HK1152713B

HK1152713B - Antioxidant inflammation modulators: c-17 homologated oleanolic acid derivatives

Info

Publication number: HK1152713B
Application number: HK11106765.7A
Authority: HK
Inventors: 江昕; 刘晓峰; 杰克‧格雷纳; 斯蒂芬‧S‧苏克斯; 麦琳‧维斯尼克
Original assignee: 里亚塔医药公司
Priority date: 2008-04-18
Filing date: 2009-04-20
Publication date: 2014-12-12

Description

Antioxidant inflammation regulator C-17 homologized oleanolic acid derivatives

Technical Field

This application claims priority to U.S. provisional application No. 61/046,366, filed on 18.2008 and 61/111,294, filed on 4.2008, both of which are hereby incorporated by reference in their entirety.

1. Field of the invention

The present disclosure relates generally to the fields of biology and medicine. More particularly, it relates to compounds and methods for the treatment and prevention of diseases, such as those associated with oxidative stress and inflammation.

Description of the related Art

Many serious and intractable human diseases are associated with a deregulation of inflammatory processes, including diseases such as cancer, atherosclerosis and diabetes, which are not traditionally considered inflammatory diseases. Similarly, autoimmune diseases such as rheumatoid arthritis, lupus, psoriasis and multiple sclerosis involve inappropriate and chronic activation of inflammatory processes in affected tissues, resulting from dysfunction of self-to non-self recognition and response mechanisms in the immune system. In neurodegenerative diseases such as alzheimer's disease and parkinson's disease, nerve damage is associated with activation of microglia and increased levels of pro-inflammatory proteins such as Inducible Nitric Oxide Synthase (iNOS).

One aspect of inflammation is the production of inflammatory prostaglandins, such as prostaglandin E, the precursor of which is produced by the cyclooxygenase enzyme (COX-2). COX-2 is found at high levels in inflamed tissues. Thus, inhibition of COX-2 is known to reduce many symptoms of inflammation, and many important anti-inflammatory drugs (e.g., ibuprofen and celecoxib) act by inhibiting COX-2 activity. However, recent studies have demonstrated that a class of cyclopentenone prostaglandins (e.g., 15-deoxy prostaglandin J2, also known as PGJ2) plays a role in stimulating the resolution of inflammation. COX-2 is also associated with the production of cyclopentenone prostaglandins. Thus, inhibition of COX-2 may interfere with complete resolution of inflammation, potentially promoting retention of activated immune cells in tissues and leading to chronic "stasis" inflammation. This effect may lead to an increased incidence of cardiovascular disease in patients who use selective COX-2 inhibitors over a prolonged period of time. Another important class of anti-inflammatory corticosteroids have many adverse side effects and are often not suitable for chronic use. Newer protein-based drugs, such as anti-TNF monoclonal antibodies, have proven effective for the treatment of certain autoimmune diseases, such as rheumatoid arthritis. However, these compounds must be administered by injection, are not effective in all patients and may have serious side effects. In many severe forms of inflammation (e.g. sepsis, acute pancreatitis), current drugs are ineffective. Furthermore, currently available drugs do not have effective antioxidant properties and are not effective in reducing oxidative stress associated with the overproduction of reactive oxygen species and related molecules such as peroxynitrite. Thus, there is an urgent need for improved therapeutic agents with antioxidant and anti-inflammatory properties.

A series of synthetic oleanolic acid triterpenoid analogues have been shown to be inhibitors of cellular inflammatory processes, such as Inducible Nitric Oxide Synthase (iNOS) and the induction of COX-2 by IFN- γ in mouse macrophages. See Honda et al (2000 a); honda et al (2000b), and Honda et al (2002), all of which are incorporated herein by reference. For example, one of 2-cyano-3, 12-dioxoolean-1, 9(11) -diene-28-oic acid methyl ester (CDDO-Me) is currently used in clinical trials for a variety of inflammation-related disorders, including cancer and diabetic nephropathy. The pharmacology of these molecules is complex, as they have been demonstrated to affect the function of multiple protein targets and thereby modulate the function of several important cellular signaling pathways associated with oxidative stress, cell cycle control, and inflammation (e.g., Dinkova-kostowa et al, 2005; Ahmad et al, 2006; Ahmad et al, 2008; Liby et al, 2007). In view of the different biological activity spectrum of known oleanolic acid derivatives and in view of the wide diversity of diseases that can be treated with compounds having strong antioxidant and anti-inflammatory effects, it is desirable to synthesize new candidates for the treatment or prevention of diseases.

Disclosure of Invention

In one aspect, the present disclosure provides novel compounds having antioxidant and anti-inflammatory properties, methods of making the same, and methods of using the same. Compounds encompassed by the following general or specific formulae or specifically named will be referred to herein as "compounds of the invention", "compounds of the disclosure" or "oleanolic acid derivatives".

In one aspect, the present disclosure provides a compound of the formula:

wherein:

y is alkanediyl_(C≤8)Alkenyldiyl group_(C≤8)Alkynediyl_(C≤8)Or substituted versions of any of these groups;

R_athe method comprises the following steps:

hydrogen, hydroxy, halogen, amino, nitro, cyano, azido, phospho, 1, 3-dioxoisoindolin-2-yl, mercapto or silyl; or

Alkyl radical_(C≤12)Alkenyl radical_(C≤12)Alkynyl group_(C≤12)Aryl radical_(C≤12)Aralkyl group_(C≤12)Heteroaryl group_(C≤12)Heteroarylalkyl group_(C≤12)Acyl group_(C≤12)Alkoxy group_(C≤12)Alkenyloxy group_(C≤12)Alkynyloxy, alkynyloxy_(C≤12)Aryloxy group_(C≤12)(iii) aralkyloxy_(C≤12)Heteroaryloxy group_(C≤12)Hetero aralkyloxy group_(C≤12)(iii) acyloxy group_(C≤12)Alkylamino group_(C≤12)Dialkylamino group_(C≤12)Alkenylamino group_(C≤12)Alkynyl amino group_(C≤12)Arylamino group_(C≤12)Aralkylamino group_(C≤12)Heteroaryl amino_(C≤12)Heteroarylalkylamino, heteroarylalkylamino_(C≤12)Alkyl sulfonyl amino_(C≤12)Amide group_(C≤12)Alkylthio group_(C≤12)Alkenylthio radicals_(C≤12)Alkynylthio radicals_(C≤12)Arylthio radicals_(C≤12)Aralkylthio group_(C≤12)Heteroarylthio radicals_(C≤12)Heteroarylalkylthio groups_(C≤12)Acylthio groups_(C≤12)Thioacyl, thioacyl_(C≤12)Alkyl sulfonyl group_(C≤12)Alkenylsulfonyl group_(C≤12)Alkynylsulfonyl, and a process for producing the same_(C≤12)Aryl sulfonyl group_(C≤12)Aralkyl sulfonyl group_(C≤12)Heteroaryl sulfonyl group_(C≤12)Heteroarylalkylsulfonyl group_(C≤12)Alkyl sulfinyl group_(C≤12)Alkenylsulfinyl group_(C≤12)Alkynylsulfinyl group _(C≤12)Aryl sulfinyl group_(C≤12)Aralkyl sulfinyl group_(C≤12)Heteroaryl sulfinyl group_(C≤12)Heteroarylalkylsulfinyl_(C≤12)Alkyl phosphono group_(C≤12)Alkyl phosphate group_(C≤12)Dialkyl phosphate group_(C≤12)Alkyl ammonium_(C≤12)Alkyl sulfonium_(C≤12)Alkyl silyl group_(C≤12)Or substituted versions of any of these groups; or

Y and R_aForm a three-to seven-membered ring, such that Y and R_aBy one or more-O-and alkanediyl radicals_(C1-5)Are further linked to each other, further wherein Y is-CH-and R_ais-CH₂-; or

Y、R_aAnd carbon numbers 13, 17 and 18 form a ring whereby R_aTo carbon 13, wherein Y is alkanediyl_(C＝1)Or substituted alkanediyl_(C＝1)And R is_ais-O-;

X₁and X₂Independently are:

hydrogen, OR_b、NR_bR_cOr SR_bWherein R is_bAnd R_cEach is independently:

hydrogen or hydroxy;

alkyl radical_(C≤8)Aryl radical_(C≤8)Aralkyl group_(C≤8)Acyl group_(C≤8)Alkoxy group_(C≤8)Aryloxy group_(C≤8)(iii) acyloxy group_(C≤8)Alkylamino group_(C≤8)Arylamino group_(C≤8)Amide group_(C≤8)Or these

Substituted forms of any of the groups; or

Substituents that can be converted in vivo to hydrogen;

provided that when bound to R_bWhen the atom(s) is part of a double bond, then R_bAbsent, with the further proviso that when R is_bWhen not present, then bind to R_bIs part of a double bond;

R₁the method comprises the following steps:

hydrogen, cyano, hydroxy, halogen or amino; or

Alkyl radical_(C≤8)Alkenyl radical_(C≤8)Alkynyl group_(C≤8)Aryl radical_(C≤8)Aralkyl group_(C≤8)Heteroaryl group_(C≤8)Heteroarylalkyl group_(C≤8)Acyl group_(C≤8)Alkoxy group_(C≤8)Aryloxy group_(C≤8)(iii) acyloxy group_(C≤8)Alkylamino group_(C≤8)Arylamino group_(C≤8)Amide group_(C≤8)Or substituted versions of any of these groups;

R₂the method comprises the following steps:

cyano, hydroxy, halogen or amino; or

Fluoroalkyl group_(C≤8)Alkenyl radical_(C≤8)Alkynyl group_(C≤8)Aryl radical_(C≤8)Heteroaryl group_(C≤8)Acyl group_(C≤8)Alkoxy group_(C≤8)Aryloxy group_(C≤8)(iii) acyloxy group_(C≤8)Alkylamino group_(C≤8)Arylamino group_(C≤8)Amide group_(C≤8)Or substituted versions of any of these groups;

R₃the method comprises the following steps:

absent or hydrogen; alkyl radical_(C≤8)Aryl radical_(C≤8)Aralkyl group_(C≤8)Acyl group_(C≤8)Or substituted versions of any of these groups; or

Substituents that can be converted in vivo to hydrogen;

provided that when bound to R₃When the oxygen atom of (A) is part of a double bond, then R₃Absent, with the further proviso that when R is₃When not present, then bind to R₃The oxygen atom of (a) is part of a double bond;

R₄and R₅Each is independently an alkyl group_(C≤8)Or substituted alkyl_(C≤8)；

R₆Is hydrogen, hydroxy or oxygen; and is

R₇Is hydrogen or hydroxy;

R₈、R₉、R₁₀and R₁₁Each is independently hydrogen, hydroxy, alkyl_(C≤8)Substituted alkyl group_(C≤8)Alkoxy group_(C≤8)Or substituted alkoxy_(C≤8)；

Or a pharmaceutically acceptable salt, ester, hydrate, solvate, tautomer, prodrug, or optical isomer thereof.

In some embodiments, the compound is further defined as:

wherein:

R_athe method comprises the following steps:

Alkyl radical_(C≤12)Alkenyl radical_(C≤12)Alkynyl group_(C≤12)Aryl radical_(C≤12)Aralkyl group_(C≤12)Heteroaryl group_(C≤12)Heteroarylalkyl group_(C≤12)Acyl group_(C≤12)Alkoxy group_(C≤12)Alkenyloxy group_(C≤12)Alkynyloxy, alkynyloxy_(C≤12)Aryloxy group_(C≤12)(iii) aralkyloxy_(C≤12)Heteroaryloxy group_(C≤12)Hetero aralkyloxy group_(C≤12)(iii) acyloxy group_(C≤12)Alkylamino group_(C≤12)Dialkylamino group_(C≤12)Alkenylamino group_(C≤12)Alkynyl amino group_(C≤12)Arylamino group_(C≤12)Aralkylamino group_(C≤12)Heteroaryl amino_(C≤12)Heteroarylalkylamino, heteroarylalkylamino_(C≤12)Alkyl sulfonyl amino_(C≤12)Amide group_(C≤12)Alkylthio group_(C≤12)Alkenylthio radicals_(C≤12)Alkynylthio radicals_(C≤12)Arylthio radicals_(C≤12)Aralkylthio group_(C≤12)Heteroarylthio radicals_(C≤12)Heteroarylalkylthio groups_(C≤12)Acylthio groups_(C≤12)Thioacyl, thioacyl_(C≤12)Alkyl sulfonyl group_(C≤12)Alkenylsulfonyl group_(C≤12)Alkynylsulfonyl, and a process for producing the same_(C≤12)Aryl sulfonyl group_(C≤12)Aralkyl sulfonyl group_(C≤12)Heteroaryl sulfonyl group_(C≤12)Heteroarylalkylsulfonyl group_(C≤12)Alkyl sulfinyl group_(C≤12)Alkenylsulfinyl group_(C≤12)Alkynylsulfinyl group _(C≤12)Aryl sulfinyl group_(C≤12)Aralkyl sulfinyl group_(C≤12)Heteroaryl sulfinyl group_(C≤12)Heteroarylalkylsulfinyl_(C≤12)Alkyl phosphono group_(C≤12)Alkyl phosphono group_(C≤12)Alkyl phosphate group_(C≤12)Dialkyl phosphate group_(C≤12)Alkyl ammonium_(C≤12)Alkyl sulfonium_(C≤12)Alkyl silyl group_(C≤12)Or substituted versions of any of these groups; or

Y and R_aForm a 3 to 6 membered ring, such that Y and R_aBy one or more-O-and alkanediyl radicals_(C1-4)Are further linked to each other, further wherein Y is-CH-and R_ais-CH₂-；

X₁And X₂Independently are:

hydrogen, OR_b、NR_bR_cOr SR_bWherein R is_bAnd R_cEach is independently: hydrogen;

alkyl radical_(C≤8)Aryl radical_(C≤8)Aralkyl group_(C≤8)Acyl group_(C≤8)Or substituted versions of any of these groups; or

Substituents that can be converted in vivo to hydrogen;

R₁the method comprises the following steps:

hydrogen, cyano, hydroxy, halogen or amino; or

R₂The method comprises the following steps:

cyano, hydroxy, halogen or amino; or

R₃the method comprises the following steps:

absent or hydrogen;

Substituents that can be converted in vivo to hydrogen;

R₄and R₅Each is independently an alkyl group_(C≤8)Or substituted alkyl_(C≤8)(ii) a And is

R₆And R₇Each is independently hydrogen or hydroxy;

In some embodiments, the compound is further defined as:

wherein:

y is alkanediyl_(C≤5)Or substituted alkanediyl_(C≤5)；

R_aThe method comprises the following steps:

hydrogen, hydroxy, halogen, amino, phosphate, 1, 3-dioxoisoindolin-2-yl, or cyano; or

Alkyl radical_(C≤12)Alkenyl radical_(C≤12)Alkynyl group_(C≤12)Aryl radical_(C≤12)Aralkyl group _(C≤12)Heteroaryl group_(C≤12)Heteroarylalkyl group_(C≤12)Acyl group_(C≤12)Alkoxy group_(C≤12)Alkenyloxy group_(C≤12)Alkynyloxy, alkynyloxy_(C≤12)Aryloxy group_(C≤12)(iii) aralkyloxy_(C≤12)Heteroaryloxy group_(C≤12)Hetero aralkyloxy group_(C≤12)(iii) acyloxy group_(C≤12)Alkylamino group_(C≤12)Dialkylamino group_(C≤12)Alkenylamino group_(C≤12)Alkynyl amino group_(C≤12)Arylamino group_(C≤12)Aralkylamino group_(C≤12)Heteroaryl amino_(C≤12)Heteroarylalkylamino, heteroarylalkylamino_(C≤12)Alkyl sulfonyl amino_(C≤12)Amide group_(C≤12)Aryl sulfonyl group_(C≤12)Aryl sulfinyl group_(C≤12)Alkyl phosphate group_(C≤12)Dialkyl phosphate group_(C≤12)Or substituted versions of any of these groups; or

Y and R_aForm a 3 to 5 membered ring, such that Y and R_aBy one or more-O-and alkanediyl radicals_(C1-3)Are further linked to each other, further wherein Y is-CH-and R_ais-CH₂-；

R₂The method comprises the following steps:

cyano, hydroxy, halogen or amino; or

Fluoroalkyl group_(C≤8)Alkenyl radical_(C≤8)Alkynyl group_(C≤8)Aryl radical_(C≤8)Heteroaryl group_(C≤8)Acyl group_(C≤8)Alkoxy group_(C≤8)Aryloxy group_(C≤8)(iii) acyloxy group_(C≤8)Alkylamino group_(C≤8)Arylamino group_(C≤8)Amide group_(C≤8)Or substituted versions of any of these groups; and is

R₃The method comprises the following steps:

absent or hydrogen;

Substituents that can be converted in vivo to hydrogen;

provided that when bound to R ₃When the oxygen atom of (A) is part of a double bond, then R₃Absent, with the further proviso that when R is₃When not present, then bind to R₃The oxygen atom of (a) is part of a double bond;

In some embodiments, the compound is further defined as:

wherein:

R_athe method comprises the following steps:

Alkyl radical_(C≤12)Alkenyl radical_(C≤12)Alkynyl group_(C≤12)Aryl radical_(C≤12)Aralkyl group_(C≤12)Heteroaryl group_(C≤12)Heteroarylalkyl group_(C≤12)Acyl group_(C≤12)Alkoxy group_(C≤12)Alkenyloxy group_(C≤12)Alkynyloxy, alkynyloxy_(C≤12)Aryloxy group_(C≤12)(iii) aralkyloxy_(C≤12)Heteroaryloxy group_(C≤12)Hetero aralkyloxy group_(C≤12)(iii) acyloxy group_(C≤12)Alkylamino group_(C≤12)Two, twoAlkylamino radical_(C≤12)Alkenylamino group_(C≤12)Alkynyl amino group_(C≤12)Arylamino group_(C≤12)Aralkylamino group_(C≤12)Heteroaryl amino_(C≤12)Heteroarylalkylamino, heteroarylalkylamino_(C≤12)Alkyl sulfonyl amino_(C≤12)Amide group_(C≤12)Alkyl ammonium_(C≤12)Alkyl sulfonium_(C≤12)Alkyl silyl group_(C≤12)Aryl sulfonyl group_(C≤12)Aryl sulfinyl group _(C≤12)Alkyl phosphate group_(C≤12)Dialkyl phosphate group_(C≤12)Or substituted versions of any of these groups; or

X₁And X₂Independently are:

OR_b、NR_bR_cor SR_bWherein R is_bAnd R_cEach is independently:

hydrogen;

Substituents that can be converted in vivo to hydrogen;

R₁the method comprises the following steps:

hydrogen, cyano, hydroxy, halogen or amino; or

R₂the method comprises the following steps:

cyano, hydroxy, halogen or amino; or

Fluoroalkyl group_(C≤8)Alkenyl radical_(C≤8)Alkynyl group_(C≤8)Aryl radical_(C≤8)Heteroaryl group_(C≤8)Acyl group_(C≤8)Alkoxy group_(C≤8)Aryloxy group_(C≤8)(iii) acyloxy group_(C≤8)Alkylamino group _(C≤8)Arylamino group_(C≤8)Amide group_(C≤8)Or substituted versions of any of these groups; and is

R₄Is an alkyl group_(C≤8)Or substituted alkyl_(C≤8)；

In some embodiments, the compound is further defined as:

wherein:

R_athe method comprises the following steps:

Alkyl radical_(C≤12)Alkenyl radical_(C≤12)Alkynyl group_(C≤12)Aryl radical_(C≤12)Aralkyl group_(C≤12)Heteroaryl group_(C≤12)Heteroarylalkyl group_(C≤12)Acyl group_(C≤12)Alkoxy group_(C≤12)Alkenyloxy group_(C≤12)Alkynyloxy, alkynyloxy_(C≤12)Aryloxy group_(C≤12)(iii) aralkyloxy_(C≤12)Heteroaryloxy group_(C≤12)Hetero aralkyloxy group_(C≤12)(iii) acyloxy group_(C≤12)Alkylamino group_(C≤12)Dialkylamino group_(C≤12)Alkenylamino group_(C≤12)Alkynyl amino group_(C≤12)Arylamino group_(C≤12)Aralkylamino group_(C≤12)Heteroaryl amino_(C≤12)Heteroarylalkylamino, heteroarylalkylamino_(C≤12)Amide group_(C≤12)Aryl sulfonyl group_(C≤12)Aryl sulfinyl group_(C≤12)Alkyl phosphate group_(C≤12)Dialkyl phosphate group_(C≤12)Alkyl phosphate group_(C≤12)Dialkyl phosphate group_(C≤12)Or substituted versions of any of these groups; or

X₁The method comprises the following steps:

OR_b、NR_bR_cor SR_bWherein R is_bAnd R_cEach is independently:

hydrogen;

alkyl radical_(C≤8)Aryl radical_(C≤8)Aralkyl group_(C≤8)Acyl ofBase of_(C≤8)Or substituted versions of any of these groups; or

Substituents that can be converted in vivo to hydrogen;

R₁the method comprises the following steps:

hydrogen, cyano, hydroxy, halogen or amino; or

Alkyl radical_(C≤8)Alkenyl radical_(C≤8)Alkynyl group_(C≤8)Aryl radical_(C≤8)Aralkyl group_(C≤8)Heteroaryl group_(C≤8)Heteroarylalkyl group_(C≤8)Acyl group_(C≤8)Alkoxy group_(C≤8)Aryloxy group_(C≤8)(iii) acyloxy group_(C≤8)Alkylamino group_(C≤8)Arylamino group_(C≤8)Amide group_(C≤8)Or substituted versions of any of these groups; and is

R₂The method comprises the following steps:

cyano, hydroxy, halogen or amino; or

Fluoroalkyl group_(C≤8)Alkenyl radical_(C≤8)Alkynyl group_(C≤8)Aryl radical_(C≤8)Heteroaryl group_(C≤8)Acyl group_(C≤8)Alkoxy group_(C≤8)Aryloxy group_(C≤8)(iii) acyloxy group_(C≤8)Alkylamino group_(C≤8)Arylamino group_(C≤8)、

Amide group_(C≤8)Or substituted versions of any of these groups;

In some embodiments, the compound is further defined as:

wherein:

R_athe method comprises the following steps:

Alkyl radical_(C≤12)Alkenyl radical_(C≤12)Alkynyl group_(C≤12)Aryl radical_(C≤12)Aralkyl group_(C≤12)Heteroaryl group_(C≤12)Heteroarylalkyl group_(C≤12)Acyl group_(C≤12)Alkoxy group_(C≤12)Alkenyloxy group_(C≤12)Alkynyloxy, alkynyloxy_(C≤12)Aryloxy group_(C≤12)(iii) aralkyloxy_(C≤12)Heteroaryloxy group_(C≤12)Hetero aralkyloxy group_(C≤12)(iii) acyloxy group_(C≤12)Alkylamino group_(C≤12)Dialkylamino group_(C≤12)Alkenylamino group_(C≤12)Alkynyl amino group_(C≤12)Arylamino group_(C≤12)Aralkylamino group_(C≤12)Heteroaryl amino_(C≤12)Heteroarylalkylamino, heteroarylalkylamino_(C≤12)Amide group_(C≤12)Aryl sulfonyl group_(C≤12)Aryl sulfinyl group_(C≤12)Alkyl phosphate group_(C≤12)Dialkyl phosphate group_(C≤12)Or substituted versions of any of these groups; and is

R₂The method comprises the following steps:

cyano, hydroxy, halogen or amino; or

In some embodiments, the compound is further defined as:

Wherein R is_aThe method comprises the following steps:

Alkyl radical_(C≤12)Alkenyl radical_(C≤12)Alkynyl group_(C≤12)Aryl radical_(C≤12)Aralkyl group_(C≤12)Heteroaryl group_(C≤12)Heteroarylalkyl group_(C≤12)Acyl group_(C≤12)Alkoxy group_(C≤12)Alkenyloxy group_(C≤12)Alkynyloxy, alkynyloxy_(C≤12)Aryloxy group_(C≤12)(iii) aralkyloxy_(C≤12)Heteroaryloxy group_(C≤12)Hetero aralkyloxy group_(C≤12)(iii) acyloxy group_(C≤12)Alkylamino group_(C≤12)Dialkylamino group_(C≤12)Alkenylamino group_(C≤12)Alkynyl amino group_(C≤12)Arylamino group_(C≤12)Aralkylamino group_(C≤12)Heteroaryl amino_(C≤12)Heteroarylalkylamino, heteroarylalkylamino_(C≤12)Amide group_(C≤12)Aryl sulfonyl group_(C≤12)Aryl sulfinyl group_(C≤12)Alkyl phosphate group_(C≤12)Dialkyl phosphate group_(C≤12)Or substituted versions of any of these groups;

In some embodiments, the compound is further defined as:

wherein:

y is alkanediyl_(C≤3)Or substituted alkanediyl_(C≤3)；

R_aThe method comprises the following steps:

Alkyl radical_(C≤12)Alkenyl radical_(C≤12)Alkynyl group_(C≤12)Aryl radical_(C≤12)Aralkyl group_(C≤12)Heteroaryl group_(C≤12)Heteroarylalkyl group_(C≤12)Acyl group_(C≤12)Alkoxy group_(C≤12)Alkenyloxy group_(C≤12)Alkynyloxy, alkynyloxy _(C≤12)Aryloxy group_(C≤12)(iii) aralkyloxy_(C≤12)Heteroaryloxy group_(C≤12)Hetero aralkyloxy group_(C≤12)(iii) acyloxy group_(C≤12)Alkylamino group_(C≤12)Dialkylamino group_(C≤12)Alkenylamino group_(C≤12)Alkynyl amino group_(C≤12)Arylamino group_(C≤12)Aralkylamino group_(C≤12)Heteroaryl amino_(C≤12)Heteroarylalkylamino, heteroarylalkylamino_(C≤12)Amide group_(C≤12)Aryl sulfonyl group_(C≤12)Aryl sulfinyl group_(C≤12)Alkyl phosphate group_(C≤12)Dialkyl phosphate group_(C≤12)Or substituted versions of any of these groups; and is

R₂The method comprises the following steps:

cyano, hydroxy, halogen or amino; or

In some embodiments, the compound is further defined as:

wherein R is_aThe method comprises the following steps:

Alkyl radical_(C≤12)Alkenyl radical_(C≤12)Alkynyl group_(C≤12)Aryl radical_(C≤12)Aralkyl group_(C≤12)Heteroaryl group_(C≤12)Heteroarylalkyl group_(C≤12)Acyl group_(C≤12)Alkoxy group_(C≤12)Alkenyloxy group_(C≤12)Alkynyloxy, alkynyloxy_(C≤12)Aryloxy group_(C≤12)(iii) aralkyloxy _(C≤12)Heteroaryloxy group_(C≤12)Hetero aralkyloxy group_(C≤12)(iii) acyloxy group_(C≤12)Alkylamino group_(C≤12)Dialkylamino group_(C≤12)Alkenylamino group_(C≤12)Alkynyl amino group_(C≤12)Arylamino group_(C≤12)Aralkylamino group_(C≤12)Heteroaryl amino_(C≤12)Heteroarylalkylamino, heteroarylalkylamino_(C≤12)Amide group_(C≤12)Aryl sulfonyl group_(C≤12)Aryl sulfinyl group_(C≤12)Alkyl phosphate group_(C≤12)Dialkyl phosphate group_(C≤12)Or substituted versions of any of these groups;

In some embodiments, the compound is further defined as:

wherein R is_aThe method comprises the following steps:

Alkyl radical_(C≤12)Alkenyl radical_(C≤12)Alkynyl group_(C≤12)Aryl radical_(C≤12)Aralkyl group_(C≤12)Heteroaryl group_(C≤12)Heteroarylalkyl group_(C≤12)Acyl group_(C≤12)Alkoxy group_(C≤12)Alkenyloxy group_(C≤12)Alkynyloxy, alkynyloxy_(C≤12)Aryloxy group_(C≤12)(iii) aralkyloxy_(C≤12)Heteroaryloxy group_(C≤12)Hetero aralkyloxy group_(C≤12)(iii) acyloxy group_(C≤12)Alkylamino group_(C≤12)Dialkylamino group_(C≤12)Alkenylamino group_(C≤12)Alkynyl amino group_(C≤12)Arylamino group_(C≤12)Aralkylamino group_(C≤12)Heteroaryl amino_(C≤12)Heteroarylalkylamino, heteroarylalkylamino_(C≤12)Amide group_(C≤12)Aryl sulfonyl group_(C≤12)Aryl sulfinyl group_(C≤12)Alkyl phosphate group _(C≤12)Dialkyl phosphate group_(C≤12)Or in these groupsSubstituted forms of any of;

or a salt, ester, hydrate, solvate, tautomer, or optical isomer thereof.

In some embodiments, the compound is further defined as:

wherein R is_aIs hydroxy, cyano, acyl_(C≤8)Substituted acyl group_(C≤8)(iii) acyloxy group_(C≤8)Or substituted acyl_(C≤8)(ii) a Or a pharmaceutically acceptable salt, hydrate, solvate, tautomer, or optical isomer thereof.

In some embodiments, the compound is further defined as:

wherein R is_aIs hydroxy, cyano, acyl_(C≤8)Substituted acyl group_(C≤8)(iii) acyloxy group_(C≤8)Substituted acyl group_(C≤8)Amide group_(C≤8)Or substituted amide group_(C≤8)(ii) a Or a pharmaceutically acceptable salt, hydrate, solvate, tautomer, or optical isomer thereof.

In some embodiments, the compound is further defined as:

wherein R is_aIs hydroxy, cyano, acyl_(C≤8)Substituted acyl group_(C≤8)(iii) acyloxy group_(C≤8)Or substitutedAcyl radical_(C≤8)(ii) a Or a pharmaceutically acceptable salt, hydrate, solvate, tautomer, or optical isomer thereof.

In some embodiments, the compound is further defined as:

wherein R is_aIs alkylamino_(C≤12)Dialkylamino group_(C≤12)Alkenylamino group_(C≤12)Alkynyl amino group_(C≤12)Arylamino group _(C≤12)Aralkylamino group_(C≤12)Heteroaryl amino_(C≤12)Heteroarylalkylamino, heteroarylalkylamino_(C≤12)Alkyl sulfonyl amino_(C≤12)Or amide group_(C≤12)Or substituted versions of any of these groups.

In a variation of each of the above embodiments comprising a Y group, Y may be an alkanediyl group_(C1-4)Or substituted alkanediyl_(C1-4). In other variations, Y may be-CH₂-. In other variations, Y may be-C (OH) HCH₂-. In other variations, Y may be-C.ident.C-.

In the presence of X₁In a variation of each of the above embodiments, X₁May be OR_bAnd R is_bIs absent. In the presence of X₂In a variation of each of the above embodiments, X₂May be hydrogen.

In the presence of R_aIn variations of each of the above embodiments, R_aMay be-OH. In other variations, R_aMay be-CN. In other variations, R_aMay be-Cl. In other variations, R_aMay be-Br. In other variations, R_aMay be-H. In other variations, R_aMay be an acyl group_(C1-6)Or substituted acyl_(C1-6). In other variations, R_aMay be an acyl group_(C4-6)Or substituted acyl_(C4-6). In other variations, R_aMay be an acyl group_(C1-4)Or substituted acyl_(C1-4). In other variations, R_aMay be an acyl group_(C1-3)Or substituted acyl_(C1-3). In other variations, R_aMay be selected from-C (═ O) OH, -C (═ O) OCH ₃、-C(＝O)NHCH₃、-C(＝O)NHCH₂CH₃and-C (═ O) NHCH₂CF₃. In other variations, R_aMay be an acyloxy group_(C1-8)Or substituted acyloxy_(C1-3). In other variations, R_aMay be a substituted acyloxy group_(C1-3). In other variations, R_aMay be an acyloxy group_(C2-8). In other variations, R_aMay contain a fluorine group. In other variations, R_aMay comprise a trifluoromethyl group. In other variations, R_aMay be alkylamino_(C≤12)Dialkylamino group_(C≤2)Alkenylamino group_(C≤12)Alkynyl amino group_(C≤12)Arylamino group_(C≤12)Aralkylamino group_(C≤12)Heteroaryl amino_(C≤12)Heteroarylalkylamino, heteroarylalkylamino_(C≤12)Alkyl sulfonyl amino_(C≤12)Or amide group_(C≤12)Or substituted versions of any of these groups. In other variations, R_aMay be an arylsulfonyl group_(C≤8)Or arylsulfinyl_(C≤8). In other variations, R_aCan be-OP (O) (OH)₂. In other variations, R_aMay be an alkyl phosphate group_(C≤12)Or dialkyl phosphate group_(C≤12). In other variations, R_aMay be a dialkyl phosphate group_(C≤8). In other variations, R_aCan be-OP (O) (OEt)₂. In other variations, R_aMay be a 1, 3-dioxoisoindolin-2-yl group. In the presence of-Y-R_aIn a variant of each of the above embodiments of the group, -Y-R_aMay be an oxirane-2-yl group. In the presence of-Y-R_aIn another variation of each of the above embodiments, -Y-R _aMay be a 1, 3-dioxolan-4-yl group.

In the presence of R₁In variations of each of the above embodiments, R₁Can be-H, -OH or-F. In some of these variants, R₁May be-H. In the presence of R₂In variations of each of the above embodiments, R₂May be-CN. In other variations, R₂May be-CF₃. In other variations, R₂May be a substituted acyl group_(C1-3). In other variations, R₂May be-C (═ O) NHS (═ O)₂CH₃. In the presence of R₃In variations of each of the above embodiments, R3 may be absent. In the presence of R₄In variations of each of the above embodiments, R₄May be a methyl group. In other variations, R₄May be a hydroxymethyl group.

In the presence of R₄And/or R₅In variations of each of the above embodiments, R₄And/or R₅Each may independently be methyl. In the presence of R₆And/or R₇In variations of each of the above embodiments, R₆And/or R₇Each may independently be hydrogen. In the presence of R₈And/or R₉In variations of each of the above embodiments, R₈And/or R₉Each may independently be hydrogen. In the presence of R₁₀And/or R₁₁In variations of each of the above embodiments, R₁₀And/or R11 each independently can be methyl.

In some variations of one or more of the above embodiments, Y, R _aAnd carbon numbers 13, 17 and 18 form a ring, wherein Y is alkanediyl_(C＝1)Or substituted alkanediyl_(C＝1)And R is_ais-O-. In some variations of one or more of the above embodiments, the bond between carbon 9 and carbon 11 is a single bond. In some variations of one or more of the above embodiments, the bond between carbon 9 and carbon 11 is a double bond.

Examples of specific compounds provided by the present disclosure include:

methyl 2- ((4aR, 6aR, 6bS, 8aR, 12aS, 14aR, 14bS) -11-cyano-2, 2, 6a, 6b, 9, 9, 12 a-heptamethyl-10, 14-dioxo-1, 2, 3, 4, 4a, 5, 6, 6a, 6b, 7, 8, 8a, 9, 10, 12a, 14, 14a, 14 b-octahydrodepicene-4 a-yl) acetate,

2- ((4aR, 6aR, 6bS, 8aR, 12aS, 14aR, 14bS) -11-cyano-2, 2, 6a, 6b, 9, 9, 12 a-heptamethyl-10, 14-dioxo-1, 2, 3, 4, 4a, 5, 6, 6a, 6b, 7, 8, 8a, 9, 10, 12a, 14, 14a, 14 b-octahydrodepicene-4 a-yl) acetic acid,

(4aR, 6aR, 6bR, 8aS, 12aS, 12bR, 14bR) -8a- (hydroxymethyl) -4, 4, 6a, 6b, 11, 11, 14 b-heptamethyl-3, 13-dioxo-3, 4, 4a, 5, 6, 6a, 6b, 7, 8, 8a, 9, 10, 11, 12, 12a, 12b, 13, 14, 14a, 14 b-didehydroapicene-2-carbonitrile,

((4aS, 6aR, 6bR, 8aR, 12aR, 14aR, 14bS) -11-cyano-2, 2, 6a, 6b, 9, 9, 12 a-heptamethyl-10, 14-dioxo-1, 2, 3, 4, 4a, 5, 6, 6a, 6b, 7, 8, 8a, 9, 10, 12a, 12b, 13, 14, 14a, 14 b-didedecahydropicene-4 a-yl) methyl acetate,

(6aR, 6bR, 8aR, 12aS, 12bR, 14bR) -4, 4, 6a, 6b, 11, 11, 14 b-heptamethyl-3, 13-dioxo-8 a-vinyl-3, 4, 4a, 5, 6, 6a, 6b, 7, 8, 8a, 9, 10, 11, 12, 12a, 12b, 13, 14, 14a, 14 b-didepicene-2-carbonitrile,

(6aR, 6bR, 8aS, 12aS, 12bR, 14bR) -8a- (aminomethyl) -4, 4, 6a, 6b, 11, 11, 14 b-heptamethyl-3, 13-dioxo-3, 4, 4a, 5, 6, 6a, 6b, 7, 8, 8a, 9, 10, 11, 12, 12a, 12b, 13, 14, 14a, 14 b-didepicene-2-carbonitrile,

(6aR, 6bR, 8aS, 12aS, 12bR, 14bR) -8a- (aminomethyl) -4, 4, 6a, 6b, 11, 11, 14 b-heptamethyl-3, 13-dioxo-3, 4, 4a, 5, 6, 6a, 6b, 7, 8, 8a, 9, 10, 11, 12, 12a, 12b, 13, 14, 14a, 14 b-didepicene-2-carbonitrile, trifluoroacetate salt,

(4aR, 6aR, 6bR, 8aS, 12aS, 12bR, 14aR, 14bR) -8a- ((cyanomethylamino) methyl) -4, 4, 6a, 6b, 11, 11, 14 b-heptamethyl-3, 13-dioxo-3, 4, 4a, 5, 6, 6a, 6b, 7, 8, 8a, 9, 10, 11, 12, 12a, 12b, 13, 14, 14a, 14 b-didehydroapicene-2-carbonitrile,

N- (((4aS, 6aR, 6bR, 12aR, 14aR, 14bS) -11-cyano-2, 2, 6a, 6b, 9, 9, 12 a-heptamethyl-10, 14-dioxo-1, 2, 3, 4, 4a, 5, 6, 6a, 6b, 7, 8, 8a, 9, 10, 12a, 12b, 13, 14, 14a, 14 b-didepicene-4 a-yl) methyl) methanesulfonamide,

(4aR, 6aR, 6bR, 8aS, 12aS, 12bR, 14aR, 14bR) -8a- ((R) -1, 2-dihydroxyethyl) -4, 4, 6a, 6b, 11, 11, 14 b-heptamethyl-3, 13-dioxo-3, 4, 4a, 5, 6, 6a, 6b, 7, 8, 8a, 9, 10, 11, 12, 12a, 12b, 13, 14, 14a, 14 b-didepicene-2-carbonitrile,

n- (((4aS, 6aR, 6bR, 8aR, 12aR, 12bR, 14aR, 14bS) -11-cyano-2, 2, 6a, 6b, 9, 9, 12 a-heptamethyl-10, 14-dioxo-1, 2, 3, 4, 4a, 5, 6, 6a, 6b, 7, 8, 8a, 9, 10, 12a, 12b, 13, 14, 14a, 14 b-didepicene-4 a-yl) methyl) -2, 2, 2-trifluoroethylsulfonamide,

n- (((4aS, 6aR, 6bR, 12aR, 14aR, 14bS) -11-cyano-2, 2, 6a, 6b, 9, 9, 12 a-heptamethyl-10, 14-dioxo-1, 2, 3, 4, 4a, 5, 6, 6a, 6b, 7, 8, 8a, 9, 10, 12a, 12b, 13, 14, 14a, 14 b-didepicene-4 a-yl) methyl) -2, 2, 2-trifluoroacetamide,

(4aR, 6aR, 6bR, 8aS, 12aS, 12bR, 14aR, 14bR) -8a- (methoxymethyl) -4, 4, 6a, 6b, 11, 11, 14 b-heptamethyl-3, 13-dioxo-3, 4, 4a, 5, 6, 6a, 6b, 7, 8, 8a, 9, 10, 11, 12, 12a, 12b, 13, 14, 14a, 14 b-didepicene-2-carbonitrile,

(4aR, 6aR, 6bR, 8aR, 12aS, 12bR, 14aR, 14bR) -8a- (2-hydroxyethyl) -4, 4, 6a, 6b, 11, 11, 14 b-heptamethyl-3, 13-dioxo-3, 4, 4a, 5, 6, 6a, 6b, 7, 8, 8a, 9, 10, 11, 12, 12a, 12b, 13, 14, 14a, 14 b-didehydroapicene-2-carbonitrile,

(4aR, 6aR, 6bR, 8aS, 12aS, 12bR, 14aR, 14bR) -4, 4, 6a, 6b, 11, 11, 14 b-heptamethyl-8 a- (((5-methyliso-oise)Oxazol-3-yl) methylamino) methyl) -3, 13-dioxo-3, 4, 4a, 5, 6, 6a, 6b, 7, 8, 8a, 9, 10, 11, 12, 12a, 12b, 13, 14, 14a, 14 b-picene-2-carbonitrile,

(4aR, 6aR, 6bR, 8aS, 12aS, 12bR, 14aR, 14bR) -4, 4, 6a, 6b, 11, 11, 14 b-heptamethyl-8 a- (((2-methyl-2H-tetrazol-5-yl) methylamino) methyl) -3, 13-dioxo-3, 4, 4a, 5, 6, 6a, 6b, 7, 8, 8a, 9, 10, 11, 12, 12a, 12b, 13, 14, 14a, 14 b-didehydropicene-2-carbonitrile,

(4aR, 6aR, 6bR, 8aS, 12aS, 12bR, 14aR, 14bR) -4, 4, 6a, 6b, 11, 11, 14 b-heptamethyl-3, 13-dioxo-8 a- (phenylthiomethyl) -3, 4, 4a, 5, 6, 6a, 6b, 7, 8, 8a, 9, 10, 11, 12, 12a, 12b, 13, 14, 14a, 14 b-didepicene-2-carbonitrile,

((4aS, 6aR, 6bR, 8aR, 12aR, 12bR, 14aR, 14bS) -11-cyano-2, 2, 6a, 6b, 9, 9, 12 a-heptamethyl-10, 14-dioxo-1, 2, 3, 4, 4a, 5, 6, 6a, 6b, 7, 8, 8a, 9, 10, 12a, 12b, 13, 14, 14a, 14 b-didepicene-4 a-yl) methyldiethylphosphate,

((4aS, 6aR, 6bR, 12aR, 14aR, 14bS) -11-cyano-2, 2, 6a, 6b, 9, 9, 12 a-heptamethyl-10, 14-dioxo-1, 2, 3, 4, 4a, 5, 6, 6a, 6b, 7, 8, 8a, 9, 10, 12a, 12b, 13, 14, 14a, 14 b-didepicene-4 a-yl) methyl carbamic acid tert-butyl ester,

(4aR, 6aR, 6bR, 8aS, 12aS, 12bR, 14aR, 14bR) -4, 4, 6a, 6b, 11, 11, 14 b-heptamethyl-3, 13-dioxo-8 a- (phenylsulfinylmethyl) -3, 4, 4a, 5, 6, 6a, 6b, 7, 8, 8a, 9, 10, 11, 12, 12a, 12b, 13, 14, 14a, 14 b-didehydroapicene-2-carbonitrile,

(4aR, 6aR, 6bR, 8aS, 12aS, 12bR, 14aR, 14bR) -4, 4, 6a, 6b, 11, 11, 14 b-heptamethyl-3, 13-dioxo-8 a- (phenylsulfonylmethyl) -3, 4, 4a, 5, 6, 6a, 6b, 7, 8, 8a, 9, 10, 11, 12, 12a, 12b, 13, 14, 14a, 14 b-didepicene-2-carbonitrile,

((4aS, 6aR, 6bR, 8aR, 12aR, 12bR, 14aR, 14bS) -11-cyano-2, 2, 6a, 6b, 9, 9, 12 a-heptamethyl-10, 14-dioxo-1, 2, 3, 4, 4a, 5, 6, 6a, 6b, 7, 8, 8a, 9, 10, 12a, 12b, 13, 14, 14a, 14 b-didepicene-4 a-yl) methylphosphonic acid dihydrogenester,

(4aR, 6aR, 6bR, 8aS, 12aS, 12bR, 14aR, 14bR) -4, 4, 6a, 6b, 11, 11, 14 b-heptamethyl-3, 13-dioxo-8 a- ((2, 2, 2-trifluoroethylamino) methyl) -3, 4, 4a, 5, 6, 6a, 6b, 7, 8, 8a, 9, 10, 11, 12, 12a, 12b, 13, 14, 14a, 14 b-didehydropicene-2-carbonitrile,

