4-hydroxyphenyl)-3- hydroxy-N-methylacrylamide MS [M H].sup. calcd for C19H12ClF2N3O3 402.0, found 402.0 Ex. 338 [00385] (Z)-N-(5-chloro-2-fluorobenzyl)-2-cyano- 3-(5-cyano-2,4-dihydroxyphenyl)-3- hydroxy-N-methylacrylamide MS [M H].sup. calcd for C19H13ClFN3O4 400.1, found 400.1 Ex. 339 [00386] (Z)-2-cyano-3-(3-cyano-2-fluoro-4- hydroxyphenyl)-N-(2-fluoro-5- methoxybenzyl)-3-hydroxy-N- methylacrylamide MS [M H].sup. calcd for C20H15F2N3O4 398.1, found 398.1 Ex. 340 [00387] (Z)-3-(3-chloro-5-cyano-2-fluoro-4- hydroxyphenyl)-2-cyano-N-(2-fluoro-5- methylbenzyl)-3-hydroxy-N- methylacrylamide MS [M H].sup. calcd for C20H14ClF2N3O3 416.1, found 416.1 Ex. 341 [00388] (Z)-2-cyano-3-(5-cyano-2-fluoro-4- hydroxy-3-methylphenyl)-N-(2-fluoro-5- methylbenzyl)-3-hydroxy-N- methylacrylamide MS [M H].sup. calcd for C21H17F2N3O3 396.1, found 396.1 Ex. 342 [00389] (Z)-2-cyano-3-(3-cyano-2-fluoro-4- hydroxy-5-methylphenyl)-N-(2-fluoro-5- methylbenzyl)-3-hydroxy-N- methylacrylamide MS [M H].sup. calcd for C21H17F2N3O3 396.1, found 396.1 Ex. 343 [00390] (Z)-3-(5-chloro-3-cyano-2-fluoro-4- hydroxyphenyl)-2-cyano-N-(2-fluoro-5- methylbenzyl)-3-hydroxy-N- methylacrylamide MS [M H].sup. calcd for C20H14ClF2N3O3 416.0, found 416.0 Ex. 344 [00391] (Z)-2-cyano-3-(3,5-dichloro-2-fluoro-4- hydroxyphenyl)-N-(2-fluoro-5- methylbenzyl)-3-hydroxy-N- methylacrylamide MS [M H].sup. calcd for C19H14Cl2F2N2O3 425.0, found 425.0 Ex. 345 [00392] (Z)-2-cyano-3-(3,5-dichloro-2-fluoro-4- hydroxyphenyl)-N-(2-fluoro-5- methylbenzyl)-3-hydroxy-N- methylacrylamide MS [M H].sup. calcd for C19H14Cl2F2N3O3 425.0, found 425.0 Ex. 346 [00393] (Z)-3-(3-chloro-2,6-difluoro-4- hydroxyphenyl)-N-(5-chloro-2- fluorobenzyl)-2-cyano-3-hydroxy-N- methylacrylamide MS [M H].sup. calcd for C18H11Cl2F3N2O3 429.0, found 429.0 Ex. 347 [00394] (Z)-3-(3-chloro-2,5,6-trifluoro-4- hydroxyphenyl)-N-(5-chloro-2- fluorobenzyl)-2-cyano-3-hydroxy-N- methylacrylamide MS [M H].sup. calcd for C18H10Cl2F4N2O3 447.0, found 447.0 Ex. 348 [00395] (Z)-N-(5-chloro-2-fluorobenzyl)-2- cyano-3-(3-ethyl-4-hydroxy-5- nitrophenyl)-3-hydroxy-N- methylacrylamide MS [M H].sup. calcd for C20H17ClFN3O5 432.1, found 432.1 Ex. 349 [00396] (Z)-N-(5-chloro-2-fluorobenzyl)-2- cyano-3-hydroxy-3-(4-hydroxy-3- (methylthio)-5-nitrophenyl)-N- methylacrylamide MS [M H].sup. calcd for C19H15ClFN3O5S 450.0, found 450.0 Ex. 350 [00397] (Z)-N-(5-chloro-2-fluorobenzyl)-2- cyano-3-hydroxy-3-(4-hydroxy-3- (methylthiomethyl)-5-nitrophenyl)-N- methylacrylamide MS [M H].sup. calcd for C20H17ClFN3O5S 464.0, found 464.0 Ex. 351 [00398] (Z)-N-(5-chloro-2-fluorobenzyl)-2- cyano-3-hydroxy-3-(4-hydroxy-3- (hydroxymethyl)-5-nitrophenyl)-N- methylacrylamide MS [M H].sup. calcd for C19H15ClFN3O6 434.0, found 434.0 Ex. 352 [00399] (Z)-N-(5-chloro-2-fluorobenzyl)-2- cyano-3-(3-ethynyl-4-hydroxy-5- nitrophenyl)-3-hydroxy-N- methylacrylamide MS [M H].sup. calcd for C20H13ClFN3O5 428.0, found 428.0 Ex. 353 [00400] (Z)-N-(5-chloro-2-fluorobenzyl)-2-cyano- 3-hydroxy-3-(4-hydroxy-3-nitro-5- vinylphenyl)-N-methylacrylamide MS [M H].sup. calcd for C20H15ClFN3O5 430.0, found 430.0 Ex. 354 [00401] (Z)-2-cyano-3-(3-fluoro-4-hydroxy-5- nitrophenyl)-N-(2-fluoro-5- methylbenzyl)-3-hydroxy-N- methylacrylamide MS [M H].sup. calcd for C19H15F2N3O5 402.1, found 402.1 Ex. 355 [00402] (Z)-3-(3-chloro-4-hydroxy-5- nitrophenyl)-2-cyano-N-(2-fluoro-5- methylbenzyl)-3-hydroxy-N- methylacrylamide MS [M H].sup. calcd for C19H15ClFN3O5 419.0, found 419.0 Ex. 356 [00403] (Z)-3-(3-chloro-4-hydroxy-5- nitrophenyl)-2-cyano-N-ethyl-N-(2- fluoro-5-methylbenzyl)-3- hydroxyacrylamide MS [M H].sup. calcd for C20H17ClFN3O5 432.1, found 432.1 Ex. 357 [00404] (Z)-3-(3-chloro-4-hydroxy-5- nitrophenyl)-2-cyano-N-(1-(2-fluoro-5- methylphenyl)ethyl)-3-hydroxy-N- methylacrylamide MS [M H].sup. calcd for C20H17ClFN3O5 432.1, found 432.1 Ex. 358 [00405] (Z)-3-(3-chloro-4-hydroxy-5- nitrophenyl)-2-cyano-N-(2-fluoro-5- methoxybenzyl)-3-hydroxy-N- methylacrylamide MS [M H].sup. calcd for C19H15ClFN3O6 434.0, found 434.0 Ex. 359 [00406] (Z)-2-cyano-N-(2-fluoro-4-(pyridin-3- yl)benzyl)-3-hydroxy-3-(4-hydroxy-3- nitrophenyl)-N-methylacrylamide MS [M H].sup. calcd for C23H17FN4O5 447.1, found 447.1 Ex. 360 [00407] (Z)-2-cyano-N-(2-fluoro-4-(pyridin-3- yl)benzyl)-3-hydroxy-3-(4-hydroxy-3- methyl-5-nitrophenyl)-N- methylacrylamide MS [M H].sup. calcd for C24H19FN4O5 461.1, found 461.1 Ex. 361 [00408] (Z)-2-cyano-N-(2-fluoro-4-(pyridin-3- yl)benzyl)-3-(3-fluoro-4-hydroxy-5- nitrophenyl)-3-hydroxy-N- methylacrylamide MS [M H].sup. calcd for C23H16F2N4O5 465.1, found 465.1 Ex. 362 [00409] (Z)-3-(3-chloro-4-hydroxy-5- nitrophenyl)-2-cyano-3-hydroxy-N- methyl-N-(2- (phenylthio)ethyl)acrylamide MS [M H].sup. calcd for C19H16ClN3O5S 432.0, found 432.0 Ex. 363 [00410] (Z)-N-(5-chloro-2-fluorobenzyl)-2- cyano-3-(3-cyano-5-(difluoromethyl)-4- hydroxyphenyl)-3-hydroxy-N- methylacrylamide MS [M H].sup. calcd for C20H13ClF3N3O3 434.0, found 434.0 Ex. 364 [00411] (Z)-N-(5-chloro-2-fluorobenzyl)-2- cyano-3-(3-cyano-5-ethyl-4- hydroxyphenyl)-3-hydroxy-N- methylacrylamide MS [M H].sup. calcd for C21H17ClFN3O3 412.1, found 412.1 Ex. 365 [00412] (Z)-N-(5-chloro-2-fluorobenzyl)-2- cyano-3-(3-cyano-4-hydroxy-5- (methylthio)phenyl)-3-hydroxy-N- methylacrylamide MS [M H].sup. calcd for C20H15ClFN3O3S 430.1, found 430.1 Ex. 366 [00413] (Z)-3-(3-chloro-4-hydroxy-5- nitrophenyl)-2-cyano-N-(2-fluoro-4- (pyrimidin-5-yl)benzyl)-3-hydroxy-N- methylacrylamide MS [M H].sup. calcd for C22H15ClFN5O5 482.1, found 482.1 Ex. 367 [00414] (Z)-N-(5-chloro-2-fluorobenzyl)-2- cyano-3-(3-cyano-4-hydroxy-5- (hydroxymethyl)phenyl)-3-hydroxy-N- methylacrylamide MS [M H].sup. calcd for C20H15ClFN3O4 414.1, found 414.1 Ex. 368 [00415] (Z)-N-(5-chloro-2-fluorobenzyl)-3-(3- chloro-5-ethynyl-4-hydroxyphenyl)-2- cyano-3-hydroxy-N-methylacrylamide MS [M H].sup. calcd for C20H13Cl2FN2O3 417.0, found 417.0 Ex. 369 [00416] (Z)-N-(5-chloro-2-fluorobenzyl)-3-(3- chloro-4-hydroxy-5-vinylphenyl)-2- cyano-3-hydroxy-N-methylacrylamide MS [M H].sup. calcd for C20H15Cl2FN2O3 419.0, found 419.0 Ex. 370 [00417] (Z)-N-(5-chloro-2-fluorobenzyl)-2- cyano-3-(3-cyano-4-hydroxy-5- (methylthiomethyl)phenyl)-3-hydroxy-N- methylacrylamide MS [M H].sup. calcd for C21H17ClFN3O3S 444.1, found 444.1 Ex. 371 [00418] (Z)-2-cyano-3-(3,5-dichloro-4- hydroxyphenyl)-N-(2-fluoro-5- (methylthio)benzyl)-3-hydroxy-N- methylacrylamide MS [M H].sup. calcd for C19H15Cl2FN2O3S 439.0, found 439.0 Ex. 372 [00419] (Z)-2-cyano-N-(5-cyano-2- fluorobenzyl)-3-(3,5-dibromo-4- hydroxyphenyl)-3-hydroxy-N- methylacrylamide MS [M H].sup. calcd for C19H12BR.sub.2FN3O3 505.9, found 505.9 Ex. 373 [00420] (Z)-2-cyano-N-(5-cyano-2- fluorobenzyl)-3-hydroxy-3-(4-hydroxy- 3,5-diiodophenyl)-N-methylacrylamide MS [M H].sup. calcd for C19H12FI2N3O3 601.9, found 601.9 Ex. 374 [00421] (Z)-2-cyano-N-(1-(5-cyano-2- fluorophenyl)ethyl)-3-(3,5-dichloro-4- hydroxyphenyl)-3-hydroxy-N- methylacrylamide MS [M H].sup. calcd for C20H14Cl2FN3O3 432.0, found 432.0 Ex. 375 [00422] (Z)-2-cyano-N-(5-cyano-2- hydroxybenzyl)-3-(3,5-dichloro-4- hydroxyphenyl)-3-hydroxy-N- methylacrylamide MS [M H].sup. calcd for C19H13Cl2N3O4 416.0, found 416.0 Ex. 376 [00423] (Z)-2-cyano-3-(3-cyano-4-hydroxy-5- methylphenyl)-N-(2-fluoro-5-(pyrimidin- 4-yl)benzyl)-3-hydroxy-N- methylacrylamide MS [M H].sup. calcd for C24H18FN5O3 442.1, found 442.1 Ex. 377 [00424] (Z)-2-cyano-N-(4-cyano-2- fluorobenzyl)-3-(3,5-dichloro-4- hydroxyphenyl)-3-hydroxy-N- methylacrylamide MS [M H].sup. calcd for C19H12Cl2FN3O3 418.0, found 418.0 Ex. 378 [00425] (Z)-2-cyano-3-(3-cyano-4-hydroxy-5- methylphenyl)-N-(2-fluoro-5- (trifluoromethyl)benzyl)-3-hydroxy-N- methylacrylamide MS [M H].sup. calcd for C21H15F4N3O3 432.1, found 432.1 Ex. 379 [00426] (Z)-2-cyano-3-(3,5-dichloro-4- hydroxyphenyl)-N-(2-fluoro-4-(4-(4- methylpiperazin-1-yl)piperidin-1- yl)benzyl)-3-hydroxy-N- methylacrylamide MS [M H] calcd for C28H32Cl2FN503 574.2, found 574.2. Ex. 380 [00427] (Z)-2-cyano-3-(3-cyano-4-hydroxy-5- methylphenyl)-N-(2-fluoro-4-((1- methylpiperidin-4-yl)methoxy)benzyl)-3- hydroxy-N-methylacrylamide MS [M H].sup. calcd for C27H29FN4O4 491.2, found 491.2 Ex. 381 [00428] (Z)-2-cyano-3-(3-cyano-4-hydroxy-5- methylphenyl)-N-(2-fluoro-4-(pyridin-3- yl)benzyl)-3-hydroxy-N- methylacrylamide MS [M H].sup. calcd for C25H19FN4O3 441.1, found 441.1 Ex. 382 [00429] (Z)-2-cyano-3-(3,5-dichloro-4- hydroxyphenyl)-N-(2-fluoro-4-(4- methylpiperazin-1-yl)benzyl)-3-hydroxy- N-methylacrylamide MS [M H].sup. calcd for C23H23Cl2FN4O3 491.1, found 491.1 Ex. 383 [00430] (Z)-2-cyano-N-((2-cyano-5- hydroxypyridin-4-yl)methyl)-3-(3,5- dichloro-4-hydroxyphenyl)-3-hydroxy-N- methylacrylamide MS [M H].sup. calcd for C18H12Cl2N4O4 417.0, found 417.0 Ex. 384 [00431] (Z)-N-(3-acetamido-5-chloro-2- fluorobenzyl)-3-(3-chloro-5-cyano-4- hydroxyphenyl)-2-cyano-3-hydroxy-N- methylacrylamide MS [M H].sup. calcd for C21H15Cl2FN4O4 475.0, found 475.0 Ex. 385 [00432] (Z)-2-cyano-3-(3,5-dichloro-4- hydroxyphenyl)-3-hydroxy-N-methyl-N- ((1-methyl-2-oxo-1,2-dihydropyridin-3- yl)methyl)acrylamide MS [M H].sup. calcd for C18H15Cl2N3O4 406.0, found 406.0 Ex. 386 [00433] (Z)-2-cyano-N-((2-cyano-5- fluoropyridin-4-yl)methyl)-3-(3,5- dichloro-4-hydroxyphenyl)-3-hydroxy-N- methylacrylamide MS [M H].sup. calcd for C18H11Cl2FN4O3 419.0, found 419.0 Ex. 387 [00434] (Z)-2-cyano-3-(3-cyano-4-hydroxy-5- methylphenyl)-3-hydroxy-N-methyl-N- ((1-phenyl-1H-1,2,3-triazol-4- yl)methyl)acrylamide MS [M H].sup. calcd for C22H18N6O3 413.1, found 413.1 Ex. 388 [00435] (Z)-2-cyano-3-(3-cyano-4-hydroxy-5- methylphenyl)-3-hydroxy-N-methyl-N- ((1-phenyl-1H-1,2,3-triazol-4- yl)methyl)acrylamide MS [M H].sup. calcd for C20H15Cl2N5O3 442.0, found 442.0 Ex. 389 [00436] (Z)-2-cyano-3-(3-cyano-4-hydroxy-5- methylphenyl)-3-hydroxy-N-methyl-N- ((3-phenylisoxazol-5- yl)methyl)acrylamide MS [M H].sup. calcd for C23H18N4O4 413.1, found 413.1 Ex. 390 [00437] (Z)-N-((5-chloro-2-oxo-1,2- dihydropyridin-3-yl)methyl)-2-cyano-3- (3,5-dichloro-4-hydroxyphenyl)-3- hydroxy-N-methylacrylamide MS [M H].sup. calcd for C17H12Cl3N3O4 426.0, found 426.0 Ex. 391 [00438] (Z)-2-cyano-3-(3,5-dichloro-4- hydroxyphenyl)-3-hydroxy-N-methyl-N- ((5-phenyloxazol-2-yl)methyl)acrylamide MS [M H].sup. calcd for C21H15Cl2N3O4 442.0, found 442.0 Ex. 392 [00439] (Z)-2-cyano-3-(3,5-dichloro-4- hydroxyphenyl)-3-hydroxy-N-methyl-N- ((4-phenylthiazol-2-yl)methyl)acrylamide MS [M H].sup. calcd for C21H15Cl2N3O3S 428.0, found 428.0 Ex. 393 [00440] (Z)-2-cyano-3-(3-cyano-4-hydroxy-5- methylphenyl)-3-hydroxy-N-methyl-N- ((4-phenyloxazol-2-yl)methyl)acrylamide MS [M H].sup. calcd for C23H18N4O4 413.1, found 413.1 Ex. 394 [00441] (Z)-3-(3-chloro-5-cyano-4- hydroxyphenyl)-2-cyano-N-((7- fluoroisoquinolin-6-yl)methyl)-3- hydroxy-N-methylacrylamide MS [M H].sup. calcd for C22H14ClFN4O3 435.1, found 435.1 Ex. 395 [00442] (Z)-2-cyano-3-(3,5-dichloro-4- hydroxyphenyl)-N-((5-fluoro-2,3- dihydrobenzofuran-6-yl)methyl)-3- hydroxy-N-methylacrylamide MS [M H].sup. calcd for C20H15Cl2FN2O4 435.0, found 435.0 Ex. 396 [00443] (Z)-2-cyano-3-(3,5-dichloro-4- hydroxyphenyl)-N-((6-fluoro-2,3- dihydrobenzofuran-5-yl)methyl)-3- hydroxy-N-methylacrylamide MS [M H].sup. calcd for C20H15Cl2FN2O4 435.0, found 435.0 Ex. 397 [00444] (Z)-2-cyano-3-(3-cyano-4-hydroxy-5- methylphenyl)-N-((3-fluoronaphthalen-2- yl)methyl)-3-hydroxy-N- methylacrylamide MS [M H].sup. calcd for C24H18FN3O3 414.1, found 414.1 Ex. 398 [00445] (Z)-2-cyano-3-(3,5-dichloro-4- hydroxyphenyl)-N-((7-fluoro-1H-indazol- 6-yl)methyl)-3-hydroxy-N- methylacrylamide MS [M H].sup. calcd for C19H13Cl2FN4O3 433.0, found 433.0 Ex. 399 [00446] (Z)-3-(3-chloro-5-cyano-4- hydroxyphenyl)-2-cyano-3-hydroxy-N- methyl-N-phenethylacrylamide MS [M H].sup. calcd for C20H16ClN3O3 380.1, found 380.1 Ex. 400 [00447] (Z)-2-cyano-3-hydroxy-3-(4-hydroxy-3- nitrophenyl)-N-methyl-N-(2- phenoxyethyl)acrylamide MS [M H].sup. calcd for C19H17N3O6 382.1, found 382.1 Ex. 401 [00448] (Z)-2-cyano-3-(3-cyano-4- hydroxyphenyl)-N-((5-fluoro-2,3- dihydrobenzofuran-6-yl)methyl)-3- hydroxy-N-methylacrylamide MS [M H].sup. calcd for C21H16FN3O4 392.1, found 392.1 Ex. 402 [00449] (Z)-3-(3-chloro-5-cyano-4- hydroxyphenyl)-2-cyano-3-hydroxy-N- methyl-N-(2-(2- (trifluoromethyl)phenoxy)ethyl)acrylamide MS [M H].sup. calcd for C21H15ClF3N3O4 464.1, found 464.1 Ex. 403 [00450] (Z)-2-cyano-3-(3-cyano-4-hydroxy-5- methylphenyl)-3-hydroxy-N-(2-(2- (hydroxymethyl)phenoxy)ethyl)-N- methylacrylamide MS [M H].sup. calcd for C22H21N3O5 406.1, found 406.1 Ex. 404 [00451] (Z)-3-(3-chloro-5-cyano-4- hydroxyphenyl)-2-cyano-3-hydroxy-N- (2-(2-(hydroxymethyl)-3- methylphenoxy)ethyl)-N- methylacrylamide MS [M H].sup. calcd for C22H20ClN3O5 440.1, found 440.1 Ex. 405 [00452] (Z)-2-cyano-3-(3,5-dichloro-4- hydroxyphenyl)-N-((7-fluoro-2,3- dihydrobenzo[b][1,4]dioxin-6-yl)methyl)- 3-hydroxy-N-methylacrylamide MS [M H].sup. calcd for C20H15Cl2FN2O5 451.0, found 451.0 Ex. 406 [00453] (Z)-N-(2-(3-acetamidophenoxy)ethyl)-2- cyano-3-(3,5-dichloro-4-hydroxyphenyl)- 3-hydroxy-N-methylacrylamide MS [M H].sup. calcd for C21H19Cl2N3O5 462.1, found 462.1 Ex. 407 [00454] (Z)-N-(2-(3-(azetidin-1- yl)phenoxy)ethyl)-3-(3-chloro-5-cyano-4- hydroxyphenyl)-2-cyano-3-hydroxy-N- methylacrylamide MS [M H].sup. calcd for C23H21ClN404 451.1, found 451.1 Ex. 408 [00455] (Z)-N-(2-(4-(azetidin-1- yl)phenoxy)ethyl)-3-(3-chloro-5-cyano-4- hydroxyphenyl)-2-cyano-2-hydroxy-N- methylacrylamide MS [M H].sup. calcd for C23H21Cl4O4 451.1, found 451.1 Ex. 409 [00456] (Z)-2-cyano-3-hydroxy-3-(4-hydroxy-3- methyl-5-nitrophenyl)-N-methyl-N-(2- phenoxyethyl)acrylamide MS [M H].sup. calcd for C20H19N3O6 396.1, found 396.1 Ex. 410 [00457] (Z)-2-cyano-3-(3,5-dichloro-4- hydroxyphenyl)-3-hydroxy-N-methyl-N- (2-(3-(pyrazin-2- yl)phenoxy)ethyl)acrylamide MS [M H].sup. calcd for C23H18Cl2N4O4 483.1, found 483.1 Ex. 411 [00458] (Z)-2-cyano-3-(3-cyano-5-fluoro-4- hydroxyphenyl)-3-hydroxy-N-methyl-N- (2-(4-methyl-3-(1H-pyrazol-1- yl)phenoxy)ethyl)acrylamide MS [M H].sup. calcd for C24H20FN5O4 460.1, found 460.1 Ex. 412 [00459] (Z)-3-(2-(2-cyano-3-(3-cyano-4- hydroxy-5-methylphenyl)-3-hydroxy-N- methylacrylamido)ethoxy)-N,N- dimethylbenzamide MS [M H].sup. calcd for C24H24N4O5 447.2, found 447.2 Ex. 413 [00460] (Z)-N-(3-(2-(2-amino-2- oxoethyl)phenyl)propyl)-2-cyano-3-(3,5- dichloro-4-hydroxyphenyl)-3-hydroxy-N- methylacrylamide MS [M H].sup. calcd for C22H21Cl2N3O4 460.1, found 460.1 Ex. 414 [00461] (Z)-2-cyano-3-(3,5-dichloro-4- hydroxyphenyl)-N-(2-(3-(2- (dimethylamino)-2- oxoethyl)phenoxy)ethyl)-3-hydroxy-N- methylacrylamide MS [M H].sup. calcd for C23H23Cl2N3O5 490.1, found 490.1 Ex. 415 [00462] (Z)-2-cyano-3-(3,5-dichloro-4- hydroxyphenyl)-3-hydroxy-N-(2-(3-(2- hydroxypropyl)phenoxy)ethyl)-N- methylacrylamide MS [M H].sup. calcd for C22H22Cl2N2O5 463.1, found 463.1 Ex. 416 [00463] (Z)-5-(2-(2-cyano-3-(3-cyano-4- hydroxy-5-methylphenyl)-3-hydroxy-N- methylacrylamido)ethoxy)-N,2- dimethylbenzamide MS [M H].sup. calcd for C24H24N4O5 447.2, found 447.2 Ex. 417 [00464] (Z)-3-(3-chloro-5-cyano-4- hydroxyphenyl)-2-cyano-3-hydroxy-N- methyl-N-(2-(4-(pyridin-2- yl)phenoxy)ethyl)acrylamide MS [M H].sup. calcd for C25H19ClN4O4 473.1, found 473.1 Ex. 418 [00465] (Z)-2-cyano-3-(3,5-dichloro-4- hydroxyphenyl)-3-hydroxy-N-methyl-N- (2-(1-methyl-1H-indazol-4- yloxy)ethyl)acrylamide MS [M H].sup. calcd for C21H18Cl2N4O4 459.1, found 459.1 Ex. 419 [00466] (Z)-2-cyano-3-(3,5-dichloro-4- hydroxyphenyl)-3-hydroxy-N-methyl-N- (2-(1-methyl-2-oxo-1,2-dihydropyridin-3- yloxy)ethyl)acrylamide MS [M H].sup. calcd for C19H17Cl2N3O5 436.0, found 436.0 Ex. 420 [00467] (Z)-2-cyano-3-(3,5-dichloro-4- hydroxyphenyl)-3-hydroxy-N-methyl-N- (2-(1-methyl-2-oxo-1,2-dihydropyridin-3- ylamino)ethyl)acrylamide MS [M H].sup. calcd for C19H18Cl2N4O4 435.1, found 435.1 Ex. 421 [00468] (Z)-2-cyano-3-(3-cyano-4-hydroxy-5- methylphenyl)-3-hydroxy-N-methyl-N- (2-(2-(2-oxopyridin-1(2H)-yl)pyridin-4- yloxy)ethyl)acrylamide MS [M H].sup. calcd for C25H21N5O5 470.1, found 470.1 Ex. 422 [00469] (Z)-N-(3-(2-chlorophenyl)prop-2-ynyl)- 2-cyano-3-hydroxy-3-(4-hydroxy-3- nitrophenyl)-N-methylacrylamide MS [M H].sup. calcd for C20H14ClN3O5 410.1, found 410.1 Ex. 423 [00470] (Z)-N-(3-(2-chlorophenyl)prop-2-ynyl)- 2-cyano-3-hydroxy-3-(4-hydroxy-3- methyl-5-nitrophenyl)-N- methylacrylamide MS [M H].sup. calcd for C21H16ClN3O5 424.1, found 424.1 Ex. 424 [00471] (Z)-N-(3-(2-chlorophenyl)prop-2-ynyl)- 2-cyano-3-(3-fluoro-4-hydroxy-5- nitrophenyl)-3-hydroxy-N- methylacrylamide MS [M H].sup. calcd for C20H13ClFN3O5 428.0, found 428.0 Ex. 425 [00472] (Z)-2-cyano-3-(3-cyano-4-hydroxy-5- methylphenyl)-3-hydroxy-N-methyl-N- (2-(1-methyl-1H-indazol-4- yloxy)ethyl)acrylamide MS [M H].sup. calcd for C23H21N5O4 430.2, found 430.2 Ex. 426 [00473] (Z)-3-(3-chloro-4-hydroxy-5- nitrophenyl)-2-cyano-3-hydroxy-N- methyl-N-(3-(1-methyl-2-oxo-1,2- dihydropyridin-3-yl)prop-2- ynyl)acrylamide MS [M H].sup. calcd for C20H15ClN4O6 441.1, found 441.1 Ex. 427 [00474] (Z)-2-cyano-3-(3-cyano-5-fluoro-4- hydroxyphenyl)-3-hydroxy-N-methyl-N- (3-phenylprop-2-ynyl)acrylamide MS [M H].sup. calcd for C21H14FN3O3 374.1, found 374.1 Ex. 428 [00475] (Z)-2-cyano-3-(3-cyano-4-hydroxy-5- methylphenyl)-3-hydroxy-N-methyl-N- (2-(pyridin-2-yloxy)ethyl)acrylamide MS [M H].sup. calcd for C20H18N4O4 377.1, found 377.1 Ex. 429 [00476] (Z)-3-(3-chloro-5-cyano-4- hydroxyphenyl)-2-cyano-3-hydroxy-N- methyl-N-(4-(pyridin-3-yl)but-3-yn-2- yl)acrylamide MS [M H].sup. calcd for C21H15ClN4O3 405.1, found 405.1 Ex. 430 [00477] (Z)-3-(3-chloro-5-cyano-4- hydroxyphenyl)-2-cyano-3-hydroxy-N- methyl-N-(3-(pyridin-4-yl)prop-2- ynyl)acrylamide MS [M H].sup. calcd for C20H13ClN4O3 391.1, found 391.1 Ex. 431 [00478] (Z)-2-cyano-N-(3-(2-cyanophenyl)prop- 2-ynyl)-3-(3,5-dichloro-4- hydroxyphenyl)-3-hydroxy-N- methylacrylamide MS [M H].sup. calcd for C21H13Cl2N3O3 424.0, found 424.0 Ex. 432 [00479] (Z)-3-(3-chloro-4-hydroxy-5- nitrophenyl)-N-(3-(2-chlorophenyl)prop- 2-ynyl)-2-cyano-3-hydroxy-N- methylacrylamide MS [M H].sup. calcd for C20H13Cl2N3O5 444.0, found 444.0 Ex. 433 [00480] (Z)-2-cyano-3-(3-cyano-4-hydroxy-5- methylphenyl)-N-(3-(2- fluorophenyl)prop-2-ynyl)-3-hydroxy-N- methylacrylamide MS [M H].sup. calcd for C22H16FN3O3 388.1, found 388.1 Ex. 434 [00481] (Z)-2-cyano-3-(3,5-dichloro-4- hydroxyphenyl)-N-(3-(3- fluorophenyl)prop-2-ynyl)-3-hydroxy-N- methylacrylamide MS [M H].sup. calcd for C20H13Cl2FN2O3 417.0, found 417.0 Ex. 435 [00482] (Z)-2-cyano-3-(3-cyano-4-hydroxy-5- methylphenyl)-N-(3-(4- fluorophenyl)prop-2-ynyl)-3-hydroxy-N- methylacrylamide MS [M H].sup. calcd for C22H16FN3O3 388.1, found 388.1 Ex. 436 [00483] (Z)-2-cyano-3-(3-cyano-4-hydroxy-5- methylphenyl)-3-hydroxy-N-methyl-N- (3-(pyridin-3-yl)prop-2-ynyl)acrylamide MS [M H].sup. calcd for C21H16N4O3 371.1, found 371.1 Ex. 437 [00484] (Z)-2-cyano-3-(3-cyano-4-hydroxy-5- methylphenyl)-3-hydroxy-N-methyl-N- (3-o-tolylprop-2-ynyl)acrylamide MS [M H].sup. calcd for C23H19N3O3 384.1, found 384.1 Ex. 438 [00485] (Z)-2-cyano-3-(3,5-dichloro-4- hydroxyphenyl)-3-hydroxy-N-methyl-N- (3-(1-methyl-2-oxo-1,2-dihydropyridin-3- yl)prop-2-ynyl)acrylamide MS [M H].sup. calcd for C20H15Cl2N3O4 430.0, found 430.0 Ex. 439 [00486] (Z)-2-cyano-3-(3,5-dichloro-4- hydroxyphenyl)-3-hydroxy-N-methyl-N- (3-(1-methyl-1H-pyrazol-4-yl)prop-2- ynyl)acrylamide MS [M H].sup. calcd for C18H14Cl2N4O3 403.0, found 403.0 Ex. 440 [00487] (Z)-3-(3-chloro-5-cyano-4- hydroxyphenyl)-N-(3-(2- chlorophenyl)prop-2-ynyl)-2-cyano-3- hydroxy-N-methylacrylamide MS [M H].sup. calcd for C21H13Cl2N3O3 424.0, found 424.0 Ex. 441 [00488] (Z)-2-cyano-3-(3,5-dichloro-4- hydroxyphenyl)-3-hydroxy-N-(3-(2- hydroxyphenyl)prop-2-ynyl)-N- methylacrylamide MS [M H].sup. calcd for C20H14Cl2N2O4 415.0, found 415.0 Ex. 442 [00489] (Z)-3-(5-chloro-2-fluoro-4- hydroxyphenyl)-2-cyano-3-hydroxy-N- methyl-N-(2-phenoxyethyl)acrylamide MS [M H].sup. calcd for C19H16ClFN2O4 389.1, found 389.1 Ex. 443 [00490] (Z)-2-cyano-3-(3,5-dichloro-2-fluoro-4- hydroxyphenyl)-3-hydroxy-N-methyl-N- (2-phenoxyethyl)acrylamide MS [M H].sup. calcd for C19H15Cl2FN2O4 423.0, found 423.0 Ex. 444 [00491] (Z)-2-cyano-N-((7-fluoro-1,2,3,4- tetrahydroquinoxalin-6-yl)methyl)-3- hydroxy-3-(4-hydroxy-3-methoxy-5- nitrophenyl)-N-methylacrylamide MS [M H].sup. calcd for C21H20FN5O6 456.1, found 456.1 Ex. 445 [00492] (Z)-2-cyano-N-((6-fluoro-3,4-dihydro- 2H-benzo[b][1,4]oxazin-7-yl)methyl)-3- hydroxy-3-(4-hydroxy-3-methoxy-5- nitrophenyl)-N-methylacrylamide MS [M H].sup. calcd for C21H19FN4O7 457.1, found 457.1 Ex. 446 [00493] (Z)-2-cyano-N-((6-fluoro-2,3- dihydrobenzo[b][1,4]oxathiin-7- yl)methyl)-3-hydroxy-3-(4-hydroxy-3- methoxy-5-nitrophenyl)-N- methylacrylamide MS [M H].sup. calcd for C21H18FN3O7S 474.1, found 474.1 Ex. 447 [00494] (Z)-2-cyano-N-((6-fluoro-4-methyl-3,4- dihydro-2H-benzo[b][1,4]thiazin-7- yl)methyl)-3-hydroxy-3-(4-hydroxy-3- methoxy-5-nitrophenyl)-N- methylacrylamide MS [M H].sup. calcd for C22H21FN4O6S 487.1, found 487.1 Ex. 448 [00495] (Z)-2-cyano-N-((2,3-dihydrobenzofuran- 6-yl)methyl)-3-hydroxy-3-(4-hydroxy-3- methoxy-5-nitrophenyl)-N- methylacrylamide MS [M H].sup. calcd for C21H19N3O7 424.1, found 424.1 Ex. 449 [00496] (Z)-3-(3-chloro-4-hydroxy-5- nitrophenyl)-2-cyano-N-((7-fluoro- 1,2,3,4-tetrahydroquinoxalin-6- yl)methyl)-3-hydroxy-N- methylacrylamide MS [M H].sup. calcd for C20H17ClFN5O5 460.1, found 460.1 Ex. 450 [00497] (Z)-2-cyano-N-((6-fluoroisochroman-7- yl)methyl)-3-hydroxy-3-(4-hydroxy-3- methoxy-5-nitrophenyl)-N- methylacrylamide MS [M H].sup. calcd for C22H20FN3O7 456.1, found 456.1 Ex. 451 [00498] (Z)-2-cyano-3-(3-cyano-4-hydroxy-5- methylphenyl)-N-((6-fluoro-3,4-dihydro- 2H-benzo[b][1,4]oxazin-7-yl)methyl)-3- hydroxy-N-methylacrylamide MS [M H].sup. calcd for C22H19FN4O4 421.1, found 421.1 Ex. 452 [00499] (Z)-3-(3-chloro-5-cyano-4- hydroxyphenyl)-2-cyano-N-((6-fluoro- 2,3-dihydrobenzo[b][1,4]oxathiin-7- yl)methyl)-3-hydroxy-N- methylacrylamide MS [M H].sup. calcd for C21H15ClFN3O4S 458.0, found 458.0 Ex. 453 [00500] (Z)-3-(3-chloro-4-hydroxy-5- nitrophenyl)-2-cyano-N-((6-fluoro-4- methyl-3,4-dihydro-2H- benzo[b][1,4]thiazin-7-yl)methyl)-3- hydroxy-N-methylacrylamide MS [M H].sup. calcd for C21H18ClFN4O5S 491.1, found 491.1 Ex. 454 [00501] (Z)-3-(3-chloro-4-hydroxy-5- nitrophenyl)-2-cyano-N-((2,3- dihydrobenzofuran-6-yl)methyl)-3- hydroxy-N-methylacrylamide MS [M H].sup. calcd for C20H16ClN3O6 428.1, found 428.1 Ex. 455 [00502] (Z)-3-(3-chloro-4-hydroxy-5- nitrophenyl)-2-cyano-N-((6- fluoroisochroman-7-yl)methyl)-3- hydroxy-N-methylacrylamide MS [M H].sup. calcd for C21H17ClFN3O6 460.1, found 460.1 Ex. 662 [00503] (Z)-2-cyano-3-(3,5-dichloro-4- hydroxyphenyl)-3-hydroxy-N-methyl-N- ((1-methyl-1H-1,2,3-triazol-4- yl)methyl)acrylamide MS [M H] calcd for C15H13Cl2N5O3 380.0, found 380.0. .sup.1H NMR (400 MHz, DMSO-d6) 8.04 (s, 1H), 7.85 (s, 2H), 4.71 (s, 2H), 4.03 (s, 3H), 3.18 (s, 3H). Ex. 663 [00504] (Z)-2-cyano-N-(2-fluorobenzyl)-3- hydroxy-3-(4-hydroxy-3-methoxy-5- nitrophenyl)-N-methylacrylamide MS [M H] calcd for C19H16FN3O6 400.1, found 400.1. .sup.1H NMR (400 MHz, CDCl3) 11.08 (s, 1H), 8.42 (s, 1H), 7.21 (s, 1H), 7.38- 7.32 (m, 2H), 7.19-7.10 (m, 2H), 4.86 (s, 2H), 4.03 (s, 3H), 3.34 (s, 3H) Ex. 664 [00505] (Z)-N-(5-bromo-2-fluorobenzyl)-2- cyano-3-hydroxy-3-(4-hydroxy-3- methoxy-5-nitrophenyl)-N- methylacrylamide MS [M H] calcd for C19H15BrFN3O6 479.1, found 479.1. .sup.1H NMR (400 MHz, CDCl3) 11.08 (s, 1H), 8.41 (s, 1H), 7.70 (s, 1H), 7.48- 7.42 (m, 2H), 7.03-6.99 (m, 1H), 4.78 (s, 2H), 4.01 (s, 3H), 3.48 (s, 3H) Ex. 665 [00506] (Z)-N-(5-chloro-2-fluorobenzyl)-2-cyano- 3-hydroxy-3-(4-hydroxy-3-nitro-5- ((trifluoromethyl)thio)phenyl)-N- methylacrylamide MS [M H] calcd for C19H12ClF4N3O5S 504.8, found 504.8. Ex. 666 [00507] (Z)-2-cyano-N-(2-fluoro-5- ((trifluoromethyl)thio)benzyl)-3-hydroxy- 3-(4-hydroxy-3-methoxy-5-nitrophenyl)- N-methylacrylamide MS [M H] calcd for C20H15F4N3O6S 500.4, found 500.4 Ex. 668 [00508] (Z)-3-(3-chloro-4-hydroxy-5- (trifluoromethoxy)phenyl)-2-cyano-N-(2- fluoro-5-methylbenzyl)-3-hydroxy-N- methylacrylamide MS [M H] calcd for C20H15ClF4N2O4 457.1, found 457.1 Ex. 669 [00509] (Z)-N-(2-(2-chlorophenoxy)ethyl)-2- cyano-3-hydroxy-3-(4-hydroxy-3,5- dinitrophenyl)-N-methylacrylamide MS [M H] calcd for C19H15ClN4O8 461.1, found 461.1 Ex. 670 [00510] (Z)-N-(5-chloro-2-fluorobenzyl)-2-cyano- 3-(3,4-dihydroxy-5-(pentafluoro-6- sulfaneyl)phenyl)-3-hydroxy-N- methylacrylamide MS [M H] calcd for C18H13ClF6N2O4S 501.02, found 501.02 Ex. 671 [00511] (Z)-N-(5-chloro-2-fluorobenzyl)-2-cyano- 3-hydroxy-3-(4-hydroxy-3-nitro-5- (pentafluoro-6-sulfaneyl)phenyl)-N- methylacrylamide MS [M H] calcd for C18H12ClF6N3O5S 530.01, found 530.01 Ex. 672 [00512] (Z)-2-cyano-N-(2-fluoro-5-(pentafluoro- 6-sulfaneyl)benzyl)-3-hydroxy-3-(4- hydroxy-3-methoxy-5-nitrophenyl)-N- methylacrylamide MS [M H] calcd for C19H15F6N3O6S 526.06, found 526.06

