# Patent

## Title
Method for treating proliferative disorders associated with mutations in c-Met

## Abstract

The present invention relates to methods of inhibiting the activity of Hsp90 in a subject in need thereof and methods for treating c-Met associated cancers, in a subject in need thereof.

## Background
RELATED APPLICATIONS
This application is a continuation of U.S. application Ser. No. 12/601,729, filed Jul. 8, 2010, which is the U.S. National Stage of International Application No. PCT/US2008/006547, filed May 22, 2008, which claims the benefit of U.S. Application No. 60/691,937, filed May 25, 2007. The entire teachings of the above applications are incorporated herein by reference.


FIELD OF THE INVENTION
The invention relates to a method of inhibiting the activity of Hsp90 in a subject in need thereof and methods for treating proliferative disorders associated with misregulation of c-Met receptor tyrosine kinase (including mutations or fusion proteins that result in constitutively active c-Met, and mutations that result in amplification or over expression of c-Met).
BACKGROUND OF THE INVENTION
Although tremendous advances have been made in elucidating the genomic abnormalities that cause malignant cancer cells, currently available chemotherapy remains unsatisfactory, and the prognosis for the majority of patients diagnosed with cancer remains dismal.
Heat shock proteins (HSPs) are a class of chaperone proteins that are up-regulated in response to elevated temperature and other environmental stresses, such as ultraviolet light, nutrient deprivation, and oxygen deprivation. HSPs act as chaperones to other cellular proteins (called client proteins) and facilitate their proper folding and repair, and aid in the refolding of misfolded client proteins. There are several known families of HSPs, each having its own set of client proteins. The Hsp90 family is one of the most abundant HSP families, accounting for about 1-2% of proteins in a cell that is not under stress and increasing to about 4-6% in a cell under stress. Inhibition of Hsp90 results in degradation of its client proteins via the ubiquitin proteasome pathway. Unlike other chaperone proteins, the client proteins of Hsp90 are mostly protein kinases or transcription factors involved in signal transduction, and a number of its client proteins have been shown to be involved in the progression of cancer.
c-Met is a receptor tyrosine kinase that is a client protein of Hsp90 and is encoded by the Met protooncogene. Hepatocyte growth factor (HGF) (also referred to as scatter factor (SF)) is the natural ligand of c-Met which binds to c-Met and leads to a variety of cellular responses such as proliferation, survival, angiogenesis, wound healing, tissue regeneration, scattering, motility, invasion and branching morphogenesis (Ma et al., Cancer and Metastasis Reviews (2003), 22: 309-325). c-Met and HGF are expressed in numerous tissues, although their expression is normally confined predominantly to cells of epithelial and mesenchymal origin, respectively. c-Met and HGF are required for normal mammalian development and have been shown to be important in cell migration, cell proliferation and survival, morphogenic differentiation, and organization of 3-dimensional tubular structures (e.g., renal tubular cells, gland formation, etc.). However, dysregulation of c-Met and/or HGF is believed to contribute to tumor growth, dissemination and invasion in several human cancers. c-Met and/or HGF are highly expressed in numerous cancers and their expression correlates with poor prognosis (Christensen, et al., Cancer Research (2003), 63:7345-7355). For example, c-Met receptor mutations have been shown to be expressed in a number of human cancers including hereditary and sporadic human papillary renal carcinomas, ovarian cancer, childhood hepatocellular carcinoma, metastatic head and neck squamous cell carcinomas, esophageal cancer and gastric cancer. Met gene amplification and over expression of c-Met has been shown to be associated with both non-small cell lung cancer (NSCLC) and small cell lung cancer (SCLC), as well as colorectal cancer, and the Tpr/Met fusion protein has been shown to be present in human osteogenic sarcoma and gastric cancer. Families with germine mutations that activate c-Met kinase are prone to multiple kidney tumors as well as tumors in other tissues. Numerous studies have correlated the expression of c-Met and/or HGF with the state of disease progression of different types of cancer (including lung, colon, breast, prostate, liver, pancreas, brain, kidney, ovarian, stomach, skin, and bone cancers).
The validity of targeting receptor tyrosine kinases (RTK) that are dysregulated in human cancers is illustrated by the successes of Gleevec targeting Bcr-Abl in chronic myelogenous leukemia and c-Kit in gastroinstinal stromal tumors, Herceptin in Her-2 overexpressing breast cancers, and Iressa in select NSCLC that have dysregulated EGFR. Compelling evidence exists for targeting c-Met in the treatment of human cancers and several small drug molecules that inhibit c-Met are currently in development. However, therapies that target specific RTK often work well initially for treating cancer but eventually fail due to additional mutations which allow RTK to maintain its activity in the presence of the drug. Moreover, the selective c-Met inhibitor SU11274, while highly affected against wild type c-Met and some mutants of c-Met, has been shown to be ineffective against other c-Met mutants (Berthou, et al., Oncogene (2004), 23:5387-5393). Therefore, a need exists to develop new anticancer therapeutics that reduce the expression and/or activity of c-Met via a different mechanism than therapeutics that directly inhibit c-Met.
SUMMARY OF THE INVENTION
The present invention provides compounds which inhibit the activity of Hsp90 and thereby increase the degradation of c-Met, a client protein of Hsp90. Thus, compounds of the invention are useful in the treating of proliferative disorders, such as cancer, including c-Met associated cancers.
In one embodiment, the present invention provides Hsp90 inhibitor compounds having the formula (I):




and tautomers, pharmaceutically acceptable salts, solvates, clathrates, and prodrugs thereof. In formula (I), ring A is an aryl or a heteroaryl, wherein the aryl or the heteroaryl are optionally further substituted with one or more substituents in addition to R3;

R1 is —OH, —SH, —NR7H, —OR26, —SR26, —NHR26, —O(CH2)mOH, —O(CH2)mSH, —O(CH2)mNR7H, —S(CH2)mOH, —S(CH2)mSH, —S(CH2)mNR7H, —OC(O)NR10R11, —SC(O)NR10R11, —NR7C(O)NR10R11, —OC(O)R7, —SC(O)R7, —NR7C(O)R7, —OC(O)OR7, —SC(O)OR7, —NR7C(O)OR7, —OCH2C(O)R7, —SCH2C(O)R7, —NR7CH2C(O)R7, —OCH2C(O)OR7, —SCH2C(O)OR7, —NR7CH2C(O)OR7, —OCH2C(O)NR10R11, —SCH2C(O)NR10R11, —NR7CH2C(O)NR10R11, —OS(O)pR7, —SS(O)pR7, —S(O)pOR7, —NR7S(O)pR7, —OS(O)pNR10R11, —SS(O)pNR10R11, —NR7S(O)pNR10R11, —OS(O)pOR7, —SS(O)pOR7, —NR7S(O)pOR7, —OC(S)R7, —SC(S)R7, —NR7C(S)R7, —OC(S)OR7, —SC(S)OR7, —NR7C(S)OR7, —OC(S)NR10R11, —SC(S)NR10R11, —NR7C(S)NR10R11, —OC(NR8)R7, —SC(NR8)R7, —NR7C(NR8)R7, —OC(NR8)OR7, —SC(NR8)OR7, —NR7C(NR8)OR7, —OC(NR8)NR10R11, —SC(NR8)NR10R11, —NR7C(NR8)NR10R11, —OP(O)(OR7)2, or —SP(O)(OR7)2;
R3 is —OH, —SH, —NR7H, —OR26, —SR26, —NHR26, —O(CH2)mOH, —O(CH2)mSH, —O(CH2)mNR7H, —S(CH2)mOH, —S(CH2)mSH, —S(CH2)mNR7H, —OC(O)NR10R11, —SC(O)NR10R11, —NR7C(O)NR10R11, —OC(O)R7, —SC(O)R7, —NR7C(O)R7, —OC(O)OR7, —SC(O)OR7, —NR7C(O)OR7, —OCH2C(O)R7, —SCH2C(O)R7, —NR7CH2C(O)R7, —OCH2C(O)OR7, —SCH2C(O)OR7, —NR7CH2C(O)OR7, —OCH2C(O)NR10R11, —SCH2C(O)NR10R11, —NR7CH2C(O)NR10R11, —OS(O)pR7, —SS(O)pR7, —S(O)pOR7, —NR7S(O)pR7, —OS(O)pNR10R11, —SS(O)pNR10R11, —NR7S(O)pNR10R11, —OS(O)pOR7, —SS(O)pOR7, —NR7S(O)pOR7, —NR7S(O)pR7, —OS(O)pNR10R11, —SS(O)pNR10R11, —NR7S(O)pNR10R11, —OS(O)pOR7, —SS(O)pOR7, —NR7S(O)pOR7, —OC(S)R7, —SC(S)R7, —NR7C(S)R7, —OC(S)OR7, —SC(S)OR7, —NR7C(S)OR7, —OC(S)NR10R11, —SC(S)NR10R11, —NR7C(S)NR10R11, —OC(NR8)R7, —SC(NR8)R7, —NR7C(NR8)R7, —OC(NR8)OR7, —SC(NR8)OR7, —NR7C(NR8)OR7, —OC(NR8)NR10R11, —SC(NR8)NR10R11, —NR7C(NR8)NR10R11, —C(O)OH, —C(O)NHR8, —C(O)SH, —S(O)OH, —S(O)2OH, —S(O)NHR8, —S(O)2NHR8, —OP(O)(OR7)2, or —SP(O)(OR7)2;
R5 is an optionally substituted heteroaryl or an optionally substituted 8 to 14 membered aryl;
R7 and R8, for each occurrence, are, independently, —H, an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, or an optionally substituted heteraralkyl;
R10 and R11, for each occurrence, are independently —H, an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, or an optionally substituted heteraralkyl; or R10 and R11, taken together with the nitrogen to which they are attached, form an optionally substituted heterocyclyl or an optionally substituted heteroaryl;
R26 is a lower alkyl;
p, for each occurrence, is, independently, 0, 1 or 2; and
m, for each occurrence, is independently, 1, 2, 3, or 4.
In one embodiment, ring A of the compounds of formula (I) is not a substituted [1,2,3]triazole, and/or compounds represented by formula (I) do not include 3-(2,4-dihydroxy-phenyl)-4-(7-naphthalen-1-yl)-5-mercapto-triazole.
The present invention also provides Hsp90 inhibitor compounds having the formula (II):




and tautomers, pharmaceutically acceptable salts, solvates, clathrates, and prodrugs thereof. In formula (II), ring A, R1, and R3 are defined as for formula (I); and

R2 is a substituted phenyl, wherein the phenyl group is substituted with:

    
    
        i) one substituent selected from nitro, cyano, a haloalkoxy, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, an optionally substituted heteraralkyl, hydroxylalkyl, alkoxyalkyl, guanadino, —NR10R11, —O—R20, —C(O)R7, —C(O)OR20, —OC(O)R7, —C(O)NR10R11, —NR8C(O)R7, —SR7, —S(O)pR7, —OS(O)pR7, —S(O)pOR7, —NR8S(O)pR7, or —S(O)pNR10R11, or
        ii) two to five substituents selected from the group consisting of an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, an optionally substituted heteraralkyl, hydroxyalkyl, alkoxyalkyl, —F, —Br, —I, cyano, nitro, guanadino, a haloalkyl, a heteroalkyl, —NR10R11, —OR7, —C(O)R7, —C(O)OR7, —OC(O)R7, —C(O)NR10R11, —NR8C(O)R7, —SR7, —S(O)pR7, —OS(O)pR7, —S(O)pOR7, —NR8S(O)pR7, or —S(O)pNR10R11; and
    
    


R20, for each occurrence, is independently an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, or an optionally substituted heteraralkyl.
In one embodiment, compounds represented by formula (II) do not include 3-(2,4-dihydroxy-phenyl)-4-(7-naphthalen-1-yl)-5-mercapto-triazole, 3-(2,4-dihydroxyphenyl)-4-(2,5-dimethoxyphenyl)-5-mercapto-triazole, 3-(1-phenyl-5-amino-pyrazol-4-yl)-4-(2,4-dichloropheny)-5-mercapto-triazole, or 3-(2-hydroxy-phenyl)4-(2,4-dimethylphenyl)-5-mercapto-triazole.
The present invention also provides Hsp90 inhibitor compounds having the formula (III):




and tautomers, pharmaceutically acceptable salts, solvates, clathrates, and prodrugs thereof. In formula (III), ring A, R1, and R3 are defined as for formula (I); and

R18 is an optionally substituted cycloalkyl, and optionally substituted cycloalkenyl, or a substituted alkyl, wherein the alkyl group is substituted with one or more substituents independently selected from the group consisting of an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heteroaryl, an optionally substituted aralkyl, an optionally substituted heteraralkyl, halo, cyano, nitro, guanadino, a haloalkyl, —NR10R11, —OR7, —C(O)R7, —C(O)OR7, —OC(O)R7, —C(O)NR10R11, —NR8C(O)R7, —SR7, —S(O)pR7, —OS(O)pR7, —S(O)pOR7, —NR8S(O)pR7, or —S(O)pNR10R11;
In one embodiment, compounds represented by formula (III) do not include compounds in which R18 is not cyclohexyl.
The invention also provides Hsp90 inhibitor compounds represented by formula (IV) or formula (V):




and tautomers, pharmaceutically acceptable salts, solvates, clathrates, and prodrugs thereof. In formulas (IV) and (V), R1 and R3 are defined as for formula (I); and

X14 is O, S, or NR7;
R21 is an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, or an optionally substituted heteraralkyl;
R22, for each occurrence, is independently a substituent selected from the group consisting of H, an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, or an optionally substituted heteraralkyl, a haloalkyl, —C(O)R7, —C(O)OR7, —OC(O)R7, —C(O)NR10R11, —NR8C(O)R7, —S(O)pR7, —S(O)pOR7, or —S(O)pNR10R11; and
R23 and R24, for each occurrence, are independently a substituent selected from the group consisting of H, an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, or an optionally substituted heteraralkyl, halo, cyano, nitro, guanadino, a haloalkyl, a heteroalkyl, —NR10R11, —OR7, —C(O)R7, —C(O)OR7, —OC(O)R7, —C(O)NR10R11, —NR8C(O)R7, —SR7, —S(O)pR7, —OS(O)pR7, —S(O)pOR7, —NR8S(O)pR7, or —S(O)pNR10R11.
In one embodiment, the present invention provides Hsp90 inhibitor compounds represented by structural formula (VI):




or a tautomer, pharmaceutically acceptable salt, solvate, clathrate, or a prodrug thereof. In formula (VI):

ring A is an aryl or a heteroaryl, wherein the aryl or the heteroaryl are optionally further substituted with one or more substituents in addition to R3;
R1 is —OH, —SH, —NR7H, —OR26, —SR26, —NHR26, —O(CH2)mOH, —O(CH2)mSH, —O(CH2)mNR7H, —S(CH2)mOH, —S(CH2)mSH, —S(CH2)mNR7H, —OC(O)NR10R11, —SC(O)NR10R11, —NR7C(O)NR10R11, —OC(O)R7, —SC(O)R7, —NR7C(O)R7, —OC(O)OR7, —SC(O)OR7, —NR7C(O)OR7, —OCH2C(O)R7, —SCH2C(O)R7, —NR7CH2C(O)R7, —OCH2C(O)OR7, —SCH2C(O)OR7, —NR7CH2C(O)OR7, —OCH2C(O)NR10R11, —SCH2C(O)NR10R11, —NR7CH2C(O)NR10R11, —OS(O)pR7, —SS(O)pR7, —S(O)pOR7, —NR7S(O)pR7, —OS(O)pNR10R11, —SS(O)pNR10R11, —NR7S(O)pNR10R11, —OS(O)pOR7, —SS(O)pOR7, —NR7S(O)pOR7, —OC(S)R7, —SC(S)R7, —NR7C(S)R7, —OC(S)OR7, —SC(S)OR7, —NR7C(S)OR7, —OC(S)NR10R11, —SC(S)NR10R11, —NR7C(S)NR10R11, —OC(NR8)R7, —SC(NR8)R7, —NR7C(NR8)R7, —OC(NR8)OR7, —SC(NR8)OR7, —NR7C(NR8)OR7, —OC(NR8)NR10R11, —SC(NR8)NR10R11, —NR7C(NR8)NR10R11, —OP(O)(OR7)2, or —SP(O)(OR7)2;
R3 is —OH, —SH, —NR7H, —OR26, —SR26, —NHR26, —O(CH2)mOH, —O(CH2)mSH, —O(CH2)mNR7H, —S(CH2)mOH, —S(CH2)mSH, —S(CH2)mNR7H, —OC(O)NR10R11, —SC(O)NR10R11, —NR7C(O)NR10R11, —OC(O)R7, —SC(O)R7, —NR7C(O)R7, —OC(O)OR7, —SC(O)OR7, —NR7C(O)OR7, —OCH2C(O)R7, —SCH2C(O)R7, —NR7CH2C(O)R7, —OCH2C(O)OR7, —SCH2C(O)OR7, —NR7CH2C(O)OR7, —OCH2C(O)NR10R11, —SCH2C(O)NR10R11, —NR7CH2C(O)NR10R11, —OS(O)pR7, —SS(O)pR7, —S(O)pOR7, —NR7S(O)pR7, —OS(O)pNR10R11, —SS(O)pNR10R11, —NR7S(O)pNR10R11, —OS(O)pOR7, —SS(O)pOR7, —NR7S(O)pOR7, —OC(S)R7, —SC(S)R7, —NR7C(S)R7, —OC(S)OR7, —SC(S)OR7, —NR7C(S)OR7, —OC(S)NR10R11, —SC(S)NR10R11, —NR7C(S)NR10R11, —OC(NR8)R7, —SC(NR8)R7, —NR7C(NR8)R7, —OC(NR8)OR7, —SC(NR8)OR7, —NR7C(NR8)OR7, —OC(NR8)NR10R11, —SC(NR8)NR10R11, —NR7C(NR8)NR10R11, —C(O)OH, —C(O)NHR8, —C(O)SH, —S(O)OH, —S(O)2OH, —S(O)NHR8, —S(O)2NHR8, —OP(O)(OR7)2, or —SP(O)(OR7)2;
R5 is an optionally substituted heteroaryl or an optionally substituted 8 to 14-membered aryl;
R7 and R8, for each occurrence, are, independently, —H, an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, or an optionally substituted heteraralkyl;
R10 and R11, for each occurrence, are independently —H, an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, or an optionally substituted heteraralkyl; or R10 and R11, taken together with the nitrogen to which they are attached, form an optionally substituted heterocyclyl or an optionally substituted heteroaryl;
R26 is a lower alkyl;
p, for each occurrence, is, independently, 0, 1 or 2; and
m, for each occurrence, is independently, 1, 2, 3, or 4.
In another embodiment, the present invention provides Hsp90 inhibitor compounds represented by structural formula (VII):




In formula (VII), R2′ is an optionally substituted phenyl group. Preferably, R2′ is substituted with one or more group represented by R30, wherein R30, for each occurrence, is independently an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, an optionally substituted heteraralkyl, halo, cyano, nitro, guanadino, a haloalkyl, a heteroalkyl, alkoxy, haloalkoxy, —NR10R11, —OR7, —C(O)R7, —C(O)OR7, —C(S)R7, —C(O)SR7, —C(S)SR7, —C(S)OR7, —C(S)NR10R11, —C(NR8)OR7, —C(NR8)R7, —C(NR8)NR10R11, —C(NR8)SR7, —OC(O)R7, —OC(O)OR7, —OC(S)OR7, —OC(NR8)OR7, —SC(O)R7, —SC(O)OR7, —SC(NR8)OR7, —OC(S)R7, —SC(S)R7, —SC(S)OR7, —OC(O)NR10R11, —OC(S)NR10R11, —OC(NR8)NR10R11, —SC(O)NR10R11, —SC(NR8)NR10R11, —SC(S)NR10R11, —OC(NR8)R7, —SC(NR8)R7, —C(O)NR10R11, —NR8C(O)R7, —NR7C(S)R7, —NR7C(S)OR7, —NR7C(NR8)R7, —NR7C(O)OR7, —NR7C(NR8)OR7, —NR7C(O)NR10R11, —NR7C(S)NR10R11, —NR7C(NR8)NR10R11, —SR7, —S(O)pR7, —OS(O)pR7, —OS(O)pOR7, —OS(O)pNR10R11, —S(O)pOR7, —NR8S(O)pR7, —NR7S(O)pNR10R11, —NR7S(O)pOR7, —S(O)pNR10R11, —SS(O)pR7, —SS(O)pOR7, —SS(O)pNR10R11, —OP(O)(OR7)2, or —SP(O)(OR7)2. The remainder of the variables in structural formula (VII) have values defined above with reference to structural formula (VI).
In another embodiment, the present invention provides Hsp90 inhibitor compounds represented by structural formula (VIII):




In formula (VIII), R18 is an optionally substituted cycloalkyl, and optionally substituted cycloalkenyl, or a substituted alkyl, wherein the alkyl group is substituted with one or more substituents independently selected from the group consisting of an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heteroaryl, an optionally substituted aralkyl, an optionally substituted heteraralkyl, halo, cyano, nitro, guanadino, a haloalkyl, —NR10R11, —OR7, —C(O)R7, —C(O)OR7, —OC(O)R7, —C(O)NR10R11, —NR8C(O)R7, —SR7, —S(O)pR7, —OS(O)pR7, —S(O)pOR7, —NR8S(O)pR7, or —S(O)pNR10R11. The remainder of the variables in structural formula (VIII) have values defined above with reference to structural formula (VI).
In another embodiment, the present invention provides Hsp90 inhibitor compounds represented by structural formula (IX):




or a tautomer, pharmaceutically acceptable salt, solvate, clathrate, or a prodrug thereof. In formula (IX):

ring A is an aryl or a heteroaryl, wherein the aryl or the heteroaryl are optionally further substituted with one or more substituents in addition to R3;
R1 is —OH, —SH, —NR7H, —OR26, —SR26, —NHR26, —O(CH2)mOH, —O(CH2)mSH, —O(CH2)mNR7H, —S(CH2)mOH, —S(CH2)mSH, —S(CH2)mNR7H, —OC(O)NR10R11, —SC(O)NR10R11, —NR7C(O)NR10R11, —OC(O)R7, —SC(O)R7, —NR7C(O)R7, —OC(O)OR7, —SC(O)OR7, —NR7C(O)OR7, —OCH2C(O)R7, —SCH2C(O)R7, —NR7CH2C(O)R7, —OCH2C(O)OR7, —SCH2C(O)OR7, —NR7CH2C(O)OR7, —OCH2C(O)NR10R11, —SCH2C(O)NR10R11, —NR7CH2C(O)NR10R11, —OS(O)pR7, —SS(O)pR7, —S(O)pOR7, —NR7S(O)pR7, —OS(O)pNR10R11, —SS(O)pNR10R11, —NR7S(O)pNR10R11, —OS(O)pOR7, —SS(O)pOR7, —NR7S(O)pOR7, —OC(S)R7, —SC(S)R7, —NR7C(S)R7, —OC(S)OR7, —SC(S)OR7, —NR7C(S)OR7, —OC(S)NR10R11, —SC(S)NR10R11, —NR7C(S)NR10R11, —OC(NR8)R7, —SC(NR8)R7, —NR7C(NR8)R7, —OC(NR8)OR7, —SC(NR8)OR7, —NR7C(NR8)OR7, —OC(NR8)NR10R11, —SC(NR8)NR10R11, —NR7C(NR8)NR10R11, —OP(O)(OR7)2, or —SP(O)(OR7)2;
R3 is —OH, —SH, —NR7H, —OR26, —SR26, —NHR26, —O(CH2)mOH, —O(CH2)mSH, —O(CH2)mNR7H, —S(CH2)mOH, —S(CH2)mSH, —S(CH2)mNR7H, —OC(O)NR10R11, —SC(O)NR10R11, —NR7C(O)NR10R11, —OC(O)R7, —SC(O)R7, —NR7C(O)R7, —OC(O)OR7, —SC(O)OR7, —NR7C(O)OR7, —OCH2C(O)R7, —SCH2C(O)R7, —NR7CH2C(O)R7, —OCH2C(O)OR7, —SCH2C(O)OR7, —NR7CH2C(O)OR7, —OCH2C(O)NR10R11, —SCH2C(O)NR10R11, —NR7CH2C(O)NR10R11, —OS(O)pR7, —SS(O)pR7, —S(O)pOR7, —NR7S(O)pR7, —OS(O)pNR10R11, —SS(O)pNR10R11, —NR7S(O)pNR10R11, —OS(O)pOR7, —SS(O)pOR7, —NR7S(O)pOR7, —OC(S)R7, —SC(S)R7, —NR7C(S)R7, —OC(S)OR7, —SC(S)OR7, —NR7C(S)OR7, —OC(S)NR10R11, —SC(S)NR10R11, —NR7C(S)NR10R11, —OC(NR8)R7, —SC(NR8)R7, —NR7C(NR8)R7, —OC(NR8)OR7, —SC(NR8)OR7, —NR7C(NR8)OR7, —OC(NR8)NR10R11, —SC(NR8)NR10R11, —NR7C(NR8)NR10R11, —C(O)OH, —C(O)NHR8, —C(O)SH, —S(O)OH, —S(O)2OH, —S(O)NHR8, —S(O)2NHR8, —OP(O)(OR7)2, or —SP(O)(OR7)2;
R5 is an optionally substituted heteroaryl or an optionally substituted 8 to 14-membered aryl;
R7 and R8, for each occurrence, are, independently, —H, an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, or an optionally substituted heteraralkyl;
R10 and R11, for each occurrence, are independently —H, an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, or an optionally substituted heteraralkyl; or R10 and R11, taken together with the nitrogen to which they are attached, form an optionally substituted heterocyclyl or an optionally substituted heteroaryl;
R26 is a lower alkyl;
p, for each occurrence, is, independently, 0, 1 or 2; and
m, for each occurrence, is independently, 1, 2, 3, or 4.
In another embodiment, the present invention provides Hsp90 inhibitor compounds represented by structural formula (X):




In formula (X), R2′ is an optionally substituted phenyl group. Preferably, R2′ is substituted with one or more group represented by R30, wherein R30, for each occurrence, are independently an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, an optionally substituted heteraralkyl, halo, cyano, nitro, guanadino, a haloalkyl, a heteroalkyl, alkoxy, haloalkoxy, —NR10R11, —OR7, —C(O)R7, —C(O)OR7, —C(S)R7, —C(O)SR7, —C(S)SR7, —C(S)OR7, —C(S)NR10R11, —C(NR8)OR7, —C(NR8)R7, —C(NR8)NR10R11, —C(NR8)SR7, —OC(O)R7, —OC(O)OR7, —OC(S)OR7, —OC(NR8)OR7, —SC(O)R7, —SC(O)OR7, —SC(NR8)OR7, —OC(S)R7, —SC(S)R7, —SC(S)OR7, —OC(O)NR10R11, —OC(S)NR10R11, —OC(NR8)NR10R11, —SC(O)NR10R11, —SC(NR8)NR10R11, —SC(S)NR10R11, —OC(NR8)R7, —SC(NR8)R7, —C(O)NR10R11, —NR8C(O)R7, —NR7C(S)R7, —NR7C(S)OR7, —NR7C(NR8)R7, —NR7C(O)OR7, —NR7C(NR8)OR7, —NR7C(O)NR10R11, —NR7C(S)NR10R11, —NR7C(NR8)NR10R11, —SR7, —S(O)pR7, —OS(O)pR7, —OS(O)pOR7, —OS(O)pNR10R11, —S(O)pOR7, —NR8S(O)pR7, —NR7S(O)pNR10R11, —NR7S(O)pOR7, —S(O)pNR10R11, —SS(O)pR7, —SS(O)pOR7, —SS(O)pNR10R11, —OP(O)(OR7)2, or —SP(O)(OR7)2. The remainder of the variables in structural formula (X) have values defined above with reference to structural formula (IX).
In another embodiment, the present invention provides Hsp90 inhibitor compounds represented by structural formula (XI):




In formula (XI), R18 is an optionally substituted cycloalkyl, and optionally substituted cycloalkenyl, or a substituted alkyl, wherein the alkyl group is substituted with one or more substituents independently selected from the group consisting of an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heteroaryl, an optionally substituted aralkyl, an optionally substituted heteraralkyl, halo, cyano, nitro, guanadino, a haloalkyl, —NR10R11, —OR7, —C(O)R7, —C(O)OR7, —OC(O)R7, —C(O)NR10R11, —NR8C(O)R7, —SR7, —S(O)pR7, —OS(O)pR7, —S(O)pOR7, —NR8S(O)pR7, or —S(O)pNR10R11. The remainder of the variables in structural formula (XI) have values defined above with reference to structural formula (IX).
In another embodiment, the present invention is a method of inducing degradation of a c-Met protein in a subject. The method comprises administering to the subject an effective amount of a compound of the invention.
In another embodiment, the present invention is a method of treating a c-Met associated cancer (e.g., a cancer which exhibits dysregulated c-Met and/or HGF) in a subject. The method comprises administering to the subject an effective amount of a compound of the invention.
In another embodiment, the invention relates to a method of treating cancer in a subject, comprising:

    
    
        a) determining whether the subject has a c-Met associated cancer; and
        b) administering to the subject an effective amount of compound of the invention, if the subject has a c-Met associated cancer.
    