(4aR, 6aR, 6bR, 8aS, 12aS, 12bR, 14aR, 14bR) -4, 4, 6a, 6b, 11, 11, 14 b-heptamethyl-8 a- ((R) -oxiran-2-yl) -3, 13-dioxo-3, 4, 4a, 5, 6, 6a, 6b, 7, 8, 8a, 9, 10, 11, 12, 12a, 12b, 13, 14, 14a, 14 b-didepicene-2-carbonitrile,

(4aR, 6aR, 6bR, 8aS, 12aS, 12bR, 14aR, 14bR) -8a- ((1, 3-dioxoisoindolin-2-yl) methyl) -4, 4, 6a, 6b, 11, 11, 14 b-heptamethyl-3, 13-dioxo-3, 4, 4a, 5, 6, 6a, 6b, 7, 8, 8a, 9, 10, 11, 12, 12a, 12b, 13, 14, 14a, 14 b-didehydropicene-2-carbonitrile,

(4aR, 6aR, 6bR, 8aS, 12aS, 12bR, 14aR, 14bR) -8a- ((R) -2-bromo-1-hydroxyethyl) -4, 4, 6a, 6b, 11, 11, 14 b-heptamethyl-3, 13-dioxo-3, 4, 4a, 5, 6, 6a, 6b, 7, 8, 8a, 9, 10, 11, 12, 12a, 12b, 13, 14, 14a, 14 b-didehydropicene-2-carbonitrile,

(4aR, 6aR, 6bR, 8aS, 12aS, 12bR, 14aR, 14bR) -8a- ((R) -2-chloro-1-hydroxyethyl) -4, 4, 6a, 6b, 11, 11, 14 b-heptamethyl-3, 13-dioxo-3, 4, 4a, 5, 6, 6a, 6b, 7, 8, 8a, 9, 10, 11, 12, 12a, 12b, 13, 14, 14a, 14 b-didehydropicene-2-carbonitrile,

(4aR, 6aR, 6bR, 8aS, 12aS, 12bR, 14aR, 14bR) -8a- ((S) -1, 3-dioxolan-4-yl) -4, 4, 6a, 6b, 11, 11, 14 b-heptamethyl-3, 13-dioxo-3, 4, 4a, 5, 6, 6a, 6b, 7, 8, 8a, 9, 10, 11, 12, 12a, 12b, 13, 14, 14a, 14 b-didehydropicene-2-carbonitrile,

((4aS, 6aR, 6bR, 8aR, 12aR, 12bR, 14aR, 14bS) -11-cyano-2, 2, 6a, 6b, 9, 9, 12 a-heptamethyl-10, 14-dioxo-1, 2, 3, 4, 4a, 5, 6, 6a, 6b, 7, 8, 8a, 9, 10, 12a, 12b, 13, 14, 14a, 14 b-didepicene-4 a-yl) methyl 2, 2, 2-trifluoroacetate,

((4aS, 6aR, 6bR, 8aR, 12aR, 12bR, 14aR, 14bS) -11-cyano-2, 2, 6a, 6b, 9, 9, 12 a-heptamethyl-10, 14-dioxo-1, 2, 3, 4, 4a, 5, 6, 6a, 6b, 7, 8, 8a, 9, 10, 12a, 12b, 13, 14, 14a, 14 b-didepicene-4 a-yl) methylpivalate,

((4aS, 6aR, 6bR, 8aR, 12aR, 12bR, 14aR, 14bS) -11-cyano-2, 2, 6a, 6b, 9, 9, 12 a-heptamethyl-10, 14-dioxo-1, 2, 3, 4, 4a, 5, 6, 6a, 6b, 7, 8, 8a, 9, 10, 12a, 12b, 13, 14, 14a, 14 b-didepicene-4 a-yl) methylbenzoate,

(4aR, 6aR, 6bR, 8aS, 12aS, 12bR, 14aR, 14bR) -8a- (2-cyano-1-hydroxyethyl) -4, 4, 6a, 6b, 11, 11, 14 b-heptamethyl-3, 13-dioxo-3, 4, 4a, 5, 6, 6a, 6b, 7, 8, 8a, 9, 10, 11, 12, 12a, 12b, 13, 14, 14a, 14 b-didepicene-2-carbonitrile,

(4aR, 6aR, 6bR, 8aS, 12aS, 12bR, 14aR, 14bR) -8 a-ethyl-4, 4, 6a, 6b, 11, 11, 14 b-heptamethyl-3, 13-dioxo-3, 4, 4a, 5, 6, 6a, 6b, 7, 8, 8a, 9, 10, 11, 12, 12a, 12b, 13, 14, 14a, 14 b-didehydroapicene-2-carbonitrile,

2- ((4aR, 6aR, 6bR, 8aR, 12aR, 12bR, 14aR, 14bS) -11-cyano-2, 2, 6a, 6b, 9, 9, 12 a-heptamethyl-10, 14-dioxo-1, 2, 3, 4, 4a, 5, 6, 6a, 6b, 7, 8, 8a, 9, 10, 12a, 12b, 13, 14, 14a, 14 b-didepicene-4 a-yl) acetic acid,

Methyl 2- ((4aR, 6aR, 6bR, 8aR, 12aR, 12bR, 14aR, 14bS) -11-cyano-2, 2, 6a, 6b, 9, 9, 12 a-heptamethyl-10, 14-dioxo-1, 2, 3, 4, 4a, 5, 6, 6a, 6b, 7, 8, 8a, 9, 10, 12a, 12b, 13, 14, 14a, 14 b-didepicene-4 a-yl) acetate,

2- ((4aR, 6aR, 6bR, 8aR, 12aR, 12bR, 14aR, 14bS) -11-cyano-2, 2, 6a, 6b, 9, 9, 12 a-heptamethyl-10, 14-dioxo-1, 2, 3, 4, 4a, 5, 6, 6a, 6b, 7, 8, 8a, 9, 10, 12a, 12b, 13, 14, 14a, 14 b-didepicene-4 a-yl) -N-ethylacetamide,

2- ((4aR, 6aR, 6bR, 8aR, 12aR, 12bR, 14aR, 14bS) -11-cyano-2, 2, 6a, 6b, 9, 9, 12 a-heptamethyl-10, 14-dioxo-1, 2, 3, 4, 4a, 5, 6, 6a, 6b, 7, 8, 8a, 9, 10, 12a, 12b, 13, 14, 14a, 14 b-didepicene-4 a-yl) -N- (2-fluoroethyl) acetamide,

2- ((4aR, 6bR, 8aR, 12bR, 14aR, 14bS) -11-cyano-2, 2, 6a, 6b, 9, 9, 12 a-heptamethyl-10, 14-dioxo-1, 2, 3, 4, 4a, 5, 6, 6a, 6b, 7, 8, 8a, 9, 10, 12a, 12b, 13, 14, 14a, 14 b-didepicene-4 a-yl) -N- (2, 2-difluoroethyl) acetamide, and

2- ((4aR, 6bR, 8aR, 12bR, 14aR, 14bS) -11-cyano-2, 2, 6a, 6b, 9, 9, 12 a-heptamethyl-10, 14-dioxo-1, 2, 3, 4, 4a, 5, 6, 6a, 6b, 7, 8, 8a, 9, 10, 12a, 12b, 13, 14, 14a, 14 b-didepicene-4 a-yl) -N- (2, 2, 2-trifluoroethyl) acetamide.

Non-limiting examples of compounds provided by the present disclosure include compounds according to the formulas shown below,

and pharmaceutically acceptable salts thereof. In certain embodiments, these compounds are substantially free of its other optical isomers.

In some embodiments, one or more of the following compounds are contemplated:

in some embodiments, the present invention provides a compound of the formula:

wherein R is_aThe method comprises the following steps: hydrogen, hydroxy, halogen, amino or cyano; or alkyl_(C≤12)Alkenyl radical_(C≤12)Alkynyl group_(C≤12)Aryl radical_(C≤12)Aralkyl group_(C≤12)Heteroaryl group_(C≤12)Heteroarylalkyl group_(C≤12)Acyl group_(C≤12)Alkoxy group_(C≤12)Alkenyloxy group_(C≤12)Alkynyloxy, alkynyloxy_(C≤12)Aryloxy group_(C≤12)(iii) aralkyloxy_(C≤12)Heteroaryloxy group_(C≤12)Hetero aralkyloxy group_(C≤12)(iii) acyloxy group_(C≤12)Alkylamino group_(C≤12)Dialkylamino group_(C≤12)Alkenylamino group_(C≤12)Alkynyl amino group_(C≤12)Arylamino group_(C≤12)Aralkylamino group_(C≤12)Heteroaryl amino_(C≤12)Heteroarylalkylamino, heteroarylalkylamino_(C≤12)Amide group _(C≤12)Or substituted versions of any of these groups; or a salt, ester, hydrate, solvate, tautomer, or optical isomer thereof. For example, the present invention provides:

or a salt, hydrate, solvate, tautomer or optical isomer thereof.

Wherein R is_aThe method comprises the following steps: hydrogen, hydroxy, halogen, amino or cyano; or alkyl_(C≤12)Alkenyl radical_(C≤12)Alkynyl group_(C≤12)Aryl radical_(C≤12)Aralkyl group_(C≤12)Heteroaryl group_(C≤12)Heteroarylalkyl group_(C≤12)Acyl group_(C≤12)Alkoxy group_(C≤12)Alkenyloxy group_(C≤12)Alkynyloxy, alkynyloxy_(C≤12)Aryloxy group_(C≤12)(iii) aralkyloxy_(C≤12)Heteroaryloxy group_(C≤12)Hetero aralkyloxy group_(C≤12)(iii) acyloxy group_(C≤12)Alkylamino group_(C≤12)Dialkylamino group_(C≤12)Alkenylamino group_(C≤12)Alkynyl amino group_(C≤12)Arylamino group_(C≤12)Aralkylamino group_(C≤12)Heteroaryl amino_(C≤12)Heteroarylalkylamino, heteroarylalkylamino_(C≤12)Amide group_(C≤12)Or substituted versions of any of these groups; or a salt, ester, hydrate, solvate, tautomer, or optical isomer thereof.

In some embodiments, the present invention provides a compound of the formula:

wherein: y is alkanediyl_(C≤8)Alkenyldiyl group_(C≤8)Alkynediyl_(C≤8)Or substituted versions of any of these groups;

R_athe method comprises the following steps: hydrogen, hydroxy, halogen, amino, nitro, cyano, azido, mercapto or silyl; or alkyl _(C≤12)Alkenyl radical_(C≤12)Alkynyl group_(C≤12)Aryl radical_(C≤12)Aralkyl group_(C≤12)Heteroaryl group_(C≤12)Heteroarylalkyl group_(C≤12)Acyl group_(C≤12)Alkoxy group_(C≤12)Alkenyloxy group_(C≤12)Alkynyloxy, alkynyloxy_(C≤12)Aryloxy group_(C≤12)(iii) aralkyloxy_(C≤12)Heteroaryloxy group_(C≤12)Hetero aralkyloxy group_(C≤12)(iii) acyloxy group_(C≤12)Alkylamino group_(C≤12)Dialkylamino group_(C≤12)Alkenylamino group_(C≤12)Alkynyl amino group_(C≤12)Arylamino group_(C≤12)Aralkylamino group_(C≤12)Heteroaryl amino_(C≤12)Heteroarylalkylamino, heteroarylalkylamino_(C≤12)Alkyl sulfonyl amino_(C≤12)Amide group_(C≤12)Alkylthio group_(C≤12)Alkenylthio radicals_(C≤12)Alkynylthio radicals_(C≤12)Arylthio radicals_(C≤12)Aralkylthio group_(C≤12)Heteroarylthio radicals_(C≤12)Heteroarylalkylthio groups_(C≤12)Acylthio groups_(C≤12)Thioacyl, thioacyl_(C≤12)Alkyl sulfonyl group_(C≤12)Alkenylsulfonyl group_(C≤12)Alkynylsulfonyl, and a process for producing the same_(C≤12)Aryl sulfonyl group_(C≤12)Aralkyl sulfonyl group_(C≤12)Alkyl ammonium_(C≤12)Alkyl sulfonium_(C≤12)Alkyl silyl group_(C≤12)Or substituted versions of any of these groups; r₁The method comprises the following steps: hydrogen, cyano, hydroxy, halogen or amino; or alkyl_(C≤8)Alkenyl radical_(C≤8)Alkynyl group_(C≤8)Aryl radical_(C≤8)Aralkyl group_(C≤8)Heteroaryl group_(C≤8)Heteroarylalkyl group_(C≤8)Acyl group_(C≤8)Alkoxy group_(C≤8)Aryloxy group_(C≤8)(iii) acyloxy group_(C≤8)Alkylamino group_(C≤8)Arylamino group_(C≤8)Amide group_(C≤8)Or substituted versions of any of these groups; r₂The method comprises the following steps: cyano, hydroxy, halogen or amino; or alkenyl_(C≤8)Alkynyl group _(C≤8)Aryl radical_(C≤8)Heteroaryl group_(C≤8)Acyl group_(C≤8)Alkoxy group_(C≤8)Aryloxy group_(C≤8)(iii) acyloxy group_(C≤8)Alkylamino group_(C≤8)Arylamino group_(C≤8)Amide group_(C≤8)Or substituted versions of any of these groups; or a salt, ester, hydrate, solvate, tautomer, or optical isomer thereof. For example, the present invention provides:

or a salt, hydrate, solvate, tautomer or optical isomer thereof, for example:

in some embodiments, the optical isomer is substantially free of its other optical isomers.

In some embodiments, the present invention provides a compound of the formula:

wherein: y is alkanediyl_(C≤8)Alkenyldiyl group_(C≤8)Alkynediyl_(C≤8)Or substituted versions of any of these groups; r_aThe method comprises the following steps: hydrogen, hydroxy, halogen, amino, nitro, cyano, azido, mercapto or silyl; or alkyl_(C≤12)Alkenyl radical_(C≤12)Alkynyl group_(C≤12)Aryl radical_(C≤12)Aralkyl group_(C≤12)Heteroaryl group_(C≤12)Heteroarylalkyl group_(C≤12)Acyl group_(C≤12)Alkoxy group_(C≤12)Alkenyloxy group_(C≤12)Alkynyloxy, alkynyloxy_(C≤12)Aryloxy group_(C≤12)(iii) aralkyloxy_(C≤12)Heteroaryloxy group_(C≤12)Hetero aralkyloxy group_(C≤12)(iii) acyloxy group_(C≤12)Alkylamino group_(C≤12)Dialkylamino group_(C≤12)Alkenylamino group_(C≤12)Alkynyl amino group_(C≤12)Arylamino group_(C≤12)Aralkylamino group_(C≤12)Heteroaryl amino _(C≤12)Heteroarylalkylamino, heteroarylalkylamino_(C≤12)Alkyl sulfonyl amino_(C≤12)Amide group_(C≤12)Alkylthio group_(C≤12)Alkenylthio radicals_(C≤12)Alkynylthio radicals_(C≤12)Arylthio radicals_(C≤12)Aralkylthio group_(C≤12)Heteroarylthio radicals_(C≤12)Heteroarylalkylthio groups_(C≤12)Acylthio groups_(C≤12)Thioacyl, thioacyl_(C≤12)Alkyl sulfonyl group_(C≤12)Alkenylsulfonyl group_(C≤12)Alkynylsulfonyl, and a process for producing the same_(C≤12)Aryl sulfonyl group_(C≤12)Aralkyl sulfonyl group_(C≤12)Alkyl ammonium_(C≤12)Alkyl sulfonium_(C≤12)Alkyl silyl group_(C≤12)Or substituted versions of any of these groups; x₁The method comprises the following steps: OR (OR)_b、NR_bR_cOr SR_bWherein R is_bAnd R_cEach is independently: hydrogen; alkyl radical_(C≤8)Aryl radical_(C≤8)Aralkyl group_(C≤8)Acyl group_(C≤8)Or substituted versions of any of these groups; or with the proviso that when bound to R_bWhen the atom(s) is part of a double bond, then R_bAbsent, with the further proviso that when R is_bWhen not present, then bind to R_bIs part of a double bond; and R is₁The method comprises the following steps: hydrogen, cyano, hydroxy, halogen or amino; or alkyl_(C≤8)Alkenyl radical_(C≤8)Alkynyl group_(C≤8)Aryl radical_(C≤8)Aralkyl group_(C≤8)Heteroaryl group_(C≤8)Heteroarylalkyl group_(C≤8)Acyl group_(C≤8)Alkoxy group_(C≤8)Aryloxy group_(C≤8)(iii) acyloxy group_(C≤8)Alkylamino group_(C≤8)Arylamino group_(C≤8)Amide group_(C≤8)Or substituted versions of any of these groups; r' is hydroxy, alkoxy_(C≤12)Substituted alkoxy group_(C≤12)Aryloxy group _(C≤12)Substituted aryloxy group_(C≤12)(iii) aralkyloxy_(C≤12)Substituted aralkyloxy group_(C≤12)(iii) acyloxy group_(C≤12)Or substituted acyloxy group_(C≤12)(ii) a Or a salt, ester, hydrate, solvate, tautomer, or optical isomer thereof. In some of these embodiments, R' is acetoxy. In other of these embodiments, R' is hydroxy. For example, the present invention provides:

or a salt, hydrate, solvate, tautomer or optical isomer thereof, for example:

in certain embodiments, the optical isomer is substantially free of its other optical isomers.

In some embodiments, the present invention provides a compound of the formula:

wherein: y is alkanediyl_(C≤8)Alkenyldiyl group_(C≤8)Alkynediyl_(C≤8)Or substituted versions of any of these groups; r_aThe method comprises the following steps: hydrogen, hydroxy, halogen, amino, nitro, cyano, azido, mercapto or silyl; or alkyl_(C≤12)Alkenyl radical_(C≤12)Alkynyl group_(C≤12)Aryl radical_(C≤12)Aralkyl group_(C≤12)Heteroaryl group_(C≤12)Heteroarylalkyl group_(C≤12)Acyl group_(C≤12)Alkoxy group_(C≤12)Alkenyloxy group_(C≤12)Alkynyloxy, alkynyloxy_(C≤12)Aryloxy group_(C≤12)(iii) aralkyloxy_(C≤12)Heteroaryloxy group_(C≤12)Hetero aralkyloxy group_(C≤12)(iii) acyloxy group_(C≤12)Alkylamino group_(C≤12)Dialkylamino group_(C≤12)Alkenylamino group _(C≤12)Alkynyl amino group_(C≤12)Arylamino group_(C≤12)Aralkylamino group_(C≤12)Heteroaryl amino_(C≤12)Heteroarylalkylamino, heteroarylalkylamino_(C≤12)Alkyl sulfonyl amino_(C≤12)Amide group_(C≤12)Alkylthio group_(C≤12)Alkenylthio radicals_(C≤12)Alkynylthio radicals_(C≤12)Arylthio radicals_(C≤12)Aralkylthio group_(C≤12)Heteroarylthio radicals_(C≤12)Heteroarylalkylthio groups_(C≤12)Acylthio groups_(C≤12)Thioacyl, thioacyl_(C≤12)Alkyl sulfonyl group_(C≤12)Alkenylsulfonyl group_(C≤12)Alkynylsulfonyl, and a process for producing the same_(C≤12)Aryl sulfonyl group_(C≤12)Aralkyl sulfonyl group_(C≤12)Alkyl ammonium_(C≤12)Alkyl sulfonium_(C≤12)Alkyl silyl group_(C≤12)Or substituted versions of any of these groups; x₁The method comprises the following steps: OR (OR)_b、NR_bR_cOr SR_bWherein R is_bAnd R_cEach is independently: hydrogen; alkyl radical_(C≤8)Aryl radical_(C≤8)Aralkyl group_(C≤8)Acyl group_(C≤8)Or substituted versions of any of these groups; or with the proviso that when bound to R_bWhen the atom(s) is part of a double bond, then R_bAbsent, with the further proviso that when R is_bWhen not present, then bind to R_bIs part of a double bond; and R is₁The method comprises the following steps: hydrogen, cyano, hydroxy, halogen or amino; or alkyl_(C≤8)Alkenyl radical_(C≤8)Alkynyl group_(C≤8)Aryl radical_(C≤8)Aralkyl group_(C≤8)Heteroaryl group_(C≤8)Heteroarylalkyl group_(C≤8)Acyl group_(C≤8)Alkoxy group_(C≤8)Aryloxy group_(C≤8)(iii) acyloxy group_(C≤8)Alkylamino group_(C≤8)Arylamino group_(C≤8)Amide group_(C≤8)Or substituted versions of any of these groups; or a salt, ester, hydrate, solvate, tautomer, or optical isomer thereof. For example, the present invention provides:

In some embodiments, the present invention provides a compound of the formula:

wherein: y is alkanediyl_(C≤8)Alkenyldiyl group_(C≤8)Alkynediyl_(C≤8)Or substituted versions of any of these groups; r_aThe method comprises the following steps: hydrogen, hydroxy, halogen, amino, nitro, cyano, azido, mercapto or silyl; or alkyl_(C≤12)Alkenyl radical_(C≤12)Alkynyl group_(C≤12)Aryl radical_(C≤12)Aralkyl group_(C≤12)Heteroaryl group_(C≤12)Heteroarylalkyl group_(C≤12)Acyl group_(C≤12)Alkoxy group_(C≤12)Alkenyloxy group_(C≤12)Alkynyloxy, alkynyloxy_(C≤12)Aryloxy group_(C≤12)(iii) aralkyloxy_(C≤12)Heteroaryloxy group_(C≤12)Hetero aralkyloxy group_(C≤12)(iii) acyloxy group_(C≤12)Alkylamino group_(C≤12)Dialkylamino group_(C≤12)Alkenylamino group_(C≤12)Alkynyl amino group_(C≤12)Arylamino group_(C≤12)Aralkylamino group_(C≤12)Heteroaryl amino_(C≤12)Heteroarylalkylamino, heteroarylalkylamino_(C≤12)Alkyl sulfonyl amino_(C≤12)Amide group_(C≤12)Alkylthio group_(C≤12)Alkenylthio radicals_(C≤12)Alkynylthio radicals_(C≤12)Arylthio radicals_(C≤12)Aralkylthio group_(C≤12)Heteroarylthio radicals_(C≤12)Heteroarylalkylthio groups_(C≤12)Acylthio groups_(C≤12)Thioacyl, thioacyl_(C≤12)Alkyl sulfonyl group_(C≤12)Alkenylsulfonyl group_(C≤12)Alkynylsulfonyl, and a process for producing the same_(C≤12)Aryl sulfonyl group_(C≤12)Aralkyl sulfonyl group_(C≤12)Alkyl ammonium_(C≤12)Alkyl sulfonium_(C≤12)Alkyl silyl group_(C≤12)Or substituted versions of any of these groups; x₁The method comprises the following steps: OR (OR)_b、NR_bR_cOr SR_bWherein R is_bAnd R_cEach is independently: hydrogen; alkyl radical _(C≤8)Aryl radical_(C≤8)Aralkyl group_(C≤8)Acyl group_(C≤8)Or substituted versions of any of these groups; or with the proviso that when bound to R_bWhen the atom(s) is part of a double bond, then R_bAbsent, with the further proviso that when R is_bWhen not present, then bind to R_bIs part of a double bond; and R is₁The method comprises the following steps: hydrogen, cyano, hydroxy, halogen or amino; or alkyl_(C≤8)Alkenyl radical_(C≤8)Alkynyl group_(C≤8)Aryl radical_(C≤8)Aralkyl group_(C≤8)Heteroaryl group_(C≤8)Heteroarylalkyl group_(C≤8)Acyl group_(C≤8)Alkoxy group_(C≤8)Aryloxy group_(C≤8)(iii) acyloxy group_(C≤8)Alkylamino group_(C≤8)Arylamino group_(C≤8)Amide group_(C≤8)Or substituted versions of any of these groups; r' is hydroxy, alkoxy_(C≤12)Substituted alkoxy group_(C≤12)Aryloxy group_(C≤12)Substituted aryloxy group_(C≤12)(iii) aralkyloxy_(C≤12)Substituted aralkyloxy group_(C≤12)(iii) acyloxy group_(C≤12)Or substituted acyloxy group_(C≤12)(ii) a Or a salt, ester, hydrate, solvate, tautomer, or optically active isomer thereofA structure body. In some of these embodiments, R' is acetoxy. Other embodiments within these embodiments

In the scheme, R' is hydroxyl. For example, the present invention provides:

or a salt, hydrate, solvate, tautomer or optical isomer thereof, for example:

In some embodiments, the present invention provides a compound of the formula:

wherein: y is alkanediyl_(C≤8)Alkenyldiyl group_(C≤8)Alkynediyl_(C≤8)Or substituted versions of any of these groups; r_aThe method comprises the following steps: hydrogen, hydroxy, halogen, amino, nitro, cyano, azido, mercapto or silyl; or alkyl_(C≤12)Alkenyl radical_(C≤12)Alkynyl group_(C≤12)Aryl radical_(C≤12)Aralkyl group_(C≤12)Heteroaryl group_(C≤12)Heteroarylalkyl group_(C≤12)Acyl group_(C≤12)Alkoxy group_(C≤12)Alkenyloxy group_(C≤12)Alkynyloxy, alkynyloxy_(C≤12)Aryloxy group_(C≤12)(iii) aralkyloxy_(C≤12)Heteroaryloxy group_(C≤12)Heteroarylalkoxy, heteroarylalkoxyBase of_(C≤12)(iii) acyloxy group_(C≤12)Alkylamino group_(C≤12)Dialkylamino group_(C≤12)Alkenylamino group_(C≤12)Alkynyl amino group_(C≤12)Arylamino group_(C≤12)Aralkylamino group_(C≤12)Heteroaryl amino_(C≤12)Heteroarylalkylamino, heteroarylalkylamino_(C≤12)Alkyl sulfonyl amino_(C≤12)Amide group_(C≤12)Alkylthio group_(C≤12)Alkenylthio radicals_(C≤12)Alkynylthio radicals_(C≤12)Arylthio radicals_(C≤12)Aralkylthio group_(C≤12)Heteroarylthio radicals_(C≤12)Heteroarylalkylthio groups_(C≤12)Acylthio groups_(C≤12)Thioacyl, thioacyl_(C≤12)Alkyl sulfonyl group_(C≤12)Alkenylsulfonyl group_(C≤12)Alkynylsulfonyl, and a process for producing the same_(C≤12)Aryl sulfonyl group_(C≤12)Aralkyl sulfonyl group_(C≤12)Alkyl ammonium_(C≤12)Alkyl sulfonium_(C≤12)Alkyl silyl group_(C≤12)Or substituted versions of any of these groups; x₁The method comprises the following steps: OR (OR)_b、NR_bR_cOr SR_bWherein R is_bAnd R_cEach is independently: hydrogen; alkyl radical _(C≤8)Aryl radical_(C≤8)Aralkyl group_(C≤8)Acyl group_(C≤8)Or substituted versions of any of these groups; or with the proviso that when bound to R_bWhen the atom(s) is part of a double bond, then R_bAbsent, with the further proviso that when R is_bWhen not present, then bind to R_bIs part of a double bond; and R is₁The method comprises the following steps: hydrogen, cyano, hydroxy, halogen or amino; or alkyl_(C≤8)Alkenyl radical_(C≤8)Alkynyl group_(C≤8)Aryl radical_(C≤8)Aralkyl group_(C≤8)Heteroaryl group_(C≤8)Heteroarylalkyl group_(C≤8)Acyl group_(C≤8)Alkoxy group_(C≤8)Aryloxy group_(C≤8)(iii) acyloxy group_(C≤8)Alkylamino group_(C≤8)Arylamino group_(C≤8)Amide group_(C≤8)Or theseSubstituted forms of any of the groups; or a salt, ester, hydrate, solvate, tautomer, or optical isomer thereof. For example, the present invention provides:

or a salt, hydrate, solvate, tautomer or optical isomer thereof, for example:

In a variation of each of the above embodiments comprising a Y group, Y may be an alkanediyl group_(C1-4)Or substituted alkanediyl_(C1-4). In some of these variants, Y may be-CH₂-. In the presence of X₁In a variation of each of the above embodiments, X₁May be OR _bAnd R is_bMay not be present.

In the presence of R_aIn variations of each of the above embodiments, R_aMay be-OH. In other variations, R_aMay be an acyl group_(C1-6)Or substituted acyl_(C1-6). In some of these variants, R_aMay be an acyl group_(C4-6)Or substituted acyl_(C4-6). In some of these variants, R_aMay be an acyl group_(C1-4)Or substituted acyl_(C1-4). In some of these variants, R_aMay be an acyl group_(C1-3)Or substituted acyl_(C1-3). In some of these variants, R_aMay be selected from-C (═ O) OH, -C (═ O) OCH₃、-C(＝O)NHCH₃、-C(＝O)NHCH₂CH₃and-C (═ O) NHCH₂CF₃. In thatIn still other variations, R_aMay be an acyloxy group_(C1-3)Or substituted acyloxy_(C1-3)。

In the presence of R₁In variations of each of the above embodiments, R₁Can be-H, -OH or-F. In some of these variants, R₁May be-H. In the presence of R₂In variations of each of the above embodiments, R₂May be-CN. In other variations, R₂May be a substituted acyl group_(C1-3). For example, R₂May be-C (═ O) NHS (═ O)₂CH₃。

In some embodiments, the present invention provides compounds for use in the prevention and/or treatment of diseases or conditions whose pathology involves oxidative stress, inflammation, and/or dysregulation of inflammatory signaling pathways. In some variations, the disease or disorder may be characterized by Inducible Nitric Oxide Synthase (iNOS) and/or inducible overexpression of cyclooxygenase (COX-2) in the affected tissue. In some variants, the disease or disorder may be characterized by overproduction of Reactive Oxygen Species (ROS) or Reactive Nitrogen Species (RNS) such as superoxide, hydrogen peroxide, nitric oxide, or peroxynitrite in the affected tissue. In some variants, the disease or disorder is characterized by the overproduction of inflammatory cytokines or other inflammation-associated proteins such as TNF α, IL-6, IL-1, IL-8, ICAM-1, VCAM-1, and VEGF. In some embodiments, such diseases or disorders may involve the undesirable proliferation of certain cells, such as in the case of cancer (e.g., solid tumors, leukemias, myelomas, lymphomas, and other cancers), fibrosis-related organ failure or excessive scar hyperplasia. Non-limiting examples of diseases or conditions include: lupus, rheumatoid arthritis, juvenile onset diabetes, multiple sclerosis, psoriasis and crohn's disease. Additional non-limiting examples include cardiovascular diseases such as atherosclerosis, heart failure, myocardial infarction, acute coronary syndrome, restenosis following vascular surgery, hypertension, and vasculitis; neurodegenerative or neuromuscular diseases such as alzheimer's disease, parkinson's disease, huntington's disease, ALS, and muscular dystrophy; neurological disorders such as epilepsy and dystonia; neuropsychiatric disorders such as major depression, bipolar disorder, post traumatic stress disorder, schizophrenia, anorexia nervosa, ADHD and autism spectrum disorder; retinal diseases such as macular degeneration, diabetic retinopathy, glaucoma, and retinitis; chronic and acute pain syndromes, including inflammatory pain and neuropathic pain; hearing impairment and tinnitus; diabetes and diabetic complications including metabolic syndrome, diabetic nephropathy, diabetic neuropathy and diabetic ulcers; respiratory diseases such as asthma, chronic obstructive pulmonary disease, acute respiratory distress syndrome, and cystic fibrosis; inflammatory bowel disease; osteoporosis, osteoarthritis, and other degenerative diseases of bone and cartilage; acute or chronic organ failure including renal failure, liver failure (including cirrhosis and hepatitis), and pancreatitis; ischemic-reperfusion injury associated with thrombotic or hemorrhagic stroke, subarachnoid hemorrhage, cerebral vasospasm, myocardial infarction, shock, or trauma; organ or tissue transplant complications including acute or chronic transplant failure or rejection and graft versus host disease; skin diseases including atopic dermatitis and acne; sepsis and septic shock; severe inflammation associated with infection, including influenza-associated respiratory inflammation and upper respiratory tract infections; cancer treatment, including radiotherapy or chemotherapy-associated mucositis; and severe burns.

In some embodiments, the compounds of the present disclosure are in the form of pharmaceutically acceptable salts. In other embodiments, the compounds of the present disclosure are not in the form of pharmaceutically acceptable salts.

In some embodiments, the compounds of the present disclosure may be esters of the above formula. The ester may, for example, be derived from a condensation reaction of a hydroxyl group in the structural formula with a carboxyl group of biotin.

In some embodiments, the compounds of the present disclosure may exist as a mixture of stereoisomers. In other embodiments, the compounds of the present disclosure exist as a single stereoisomer.

In some embodiments, the compounds of the present disclosure may be IFN- γ -induced ones in macrophagesInhibitors of dinitrogen oxide (NO) production, e.g., having an IC of less than 0.2. mu.M₅₀The value is obtained.

Other general aspects of the present disclosure contemplate pharmaceutical compositions comprising a compound of the present disclosure as an active ingredient and a pharmaceutically acceptable carrier. The composition may be adapted for administration by, for example, a route selected from: oral, intralipid, intraarterial, intraarticular, intracranial, intradermal, intralesional, intramuscular, intranasal, intraocular, intrapericardial, intraperitoneal, intrapleural, intraprostatic, intrarectal, intrathecal, intratracheal, intratumoral, intraumbilical, intravaginal, intravenous, intracapsular, intravitreal, liposomal, topical, transmucosal, oral, parenteral, rectal, subconjunctival, subcutaneous, sublingual, topical, buccal, transdermal, vaginal, in emulsion, in a lipid composition, by catheter, by lavage, by continuous infusion, by inhalation, by injection, by local delivery, by local perfusion, by direct bathing of target cells, or any combination thereof. In particular embodiments, the compositions may be formulated for oral delivery. In particular embodiments, the compositions are formulated as hard or soft capsules, tablets, syrups, suspensions, cachets, or elixirs. In certain embodiments, the soft capsule is a gelatin capsule. Certain compositions may comprise a protective coating, such as those formulated for oral delivery. Certain compositions also comprise agents that retard absorption, such as those compositions formulated for oral delivery. Certain compositions may also comprise agents that increase solubility or dispersibility, such as those compositions formulated for oral delivery. Certain compositions may comprise a compound of the present disclosure, wherein the compound is dispersed in liposomes, oil and water emulsions, or water and oil emulsions.

Yet another general aspect of the present disclosure contemplates a method of treatment comprising administering to a subject a pharmaceutically effective amount of a compound of the present disclosure. The subject may be, for example, a human. These methods, or any other method of the present disclosure, can further comprise identifying a subject in need of treatment.

Another method of the present disclosure contemplates a method of treating cancer in a subject comprising administering to the subject a pharmaceutically effective amount of a compound of the present disclosure. The cancer may be any type of cancer, such as carcinoma, sarcoma, lymphoma, leukemia, melanoma, mesothelioma, multiple myeloma, or seminoma. Other types of cancer include cancers of the bladder, blood, bone, brain, breast, central nervous system, colon, endometrium, esophagus, genitourinary tract, head, larynx, liver, lung, neck, ovary, pancreas, prostate, spleen, small intestine, large intestine, stomach, or testis. In these methods or any other method, the subject may be a primate. The method or any other method may further comprise identifying a subject in need of treatment. The subject may have a family history or medical history of cancer. In certain embodiments, the subject has symptoms of cancer. The compounds of the invention may be administered by any of the methods described herein, e.g., topically. In certain embodiments, the compound is administered by direct intratumoral injection or by injection into the tumor vasculature. In certain embodiments, the compound may be administered systemically. In certain embodiments, the compound may be administered intravenously, intraarterially, intramuscularly, intraperitoneally, subcutaneously, or orally.

In certain embodiments of the methods for treating cancer in a subject, the method comprises administering to the subject a pharmaceutically effective amount of a compound of the present disclosure, the pharmaceutically effective amount being 0.1-1000 mg/kg. In certain embodiments, the pharmaceutically effective amount is administered as a single dose per day. In certain embodiments, a pharmaceutically effective amount is administered in two or more doses per day. The compounds may be administered by contacting tumor cells, for example, in an ex vivo purging procedure. The method of treatment may include any one or more of the following: a) inducing cytotoxicity in tumor cells; b) killing the tumor cells; c) inducing apoptosis of tumor cells d) inducing differentiation of tumor cells; or e) inhibiting the growth of tumor cells. The tumor cells may be any type of tumor cells, such as leukemia cells. Other types of cells include, for example, bladder cancer cells, breast cancer cells, lung cancer cells, colon cancer cells, prostate cancer cells, liver cancer cells, pancreatic cancer cells, stomach cancer cells, testicular cancer cells, brain cancer cells, ovarian cancer cells, lymphatic cancer cells, skin cancer cells, brain cancer cells, bone cancer cells, or soft tissue cancer cells.

Combination therapy therapies are also contemplated by the present disclosure. For example, with respect to a method of treating cancer in a subject, the method comprising administering to the subject a pharmaceutically effective amount of a compound of the present disclosure, the method may further comprise a treatment selected from the group consisting of: administering a pharmaceutically effective amount of a second drug, radiation therapy, gene therapy, and surgery. Such methods can further comprise (1) contacting the tumor cell with the compound prior to contacting the tumor cell with the second agent, (2) contacting the tumor cell with the second agent prior to contacting the tumor cell with the compound, or (3) simultaneously contacting the tumor cell with the compound and the second agent. In certain embodiments, the second drug can be an antibiotic, an anti-inflammatory drug, an antineoplastic drug, an antiproliferative drug, an antiviral drug, an immunomodulatory drug, or an immunosuppressive drug. The second agent may be an alkylating agent, an androgen receptor modulator, a cytoskeletal disrupting agent, an estrogen receptor modulator, a histone-deacetylase inhibitor, an HMG-CoA reductase inhibitor, a prenyl-protein transferase inhibitor, a retinoid receptor modulator, a topoisomerase inhibitor, or a tyrosine kinase inhibitor. In certain embodiments, the second drug is 5-azacytidine, 5-fluorouracil, 9-cis-retinoic acid, actinomycin D, alitretinoin (alitretinin), all-trans retinoic acid, anamycin, axitinib, belinostat, bevacizumab, bexarotene, bosutin, busulfan, capecitabine, carboplatin, carmustine, CD437, cediranib, cetuximab, chlorambucil, cisplatin, cyclophosphamide, cytarabine, dacarbazine, dasatinib, daunorubicin, decitabine, docetaxel, dolastatin (dolastatin) -10, doxifluridine, doxorubicin, adriamycin, epirubicin, erlotinib, epipodophyllotoxin, gefitinib, gemcitabine, gemtuzumab, oxmil, hexametamide, imatinib, ifosfamide, imatinib, and imatinib, Irinotecan, isotretinoin, ixabepilone, lapatinib, LBH589, romotene, mechlorethamine, melphalan, mercaptopurine, methotrexate, mitomycin, mitoxantrone, MS-275, lenatinib, nilotinib, nitrosourea, platinum oxalate, paclitaxel, plicamycin, procarbazine, semaxanib, semustine, sodium butyrate, sodium phenylacetate, streptozotocin, suberoylanilide hydroxamic acid, sunitinib, tamoxifen, teniposide, thiotepa, thioguanine, topotecan, TRAIL, trastuzumab, tretinoin, trichostatin A, valproic acid, valrubicin, vandetanib, vinblastine, vincristine, vindesine, or vinorelbine.

Also contemplated are methods of treating or preventing a disease having an inflammatory component in a subject, comprising administering to the subject a pharmaceutically effective amount of a compound of the present disclosure. The disease may be, for example, lupus or rheumatoid arthritis. The disease may be an inflammatory bowel disease, such as crohn's disease or ulcerative colitis. The disease with an inflammatory component may be a cardiovascular disease. The disease having an inflammatory component may be diabetes, such as type 1 or type 2 diabetes. The compounds of the present disclosure may also be useful in the treatment of complications associated with diabetes. Such complications are well known in the art and include, for example, obesity, hypertension, atherosclerosis, coronary heart disease, stroke, peripheral vascular disease, hypertension, nephropathy, neuropathy, muscle necrosis, retinopathy and metabolic syndrome (syndrome X). The disease having an inflammatory component may be a skin disease, such as psoriasis, acne or atopic dermatitis. Administration of the compounds of the present disclosure in methods of treating such skin diseases may be, for example, topical or oral.

The disease having an inflammatory component may be metabolic syndrome (syndrome X). Patients with this syndrome are characterized as having three or more symptoms selected from the following 5 symptoms: (1) abdominal obesity; (2) hypertriglyceridemia; (3) low high density lipoprotein cholesterol (HDL); (4) high blood pressure; and (5) elevated fasting glucose, which may be within the range of type 2 diabetes if the patient also suffers from diabetes. Each of these symptoms is defined in the Third Report of the National Cholesterol equivalent program Expert Panel on Detection, Evaluation and Treatment of High bloodCholesterol in additives (additive Treatment Panel IH, or ATP III), National institutes of Health, 2001, NIH Publication No.01-3670, which is incorporated herein by reference. Patients with metabolic syndrome, whether or not they have or develop overt diabetes, have an increased risk of developing the large and micro-vascular complications listed above that accompany type 2 diabetes, such as atherosclerosis and coronary heart disease.

Another general method of the present disclosure relates to a method of treating or preventing a cardiovascular disease in a subject, comprising administering to the subject a pharmaceutically effective amount of a compound of the present disclosure. The cardiovascular disease may be, for example, atherosclerosis, cardiomyopathy, congenital heart disease, congestive heart failure, myocarditis, rheumatic heart disease, valvular disease, coronary artery disease, endocarditis, or myocardial infarction. Combination therapy is also contemplated for such methods. For example, such methods may further comprise administering a pharmaceutically effective amount of a second drug. The second agent may be, for example, a cholesterol-lowering agent, a lipid-lowering agent, a calcium channel blocker, a hypotensive agent, or an HMG-CoA reductase inhibitor. Non-limiting examples of the second drug include amlodipine, aspirin, ezetimibe, felodipine, lacidipine, lercanidipine, nicardipine, nifedipine, nimodipine, nisoldipine, or nitrendipine. Additional non-limiting examples of the second drug include atenolol, bucindolol, carvedilol, clonidine, doxazosin, indoramine, labetalol, methyldopa, metoprolol, nadolol, oxprenolol, phenoxybenzamine, phentolamine, pindolol, prazosin, propranolol, terazosin, timolol, or tolazoline. The second drug may be, for example, a statin, such as atorvastatin, cerivastatin, fluvastatin, lovastatin, mevastatin, pitavastatin, pravastatin, rosuvastatin, or simvastatin.

Also contemplated are methods of treating or preventing a neurodegenerative disease in a subject comprising administering to the subject a pharmaceutically effective amount of a compound of the present disclosure. The neurodegenerative disease may for example be selected from parkinson's disease, alzheimer's disease, Multiple Sclerosis (MS), huntington's disease and amyotrophic lateral sclerosis. In a particular embodiment, the neurodegenerative disease is alzheimer's disease. In particular embodiments, the neurodegenerative disease is MS, e.g., primary progressive, relapsing-remitting secondary progressive or progressive relapsing MS. The subject can be, for example, a primate. The subject may be a human.

In a particular embodiment of a method of treating or preventing a neurodegenerative disease in a subject, the method comprises administering to the subject a pharmaceutically effective amount of a compound of the present disclosure, the treatment inhibiting demyelination of neurons in the brain or spinal cord of the subject. In certain embodiments, the treatment inhibits inflammatory demyelination. In certain embodiments, the treatment inhibits transection of a neuronal axon in the brain or spinal cord of the subject. In certain embodiments, the treatment inhibits neurite transection in the brain or spinal cord of the subject. In certain embodiments, the treatment inhibits neuronal apoptosis in the brain or spinal cord of the subject. In certain embodiments, the treatment stimulates remyelination of neuronal axons in the brain or spinal cord of the subject. In certain embodiments, the treatment restores function lost after onset of MS. In certain embodiments, the treatment prevents the onset of new MS. In certain embodiments, treatment prevents disability resulting from the onset of MS.

One general aspect of the present disclosure contemplates a method of treating or preventing a disorder characterized by overexpression of an iNOS gene in a subject, the method comprising administering to the subject a pharmaceutically effective amount of a compound of the present disclosure.

Another general aspect of the present disclosure contemplates a method of inhibiting IFN- γ -induced nitric oxide production in a cell of a subject, comprising administering to the subject a pharmaceutically effective amount of a compound of the present disclosure.

Yet another general aspect of the present disclosure contemplates a method of treating or preventing a disorder characterized by overexpression of a COX-2 gene in a subject, comprising administering to the subject a pharmaceutically effective amount of a compound of the present disclosure.