Example 456: (Z)-2-cyano-N-cyclopropyl-3-(3,4-dihydroxy-5-nitrophenyl)-3-hydroxy-N-methylacrylamide

##STR00513##

[0295] The mixture of (Z)-2-cyano-N-cyclopropyl-3-hydroxy-3-(4-hydroxy-3-methoxy-5-nitrophenyl)-N-methylacrylamide (140 mg, 0.4 mmol) in DCM (20 mL) was stirred at 10 C. for 15 min. Then BBr.sub.3 (0.1 mL) was added to the above mixture. The mixture was warmed to RT and stirred overnight. The reaction was quenched with ice, and the mixture was extracted with DCM (150 mL*3). The combined extraction was dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated in vacuo to dryness. The residue was purified by Prep-HPLC (H2O/MeCN-40/60, 0.1% TFA, 2 times) to obtain the product (23 mg, HPLC: 98.4%). MS [MH].sup. calcd for C.sub.14H.sub.13N.sub.3O.sub.6 318.1, found 318.1. .sup.1H NMR (400 MHz, DMSO) 7.83 (s, 1H), 7.52 (s, 1H), 2.98 (s, 3H), 2.46 (t, J=4.0 Hz, 1H), 0.92 (s, 4H).

[0296] The following examples were synthesized in a manner similar to the above.

