NATURAL PRODUCT ANALOGS INCLUDING AN ANTI-INFLAMMATORY CYANOENONE PHARMACORE AND METHODS OF USE

1 . A compound comprising:

a) the basic skeleton of an organic compound having two to eight five and/or six-membered rings provided that the basic skeleton is not the basic skeleton of argentatin, betulinic acid, lanostane, oleanic acid, boswellic acid, glycyrrhetinic acid, ursolic acid, or tricyclic-bis-enone;

b) a structural unit of the formula:

wherein:

the carbon atoms labeled 1, 2 and 3 are part of a five or six-membered ring;

X is cyano or —C(O)R a , wherein R a is:

hydrogen, hydroxy, halo, amino, hydroxyamino, azido or mercapto; or

alkyl (C≤12) , alkenyl (C≤12) , alkynyl (C≤12) , aryl (C≤12) , aralkyl (C≤12) , heteroaryl (C≤12) , heteroaralkyl (C≤12) , alkoxy (C≤12) , alkenyl-oxy (C≤12) , alkynyloxy (C≤12) , aryloxy (C≤12) , aralkoxy (C≤12) , heteroaryloxy (C≤12) , heteroaralkoxy (C≤12) , acyloxy (C≤12) , alkylamino (C≤12) , dialkylamino (C≤12) , alkoxyamino (C≤12) , alkenylamino (C≤12) , alkynylamino (C≤12) , arylamino (C≤12) , aralkylamino (C≤12) , heteroarylamino (C≤12) , heteroaralkyl-amino (C≤12) , alkylsulfonylamino (C≤12) , amido (C≤12) , alkyl-silyloxy (C≤12) , or substituted versions of any of these groups; and

R 1 and R 2 are each independently:

hydrogen; or

alkyl (C≤12) , alkenyl (C≤12) , alkynyl (C≤12) , aryl (C≤12) , aralkyl (C≤8) , heteroaryl (C≤12) , heteroaralkyl (C≤12) , acyl (C≤12) , alkoxy (C≤12) , aryloxy (C≤12) , aralkoxy (C≤12) , heteroaryloxy (C≤12) , hetero-aralkoxy (C≤12) , acyloxy (C≤12) , alkylamino (C≤12) , dialkyl-amino (C≤12) , arylamino (C≤12) , aralkylamino (C≤12) , hetero-arylamino (C≤12) , heteroaralkylamino (C≤12) , amido (C≤12) , or a substituted version of any of these groups; or

R 1 and R 2 are taken together and are alkanediyl (C≤12) , alkenediyl (C≤12) , alkanediyl (C≤12) or alkenediyl (C≤12) ; and

c) from 0 to 8 chemical groups attached to a carbon atom of the basic skeleton other than carbon atoms 1, 2, 3 or 4, wherein each chemical group is independently:

hydroxy, halo, oxo, amino, hydroxyamino, nitro, imino, cyano, azido, mercapto, or thio; or

alkyl (C≤12) , alkenyl (C≤12) , alkynyl (C≤12) , aryl (C≤12) , aralkyl (C≤12) , heteroaryl (C≤12) , heteroaralkyl (C≤12) , acyl (C≤12) , alkylidene (C≤12) , alkoxy (C≤12) , alkenyloxy (C≤12) , alkynyloxy (C≤12) , aryloxy (C≤12) , aralkoxy (C≤12) , heteroaryloxy (C≤12) , heteroaralkoxy (C≤12) , acyl-oxy (C≤12) , alkylamino (C≤12) , dialkylamino (C≤12) , alkoxyamino (C≤12) , alkenylamino (C≤12) , alkynylamino (C≤12) , arylamino (C≤12) , aralkyl-amino (C≤12) , heteroarylamino (C≤12) , heteroaralkylamino (C≤12) , alkylsulfonylamino (C≤12) , amido (C≤12) , alkylimino (C≤12) , alkenyl-imino (C≤12) , alkynylimino (C≤12) , arylimino (C≤12) , aralkylimino (C≤12) , heteroarylimino (C≤12) , heteroaralkylimino (C≤12) , acylimino (C≤12) , alkylthio (C≤12) , alkenylthio (C≤12) , alkynylthio (C≤12) , arylthio (C≤12) , aralkylthio (C≤12) , heteroarylthio (C≤12) , heteroaralkylthio (C≤12) , acyl-thio (C≤12) , thioacyl (C≤12) , alkylsulfonyl (C≤12) , alkenylsulfonyl (C≤8) , alkynylsulfonyl (C≤12) , arylsulfonyl (C≤12) , aralkylsulfonyl (C≤12) , heteroarylsulfonyl (C≤12) , heteroaralkylsulfonyl (C≤12) , alkyl-ammonium (C≤12) , alkylsulfonium (C≤12) , alkylsilyl (C≤12) , alkylsilyl-oxy (C≤12) , or a substituted version of any of these groups;

or pharmaceutically acceptable salts, esters, hydrates, solvates, tautomers, acetals, ketals, prodrugs, or optical isomers thereof.

2 . The compound of claim 1 , wherein R 1 and R 2 are each independently hydrogen, alkyl (C≤8) or substituted alkyl (C≤8) .