Also contemplated are methods of treating kidney/renal disease (RKD) in a subject comprising administering to the subject a pharmaceutically effective amount of a compound of the disclosure. See U.S. patent application 12/352,473, which is incorporated herein by reference in its entirety. RKD may be derived from, for example, toxic injury. The toxic injury may be derived, for example, from an imaging agent or drug. The drug may be, for example, a chemotherapeutic agent. In certain embodiments, RKD may be derived from ischemia/reperfusion injury. In certain embodiments, RKD is derived from diabetes or hypertension. RKD may be derived from autoimmune diseases. RKD may be further defined as chronic RKD or acute RKD.

In certain methods of treating kidney/renal disease (RKD) in a subject, the method comprises administering a pharmaceutically effective amount of a compound of the present disclosure to a subject who has undergone or is undergoing dialysis. In certain embodiments, the subject has undergone a kidney transplant or is a candidate for undergoing a kidney transplant. The subject may be a primate. The primate can be a human. The subject in this or any other method may be, for example, a cow, horse, dog, cat, pig, mouse, rat, or guinea pig.

The present disclosure also contemplates a method for improving glomerular filtration rate or creatinine clearance in a subject comprising administering to the subject a pharmaceutically effective amount of a compound of the present disclosure.

Methods of synthesizing the compounds of the disclosure are also contemplated. In particular embodiments, such methods may include methods of making a target compound defined by the formula:

comprising reacting a compound of the formula:

the present disclosure also contemplates a kit, e.g., a kit comprising: a compound of the present disclosure; and instructions containing information in one or more forms selected from the group consisting of: indicating the disease state to which the compound is to be administered, stored information on the compound, dosage information and instructions on how to administer the compound. Kits may comprise a compound of the disclosure in a multiple dose form.

Other objects, features and advantages of the present disclosure will become apparent from the following detailed description. It should be understood, however, that the detailed description and the specific examples, while indicating specific embodiments of the invention, are given by way of illustration only, since various changes and modifications within the spirit and scope of the invention will become apparent to those skilled in the art from this detailed description. Note that simply because a particular compound is assigned to one particular formula does not mean that it cannot be assigned to another formula.

Drawings

The following drawings form part of the present specification and are included to further illustrate certain aspects of the present disclosure. The invention may be better understood by reference to one of these drawings in combination with the detailed description of specific embodiments presented herein.

FIGS. 1-4, 6 and 8. Inhibition of NO production. RAW264.7 macrophages were pretreated with DMSO or different concentrations of drug (nM) for 2 hours and then with 20ng/ml IFN γ for 24 hours. Determining the concentration of NO in the culture medium using a Griess reagent system; cell viability was determined using WST-1 reagent.

Fig. 5. Repression of IL-6 induced STAT3 phosphorylation. HeLa cells were treated with DMSO or 2. mu.M of the indicated compound for 6 hours and then stimulated with 20ng/ml IL-6 for 15 minutes. Phosphorylated STAT3 and total STAT3 levels were determined by immunoblotting. Compounds 402, 402-02, 402-55, 402-56 and 402-57 are comparative compounds (see example 1).

Fig. 7. CDDO-TFEA (TP-500) was detected at higher levels in mouse brain than CDDO-EA (TP-319). CD-1 mice were fed TP-319 or TP-500 at 200 or 400mg/kg for 3.5 days, and TP levels in the mice brain were analyzed by LC/MS. The structures of TP-319 and TP-500 are shown herein.

Description of illustrative embodiments

Disclosed herein are novel compounds, e.g., having antioxidant and anti-inflammatory properties, methods of making the same, and methods of using the same, including methods for treating and/or preventing diseases.

I. Definition of

As used herein, "hydrogen" means-H; "hydroxy" means-OH; "oxygen" means ═ O; "halo" means independently-F, -Cl, -Br, or-I; "amino" means-NH₂(see below for the definition of chemical groups comprising the term amino, e.g. alkylamino); "hydroxyamino" means-NHOH; "nitro" means-NO₂(ii) a Imino means ═ NH (see below for the definition of chemical groups containing the term imino, e.g. alkylamino); "cyano" means-CN; "azido" means-N₃(ii) a "phosphoric acid group" means-OP (O) (OH)₂(ii) a "mercapto" means-SH; "sulfur" means ═ S; "sulfonamido" means-NHS (O) ₂- (see below for definitions of chemical groups, e.g. alkylsulfonamide groups, including the term sulfonamido); "Sulfonyl" means-S (O)₂- (see definition below for chemical groups comprising the term sulfonyl, e.g. alkylsulfonyl); "sulfinyl" means-S (O) - (see below for definition of chemical groups including the term sulfinyl, e.g., alkylsulfinyl); and "silyl" means-SiH₃(see below for a definition of chemical groups, e.g. alkylsilyl groups, comprising the term silyl).

For the followingThe following parenthesized subscripts are further defined as follows: "(Cn)" is defined as the exact number of carbon atoms in a chemical group (n). "(C.ltoreq.n)" is defined as the maximum number of carbon atoms (n) that can be present in a chemical group, as such the minimum number of carbon atoms is at least one, but others may be as small a number as possible for the chemical group. For example, it is understood that the chemical group "alkenyl_(C≤8)"the minimum number of carbon atoms is 2. For example, "alkoxy group_(C≤10)Those alkoxy groups having from 1 to 10 carbon atoms (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10, or any range derivable therein (e.g., 3-10 carbon atoms)) are named. (Cn-n ') defines the minimum (n) and maximum (n') values of carbon atoms in the chemical group. Similarly, "alkyl group _(C2-10)Those alkyl groups having from 2 to 10 carbon atoms (e.g., 2, 3, 4, 5, 6, 7, 8, 9, or 10, or any range derivable therein (e.g., 3-10 carbon atoms)) are named.

The term "alkyl", when used without the "substituted" modifier, refers to a non-aromatic monovalent radical having a saturated carbon atom as the point of attachment, which is a linear or branched, cyclic or acyclic structure, no carbon-carbon double or triple bonds, and no other atoms besides carbon and hydrogen. Chemical group-CH₃(Me)、-CH₂CH₃(Et)、-CH₂CH₂CH₃(n-Pr)、-CH(CH₃)₂(iso-Pr)、-CH(CH₂)₂(cyclopropyl), -CH₂CH₂CH₂CH₃(n-Bu)、-CH(CH₃)CH₂CH₃(sec-butyl), -CH₂CH(CH₃)₂(isobutyl), -C (CH)₃)₃(tert-butyl), -CH₂C(CH₃)₃(neopentyl), cyclobutyl, cyclopentyl, cyclohexyl and cyclohexylmethyl are non-limiting examples of alkyl groups. The term "substituted alkyl" refers to a non-aromatic monovalent radical having a saturated carbon atom as the point of attachment, which is linear or branched, cyclic or acyclic, free of carbon-carbon double or triple bonds, and at least one atom is independently selected from N, O, F, Cl,br, I, Si, P and S. The following chemical groups are non-limiting examples of substituted alkyls: -CH₂OH、-CH₂Cl、-CH₂Br、-CH₂SH、-CF₃、-CH₂CN、-CH₂C(O)H、-CH₂C(O)OH、-CH₂C(O)OCH₃、-CH₂C(O)NH₂、-CH₂C(O)NHCH₃、-CH₂C(O)CH₃、-CH₂OCH₃、-CH₂OCH₂CF₃、-CH₂OC(O)CH₃、-CH₂NH₂、-CH₂NHCH₃、-CH₂N(CH₃)₂、-CH₂CH₂Cl 、-CH₂CH₂OH 、-CH₂CF₃、-CH₂CH₂OC(O)CH₃、-CH₂CH₂NHCO₂C(CH₃)₃and-CH₂Si(CH₃)₃。

The term "alkanediyl", when used without the "substituted" modifier, refers to a non-aromatic divalent radical wherein alkanediyl is two σ -bonded, has one or two saturated carbon atoms as the point of attachment, is linear or branched, cyclic or acyclic, has no carbon-carbon double or triple bonds, and has no atoms other than carbon and hydrogen. Chemical group-CH ₂- (methylene), -CH₂CH₂-、-CH₂C(CH₃)₂CH₂-、-CH₂CH₂CH₂-andare non-limiting examples of alkanediyl. The term "substituted alkanediyl" refers to a non-aromatic monovalent group in which an alkynediyl group is linked in two sigma bonds, has as a point of attachment one or two saturated carbon atoms, which are linear or branched, cyclic or acyclic, free of carbon-carbon double or triple bonds, and at least one atom is independently selected from N, O, F, Cl, Br, I, Si, P, and S. The following chemical groups are non-limiting examples of substituted alkanediyl groups: -CH (F) -, -CF₂-、-CH(Cl)-、-CH(OH)-、-CH(OCH₃) -and-CH₂CH(Cl)-。

The term "alkenyl", when used without the "substituted" modifier, refers to a monovalent group having as a point of attachment a non-aromatic carbon atom that is linear or branched, cyclic, or acyclic, has at least one non-aromatic carbon-carbon double bond, no carbon-carbon triple bonds, and no atoms other than carbon and hydrogen. Non-limiting examples of alkenyl groups include: -CH ═ CH₂(vinyl), -CH ═ CHCH₃、-CH＝CHCH₂CH₃、-CH₂CH＝CH₂(allyl), -CH₂CH＝CHCH₃and-CH ═ CH-C₆H₅. The term "substituted alkenyl" refers to a monovalent group having a non-aromatic carbon atom as the point of attachment, having at least one non-aromatic carbon-carbon double bond, no carbon-carbon triple bond, linear or branched, cyclic, or acyclic structure, and at least one atom is independently selected from the group consisting of N, O, F, Cl, Br, I, Si, P, and S. The chemical groups-CH ═ CHF, -CH ═ CHCl and-CH ═ CHBr are non-limiting examples of substituted alkenyl groups.

The term "alkenediyl," when used without the "substituted" modifier, refers to a non-aromatic divalent radical in which the alkenediyl is connected by two sigma bonds, has two carbon atoms as points of attachment, is linear or branched, cyclic, or acyclic, has at least one non-aromatic carbon-carbon double bond, has no carbon-carbon triple bonds, and has no atoms other than carbon and hydrogen. Chemical groups-CH ═ CH-, -CH ═ C (CH)₃)CH₂-、-CH＝CHCH₂-andare non-limiting examples of alkenediyl groups. The term "substituted enediyl" refers to a non-aromatic divalent radical in which the enediyl group is linked in two sigma-bonds, has two carbon atoms as points of attachment, is linear or branched, cyclic or acyclic, has at least one non-aromatic carbon-carbon double bond, has no carbon-carbon triple bond, and has at least one atom independently selected from the group consisting of N, O, F, Cl, Br, I, Si, P, and S. The following are presentedChemical groups are non-limiting examples of substituted alkenediyl groups: -CF ═ CH-, -c (oh) ═ CH-, and-CH₂CH＝C(Cl)-。

The term "alkynyl", when used without the "substituted" modifier, refers to a monovalent group having a non-aromatic carbon atom as the point of attachment, having a linear or branched, cyclic or acyclic structure, at least one carbon-carbon triple bond, and no other atoms besides carbon and hydrogen. Chemical groups-C.ident.CH, -C.ident.CCH ₃、-C≡CC₆H₅and-CH₂C≡CCH₃Are non-limiting examples of alkynyl groups. The term "substituted alkynyl" refers to a monovalent group having a non-aromatic carbon atom as the point of attachment, and having at least one carbon-carbon triple bond, being linear or branched, cyclic or acyclic, and at least one atom being independently selected from N, O, F, Cl, Br, I, Si, P, and S. Chemical group-C ≡ CSi (CH)₃)₃Are non-limiting examples of substituted alkynyl groups.

The term "alkynediyl", when used without the "substituted" modifier, refers to a non-aromatic divalent radical in which the alkynediyl is linked by two sigma-bonds, has two carbon atoms as points of attachment, has a linear or branched, cyclic or acyclic structure, at least one carbon-carbon triple bond, and no atoms other than carbon and hydrogen. Chemical groups-C.ident.C-, -C.ident.CCH₂-and-C ≡ CCH (CH)₃) -is a non-limiting example of an alkyndiyl group. The term "substituted alkynediyl" refers to a non-aromatic divalent radical in which the alkynediyl is linked in two sigma-bonds, has two carbon atoms as points of attachment, has a linear or branched, cyclic or acyclic structure, at least one carbon-carbon triple bond, and at least one atom is independently selected from the group consisting of N, O, F, Cl, Br, I, Si, P, and S. The chemical groups-C.ident.CCFH-and-C.ident.CHCH (Cl) -are non-limiting examples of substituted alkynediyl groups.

The term "aryl", when used without the modifier "substituted", refers to a monovalent group having, as the point of attachment, an aromatic carbon atom that forms part of a six-membered aromatic ring structure in which the ring atoms are all carbon,and wherein the monovalent group does not contain atoms other than carbon and hydrogen. Non-limiting examples of aryl groups include phenyl (Ph), methylphenyl, (dimethyl) phenyl, -C₆H₄CH₂CH₃(ethylphenyl), -C₆H₄CH₂CH₂CH₃(propylphenyl), -C₆H₄CH(CH₃)₂、-C₆H₄CH(CH₂)₂、-C₆H₃(CH₃)CH₂CH₃(methylethylphenyl), -C₆H₄CH＝CH₂(vinylphenyl), -C₆H₄CH＝CHCH₃、-C₆H₄C≡CH、-C₆H₄C≡CCH₃Naphthyl and monovalent radicals derived from biphenyl. The term "substituted aryl" refers to a monovalent group having, as a point of attachment, an aromatic carbon atom that forms part of a six-membered aromatic ring structure, wherein the ring atoms are all carbon, and wherein the monovalent group further has at least one atom independently selected from the group consisting of N, O, F, Cl, Br, I, Si, P, and S. Non-limiting examples of substituted aryl groups include the chemical groups: -C₆H₄F、-C₆H₄Cl、-C₆H₄Br、-C₆H₄I、-C₆H₄OH、-C₆H₄OCH₃、-C₆H₄OCH₂CH₃、-C₆H₄OC(O)CH₃、-C₆H₄NH₂、-C₆H₄NHCH₃、-C₆H₄N(CH₃)₂、-C₆H₄CH₂OH、-C₆H₄CH₂OC(O)CH₃、-C₆H₄CH₂NH₂、-C₆H₄CF₃、-C₆H₄CN、-C₆H₄CHO、-C₆H₄CHO、-C₆H₄C(O)CH₃、-C₆H₄C(O)C₆H₅、-C₆H₄CO₂H、-C₆H₄CO₂CH₃、-C₆H₄CONH₂、-C₆H₄CONHCH₃and-C₆H₄CON(CH₃)₂。

The term "aryldiyl," when used without the "substituted" modifier, refers to a divalent group wherein the aryldiyl group is two sigma-linked, having as a point of attachment two aromatic carbon atoms that form part of one or more six-membered aromatic ring structures wherein the ring atoms are all carbon, and wherein the monovalent group contains no atoms other than carbon and hydrogen. Non-limiting examples of aryldiyl groups include:

The term "substituted aryldiyl" refers to a divalent group wherein the aryldiyl is connected in two sigma-bonds, having as a point of attachment two aromatic carbon atoms that form part of one or more six-membered aromatic ring structures wherein the ring atoms are all carbon, and wherein the divalent group further has at least one atom independently selected from the group consisting of N, O, F, Cl, Br, I, Si, P, and S.

The term "aralkyl", when used without the "substituted" modifier, refers to a monovalent radical-alkanediyl-aryl, wherein the terms alkanediyl and aryl are each used in a manner consistent with the definition provided above. Non-limiting examples of aralkyl groups are: phenylmethyl (benzyl, Bn), 1-phenyl-ethyl, 2-phenyl-ethyl, indenyl and 2, 3-dihydro-indenyl, with the proviso that indenyl and 2, 3-dihydro-indenyl are the only examples of aralkyl groups at present whose point of attachment is in each case one of the saturated carbon atoms. When the term "aralkyl" is used in the "substituted" modification, either or both of the alkanediyl and aryl groups are substituted. Non-limiting examples of substituted aralkyl groups are: (3-chlorophenyl) -methyl, 2-oxo-2-phenyl-ethyl (phenylcarbonylmethyl), 2-chloro-2-phenyl-ethyl, chromanyl wherein the point of attachment is one of the saturated carbon atoms, and tetrahydroquinolinyl wherein the point of attachment is one of the saturated atoms.

The term "heteroaryl", when used without the "substituted" modifier, refers to a monovalent group having an aromatic carbon or nitrogen atom as the point of attachment, said carbon or nitrogen atom forming part of an aromatic ring structure in which at least one of the ring atoms is nitrogen, oxygen, or sulfur, and in which the monovalent group contains no atoms other than carbon, hydrogen, aromatic nitrogen, aromatic oxygen, and aromatic sulfur. Non-limiting examples of aryl groups include acridinyl, furyl, imidazoimidazolyl, imidazopyrazolyl, imidazopyridyl, imidazopyrimidinyl, indolyl, imidazolinyl, methylpyridyl, oxazolyl, phenylimidazolyl, pyridyl, pyrrolyl, pyrimidinyl, pyrazinyl, quinolyl, quinazolinyl, quinoxalyl, tetrahydroquinolyl, thienyl, triazinyl, pyrrolopyridyl, pyrrolopyrimidyl, pyrrolopyrazinyl, pyrrolotriazinyl, pyrroloimidazolyl, benzopyranyl (where the point of attachment is one of the aromatic atoms), and chromanyl (where the point of attachment is one of the aromatic atoms). The term "substituted heteroaryl" refers to a monovalent group having an aromatic carbon or nitrogen atom as the point of attachment, said carbon or nitrogen atom forming part of an aromatic ring structure, wherein at least one of the ring atoms is nitrogen, oxygen, or sulfur, and wherein the monovalent group further has at least one atom independently selected from the group consisting of non-aromatic nitrogen, non-aromatic oxygen, non-aromatic sulfur, F, Cl, Br, I, Si, and P.

The term "heteroaryldiyl," when used without the modifier "substituted," refers to a divalent group wherein the heteroaryldiyl group is joined in two sigma-bonds with an aromatic carbon or nitrogen atom as the point of attachment, the carbon or nitrogen atom having two aromatic atoms as the point of attachment, the carbon atom forming part of one or more six-membered aromatic ring structures wherein the ring atoms are all carbon, and wherein the monovalent group contains no atoms other than carbon and hydrogen. Non-limiting examples of heteroaryl diradicals include:

the term "substituted heteroaryldiyl" refers to a divalent group wherein the heteroaryldiyl group is connected by two sigma-bonds, having as a point of attachment two aromatic carbon atoms that form part of one or more six-membered aromatic ring structures wherein the ring atoms are all carbon, and wherein the divalent group further has at least one atom independently selected from the group consisting of N, O, F, Cl, Br, I, Si, P, and S.

The term "heteroaralkyl", when used without the "substituted" modifier, refers to a monovalent radical-alkanediyl-heteroaryl, wherein the terms alkanediyl and heteroaryl are each used in a manner consistent with the definition provided above. Non-limiting examples of aralkyl groups are: pyridylmethyl and thienylmethyl. When the term "heteroaralkyl" is used in the "substituted" modification, either or both of alkanediyl and heteroaryl are substituted.

The term "acyl", when used without the "substituted" modifier, refers to a monovalent group having a carbonyl carbon atom as the point of attachment, and also having a linear or branched, cyclic or acyclic structure, with no atoms other than carbon or hydrogen other than the oxygen atom of the carbonyl group. Chemical group-CHO, -C (O) CH₃(acetyl, Ac), -C (O) CH₂CH₃、-C(O)CH₂CH₂CH₃、-C(O)CH(CH₃)₂、-C(O)CH(CH₂)₂、-C(O)C₆H₅、-C(O)C₆H₄CH₃、-C(O)C₆H₄CH₂CH₃、-COC₆H₃(CH₃)₂and-C (O) CH₂C₆H₅Are non-limiting examples of acyl groups. Thus, the term "acyl" includes, but is not limited to, chemical groups that are oftentimes referred to as "alkylcarbonyl" and "arylcarbonyl". The term "substituted acyl" refers to a monovalent radical having a carbonyl carbon atom as the point of attachment, and also having a linear or branched, cyclic, or acyclic, structureThe ring structure, in addition to the carbonyl oxygen, has at least one atom independently selected from the group consisting of N, O, F, Cl, Br, I, Si, P, and S. Chemical group-C (O) CH₂CF₃、-CO₂H (carboxyl), -CO₂CH₃(methyl carboxyl), -CO₂CH₂CH₃、-CO₂CH₂CH₂CH₃、-CO₂C₆H₅、-CO₂CH(CH₃)₂、-CO₂CH(CH₂)₂、-C(O)NH₂(carbamoyl), -C (O) NHCH₃、-C(O)NHCH₂CH₃、-CONHCH(CH₃)₂、-CONHCH(CH₂)₂、-CON(CH₃)₂、-CONHCH₂CF₃-CO-pyridyl, -CO-imidazolyl and-C (O) N₃Are non-limiting examples of substituted acyl groups. The term "substituted acyl" includes, but is not limited to, "heteroarylcarbonyl".

The term "alkylene", when used without the "substituted" modifier, refers to a divalent radical ═ CRR ', where the alkylene is connected by one sigma-bond and one pi-bond, where R and R ' are independently hydrogen, alkyl, or R and R ' together represent an alkanediyl group. Non-limiting examples of alkylene groups include: CH (CH) ₂、＝CH(CH₂CH₃) And ═ C (CH)₃)₂. The term "substituted alkylene" refers to a chemical group ═ CRR ', where the alkylene is connected by one sigma-bond and one pi-bond, where R and R ' are independently hydrogen, alkyl, substituted alkyl, or R and R ' together represent a substituted alkanediyl, provided that either R and R ' are substituted alkyl or R and R ' together represent a substituted alkanediyl.

The term "alkoxy", when used without the "substituted" modifier, refers to the chemical group — OR, where R is alkyl, as defined above for that term. Non-limiting examples of alkoxy groups include: -OCH₃、-OCH₂CH₃、-OCH₂CH₂CH₃、-OCH(CH₃)₂、-OCH(CH₂)₂-O-cyclopentyl and-O-cyclohexyl. Operation of the artThe term "substituted alkoxy" refers to the chemical group-OR, where R is substituted alkyl, as defined above for the term. For example, -OCH₂CF₃Is a substituted alkoxy group.

Similarly, the terms "alkenyloxy," "alkynyloxy," "aryloxy," "aralkyloxy," "heteroaryloxy," "heteroarylalkoxy," and "acyloxy," when used without the "substituted" modifier, refer to a chemical group defined as-OR, wherein R is independently alkenyl, alkynyl, aryl, aralkyl, heteroaryl, heteroaralkyl, and acyl, as defined above for those terms. When any of the terms alkenyloxy, alkynyloxy, aryloxy, aralkyloxy, and acyloxy are modified by "substitution," it refers to the chemical group-OR, where R is substituted alkenyl, alkynyl, aryl, aralkyl, heteroaryl, heteroaralkyl, and acyl, respectively.

The term "alkylamino", when used without the "substituted" modifier, refers to the chemical group — NHR, where R is alkyl, as defined above for that term. Non-limiting examples of alkylamino groups include: -NHCH₃、-NHCH₂CH₃、-NHCH₂CH₂CH₃、-NHCH(CH₃)₂、-NHCH(CH₂)₂、-NHCH₂CH₂CH₂CH₃、-NHCH(CH₃)CH₂CH₃、-NHCH₂CH(CH₃)₂、-NHC(CH₃)₃-NH-cyclopentyl and-NH-cyclohexyl. The term "substituted alkylamino" refers to a chemical group-NHR, where R is substituted alkyl, as defined above for the term. For example, -NHCH₂CF₃Is a substituted alkylamino group.

The term "dialkylamino," when used without the "substituted" modifier, refers to the chemical group-NRR ', where R and R ' can be the same or different alkyl groups, or R and R ' taken together can represent an alkanediyl group having two or more saturated carbon atoms wherein at least two saturated carbon atoms are attached to a nitrogen atom. Non-limiting examples of dialkylamino groups include：-NHC(CH₃)₃、-N(CH₃)CH₂CH₃、-N(CH₂CH₃)₂N-pyrrolidinyl and N-piperidinyl. The term "substituted dialkylamino" refers to the chemical group-NRR ', where R and R' can be the same or different substituted alkyl groups, one of R or R 'is an alkyl group and the other is a substituted alkyl group, or R and R' taken together appear as a substituted alkanediyl group having two or more saturated carbon atoms wherein at least two saturated carbon atoms are attached to a nitrogen atom.

The terms "alkoxyamino", "alkenylamino", "alkynylamino", "arylamino", "aralkylamino", "heteroarylamino", "heteroaralkylamino", and "alkylsulfonylamino", when used without the "substituted" modifier, refer to chemical groups defined as — NHR, wherein R is alkoxy, alkenyl, alkynyl, aryl, aralkyl, heteroaryl, heteroaralkyl, and alkylsulfonyl, respectively, as defined above for those terms. A non-limiting example of an arylamino group is-NHC₆H₅. When any of the terms alkoxyamino, alkenylamino, alkynylamino, arylamino, aralkylamino, heteroarylamino, heteroaralkylamino, and alkylsulfonylamino is modified by "substitution", it refers to the chemical group-NHR, where R is substituted alkoxy, alkenyl, alkynyl, aryl, aralkyl, heteroaryl, heteroaralkyl, and alkylsulfonyl, respectively.

The term "acylamino" (acylamino), when used without the modifier "substituted", refers to the chemical group — NHR, where R is acyl, as defined above for the term. A non-limiting example of an acylamino group is-NHC (O) CH₃. When the term amide is used in the context of a "substituted" modifier, it refers to a chemical group defined as-NHR, where R is a substituted acyl group, as defined above for the term. Chemical group-NHC (O) OCH ₃And NHC (O) NHCH₃Are non-limiting examples of substituted amide groups.

The term "alkylimino", when used without the modifier "substituted", meansThe chemical group NR, where alkylimino is linked by one σ -bond and one pi-bond, where R is alkyl, as defined above for this term. Non-limiting examples of alkylimino groups include: as NCH₃、＝NCH₂CH₃And ═ N-cyclohexyl. The term "substituted alkylimino" refers to a chemical group, NR, in which alkylimino groups are linked by one sigma-and one pi-bond, where R is substituted alkyl, as defined above for the term. E.g., ═ NCH₂CF₃Is a substituted alkylimino group.

Similarly, the terms "alkenylimino", "alkynylimino", "arylimino", "aralkylimino", "heteroarylimino", "heteroaralkylimino", and "acylimino", when used without the "substituted" modifier, refer to a chemical group defined as NR, wherein the alkylimino group is connected by one σ -bond and one pi-bond, wherein R is alkenyl, alkynyl, aryl, aralkyl, heteroaryl, heteroaralkyl, and acyl, respectively, as defined above for those terms. When any of the terms alkenylimino, alkynylimino, arylimino, aralkylimino, and acylimino is modified by "substituted," it refers to the chemical group ═ NR where the alkylimino groups are connected by one sigma-and one pi-bond, where R is the substituted alkenyl, alkynyl, aryl, aralkyl, heteroaryl, heteroaralkyl, and acyl group, respectively.

The term "fluoroalkyl", when used without the "substitution" modifier, refers to an alkyl group, as defined above for the term, in which one or more fluorine has been replaced with hydrogen. Chemical group-CH₂F、-CF₃and-CH₂CF₃Are non-limiting examples of fluoroalkyl groups. The term "substituted fluoroalkyl" refers to a non-aromatic monovalent radical having a saturated carbon atom as the point of attachment, having a linear or branched, cyclic or acyclic structure, at least one fluorine atom, no carbon-carbon double or triple bonds, and at least one atom independently selected from the group consisting of N, O, Cl, Br, I, Si, P, and S. The following chemical groups are non-limiting examples of substituted fluoroalkyl groups: -CFHOH。

The term "alkylphosphoryl", when used without the modifier "substituted", refers to the chemical group-OP (O) (OH) (OR) wherein R is alkyl, as defined above for that term. Non-limiting examples of alkyl phosphate groups include: (O) OP (O), (OH) (OMe) and (O) (OH) (OEt). The term "substituted alkylphosphoryl group" refers to the chemical group-OP (O) (OH) (OR) wherein R is substituted alkyl, as defined above for the term.

The term "dialkylphosphate", when used without the "substituted" modifier, refers to the chemical group-op (o), (OR) (OR '), wherein R and R ' may be the same OR different alkyl groups, OR R and R ' taken together appear as an alkanediyl group having two OR more saturated carbon atoms, wherein at least two saturated carbon atoms are attached to the phosphorus atom through an oxygen atom. Non-limiting examples of dialkylphosphate groups include: -OP (O) (OMe) ₂OP (O) (OEt) (OMe) and OP (O) (OEt)₂. The term "substituted dialkylphosphate group" refers to the chemical group-OP (O) (OR '), where R and R' may be the same OR different substituted alkyl groups, one of R OR R 'is an alkyl group and the other is a substituted alkyl group, OR R and R' taken together represent a substituted alkanediyl group having two OR more saturated carbon atoms, at least two of which are connected to the phosphorus atom through an oxygen atom.

The term "alkylthio", when used without the "substituted" modifier, refers to the chemical group-SR, wherein R is alkyl, as defined above for the term. Non-limiting examples of alkylthio groups include: -SCH₃、-SCH₂CH₃、-SCH₂CH₂CH₃、-SCH(CH₃)₂、-SCH(CH₂)₂-S-cyclopentyl and-S-cyclohexyl. The term "substituted alkylthio" refers to the chemical group-SR, where R is substituted alkyl, as defined above for the term. For example, -SCH₂CF₃Is a substituted alkylthio group.

Similarly, the terms "alkenylthio", "alkynylthio", "arylthio", "aralkylthio", "heteroarylthio", "heteroarylalkylthio", and "acylthio", when used without the "substituted" modifier, refer to a chemical group defined as-SR, wherein R is independently alkenyl, alkynyl, aryl, aralkyl, heteroaryl, heteroaralkyl, and acyl, as defined above for those terms. When any of the terms alkenylthio, alkynylthio, arylthio, aralkylthio, heteroarylthio, heteroaralkylthio, and acylthio is modified by "substitution," it refers to the chemical group-SR, wherein R is substituted alkenyl, alkynyl, aryl, aralkyl, heteroaryl, heteroaralkyl, and acyl, respectively.

The term "thioacyl", when used without the "substituted" modifier, refers to a monovalent radical having the carbon atom of the thiocarbonyl group as the point of attachment, and also having a linear or branched, cyclic or acyclic structure, with no additional atoms other than carbon or hydrogen other than the carbonyl sulfide atom. Chemical group-CHS, -C (S) CH₃、-C(S)CH₂CH₃、-C(S)CH₂CH₂CH₃、-C(S)CH(CH₃)₂、-C(S)CH(CH₂)₂、-C(S)C₆H₅、-C(S)C₆H₄CH₃、-C(S)C₆H₄CH₂CH₃、-C(S)C₆H₃(CH₃)₂and-C (S) CH₂C₆H₅Are non-limiting examples of thioacyl groups. The term "thioacyl" thus includes, but is not limited to, chemical groups that are often referred to as "alkylthiocarbonyl" and "arylthiocarbonyl". The term "substituted thioacyl" refers to a radical having as a point of attachment a carbon atom that is part of a thiocarbonyl group, and also having a linear or branched, cyclic or acyclic structure, and, in addition to a carbonylthio atom, at least one atom independently selected from the group consisting of N, O, F, Cl, Br, I, Si, P, and S. Chemical group-C (S) CH₂CF₃、-C(S)O₂H、-C(S)OCH₃、-C(S)OCH₂CH₃、-C(S)OCH₂CH₂CH₃、-C(S)OC₆H₅、-C(S)OCH(CH₃)₂、-C(S)OCH(CH₂)₂、-C(S)NH₂and-C (S) NHCH₃Are non-limiting examples of substituted thioacyl groups. The term "substituted thioacyl" includes, but is not limited to, "heteroarylthiocarbonyl".

The term "alkylsulfonyl", when used without the modifier "substituted", refers to the chemical group-S (O) ₂R, wherein R is alkyl, as defined above for the term. Non-limiting examples of alkylsulfonyl groups include: -S (O)₂CH₃、-S(O)₂CH₂CH₃、-S(O)₂CH₂CH₂CH₃、-S(O)₂CH(CH₃)₂、-S(O)₂CH(CH₂)₂、-S(O)₂-cyclopentyl and-S (O)₂-cyclohexyl. The term "substituted alkylsulfonyl" refers to the chemical group-S (O)₂R, wherein R is substituted alkyl, as defined above for the term. For example, -S (O)₂CH₂CF₃Is a substituted alkylsulfonyl group.

Similarly, the terms "alkenylsulfonyl", "alkynylsulfonyl", "arylsulfonyl", "aralkylsulfonyl", "heteroarylsulfonyl", and "heteroaralkylsulfonyl", when used without the "substituted" modifier, refer to the substituents defined as-S (O)₂Chemical groups of R, wherein R is independently alkenyl, alkynyl, aryl, aralkyl, heteroaryl, and heteroaralkyl, as defined above for those terms. When any of the terms alkenylsulfonyl, alkynylsulfonyl, arylsulfonyl, aralkylsulfonyl, heteroarylsulfonyl and heteroaralkylsulfonyl is modified by "substitution", it refers to the chemical group-S (O)₂R, wherein R is independently substituted alkenyl, alkynyl, aryl, aralkyl, heteroaryl, and heteroaralkyl.

The term "alkylsulfinyl", when used without the "substituted" modifier, refers to the chemical group-s (o) R, where R is alkyl, as defined above for that term. Non-limiting examples of alkylsulfinyl groups include: -S (O) CH ₃、-S(O)CH₂CH₃、-S(O)CH₂CH₂CH₃、-S(O)CH(CH₃)₂、-S(O)CH(CH₂)₂-S (O) -cyclopentyl and-S (O) -cyclohexyl. The term "substituted alkylsulfinyl" refers to the chemical group-s (o) R, where R is substituted alkyl, as defined above for the term. For example, -S (O) CH₂CF₃Is a substituted alkylsulfinyl group.

Similarly, the terms "alkenylsulfinyl", "alkynylsulfinyl", "arylsulfinyl", "aralkylsulfinyl", "heteroarylsulfinyl", and "heteroaralkylsulfinyl", when used without the "substituted" modifier, refer to a chemical group defined as-s (o) R, wherein R is independently alkenyl, alkynyl, aryl, aralkyl, heteroaryl, and heteroaralkyl, as defined above for those terms. When any of the terms alkenylsulfinyl, alkynylsulfinyl, arylsulfinyl, aralkylsulfinyl, heteroarylsulfinyl, and heteroaralkylsulfinyl is modified by "substitution", it refers to the chemical group-s (o) R, where R is the substituted alkenyl, alkynyl, aryl, aralkyl, heteroaryl, and heteroaralkyl group, respectively.

The term "alkylammonium," when used without the modifier "substituted," is defined as-NH₂R⁺、-NHRR′⁺or-NRR' R⁺Wherein R, R 'and R "are the same or different alkyl groups, or any combination of any two of R, R' and R" taken together appear as an alkanediyl group. Non-limiting examples of alkylammonium cations include: -NH ₂(CH₃)⁺、-NH₂(CH₂CH₃)+、-NH₂(CH₂CH₂CH₃)+、-NH(CH₃)₂ ⁺、-NH(CH₂CH₃)₂ ⁺、-NH(CH₂CH₂CH₃)₂ ⁺、-N(CH₃)₃ ⁺、-N(CH₃)(CH₂CH₃)₂ ⁺、-N(CH₃)₂(CH₂CH₃)⁺、-NH₂C(CH₃)₃ ⁺-NH (cyclopentyl)₂ ⁺and-NH₂(cyclohexyl group)⁺. The term "substituted alkylammonium" refers to-NH₂R⁺、-NHRR′⁺or-NRR' R⁺Wherein at least one of R, R 'and R' is a substituted alkyl group or two of R, R 'and R' taken together are present as a substituted alkanediyl group. When more than one of R, R 'and R' are substituted alkyl, they may be the same or different. Any of R, R 'and R' which are neither substituted alkyl nor substituted alkanediyl are either alkyl groups, either the same or different, or taken together are alkanediyl having two or more carbon atoms wherein at least two carbon atoms are attached to the nitrogen atom shown in the formula.

The term "alkylsulfonium", when used without the modifier "substituted", refers to the chemical group-SRR'⁺Wherein R and R 'may be the same or different alkyl groups, or R and R' taken together may represent an alkanediyl group. Non-limiting examples of alkyl sulfonium groups include: -SH (CH)₃)⁺、-SH(CH₂CH₃)⁺、-SH(CH₂CH₂CH₃)⁺、-S(CH₃)₂ ⁺、-S(CH₂CH₃)₂ ⁺、-S(CH₂CH₂CH₃)₂ ⁺-SH (cyclopentyl)⁺and-SH (cyclohexyl)⁺. The term "substituted alkylsulfonium" refers to the chemical group-SRR'⁺Wherein R and R ' may be the same or different substituted alkyl groups, one of R or R ' is an alkyl group and the other is a substituted alkyl group, or R and R ' taken together are present as a substituted alkanediyl group. For example, -SH (CH) ₂CF₃)⁺Is a substituted alkyl sulfonium group.

The term "alkylsilyl", when used without the "substituted" modifier, means defined as-SiH₂A monovalent radical of R, -SiHRR ' or-SiRR ' R ', where R, R ' and R ' may be the same or different alkyl groups,or R, R 'and R' taken together in any combination appear as alkanediyl. Chemical group-SiH₂CH₃、-SiH(CH₃)₂、-Si(CH₃)₃and-Si (CH)₃)₂C(CH₃)₃Non-limiting examples of unsubstituted alkylsilyl groups. The term "substituted alkylsilyl" refers to-SiH₂R, -SiHRR ' or-SiRR ' R ', wherein at least one of R, R ' and R ' is a substituted alkyl or two of R, R ' and R ' taken together are present as a substituted alkanediyl group. When more than one of R, R 'and R' are substituted alkyl, they may be the same or different. Any of the chemical groups R, R' and R ", which are neither substituted alkyl nor substituted alkanediyl, may be alkyl, either the same or different, or taken together appear as alkanediyl having two or more saturated carbon atoms wherein at least two carbon atoms are attached to a silicon atom.

Further, the atoms comprising the compounds of the present invention are intended to include all isotopic forms of such atoms. Isotopes, as used herein, include those atoms having the same number of atoms but different mass numbers. By way of general example and not limitation, isotopes of hydrogen include tritium and deuterium, and isotopes of carbon include ¹³C and¹⁴C. similarly, it is contemplated that one or more of the carbon atoms of the compounds of the present invention may be replaced by one or more silicon atoms. Furthermore, it is contemplated that one or more of the oxygen atoms of the compounds of the present invention may be replaced by one or more sulfur or selenium atoms.

Compounds having a formula represented by a dashed chemical bond are intended to include chemical formulas that optionally have zero, one, or multiple double bonds. Thus, for example, the structureComprises a structureAnd

as will be understood by those skilled in the art, none of such ring atoms form part of more than one double bond.

Any undefined valency on a structural atom shown in this application implicitly represents a hydrogen atom bonded to the atom.

Showing a ring structure with an unconnected "R" group indicates that any implied hydrogen atom on the ring may be substituted with an R group. In the case of a divalent R group (e.g., oxo, imino, thio, alkylene, etc.), any pair of implied hydrogen atoms attached to one atom of the ring may be substituted with the R group. This concept is exemplified as follows:representsOr

As used herein, "chiral auxiliary" refers to a removable chiral chemical group capable of affecting the stereoselectivity of a reaction. Those skilled in the art are familiar with such compounds, and many such compounds are commercially available.

The words "a" or "an" when used in conjunction with the term "comprising" in the claims and/or the specification mean "a", but they also have the meaning "one or more", "at least one" and "one or more".

Throughout this application, the term "about" is used to refer to a value that includes variations in the inherent error of the instrument, the method used to determine the value, or variations that exist in the study subject.

The terms "comprising," "having," and "including" are open-ended linking verbs. Any form or tense of one or more of these verbs, such as "comprising," "including," "having," "including," and "including," is open-ended. For example, any method that "comprises," "has," or "has" one or more steps is not limited to possessing only those one or more steps, and also encompasses other unlisted steps.

The term "effective" as used in the specification and/or claims means sufficient to achieve a desired, expected, or expected result.

The term "hydrate" when used as a modifier of a compound means that the compound has less than one (e.g., hemihydrate), one (e.g., monohydrate), or more than one (e.g., dihydrate) water molecule associated with each chemical molecule, e.g., the compound in solid form.

As used herein, the term "IC₅₀"refers to the amount of inhibitor that achieves 50% of maximal response.

An "isomer" of a first compound is a separate compound in which each molecule contains the same constituent atoms as the first compound, but the atoms are in different positions in three-dimensional space.

As used herein, the term "patient" or "subject" refers to a living mammalian organism, such as a human, monkey, cow, sheep, goat, dog, cat, mouse, rat, guinea pig, or transgenic species thereof. In certain embodiments, the patient or subject is a primate. Non-limiting examples of human subjects are adults, adolescents, infants and fetuses.

By "pharmaceutically acceptable" it is meant that it is useful in preparing pharmaceutical compositions that are generally safe, non-toxic, biologically and otherwise undesirable, and include those acceptable for veterinary use as well as human pharmaceutical use.

By "pharmaceutically acceptable salt" is meant a salt of a compound of the invention as defined above which is pharmaceutically acceptable and which has the desired pharmacological activity. Such salts include acid addition salts formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid and the like; or with organic acids such as 1, 2-ethanedisulfonic acid, 2-hydroxyethanesulfonic acid, 2-naphthalenesulfonic acid, 3-phenylpropionic acid, 4' -methylenebis (3-hydroxy-2-ene-1-carboxylic acid), 4-methylbicyclo [2.2.2] oct-2-ene-1-carboxylic acid, acetic acid, aliphatic monocarboxylic and dicarboxylic acids, aliphatic sulfuric acid, aromatic sulfuric acid, benzenesulfonic acid, benzoic acid, camphorsulfonic acid, carbonic acid, cinnamic acid, citric acid, cyclopentylpropionic acid, ethanesulfonic acid, fumaric acid, glucoheptonic acid, gluconic acid, glutamic acid, glycolic acid, heptanoic acid, hexanoic acid, hydroxynaphthoic acid, lactic acid, dodecylsulfuric acid, maleic acid, malic acid, malonic acid, mandelic acid, methanesulfonic acid, muconic acid, o- (4-hydroxybenzoyl) benzoic acid, Oxalic acid, p-chlorobenzenesulfonic acid, phenyl-substituted alkanoic acid, propionic acid, p-methylbenzenesulfonic acid, pyruvic acid, salicylic acid, stearic acid, succinic acid, tartaric acid, t-butylacetic acid, trimethylacetic acid, and the like. Pharmaceutically acceptable salts also include base addition salts, which may be formed when a protic acid is present which is capable of reacting with an inorganic or organic base. Acceptable inorganic bases include sodium hydroxide, sodium carbonate, potassium hydroxide, aluminum hydroxide, and calcium hydroxide. Acceptable organic bases include ethanolamine, diethanolamine, triethanolamine, tromethamine, N-methylglucamine, and the like. It will be appreciated that the particular anion or cation forming part of any salt of the invention is not critical, so long as the salt as a whole is pharmaceutically acceptable. Additional examples of pharmaceutically acceptable Salts and methods of making and using the same are found in the Handbook of Pharmaceutical Salts: properties, and Use (P.H.Stahl and C.G.Wermuth eds., Verlag Helvetica Chimica Acta, 2002).

As used herein, "predominantly one enantiomer" means that the compound contains at least about 85% of one enantiomer, or more preferably at least about 90% of one enantiomer, or even more preferably at least about 95% of one enantiomer, or most preferably at least about 99% of one enantiomer. Similarly, the phrase "substantially free of other optical isomers" means that the composition comprises at most about 15% of another enantiomer or diastereomer, more preferably at most about 10% of the other enantiomer or diastereomer, even more preferably at most about 5% of the other enantiomer or diastereomer, and most preferably at most about 1% of the other enantiomer or diastereomer.

"preventing" or "preventing" includes: (1) inhibiting the onset of disease in a subject or patient at risk for and/or susceptible to disease but not yet experiencing or exhibiting any or all of the pathology or symptomology of disease, and/or (2) slowing the onset of disease pathology or symptomology in a subject or patient at risk for and/or susceptible to disease but not yet experiencing or exhibiting any or all of the pathology or symptomology of disease.