TABLE-US-00006 No. Structure Name Analysis Ex. 43 [00514] (Z)-2-cyano-3-(3,4-dihydroxy-5- (trifluoromethyl) phenyl)-3- hydroxy-N-isopropyl-N- methylacrylamide MS [M H].sup. calcd for C.sub.15H.sub.15F.sub.3N.sub.2O.sub.4 342.7, found 342.7. .sup.1H NMR (400 MHz, DMSO) 10.70 (s, 1H), 10.55 (s, 1H), 7.53 (d, J = m, 2H), 4.65 (s, 1H), 2.99 (s, 3H), 1. 19 (d, J = 8.0 Hz, 6H). Ex. 44 [00515] (Z)-2-cyano-3-(3,4-dihydroxy-5- (trifluoromethyl) phenyl)-3- hydroxy-N,N-dimethylacrylamide MS [M H].sup. calcd for C.sub.13H.sub.11F.sub.3N.sub.2O.sub.4 314.9, found 314.9.sup.1H NMR (400 MHz, DMSO-d.sub.6) 10.71 (s, 1H), 10.57 (s, 1H), 7.55 (s, 1H), 7.51 (s, 1H), 3.15 (s, 6H) Ex. 457 [00516] (Z)-2-cyano-3-(3-cyano-4,5- dihydroxyphenyl)-N,N-diethyl-3- hydroxyacrylamide MS [M H].sup. calcd for C15H15N3O4 299.8, found 299.8.sub. .sup.1H NMR (400 MHz, DMSO- d.sub.6) 11.182 (s, 1H), 10.761 (s, 1H), 7.623 (s, 1H), 7.445 (s, 1H), 3.570 (d, J = 6.8 Hz, 4H), 1.210 (t, J = 6.8 Hz, 6H). Ex. 458 [00517] (Z)-2-cyano-3-(3,4-dihydroxy-5- nitrophenyl)-N-ethyl-3-hydroxy-N- (2-methoxyethyl)acrylamide MS [M H].sup. calcd for C15H17N3O7 349.8, found 349.8. .sup.1HNMR (400 MHz, DMSO-d.sub.6) 7.879-7.845(m, 1H), 7.477 (s, 1H), 3.686- 3.578 (m, 5H), 3.290- 3.276 (m, 4H), 1.2O4 (s, 3H). Ex. 459 [00518] (Z)-2-cyano-3-(3,4-dihydroxy-5- (trifluoromethyl)phenyl)-N,N- diethyl-3-hydroxyacrylamide MS [MH].sup. calcd for C15H15F3N2O4 342.8, found 342.8. .sup.1H NMR (400 MHz, DMSO) 10.72 (s, 1H), 7.52 (s, 2H), 3.56 (d, J = 5.8 Hz, 4H), 1.21 (s, 6H) Ex. 460 [00519] (Z)-2-cyano-3-(3,4-dihydroxy-5- nitrophenyl)-N-ethyl-3-hydroxy-N- (3-phenylpropyl)acrylamide MS [MH].sup. calcd for C21H21N3O6 409.8, found 409.8. .sup.1H NMR (400 MHz, DMSO) 10.80 (s, 1H), 7.83 (s, 1H), 7.48 (s, 1H), 7.25 (m, 5H), 3.55 (d, J = 6.7 Hz, 4H), 2.61 (d, J = 7.5 Hz, 2H), 1.94 (s, 2H), 1.19 (s, 3H). Ex. 461 [00520] (Z)-2-cyano-3-(3,4-dihydroxy-5- nitrophenyl)-3-hydroxy-N-methyl- N-(pyridin-2-ylmethyl)acrylamide MS [M H].sup. calcd for C17H14N4O6 369.3, found 368.8. .sup.1H NMR (400 MHz, DMSO-d.sub.6) 8.544 (s, 1H), 7.813 (s, 2H), 7.336 (s, 3H), 4.721 (s, 2H), 3.450- 3.175 (m, 3H). Ex. 462 [00521] (Z)-2-cyano-3-(3,4-dihydroxy-5- nitrophenyl)-3-hydroxy-N- methoxy-N-methylacrylamide MS[M H].sup. calcd for C.sub.12H.sub.11N.sub.3O.sub.7 308.0, found 308.0. .sup.1HNMR (400 MHz, DMSO-d.sub.6) 7.893(s, 1H), 7.535(s, 1H), 3.799 (s, 3H), 3.296(s, 3H) Ex. 463 [00522] (Z)-N-butyl-2-cyano-3-(3,4- dihydroxy-5-nitrophenyl)-N-ethyl- 3-hydroxyacrylamide MS [M H].sup. calcd for C.sub.16H.sub.19N.sub.3O.sub.6 348.3, found 347.8. .sup.1HNMR (400 MHz, DMSO-d.sub.6) 7.850(s, 1H), 7.489(s, 1H), 3.586-3.570(m, 2H), 3.505(s, 2H), 1.619(s, 2H), 1.332-1.192 (m, 2H), 0.93-0 .92 (m,3H), 0.89-0.88(m, 3H) Ex. 464 [00523] (Z)-N-butyl-2-cyano-3-(3,4- dihydroxy-5-nitrophenyl)-3- hydroxy-N-methylacrylamide MS [MH].sup. calcd for C15H17N3O6 333.8, found 333.8. .sup.1H NMR (400 MHz, DMSO-d.sub.6) 10.92 (s, 1H), 7.87 (s, 1H), 7.50 (s, 1H), 3.52 (s, 2H), 3.16 (s, 3H), 1.60 (s, 2H), 1.30 (d, J = 6.9 Hz, 2H), 0.92 (t, J = 6.8 Hz, 3H) Ex. 465 [00524] (Z)-2-cyano-3-(3,4-dihydroxy-5- nitrophenyl)-N-ethyl-3-hydroxy-N- (2-(pyrimidin-2- yloxy)ethyl)acrylamide MS [MH].sup. calcd for C18H17N5O7 413.8, found 413.8. .sup.1H NMR (400 MHz, DMSO-d.sub.6) 10.84 (s, 1H), 8.61 (d, J = 4.5 Hz, 2H), 7.82 (s, 1H), 7.46 (s, 1H), 7.16 (t, J = 4.7 Hz, 1H), 4.56 (s, 2H), 3.94 (s, 2H), 3.68 (s, 2H), 1.22 (s, 3H). Ex. 466 [00525] (Z)-2-cyano-3-(3,4-dihydroxy-5- nitrophenyl)-3-hydroxy-N-(2- methoxyethyl)-N-methylacrylamide MS [M H].sup. calcd for C.sub.14H.sub.15N.sub.3O.sub.7 336.3, found 335.8.sup.1HNMR (400 MHz, DMSO-d.sub.6) 7.865(s, 1H), 7.484 (s, 1H), 3.688-3.562(m, 4H), 3.278(s, 3H), 3.185(s, 3H) Ex. 468 [00526] (Z)-2-cyano-3-(3,4-dihydroxy-5- nitrophenyl)-3-hydroxy-N-methyl- N-(3-phenylpropyl)acrylamide MS [M + H].sup.+ calcd for C.sub.20H.sub.19N.sub.3O.sub.6 398.1 found 397.8. .sup.1HNMR (400 MHz, DMSO-d.sub.6) 7.853 (s, 1H), 7.483 (s, 1H), 7.307-7.165 (m, 5H), 3.553 (s, 2H), 3.153 (s, 3H), 2.515- 2.502(m, 2H), 1.936 (s, 2H) Ex. 469 [00527] (Z)-2-cyano-N-(2-fluorobenzyl)-3- hydroxy-3-(4-hydroxy-3-methoxy- 5-nitrophenyl)-N-methylacrylamide MS [M + H].sup.+ calcd for C.sub.18H.sub.14FN.sub.3O.sub.6 388.1 found 387.7. .sup.1H NMR (400 MHz, DMSO-d.sub.6) 7.880 (s, 1H), 7.481 (s, 1H), 7.374 (s, 2H), 7.241 (s, 2H), 4.785 (s, 2H), 3.149 (s, 3H) Ex. 470 [00528] (Z)-2-cyano-N-(3-(2- cyanophenyl)propyl)-3-(3,4- dihydroxy-5-nitrophenyl)-N-ethyl- 3-hydroxyacrylamide MS [MH].sup. calcd for C22H20N4O6 434.7, found 434.7. .sup.1H NMR (400 MHz, DMSO-d.sub.6) 10.84 (s, 1H), 7.81 (m, 2H), 7.66 (t, J = 7.7 Hz, 1H), 7.47 (m, 3H), 3.59 (d, J= 7.0 Hz, 4H), 2.85 (s, 2H), 2.00 (s, 2H), 1.22 (d, J = 6.7 Hz, 3H) Ex. 471 [00529] (Z)-N-(3-(2-chlorophenyl)propyl)- 2-cyano-3-(3,4-dihydroxy-5- nitrophenyl)-N-ethyl-3- hydroxyacrylamide MS [MH].sup. calcd for C21H20ClN3O6 443.5, found 443.5. .sup.1H NMR (400 MHz, DMSO-d.sub.6) 10.83 (s, 1H), 7.84 (s, 1H), 7.48 (s, 1H), 7.41 (m, 2H), 7.26 (m, 2H), 3.59 (s, 4H), 2.73 (d, J = 7.5 Hz, 2H), 1.94 (s, 2H), 1.21 (t, J = 6.2 Hz, 3H). Ex. 472 [00530] (Z)-2-cyano-3-(3,4-dihydroxy-5- nitrophenyl)-N-ethyl-3-hydroxy-N- (3-(2- methoxyphenyl)propyl)acrylamide MS [M + H].sup.+ calcd for C22H23N3O7 442.1, found 441.7. .sup.1H NMR (400 MHz, DMSO-d.sub.6) 7.826 (s, 1H), 7.479 (s, 1H), 7.170-7.150 (m, 2H), 6.956-6.885 (m, 1H), 6.885-6.849 (m, 1H), 3.776 (s, 3H), 3.556-3.539 (m, 2H), 2.585-2.511 (m, 2H), 1.892 (s, 2H), 1.237-1.189 (m, 5H) Ex. 473 [00531] (Z)-2-cyano-3-(3,4-dihydroxy-5- nitrophenyl)-N-ethyl-3-hydroxy-N- (2,2,2-trifluoroethyl)acrylamide MS [M H].sup. calcd C14H12F3N3O6 374.1, found 374.1. .sup.1H NMR (400 MHz, DMSO-d.sub.6) 10.69(s, 2H), 7.63 (s, 1H), 7.32 (s, 1H), 4.26 (s, 2H), 3.52 (s, 2H), 1.20 (s, 3H). Ex. 474 [00532] (Z)-2-cyano-3-(3,4-dihydroxy-5- nitrophenyl)-N-((3-fluoro-[1,1- biphenyl]-4-yl)methyl)-3-hydroxy- N-methylacrylamide MS [M H].sup. calcd for C.sub.24H.sub.18FN.sub.3O.sub.6 462.1, found 461.6. .sup.1HNMR (400 MHz, DMSO-d.sub.6) 7.87 (s, 1H), 7.73-7.71 (m, 2H), 7.59-7.56 (m, 2H), 7.49-7.47 (m, 4H), 7.42-7.40 (m, 1H), 4.82(s, 2H), 3.37-3.15 (m, 3H) Ex. 475 [00533] (Z)-2-cyano-3-(3,4-dihydroxy-5- nitrophenyl)-N-((4-fluoro-[1,1- biphenyl]-3-yl)methyl)-3-hydroxy- N-methylacrylamide MS [MH].sup. calcd for C24H18FN3O6 461.6, found 461.6. .sup.1H NMR (400 MHz, DMSO-d.sub.6) 10.82 (s, 2H), 7.85 (s, 1H), 7.64 (d, J = 7.1 Hz, 4H), 7.47 (t, J = 7.6 Hz, 3H), 7.37(dd, J = 14.3, 7.0 Hz, 2H), 4.83(s, 2H), 3.17 (s, 3H) Ex. 476 [00534] ((Z)-2-cyano-3-(3,4-dihydroxy-5- nitrophenyl)-N-(2-fluoro-4- (pyridin-3-yl)benzyl)-3-hydroxy-N- methylacrylamide MS [M + H].sup.+ calcd for C.sub.23H.sub.17FN.sub.4O.sub.6 465.1, found 464.6. .sup.1H NMR (400 MHz, DMSO-d.sub.6) 8.96 (s, 1H), 8.61 (s, 1H), 8.14 (s, 1H), 7.67 (s, 1H), 7.53 (s, 1H), 7.47 (s, 1H), 7.47-7.45 (m, 3H), 4.81 (s, 2H), 3.02(s, 3H). Ex. 477 [00535] (Z)-2-cyano-3-(3,4-dihydroxy-5- nitrophenyl)-3-hydroxy-N-(2- hydroxybenzyl)-N- methylacrylamide MS [MH].sup. calcd for C18H15N3O7 383.7, found 383.7. .sup.1H NMR (400 MHz, DMSO-d.sub.6) 10.73 (m, 1H), 9.86 (s, 1H), 7.85 (d, J = 19.8 Hz, 1H), 7.46 (s, 1H), 7.13 (m, 2H), 6.82 (m, 2H), 4.63 (s, 2H), 3.06 (s, 3H). Ex. 478 [00536] (Z)-2-cyano-3-(3,4-dihydroxy-5- nitrophenyl)-N-ethyl-3-hydroxy-N- methylacrylamide MS [MH].sup. calcd for C13H13N3O6 305.8, found 305.8. .sup.1H NMR (400 MHz, DMSO-d.sub.6) 10.96 (s, 2H), 7.88 (s, 1H), 7.50 (s, 1H), 3.57 (d, J = 6.1 Hz, 2H), 3.13 (d, J = 12.9 Hz, 3H), 1.19 (t, J = 5.5 Hz, 3H). Ex. 479 [00537] (Z)-N-(2-chlorobenzyl)-2-cyano-3- (3,4-dihydroxy-5-nitrophenyl)-3- hydroxy-N-methylacrylamide MS [M H].sup. calcd for C.sub.18H.sub.14ClN.sub.3O.sub.6 402.1, found 401.6. .sup.1H NMR (400 MHz, DMSO-d.sub.6) 10.860(s, 1H), 7.865 (s, 1H), 7.493 (s, 2H), 7.365 (s, 3H), 4.802 (s, 2H), 3.145 (s, 3H) Ex. 480 [00538] (Z)-2-cyano-3-(3,4-dihydroxy-5- nitrophenyl)-N-(2-fluoro-4- methylbenzyl)-3-hydroxy-N- methylacrylamide MS [MH] calcd for C19H16FN3O6 399.6, found 399.6. .sup.1H NMR (400 MHz, DMSO-d.sub.6) 10.83 (s, 2H), 7.87 (m, 1H), 7.48 (s, 1H), 7.24 (s, 1H), 7.06 (d, J = 12.2 Hz, 2H), 4.73 (s, 2H), 3.12 (s, 3H), 2.31 (s, 3H). Ex. 481 [00539] (Z)-2-cyano-3-(3,4-dihydroxy-5- nitrophenyl)-N-(2-fluoro-3- methylbenzyl)-3-hydroxy-N- methylacrylamide MS [MH].sup. calcd for C19H16FN3O6 399.6, found 399.6. .sup.1H NMR (400 MHz, DMSO-d.sub.6) 10.87 (s, 2H), 7.86 (s, 1H), 7.48 (s, 1H), 7.24 (s, 1H), 7.11 (s, 2H), 4.77 (s, 2H), 3.12 (d, J = 10.6 Hz, 3H), 2.25 (s, 3H). Ex. 482 [00540] (Z)-2-cyano-3-(3,4-dihydroxy-5- nitrophenyl)-3-hydroxy-N-(2- hydroxy-3-methylbenzyl)-N- methylacrylamide MS [M H].sup. calcd for C.sub.19H.sub.17N.sub.3O.sub.7 398.1, found 397.7. .sup.1HNMR (400 MHz, DMSO-d.sub.6) 10.817 (s, 1H), 7.801 (s, 1H), 7.448 (s, 1H), 6.968 (s, 2H), 6.739 (s, 1H), 4.631 (s, 2H), 3.050 (s, 3H), 2.179 (s, 3H). Ex. 483 [00541] (Z)-2-cyano-3-(3,4-dihydroxy-5- nitrophenyl)-N-(2-fluoro-5- methylbenzyl)-3-hydroxy-N- methylacrylamide MS [M H].sup. calcd for C.sub.19H.sub.16FN.sub.3O.sub.6 400.1, found 399.7. .sup.1HNMR (400 MHz, DMSO-d.sub.6) 7.853(s, 1H), 7.490 (s, 1H), 7.156 (m, 3H), 4.726 (s, 2H), 3.105 (s, 3H), 2.282 (s, 3H) Ex. 484 [00542] (Z)-2-cyano-N-(3-(2- cyanophenyl)propyl)-3-(3,4- dihydroxy-5-nitrophenyl)-3- hydroxy-N-methylacrylamide MS [M H].sup. calcd for C.sub.21H.sub.18N.sub.4O.sub.6 421.1, found 420.6. .sup.1HNMR (400 MHz, DMSO-d.sub.6) 7.847 (s, 1H), 7.798- 7.779 (m, 1H), 7.673- 7.636 (m, 1H), 7.536- 7.518 (m, 2H),7.483- 7.394 (m, 1H), 3.591 (s, 2H), 3.186 (s, 3H), 2.827 (s, 2H), 1.984 (s, 2H) Ex. 485 [00543] (Z)-2-cyano-3-(3,4-dihydroxy-5- nitrophenyl)-3-hydroxy-N-methyl- N-phenethylacrylamide MS [M H].sup. calcd for C.sub.19H.sub.17N.sub.3O.sub.6 381.8, found 381.8. .sup.1H NMR (400 MHz, DMSO-d.sub.6) 7.840 (s,1H), 7.479 (s, 1H), 7.298 (s, 4H), 7.189-7.231 (m, 1H), 3.776 (s,2H), 3.153 (s, 3H), 2.917 (s, 2H) Ex. 486 [00544] (Z)-2-cyano-3-(3,4-dihydroxy-5- nitrophenyl)-3-hydroxy-N,N- dimethylacrylamide MS [M H].sup. calcd for C.sub.12H.sub.11N.sub.3O.sub.6 291.9, found 291.9. .sup.1H NMR (400 MHz, DMSO-d.sub.6) 7.71 (s, 1H), 6.87 (s, 1H), 2.84 (s, 6H) Ex. 487 [00545] (Z)-2-cyano-N-(2-fluoro-5- (pyrimidin-4-yl)benzyl)-3-hydroxy- 3-(4-hydroxy-3-methoxy-5- nitrophenyl)-N-methylacrylamide MS [M H].sup. calcd for C.sub.22H.sub.16FN.sub.5O.sub.6 463.8, found 463.8. .sup.1H NMR (400 MHz, DMSO-d.sub.6) 9.244 (s, 1H), 8.874 (d, J = 2.4 Hz, 1H), 8.238 (s, 2H), 8.121 (s, 1H), 7.844 (s, 1H), 7.443 (d, J = 8.8 Hz, 2H), 4.841 (s, 2H), 3.154 (s, 3H) Ex. 488 [00546] (Z)-2-cyano-3-(3,4-dihydroxy-5- (methylsulfonyl) phenyl)-N,N- diethyl-3-hydroxyacrylamide MS [M H].sup. calcd for C.sub.15H.sub.18N.sub.2O.sub.6S 352.7, found 352.7. .sup.1H NMR (400 MHz, DMSO-d.sub.6) 9.549 (s, 1H), 7.880 (d, J = 0.8 Hz, 1H), 7.647 (d, J = 0.8 Hz, 1H), 3.641 (d, J = 2.8 Hz, 4H), 3.215 (s, 3H), 1.319 (t, J = 7.2 Hz, 6H) Ex. 489 [00547] (Z)-2-cyano-3-(3,4-dihydroxy-5- nitrophenyl)-N-((7- fluoroisoquinolin-6-yl) methyl)-3- hydroxy-N-methylacrylamide MS [M H].sup. calcd for C.sub.21H.sub.15FN.sub.4O.sub.6 436.7, found 436.7. .sup.1H NMR (400 MHz, DMSO-d.sub.6) 9.317 (s, 1H), 8.517 (d, J = 5.6 Hz, 1H), 7.988 (d, J = 9.6 Hz, 2H), 7.870 (d, J = 2.0 Hz, 2H), 7.450 (s, 1H), 4.959 (s, 2H), 3.208 (s, 3H) Ex. 490 [00548] (Z)-2-cyano-3-(3,4-dihydroxy-5- nitrophenyl)-N-(2-fluoro-5- (trifluoromethyl)benzyl)-3- hydroxy-N-methylacrylamide MS [M H].sup. calcd for C.sub.19H.sub.13F.sub.4N.sub.3O.sub.6 454.1, found 454.1. .sup.1HNMR (400 MHz, DMSO-d.sub.6) 10.84(s, 2H), 7.83-7.75 (m, 3H), 7.52-7.45 (m, 2H), 4.82 (s, 2H), 3.14 (s, 3H) Ex. 491 [00549] (Z)-2-cyano-3-(3,4-dihydroxy-5- (trifluoromethyl)phenyl)-N-(2- fluoro-5-methylbenzyl)-3-hydroxy- N-methylacrylamide MS [M + H].sup.