3 - 6 . (canceled)

7 . A compound comprising:

a) the basic skeleton of a natural product having two to eight rings, provided that the natural product is not argentatin, betulinic acid, lanostane, oleanic acid, or ursolic acid;

b) a structural unit of the formula:

wherein:

the carbon atoms labeled 1, 2 and 3 are part of a six-membered ring;

X is cyano, fluoroalkyl (C≤8) , substituted, fluoroalkyl (C≤8) , or —C(O)R a , wherein R a is:

hydrogen, hydroxy, halo, amino, hydroxyamino, azido or mercapto; or

alkyl (C≤12) , alkenyl (C≤12) , alkynyl (C≤12) , aryl (C≤12) , aralkyl (C≤12) , heteroaryl (C≤12) , heteroaralkyl (C≤12) , alkoxy (C≤12) , alkenyl-oxy (C≤12) , alkynyloxy (C≤12) , aryloxy (C≤12) , aralkoxy (C≤12) , heteroaryloxy (C≤12) , heteroaralkoxy (C≤12) , acyloxy (C≤12) , alkylamino (C≤12) , dialkylamino (C≤12) , alkoxyamino (C≤12) , alkenylamino (C≤12) , alkynylamino (C≤12) , arylamino (C≤12) , aralkylamino (C≤12) , heteroarylamino (C≤12) , heteroaralkyl-amino (C≤12) , alkylsulfonylamino (C≤12) , amido (C≤12) , alkyl-silyloxy (C≤12) , or substituted versions of any of these groups; and

R 1 and R 2 are each independently:

hydrogen; or

alkyl (C≤12) , alkenyl (C≤12) , alkynyl (C≤12) , aryl (C≤12) , aralkyl (C≤12) , heteroaryl (C≤12) , heteroaralkyl (C≤12) , acyl (C≤12) , alkoxy (C≤12) , aryloxy (C≤12) , aralkoxy (C≤12) , heteroaryloxy (C≤12) , hetero-aralkoxy (C≤12) , acyloxy (C≤12) , alkylamino (C≤12) , dialkyl-amino (C≤12) , arylamino (C≤12) , aralkylamino (C≤12) , hetero-arylamino (C≤12) , heteroaralkylamino (C≤12) , amido (C≤12) , or a substituted version of any of these groups; or

R 1 and R 2 are taken together and are alkanediyl (C≤12) , alkenediyl (C≤12) , alkanediyl (C≤12) or alkenediyl (C≤12) ; and

c) from 0 to 8 chemical groups attached to a carbon atom of the basic skeleton other than carbon atoms 1, 2, 3 or 4, wherein each chemical group is independently:

hydroxy, halo, oxo, amino, hydroxyamino, nitro, imino, cyano, azido, mercapto, or thio; or

alkyl (C≤12) , alkenyl (C≤12) , alkynyl (C≤12) , aryl (C≤12) , aralkyl (C≤12) , heteroaryl (C≤12) , heteroaralkyl (C≤12) , acyl (C≤12) , alkylidene (C≤12) , alkoxy (C≤12) , alkenyloxy (C≤12) , alkynyloxy (C≤12) , aryloxy (C≤12) , aralkoxy (C≤12) , heteroaryloxy (C≤12) , heteroaralkoxy (C≤12) , acyl-oxy (C≤12) , alkylamino (C≤12) , dialkylamino (C≤12) , alkoxyamino (C≤12) , alkenylamino (C≤12) , alkynylamino (C≤12) , arylamino (C≤12) , aralkyl-amino (C≤12) , heteroarylamino (C≤12) , heteroaralkylamino (C≤12) , alkylsulfonylamino (C≤12) , amido (C≤12) , alkylimino (C≤12) , alkenyl-imino (C≤12) , alkynylimino (C≤12) , arylimino (C≤12) , aralkylimino (C≤12) , heteroarylimino (C≤12) , heteroaralkylimino (C≤12) , acylimino (C≤12) , alkylthio (C≤12) , alkenylthio (C≤12) , alkynylthio (C≤12) , arylthio (C≤12) , aralkylthio (C≤12) , heteroarylthio (C≤12) , heteroaralkylthio (C≤12) , acyl-thio (C≤12) , thioacyl (C≤8) , alkylsulfonyl (C≤12) , alkenylsulfonyl (C≤12) , alkynylsulfonyl (C≤12) , arylsulfonyl (C≤12) , aralkylsulfonyl (C≤12) , heteroarylsulfonyl (C≤12) , heteroaralkylsulfonyl (C≤12) , alkyl-ammonium (C≤12) , alkylsulfonium (C≤12) , alkylsilyl (C≤12) , alkylsilyl-oxy (C≤12) , or a substituted version of any of these groups;

or pharmaceutically acceptable salts, esters, hydrates, solvates, tautomers, acetals, ketals, prodrugs, or optical isomers thereof.

8 . The compound of claim 7 , wherein R 1 and R 2 are each independently hydrogen, alkyl (C≤8) or substituted alkyl (C≤8) .

9 - 15 . (canceled)

16 . The compound of claim 7 , wherein X is —CN.

17 - 18 . (canceled)

19 . The compound of claim 16 , wherein the structural unit is further defined as:

20 - 173 . (canceled)

174 . A method of making a compound of claim 1 , comprising:

(a) obtaining an organic compound having two to eight five and/or six-membered rings, provided that the organic compounds is not argentatin, betulinic acid, lanostane, oleanic acid, boswellic acid, glycyrrhetinic acid, ursolic acid, or tricyclic-bis-enone;

(b) reacting the organic compound in a series of one of more steps to obtain a compound according to claim 1 .

175 . The method of claim 174 , wherein the compound's induction of Nrf2 activity is at least ten times higher than the organic compound's induction of Nrf2 activity.

176 . The method of claim 174 , wherein the compound's inhibition of NF-κB activity is at least ten times higher than the organic compound's inhibition of NF-κB activity.

177 . The method of claim 174 , wherein the compound's inhibition of IFNγ induced NO activity is at least ten times higher than the organic compound's inhibition of IFNγ induced NO activity.