By "prodrug" is meant a compound that is metabolically converted in vivo to an inhibitor of the invention. The prodrug itself may or may not also have activity against a particular target protein. For example, a compound containing a hydroxyl group may be administered as an ester, which is converted to a hydroxyl compound in vivo by hydrolysis. Suitable esters that can be converted in vivo to hydroxy compounds include acetate, citrate, lactate, phosphate, tartrate, malonate, oxalate, salicylate, propionate, succinate, fumarate, maleate, methylene-bis- β -hydroxynaphthoate, cholate, isethionate, di-p-methylbenzoyl tartrate, mesylate, ethanesulfonate, benzenesulfonate, p-toluenesulfonate, cyclohexylsulfamate, quinic acid ester, amino acid ester, and the like. Similarly, compounds containing amine groups may be administered as amides that are converted to amine compounds by hydrolysis in vivo.

The term "saturated" when referring to an atom means that the atom is attached to other atoms only by single bonds.

"stereoisomers" or "optical isomers" are isomers of a given compound in which the same atom is bonded to the same other atom, but those atoms are not in the same configuration in three-dimensional space. "enantiomers" are stereoisomers of a given compound that are mirror images of each other, as are left and right handed. "diastereomer" is a stereoisomer of a given compound that is not an enantiomer.

The present invention contemplates that, for any chiral stereocenter or axis for which stereochemistry is not yet defined, the chiral stereocenter or axis may exist in its R form, S form, or as a mixture of R and S forms, including racemic and non-racemic mixtures.

By "substituent converted to hydrogen in vivo" is meant any chemical group that is converted to a hydrogen atom by enzymatic or chemical means, including but not limited to hydrolysis and hydrogenolysis. Examples include hydrolyzable chemical groups such as acyl groups, chemical groups having oxycarbonyl groups, amino acid residues, peptide residues, o-nitrophenylthio groups, trimethylsilyl groups, tetrahydropyranyl groups, diphenylphosphinyl groups (phosphinyl groups), and the like. Examples of acyl groups include formyl, acetyl, trifluoroacetyl, and the like. Examples of chemical groups having an oxycarbonyl group include ethoxycarbonyl, t-butoxycarbonyl (-C (O) OC (CH) ₃)₃) Benzyloxycarbonyl, p-methoxybenzyloxycarbonyl, vinyloxycarbonyl, β - (p-methylbenzenesulfonyl) ethoxycarbonyl, and the like. Suitable amino acid residues include, but are not limited to, Gly (glycine), Ala (alanine), Arg (arginine), Asn (asparagine), Asp (aspartic acid), Cys (cysteine), Glu (glutamic acid), His (histidine), Ile (isoleucine), Leu (leucine), Lys (lysine), Met (methionine), Phe (phenylalanine), Pro (proline), Ser (serine), Thr (threonine), Trp (tryptophan), Tyr (tyrosine), Val (valine), Nva (norvaline), Hse (homoserine), 4-Hyp (4-hydroxyproline), 5-Hyl (5-hydroxylysine), Orn (ornithine), and β -Ala residues. Examples of suitable amino acid residues also include amino acid residues protected with a protecting group. Examples of suitable protecting groups include those typically employed in peptide synthesis, including acyl groups (e.g., formyl and acetyl), arylmethyloxycarbonyl groups (e.g., benzyloxycarbonyl and p-nitrobenzyloxycarbonyl), t-butyloxycarbonyl (-C (O) OC (CH)₃)₃) And so on. Is suitable forThe peptide residue of (a) includes peptide residues comprising 2 to 5 and optionally amino acid residues. The residues of these amino acids or peptides may exist in stereochemical configuration in D-form, L-form or mixtures thereof. Furthermore, the amino acid or peptide residue may have asymmetric carbon atoms. Examples of suitable amino acid residues having asymmetric carbon atoms include Ala, Leu, Phe, Trp, Nva, Val, Met, Ser, Lys, Thr and Tyr residues. Examples of peptide residues having asymmetric carbon atoms include peptide residues having one or more constituent amino acid residues containing asymmetric carbon atoms. Examples of suitable amino acid protecting groups include those typically employed in peptide synthesis, including acyl groups (e.g., formyl and acetyl), arylmethyloxycarbonyl groups (e.g., benzyloxycarbonyl and p-nitrobenzyloxycarbonyl), t-butyloxycarbonyl (-C (O) OC (CH) ₃)₃) And so on. Other examples of substituents "converted to hydrogen in vivo" include reductively eliminable hydrogenolyzable chemical groups. Suitable examples of reductively eliminable hydrogenolyzable chemical groups include, but are not limited to, arylsulfonyl groups (e.g., o-toluenesulfonyl); methyl substituted with phenyl or benzyloxy (e.g., benzyl, trityl, and benzyloxymethyl); arylmethoxycarbonyl (e.g., benzyloxycarbonyl and o-methoxybenzyloxycarbonyl); and haloethoxycarbonyl groups such as β, β, β -trichloroethoxycarbonyl and β -iodoethoxycarbonyl).

By "therapeutically effective amount" or "pharmaceutically effective amount" is meant an amount sufficient to effect such treatment of a disease when administered to a subject or patient for the purpose of treating the disease.

"treating" or "treatment" includes (1) inhibiting a disease in a subject or patient experiencing or exhibiting a disease pathology or syndrome (e.g., arresting further development of the pathology and/or syndrome), (2) ameliorating a disease in a subject or patient experiencing or exhibiting a disease pathology or syndrome (e.g., reversing the pathology and/or syndrome), and/or (3) causing measurable regression of a disease in a subject or patient experiencing or exhibiting a disease pathology or syndrome.

As used herein, the term "water soluble" means that the compound is dissolved in water to the extent of at least 0.010 moles/liter or classified as soluble according to literature knowledge.

Other abbreviations used herein are as follows: DMSO, dimethyl sulfoxide; NO, nitric oxide; iNOS, inducible nitric oxide synthase; COX-2, cyclooxygenase-2; NGF, nerve growth factor; IBMX, isobutylmethylxanthine; FBS, peptide bovine serum; GPDH, glycerol 3-phosphate dehydrogenase; RXR, retinoid X receptor; TGF- β, transforming growth factor- β; IFN gamma or IFN-gamma, interferon-gamma; LPS, bacterial endotoxin lipopolysaccharide; TNF α or TNF- α, tumor necrosis factor- α; IL-1 β, interleukin-1 β; GAPDH, glyceraldehyde-3-phosphate dehydrogenase; MTT, 3- [4, 5-dimethylthiazol-2-yl ] -2, 5-diphenyltetrazolium bromide; TCA, trichloroacetic acid; HO-1, inducible heme oxygenase.

The above definitions supersede any conflicting definition in any reference incorporated herein by reference. However, the fact that certain terms are defined should not be understood to imply that any of the undefined terms are ambiguous. Rather, it is to be understood that all terms used are intended to describe the invention under such conditions as would be understood by one of ordinary skill in the art to which the invention pertains and which is in practice.

Synthesis Process

The compounds of the present disclosure can be made using the methods generally described in scheme 1 and/or the examples section (examples 2 and 3) below. These methods can be further modified and optimized using organic chemistry principles and techniques as applied by those skilled in the art. Such principles and techniques are described, for example, in March's Advanced organic chemistry: reactions, Mechanisms, and Structure (2007), which is incorporated herein by reference.

Biological Activity of Oleanolic acid derivatives

The disclosed compounds have been tested for: inhibition of NO production, induction of iNOS, induction of Nrf2 target genes, inhibition of COX-2 induction, inhibition of STAT3 phosphorylation, suppression of IL-6 induced phosphorylation, inhibition of TNF α -induced IkappaB α degradation, inhibition of NF κ B activation, induction of HO-1, induction of TrxR1, induction of γ -GCS, and/or induction of ferritin heavy chains. Some experimental results are shown in the figure and in table 1 below. Additional experimental details are provided in example 1.

Table 1: biological activity

Empty item: no measurement was made.

BLD: below the detection limit.

^*Data are expressed as fold induction over DMSO control.

Diseases associated with inflammation and/or oxidative stress

Inflammation is a biological process that provides protection against infectious or parasitic organisms and repairs damaged tissues. Inflammation is generally characterized by local vasodilation, redness, swelling, and pain, recruitment of leukocytes to the site of infection or injury, production of inflammatory cytokines such as TNF- α and IL-1, and production of reactive oxygen or nitrogen clusters, such as hydrogen peroxide, superoxide, and peroxynitrite. In the later stages of inflammation, tissue remodeling, angiogenesis and scarring (fibrosis) may occur as part of the wound healing process. Under normal circumstances, the inflammatory response is regulatory and transient, and subsides in a coordinated fashion once the infection or injury has been adequately treated. However, if the regulatory mechanisms fail, acute inflammation can become severe and life threatening. Alternatively, inflammation can become chronic and lead to cumulative tissue damage or systemic complications.

Many serious and intractable human diseases involve dysregulation of inflammatory processes, including diseases such as cancer, atherosclerosis and diabetes, which are not conventionally considered inflammatory diseases. In the case of cancer, the inflammatory process is associated with tumor formation, progression, metastasis and resistance to treatment. Atherosclerosis, which has long been regarded as a disorder of lipid metabolism, is now understood to be primarily an inflammatory disease in which activated macrophages play an important role in the formation and eventual rupture of atherosclerotic plaques. Activation of inflammatory signaling pathways has also been shown to play a role in the development of insulin resistance and in peripheral tissue damage associated with diabetic hyperglycemia. Overproduction of reactive oxygen and nitrogen clusters such as superoxide, hydrogen peroxide, nitric oxide and peroxynitrite is a hallmark of inflammatory diseases. Evidence of deregulated peroxynitrite production has been reported in a wide variety of diseases (Szabo et al, 2007; Schulz et al, 2008; Forstermann, 2006; Pall, 2007).

Autoimmune diseases such as rheumatoid arthritis, lupus, psoriasis and multiple sclerosis involve inappropriate and chronic activation of inflammatory processes in affected tissues, resulting from dysfunction of self-to non-self recognition and response mechanisms in the immune system. In neurodegenerative diseases such as alzheimer's disease and parkinson's disease, nerve damage is associated with activation of microglia and increased levels of proinflammatory proteins such as Inducible Nitric Oxide Synthase (iNOS). Chronic organ failure, such as renal failure, heart failure and chronic obstructive pulmonary disease, is closely associated with the presence of chronic oxidative stress and inflammation, which leads to the development of fibrosis and ultimately the loss of organ function.

Many other conditions involve oxidative stress and inflammation in affected tissues, including inflammatory bowel disease; inflammatory skin diseases; mucositis associated with radiation therapy and chemotherapy; eye diseases such as uveitis, glaucoma, macular degeneration, and various forms of retinopathy; graft failure and rejection; ischemia-reperfusion injury; chronic pain; degenerative diseases of bones and joints, including osteoarthritis and osteoporosis; asthma and cystic fibrosis; epilepsy; and neuropsychiatric disorders including schizophrenia, depression, bipolar disorder, post-traumatic stress disorder, attention deficit disorder, autism spectrum disorder, and eating disorders such as anorexia nervosa. Dysregulation of inflammatory signaling pathways is believed to be a major factor in muscle wasting diseases, including muscular dystrophy and the pathology of various forms of cachexia.

A variety of life-threatening acute conditions are also involved in dysregulated inflammatory signaling, including acute organ failure involving the pancreas, kidneys, liver or lungs, myocardial infarction or acute coronary syndrome, stroke, septic shock, trauma, severe burns and anaphylaxis.

Many complications of infectious diseases also involve dysregulation of the inflammatory response. While the inflammatory response can kill invading pathogens, a severe inflammatory response can also be completely destructive and in some cases can be a major source of damage in infected tissue. In addition, severe inflammatory responses can lead to systemic complications due to the overproduction of inflammatory cytokines such as TNF- α and IL-1. It is believed that this is a cause of death due to severe influenza, severe acute respiratory syndrome, and sepsis.

Aberrant or overexpression of either iNOS or the cyclooxygenase-2 (COX-2) enzyme has been implicated in the pathogenesis of a number of diseases. For example, it has been shown that NO is a potent mutagen (Tamir and Tannebaum, 1996), and that nitric oxide can also activate COX-2(Salvemini et al, 1994). Furthermore, iNOS is significantly increased in large intestine colon tumors induced by the carcinogen azoxymethane (Takahashi et al, 1997). A series of synthetic oleanolic acid triterpenoid analogs have been shown to be potent inhibitors of cellular inflammatory processes, such as the induction of Inducible Nitric Oxide Synthase (iNOS) and COX-2 by IFN-. gamma.in mouse macrophages. See Honda et al (2000 a); honda et al (2000b), and Honda et al (2002), all of which are incorporated herein by reference.

In one aspect, the compounds of the invention are characterized by their inhibitory ability to the induction of nitric oxide production in macrophage-derived RAW 264.7 cells by gamma-interferon. They are further characterized by their ability to induce the expression of antioxidant proteins such as NQO1 and to reduce the expression of pro-inflammatory proteins such as COX-2 and Inducible Nitric Oxide Synthase (iNOS). These properties are associated with the treatment of a wide range of diseases involving disturbances of oxidative stress and inflammatory processes, including cancer, mucositis from radiotherapy or chemotherapy, autoimmune diseases, cardiovascular diseases including atherosclerosis, ischemia-reperfusion injury, acute and chronic organ failure including renal failure and heart failure, respiratory diseases, diabetes and diabetic complications, severe allergies, transplant rejection, graft-versus-host disease, neurodegenerative diseases, eye and retinal diseases, acute and chronic pain, degenerative bone diseases including osteoarthritis and osteoporosis, inflammatory bowel disease, dermatitis and other skin diseases, sepsis, burns, epilepsy and neuropsychiatric disorders.

Without wishing to be bound by theory, activation of the antioxidant/anti-inflammatory Keap1/Nrf2/ARE pathway is believed to be related to both the anti-inflammatory and anti-carcinogenic properties of the oleanolic acid derivatives of the present invention.

In another aspect, the compounds of the invention may be used to treat a subject suffering from a disease caused by an elevated level of oxidative stress in one or more tissues. Oxidative stress results from abnormally high or sustained long levels of reactive oxygen species such as superoxide, hydrogen peroxide, nitric oxide and peroxynitrite (formed by the nitric oxide and superoxide reactions). Oxidative stress may be accompanied by acute or chronic inflammation. Oxidative stress can be caused by mitochondrial dysfunction, activation of immune cells such as macrophages and neutrophils, acute exposure to external agents such as ionizing radiation or cytotoxic chemotherapeutic agents (e.g., doxorubicin), trauma or other acute tissue injury, ischemia/reperfusion, poor circulation or anemia, local or systemic hypoxia or hyperoxia, elevated levels of inflammatory cytokines and other inflammation-related proteins, and/or other abnormal physiological states such as hyperglycemia or hypoglycemia.

In many animal models of such diseases, stimulation of Nrf2 pathway target genes has been shown to induce the expression of heme oxygenase (HO-1) with significant therapeutic effects, including formally diverse myocardial infarction, renal failure, graft failure and rejection, stroke, cardiovascular disease, and autoimmune disease (e.g., Sacerdoti et al, 2005; Abraham and Kappas, 2005; Bach, 2006; arajo et al, 2003; Liu et al, 2006; Ishikawa et al, 2001; Kruger et al, 2006; Satoh et al, 2006; Zhou et al, 2005; Morse and Choi, 2002). This enzyme breaks down free heme into iron, carbon monoxide (CO) and biliverdin, which is subsequently converted into the potent antioxidant molecule bilirubin.

In another aspect, the compounds of the present invention may be used for the prevention or treatment of acute and chronic tissue injury or organ failure caused by oxidative stress exacerbated by inflammation. Examples of diseases in this class include: heart failure, liver failure, graft failure and rejection, renal failure, pancreatitis, fibrotic lung diseases (especially cystic fibrosis and COPD), diabetes (including complications), atherosclerosis, ischemia-reperfusion injury, glaucoma, stroke, autoimmune diseases, autism, macular degeneration, and muscular dystrophy. For example, in the case of autism, studies have shown that increased oxidative stress in the central nervous system contributes to disease progression (Chauhan and Chauhan, 2006).

Evidence also links oxidative stress and inflammation to the development and pathology of many other disorders of the central nervous system, including neuropathies such as psychosis, major depression, and bipolar disorder; epilepsy such as epilepsy; pain and sensory syndromes such as migraine, neuropathic pain or tinnitus; and behavioral syndromes such as attention deficit disorder. See, e.g., Dickerson et al, 2007; hanson et al, 2005; kendall-tatkett, 2007; lencz et al, 2007; dudhgaonkar et al, 2006; lee et al, 2007; morris et al, 2002; ruster et al, 2005; McIver et al, 2005; sarchielli et al, 2006; kawakami et al, 2006; ross et al, 2003, which are incorporated herein by reference in their entirety. For example, elevated levels of inflammatory cytokines, including TNF, interferon-gamma and IL-6, are associated with most psychological disorders (Dickerson et al, 2007). Microglial activation is also associated with most psychological disorders. Therefore, down-regulation of inflammatory cytokines and inhibition of excessive activation of microglia would be beneficial to patients with schizophrenia, major depression, bipolar disorder, autism spectrum disorder, and other neuropsychiatric conditions.

Thus, in pathologies involving only oxidative stress or oxidative stress exacerbated by inflammation, treatment may comprise administering to the subject a therapeutically effective amount of a compound of the invention, such as those described above or throughout this specification. The treatment may be administered prophylactically in advance at a predictable oxidative stress state (e.g., organ transplantation or radiation therapy to a cancer patient), or it may be administered therapeutically in situations involving established oxidative stress and inflammation.

The compounds of the present invention may be used in general for the treatment of inflammatory diseases such as sepsis, dermatitis, autoimmune diseases and osteoarthritis. In one aspect, the compounds of the invention may be used to treat inflammatory pain and/or neuropathic pain, for example, by inducing Nrf2 and/or inhibiting NF- κ B.

In one aspect, the compounds of the present invention may function as Antioxidant Inflammation Modulators (AIMs) with potent anti-inflammatory properties that mimic the biological activity of cyclopentenone prostaglandins (cypgs). In one embodiment, the compounds of the invention may be used to control the production of pro-inflammatory cytokines by selectively targeting Regulatory Cysteine Residues (RCRs) on proteins that regulate the transcriptional activity of reduction-oxidation sensitive transcription factors. It has been demonstrated that activation of RCR by cyPG or AIM initiates a pro-resolution procedure in which the activities of antioxidant and cytoprotective transcription factor Nrf2 are effectively induced and the activities of pro-oxidant and pro-inflammatory transcription factors NF-. kappa.B and STAT are suppressed. This increases the production of antioxidant and reducing molecules (e.g., NQO1, HO-1, SOD1, and/or γ -GCS) and/or decreases the production of oxidative stress and pro-oxidant and pro-inflammatory molecules (e.g., iNOS, COX-2, and/or TNF- α).

In some embodiments, the compounds of the invention may be used in the treatment and prevention of diseases such as cancer, inflammation, alzheimer's disease, parkinson's disease, multiple sclerosis, autism, amyotrophic lateral sclerosis, autoimmune diseases such as rheumatoid arthritis, lupus and MS, inflammatory bowel disease, all other diseases whose pathogenesis is believed to involve overproduction of any one of nitric oxide or prostaglandins, and pathologies involving oxidative stress alone or exacerbated by inflammation.

Another aspect of inflammation is the production of inflammatory prostaglandins such as prostaglandin E. These molecules promote vasodilation, plasma extravasation, local pain, elevated temperature and other symptoms of inflammation. The enzyme COX-2 in its inducible form is associated with their production and high levels of COX-2 are found in inflamed tissues. Thus, inhibition of COX-2 can alleviate many symptoms of inflammation and many important anti-inflammatory drugs (e.g., ibuprofen and celecoxib) act by inhibiting COX-2 activity. However, recent studies have shown that a class of cyclopentenone prostaglandins (cypgs) (e.g., 15-deoxy prostaglandin J2, also known as PGJ2) play a role in stimulating the resolution of a coordinated fashion of inflammation (e.g., Rajakariar et al, 2007). COX-2 is also associated with the production of cyclopentenone prostaglandins. Thus, inhibition of COX-2 will interfere with complete resolution of inflammation, potentially promoting sustained retention of activated immune cells in the tissue and leading to chronic "stasis" inflammation. This result has led to an increased incidence of cardiovascular disease in patients who have been administered selective COX-2 inhibitors over a prolonged period of time.

In one aspect, the compounds of the invention are useful for controlling the production of proinflammatory cytokines in a cell by selectively activating Regulatory Cysteine Residues (RCRs) on proteins that modulate the activity of redox-sensitive transcription factors. It has been shown that activation of RCR by cyPG initiates a pro-resolution procedure in which the activities of antioxidant and cytoprotective transcription factor Nrf2 are effectively induced and the activities of pro-oxidant and pro-inflammatory transcription factors NF-. kappa.B and STAT are suppressed. In some embodiments, this increases the production of antioxidants and reducing molecules (NQO1, HO-1, SOD1, γ -GCS) and decreases the production of oxidative stress and pro-oxidant and pro-inflammatory molecules (iNOS, COX-2, TNF- α). In some embodiments, the compounds of the invention will restore cells in an inflammatory event to a non-inflammatory state by promoting resolution of inflammation and limiting excessive tissue damage to the host.

A. Cancer treatment

In addition, the compounds of the present disclosure may be used to induce tumor cell apoptosis, induce cell differentiation, inhibit cancer cell proliferation, inhibit inflammatory responses, and/or play a role in chemopreventive capacity. For example, the present invention provides novel compounds having one or more of the following properties: (1) the ability to induce apoptosis and differentiation in malignant and non-malignant cells, (2) activity as inhibitors of proliferation in many malignant or pre-malignant cells at submicromolar or nanomolar levels, (3) the ability to suppress de novo synthesis of inflammatory enzymes Inducible Nitric Oxide Synthase (iNOS), (4) the ability to inhibit activation of NF- κ B, and (5) the ability to induce expression of heme oxygenase-1 (HO-1).

Levels of iNOS and COX-2 are elevated in certain cancers and have been implicated in carcinogenesis, and COX-2 inhibitors have been shown to reduce the incidence of primary colon adenomas in humans (Rostom et al, 2007; Brown and DuBois, 2005; Crowlel et al, 2003). iNOS is expressed in Myeloid Derived Suppressor Cells (MDSC) (Angulo et al, 2000), and COX-2 activity in cancer cells has been shown to result in prostaglandin E₂(PGE₂) Has demonstrated production of prostaglandin E₂Arginase expression was induced in MDSCs (Sinha et al, 2007). Arginase and iNOS are enzymes that utilize L-arginine as a substrate and produce L-ornithine and urea and L-citrulline and NO, respectively. Arginine depletion from the tumor microenvironment by MDSC has been demonstrated with NO and peroxygenThe production of nitrite in combination inhibits the proliferation and induces apoptosis in T cells (Bronte et al, 2003). Inhibition of COX-2 and iNOS has been shown to reduce MDSC accumulation, restore cytotoxic activity of tumor-associated T cells, and delay tumor growth (Sinha et al, 2007; Mazzoni et al, 2002; Zhou et al, 2007).

Inhibition of NF-. kappa.B and JAK/STAT signaling pathways has been implicated as a strategy for inhibiting proliferation and inducing apoptosis in cancer epithelial cells. Activation of STAT3 and NF-. kappa.B has been shown to lead to suppression of apoptosis in cancer cells, and promotion of proliferation, invasion, and metastasis. Many target genes involved in these processes have been shown to be transcriptionally regulated by NF-. kappa.B and STAT3 (Yu et al, 2007).

In addition to their direct role in cancer epithelial cells, NF- κ B and STAT3 also play important roles in other cells present in the tumor microenvironment. Experiments in animal models have demonstrated that NF-. kappa.B is required in both cancer and hematopoietic cells to transmit the effects of inflammation on cancer initiation and progression (Greten et al, 2004). Inhibition of NF-. kappa.B in cancer and myeloid cells reduces the number and size of tumors formed, respectively. Activation of STAT3 in cancer cells results in the production of several cytokines (IL-6, IL-10), which suppresses the maturation of tumor-associated Dendritic Cells (DCs). In addition, STAT3 is activated by these cytokines within the dendritic cells themselves. STAT3 inhibition restores DC maturation, promotes anti-tumor immunity, and inhibits tumor growth in a mouse cancer model (Kortylewski et al, 2005).

B. Treatment of multiple sclerosis and other neurodegenerative diseases

The compounds and methods of the invention may be used to treat Multiple Sclerosis (MS) patients. MS is known to be an inflammatory disorder of the central nervous system (Williams et al, 1994; Merrill and Benvenist, 1996; Genain and Nauser, 1997). Based on several studies, there is evidence to suggest that inflammatory, oxidative and/or immunological mechanisms are involved in the pathogenesis of Alzheimer's Disease (AD), Parkinson's Disease (PD), Amyotrophic Lateral Sclerosis (ALS) and MS (Bagasra et al, 1995; McGeer and McGeer, 1995; Simonian and Coyle, 1996; Kaltschmidt et al, 1997). Both activated astrocytes and activated microglia are involved in causing neurodegenerative diseases (NDD) and neuroinflammatory diseases (NID); here, a particularly potent microglia is one that synthesizes both NO and prostaglandin, which are the products of the respective iNOS and COX-2 enzymes. De novo formation of these enzymes may be driven by inflammatory cytokines such as interferon-gamma or interleukin-1. In turn, overproduction of NO can lead to inflammatory cascades and/or oxidative damage in cells and tissues of many organs, including neurons and oligodendrocytes of the nervous system, with consequent manifestations of AD and MS, and possibly PD and ALS (Coyle and Putffarcken, 1993; Beal, 1996; Merrill and Benvenist, 1996; Simonia and Coyle, 1996; Vodovotz et al, 1996). Epidemiological data suggest that chronic use of NSAIDs, which block the synthesis of prostaglandins from arachidonic acid, significantly reduces the risk of developing AD (McGeer et al, 1996; Stewart et al, 1997). Thus, agents that block the formation of NO and prostaglandins may be used in methods of preventing and treating NDD. The ability to cross the blood-brain barrier is typically required for successful therapeutic candidates for the treatment of this disease. See, e.g., U.S. patent publication No. 2009/0060873, which is incorporated by reference herein in its entirety.

C. Inflammation of nerve

The compounds and methods of the invention may be used to treat patients suffering from neuroinflammation. Neuroinflammation is a generalization of the concept that the responses and actions of microglia and astrocytes in the central nervous system have essentially inflammation-like characteristics, and these responses are central to the pathogenesis and progression of a wide variety of neurological disorders. This concept originates from the field of Alzheimer's disease (Griffin et al, 1989; Rogers et al, 1988), where it revolutionized our understanding of the disease (Akiyama et al, 2000). These concepts have been extended to other neurodegenerative diseases (Eikelenboom et al, 2002; Ishizawa and Dickson, 2001), ischemic/toxic diseases (Gehrmann et al, 1995; Touzani et al, 1999), tumor biology (Graeber et al, 2002) and even normal brain development.

Neuroinflammation incorporates a broad spectrum of complex cellular responses including activation of microglia and astrocytes and induction of cytokines, chemokines, complement proteins, acute phase proteins, oxidative damage and related molecular processes. These events will have a deleterious effect on neuronal function, leading to neuronal damage, further to glial activation, and ultimately to neurodegeneration.

D. Treatment of renal failure

The compounds and methods of the present invention can be used to treat patients with renal failure. See U.S. patent application 12/352,473, which is incorporated herein by reference in its entirety. Another aspect of the present disclosure relates to novel methods and compounds for the treatment and prevention of renal disease. Renal failure, which results from inadequate clearance of metabolic wastes in the blood and abnormal electrolyte concentrations in the blood, is an important medical problem worldwide, especially in developed countries. Diabetes and hypertension are among the most important causes of chronic renal failure, also known as Chronic Kidney Disease (CKD), but are also associated with other diseases such as lupus. Acute renal failure can result from contact with certain drugs (e.g., acetaminophen) or toxic chemicals, or from ischemia-reperfusion injury associated with shock or surgery, such as transplantation, and can lead to chronic renal failure. In many patients, renal failure can progress to a stage where the patient requires routine dialysis or kidney transplantation to sustain life. These processes are both highly invasive and associated with significant side effects and quality of life issues. Although effective treatments exist for some of the complications of renal failure, such as hyperparathyroidism and hyperphosphatemia, there is no available method to stop or reverse the underlying progression of renal failure. Thus, agents that can improve compromised kidney function would represent a significant advance in the treatment of renal failure.

Inflammation contributes significantly to the pathology of CKD. There is also a mechanistic link between oxidative stress and renal dysfunction. The NF-. kappa.B signaling pathway plays an important role in the progression of CKD, because NF-. kappa.B regulates the transcription of MCP-1, a chemokine responsible for recruiting monocytes/macrophages to cause an inflammatory response and ultimately damage the kidney (Wardle, 2001). The Keap1/Nrf2/ARE pathway controls transcription of several genes encoding antioxidant enzymes, including heme oxygenase-1 (HO-1). Excision of the Nrf2 gene in female mice resulted in the development of lupus-like glomerulonephritis (Yoh et al, 2001). Furthermore, several studies have demonstrated that HO-1 expression is induced in response to renal injury and inflammation and that the enzyme and its products bilirubin and carbon monoxide play a protective role in the kidney (Nath et al, 2006).

The glomerulus and the surrounding Bowman's capsule constitute the basic functional unit of the kidney. Glomerular Filtration Rate (GFR) is a standard measure of kidney function. Creatinine clearance is commonly used to measure GFR. However, serum creatinine levels are often used as a surrogate measure of creatinine clearance. For example, excessive levels of serum creatinine are generally recognized as indicative of insufficient kidney function, and a decrease in serum creatinine over time is recognized as indicative of improved kidney function. Normal levels of creatinine in the blood are about 0.6 to 1.2 milligrams (mg) per deciliter (dl) in adult males and 0.5 to 1.1 milligrams per deciliter in adult females.

Acute Kidney Injury (AKI) can occur following ischemia-reperfusion, following treatment with certain pharmaceutical agents such as cisplatin and rapamycin, and following intravenous injection of radiocontrast agents for medical imaging. As in CKD, inflammation and oxidative stress contribute to the pathology of AKI. The molecular mechanism of radiocontrast induced nephropathy (RCN) is not well understood; however, it is likely that the combination of events including prolonged vasoconstriction, impaired renal self-regulation and direct contrast agent toxicity all contribute to renal failure (Tumlin et al, 2006). Vasoconstriction results in reduced renal blood flow and produces ischemia-reperfusion and the production of reactive oxygen species. HO-1 is strongly induced in these conditions and strong induction of HO-1 has been demonstrated to prevent ischemia-reperfusion injury in several different organs, including the kidney (Nath et al, 2006). In particular, the induction of HO-1 has been shown to be protective in a rat model of RCN (Goodman et al, 2007). Reperfusion also causes an inflammatory response, in part through activation of NF- κ B signaling (Nichols, 2004). Targeting NF- κ B has been proposed as a therapeutic strategy to prevent organ damage (Zingarelli et al, 2003).

E. Cardiovascular diseases

The compounds and methods of the invention may be used to treat patients suffering from cardiovascular disease. See U.S. patent application 12/352,473, which is incorporated herein by reference in its entirety. Cardiovascular (CV) disease is the leading cause of death worldwide, and in many developed countries the leading cause of death. The etiology of CV disease is complex, but most causes are associated with inadequate or complete disruption of blood supply to critical organs or tissues. Such diseases often result from the rupture of one or more atherosclerotic plaques, which leads to the formation of a thrombus that blocks blood flow in critical blood vessels. Such thrombosis is a major cause of heart attack in which one or more coronary arteries are occluded and blood flow to the heart itself is interrupted. The resulting ischemia highly damages cardiac tissue due to both hypoxia during the ischemic event and excessive formation of free radicals from after restoration of blood flow (a phenomenon known as ischemia-reperfusion injury). Similar damage occurs in the brain during thrombotic stroke when cerebral arteries or other major blood vessels become occluded by thrombosis. In contrast, hemorrhagic stroke involves the rupture of blood vessels and the influx of blood into the surrounding brain tissue. This can result in oxidative stress in the immediate area of bleeding due to the presence of large amounts of free heme and other active species and other ischemia of other parts of the brain due to impaired blood flow. Subarachnoid hemorrhage, often accompanied by cerebral vasospasm, also leads to ischemia/reperfusion injury in the brain.

Alternatively, atherosclerosis is so extensive in critical blood vessels that it develops into stenosis (narrowing of the artery) and blood flow to critical organs, including the heart, is chronically inadequate. Such chronic ischemia can result in many types of end organ damage, including cardiac hypertrophy associated with congestive heart failure.

When physical defects or damage to the inner layer of the artery (endothelium) trigger an inflammatory response, including proliferation of vascular smooth muscle and infiltration of leukocytes into the affected area, a potential defect occurs leading to atherosclerosis in various forms of cardiovascular disease. Eventually, a complicated lesion called atherosclerotic plaque may form, consisting of the above cells in combination with deposits of cholesterol-carrying lipoproteins and other substances (e.g., Hansson et al, 2006).

Drug treatment of cardiovascular disease includes prophylactic treatment, such as the use of drugs aimed at lowering blood pressure or circulating levels of cholesterol and lipoproteins, and treatment designed to reduce platelet and other blood cell attachment tendencies (and thus reduce platelet aggregation rate and thrombosis risk). More recently, drugs such as streptokinase and tissue plasminogen activator have been introduced and used to dissolve thrombi and restore blood flow. Surgical treatments include coronary artery bypass grafting to create an alternative blood supply, balloon angioplasty to compress plaque tissue and increase the diameter of the arterial lumen, and carotid endarterectomy to remove plaque tissue in the carotid artery. Such treatments, particularly balloon angioplasty, are accompanied by the use of stents, expandable mesh tubes designed to support the arterial wall of the affected area and maintain vessel patency. Recently, the use of drug eluting stents has become common to prevent post-operative restenosis (restenosis of the artery) in the affected area. These devices are metal stents overcoated with a biocompatible polymeric matrix containing a drug that inhibits cell proliferation (e.g., paclitaxel or rapamycin). The polymer allows for slow, localized release of the drug in the affected area, minimizing non-target tissue contact. Despite the obvious benefits of such treatments, mortality from cardiovascular disease remains high and clearly does not meet the needs of cardiovascular disease treatment.

As mentioned above, it has been demonstrated that the induction of HO-1 is beneficial in many cardiovascular disease models and that low levels of HO-1 expression are clinically relevant for high risk of CV disease. Thus, the compounds of the present invention may be used to treat or prevent a wide variety of cardiovascular diseases, including but not limited to atherosclerosis, hypertension, myocardial infarction, chronic heart failure, stroke, subarachnoid hemorrhage and restenosis.

F. Diabetes mellitus

The compounds and methods of the present invention may be used to treat patients suffering from diabetes. See U.S. patent application 12/352,473, which is incorporated herein by reference in its entirety. Diabetes mellitus is a complex disease characterized by the inability of the body to regulate circulating levels of glucose. This deficiency may result from insulin deficiency, a peptide hormone that regulates glucose production and absorption in a variety of tissues. Insulin deficiency impairs the ability of muscle, fat and other tissues to properly absorb glucose, resulting in hyperglycemia (abnormally high levels of glucose in the blood). Most often, such insulin deficiencies result from insufficient production of islet cells in the pancreas. In most cases, this results from autoimmune destruction of these cells, a disease known as type 1 or juvenile-onset diabetes, but may also be due to physical injury or other causes.

Diabetes also results when muscle and fat cells become poorly responsive to insulin and are unable to properly absorb glucose, resulting in hyperglycemia. This phenomenon is called insulin resistance, and the resulting disease is called type 2 diabetes. Type 2 diabetes is the most common type, which is highly associated with obesity and hypertension. Obesity is associated with the inflammatory state of adipose tissue, which is thought to play a major role in the development of insulin resistance (e.g., Hotamisigil, 2006; Guilherm et al, 2008).

Diabetes is associated with damage to many tissues, primarily because hyperglycemia (and hypoglycemia, which may result from excessive or poor timed doses of insulin) is a significant source of oxidative stress. The development of chronic renal failure, retinopathy, peripheral neuropathy, peripheral vasculitis, and slow or impossible skin ulcers is among the most common complications of diabetes. Due to their ability to resist oxidative stress, in particular by inducing the expression of HO-1, the compounds of the invention can be used for the treatment of various complications of diabetes. As mentioned above (Cai et al, 2005), chronic inflammation and oxidative stress in the liver are suspected to be the major causative factors in the development of type 2 diabetes. In addition, PPAR γ agonists such as thiazolinediones are capable of reducing insulin resistance and are known to be effective therapeutic agents for type 2 diabetes.

The therapeutic effect of diabetes can be evaluated as follows. Both the biological and, if possible, clinical efficacy of the treatment method is assessed. For example, since the disease manifests itself as an increase in blood glucose, the biological efficacy of the treatment can be assessed by, for example, observing the return of the assessed blood glucose to normal levels. Measurement of glycated hemoglobin, also known as A1c or HbA1c, is another commonly used parameter for blood glucose control. Measurement of the clinical endpoint, which may give an indication of b-cell regeneration after a period of, for example, 6-months, may give an indication of the clinical efficacy of the treatment regimen.

G. Rheumatoid arthritis

The compounds and methods of the invention may be used to treat patients suffering from RA. Typically, the initial symptoms of Rheumatoid Arthritis (RA) occur in the synovial lining, the initial symptoms being synovial fibroblast proliferation and their attachment to the articular surface of the articular margin (Lipsky, 1998). Macrophages, T cells and other inflammatory cells are subsequently recruited into the joint where they produce a variety of mediators, including the cytokine interleukin-1 (IL-1), which promotes chronic sequelae that lead to bone and cartilage destruction, and tumor necrosis factor (TNF-. alpha.), which plays a role in inflammation (Dinarello, 1998; Arend and Dayer, 1995; vanden Berg, 2001). Plasma IL-1 concentrations in patients with RA are significantly higher than in healthy individuals, and it is notable that plasma IL-1 levels are associated with RA disease activity (Eastgate et al, 1988). In addition, IL-1 levels in synovial fluid are associated with a variety of imaging and histological features of RA (Kahle et al, 1992; Rooney et al, 1990).

In normal joints, the actions of these and other proinflammatory cytokines are balanced by a variety of anti-inflammatory cytokines and regulators (Burger and Dayer, 1995). The significance of this cytokine balance is demonstrated in juvenile RA patients who clinically develop fever throughout the day (Prieur et al, 1987). After each peak of fever, factors that block the action of IL-1 are found in serum and urine. This factor has been isolated, cloned and identified as an IL-1 receptor antagonist (IL-1ra), which is a member of the IL-1 gene family (Hannum et al, 1990). As the name suggests, IL-1ra is a natural receptor antagonist that competes with IL-1 for binding to type 1 IL-1 receptors, and as a result blocks the action of IL-1 (Arend et al, 1998). To effectively block IL-1 action, a 10 to 100-fold excess of IL-1ra is required; however, synovial cells isolated from RA patients do not appear to produce sufficient amounts of IL-1RA to counteract the effects of IL-1 (Firestein et al, 1994; Fujikawa et al, 1995).

H. Psoriatic arthritis

The compounds and methods of the present invention may be used to treat patients with psoriatic arthritis. Psoriasis is an inflammatory and proliferative skin disease with an incidence of 1.5-3%. Approximately 20% of psoriatic patients develop a characteristic form of arthritis with several patterns (Gladman, 1992; Jones et al, 1994; Gladman et al, 1995). Some individuals present joint symptoms first, but most individuals present skin psoriasis first. Approximately one third of patients have a simultaneous exacerbation of skin and joint disease (Gladman et al, 1987), and there is an anatomical correlation between nail and distal interphalangeal arthropathy (Jones et al, 1994; Wright, 1956). Although the inflammatory process that links skin, nail and joint diseases has not yet been elucidated, immune-mediated pathologies are involved.

Psoriatic arthritis (PsA) is a chronic inflammatory joint disease characterized by a combination of arthritis and psoriasis, and was recognized in 1964 as a clinical disease distinct from Rheumatoid Arthritis (RA) (Blumberg et al, 1964). Subsequent studies have revealed that PsA shares many genetic, pathological and clinical features with other spondyloarthropathies (SpA), a group of diseases that includes ankylosing spondylitis, reactive arthritis and enteropathic arthritis (Wright, 1979). The idea that PsA belongs to the group of SpA was recently further supported from imaging studies that showed that generalized osteomyelitis is present in PsA but not in RA (McGonagle et al, 1999; McGonagle et al, 1998). More specifically, osteosynthesis has been postulated to be one of the earliest events occurring in SpA, leading to bone remodeling and joint stiffness in the spine, and arthromeningitis when inflamed bone sites are close to peripheral joints. However, the link between osteosynthesis and clinical presentation of PsA remains unclear, since PsA exists as a rather heterogeneous pattern of joint involvement with varying degrees of severity (Marsal et al, 1999; Salvarani et al, 1998). Therefore, other factors must be added to account for the wide variety of characteristics of PsA, only a few of which (e.g. the expression of the HLA-B27 molecule, which is highly associated with axial axis disease) are identified. As a result, it remains difficult to delineate disease signatures for specific pathogenic mechanisms, which means that treatment of the disease remains largely empirical.

Family studies have shown that genetic factors contribute to the development of PsA (Moll and Wright, 1973). Other chronic inflammatory arthritis, such as ankylosing spondylitis and rheumatoid arthritis, are considered to have a complex genetic basis. However, it is difficult to assess the genetic composition of PsA for a number of reasons. There is strong evidence that the genetic predisposition of psoriasis alone would mask genetic factors important for PsA development. Although most will receive PsA as a different disease, sometimes the phenotype overlaps with rheumatoid arthritis and ankylosing spondylitis. Likewise, PsA is not a single disease by itself and multiple subtypes have been proposed.

Increased amounts of TNF- α have been reported in psoriatic skin (Ettehadi et al, 1994) and synovial fluid (Partsch et al, 1997). Recent trials have shown that anti-TNF treatment has positive benefits in PsA (Mease et al, 2000) and ankylosing spondylitis (Brandt et al, 2000).

I. Reactive arthritis

The compounds and methods of the invention may be used to treat patients suffering from reactive arthritis. In reactive arthritis (ReA), the mechanism of joint damage is unclear, but it is likely that cytokines play a key role. A more general Th1 profile has been reported with high levels of interferon gamma (IFN-. gamma.) and low levels of interleukin 4(IL-4) (Lahesmaa et al, 1992; Schlaak et al, 1992; Simon et al, 1993; Schlaak et al, 1996; Kotake et al, 1999; Ribbens et al, 2000), but several studies have shown that IL-4 and IL-10 are relatively predominant and IFN-. gamma.and tumor necrosis factor alpha (TNF-. alpha.) are relatively deficient in synovium (Simon et al, 1994; Yin et al, 1999) and Synovial Fluid (SF) (Yin et al, 1999; Yin et al, 1997) in reactive arthritis patients compared to Rheumatoid Arthritis (RA) patients. It has also been reported that TNF- α secretion levels in reactive arthritis are lower than in RA patients following ex vivo stimulation of Peripheral Blood Mononuclear Cells (PBMC) (Braun et al, 1999).

It has been discussed that clearance of reactive arthritis-associated bacteria requires the production of appropriate levels of IFN- γ and TNF- α, and that IL-10 acts by suppressing these reactions (Autenieth et al, 1994; Sieper and Braun, 1995). IL-10 is a regulatory cytokine that inhibits the synthesis of IL-12 and TNF- γ by activated macrophages (de Waal et al, 1991; Hart et al, 1995; Chomarat et al, 1995) and the synthesis of IFN- γ by T cells (Macatonia et al, 1993).

J. Enteropathy arthritis

The compounds and methods of the present invention may be used to treat patients with enteropathic arthritis. Typically intestinal inflammatory arthritis (EA) occurs in combination with Inflammatory Bowel Disease (IBD) such as crohn's disease or ulcerative colitis. It also affects the spine and sacroiliac joints. Enteropathic arthritis involves peripheral joints, usually in the lower extremities such as the knee and ankle. It usually involves only a few or a limited number of joints and is closely associated with the bowel disease. This occurs in approximately 11% of patients with ulcerative colitis and 21% of patients with crohn's disease. Synovitis is usually self-limiting and non-deforming.

Enteropathic arthropathy comprises a group of rheumatic diseases that share a link to GI pathology. These diseases include reactive (i.e. infection-related) arthritis and Inflammatory Bowel Disease (IBD) associated spondyloarthropathies due to bacteria (e.g. Shigella (Shigella), Salmonella (Salmonella), Campylobacter (Campylobacter), Yersinia (Yersinia) species, Clostridium difficile), parasites (e.g. Strongyloides stercoralis, Taenia bovis (Taenia sanguinata), Giardia lamblia (Giardia lamblia), ascariasis (Ascaris lumbricoides), Cryptosporidium species). Other diseases and conditions include intestinal bypass surgery (jejunum ileum), arthritis, celiac disease, Whipple's disease, and collagenous colitis.