+ calcd for C20H16F4N2O4 425.1, found 425.1.sup.1H NMR (400 MHz, DMSO-d.sub.6) 10.73 (s, 1H), 10.56 (s, 1H), 7.50 (m, 2H), 7.15 (m, 3H), 4.74 (s, 2H), 3.14(s, 3H), 2.28 (s, 3H) Ex. 492 [00550] (Z)-2-cyano-3-(3-cyano-4,5- dihydroxyphenyl)-N-(2-fluoro-5- methylbenzyl)-3-hydroxy-N- methylacrylamide MS [M H].sup. calcd for C.sub.20H.sub.16FN.sub.3O.sub.4 380.1, found 380.2. .sup.1H NMR (400 MHz, DMSO-d.sub.6) 10.806(s, 1H), 7.619 (s, 1H), 7.436 (s, 1H), 7.159 (s, 3H), 4.733 (s, 2H), 3.128(s, 3H), 2.284(s, 3H) Ex. 493 [00551] (Z)-2-cyano-3-(3,4-dihydroxy-5- nitrophenyl)-N-(2-fluoro-3,5- dimethylbenzyl)-3-hydroxy-N- methylacrylamide MS [M H].sup. calcd for C.sub.20H.sub.18FN.sub.3O.sub.6 414.1, found 413.6. .sup.1H NMR (400 MHz, DMSO-d.sub.6) 11.37(s, 1H), 7.97 (s, 1H), 7.66(s, 1H), 7.14 (s, 2H), 4.75 (s, 2H), 3.93 (s, 3H), 3.14(s, 3H), 2.28 (s, 3H). Ex. 494 [00552] (Z)-N-(3-(2-chlorophenyl) prop-2- yn-1-yl)-2-cyano-3-(3,4-dihydroxy- 5-nitrophenyl)-3-hydroxy-N- methylacrylamide MS [M H].sup. calcd for C.sub.20H.sub.14ClN.sub.3O.sub.6 426.1, found 426.1. .sup.1H NMR (400 MHz, DMSO-d.sub.6) 7.94 (s, 1H), 7.52 (d, J = 8.0 Hz, 3H), 7.31- 7.41 (m, 2H), 4.62 (s, 2H), 3.25 (s, 3H) Ex. 495 [00553] (Z)-N-(but-2-yn-1-yl)-2-cyano-3- (3,4-dihydroxy-5-nitrophenyl)-3- hydroxy-N-methylacrylamide MS [M-H] calcd for C15H13N3O6 330.1, found 330.1. .sup.1H NMR (400 MHz, DMSO-d.sub.6) 7.83 (s, 1H), 7.45 (s, 1H), 4.23 (s, 2H), 3.14 (s, 3H), 1.78 (s, 3H). Ex. 496 [00554] (Z)-N-(5-chloro-2-fluorobenzyl)-2- cyano-3-(3,4-dihydroxy-5- (methylsulfonyl) phenyl)-3- hydroxy-N-methylacrylamide MS [M H].sup. calcd for C.sub.19H.sub.16ClFN.sub.2O.sub.6S 452.8, found 452.8.sup.1H NMR (400 MHz, DMSO-d.sub.6) 7.61 (s, 1H), 7.46 (s, 1H), 7.39 (s, 2H), 7.26 (t, J = 8.0 Hz, 1H), 4.67 (s, 2H), 3.21 (s, 3H), 3.06 (s, 3H) Ex. 497 [00555] (Z)-2-cyano-3-(3,4-dihydroxy-5- nitrophenyl)-3-hydroxy-N- isopropyl-N-methylacrylamide MS [M H].sup. calcd for C14H15N3O6 320.1, found 320.1 Ex. 498 [00556] (Z)-2-cyano-3-(3,4-dihydroxy-5- nitrophenyl)-3-hydroxy-N-methyl- N-propylacrylamide MS [M H].sup. calcd for C14H15N3O6 320.1, found 320.1 Ex. 499 [00557] (Z)-2-cyano-3-(3,4-dihydroxy-5- nitrophenyl)-3-hydroxy-N-isobutyl- N-methylacrylamide MS [M H].sup. calcd for C15H17N3O6 334.1, found 334.1 Ex. 500 [00558] (Z)-2-cyano-3-(3,4-dihydroxy-5- nitrophenyl)-3-hydroxy-N-methyl- N-(2-(methylthio)ethyl)acrylamide MS [M H].sup. calcd for C14H15N3O6S 352.1, found 352.1 Ex. 501 [00559] (Z)-2-cyano-3-(3,4-dihydroxy-5- nitrophenyl)-3-hydroxy-N-methyl- N-(trifluoromethyl)acrylamide MS [M H].sup. calcd for C12H8F3N3O6 346.0, found 346.0 Ex. 502 [00560] (Z)-2-cyano-N,N-diethyl-3-(3- ethynyl-4,5-dihydroxyphenyl)-3- hydroxyacrylamide MS [M H].sup. calcd for C16H16N2O4 299.1, found 299.1 Ex. 503 [00561] (Z)-2-cyano-3-(3,4-dihydroxy-5- vinylphenyl)-N,N-diethyl-3- hydroxyacrylamide MS [M H].sup. calcd for C16H18N2O4 301.1, found 301.1 Ex. 504 [00562] (Z)-2-cyano-3-(3-cyano-4,5- dihydroxyphenyl)-3-hydroxy-N,N- dimethylacrylamide MS [M H].sup. calcd for C13H11N3O4 272.1, found 272.1 Ex. 505 [00563] (Z)-2-cyano-3-(3,4-dihydroxy-5- nitrophenyl)-3-hydroxy-N-methyl- N-(2- (methylamino)ethyl)acrylamide MS [M H].sup. calcd for C14H16N4O6 335.1, found 335.1 Ex. 506 [00564] (Z)-2-cyano-3-(3,4-dihydroxy-5- nitrophenyl)-3-hydroxy-N-methyl- N-(prop-2-ynyl)acrylamide MS [M H].sup. calcd for C14H1IN3O6 316.0, found 316.0 Ex. 507 [00565] (Z)-2-cyano-N-(cyanomethyl)-3- (3,4-dihydroxy-5-nitrophenyl)-3- hydroxy-N-methylacrylamide MS [M H].sup. calcd for C13H10N4O6 317.1, found 317.1 Ex. 508 [00566] (Z)-N-(but-2-ynyl)-2-cyano-3-(3,4- dihydroxy-5-nitrophenyl)-N-ethyl- 3-hydroxyacrylamide MS [M H].sup. calcd for C16H15N3O6 344.1, found 344.1 Ex. 509 [00567] (Z)-N-(but-2-ynyl)-2-cyano-3-(3,4- dihydroxy-5-nitrophenyl)-3- hydroxy-N- (trifluoromethyl)acrylamide MS [M H].sup. calcd for C15H10F3N3O6 384.0, found 384.0 Ex. 510 [00568] (Z)-2-cyano-3-(3,4-dihydroxy-5- nitrophenyl)-3-hydroxy-N-methyl- N-(4,4,4-trifluorobut-2- ynyl)acrylamide MS [M H].sup. calcd for C15H10F3N3O6 384.0, found 384.0 Ex. 511 [00569] (Z)-2-cyano-N-(3- cyclopropylprop-2-ynyl)-3-(3,4- dihydroxy-5-nitrophenyl)-3- hydroxy-N-methylacrylamide MS [M H].sup. calcd for C17H15N3O6 356.1, found 356.1 Ex. 512 [00570] (Z)-2-cyano-3-(3,4-dihydroxy-5- nitrophenyl)-N-ethynyl-3-hydroxy- N-methylacrylamide MS [M H].sup. calcd for C13H9N3O6 302.0, found 302.0 Ex. 513 [00571] (Z)-2-cyano-3-(3,4-dihydroxy-5- nitrophenyl)-N-(4,4-dimethylpent- 2-ynyl)-3-hydroxy-N- methylacrylamide MS [M H].sup. calcd for C18H19N3O6 372.1, found 372.1 Ex. 514 [00572] (Z)-5-(2-cyano-3-(3,4-dihydroxy- 5-nitrophenyl)-3-hydroxy-N- methylacrylamido)-N,N- dimethylpent-3-ynamide MS [M H].sup. calcd for C18H18N4O7 401.1, found 401.1 Ex. 515 [00573] (Z)-5-(2-cyano-3-(3,4-dihydroxy- 5-nitrophenyl)-3-hydroxy-N- methylacrylamido)-N,N,2- trimethylpent-3-ynamide MS [M H].sup. calcd for C19H20N4O7 415.1, found 415.1 Ex. 516 [00574] (Z)-2-cyano-3-(3,4-dihydroxy-5- nitrophenyl)-3-hydroxy-N-methyl- N-(pent-3-yn-2-yl)acrylamide MS [M H].sup. calcd for C16H15N3O6 346.1, found 346.1 Ex. 517 [00575] (Z)-2-cyano-3-(3,4-dihydroxy-5- nitrophenyl)-3-hydroxy-N-methyl- N-(4-(1-methyl-2-oxopiperidin-3- yl)but-3-yn-2-yl)acrylamide MS [M H].sup. calcd for C21H22N4O7 441.1, found 441.1 Ex. 518 [00576] (Z)-2-cyano-3-(3,4-dihydroxy-5- nitrophenyl)-3-hydroxy-N-(5- hydroxyhex-2-ynyl)-N- methylacrylamide MS [M H].sup. calcd for C17H17N3O7 374.1, found 374.1 Ex. 519 [00577] (Z)-2-cyano-3-(3,4-dihydroxy-5- nitrophenyl)-N-(5,6-dihydroxyhex- 2-ynyl)-3-hydroxy-N- methylacrylamide MS [M H].sup. calcd for C17H17N3O8 390.1, found 390.1 Ex. 520 [00578] (Z)-2-cyano-3-(3,4-dihydroxy-5- nitrophenyl)-3-hydroxy-N-(3-(1- hydroxycyclopropyl)prop-2-ynyl)- N-methylacrylamide MS [M H].sup. calcd for C17H15N3O7 372.1, found 372.1 Ex. 521 [00579] (Z)-2-cyano-3-(3,4-dihydroxy-5- nitrophenyl)-3-hydroxy-N-methyl- N-(4-(pyridin-2-yl)but-2- ynyl)acrylamide MS [M H].sup. calcd for C20H16N4O6 407.1 , found 407.1 Ex. 522 [00580] (Z)-2-cyano-3-(3,4-dihydroxy-5- nitrophenyl)-3-hydroxy-N-methyl- N-(4-(pyrazin-2-yl)but-2- ynyl)acrylamide MS [M H].sup. calcd for C19H15N5O6 408.1, found 408.1 Ex. 523 [00581] (Z)-2-cyano-3-(3,4-dihydroxy-5- nitrophenyl)-3-hydroxy-N-methyl- N-(4-(pyridin-2-yl)pent-2- ynyl)acrylamide MS [M H].sup. calcd for C21H18N4O6 421.1, found 421.1 Ex. 524 [00582] (Z)-2-cyano-3-(3,4-dihydroxy-5- nitrophenyl)-3-hydroxy-N-methyl- N-(3-(1-methyl-2-oxopiperidin-3- yl)prop-2-ynyl)acrylamide MS [M H].sup. calcd for C20H20N4O7 427.1, found 427.1 Ex. 525 [00583] (Z)-2-cyano-3-(3,4-dihydroxy-5- nitrophenyl)-3-hydroxy-N,N,N- trimethylacrylohydrazide MS [M H].sup. calcd for C13H14N4O6 321.1, found 321.1 Ex. 526 [00584] (Z)-2-cyano-3-(3,4-dihydroxy-5- nitrophenyl)-N-(2-fluoro-5- methylphenyl)-3-hydroxy-N,N- dimethylacrylohydrazide MS [M H].sup. calcd for C19H17FN4O6 415.1, found 415.1 Ex. 527 [00585] (Z)-N-carbamoyl-2-cyano-3-(3,4- dihydroxy-5-nitrophenyl)-3- hydroxy-N-methylacrylamide MS [M H].sup. calcd for C12H10N4O7 321.0, found 321.0 Ex. 528 [00586] (Z)-2-cyano-3-(3,4-dihydroxy-5- nitrophenyl)-3-hydroxy-N-(5- hydroxy-4-methylpent-2-ynyl)-N- methylacrylamide MS [M H].sup. calcd for C17H17N3O7 374.1, found 374.1 Ex. 529 [00587] (Z)-2-(2-cyano-3-(3,4-dihydroxy- 5-nitrophenyl)-3-hydroxy-N- methylacrylamido)propanoic acid MS [M H].sup. calcd for C14H13N3O8 350.1, found 350.1 Ex. 530 [00588] (Z)-methyl 2-(2-cyano-3-(3,4- dihydroxy-5-nitrophenyl)-3- hydroxy-N- methylacrylamido)acetate MS [M H].sup. calcd for C14H13N3O8 350.1, found 350.1 Ex. 531 [00589] (Z)-2-cyano-3-(3,4-dihydroxy-5- nitrophenyl)-3-hydroxy-N-methyl- N-(2-oxobutyl)acrylamide MS [M H].sup. calcd for C15H15N3O7 348.1, found 348.1 Ex. 532 [00590] (Z)-2-cyano-3-(3,4-dihydroxy-5- nitrophenyl)-3-hydroxy-N,N- dimethylacrylohydrazide MS [M H].sup. calcd for C12H12N4O6 307.1, found 307.1 Ex. 533 [00591] (Z)-N-(1-amino-1-oxopropan-2- yl)-2-cyano-3-(3,4-dihydroxy-5- nitrophenyl)-3-hydroxy-N- methylacrylamide MS [M H].sup. calcd for C14H14N4O7 349.1, found 349.1 Ex. 534 [00592] (Z)-2-cyano-3-(3,4-dihydroxy-5- nitrophenyl)-3-hydroxy-N-methyl- N-(2-(methylamino)-2- oxoethyl)acrylamide MS [M H].sup. calcd for C14H14N4O7 349.1, found 349.1 Ex. 535 [00593] (Z)-2-cyano-3-(3,4-dihydroxy-5- nitrophenyl)-3-hydroxy-N-methyl- N-(2-oxo-2-(pyridin-4- ylamino)ethyl)acrylamide MS [M H].sup. calcd for C18H15N5O7 412.1, found 412.1 Ex. 536 [00594] (Z)-2-cyano-3-(3,4-dihydroxy-5- nitrophenyl)-3-hydroxy-N-methyl- N-(methylsulfonyl)acrylamide MS [M H].sup. calcd for C12H11N3O8S 356.0, found 356.0 Ex. 537 [00595] (Z)-2-cyano-3-(3,4-dihydroxy-5- nitrophenyl)-3-hydroxy-N-(2- (methoxyamino)-2-oxoethyl)-N- methylacrylamide MS [M H].sup. calcd for C14H14N4O8 365.1, found 365.1 Ex. 538 [00596] (Z)-2-cyano-3-(3,4-dihydroxy-5- nitrophenyl)-N-(3- (dimethylamino)-3-oxopropyl)-3- hydroxy-N-methylacrylamide MS [M H].sup. calcd for C16H18N4O7 377.1, found 377.1 Ex. 539 [00597] (Z)-N-(3-(azetidin-1-yl)-3- oxopropyl)-2-cyano-3-(3,4- dihydroxy-5-nitrophenyl)-3- hydroxy-N-methylacrylamide MS [M H].sup. calcd for C17H18N4O7 389.1, found 389.1 Ex. 540 [00598] (Z)-N-(2-amino-2-oxoethyl)-2- cyano-3-(3,4-dihydroxy-5- nitrophenyl)-3-hydroxy-N- methylacrylamide MS [M H].sup. calcd for C13H12N4O7 335.1, found 335.1 Ex. 541 [00599] (Z)-N-(2-acetamidoethyl)-2-cyano- 3-(3,4-dihydroxy-5-nitrophenyl)-3- hydroxy-N-methylacrylamide MS [M H].sup. calcd for C15H16N4O7 363.1, found 363.1 Ex. 542 [00600] (Z)-2-(2-cyano-3-(3,4-dihydroxy-5- nitrophenyl)-3-hydroxy-N- methylacrylamido)ethyl dimethylcarbamate MS [M H].sup. calcd for C16H18N4O8 393.1, found 393.1 Ex. 543 [00601] (Z)-2-cyano-N-cyclopropyl-3-(3,4- dihydroxy-5-nitrophenyl)-N-ethyl- 3-hydroxyacrylamide MS [M H].sup. calcd for C15H15N3O6 332.1, found 332.1 Ex. 544 [00602] (Z)-2-cyano-3-(3,4-dihydroxy-5- nitrophenyl)-N-(2- (dimethylamino)-2-oxoethyl)-3- hydroxy-N-methylacrylamide MS [M H].sup. calcd for C15H16N4O7 363.1 , found 363.1 Ex. 545 [00603] (Z)-N-(2-chloro-5-fluorophenyl)-2- cyano-3-(3,4-dihydroxy-5- nitrophenyl)-3-hydroxy-N- methylacrylamide MS [M H].sup. calcd for C17H11ClFN3O6 406.0 ,found 406.0 Ex. 546 [00604] (Z)-2-cyano-N-(2-cyano-5- fluorophenyl)-3-(3,4-dihydroxy-5- nitrophenyl)-3-hydroxy-N- methylacrylamide MS [M H].sup. calcd for C18H11FN4O6 397.1, found 397.1 Ex. 547 [00605] (Z)-2-cyano-3-(3,4-dihydroxy-5- nitrophenyl)-N-ethyl-N-(5-fluoro-2- methylphenyl)-3- hydroxyacrylamide MS [M H].sup. calcd for C19H16FN3O6 400.1, found 400.1 Ex. 548 [00606] (Z)-2-cyano-3-(3,4-dihydroxy-5- nitrophenyl)-3-hydroxy-N-methyl- N-(3-oxo-3- phenylpropyl)acrylamide MS [M H].sup. calcd for C20H17N3O7 410.1, found 410.1 Ex. 549 [00607] (Z)-2-cyano-3-(3,4-dihydroxy-5- nitrophenyl)-3-hydroxy-N-(4- methoxypyridin-3-yl)-N- methylacrylamide MS [M H].sup. calcd for C17H14N4O7 385.1, found 385.1 Ex. 550 [00608] (Z)-2-cyano-3-(3,4-dihydroxy-5- nitrophenyl)-3-hydroxy-N-methyl- N-(4-methylpyrimidin-5- yl)acrylamide MS [M H].sup. calcd for C16H13N5O6 370.1, found 370.1 Ex. 551 [00609] (Z)-2-cyano-3-(3,4-dihydroxy-5- nitrophenyl)-N-ethyl-3-hydroxy-N- (4-methylpyridin-3-yl)acrylamide MS [M H].sup. calcd for C18H16N4O6 383.1, found 383.1 Ex. 552 [00610] (Z)-2-cyano-3-(3,4-dihydroxy-5- nitrophenyl)-N-(5-fluoro-2- methylphenyl)-3-hydroxy-N- methylacrylamide MS [M H].sup. calcd for C18H14FN3O6 386.1, found 386.1 Ex. 553 [00611] (Z)-2-cyano-3-(3,4-dihydroxy-5- nitrophenyl)-3-hydroxy-N-(5- methoxypyridin-3-yl)-N- methylacrylamide MS [M H].sup. calcd for C17H14N4O7 385.1, found 385.1 Ex. 554 [00612] (Z)-2-cyano-3-(3,4-dihydroxy-5- nitrophenyl)-3-hydroxy-N-methyl- N-(5-phenoxypyridin-3- yl)acrylamide MS [M H].sup. calcd for C22H16N4O7 447.1, found 447.1 Ex. 555 [00613] (Z)-2-cyano-3-(3,4-dihydroxy-5- nitrophenyl)-N-(5-fluoro-4- methylpyridin-3-yl)-3-hydroxy-N- methylacrylamide MS [M H].sup. calcd for C17H13FN4O6 387.1, found 387.1 Ex. 556 [00614] (Z)-2-cyano-3-(3,4-dihydroxy-5- nitrophenyl)-3-hydroxy-N-methyl- N-(4-methylpyridin-3- yl)acrylamide MS [M H].sup. calcd for C17H14N4O6 369.1 , found 369.1 Ex. 557 [00615] (Z)-N-(6-amino-4-methylpyridin-3- yl)-2-cyano-3-(3,4-dihydroxy-5- nitrophenyl)-3-hydroxy-N- methylacrylamide MS [M H].sup. calcd for C17H15N5O6 384.1, found 384.1 Ex. 558 [00616] (Z)-N-(6-acetamido-4- methylpyridin-3-yl)-2-cyano-3- (3,4-dihydroxy-5-nitrophenyl)-3- hydroxy-N-methylacrylamide MS [M-H] calcd for C19H17N5O7 426.1, found 426.1 Ex. 559 [00617] (Z)-2-cyano-3-(3,4-dihydroxy-5- nitrophenyl)-3-hydroxy-N-methyl- N-(4-methyl-6-(3- methylureido)pyridin-3- yl)acrylamide MS [M H].sup. calcd for C19H18N6O7 441.1, found 441.1 Ex. 560 [00618] (Z)-N-(4-benzylpyridin-3-yl)-2- cyano-3-(3,4-dihydroxy-5- nitrophenyl)-3-hydroxy-N- methylacrylamide MS [M H].sup. calcd for C23H18N4O6 445.1, found 445.1 Ex. 561 [00619] (Z)-2-cyano-3-(3,4-dihydroxy-5- nitrophenyl)-3-hydroxy-N- (isoxazol-5-yl)-N- methylacrylamide MS [M H].sup. calcd for C14H10N4O7 345.0, found 345.0 Ex. 562 [00620] (Z)-2-cyano-3-(3,4-dihydroxy-5- nitrophenyl)-3-hydroxy-N-methyl- N-(4-methylisoxazol-5- yl)acrylamide MS [M H].sup. calcd for C15H12N4O7 359.1, found 359.1 Ex. 563 [00621] (Z)-2-cyano-3-(3,4-dihydroxy-5- nitrophenyl)-3-hydroxy-N-methyl- N-(4-methyl-4H-1,2,4-triazol-3- yl)acrylamide