    


In another embodiment, the present invention is a pharmaceutical composition for treating a c-Met associated cancer, comprising a compound of the invention and a pharmaceutically acceptable carrier. The pharmaceutical compositions can be used in therapy, e.g., to inhibit Hsp90 activity in a mammal in need of such inhibition, to treat a mammal with a proliferative disorder, or to treat a mammal with cancer, for example a c-Met associated cancer. Preferably, the mammal is a human. In another embodiment, the pharmaceutical composition includes an additional therapeutic agent. In another embodiment, the additional therapeutic agent is an anticancer agent.
In another embodiment of the present invention is the use of a compound of the invention for the manufacture of a medicament for inhibiting Hsp90 in a mammal in need of such inhibition or for treating a mammal with cancer, for example a c-Met associated cancer.
The compounds shown in Tables 5, 6, and 7, or compounds of any formula herein, or tautomers, pharmaceutically acceptable salts, solvates, clathrates, hydrates, polymorphs or prodrugs thereof, inhibit the activity of Hsp90 and, thereby cause the degradation of Hsp90 client proteins, such as c-Met. Hsp90 is necessary for the survival of normal eukaryotic cells. However, Hsp90 is over expressed in many tumor types indicating that it may play a significant role in the survival of cancer cells and that cancer cells may be more sensitive to inhibition of Hsp90 than normal cells. Thus, the compounds shown in Table 5, 6, or 7, or compounds of any formula herein, or tautomers, pharmaceutically acceptable salts, solvates, clathrates, hydrates, polymorphs or prodrugs thereof, are useful treating cancer, such as c-Met associated cancers.
Although chemotherapeutic agents initially cause tumor regression, most agents that are currently used to treat cancer target only one pathway to tumor progression. Therefore, in many instances, after treatment with one or more chemotherapeutic agents, a tumor develops multidrug resistance and no longer responses positively to treatment. One of the advantages of inhibiting Hsp90 activity is that several of its client proteins, which are mostly protein kinases or transcription factors involved in signal transduction, have been shown to be involved in the progression of cancer. Thus, inhibition of Hsp90 provides a method of short circuiting several pathways for tumor progression simultaneously. Moreover, treatment of cancers with kinase inhibitors, such as Gleevec, has been shown to be initially highly successful but ultimately fails in most cases because the inhibited kinase develops one or more mutation that makes it resistant to the kinase inhibitor. Therefore, treatment of cancers with an Hsp90 inhibitor of the invention either alone, or in combination with other chemotherapeutic agents, is more likely to result in regression or elimination of the cancer, and less likely to result in the development of more aggressive multidrug resistant cancers than other currently available therapeis.



BRIEF DESCRIPTION OF THE FIGURES
FIG. 1 is a graph showing the ATPase activity of Hsp90 when untreated, when treated with 40 mM of Geldanamycin, a known Hsp90 inhibitor as a positive control, and when treated with 40 μM or 4 μM of Compound 108 of the invention.
FIG. 2 is gel showing the amount of Her2, an Hsp90 client protein, in cells that are untreated, in cells that have been treated with 0.5 μM, 2 μM, or 5 μM of 17AAG, a known Hsp90 inhibitor, and in cells that have been treated with 0.5 μM, 2 μM, or 5 μM of Compound 108 or Compound 49.
FIG. 3 is a Western blot analysis of the c-Met from NCI-H1193 cells treated with Hsp90 inhibitors of the invention or 17AAG (as a positive control).
FIG. 4 is a graph showing an FACSCalibur flow cytometer analysis of c-Met on the surface of ACHN human renal cell carcinoma cells after treated with Compound 226 of the invention, 17AAG (as a positive control) or 17DMAG (as a positive control). The results indicate that the Hsp90 inhibitors of the invention induce c-Met degradation at a lower concentration than 17AAG or 17DMAG.
FIG. 5 is a graph showing an FACSCalibur flow cytometer analysis of c-Met on the surface of MKN45 human gastric carcinoma cells after treated with Compound 226 of the invention, 17AAG (as a positive control) or 17DMAG (as a positive control). The results indicate that the Hsp90 inhibitors of the invention induce c-Met degradation at a lower concentration than 17AAG or 17DMAG.
FIG. 6 is a graph of showing cell survival of MKN-45 human gastric carcinoma cells, which carry an amplified c-Met locus, after treatment with Compound 226 of the invention or after treatment with 17AAG or DMAG.
FIG. 7 shows the results of a nude mouse xenograft study to determine the effects of Compound #226 on the in vivo growth rate of the human c-MET amplified gastric carcinoma tumor cell line MKN-45. Tumor bearing animals (8 mice/group) were i.v. injected 3 time per week for a total of 9 doses (arrowheads) and the average tumor volumes for each group (error bars represent SEM) were determined every 3-4 days. Treatment with a dose of 50 mg/kg body weight of Compound #226 substantially inhibited tumor growth, with a % T/C value of 8 observed on day 36 (indicated on right). Overt toxicity was not observed, with the 50 mg/kg Compound #226-treated group having an average bodyweight loss relative to the start of the study of −3.5% (+/−0.8 SEM) on day 36.