K. Juvenile rheumatoid arthritis

The compounds and methods of the invention can be used to treat JRA patients. Juvenile Rheumatoid Arthritis (JRA), the most prevalent form of arthritis in children, is a term applied to a family of diseases characterized by chronic inflammation and hypertrophy of the synovium. The term overlaps with, but is not fully synonymous with, a family of diseases referred to in europe as juvenile chronic arthritis and/or juvenile idiopathic arthritis.

Both the innate and adaptive immune systems use a diverse array of cell types, a large array of cell surface and secreted proteins, and an interconnected network of positive and negative feedback (Lo et al, 1999). Furthermore, when the innate and adaptive parts of the immune system are considered to be separable, they are functionally separated from each other (Fearon and Locksley, 1996), and the pathological events present at these intersections may be highly correlated with our understanding of the pathogenesis of adult and childhood forms of chronic arthritis (Warrington et al, 2001).

Polyarticular JRA is a distinct clinical subtype characterized by inflammation and synovial proliferation in multiple joints (four or more), including in the small joints of the hand (Jarvis, 2002). This subtype of JRA can be severe because of its involvement in multiple joints and its ability to progress rapidly over time. Although clinically different, polyarticular JRA is not uniform and patients vary in disease manifestation, age of onset, prognosis and treatment response. These differences are likely to reflect a series of variations in the immune nature and inflammatory attack that can occur in the disease (Jarvis, 1998).

Early inflammatory arthritis

The compounds and methods of the present invention may be used to treat patients with early stage inflammatory arthritis. The clinical manifestations of different inflammatory arthropathies are similar in the early stages of the disease process. As a result, it is often difficult to distinguish patients who are at risk of developing severity and persistent synovitis leading to erosive joint damage from patients who are more self-limiting with respect to their arthritis. Such differentiation is crucial in order to properly target therapy, aggressively treat patients with aggressive disease and avoid unnecessary toxicity in patients with more self-limiting disease. Current clinical criteria for diagnosing erosive arthropathies, such as Rheumatoid Arthritis (RA), are poorly effective in early stages of disease, and traditional markers of disease activity, such as joint count and acute phase response, do not adequately identify patients who may have a poor prognosis (Harrison et al, 1998). The parameter that reflects the presence of a pathological event in the synovium is most likely a meaningful prognostic value.

Recent work on identifying poor prognostic predictors of early inflammatory arthritis identified the presence of RA-specific autoantibodies, in particular, the antibody anti-citrullinated peptide, associated with aggressive and persistent disease in early inflammatory arthritis-type diseases. Based on this, Cyclic Citrullinated Peptide (CCP) has been developed to help identify anti-CCP antibodies in patient sera. Using this approach, the presence of anti-CCP antibodies has been demonstrated to be RA-specific and sensitive, can distinguish RA from other arthropathies, and can predict persistent, erosive synovitis before their prognosis becomes clinically manifest. Importantly, anti-CCP antibodies in serum are often detectable in many years before clinical symptoms appear, suggesting that they may reflect subclinical immune events (Nielen et al, 2004; Rantapaa-Dahlqvist et al, 2003).

Ankylosing spondylitis

The compounds and methods of the present invention may be used to treat patients with ankylosing spondylitis. AS is a subgroup of diseases within the broader disease category of spondyloarthropathies. Patients affected by multiple subgroups of spondyloarthropathies have disease etiologies in that they are often very diverse, ranging from bacterial infection to genetics. However, in all subgroups, the end result of the disease process is axial arthritis. Although early clinical differences were observed in different patient populations, many of them end up with nearly identical performance after a 10-20 year course. Recent studies have shown that the mean time from onset of ankylosing spondylitis disease to clinical diagnosis is 7.5 years (Khan, 1998). These same studies indicate that spondyloarthropathy can approach the incidence of rheumatoid arthritis (Feldtkeller et al, 2003; Doran et al, 2003).

AS is a chronic systemic inflammatory rheumatic disease with or without extraosseous manifestations of the axial skeleton. The main waist involves the sacroiliac joint and the spine, but also involves the hip and shoulder joints, and is generally less involved in peripheral joints or certain extra-articular structures, such as the eye, vasculature, nervous system, and gastrointestinal system. The etiology is not fully understood (Wordsworth, 1995; Calin and Taurog, 1998). It is highly associated with the major histocompatibility class I (MHC I) HLA-B27 allele (Calin and Taurog, 1998). AS affects the prime stages of an individual's life and is terrorist because it potentially causes chronic pain and irreversible damage to tendons, ligaments, joints and bones (Brewerton et al, 1973 a; Brewerton et al, 1973 b; Schlosstein et al, 1973). AS may occur alone or in combination with another form of spondyloarthropathy such AS reactive arthritis, psoriasis, psoriatic arthritis, osteoarthritis, ulcerative colitis, irritable bowel disease or crohn's disease, in which case it is classified AS secondary AS.

Representatively, affected sites include discoverterbral joints of the spine, apophyseal joints, costovertebral and costal joints, and paraspinal ligament structures. Inflammation of the bone-knitting sites where tendons and ligaments attach to bone is also prominent in this disease (cain and Taurog, 1998). Bone site sites are known to be infiltrated by plasma cells, lymphocytes and polymorphonuclear cells. The inflammatory process often results in progressive fibrous and bony arthritic stiffness (Ball, 1971; Khan, 1990).

Diagnosis is often delayed because symptoms often present more of the more common background problems. An acute loss of lumbar flexibility is an early predictor of AS. Other common symptoms include chronic pain and stiffness in the waist, which often begins at the site where the lower spine is connected to the pelvis or hip. Although most symptoms begin in the lumbar and sacroiliac regions, they also involve the neck and upper back. Arthritis can also occur in the shoulders, hips and feet. Some patients have ocular inflammation and more severe patients must observe involvement of the heart valve.

The most frequent manifestation is back pain, but the disease can typically begin in peripheral joints, especially in middle-aged children and women, and rarely has acute iritis (anterior uveitis). Additional early symptoms and signs are reduced, i.e. chest fullness, low fever, fatigue, anorexia, weight loss and anemia due to diffuse rib vertebral involvement. Recurrent back pain, which is often nocturnal back pain and back pain of varying intensity, is the ultimate complaint of the disease, as morning stiffness is typically relieved by activity. A bent or bent posture relieves back pain and paraspinal muscle spasm; some degree of kyphosis is therefore common in untreated patients.

Systemic symptoms appeared in 1/3 patients. Recurrent acute iritis (anterior uveitis), which is usually self-limiting, is rarely prolonged and rarely severe enough to impair vision. Occasionally, neurological signs arise from crushed radiculitis or sciatica, spinal fractures or subluxation, and cauda equina complex (which includes impotence, nocturnal urinary incontinence, decreased bladder and rectal sensation, and lack of ankle reflexes). Cardiovascular manifestations may include aortic valve insufficiency, angina, pericarditis, and ECG conduction abnormalities. A rare finding in the lung is upper lobe fibrosis, occasionally with cavities that may be mistaken for TB and may be involved in aspergillus infection.

AS is characterized by a mild or moderately active onset of spondylitis that alternates with periods of inflammation that are nearly or completely inactive. Proper treatment in most patients results in minimal or no disability and can lead to a full life despite back stiffness. Occasionally, the course of the disease is severe and progressive, resulting in significant disability. The prognosis of patients with refractory iritis and rare patients with secondary amyloidosis is tragic.

Ulcerative colitis

The compounds and methods of the invention can be used to treat patients with ulcerative colitis. Ulcerative colitis is a disease that causes inflammation within the large intestine and sores called ulcers. Inflammation often occurs in the rectum and lower colon, but it can affect the entire colon. Ulcerative colitis affects the small intestine very little in addition to the terminal portion of the small intestine called the terminal ileum. Ulcerative colitis may also be referred to as colitis or proctitis. Inflammation often empties the colon, resulting in diarrhea. Ulceration where inflammation kills cells in the lining of the colon; ulcers lead to bleeding and suppuration.

Ulcerative colitis is an Inflammatory Bowel Disease (IBD), a common name for diseases that cause inflammation in the small intestine and colon. Ulcerative colitis is difficult to diagnose because its symptoms are similar to other bowel diseases and another type of IBD, crohn's disease. Crohn's disease differs from ulcerative colitis in that it causes deeper inflammation within the intestinal wall. Also, crohn's disease often occurs in the small intestine, although it may also occur in the mouth, esophagus, stomach, duodenum, large intestine, caecum and anus.

Ulcerative colitis may occur in people of any age, but most commonly occurs between the ages of 15 and 30, or less between the ages of 50 and 70. Sometimes children and adolescents develop the disease. Ulcerative colitis affects men and women equally and appears to occur in families. The theories as to what causes ulcerative colitis are numerous, but none have been demonstrated. The most prevalent theory is that the body's immune system reacts with viruses or bacteria through a persistent inflammatory reaction within the intestinal wall. The immune system of humans with ulcerative colitis is abnormal, but physicians are unaware of whether these abnormalities are the cause or the outcome of the disease. Ulcerative colitis is not caused by emotional distress or sensitivity to certain foods or food products, but these factors can trigger symptoms in some people.

The most common symptoms of ulcerative colitis are abdominal pain and bloody diarrhea. Patients also experience fatigue, weight loss, loss of appetite, rectal bleeding, and loss of body fluids and nutrients. About half of the patients had mild symptoms. Other patients are often with fever, bloody diarrhea, nausea and severe abdominal cramps. Ulcerative colitis may also cause problems such as arthritis, ocular inflammation, liver disease (hepatitis, cirrhosis and primary sclerosing cholangitis), osteoporosis, skin rashes and anemia. No one knows exactly why the problem occurs outside the colon. Scientists believe that these complications occur when the immune system triggers inflammation in other parts of the body. Some of these problems disappear when colitis is treated.

Diagnosis of ulcerative colitis requires a thorough physical examination and a series of tests. Blood tests can be performed to check for anemia, which would indicate bleeding in the colon or rectum. Blood tests may also reveal high white blood cell counts, which are indicative of inflammation present somewhere in the body. By examining the stool sample, the physician can detect bleeding or infection in the colon or rectum. The physician may perform a colonoscopy or sigmoidoscopy. For either test, the physician will insert an endoscope, a long, flexible, lighted tube connected to a computer and TV monitor, into the anus to view the interior of the colon and rectum. Any inflammation, bleeding or ulceration on the colon wall will have been observed. During the examination, the physician will perform a biopsy, which involves removing a tissue sample from the inner layer of the colon for microscopic observation. Barium enema x-ray examination of the colon may also be required. The method involves filling the colon with barium, a white powder solution. Barium appears white on x-ray film, which allows the physician to clearly visualize the colon, including any ulcers or other abnormalities that may be present.

Treatment of ulcerative colitis depends on the severity of the disease. Most people are treated with drugs. In severe cases, the patient will require surgery to remove the diseased colon. For ulcerative colitis, surgery is the only treatment. Some people, whose symptoms are triggered by certain foods, can control the condition by avoiding the sugars (lactose) in foods that cause bowel disorders, such as irritating foods, raw fruits and vegetables, or milk. Each one experiences ulcerative colitis will be different and therefore the treatment needs to be adjusted for each individual. Emotional and psychological support is important. Some people will relieve, i.e. the phase when symptoms disappear, which lasts for months or years. However, symptoms eventually recur in most patients. This changing pattern of disease means that people often cannot tell when treatment is helpful. Some patients with ulcerative colitis sometimes require medical care, with doctors regularly visiting to detect the condition.

Crohn's disease

The compounds and methods of the invention may be used to treat patients with crohn's disease. Another condition for which immunosuppression has been attempted is crohn's disease. Symptoms of crohn's disease include intestinal inflammation and intestinal stenosis and development of intestinal fistulas; neuropathy is often accompanied by these symptoms. Anti-inflammatory drugs such as 5-aminosalicylates (e.g. mesalazine) or corticosteroids are representative prescription drugs, but they are not often effective (reviewed in Botoman et al, 1998). Immunosuppression with cyclosporine is sometimes beneficial for patients resistant or intolerant to corticosteroids (Brynskov et al, 1989).

Efforts to develop diagnostic and therapeutic tools for Crohn's disease have focused on the central role of cytokines (Schreiber, 1998; van Hogezand and Verspagent, 1998). Cytokines are small secreted proteins or factors (5 to 20kD) that have specific effects on cell-cell interactions, cell-cell communication or other cellular behaviors. The cytokines being derived from lymphocytes, particularly T_H1 and T_H2 lymphocytes, monocytes, intestinal macrophages, granulocytes, epithelial cells and fibroblasts (reviewed in Rogler and Andus, 1998; Galley and Webster, 1996). Some cytokines are pro-inflammatory (e.g., TNF- α, IL-1(α and β), IL-6, IL-8, IL-12 or leukemia inhibitory factor [ LIF ]]) (ii) a Others are anti-inflammatory (e.g. IL-1 receptor antagonists, IL-4, IL-10, IL)-11 and TGF- β). However, there are overlaps and functional repeats in certain inflammatory diseases.

In the case of activation of Crohn's disease, the concentration of TNF-alpha and IL-6 secreted into the blood circulation is increased, and mucosal cells overproduce TNF-alpha, IL-1, IL-6 and IL-8 locally (supra; Funakoshi et al, 1998). These cytokines can have a wide range of effects on physiological systems including bone development, hematopoiesis and liver, thyroid and neuropsychiatric functions. Also, an imbalance in the IL-1 β/IL-1ra ratio of pro-inflammatory IL-1 β predominance has been observed in Crohn's disease patients (Rogler and Andus, 1998; Saiki et al, 1998; Dionne et al, 1998; see Kuboyama, 1998). One study has shown that cytokine profiles in fecal samples would be a useful diagnostic tool for Crohn's disease (Saiki et al, 1998).

Treatments that have been proposed for Crohn's disease include the use of various cytokine antagonists (e.g., IL-1ra), inhibitors (e.g., inhibitors of IL-1. beta. converting enzyme and antioxidants), and anti-cytokine antibodies (Rogler and Andus, 1998; van Hogezand and Verspagent, 1998; Reimund et al, 1998; Lugering et al, 1998; McAllndon et al, 1998). In particular, monoclonal antibodies against TNF- α have met with some success in treating Crohn's disease (Targan et al, 1997; Stack et al, 1997; van Dullemen et al, 1995). These compounds may be used in combination therapy with the disclosed compounds.

Another approach to treating crohn's disease focuses on at least partially destroying the bacterial flora that will trigger the inflammatory response, and replacing it with a non-pathogenic flora. For example, U.S. Pat. No. 5,599,795 discloses methods for preventing and treating Crohn's disease in human patients. Their method involves sterilizing the intestinal tract with at least one antibiotic and at least one antifungal agent to kill the existing flora and replacing it with a different, selected, well characterized, bacteria obtained from normal humans. Borodys teaches a method of treating Crohn's disease by: the intestinal microflora present is at least partially removed by lavage and replaced by a new bacterial flora introduced either by fecal inoculum from a disease-free human donor or by a composition comprising Bacteroides (Bacteroides) and Escherichia coli (Escherichia coli) species (us patent 5,443,826).

P. systemic lupus erythematosus

The compounds and methods of the invention can be used to treat SLE patients. The cause of autoimmune diseases such as systemic lupus erythematosus is also unknown. Systemic Lupus Erythematosus (SLE) is an autoimmune rheumatic disease characterized by the deposition of immune antibodies and immune complexes in tissues, resulting in tissue damage (Kotzin, 1996). SLE may be directly involved in multiple organ systems and the clinical manifestations are diverse and variable compared to autoimmune diseases such as MS and type 1 diabetes (reviewed in Kotzin and O' Dell, 1995). For example, some patients develop primarily rashes and joint pain, exhibit spontaneous relief and require less medication. At the other end of the range of symptoms are patients with severe and progressive renal involvement, which require treatment with high doses of steroids and cytotoxic drugs such as cyclophosphamide (Kotzin, 1996).

Serological markers and the main diagnostic test available for SLE are elevated levels of IgG antibodies against nuclear components such as double stranded DNA (dsdna), single stranded DNA (ss-DNA) and chromatin. Among these autoantibodies, the anti-dsDNA antibody IgG plays a major role in the development of lupus glomerulonephritis (G N) (Hahn and Tsao, 1993; Ohnishi et al, 1994). Glomerulonephritis is a serious disease in which the blood of the kidney purifies the capillary walls of the glomeruli to become thickened due to proliferation of the glomerular basement membrane on the epithelial side. The disease is often chronic and progressive and eventually leads to renal failure.

Irritable bowel syndrome

The compounds and methods of the present invention may be used to treat Irritable Bowel Syndrome (IBS) patients. IBS is a functional disorder marked by abdominal pain and altered bowel habits. The syndrome may begin in young adults and may be associated with significant disability. The syndrome is not a single disorder. But rather as a subtype of IBS based on the main symptoms diarrhea, constipation or pain. In the absence of "warning" symptoms such as fever, weight loss, and gastrointestinal bleeding, limited disease detection is required. Once a diagnosis of IBS is made, the overall treatment is effective in reducing the severity of the symptoms. IBS is a common disease, although its prevalence varies. Generally speaking, IBS affects about 15% of american adults and is often about 3-fold more frequent in women than in men (Jailwala et al, 2000).

IBS results in between 240 and 350 million visits per year. Not only are the most common diseases seen by gastroenterologists, but also the most common gastrointestinal diseases seen by primary care physicians (Everhart et al, 1991; Sandler, 1990).

IBS is also a costly disease. People with IBS lose 3 times the working day and are more likely to report a failure to work due to the disease than people without bowel symptoms (Drossman et al, 1993; Drossman et al, 1997). In addition, those with IBS cost hundreds of dollars in medical costs over those without bowel disorder (Talley et al, 1995).

The absence of specific abnormalities explains the exacerbation and elimination of abdominal pain and the altered bowel habits experienced by IBS patients. The evolutionary theory of IBS suggests that there are disorders at multiple levels of the brain-gut axis. Dyskinesia, visceral hypersensitivity, abnormal regulation of the Central Nervous System (CNS) and infections are all involved. In addition, psychological factors play an important role in modification. Abnormal bowel movement has long been considered to be a factor in the pathogenesis of IBS. The transit time of the diet through the small intestine has been shown to be shorter in patients with diarrhea predominant IBS than in patients with constipation or pain predominant subtypes (Cann et al, 1983).

Both discontinuous, cluster and prolonged disseminated contractions have been reported in IBS patients in studies of the small intestine during fasting (Kellow and Phillips, 1987). They also experience pain with irregular contractions more frequently than healthy people (Kellow and Phillips, 1987; Horwitz and Fisher, 2001).

These motor findings do not account for the entire syndrome in IBS patients; in fact, most of these patients have no demonstrable abnormalities (Rothstein, 2000). IBS patients have increased sensitivity to visceral pain. Studies involving rectosigmoid sac distension have shown that IBS patients experience pain and bloating at much lower pressures and volumes than control subjects (Whitehead et al, 1990). These patients maintain normal perception of physical stimuli.

Several theories have been proposed to explain this phenomenon. For example, receptors in the gut may increase sensitivity in response to expansion or the contents of the lumen. Neurons in the dorsal horn of the spinal cord may have increased excitability. In addition, alterations in CNS sensory processes may be involved (Drossman et al, 1997). Recent functional magnetic resonance imaging studies have demonstrated that IBS patients increase activation of the anterior cingulate cortex in response to painful rectal stimulation compared to control subjects (Mertz et al, 2000).

Gradually, there is evidence of a correlation between infectious enteritis and later IBS development. Inflammatory cytokines play a role. In a survey of patients with a defined history of bacterial gastroenteritis (Neal et al, 1997), a persistent change in intestinal faecal cells was reported in 25% of patients. The persistence of symptoms results from psychological stress at the time of acute infection (Gwee et al, 1999).

Recent data indicate that bacterial overgrowth in the small intestine can play a role in IBS symptoms. In one study (Pimentel et al, 2000), 157 of the 202 IBS patients assigned to the hydrogen breathing test (78%) gave positive bacterial overgrowth. Of the 47 subjects receiving the supplemental trial, 25 subjects (53%) reported improvement with antibiotic treatment symptoms (i.e., abdominal pain and diarrhea).

IBS can manifest a wide range of symptoms. However, abdominal pain and altered bowel habits remain the primary features. Although the severity and location of abdominal discomfort varies greatly, abdominal discomfort is often described as spastic and located in the lower left quadrant. The patient reported diarrhea, constipation or alternating episodes of diarrhea and constipation. Symptoms of diarrhea are typically described as small loose stools, and stool is sometimes accompanied by mucous discharge. Patients also reported bloating, urgency, incomplete evacuation, and abdominal distension. Upper gastrointestinal symptoms such as gastroesophageal reflux, dyspepsia or nausea may also occur (Lynn and Friedman, 1993).

The duration of the symptoms was not an indication for further testing; it is a characteristic of IBS and is an expected symptom of its own syndrome. A more in-depth diagnostic assessment indicates a patient whose symptoms are worsening or changing. Indications for further examination also included the presence of alarm symptoms, onset of symptoms after age 50 and a family history of colon cancer. The tests may include colonoscopy, computed tomography imaging of the abdomen and pelvis, and barium studies of the small or large intestine.

R. sicca syndrome

The compounds and methods of the invention may be used to treat SS patients. Primary Sjogren's Syndrome (SS) is a chronic, slowly progressive systemic autoimmune disease that affects primarily middle-aged women (female to male ratio 9: 1), but can be observed in all ages, including children (Jonsson et al, 2002). It is characterized by lymphocytic infiltration and destruction of the exocrine glands by monocytes, including CD4+, CD8+ lymphocytes and B cells (Jonsson et al, 2002). Furthermore, extraglandular (systemic) manifestations were observed in 1/3 patients (Jonsson et al, 2001).

Lymphocyte infiltration of the gland is a progressive feature (Jonsson et al, 1993) that displaces a large proportion of the organs when extensively infiltrated. Interestingly, in some patients, the glandular infiltration in the salivary glands closely resembles the ectopic lymphocyte microstructure (named germinal center) (Salomonsson et al, 2002; Xanthou et al, 2001). In SS, ectopic GC is defined as a T cell and B cell mass with follicular dendritic cells and proliferating cells that activate the endothelial cell network. These GC-like structures formed in the target tissues also characterize the functional properties of generating autoantibodies (anti-Ro/SSA and anti-La/SSB) (Salomonson and Jonsson, 2003).

In other systemic autoimmune diseases, such as RA, factors that are critical for GC have been identified. Rheumatoid synovial tissue with GC was shown to produce the chemokines CXCL13, CCL21 and Lymphotoxin (LT) - β (detected in follicular center and mantle B cells). Multivariate regression analysis of these analytes identified CXCL13 and LT- β as the only cytokines predictive of GC in rheumatoid synovitis (Weyand and Goronzy, 2003). It has recently been demonstrated that CXCL13 and CXCR5 in salivary glands play an essential role in inflammatory processes by recruiting B and T cells, thus promoting lymphocyte regeneration and ectopic GC formation in SS (salomonson et al, 2002).

Psoriasis S

The compounds and methods of the present invention may be used to treat patients with psoriasis. Psoriasis is a chronic skin peeling and inflammatory disease that affects 2% to 2.6% of americans, or between 580 and 750 million people. Although the disease occurs in all age groups, it primarily affects adults. Roughly equal between men and women. Psoriasis occurs when skin cells rise rapidly from a source below the skin surface and accumulate on the surface before they have a chance to mature. Typically, this movement (also called renewal) takes about 1 month, but in psoriasis it occurs only within a few days. In its typical form, psoriasis results in a thick red (inflamed) skin patch overcoated with silvery scales. These patches, sometimes referred to as plaques, are often itchy or painful. They most often occur on the elbows, knees, other parts of the legs, scalp, lower back, face, palms, and soles of the feet, but they also occur on the skin of any part of the body. The disease can also affect the nails, toenails, and genitals and soft tissues within the mouth. Although the skin around the affected joint is usually cracked open, approximately 100 million patients with psoriasis experience inflammation of the joint, producing arthritic symptoms. The disease is called psoriatic arthritis.

Psoriasis is an immune system, and in particular relates to immune system-driven skin disorders of the type known as T-cell leukocytes. Normally, T cells help protect the body against infection and disease. In the case of psoriasis, T cells function incorrectly and become so active that they trigger other immune responses, which lead to inflammation and rapid renewal of skin cells. In about 1/3 cases, there is a family history of psoriasis. Researchers have studied a large number of psoriasis-affected families and identified genes associated with the disease. People with psoriasis notice the time for their skin to deteriorate and then improve. Conditions that lead to redness include infection, stress, and climate change that dries the skin. Likewise, some medications, including hypertensive medications lithium and beta blockers, can trigger outbreaks or exacerbations of the disease.

Infectious diseases

The compounds of the present disclosure may be used to treat infectious diseases, including viral infections and bacterial infections. As mentioned above, such infections may be associated with severe local or systemic inflammatory responses. For example, influenza can produce severe pneumonia, and bacterial infections can lead to high systemic inflammatory responses, including overproduction of diverse inflammatory cytokines, which are hallmarks of sepsis. In addition, the compounds of the present invention may be used to directly inhibit the replication of viral pathogens. Previous studies have demonstrated that related compounds such as CDDO can inhibit HIV replication in macrophages (Vazquez et al, J.Virol.2005, 4 months; 79 (7): 4479-91). Other studies have shown that inhibition of the NF-. kappa.B signaling pathway inhibits replication of influenza virus, and that cyclopentenone prostaglandins inhibit viral replication (e.g., Mazur et al, 2007; Pica et al, 2000).

Pharmaceutical formulations and routes of administration

The compounds of the present disclosure can be administered by a variety of methods, such as orally or by injection (e.g., subcutaneously, intravenously, intraperitoneally, etc.). Depending on the route of administration, the active compound may be coated in a material to protect the compound from the action of acids and other natural conditions that would inactivate the compound. They may also be administered by continuous perfusion/perfusion at the site of disease or trauma.

In order to administer therapeutic compounds by means other than parenteral administration, it is necessary to coat the compounds or co-administered compounds with a material that protects them from inactivation. For example, the therapeutic compound may be administered to the patient in a suitable carrier such as a liposome or diluent. Pharmaceutically acceptable diluents include salts and aqueous buffers. Liposomes include water-in-oil-in-water CGF emulsions as well as conventional liposomes (Strejan et al, 1984).

The therapeutic compounds may also be administered parenterally, intraperitoneally, intravertebrally, or intracerebrally. Dispersions can be prepared in glycerol, liquid polyethylene glycols and mixtures thereof and in oils. Under normal conditions of storage and use, these formulations will contain a preservative to prevent microbial growth.

Pharmaceutical compositions suitable for injectable use include sterile aqueous solutions (when water soluble) or dispersions and sterile powders for the extemporaneous preparation of sterile injectable solutions or dispersions. In all cases, the composition must be sterile and must be fluid to the extent that easy syringability exists. It must be stable under the conditions of manufacture and storage and must be preserved against the contaminating action of microorganisms such as bacteria and fungi. The carrier can be a solvent or dispersion vehicle including, for example, water, ethanol, polyol (for example, glycerol, propylene glycol, and liquid polyethylene glycol, and the like), suitable mixtures thereof, and vegetable oils. Proper fluidity can be maintained, for example, by the use of a coating such as lecithin, by the maintenance of the required particle size in the case of dispersants, and by the use of surfactants. Prevention of the action of microorganisms can be achieved by various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol, ascorbic acid, thimerosal, and the like. In many cases, it will be better to include isotonic agents, for example, sugars, sodium chloride or polyalcohols such as mannitol and sorbitol in the composition. Prolonged absorption of the injectable compositions can be brought about by including in the composition an agent which delays absorption, for example, aluminum monostearate or gelatin.

Sterile injectable solutions can be prepared by incorporating the therapeutic compound in the required amount in the appropriate solvent with one or a combination of the ingredients enumerated above, as required, followed by filtered sterilization. Generally, dispersions are prepared by incorporating the therapeutic compound into a sterile vehicle which contains the basic dispersion vehicle and the required other ingredients from those enumerated above. In the case of sterile powders for the preparation of sterile injectable solutions, the preferred methods of preparation are vacuum drying and freeze-drying which yields a powder of the active ingredient (i.e., the therapeutic compound) plus any additional desired ingredient from a previously sterile-filtered solution thereof.

The therapeutic compound may be administered orally, for example, with an inert diluent or an assimilable edible carrier. The therapeutic compound and other ingredients may also be enclosed in hard or soft shell gelatin capsules, compressed in tablets or incorporated directly into the subject's food. For oral therapeutic administration, the therapeutic compound may be admixed with excipients and used in the form of ingestible tablets, buccal tablets, troches, capsules, elixirs, suspensions, syrups, cachets and the like. Of course, the percentage of therapeutic compound in the compositions and formulations can vary. The amount of therapeutic compound in such therapeutically useful compositions is such that a suitable dosage will be obtained.

It is particularly advantageous to formulate parenteral compositions in unit dosage form for ease of administration and uniformity of dosage. As used herein, dosage form refers to physically discrete units suitable as unitary dosages for the subjects to be treated; each unit containing a predetermined quantity of therapeutic compound calculated to produce the desired therapeutic effect in association with the required pharmaceutical carrier. The specifications for the dosage unit forms of the invention are determined by and directly depend upon (a) the unique characteristics of the therapeutic compound and the particular therapeutic effect to be achieved, and (b) the limitations inherent in the art of compounding such therapeutic compounds for the treatment of selected patient conditions.

The therapeutic compounds may also be administered topically to the skin, eye or mucosa. Alternatively, if local delivery to the lung is desired, the therapeutic compound may be administered by inhalation of a dry powder or aerosol formulation.

The active compound is administered in a therapeutically effective amount sufficient to treat a condition associated with the condition in the patient. A "therapeutically effective amount" preferably reduces the total number of disease symptoms in an infected patient by at least about 20%, more preferably by at least about 40%, even more preferably by at least about 60%, and still more preferably by at least about 80% compared to an untreated subject. For example, the efficacy of a compound can be assessed in an animal model system, such as the model systems shown in the examples and figures, which predicts the efficacy of treatment of a human disease.

The actual dose of a compound of the present disclosure or a composition comprising a compound of the present disclosure administered to a subject may be determined by physical and physiological factors such as age, sex, body weight, severity of the disease, type of disease to be treated, previous or concurrent therapeutic measures, specific symptoms of the subject, and route of administration. These factors can be determined by the skilled artisan. The practitioner responsible for administration will typically determine the concentration of one or more active ingredients in the composition and one or more appropriate dosages for the individual subject. The dosage can be adjusted by the individual physician in the event of any complications.

An effective amount will typically vary from about 0.001mg/kg to about 1,000mg/kg, from about 0.01mg/kg to about 750mg/kg, from about 100mg/kg to about 500mg/kg, from about 1.0mg/kg to about 250mg/kg, from about 10.0mg/kg to about 150mg/kg, in one or more doses per day for one or more days (depending, of course, on the mode of administration and the factors described above). Other suitable dosage ranges include 1mg to 10,000 mg/day, 100mg to 10,000 mg/day, 500mg to 10,000 mg/day, and 500mg to 1,000 mg/day. In some particular embodiments, the amount is less than 10,000 mg/day, with an amplitude ranging from 750mg to 9,000 mg/day.

The effective amount may be less than 1 mg/kg/day, less than 500 mg/kg/day, less than 250 mg/kg/day, less than 100 mg/kg/day, less than 50 mg/kg/day, less than 25 mg/kg/day, or less than 10 mg/kg/day. Alternatively, it is in the range of 1 mg/kg/day to 200 mg/kg/day. For example, for the treatment of a diabetic patient, the dosage unit may be an amount that reduces blood glucose by at least 40% compared to an untreated subject. In another embodiment, the unit dose is an amount that reduces blood glucose to a level of ± 10% of the blood glucose level of the non-diabetic subject.

In other non-limiting examples, the dosage may also include a dosage selected from the group consisting of about 1 μ g/kg/body weight, about 5 μ g/kg/body weight, about 10 μ g/kg/body weight, about 50 μ g/kg/body weight, about 100 μ g/kg/body weight, about 200 μ g/kg/body weight, about 350 μ g/kg/body weight, about 500 μ g/kg/body weight, about 1 mg/kg/body weight, about 5 mg/kg/body weight, about 10 mg/kg/body weight, about 50 mg/kg/body weight, about 100 mg/kg/body weight, about 200 mg/kg/body weight, about 350 mg/kg/body weight, about 500 mg/kg/body weight to about 1,000 mg/kg/body weight or higher, any range derivable therein. In non-limiting examples of ranges derived from the values listed above, ranges of about 5 mg/kg/body weight to about 100 mg/kg/body weight, about 5 μ g/kg/body weight to about 500 mg/kg/body weight, and the like, may be administered based on the above values.

In certain embodiments, a pharmaceutical composition of the present disclosure may comprise, for example, at least about 0.1% of a compound of the present disclosure. In further embodiments, the compounds of the present disclosure may comprise between about 2% to about 75% weight units or between about 25% to about 60% weight units, and any range derivable therein.

Single or multiple doses of the agent are contemplated. The desired time interval for multiple dose delivery can be determined by one of ordinary skill in the art, using no more than routine experimentation. For example, a subject may be administered doses twice daily at approximately 12 hour intervals. In some embodiments, the agent is administered once daily.

The one or more agents may be administered on a conventional schedule. As used herein, a conventional schedule refers to a predetermined period of time. The regular schedule may include time periods that are the same or different in length, so long as the schedule is preset. For example, a conventional schedule may include administration twice daily, once every two days, once every three days, once every four days, once every five days, once every six days, once weekly, once monthly, or any set number of days or weeks therebetween. In other embodiments, the invention provides that one or more agents may be orally ingested and with a time frame that is dependent or independent of food intake. Thus, for example, the agent may be ingested daily in the morning and/or daily in the evening, regardless of when the subject is or will be eating.

Combination therapy

In addition to use as monotherapeutic agents, the compounds of the present disclosure may also be used in combination therapy. Effective combination therapy can be achieved using a single composition or pharmaceutical formulation comprising two agents, or using two different compositions or formulations simultaneously, wherein one composition comprises the oleanolic acid derivative according to the methods of the present invention and the other comprises one or more second agents. Alternatively, the treatment may precede or follow treatment with other agents at intervals ranging from minutes to months.

Various combinations may be employed, for example, when a compound of the present disclosure is "a" and "B" represents a second agent, non-limiting examples of which are described below:

A/B/A B/A/B B/B/A A/A/B A/B/B B/A/A A/B/B/B B/A/B/B

B/B/B/A B/B/A/B A/A/B/B A/B/A/B A/B/B/A B/B/A/A

B/A/B/A B/A/A/B A/A/A/B B/A/A/A A/B/A/A A/A/B/A

administration of the compounds of the present disclosure to patients will follow the general protocol for drug administration, taking into account the toxicity of the drug if present. It is contemplated that the treatment cycle will be repeated as needed.

Interferon beta will be a suitable second agent. There are human cytokine-derived drugs that help modulate the immune system. They include interferon beta-1 b and interferon beta-1 a. Betaseron has been approved by the FDA for relapsing secondary progressive MS. In addition, the FDA has approved several interferon betas for use as therapeutic agents to treat patients who have experienced a single episode that has been demonstrated to be multiple sclerosis and patients who may be at risk for further episodes and develop clear MS. For example, when an MRI scan of the brain shows a high risk of damage that predicts a shift to clear MS, a risk of MS is indicated.

Glatiramer acetate is another example of a second agent that may be used in combination therapy. Glatiramer is currently used to treat relapsing remitting MS. It consists of four amino acids found in myelin. The drug reportedly stimulates T cells in the immune response of the body to change from a harmful pro-inflammatory agent to a beneficial anti-inflammatory agent that reduces inflammation at the site of injury.

Another potential second agent is mitoxantrone, a chemotherapeutic drug for many cancers. The drug is also FDA approved for the treatment of aggressive forms of relapsing-remitting MS, as well as certain forms of progressive MS. Typically, it is administered intravenously every three months. The drug is effective, but is limited by cardiotoxicity. Norstrin has been approved by the FDA for secondary progressive, progressive-relapsing, and exacerbation relapsing-remitting MS.

Another potential second agent is natalizumab. In general, natalizumab acts by blocking the attachment of immune cells to the brain blood vessels, which is an essential step in the entry of immune cells into the brain, thus reducing the inflammatory effects of immune cells on brain neurons. Natalizumab has been shown to significantly reduce the frequency of episodes in patients with relapsing MS.

In the case of relapsing-remitting MS, a corticosteroid, such as methylprednisolone, may be administered intravenously to the patient as a second agent to more quickly terminate the challenge and leave less persistent deficiency.

Other commonly used drugs for MS that may be used in combination therapy with oleanolic acid derivatives include immunosuppressive drugs such as azathioprine, cladribine, and cyclophosphamide.

It is contemplated that other anti-inflammatory agents may be used in combination with the therapeutic agents of the present invention. Other COX inhibitors may be used, including arylcarboxylic acids (salicylic acid, acetylsalicylic acid, diflunisal, choline magnesium trisalicylate, salicylates, paracetamol, flufenamic acid, mefenamic acid, meclofenamic acid, and triflumic acid), arylalkanoic acids (diclofenac, fenclofenac, fentiazac, ibuprofen, flurbiprofen, ketoprofen, naproxen, fenoprofen, fenbufen, suprofen, indoprofen, tiaprofenic acid, benoxaprofen, pirprofen, tolmetin, zomepirac, clinacac, indomethacin, and sulindac), and enolic acids (phenylbutazone, oxybutyzone, azapropazone, feprazone, piroxicam, and isoxicam-see also U.S. patent No. 6,025,395, which is incorporated herein by reference.

Histamine H2 receptor blocking agents may also be used in combination with the compounds of the present invention, including cimetidine, ranitidine, famotidine and nizatidine.

Acetylcholinesterase inhibitor therapies, such as tacrine, donepezil, metrazoxane, and rivastigmine, for the treatment of alzheimer's disease and other diseases are also contemplated for use in combination with the disclosed compounds. Other acetylcholinesterase inhibitors developed that can be used once approved include rivastigmine and metrazine. Acetylcholinesterase inhibitors increase the amount of neurotransmitter acetylcholine at nerve terminals by reducing the destruction of acetylcholine by cholinesterase.

MAO-B inhibitors such as selegiline may be used in combination with the compounds of the present invention. Selegiline is used in parkinson's disease and irreversibly inhibits type B monoamine oxidase (MAO-B). Monoamine oxidase is an enzyme that inactivates the monoamine neurotransmitters norepinephrine, serotonin and dopamine.

Food and nutritional supplements that are reported to be beneficial for the treatment or prevention of parkinson's disease, alzheimer's disease, multiple sclerosis, amyotrophic lateral sclerosis, rheumatoid arthritis, inflammatory bowel disease and all other diseases whose pathogenesis is believed to involve overproduction of any of Nitric Oxide (NO) or prostaglandins, for example acetyl-L-carnitine, octacosanol, evening primrose oil, vitamin B6, tyrosine, phenylalanine, vitamin C, L-dopa or several antioxidant combinations may be used in combination with the compounds of the present invention.

For the treatment or prevention of cancer, the compounds of the present invention may be used in combination with one or more of the following therapeutic agents: radiation, chemotherapeutic agents (e.g., cytotoxic agents such as anthracyclines, vincristine, vinblastine, agents targeting microtubules such as paclitaxel and docetaxel, 5-FU and related agents, cisplatin and other platinum-containing compounds, irinotecan and topotecan, gemcitabine, temozolomide, etc.), targeted therapeutic agents (e.g., imatinib, bortezomib, bevacizumab, rituximab), or vaccine therapeutic agents designed to promote enhanced immune responses targeting cancer cells.

For the treatment or prevention of autoimmune diseases, the compounds of the present invention may be used in combination with one or more of the following drugs: corticosteroids, methotrexate, anti-TNF antibodies, other TNF-targeted protein therapeutics, and NSAIDs. For the treatment or prevention of cardiovascular diseases, the compounds of the present invention may be used in combination with antithrombotic therapeutic agents, anticholesterol therapeutic agents such as statins (e.g. atorvastatin) and surgical interventions such as stents or coronary artery bypass grafts. For the treatment of osteoporosis, the compounds of the invention may be used in combination with anti-resorptive agents such as the bisphosphonates or anabolic therapeutic agents such as teriparatide or parathyroid hormone. For the treatment of neuropsychiatric disorders, the compounds of the present invention may be used in combination with antidepressants (e.g., imipramine or SSRI such as fluoxetine), antipsychotics (e.g., olanzapine, sertindole, risperidone), mood stabilizers (e.g., lithium, half sodium valproate), or other standard agents such as anxiolytic agents. For the treatment of neurological disorders, the compounds of the invention may be used in combination with anticonvulsants (e.g. monosodium valproate, gabapentin, phenytoin, carbamazepine and topiramate), antithrombotic agents (e.g. tissue plasminogen activator) or analgesics (e.g. opiates, sodium channel blockers and other anti-pain-sensing agents).

For the treatment of conditions involving oxidative stress, the compounds of the present disclosure may be used in combination with tetrahydrobiopterin (BH4) or related compounds. BH4 is a cofactor for constitutive nitric oxide synthase and can be depleted by reaction with peroxynitrite. Peroxynitrite is formed by the reaction of nitric oxide and superoxide. Thus, under conditions of oxidative stress, excess levels of superoxide will deplete normal, beneficial levels of nitric oxide by converting NO to peroxynitrite. The depletion of BH4 by reaction with peroxynitrite results in "uncoupling" of the nitric oxide synthases, whereby they form superoxides, not NO. This increases the over-supply of superoxide and prolongs the depletion of NO. The addition of exogenous BH4 reverses this uncoupling phenomenon, restoring NO production in the tissues and reducing oxidative stress levels. This mechanism is expected to complement the effect of the compounds of the invention, which reduces oxidative stress by other methods as described above and throughout the present invention.

Examples

The following examples are included to illustrate preferred embodiments of the invention. It should be appreciated by those of skill in the art that the techniques disclosed in the examples which follow represent techniques disclosed by the inventors to function well in the practice of the invention, and thus can be considered to constitute preferred modes for its practice. However, those of skill in the art should, in light of the present disclosure, appreciate that many changes can be made in the specific embodiments which are disclosed and still obtain a like or similar result without departing from the spirit and scope of the invention.

Example 1 methods and materials

Nitric oxide production and cell viability. RAW264.7 macrophages were pretreated with DMSO or drug for 2 hours and then treated with recombinant mouse IFN γ (Sigma) for 24 hours. The NO concentration in the medium was determined using the Griess reagent System (Promega). Cell viability was determined using WST-1 reagent (Roche).

STAT3 is phosphorylated. HeLa cells were treated with the indicated compounds and concentrations for 6 hours, followed by stimulation with 20ng/ml recombinant human IL-6(R & D Systems) for 15 minutes. Lysates were immunoblotted with anti-phosphorylated STAT3 or total STAT3 antibody (Cell Signaling).

NF- κ B activation. HeLa cells were transfected with pNF-. kappa.B-Luc (inducible, Stratagene) and pRL-TK (constitutive, Promega) reporter plasmids. After 24 hours, cells were pretreated for 2 hours with the indicated compound. DMSO served as vehicle control. After pretreatment, cells were stimulated with 20ng/ml recombinant human TNF α (BD Biosciences) for 3 hours. Reporter activity was measured using the DualGlo luciferase reporter System (Promega) and pNF-. kappa.B luciferase activity was normalized to pRL-TK luciferase activity. Mean fold induction of luciferase activity relative to unstimulated (-TNF α) samples is shown. Error bars represent SD of the mean of 6 samples.

And degrading the I kappa B alpha. HeLa cells were treated with the indicated compounds and concentrations for 6 hours and then stimulated with 20ng/ml TNF α for 15 minutes. Lysates were blotted with anti-I κ B α antibody (Santa Cruz) and anti-actin antibody (Chemicon).

COX-2 induced Western blots. RAW264.7 cells were pretreated with the indicated compounds for 2 hours and subsequently stimulated with 10ng/ml IFN γ for 24 hours. COX-2 protein levels were determined by immunoblotting using antibodies from Santa Cruz. Actin was used as loading control.

Nrf2 targets gene induction. MDA-MB-435 human melanoma cells were treated with vehicle (DMSO) or indicated compounds and concentrations for 16 hours. HO-1, thioredoxin reductase-1 (TrxR1), gamma-glutamylcysteine synthetase (gamma-GCS) and ferritin heavy chain mRNA levels were quantified using qPCR and normalized to DSMO-treated samples run in parallel. Values are the average of duplicate wells. The primer sequences are as follows.