MS [M H].sup. calcd for C14H12N6O6 359.1, found 359.1 Ex.564 [00622] (Z)-2-cyano-3-(3,4-dihydroxy-5- nitrophenyl)-N-(4,6- dimethylpyridin-3-yl)-3-hydroxy- N-methylacrylamide MS [M H].sup. calcd for C18H16N4O6 383.1, found 383.1 Ex. 565 [00623] (Z)-2-cyano-3-(3,4-dihydroxy-5- nitrophenyl)-3-hydroxy-N-methyl- N-(4-phenylisoxazol-5- yl)acrylamide MS [M H].sup. calcd for C20H14N4O7 421.1, found 421.1 Ex. 566 [00624] (Z)-2-cyano-3-(3,4-dihydroxy-5- nitrophenyl)-N-(3,4- dimethylisoxazol-5-yl)-3-hydroxy- N-methylacrylamide MS [M H].sup. calcd for C16H14N4O7 373.1, found 373.1 Ex. 567 [00625] (Z)-2-cyano-3-(3,4-dihydroxy-5- nitrophenyl)-3-hydroxy-N-methyl- N-(3-methyl-4-phenylisoxazol-5- yl)acrylamide MS [M H].sup. calcd for C21H16N4O7 435.1, found 435.1 Ex. 568 [00626] (Z)-2-cyano-3-(3,4-dihydroxy-5- nitrophenyl)-3-hydroxy-N-methyl- N-(5-methyl-2-oxo-1,2- dihydropyridin-4-yl)acrylamide MS [M H].sup. calcd for C17H14N4O7 385.1, found 385.1 Ex. 569 [00627] (Z)-2-cyano-3-(3,4-dihydroxy-5- nitrophenyl)-3-hydroxy-N-methyl- N-(4-methyl-3-(pyridin-2- yl)isoxazol-5-yl)acrylamide MS [M H].sup. calcd for C20H15N5O7 436.1, found 436.1 Ex. 570 [00628] (Z)-N-(benzo[c]isoxazol-3-yl)-2- cyano-3-(3,4-dihydroxy-5- nitrophenyl)-3-hydroxy-N- methylacrylamide MS [M H].sup. calcd for C18H12N4O7 395.1, found 395.1 Ex. 571 [00629] (Z)-2-cyano-N-(6,8-dihydro-5H- [1,2,4]triazolo[3,4-c][1,4]oxazin-3- yl)-3-(3,4-dihydroxy-5- nitrophenyl)-3-hydroxy-N- methylacrylamide MS [M H].sup. calcd for C16H14N6O7 401.1, found 401.1 Ex. 572 [00630] (Z)-2-cyano-3-(3,4-dihydroxy-5- nitrophenyl)-3-hydroxy-N-methyl- N-(4-methylisoxazol-3- yl)acrylamide MS [M H].sup. calcd for C15H12N4O7 359.1, found 359.1 Ex. 573 [00631] (Z)-2-cyano-N-(6,7-dihydro-4H- [1,2,3]triazolo[5,1-c][1,4]oxazin-3- yl)-3-(3,4-dihydroxy-5- nitrophenyl)-3-hydroxy-N- methylacrylamide MS [M H].sup. calcd for C16H14N6O7 401.1, found 401.1 Ex. 574 [00632] (Z)-2-cyano-N- (cyclopropylmethyl)-3-(3,4- dihydroxy-5-nitrophenyl)-3- hydroxy-N-methylacrylamide MS [M H].sup. calcd for C15H15N3O6 332.1, found 332.1 Ex. 575 [00633] (Z)-N-benzyl-2-cyano-3-(3,4- dihydroxy-5-nitrophenyl)-3- hydroxy-N-methylacrylamide MS [M H].sup. calcd for C18H15N3O6 368.1, found 368.1 Ex. 576 [00634] (Z)-2-cyano-3-(3,4-dihydroxy-5- nitrophenyl)-3-hydroxy-N-methyl- N-(4-methyl-3-phenylisoxazol-5- yl)acrylamide MS [M H].sup. calcd for C21H16N4O7 435.1, found 435.1 Ex. 577 [00635] (Z)-2-cyano-3-(3,4-dihydroxy-5- nitrophenyl)-3-hydroxy-N-methyl- N-(pyridin-4-ylmethyl)acrylamide MS [M H].sup. calcd for C17H14N4O6 369.1, found 369.1 Ex. 578 [00636] (Z)-2-cyano-3-(3,4-dihydroxy-5- nitrophenyl)-3-hydroxy-N-methyl- N-(pyrazin-2-ylmethyl)acrylamide MS [M H].sup. calcd for C16H13N5O6 370.1, found 370.1 Ex. 579 [00637] (Z)-2-cyano-3-(3,4-dihydroxy-5- nitrophenyl)-3-hydroxy-N-methyl- N-((4-methylpyridin-2- yl)methyl)acrylamide MS [M H].sup. calcd for C18H16N4O6 383.1, found 383.1 Ex. 580 [00638] (Z)-2-cyano-3-(3,4-dihydroxy-5- nitrophenyl)-3-hydroxy-N-methyl- N-(5,6,7,8-tetrahydro- [1,2,4]triazolo[4,3-a]pyridin-3- yl)acrylamide MS [M H].sup. calcd for C17H16N6O6 399.1, found 399.1 Ex. 581 [00639] (Z)-N-(5-chloro-2-hydroxybenzyl)- 2-cyano-3-(3,4-dihydroxy-5- nitrophenyl)-3-hydroxy-N- methylacrylamide MS [M H].sup. calcd for C18H14ClN3O7 418.0, found 418.0 Ex. 582 [00640] (Z)-2-cyano-N-(5-cyano-2- hydroxybenzyl)-3-(3,4-dihydroxy- 5-nitrophenyl)-3-hydroxy-N- methylacrylamide MS [M H].sup. calcd for C19H14N4O7 409.1, found 409.1 Ex. 583 [00641] (Z)-2-cyano-N-(5-cyano-2- fluorobenzyl)-3-(3,4-dihydroxy-5- nitrophenyl)-3-hydroxy-N- methylacrylamide MS [M H].sup. calcd for C19H13FN4O6 411.1, found 411.1 Ex. 584 [00642] (Z)-2-cyano-3-(3,4-dihydroxy-5- nitrophenyl)-3-hydroxy-N-methyl- N-(pyridin-3-ylmethyl)acrylamide MS [M H].sup. calcd for C17H14N4O6 369.1 , found 369.1 Ex. 585 [00643] (Z)-2-cyano-3-(3,4-dihydroxy-5- nitrophenyl)-N-(2-fluoro-5- morpholinobenzyl)-3-hydroxy-N- methylacrylamide MS [M H].sup. calcd for C22H21FN4O7 471.1, found 471.1 Ex. 586 [00644] (Z)-2-cyano-N-(2-cyano-5- methylbenzyl)-3-(3,4-dihydroxy-5- nitrophenyl)-3-hydroxy-N- methylacrylamide MS [M H].sup. calcd for C20H16N4O6 407.1, found 407.1 Ex. 587 [00645] (Z)-2-cyano-N-(4-cyano-2- fluorobenzyl)-3-(3,4-dihydroxy-5- nitrophenyl)-3-hydroxy-N- methylacrylamide MS [M H].sup. calcd for C19H13FN4O6 411.1, found 411.1 Ex. 588 [00646] (Z)-2-cyano-N-(2-cyanobenzyl)-3- (3,4-dihydroxy-5-nitrophenyl)-3- hydroxy-N-methylacrylamide MS [M H].sup. calcd for C19H14N4O6 393.1, found 393.1 Ex. 589 [00647] (Z)-2-cyano-3-(3,4-dihydroxy-5- nitrophenyl)-N-((5-fluoro-2- methylpyridin-4-yl)methyl)-3- hydroxy-N-methylacrylamide MS [M H].sup. calcd for C18H15FN4O6 401.1, found 401.1 Ex. 590 [00648] (Z)-2-cyano-3-(3,4-dihydroxy-5- nitrophenyl)-N-((3-fluoro-6- methylpyridin-2-yl)methyl)-3- hydroxy-N-methylacrylamide MS [M H].sup. calcd for C18H15FN4O6 401.1, found 401.1 Ex. 591 [00649] (Z)-2-cyano-3-(3,4-dihydroxy-5- nitrophenyl)-3-hydroxy-N-methyl- N-((1-phenyl-1H-1,2,3-triazol-4- yl)methyl)acrylamide MS [M H].sup. calcd for C20H16N6O6 435.1, found 435.1 Ex. 592 [00650] (Z)-N-(5-chloro-2-fluorobenzyl)-2- cyano-3-(3,4-dihydroxy-5- nitrophenyl)-3-hydroxy-N- methylacrylamide MS [M H].sup. calcd for C18H13ClFN3O6 420.0, found 420.0 Ex. 593 [00651] (Z)-2-cyano-3-(3,4-dihydroxy-5- nitrophenyl)-3-hydroxy-N-methyl- N-((1-phenyl-1H-imidazol-4- yl)methyl)acrylamide MS [M H].sup. calcd for C21H17N5O6 434.1, found 434.1 Ex. 594 [00652] (Z)-2-cyano-3-(3,4-dihydroxy-5- nitrophenyl)-3-hydroxy-N-methyl- N-((1-(pyridin-4-yl)-1H-1,2,3- triazol-4-yl)methyl)acrylamide MS [M H].sup. calcd for C19H15N7O6 436.1, found 436.1 Ex. 595 [00653] (Z)-2-cyano-3-(3,4-dihydroxy-5- nitrophenyl)-N-((7-fluoro-1H- indazol-6-yl)methyl)-3-hydroxy-N- methylacrylamide MS [M H].sup. calcd for C19H14FN5O6 426.1, found 426.1 Ex. 596 [00654] (Z)-2-cyano-3-(3,4-dihydroxy-5- nitrophenyl)-N-(2-fluoro-4-(4- methylpiperazin-1-yl)benzyl)-3- hydroxy-N-methylacrylamide MS [M H].sup. calcd for C23H24FN5O6 484.2, found 484.2 Ex. 597 [00655] (Z)-N-(5-chloro-2-fluorobenzyl)-2- cyano-3-(3,4-dihydroxy-5- vinylphenyl)-3-hydroxy-N- methylacrylamide MS [M H].sup. calcd for C20H16ClFN2O4 401.1, found 401.1 Ex. 598 [00656] (Z)-2-cyano-3-(3,4-dihydroxy-5- nitrophenyl)-3-hydroxy-N-methyl- N-(2-(3-(pyrazin-2- yl)phenoxy)ethyl)acrylamide MS [M H].sup. calcd for C23H19N5O7 476.1, found 476.1 Ex. 599 [00657] (Z)-2-cyano-3-(3,4-dihydroxy-5- nitrophenyl)-3-hydroxy-N-methyl- N-(3-phenylprop-2-ynyl)acrylamide MS [M H].sup. calcd for C20H15N3O6 392.1, found 392.1 Ex. 600 [00658] (Z)-2-cyano-3-(3,4-dihydroxy-5- nitrophenyl)-3-hydroxy-N-methyl- N-((1-phenyl-1H-1,2,4-triazol-3- yl)methyl)acrylamide MS [M H].sup. calcd for C20H16N6O6 435.1, found 435.1 Ex. 601 [00659] (Z)-2-cyano-3-(3,4-dihydroxy-5- nitrophenyl)-3-hydroxy-N-methyl- N-(3-(pyridin-4-yl)prop-2- ynyl)acrylamide MS [M H].sup. calcd for C19H14N4O6 393.1, found 393.1 Ex. 602 [00660] (Z)-2-cyano-N-(3-(2- cyanophenyl)prop-2-ynyl)-3-(3,4- dihydroxy-5-nitrophenyl)-3- hydroxy-N-methylacrylamide MS [M H].sup. calcd for C21H14N4O6 417.1, found 417.1 Ex. 603 [00661] (Z)-2-cyano-3-(3,4-dihydroxy-5- nitrophenyl)-N-(3-(2- fluorophenyl)prop-2-ynyl)-3- hydroxy-N-methylacrylamide MS [M H].sup. calcd for C20H14FN3O6 410.1, found 410.1 Ex. 604 [00662] (Z)-N-(5-chloro-2-fluorobenzyl)-2- cyano-3-(3-ethynyl-4,5- dihydroxyphenyl)-3-hydroxy-N- methylacrylamide MS [M H].sup. calcd for C20H14ClFN2O4 399.1, found 399.1 Ex. 605 [00663] (Z)-2-cyano-3-(3,4-dihydroxy-5- nitrophenyl)-N-(3-(4- fluorophenyl)prop-2-ynyl)-3- hydroxy-N-methylacrylamide MS [M H].sup. calcd for C20H14FN3O6 410.1, found 410.1 Ex. 606 [00664] (Z)-2-cyano-3-(3,4-dihydroxy-5- nitrophenyl)-3-hydroxy-N-(3-(2- hydroxyphenyl)prop-2-ynyl)-N- methylacrylamide MS [M H].sup. calcd for C20H15N3O7 408.1, found 408.1 Ex. 607 [00665] (Z)-2-cyano-3-(3,4-dihydroxy-5- nitrophenyl)-3-hydroxy-N-methyl- N-(3-o-tolylprop-2-ynyl)acrylamide MS [M H].sup. calcd for C21H17N3O6 407.1, found 407.1 Ex. 608 [00666] (Z)-2-cyano-3-(3,4-dihydroxy-5- nitrophenyl)-3-hydroxy-N-methyl- N-(3-(pyridin-3-yl)prop-2- ynyl)acrylamide MS [M H].sup. calcd for C19H14N4O6 393.1, found 393.1 Ex. 609 [00667] (Z)-2-cyano-3-(3,4-dihydroxy-5- nitrophenyl)-3-hydroxy-N-methyl- N-(3-(1-methyl-1 H-pyrazol-4- yl)prop-2-ynyl)acrylamide MS [M H].sup. calcd for C18H15N5O6 396.1, found 396.1 Ex. 610 [00668] (Z)-2-cyano-N,N-diethyl-3-(2- fluoro-3,4-dihydroxy-5- nitrophenyl)-3-hydroxyacrylamide MS [M H].sup. calcd for C14H14FN3O6 338.1, found 338.1 Ex. 611 [00669] (Z)-2-cyano-N,N-diethyl-3-(2- fluoro-4,5-dihydroxy-3- nitrophenyl)-3-hydroxyacrylamide MS [M H].sup. calcd for C14H14FN3O6 338.1, found 338.1 Ex. 612 [00670] (Z)-2-cyano-3-(3,4-dihydroxy-5- nitrophenyl)-N-(3-(3- fluorophenyl)prop-2-ynyl)-3- hydroxy-N-methylacrylamide MS [M H].sup. calcd for C20H14FN3O6 410.1, found 410.1 Ex. 613 [00671] (Z)-2-cyano-3-(2-fluoro-3,4- dihydroxy-5-nitrophenyl)-3- hydroxy-N,N-dimethylacrylamide MS [M H].sup. calcd for C12H10FN3O6 310.1, found 310.1 Ex. 614 [00672] (Z)-2-cyano-3-(2-fluoro-4,5- dihydroxy-3-nitrophenyl)-3- hydroxy-N,N-dimethylacrylamide MS [M H].sup. calcd for C12H10FN3O6 310.1, found 310.1 Ex. 615 [00673] (Z)-2-cyano-3-(2-fluoro-3,4- dihydroxy-5-nitrophenyl)-3- hydroxy-N-methyl-N-(3-(1-methyl- 2-oxopiperidin-3-yl)prop-2- ynyl)acrylamide MS [M H].sup. calcd for C20H19FN4O7 445.1, found 445.1 Ex. 616 [00674] (Z)-2-cyano-3-(3,4-dihydroxy-5- nitrophenyl)-3-hydroxy-N-methyl- N-(3-(1-methyl-2-oxo-1,2- dihydropyridin-3-yl)prop-2- ynyl)acrylamide MS [M H].sup. calcd for C20H16N4O7 423.1, found 423.1 Ex. 617 [00675] (Z)-N-(5-chloro-2-fluorophenoxy)- 2-cyano-3-(2-fluoro-3,4-dihydroxy- 5-nitrophenyl)-3-hydroxy-N- methylacrylamide MS [M H].sup. calcd for C17H10ClF2N3O7 440.0 found 440.0 Ex. 618 [00676] (Z)-N-(5-chloro-2-fluorophenoxy)- 2-cyano-3-(2-fluoro-4,5-dihydroxy- 3-nitrophenyl)-3-hydroxy-N- methylacrylamide MS [M H].sup. calcd for C17H10ClF2N3O7 440.0 found 440.0 Ex. 619 [00677] (Z)-2-cyano-3-(3-cyano-2-fluoro- 4,5-dihydroxyphenyl)-N,N-diethyl- 3-hydroxyacrylamide MS [M H].sup. calcd for C15H14FN3O4 318.1, found 318.1 Ex. 620 [00678] (Z)-2-cyano-3-(2,6-difluoro-3,4- dihydroxy-5-nitrophenyl)-N,N- diethyl-3-hydroxyacrylamide MS [M H].sup. calcd for C14H13F2N3O6 356.1, found 356.1 Ex. 621 [00679] (Z)-3-(3-chloro-2,6-difluoro-4,5- dihydroxyphenyl)-N-(5-chloro-2- fluorobenzyl)-2-cyano-3-hydroxy- N-methylacrylamide MS [M H].sup. calcd for C18H11Cl2F3N2O4 445.0, found 445.0 Ex. 622 [00680] (Z)-2-cyano-3-(5-cyano-2-fluoro- 3,4-dihydroxyphenyl)-N,N-diethyl- 3-hydroxyacrylamide MS [M H].sup. calcd for C15H14FN3O4 318.1, found 318.1 Ex. 623 [00681] (Z)-2-cyano-3-(2-fluoro-4,5- dihydroxy-3-nitrophenyl)-3- hydroxy-N-methyl-N-(3-(1- methyl-2-oxopiperidin- 3-yl)prop-2- ynyl)acrylamide MS [M H].sup. calcd for C20H19FN4O7 445.1, found 445.1 Ex. 624 [00682] (Z)-3-(3-chloro-2,6-difluoro-4,5- dihydroxyphenyl)-N-(5-chloro-2- fluorobenzyl)-2-cyano-3-hydroxy- N-methylacrylamide MS [M H].sup. calcd for C18H11Cl2F3N2O4 445.0, found 445.0 Ex. 625 [00683] (Z)-2-cyano-3-(3,4-dihydroxy-5- nitrophenyl)-N-((7-fluoro-1,2,3,4- tetrahydroquinoxalin-6-yl)methyl)- 3-hydroxy-N-methylacrylamide MS [M H].sup. calcd for C20H18FN5O6 442.1, found 442.1 Ex. 626 [00684] (Z)-2-cyano-3-(3,4-dihydroxy-5- nitrophenyl)-N-((6-fluoro-2,3- dihydrobenzo[b][1,4]oxathiin-7- yl)methyl)-3-hydroxy-N- methylacrylamide MS [M H].sup. calcd for C20H16FN3O7S 460.1, found 460.1 Ex. 627 [00685] (Z)-2-cyano-N-((2,3- dihydrobenzofuran-6-yl)methyl)-3- (3,4-dihydroxy-5-nitrophenyl)-3- hydroxy-N-methylacrylamide MS [M H].sup. calcd for C20H17N3O7 410.1, found 410.1 Ex. 628 [00686] (Z)-2-cyano-3-(3,4-dihydroxy-5- nitrophenyl)-N-((6-fluoro-3,4- dihydro-2H-benzo[b][1,4]oxazin-7- yl)methyl)-3-hydroxy-N- methylacrylamide MS [M H].sup. calcd for C20H17FN4O7 443.1, found 443.1 Ex. 629 [00687] (Z)-2-cyano-3-(3,4-dihydroxy-5- nitrophenyl)-N-((6- fluoroisochroman-7-yl)methyl)-3- hydroxy-N-methylacrylamide MS [M H].sup. calcd for C21H18FN3O7 442.1, found 442.1 Ex. 630 [00688] (Z)-2-cyano-3-(3,4-dihydroxy-5- nitrophenyl)-N-((6-fluoro-4- methyl-3,4-dihydro-2H- benzo[b][1,4]thiazin-7-yl)methyl)- 3-hydroxy-N-methylacrylamide MS [M H].sup. calcd for C21H19FN4O6S 473.1, found 473.1 Ex. 631 [00689] (Z)-2-cyano-3-(3,4-dihydroxy-5- nitrophenyl)-N-(2-fluoro-5- methylphenoxy)-3-hydroxy-N- methylacrylamide MS [M H].sup. calcd for C18H14FN3O7 402.1, found 402.1