DETAILED DESCRIPTION OF THE INVENTION
The present invention provides compounds and uses of said compounds. The present invention encompasses the use of the compounds of the invention to inhibit Hsp90 activity and for the treatment of a proliferative disorder, such as cancer, including c-Met associated cancers. In particular, the present invention encompasses the use of compounds of the invention to slow or stop the growth of c-Met associated cancerous cells, to reduce metastasis of cancerous cells, and/or to reduce or eliminate cancerous cells in a mammal.
In certain embodiments, the compounds of the invention can be used in combination with other chemotherapeutic agents and may help to prevent or reduce the development of multidrug resistant cancerous cells in a mammal. In this embodiment, the compounds of the invention may allow a reduced efficacious amount of a second chemotherapeutic agent given to a mammal. In addition, compounds of the invention are expected to be efficacious against cancers that has become resistant to chemotherapy with c-Met tyrosine kinase inhibits, such as SU11274.
A. Terminology
Unless otherwise specified, the below terms used herein are defined as follows:
As used herein, the term “alkyl” means a saturated straight chain or branched non-cyclic hydrocarbon having from 1 to 10 carbon atoms. Representative saturated straight chain alkyls include methyl, ethyl, n-propyl, n-butyl, n-pentyl, n-hexyl, n-heptyl, n-octyl, n-nonyl and n-decyl; while saturated branched alkyls include isopropyl, sec-butyl, isobutyl, tert-butyl, isopentyl, 2-methylbutyl, 3-methylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2-methylhexyl, 3-methylhexyl, 4-methylhexyl, 5-methylhexyl, 2,3-dimethylbutyl, 2,3-dimethylpentyl, 2,4-dimethylpentyl, 2,3-dimethylhexyl, 2,4-dimethylhexyl, 2,5-dimethylhexyl, 2,2-dimethylpentyl, 2,2-dimethylhexyl, 3,3-dimtheylpentyl, 3,3-dimethylhexyl, 4,4-dimethylhexyl, 2-ethylpentyl, 3-ethylpentyl, 2-ethylhexyl, 3-ethylhexyl, 4-ethylhexyl, 2-methyl-2-ethylpentyl, 2-methyl-3-ethylpentyl, 2-methyl-4-ethylpentyl, 2-methyl-2-ethylhexyl, 2-methyl-3-ethylhexyl, 2-methyl-4-ethylhexyl, 2,2-diethylpentyl, 3,3-diethylhexyl, 2,2-diethylhexyl, 3,3-diethylhexyl and the like. The term “(C1-C6)alkyl” means a saturated straight chain or branched non-cyclic hydrocarbon having from 1 to 6 carbon atoms. Representative (C1-C6)alkyl groups are those shown above having from 1 to 6 carbon atoms. Alkyl groups included in compounds of this invention may be optionally substituted with one or more substituents.
As used herein, the term “alkenyl” means a saturated straight chain or branched non-cyclic hydrocarbon having from 2 to 10 carbon atoms and having at least one carbon-carbon double bond. Representative straight chain and branched (C2-C10)alkenyls include vinyl, allyl, 1-butenyl, 2-butenyl, isobutylenyl, 1-pentenyl, 2-pentenyl, 3-methyl-1-butenyl, 2-methyl-2-butenyl, 2,3-dimethyl-2-butenyl, 1-hexenyl, 2-hexenyl, 3-hexenyl, 1-heptenyl, 2-heptenyl, 3-heptenyl, 1-octenyl, 2-octenyl, 3-octenyl, 1-nonenyl, 2-nonenyl, 3-nonenyl, 1-decenyl, 2-decenyl, 3-decenyl and the like. Alkenyl groups may be optionally substituted with one or more substituents.
As used herein, the term “alkynyl” means a saturated straight chain or branched non-cyclic hydrocarbon having from 2 to 10 carbon atoms and having at lease one carbon-carbon triple bond. Representative straight chain and branched alkynyls include acetylenyl, propynyl, 1-butynyl, 2-butynyl, 1-pentynyl, 2-pentynyl, 3-methyl-1-butynyl, 4-pentynyl, 1-hexynyl, 2-hexynyl, 5-hexynyl, 1-heptynyl, 2-heptynyl, 6-heptynyl, 1-octynyl, 2-octynyl, 7-octynyl, 1-nonynyl, 2-nonynyl, 8-nonynyl, 1-decynyl, 2-decynyl, 9-decynyl, and the like. Alkynyl groups may be optionally substituted with one or more substituents.
As used herein, the term “cycloalkyl” means a saturated, mono- or polycyclic alkyl radical having from 3 to 20 carbon atoms. Representative cycloalkyls include cyclopropyl, 1-methylcyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, -cyclodecyl, octahydro-pentalenyl, and the like. Cycloalkyl groups may be optionally substituted with one or more substituents.
As used herein, the term “cycloalkenyl” means a mono- or poly-cyclic non-aromatic alkyl radical having at least one carbon-carbon double bond in the cyclic system and from 3 to 20 carbon atoms. Representative cycloalkenyls include cyclopentenyl, cyclopentadienyl, cyclohexenyl, cyclohexadienyl, cycloheptenyl, cycloheptadienyl, cycloheptatrienyl, cyclooctenyl, cyclooctadienyl, cyclooctatrienyl, cyclooctatetraenyl, cyclononenyl, cyclononadienyl, cyclodecenyl, cyclodecadienyl, 1,2,3,4,5,8-hexahydronaphthalenyl and the like. Cycloalkenyl groups may be optionally substituted with one or more substituents.
As used herein, the term “haloalkyl” means and alkyl group in which one or more (including all) the hydrogen radicals are replaced by a halo group, wherein each halo group is independently selected from —F, —Cl, —Br, and —I. The term “halomethyl” means a methyl in which one to three hydrogen radical(s) have been replaced by a halo group. Representative haloalkyl groups include trifluoromethyl, bromomethyl, 1,2-dichloroethyl, 4-iodobutyl, 2-fluoropentyl, and the like.
As used herein, an “alkoxy” is an alkyl group which is attached to another moiety via an oxygen linker.
As used herein, a “haloalkoxy” is an haloalkyl group which is attached to another moiety via an oxygen linker.
As used herein, the term an “aromatic ring” or “aryl” means a hydrocarbon monocyclic or polycyclic radical in which at least one ring is aromatic. Examples of suitable aryl groups include, but are not limited to, phenyl, tolyl, anthracenyl, fluorenyl, indenyl, azulenyl, and naphthyl, as well as benzo-fused carbocyclic moieties such as 5,6,7,8-tetrahydronaphthyl. Aryl groups may be optionally substituted with one or more substituents. In one embodiment, the aryl group is a monocyclic ring, wherein the ring comprises 6 carbon atoms, referred to herein as “(C6)aryl.”
As used herein, the term “aralkyl” means an aryl group that is attached to another group by a (C1-C6)alkylene group. Representative aralkyl groups include benzyl, 2-phenyl-ethyl, naphth-3-yl-methyl and the like. Aralkyl groups may be optionally substituted with one or more substituents.
As used herein, the term “alkylene” refers to an alkyl group that has two points of attachment. The term “(C1-C6)alkylene” refers to an alkylene group that has from one to six carbon atoms. Straight chain (C1-C6)alkylene groups are preferred. Non-limiting examples of alkylene groups include methylene (—CH2—), ethylene (—CH2CH2—), n-propylene (—CH2CH2CH2—), isopropylene (—CH2CH(CH3)—), and the like. Alkylene groups may be optionally substituted with one or more substituents.
As used herein, the term “heterocyclyl” means a monocyclic (typically having 3- to 10-members) or a polycyclic (typically having 7- to 20-members) heterocyclic ring system which is either a saturated ring or an unsaturated non-aromatic ring. A 3- to 10-membered heterocycle can contain up to 5 heteroatoms; and a 7- to 20-membered heterocycle can contain up to 7 heteroatoms. Typically, a heterocycle has at least on carbon atom ring member. Each heteroatom is independently selected from nitrogen, which can be oxidized (e.g., N(O)) or quaternized; oxygen; and sulfur, including sulfoxide and sulfone. The heterocycle may be attached via any heteroatom or carbon atom. Representative heterocycles include morpholinyl, thiomorpholinyl, pyrrolidinonyl, pyrrolidinyl, piperidinyl, piperazinyl, hydantoinyl, valerolactamyl, oxiranyl, oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, tetrahydropyrindinyl, tetrahydropyrimidinyl, tetrahydrothiophenyl, tetrahydrothiopyranyl, and the like. A heteroatom may be substituted with a protecting group known to those of ordinary skill in the art, for example, the hydrogen on a nitrogen may be substituted with a tert-butoxycarbonyl group. Furthermore, the heterocyclyl may be optionally substituted with one or more substituents. Only stable isomers of such substituted heterocyclic groups are contemplated in this definition.
As used herein, the term “heteroaromatic”, “heteroaryl” or like terms means a monocyclic or polycyclic heteroaromatic ring comprising carbon atom ring members and one or more heteroatom ring members. Each heteroatom is independently selected from nitrogen, which can be oxidized (e.g., N(O)) or quaternized; oxygen; and sulfur, including sulfoxide and sulfone. Representative heteroaryl groups include pyridyl, 1-oxo-pyridyl, furanyl, benzo[1,3]dioxolyl, benzo[1,4]dioxinyl, thienyl, pyrrolyl, oxazolyl, imidazolyl, thiazolyl, a isoxazolyl, quinolinyl, pyrazolyl, isothiazolyl, pyridazinyl, pyrimidinyl, pyrazinyl, a triazinyl, triazolyl, thiadiazolyl, isoquinolinyl, indazolyl, benzoxazolyl, benzofuryl, indolizinyl, imidazopyridyl, tetrazolyl, benzimidazolyl, benzothiazolyl, benzothiadiazolyl, benzoxadiazolyl, indolyl, tetrahydroindolyl, azaindolyl, imidazopyridyl, quinazolinyl, purinyl, pyrrolo[2,3]pyrimidinyl, pyrazolo[3,4]pyrimidinyl, imidazo[1,2-a]pyridyl, and benzothienyl. In one embodiment, the heteroaromatic ring is selected from 5-8 membered monocyclic heteroaryl rings. The point of attachment of a heteroaromatic or heteroaryl ring to another group may be at either a carbon atom or a heteroatom of the heteroaromatic or heteroaryl rings. Heteroaryl groups may be optionally substituted with one or more substituents.
As used herein, the term “(C5)heteroaryl” means an aromatic heterocyclic ring of 5 members, wherein at least one carbon atom of the ring is replaced with a heteroatom such as, for example, oxygen, sulfur or nitrogen. Representative (C5)heteroaryls include furanyl, thienyl, pyrrolyl, oxazolyl, imidazolyl, thiazolyl, isoxazolyl, pyrazolyl, isothiazolyl, pyrazinyl, triazolyl, thiadiazolyl, and the like.
As used herein, the term “(C6)heteroaryl” means an aromatic heterocyclic ring of 6 members, wherein at least one carbon atom of the ring is replaced with a heteroatom such as, for example, oxygen, nitrogen or sulfur. Representative (C6)heteroaryls include pyridyl, pyridazinyl, pyrazinyl, triazinyl, tetrazinyl and the like.
As used herein, the term “heteroaralkyl” means a heteroaryl group that is attached to another group by a (C1-C6)alkylene. Representative heteroaralkyls include 2-(pyridin-4-yl)-propyl, 2-(thien-3-yl)-ethyl, imidazol-4-yl-methyl and the like. Heteroaralkyl groups may be optionally substituted with one or more substituents.
As used herein, the term “halogen” or “halo” means —F, —Cl, —Br or —I.
Suitable substituents for an alkyl, alkylene, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocyclyl, aryl, aralkyl, heteroaryl, and heteroaralkyl groups include any substituent which will form a stable compound of the invention. Examples of substituents for an alkyl, alkylene, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocyclyl, aryl, aralkyl, heteroaryl, and heteroarylalkyl include an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, an optionally substituted heteraralkyl, a haloalkyl, —C(O)NR28R29, —C(S)NR28R29, —C(NR32)NR28R29, —NR30C(O)R31, —NR30C(S)R31, —NR30C(NR32)R31, halo, —OR30, cyano, nitro, haloalkoxy, —C(O)R30, —C(S)R30, —C(NR32)R30, —NR28R29, —C(O)OR30, —C(S)OR30, —C(NR32)OR30, —OC(O)R30, —OC(S)R30, —OC(NR32)R30, —NR30C(O)NR28R29, —NR30C(S)NR28R20, —NR30C(NR32)NR28R29, —OC(O)NR28R29, —OC(S)NR28R29, —OC(NR32)NR28R29, —NR30C(O)OR31, —NR30C(S)OR31, —NR30C(NR32)OR31, —S(O)hR30, —OS(O)pR30, —NR30S(O)pR30, —S(O)pNR28R29, —OS(O)pNR28R29, or —NR30S(O)pNR28R29, wherein R28 and R29, for each occurrence are, independently, H, an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, or an optionally substituted heteraralkyl; or R28 and R29 taken together with the nitrogen to which they are attached is optionally substituted heterocyclyl or optionally substituted heteroaryl.
R30 and R31 for each occurrence are, independently, H, an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, or an optionally substituted heteraralkyl; and
R32, for each occurrence is, independently, H, an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, an optionally substituted heteraralkyl, —C(O)R30, —C(O)NR28R29, —S(O)pR30, or —S(O)pNR28R29; and
h is 0, 1 or 2.
In addition, alkyl, cycloalkyl, alkylene, a heterocyclyl, and any saturated portion of a alkenyl, cycloalkenyl, alkynyl, aralkyl, and heteroaralkyl groups, may also be substituted with ═O, ═S, ═N—R32.
When a heterocyclyl, heteroaryl, or heteroaralkyl group contains a nitrogen atom, it may be substituted or unsubstituted. When a nitrogen atom in the aromatic ring of a heteroaryl group has a substituent, the nitrogen may be a quaternary nitrogen.
As used herein, the terms “subject”, “patient” and “mammal” are used interchangeably. The terms “subject” and “patient” refer to an animal (e.g., a bird such as a chicken, quail or turkey, or a mammal), preferably a mammal including a non-primate (e.g., a cow, pig, horse, sheep, rabbit, guinea pig, rat, cat, dog, and mouse) and a primate (e.g., a monkey, chimpanzee and a human), and more preferably a human. In one embodiment, the subject is a non-human animal such as a farm animal (e.g., a horse, cow, pig or sheep), or a pet (e.g., a dog, cat, guinea pig or rabbit). In a preferred embodiment, the subject is a human.
As used herein, the term “lower” refers to a group having up to four carbon atoms. For example, a “lower alkyl” refers to an alkyl radical having from 1 to 4 carbon atoms, “lower alkoxy” refers to “—O—(C1-C4)alkyl and a “lower alkenyl” or “lower alkynyl” refers to an alkenyl or alkynyl radical having from 2 to 4 carbon atoms, respectively.
Unless indicated otherwise, the compounds of the invention containing reactive functional groups (such as (without limitation) carboxy, hydroxy, thiol, and amino moieties) also include protected derivatives thereof. “Protected derivatives” are those compounds in which a reactive site or sites are blocked with one ore more protecting groups. Examples of suitable protecting groups for hydroxyl groups include benzyl, methoxymethyl, allyl, trimethylsilyl, tert-butyldimethylsilyl, acetate, and the like. Examples of suitable amine protecting groups include benzyloxycarbonyl, tert-butoxycarbonyl, tert-butyl, benzyl and fluorenylmethyloxy-carbonyl (Fmoc). Examples of suitable thiol protecting groups include benzyl, tert-butyl, acetyl, methoxymethyl and the like. Other suitable protecting groups are well known to those of ordinary skill in the art and include those found in T. W. Greene, Protecting Groups in Organic Synthesis, John Wiley & Sons, Inc. 1981.
As used herein, the term “compound(s) of this invention” and similar terms refers to a compound of formula (I) through (LXXII) and Tables 5, 6, and 7, or a pharmaceutically acceptable salt, solvate, clathrate, hydrate, polymorph or prodrug thereof, and also include protected derivatives thereof.
Compounds of the invention may contain one or more chiral centers and/or double bonds and, therefore, exist as stereoisomers, such as double-bond isomers (i.e., geometric isomers), enantiomers, or diastereomers. According to this invention, the chemical structures depicted herein, including the compounds of this invention, encompass all of the corresponding compounds' enantiomers, diastereomers and geometric isomers, that is, both the stereochemically pure form (e.g., geometrically pure, enantiomerically pure, or diastereomerically pure) and isomeric mixtures (e.g., enantiomeric, diastereomeric and geometric isomeric mixtures). In some cases, one enantiomer, diastereomer or geometric isomer will possess superior activity or an improved toxicity or kinetic profile compared to other isomers. In those cases, such enantiomers, diastereomers and geometric isomers of compounds of this invention are preferred.
When a disclosed compound is named or depicted by structure, it is to be understood that solvates (e.g., hydrates) of the compound or its pharmaceutically acceptable salts are also included. “Solvates” refer to crystalline forms wherein solvent molecules are incorporated into the crystal lattice during crystallization. Solvate may include water or nonaqueous solvents such as ethanol, isopropanol, DMSO, acetic acid, ethanolamine, and EtOAc. Solvates, wherein water is the solvent molecule incorporated into the crystal lattice, are typically referred to as “hydrates”. Hydrates include stoichiometric hydrates as well as compositions containing variable amounts of water.
When a disclosed compound is named or depicted by structure, it is to be understood that the compound, including solvates thereof, may exist in crystalline forms, non-crystalline forms or a mixture thereof. The compounds or solvates may also exhibit polymorphism (i.e. the capacity to occur in different crystalline forms). These different crystalline forms are typically known as “polymorphs.” It is to be understood that when named or depicted by structure, the disclosed compounds and solvates (e.g., hydrates) also include all polymorphs thereof. Polymorphs have the same chemical composition but differ in packing, geometrical arrangement, and other descriptive properties of the crystalline solid state. Polymorphs, therefore, may have different physical properties such as shape, density, hardness, deformability, stability, and dissolution properties. Polymorphs typically exhibit different melting points, IR spectra, and X-ray powder diffraction patterns, which may be used for identification. One of ordinary skill in the art will appreciate that different polymorphs may be produced, for example, by changing or adjusting the conditions used in solidfying the compound. For example, changes in temperature, pressure, or solvent may result in different polymorphs. In addition, one polymorph may spontaneously convert to another polymorph under certain conditions.
When a disclosed compound is named or depicted by structure, it is to be understood that clathrates (“inclusion compounds”) of the compound or its pharmaceutically acceptable salts, solvates or polymorphs are also included. “Clathrate” refers to a chemical substance consisting of a lattice of one type of molecule trapping and containing a second type of molecule. For examples, the a clathrate can be compound of the present invention or a salt thereof in the form of a crystal lattice that contains spaces (e.g., channels) that have a guest molecule (e.g., a solvent or water) trapped within.
As used herein and unless otherwise indicated, the term “prodrug” means a derivative of a compound that can hydrolyze, oxidize, or otherwise react under biological conditions (in vitro or in vivo) to provide a compound of this invention. Prodrugs may become active upon such reaction under biological conditions, or they may have activity in their unreacted forms. Examples of prodrugs contemplated in this invention include, but are not limited to, analogs or derivatives of compounds of formula (I) through (LXXII) and Tables 5, 6, and 7 that comprise biohydrolyzable moieties such as biohydrolyzable amides, biohydrolyzable esters, biohydrolyzable carbamates, biohydrolyzable carbonates, biohydrolyzable ureides, and biohydrolyzable phosphate analogues. Other examples of prodrugs include derivatives of compounds of formula (I) through (LXXII), and Tables 5, 6, and 7, that comprise —NO, —NO2, —ONO, or —ONO2 moieties. Prodrugs can typically be prepared using well-known methods, such as those described by 1 BURGER'S MEDICINAL CHEMISTRY AND DRUG DISCOVERY (1995) 172-178, 949-982 (Manfred E. Wolff ed., 5th ed).
As used herein and unless otherwise indicated, the terms “biohydrolyzable amide”, “biohydrolyzable ester”, “biohydrolyzable carbamate”, “biohydrolyzable carbonate”, “biohydrolyzable ureide” and “biohydrolyzable phosphate analogue” mean an amide, ester, carbamate, carbonate, ureide, or phosphate analogue, respectively, that either: 1) does not destroy the biological activity of the compound and confers upon that compound advantageous properties in vivo, such as improved water solubility, improved circulating half-life in the blood (e.g., because of reduced metabolism of the prodrug), improved uptake, improved duration of action, or improved onset of action; or 2) is itself biologically inactive but is converted in vivo to a biologically active compound. Examples of biohydrolyzable amides include, but are not limited to, lower alkyl amides, α-amino acid amides, alkoxyacyl amides, and alkylaminoalkylcarbonyl amides. Examples of biohydrolyzable esters include, but are not limited to, lower alkyl esters, alkoxyacyloxy esters, alkyl acylamino alkyl esters, and choline esters. Examples of biohydrolyzable carbamates include, but are not limited to, lower alkylamines, substituted ethylenediamines, aminoacids, hydroxyalkylamines, heterocyclic and heteroaromatic amines, and polyether amines.
As used herein, “Hsp90” includes each member of the family of heat shock proteins having a mass of about 90-kiloDaltons. For example, in humans the highly conserved Hsp90 family includes cytosolic Hsp90α and Hsp90β isoforms, as well as GRP94, which is found in the endoplasmic reticulum, and HSP75/TRAP1, which is found in the mitochondrial matrix.
c-Met is a receptor tyrosine kinase that is expressed in normal and malignant cells and has been identified as a proto-oncogene. HGF/c-Met signaling triggers an invasive growth program that is thought to be essential in early embryonic development but when dysregulated can result malignant growth, motility, migration and invasion by a mechanism that is not yet completely understood. The human Met gene is located on chromosome 7 band 7q21-q31 and spans more than 120 kb (Ma, et al., Cancer and Metastasis Reviews (2003), 22:309-325). In wild type cells, c-Met is a heterodimer that consists of an extracellular α-subunit and a β-subunit with a large extracellular domain, a membrane spanning segment and an intracellular tyrosine kinase domain. Functional structures and domains of c-Met include 1) Sema domain at the N-terminus which includes a MRS cysteine-rich region; 2) PSI domain which is also found in plexins, semaphorins and integrins; 3) IPT repeats which are found in immunoglobulin, plexins and transcription factors; 4) transmembrane domain; 5) juxtamembrane domain; and 6) the intracellular tyrosine kinase domain at the C-terminus.
Activation of c-Met signaling is dependent on phosphorylation of multiple residues on c-Met. Upon binding of HGF, c-Met undergoes autophosphorylation at Y1230, Y1234, and Y1235 in the activation loop of the tyrosine kinase domain which activates the kinase activity of c-Met. Y1313 can also be phosphorylated in response to HGF binding and is important in binding PI3-K which is implicated in prosurvival signaling. Phosphorylation of Y1349 and Y1356 at the C-terinus of c-Met activates the multisubstrate signal transducer docking site which has been implicated in Met-mediated signal transduction and mediates the interactions of SHC, Src, and Gab1, while recruitment of Grb2, PI3-K, PLC-γ and SHP2 is dependent on phosphorylation of Y1356 alone. Regultation of cell morphogenesis is mediated via Y1365. Phosphorylation of the Y1003 residue in the juxtamembrane domain mediates the binding of c-Cbl. c-Cbl acts as a negative regulator protein of c-Met by promoting the polyubiquitinization of c-Met which leads to degradation.
Dysregulation of HGF/c-Met signaling can be caused by 1) increased expression of HGF; 2) activating mutations which typically occur in the tyrosine kinase domain or the juxtamembrane domain of c-Met and confer constitutive kinase activity; 3) intra-chromosomal amplification of the Met gene and over expression of c-Met; 4) chromosomal translocation such as in the Trp/Met fusion protein which results in the loss of the juxtamembrane domain and leads to constitutive activation; and 5) alternate splicing variants c-Met mRNA which lead to loss of the juxtamembrane domain and also lead to constitutive activation.
Activating mutation in the tyrosine kinase domain or in the juxtamembrane domain of c-Met which result in increased activation of the tyrosine kinase activity have been observed in hereditary and sporatic papillary renal carcinoma, ovarian cancer, hepatocellular carcinoma, metastatic head and neck squamous cell carcinomas, NSCLC, SCLC, glioma, breast cancer, and gastric cancer. In somatic papillary renal cell carcinoma activating mutations have been found at amino acid residues M1268 (e.g., M1268T), Y1248 (e.g., Y1248D, Y1248H), Y1246 (e.g., Y1246H), Y1230 (e.g., Y1230C), L1213 (e.g., L1213V), H1124 (e.g., H1124D, H1112L, and H1112Y), and V1110 (V1110I). In germline papillary renal cell carcinoma activating mutations have been found at amino acid residues Y1248 (e.g., Y1248C), Y1246 (e.g., Y1246N), V1238 (e.g., V1238I), Y1230 (e.g., Y1230C and Y1230H), V1206 (e.g., V1206L), M1149 (e.g., M1149T), and H1112 (e.g., H1112R). In hepatocellular carcinoma activating mutations have been found at amino acid residues M1268 (e.g., M1268I), K1262 (e.g., K1262R), and T1191 (e.g., T1191I). In head and neck squamous cell carcinoma activating mutations have been found at amino acid residues Y1253 (e.g., Y1253D), Y1235 (e.g., Y1235D), and Y1230 (e.g., Y1230C and Y1230D). In glioma activating mutations have been found at amino acid residue G1137 (e.g., G1137V). In NSCLC activating mutations have been found at amino acid residue T1010 (e.g., T1010I). In SCLC activating mutations have been found at amino acid residues R988 (e.g., R988C) and T1010 (e.g., T1010I). In breast cancer activating mutations have been found at amino acid residues T1010 (e.g., T1010I). In gastric cancer activating mutations have been found at amino acid residue P1009 (e.g., P1009S) Amino acids listed herein for c-Met are numbered as in Schmit, et al., Onogene (1999), 18:2343-2350. Compounds of the invention cause the degradation of c-Met and can be used either alone or in combination with other anticancer therapies to treat patients with cancers that have activating mutations in the tyrosine kinase domain or in the juxtamembrane domain of c-Met.
The juxtamembrane of receptor tyrosine kinases has been shown to repress catalytic function and mutation in the juxtamembrane relieve this repression and can lead to oncogenesis. The Tpr/Met fusion protein results from replacement of the 5′ region of the Met gene with Tpr which provides two strong dimerization motifs. Dimerization activates the Met kinase activity and results in transforming and metastatic properties. The Tpr/Met fusion protein has been found in gastric cancer and results in increased Met kinase activity. In addition, an alternative splicing form of Met mRNA has been found in small cell lung cancer which results in skipping the juxtamembrane domain. Loss of the juxtamembrane domain leads to increased Met kinase activity and oncogenesis. Compounds of the invention cause the degradation of c-Met and can be used either alone or in combination with other anticancer therapies to treat patients with cancers that have juxtamembrane mutations or deletions in c-Met.
Amplification of the Met gene and overexpression of c-Met has been found in several types of cancers including gastric cancer, esophageal cancer, small cell lung cancer, non-small cell lung cancer, breast cancer, multiple myeloma, and colorectal cancer metastases. Compounds of the invention cause the degradation of c-Met and can be used either alone or in combination with other anticancer therapies to treat patients with cancers that have Met gene amplification and/or c-Met overexpression.
Met amplification and mutation has also been implicated as a strategy by which certain cancers become resistant to therapy (e.g., chemotherapy or radiation therapy). For example, certain non-small cell lung cancers contain an activating mutation in receptor tyrosine kinase EGFR which results in oncogenesis. Most EGFR mutant NSCLCs initially respond to EGFR inhibitors such as Iressa and Tarceva but the vast majority of these tumors ultimately become resistant to the drug. A subset of these resistant cancers have been shown to have amplified Met, and it is thought that Met amplification is a mechanisms of acquired resistance, and in particular acquired resistance to kinase inhibitors such as Iressa and Tarceva (EGFR inhibitors), Gleevec (a Bcr-Abl, PDGF, and c-Kit inhibitor) (Engelman et al., Sciencexpress, www.sciencexpress.org/26 Apr. 2007/page 1/10.1126/science. 1141478). Compounds of the invention cause the degradation of c-Met and can be used either alone or in combination with other anticancer therapies, such as treatment with kinase inhibitors, to treat patients with cancer that has become resistant to other anticancer therapies.
As used herein, the term “c-Met associated cancer” refers to a cancer which has aberrant expression and/or activation of c-Met which causes or enhances growth or metastasis of the cancer. For example, c-Met associated cancers include cancer that have 1) increased expression of HGF; 2) activating mutations which typically occur in the tyrosine kinase domain or the juxtamembrane domain of c-Met and confer increase or constitutive kinase activity; 3) intra-chromosomal amplification of the Met gene and over expression of c-Met; 4) chromosomal translocation such as in the Trp/Met fusion protein which results in the loss of the juxtamembrane domain and leads to constitutive activation; or 5) alternate splicing variants c-Met mRNA which lead to loss of the juxtamembrane domain and also lead to constitutive activation. Any of the above defects in c-Met regulation indicate that a cancer is a c-Met associated cancer and can be assayed for by methods known to those skilled in the art.
As used herein, the term “tyrosine kinase inhibitor” refers to an anticancer agent, such as a small molecule or protein that inhibits the activity of one or more tyrosine kinase. In one embodiment, the tyrosine kinase inhibitor inhibits the tyrosine kinase by binding directly to it and inhibiting its kinase activity. Examples of tyrosine kinase inhibitors include Iressa and Tarceva (EGFR inhibitors), Gleevec (a Bcr-Abl, PDGF, and c-Kit inhibitor), and SU11274 (a c-Met inhibitor).
As used herein, the term “tyrosine kinase inhibitor that does not inhibit c-Met” refers to an anticancer agent, such as a small molecule or protein that inhibits the activity of one or more tyrosine kinase but does not substantially inhibit the kinase activity of c-Met. A tyrosine kinase inhibitor does not substantially inhibit the kinase activity of c-Met if it does not affect the phosphorylation pattern of c-Met in cells that are treated with up to 10 μM of the tyrosine kinase inhibitor.
The phrase “gene amplification,” as used herein, means the selective synthesis of a DNA fragment that results in multiple copies of the Met gene or fragment of the chromosome in which Met is encoded.
The term “level of expression” or “expression level” generally refers to the amount of an amino acid product or protein in the sample, preferably the amount of a phosphorylated amino acid product or phosphorylated protein in the sample according to the invention. “Expression” refers to the process by which gene coded information is converted into proteins operating in the cell. As used herein, “expressed genes” include those that are transcribed into mRNA and then translated into protein. The terms “overexpression” refers to an upward deviation in levels of expression as compared to the baseline expression level in non-cancerous tissue of the same type. “Overexpression” is therefore also “increased expression”.
As used herein, a “proliferative disorder” or a “hyperproliferative disorder,” and other equivalent terms, means a disease or medical condition involving pathological growth of cells. Proliferative disorders include cancer, smooth muscle cell proliferation, systemic sclerosis, cirrhosis of the liver, adult respiratory distress syndrome, idiopathic cardiomyopathy, lupus erythematosus, retinopathy, e.g., diabetic retinopathy or other retinopathies, cardiac hyperplasia, reproductive system associated disorders such as benign prostatic hyperplasia and ovarian cysts, pulmonary fibrosis, endometriosis, fibromatosis, harmatomas, lymphangiomatosis, sarcoidosis, desmoid tumors.
Smooth muscle cell proliferation includes hyperproliferation of cells in the vasculature, for example, intimal smooth muscle cell hyperplasia, restenosis and vascular occlusion, particularly stenosis following biologically- or mechanically-mediated vascular injury, e.g., vascular injury associated with angioplasty. Moreover, intimal smooth muscle cell hyperplasia can include hyperplasia in smooth muscle other than the vasculature, e.g., bile duct blockage, bronchial airways of the lung in patients with asthma, in the kidneys of patients with renal interstitial fibrosis, and the like.
Non-cancerous proliferative disorders also include hyperproliferation of cells in the skin such as psoriasis and its varied clinical forms, Reiter's syndrome, pityriasis rubra pilaris, and hyperproliferative variants of disorders of keratinization (e.g., actinic keratosis, senile keratosis), scleroderma, and the like.
In a preferred embodiment, the proliferative disorder is cancer. Cancers that can be treated or prevented by the methods of the present invention include, but are not limited to human sarcomas and carcinomas, e.g., fibrosarcoma, myxosarcoma, liposarcoma, chondrosarcoma, osteogenic sarcoma, chordoma, angiosarcoma, endotheliosarcoma, lymphangiosarcoma, lymphangioendotheliosarcoma, synovioma, mesothelioma, Ewing's tumor, leiomyosarcoma, rhabdomyosarcoma, colon carcinoma, pancreatic cancer, breast cancer, ovarian cancer, prostate cancer, squamous cell carcinoma, basal cell carcinoma, adenocarcinoma, sweat gland carcinoma, sebaceous gland carcinoma, papillary carcinoma, papillary adenocarcinomas, cystadenocarcinoma, medullary carcinoma, bronchogenic carcinoma, renal cell carcinoma, hepatoma, bile duct carcinoma, choriocarcinoma, seminoma, embryonal carcinoma, Wilms' tumor, cervical cancer, testicular tumor, lung carcinoma, small cell lung carcinoma, bladder carcinoma, epithelial carcinoma, glioma, astrocytoma, medulloblastoma, craniopharyngioma, ependymoma, pinealoma, hemangioblastoma, acoustic neuroma, oligodendroglioma, meningioma, melanoma, neuroblastoma, retinoblastoma; leukemias, e.g., acute lymphocytic leukemia and acute myelocytic leukemia (myeloblastic, promyelocytic, myelomonocytic, monocytic and erythroleukemia); chronic leukemia (chronic myelocytic (granulocytic) leukemia and chronic lymphocytic leukemia); and polycythemia vera, lymphoma (Hodgkin's disease and non-Hodgkin's disease), multiple myeloma, Waldenstrobm's macroglobulinemia, and heavy chain disease.
Other examples of leukemias include acute and/or chronic leukemias, e.g., lymphocytic leukemia (e.g., as exemplified by the p388 (murine) cell line), large granular lymphocytic leukemia, and lymphoblastic leukemia; T-cell leukemias, e.g., T-cell leukemia (e.g., as exemplified by the CEM, Jurkat, and HSB-2 (acute), YAC-1(murine) cell lines), T-lymphocytic leukemia, and T-lymphoblastic leukemia; B cell leukemia (e.g., as exemplified by the SB (acute) cell line), and B-lymphocytic leukemia; mixed cell leukemias, e.g., B and T cell leukemia and B and T lymphocytic leukemia; myeloid leukemias, e.g., granulocytic leukemia, myelocytic leukemia (e.g., as exemplified by the HL-60 (promyelocyte) cell line), and myelogenous leukemia (e.g., as exemplified by the K562(chronic)cell line); neutrophilic leukemia; eosinophilic leukemia; monocytic leukemia (e.g., as exemplified by the THP-1(acute) cell line); myelomonocytic leukemia; Naegeli-type myeloid leukemia; and nonlymphocytic leukemia. Other examples of leukemias are described in Chapter 60 of The Chemotherapy Sourcebook, Michael C. Perry Ed., Williams & Williams (1992) and Section 36 of Holland Frie Cancer Medicine 5th Ed., Bast et al. Eds., B. C. Decker Inc. (2000). The entire teachings of the preceding references are incorporated herein by reference.
In one embodiment, the disclosed method is believed to be particularly effective in treating subject with non-solid tumors such as multiple myeloma. In another embodiment, the disclosed method is believed to be particularly effective against T-leukemia (e.g., as exemplified by Jurkat and CEM cell lines); B-leukemia (e.g., as exemplified by the SB cell line); promyelocytes (e.g., as exemplified by the HL-60 cell line); uterine sarcoma (e.g., as exemplified by the MES-SA cell line); monocytic leukemia (e.g., as exemplified by the THP-1(acute) cell line); and lymphoma (e.g., as exemplified by the U937 cell line).
In one embodiment, the compounds of the invention are believed to be particularly effective in treating a subject with c-Met associated cancers.
Some of the disclosed methods can be particularly effective at treating subjects whose cancer has become “multi-drug resistant”. A cancer which initially responded to an anti-cancer drug, such as a tyrosin kinase inhibitor, becomes resistant to the anti-cancer drug when the anti-cancer drug is no longer effective in treating the subject with the cancer. For example, many tumors will initially respond to treatment with an anti-cancer drug by decreasing in size or even going into remission, only to develop resistance to the drug. Drug resistant tumors are characterized by a resumption of their growth and/or reappearance after having seemingly gone into remission, despite the administration of increased dosages of the anti-cancer drug. Cancers that have developed resistance to two or more anti-cancer drugs are said to be “multi-drug resistant”. For example, it is common for cancers to become resistant to three or more anti-cancer agents, often five or more anti-cancer agents and at times ten or more anti-cancer agents.
In one embodiment, the compounds of the invention are believed to be particularly effective in treating a subject that has a cancer that has become resistant to treatment with one or more tyrosine kinase inhibitor. In another embodiment, the compounds of the invention are believed to be particularly effective in treating a subject that has a cancer that has become resistant to treatment with a c-Met inhibitor. In another embodiment, the compounds of the invention are believed to be particularly effective in treating a subject that has a cancer that has become resistant to treatment with a tyrosine kinase inhibitor that does not substantially inhibit c-Met.
As used herein, the term “pharmaceutically acceptable salt,” is a salt formed from, for example, an acid and a basic group of one of the compounds of formula (I) through (LXXII) and Tables 5, 6, and 7. Illustrative salts include, but are not limited, to sulfate, citrate, acetate, oxalate, chloride, bromide, iodide, nitrate, bisulfate, phosphate, acid phosphate, isonicotinate, lactate, salicylate, acid citrate, tartrate, oleate, tannate, pantothenate, bitartrate, ascorbate, succinate, maleate, besylate, gentisinate, fumarate, gluconate, glucaronate, saccharate, formate, benzoate, glutamate, methanesulfonate, ethanesulfonate, benzenesulfonate, p-toluenesulfonate, and pamoate (i.e., 1,1′-methylene-bis-(2-hydroxy-3-naphthoate)) salts. The term “pharmaceutically acceptable salt” also refers to a salt prepared from a compound of formula (I) through (LXXII) and Tables 5, 6, and 7 having an acidic functional group, such as a carboxylic acid functional group, and a pharmaceutically acceptable inorganic or organic base. Suitable bases include, but are not limited to, hydroxides of alkali metals such as sodium, potassium, and lithium; hydroxides of alkaline earth metal such as calcium and magnesium; hydroxides of other metals, such as aluminum and zinc; ammonia, and organic amines, such as unsubstituted or hydroxy-substituted mono-, di-, or trialkylamines; dicyclohexylamine; tributyl amine; pyridine; N-methyl,N-ethylamine; diethylamine; triethylamine; mono-, bis-, or tris-(2-hydroxy-lower alkyl amines), such as mono-, bis-, or tris-(2-hydroxyethyl)amine, 2-hydroxy-tert-butylamine, or tris-(hydroxymethyl)methylamine, N, N,-di-lower alkyl-N-(hydroxy lower alkyl)-amines, such as N,N-dimethyl-N-(2-hydroxyethyl)amine, or tri-(2-hydroxyethyl)amine; N-methyl-D-glucamine; and amino acids such as arginine, lysine, and the like. The term “pharmaceutically acceptable salt” also refers to a salt prepared from a compound of formula (I) through (LXXII) and Tables 5, 6, and 7 having a basic functional group, such as an amine functional group, and a pharmaceutically acceptable inorganic or organic acid. Suitable acids include, but are not limited to, hydrogen sulfate, citric acid, acetic acid, oxalic acid, hydrochloric acid (HCl), hydrogen bromide (HBr), hydrogen iodide (HI), nitric acid, hydrogen bisulfide, phosphoric acid, lactic acid, salicylic acid, tartaric acid, bitartratic acid, ascorbic acid, succinic acid, maleic acid, besylic acid, fumaric acid, gluconic acid, glucaronic acid, formic acid, benzoic acid, glutamic acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, and p-toluenesulfonic acid.
As used herein, the term “pharmaceutically acceptable solvate,” is a solvate formed from the association of one or more pharmaceutically acceptable solvent molecules to one of the compounds of formula (I) through (LXXII) and Tables 5, 6, and 7. The term solvate includes hydrates (e.g., hemihydrate, monohydrate, dihydrate, trihydrate, tetrahydrate, and the like).
A pharmaceutically acceptable carrier may contain inert ingredients which do not unduly inhibit the biological activity of the compounds. The pharmaceutically acceptable carriers should be biocompatible, i.e., non-toxic, non-inflammatory, non-immunogenic and devoid of other undesired reactions upon the administration to a subject. Standard pharmaceutical formulation techniques can be employed, such as those described in Remington's Pharmaceutical Sciences, ibid. Suitable pharmaceutical carriers for parenteral administration include, for example, sterile water, physiological saline, bacteriostatic saline (saline containing about 0.9% mg/ml benzyl alcohol), phosphate-buffered saline, Hank's solution, Ringer's-lactate and the like. Methods for encapsulating compositions (such as in a coating of hard gelatin or cyclodextran) are known in the art (Baker, et al., “Controlled Release of Biological Active Agents”, John Wiley and Sons, 1986).
As used herein, the term “effective amount” refers to an amount of a compound of this invention which is sufficient to reduce or ameliorate the severity, duration, progression, or onset of a proliferative disorder, prevent the advancement of a proliferative disorder, cause the regression of a proliferative, prevent the recurrence, development, onset or progression of a symptom associated with a proliferative disorder, or enhance or improve the prophylactic or therapeutic effect(s) of another therapy. The precise amount of compound administered to a subject will depend on the mode of administration, the type and severity of the disease or condition and on the characteristics of the subject, such as general health, age, sex, body weight and tolerance to drugs. It will also depend on the degree, severity and type of cell proliferation, and the mode of administration. The skilled artisan will be able to determine appropriate dosages depending on these and other factors. When co-administered with other agents, e.g., when co-administered with an anti-cancer agent, an “effective amount” of the second agent will depend on the type of drug used. Suitable dosages are known for approved agents and can be adjusted by the skilled artisan according to the condition of the subject, the type of condition(s) being treated and the amount of a compound of the invention being used. In cases where no amount is expressly noted, an effective amount should be assumed.
Non-limiting examples of an effective amount of a compound of the invention are provided herein below. In a specific embodiment, the invention provides a method of preventing, treating, managing, or ameliorating a proliferative disorder or one or more symptoms thereof, said methods comprising administering to a subject in need thereof a dose of at least 150 μg/kg, preferably at least 250 μg/kg, at least 500 μg/kg, at least 1 mg/kg, at least 5 mg/kg, at least 10 mg/kg, at least 25 mg/kg, at least 50 mg/kg, at least 75 mg/kg, at least 100 mg/kg, at least 125 mg/kg, at least 150 mg/kg, or at least 200 mg/kg or more of one or more compounds of the invention once every day, preferably, once every 2 days, once every 3 days, once every 4 days, once every 5 days, once every 6 days, once every 7 days, once every 8 days, once every 10 days, once every two weeks, once every three weeks, or once a month.
The dosages of a chemotherapeutic agents other than compounds of the invention, which have been or are currently being used to prevent, treat, manage, or ameliorate a proliferative disorder, or one or more symptoms thereof, can be used in the combination therapies of the invention. Preferably, dosages lower than those which have been or are currently being used to prevent, treat, manage, or ameliorate a proliferative disorder, or one or more symptoms thereof, are used in the combination therapies of the invention. The recommended dosages of agents currently used for the prevention, treatment, management, or amelioration of a proliferative disorder, or one or more symptoms thereof, can obtained from any reference in the art including, but not limited to, Hardman et al., eds., 1996, Goodman & Gilman's The Pharmacological Basis Of Basis Of Therapeutics 9th Ed, McGraw-Hill, New York; Physician's Desk Reference (PDR) 57th Ed., 2003, Medical Economics Co., Inc., Montvale, N.J., which are incorporated herein by reference in its entirety.
As used herein, the terms “treat”, “treatment” and “treating” refer to the reduction or amelioration of the progression, severity and/or duration of a proliferative disorder, or the amelioration of one or more symptoms (preferably, one or more discernible symptoms) of a proliferative disorder resulting from the administration of one or more therapies (e.g., one or more therapeutic agents such as a compound of the invention). In specific embodiments, the terms “treat”, “treatment” and “treating” refer to the amelioration of at least one measurable physical parameter of a proliferative disorder, such as growth of a tumor, not necessarily discernible by the patient. In other embodiments the terms “treat”, “treatment” and “treating” refer to the inhibition of the progression of a proliferative disorder, either physically by, e.g., stabilization of a discernible symptom, physiologically by, e.g., stabilization of a physical parameter, or both. In other embodiments the terms “treat”, “treatment” and “treating” refer to the reduction or stabilization of tumor size or cancerous cell count.
As used herein, the terms “prevent”, “prevention” and “preventing” refer to the reduction in the risk of acquiring or developing a given proliferative disorder, or the reduction or inhibition of the recurrence or a proliferative disorder. In one embodiment, a compound of the invention is administered as a preventative measure to a patient, preferably a human, having a genetic predisposition to any of the disorders described herein.
As used herein, the terms “therapeutic agent” and “therapeutic agents” refer to any agent(s) which can be used in the treatment, management, or amelioration of a proliferative disorder or one or more symptoms thereof. In certain embodiments, the term “therapeutic agent” refers to a compound of the invention. In certain other embodiments, the term “therapeutic agent” refers does not refer to a compound of the invention. Preferably, a therapeutic agent is an agent which is known to be useful for, or has been or is currently being used for the treatment, management, prevention, or amelioration a proliferative disorder or one or more symptoms thereof.
As used herein, the term “synergistic” refers to a combination of a compound of the invention and another therapy (e.g., a prophylactic or therapeutic agent), which is more effective than the additive effects of the therapies. A synergistic effect of a combination of therapies (e.g., a combination of prophylactic or therapeutic agents) permits the use of lower dosages of one or more of the therapies and/or less frequent administration of said therapies to a subject with a proliferative disorder. The ability to utilize lower dosages of a therapy (e.g., a prophylactic or therapeutic agent) and/or to administer said therapy less frequently reduces the toxicity associated with the administration of said therapy to a subject without reducing the efficacy of said therapy in the prevention, management or treatment of a proliferative disorder. In addition, a synergistic effect can result in improved efficacy of agents in the prevention, management or treatment of a proliferative disorder. Finally, a synergistic effect of a combination of therapies (e.g., a combination of prophylactic or therapeutic agents) may avoid or reduce adverse or unwanted side effects associated with the use of either therapy alone.
As used herein, the phrase “side effects” encompasses unwanted and adverse effects of a therapy (e.g., a prophylactic or therapeutic agent). Side effects are always unwanted, but unwanted effects are not necessarily adverse. An adverse effect from a therapy (e.g., prophylactic or therapeutic agent) might be harmful or uncomfortable or risky. Side effects include, but are not limited to fever, chills, lethargy, gastrointestinal toxicities (including gastric and intestinal ulcerations and erosions), nausea, vomiting, neurotoxicities, nephrotoxicities, renal toxicities (including such conditions as papillary necrosis and chronic interstitial nephritis), hepatic toxicities (including elevated serum liver enzyme levels), myelotoxicities (including leukopenia, myelosuppression, thrombocytopenia and anemia), dry mouth, metallic taste, prolongation of gestation, weakness, somnolence, pain (including muscle pain, bone pain and headache), hair loss, asthenia, dizziness, extra-pyramidal symptoms, akathisia, cardiovascular disturbances and sexual dysfunction.
As used herein, the term “in combination” refers to the use of more than one therapies (e.g., one or more prophylactic and/or therapeutic agents). The use of the term “in combination” does not restrict the order in which therapies (e.g., prophylactic and/or therapeutic agents) are administered to a subject with a proliferative disorder. A first therapy (e.g., a prophylactic or therapeutic agent such as a compound of the invention) can be administered prior to (e.g., 5 minutes, 15 minutes, 30 minutes, 45 minutes, 1 hour, 2 hours, 4 hours, 6 hours, 12 hours, 24 hours, 48 hours, 72 hours, 96 hours, 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 8 weeks, or 12 weeks before), concomitantly with, or subsequent to (e.g., 5 minutes, 15 minutes, 30 minutes, 45 minutes, 1 hour, 2 hours, 4 hours, 6 hours, 12 hours, 24 hours, 48 hours, 72 hours, 96 hours, 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 8 weeks, or 12 weeks after) the administration of a second therapy (e.g., a prophylactic or therapeutic agent such as an anti-cancer agent) to a subject with a proliferative disorder, such as cancer.
As used herein, the terms “therapies” and “therapy” can refer to any protocol(s), method(s), and/or agent(s) that can be used in the prevention, treatment, management, or amelioration of a proliferative disorder or one or more symptoms thereof.
A used herein, a “protocol” includes dosing schedules and dosing regimens. The protocols herein are methods of use and include prophylactic and therapeutic protocols.
As used herein, the terms “manage,” “managing,” and “management” refer to the beneficial effects that a subject derives from a therapy (e.g., a prophylactic or therapeutic agent), which does not result in a cure of the disease. In certain embodiments, a subject is administered one or more therapies (e.g., one or more prophylactic or therapeutic agents) to “manage” a disease so as to prevent the progression or worsening of the disease.
As used herein, a composition that “substantially” comprises a compound means that the composition contains more than about 80% by weight, more preferably more than about 90% by weight, even more preferably more than about 95% by weight, and most preferably more than about 97% by weight of the compound.
As used herein, a reaction that is “substantially complete” means that the reaction contains more than about 80% by weight of the desired product, more preferably more than about 90% by weight of the desired product, even more preferably more than about 95% by weight of the desired product, and most preferably more than about 97% by weight of the desired product.
As used herein, a racemic mixture means about 50% of one enantiomer and about 50% of is corresponding enantiomer relative to a chiral center in the molecule. The invention encompasses all enantiomerically-pure, enantiomerically-enriched, diastereomerically pure, diastereomerically enriched, and racemic mixtures of the compounds of the invention.
Enantiomeric and diastereomeric mixtures can be resolved into their component enantiomers or diastereomers by well known methods, such as chiral-phase gas chromatography, chiral-phase high performance liquid chromatography, crystallizing the compound as a chiral salt complex, or crystallizing the compound in a chiral solvent. Enantiomers and diastereomers can also be obtained from diastereomerically- or enantiomerically-pure intermediates, reagents, and catalysts by well known asymmetric synthetic methods.
The compounds of the invention are defined herein by their chemical structures and/or chemical names. Where a compound is referred to by both a chemical structure and a chemical name, and the chemical structure and chemical name conflict, the chemical structure is determinative of the compound's identity.
When administered to a patient, e.g., to a non-human animal for veterinary use or for improvement of livestock, or to a human for clinical use, the compounds of the invention are administered in isolated form or as the isolated form in a pharmaceutical composition. As used herein, “isolated” means that the compounds of the invention are separated from other components of either (a) a natural source, such as a plant or cell, preferably bacterial culture, or (b) a synthetic organic chemical reaction mixture. Preferably, the compounds of the invention are purified via conventional techniques. As used herein, “purified” means that when isolated, the isolate contains at least 95%, preferably at least 98%, of a compound of the invention by weight of the isolate either as a mixture of stereoisomers or as a diastereomeric or enantiomeric pure isolate. An “isolated agent” can be a synthetic or naturally occurring molecule having a molecular weight of about 1000 daltons or less, or a natural product having a molecular weight of greater than 1000 daltons. For example, an isolated agent can be an antibody, or fragment thereof, or an antibiotic.
As used herein, a composition that is “substantially free” of a compound means that the composition contains less than about 20% by weight, more preferably less than about 10% by weight, even more preferably less than about 5% by weight, and most preferably less than about 3% by weight of the compound.
Only those choices and combinations of substituents that result in a stable structure are contemplated. Such choices and combinations will be apparent to those of ordinary skill in the art and may be determined without undue experimentation.
The invention can be understood more fully by reference to the following detailed description and illustrative examples, which are intended to exemplify non-limiting embodiments of the invention.
B. The Compounds of the Invention
The present invention encompasses compounds having formula (I) through (LXXII), or any embodiment thereof, or a compound shown in Table 5, 6, or 7, and tautomers, pharmaceutically acceptable salts, solvates, clathrates, hydrates, polymorphs and prodrugs thereof. In one aspect, the invention provides compounds of formula (I) as set forth below:




and tautomers, pharmaceutically acceptable salts, solvates, clathrates, and prodrugs thereof, wherein ring A, R1, R3 and R5 are defined as above.