HO-1 FW：TCCGATGGGTCCTTACACTC(SEQ ID NO：1)，

HO-1 REV：TAGGCTCCTTCCTCCTTTCC(SEQ ID NO：2)，

TrxR1 FW：GCAGCACTGAGTGGTCAAAA(SEQ ID NO：3)，

TrxR1 REV：GGTCAACTGCCTCAATTGCT(SEQ ID NO：4)，

γ-GCS FW：GCTGTGGCTACTGCGGTATT(SEQ ID NO：5)，

γ-GCS REV ATCTGCCTCAATGACACCAT(SEQ ID NO：6)，

Ferritin HC FW: ATGAGCAGGTGAAAGCCATC (SEQ ID NO: 7),

ferritin HC REV: TAAAGGAAACCCCAACATGC (SEQ ID NO: 8),

S9 FW：GATTACATCCTGGGCCTGAA(SEQ ID NO：9)，

S9 REV：GAGCGCAGAGAGAAGTCGAT(SEQ ID NO：10)。

the compounds were compared. In some experiments (see fig. 5), certain compounds of the invention were compared to other compounds, such as those shown herein.

Compounds 402 and 402-56 can be prepared according to the methods taught in Honda et al (1998), Honda et al (2000b), Honda et al (2002), Yates et al (2007), U.S. Pat. No. 6,974,801, U.S. provisional application Nos. 61/046,332, 61/046,342, 61/046,352, 61/046,363, 61/111,333, and 61/111,269, which are all incorporated herein by reference. The synthesis of other mixtures is also disclosed in the following separate applications filed concurrently herewith, each of which is incorporated by reference herein in its entirety: U.S. patent applications to Eric Anderson, gary l.bolton, Deborah Ferguson, Xin Jiang, Robert m.kral, jr., Patrick M.O' Brian and Melean Visnick, entitled "natural products comprising an anti-inflammatory pharmacophore and methods of use", filed 4/20/2009; eric Anderson, Xin Jiang, Xiaofeng Liu; U.S. patent application to Melean Visnick, entitled "antioxidant inflammation modulators: oleanolic acid derivatives "with saturated C-ring, proposed 4/20 in 2009; U.S. patent application to Eric Anderson, Xin Jiang and mean Visnick, entitled "antioxidant inflammation modulators: oleanolic acid derivatives "with amino and other modifications at C-17, proposed at 20/4 in 2009; U.S. patent application entitled "antioxidant inflammation modulators: new oleanolic acid derivatives ", were proposed at 20/4/2009.

And (4) measuring the water solubility. The following procedure was used to obtain the water solubility results, which are summarized in example 8. Step 1. determination of optimal UV/visible wavelengths and generation of standard curves for the compounds of interest:

(1) for 8 standard calibration curves (one plate), 34mL of 50: 50 (v: v) universal buffer were prepared in 50mL tubes: and (3) acetonitrile.

(2) Using a multi-tube pipette, buffer: acetonitrile was added (in μ L) to a deep well plate as follows:

(3) DMSO was added to the same plate using a multi-tube pipettor as follows:

(4) 10mM of compound dissolved in DMSO was added to the plate as follows:

(5) mix columns 1 and 2 by pipetting up and down 10 times. Mix columns 3 and 4 by pipetting up and down 10 times. Serial dilutions were as follows (10 puffs up and down with a pipette after each transfer):

note that column 11 and mimosa 2 contain only DMSO and therefore no compound was added to these wells.

(6) The plate was covered with a lid and shaken at room temperature (200-.

(7) Mix all the wells by pipetting up and down 10 times.

(8) 120pL was removed from each well and transferred to a UV transparent plate. The lid was closed and shaken for 3-5 minutes. Any air bubbles in the wells were removed using a pipette.

(9) On a spectrophotometer (e.g. SpectraMax)) Increased by 10nmThe amount was read from 220nm to 500 nm.

And 2. step 2. Use of Millipore^TM MultiscreenSolubility filter plate compound solubility test procedure.

Consumable productMillipore^TM MultiscreenSolubility Filter plate # MSSLBPC10

Greiner96-well disposable ur-Star assay plate, VWR #655801

Greiner96-well Polypropylene V-bottom Collection plate, VWR #651201

Universal aqueous buffer：

(a) To prepare 500mL of universal buffer, 250mL of Nanopure water was added; 1.36mL (45mM) ethanolamine; 3.08g (45mM) of potassium dihydrogen phosphate; 2.21g (45mM) potassium acetate; mixing well.

(b) The pH was adjusted to 7.4 with HCl and made up to 500mL with 0.15M KCl.

(c) Filtration removes particulates and reduces bacterial growth.

(d) Storing at 4 ℃ in the dark.

Solubility protocol：

(a) In Millipore^TM MultiscreenSolubility Filter plates 285. mu.L of general purpose water was added to the expected wellsAnd (4) a neutral buffer.

(b) To the appropriate wells 15. mu.L of compound in 10mM DMSO was added. Only 6 wells of the filter plate were filled with 15 μ L of 100% DMSO as a blank.

(c) Mix the wells evenly by blowing and sucking up and down 10 times using a multitube pipettor. Care was taken not to touch the filter in the plate with the tip.

(d) The lid was closed and the filter plate was gently shaken (200-.

(e) Removing the aqueous solution from Multiscreen And (4) carrying out vacuum filtration on the solubility filter plate to a polypropylene V-shaped bottom plate.

(f) Transfer 60 μ L of filtrate to UV-transparent plates (Greiner)UV-Star assay plate).

(g) To each well was added 60 μ L of acetonitrile and mixed by pipetting up and down 10 times.

(h) Cover and gently shake for 3-5 minutes. Any air bubbles were removed with a pipette.

(i) The absorbance in each well of the plate was measured at the desired wavelength on a spectrophotometer (UV/vis). For compounds with different absorbance peaks in the plate, the spectrophotometer is set up to read the spectrum (e.g., from 220nm to 460 nm).

(j) The concentration was identified using the measured absorbance of each compound and a predetermined standard curve (see step 1).

EXAMPLE 2 Synthesis of Oleanolic acid derivatives

Scheme 1:

reagents and conditions suitable for scheme 1 are: (a) LAH, room temperature to 65 ℃, 1.5h, 52% (compound 2) and 27% (compound 3). Compound 2 is converted in 5 steps to compounds 402-63 (scheme 2). The compound 2 is treated with a bleaching agent to selectively oxidize secondary alcohols to give compound 4 in 83% yield. Formylation of 4 with ethyl formate using sodium methoxide as base gave compound 5, which was treated with hydroxylamine hydrochloride in aqueous EtOH at 60 ℃ to give iso-isomers Oxazole 6, yield 76% (starting from 4). Under alkaline conditionOxazole cleavage gives α -cyanoketone 7 as a mixture of keto and enol forms in quantitative yield. Compound 7 was treated with 1, 3-dibromo-5, 5-dimethylhydantoin followed by removal of HBr using pyridine as the base to give compounds 402-63 in 79% yield. With Ac₂O/pyridine treatment of alcohol 402-63 gave 402-65 in 70% yield.

Reagents and conditions suitable for scheme 2 are: (a) AcOH, bleach, room temperature, 1h, 83%; (b) HCO₂Et, NaOMe, 0 ℃ to room temperature, 1 h; (c) NH2OH & HCl, 60 ℃, 16h, 76% (from 4); (d) NaOMe, 55 ℃, 2 h; (e) (i)1, 3-dibromo-5, 5-dimethylhydantoin at room temperature for 2 h; (ii) pyridine, 55 ℃, 3h, 79% (from 6); (f) ac of₂O, Py, DMAP, room temperature, 30min, 70%.

The synthesis of 402-50 and 402-54 starts with acid 8 (scheme 3). Compound 8 is converted to the acid chloride by treatment with oxalyl chloride and subsequently treated with trimethylsilyldiazomethane to give diazomethyl ketone 9. Wolff rearrangement of diazomethyl ketone 9 by reaction with silver benzoateA homologated methyl ester was obtained. The differences were carried out in three steps according to the same protocol as protocol 2The conversion of oxazole ring to alpha-cyanoketene gives 402-50 with a total yield of 8% (from 9). Treatment of the ester 402-50 with aqueous lithium hydroxide gave the acid 402-54 in 52% yield.

Scheme 3:

reagents and conditions suitable for scheme 3 are: (a) TMSI, CHCl3, 50 ℃ to 55 ℃, 9h, 39%; (b) (i) (COCl)₂，CH₂Cl₂Room temperature, 15 h; (ii) TMSCHN₂，CH₃CN, 50 ℃ to room temperature, 24h, 74%; (c) (i) AgCO₂Ph，Et₃N, MeOH, 50 ℃, 2 h; (ii) NaOMe, MeOH, 50 ℃, 3 h; (iii)1, 3-dibromo-5, 5-dimethylhydantoin at room temperature for 20 min; (iv) pyridine, 50 to 60 ℃, 11h, 8% (counting from 9); (d) LiOH, MeOH, H₂O, room temperature to 50 ℃, 19h, 52%.

Scheme 4:

reagents and conditions suitable for scheme 4 are: (a) et (Et)₃N，(EtO)₂POCl，CH₂Cl₂Room temperature, 94h, 34%.

Reagents and conditions suitable for scheme 5 are: (a) n- (phenylthio) -phthaloylImine, Bu₃P, benzene, room temperature, 22h, 42%; (b) oxone, EtOH, H₂O，CH₃CN, at 0 ℃ to room temperature, for 70h, d.r. about 3: 1; (c) (i) NaOMe, 55 ℃, 4 h; (ii)1, 3-dibromo-5, 5-dimethylhydantoin at 0 ℃ for 2.5 h; (iii) pyridine, 55 ℃, 4h, 64% (63255) and 6% (63288), calculated starting from 11.

Scheme 6:

reagents and conditions suitable for scheme 6 are: (a) oxone, EtOH, H₂O，CH₃CN, room temperature, 24h, 91%; (b) NaOMe, 55 ℃, 2 h; (c) (i)1, 3-dibromo-5, 5-dimethylhydantoin, at 0 ℃ for 1.5 h; (ii) pyridine, 55 ℃, 3.5h, 64%, calculated starting from 13.

Reagents and conditions suitable for scheme 7 are: (a) (i) oxalyl chloride, 0 ℃ to room temperature, for 2 h; (ii) NH (NH)₃(2M in MeOH), 0 ℃ to room temperature, 1h, 94%; (b) LAH, room temperature to 65 ℃, 4 h; (c) (Boc)₂O，NaHCO₃Room temperature, 4h, 60%, calculated from 16; (d) PCC, NaOAc, room temperature, 4h, 94%; (e) HCO₂Et, NaOMe, room temperature, 1.5 h; (f) NH (NH)₂OH-HCl, 60 ℃, 2.5h, 75%; (g) NaOMe, 55 ℃, 2h, 89%; (h)1, 3-dibromo-5, 5-dimethylhydantoin at room temperature for 2 hours; (i) pyridine, 55 ℃, 3h, 94%; (j) CF (compact flash)₃CO₂H, 0 ℃, 4H, 99%; (k) RX, base, for details see table 1.

Table 2.

Scheme 8:

reagents and conditions suitable for scheme 8 are: (a) TEMPO, IPh (OAc)₂Room temperature, 72h, 77%; (b) CH (CH)₃PPh₃ ⁺Br^-KOt-Bu, room temperature, 14h, 95%; (c) PCC, NaOAc, room temperature, 2h, 87%; (d) (i) HCO₂Et, NaOMe, room temperature, 1.5 h; (ii) NH (NH)₂OH-HCl, 60 ℃, 3h, 90%; (e) NaOMe, 55 ℃, 2 h; (f) DDQ, 80 ℃, 34%, calculated starting from 24.

Scheme 9:

reagents and conditions suitable for scheme 9 are: (a) NMO, OsO₄(catalyst), room temperature, 24h, 79%; (b) NaOMe, 55 ℃, 3 h; (c) (i)1, 3-dibromo-5, 5-dimethylhydantoin at room temperature for 2 h; (ii) pyridine, 55 ℃, 16h, 42% yield calculated from 26 for 63221; the yield was 18% calculated from 26 for 63224.

Scheme 10:

reagents and conditions suitable for scheme 10 are: (a) et (Et)₃N，CF₃CH₂SO₂Cl，CH₂Cl₂，0℃，1.5h，53％。

Scheme 11:

reagents and conditions suitable for scheme 11 are: (a) CF (compact flash)₃SO₃CH₃2, 6-di-tert-butyl-4-methylpyridine, CH₂Cl₂Room temperature, 72h, 66%.

Reagents and conditions suitable for scheme 12 are: (a) (i) BH₃-THF, 0 ℃ to room temperature, 3 h; (ii) h₂O₂NaOH, room temperature, 14h, 86%; (b) TBSCl, imidazole, 0 ℃ to room temperature, 1h, 69%; (c) NMO, TPAP, room temperature, 1h, 95%; (d) (i) LDA, -78 ℃, 30 min; (ii) TsCN, at-78 ℃ for 2 h; (e)3N HCl (aq.), room temperature, 20min, 49%; (f)1, 3-dibromo-5, 5-dimethylhydantoin at room temperature for 2 hours; (g) pyridine, 55 ℃, 14h, 51%.

Scheme 13:

reagents and conditions suitable for scheme 13 are: (a) NaOMe, 55 ℃, 8 h; (b) (i)1, 3-dibromo-5, 5-dimethylhydantoin, at 0 ℃ for 3 h; (ii) pyridine, 55 ℃, 3h, 35%, calculated starting from 11.

Scheme 14:

reagents and conditions: (a) (i) POCl₃Pyridine, 4-DMAP, THF, 0 ℃ for 2h, howeverThen, the temperature is kept at room temperature for 1 h; (ii)1N HCl (aq), THF, room temperature, 23h, 48%.

Reagents and conditions suitable for scheme 15 are: (a) dess-martin oxidizer, NaHCO₃Room temperature, 1h, 48%; (b) CF (compact flash)₃CH₂NH₂，NaBH₃CN, AcOH, room temperature, 3h, 85%; (c) NaOMe, 55 ℃, 1h, 74%; (d) (i) DBDMH, 0 ℃, 1 h; (ii) pyridine, 55 ℃, 3h, 55%.

Scheme 16:

reagents and conditions for scheme 16 were: (a) m-CPBA, room temperature, 24h, 81%; (b) (i) NaOMe, 55 ℃, 3 h; (ii)1N (aq.) HCl, room temperature, 5min, 66% (for compound 37) and 20% (for compound 38); (c) (i) DBDMH, 0 ℃, 1.5 h; (ii) pyridine, 55 ℃, 4h, 15% (for 63283) and 32% (for 63284); (d) NaH, room temperature, 45min, 43% (from 63283 to 63287), 55% (from 63284 to 63286).

Scheme 17:

reagents and conditions suitable for scheme 17 are: (a) n- (methylthio) -phthalimide, Bu₃P, benzene, room temperature, 143h, 6.5%; (b) NaOMe, 55 ℃, 1.5 h; (c)1, 3-dibromo-5, 5-dimethylhydantoin, DMF, 0 ℃, 3 h; (ii) pyridine, 55 ℃, 5h, 30%, calculated from 39.

Scheme 18:

reagents and conditions suitable for scheme 18 are: (a) (i) DBDMH, DMF, 0 ℃, 1.5 h; (ii) pyridine, 55 ℃, 4h, 78%.

Scheme 19:

reagents and conditions suitable for scheme 19 are: (a) paraformaldehyde, TsOH, 110 ℃, 1h, 38%.

Scheme 20:

reagents and conditions suitable for protocol 20 are: (a) (RCO)₂O, pyridine, DMF, 80 ℃.

Table 3.

Name of Compound	R	Acylating agents	Time of Rxn	Yield (%)
					63294	CF₃	(CF₃CO)₂O(1.2eq)	14h	12
63297	Tert-butyl radical	(t-BuCO)₂O(1.2eq)	14h	36
					63298	Ph	(PhCO)₂O(1.2eq)	14h	28

Reagents and conditions suitable for scheme 21 are: (a) (i) NaOMe, 55 ℃, 2 h; (ii) KCN, room temperature, 21h, then 55 ℃, 49h, 35%; (b) (i)1, 3-dibromo-5, 5-dimethylhydantoin, at 0 ℃ for 3.5 h; (ii) pyridine, 55 ℃, 20h, 66%, calculated starting from 42.

Reagents and conditions suitable for protocol 22 are: (a) CrO₃，H₂SO₄/H₂O, acetone, 1h, 57% at-4 ℃ to 11 ℃; (b) HCO₂Et, NaOMe, MeOH, -10 ℃ to 3 ℃, 1.5h, 93%; (c) NH (NH)₂OH-HCl，EtOH，H₂O, 54 ℃, 1.5h, 97%; (d) NaOMe, MeOH, 55 ℃, 2.5 h; (e) (i)1, 3-dibromo-5, 5-dimethylhydantoin, DMF from-35 ℃ to 0 ℃ to room temperature, 30 min; (ii) pyridine, 55 ℃, 3h, 92%, calculated from 45; (f) dimethyl sulfate, Na₂CO₃THF, rt, 18h, then 50 ℃, 5h, then 80 ℃, 3h, 48%.

Reagents and conditions suitable for scheme 23 are: (a) (i) oxalyl chloride, 35 ℃, 20min, quantitative; (b) RNH₂-HCl，Et₃N, THF, for details see table 1.

Table 4.

ID	R	Reaction time	Reaction temperature	% yield
					63334	CH₃CH₂	40min	At room temperature	39
63335	FCH₂CH₂	40min	At room temperature	28
					63336	F₂CHCH₂	40min	At room temperature	36
63337	F₃CCH₂	40min	At room temperature	39

63332 is not straightforward, requiring several different approaches before successful synthesis (scheme 22). The synthetic route for successful synthesis of 402-54 (scheme 3) is not efficient for the synthesis of 63332 (scheme 24). This pathway is ineffective when 49 cannot be successfully converted to the diazoketone 50. An alternative synthesis scheme (scheme 25) starting from alkene 24 was also attempted. The hydroboration reaction of 24 fails to yield the requisite primary alcohol 52, resulting in termination of the process.

Reagents and conditions suitable for protocol 24 are: (a) (i) PhSiMe₃，I₂，39％；(b)(COCl)₂，CH₂Cl₂Room temperature, 3h, 93%; (c) TMSCH₂，Et₃N，CH₂Cl₂Or CH₃CN；(d)Ag⁺，Et₃N。

Scheme 25:

reagents and conditions suitable for protocol 25 are: (a) dicyclohexylborane or cathechoborone.

Example 3 characterization of certain oleanolic acid derivatives

Compounds 2 and 3: at room temperature under N₂In the presence of LiAlH₄A solution (1.0M in THF, 42mL, 42mmol) was added to a solution of compound 1(5.0g, 10.3mmol) in THF (100 mL). Stirring at room temperature for 20min, adding LiAlH again₄Solution (1.0M in THF, 21mL, 21mmol) and the reaction mixture was refluxed for 1 h. After cooling to 0 ℃, water (10mL) was added dropwise, followed by 1n hcl (aq) (300 mL). The mixture was extracted with EtOAc. The combined extracts were washed with water and MgSO₄Dried and concentrated. The residue obtained is reacted with CH₂Cl₂(200mL) and mixed. The precipitated white solid was collected by filtration and used with CH₂Cl₂(2X 100mL) to give Compound 3(500mg, 10%). The combined filtrates were loaded onto a silica gel column and eluted with 0% to 100% EtOAc in hexanes to give compound 2(2.60g, 52%) and additional compound 3(800mg, 17%). Compounds 2 and 3 were both white solids. Compound 2:¹H NMR(400MHz，CDCl₃)δ3.98(bs，1H)，3.54(m，2H)，3.22(dd，1H，J＝4.8，11.2Hz)，1.46-1.86(m，19H)，1.34(s，3H)，1.15-1.42(m，6H)，1.02(s，3H)，0.99(s，3H)，0.93(s，3H)，0.87(s，3H)，0.85-1.06(m，2H)，0.86(s，3H)，0.77(s，3H)；m/z 443.3(M-H₂O+1)，425.3(100％，M-2×H₂o + 1). Compound 3:¹H NMR(400MHz，CDCl₃)δ3.79(m，1H)，3.54(m，2H)，3.20(dd，1H，J＝4.8，10.8Hz)，1.98(m，1H)，1.12-1.88(m，23H)，1.03(s，3H)，0.98(s，6H)，0.91(s，3H)，0.86(s，3H)，0.85(s，3H)，0.77(s，3H)，0.65-1.10(m，3H)；m/z 443.3(M-H₂O+1)，425.3(100％，M-2×H₂O+1)。

compound 4: bleach (5.25% NaClO (aq), 9.3mL, 6.52mmol) was added dropwise to a solution of compound 2(1.00g, 2.17mmol) in AcOH (30mL) at room temperature. After stirring for 1h, water (300mL) was added. After stirring for 5min, the precipitate was collected by filtration and washed. The resulting white solid was dissolved in EtOAc and the solution was taken up with NaHCO ₃(aq) solution washing, then MgSO₄Dried and concentrated. The white foamed solid obtained is purified by column chromatography (silica gel, CH)₂Cl₂Medium 0% to 40% EtOAc) to afford compound 4(830mg, 83%):¹H NMR(400MHz，CDCl₃)δ3.51(m，2H)，2.67(d，1H，J＝4.8Hz)，2.54(ddd，1H，J＝7.2，10.8，18.0Hz)，2.39(ddd，1H，J＝3.6，7.2，16.0Hz)，2.28(dd，1H，J＝5.2，16.8Hz)，2.23(d，1H，J＝12.0Hz)，2.18(m，1H)，1.56-1.90(m，8H)，1.50(m，1H)，1.20-1.45(m，8H)，1.18(s，3H)，1.10(s，3H)，1.06(s，3H)，1.03-1.14(m，2H)，1.01(s，3H)，0.98(s，3H)，0.93(s，3H)，0.89(s，3H)；m/z 457.3(M+1)。

compound 5: at 0 ℃ in N₂NaOMe solution (25% w/w in MeOH, 6.24mL, 27.3mmol) was added dropwise to Compound 4(830mg, 1.82mmol) and HCO in the presence of₂Et (4.40mL, 54.6mmol) in a mixture. After stirring at room temperature for 1h, t-BuOMe (50mL) was added. The mixture was cooled to 0 ℃ and 12N HCl (aq) (2.28mL, 27.3mmol) was added slowly. The mixture was extracted with EtOAc and the combined extracts were washed with water, MgSO₄Dried and concentrated. Crude compound 5 was obtained and used in the next step. Compound 5:¹H NMR(400MHz，CDCl₃)δ14.90(d，1H，J＝2.4Hz)，8.61(d，1H，J＝3.6Hz)，3.51(m，2H)，2.70(d，1H，J＝4.8Hz)，2.14-2.36(m，5H)，1.21(s，3H)，1.19(s，3H)，1.13(s，3H)，1.02-1.92(m，17H)，1.00(s，3H)，0.94(s，3H)，0.90(s，3H)，0.88(s，3H)；m/z 485.3(M+1)。

compound 6: reacting compound 5, NH₂OH HCl (190mg, 2.73mmol), EtOH (75mL) and water (10mL) were mixed together and heated at 60 ℃ for 16 h. EtOH was removed by evaporation and the resulting white slurry was washed with CH₂Cl₂And (4) extracting. The combined extracts were washed with water and MgSO₄Dried and concentrated. The resulting residue was purified by column chromatography (silica gel, 0% to 60% EtOAc in hexanes) to give compound 6(662mg, 76%, calculated from 4) as a white solid: ¹H NMR(400MHz，CDCl₃)δ7.99(s，1H)，3.51(m，2H)，2.70(d，1H，4.8Hz)，2.23-2.39(m，3H)，2.19(m，1H)，1.97(d，1H，J＝14.8Hz)，1.42-1.92(m，10H)，1.33(s，3H)，1.24(s，3H)，1.19(s，3H)，1.12-1.40(m，7H)，1.01(s，3H)，0.94(s，3H)，0.90(s，3H)，0.86(s，3H)；m/z 482.3(M+1)。

Compound 7: NaOMe solution (25% w/w in MeOH, 114. mu.L, 0.50mmol) was added to the iso-isomerOxazole 6(200mg, 0.42mmol) was in suspension in MeOH (2.5mL) and THF (0.25 mL). The mixture was stirred at 55 ℃ for 2h and cooled to 0 ℃. t-BuOMe (10mL) and 1N HCl (aq) (10mL) were added sequentially. The mixture was extracted with EtOAc and the combined extracts were washed with water, MgSO₄Dried and concentrated. White foamy solid 7(200mg) was used in the next step without further purification. Compound 7 is a mixture of two equilibrium forms, the enol form (primary, as shown in scheme 2) and the keto form (secondary). In a mixture¹In H NMR, the peaks identified as enolic forms are: (400MHz, CDCl)₃)5.88(bs，1H)，3.50(m，2H)，2.67(d，1H，J＝4.8Hz)，1.18(s，3H)，1.16(s，3H)，1.09(s，3H)，0.97(s，3H)，0.93(s，3H)，0.92(s，3H)，0.90(s，3H)；m/z 482.3(M+1)。

Compounds 402-63: 1, 3-dibromo-5, 5-dimethylhydantoin (52mg, 0.18mmol) was added to a solution of compound 7(145mg, 0.30mmol) in DMF (0.70mL) at room temperature. After stirring for 2h, pyridine (73uL, 0.90mmol) was added and the reaction mixture was heated to 55 ℃ for 3 h. After cooling to room temperature, EtOAc (30mL) was added and the mixture was washed with 1N HCl (aq), water, then MgSO₄Dried and concentrated. The resulting residue was purified by column chromatography (silica gel, 0% to 70% EtOAc in hexanes) to give compounds 402-63(115mg, 79%) as a white solid: ¹H NMR(400MHz，CDCl₃)δ7.65(s，1H)，3.50(d，2H，J＝4.8Hz)，2.71(d，1H，J＝4.0Hz)，2.47(dd，1H，J＝4.8，16.0Hz)，2.36(dd，1H，J＝13.6，15.6Hz)，2.21(m，1H)，2.02(dd，1H，J＝4.8，13.6Hz)，1.64-1.92(m，7H)，1.46-1.56(m，2H)，1.23(s，3H)，1.18(s，3H)，1.16(s，3H)，1.10-1.35(m，6H)，1.05(m，1H)，1.00(s，3H)，0.94(s，3H)，0.91(s，3H)；m/z 480.3(M+1)。

Compounds 402-65: DMAP (1mg, 0.008mmol) was added to a mixture of 402-63(18mg, 37.5mmol), acetic anhydride (50. mu.L) and pyridine (0.2 mL). After stirring at room temperature for 30min, NaHCO was added₃(aq) solution and stirred for 5 min. The mixture was extracted with EtOAc and the combined extracts were extracted with NaHCO₃(aq), 1N HCl (aq) and water, then MgSO₄Dried and concentrated. The resulting residue was purified by column chromatography (silica gel, 0% to 30% EtOAc in hexanes) to afford compounds 402-65(13.6mg, 70%) as a white foamy solid:¹H NMR(400MHz，CDCl₃)δ7.63(s，1H)，4.13(d，1H，J＝11.2Hz)，3.86(d，1H，J＝11.2Hz)，2.78(d，1H，J＝4.0Hz)，2.44(dd，1H，J＝5.2，16.0Hz)，2.36(dd，1H，J＝13.2，16.0Hz)，2.18(m，1H)，2.07(s，3H)，2.00(dd，1H，J＝5.2，12.8Hz)，1.93(m，1H)，1.60-1.85(m，6H)，1.49(m，2H)，1.26(s，3H)，1.22(s，3H)，1.17(s，3H)，1.16-1.33(m，4H)，1.15(s，3H)，1.06(m，1H)，1.02(m，1H)，0.98(s，3H)，0.92(s，3H)，0.89(s，3H)；m/z 522.3(M+1)。

compound 9: a mixture of Compound 8(362mg, 0.71mmol) and TMSI (0.11mL, 0.77mmol) in chloroform (2.1mL) was heated in an oil bath at 50 ℃ for 1.5 h. A second portion of TMSI (0.22mL, 1.5mmol) was added and heated for an additional 4 hours. A third portion of TMSI (0.33mL, 2.32mmol) was added and the solution was heated at 50 ℃ for 2h, then a fourth portion of TMSI (1.0mL, 7.0mmol) was added and stirred at 55 ℃ for 1.5 h. During cooling to room temperature, the solution was in water (10mL) and CH₂Cl₂(70 mL). CH (CH)₂Cl₂The extract was washed with brine (20mL) and dried (MgSO)₄). The filtrate was concentrated, and the resulting residue was purified by column chromatography (silica gel, 20% EtOAc in hexanes) to give compound 9(136mg, 39%) as a white solid.

Compound 10: adding 9(2.20g, 4.45mmol) in CH₂Cl₂(100mL) and oxalyl Chloride (CH)₂Cl₂Medium 2M, 12.5mL, 25mmol) was stirred at room temperature for 15 h. The mixture was concentrated under reduced pressure, followed by addition of oxalyl Chloride (CH)₂Cl₂Medium 2M, 5.0mL, 10mmol) and CH₂Cl₂(100 mL). The solution was stirred for 1 hour and the mixture was again concentrated under reduced pressure to give the compound crude acid chloride, which was used directly in the next step. To a solution of the acid chloride in acetonitrile (40mL) was added (trimethylsilyl) diazomethane (2M in hexane, 6.0mL, 12.0mmol) and the mixture was heated to 50 ℃. After 3 hours, additional (trimethylsilyl) diazomethane (2M in hexane, 3.0mL, 6.0mmol) was added. The reaction mixture was stirred at room temperature for 15h, and a third portion of (trimethylsilyl) diazomethane (2M in hexanes, 0.5mL, 1.0mmol) was added. Incubation of the solution at 50 ℃ for 4h did not lead to any further progress based on TLC analysis (40% EtOAc in hexanes). The solution was partitioned in 1M citric acid (100mL) and the dichloromethane phase was successively treated with saturated NaHCO₃Washed (100mL) and brine (100mL) and dried (MgSO)₄). The filtrate was concentrated and the resulting residue was purified by column chromatography (silica gel, 40% EtOAc in hexanes) to give diazomethyl ketone 10(1.78g, 74% yield).

Compounds 402-50: a solution of diazoketone 10(498mg, 0.963mmol), silver benzoate (106mg, 0.46mmol) and triethylamine (8.0mL, 57mmol) in MeOH (100mL) was prepared and heated at 50 deg.C for 2 h. After the reaction mixture was stirred in ethyl acetate (200mL) and saturated aqueous NaHCO₃After partitioning between (100mL), the ethyl acetate layer was washed with water (100mL) and brine (100mL) and dried (MgSO)₄). The crude product isolated upon concentration of the filtrate was dissolved in MeOH (3mL) and treated dropwise by addition of NaOMe (30 wt% solution in methanol, 0.24g, 1.33 mmol). After heating the solution at 50 ℃ for 3h, the reaction mixture was washed with EtOAc (50mL) and saturated aqueous NaHCO₃(50 mL). The solution was washed with water (50mL) and brine (50mL) in that order and dried (MgSO)₄). The crude ester isolated upon concentration of the filtrate was used without further purification. To a solution of the ester in DMF (10mL) was added 1, 3-dibromo-5, 5-dimethylhydantoin (173mg, 0.60mmol), and the reaction was stirred at room temperature for 20 min. Pyridine (4.6mL, 56.87mmol) was then added and the mixture was heated at 50 ℃ for 7.5h and then at 60 ℃ for 3 h. After cooling to room temperature, the reaction was quenched with ethyl acetate (250mL) and saturated aqueous NaHCO₃(50 mL). The ethyl acetate layer was washed with water (100mL) and brine (100mL) in that order and dried (MgSO) ₄). The filtrate was concentrated and the residue (10 g) was removed through a small plug of silica gel using EtOAc (250 mL). The filtrate was concentrated and the crude ester was purified on reverse phase preparative TLC plates to give 402-50 as an off-white solid (44mg, 8% yield):¹HNMR(400MHz，CDCl₃)δ8.05(s，1H)，5.99(s，1H)，3.67(s，3H)，3.04(br d，1H，J＝4.8Hz)，2.52(d，1H，J＝13.2Hz)，2.32(m，1H)，2.27(d，1H，J＝13.2Hz)，1.04-1.96(m，15H)，1.50(s，3H)，1.27(s，6H)，1.19(s，3H)，1.02(s，3H)，0.94(s，3H)，0.88(s，3H)；m/z 520.44(M+1)，561.39(M+1+CH₃CN)。

compounds 402-54: to a solution of 402-50(26mg, 0.05mmol) in 3: 1 MeOH: to a solution in water (6mL) was added lithium hydroxide monohydrate (138mg, 3.3mmol) and the reaction was stirred at room temperature for 15h, then at 50 ℃ for 4 h. After the solution was partitioned between EtOAc (75mL) and 1M HCl (25mL), the ethyl acetate organic phase was washed successively with water (25mL) and brine (25mL) and dried (MgSO)₄). The crude product isolated upon concentration of the filtrate was chromatographed using preparative TLC to give 402-54(13mg, 52% yield) as a pale yellow solid:¹H NMR(400MHz，CDCl₃)δ8.05(s，1H)，6.01(s，1H)，3.04(br d，1H，J＝4.4Hz)，2.54(d，1H，J＝13.2Hz)，2.37(m，1H)，2.30(d，1H，J＝12.8Hz)，1.12-2.02(m，15H)，1.27(s，3H)，1.26(s，3H)，1.19(s，3H)，1.03(s，3H)，0.95(s，3H)，0.89(s，3H)；m/z 506.38(M+1)，547.43(M+1+CH₃CN)。

compound 63239: at room temperature 402-63(24.0mg, 50. mu. mol) and Et₃N (0.5mL) in CH₂Cl₂(1.0mL) to the solution was added (EtO)₂POCl (7.2. mu.l, 50. mu. mol) in CH₂Cl₂(1.0 mL). The reaction mixture was stirred at rt for 5.5 h. Adding another part (EtO)₂POCl (72. mu.l, 500. mu. mol) and the reaction mixture was stirred at room temperature for 88.5 h. The reaction mixture was diluted with EtOAc (30mL) and then H₂The reaction was stopped with O (10 mL). The organic phase was washed with brine and Na ₂SO₄Dried, filtered, and concentrated. The crude product was purified by column chromatography (silica gel, 0% to 40% to 50% EtOAc in hexanes) to give product 63239(10.6mg, 34%) as a white foam:¹H NMR(400MHz，CDCl3)δ7.64(1H，s)，4.20-4.31(1H，m)，3.98-4.15(4H，m)，3.74-3.82(1H，m)，2.82(1H，d，J＝4.4Hz)，2.31-2.50(2H，m)，2.22-2.31(1H，m)，1.72-2.04(5H，m)，1.56-1.72(5H，m)，1.43-1.56(2H，m)，1.27-1.41(7H，m)，1.02-1.26(3H，m)，1.28(3H，s)，1.22(3H，s)，1.18(3H，s)，1.15(3H，s)，0.98(3H，s)，0.93(3H，s)，0.90(3H，s)；m/z 616.3(M+1)。

compound 11: to a stirred suspension of N- (phenylthio) -phthalimide (228mg, 900. mu. mol) in benzene (2.5mL) was added tributylphosphine (238. mu.L, 900. mu. mol) at room temperature. The reaction mixture was stirred at room temperature for 10min to form a pale yellow clear solution. This solution was added to a stirred solution of 6(204.5mg, 425. mu. mol) in benzene (5.0mL) at room temperature. The reaction mixture was stirred at room temperature for 22h, after which it was loaded directly onto a silica gel column and purified by column chromatography (0% to 10% to 30% EtOAc in hexanes) to give 11(103.3mg, 42%) as a pale yellow foam.

Compound 12 a: to a solution of 11(53.0mg, 92.4. mu. mol) in EtOH (5.0mL) at 0 deg.C was added Oxone (34.6mg, 56. mu. mol) in H₂Solution in O (5.0 mL). The reaction mixture was stirred at 0 ℃ for 1.5h, then at room temperature for 27 h. Adding CH₃CN (5.0 mL). The reaction mixture was stirred at room temperature for 42h, and the organic solvent was removed under reduced pressure. The remaining aqueous mixture was diluted with water (5.0mL) and CH ₂Cl₂(2X 20.0 mL). Mixed organic phases with Na₂SO₄Dried, filtered, and concentrated. The crude product was purified by column chromatography (silica gel, 0% to 20% to 40% EtOAc in hexanes) to give 12a (35.5mg, 65%, major diastereomer) as a white foam.

Compound 63255: compound 12a (35mg, 59 μmol) was converted to 63255(22.4mg, 64%) as a pale yellow foam using the procedure described for the synthesis of compounds 402-63 from 6 (scheme 2):¹HNMR(400MHz，CDCl3)δ7.62(s，1H)，7.60-7.65(m，2H)，7.46-7.55(m，3H)，3.19(d，1H，J＝13.6Hz)，2.48-2.58(m，2H)，2.43(dd，1H，J＝16.8，4.4Hz)，2.23(dd，1H，J＝16.4，13.2Hz)，1.94-2.10(m，3H)，1.84-1.94(m，2H)，1.76-1.84(m，1H)，1.38-1.74(m，9H)，1.23-1.37(m，2H)，1.22(s，3H)，1.16(s，3H)，1.15(s，3H)，1.40(s，3H)，0.97(s，3H)，0.96(s，3H)，0.93(s，3H)；m/z 588.3(M+1)。

compound 12 b: to a solution of Compound 11(53.0mg, 92.4. mu. mol) in EtOH (5.0mL) at 0 deg.C was added Oxone (34.6mg, 56. mu. mol) in H₂Solution in O (5.0 mL). The reaction mixture was stirred at 0 ℃ for 1.5h,then stirred at room temperature for 26.5 h. Adding CH₃CN (5.0 mL). The reaction mixture was stirred at room temperature for 42h and the organic solvent was removed under reduced pressure. The remaining aqueous mixture was diluted with water (5.0mL) and CH₂Cl₂(2X 20 mL). Mixed organic phases with Na₂SO₄Dried, filtered, and concentrated. The crude product was purified by column chromatography (silica gel, 0% to 20% to 40% EtOAc in hexanes) followed by a second column chromatography (silica gel, 0% to 30% EtOAc in hexanes) to give 12b (5.2mg, 9.5%, minor diastereomer) as a white foam.

Compound 63288: compound 12b (5.2mg, 8.8 μmol) was converted to 63288(2.4mg, 46%) as a white foam using the procedure described for the synthesis of compounds 402-63 from 6:¹H NMR(400MHz，CDCl₃)δ7.66(s，1H)，7.58-7.64(m，2H)，7.46-7.56(m，3H)，3.05-3.15(m，2H)，2.51-2.66(m，2H)，2.36-2.53(m，3H)，2.07-2.24(m，3H)，1.84-2.06(m，3H)，0.96-1.78(m，9H)，1.26(s，3H)，1.23(s，3H)，1.18(s，3H)，1.16(s，3H)，1.06(s，3H)，1.00(s，3H)，0.95(s，3H)。m/z 588.3(M+1)。

compound 13: to 11(50.3mg, 87.7. mu. mol) in EtOH-CH at room temperature₃CN (1: 1 v/v, 6.0mL) was added Oxone (270.8mg, 438. mu. mol) in H₂Solution in O (1.0 mL). The reaction mixture was stirred at room temperature for 24h and the organic solvent was removed under reduced pressure. The remaining aqueous mixture was diluted with water (15.0mL) and extracted with EtOAc (30 mL). The organic phase was washed with brine and Na₂SO₄Dried, filtered, and concentrated. The crude product was purified by column chromatography (silica gel, 0% to 30% EtOAc in hexanes) to give compound 13(48.5mg, 91.3%) as a colorless solid.

Compound 63266: compound 13(48mg, 79 μmol) was converted to 63266(8.5mg, 17.6%, calculated starting from 8) as a pale yellow foam using the procedure described for the synthesis of compounds 402-63 from 6 (scheme 2);¹H NMR(400MHz，CDCl3)δ77.86-7.94(2H，m)，7.62-7.68(1H，m)，7.62(1H，s)，7.53-7.59(2H，m)，3.18(1H，d，J＝14.4Hz)，3.11(1H，d，J＝14.4Hz)，2.64(1H，d，J＝4.4Hz)，2.32-2.54(2H，m)，2.14-2.32(2H，m)，1.94-2.11(2H，m)，1.42-1.88(9H，m)，1.19-1.40(2H，m)，1.23-1.37(2H，m)，1.23(3H，s)，1.17(3H，s)，1.16(6H，s)，1.00(3H，s)，0.98(3H，s)，0.90(3H，s)；m/z 604.3(M+1)。

compound 16: oxalyl chloride (1.54mL, 18.19mmol) and a catalytic amount of DMF were added sequentially to compound 15(2.85g, 6.07mmol) in CH at 0 deg.C₂Cl₂(60 mL). The reaction mixture was warmed to room temperature and stirred for 2 h. After removal of the solvent by evaporation, the crude acid chloride was obtained as a white foamy solid, which was then dissolved in THF (60mL) and washed with NH at 0 deg.C ₃(2.0M in MeOH, 30 mL). The reaction mixture was stirred at room temperature for 1h, after which the solvent was removed by evaporation. The residue was dissolved in EtOAc, transferred to a separatory funnel, and washed with water. Separating the organic phase with MgSO₄Dried and evaporated. The residue was purified by column chromatography (silica gel, 0% to 100% EtOAc in hexanes) to give compound 16(2.70g, 94% yield) as a yellow foamy solid: m/z 470.3(M + 1).

Compound 17: LAH (2.0M in THF, 17.2mL, 34.4mmol) was added to a solution of compound 16(2.70g, 5.76mmol) in THF (115mL) at room temperature. The reaction was heated to reflux for 4h and then cooled to 0 ℃. EtOAc (10mL) and water (5mL) were added sequentially and the reaction was quenched slowly. The resulting mixture was heated under reflux for 5min and then filtered through a pad of celite. The celite was washed with additional hot THF. The combined filtrates were concentrated to give product 17(2.69g) as a white foamy solid. Compound 17 is a mixture of the C3 and C12 epimers, both of which have M/z 460.3(M + 1).

Compound 18: at room temperature (Boc)₂O (1.61mL, 7.02mmol) was added to Compound 17(2.69g, 5.86mmol), NaHCO₃(3.20g, 38.09mmol), water (12mL) and THF (59 mL). After stirring at room temperature for 4h, the reaction mixture was diluted with EtOAc, transferred to a separatory funnel, and washed with water. Separating the organic phase with MgSO ₄Dried and evaporated. Residue is remainedPurification by column chromatography (silica gel, 0% to 60% EtOAc in hexanes) afforded compound 18(1.96g, 60% yield) as a white foamy solid. Compound 18 is a mixture of the C3 and C12 epimers, all of which have M/z468.3 (M-C)₄H₈-2×H₂O+1)。

Compound 19: using the method described for the synthesis of mixture 4 from compound 3, compound 19(680mg, 94% yield) was produced from compound 18(725mg, 1.30mmol) as a white foamy solid: m/z500.3 (M-C)₄H₈+1)，456.3(M-Boc+1+1)。

Compound 20: using the procedure described for the synthesis of compound 6 from compound 4, compound 20(545mg, 75% yield) was produced from compound 19(700mg, 1.26mmol) as a white foamy solid: m/z581.4(M + 1).

Compound 63253: using the procedure described for the synthesis of compounds 402-63 from compound 6, product 63253 was produced as a white foamy solid from compound 20(545mg, 0.94mmol) (460mg, 84% yield): m/z 523.3 (M-C)₄H₈+1)，479.3(M-Boc+1+1)。

Compound 63214: CF at 0 DEG C₃CO₂H (2.98mL, 38.7mmol) was added to compound 63253(458mg, 0.79mmol) in CH₂Cl₂(15 mL). After stirring the reaction mixture at 0 ℃ for 4h, the solvent was removed by evaporation. The residue was dissolved in EtOAc, transferred to a separatory funnel, and washed with NaHCO ₃(aq.) solution wash. Separating the organic phase with MgSO₄Drying and evaporation gave product 63214 as a white foamy solid:¹H NMR(400MHz，CDCl₃)δ7.63(s，1H)，2.65-2.70(m，2H)，2.52(d，1H，J＝12.8Hz)，2.45(dd，1H，J＝5.2，16.8Hz)，2.35(dd，1H，J＝12.8，16.4Hz)，2.09(m，1H)，2.00(dd，1H，J＝5.2，12.8Hz)，1.49-1.87(m，13H)，1.21(s，6H)，1.17(s，3H)，1.15(s，3H)，1.06-1.33(m，3H)，1.02(m，1H)，0.98(s，3H)，0.91(s，3H)，0.89(s，3H)；m/z 479.3(M+1)。

manufacture ofGeneral procedure for derivatives of compound 63214: RX was added to a solution of compound 63214 and a base in a solvent (see table 1 for details). After stirring for the time indicated in table 1, EtOAc was then added. The mixture was then transferred to a separatory funnel using NaHCO₃(aq.) solution wash. Separating the organic phase with MgSO₄Dried and evaporated. The residue was purified by column chromatography to give the desired target compound.