Example 632: (Z)-2-cyano-N,N-diethyl-3-(3-fluoro-4-hydroxy-5-(trifluoromethyl)phenyl)-3-hydroxyacrylamide

##STR00690##

Step1: Synthesis of (Z)-2-cyano-N,N-diethyl-3-(3-fluoro-4-methoxy-5-(trifluoromethyl)phenyl)-3-hydroxyacrylamide

[0297] A solution of 3-fluoro-4-methoxy-5-(trifluoromethyl) benzoic acid (150 mg, 0.6 mmol) in SOCl.sub.2 (20 mL) was stirred at 80 C. for 2 h, then it was concentrated in vacuo to get an acyl chloride.Math.NaH (30 mg, 1.2 mmol) was added to a solution of 2-cyano-N,N-diethylacetamide (84 mg, 0.6 mmol) in THF (15 mL) at 0 C. The mixture was stirred for 1 h, then the acyl chloride was added. The mixture was stirred at 0 C. for 1 h, then at room temperature overnight. The mixture was washed with 1 N HCl (15 mL) and water (20 mL). The mixture was extracted with ethyl acetate (20 mL3). The combined extraction was dried over anhydrous Na.sub.2SO.sub.4, then filtered and concentrated in vacuo to afford the crude product. Further purification by Prep-HPLC (0.05% TFA; ACNH.sub.2O) to (Z)-2-cyano-N,N-diethyl-3-(3-fluoro-4-methoxy-5-(trifluoromethyl)phenyl)-3-hydroxyacrylamide (150 mg, 66%). MS [MH].sup. calcd for C.sub.16H.sub.16F.sub.4N.sub.2O.sub.3 359.0, found 359.0.

Step2: Synthesis of (Z)-2-cyano-N,N-diethyl-3-(3-fluoro-4-hydroxy-5-(trifluoromethyl)phenyl)-3-hydroxyacrylamide (Ex. 632)

[0298] The mixture of (Z)-2-cyano-N,N-diethyl-3-(3-fluoro-4-methoxy-5-(trifluoromethyl)phenyl)-3-hydroxyacrylamide (150 mg, 0.4 mmol) in DCM (20 mL) was stirred at 10T for 15 min. Then BBr.sub.3 (0.1 mL) was added to the above mixture. The reaction mixture was warmed to RT and stirred for overnight. The reaction was quenched with ice. The mixture was extracted with DCM (150 mL*3). The combined extraction was dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated in vacuo to dryness. The residue was purified by Prep-HPLC (H2O/MeCN=40/60, 0.1% TFA, 2 times) to obtain the product (70 mg, HPLC: 96.3%). MS [MH].sup. calcd for C.sub.15H.sub.14F.sub.4N.sub.2O.sub.3 344.8, found 344.8. .sup.1H NMR (400 MHz, DMSO-d.sub.6) 12.04 (s, 1H), 7.99 (d, J=12.0 Hz, 111), 7.87 (s, 1H), 3.56 (d, J=8.0 Hz, 4H), 1.2 (s, 6H).

Example 633: (Z)-2-cyano-3-(2,4-dihydroxy-5-nitrophenyl)-N,N-diethyl-3-hydroxyacrylamide

##STR00691##

Step1: Synthesis of (Z)-2-cyano-N,N-diethyl-3-hydroxy-3-(4-hydroxy-2-methoxy-5-nitrophenyl)acrylamide

[0299] The mixture of methyl 4-hydroxy-2-methoxy-5-nitrobenzoic acid (1.0 g, 4.7 mmol) in SOCl.sub.2 (40 mL) was heated to 80 C. for 2 hours. Then it was concentrated in vacuo to obtain an acyl chloride. A solution of 2-cyano-N,N-diethylacetamide (657 mg, 4.7 mmol) in THF (20 mL) was stirred at 78 C. for 10 min under N.sub.2 atmosphere, subsequently LiHMDS (0.7 mL, 11.8 mmol) was added. The mixture was stirred for 1 hour. The acyl chloride was added to the reaction mixture. The mixture was warmed to RT, and stirred overnight. The mixture was acidified to pH 5-6 with 1N HCl, extracted with DCM (200 mL*3). The combined extraction was dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated in vacuo. The residue was purified by Prep-HPLC (H2O/MeCN=45/55, 0.1% TFA, 2 times) to obtain the crude product (1.0 mg, 68%). MS [MH].sup.+ calcd for C.sub.15H.sub.17N.sub.3O.sub.6 334.1, found 334.1.

Step2: Synthesis of (Z)-2-cyano-3-(2,4-dihydroxy-5-nitrophenyl)-N,N-diethyl-3-hydroxyacrylamide (Ex. 633)

[0300] The mixture of (Z)-2-cyano-N,N-diethyl-3-hydroxy-3-(4-hydroxy-2-methoxy-5-nitrophenyl)acrylamide (100 mg, 0.3 mmol) in DCM (20 mL) was stirred at 10 C. for 15 mins. Then BBr.sub.3 (0.3 mL) was added to the above mixture. The reaction mixture was warmed to RT and stirred overnight. The reaction was quenched with ice. The mixture was extracted with DCM (150 mL*3) The combined extraction was dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated in vacuo. The residue was purified by Prep-HPLC (H2O/MeCN=40/60, 0.1% TFA, 2 times) to obtain the product (32 mg, HPLC: 99.8%). MS [MH].sup. calcd for C.sub.14H.sub.15N.sub.3O.sub.6 319.8, found 319.8. .sup.1H NMR (400 MHz, DMSO-d6) 11.93 (s, 1H), 8.35 (s, 1H), 7.72 (s, 2H), 6.96 (s, 1H), 3.39 (d, J=16.0 Hz, 2H), 3.19 (t, J=8.0 Hz, 2H), 1.13 (t, J=8.0 Hz, 3H), 1.06 (t, J=8.0 Hz, 3H).

[0301] Examples 634 and 635: tert-butyl (Z)-2-cyano-3-hydroxy-3-(4-hydroxy-3-methoxy-5-nitrophenyl)-N-methyl-N-(2-oxo-2-(phenylamino) ethyl) acrylamide (Example 634) and (Z)-2-cyano-3-(3,4-dihydroxy-5-nitrophenyl)-3-hydroxy-N-methyl-N-(2-oxo-2-(phenylamino) ethyl) acrylamide (Example 635)

##STR00692##

Step1: Synthesis of N-(but-2-yn-1-yl)-2-cyano-N-methylacetamide

[0302] The solution of 2-(methylamino)-N-phenylacetamide (1.2 mg, 7.3 mmol) and 2-cyanoacetic acid (622 mg, 7.3 mmol) in DCM (50 mL) were added T.sub.3P (3.5 g, 11.0 mmol) and DIEA (2.8 g, 22.0 mmol). The flask was degassed with nitrogen. The mixture was stirred for 8 h at 25 C. The reaction mixture was washed with water (20 mL), extracted with DCM (150 mL*3). The combined extraction was dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated in vacuo The residue was purified by silica gel chromatography (PE/EA=2/3) to obtain the product (450 mg, 27%). MS [MH].sup.+ calcd for C.sub.12H.sub.13N.sub.3O.sub.2 231.9, found 231.9.

Step2: Synthesis of 2-cyano-N-methyl-N-(2-oxo-2-(phenylamino) ethyl) acetamide

[0303] A mixture of N-(but-2-yn-1-yl)-2-cyano-N-methylacetamide (450 mg, 1.9 mmol), (Boc).sub.20 (637 mg, 2.9 mmol), 4-dimethylaminopyridine (356 mg, 2.9 mmol), Et.sub.3N (13.0 g, 129.1 mmol) in DCM (100 mL) was stirred for overnight at 25 C. The reaction mixture was washed with water (20 mL), extracted with DCM (150 mL*3). The combined extraction was dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated in vacuo The residue was purified by silica gel chromatography (DCM/MeOH=30/1) to obtain the product (350 g, 54%). MS [MH].sup.+ calcd for C.sub.17H.sub.21N.sub.3O.sub.4 331.9, found 331.9.

Step3: Synthesis of tert-butyl (N-(2-cyanoacetyl)-N-methylglycyl) (phenyl)carbamate

[0304] The mixture of 4-hydroxy-3-methoxy-5-nitrobenzoic acid (234 mg, 1.1 mmol) in SOCl.sub.2 (50 mL) was heated to 80 C. for 2 hours. Then it was concentrated in vacuo to obtain an acyl chloride. A solution of 2-cyano-N-methyl-N-(2-oxo-2-(phenylamino) ethyl) acetamide (350 mg, 1.1 mmol) in THF (30 mL) was stirred at 78 C. for 10 min under N.sub.2 atmosphere, subsequently LiHMDS (2.6 mL, 2.6 mmol) was added. The mixture was stirred for 1 hour. The acyl chloride was added to the reaction mixture. The solution was warmed to RT, and stirred overnight. The mixture was acidified to pH 5-6 with 1N HCl, extracted with DCM (150 mL*3). The combined extraction was dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated in vacuo The residue was purified by Prep-HPLC (H2O/MeCN=55/45, 0.1% TFA, 2 times) to obtain the product (250 mg, 45%). MS [MH].sup. calcd for C.sub.25H.sub.26N.sub.4O.sub.9 525.1, found 525.1.

Step4: Synthesis of tert-butyl (Z)-2-cyano-3-hydroxy-3-(4-hydroxy-3-methoxy-5-nitrophenyl)-N-methyl-N-(2-oxo-2-(phenylamino) ethyl) acrylamide (Ex. 634)

[0305] A mixture of tert-butyl (N-(2-cyanoacetyl)-N-methylglycyl) (phenyl)carbamate (150 mg, 0.3 mmol), TFA (0.5 mL) in DCM (20 mL) was stirred overnight at 25 C. The mixture was evaporated to obtain the product (100 mg, 83%). MS [MH].sup. calcd for C.sub.20H.sub.18N.sub.4O.sub.7 424.9, found 424.9. .sup.1H NMR (400 MHz, DMSO-d.sub.6) 10.19 (s, 1H), 8.00 (s, 1H), 7.58 (s, 1H), 7.34 (s, 2H), 7.31 (t, J=4.0 Hz, 2H), 7.06 (t, J=8.0 Hz, 1H), 4.39 (s, 2H), 3.93 (s, 3H), 3.29 (s, 3H).