Compounds of formula (I) inhibit the activity of Hsp90 and are particularly useful for treating or preventing proliferative disorders, such as cancer. In addition, compounds of formula (I) are particularly useful in treating cancer when given in combination with other anti-cancer agent.
In one embodiment, in the compounds of formula (I), R5 is an optionally substituted naphthyl.
In another embodiment, in the compounds of formula (I), R5 is represented by the following formula:




wherein:
R9, for each occurrence, is independently a substituent selected from the group consisting of an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, an optionally substituted heteraralkyl, hydroxyalkyl, alkoxyalkyl, halo, cyano, nitro, guanadino, a haloalkyl, a heteroalkyl, —NR10R11, —OR7, —C(O)R7, —C(O)OR7, —OC(O)R7, —C(O)NR10R11, —NR8C(O)R7, —SR7, —S(O)pR7, —OS(O)pR7, —S(O)pOR7, —NR8S(O)pR7, or —S(O)pNR10R11; or two R9 groups taken together with the carbon atoms to which they are attached form a fused ring; and
m is zero or an integer from 1 to 7, wherein R7, R8, R10, R11, and p are defined as above.
In another embodiment, in the compounds represented by formula (I), R5 is represented by one of the following formulas:




wherein R9 is defined as above;
q is zero or an integer from 1 to 7; and
u is zero or an integer from 1 to 8.
In another embodiment, in the compounds represented by formula (I), R5 is selected from the group consisting of:




wherein:
X6, for each occurrence, is independently CH, CR9, N, N(O), N+(R17), provided that at least three X6 groups are independently selected from CH and CR9;
X7, for each occurrence, is independently CH, CR9, N, N(O), N+(R17), provided that at least three X7 groups are independently selected from CH and CR9;
X8, for each occurrence, is independently CH2, CHR9, CR9R9, O, S, S(O)p, NR7, or NR17;
X9, for each occurrence, is independently N or CH;
X10, for each occurrence, is independently CH, CR9, N, N(O), N+(R17), provided that at least one X10 is selected from CH and CR9;
R17, for each occurrence, is independently —H, an alkyl, an aralkyl, —C(O)R7, —C(O)OR7, or —C(O)NR10R11; wherein R7, R9, R10, R11 and p are defined as above.
In another embodiment, in the compounds represented by formula (I), R5 is an optionally substituted indolyl, an optionally substituted benzoimidazolyl, an optionally substituted indazolyl, an optionally substituted 3H-indazolyl, an optionally substituted indolizinyl, an optionally substituted quinolinyl, an optionally substituted isoquinolinyl, an optionally substituted benzoxazolyl, an optionally substituted benzo[1,3]dioxolyl, an optionally substituted benzofuryl, an optionally substituted benzothiazolyl, an optionally substituted benzoldlisoxazolyl, an optionally substituted benzoldlisothiazolyl, an optionally substituted thiazolo[4,5-c]pyridinyl, an optionally substituted thiazolo[5,4-c]pyridinyl, an optionally substituted thiazolo[4,5-b]pyridinyl, an optionally substituted thiazolo[5,4-b]pyridinyl, an optionally substituted oxazolo[4,5-c]pyridinyl, an optionally substituted oxazolo[5,4-c]pyridinyl, an optionally substituted oxazolo[4,5-b]pyridinyl, an optionally substituted oxazolo[5,4-b]pyridinyl, an optionally substituted imidazopyridinyl, an optionally substituted benzothiadiazolyl, benzoxadiazolyl, an optionally substituted benzotriazolyl, an optionally substituted tetrahydroindolyl, an optionally substituted azaindolyl, an optionally substituted quinazolinyl, an optionally substituted purinyl, an optionally substituted imidazo[4,5-a]pyridinyl, an optionally substituted imidazo[1,2-a]pyridinyl, an optionally substituted 3H-imidazo[4,5-b]pyridinyl, an optionally substituted 1H-imidazo[4,5-b]pyridinyl, an optionally substituted 1H-imidazo[4,5-c]pyridinyl, an optionally substituted 3H-imidazo[4,5-c]pyridinyl, an optionally substituted pyridopyrdazinyl, and optionally substituted pyridopyrimidinyl, an optionally substituted pyrrolo[2,3]pyrimidyl, an optionally substituted pyrazolo[3,4]pyrimidyl an optionally substituted cyclopentaimidazolyl, an optionally substituted cyclopentatriazolyl, an optionally substituted pyrrolopyrazolyl, an optionally substituted pyrroloimidazolyl, an optionally substituted pyrrolotriazolyl, or an optionally substituted benzo(b)thienyl.
In another embodiment, in the compounds represented by formula (I), R5 is an optionally substituted indolyl. Preferably, R5 is an indolyl represented by the following structural formula:




wherein:
R33 is —H, a halo, lower alkyl, a lower alkoxy, a lower haloalkyl, a lower haloalkoxy, and lower alkyl sulfanyl;
R34 is H, a lower alkyl, or a lower alkylcarbonyl; and
Ring B and Ring C are optionally substituted with one or more substituents.
In another embodiment, in the compounds represented by formula (I), R5 is selected from the group consisting of:




wherein:
X11, for each occurrence, is independently CH, CR9, N, N(O), or N+(R17), provided that at least one X11 is N, N(O), or N+(R17) and at least two X11 groups are independently selected from CH and CR9;
X12, for each occurrence, is independently CH, CR9, N, N(O), N+(R17), provided that at least one X12 group is independently selected from CH and CR9;
X13, for each occurrence, is independently O, S, S(O)p, NR7, or NR17; wherein R7, R9 and R17 are defined as above.
In another embodiment, in compounds represented by formula (I), or any of the embodiments of formula (I) in which particular groups are disclosed, the compound is represented by formula (XII):




wherein R1, R3, and R5 are defined as above; and
R6, for each occurrence, is independently a substituent selected from the group consisting of an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, an optionally substituted heteraralkyl, halo, cyano, nitro, guanadino, a haloalkyl, a heteroalkyl, —NR10R11, —OR7, —C(O)R7, —C(O)OR7, —OC(O)R7, —C(O)NR10R11, —NR8C(O)R7, —SR7, —S(O)pR7, —OS(O)pR7, —S(O)pOR7, —NR8S(O)pR7, or —S(O)pNR10R11; and
n is zero of an integer from 1 to 4, wherein R7, R8, R10, R11, and p are defined as above.
In another embodiment, in compounds represented by formula (I), or any of the embodiments of formula (I) in which particular groups are disclosed, the compound is represented by structural formula (XIII):




wherein R1, R3, R5, and R6 are defined as above; and
R25 is a halo, a haloalkyl, a haloalkoxy, a heteroalkyl, —OH, —SH, —NHR7, —(CH2)kOH, —(CH2)kSH, —(CH2)kNR7H, —OCH3, —SCH3, —NHCH3, —OCH2CH2OH, —OCH2CH2SH, —OCH2CH2NR7H, —SCH2CH2OH, —SCH2CH2SH, —SCH2CH2NR7H, —OC(O)NR10R11, —SC(O)NR10R11, —NR7C(O)NR10R11, —OC(O)R7, —SC(O)R7, —NR7C(O)R7, —OC(O)OR7, —SC(O)OR7, —NR7C(O)OR7, —OCH2C(O)R7, —SCH2C(O)R7, —NR7CH2C(O)R7, —OCH2C(O)OR7, —SCH2C(O)OR7, —NR7CH2C(O)OR7, —OCH2C(O)NR10R11, —SCH2C(O)NR10R11, —NR7CH2C(O)NR10R11, —OS(O)pR7, —SS(O)pR7, —NR7S(O)pR7, —OS(O)pNR10R11, —SS(O)pNR10R11, —NR7S(O)pNR10R11, —OS(O)pOR7, —SS(O)pOR7, —NR7S(O)pOR7, —OC(S)R7, —SC(S)R7, —NR7C(S)R7, —OC(S)OR7, —SC(S)OR7, —NR7C(S)OR7, —OC(S)NR10R11, —SC(S)NR10R11, —NR7C(S)NR10R11, —OC(NR8)R7, —SC(NR8)R7, —NR7C(NR8)R7, —OC(NR8)OR7, —SC(NR8)OR7, —NR7C(NR8)OR7, —OC(NR8)NR10R11, —SC(NR8)NR10R11, —NR7C(NR8)NR10R11, —C(O)R7, —C(O)OR7, —C(O)NR10R11, —C(O)SR7, —C(S)R7, —C(S)OR7, —C(S)NR10R11, —C(S)SR7, —C(NR8)OR7, —C(NR8)R7, —C(NR8)NR10R11, —C(NR8)SR7, —S(O)pOR7, —S(O)pNR10R11, or —S(O)pR7;
k is 1, 2, 3, or 4; and
r is zero or an integer from 1 to 3, wherein R7, R8, R10, R11, and p are defined as above.
In another embodiment, in compounds represented by formula (I), or any of the embodiments of formula (I) in which particular groups are disclosed, R1 and R3 are each, independently, —OH, —SH, or —NHR7.
In another embodiment, in compounds represented by formula (I), or any of the embodiments of formula (I) in which particular groups are disclosed, the compound is represented by structural formula (XIV):




wherein R1, R3, R5, and R25 are defined as above; and
R12 is an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, cyano, halo, nitro, an optionally substituted cycloalkyl, haloalkyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, an optionally substituted heteroaralkyl, —OR7, —SR7, —NR10R11, —OC(O)NR10R11, —SC(O)NR10R11, —NR7C(O)NR10R11, —OC(O)R7, —SC(O)R7, —NR7C(O)R7, —OC(O)OR7, —SC(O)OR7, —NR7C(O)OR7, —OCH2C(O)R7, —SCH2C(O)R7, —NR7CH2C(O)R7, —OCH2C(O)OR7, —SCH2C(O)OR7, —NR7CH2C(O)OR7, —OCH2C(O)NR10R11, —SCH2C(O)NR10R11, —NR7CH2C(O)NR10R11, —OS(O)pR7, —SS(O)pR7, —NR7S(O)pR7, —OS(O)pNR10R11, —SS(O)pNR10R11, —NR7S(O)pNR10R11, —OS(O)pOR7, —SS(O)pOR7, —NR7S(O)pOR7, —OC(S)R7, —SC(S)R7, —NR7C(S)R7, —OC(S)OR7, —SC(S)OR7, —NR7C(S)OR7, —OC(S)NR10R11, —SC(S)NR10R11, —NR7C(S)NR10R11, —OC(NR8)R7, —SC(NR8)R7, —NR7C(NR8)R7, —OC(NR8)OR7, —SC(NR8)OR7, —NR7C(NR8)OR7, —OC(NR8)NR10R11, —SC(NR8)NR10R11, —NR7C(NR8)NR10R11, —C(O)R7, —C(O)OR7, —C(O)NR10R11, —C(O)SR7, —C(S)R7, —C(S)OR7, —C(S)NR10R11, —C(S)SR7, —C(NR8)OR7, —C(NR8)R7, —C(NR8)NR10R11, —C(NR8)SR7, —S(O)pOR7, —S(O)pNR10R11, or —S(O)pR7, wherein R7, R8, R10, R11, and p are defined as above. In a preferred embodiment, R1 is —SH or —OH; R3 and R25 are —OH; R12 is a lower alkyl, lower alkoxy, a lower alkyl sulfanyl, or —NR10R11; and R9, for each occurrence, is independently selected from the group consisting of —OH, —SH, halo, a lower haloalkyl, cyano, a lower alkyl, a lower alkoxy, and a lower alkyl sulfanyl.
In another embodiment, in compounds represented by formula (I), or any of the embodiments of formula (I) in which particular groups are disclosed, the compound is represented by one of the following structural formulas:




wherein R1, R3, R5, R6 and n are as defined above; and
X3 and X4 are each, independently, N, N(O), N+(R17), CH or CR6; and
X5 is O, S, NR17, CH═CH, CH═CR6, CR6═CH, CR6═CR6, CH═N, CR6═N, CH═N(O), CR6═N(O), N═CH, N═CR6, N(O)═CH, N(O)═CR6, N+(R17)═CH, N+(R17)═CR6, CH═N+(R17), CR6═N+(R17), or N═N; wherein R17 is defined as above.
In another embodiment, in compounds represented by formula (I), or any of the embodiments of formula (I) in which particular groups are disclosed, the compound is selected from the group consisting of:




wherein R1, R3, R5, and R25 are defined as above.
In another aspect, the invention provides compounds of formula (II) as set forth below:




and tautomers, pharmaceutically acceptable salts, solvates, clathrates, and prodrugs thereof, wherein ring A, R1 and R3 are defined as above; and

R2 is a substituted phenyl, wherein the phenyl group is substituted with:

    
    
        i) one substituent selected from nitro, cyano, a haloalkoxy, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, an optionally substituted heteraralkyl, hydroxylalkyl, alkoxyalkyl, guanadino, —NR10R11, —O—R20, —C(O)R7, —C(O)OR20, —OC(O)R7, —C(O)NR10R11, —NR8C(O)R7, —SR7, —S(O)pR7, —OS(O)pR7, —S(O)pOR7, —NR8S(O)pR7, or —S(O)pNR10R11, or
        ii) two to five substituents selected from the group consisting of an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, an optionally substituted heteraralkyl, hydroxyalkyl, alkoxyalkyl, —F, —Br, —I, cyano, nitro, guanadino, a haloalkyl, a heteroalkyl, —NR10R11, —OR7, —C(O)R7, —C(O)OR7, —OC(O)R7, —C(O)NR10R11, —NR8C(O)R7, —SR7, —S(O)pR7, —OS(O)pR7, —S(O)pOR7, —NR8S(O)pR7, or —S(O)pNR10R11;
    
    


R20, for each occurrence, is independently an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, or an optionally substituted heteraralkyl;
p, for each occurrence, is, independently, 0, 1 or 2.
Compounds of formula (II) inhibit the activity of Hsp90 and are particularly useful for treating or preventing proliferative disorders, such as cancer. In addition, compounds of formula (II) are particularly useful in treating cancer when given in combination with other anti-cancer agent.
In one embodiment, the compounds represented by formula (II) do not include 3-(2,4-dihydroxy-phenyl)-4-(7-naphthalen-1-yl)-5-mercapto-triazole, 3-(2,4-dihydroxyphenyl)-4-(2,5-dimethoxyphenyl)-5-mercapto-triazole, 3-(1-phenyl-5-amino-pyrazol-4-yl)-4-(2,4-dichloropheny)-5-mercapto-triazole, and 3-(2-hydroxy-phenyl)4-(2,4-dimethylphenyl)-5-mercapto-triazole.
In another embodiment, in compounds represented by formula (II), or any of the embodiments of formula (II) in which particular groups are disclosed, the compound is represented by structural formula (XVIII):




wherein R1, R2, R3, R6, and n are defined as above.
In another embodiment, in compounds represented by formula (II), or any of the embodiments of formula (II) in which particular groups are disclosed, the compound is represented by structural formula (XIX):




wherein R1, R2, R3, R6, R25 and r are defined as above.
In another embodiment, in compounds represented by formula (II), or any of the embodiments of formula (II) in which particular groups are disclosed, R1 and R3 are each, independently, —OH, —SH, or —NHR7.
In another embodiment, in compounds represented by formula (II), or any of the embodiments of formula (II) in which particular groups are disclosed, the compound is represented by structural formula (XX):




wherein R1, R2, R3, R12 and R25 are defined as above. In a preferred embodiment, R1 is —SH or —OH; R3 and R25 are —OH; R12 is a lower alkyl, lower alkoxy, a lower alkyl sulfanyl, or —NR10R11; and R9, for each occurrence, is independently selected from the group consisting of —OH, —SH, halo, a lower haloalkyl, cyano, a lower alkyl, a lower alkoxy, and a lower alkyl sulfanyl.
In another embodiment, in compounds represented by formula (II), or any of the embodiments of formula (II) in which particular groups are disclosed, the compound is represented by one of the following structural formulas:




wherein R1, R2, R3, R6, X3, X4, X5 and n are defined as above.
In another embodiment, in compounds represented by formula (II), or any of the embodiments of formula (II) in which particular groups are disclosed, the compound is selected from the group consisting of:




wherein R1, R2, R3, and R25 are defined as above.

In another aspect, the invention provides compounds of formula (III) as set forth below:




and tautomers, pharmaceutically acceptable salts, solvates, clathrates, and prodrugs. In formula (III), ring A, R1, and R3 are defined as above; and

R18 is an optionally substituted cycloalkyl, and optionally substituted cycloalkenyl, or a substituted alkyl, wherein the alkyl group is substituted with one or more substituents independently selected from the group consisting of an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heteroaryl, an optionally substituted aralkyl, an optionally substituted heteraralkyl, halo, cyano, nitro, guanadino, a haloalkyl, —NR10R11, —OR7, —C(O)R7, —C(O)OR7, —OC(O)R7, —C(O)NR10R11, —NR8C(O)R7, —SR7, —S(O)pR7, —OS(O)pR7, —S(O)pOR7, —NR8S(O)pR7, or —S(O)pNR10R11, wherein R7, R8, R10, R11, and p are defined as above.
Compounds of formula (III) inhibit the activity of Hsp90 and are particularly useful for treating or preventing proliferative disorders, such as cancer. In addition, compounds of formula (III) are particularly useful in treating cancer when given in combination with other anti-cancer agent.
In one embodiment, in formula (III) R18 is not cyclohexyl.
In another embodiment, in formula (III) R18 is an optionally substituted cycloalkyl or an optionally substituted cycloalkenyl.
In another embodiment, in formula (III) R18 is a substituted alkyl.
In another embodiment, in compounds represented by formula (III), or any of the embodiments of formula (III) in which particular groups are disclosed, the compound is represented by structural formula (XXIV):




wherein R1, R3, R6, R18, and n are defined as above.
In another embodiment, in compounds represented by formula (III), or any of the embodiments of formula (III) in which particular groups are disclosed, the compound is represented by structural formula (XXV):




wherein R1, R3, R6, R18, R25 and r are defined as above.
In another embodiment, in compounds represented by formula (III), or any of the embodiments of formula (III) in which particular groups are disclosed, R1 and R3 are each, independently, —OH, —SH, or —NHR7.
In another embodiment, in compounds represented by formula (III), or any of the embodiments of formula (III) in which particular groups are disclosed, the compound is represented by structural formula (XXVI):




wherein R1, R3, R12, R18, and R25 are defined as above. In a preferred embodiment, R1 is —SH or —OH; R3 and R25 are —OH; and R12 is a lower alkyl, lower alkoxy, a lower alkyl sulfanyl, or —NR10R11.
In another embodiment, in compounds represented by formula (III), or any of the embodiments of formula (III) in which particular groups are disclosed, the compound is represented by one of the following structural formulas:




wherein R1, R3, R6, R18, X3, X4, X5, and n are defined as above.
In another embodiment, in compounds represented by formula (III), or any of the embodiments of formula (III) in which particular groups are disclosed, the compound is selected from the group consisting of:




wherein R1, R3, R18, and R25 are defined as above.
In another aspect, the invention provides compounds of formula (IV) or (V) as set forth below:




and tautomers, pharmaceutically acceptable salts, solvates, clathrates, and prodrugs thereof. In formulas (IV) and (V), R1 and R3 are as defined above; and

X14 is O, S, or NR7;
R21 is an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, or an optionally substituted heteraralkyl;
R22, for each occurrence, is independently a substituent selected from the group consisting of H, an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, or an optionally substituted heteraralkyl, a
haloalkyl, —C(O)R7, —C(O)OR7, —OC(O)R7, —C(O)NR10R11, —NR8C(O)R7, —S(O)pR7, —S(O)pOR7, or —S(O)pNR10R11; and
R23 and R24, for each occurrence, are independently a substituent selected from the group consisting of H, an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, or an optionally substituted heteraralkyl, halo, cyano, nitro, guanadino, a haloalkyl, a heteroalkyl, —NR10R11, —OR7, —C(O)R7, —C(O)OR7, —OC(O)R7, —C(O)NR10R11, —NR8C(O)R7, —SR7, —S(O)pR7, —OS(O)pR7, —S(O)pOR7, —NR8S(O)pR7, or —S(O)pNR10R11;
wherein R7, R8, R10, R11 and p are defined as above.
In one embodiment, in formulas (IV) and (V), R21 is an optionally substituted alkyl, an optionally substituted cycloalkyl, an optionally substituted aryl or an optionally substituted heteroaryl.
In another embodiment, in the formulas (IV) and (V), R1 is —OH, —SH, or —NHR7.
In another embodiment, in the formulas (IV) and (V), R22 is an alkyl, an aralkyl, —C(O)R7, —C(O)OR7, or —C(O)NR10R11.
In another embodiment, in the formulas (IV) and (V), X14 is O.
Compounds of formula (IV) or (V) inhibit the activity of Hsp90 and are particularly useful for treating or preventing proliferative disorders, such as cancer. In addition, compounds of formula (IV) or (V) are particularly useful in treating cancer when given in combination with other anti-cancer agent.
In another embodiment, the invention provides compounds represented by formula (XXX):




and tautomers, pharmaceutically acceptable salts, solvates, clathrates, and prodrugs thereof, wherein:
X41 is O, S, or NR42;
X42 is CR44 or N;
Y40 is N or CR43;
Y41 is N or CR45;
Y42, for each occurrence, is independently N, C or CR46;
Z is OH, SH, or NHR7;
R41 is —H, —OH, —SH, an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, an optionally substituted heteraralkyl, halo, cyano, nitro, guanadino, a haloalkyl, a heteroalkyl, an alkoxy or cycloalkoxy, a haloalkoxy, —NR10R11, —OR7, —C(O)R7, —C(O)OR7, —C(S)R7, —C(O)SR7, —C(S)SR7, —C(S)OR7, —C(S)NR10R11, —C(NR8)OR7, —C(NR8)R7, —C(NR8)NR10R11, —C(NR8)SR7, —OC(O)R7, —OC(O)OR7, —OC(S)OR7, —OC(NR8)OR7, —SC(O)R7, —SC(O)OR7, —SC(NR8)OR7, —OC(S)R7, —SC(S)R7, —SC(S)OR7, —OC(O)NR10R11, —OC(S)NR10R11, —OC(NR8)NR10R11, —SC(O)NR10R11, —SC(NR8)NR10R11, —SC(S)NR10R11, —OC(NR8)R7, —SC(NR8)R7, —C(O)NR10R11, —NR8C(O)R7, —NR7C(S)R7, —NR7C(S)OR7, —NR7C(NR8)R7, —NR7C(O)OR7, —NR7C(NR8)OR7, —NR7C(O)NR10R11, —NR7C(S)NR10R11, —NR7C(NR8)NR10R11, —SR7, —S(O)pR7, —OS(O)pR7, —OS(O)pOR7, —OS(O)pNR10R11, —S(O)pOR7, —NR8S(O)pR7, —NR7S(O)pNR10R11, —NR7S(O)pOR7, —S(O)pNR10R11, —SS(O)pR7, —SS(O)pOR7, —SS(O)pNR10R11, —OP(O)(OR7)2, or —SP(O)(OR7)2;
R42 is —H, an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, an optionally substituted heteraralkyl, hydroxyalkyl, alkoxyalkyl, a haloalkyl, a heteroalkyl, —C(O)R7, —(CH2)mC(O)OR7, —C(O)OR7, —OC(O)R7, —C(O)NR10R11, —S(O)pR7, —S(O)pOR7, or —S(O)pNR10R11;
R43 and R44 are, independently, —H, —OH, an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, an optionally substituted heteraralkyl, hydroxyalkyl, alkoxyalkyl, halo, cyano, nitro, guanadino, a haloalkyl, a heteroalkyl, —C(O)R7, —C(O)OR7, —OC(O)R7, —C(O)NR10R11, —NR8C(O)R7, —SR7, —S(O)pR7, —OS(O)pR7, —S(O)pOR7, —NR8S(O)pR7, —S(O)pNR10R11, or R43 and R44 taken together with the carbon atoms to which they are attached form an optionally substituted cycloalkenyl, an optionally substituted aryl, an optionally substituted heterocyclyl, or an optionally substituted heteroaryl;
R45 is —H, —OH, —SH, —NR7H, —OR26, —SR26, —NHR26, —O(CH2)mOH, —O(CH2)mSH, —O(CH2)mNR7H, —S(CH2)mOH, —S(CH2)mSH, —S(CH2)mNR7H, —OC(O)NR10R11, —SC(O)NR10R11, —NR7C(O)NR10R11, —OC(O)R7, —SC(O)R7, —NR7C(O)R7, —OC(O)OR7, —SC(O)OR7, —NR7C(O)OR7, —OCH2C(O)R7, —SCH2C(O)R7, —NR7CH2C(O)R7, —OCH2C(O)OR7, —SCH2C(O)OR7, —NR7CH2C(O)OR7, —OCH2C(O)NR10R11, —SCH2C(O)NR10R11, —NR7CH2C(O)NR10R11, —OS(O)pR7, —SS(O)pR7, —NR7S(O)pR7, —OS(O)pNR10R11, —SS(O)pNR10R11, —NR7S(O)pNR10R11, —OS(O)pOR7, —SS(O)pOR7, —NR7S(O)pOR7, —OC(S)R7, —SC(S)R7, —NR7C(S)R7, —OC(S)OR7, —SC(S)OR7, —NR7C(S)OR7, —OC(S)NR10R11, —SC(S)NR10R11, —NR7C(S)NR10R11, —OC(NR8)R7, —SC(NR8)R7, —NR7C(NR8)R7, —OC(NR8)OR7, —SC(NR8)OR7, —NR7C(NR8)OR7, —OC(NR8)NR10R11, —SC(NR8)NR10R11, or —NR7C(NR8)NR10R11;
R46, for each occurrence, is independently selected from the group consisting of H, an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, an optionally substituted heteraralkyl, halo, cyano, nitro, guanadino, a haloalkyl, a heteroalkyl, —NR10R11, —OR7, —C(O)R7, —C(O)OR7, —OC(O)R7, —C(O)NR10R11, —NR8C(O)R7, —SR7, —S(O)pR7, —OS(O)pR7, —S(O)pOR7, —NR8S(O)pR7, or —S(O)pNR10R11;
R7, R8, R10, R11, R26, p, and m are defined as above.
In one embodiment, in formula (XXX), X41 is NR42 and X42 is CR44.
In another embodiment, in formula (XXX), X41 is NR42 and X42 is N.
In another embodiment, in formula (XXX), R41 is selected from the group consisting of —H, lower alkyl, lower alkoxy, lower cycloalkyl, and lower cycloalkoxy.
In another embodiment, in formula (XXX), R41 is selected from the group consisting of —H, methyl, ethyl, propyl, isopropyl, cyclopropyl, methoxy, ethoxy, propoxy, and cyclopropoxy.
In another embodiment, in formula (XXX), X41 is NR42, and R42 is selected from the group consisting of —H, a lower alkyl, a lower cycloalkyl, —C(O)N(R27)2, and —C(O)OH, wherein R27, for each occurrence, is independently is —H or a lower alkyl.
In another embodiment, in formula (XXX), X41 is NR42, and R42 is selected from the group consisting of —H, methyl, ethyl, n-propyl, isopropyl, cyclopropyl, n-butyl, sec-butyl, tert-butyl, n-pentyl, n-hexyl, —C(O)OH, —(CH2)mC(O)OH, —CH2OCH3, —CH2CH2OCH3, and —C(O)N(CH3)2.
In one embodiment, Y40 is CR43. Preferably, Y40 is CR43 and R43 is H or a lower alkyl.
In another embodiment, in formula (XXX), R43 and R44 are, independently, selected from the group consisting of —H, methyl, ethyl, propyl, isopropyl, cyclopropyl, methoxy, ethoxy, propoxy, and cyclopropoxy.
In another embodiment, in formula (XXX), X42 is CR44; Y is CR43; and R43 and R44 together with the carbon atoms to which they are attached form a cycloalkenyl, an aryl, heterocyclyl, or heteroaryl ring. In one aspect of this embodiment, R43 and R44 together with the carbon atoms to which they are attached form a C5-C8 cycloalkenyl or a C5-C8 aryl.
In another embodiment, in formula (XXX), R45 is selected from the group consisting of —H, —OH, —SH, —NH2, a lower alkoxy, a lower alkyl amino, and a lower dialkyl amino.
In another embodiment, in formula (XXX), R45 is selected from the group consisting of —H, —OH, methoxy and ethoxy.
In another embodiment, in formula (XXX), X41 is O.
In another embodiment, the compound is selected from the group consisting of:
3-(2,4-dihydroxy-5-ethyl-phenyl)-4-(2-methyl-7-methoxy-benzofuran-4-yl)-5-mercapto-[1,2,4]triazole,
3-(2,4-dihydroxy-5-ethyl-phenyl)-4-(benzofuran-5-yl)-5-mercapto-[1,2,4]triazole,
3-(2,4-dihydroxy-5-ethyl-phenyl)-4-(2-methyl-1,3-benzoxaz-5-yl)-5-mercapto-[1,2,4]triazole, and
tautomers, pharmaceutically acceptable salts, solvates, clathrates, and prodrugs thereof.
In another embodiment, in formula (XXX), Z is —OH.
In another embodiment, the compound is selected from the group consisting of:
3-(2,4-dihydroxy-5-ethyl-phenyl)-4-(1,3-dimethyl-indol-5-yl)-5-hydroxy-[1,2,4]triazole,
3-(2,4-dihydroxy-5-isopropyl-phenyl)-4-(1,3-dimethyl-indol-5-yl)-5-hydroxy-[1,2,4]triazole,
3-(2,4-dihydroxy-5-isopropyl-phenyl)-4-(1-methyl-indol-5-yl)-5-hydroxy-[1,2,4]triazole,
3-(2,4-dihydroxy-5-isopropyl-phenyl)-4-(1-isopropyl-indol-4-yl)-5-hydroxy-[1,2,4]triazole, and
tautomers, pharmaceutically acceptable salts, solvates, clathrates, and prodrugs thereof.
In another embodiment, Z is —SH.
In another embodiment, the compound is selected from the group consisting of:
3-(2,4-dihydroxy-5-isopropyl-phenyl)-4-(1-methyl-indazol-5-yl)-5-mercapto-[1,2,4]triazole,
3-(2,4-dihydroxy-5-isopropyl-phenyl)-4-(1-methyl-indazol-6-yl)-5-mercapto-[1,2,4]triazole, and
tautomers, pharmaceutically acceptable salts, solvates, clathrates, and prodrugs thereof.
Compounds of formula (XXX) inhibit the activity of Hsp90 and are particularly useful for treating or preventing proliferative disorders, such as cancer. In addition, compounds of formula (XXX) are particularly useful in treating cancer when given in combination with other anti-cancer agent.
In another aspect, the invention provides compounds represented by formula (XXXI):