Compound 63218: a white foamy solid;¹H NMR(500MHz，CDCl₃)7.65(s，1H)，3.61(s，2H)，2.73(d，1H，J＝4.0Hz)，2.63(s，2H)，2.47(dd，1H，J＝5.0，16.5Hz)，2.38(dd，1H，J＝13.5，16.5Hz)，2.16(m，1H)，2.02(dd，1H，J＝5.0，13.0Hz)，1.92(m，1H)，1.74-1.83(m，2H)，1.60-1.71(m，4H)，1.49-1.57(m，2H)，1.31(m，1H)，1.29(s，3H)，1.28(m，1H)，1.23(s，3H)，1.18(s，3H)，1.17-1.23(m，2H)，1.16(s，3H)，1.04-1.12(m，3H)，0.99(s，3H)，0.92(s，3H)，0.90(s，3H)；m/z 518.3(M+1)。

compound 63220: a white foamy solid;¹H NMR(400MHz，CDCl₃)7.63(s，1H)，4.28(dd，1H，J＝6.4，7.6Hz)，3.16(dd，1H，J＝8.0，12.8Hz)，2.95(s，3H)，2.95(m，1H)，2.76(d，1H，J＝4.0Hz)，2.33-2.48(m，2H)，2.12(m，1H)，1.99(dd，1H，J＝4.8，12.4Hz)，1.78-1.94(m，3H)，1.58-1.70(m，3H)，1.46-1.54(m，3H)，1.27(s，3H)，1.24-1.36(m，2H)，1.21(s，3H)，1.17(s，3H)，1.15(s，3H)，1.13-1.20(m，2H)，1.05(m，1H)，0.98(s，3H)，0.94(m，1H)，0.91(s，3H)，0.90(s，3H)；m/z557.3(M+1)。

compound 63226: a white foamy solid;¹H NMR(400MHz，CDCl₃)7.63(s，1H)，6.32(m，1H)，3.50(dd，1H，J＝7.2，13.6Hz)，3.22(dd，1H，J＝6.0，13.6Hz)，2.93(d，1H，J＝4.0Hz)，2.36-2.47(m，2H)，1.85-2.04(m，6H)，1.61-1.71(m，3H)，1.52(m，2H)，1.34(s，3H)，1.19-1.34(m，4H)，1.22(s，3H)，1.18(s，3H)，1.15(s，3H)，1.05(m，1H)，0.97(s，3H)，0.94(m，1H)，0.90(s，6H)；m/z 575.3(M+1)。

compound 63232: a white foamy solid;¹H NMR(400MHz，CDCl₃)7.63(s，1H)，5.96(d，1H，J＝0.8Hz)，3.81(s，2H)，3.49(s，2H)，2.56(d，1H，J＝4.0Hz)，2.40(d，3H，J＝0.8Hz)，2.38-2.51(m，3H)，2.28(m，1H)，2.16(m，1H)，1.97(m，1H)，1.73-1.86(m，2H)，1.40-1.69(m，8H)，1.30(m，1H)，1.22(s，3H)，1.19(m，1H)，1.17(s，3H)，1.16(s，3H)，1.10(m，1H)，1.06(s，3H)，0.96(m，1H)，0.94(s，3H)，0.92(s，3H)，0.88(s，3H)；m/z 574.4(M+1)。

compound 63233: a white foamy solid;¹H NMR(400MHz，CDCl₃)7.64(s，1H)，4.33(s，3H)，4.07(s，2H)，2.67(d，1H，J＝4.0Hz)，2.61(d，1H，J＝11.6Hz)，2.44(dd，1H，J＝5.2，16.4Hz)，2.41(d，1H，J＝11.2Hz)，2.34(dd，1H，J＝13.2，16.4Hz)，2.10(m，1H)，2.00(dd，1H，J＝5.2，l2.8Hz)，1.75-1.87(m，2H)，1.61-1.72(m，5H)，1.44-1.59(m，3H)，1.22(s，3H)，1.13-1.33(m，5H)，1.18(s，3H)，1.16(s，3H)，1.15(s，3H)，1.00(m，1H)，0.96(s，3H)，0.91(s，3H)，0.88(s，3H)；m/z 575.4(M+1)。

compound 21: TEMPO (27mg X4, 0.17mmol X4) and IPh (OAc) at room temperature at 0h, 2h, 24h and 48h₂(563 mg. times.4, 1.74 mmol. times.4) was added to the reactionCompound 3(725mg, 1.59mmol) in CH₂Cl₂(200mL) and water (0.1 mL). After stirring at room temperature for 72h (total reaction time), the reaction mixture became a clear pink solution, which was then transferred to a separatory funnel and washed with Na₂SO₃(aq) solution wash. Separating the organic phase with MgSO ₄Dried, filtered and evaporated. The residue was purified by silica gel chromatography (0% to 75% EtOAc in hexanes) to give compound 21(560mg, 77%) as a white solid:¹H NMR(400MHz，CDCl₃)9.37(d，1H，J＝1.2Hz)，3.77(m，1H)，3.18(dd，1H，J＝4.8，11.2Hz)，2.51(m，1H)，0.98-1.87(m，23H)，0.97(s，3H)，0.96(s，3H)，0.94(s，3H)，0.92(m，1H)，0.90(s，3H)，0.86(s，3H)，0.82(s，3H)，0.75(s，3H)，0.65(m，1H)；m/z 441.3(M-H₂O+1)，423.3(M-2×H₂O+1)。

compound 22: to a suspension of KOt-Bu (100mg, 0.89mmol) in THF (2.5mL) was added methyltriphenylphosphine bromide (390mg, 1.09 mmol). The resulting yellow slurry was stirred at room temperature for 30 min. To the reaction mixture was added a solution of compound 21(100mg, 0.22mmol) in THF (2.5 mL); the addition was washed with THF (. about.0.5 mL) using a syringe and the wash was added to the reaction mixture. The reaction mixture was stirred at rt for 14h (TLC showed the reaction was complete within 1 h). The reaction mixture was extracted with EtOAc (. about.100 mL) and washed with water (. about.50 mL) and brine (. about.50 mL). The organic phase is MgSO₄Dried, filtered and evaporated. The resulting yellow oil was purified by silica gel chromatography (0% to 60% EtOAc in hexanes) to give compound 22(95mg, 95% yield) as a white solid.

Compound 23: sodium acetate (81mg, 0.99mmol) and PCC (160mg, 0.74mmol) were added to compound 22(113mg, 0.25mmol) in CH₂Cl₂(5 mL). The reaction mixture was stirred at room temperature for 2h, after which 1: 1 hexanes to EtOAc (. about.20 mL) was added. The reaction mixture was stirred for 5min and then filtered through a pad of silica gel. The silica gel was washed thoroughly with additional 1: 1 hexanes EtOAc. The filtrate was concentrated, and the residue was purified by silica gel chromatography (0% to 30% EtOAc in hexanes) to give compound 23(97mg, 87% yield) as a white foamy solid: m/z 453.3.

Compound 24: compound 23(643mg, 1.42mmol) was suspended in ethyl formate (3.43mL, 42.64mmol) and cooled to 0 ℃. Sodium methoxide (25 wt% solution in MeOH) (4.88mL, 21.34mmol) was added to the reaction mixture. The reaction mixture was stirred at room temperature for 1.5h, then cooled to 0 ℃. EtOH (22mL) and 12N HCl (aq) (1.79mL, 21.48mmol) were added sequentially followed by NH₂OH-HCl (198mg, 2.85mmol) and water (1.1 mL). The resulting mixture was heated at 60 ℃ for 3 h. EtOH was removed by evaporation and the residue was extracted with EtOAc and washed with water. The organic phase extract is extracted with MgSO 2₄Dried, filtered and evaporated. The residue was purified by silica gel chromatography (0% to 20% EtOAc in hexanes) to give compound 24(613mg, 90% yield) as a white crystalline solid: m/z 478.3(M + 1).

Compound 25: NaOMe solution (25% w/w in MeOH, 0.13mL, 0.56mmol) was added to the iso-isomerOxazole 24(200mg, 0.42mmol) in MeOH (4mL) and THF (1 mL). The mixture was stirred at 55 ℃ for 2h and cooled to 0 ℃. t-BuOMe (10mL) and 1N HCl (aq) (1mL) were added sequentially. The mixture was extracted with EtOAc and the combined extracts were washed with water, MgSO ₄Dried, filtered and concentrated to give crude cyanoketone 25(200mg, 100% yield) as a white foamy solid: m/z 478.3(M + 1).

Compound 63213: DDQ (100mg, 0.44mmol) in benzene (2mL) was added over 30min to a refluxing solution of crude cyanoketone 25(200mg, 0.42mmol) in benzene (6 mL). After addition, the reaction mixture was continued to reflux for 1h, then cooled to room temperature and transferred to a separatory funnel. NaHCO for reaction mixture₃(aq.) washing with MgSO₄Dried, filtered and evaporated. The residue was chromatographed on silica gel (hexane)0% to 20% EtOAc in alkane) to give a mixture of product 63213 and unchanged compound 25(154mg) as a white foamy solid, which was then dissolved in pyridine (1mL) and treated with Ac₂O (0.2mL) and a catalytic amount of DMAP. The mixture was stirred at room temperature for 15min, after which NaHCO was added₃(aq.) solution, and stirred for 5 min. The crude product was transferred to a separatory funnel and extracted with EtOAc. The combined organic extracts were washed with 1N HCl (aq.) and water, over MgSO₄Dried, filtered and evaporated. The residue was purified by silica gel chromatography (0% to 20% EtOAc in hexanes) to give product 63213(67mg, 34% yield) as a white foamy solid: ¹H NMR(400MHz，CDCl₃)δ7.63(s，1H)，5.64(dd，1H，J＝11.2，18.0Hz)，5.09(dd，1H，J＝0.8，11.2Hz)，5.00(dd，1H，J＝0.8，18.0Hz)，2.77(d，1H，J＝4.4Hz)，2.43(dd，1H，J＝4.8，16.4Hz)，2.32(dd，1H，J＝12.8，16.4Hz)，2.24(m，1H)，1.94-1.99(m，2H)，1.85(m，1H)，1.78(m，1H)，1.60-1.68(m，3H)，1.42-1.56(m，4H)，1.24-1.36(m，3H)，1.21(s，3H)，1.17(m，1H)，1.15(s，3H)，1.14(s，3H)，1.12(s，3H)，0.99(m，1H)，0.95(s，6H)，0.90(s，3H)；m/z 476.3(M+1)。

Compound 26: OsO is added at room temperature₄(0.1M in t-BuOH, 0.30mL, 0.01mmol) was added to a solution of compound 24(145mg, 0.30mmol) and NMO (142mg, 1.21mmol) in THF (3.0mL) and water (0.3 mL). The reaction mixture was stirred for 24h, after which EtOAc was added. The mixture was transferred to a separatory funnel and washed with Na₂SO₃(aq.) solution and water washing with MgSO 2₄Dried, filtered and evaporated. The residue was purified by silica gel chromatography (0% to 80% EtOAc in hexanes) to give compound 25(123mg, 79% yield) as a white foamy solid. Compound 26 is a mixture of two C28 epimers, each having: m/z 512.3(M + 1).

Compound 27: compound 27(157mg, 100% yield) was produced as a white foamy solid from compound 26(156mg, 0.30mmol) using the procedure described for the synthesis of compound 6 from compound 5. Compound 27 is a mixture of two C28 epimers with the a-cyclic keto-enol isomer. All 4 isomers have: m/z 494.3(M-18+ 1).

Compounds 63221 and 63224: a solution of 1, 3-dibromo-5, 5-dimethylhydantoin (57mg, 0.20mmol) in DMF (0.5mL) was added to a solution of compound 27(157mg, 0.30mmol) in DMF (1mL) at room temperature. The reaction mixture was stirred at room temperature for 2h, after which pyridine (74uL, 0.91mmol) was added. The reaction mixture was heated at 55 ℃ for 16h and then cooled to room temperature. EtOAc was added and the mixture was transferred to a separatory funnel, washed with 1N HCl (aq), water, MgSO ₄Dried and evaporated. The resulting residue was purified by column chromatography (silica gel, 0% to 100% EtOAc in hexanes) to give 63221(67mg, 42% yield) and 63224(29mg, 18% yield), both as white solids.

Compound 63221 (1.2: 1 mixture of C28-epimers):¹H NMR(400MHz，CDCl₃)7.66(s，0.55H)，7.65(s，0.45H)，3.97(m，1.1H)，3.76(m，0.9H)，3.68(t，0.45H，J＝9.6Hz)，3.58(t，0.55H，J＝10.0Hz)，2.86(d，0.55H，J＝4.4Hz)，2.73(d，0.45H，J＝4.0Hz)，2.66(m，0.55H)，2.33-2.52(m，4H)，2.16(m，0.45H)，0.92-2.05(m，16H)，1.27(s，3H)，1.24(s，3H)，1.19(s，3H)，1.17(s，3H)，1.01(s，3H)，0.96(s，1.35H)，0.91(s，1.35H)，0.90(s，1.65H)，0.89(s，1.65H)；m/z492.3(M-18+1)；492.3(M-18+1)。

compound 63224:¹H NMR(500MHz，CDCl₃)7.71(s，1H)，4.05(m，1H)，3.71(ddd，1H，J＝4.0，8.0，12.0Hz)，3.61(dd，1H，J＝3.5，9.0Hz)，2.95(dd，1H，J＝14.0，14.5Hz)，2.40(dd，1H，J＝3.0，14.0Hz)，2.33(dd，1H，J＝4.0，12.0Hz)，2.06(m，1H)，1.96(m，1H)，1.79(dd，1H，J＝3.0，14.0Hz)，1.48(s，3H)，1.29-1.75(m，11H)，1.22(s，3H)，1.20(s，3H)，1.17(s，3H)，1.10-1.24(m，3H)，0.98(s，3H)，0.97(s，3H)，0.89(s，3H)；m/z 508.3(M+1)，490.3(M-18+1)。

compound 63225: 63214(35.8mg, 75. mu. mol) in CH at 0 deg.C₂Cl₂Et (3.0mL) was added to the solution₃N (15.2. mu.l), followed by addition of CF₃CH₂SO₂Cl (11.1. mu.l, 100.4. mu. mol). The reaction mixture was stirred at 0 ℃ for 1.5 h. The reaction mixture was diluted with EtOAc (30mL) and then NaHCO₃The reaction was terminated (5 mL). The organic phase was washed with brine and Na₂SO₄Dried, filtered and concentrated to give crude 63225(56.4 mg). The crude product was purified by column chromatography (silica gel, 0% to 10% to 30% EtOAc in hexanes) to give product 63225(29.4mg, 53%) as a white foam:¹H NMR(400MHz，CDCl3)δ7.65(1H，s)，4.71(1H，dd，J＝7.6，5.6Hz)，3.81(2H，q，J＝9.2Hz)，3.23(1H，dd，J＝12.8，8.0Hz)，2.97(1H，d，J＝12.8，5.2Hz)，2.75(1H，d，J＝4.0Hz)，2.30-2.52(2H，m)，2.07-2.14(1H，m)，1.98-2.04(1H，m)，1.76-1.96(3H，m)，1.60-1.73(3H，m)，1.44-1.56(3H，m)，1.18-1.41(4H，m)，1.26(3H，s)，1.22(3H，s)，1.18(3H，s)，1.16(3H，s)，1.02-1.15(2H，m)，0.99(3H，s)，0.92(3H，s)，0.91(3H，s)；m/z 625.3(M+1)。

compound 63228: to compound 402-63(43.2mg, 90. mu. mol) and 2, 6-di-tert-butyl-4-methylpyridine (37.8mg, 0.18mmol) in CH at room temperature₂Cl₂(1.0mL) to the solution was added CF₃SO₃CH₃(18.1. mu.l, 162. mu. mol). The reaction mixture was stirred at room temperature for 72 h. The reaction mixture was diluted with EtOAc (50mL) and quenched with HCl (1N, 5 mL). The organic phase was washed with brine and Na ₂SO₄Dried, filtered, and concentrated. The crude product was purified by column chromatography (silica gel, 0% to 10% to 20% EtOAc in hexanes) to afford 63228(29.3mg, 66%) as a white solid:¹H NMR(400MHz，CDCl3)δ7.65(1H，s)，3.31(3H，s)，3.19(2H，q，J＝8.8Hz)，2.76(1H，d，J＝4.4Hz)，2.30-2.50(2H，m)，2.20-2.28(1H，m)，2.02(1H，dd，J＝12.8，5.2Hz)，1.60-1.90(7H，m)，1.45-1.56(2H，m)，1.06-1.32(5H，m)，1.24(3H，s)，1.23(3H，s)，1.18(3H，s)，1.16(3H，s)，0.97-1.05(1H，m)，0.98(3H，s)，0.93(3H，s)，0.88(3H，s)；m/z 494.3(M+1)。

compound 28: at 0 ℃ bringing BH₃-THF (1.0M in THF, 1.80mL, 1.80mmol) was added to a solution of compound 22(165mg, 0.36mmol) in THF (7.2 mL). The reaction mixture was stirred at room temperature for 3h and then cooled again to 0 ℃. Water (0.60mL) was added carefully followed by 3N NaOH (aq.) (1.20mL) and 30% H₂O₂(aq.) (1.20 mL). The resulting reaction mixture was stirred at rt for 14h, then transferred to a separatory funnel and extracted with EtOAc. The combined extracts were washed with water and MgSO₄Dried and evaporated. The residue was purified by column chromatography (silica gel, 20% to 100% EtOAc in hexanes) to give compound 2(148mg, 86% yield) as a white foamy solid: m/z 439.3 (M-2X 18+ 1).

Compound 29: TBSCl (51mg, 0.34mmol) was added to a solution of compound 28(133mg, 0.28mmol) and imidazole (38mg, 0.56mmol) in DMF (2.7mL) at 0 ℃. Stirring at 0 deg.C for 10min, and adding NaHCO₃(aq.) the reaction was stopped and stirred for 30 min. The mixture was then transferred to a separatory funnel and washed with CH ₂Cl₂And (4) extracting. The combined extracts were washed with water and MgSO₄Dried and evaporated. The residue was purified by column chromatography (silica gel, 0% to 40% EtOAc in hexanes) to give compound 29(122mg, 69% yield) as a white foamy solid.

Compound 30: NMO (66mg, 0.56mmol) and TPAP (10mg, 0.028mmol) were added successively to compound 29(110mg, 0.19mmol) andmolecular sieves (110mg) in CH₂Cl₂(3.7 mL). The reaction mixture was stirred at room temperature for 1h, after which Na was added₂SO₃(aq.) solution, and stirred for 5 min.The mixture was filtered through a pad of celite and supplemented with additional CH₂Cl₂The diatomaceous earth was washed. The filtrate was transferred to a separatory funnel, washed with water, and MgSO₄Dried and evaporated. The residue was purified by column chromatography (silica gel, 0% to 30% EtOAc in hexanes) to give compound 30(105mg, 95% yield) as a white foamy solid.

Compound 31: LDA (1.0M in THF, 0.264mL, 0.264mmol) was added to a solution of compound 30(103mg, 0.18mmol) in THF (1.76mL) at-78 deg.C. After stirring for 30min, TsCN (64mg, 0.35mmol) in THF (0.5mL) was added and the mixture was stirred for a further 2 h. By NH₄The reaction was stopped with a solution of Cl (aq.) and then warmed to room temperature. The crude product was extracted with EtOAc and the combined extracts were washed with water, MgSO ₄Dried and evaporated. The residue was purified by column chromatography (silica gel, 0% to 10% EtOAc in hexanes) and the resulting product was dissolved in THF (1.0mL) and then treated with 3N HCl (aq.) (0.33mL, 0.99mmol) at room temperature. The mixture was stirred for 20min, after which EtOAc was added. The mixture was transferred to a separatory funnel and washed with water. Separating the organic phase with MgSO₄Dried and evaporated. The residue was purified by column chromatography (silica gel, 0% to 70% EtOAc in hexanes) to give compound 31(43mg, 49% yield) as a white foamy solid. Compound 31 is a mixture of a-cyclic keto-enol isomers, and both isomers have M/z 496.3(M + 1).

Compound 63231: using the procedure described for the synthesis of compounds 402-63 from compound 7, product 63231 was produced as a white foamy solid from compound 31(43mg, 0.087mmol) (22mg, 51% yield):¹H NMR(400MHz，CDCl₃)δ7.65(s，1H)，3.73(m，2H)，2.88(d，1H，J＝4.4Hz)，2.46(dd，1H，J＝5.2，16.4Hz)，2.37(dd，1H，J＝12.8，16.4Hz)，2.00-2.08(m，2H)，1.78-1.96(m，2H)，1.50-1.77(m，10H)，1.30(m，1H)，1.27(s，3H)，1.23(s，3H)，1.19(s，3H)，1.16(s，3H)，1.13-1.23(m，3H)，1.00-1.06(m，2H)，0.98(s，3H)，0.92(s，3H)，0.89(s，3H)；m/z 494.3(M+1)。

compound 63235: using the procedure for the synthesis of compounds 402-63 from compound 6 (scheme 2), product 63235(8.6mg, 35%, calculated starting from 11) was produced from compound 11(25mg, 44 μmol) as a white foam:¹h NMR (400MHz, CDCl3) δ 7.61(1H, s), 7.37-7.45(2H, m), 7.23-7.30(2H, m), 7.16-7.20(1H, m), 3.06(1H, d, J ═ 12.8Hz), 2.87(1H, d, J ═ 12.8Hz), 2.29-2.46(3H, m), 1.76-2.16(5H, m), 1.54-1.73(6H, m), 1.16-1.53(6H, m), 1.21(3H, s), 1.14(3H, s), 1.11(3H, s), 1.01(3H, s), 0.99(3H, s), 0.93(3H, s), 0.90(3H, s). LC-MS (MS spectrum, ESI); m/z 572.3(M + 1).

Compound 63269: to a solution of 402-63(36.0mg, 75. mu. mol), pyridine (48.2. mu.L, 0.6mmol) and 4-DMAP (9.2mg, 75. mu. mol) in THF (0.5mL) at 0 deg.C was added POCl₃(68. mu.l, 75. mu. mol). The reaction mixture was stirred at 0 ℃ for 2h and then at room temperature for 1 h. The reaction mixture was diluted with THF (2.5mL) and 1N HCl (aq) (3.0mL) and then stirred at room temperature for 23 h. The organic volatiles were removed in vacuo. The remaining mixture was diluted with water (10mL) and extracted with EtOAc (2X 30 mL). The combined organic phases were washed with 1N HCl (aq) and brine, Na₂SO₄Drying, filtration and concentration gave compound 63269. The crude product was purified by column chromatography (silica gel, 5% to 10% to 35% EtOAc in hexanes) to afford compound 63269(20.0mg, 48%) as a white solid:¹H NMR(400MHz，CD₃OD)δ7.96(s，1H)，3.82-3.94(m，1H)，3.56-3.70(m，1H)，2.98(d，1H，J＝3.6Hz)，2.46-2.58(m，2H)，2.30-2.40(m，1H)，2.04-2.12(m，1H)，1.65-2.02(m，7H)，1.45-1.64(m，2H)，0.97-1.40(m，6H)，1.33(s，3H)，1.22(s，3H)，1.21(s，3H)，1.15(s，3H)，1.00(s，3H)，0.94(s，3H)，0.88(s，3H)；m/z 558.3(M+1)。

compound 33: NaHCO is added at room temperature₃(87mg, 1.04mmol) and dess-Martin oxidant (110mg, 0.26mmol) were added sequentially to compound 6(50mg, 0.10mmol) in CH₂Cl₂(1.0 mL). After stirring for 1h, Na was added₂SO₃(aq.) the reaction was stopped and stirred for 5 min. Inverse directionThe mixture was extracted with EtOAc and the combined EtOAc extract was extracted with NaHCO₃(aq) solution and water wash. Separating the organic layer, and reacting with MgSO₄Dried, filtered, and concentrated. The crude product was purified by column chromatography (silica gel, 0% to 25% EtOAc in hexanes) to give product 33(24mg, 48% yield) as a white foamy solid: m/z 480.3(M + 1).

Compound 34: reacting CF at room temperature₃CH₂NH₂(36. mu.L, 0.46mmol) was added to a solution of compound 33(22mg, 0.046mmol) in MeOH (0.4mL) and THF (0.4 mL). After stirring for 1h, AcOH (26. mu.L, 0.46mmol) was added. After stirring for an additional 5min, NaBH in MeOH (0.2mL) was added₃CN (43mg, 0.68 mmol). The reaction mixture was stirred at room temperature for 2h, after which NH was used₄Cl (aq) solution to stop the reaction. The reaction mixture was extracted with EtOAc, and the combined EtOAc extracts were washed with water. The organic layer was separated and then MgSO₄Dried, filtered, and concentrated. The crude product was purified by column chromatography (silica gel, 0% to 20% EtOAc in hexanes) to give product 34(22mg, 85% yield) as a white foamy solid: m/z 563.3(M + 1).

Compound 35: NaOMe (25 w/w% solution in MeOH, 18. mu.L, 0.079mmol) was added to a solution of compound 34(22mg, 0.039mmol) in MeOH (0.2mL) at room temperature. The reaction mixture was then heated to 55 ℃ and stirred for 1 h. After cooling to 0 ℃, t-BuOMe and 1N HCl (aq) were added and the mixture was stirred for 5 min. The reaction mixture was transferred to a separatory funnel and extracted with EtOAc. The combined EtOAc extracts were washed with water and MgSO₄Dried, filtered, and concentrated. The crude product was purified by column chromatography (silica gel, 0% to 25% EtOAc in hexanes) to give product 35(16mg, 74% yield) as a white foamy solid: m/z 563.3(M + 1). Compound 35 is an isomeric mixture of the C3 keto and enol forms.

Compound 63273: to a solution of compound 35(16mg, 0.028mmol) in DMF (0.3mL) at 0 deg.C was added 1, 3-dibromo-5, 5-dimethylhydantoin (4.2mg, 0.015mmol) and the reaction mixture was stirred at 0 deg.C for 1 h. Pyridine (7.0. mu.L, 0.0) was then added87mmol) and the mixture was heated at 55 ℃ for 3 h. After cooling to room temperature, the reaction mixture was diluted with EtOAc and transferred to a separatory funnel, which was then diluted with Na₂SO₃(aq) solution and water wash. Separating the organic phase with MgSO₄Dried, filtered, and concentrated. The crude product was purified by preparative TLC plate (silica gel, eluting with 28% EtOAc in hexanes) to give product 63273(9mg, 55% yield) as a white foamy solid: m/z 561.3(M + 1);¹HNMR(400MHz，CDCl₃)δ7.66(s，1H)，3.18(m，2H)，2.70(d，1H，J＝4.4Hz)，2.67(d，1H，J＝12.0Hz)，2.59(d，1H，J＝12.0Hz)，2.47(dd，1H，J＝5.2，16.4Hz)，2.37(dd，1H，J＝13.2，16.4Hz)，2.14(m，1H)，2.03(dd，1H，J＝5.2，13.2Hz)，1.48-1.88(m，11H)，1.23(s，3H)，1.22(s，3H)，1.19(s，3H)，1.17(s，3H)，1.14-1.30(m，3H)，0.99(s，3H)，0.96-1.07(m，2H)，0.92(s，3H)，0.90(s，3H)。

compound 36: m-CPBA (77%, 299mg, 1.34mmol) was added to compound 24(213mg, 0.045mmol) in CH at room temperature₂Cl₂(4.5 mL). After stirring for 24h, Na was added₂SO₃(aq) solution termination reaction. After stirring for 10min, the reaction mixture was transferred to a separatory funnel, which was extracted with EtOAc. Mixed EtOAc extracts with NaHCO₃(aq) washing with MgSO 2₄Dried, filtered, and concentrated. The crude product was purified by column chromatography (silica gel, 0% to 20% EtOAc in hexanes) to give product 36(179mg, 81% yield) as a white foamy solid. Compound 36 is a mixture of the C28 epimer in a 2.8: 1 ratio, both having M/z 494.3(M + 1).

Compound 37 and compound 38: NaOMe (25 w/w% solution in MeOH, 100. mu.L, 0.44mmol) was added to a solution of compound 36(179mg, 0.36mmol) in MeOH (3.6mL) and THF (0.72mL) at room temperature. The reaction mixture was then heated at 55 ℃ for 3 h. After cooling to 0 deg.C, t-BuOMe and 1N HCl (aq) were added. After stirring at room temperature for an additional 5min, the reaction mixture was transferred to a separatory funnel and extracted with EtOAc. The combined EtOAc extracts were washed with water and MgSO₄Dried, filtered, and concentrated. The crude product was purified by column chromatography (silica gel, 0% to 25% EtOAc in hexanes) to give product 37(118mg, 66% yield) as a white foamy solid: m/z 494.3(M + 1). Compound 37 is the C28 epimer epoxide a mixture of C3 keto and enol isomers. Compound 38 was also obtained from the column as a white foamy solid (38mg, 20% yield): m/z 530.2, 532.3(M +1, isotopic isomer). Compound 38 is an isomeric mixture of the C3 keto and enol forms. The stereochemical configuration of C28 is not specified.

Compounds 63283 and 63284: to a solution of compound 37(118mg, 0.24mmol) in DMF (2.0mL) at 0 deg.C was added 1, 3-dibromo-5, 5-dimethylhydantoin (34.2mg, 0.12mmol) in DMF (0.4 mL). After stirring at 0 ℃ for 1.5h, the reaction mixture was treated with pyridine (58. mu.L, 0.72mmol) and heated at 55 ℃ for 3 h. After cooling to room temperature, the reaction mixture was diluted with EtOAc and transferred to a separatory funnel, which was then diluted with Na ₂SO₃(aq), 1N HCl (aq) and water. Separating the organic extract, then using MgSO₄Dried, filtered, and concentrated. The crude product is purified by column chromatography (silica gel, CH)₂Cl₂Medium 0% to 10% EtOAc) to afford product 63283(20mg, 15% yield) and 63284(44mg, 32% yield), both as white foamy solids.

Compound 63283:¹H NMR(400MHz，CDCl₃) δ 7.63(s, 1H), 4.07(m, 1H), 3.69(dd, 1H, J ═ 1.6, 10.4Hz), 3.52(t, 1H, J ═ 10.4Hz), 2.66(d, 1H, J ═ 4.0Hz), 2.47(dd, 1H, J ═ 5.2, 16.4Hz), 2.37(dd, 1H, J ═ 12.8, 16.4Hz), 2.19(m, 1H), 2.18(d, 1H, J ═ 3.6Hz), 2.02(dd, 1H, J ═ 4.8, 12.8Hz), 1.76-1.86(m, 3H), 1.56-1.64(m, 4H), 1.36-1.52(m, 4H), 1.24-1.32(m, 3H), 1.89 (s, 3H), 1H, 3.0.0, 3H, 89(s, 3.0H), 1H, 3.0 (s, 3H, 3.00); m/z 572.3, 574.3(M +1, isotopic isomer). The stereochemical configuration of C28 is not specified.

Compound 63284:¹H NMR(400MHz，CDCl₃) δ 7.64(s, 1H), 4.06(m, 1H), 3.66(dd, 1H, J ═ 1.6, 10.4Hz), 3.42(t, 1H, J ═ 10.4Hz), 2.78(m, 2H), 2.47(dd, 1H, J ═ 4.8, 16.4Hz), 2.37(dd, 1H, J ═ 12.8, 16.4Hz), 2.18(d, 1H, J ═ 2.8Hz), 1.92-2.08(m, 3H), 1.86(m, 1H), 1.62-1.76(m, 4H), 1.46-1.56(m, 2H), 1.25(s, 3H), 1.22(s, 3H), 1.18-1.27(m, 3H), 1.18(s, 3H), 1.15(s, 3H), 1.01 (m, 3H), 1.94 (m, 3H), 0.1.8H), 1.8 (m, 3H); m/z 572.3, 574.3(M +1, isotopic isomer). The stereochemical configuration of C28 is not specified.

Compound 63287: THF was added to a mixture of NaH (10mg, 0.25mmol) and 63283(19mg, 0.033mmol) at room temperature. After stirring for 50min, the reaction mixture was treated with water (1 drop). After 5min, the reaction mixture was diluted with EtOAc and transferred to a separatory funnel, washed with water. Separating the organic extract with MgSO 2₄Dried, filtered, and concentrated. The crude product was passed through preparative TLC plates (silica gel, with CH)₂Cl₂Medium 7% EtOAc elution) to give product 63287 as a white foamy solid (7mg, 43% yield):¹H NMR(400MHz，CDCl₃) δ 7.65(s, 1H), 3.02(d, 1H, J ═ 4.4Hz), 2.76(dd, 1H, J ═ 2.8, 3.6Hz), 2.62(d, 2H, J ═ 3.6Hz), 2.37-2.50(m, 2H), 2.29(m, 1H), 2.10(m, 1H), 2.00(dd, 1H, J ═ 5.6, 12.4Hz), 1.44-1.80(m, 8H), 1.30(s, 3H), 1.22(s, 3H), 1.20-1.32(m, 3H), 1.18(s, 3H), 1.16(s, 3H), 1.07(m, 1H), 0.97(s, 3H), 0.96(s, 3H), 0.91(s, 3H), 0.94 (s, 86H), 0.94(m, 2H); m/z 492.3(M + 1). The stereochemical configuration of C28 is not specified.

Compound 63286: compound 63284(36mg, 0.063mmol) in THF (0.5mL) was added by syringe to a suspension of NaH (10mg, 0.25mmol) in THF (0.5mL) at room temperature. The syringe was washed with additional THF (0.5mL) and added to the reaction mixture. After stirring for 45min, the reaction mixture was washed with CH ₂Cl₂Treated (5mL) and water (0.2mL) and transferred to a separatory funnel. Reaction mixture with CH₂Cl₂And (4) extracting.Mixed CH₂Cl₂The extract was washed with water and MgSO₄Dried, filtered, and concentrated. The crude product obtained is a 1: 1 mixture of compounds 63284 and 63286, which is again subjected to the reaction conditions described above. After stirring at room temperature for 3h, the reaction mixture was treated with water (1 drop). After 5min, the reaction mixture was diluted with EtOAc and transferred to a separatory funnel, which was then washed with water. Separating the organic extract with MgSO 2₄Dried, filtered, and concentrated. The crude product was purified by column chromatography (silica gel, 0% to 7% EtOAc in hexanes) to give product 63286(17mg, 55% yield) as a white foamy solid:¹HNMR(400MHz，CDCl₃) δ 7.64(s, 1H), 3.28(d, 1H, J ═ 4.0Hz), 2.86(dd, 1H, J ═ 3.2, 4.0Hz), 2.69(dd, 1H, J ═ 3.2, 4.4Hz), 2.63(t, 1H, J ═ 4.4Hz), 2.32-2.46(m, 2H), 1.94-2.14(m, 4H), 1.83(m, 1H), 1.62-1.73(m, 3H), 1.48-1.56(m, 3H), 1.26(s, 3H), 1.23(s, 3H), 1.18(s, 3H), 1.16(s, 3H), 1.13-1.31(m, 6H), 1.00(s, 3H), 0.89(s, 6H); m/z 492.3(M + 1). The stereochemical configuration of C28 is not specified.

Compound 39: compound 12(4.0mg, 6.5%) was produced as a white solid from compound 6(49mg, 101 μmol) using the procedure described for the synthesis of compound 11 from compound 6 (scheme 5). And (3) purification conditions: 2X column chromatography (column 1: silica gel, 0% to 10% to 100% EtOAc in hexane; column 2: silica gel, 0% to 15% to 25% EtOAc in hexane), followed by PTLC (silica gel plate, EtOAc/hexane/Et₃N＝1/4/0.1)；m/z 611.4(M+1)。

Compound 63276: product 63276(1.2mg, 30%) was obtained as a white foam from compound 39(4mg, 6.5 μmol) using the procedure described for the synthesis of compounds 402-63 from 6 (scheme 2):¹HNMR(400MHz，CDCl₃)δ7.80-7.87(m，2H)，7.70-7.76(m，2H)，7.68(s，1H)，3.73(d，1H，J＝13.6Hz)，3.59(d，1H，J＝13.6Hz)，3.46(d，1H，J＝3.6Hz)，2.42-2.58(m，2H)，1.88-2.28(m，6H)，0.80-1.76(m，11H)，1.25(s，3H)，1.24(s，3H)，1.23(s，3H)，1.18(s，3H)，1.02(s，3H)，0.86(s，3H)，0.82(s，3H)；m/z609.3(M+1)。

compound 63282: to a solution of compound 38(36mg, 0.068mmol) in DMF (0.73mL) at 0 deg.C was added 1, 3-dibromo-5, 5-dimethylhydantoin (10.4mg, 0.036 mmol). After stirring at 0 ℃ for 1h, the reaction mixture was treated with pyridine (18. mu.L, 0.22mmol) and heated at 55 ℃ for 3 h. After cooling to room temperature, the reaction mixture was diluted with EtOAc and transferred to a separatory funnel, which was then diluted with Na₂SO₃(aq), 1N HCl (aq) and water. Separating the organic extract, then using MgSO₄Dried, filtered, and concentrated. The crude product was purified by column chromatography (silica gel, 0% to 25% EtOAc in hexanes) to give product 63282(28mg, 78% yield) as a white foamy solid: ¹H NMR(400MHz，CDCl₃) δ 7.64(s, 1H), 3.99(m, 1H), 3.74(dd, 1H, J ═ 1.6, 11.2Hz), 3.52(t, 1H, J ═ 10.4Hz), 2.77(m, 2H), 2.46(dd, 1H, J ═ 4.8, 16.4Hz), 2.37(dd, 1H, J ═ 12.8, 16.4Hz), 2.19(d, 1H, J ═ 2.4Hz), 1.92-2.08(m, 3H), 1.86(m, 1H), 1.62-1.77(m, 4H), 1.52(m, 2H), 1.25(s, 3H), 1.22(s, 3H), 1.19-1.26(m, 3H), 1.18(s, 3H), 1.15 (m, 1H), 1.95 (m, 0.06H), 1.95 (m, 3H), 1.06(m, 3H), 1.95H, 0.95 (m, 1H); m/z 528.3, 530.3(M +1, isotopic isomer). The stereochemical configuration of C28 is not specified.

Compound 63285: a mixture of 63221(54.5mg, 0.11mmol), paraformaldehyde (31mg), and TsOH (12mg, 0.063mmol) in toluene (1.1mL) was heated at 110 ℃ for 1h in a sealed tube. After cooling to room temperature, the reaction mixture was diluted with EtOAc and transferred to a separatory funnel. The mixture was then washed with NaHCO₃(aq) solution and water washing, MgSO 2₄Dried, filtered, and concentrated. The crude product was purified by column chromatography (silica gel, 0% to 30% EtOAc in hexanes) to give product 63285(21mg, 38% yield) as a white foamy solid. Compound 63285 is a C28 epimer mixture in a 1.3: 1 ratio: ¹HNMR(400MHz，CDCl₃) (mixture of two epimers) δ 7.65(s, 1H), 7.64(s, 1H), 5.06(s, 1H), 5.05(s,1H)，4.84(s，1H)，4.81(s，1H)，4.22(m，2H)，3.75-3.86(m，3H)，3.73(t，1H，J＝7.6Hz)，3.00(d，1H，J＝4.4Hz)，2.86(d，1H，J＝4.4Hz)，2.58(m，1H)，2.32-2.50(m，4H)，1.40-2.08(m，23H)，1.25(s，3H)，1.23(s，9H)，1.20-1.32(m，7H)，1.18(s，6H)，1.16(s，6H)，1.02-1.10(m，3H)，1.01(s，3H)，1.01(s，3H)，0.94(s，3H)，0.91(s，3H)，0.89(s，6H)；m/z 522.3(M+1)。

compound 63294: a mixture of compounds 402-63(0.10g, 0.208mmol) and trifluoroacetic anhydride (0.052g, 0.25mmol) was placed in DMF (2mL) and then anhydrous pyridine (2mL) was added. The solution was heated to 80 ℃ and stirred overnight (. about.14 h). The hot solution was cooled to room temperature and diluted with ethyl acetate (70mL) and 1N Cl (aq) (30 mL). The organic phase was separated and washed with 1N HCl (aq) (30mL) then MgSO₄And (5) drying. The drying agent was filtered and the filtrate was concentrated in vacuo to give a viscous liquid. The crude product was purified by column chromatography (silica gel, 30% EtOAc in hexanes) to afford product 63294(0.014g, 12%) as a white solid:¹H NMR(500MHz，CDCl₃) δ 7.65(s, 1H), 4.30(s, 2H), 2.71(d, 1H, J ═ 4Hz), 2.49(dd, 1H, J ═ 16 and 4Hz "), 2.40(dd, 1H, J ═ 15 and 13 Hz"), 2.19(m, 1H), 2.05-1.95(m, 2H), 1.88(br d, 1H, J ═ 12Hz "), 1.80-1.45(m, 7H), 1.33-0.98(m, 9H), 1.22(s, 3H), 1.20(s, 3H), 1.17(s, 3H), 1.13(s, 3H), 0.94(s, 3H), 0.92(s, 3H); m/z 576.1(M + 1).

Compound 63297: a mixture of compounds 402-63(0.10g, 0.208mmol) and trimethylacetic anhydride (0.047g, 0.25mmol) was placed in DMF (2mL) and anhydrous pyridine (2mL) was added. The solution was heated to 80 ℃ and stirred overnight (. about.14 h). The hot solution was cooled to room temperature and diluted with ethyl acetate (70mL) and 1N HCl (aq) (30 mL). The organic phase was separated and washed with 1N HCl (aq) (30mL), 1N NaOH (aq) (30ML) and then MgSO ₄And (5) drying. The drying agent was filtered and the filtrate was concentrated in vacuo to give a viscous liquid. The crude product was purified by column chromatography (silica gel, 30% EtOAc in hexanes) to give product 63297(0.042g, 36%) as a white foam:¹H NMR(500MHz，CDCl₃) δ 7.65(s, 1H), 4.18(d, 1H, J ═ 11Hz), 3.83(d, 1H, J ═ 11Hz), 2.78(d, 1H, J ═ 4Hz), 2.45(dd, 1H, J ═ 17 and 4Hz), 2.38(dd, 1H, J ═ 16 and 13Hz), 2.19(br d, 1H, J ═ 13Hz), 2.03-1.93(m, 3H), 1.92-1.29(m, 8H), 1.26-0.88(m, 5H), 1.33(s, 3H), 1.31(s, 3H), 1.30(s, 9H), 1.27(s, 3H), 1.26(s, 3H), 0.99(s, 3H), 0.88(s, 3H), 0.86(s, 3H); m/z 564.3(M + 1).

Compound 63298: a mixture of alcohols 402-63(0.10g, 0.208mmol) and benzoic anhydride (0.056g, 0.25mmol) was placed in DMF (2mL) and anhydrous pyridine (2mL) was added. The solution was heated to 80 ℃ and stirred overnight (. about.14 h). The hot solution was cooled to room temperature and diluted with ethyl acetate (70mL) and 1N Cl (aq) (30 mL). The organic phase was separated and washed with 1N HCl (aq) (30mL), 1N NaOH (aq) (30mL) then MgSO₄And (5) drying. The drying agent was filtered and the filtrate was concentrated in vacuo to give a viscous liquid. The crude product was purified by column chromatography (silica gel, 30% EtOAc in hexanes) to afford product 63298(0.034g, 28%) as a pale yellow solid: ¹H NMR(500MHz，CDCl₃)δ8.05(d，2H，J＝7Hz)，7.66(s，1H)，7.59(t，1H，J＝7Hz)，7.47(t，2H，J＝7Hz)，4.31(d，1H，，J＝10Hz)，4.20(d，1H，J＝10Hz)，2.86(d，1H，J＝4Hz)，2.51-2.28(m，3H)，2.07-1.81(m，5H)，1.73-1.38(m，6H)，1.36-0.86(m，5H)，1.31(s，3H)，1.28(s，3H)，1.24(s，3H)，1.21(s，3H)，1.02(s，3H)，0.99(s，3H)，0.93(s，3H)；m/z 584.2(M+1)。

Compound 41: to a stirred solution of compound 37(98.7mg, 0.2mmol) in a solvent mixture of MeOH (3.0mL) and THF (0.5mL) at 55 deg.C was added NaOMe solution (109. mu.L, 0.48mmol, 25% w/w in MeOH). The mixture was stirred at 55 ℃ for 2h and then cooled to room temperature. KCN (18.2mg, 0.28mmol) was added to the mixture in one portion. The solution was stirred at room temperature for 21.5h, then at 55 ℃ for 49.5 h. The reaction mixture was cooled to room temperature and quenched with 1N HCl (aq) (10 mL). The mixture was extracted quickly with EtOAc (30 mL). The organic phase was washed with water and brine, washed with Na₂SO₄Drying, filtering, andconcentration afforded a white solid which was purified by column chromatography (silica gel, 0% to 15% to 35% EtOAc in hexanes) to afford compound 41(36.7mg, 35%) as a white solid (mixture of two diastereomers): m/z 521.3(M + 1).