Step5: Synthesis of (Z)-2-cyano-3-(3,4-dihydroxy-5-nitrophenyl)-3-hydroxy-N-methyl-N-(2-oxo-2-(phenylamino) ethyl) acrylamide (Ex. 635)

[0306] The mixture of (Z)-2-cyano-3-hydroxy-3-(4-hydroxy-3-methoxy-5-nitrophenyl)-N-methyl-N-(2-oxo-2-(phenylamino) ethyl) acrylamide (100 mg, 0.3 mmol) in DCM (20 mL) was stirred at 10 T for 15 min. Then BBr.sub.3 (0.1 mL) was added to the above mixture. The mixture was warmed to RT and stirred overnight. The mixture was washed with ice water, extracted with DCM (150 mL*3). The combined extraction was dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated in vacuo. The residue was purified by Prep-HPLC (H2O/MeCN=40/60, 0.1% TFA, 2 times) to obtain the product (1 mg, HPLC: 86.6%). MS [MH].sup. calcd for C.sub.19H.sub.16N.sub.4O.sub.7 410.9, found 410.9. .sup.1H NMR (400 MHz, DMSO-d.sub.6) 10.20 (s, 1H), 7.84 (s, 2H), 7.55 (s, 2H), 7.45 (s, 1H), 7.28 (s, 1H), 7.04 (t, J=4.0 Hz, 1H), 4.32 (s, 2H), 3.21 (s, 3H).

[0307] The following examples were synthesized in a manner similar to the above generally following Schemes 2 starting from the appropriate intermediates C of which L.sub.1 is a single bond.

Example 636: (Z)-5-(2-cyano-3-cyclopropyl-1-hydroxy-3-oxoprop-1-en-1-yl)-2-hydroxybenzonitrile

##STR00693##

[0308] The mixture of 3-cyano-4-hydroxybenzoic acid (200 mg, 1.23 mmol) in SOCl.sub.2 (20 mL) was heated to 80 C. for 2 hour. Then it was concentrated in vacuo to dryness and the residue was used for next step. A solution of 3-cyclopropyl-3-oxopropanenitrile (134 mg, 1.23 mmol) in THF (20 mL) was stirred at 78 TC for 10 min under N.sub.2 atmosphere, after LiHMDS (1.23 mL, 1.23 mmol) was added, stirred for another 1 hour. The above concentrated acyl chloride was added the reaction mixture, warmed to RT, and stirred for overnight. After the completion of the reaction, the mixture was acidified to pH about 5-6 by HCl, extracted with DCM (20 mL*3) The combined extraction was dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated in vacuo The residue was purified by Prep-HPLC (H2O/MeCN=4/5, 0.1% TFA, 2 times) to obtain the product (16.9 mg, HPLC: 98.9%). MS [MH].sup. calcd for C14H10N2O3 253.0, found 253.0. .sup.1H NMR (400 MHz, DMSO-d6) 8.245 (d, J=4.0 Hz, 1H), 8.10-8.08 (m, 1H), 7.18 (d, J=8.0 Hz, 1H), 2.45-2.42 (m, 1H), 1.28-1.21 (m, 4H).

[0309] Examples 637 and 638: (Z)-2-(cyclopropanecarbonyl)-3-hydroxy-3-(4-hydroxy-3-methoxy-5-nitrophenyl) acrylonitrile (Example 637) and (Z)-2-(cyclopropanecarbonyl)-3-hydroxy-3-(4-hydroxy-3-methoxy-5-nitrophenyl) acrylonitrile (Example 638)

##STR00694##

Step1: Synthesis of (Z)-2-(cyclopropanecarbonyl)-3-hydroxy-3-(4-hydroxy-3-methoxy-5-nitrophenyl) acrylonitrile (Ex. 637)

[0310] The mixture of 4-hydroxy-3-methoxy-5-nitrobenzoic acid (977 mg, 4.6 mmol) in SOCl.sub.2 (100 mL) was heated to 80 C. for 2 hours. Then it was concentrated in vacuo to obtain an acyl chloride. A solution of 3-cyclopropyl-3-oxopropanenitrile (500 mg, 4.6 mmol) in THF (50 mL) was stirred at 78 C. for 10 min under N.sub.2 atmosphere, subsequently LiHMDS (11.5 mL, 11.5 mmol) was added. The mixture was stirred for 1 hour. The above acyl chloride was added to the reaction mixture. The mixture was warmed to RT, and stirred overnight. The mixture was acidified to pH 5-6 with 1N HCl, extracted with DCM (200 mL*3). The combined extraction was dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated in vacuo The residue was purified by Prep-HPLC (H.sub.2O/MeCN=40/60, 0.1% TFA, 2 times) to obtain the crude product (100 mg, HPLC: 99%). MS [MH].sup.+ calcd for C.sub.14H.sub.12N.sub.2O.sub.6 305.1, found 305.1. .sup.1H NMR (400 MHz, DMSO-d6) 8.15 (s, 1H), 7.77 (s, 1H), 3.95 (s, 3H), 2.44-2.48 (m, 1H), 1.23-1.30 (m, 4H).

Step2: Synthesis of (Z)-2-(cyclopropanecarbonyl)-3-hydroxy-3-(4-hydroxy-3-methoxy-5-nitrophenyl) acrylonitrile (Ex. 638)

[0311] The mixture of 4-hydroxy-3-methoxy-5-nitrobenzoic acid (92 mg, 0.5 mmol) in SOCl.sub.2 (10 mL) was heated to 80 C. for 2 hours. Then it was concentrated in vacuo to obtain an acyl chloride. A solution of 3-cyclopropyl-3-oxopropanenitrile (50 mg, 0.5 mmol) in THF (10 mL) was stirred at 78 C. for 10 min under N.sub.2 atmosphere, subsequently LiHMDS (0.1 mL, 0.1 mmol) was added. The solution was stirred for 1 hour. The above acyl chloride was added to the reaction mixture. The mixture was warmed to RT, and stirred overnight. The mixture was acidified to pH 5-6 with 1N HCl, extracted with DCM (200 mL*3). The combined extraction was dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated in vacuo The residue was purified by Prep-HPLC (H.sub.2O/MeCN=40/60, 0.1% TFA, 2 times) to obtain the crude product (7 mg, HPLC: 98%). MS [MH].sup.+ calcd for C.sub.13H.sub.10N.sub.2O.sub.6 291.1, found 291.1. .sup.1H NMR (400 MHz, DMSO) 8.26 (s, 1H), 7.66 (s, 1H), 2.38-2.44 (m, 1H), 1.20 (d, J=4.0 Hz, 4H).

Examples 639 and 640: ethyl (Z)-2-cyano-3-hydroxy-3-(4-hydroxy-3-methoxy-5-nitrophenyl)acrylate (Example 639) and ethyl (Z)-2-cyano-3-(3,4-dihydroxy-5-nitrophenyl)-3-hydroxyacrylate (Example 640)

##STR00695##

Step1: Synthesis of ethyl (Z)-2-cyano-3-hydroxy-3-(4-hydroxy-3-methoxy-5-nitrophenyl)acrylate (Ex. 639)

[0312] A solution of 3,4-dihydroxy-5-nitrobenzoic acid (18.5 g, 86.79 mmol) in SOCl.sub.2 (200 mL) was stirred at 80 C. for 4 h, then it was concentrated in vacuo to get an acyl chloride. NaH (7.64 g, 190.94 mmol) was added to a solution of ethyl 2-cyanoacetate (9.82 g, 86.79 mmol) in THF (150 mL) at 0 C. and stirred for 1 h, then acyl chloride was added to the above solution. The mixture was stirred at 0 C. for 1 h, then stirred at room temperature overnight. The reaction mixture was diluted with 1 N HCl (150 mL) and water (200 mL). The mixture was extracted with ethyl acetate (200 mL3) The combined extraction was dried over anhydrous Na.sub.2SO.sub.4, then filtered and concentrated in vacuo to afford the crude product. Further purification by column chromatography (silica gel, PE/EA=2/1) afforded ethyl (Z)-2-cyano-3-hydroxy-3-(4-hydroxy-3-methoxy-5-nitrophenyl)acrylate (15 g, 56%). MS [MH].sup. calcd for C13H12N2O7 307, found 307. .sup.1H NMR (400 MHz, DMSO-d.sub.6) 7.94 (s, 1H), 7.65 (s, 1H), 4.26 (s, 2H), 3.93 (s, 3H), 1.25 (s, 3H).

Step2: Synthesis of ethyl (Z)-2-cyano-3-(3,4-dihydroxy-5-nitrophenyl)-3-hydroxyacrylate (Ex. 640)

[0313] A solution of ethyl (Z)-2-cyano-3-hydroxy-3-(4-hydroxy-3-methoxy-5-nitrophenyl)acrylate (100 mg, 0.32 mmol) in DCM (10 mL) was added BBr.sub.3 (0.1 mL) at 5 C. The reaction mixture was stirred at room temperature overnight. The mixture was cooled to 5 C. and washed with water (10 mL). The mixture was extracted with ethyl acetate (10 mL3). The combined extraction was dried over anhydrous Na.sub.2SO.sub.4, then filtered and concentrated in vacuo to afford the crude product. Further purification was performed by Prep-HPLC (0.05% TFA; ACNH.sub.2O) to afford ethyl (Z)-2-cyano-3-(3,4-dihydroxy-5-nitrophenyl)-3-hydroxyacrylate (35 mg, 37%). MS [MH].sup. calcd for C12H10N2O7 294.8, found 294.8. .sup.1H NMR (400 MHz, DMSO-d.sub.6) 10.85 (s, 1H), 7.84 (s, 1H), 7.49 (s, 1H), 4.26 (s, 2H), 1.25 (t, J=4.0 Hz, 3H).

Example 641: 5-chloro-2-fluorobenzyl (Z)-2-cyano-3-hydroxy-3-(4-hydroxy-3-methoxy-5-nitrophenyl) acrylate

##STR00696##

Step1: Synthesis of 5-chloro-2-fluorobenzyl 2-cyanoacetate (C-3)

[0314] The mixture of methyl (5-chloro-2-fluorophenyl) methanol (500 mg, 3.1 mmol), 2-cyanoacetic acid (395 mg, 4.7 mmol) and PPh.sub.3 (1.2 g, 4.7 mmol) in DCM (50 mL) was stirred at 0C for 10 mins. Then DIAD (949 mg, 4.7 mmol) was added the above mixture. The reaction was warmed to RT and stirred for overnight. The mixture was quenched with ice, extracted with DCM (200 mL*3) The combined extraction was dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated in vacuo The residue was purified by silica gel chromatography (PE/EA=1/1) to obtain the product (380 mg, 53%). MS [M+H].sup. calcd for C.sub.10H.sub.7ClFNO.sub.2 228.0, found 228.0.

Step2: Synthesis of 5-chloro-2-fluorobenzyl (Z)-2-cyano-3-hydroxy-3-(4-hydroxy-3-methoxy-5-nitrophenyl) acrylate (Ex. 641)

[0315] The mixture of methyl 4-hydroxy-3-methoxy-5-nitrobenzoic acid (94 mg, 0.4 mmol) in SOCl.sub.2 (20 mL) was heated to 80 C. for 2 hours. Then it was concentrated in vacuo to obtain an acyl chloride. A solution of 5-chloro-2-fluorobenzyl 2-cyanoacetate (100 mg, 0.4 mmol) in THF (20 mL) was stirred at 78 C. for 10 min under N.sub.2 atmosphere, subsequently Lithium bis(trimethylsilyl)amide (1.1 mL, 1.1 mmol) was added. The mixture was stirred for 1 hour. The above acyl chloride was added to the reaction mixture. The mixture was warmed to RT, and stirred overnight. The mixture was acidified to pH 5-6 with 1N HCl, extracted with DCM (200 mL*3). The combined extraction was dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated in vacuo The residue was purified by Prep-HPLC (H2O/MeCN=45/55, 0.10% TFA, 2 times) to obtain the product (60 mg, HPLC: 1000%). MS [MH]f calcd for C.sub.18H.sub.12ClFN.sub.2O.sub.7 423.1, found 423.1. .sup.1H NMR (400 MHz, DMSO-d.sub.6) 7.70 (s, 1H), 7.44-7.48 (m, 3H), 7.29 (t, J=8.0 Hz, 1H), 5.15 (s, 2H), 3.87 (s, 3H).

[0316] The following analogous compounds are obtained by generally following Scheme 2 starting from the appropriate intermediates B and C:

TABLE-US-00007 Ex. 642 [00697] (Z)-ethyl 2-cyano-3-hydroxy- 3-(4-hydroxy-3-methyl-5- nitrophenyl)acrylate MS [M H].sup. calcd for C13H12N2O6 291.1, found 291.1 Ex. 643 [00698] (Z)-ethyl 3-(3-chloro-4- hydroxy-5-nitrophenyl)-2- cyano-3-hydroxyacrylate MS [M H].sup. calcd for C12H9ClN2O6 311.0, found 311.0 Ex. 644 [00699] (Z)-ethyl 2-cyano-3-hydroxy- 3-(4-hydroxy-3- nitrophenyl)acrylate MS [M H].sup. calcd for C12H10N2O6 277.0, found 277.0 Ex. 645 [00700] (Z)-S-ethyl 2-cyano-3-(3,4- dihydroxy-5-nitrophenyl)-3- hydroxyprop-2-enethioate MS [M H].sup. calcd for C12H10N2O6S 309.0, found 309.0 Ex. 646 [00701] (Z)-2-((3,4-dihydroxy-5- nitrophenyl)(hydroxy) methylene)-4,4-dimethyl-3- oxopentanenitrile MS [M H].sup. calcd for C14H14N2O6 305.1, found 305.1 Ex. 647 [00702] (Z)-methyl 2-cyano-3-(3,4- dihydroxy-5-nitrophenyl)-3- hydroxyacrylate (Z)-ethyl 2-cyano-3-(3-fluoro- MS [M H].sup. calcd for C11H8N2O7 279.0, found 279.0 Ex. 648 [00703] 4-hydroxy-5-nitrophenyl)-3- hydroxyacrylate(Z)-ethyl 2- cyano-3-(3-fluoro-4-hydroxy-5- nitrophenyl)-3-hydroxyacrylate MS [M H].sup. calcd for C12H9FN2O6 295.0, found 295.0 Ex. 649 [00704] (Z)-2-((3,4-dihydroxy-5- nitrophenyl)(hydroxy)methylene)- 3-oxopent-4-ynenitrile MS [M H].sup. calcd for C12H6N2O6 273.0, found 273.0 Ex. 650 [00705] (Z)-2-((3,4-dihydroxy-5- nitrophenyl)(hydroxy)methylene)- 4-methyl-3-oxopentanenitrile MS [M H].sup. calcd for C13H12N2O6 291.1, found 291.1 Ex. 651 [00706] (Z)-3-(3-chloro-4-hydroxy-5- nitrophenyl)-2- (cyclopropanecarbonyl)-3- hydroxyacrylonitrile MS [M H].sup. calcd for C13H9ClN205 307.0, found 307.0 Ex. 652 [00707] (Z)-2-((3,4-dihydroxy-5- nitrophenyl)(hydroxy)methylene)- 3-oxohexanenitrile MS [M-H] calcd for C13H12N2O6 291.1, found 291.1 Ex. 653 [00708] (Z)-3-(3,4-dihydroxy-5- nitrophenyl)-3-hydroxy-2-(1 - methylcyclopropanecarbonyl) acrylonitrile MS [M H].sup. calcd for C14H12N2O6 303.1, found 303.1 .sup.1H NMR (400 MHz, DMSO-d.sub.6) 7.94 (s, 1H), 7.29 (s, 1H), 1.40 (s, 3H), 1.22 (s, 2H), 1.18 (t, J = 7.3 Hz, 2H). Ex. 654 [00709] (Z)-3-(3,4-dihydroxy-5- nitrophenyl)-3-hydroxy-2-(1- (trifluoromethyl)cyclopropane- 1-carbonyl)acrylonitrile MS [M H].sup. calcd for C14H9F3N2O6 357.0, found 357.0 Ex. 655 [00710] (Z)-2-((3,4-dihydroxy-5- nitrophenyl)(hydroxy)methylene)- 3-oxopent-4-enenitrile MS [M H].sup. calcd for C12H8N2O6 275.0, found 275.0 Ex. 656 [00711] (Z)-2-(cyclopropanecarbonyl)- 3-(3,5-dichloro-4- hydroxyphenyl)-3- hydroxyacrylonitrile MS [M H].sup. calcd for C13H9Cl2NO3 296.0, found 295.9. .sup.1HNMR (400 MHz, CD3OD) 8.07 (s, 2H), 2.50-2.47 (m, 1H), 1.36-1.29 (m, 4H). Ex. 667 [00712] (Z)-3-hydroxy-3-(4-hydroxy-3- methoxy-5-nitrophenyl)-2-(1- methylcyclopropane-1- carbonyl)acrylonitrile MS [M H].sup. calcd for C15H14N2O6 317.1, found 317.1 .sup.1H NMR (400 MHz, DMSO-d.sub.6) 8.04 (d, J = 1.7 Hz, 1H), 7.65 (d, J = 1.9 Hz, 1H), 3.90 (s, 3H), 1.45 (s, 3H), 1.21 (d, J = 1.6 Hz, 2H), 0.82 (d, J = 1.8 Hz, 2H).

Example 657: (Z)-2-cyano-3-(3,4-dihydroxy-5-nitrophenyl)-N-ethyl-3-hydroxy-N-(2-hydroxyethyl)acrylamide

##STR00713##

Step1: Synthesis of 2-cyano-N-ethyl-N-(2-hydroxyethyl)acetamide (A-3)

[0317] A solution of 2-(ethylamino)ethan-1-ol (2.1 g, 23.51 mmol), 2-cyanoacetic acid (2 g, 23.51 mmol), HATU (10.73 g, 28.21 mmol) and DIPEA (3.64 g, 28.21 mmol) in DCM (30 mL) was stirred at room temperature for 5 h, then the solution was washed with water (30 mL). The mixture was extracted with ethyl acetate (30 mL3). The combined extraction was dried over anhydrous Na.sub.2SO.sub.4, then filtered and concentrated in vacuo to afford the crude product. Further purification by column chromatography (silica gel, PE/EA=1/1) afforded the desired product (814 mg, 22%). MS [MH].sup.+ calcd for C71H12N2O2 155, found 155.

Step2: Synthesis of 2-cyano-N-ethyl-N-(2-((tetrahydro-2H-pyran-2- (A-4)

[0318] A solution of 3,4-dihydro-2H-pyran (526 mg, 6.25 mmol), 2-cyano-N-ethyl-N-(2-hydroxyethyl)acetamide (814 mg, 5.21 mmol), Pyridinium p-toluenesulfonate (1.96 g, 7.82 mmol) in DCM (10 mL) was stirred at 40 C. for 5 h, then it was concentrated in vacuo to afford the crude product. Further purification by column chromatography (silica gel, PE/BA=2/1) afforded the desired product (430 mg, 34%). MS [MH].sup.+ calcd for C12H20N2O3 241, found 241.