and tautomers, pharmaceutically acceptable salts, solvates, clathrates, and prodrugs thereof, wherein:
Z1 is —OH or —SH;
X42, R41, R42, R43, and R45 are defined as above.
In one embodiment, in formula (XXXI), Z1 is —OH.
In another embodiment, in formula (XXXI), Z1 is —SH.
In another embodiment, in formula (XXXI), R41 is selected from the group consisting of —H, lower alkyl, lower alkoxy, lower cycloalkyl, and lower cycloalkoxy.
In another embodiment, in formula (XXXI), R41 is selected from the group consisting of —H, methyl, ethyl, propyl, isopropyl, cyclopropyl, methoxy, ethoxy, propoxy, and cyclopropoxy.
In another embodiment, in formula (XXXI), R42 is selected from the group consisting of lower alkyl, lower cycloalkyl, —C(O)N(R27)2, or —C(O)OH, wherein R27, for each occurrence, is independently is —H or a lower alkyl.
In another embodiment, in formula (XXXI), R42 is selected from the group consisting of —H, methyl, ethyl, n-propyl, isopropyl, cyclopropyl, n-butyl, sec-butyl, tert-butyl, n-pentyl, n-hexyl, —C(O)OH, —(CH2)mC(O)OH, —CH2OCH3, —CH2CH2OCH3, and —C(O)N(CH3)2.
In another embodiment, R43 is H or a lower alkyl.
In another embodiment, in formula (XXXI), X42 is CR44, and R43 and R44 are, independently, selected from the group consisting of —H, methyl, ethyl, propyl, isopropyl, cyclopropyl, methoxy, ethoxy, propoxy, and cyclopropoxy.
In another embodiment, in formula (XXXI), X42 is CR44, and R43 and R44, taken together with the carbon atoms to which they are attached, form a cycloalkenyl, aryl, heterocyclyl, or heteroaryl ring. Preferably, in this embodiment, R43 and R44, taken together with the carbon atoms to which they are attached, form a C5-C8 cycloalkenyl or a C5-C8 aryl.
In another embodiment, in formula (XXXI), R45 is selected from the group consisting of —H, —OH, —SH, —NH2, a lower alkoxy, a lower alkyl amino, and a lower dialkyl amino.
In another embodiment, in formula (XXXI), R45 is selected from the group consisting of —H, —OH, methoxy, and ethoxy.
In another embodiment, in formula (XXXI), X43 is CR44.
In another embodiment, the compound is selected from the group consisting of:
3-(2,4-dihydroxyphenyl)-4-(1-ethyl-indol-4-yl)-5-mercapto-[1,2,4]triazole,
3-(2,4-dihydroxyphenyl)-4-(1-isopropyl-indol-4-yl)-5-mercapto-[1,2,4]triazole,
3-(2,4-dihydroxyphenyl)-4-(indol-4-yl)-5-mercapto-[1,2,4]triazole,
3-(2,4-dihydroxyphenyl)-4-(1-methoxyethyl-indol-4-yl)-5-mercapto-[1,2,4]triazole,
3-(2,4-dihydroxy-5-ethyl-phenyl)-4-(1-isopropyl-indol-4-yl)-5-mercapto-[1,2,4]triazole,
3-(2,4-dihydroxyphenyl)-4-(1-dimethylcarbamoyl-indol-4-yl)-5-mercapto-[1,2,4]triazole,
3-(2,4-dihydroxy-5-ethyl-phenyl)-4-(1-propyl-indol-4-yl)-5-mercapto-[1,2,4]triazole,
3-(2,4-dihydroxy-5-ethyl-phenyl)-4-(1,2,3-trimethyl-indol-5-yl)-5-mercapto-[1,2,4]triazole,
3-(2,4-dihydroxy-5-ethyl-phenyl)-4-(2,3-dimethyl-indol-5-yl)-5-mercapto-[1,2,4]triazole,
3-(2,4-dihydroxy-5-ethyl-phenyl)-4-(1-acetyl-2,3-dimethyl-indol-5-yl)-5-mercapto-[1,2,4]triazole,
3-(2,4-dihydroxy-5-ethyl-phenyl)-4-(1-isopropyl-7-methoxy-indol-4-yl)-5-mercapto-[1,2,4]triazole,
3-(2,4-dihydroxy-5-ethyl-phenyl)-4-(1-propyl-2,3-dimethyl-indol-5-yl)-5-mercapto-[1,2,4]triazole,
3-(2,4-dihydroxy-5-ethyl-phenyl)-4-(N-methyl-tetrahydrocarbozol-7-yl)-5-mercapto-[1,2,4]triazole,
3-(2,4-dihydroxy-5-ethyl-phenyl)-4-(N-methyl-cyclononanlalindol-5-yl)-5-mercapto-[1,2,4]triazole,
3-(2,4-dihydroxy-5-ethyl-phenyl)-4-(1-n-butyl-indol-4-yl)-5-mercapto-[1,2,4]triazole,
3-(2,4-dihydroxy-5-ethyl-phenyl)-4-(1-n-pentyl-indol-4-yl)-5-mercapto-[1,2,4]triazole,
3-(2,4-dihydroxy-5-ethyl-phenyl)-4-(1-n-hexyl-indol-4-yl)-5-mercapto-[1,2,4]triazole,
3-(2,4-dihydroxy-5-cyclopropyl-phenyl)-4-(1-(1-methylcyclopropyl)-indol-4-yl)-5-mercapto-[1,2,4]triazole,
3-(2,4-dihydroxy-5-cyclopropyl-phenyl)-4-(1-isopropyl-7-methoxy-indol-4-yl)-5-mercapto-[1,2,4]triazole,
3-(2,4-dihydroxy-5-cyclopropyl-phenyl)-4-(1,2,3-trimethyl-indol-5-yl)-5-mercapto-[1,2,4]triazole,
3-(2,4-dihydroxy-5-ethyl-phenyl)-4-(1-isopropyl-7-methoxy-indol-4-yl)-5-mercapto-[1,2,4]triazole disodium salt,
3-(2,4-dihydroxy-5-tert-butyl-phenyl)-4-(1-isopropyl-7-methoxy-indol-4-yl)-5-mercapto-[1,2,4]triazole,
3-(2,4-dihydroxy-5-cyclopropyl-phenyl)-4-(1-propyl-7-methoxy-indol-4-yl)-5-mercapto-[1,2,4]triazole,
3-(2,4-dihydroxy-5-ethyl-phenyl)-4-(1-methyl-3-ethyl-indol-5-yl)-5-mercapto-[1,2,4]triazole,
3-(2,4-dihydroxy-5-ethyl-phenyl)-4-(1,3-dimethyl-indol-5-yl)-5-mercapto-[1,2,4]triazole,
3-(2,4-dihydroxy-5-isopropyl-phenyl)-4-(1-isopropyl-7-methoxy-indol-4-yl)-5-mercapto-[1,2,4]triazole,
3-(2,4-dihydroxy-5-ethyl-phenyl)-4-(1-methyl-3-isopropyl-indol-5-yl)-5-mercapto-[1,2,4]triazole,
3-(2,4-dihydroxy-5-ethyl-phenyl)-4-(N-ethyl-carbozol-7-yl)-5-mercapto-[1,2,4]triazole,
3-(2,4-dihydroxy-5-ethyl-phenyl)-4-(1-isopropyl-7-hydroxy-indol-4-yl)-5-mercapto-[1,2,4]triazole,
3-(2,4-dihydroxy-5-ethyl-phenyl)-4-(1-isopropyl-7-ethoxy-indol-4-yl)-5-mercapto-[1,2,4]triazole,
3-(2,4-dihydroxy-5-ethyl-phenyl)-4-(1,2-dimethyl-indol-5-yl)-5-mercapto-[1,2,4]triazole,
3-(2,4-dihydroxy-5-ethyl-phenyl)-4-(N-methyl-indol-5-yl)-5-mercapto-[1,2,4]triazole,
3-(2,4-dihydroxy-5-isopropyl-phenyl)-4-(1,3-dimethyl-indol-5-yl)-5-mercapto-[1,2,4]triazole,
3-(2,4-dihydroxy-5-cyclopropyl-phenyl)-4-(1,3-dimethyl-indol-5-yl)-5-mercapto-[1,2,4]triazole,
3-(2,4-dihydroxy-5-cyclopropyl-phenyl)-4-(1-methyl-indol-5-yl)-5-mercapto-[1,2,4]triazole,
3-(2,4-dihydroxy-5-isopropyl-phenyl)-4-(1H-indol-5-yl)-5-mercapto-[1,2,4]triazole,
3-(2,4-dihydroxy-5-ethyl-phenyl)-4-(1,2-dimethyl-indol-5-yl)-5-mercapto-[1,2,4]triazole,
3-(2,4-dihydroxy-5-isopropyl-phenyl)-4-(1-ethyl-indol-5-yl)-5-mercapto-[1,2,4]triazole,
3-(2,4-dihydroxy-5-isopropyl-phenyl)-4-(1-propyl-indol-5-yl)-5-mercapto-[1,2,4]triazole, and
tautomers, pharmaceutically acceptable salts, solvates, clathrates, and prodrugs thereof.
In another embodiment, in formula (XXXI), X42 is N.
In another embodiment, the compound is selected from the group consisting of
3-(2,4-dihydroxy-5-ethyl-phenyl)-4-(1-ethyl-benzimidazol-4-yl)-5-mercapto-[1,2,4]triazole,
3-(2,4-dihydroxy-5-ethyl-phenyl)-4-(1-ethyl-benzimidazol-4-yl)-5-mercapto-[1,2,4]triazole HCL salt,
3-(2,4-dihydroxy-5-ethyl-phenyl)-4-(2-methyl-3-ethyl-benzimidazol-5-yl)-5-mercapto-[1,2,4]triazole,
3-(2,4-dihydroxy-5-ethyl-phenyl)-4-(1-ethyl-2-methyl-benzimidazol-5-yl)-5-mercapto-[1,2,4]triazole,
3-(2,4-dihydroxy-5-isopropyl-phenyl)-4-(1-methyl-2-trifluoromethyl-benzimidazol-5-yl)-5-mercapto-[1,2,4]triazole, and
tautomers, pharmaceutically acceptable salts, solvates, clathrates, and prodrugs thereof.
Compounds of formula (XXXI) inhibit the activity of Hsp90 and are particularly useful for treating or preventing proliferative disorders, such as cancer. In addition, compounds of formula (XXXI) are particularly useful in treating cancer when given in combination with other anti-cancer agent.
In another aspect, the invention provides compounds represented by formula (XXXII):




and tautomers, pharmaceutically acceptable salts, solvates, clathrates, and prodrugs thereof, wherein:
X45 is CR54 or N;
Z1 is —OH or —SH;
R52 is selected from the group consisting of —H, methyl, ethyl, n-propyl, isopropyl, n-butyl, n-pentyl, n-hexyl, —(CH2)2OCH3, —CH2C(O)OH, and —C(O)N(CH3)2;
R53 and R54 are each, independently, —H, methyl, ethyl, or isopropyl; or R53 and R54 taken together with the carbon atoms to which they are attached form a phenyl, cyclohexenyl, or cyclooctenyl ring;
R55 is selected from the group consisting of —H, —OH, —OCH3, and —OCH2CH3; and
R56 is selected from the group consisting of —H, methyl, ethyl, isopropyl, and cyclopropyl.
In one embodiment, in formula (XXXII), Z1 is —OH.
In another embodiment, in formula (XXXII), Z1 is —SH.
In another embodiment, in formula (XXXII), R53 is H or a lower alkyl.
In another embodiment, in formula (XXXII), X45 is CR54. Preferably, R54 is H or a lower alkyl.
In another embodiment, X45 is N.
In another embodiment, the compound is 3-(2,4-dihydroxy-5-isopropyl-phenyl)-4-(N-methyl-indol-5-yl)-5-mercapto-[1,2,4]triazole.
Compounds of formula (XXXII) inhibit the activity of Hsp90 and are particularly useful for treating or preventing proliferative disorders, such as cancer. In addition, compounds of formula (XXXII) are particularly useful in treating cancer when given in combination with other anti-cancer agent.
In another aspect, the invention provides compounds represented by formula (XXXIII):




and tautomers, pharmaceutically acceptable salts, solvates, clathrates, and prodrugs thereof, wherein,
X44, for each occurrence, is independently, O, NR42 or C(R46)2;
Y43 is NR42 or C(R46)2;
Y41, Y42, Z, R41, R42, and R46 are defined as above.
In one embodiment, in formula (XXXIII), R41 is selected from the group consisting of —H, lower alkyl, lower alkoxy, lower cycloalkyl, and lower cycloalkoxy.
In another embodiment, in formula (XXXIII), R41 is selected from the group consisting of —H, methyl, ethyl, propyl, isopropyl, cyclopropyl, methoxy, ethoxy, propoxy, and cyclopropoxy.
In another embodiment, in formula (XXXIII), R42 is selected from the group consisting of —H, methyl, ethyl, n-propyl, isopropyl, cyclopropyl, n-butyl, sec-butyl, tert-butyl, n-pentyl, n-hexyl, —C(O)OH, —(CH2)mC(O)OH, —CH2OCH3, —CH2CH2OCH3, and —C(O)N(CH3)2.
In another embodiment, in formula (XXXIII), Y41 is CR45. Preferably, R45 is H, a lower alkoxy, or —OH.
In another embodiment, in formula (XXXIII), Y42 is CH.
In another embodiment, in formula (XXXIII), Y43 is CH2.
In another embodiment, in formula (XXXIII), Y43 is NR42, wherein R42 is H or a lower alkyl.
In another embodiment, in formula (XXXIII), one of X44 is NR42 and the other is CH2 or C(R6)2. Preferably, one of X44 is NR42 and the other is CH2.
In another embodiment, in formula (XXXIII), Z is —OH.
In another embodiment, Z is —SH.
Compounds of formula (XXXIII) inhibit the activity of Hsp90 and are particularly useful for treating or preventing proliferative disorders, such as cancer. In addition, compounds of formula (XXXIII) are particularly useful in treating cancer when given in combination with other anti-cancer agent.
In another aspect, the invention provides compounds represented by formula (XXXIV):




and tautomers, pharmaceutically acceptable salts, solvates, clathrates, and prodrugs thereof, wherein:
X41, Y41, Y42, Z, R7, R8, R10, R11, R41, R46, and p are defined as above.
In one embodiment, in formula (XXXIV), R41 is selected from the group consisting of —H, lower alkyl, lower alkoxy, lower cycloalkyl, and lower cycloalkoxy.
In another embodiment, in formula (XXXIV), R41 is selected from the group consisting of —H, methyl, ethyl, propyl, isopropyl, cyclopropyl, methoxy, ethoxy, propoxy, and cyclopropoxy.
In another embodiment, in formula (XXXIV), X41 is NR42. Preferably, R42 is selected from the group consisting of —H, methyl, ethyl, n-propyl, isopropyl, cyclopropyl, n-butyl, sec-butyl, tert-butyl, n-pentyl, n-hexyl, —C(O)OH, —(CH2)mC(O)OH, —CH2OCH3, —CH2CH2OCH3, and —C(O)N(CH3)2. More preferably, R42 is H or a lower alkyl.
In another embodiment, in formula (XXXIV), X41 is O.
In another embodiment, in formula (XXXIV), X41 is S.
In another embodiment, in formula (XXXIV), Y41 is CR45. Preferably, R45 is H, a lower alkoxy, or —OH.
In another embodiment, in formula (XXXIV), Y42 is CH.
In another embodiment, in formula (XXXIV), R46 is H or a lower alkyl.
In one embodiment, the compound is 3-(2,4-dihydroxy-5-isopropyl-phenyl)-4-(2-methyl-indazol-6-yl)-5-mercapto-[1,2,4]triazole.
Compounds of formula (XXXIV) inhibit the activity of Hsp90 and are particularly useful for treating or preventing proliferative disorders, such as cancer. In addition, compounds of formula (XXXIV) are particularly useful in treating cancer when given in combination with other anti-cancer agent.
In one embodiment the present invention provides compounds having formula (I) as described above or a tautomer, pharmaceutically acceptable salt, solvate, clathrate or a prodrug thereof.
In another embodiment, the compounds of the present invention can be represented by structural formula (XXXV):




or a tautomer, pharmaceutically acceptable salt, solvate, clathrate or a prodrug thereof.
In formula (XXXV), R1 is —OH, —SH, —NR7H, —OR26, —SR26, —NHR26, —O(CH2)mOH, —O(CH2)mSH, —O(CH2)mNR7H, —S(CH2)mOH, —S(CH2)mSH, —S(CH2)mNR7H, —OC(O)NR10R11, —SC(O)NR10R11, —NR7C(O)NR10R11, —OC(O)R7, —SC(O)R7, —NR7C(O)R7, —OC(O)OR7, —SC(O)OR7, —NR7C(O)OR7, —OCH2C(O)R7, —SCH2C(O)R7, —NR7CH2C(O)R7, —OCH2C(O)OR7, —SCH2C(O)OR7, —NR7CH2C(O)OR7, —OCH2C(O)NR10R11, —SCH2C(O)NR10R11, —NR7CH2C(O)NR10R11, —OS(O)pR7, —SS(O)pR7, —S(O)pOR7, —NR7S(O)pR7, —OS(O)pNR10R11, —SS(O)pNR10R11, —NR7S(O)pNR10R11, —OS(O)pOR7, —SS(O)pOR7, —NR7S(O)pOR7, —OC(S)R7, —SC(S)R7, —NR7C(S)R7, —OC(S)OR7, —SC(S)OR7, —NR7C(S)OR7, —OC(S)NR10R11, —SC(S)NR10R11, —NR7C(S)NR10R11, —OC(NR8)R7, —SC(NR8)R7, —NR7C(NR8)R7, —OC(NR8)OR7, —SC(NR8)OR7, —NR7C(NR8)OR7, —OC(NR8)NR10R11, —SC(NR8)NR10R11, —NR7C(NR8)NR10R11, —OP(O)(OR7)2, or —SP(O)(OR7)2. Preferably, R1 is —OH, —SH, —NHR7, —OC(O)NR10R11, —SC(O)NR10R11, —OC(O)R7, —SC(O)R7, —OC(O)OR7, —SC(O)OR7, —OS(O)pR7, —S(O)pOR7, —SS(O)pR7, —OS(O)pOR7, —SS(O)pOR7, —OC(S)R7, —SC(S)R7, —OC(S)OR7, —SC(S)OR7, —OC(S)NR10R11, —SC(S)NR10R11, —OC(NR8)R7, —SC(NR8)R7, —OC(NR8)OR7, —SC(NR8)OR7, —OP(O)(OR7)2 or —SP(O)(OR7)2. More preferably, R1 is —OH, —SH, or —NHR7. Even more preferably, R1, is —SH or —OH;
R3 is —OH, —SH, —NR7H, —NHR26, —O(CH2)mOH, —O(CH2)mSH, —O(CH2)mNR7H, —S(CH2)mOH, —S(CH2)mSH, —S(CH2)mNR7H, —OC(O)NR10R11, —SC(O)NR10R11, —NR7C(O)NR10R11, —OC(O)R7, —SC(O)R7, —NR7C(O)R7, —OC(O)OR7, —SC(O)OR7, —NR7C(O)OR7, —OCH2C(O)R7, —SCH2C(O)R7, —NR7CH2C(O)R7, —OCH2C(O)OR7, —SCH2C(O)OR7, —NR7CH2C(O)OR7, —OCH2C(O)NR10R11, —SCH2C(O)NR10R11, —NR7CH2C(O)NR10R11, —OS(O)pR7, —SS(O)pR7, —S(O)pOR7, —NR7S(O)pR7, —OS(O)pNR10R11, —SS(O)pNR10R11, —NR7S(O)pNR10R11, —OS(O)pOR7, —SS(O)pOR7, —NR7S(O)pOR7, —OC(S)R7, —SC(S)R7, —NR7C(S)R7, —OC(S)OR7, —SC(S)OR7, —NR7C(S)OR7, —OC(S)NR10R11, —SC(S)NR10R11, —NR7C(S)NR10R11, —OC(NR8)R7, —SC(NR8)R7, —NR7C(NR8)R7, —OC(NR8)OR7, —SC(NR8)OR7, —NR7C(NR8)OR7, —OC(NR8)NR10R11, —SC(NR8)NR10R11, —NR7C(NR8)NR10R11, —C(O)OH, —C(O)NHR8, —C(O)SH, —S(O)OH, —S(O)2OH, —S(O)NHR8, —S(O)2NHR8, —OP(O)(OR7)2, or —SP(O)(OR7)2. In another embodiment, —OR26 and —SR26, are additional values for R3. Preferably, R3 is —OH, —SH, —NHR7, —OC(O)NR10R11, —SC(O)NR10R11, —OC(O)R7, —SC(O)R7, —OC(O)OR7, —SC(O)OR7, —OS(O)pR7, —S(O)pOR7, —SS(O)pR7, —OS(O)pOR7, —SS(O)pOR7, —OC(S)R7, —SC(S)R7, —OC(S)OR7, —SC(S)OR7, —OC(S)NR10R11, —SC(S)NR10R11, —OC(NR8)R7, —SC(NR8)R7, —OC(NR8)OR7, —SC(NR8)OR7, —OP(O)(OR7)2 or —SP(O)(OR7)2. More preferably, R3 is —OH, —SH, or —NHR7. Even more preferably, R3 is —SH or —OH;
R70 for each occurrence, is independently an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, an optionally substituted heteraralkyl, halo, cyano, nitro, guanadino, a haloalkyl, a heteroalkyl, alkoxy, haloalkoxy, —NR10R11, —OR7, —C(O)R7, —C(O)OR7, —C(S)R7, —C(O)SR7, —C(S)SR7, —C(S)OR7, —C(S)NR10R11, —C(NR8)OR7, —C(NR8)R7, —C(NR8)NR10R11, —C(NR8)SR7, —OC(O)R7, —OC(O)OR7, —OC(S)OR7, —OC(NR8)OR7, —SC(O)R7, —SC(O)OR7, —SC(NR8)OR7, —OC(S)R7, —SC(S)R7, —SC(S)OR7, —OC(O)NR10R11, —OC(S)NR10R11, —OC(NR8)NR10R11, —SC(O)NR10R11, —SC(NR8)NR10R11, —SC(S)NR10R11, —OC(NR8)R7, —SC(NR8)R7, —C(O)NR10R11, —NR8C(O)R7, —NR7C(S)R7, —NR7C(S)OR7, —NR7C(NR8)R7, —NR7C(O)OR7, —NR7C(NR8)OR7, —NR7C(O)NR10R11, —NR7C(S)NR10R11, —NR7C(NR8)NR10R11, —SR7, —S(O)pR7, —OS(O)pR7, —OS(O)pOR7, —OS(O)pNR10R11, —S(O)pOR7, —NR8S(O)pR7, —NR7S(O)pNR10R11, —NR7S(O)pOR7, —S(O)pNR10R11, —SS(O)pR7, —SS(O)pOR7, —SS(O)pNR10R11, —OP(O)(OR7)2, or —SP(O)(OR7)2. Preferably, R70 for each occurrence, is independently an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, cyano, halo, nitro, an optionally substituted cycloalkyl, haloalkyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, an optionally substituted heteroaralkyl, —OR7, —SR7, —NR10R11, —OC(O)NR10R11, —SC(O)NR10R11, —NR7C(O)NR10R11, —OC(O)R7, —SC(O)R7, —NR7C(O)R7, —OC(O)OR7, —SC(O)OR7, —NR7C(O)OR7, —OCH2C(O)R7, —SCH2C(O)R7, —NR7CH2C(O)R7, —OCH2C(O)OR7, —SCH2C(O)OR7, —NR7CH2C(O)OR7, —OCH2C(O)NR10R11, —SCH2C(O)NR10R11, —NR7CH2C(O)NR10R11, —OS(O)pR7, —SS(O)pR7, —NR7S(O)pR7, —OS(O)pNR10R11, —SS(O)pNR10R11, —NR7S(O)pNR10R11, —OS(O)pOR7, —SS(O)pOR7, —NR7S(O)pOR7, —OC(S)R7, —SC(S)R7, —NR7C(S)R7, —OC(S)OR7, —SC(S)OR7, —NR7C(S)OR7, —OC(S)NR10R11, —SC(S)NR10R11, —NR7C(S)NR10R11, —OC(NR8)R7, —SC(NR8)R7, —NR7C(NR8)R7, —OC(NR8)OR7, —SC(NR8)OR7, —NR7C(NR8)OR7, —OC(NR8)NR10R11, —SC(NR8)NR10R11, —NR7C(NR8)NR10R11, —C(O)R7, —C(O)OR7, —C(O)NR10R11, —C(O)SR7, —C(S)R7, —C(S)OR7, —C(S)NR10R11, —C(S)SR7, —C(NR8)OR7, —C(NR8)R7, —C(NR8)NR10R11, —C(NR8)SR7, —S(O)pOR7, —S(O)pNR10R11, or —S(O)pR7. More preferably, R70 for each occurrence, is independently a C1-C6 alkyl, a C1-C6 haloalkyl, a C1-C6 alkoxy, a C1-C6 haloalkoxy, a C1-C6 alkyl sulfanyl or a C3-C6 cycloalkyl. Even more preferably, R70 for each occurrence, is independently cyclopropyl or isopropyl;
R7 and R8, for each occurrence, is independently, —H, an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, or an optionally substituted heteroaralkyl. Preferably, R7 and R8, for each occurrence, is independently —H, C1-C3 alkyl, C1-C6 cycloalkyl, an optionally substituted aryl or an optionally substituted heteroaryl. More preferably, R7 and R8, for each occurrence, is independently —H or C1-C3 alkyl.
R10 and R11, for each occurrence, is independently —H, an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, or an optionally substituted heteroaralkyl. Preferably, R10 and R11, for each occurrence, is independently —H, C1-C3 alkyl, C1-C6 cycloalkyl, an optionally substituted aryl or an optionally substituted heteroaryl. More preferably, R10 and R11, for each occurrence, is independently —H or C1-C3 alkyl.
Alternatively, R10 and R11, taken together with the nitrogen to which they are attached, form an optionally substituted heterocyclyl or an optionally substituted heteroaryl. Preferably R10 and R11, taken together with the nitrogen to which they are attached, form an optionally substituted imidazolyl, pyrrolyl, pyrazolyl, triazolyl, tetrazolyl, pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl, oxazolyl, iosoxazolyl, oxadiazolyl, thiazolyl, isothiazolyl, thiadiazolyl, pyrrolidinyl, piperidinyl, morpholinyl, pyrazinyl, thiomorpholinyl, pyrrolidinyl, piperidinyl, pyranzinyl, thiomorpholinyl, tetrahydroquinolinyl or tetrahydroisoquinolinyl. More preferably R10 and R11, taken together with the nitrogen to which they are attached, form an optionally substituted pyrrolidinyl, piperidinyl, piperazinyl, tetrahydroisoquinolinyl, morpholinyl or pyrazolyl.
R71 for each occurrence, is independently an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, an optionally substituted heteraralkyl, halo, cyano, nitro, guanadino, a haloalkyl, a heteroalkyl, alkoxy, haloalkoxy, —NR10R11, —OR7, —C(O)R7, —C(O)OR7, —C(S)R7, —C(O)SR7, —C(S)SR7, —C(S)OR7, —C(S)NR10R11, —C(NR8)OR7, —C(NR8)R7, —C(NR8)NR10R11, —C(NR8)SR7, —OC(O)R7, —OC(O)OR7, —OC(S)OR7, —OC(NR8)OR7, —SC(O)R7, —SC(O)OR7, —SC(NR8)OR7, —OC(S)R7, —SC(S)R7, —SC(S)OR7, —OC(O)NR10R11, —OC(S)NR10R11, —OC(NR8)NR10R11, —SC(O)NR10R11, —SC(NR8)NR10R11, —SC(S)NR10R11, —OC(NR8)R7, —SC(NR8)R7, —C(O)NR10R11, —NR8C(O)R7, —NR7C(S)R7, —NR7C(S)OR7, —NR7C(NR8)R7, —NR7C(O)OR7, —NR7C(NR8)OR7, —NR7C(O)NR10R11, —NR7C(S)NR10R11, —NR7C(NR8)NR10R11, —SR7, —S(O)pR7, —OS(O)pR7, —OS(O)pOR7, —OS(O)pNR10R11, —S(O)pOR7, —NR8S(O)pR7, —NR7S(O)pNR10R11, —NR7S(O)pOR7, —S(O)pNR10R11, —SS(O)pR7, —SS(O)pOR7, —SS(O)pNR10R11, —OP(O)(OR7)2, or —SP(O)(OR7)2. Preferably R71 for each occurrence, is independently —OH, —SH, —NHR7, —(CH2)kOH, —(CH2)kSH, —(CH2)kNR7H, —OCH3, —SCH3, —NHCH3, —OCH2CH2OH, —OCH2CH2SH, —OCH2CH2NR7H, —SCH2CH2OH, —SCH2CH2SH, —SCH2CH2NR7H, —OC(O)NR10R11, —SC(O)NR10R11, —NR7C(O)NR10R11, —OC(O)R7, —SC(O)R7, —NR7C(O)R7, —OC(O)OR7, —SC(O)OR7, —NR7C(O)OR7, —OCH2C(O)R7, —SCH2C(O)R7, —NR7CH2C(O)R7, —OCH2C(O)OR7, —SCH2C(O)OR7, —NR7CH2C(O)OR7, —OCH2C(O)NR10R11, —SCH2C(O)NR10R11, —NR7CH2C(O)NR10R11, —OS(O)pR7, —SS(O)pR7, —NR7S(O)pR7, —OS(O)pNR10R11, —SS(O)pNR10R11, —NR7S(O)pNR10R11, —OS(O)pOR7, —SS(O)pOR7, —NR7S(O)pOR7, —OC(S)R7, —SC(S)R7, —NR7C(S)R7, —OC(S)OR7, —SC(S)OR7, —NR7C(S)OR7, —OC(S)NR10R11, —SC(S)NR10R11, —NR7C(S)NR10R11, —OC(NR8)R7, —SC(NR8)R7, —NR7C(NR8)R7, —OC(NR8)OR7, —SC(NR8)OR7, —NR7C(NR8)OR7, —OC(NR8)NR10R11, —SC(NR8)NR10R11, —NR7C(NR8)NR10R11, —C(O)R7, —C(O)OR7, —C(O)NR10R11, —C(O)SR7, —C(S)R7, —C(S)OR7, —C(S)NR10R11, —C(S)SR7, —C(NR8)OR7, —C(NR8)R7, —C(NR8)NR10R11, —C(NR8)SR7, —S(O)pOR7, —S(O)pNR10R11, or —S(O)pR7. More preferably, R71 for each occurrence, is independently —OH, —SH, —NHR7, —OC(O)NR10R11, —SC(O)NR10R11, —OC(O)R7, —SC(O)R7, —OC(O)OR7, —SC(O)OR7, —OS(O)pR7, —S(O)pOR7, —SS(O)pR7, —OS(O)pOR7, —SS(O)pOR7, —OC(S)R7, —SC(S)R7, —OC(S)OR7, —SC(S)OR7, —OC(S)NR10R11, —SC(S)NR10R11, —OC(NR8)R7, —SC(NR8)R7, —OC(NR8)OR7, —SC(NR8)OR7, —OP(O)(OR7)2 or —SP(O)(OR7)2. Even more preferably, R71 for each occurrence, is independently —SH or —OH;
R26 is a C1-C6 alkyl;
R30 for each occurrence, is independently an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, an optionally substituted heteraralkyl, halo, cyano, nitro, guanadino, a haloalkyl, a heteroalkyl, alkoxy, haloalkoxy, —NR10R11, —OR7, —C(O)R7, —C(O)OR7, —C(S)R7, —C(O)SR7, —C(S)SR7, —C(S)OR7, —C(S)NR10R11, —C(NR8)OR7, —C(NR8)R7, —C(NR8)NR10R11, —C(NR8)SR7, —OC(O)R7, —OC(O)OR7, —OC(S)OR7, —OC(NR8)OR7, —SC(O)R7, —SC(O)OR7, —SC(NR8)OR7, —OC(S)R7, —SC(S)R7, —SC(S)OR7, —OC(O)NR10R11, —OC(S)NR10R11, —OC(NR8)NR10R11, —SC(O)NR10R11, —SC(NR8)NR10R11, —SC(S)NR10R11, —OC(NR8)R7, —SC(NR8)R7, —C(O)NR10R11, —NR8C(O)R7, —NR7C(S)R7, —NR7C(S)OR7, —NR7C(NR8)R7, —NR7C(O)OR7, —NR7C(NR8)OR7, —NR7C(O)NR10R11, —NR7C(S)NR10R11, —NR7C(NR8)NR10R11, —SR7, —S(O)pR7, —OS(O)pR7, —OS(O)pOR7, —OS(O)pNR10R11, —S(O)pOR7, —NR8S(O)pR7, —NR7S(O)pNR10R11, —NR7S(O)pOR7, —S(O)pNR10R11, —SS(O)pR7, —SS(O)pOR7, —SS(O)pNR10R11, —OP(O)(OR7)2, or —SP(O)(OR7)2. Preferably R30 for each occurrence, is independently an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, cyano, halo, nitro, an optionally substituted cycloalkyl, haloalkyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, an optionally substituted heteroaralkyl, —OR7, —SR7, —NR10R11, —OC(O)NR10R11, —SC(O)NR10R11, —NR7C(O)NR10R11, —OC(O)R7, —SC(O)R7, —NR7C(O)R7, —OC(O)OR7, —SC(O)OR7, —NR7C(O)OR7, —OCH2C(O)R7, —SCH2C(O)R7, —NR7CH2C(O)R7, —OCH2C(O)OR7, —SCH2C(O)OR7, —NR7CH2C(O)OR7, —OCH2C(O)NR10R11, —SCH2C(O)NR10R11, —NR7CH2C(O)NR10R11, —OS(O)pR7, —SS(O)pR7, —NR7S(O)pR7, —OS(O)pNR10R11, —SS(O)pNR10R11, —NR7S(O)pNR10R11, —OS(O)pOR7, —SS(O)pOR7, —NR7S(O)pOR7, —OC(S)R7, —SC(S)R7, —NR7C(S)R7, —OC(S)OR7, —SC(S)OR7, —NR7C(S)OR7, —OC(S)NR10R11, —SC(S)NR10R11, —NR7C(S)NR10R11, —OC(NR8)R7, —SC(NR8)R7, —NR7C(NR8)R7, —OC(NR8)OR7, —SC(NR8)OR7, —NR7C(NR8)OR7, —OC(NR8)NR10R11, —SC(NR8)NR10R11, —NR7C(NR8)NR10R11, —C(O)R7, —C(O)OR7, —C(O)NR10R11, —C(O)SR7, —C(S)R7, —C(S)OR7, —C(S)NR10R11, —C(S)SR7, —C(NR8)OR7, —C(NR8)R7, —C(NR8)NR10R11, —C(NR8)SR7, —S(O)pOR7, —S(O)pNR10R11, or —S(O)pR7. More preferably, R30 for each occurrence, is independently a hydrogen, —OH, —SH, halogen, cyano, a C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy or C1-C6 alkyl sulfanyl. Even more preferably, R30 for each occurrence, is independently a hydrogen, methyl, ethyl, propyl, isopropyl, methoxy or ethoxy;
R35 is —H, a C1-C4 alkyl or a C1-C4 acyl;
Ra and Rb, for each occurrence, is independently —H, an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aryl or heteroaryl, an optionally substituted aralkyl. Preferably, Ra and Rb for each occurrence, is independently a hydrogen, a C1-C6 straight or branched alkyl, optionally substituted by —OH, —CN, —SH, amino, a C1-C6 alkoxy, alkylsulfanyl, alkylamino, dialkylamino or a cycloalkyl. More preferably, Ra and Rb for each occurrence, is independently a hydrogen, methyl, ethyl, propyl, isopropyl;
Alternatively, Ra and Rb, taken together with the nitrogen to which they are attached, form an optionally substituted heteroaryl or heterocyclyl. Preferably, Ra and Rb taken together with the nitrogen to which they are attached form a substituted or unsubstituted nonaromatic, nitrogen-containing heterocyclyl. More preferably, Ra and Rb taken together with the nitrogen to which they are attached, are:




k is 1, 2, 3 or 4;
p, for each occurrence, is independently, 0, 1 or 2;
m, for each occurrence, is independently, 1, 2, 3 or 4;
z and y for each occurrence, is independently an integer from 0 to 4. Preferably z and y for each occurrence, is independently 0, 1, or 2. More preferably z and y for each occurrence, is independently 0 or 1; and
x is 0 or 1, provided that z+x is less than or equal to 4.
In a first preferred embodiment, the values for the variables in formula (IV) are as described in the following paragraphs;
R70, R71 and R30, for each occurrence, is independently an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, an optionally substituted heteraralkyl, halo, cyano, nitro, guanadino, a haloalkyl, a heteroalkyl, alkoxy, haloalkoxy, —NR10R11, —OR7, —C(O)R7, —C(O)OR7, —C(S)R7, —C(O)SR7, —C(S)SR7, —C(S)OR7, —C(S)NR10R11, —C(NR8)OR7, —C(NR8)R7, —C(NR8)NR10R11, —C(NR8)SR7, —OC(O)R7, —OC(O)OR7, —OC(S)OR7, —OC(NR8)OR7, —SC(O)R7, —SC(O)OR7, —SC(NR8)OR7, —OC(S)R7, —SC(S)R7, —SC(S)OR7, —OC(O)NR10R11, —OC(S)NR10R11, —OC(NR8)NR10R11, —SC(O)NR10R11, —SC(NR8)NR10R11, —SC(S)NR10R11, —OC(NR8)R7, —SC(NR8)R7, —C(O)NR10R11, —NR8C(O)R7, —NR7C(S)R7, —NR7C(S)OR7, —NR7C(NR8)R7, —NR7C(O)OR7, —NR7C(NR8)OR7, —NR7C(O)NR10R11, —NR7C(S)NR10R11, —NR7C(NR8)NR10R11, —SR7, —S(O)pR7, —OS(O)pR7, —OS(O)pOR7, —OS(O)pNR10R11, —S(O)pOR7, —NR8S(O)pR7, —NR7S(O)pNR10R11, —NR7S(O)pOR7, —S(O)pNR10R11, —SS(O)pR7, —SS(O)pOR7, —SS(O)pNR10R11, —OP(O)(OR7)2, or —SP(O)(OR7)2. Preferably, R70 and R30 are as just described and R71 is —OH, —SH, —NHR7, —(CH2)kOH, —(CH2)kSH, —(CH2)kNR7H, —OCH3, —SCH3, —NHCH3, —OCH2CH2OH, —OCH2CH2SH, —OCH2CH2NR7H, —SCH2CH2OH, —SCH2CH2SH, —SCH2CH2NR7H, —OC(O)NR10R11, —SC(O)NR10R11, —NR7C(O)NR10R11, —OC(O)R7, —SC(O)R7, —NR7C(O)R7, —OC(O)OR7, —SC(O)OR7, —NR7C(O)OR7, —OCH2C(O)R7, —SCH2C(O)R7, —NR7CH2C(O)R7, —OCH2C(O)OR7, —SCH2C(O)OR7, —NR7CH2C(O)OR7, —OCH2C(O)NR10R11, —SCH2C(O)NR10R11, —NR7CH2C(O)NR10R11, —OS(O)pR7, —SS(O)pR7, —NR7S(O)pR7, —OS(O)pNR10R11, —SS(O)pNR10R11, —NR7S(O)pNR10R11, —OS(O)pOR7, —SS(O)pOR7, —NR7S(O)pOR7, —OC(S)R7, —SC(S)R7, —NR7C(S)R7, —OC(S)OR7, —SC(S)OR7, —NR7C(S)OR7, —OC(S)NR10R11, —SC(S)NR10R11, —NR7C(S)NR10R11, —OC(NR8)R7, —SC(NR8)R7, —NR7C(NR8)R7, —OC(NR8)OR7, —SC(NR8)OR7, —NR7C(NR8)OR7, —OC(NR8)NR10R11, —SC(NR8)NR10R11, —NR7C(NR8)NR10R11, —C(O)R7, —C(O)OR7, —C(O)NR10R11, —C(O)SR7, —C(S)R7, —C(S)OR7, —C(S)NR10R11, —C(S)SR7, —C(NR8)OR7, —C(NR8)R7, —C(NR8)NR10R11, —C(NR8)SR7, —S(O)pOR7, —S(O)pNR10R11, or —S(O)pR7;
k is 1, 2, 3, or 4;
z and y for each occurrence, is independently an integer from 0 to 4;
x is 0 or 1, provided that n+x less than or equal to 4; and
the values and preferred values for the remainder of the variables in formula (IV) are as described immediately above.
In a second preferred embodiment, the present invention provides compounds represented by structural formula (XXXVI):




The values and preferred values for the variables in formula (XXXVI) are as described above for formula (XXXV). Alternatively, the values and preferred values for the variables in formula (XXXVI) are as described in the first preferred embodiment for formula (XXXV) immediately above.

In a third preferred embodiment, the present invention provides compounds represented by structural formula (XXXVII):




or a tautomer, pharmaceutically acceptable salt, solvate, clathrate or a prodrug thereof.
The values and preferred values for the variables in formula (XXXVII) are as described above for formula (XXXV). Preferably, the values and preferred values for the variables in formula (XXXVII) are as described for formula (XXXVI). More preferably, the values for the variables in formula (XXXVII) are described in the following paragraphs:
R30 is an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, cyano, halo, nitro, an optionally substituted cycloalkyl, haloalkyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, an optionally substituted heteroaralkyl, —OR7, —SR7, —NR10R11, —OC(O)NR10R11, —SC(O)NR10R11, —NR7C(O)NR10R11, —OC(O)R7, —SC(O)R7, —NR7C(O)R7, —OC(O)OR7, —SC(O)OR7, —NR7C(O)OR7, —OCH2C(O)R7, —SCH2C(O)R7, —NR7CH2C(O)R7, —OCH2C(O)OR7, —SCH2C(O)OR7, —NR7CH2C(O)OR7, —OCH2C(O)NR10R11, —SCH2C(O)NR10R11, —NR7CH2C(O)NR10R11, —OS(O)pR7, —SS(O)pR7, —NR7S(O)pR7, —OS(O)pNR10R11, —SS(O)pNR10R11, —NR7S(O)pNR10R11, —OS(O)pOR7, —SS(O)pOR7, —NR7S(O)pOR7, —OC(S)R7, —SC(S)R7, —NR7C(S)R7, —OC(S)OR7, —SC(S)OR7, —NR7C(S)OR7, —OC(S)NR10R11, —SC(S)NR10R11, —NR7C(S)NR10R11, —OC(NR8)R7, —SC(NR8)R7, —NR7C(NR8)R7, —OC(NR8)OR7, —SC(NR8)OR7, —NR7C(NR8)OR7, —OC(NR8)NR10R11, —SC(NR8)NR10R11, —NR7C(NR8)NR10R11, —C(O)R7, —C(O)OR7, —C(O)NR10R11, —C(O)SR7, —C(S)R7, —C(S)OR7, —C(S)NR10R11, —C(S)SR7, —C(NR8)OR7, —C(NR8)R7, —C(NR8)NR10R11, —C(NR8)SR7, —S(O)pOR7, —S(O)pNR10R11, or —S(O)pR7; and the values and preferred values for the remainder of the variables are as described above for formula (XXXV). Preferably, the values and preferred values for the remainder of the variables in formula (XXXVII) are as described for formula (XXXVI).
More preferably for formula (XXXVII), R70 is an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, cyano, halo, nitro, an optionally substituted cycloalkyl, haloalkyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, an optionally substituted heteroaralkyl, —OR7, —SR7, —NR10R11, —OC(O)NR10R11, —SC(O)NR10R11, —NR7C(O)NR10R11, —OC(O)R7, —SC(O)R7, —NR7C(O)R7, —OC(O)OR7, —SC(O)OR7, —NR7C(O)OR7, —OCH2C(O)R7, —SCH2C(O)R7, —NR7CH2C(O)R7, —OCH2C(O)OR7, —SCH2C(O)OR7, —NR7CH2C(O)OR7, —OCH2C(O)NR10R11, —SCH2C(O)NR10R11, —NR7CH2C(O)NR10R11, —OS(O)pR7, —SS(O)pR7, —NR7S(O)pR7, —OS(O)pNR10R11, —SS(O)pNR10R11, —NR7S(O)pNR10R11, —OS(O)pOR7, —SS(O)pOR7, —NR7S(O)pOR7, —OC(S)R7, —SC(S)R7, —NR7C(S)R7, —OC(S)OR7, —SC(S)OR7, —NR7C(S)OR7, —OC(S)NR10R11, —SC(S)NR10R11, —NR7C(S)NR10R11, —OC(NR8)R7, —SC(NR8)R7, —NR7C(NR8)R7, —OC(NR8)OR7, —SC(NR8)OR7, —NR7C(NR8)OR7, —OC(NR8)NR10R11, —SC(NR8)NR10R11, —NR7C(NR8)NR10R11, —C(O)R7, —C(O)OR7, —C(O)NR10R11, —C(O)SR7, —C(S)R7, —C(S)OR7, —C(S)NR10R11, —C(S)SR7, —C(NR8)OR7, —C(NR8)R7, —C(NR8)NR10R11, —C(NR8)SR7, —S(O)pOR7, —S(O)pNR10R11, or —S(O)pR7; the values for R30 are as described in the preceding paragraph; and the values and preferred values for the remainder of the variables are as described above for formula (XXXV). Preferably, the values and preferred values for the variables in formula (XXXVII) are as described for formula (XXXVI).
In a fourth preferred embodiment, the present invention provides compounds represented by a structural formula selected from formulas (XXXVIII) and (XXXIX)




or a tautomer, pharmaceutically acceptable salt, solvate, clathrate or a prodrug thereof.
The values and preferred values for formulas (XXXVIII) and (XXXIX) are as described above for formula (XXXV). Preferably, the values and preferred values for formulas (XXXVIII) and (XXXIX) are as described above for formula (XXXVII). More preferably, the values for the variables in formulas (XXXVIII) and (XXXIX) are described in the following paragraphs:
R1, R3 or R71 are each independently —OH, —SH, —NHR7, —OC(O)NR10R11, —SC(O)NR10R11, —OC(O)R7, —SC(O)R7, —OC(O)OR7, —SC(O)OR7, —OS(O)pR7, —S(O)pOR7, —SS(O)pR7, —OS(O)pOR7, —SS(O)pOR7, —OC(S)R7, —SC(S)R7, —OC(S)OR7, —SC(S)OR7, —OC(S)NR10R11, —SC(S)NR10R11, —OC(NR8)R7, —SC(NR8)R7, —OC(NR8)OR7, —SC(NR8)OR7, —OP(O)(OR7)2 or —SP(O)(OR7)2. Preferably, R1 and R3 are each, independently, —OH, —SH, or —NHR7 and R71 is as just described; and
the values and preferred values for the remainder of the variables are as described above for formula (XXXV) or formula (XXXVII).
In a first more preferred embodiment for formulas (XXXVIII) and (XXXIX), R1, R3 and R71 are as described in the immediately preceeding two paragraphs: and
Ra and Rb are each independently a hydrogen, a C1-C6 straight or branched alkyl, optionally substituted by —OH, —CN, —SH, amino, a C1-C6 alkoxy, alkylsulfanyl, alkylamino, dialkylamino or a cycloalkyl; or Ra and Rb taken together with the nitrogen to which they are attached form a substituted or unsubstituted nonaromatic, nitrogen-containing heterocyclyl; and
the values and preferred values for the remainder of the variables are as described above for formula (XXXV) formula (XXXVII).
In a second more preferred embodiment for formulas (XXXVIII) and (XXXIX), R70 is a C1-C6 alkyl, a C1-C6 haloalkyl, a C1-C6 alkoxy, a C1-C6 haloalkoxy, a C1-C6 alkyl sulfanyl or a C3-C6 cycloalkyl; and the values and preferred values for the remainder of the variables are as described above for first more preferred embodiment for formulas (XXXVIII) and (XXXIX).
In a third more preferred embodiment for formulas (XXXVIII) and (XXXIX):
R1 and R3 are each, independently, —OH, —SH, or —NHR7;
R70 is a C1-C6 alkyl, a C1-C6 haloalkyl, a C1-C6 alkoxy, a C1-C6 haloalkoxy, a C1-C6 alkyl sulfanyl or a C3-C6 cycloalkyl;
R71 is —OH, —SH, —NHR7, —OC(O)NR10R11, —SC(O)NR10R11, —OC(O)R7, —SC(O)R7, —OC(O)OR7, —SC(O)OR7, —OS(O)pR7, —S(O)pOR7, —SS(O)pR7, —OS(O)pOR7, —SS(O)pOR7, —OC(S)R7, —SC(S)R7, —OC(S)OR7, —SC(S)OR7, —OC(S)NR10R11, —SC(S)NR10R11, —OC(NR8)R7, —SC(NR8)R7, —OC(NR8)OR7, —SC(NR8)OR7, —OP(O)(OR7)2 or —SP(O)(OR7)2;
R30 is —OH, —SH, halogen, cyano, a C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy or C1-C6 alkyl sulfanyl. Preferably, R30 is methyl, ethyl, propyl, isopropyl, methoxy or ethoxy;
Ra and Rb are each independently a hydrogen, a C1-C6 straight or branched alkyl, optionally substituted by —OH, —CN, —SH, amino, a C1-C6 alkoxy, alkylsulfanyl, alkylamino, dialkylamino or a cycloalkyl; or Ra and Rb taken together with the nitrogen to which they are attached form a substituted or unsubstituted nonaromatic, nitrogen-containing heterocyclyl; and
the values and preferred values for the remainder of the variables are as described above for formula (XXXVII).
In a fourth more preferred embodiment for formulas (XXXVIII) and (XXXIX):
R1, R3 and R71 for each occurrence, is independently —SH or —OH;
R70 is cyclopropyl or isopropyl; and
the remainder of the variables are as described for the third more preferred embodiment for formulas (XXXVIII) and (XXXIX). More preferably R30 is methyl, ethyl, propyl, isopropyl, methoxy or ethoxy. Even more preferably, R30 is methyl, ethyl, propyl, isopropyl, methoxy or ethoxy and Ra and Rb are each independently a hydrogen, methyl, ethyl, propyl, isopropyl, or taken together with the nitrogen to which they are attached, are:




wherein R35 is —H, a C1-C4 alkyl or a C1-C4 acyl; and

the values and preferred values for the remainder of the variables are as described above for formula (XXXVII).
In another preferred embodiment, the present invention is a compound represented by formula (XXXV), (XXXVI), (XXXVII), (XXXVIII) or (XXXIX), wherein R1, R3 and R71 are —SH or —OH and R6 is cyclopropyl or isopropyl and the remainder of the variables are as described for Formula (XXXV), (XXXVI), (XXXVII), (XXXVIII) or (XXXIX), respectively.
In another embodiment, the present invention provides compounds represented by a structural formula selected from formulas (XL) and (XLI):




or a tautomer, pharmaceutically acceptable salt, solvate, clathrate or a prodrug thereof.
In formulas (XL) and (XLI), ring B is further optionally substituted with one or more substituents in addition to —NRaRb. Preferably ring B is substituted with (R30)y where y is 0, 1, 2, 3 or 4, preferably y is 0 or 1;
R1 is —OH, —SH, —NR7H, —OR26, —SR26, —NHR26, —O(CH2)mOH, —O(CH2)mSH, —O(CH2)mNR7H, —S(CH2)mOH, —S(CH2)mSH, —S(CH2)mNR7H, —OC(O)NR10R11, —SC(O)NR10R11, —NR7C(O)NR10R11, —OC(O)R7, —SC(O)R7, —NR7C(O)R7, —OC(O)OR7, —SC(O)OR7, —NR7C(O)OR7, —OCH2C(O)R7, —SCH2C(O)R7, —NR7CH2C(O)R7, —OCH2C(O)OR7, —SCH2C(O)OR7, —NR7CH2C(O)OR7, —OCH2C(O)NR10R11, —SCH2C(O)NR10R11, —NR7CH2C(O)NR10R11, —OS(O)pR7, —SS(O)pR7, —S(O)pOR7, —NR7S(O)pR7, —OS(O)pNR10R11, —SS(O)pNR10R11, —NR7S(O)pNR10R11, —OS(O)pOR7, —SS(O)pOR7, —NR7S(O)pOR7, —OC(S)R7, —SC(S)R7, —NR7C(S)R7, —OC(S)OR7, —SC(S)OR7, —NR7C(S)OR7, —OC(S)NR10R11, —SC(S)NR10R11, —NR7C(S)NR10R11, —OC(NR8)R7, —SC(NR8)R7, —NR7C(NR8)R7, —OC(NR8)OR7, —SC(NR8)OR7, —NR7C(NR8)OR7, —OC(NR8)NR10R11, —SC(NR8)NR10R11, or —NR7C(NR8)NR10R11, —OP(O)(OR7)2 or —SP(O)(OR7)2. Preferably, R1 is —OH, —SH, —HNR7, —OC(O)NR10R11, —SC(O)NR10R11, —OC(O)R7, —SC(O)R7, —OC(O)OR7, —SC(O)OR7, —OS(O)pR7, —S(O)pOR7, —SS(O)pR7, —OS(O)pOR7, —SS(O)pOR7, —OC(S)R7, —SC(S)R7, —OC(S)OR7, —SC(S)OR7, —OC(S)NR10R11, —SC(S)NR10R11, —OC(NR8)R7, —SC(NR8)R7, —OC(NR8)OR7, —SC(NR8)OR7, —OP(O)(OR7)2 or —SP(O)(OR7)2. More preferably, R1 is —OH, —SH, or —NHR7. Even more preferably, R1 is —SH or —OH;
R3 is —OH, —SH, —NR7H, —OR26, —SR26, —NHR26, —O(CH2)mOH, —O(CH2)mSH, —O(CH2)mNR7H, —S(CH2)mOH, —S(CH2)mSH, —S(CH2)mNR7H, —OC(O)NR10R11, —SC(O)NR10R11, —NR7C(O)NR10R11, —OC(O)R7, —SC(O)R7, —NR7C(O)R7, —OC(O)OR7, —SC(O)OR7, —NR7C(O)OR7, —OCH2C(O)R7, —SCH2C(O)R7, —NR7CH2C(O)R7, —OCH2C(O)OR7, —SCH2C(O)OR7, —NR7CH2C(O)OR7, —OCH2C(O)NR10R11, —SCH2C(O)NR10R11, —NR7CH2C(O)NR10R11, —OS(O)pR7, —SS(O)pR7, —S(O)pOR7, —NR7S(O)pR7, —OS(O)pNR10R11, —SS(O)pNR10R11, —NR7S(O)pNR10R11, —OS(O)pOR7, —SS(O)pOR7, —NR7S(O)pOR7, —OC(S)R7, —SC(S)R7, —NR7C(S)R7, —OC(S)OR7, —SC(S)OR7, —NR7C(S)OR7, —OC(S)NR10R11, —SC(S)NR10R11, —NR7C(S)NR10R11, —OC(NR8)R7, —SC(NR8)R7, —NR7C(NR8)R7, —OC(NR8)OR7, —SC(NR8)OR7, —NR7C(NR8)OR7, —OC(NR8)NR10R11, —SC(NR8)NR10R11, —NR7C(NR8)NR10R11, —C(O)OH, —C(O)NHR8, —C(O)SH, —S(O)OH, —S(O)2OH, —S(O)NHR8, —S(O)2NHR8, —OP(O)(OR7)2, or —SP(O)(OR7)2. Preferably, R3 is —OH, —SH, —HNR7, —OC(O)NR10R11, —SC(O)NR10R11, —OC(O)R7, —SC(O)R7, —OC(O)OR7, —SC(O)OR7, —OS(O)pR7, —S(O)pOR7, —SS(O)pR7, —OS(O)pOR7, —SS(O)pOR7, —OC(S)R7, —SC(S)R7, —OC(S)OR7, —SC(S)OR7, —OC(S)NR10R11, —SC(S)NR10R11, —OC(NR8)R7, —SC(NR8)R7, —OC(NR8)OR7, —SC(NR8)OR7, —OP(O)(OR7)2 or —SP(O)(OR7)2. More preferably, R3 is —OH, —SH, or —NHR7. Even more preferably, R3 is —SH or —OH;
R70, for each occurrence, is independently an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, an optionally substituted heteraralkyl, halo, cyano, nitro, guanadino, a haloalkyl, a heteroalkyl, alkoxy, haloalkoxy, —NR10R11, —OR7, —C(O)R7, —C(O)OR7, —C(S)R7, —C(O)SR7, —C(S)SR7, —C(S)OR7, —C(S)NR10R11, —C(NR8)OR7, —C(NR8)R7, —C(NR8)NR10R11, —C(NR8)SR7, —OC(O)R7, —OC(O)OR7, —OC(S)OR7, —OC(NR8)OR7, —SC(O)R7, —SC(O)OR7, —SC(NR8)OR7, —OC(S)R7, —SC(S)R7, —SC(S)OR7, —OC(O)NR10R11, —OC(S)NR10R11, —OC(NR8)NR10R11, —SC(O)NR10R11, —SC(NR8)NR10R11, —SC(S)NR10R11, —OC(NR8)R7, —SC(NR8)R7, —C(O)NR10R11, —NR8C(O)R7, —NR7C(S)R7, —NR7C(S)OR7, —NR7C(NR8)R7, —NR7C(O)OR7, —NR7C(NR8)OR7, —NR7C(O)NR10R11, —NR7C(S)NR10R11, —NR7C(NR8)NR10R11, —SR7, —S(O)pR7, —OS(O)pR7, —OS(O)pOR7, —OS(O)pNR10R11, —S(O)pOR7, —NR8S(O)pR7, —NR7S(O)pNR10R11, —NR7S(O)pOR7, —S(O)pNR10R11, —SS(O)pR7, —SS(O)pOR7 or —SS(O)pNR10R11. Preferably, R70 is for each occurrence, is independently an optionally substituted C1-C6 alkyl, an optionally substituted C3-C6 cycloalkyl, an optionally substituted C3-C6 cycloalkenyl, an optionally substituted heterocyclyl, a halo, a haloalkyl, a haloalkoxy, a heteroalkyl, an alkoxy, an alkylsulfanyl, —OH, —SH, —NHR7, —(CH2)kOH, —(CH2)kSH, —(CH2)kNR7H, —OCH3, —SCH3, —NHCH3, —OCH2CH2OH, —OCH2CH2SH, —OCH2CH2NR7H, —SCH2CH2OH, —SCH2CH2SH, —SCH2CH2NR7H, —OC(O)NR10R11, —SC(O)NR10R11, —NR7C(O)NR10R11, —OC(O)R7, —SC(O)R7, —NR7C(O)R7, —OC(O)OR7, —SC(O)OR7, —NR7C(O)OR7, —OCH2C(O)R7, —SCH2C(O)R7, —NR7CH2C(O)R7, —OCH2C(O)OR7, —SCH2C(O)OR7, —NR7CH2C(O)OR7, —OCH2C(O)NR10R11, —SCH2C(O)NR10R11, —NR7CH2C(O)NR10R11, —OS(O)pR7, —SS(O)pR7, —NR7S(O)pR7, —OS(O)pNR10R11, —SS(O)pNR10R11, —NR7S(O)pNR10R11, —OS(O)pOR7, —SS(O)pOR7, —NR7S(O)pOR7, —OC(S)R7, —SC(S)R7, —NR7C(S)R7, —OC(S)OR7, —SC(S)OR7, —NR7C(S)OR7, —OC(S)NR10R11, —SC(S)NR10R11, —NR7C(S)NR10R11, —OC(NR8)R7, —SC(NR8)R7, —NR7C(NR8)R7, —OC(NR8)OR7, —SC(NR8)OR7, —NR7C(NR8)OR7, —OC(NR8)NR10R11, —SC(NR8)NR10R11, —NR7C(NR8)NR10R11, —C(O)R7, —C(O)OR7, —C(O)NR10R11, —C(O)SR7, —C(S)R7, —C(S)OR7, —C(S)NR10R11, —C(S)SR7, —C(NR8)OR7, —C(NR8)R7, —C(NR8)NR10R11, —C(NR8)SR7, —S(O)pOR7, —S(O)pNR10R11, —S(O)pR7, —OP(O)(OR7)2 or —SP(O)(OR7)2. More preferably, R70, for each occurrence, is independently an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, —OH, —SH, —HNR7, —OC(O)NR10R11, —SC(O)NR10R11, —OC(O)R7, —SC(O)R7, —OC(O)OR7, —SC(O)OR7, —OS(O)pR7, —S(O)pOR7, —SS(O)pR7, —OS(O)pOR7, —SS(O)pOR7, —OC(S)R7, —SC(S)R7, —OC(S)OR7, —SC(S)OR7, —OC(S)NR10R11, —SC(S)NR10R11, —OC(NR8)R7, —SC(NR8)R7, —OC(NR8)OR7, —SC(NR8)OR7, —OP(O)(OR7)2 or —SP(O)(OR7)2. Even more preferably, R70 is for each occurrence, is independently a C1-C6 alkyl, a C1-C6 haloalkyl, a C1-C6 alkoxy, a C1-C6 haloalkoxy, a C1-C6 alkyl sulfanyl or a C3-C6 cycloalkyl. Still more preferably, R70 for each occurrence, is independently a cyclopropyl or isopropyl;
R7 and R8, for each occurrence, is independently, —H, an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, or an optionally substituted heteroaralkyl. Preferably, R7 and R8, for each occurrence, is independently —H, C1-C3 alkyl, C1-C6 cycloalkyl, an optionally substituted aryl or an optionally substituted heteroaryl. More preferably, R7 and R8, for each occurrence, is independently —H or C1-C3 alkyl;
R10 and R11, for each occurrence, is independently —H, an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, or an optionally substituted heteroaralkyl. Preferably, R10 and R11, for each occurrence, is independently —H, C1-C3 alkyl, C1-C6 cycloalkyl, an optionally substituted aryl or an optionally substituted heteroaryl. More preferably, R10 and R11, for each occurrence, is independently —H or C1-C3 alkyl;
alternatively, R10 and R11, taken together with the nitrogen to which they are attached, form an optionally substituted heterocyclyl or an optionally substituted heteroaryl. Preferably R10 and R11, taken together with the nitrogen to which they are attached, form an optionally substituted imidazolyl, pyrrolyl, pyrazolyl, triazolyl, tetrazolyl, pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl, oxazolyl, iosoxazolyl, oxadiazolyl, thiazolyl, isothiazolyl, thiadiazolyl, pyrrolidinyl, piperidinyl, morpholinyl, pyrazinyl, thiomorpholinyl, pyrrolidinyl, piperidinyl, pyranzinyl, thiomorpholinyl, tetrahydroquinolinyl or tetrahydroisoquinolinyl. More preferably R10 and R11, taken together with the nitrogen to which they are attached, form an optionally substituted pyrrolidinyl, piperidinyl, piperazinyl, tetrahydroisoquinolinyl, morpholinyl or pyrazolyl;
R17, for each occurrence, is independently an alkyl or an aralkyl. Preferably R17 for each occurrence is independently a C1-C6 alkyl;
R26 is a C1-C6 alkyl;
R30, for each occurrence, is independently an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, an optionally substituted heteraralkyl, halo, cyano, nitro, guanadino, a haloalkyl, a heteroalkyl, alkoxy, haloalkoxy, —H, —NR10R11, —OR7, —C(O)R7, —C(O)OR7, —C(S)R7, —C(O)SR7, —C(S)SR7, —C(S)OR7, —C(S)NR10R11, —C(NR8)OR7, —C(NR8)R7, —C(NR8)NR10R11, —C(NR8)SR7, —OC(O)R7, —OC(O)OR7, —OC(S)OR7, —OC(NR8)OR7, —SC(O)R7, —SC(O)OR7, —SC(NR8)OR7, —OC(S)R7, —SC(S)R7, —SC(S)OR7, —OC(O)NR10R11, —OC(S)NR10R11, —OC(NR8)NR10R11, —SC(O)NR10R11, —SC(NR8)NR10R11, —SC(S)NR10R11, —OC(NR8)R7, —SC(NR8)R7, —C(O)NR10R11, —NR8C(O)R7, —NR7C(S)R7, —NR7C(S)OR7, —NR7C(NR8)R7, —NR7C(O)OR7, —NR7C(NR8)OR7, —NR7C(O)NR10R11, —NR7C(S)NR10R11, —NR7C(NR8)NR10R11, —SR7, —S(O)pR7, —OS(O)pR7, —OS(O)pOR7, —OS(O)pNR10R11, —S(O)pOR7, —NR8S(O)pR7, —NR7S(O)pNR10R11, —NR7S(O)pOR7, —S(O)pNR10R11, —SS(O)pR7, —SS(O)pOR7, or —SS(O)pNR10R11. Preferably R30 for each occurrence, is independently an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, cyano, halo, nitro, an optionally substituted cycloalkyl, haloalkyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, an optionally substituted heteroaralkyl, —OR7, —SR7, —NR10R11, —OC(O)NR10R11, —SC(O)NR10R11, —NR7C(O)NR10R11, —OC(O)R7, —SC(O)R7, —NR7C(O)R7, —OC(O)OR7, —SC(O)OR7, —NR7C(O)OR7, —OCH2C(O)R7, —SCH2C(O)R7, —NR7CH2C(O)R7, —OCH2C(O)OR7, —SCH2C(O)OR7, —NR7CH2C(O)OR7, —OCH2C(O)NR10R11, —SCH2C(O)NR10R11, —NR7CH2C(O)NR10R11, —OS(O)pR7, —SS(O)pR7, —NR7S(O)pR7, —OS(O)pNR10R11, —SS(O)pNR10R11, —NR7S(O)pNR10R11, —OS(O)pOR7, —SS(O)pOR7, —NR7S(O)pOR7, —OC(S)R7, —SC(S)R7, —NR7C(S)R7, —OC(S)OR7, —SC(S)OR7, —NR7C(S)OR7, —OC(S)NR10R11, —SC(S)NR10R11, —NR7C(S)NR10R11, —OC(NR8)R7, —SC(NR8)R7, —NR7C(NR8)R7, —OC(NR8)OR7, —SC(NR8)OR7, —NR7C(NR8)OR7, —OC(NR8)NR10R11, —SC(NR8)NR10R11, —NR7C(NR8)NR10R11, —C(O)R7, —C(O)OR7, —C(O)NR10R11, —C(O)SR7, —C(S)R7, —C(S)OR7, —C(S)NR10R11, —C(S)SR7, —C(NR8)OR7, —C(NR8)R7, —C(NR8)NR10R11, —C(NR8)SR7, —S(O)pOR7, —S(O)pNR10R11 or —S(O)pR7. More preferably, R30 for each occurrence, is independently a hydrogen, —OH, —SH, halogen, cyano, a C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy or C1-C6 alkyl sulfanyl. Even more preferably, R30 for each occurrence, is independently a hydrogen, methyl, ethyl, propyl, isopropyl, methoxy or ethoxy;
Ra and Rb, for each occurrence, is independently —H, an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aryl or heteroaryl, an optionally substituted aralkyl. Preferably, Ra and Rb for each occurrence, is independently a hydrogen, a C1-C6 straight or branched alkyl, optionally substituted by —OH, —CN, —SH, amino, a C1-C6 alkoxy, alkylsulfanyl, alkylamino, dialkylamino or a cycloalkyl. More preferably, Ra and Rb for each occurrence, is independently a hydrogen, methyl, ethyl, propyl, isopropyl;
Alternatively, Ra and Rb, taken together with the nitrogen to which they are attached, form an optionally substituted heteroaryl or heterocyclyl. Preferably, Ra and Rb taken together with the nitrogen to which they are attached form a substituted or unsubstituted nonaromatic, nitrogen-containing heterocyclyl. More preferably, Ra and Rb taken together with the nitrogen to which they are attached, are:




X3′ and X4′ are each, independently, N, N(O), N+(R17), CH or CR70;
X5′ is O, S, NR17, CH2, CH(R70), C(R70)2, CH═CH, CH═CR70, CR70═CH, CR70═CR70, CH═N, CR70═N, CH═N(O), CR70═N(O), N═CH, N═CR70, N(O)═CH, N(O)═CR70, N+(R17)═CH, N+(R17)═CR70, CH═N+(R17), CR70═N+(R17), or N═N, provided that at least one X3′, X4′ or X5′ is a heteroatom;
k is 1, 2, 3, or 4;
p, for each occurrence, is independently, 0, 1 or 2; and
m, for each occurrence, is independently, 1, 2, 3, or 4.
In a fifth preferred embodiment, the present invention provides a compound represented by a structural formula selected from formulas (XLII) and (XLIII):




or a tautomer, pharmaceutically acceptable salt, solvate, clathrate or a prodrug thereof.
Preferably the values and preferred values for formulas (XLII) and (XLIII) are as described above for formulas (XL) and (XLI), and more preferably:
R70 is for each occurrence, is independently an optionally substituted C1-C6 alkyl, an optionally substituted C3-C6 cycloalkyl, an optionally substituted C3-C6 cycloalkenyl, an optionally substituted heterocyclyl, a halo, a haloalkyl, a haloalkoxy, a heteroalkyl, an alkoxy, an alkylsulfanyl, —OH, —SH, —NHR7, —(CH2)kOH, —(CH2)kSH, —(CH2)kNR7H, —OCH3, —SCH3, —NHCH3, —OCH2CH2OH, —OCH2CH2SH, —OCH2CH2NR7H, —SCH2CH2OH, —SCH2CH2SH, —SCH2CH2NR7H, —OC(O)NR10R11, —SC(O)NR10R11, —NR7C(O)NR10R11, —OC(O)R7, —SC(O)R7, —NR7C(O)R7, —OC(O)OR7, —SC(O)OR7, —NR7C(O)OR7, —OCH2C(O)R7, —SCH2C(O)R7, —NR7CH2C(O)R7, —OCH2C(O)OR7, —SCH2C(O)OR7, —NR7CH2C(O)OR7, —OCH2C(O)NR10R11, —SCH2C(O)NR10R11, —NR7CH2C(O)NR10R11, —OS(O)pR7, —SS(O)pR7, —NR7S(O)pR7, —OS(O)pNR10R11, —SS(O)pNR10R11, —NR7S(O)pNR10R11, —OS(O)pOR7, —SS(O)pOR7, —NR7S(O)pOR7, —OC(S)R7, —SC(S)R7, —NR7C(S)R7, —OC(S)OR7, —SC(S)OR7, —NR7C(S)OR7, —OC(S)NR10R11, —SC(S)NR10R11, —NR7C(S)NR10R11, —OC(NR8)R7, —SC(NR8)R7, —NR7C(NR8)R7, —OC(NR8)OR7, —SC(NR8)OR7, —NR7C(NR8)OR7, —OC(NR8)NR10R11, —SC(NR8)NR10R11, —NR7C(NR8)NR10R11, —C(O)R7, —C(O)OR7, —C(O)NR10R11, —C(O)SR7, —C(S)R7, —C(S)OR7, —C(S)NR10R11, —C(S)SR7, —C(NR8)OR7, —C(NR8)R7, —C(NR8)NR10R11, —C(NR8)SR7, —S(O)pOR7, —S(O)pNR10R11, —S(O)pR7, —OP(O)(OR7)2 or —SP(O)(OR7)2;
R30, for each occurrence, is independently an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, an optionally substituted heteroaralkyl, halo, cyano, nitro, guanadino, a haloalkyl, a heteroalkyl, alkoxy, haloalkoxy, —NR10R11, —OR7, —C(O)R7, —C(O)OR7, —C(S)R7, —C(O)SR7, —C(S)SR7, —C(S)OR7, —C(S)NR10R11, —C(NR8)OR7, —C(NR8)R7, —C(NR8)NR10R11, —C(NR8)SR7, —OC(O)R7, —OC(O)OR7, —OC(S)OR7, —OC(NR8)OR7, —SC(O)R7, —SC(O)OR7, —SC(NR8)OR7, —OC(S)R7, —SC(S)R7, —SC(S)OR7, —OC(O)NR10R11, —OC(S)NR10R11, —OC(NR8)NR10R11, —SC(O)NR10R11, —SC(NR8)NR10R11, —SC(S)NR10R11, —OC(NR8)R7, —SC(NR8)R7, —C(O)NR10R11, —NR8C(O)R7, —NR7C(S)R7, —NR7C(S)OR7, —NR7C(NR8)R7, —NR7C(O)OR7, —NR7C(NR8)OR7, —NR7C(O)NR10R11, —NR7C(S)NR10R11, —NR7C(NR8)NR10R11, —SR7, —S(O)pR7, —OS(O)pR7, —OS(O)pOR7, —OS(O)pNR10R11, —S(O)pOR7, —NR8S(O)pR7, —NR7S(O)pNR10R11, —NR7S(O)pOR7, —S(O)pNR10R11, —SS(O)pR7, —SS(O)pOR7 or —SS(O)pNR10R11;
s is 0, 1, 2, 3 or 4;
k is 1, 2, 3, or 4; and
the values and preferred values for the remainder of the variables are as described above for formulas (XL) and (XLI).
In a sixth preferred embodiment, the present invention provides a compound represented by a structural formula selected from formulas (XLIV) and (XLV):




or a tautomer, pharmaceutically acceptable salt, solvate, clathrate or a prodrug thereof.
The values and preferred values for formulas (XLIV) and (XLV) are as described above for formulas (XL) and (XLI). Preferably the values and preferred values for formulas (XLIV) and (XLV) are as described for formulas (XLII) and (XLIII). More preferably, the values for formulas (XLIV) and (XLV) are described in the following paragraphs:
R30 is an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, cyano, halo, nitro, an optionally substituted cycloalkyl, haloalkyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, an optionally substituted heteroaralkyl, —OR7, —SR7, —NR10R11, —OC(O)NR10R11, —SC(O)NR10R11, —NR7C(O)NR10R11, —OC(O)R7, —SC(O)R7, —NR7C(O)R7, —OC(O)OR7, —SC(O)OR7, —NR7C(O)OR7, —OCH2C(O)R7, —SCH2C(O)R7, —NR7CH2C(O)R7, —OCH2C(O)OR7, —SCH2C(O)OR7, —NR7CH2C(O)OR7, —OCH2C(O)NR10R11, —SCH2C(O)NR10R11, —NR7CH2C(O)NR10R11, —OS(O)pR7, —SS(O)pR7, —NR7S(O)pR7, —OS(O)pNR10R11, —SS(O)pNR10R11, —NR7S(O)pNR10R11, —OS(O)pOR7, —SS(O)pOR7, —NR7S(O)pOR7, —OC(S)R7, —SC(S)R7, —NR7C(S)R7, —OC(S)OR7, —SC(S)OR7, —NR7C(S)OR7, —OC(S)NR10R11, —SC(S)NR10R11, —NR7C(S)NR10R11, —OC(NR8)R7, —SC(NR8)R7, —NR7C(NR8)R7, —OC(NR8)OR7, —SC(NR8)OR7, —NR7C(NR8)OR7, —OC(NR8)NR10R11, —SC(NR8)NR10R11, —NR7C(NR8)NR10R11, —C(O)R7, —C(O)OR7, —C(O)NR10R11, —C(O)SR7, —C(S)R7, —C(S)OR7, —C(S)NR10R11, —C(S)SR7, —C(NR8)OR7, —C(NR8)R7, —C(NR8)NR10R11, —C(NR8)SR7, —S(O)pOR7, —S(O)pNR10R11, or —S(O)pR7; and
the values and preferred values for the remainder of the variables are as described above for formulas (XLIV) and (XLV) are as described above for formulas (XL) and (XLI). Preferably the values and preferred values for the remainder of the variables in formulas (XLIV) and (XLV) are as described for formulas (XLII) and (XLIII).
In a seventh more preferred embodiment, the present invention provides a compound represented by a structural formula selected from formulas (XLVI)-(XLIX):




or a tautomer, pharmaceutically acceptable salt, solvate, clathrate or a prodrug thereof.
The values and preferred values for formulas (XLVI)-(XLIX) are as described above for formulas (XL) and (XLI). Preferably the values and preferred values for formulas (XLVI)-(XLIX) are as described above for formulas (XLIV) and (XLV). More preferably, the values for formulas (XLVI)-(XLIX) are provided below in the following paragraphs:
R1 and R3 are each independently —OH, —SH, —HNR7, —OC(O)NR10R11, —SC(O)NR10R11, —OC(O)R7, —SC(O)R7, —OC(O)OR7, —SC(O)OR7, —OS(O)pR7, —S(O)pOR7, —SS(O)pR7, —OS(O)pOR7, —SS(O)pOR7, —OC(S)R7, —SC(S)R7, —OC(S)OR7, —SC(S)OR7, —OC(S)NR10R11, —SC(S)NR10R11, —OC(NR8)R7, —SC(NR8)R7, —OC(NR8)OR7, —SC(NR8)OR7, —OP(O)(OR7)2 or —SP(O)(OR7)2; and
R70, for each occurrence, is independently an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, —OH, —SH, —HNR7, —OC(O)NR10R11, —SC(O)NR10R11, —OC(O)R7, —SC(O)R7, —OC(O)OR7, —SC(O)OR7, —OS(O)pR7, —S(O)pOR7, —SS(O)pR7, —OS(O)pOR7, —SS(O)pOR7, —OC(S)R7, —SC(S)R7, —OC(S)OR7, —SC(S)OR7, —OC(S)NR10R11, —SC(S)NR10R11, —OC(NR8)R7, —SC(NR8)R7, —OC(NR8)OR7, —SC(NR8)OR7, —OP(O)(OR7)2 or —SP(O)(OR7)2; and
the values and preferred values for the remainder of the variables are as described for formulas (XLIV) and (XLV).
Still more preferably for formulas (XLVI)-(XLIX), R1, R3 and R70 are as described in the immediately preceeding paragraphs; and
Ra and Rb are each independently a hydrogen, a C1-C6 straight or branched alkyl, optionally substituted by —OH, —CN, —SH, amino, a C1-C6 alkoxy, alkylsulfanyl, alkylamino, dialkylamino or a cycloalkyl; or Ra and Rb taken together with the nitrogen to which they are attached form a substituted or unsubstituted nonaromatic, nitrogen-containing heterocyclyl; and
the values and preferred values for the remainder of the variables are as described for formulas (XLIV) and (XLV).
Still more preferably for formulas (XLVI)-(XLIX), R1, R3, R6, Ra and Rb are as described in the immediately preceeding paragraphs; and
R70 is a C1-C6 alkyl, a C1-C6 haloalkyl, a C1-C6 alkoxy, a C1-C6 haloalkoxy, a C1-C6 alkyl sulfanyl or a C3-C6 cycloalkyl; and
the values and preferred values for the remainder of the variables are as described above for formulas (XL) and (XLI). More preferably, the values and preferred values for the remainder of the variables are as described above for formulas (XLIV) and (XLV).
In an eighth preferred embodiment, the present invention provides a compound represented by a structural formula selected from formulas (La)-(Lp):










or a tautomer, pharmaceutically acceptable salt, solvate, clathrate or a prodrug thereof.
The values and preferred values for formulas (La) through (Lp) are as described above for formulas (XL) and (XLI). Preferably the values and preferred values for formulas (La)-(Lp) are as described for formulas (XLVI)-(XLIX). More preferably, R1 and R3 are each, independently, —OH, —SH, or —NHR7. Even more preferable, R1 and R3 are each, independently, —OH, —SH, or —NHR7; and R30 is —OH, —SH, halogen, cyano, a C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy or C1-C6 alkyl sulfanyl (preferably methyl, ethyl, propyl, isopropyl, methoxy or ethoxy). Even more preferably, R1 and R3 for each occurrence, is independently —SH or —OH; R70 is cyclopropyl or isopropyl; and R30 is —OH, —SH, halogen, cyano, a C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy or C1-C6 alkyl sulfanyl (preferably methyl, ethyl, propyl, isopropyl, methoxy or ethoxy). Even more preferably yet, R1, R3, R70 and R30 are as just described and Ra and Rb are each independently a hydrogen, methyl, ethyl, propyl, isopropyl, or taken together with the nitrogen to which they are attached, are:




R35 is —H, a C1-C4 alkyl or a C1-C4 acyl; and
the values and preferred values for the remainder of the variables are as defined for formulas (XLVI)-(XLIX).
In another embodiment the compounds of the present invention are represented by a structural formula selected from formulas (LIa) and (LIb):




    
    
        or a tautomer, pharmaceutically acceptable salt, solvate, clathrate or a prodrug thereof.
    
    


In formulas (LIa) and (LIb), ring B is further optionally substituted with one or more substituents in addition to —NRaRb. Preferably ring B is further substituted with (R30)s where s is 0, 1, 2, 3 or 4, preferably s is 0 or 1;
R1 is —OH, —SH, —NR7H, —OR26, —SR26, —NHR26, —O(CH2)mOH, —O(CH2)mSH, —O(CH2)mNR7H, —S(CH2)mOH, —S(CH2)mSH, —S(CH2)mNR7H, —OC(O)NR10R11, —SC(O)NR10R11, —NR7C(O)NR10R11, —OC(O)R7, —SC(O)R7, —NR7C(O)R7, —OC(O)OR7, —S C(O)OR7, —NR7C(O)OR7, —OCH2C(O)R7, —SCH2C(O)R7, —NR7CH2C(O)R7, —OCH2C(O)OR7, —SCH2C(O)OR7, —NR7CH2C(O)OR7, —OCH2C(O)NR10R11, —SCH2C(O)NR10R11, —NR7CH2C(O)NR10R11, —OS(O)pR7, —SS(O)pR7, —S(O)pOR7, —NR7S(O)pR7, —OS(O)pNR10R11, —SS(O)pNR10R11, —NR7S(O)pNR10R11, —OS(O)pOR7, —SS(O)pOR7, —NR7S(O)pOR7, —OC(S)R7, —SC(S)R7, —NR7C(S)R7, —OC(S)OR7, —SC(S)OR7, —NR7C(S)OR7, —OC(S)NR10R11, —SC(S)NR10R11, —NR7C(S)NR10R11, —OC(NR8)R7, —SC(NR8)R7, —NR7C(NR8)R7, —OC(NR8)OR7, —SC(NR8)OR7, —NR7C(NR8)OR7, —OC(NR8)NR10R11, —SC(NR8)NR10R11, —NR7C(NR8)NR10R11, —OP(O)(OR7)2 or —SP(O)(OR7)2. Preferably, R1 is —OH, —SH, —HNR7, —OC(O)NR10R11, —SC(O)NR10R11, —OC(O)R7, —SC(O)R7, —OC(O)OR7, —SC(O)OR7, —OS(O)pR7, —S(O)pOR7, —SS(O)pR7, —OS(O)pOR7, —SS(O)pOR7, —OC(S)R7, —SC(S)R7, —OC(S)OR7, —SC(S)OR7, —OC(S)NR10R11, —SC(S)NR10R11, —OC(NR8)R7, —SC(NR8)R7, —OC(NR8)OR7, —SC(NR8)OR7, —OP(O)(OR7)2 or —SP(O)(OR7)2. More preferably, R1 is —OH, —SH, or —NHR7. Even more preferably, R1 is —SH or —OH;
R3 is —OH, —SH, —NR7H, —OR26, —SR26, —NHR26, —O(CH2)mOH, —O(CH2)mSH, —O(CH2)mNR7H, —S(CH2)mOH, —S(CH2)mSH, —S(CH2)mNR7H, —OC(O)NR10R11, —SC(O)NR10R11, —NR7C(O)NR10R11, —OC(O)R7, —SC(O)R7, —NR7C(O)R7, —OC(O)OR7, —SC(O)OR7, —NR7C(O)OR7, —OCH2C(O)R7, —SCH2C(O)R7, —NR7CH2C(O)R7, —OCH2C(O)OR7, —SCH2C(O)OR7, —NR7CH2C(O)OR7, —OCH2C(O)NR10R11, —SCH2C(O)NR10R11, —NR7CH2C(O)NR10R11, —OS(O)pR7, —SS(O)pR7, —S(O)pOR7, —NR7S(O)pR7, —OS(O)pNR10R11, —SS(O)pNR10R11, —NR7S(O)pNR10R11, —OS(O)pOR7, —SS(O)pOR7, —NR7S(O)pOR7, —OC(S)R7, —SC(S)R7, —NR7C(S)R7, —OC(S)OR7, —SC(S)OR7, —NR7C(S)OR7, —OC(S)NR10R11, —SC(S)NR10R11, —NR7C(S)NR10R11, —OC(NR8)R7, —SC(NR8)R7, —NR7C(NR8)R7, —OC(NR8)OR7, —SC(NR8)OR7, —NR7C(NR8)OR7, —OC(NR8)NR10R11, —SC(NR8)NR10R11, —NR7C(NR8)NR10R11, —C(O)OH, —C(O)NHR8, —C(O)SH, —S(O)OH, —S(O)2OH, —S(O)NHR8, —S(O)2NHR8, —OP(O)(OR7)2, or —SP(O)(OR7)2. Preferably, R3 is —OH, —SH, —HNR7, —OC(O)NR10R11, —SC(O)NR10R11, —OC(O)R7, —SC(O)R7, —OC(O)OR7, —SC(O)OR7, —OS(O)pR7, —S(O)pOR7, —SS(O)pR7, —OS(O)pOR7, —SS(O)pOR7, —OC(S)R7, —SC(S)R7, —OC(S)OR7, —SC(S)OR7, —OC(S)NR10R11, —SC(S)NR10R11, —OC(NR8)R7, —SC(NR8)R7, —OC(NR8)OR7, —SC(NR8)OR7, —OP(O)(OR7)2 or —SP(O)(OR7)2. More preferably, R3 is —OH, —SH, or —NHR7. Even more preferably, R3 is —SH or —OH;
R7 and R8, for each occurrence, is independently, —H, an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, or an optionally substituted heteroaralkyl. Preferably, R7 and R8, for each occurrence, is independently —H, C1-C3 alkyl, C1-C6 cycloalkyl, an optionally substituted aryl or an optionally substituted heteroaryl. More preferably, R7 and R8, for each occurrence, is independently —H or C1-C3 alkyl;
R10 and R11, for each occurrence, is independently —H, an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, or an optionally substituted heteroaralkyl. Preferably, R10 and R11, for each occurrence, is independently —H, C1-C3 alkyl, C1-C6 cycloalkyl, an optionally substituted aryl or an optionally substituted heteroaryl. More preferably, R10 and R11, for each occurrence, is independently —H or C1-C3 alkyl;
Alternatively, R10 and R11, taken together with the nitrogen to which they are attached, form an optionally substituted heterocyclyl or an optionally substituted heteroaryl. Preferably R10 and R11, taken together with the nitrogen to which they are attached, form an optionally substituted imidazolyl, pyrrolyl, pyrazolyl, triazolyl, tetrazolyl, pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl, oxazolyl, iosoxazolyl, oxadiazolyl, thiazolyl, isothiazolyl, thiadiazolyl, pyrrolidinyl, piperidinyl, morpholinyl, pyrazinyl, thiomorpholinyl, pyrrolidinyl, piperidinyl, pyranzinyl, thiomorpholinyl, tetrahydroquinolinyl or tetrahydroisoquinolinyl. More preferably R10 and R11, taken together with the nitrogen to which they are attached, form an optionally substituted pyrrolidinyl, piperidinyl, piperazinyl, tetrahydroisoquinolinyl, morpholinyl or pyrazolyl;
R22, for each occurrence, is independently —H, an optionally substituted alky, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, or an optionally substituted heteroaralkyl, a haloalkyl, —C(O)R7, —C(O)OR7, —OC(O)R7, —C(O)NR10R11, —NR8C(O)R7, —S(O)pR7, —S(O)pOR7, or —S(O)pNR10R11. Preferably, R22 is —H, an alkyl, an aralkyl, —C(O)R7, —C(O)OR7, or —C(O)NR10R11;
R23 and R24, for each occurrence, is independently —H, an optionally substituted alky, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, or an optionally substituted heteroaralkyl, halo, cyano, nitro, guanadino, a haloalkyl, a heteroalkyl, —NR10R11, —OR7, —C(O)R7, —C(O)OR7, —OC(O)R7, —C(O)NR10R11, —NR8C(O)R7, —SR7, —S(O)pR7, —OS(O)pR7, —S(O)pOR7, —NR8S(O)pR7, or —S(O)pNR10R11. Preferably, R23 and R24 for each occurrence is independently —H;
R26 is a C1-C6 alkyl;
Ra and Rb, for each occurrence, is independently —H, an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aryl or heteroaryl, an optionally substituted aralkyl. Preferably, Ra and Rb for each occurrence, is independently a hydrogen, a C1-C6 straight or branched alkyl, optionally substituted by —OH, —CN, —SH, amino, a C1-C6 alkoxy, alkylsulfanyl, alkylamino, dialkylamino or a cycloalkyl. More preferably, Ra and Rb for each occurrence, is independently a hydrogen, methyl, ethyl, propyl or isopropyl;
Alternatively, Ra and Rb, taken together with the nitrogen to which they are attached, form an optionally substituted heteroaryl or heterocyclyl. Preferably, Ra and Rb taken together with the nitrogen to which they are attached form a substituted or unsubstituted nonaromatic, nitrogen-containing heterocyclyl. More preferably, Ra and Rb taken together with the nitrogen to which they are attached, are:




X14 is O, S, or NR7. Preferably, X14 is O;
p, for each occurrence, is independently, 0, 1 or 2; and
m, for each occurrence, is independently, 1, 2, 3, or 4.
Preferably for the compound represented by formulas (LIa) and (LIb), R1 is —OH, —SH, or —NHR7; and R22 is —H, an alkyl, an aralkyl, —C(O)R7, —C(O)OR7, or —C(O)NR10R11. More preferably, R1 is —OH, —SH, or —NHR7; R22 is —H, an alkyl, an aralkyl, —C(O)R7, —C(O)OR7, or —C(O)NR10R11; and X14 is O. The values and preferred values for the remainder of the variables are as described above.
In one embodiment, a compound of the present invention is represented by the structural formulas (VI)-(VIII):