Compound 63310: compound 41(23mg, 0.044mmol) was converted to product 63310(15.0mg, 66%) as a white solid using the procedure described for the synthesis of compounds 402-63 from 7 (scheme 2). 63310 is a mixture of two diastereomers in a ratio of-3.56: 1:¹H NMR(400MHz，CDCl₃) δ 7.66 (primary) and 7.65 (secondary) (s, 1H), 4.18-4.30(m, 1H), 2.76(d, 1H, J ═ 4.0Hz), 2.45-2.70(m, 4H), 2.33-2.44(m, 1H), 2.30(d, 1H, J ═ 5.6Hz), 1.98-2.18(m, 2H), 1.77-1.94(m, 2H), 0.90-1.76(m, 12H), 1.26(s, 3H), 1.23(s, 3H), 1.20(s, 3H), 1.17(s, 3H), 1.01(s, 3H), 0.94(s, 3H), 0.90(s, 3H); m/z 519.3(M + 1).

Compound 42: to a magnetically stirred solution of chromium (VI) oxide (4.56g, 45.6mmol), water (17.2mL) and concentrated sulfuric acid (3.85mL) cooled to-8 ℃ under nitrogen was added a solution of compound 42(4.80g, 10.1mmol) in acetone (425mL) previously purged with nitrogen for 20 min. The solution was added over a period of 30-min while maintaining a temperature of-9 to-3 ℃. The resulting brown suspension was stirred at-4 ℃ for-40 min to give an orange suspension containing a green precipitate. After heating to 11 ℃ over a period of 15-min, the suspension was transferred to a beaker and acetone was removed using a rotary evaporator set to a bath temperature of-20 ℃. In the case of black residues in H₂After partitioning between O (1010mL) and MTBE (506mL), the lower aqueous phase was removed and extracted with MTBE (4X 300 mL). Mixing the mixed MTBE solution with H₂O (100mL), saturated aqueous NaCl solution (100mL) and dried (MgSO)₄). After removal of the solvent and drying in vacuo, two samples of compound 42 were obtained. A sample was directly isolated to give compound 42(1.81g) as a white crystalline solid. Chromatography of the second sample on silica gel afforded compound 42(1.0g) as a white crystalline solid. The two samples were combined to give compound 42(2.81g, 57% yield): m/z 48 5.5(M+1)，517.6(M+33)。

Compound 43: to a magnetically stirred slurry of compound 42(2.67g, 5.51mmol) and ethyl formate (30.2mL, 375mmol) cooled to-8 to-15 ℃ under nitrogen was added a solution of 30 wt% NaOMe (9.82mL, 54.5mmol) in MeOH over a period of 15 min. During this time the viscosity of the suspension became less, undergoing a color transition from green to brown to finally give a rust red solution. After stirring for a further 25min an orange slurry was formed. Analysis of the slurry after 1 additional hour of stirring at-3 ℃ (TLC and HPLC) indicated complete reaction. The orange reaction mixture was heated and transferred to a beaker at 14 ℃ and the solvent was partially removed (bath temperature 25-30 ℃) to give a thick red orange slurry (-10.6 g). Ice water (150g) was added to the residue to give a cloudy solution, and 10% HCl (34mL) was added dropwise to the solution over a period of 15min at-3 to-0 ℃. The off-white slurry obtained is filtered and filtered over a filter with H₂O (3X 33mL) washed the wet cake. The wet cake was dissolved in EtOAc (50mL) and after removal of the residual aqueous layer, the ethyl acetate phase was washed with brine (4X 10mL) and dried (MgSO 4)₄). Compound 43(2.62g, 92.9%) was obtained as a pale pink solid after removal of the solvent and drying in vacuo: m/z 513.5(M +1), 545.6(M + 33).

Compound 44: to a magnetically stirred cloudy orange solution of compound 44(2.62g, 5.11mmol) in anhydrous EtOH (37mL) at room temperature over a period of 6 minutes was added NH₂OH HCl (0.426g, 6.13mmol) in H₂Solution in O (6.4 mL). The mixture was heated at 54 ℃ for 1.5 h. Analysis of the mixture after 0.5h (TLC, HPLC, LCMS) indicated complete conversion. The mixture was cooled and concentrated. After the residue in EtOAc and H₂After partitioning between O, the lower aqueous layer was extracted with ethyl acetate. Mixed ethyl acetate layer with H₂O and brine (2X) and over MgSO₄And (5) drying. Compound 44(2.53g, 97.1%) was isolated as a light brown solid after removal of the solvent and drying in vacuo: m/z510.4(M +1), 542(M + 33).

Compound 45: over a period of 5 minutes, the process isCompound 45(2.50g, 4.90mmol) cooled to-3 deg.C under nitrogen was magnetically stirred into a pale yellow solution in anhydrous MeOH (40mL) and a solution of 30 wt% NaOMe (1.86mL, 10.35mmol) in MeOH was added. The mixture was warmed to room temperature and heated at-55 ℃ for 2.5 h. Preliminary analysis (TLC, HPLC) after only 1.3h of heating indicated almost complete conversion. Methanol was removed by rotary evaporator and the residue was transferred to a column with H ₂O (50mL) and MTBE (130 mL). The two-phase system is vigorously stirred until all solids initially coagulated have dispersed. During constant stirring, 1N HCl (. about.13 mL) was added in portions to give two clear layers. The lower acidic aqueous layer was removed and extracted with MTBE (3X 25 mL). Mixed yellow organic solution with H₂O (1X 50mL) and saturated NaCl (1X 50mL) were washed and dried (MgSO₄). Removal of the solvent and drying in vacuo afforded compound 45(2.50g, quantitative yield) as a pale yellow solid: m/z 510.4(M + 1).

Compound 63332: to a magnetically stirred yellow solution of cyanoketo acid 45(2.50g, 4.90mmol) in anhydrous DMF (13mL) cooled to-32 to-35 ℃ (dry ice/acetone bath) under a nitrogen environment was added a solution of 1, 3-dibromo-5, 5-dimethylhydantoin (0.78g, 2.7mmol) in DMF (4mL) over a period of 7-min. After complete addition, the temperature of the mixture was raised and maintained at-0 ℃ for 25min, then heated to room temperature. Analysis of the sample (TLC, HPLC, LC-MS) indicated almost complete conversion of compound 45 to the monobromo intermediate. Pyridine (l.71mL, 21.0mmol) was added in one portion and the solution was heated to-55 ℃ for 4 h. The reaction mixture was cooled to room temperature and quenched by pouring it into a stirred solution of ice water (200mL) and 1N HCl (aq) (10 mL). After addition of additional ice water (100mL), the off-white slurry of solids was stirred for 0.5 h. The mixture was transferred to a separatory funnel with EtOAc (200mL) and partitioned. The lower aqueous layer was extracted with EtOAc (3X 50 mL). The extract was mixed with the original EtOAc solution and washed with H ₂O (50mL) and brine (3X 50 mL). Over MgSO₄After drying, the yellow solution was concentrated and the resulting product was dried in vacuo to afford compound 63332(2.30g, 92.4%) as a light brown solid:¹H NMR(400MHz，CDCl₃)δ7.67(s，1H)，2.83(d，1H)，2.28-2.52(m，4H)，2.21(br d，1H)，1.96-2.05(m，2H)，1.92-1.98(m，1H)，1.78-1.90(m，3H)，1.63-1.72(m，4H)，1.53(br，3H)，1.30-1.40(m，2H)，1.29(s，3H)，1.24-1.27(m，2H)，1.23(s，3H)，1.20(s，3H)，1.17(s，3H)，1.07-1.11(m，2H)，0.99(s，3H)，0.93(s，3H)，0.90(s，3H)；m/z 508.5(M+1)，450.6(M+33)。

compound 63333: to a magnetically stirred water white solution of compound 63332(23.7mg, 0.0467mmol) in sieve dried THF (1.0mL) at room temperature under nitrogen was added dimethyl sulfate (7.6mg, 0.060mmol) followed by sodium carbonate (7.2mg, 0.0679 mmol). The suspension was stirred at room temperature for 18 h. TLC analysis (hexane/ethyl acetate: 75/25) showed a new spot of less polar product in addition to the apparent unreacted starting material. The suspension was stirred at 50 ℃ for 5 hours and at 80 ℃ for a further 3 hours, the majority of the remaining starting materials being converted. THF was removed by rotary evaporation and the residue was partitioned between EtOAc (75mL) and water (20 mL). The ethyl acetate layer was washed with water (2X 20mL) and saturated NaCl (10mL) and dried (Na)₂SO₄). The filtered solution was concentrated to give the crude product. By preparative TLC (CH)₂Cl₂MeOH: 97.5/2.5) to afford product 63333(11.9mg, 48%) as a white solid:¹HNMR(400MHz，CDCl₃)δ7.66(s，1H)，3.66(s，3H)，2.82(d，1H，J＝3.6Hz)，2.34-2.50(m，3H)，2.24(d，1H，J＝12.8Hz)，2.13(m，1H)，1.50-2.05(m，12H)，1.28(s，3H)，1.23(s，3H)，1.19(s，3H)，1.16(s，3H)，1.14-1.34(m，3H)，1.08(m，1H)，0.99(s，3H)，0.92(s，3H)，0.89(s，3H)；m/z 522.6(M+1)，554.6(M+33)。

compound 46: to compound 63332(160mg, 0.315mmol) was dried CH on a sieve over a period of 10 minutes at room temperature ₂Cl₂To a magnetically stirred solution (10mL) was added oxalyl chloride (0.054mL, 0.63mmol) in CH₂Cl₂(4 mL). The solution was refluxed gently (. about.35-38 ℃ C.) for 20min using a hot water bath. Removal of the solvent by rotary evaporationAfter dosing, more CH was added to the residue₂Cl₂And stripping is continued to remove excess oxalyl chloride. After complete evaporation, compound 46(170mg, quantitative) was isolated and used directly to prepare compounds 63334-63337.

General procedure for the preparation of compounds 63334-63337: at room temperature over a period of 3 minutes to R₁R₂NH in CH₂Cl₂Adding triethylamine into the suspension with magnetic stirring, and adding into CH₂Cl₂Solution of (1) (see table 4 for details). To the resulting clear solution cooled at-0 ℃ was added a solution of compound 46 over a period of 15 min. The cooling bath was removed and the pale yellow solution was stirred at room temperature for-40 min. Analysis of the sample (TLC, HPLC) indicated the absence of acid chloride. The reaction solution was transferred to a separatory funnel and successively treated with H₂O, 1N HCl (aq) and brine. After drying (MgSO)₄) After this time, the solution was back extracted and dried in vacuo to give the crude product. The crude product was purified by column chromatography (silica gel, 0% to 50% EtOAc in hexanes) to afford the desired target compound.

Compound 63334: an off-white solid;¹H NMR(400MHz，CDCl₃)δ7.68(s，1H)，5.58(t，1H，J＝4.4Hz)，3.28(m，2H)，2.91(d，1H，J＝4.0Hz)，2.35-2.50(m，3H)，2.14(m，1H)，1.52-2.04(m，12H)，1.29(s，3H)，1.23(s，3H)，1.19(s，3H)，1.16(s，3H)，1.14(t，3H，J＝7.2Hz)，1.07-1.40(m，5H)，0.98(s，3H)，0.92(s，3H)，0.90(s，3H)。

compound 63335: an off-white solid;¹H NMR(400MHz，CDCl₃)δ7.68(s，1H)，5.97(dd，1H，J＝5.8Hz)，4.49(dt，2H，J＝5.0，47.2Hz)，3.56(ddt，2H，J＝5.0，5.8，28.0Hz)，2.90(d，1H，J＝4.4Hz)，2.35-2.50(m，3H)，2.16(m，1H)，1.90-2.05(m，5H)，1.81(m，1H)，1.52-1.71(m，6H)，1.29(s，3H)，1.23(s，3H)，1.19(s，3H)，1.16(s，3H)，1.08-1.34(m，5H)，0.99(s，3H)，0.92(s，3H)，0.90(s，3H)。

compound 63336:an off-white solid;¹H NMR(400MHz，CDCl₃)δ7.67(s，1H)，5.77-6.03(m，2H)，3.50-3.72(m，2H)，2.87(d，1H，J＝4.0Hz)，2.32-2.54(m，3H)，1.56-2.22(m，13H)，1.04-1.40(m，5H)，1.28(s，3H)，1.23(s，3H)，1.19(s，3H)，1.16(s，3H)，0.99(s，3H)，0.92(s，3H)，0.90(s，3H)。

compound 63337: an off-white solid;¹H NMR(400MHz，CDCl₃)δ7.65(s，1H)，5.74(t，1H，J＝6.4Hz)，3.70-4.02(m，2H)，2.85(d，1H，J＝3.6Hz)，2.32-2.54(m，3H)，1.56-2.22(m，13H)，1.04-1.46(m，5H)，1.28(s，3H)，1.23(s，3H)，1.19(s，3H)，1.16(s，3H)，0.99(s，3H)，0.92(s，6H)，0.90(s，3H)；m/z 589.5(M+1)。

example 4 Water solubility of Oleanolic acid derivatives

The water solubility of the mixtures shown here was determined using the method outlined in example 1.

****************

All methods disclosed and claimed herein can be made and executed without undue experimentation in light of the present disclosure. While the compositions and methods of this invention have been described in terms of preferred embodiments, it will be apparent to those of skill in the art that variations may be applied to the methods and in the steps or in the sequence of steps of the methods described herein without departing from the concept, spirit and scope of the invention. More specifically, it will be apparent that certain agents which are chemically or physiologically related may be substituted for the agents described herein while the same or similar results would be achieved. All such substitutions and modifications apparent to those skilled in the art are deemed to be within the spirit, scope and concept of the invention as defined by the appended claims.

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Claims

1. A compound of the formula:

wherein:

y is alkanediyl_C≤8Alkenyldiyl group_C≤8Alkynediyl_C≤8or-C (OH) HCH₂-；

R_aThe method comprises the following steps:

hydrogen, hydroxy, halogen, aminoNitro, cyano, azido, phospho, 1, 3-dioxoisoindolin-2-yl, mercapto, silyl, -C (═ O) OH, -C (═ O) OCH₃、-C(＝O)NHCH₃、-C(＝O)NHCH₂CH₃、-C(＝O)NHCH₂CF₃or-NHCH₂CN; or

Alkyl radical_C≤12Alkenyl radical_C≤12Alkynyl group_C≤12)Aryl radical_C≤12Aralkyl group_C≤12Heteroaryl group_C≤12Heteroarylalkyl group_C≤12Acyl group_C≤12Alkoxy group_C≤12Alkenyloxy group_C≤12Alkynyloxy, alkynyloxy_C≤12Aryloxy group_C≤12(iii) aralkyloxy_C≤12Heteroaryloxy group_C≤12Hetero aralkyloxy group_C≤12(iii) acyloxy group_C≤12Alkylamino group_C≤12Dialkylamino group_C≤12Alkenylamino group_C≤12Alkynyl amino group_C≤12Arylamino group_C≤12Aralkylamino group_C≤12Heteroaryl amino_C≤12Heteroarylalkylamino, heteroarylalkylamino_C≤12Alkyl sulfonyl amino_C≤12Amide group_C≤12Alkyl ammonium_C≤12Alkyl sulfonium_C≤12Alkyl silyl group_C≤12Aryl sulfonyl group_C≤12Aryl sulfinyl group_C≤12Alkyl phosphate group_C≤12Dialkyl phosphate group_C≤12Or a fluorine substituted form of at least one hydrogen atom of any of these groups; or

Or a pharmaceutically acceptable salt, tautomer or optical isomer thereof.

2. The compound of claim 1, further defined as:

wherein:

R_aThe method comprises the following steps:

hydrogen, hydroxy, halogen, amino, nitro, cyano, azido, phosphate, 1, 3-dioxoisoindolin-2-yl, mercapto, silyl, -C (═ O) OH, -C (═ O) OCH₃、-C(＝O)NHCH₃、-C(＝O)NHCH₂CH₃、-C(＝O)NHCH₂CF₃or-NHCH₂CN; or

Alkyl radical_C≤12Alkenyl radical_C≤12Alkynyl group_C≤12Aryl radical_C≤12Aralkyl group_C≤12Heteroaryl group_C≤12Heteroarylalkyl group_C≤12Acyl group_C≤12Alkoxy group_C≤12Alkenyloxy group_C≤12Alkynyloxy, alkynyloxy_C≤12Aryloxy group_C≤12(iii) aralkyloxy_C≤12Heteroaryloxy group_C≤12Hetero aralkyloxy group_C≤12(iii) acyloxy group_C≤12Alkylamino group_C≤12Dialkylamino group_C≤12Alkenylamino group_C≤12Alkynyl amino group_C≤12Arylamino group_C≤12Aralkylamino group_C≤12Heteroaryl amino_C≤12Heteroarylalkylamino, heteroarylalkylamino_C≤12Amide group_C≤12Aryl sulfonyl group_C≤12Aryl sulfinyl group_C≤12Alkyl phosphate group_C≤12Dialkyl phosphate group_C≤12Alkyl phosphate group_C≤12Dialkyl phosphate group_C≤12Or a fluorine substituted form of at least one hydrogen atom of any of these groups; or

Y and R_aForm a 3 to 5 membered ring, such that Y and R_aBy one or more-O-and alkanediyl radicals_(C1-3)

Are further linked to each other, further wherein Y is-CH-and R_ais-CH₂-；

Or a pharmaceutically acceptable salt, tautomer or optical isomer thereof.

3. The compound of claim 2, further defined as:

wherein:

R_athe method comprises the following steps:

hydrogen, hydroxy, halogen, amino, phosphate, 1, 3-dioxoisoindolin-2-yl, cyano, -C (═ O) OH, -C (═ O) OCH₃、-C(＝O)NHCH₃、-C(＝O)NHCH₂CH₃、-C(＝O)NHCH₂CF₃or-NHCH₂CN; or

Alkyl radical_C≤12Alkenyl radical_C≤12Alkynyl group_C≤12Aryl radical_C≤12Aralkyl group_C≤12Heteroaryl group_C≤12Heteroarylalkyl group_C≤12Acyl group_C≤12Alkoxy group_C≤12Alkenyloxy group_C≤12Alkynyloxy, alkynyloxy_C≤12Aryloxy group_C≤12(iii) aralkyloxy_C≤12Heteroaryloxy group_C≤12Hetero aralkyloxy group_C≤12(iii) acyloxy group_C≤12Alkylamino group_C≤12Dialkylamino group_C≤12Alkenylamino group_C≤12Alkynyl amino group_C≤12Arylamino group_C≤12Aralkylamino group_C≤12Heteroaryl amino_C≤12Heteroarylalkylamino, heteroarylalkylamino_C≤12Amide group_C≤12Aryl sulfonyl group_C≤12Aryl sulfinyl group_C≤12Alkyl phosphate group_C≤12Dialkyl phosphate group_C≤12Or a fluorine substituted form of at least one hydrogen atom of any of these groups;

or a pharmaceutically acceptable salt, tautomer or optical isomer thereof.

4. A compound of claim 3, further defined as:

wherein R is_aThe method comprises the following steps:

Alkyl radical_C≤12Alkenyl radical_C≤12Alkynyl group_C≤12Aryl radical_C≤12Aralkyl group_C≤12Heteroaryl group _C≤12Heteroarylalkyl group_C≤12Acyl group_C≤12Alkoxy group_C≤12Alkenyloxy group_C≤12Alkynyloxy, alkynyloxy_C≤12Aryloxy group_C≤12(iii) aralkyloxy_C≤12Heteroaryloxy group_C≤12Hetero aralkyloxy group_C≤12(iii) acyloxy group_C≤12Alkylamino group_C≤12Dialkylamino group_C≤12Alkenylamino group_C≤12Alkynyl amino group_C≤12Arylamino group_C≤12Aralkylamino group_C≤12Heteroaryl amino_C≤12Heteroarylalkylamino, heteroarylalkylamino_C≤12Amide group_C≤12Aryl sulfonyl group_C≤12Aryl sulfinyl group_C≤12Alkyl phosphate group_C≤12Dialkyl phosphate group_C≤12Or a fluorine substituted form of at least one hydrogen atom of any of these groups;

or a pharmaceutically acceptable salt, tautomer or optical isomer thereof.

5. The compound of claim 2, further defined as:

wherein:

y is alkanediyl_C≤3or-C (OH) HCH₂-；

R_aThe method comprises the following steps:

Alkyl radical_C≤12Alkenyl radical_C≤12Alkynyl group_C≤12Aryl radical_C≤12Aralkyl group_C≤12Heteroaryl group_C≤12Heteroarylalkyl group_C≤12Acyl group_C≤12Alkoxy group_C≤12Alkenyloxy group_C≤12Alkynyloxy, alkynyloxy_C≤12Aryloxy group_C≤12(iii) aralkyloxy_C≤12Heteroaryloxy group_C≤12Hetero aralkyloxy group_C≤12(iii) acyloxy group_C≤12Alkylamino group_C≤12Dialkylamino group_C≤12Alkenylamino group_C≤12Alkynyl amino group_C≤12Arylamino group _C≤12Aralkylamino group_C≤12Heteroaryl amino_C≤12Heteroarylalkylamino, heteroarylalkylamino_C≤12Amide group_C≤12Aryl sulfonyl group_C≤12Aryl sulfinyl group_C≤12Alkyl phosphate group_C≤12Dialkyl phosphate group_C≤12Or a fluorine substituted form of at least one hydrogen atom of any of these groups;

or a pharmaceutically acceptable salt, tautomer or optical isomer thereof.

6. The compound of claim 5, further defined as:

wherein R is_aThe method comprises the following steps:

hydrogen, hydroxy, halogen, amino, phosphate, 1, 3-dioxoisoindoleIndolin-2-yl, cyano, -C (═ O) OH, -C (═ O) OCH₃、-C(＝O)NHCH₃、-C(＝O)NHCH₂CH₃、-C(＝O)NHCH₂CF₃or-NHCH₂CN; or

or a pharmaceutically acceptable salt, tautomer or optical isomer thereof.

7. The compound of claim 4, further defined as:

wherein R is_aIs hydroxy, cyano, -C (═ O) OH, -C (═ O) OCH₃、-C(＝O)NHCH₃、-C(＝O)NHCH₂CH₃、-C(＝O)NHCH₂CF₃Acyl group_C≤8(iii) acyloxy group_C≤8Or a fluorine substituted form of at least one hydrogen atom of either of the latter two groups; or a pharmaceutically acceptable salt, tautomer, or thereofOptical isomers.

8. The compound of claim 2, further defined as:

wherein R is_aIs hydroxy, cyano, -C (═ O) OH, -C (═ O) OCH₃、-C(＝O)NHCH₃、-C(＝O)NHCH₂CH₃、-C(＝O)NHCH₂CF₃Acyl group_C≤8(iii) acyloxy group_C≤8Amide group_C≤8Or a fluorine substituted form of at least one hydrogen atom of any of the latter three groups; or a pharmaceutically acceptable salt, tautomer, or optical isomer thereof.

9. The compound of claim 6, further defined as:

wherein R is_aIs hydroxy, cyano, -C (═ O) OH, -C (═ O) OCH₃、-C(＝O)NHCH₃、-C(＝O)NHCH₂CH₃、-C(＝O)NHCH₂CF₃Acyl group_C≤8(iii) acyloxy group_C≤8Or a fluorine substituted form of at least one hydrogen atom of either of the latter two groups; or a pharmaceutically acceptable salt, tautomer, or optical isomer thereof.

10. The compound of claim 2, further defined as:

wherein R is_ais-NHCH₂CN, alkylamino_C≤12Dialkylamino group_C≤12Alkenylamino group_C≤12Alkynyl amino group_C≤12Arylamino group_C≤12Aralkylamino group_C≤12Heteroaryl amino_C≤12Heteroarylalkylamino, heteroarylalkylamino_C≤12Alkyl sulfonyl amino _C≤12Amide group_C≤12Or a fluorine substituted form of at least one hydrogen atom of any of the latter ten groups.

11. A compound according to any one of claims 2 and 5, wherein Y is alkanediyl_(C1-4)or-C (OH) HCH₂-。

12. The compound of claim 11, wherein Y is-CH₂-。

13. The compound of claim 11, wherein Y is-C (OH) HCH₂-。

14. The compound of claim 1, wherein Y is-C ≡ C-.

15. The compound according to any one of claims 1-9 and 13, wherein R_ais-OH.

16. The compound according to any one of claims 1-9 and 13, wherein R_ais-CN.

17. The compound according to any one of claims 1-6 and 13, wherein R_ais-Cl.

18. The compound according to any one of claims 1-6 and 13, wherein R_ais-Br.

19. The compound according to any one of claims 1-6 and 14, wherein R_ais-H.

20. The compound according to any one of claims 1-9, wherein R_ais-C (═ O) OH, -C (═ O) OCH₃、-C(＝O)NHCH₃、-C(＝O)NHCH₂CH₃、-C(＝O)NHCH₂CF₃Acyl group_C1-6Or a substituted acyl group_C1-6Wherein the acyl group is substituted_C1-6Is a fluorine substituted form of at least one hydrogen atom.

21. The compound according to any one of claims 1-9, wherein R_aIs acyl_C4-6、C(＝O)OH、-C(＝O)OCH₃、-C(＝O)NHCH₃、-C(＝O)NHCH₂CH₃、-C(＝O)NHCH₂CF₃Or substituted acyl_C4-6Wherein the acyl group is substituted_C4-6Is a fluorine substituted form of at least one hydrogen atom.

22. The compound according to any one of claims 1-9, wherein R_ais-C (═ O) OH, -C (═ O) OCH₃、-C(＝O)NHCH₃、-C(＝O)NHCH₂CH₃、-C(＝O)NHCH₂CF₃Acyl group_C1-4Or substituted acyl_C1-4Wherein the acyl group is substituted_C1-4Is a fluorine substituted form of at least one hydrogen atom.

23. The compound according to any one of claims 1-9, wherein R_ais-C (═ O) OH, -C (═ O) OCH₃、-C(＝O)NHCH₃、-C(＝O)NHCH₂CH₃、-C(＝O)NHCH₂CF₃Acyl group_C1-3Or substituted acyl_C1-3Wherein the acyl group is substituted_C1-3Is a fluorine substituted form of at least one hydrogen atom.

24. The compound of claim 23, wherein R_aSelected from-C (═ O) OH, -C (═ O) OCH₃、-C(＝O)NHCH₃、-C(＝O)NHCH₂CH₃and-C (═ O) NHCH₂CF₃。

25. The compound according to any one of claims 1-9, wherein R_aIs acyloxy_C1-8Or substituted acyloxy_C1-3Wherein substituted acyloxy group_C1-3Is a fluorine substituted form of at least one hydrogen atom.

26. The compound of claim 25, wherein R_aIs a substituted acyloxy group_C1-3Wherein substituted acyloxy group_C1-3Is a fluorine substituted form of at least one hydrogen atom.

27. The compound of claim 25, wherein R_aIs acyloxy_C2-8。

28. A compound according to any one of claims 1 and 10, wherein R_ais-NHCH₂CN, alkylamino_C≤12Dialkylamino group_C≤12Alkenylamino group_C≤12Alkynyl amino group_C≤12Arylamino group_C≤12Aralkylamino group_C≤12Heteroaryl amino_C≤12Heteroarylalkylamino, heteroarylalkylamino_C≤12Alkyl sulfonyl amino _C≤12Or amide group_C≤12Or a fluorine substituted form of at least one hydrogen atom of any of the latter ten groups.

29. Compounds according to claims 1-6, wherein R_aIs an arylsulfonyl group_C≤8Or arylsulfinyl_C≤8Or a fluorine substituted form of at least one hydrogen atom of any of these groups.

30. Compounds according to claims 1-6, wherein R_ais-OP (O) (OH)₂。

31. Compounds according to claims 1-6, wherein R_aIs an alkyl phosphate group_C≤12Or dialkyl phosphate group_C≤12。

32. The compound of claim 31, wherein R_aIs a dialkyl phosphate group_C≤8。

33. The compound of claim 32, wherein R_ais-OP (O) (OEt)₂。

34. Compounds according to claims 1-6, wherein R_aIs a 1, 3-dioxoisoindolin-2-yl group.

35. A compound according to claim 1, wherein-Y-R_aIs an oxirane-2-yl group.

36. A compound according to claim 1, wherein-Y-R_aIs a 1, 3-dioxolan-4-yl group.

37. A compound according to claim 2, wherein the bond between carbon 9 and carbon 11 is a single bond.

38. A compound according to claim 2, wherein the bond between carbon 9 and carbon 11 is a double bond.

39. The compound of claim 1, further defined as:

or a pharmaceutically acceptable salt thereof.

40. The compound of claim 1, further defined as:

Or a pharmaceutically acceptable salt thereof.

41. The compound of claim 9, further defined as:

or a pharmaceutically acceptable salt thereof.

42. The compound of claim 9, further defined as:

or a pharmaceutically acceptable salt thereof.

43. The compound of claim 1, further defined as:

or a pharmaceutically acceptable salt thereof.

44. The compound of claim 17, further defined as:

or a pharmaceutically acceptable salt thereof.

45. The compound of claim 18, further defined as:

or a pharmaceutically acceptable salt thereof.

46. The compound of claim 16, further defined as:

or a pharmaceutically acceptable salt thereof.

47. The compound of claim 35, further defined as:

or a pharmaceutically acceptable salt thereof.

48. The compound of claim 36, further defined as:

or a pharmaceutically acceptable salt thereof.

49. The compound of claim 11, further defined as:

or a pharmaceutically acceptable salt thereof.

50. The compound of claim 26, further defined as:

or a pharmaceutically acceptable salt thereof.

51. The compound of claim 27, further defined as:

or a pharmaceutically acceptable salt thereof.

52. The compound of claim 27, further defined as:

or a pharmaceutically acceptable salt thereof.

53. A compound of the formula:

or a pharmaceutically acceptable salt thereof.

54. A compound according to claim 1, further defined as:

Or a pharmaceutically acceptable salt thereof.

55. The compound of claim 19, further defined as:

or a pharmaceutically acceptable salt thereof.

56. A compound according to claim 1, further defined as:

or a pharmaceutically acceptable salt thereof.

57. A compound according to claim 1, further defined as:

58. a compound according to claim 1, further defined as:

or a pharmaceutically acceptable salt thereof.

59. A compound according to claim 1, further defined as:

or a pharmaceutically acceptable salt thereof.

60. A compound according to claim 1, further defined as:

or a pharmaceutically acceptable salt thereof.

61. A compound of the formula:

or a pharmaceutically acceptable salt thereof.

62. A compound according to claim 1, further defined as:

or a pharmaceutically acceptable salt thereof.

63. The compound of claim 10, further defined as:

or a pharmaceutically acceptable salt thereof.

64. A compound according to claim 1, further defined as:

or a pharmaceutically acceptable salt thereof.

65. A compound according to claim 1, further defined as:

or a pharmaceutically acceptable salt thereof.

66. A compound according to claim 1, further defined as:

or a pharmaceutically acceptable salt thereof.

67. A compound according to claim 1, further defined as:

or a pharmaceutically acceptable salt thereof.

68. A compound according to claim 1, further defined as:

Or a pharmaceutically acceptable salt thereof.

69. The compound of claim 34, further defined as:

or a pharmaceutically acceptable salt thereof.

70. A compound according to claim 1, further defined as:

or a pharmaceutically acceptable salt thereof.

71. The compound of claim 33, further defined as:

or a pharmaceutically acceptable salt thereof.

72. The compound of claim 30, further defined as:

or a pharmaceutically acceptable salt thereof.

73. A compound of the formula:

or a pharmaceutically acceptable salt thereof.

74. The compound of claim 29, further defined as:

or a pharmaceutically acceptable salt thereof.

75. The compound of claim 29, further defined as:

or a pharmaceutically acceptable salt thereof.

76. A compound according to claim 1, further defined as:

or a pharmaceutically acceptable salt thereof.

77. A compound of the formula:

or a pharmaceutically acceptable salt thereof.

78. A compound of the formula:

or a pharmaceutically acceptable salt thereof.

79. A compound according to claim 1, further defined as:

or a pharmaceutically acceptable salt thereof.

80. A compound selected from:

methyl 2- ((4aR,6aR,6bS,8aR,12aS,14aR,14bS) -11-cyano-2, 2,6a,6b,9,9,12 a-heptamethyl-10, 14-dioxo-1, 2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,12a,14,14a,14 b-octahydrodepicene-4 a-yl) acetate,

2- ((4aR,6aR,6bS,8aR,12aS,14aR,14bS) -11-cyano-2, 2,6a,6b,9,9,12 a-heptamethyl-10, 14-dioxo-1, 2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,12a,14,14a,14 b-octahydrodepicene-4 a-yl) acetic acid,

(4aR,6aR,6bR,8aS,12aS,12bR,14bR) -8a- (hydroxymethyl) -4,4,6a,6b,11,11,14 b-heptamethyl-3, 13-dioxo-3, 4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14,14a,14 b-didehydroapicene-2-carbonitrile,

((4aS,6aR,6bR,8aR,12aR,14aR,14bS) -11-cyano-2, 2,6a,6b,9,9,12 a-heptamethyl-10, 14-dioxo-1, 2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,12a,12b,13,14,14a,14 b-didedecahydropicene-4 a-yl) methyl acetate,

(6aR,6bR,8aR,12aS,12bR,14bR) -4,4,6a,6b,11,11,14 b-heptamethyl-3, 13-dioxo-8 a-vinyl-3, 4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14,14a,14 b-didepicene-2-carbonitrile,

(6aR,6bR,8aS,12aS,12bR,14bR) -8a- (aminomethyl) -4,4,6a,6b,11,11,14 b-heptamethyl-3, 13-dioxo-3, 4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14,14a,14 b-didepicene-2-carbonitrile,

(6aR,6bR,8aS,12aS,12bR,14bR) -8a- (aminomethyl) -4,4,6a,6b,11,11,14 b-heptamethyl-3, 13-dioxo-3, 4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14,14a,14 b-didepicene-2-carbonitrile, trifluoroacetate salt,

(4aR,6aR,6bR,8aS,12aS,12bR,14aR,14bR) -8a- ((cyanomethylamino) methyl) -4,4,6a,6b,11,11,14 b-heptamethyl-3, 13-dioxo-3, 4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14,14a,14 b-didehydroapicene-2-carbonitrile,

N- (((4aS,6aR,6bR,12aR,14aR,14bS) -11-cyano-2, 2,6a,6b,9,9,12 a-heptamethyl-10, 14-dioxo-1, 2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,12a,12b,13,14,14a,14 b-didepicene-4 a-yl) methyl) methanesulfonamide,

(4aR,6aR,6bR,8aS,12aS,12bR,14aR,14bR) -8a- ((R) -1, 2-dihydroxyethyl) -4,4,6a,6b,11,11,14 b-heptamethyl-3, 13-dioxo-3, 4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14,14a,14 b-didepicene-2-carbonitrile,

n- (((4aS,6aR,6bR,8aR,12aR,12bR,14aR,14bS) -11-cyano-2, 2,6a,6b,9,9,12 a-heptamethyl-10, 14-dioxo-1, 2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,12a,12b,13,14,14a,14 b-didepicene-4 a-yl) methyl) -2,2, 2-trifluoroethylsulfonamide,

n- (((4aS,6aR,6bR,12aR,14aR,14bS) -11-cyano-2, 2,6a,6b,9,9,12 a-heptamethyl-10, 14-dioxo-1, 2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,12a,12b,13,14,14a,14 b-didepicene-4 a-yl) methyl) -2,2, 2-trifluoroacetamide,

(4aR,6aR,6bR,8aS,12aS,12bR,14aR,14bR) -8a- (methoxymethyl) -4,4,6a,6b,11,11,14 b-heptamethyl-3, 13-dioxo-3, 4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14,14a,14 b-didepicene-2-carbonitrile,

(4aR,6aR,6bR,8aR,12aS,12bR,14aR,14bR) -8a- (2-hydroxyethyl) -4,4,6a,6b,11,11,14 b-heptamethyl-3, 13-dioxo-3, 4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14,14a,14 b-didehydroapicene-2-carbonitrile,

(4aR,6aR,6bR,8aS,12aS,12bR,14aR,14bR) -4,4,6a,6b,11,11,14 b-heptamethyl-8 a- (((5-methylisoxazol-3-yl) methylamino) methyl) -3, 13-dioxo-3, 4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14,14a,14 b-didehydropicene-2-carbonitrile,

(4aR,6aR,6bR,8aS,12aS,12bR,14aR,14bR) -4,4,6a,6b,11,11,14 b-heptamethyl-8 a- (((2-methyl-2H-tetrazol-5-yl) methylamino) methyl) -3, 13-dioxo-3, 4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14,14a,14 b-didehydropicene-2-carbonitrile,

(4aR,6aR,6bR,8aS,12aS,12bR,14aR,14bR) -4,4,6a,6b,11,11,14 b-heptamethyl-3, 13-dioxo-8 a- (phenylthiomethyl) -3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14,14a,14 b-didepicene-2-carbonitrile,

((4aS,6aR,6bR,8aR,12aR,12bR,14aR,14bS) -11-cyano-2, 2,6a,6b,9,9,12 a-heptamethyl-10, 14-dioxo-1, 2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,12a,12b,13,14,14a,14 b-didepicene-4 a-yl) methyldiethylphosphate,

((4aS,6aR,6bR,12aR,14aR,14bS) -11-cyano-2, 2,6a,6b,9,9,12 a-heptamethyl-10, 14-dioxo-1, 2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,12a,12b,13,14,14a,14 b-didepicene-4 a-yl) methyl carbamic acid tert-butyl ester,

(4aR,6aR,6bR,8aS,12aS,12bR,14aR,14bR) -4,4,6a,6b,11,11,14 b-heptamethyl-3, 13-dioxo-8 a- (phenylsulfinylmethyl) -3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14,14a,14 b-didehydroapicene-2-carbonitrile,

(4aR,6aR,6bR,8aS,12aS,12bR,14aR,14bR) -4,4,6a,6b,11,11,14 b-heptamethyl-3, 13-dioxo-8 a- (phenylsulfonylmethyl) -3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14,14a,14 b-didepicene-2-carbonitrile,

((4aS,6aR,6bR,8aR,12aR,12bR,14aR,14bS) -11-cyano-2, 2,6a,6b,9,9,12 a-heptamethyl-10, 14-dioxo-1, 2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,12a,12b,13,14,14a,14 b-didepicene-4 a-yl) methylphosphonic acid dihydrogenester,

(4aR,6aR,6bR,8aS,12aS,12bR,14aR,14bR) -4,4,6a,6b,11,11,14 b-heptamethyl-3, 13-dioxo-8 a- ((2,2, 2-trifluoroethylamino) methyl) -3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14,14a,14 b-didehydropicene-2-carbonitrile,

(4aR,6aR,6bR,8aS,12aS,12bR,14aR,14bR) -4,4,6a,6b,11,11,14 b-heptamethyl-8 a- ((R) -oxiran-2-yl) -3, 13-dioxo-3, 4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14,14a,14 b-didepicene-2-carbonitrile,

(4aR,6aR,6bR,8aS,12aS,12bR,14aR,14bR) -8a- ((1, 3-dioxoisoindolin-2-yl) methyl) -4,4,6a,6b,11,11,14 b-heptamethyl-3, 13-dioxo-3, 4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14,14a,14 b-didehydropicene-2-carbonitrile,

(4aR,6aR,6bR,8aS,12aS,12bR,14aR,14bR) -8a- ((R) -2-bromo-1-hydroxyethyl) -4,4,6a,6b,11,11,14 b-heptamethyl-3, 13-dioxo-3, 4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14,14a,14 b-didehydropicene-2-carbonitrile,

(4aR,6aR,6bR,8aS,12aS,12bR,14aR,14bR) -8a- ((R) -2-chloro-1-hydroxyethyl) -4,4,6a,6b,11,11,14 b-heptamethyl-3, 13-dioxo-3, 4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14,14a,14 b-didehydropicene-2-carbonitrile,

(4aR,6aR,6bR,8aS,12aS,12bR,14aR,14bR) -8a- ((S) -1, 3-dioxolan-4-yl) -4,4,6a,6b,11,11,14 b-heptamethyl-3, 13-dioxo-3, 4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14,14a,14 b-didehydropicene-2-carbonitrile,

((4aS,6aR,6bR,8aR,12aR,12bR,14aR,14bS) -11-cyano-2, 2,6a,6b,9,9,12 a-heptamethyl-10, 14-dioxo-1, 2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,12a,12b,13,14,14a,14 b-didepicene-4 a-yl) methyl 2,2, 2-trifluoroacetate,

((4aS,6aR,6bR,8aR,12aR,12bR,14aR,14bS) -11-cyano-2, 2,6a,6b,9,9,12 a-heptamethyl-10, 14-dioxo-1, 2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,12a,12b,13,14,14a,14 b-didepicene-4 a-yl) methylpivalate,

((4aS,6aR,6bR,8aR,12aR,12bR,14aR,14bS) -11-cyano-2, 2,6a,6b,9,9,12 a-heptamethyl-10, 14-dioxo-1, 2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,12a,12b,13,14,14a,14 b-didepicene-4 a-yl) methylbenzoate,

(4aR,6aR,6bR,8aS,12aS,12bR,14aR,14bR) -8a- (2-cyano-1-hydroxyethyl) -4,4,6a,6b,11,11,14 b-heptamethyl-3, 13-dioxo-3, 4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14,14a,14 b-didepicene-2-carbonitrile,

(4aR,6aR,6bR,8aS,12aS,12bR,14aR,14bR) -8 a-ethyl-4, 4,6a,6b,11,11,14 b-heptamethyl-3, 13-dioxo-3, 4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14,14a,14 b-didehydroapicene-2-carbonitrile,

2- ((4aR,6aR,6bR,8aR,12aR,12bR,14aR,14bS) -11-cyano-2, 2,6a,6b,9,9,12 a-heptamethyl-10, 14-dioxo-1, 2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,12a,12b,13,14,14a,14 b-didepicene-4 a-yl) acetic acid,

methyl 2- ((4aR,6aR,6bR,8aR,12aR,12bR,14aR,14bS) -11-cyano-2, 2,6a,6b,9,9,12 a-heptamethyl-10, 14-dioxo-1, 2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,12a,12b,13,14,14a,14 b-didepicene-4 a-yl) acetate,

2- ((4aR,6aR,6bR,8aR,12aR,12bR,14aR,14bS) -11-cyano-2, 2,6a,6b,9,9,12 a-heptamethyl-10, 14-dioxo-1, 2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,12a,12b,13,14,14a,14 b-didepicene-4 a-yl) -N-ethylacetamide,

2- ((4aR,6aR,6bR,8aR,12aR,12bR,14aR,14bS) -11-cyano-2, 2,6a,6b,9,9,12 a-heptamethyl-10, 14-dioxo-1, 2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,12a,12b,13,14,14a,14 b-didepicene-4 a-yl) -N- (2-fluoroethyl) acetamide,

2- ((4aR, 6bR,8aR,12 bR,14aR,14bS) -11-cyano-2, 2,6a,6b,9,9,12 a-heptamethyl-10, 14-dioxo-1, 2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,12a,12b,13,14,14a,14 b-didepicene-4 a-yl) -N- (2, 2-difluoroethyl) acetamide, and

2- ((4aR, 6bR,8aR,12 bR,14aR,14bS) -11-cyano-2, 2,6a,6b,9,9,12 a-heptamethyl-10, 14-dioxo-1, 2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,12a,12b,13,14,14a,14 b-didepicene-4 a-yl) -N- (2,2, 2-trifluoroethyl) acetamide.

81. A compound of the formula:

82. a pharmaceutical composition comprising as active ingredient a compound according to any one of claims 1-80 and a pharmaceutically acceptable carrier.

83. The composition of claim 82, wherein the composition is formulated for oral delivery.

84. Use of a compound of any one of claims 1-80 in the manufacture of a medicament for treating or preventing a disease having an inflammatory component in a subject.