Step3: Synthesis of (Z)-2-cyano-3-(3,4-dimethoxy-5-nitrophenyl)-N-ethyl-3-hydroxy-N-(2-((tetrahydro-2H-pyran-2-yl)oxy)ethyl)acrylamide (2)

[0319] A solution of 3,4-dimethoxy-5-nitrobenzoic acid (407 mg, 1.79 mmol) in SOCl.sub.2 (10 mL) was stirred at 80 C. for 2 h, then it was concentrated in vacuo to get an acyl chloride. NaH (179 mg, 4.47 mmol) was added to a solution of 2-cyano-N-ethyl-N-(2-((tetrahydro-2H-pyran-2-yl)oxy)ethyl)acetamide (430 mg, 1.79 mmol) in THF (15 mL) at 0 C. The mixture was stirred for 1 h, then the acyl chloride was added to the above solution. The mixture was stirred at 0 C. for 1 h, then stirred at room temperature overnight. The mixture was washed with 1 N HCl (5 mL) and water (15 mL). The mixture was extracted with ethyl acetate (20 mL3). The combined extraction was dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated in vacuo to afford the crude product (11 mg, crude). MS [MH].sup. calcd for C21H27N3O8 448, found 448.

Step4: Synthesis of (Z)-2-cyano-3-(3,4-dihydroxy-5-nitrophenyl)-N-ethyl-3-hydroxy-N-(2-hydroxyethyl)acrylamide (Ex. 657)

[0320] A solution of (Z)-2-cyano-3-(3,4-dimethoxy-5-nitrophenyl)-N-ethyl-3-hydroxy-N-(2-((tetrahydro-2H-pyran-2-yl)oxy)ethyl)acrylamide (11 mg, 0.024 mmol) in DCM (10 mL) was added BBr.sub.3 (0.01 mL) at 5 C. The reaction mixture was stirred in a tube at room temperature overnight. The mixture was cooled to 5 C. and washed with water (10 mL). The mixture was extracted with ethyl acetate (10 mL2). The combined extraction was dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated in vacuo to afford the crude product. Further purification was performed by Prep-HPLC (0.05% TFA; ACNH2O) to afford (Z)-2-cyano-3-(3,4-dihydroxy-5-nitrophenyl)-N-ethyl-3-hydroxy-N-(2-hydroxyethyl)acrylamide (4 mg, 49%). MS [MH].sup. calcd for C14H15N3O7 336, found 336.

Example 658: (Z)N-(2-cyano-3-(3,4-dihydroxy-5-nitrophenyl)-3-hydroxyacryloyl)-N-methylglycine

##STR00714##

Step1: Synthesis of methyl N-(2-cyanoacetyl)-N-methylglycinate

[0321] To a solution of N-methylglycinate hydrochloride (1.0 g, 7.2 mmol) and 2-cyanoacetic acid (0.6 g, 7.2 mmol) were added T.sub.3P (3.4 g, 10.8 mmol) and DIEA (2.8 g, 21.6 mmol). The flask was degassed with nitrogen. The mixture was stirred for 8 h at 25 C. The reaction mixture was washed with water (20 ML), extracted with DCM (150 mL*3). The combined extraction was dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated in vacuo The residue was purified by silica gel chromatography (PE/EA=2/3) to obtain the product (710 mg, 58%). MS [MH].sup.+ calcd for C.sub.7H.sub.10N.sub.2O.sub.3 171.1, found 171.1.

Step2: Synthesis of methyl methyl (Z)N-(2-cyano-3-(3,4-dihydroxy-5-nitrophenyl)-3-hydroxyacryloyl)-N-methylglycinate

[0322] The mixture of 3,4-dihydroxy-5-nitrobenzoic acid (200 mg, 1.0 mmol) in SOCl.sub.2 (10 mL) was heated to 80 C. for 2 hours. Then it was concentrated in vacuo to obtain an acyl chloride. A solution of N-(2-cyanoacetyl)-N-methylglycinate (170 mg, 1.0 mmol) in THF (20 mL) was stirred at 78 C. for 10 min under N.sub.2 atmosphere, subsequently LiHMDS (1.5 mL, 1.5 mmol) was added. The mixture was stirred for 1 hour. The above acyl chloride was added to the reaction mixture. The mixture was warmed to RT, and stirred overnight. The mixture was acidified to pH 5-6 with 1N HCl, extracted with DCM (50 mL*3). The combined extraction was dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated in vacuo The residue was purified by Prep-HPLC (H2O/MeCN=55/45, 0.1% TFA, 3 times) to obtain the crude product (100 mg, 28.6%). MS [MH].sup. calcd for C14H13N3O8 350.1, found 350.1.

Step3: Synthesis of (Z)N-(2-cyano-3-(3,4-dihydroxy-5-nitrophenyl)-3-hydroxyacryloyl)-N-methylglycine (Ex. 658)

[0323] A mixture of methyl (Z)N-(2-cyano-3-(3,4-dihydroxy-5-nitrophenyl)-3-hydroxyacryloyl)-N-methylglycinate (100 mg, 0.29 mmol) in THF/H.sub.2O (10 mL/10 mL) was added LiOH (17 mg, 0.58 mmol). The reaction was stirred at RT for 6 h. The mixture was acidified to pH 5-6 with 1N HCl, extracted with DCM (20 mL*3). The combined extraction was dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated in vacuo The residue was purified by silica gel chromatography (DCM/MeOH=20/1) to obtain the product (80 mg, 82.5%). MS [MH].sup. calcd for C13H11N3O8 336.1, found 336.1.

Example 659: (Z)-2-cyano-3-(3,5-dichloro-4-hydroxyphenyl)-3-hydroxy-N-(2-((2-methoxyethyl)amino)-2-oxoethyl)-N-methylacrylamide

##STR00715##

[0324] To a mixture of 2-methoxyethan-1-amine (22 mg, 0.3 mmol) in DCM (30 mL) were added (Z)N-(2-cyano-3-(3,5-dichloro-4-hydroxyphenyl)-3-hydroxyacryloyl)-N-methylglycine (100 mg, 0.3 mmol), T.sub.3P (138 mg, 0.43 mmol) and DIEA (112 g, 0.87 mmol). The reaction was stirred at rt for 16 h. The reaction was quenched with ice water (20 ML). The mixture was extracted with DCM (150 mL*3). The combined extraction was dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated in vacuo. The residue was purified by Prep-HPLC (H2O/MeCN=60/40, 0.1% TFA, 3 times) to obtain the product (59 mg, HPLC: 99.4%). MS [MH].sup.+ calcd for C.sub.16H17Cl2N3O5 399.9, found 399.9. .sup.1H NMR (400 MHz, DMSO-d.sub.6) 8.31 (s, 1H), 7.82 (s, 2H), 4.12 (s, 2H), 3.35-3.37 (t, J=4.0 Hz, 2H), 3.27 (s, 2H), 3.17 (s, 3H), 3.14 (s, 3H).

Examples 660 and 661: methyl (Z)-5-(2-cyano-3-(diethylamino)-1-hydroxy-3-oxoprop-1-en-1-yl)-2,3-dihydroxybenzoate (Ex. 660) and (Z)-5-(2-cyano-3-(diethylamino)-1-hydroxy-3-oxoprop-1-en-1-yl)-2,3-dihydroxybenzoic acid (Ex. 661)

##STR00716##

Step1: Synthesis of (Z)-3-(3-bromo-4-hydroxy-5-methoxyphenyl)-2-cyano-N,N-diethyl-3-hydroxyacrylamide

[0325] A solution of 3-bromo-4-hydroxy-5-methoxybenzoic acid (1.4 g, 5.67 mmol) in SOCl.sub.2 (20 mL) was stirred at 80 C. for 2 h, then it was concentrated in vacuo to get an acyl chloride. NaH (567 mg, 14.17 mmol) was added to a solution of 2-cyano-N,N-diethylacetamide (794 mg, 5.67 mmol) in THF (15 mL) at 0 C. The mixture was stirred for 1 h, then the acyl chloride was added to the above solution. The mixture was stirred at 0 C. for 1 h, then stirred at room temperature overnight. The reaction mixture was washed with 1 N HCl (15 mL) and water (30 mL). The mixture was extracted with ethyl acetate (20 mL3). The combined extraction was dried over anhydrous Na.sub.2SO.sub.4, then filtered and concentrated in vacuo to afford the crude product (410 mg, crude). MS [MH].sup. calcd for C15H17BrN2O4 367 and 369 found 367 and 369.

Step2: Synthesis of methyl (Z)-5-(2-cyano-3-(diethylamino)-1-hydroxy-3-oxoprop-1-en-1-yl)-2-hydroxy-3-methoxybenzoate

[0326] A solution of (Z)-3-(3-bromo-4-hydroxy-5-methoxyphenyl)-2-cyano-N,N-diethyl-3-hydroxyacrylamide (500 mg, 1.35 mmol), Et.sub.3N (274 mg, 2.71 mmol) and Pd(dppf)Cl.sub.2 (99 mg, 0.14 mmol) in MeOH (10 mL) and was stirred under CO at 120 C. for 4 h. The mixture was washed with water, extracted with EA. The solvent of the combined extraction was removed in vacuo to afford crude product. Further purification by column chromatography (silica gel, PE/EA=1/1) afforded the desired product (60 mg, 13%). MS [MH]-calcd for C17H20N2O6 347 found 347.

Step3: Synthesis of methyl (Z)-5-(2-cyano-3-(diethylamino)-1-hydroxy-3-oxoprop-1-en-1-yl)-2,3-dihydroxybenzoate (Ex. 660)

[0327] A solution of methyl (Z)-5-(2-cyano-3-(diethylamino)-1-hydroxy-3-oxoprop-1-en-1-yl)-2-hydroxy-3-methoxybenzoate (60 mg, 0.17 mmol) in DCM (10 mL) was added BBr.sub.3 (0.1 mL) at 5 C. The reaction mixture was stirred in a tube at room temperature overnight. The mixture was cooled to 5 C. and washed with water (15 mL). The mixture was extracted with ethyl acetate (10 mL2) The combined extraction was dried over anhydrous Na.sub.2SO.sub.4, then filtered and concentrated in vacuo to afford the crude product. Further purification was performed by Prep-HPLC (0.05% TFA; ACNH.sub.2O) to afford methyl (Z)-5-(2-cyano-3-(diethylamino)-1-hydroxy-3-oxoprop-1-en-1-yl)-2,3-dihydroxybenzoate (27 mg, 47%). .sup.1H NMR (400 MHz, DMSO-d.sub.6) 10.790 (s, 1H), 10.095 (s, 1H), 7.782 (s, 1H), 7.481 (s, 1H), 3.916 (s, 3H), 3.564 (d, J=6.8 Hz, 4H), 1.208 (t, J=6.8 Hz, 6H). MS [MH].sup.+ calcd for C.sub.16H18N2O6 333, found 333.

Step4: Synthesis of (Z)-5-(2-cyano-3-(diethylamino)-1-hydroxy-3-oxoprop-1-en-1-yl)-2,3-dihydroxybenzoic acid (Ex. 661)

[0328] NaOH (5 mg, 0.12 mmol) was added to a solution of methyl (Z)-5-(2-cyano-3-(diethylamino)-1-hydroxy-3-oxoprop-1-en-1-yl)-2,3-dihydroxybenzoate (20 mg, 0.060 mmol) in THF/water (10 mL/10 mL) at 0 C. The reaction mixture was stirred at room temperature overnight. The mixture was cooled to 5 C. and washed with 1 N HCl (5 mL). The mixture was extracted with ethyl acetate (10 mL2) The combined extraction was dried over anhydrous Na.sub.2SO.sub.4, then filtered and concentrated in vacuo to afford the crude product. Further purification was performed by Prep-HPLC (0.05% TFA; ACNH2O) to afford (Z)-5-(2-cyano-3-(diethylamino)-1-hydroxy-3-oxoprop-1-en-1-yl)-2,3-dihydroxybenzoic acid (7 mg, 36%). .sup.1H NMR (400 MHz, DMSO) 9.795 (s, 1H), 7.837 (s, 1H), 7.431 (s, 1H), 3.565 (d, J=6.8 Hz, 4H), 1.210 (t, J=6.8 Hz, 6H). MS [MH].sup. calcd for C15H16N2O6 319, found 319.

Biological Assay

[0329] FTO inhibition Assay (Enzymatic Inhibition). The inhibition assay was adapted from a publication about Maz-F coupled FTO demethylase activity assay (Chem Commun. 2017 Nov. 30; 53(96):12930-12933. doi: 10.1039/c7cc07699a). FTO-catalyzed demethylation activity was measured in a 10 l reaction system containing 20 mM HEPES buffer (pH 7.5), 20 M a-KG, 10 M (NH4)2Fe(SO4)2, 1.5 mM L-ascorbic acid, 2 M DRNA with m6A (5-FAM-d(CAT)r(GG-m6A-CA)d(TATGT)-BHQ1-3), 0.15 M FTO protein. The reaction system was incubated at 32 C. for 45 min. Aliquot MazF into each well above (40 ul 1Maz-F+10 ul the reaction/well), the final concentration is 50 nM, and the reaction system was incubated at 37 C. for 25 min. MazF cleaves only nonmethylated DRNA (-ACA-), permitting specific detection of the methylation states of DRNA. Maz-F readily cleaves the DRNA and eventually liberates 5-FAM, which gives a strong fluorescence signal around 535 nm (485 nm excitation-535 emission).

[0330] COMT Inhibition Assay. The inhibition of the compounds against COMT was measured in the reaction kinetic model. The test compound was diluted with assay buffer to desired concentration. The COMT enzyme was also diluted with assay buffer. Then 5 L diluted test article, 5 L diluted COMT and 5 L Esculetin were added into plate and incubated for 5 min at 37 C., sealed with TopSeal-A 384, Clear Adhesive (PE). Then 5 L AdoMet was added into the plate. The reaction system contains 1 U COMT enzyme, test compound, 4 M Esculetin, 0.6 mM AdoMet, 50 mM K.sub.3PO.sub.4, and 10 mM MgCl.sub.2. Read plate by using kinetics model (Excitation at 360 nm & emission at 460 nm). The inhibition was calculated from the slope.

TABLE-US-00008 FTO IC.sub.50 COMT IC.sub.50 Ex No. (M) (M) Ref1 0.80 0.50 Ref2 19.70 INACTIVE Ex. 486 0.15 0.65 Ex. 478 0.40 0.29 Ex. 464 1.2 0.32 Ex. 463 0.85 0.50 Ex. 466 1.48 2.75 Ex. 458 2.47 ND (not determined) Ex. 657 >100 1.60 Ex. 473 1.62 0.54 Ex. 12 15.80 INACTIVE Ex. 10 25.10 INACTIVE Ex. 33 0.5 INACTIVE Ex. 34 1.08 INACTIVE Ex. 31 1.27 INACTIVE Ex. 35 1.47 INACTIVE Ex. 1 1.04 INACTIVE Ex. 36 1.12 INACTIVE Ex. 457 0.50 1.07 Ex. 459 1.10 INACTIVE Ex. 488 2.55 INACTIVE Ex. 37 2.37 INACTIVE Ex. 32 2.49 INACTIVE Ex. 41 2.22 INACTIVE Ex. 632 2.10 INACTIVE Ex. 38 9.57 INACTIVE Ex. 42 1.67 INACTIVE Ex. 40 2.25 INACTIVE Ex. 46 1.45 INACTIVE Ex. 45 1.46 INACTIVE Ex. 47 1.16 INACTIVE Ex. 44 0.82 INACTIVE Ex. 48 2.86 INACTIVE Ex. 43 2.56 INACTIVE Ex. 495 0.82 0.38 Ex. 30 4.05 INACTIVE Ex. 658 0.80 0.40 Ex. 635 0.82 0.41 Ex. 634 1.5 INACTIVE Ex. 456 1.22 0.51 Ex. 28 70.20 INACTIVE Ex. 461 1.5 0.58 Ex. 469 0.53 0.17 Ex. 479 1.0 0.13 Ex. 477 0.33 0.11 Ex. 483 0.4 0.16 Ex. 490 0.4 0.17 Ex. 475 1.54 0.08 Ex. 487 0.50 0.14 Ex. 482 0.44 0.12 Ex. 481 0.47 0.12 Ex. 480 0.53 0.15 Ex. 474 1.0 0.41 Ex. 476 0.56 0.11 Ex. 493 0.71 0.27 Ex. 489 0.71 0.25 Ex. 11 0.16 INACTIVE Ex. 16 0.33 INACTIVE Ex. 13 0.16 INACTIVE Ex. 19 0.12 INACTIVE Ex. 75 0.26 INACTIVE Ex. 27 0.31 INACTIVE Ex. 66 0.29 INACTIVE Ex. 67 0.61 INACTIVE Ex. 25 0.47 INACTIVE Ex. 26 1.14 INACTIVE Ex. 15 0.57 INACTIVE Ex. 21 0.31 INACTIVE Ex. 17 0.37 INACTIVE Ex. 14 0.56 INACTIVE Ex. 20 0.26 INACTIVE Ex. 22 0.41 INACTIVE Ex. 24 0.73 INACTIVE Ex. 4 1.26 INACTIVE Ex. 76 0.81 INACTIVE Ex. 659 2.45 INACTIVE Ex. 57 0.72 INACTIVE Ex. 58 0.97 INACTIVE Ex. 50 0.09 INACTIVE Ex. 49 0.11 INACTIVE Ex. 491 1.40 INACTIVE Ex. 492 0.48 0.82 Ex. 53 0.16 INACTIVE Ex. 68 0.09 INACTIVE Ex. 54 0.14 INACTIVE Ex. 55 0.06 INACTIVE Ex. 56 0.15 INACTIVE Ex. 65 0.11 INACTIVE Ex. 70 0.13 INACTIVE Ex. 72 0.21 INACTIVE Ex. 59 0.08 INACTIVE Ex. 61 0.20 INACTIVE Ex. 62 0.13 INACTIVE Ex. 51 0.23 INACTIVE Ex. 496 3.0 INACTIVE Ex. 79 0.25 INACTIVE Ex. 656 0.5 INACTIVE Ex. 73 0.06 INACTIVE Ex. 74 0.07 INACTIVE Ex. 52 0.11 INACTIVE Ex. 78 0.25 INACTIVE Ex. 485 1.44 0.17 Ex. 468 1.24 0.21 Ex. 460 0.92 0.30 Ex. 472 2.32 0.77 Ex. 471 1.29 0.20 Ex. 484 0.83 0.15 Ex. 470 0.75 0.30 Ex. 5 0.60 0.21 Ex. 465 0.67 0.51 Ex. 7 0.97 INACTIVE Ex. 23 0.48 INACTIVE Ex. 39 0.25 INACTIVE Ex. 3 0.32 INACTIVE Ex. 2 0.15 INACTIVE Ex. 6 0.25 INACTIVE Ex. 8 0.21 INACTIVE Ex. 9 0.26 INACTIVE Ex. 60 0.08 INACTIVE Ex. 63 0.09 INACTIVE Ex. 64 0.70 INACTIVE Ex. 71 0.70 INACTIVE Ex. 494 0.64 0.27 Ex. 29 0.43 INACTIVE Ex. 640 0.08 0.05 Ex. 639 50.60 INACTIVE Ex. 641 2.11 INACTIVE Ex. 638 0.12 0.15 Ex. 636 0.29 INACTIVE Ex. 637 1.97 INACTIVE Ex. 633 >100 INACTIVE Ex. 77 18.30 INACTIVE Ex. 69 0.15 INACTIVE Ex. 462 0.35 0.32 Ex. 325 0.09 INACTIVE Ex. 662 0.8 INACTIVE Ex. 663 0.45 INACTIVE Ex. 664 0.22 INACTIVE Ex. 653 0.56 ND (not determined)

[0331] Ref1 compound has the structure of

##STR00717##

and Ref2 compound has the structure of

##STR00718##

[0332] Although the foregoing invention has been described in some detail by way of illustration and example for purposes of clarity of understanding, it is apparent to those skilled in the art that certain minor changes and modifications will be practiced. Therefore, the description and Examples should not be construed as limiting the scope of the invention.