In formulas (VI-VIII):

ring A is an aryl or a heteroaryl, optionally further substituted with one or more substituents in addition to R3. Preferably, Ring A is represented one of the following structural formulas:




where z is 0, 1, 2, 3 or 4; x is 0 or 1; and z+x is less than or equal to 4.
R1 is —OH, —SH, —NR7H, —OR26, —SR26, —NHR26, —O(CH2)mOH, —O(CH2)mSH, —O(CH2)mNR7H, —S(CH2)mOH, —S(CH2)mSH, —S(CH2)mNR7H, —OC(O)NR10R11, —SC(O)NR10R11, —NR7C(O)NR10R11, —OC(O)R7, —SC(O)R7, —NR7C(O)R7, —OC(O)OR7, —SC(O)OR7, —NR7C(O)OR7, —OCH2C(O)R7, —SCH2C(O)R7, —NR7CH2C(O)R7, —OCH2C(O)OR7, —SCH2C(O)OR7, —NR7CH2C(O)OR7, —OCH2C(O)NR10R11, —SCH2C(O)NR10R11, —NR7CH2C(O)NR10R11, —OS(O)pR7, —SS(O)pR7, —S(O)pOR7, —NR7S(O)pR7, —OS(O)pNR10R11, —SS(O)pNR10R11, —NR7S(O)pNR10R11, —OS(O)pOR7, —SS(O)pOR7, —NR7S(O)pOR7, —OC(S)R7, —SC(S)R7, —NR7C(S)R7, —OC(S)OR7, —SC(S)OR7, —NR7C(S)OR7, —OC(S)NR10R11, —SC(S)NR10R11, —NR7C(S)NR10R11, —OC(NR8)R7, —SC(NR8)R7, —NR7C(NR8)R7, —OC(NR8)OR7, —SC(NR8)OR7, —NR7C(NR8)OR7, —OC(NR8)NR10R11, —SC(NR8)NR10R11, —NR7C(NR8)NR10R11, —OP(O)(OR7)2, or —SP(O)(OR7)2. Preferably, R1 is —OH, —SH, —NHR7, —OC(O)NR10R11, —SC(O)NR10R11, —OC(O)R7, —SC(O)R7, —OC(O)OR7, —SC(O)OR7, —OS(O)pR7, —S(O)pOR7, —SS(O)pR7, —OS(O)pOR7, —SS(O)pOR7, —OC(S)R7, —SC(S)R7, —OC(S)OR7, —SC(S)OR7, —OC(S)NR10R11, —SC(S)NR10R11, —OC(NR8)R7, —SC(NR8)R7, —OC(NR8)OR7, —SC(NR8)OR7, —OP(O)(OR7)2 or —SP(O)(OR7)2. More preferably, R1 is —OH, —SH, or —NHR7. Even more preferably, R1, is —SH or —OH;
R2′ is an optionally substituted phenyl group. Preferably, R2′ is substituted with one or more group represented by R30, wherein R30, for each occurrence, are independently an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, an optionally substituted heteraralkyl, halo, cyano, nitro, guanadino, a haloalkyl, a heteroalkyl, alkoxy, haloalkoxy, —NR10R11, —OR7, —C(O)R7, —C(O)OR7, —C(S)R7, —C(O)SR7, —C(S)SR7, —C(S)OR7, —C(S)NR10R11, —C(NR8)OR7, —C(NR8)R7, —C(NR8)NR10R11, —C(NR8)SR7, —OC(O)R7, —OC(O)OR7, —OC(S)OR7, —OC(NR8)OR7, —SC(O)R7, —SC(O)OR7, —SC(NR8)OR7, —OC(S)R7, —SC(S)R7, —SC(S)OR7, —OC(O)NR10R11, —OC(S)NR10R11, —OC(NR8)NR10R11, —SC(O)NR10R11, —SC(NR8)NR10R11, —SC(S)NR10R11, —OC(NR8)R7, —SC(NR8)R7, —C(O)NR10R11, —NR8C(O)R7, —NR7C(S)R7, —NR7C(S)OR7, —NR7C(NR8)R7, —NR7C(O)OR7, —NR7C(NR8)OR7, —NR7C(O)NR10R11, —NR7C(S)NR10R11, —NR7C(NR8)NR10R11, —SR7, —S(O)pR7, —OS(O)pR7, —OS(O)pOR7, —OS(O)pNR10R11, —S(O)pOR7, —NR8S(O)pR7, —NR7S(O)pNR10R11, —NR7S(O)pOR7, —S(O)pNR10R11, —SS(O)pR7, —SS(O)pOR7, —SS(O)pNR10R11, —OP(O)(OR7)2, or —SP(O)(OR7)2. More preferably, R2′ is an optionally substituted indolyl group or a phenyl group substituted with NR10R11 and optionally with at least one other substitutent represented by R30;
R3 is —OH, —SH, —NR7H, —NHR26, —O(CH2)mOH, —O(CH2)mSH, —O(CH2)mNR7H, —S(CH2)mOH, —S(CH2)mSH, —S(CH2)mNR7H, —OC(O)NR10R11, —SC(O)NR10R11, —NR7C(O)NR10R11, —OC(O)R7, —SC(O)R7, —NR7C(O)R7, —OC(O)OR7, —SC(O)OR7, —NR7C(O)OR7, —OCH2C(O)R7, —SCH2C(O)R7, —NR7CH2C(O)R7, —OCH2C(O)OR7, —SCH2C(O)OR7, —NR7CH2C(O)OR7, —OCH2C(O)NR10R11, —SCH2C(O)NR10R11, —NR7CH2C(O)NR10R11, —OS(O)pR7, —SS(O)pR7, —S(O)pOR7, —NR7S(O)pR7, —OS(O)pNR10R11, —SS(O)pNR10R11, —NR7S(O)pNR10R11, —OS(O)pOR7, —SS(O)pOR7, —NR7S(O)pOR7, —OC(S)R7, —SC(S)R7, —NR7C(S)R7, —OC(S)OR7, —SC(S)OR7, —NR7C(S)OR7, —OC(S)NR10R11, —SC(S)NR10R11, —NR7C(S)NR10R11, —OC(NR8)R7, —SC(NR8)R7, —NR7C(NR8)R7, —OC(NR8)OR7, —SC(NR8)OR7, —NR7C(NR8)OR7, —OC(NR8)NR10R11, —SC(NR8)NR10R11, —NR7C(NR8)NR10R11, —C(O)OH, —C(O)NHR8, —C(O)SH, —S(O)OH, —S(O)2OH, —S(O)NHR8, —S(O)2NHR8, —OP(O)(OR7)2, or —SP(O)(OR7)2. In another embodiment, —OR26 and —SR26, are additional values for R3. Preferably, R3 is —OH, —SH, —NHR7, —OC(O)NR10R11, —SC(O)NR10R11, —OC(O)R7, —SC(O)R7, —OC(O)OR7, —SC(O)OR7, —OS(O)pR7, —S(O)pOR7, —SS(O)pR7, —OS(O)pOR7, —SS(O)pOR7, —OC(S)R7, —SC(S)R7, —OC(S)OR7, —SC(S)OR7, —OC(S)NR10R11, —SC(S)NR10R11, —OC(NR8)R7, —SC(NR8)R7, —OC(NR8)OR7, —SC(NR8)OR7, —OP(O)(OR7)2 or —SP(O)(OR7)2. More preferably, R3 is —OH, —SH, or —NHR7. Even more preferably, R3 is —SH or —OH;
R5 is an optionally substituted heteroaryl; an optionally substituted 6 to 14-membered aryl.
R70, for each occurrence, is independently, an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, an optionally substituted heteraralkyl, halo, cyano, nitro, guanadino, a haloalkyl, a heteroalkyl, an alkoxy or cycloalkoxy, a haloalkoxy, —NR10R11, —OR7, —C(O)R7, —C(O)OR7, —C(S)R7, —C(O)SR7, —C(S)SR7, —C(S)OR7, —C(S)NR10R11, —C(NR8)OR7, —C(NR8)R7, —C(NR8)NR10R11, —C(NR8)SR7, —OC(O)R7, —OC(O)OR7, —OC(S)OR7, —OC(NR8)OR7, —SC(O)R7, —SC(O)OR7, —SC(NR8)OR7, —OC(S)R7, —SC(S)R7, —SC(S)OR7, —OC(O)NR10R11, —OC(S)NR10R11, —OC(NR8)NR10R11, —SC(O)NR10R11, —SC(NR8)NR10R11, —SC(S)NR10R11, —OC(NR8)R7, —SC(NR8)R7, —C(O)NR10R11, —NR8C(O)R7, —NR7C(S)R7, —NR7C(S)OR7, —NR7C(NR8)R7, —NR7C(O)OR7, —NR7C(NR8)OR7, —NR7C(O)NR10R11, —NR7C(S)NR10R11, —NR7C(NR8)NR10R11, —SR7, —S(O)pR7, —OS(O)pR7, —OS(O)pOR7, —OS(O)pNR10R11, —S(O)pOR7, —NR8S(O)pR7, —NR7S(O)pNR10R11, —NR7S(O)pOR7, —S(O)pNR10R11, —SS(O)pR7, —SS(O)pOR7, —SS(O)pNR10R11, —OP(O)(OR7)2, or —SP(O)(OR7)2. Preferably, R70 is selected from the group consisting of —H, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 cycloalkyl, and C1-C6 cycloalkoxy, more preferably from the group consisting of —H, methyl, ethyl, propyl, isopropyl, cyclopropyl, methoxy, ethoxy, propoxy, and cyclopropoxy.
R71, for each occurrence, is independently an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, an optionally substituted heteraralkyl, halo, cyano, nitro, guanadino, a haloalkyl, a heteroalkyl, alkoxy, haloalkoxy, —NR10R11, —OR7, —C(O)R7, —C(O)OR7, —C(S)R7, —C(O)SR7, —C(S)SR7, —C(S)OR7, —C(S)NR10R11, —C(NR8)OR7, —C(NR8)R7, —C(NR8)NR10R11, —C(NR8)SR7, —OC(O)R7, —OC(O)OR7, —OC(S)OR7, —OC(NR8)OR7, —SC(O)R7, —SC(O)OR7, —SC(NR8)OR7, —OC(S)R7, —SC(S)R7, —SC(S)OR7, —OC(O)NR10R11, —OC(S)NR10R11, —OC(NR8)NR10R11, —SC(O)NR10R11, —SC(NR8)NR10R11, —SC(S)NR10R11, —OC(NR8)R7, —SC(NR8)R7, —C(O)NR10R11, —NR8C(O)R7, —NR7C(S)R7, —NR7C(S)OR7, —NR7C(NR8)R7, —NR7C(O)OR7, —NR7C(NR8)OR7, —NR7C(O)NR10R11, —NR7C(S)NR10R11, —NR7C(NR8)NR10R11, —SR7, —S(O)pR7, —OS(O)pR7, —OS(O)pOR7, —OS(O)pNR10R11, —S(O)pOR7, —NR8S(O)pR7, —NR7S(O)pNR10R11, —NR7S(O)pOR7, —S(O)pNR10R11, —SS(O)pR7, —SS(O)pOR7, —SS(O)pNR10R11, —OP(O)(OR7)2, or —SP(O)(OR7)2.
R7 and R8, for each occurrence, are, independently, —H, an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, or an optionally substituted heteraralkyl;
R10 and R11, for each occurrence, are independently —H, an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, or an optionally substituted heteraralkyl; or R10 and R11, taken together with the nitrogen to which they are attached, form an optionally substituted heterocyclyl or an optionally substituted heteroaryl;
R18 is an optionally substituted cycloalkyl, and optionally substituted cycloalkenyl, or a substituted alkyl, wherein the alkyl group is substituted with one or more substituents independently selected from the group consisting of an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heteroaryl, an optionally substituted aralkyl, an optionally substituted heteraralkyl, halo, cyano, nitro, guanadino, a haloalkyl, —NR10R11, —OR7, —C(O)R7, —C(O)OR7, —OC(O)R7, —C(O)NR10R11, —NR8C(O)R7, —SR7, —S(O)pR7, —OS(O)pR7, —S(O)pOR7, —NR8S(O)pR7, or —S(O)pNR10R11;
R26 is a lower alkyl;
p, for each occurrence, is, independently, 0, 1 or 2; and
m, for each occurrence, is independently, 1, 2, 3, or 4.
R5 in structural formula (VI) is preferably represented by the following structural formula:




wherein:
R9, for each occurrence, is independently a substituent selected from the group consisting of an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, an optionally substituted heteraralkyl, hydroxyalkyl, alkoxyalkyl, halo, cyano, nitro, guanadino, a haloalkyl, a heteroalkyl, —NR10R11, —OR7, —C(O)R7, —C(O)OR7, —OC(O)R7, —C(O)NR10R11, —NR8C(O)R7, —SR7, —S(O)pR7, —OS(O)pR7, —S(O)pOR7, —NR8S(O)pR7, or —S(O)pNR10R11; or two R9 groups taken together with the carbon atoms to which they are attached form a fused ring; and
m is zero or an integer from 1 to 7.
More preferably, substituent R5 in structural formula (VI) is represented by one of the following structural formulas:




wherein:
R9 is as defined as above, q is zero or an integer from 1 to 7 and u is zero or an integer from 1 to 8.
In another alternative, R5 in structural formula (VI) is represented by the following structural formula:




wherein:
R33 is —H, a halo, lower alkyl, a lower alkoxy, a lower haloalkyl, a lower haloalkoxy, and lower alkyl sulfanyl; R34 is H, a lower alkyl, or a lower alkylcarbonyl; and ring B and ring C are optionally substituted with one or more substituents.
In another alternative, R5 in structural formula (VI) is selected from a group listed in Table 1.










TABLE 1







#
R5



















1







 



2







 



3







 



4







 



5







 



6







 



7







 



8







 



9







 



10







 



11







 



12







 



13







 



14







 



15







 



16







 



17







 



18







 



19














In the structural formulas of Table 1:

X6, for each occurrence, is independently CH, CR9, N, N(O), N+(R17), provided that at least three X6 groups are independently selected from CH and CR9;
X7, for each occurrence, is independently CH, CR9, N, N(O), N+(R17), provided that at least three X7 groups are independently selected from CH and CR9;
X8, for each occurrence, is independently CH2, CHR9, CR9R9, O, S, S(O)p, NR7, or NR17;
X9, for each occurrence, is independently N or CH;
X10, for each occurrence, is independently CH, CR9, N, N(O), N+(R17), provided that at least one X10 is selected from CH and CR9;
R9, for each occurrence, is independently a substituent selected from the group consisting of an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, an optionally substituted heteraralkyl, hydroxyalkyl, alkoxyalkyl, halo, cyano, nitro, guanadino, a haloalkyl, a heteroalkyl, —NR10R11, —OR7, —C(O)R7, —C(O)OR7, —OC(O)R7, —C(O)NR10R11, —NR8C(O)R7, —SR7, —S(O)pR7, —OS(O)pR7, —S(O)pOR7, —NR8S(O)pR7, or —S(O)pNR10R11; or two R9 groups taken together with the carbon atoms to which they are attached form a fused ring; and
R17, for each occurrence, is independently —H, an alkyl, an aralkyl, —C(O)R7, —C(O)OR7, or —C(O)NR10R11.
Preferred R5 groups from Table 1 are selected from the group consisting of an optionally substituted indolyl, an optionally substituted benzoimidazolyl, an optionally substituted indazolyl, an optionally substituted 3H-indazolyl, an optionally substituted indolizinyl, an optionally substituted quinolinyl, an optionally substituted isoquinolinyl, an optionally substituted benzoxazolyl, an optionally substituted benzo[1,3]dioxolyl, an optionally substituted benzofuryl, an optionally substituted benzothiazolyl, an optionally substituted benzo[d]isoxazolyl, an optionally substituted benzo[d]isothiazolyl, an optionally substituted thiazolo[4,5-c]pylidinyl, an optionally substituted thiazolo[5,4-c]pyridinyl, an optionally substituted thiazolo[4,5-b]pylidinyl, an optionally substituted thiazolo[5,4-b]pyridinyl, an optionally substituted oxazolo[4,5-c]pylidinyl, an optionally substituted oxazolo[5,4-c]pyridinyl, an optionally substituted oxazolo[4,5-b]pylidinyl, an optionally substituted oxazolo[5,4-b]pylidinyl, an optionally substituted imidazopyridinyl, an optionally substituted benzothiadiazolyl, benzoxadiazolyl, an optionally substituted benzotnazolyl, an optionally substituted tetrahydroindolyl, an optionally substituted azaindolyl, an optionally substituted quinazolinyl, an optionally substituted purinyl, an optionally substituted imidazo[4,5-a]pyridinyl, an optionally substituted imidazo[1,2-a]pyridinyl, an optionally substituted 3H-imidazo[4,5-b]pyridinyl, an optionally substituted 1H-imidazo[4,5-b]pyridinyl, an optionally substituted 1H-imidazo[4,5-c]pyridinyl, an optionally substituted 3H-imidazo[4,5-c]pyridinyl, an optionally substituted pyridopyrdazinyl, and optionally substituted pyridopyrimidinyl, an optionally substituted pyrrolo[2,3]pyrimidyl, an optionally substituted pyrazolo[3,4]pyrimidyl an optionally substituted cyclopentaimidazolyl, an optionally substituted cyclopentatriazolyl, an optionally substituted pyrrolopyrazolyl, an optionally substituted pyrroloimidazolyl, an optionally substituted pyrrolotriazolyl, or an optionally substituted benzo(b)thienyl.
In another alternative, R5 in structural formula (VI) is selected from the group consisting of:




wherein:
X11, for each occurrence, is independently CH, CR9, N, N(O), or N+(R17), provided that at least one X11 is N, N(O), or N+(R17) and at least two X11 groups are independently selected from CH and CR9;
X12, for each occurrence, is independently CH, CR9, N, N(O), N+(R17), provided that at least one X12 group is independently selected from CH and CR9;
X13, for each occurrence, is independently O, S, S(O)p, NR7, or NR17;
R9, for each occurrence, is independently a substituent selected from the group consisting of an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, an optionally substituted heteraralkyl, halo, cyano, nitro, guanadino, a hydroxyalkyl, alkoxyalkyl, haloalkyl, a heteroalkyl, —NR10R11, —OR7, —C(O)R7, —C(O)OR7, —OC(O)R7, —C(O)NR10R11, —NR8C(O)R7, —SR7, —S(O)pR7, —OS(O)pR7, —S(O)pOR7, —NR8S(O)pR7, or —S(O)pNR10R11; or two R9 groups taken together with the carbon atoms to which they are attached form a fused ring; and R17, for each occurrence, is independently an alkyl or an aralkyl. The remainder of the variables have values defined above with reference to structural formula (I).
In a preferred embodiment, the compound of the invention is represented by structural formula (LII):




In structural formula (LII):

X101 is O, S, or NR102 and X102 is CR104 or N. Preferably, X101 is NR102 and X102 is CR104. Alternatively, X101 is NR102 and X102 is N;
Y, for each occurrence, is independently N or CR103;
Y101 is N or CR105;
Y102 is N, C or CR106;
R1 is —OH, —SH, or NHR7. Preferably, R1 is —OH or —SH;
R70 is an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, an optionally substituted heteraralkyl, halo, cyano, nitro, guanadino, a haloalkyl, a heteroalkyl, an alkoxy, cycloalkoxy, a haloalkoxy, —NR10R11, —OR7, —C(O)R7, —C(O)OR7, —C(S)R7, —C(O)SR7, —C(S)SR7, —C(S)OR7, —C(S)NR10R11, —C(NR8)OR7, —C(NR8)R7, —C(NR8)NR10R11, —C(NR8)SR7, —OC(O)R7, —OC(O)OR7, —OC(S)OR7, —OC(NR8)OR7, —SC(O)R7, —SC(O)OR7, —SC(NR8)OR7, —OC(S)R7, —SC(S)R7, —SC(S)OR7, —OC(O)NR10R11, —OC(S)NR10R11, —OC(NR8)NR10R11, —SC(O)NR10R11, —SC(NR8)NR10R11, —SC(S)NR10R11, —OC(NR8)R7, —SC(NR8)R7, —C(O)NR10R11, —NR8C(O)R7, —NR7C(S)R7, —NR7C(S)OR7, —NR7C(NR8)R7, —NR7C(O)OR7, —NR7C(NR8)OR7, —NR7C(O)NR10R11, —NR7C(S)NR10R11, —NR7C(NR8)NR10R11, —SR7, —S(O)pR7, —OS(O)pR7, —OS(O)pOR7, —OS(O)pNR10R11, —S(O)pOR7, —NR8S(O)pR7, —NR7S(O)pNR10R11, —NR7S(O)pOR7, —S(O)pNR10R11, —SS(O)pR7, —SS(O)pOR7, —SS(O)pNR10R11, —OP(O)(OR7)2, or —SP(O)(OR7)2. Preferably, R70 is selected from the group consisting of —H, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 cycloalkyl, and C1-C6 cycloalkoxy, more preferably from the group consisting of —H, methyl, ethyl, propyl, isopropyl, cyclopropyl, methoxy, ethoxy, propoxy, and cyclopropoxy;
R102 is —H, an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, an optionally substituted heteraralkyl, hydroxyalkyl, alkoxyalkyl, a haloalkyl, a heteroalkyl, —C(O)R7, —(CH2)mC(O)OR7, —C(O)OR7, —OC(O)R7, —C(O)NR10R11, —S(O)pR7, —S(O)pOR7, or —S(O)pNR10R11; preferably, R102 is selected from the group consisting of —H, a C1-C6 alkyl, a C1-C6 cycloalkyl, —C(O)N(R27)2, and —C(O)OH, wherein R27, for each occurrence, is independently is —H or a lower alkyl;
R103 and R104 are, independently, —H, —OH, an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, an optionally substituted heteraralkyl, hydroxyalkyl, alkoxyalkyl, halo, cyano, nitro, guanadino, a haloalkyl, a heteroalkyl, —C(O)R7, —C(O)OR7, —OC(O)R7, —C(O)NR10R11, —NR8C(O)R7, —SR7, —S(O)pR7, —OS(O)pR7, —S(O)pOR7, —NR8S(O)pR7, —S(O)pNR10R11, or R103 and R104 taken together with the carbon atoms to which they are attached form an optionally substituted cycloalkenyl, an optionally substituted aryl, an optionally substituted heterocyclyl, or an optionally substituted heteroaryl; preferably, R103 and R104 are independently, selected from the group consisting of —H, methyl, ethyl, propyl, isopropyl, cyclopropyl, methoxy, ethoxy, propoxy, and cyclopropoxy;
R105 is —H, —OH, —SH, —NR7H, —OR26, —SR26, —NHR26, —O(CH2)mOH, —O(CH2)mSH, —O(CH2)mNR7H, —S(CH2)mOH, —S(CH2)mSH, —S(CH2)mNR7H, —OC(O)NR10R11, —SC(O)NR10R11, —NR7C(O)NR10R11, —OC(O)R7, —SC(O)R7, —NR7C(O)R7, —OC(O)OR7, —SC(O)OR7, —NR7C(O)OR7, —OCH2C(O)R7, —SCH2C(O)R7, —NR7CH2C(O)R7, —OCH2C(O)OR7, —SCH2C(O)OR7, —NR7CH2C(O)OR7, —OCH2C(O)NR10R11, —SCH2C(O)NR10R11, —NR7CH2C(O)NR10R11, —OS(O)pR7, —SS(O)pR7, —NR7S(O)pR7, —OS(O)pNR10R11, —SS(O)pNR10R11, —NR7S(O)pNR10R11, —OS(O)pOR7, —SS(O)pOR7, —NR7S(O)pOR7, —OC(S)R7, —SC(S)R7, —NR7C(S)R7, —OC(S)OR7, —SC(S)OR7, —NR7C(S)OR7, —OC(S)NR10R11, —SC(S)NR10R11, —NR7C(S)NR10R11, —OC(NR8)R7, —SC(NR8)R7, —NR7C(NR8)R7, —OC(NR8)OR7, —SC(NR8)OR7, —NR7C(NR8)OR7, —OC(NR8)NR10R11, —SC(NR8)NR10R11, or —NR7C(NR8)NR10R11; preferably, R105 is selected from the group consisting of —H, —OH, —SH, —NH2, a C1-C6 alkoxy, a C1-C6 alkyl amino, and a C1-C6 dialkyl amino, more preferably from the group consisting of —H, —OH, methoxy and ethoxy; and
R106, for each occurrence, is independently —H, an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, an optionally substituted heteraralkyl, halo, cyano, nitro, guanadino, a haloalkyl, a heteroalkyl, —NR10R11, —OR7, —C(O)R7, —C(O)OR7, —OC(O)R7, —C(O)NR10R11, —NR8C(O)R7, —SR7, —S(O)pR7, —OS(O)pR7, —S(O)pOR7, —NR8S(O)pR7, or —S(O)pNR10R11.
The remainder of the variables of the compounds of structural formula (LII) has values defined above with reference to structural formula (VI).
In one preferred set of values for the variables of the Hsp90 inhibitor represented by formula (LII), X101 is NR102, R102 is selected from the group consisting of —H, a C1-C6 alkyl, a C1-C6 cycloalkyl, —C(O)N(R27)2, and —C(O)OH, each R27, for each occurrence, is independently is —H or a lower alkyl, and the values for the remainder of the variables are as described above for formula (LII).
In a second preferred set of values for the variables of the Hsp90 inhibitor represented by formula (LII), X101 is NR102, R102 is selected from the group consisting of —H, methyl, ethyl, n-propyl, isopropyl, cyclopropyl, n-butyl, sec-butyl, tert-butyl, n-pentyl, n-hexyl, —C(O)OH, —(CH2)mC(O)OH, —CH2OCH3, —CH2CH2OCH3, and —C(O)N(CH3)2 and the values for the remainder of the variables are as described above for formula (LII).
In third preferred set of values for the variables of the Hsp90 inhibitor represented by formula (LII), X102 is CR104; Y is CR103; and R103 and R104 together with the carbon atoms to which they are attached form a cycloalkenyl, an aryl, heterocyclyl, or heteroaryl ring. Preferably, R103 and R104 together with the carbon atoms to which they are attached form a C5-C8 cycloalkenyl or a C5-C8 aryl and the values for the remainder of the variables are as described above for formula (LII).
In fourth preferred set of values for the variables of the Hsp90 inhibitor represented by formula (LII), R1 is —OH or —SH and the values for the remainder of the variables are as described above for formula (LII).
In another preferred embodiment, the Hsp90 inhibitor of the invention is represented by structural formula (LIII):




where X103 is CR104 or N and the remainder of the variables is defined above with reference with structural formulas (LII).

In another preferred embodiment, the Hsp90 inhibitor of the invention is represented by a structural formula selected from formulas (LIVa)-(LIVi):




The values for the variables in structural formulas (LIVa)-(LIVi) are as described in structural formulas (VI), (VII), and (VIII).

In one preferred set of values for the variables of the Hsp90 inhibitor represented by structural formulas (LIVa)-(LIVi):
R5 is as described for structural formula (VI), (VII), and (VIII) or a structural formula from Table 1;
R70 and R71, for each occurrence, are independently an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, an optionally substituted heteraralkyl, halo, cyano, nitro, guanadino, a haloalkyl, a heteroalkyl, alkoxy, haloalkoxy, —NR10R11, —OR7, —C(O)R7, —C(O)OR7, —C(S)R7, —C(O)SR7, —C(S)SR7, —C(S)OR7, —C(S)NR10R11, —C(NR8)OR7, —C(NR8)R7, —C(NR8)NR10R11, —C(NR8)SR7, —OC(O)R7, —OC(O)OR7, —OC(S)OR7, —OC(NR8)OR7, —SC(O)R7, —SC(O)OR7, —SC(NR8)OR7, —OC(S)R7, —SC(S)R7, —SC(S)OR7, —OC(O)NR10R11, —OC(S)NR10R11, —OC(NR8)NR10R11, —SC(O)NR10R11, —SC(NR8)NR10R11, —SC(S)NR10R11, —OC(NR8)R7, —SC(NR8)R7, —C(O)NR10R11, —NR8C(O)R7, —NR7C(S)R7, —NR7C(S)OR7, —NR7C(NR8)R7, —NR7C(O)OR7, —NR7C(NR8)OR7, —NR7C(O)NR10R11, —NR7C(S)NR10R11, —NR7C(NR8)NR10R11, —SR7, —S(O)pR7, —OS(O)pR7, —OS(O)pOR7, —OS(O)pNR10R11, —S(O)pOR7, —NR8S(O)pR7, —NR7S(O)pNR10R11, —NR7S(O)pOR7, —S(O)pNR10R11, —SS(O)pR7, —SS(O)pOR7, —SS(O)pNR10R11, —OP(O)(OR7)2, or —SP(O)(OR7)2;
z in structural formula (LIVa)-(LIVc) is zero or an integer from 1 to 4; z in structural formula (LIVd)-(LIVf) is zero or an integer from 1 to 3;
x is 0 or 1;
z+x in structural formula (LIVa)-(LIVc) is less than or equal to 4; and
the remainder of the variables in formulas (LIVa)-(LIVi) have values defined above with reference to structural formula (VI), (VII) and (VIII).
A second preferred set of values for the variables of the Hsp90 inhibitor represented by structural formula (LIVa)-(LIVc) is provided in the following paragraphs:
R71 is a halo, a haloalkyl, a haloalkoxy, a heteroalkyl, —OH, —SH, —NHR7, —(CH2)kOH, —(CH2)kSH, —(CH2)kNR7H, —OCH3, —SCH3, —NHCH3, —OCH2CH2OH, —OCH2CH2SH, —OCH2CH2NR7H, —SCH2CH2OH, —SCH2CH2SH, —SCH2CH2NR7H, —OC(O)NR10R11, —SC(O)NR10R11, —NR7C(O)NR10R11, —OC(O)R7, —SC(O)R7, —NR7C(O)R7, —OC(O)OR7, —SC(O)OR7, —NR7C(O)OR7, —OCH2C(O)R7, —SCH2C(O)R7, —NR7CH2C(O)R7, —OCH2C(O)OR7, —SCH2C(O)OR7, —NR7CH2C(O)OR7, —OCH2C(O)NR10R11, —SCH2C(O)NR10R11, —NR7CH2C(O)NR10R11, —OS(O)pR7, —SS(O)pR7, —NR7S(O)pR7, —OS(O)pNR10R11, —SS(O)pNR10R11, —NR7S(O)pNR10R11, —OS(O)pOR7, —SS(O)pOR7, —NR7S(O)pOR7, —OC(S)R7, —SC(S)R7, —NR7C(S)R7, —OC(S)OR7, —SC(S)OR7, —NR7C(S)OR7, —OC(S)NR10R11, —SC(S)NR10R11, —NR7C(S)NR10R11, —OC(NR8)R7, —SC(NR8)R7, —NR7C(NR8)R7, —OC(NR8)OR7, —SC(NR8)OR7, —NR7C(NR8)OR7, —OC(NR8)NR10R11, —SC(NR8)NR10R11, —NR7C(NR8)NR10R11, —C(O)R7, —C(O)OR7, —C(O)NR10R11, —C(O)SR7, —C(S)R7, —C(S)OR7, —C(S)NR10R11, —C(S)SR7, —C(NR8)OR7, —C(NR8)R7, —C(NR8)NR10R11, —C(NR8)SR7, —S(O)pOR7, —S(O)pNR10R11, or —S(O)pR7; and k is 1, 2, 3, or 4; and R1, R3, R70 and the remainder of the variables are as described in the first preferred set of values for the variables in structural formulas (LIVa)-(LIVc). Preferably, R1 and R3 are each, independently, —OH, —SH, or —NHR7.
A third preferred set of values for the variables of the Hsp90 inhibitor represented by formula (LIVa)-(LIVc) is provided in the following paragraphs:
R1 and R3 are each, independently, —OH, —SH, or —NHR7;
R70 is an optionally substituted alkyl or cycloalkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, cyano, halo, nitro, an optionally substituted cycloalkyl, haloalkyl, alkoxy, haloalkoxy, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, an optionally substituted heteroaralkyl, —OR7, —SR7, —NR10R11, —OC(O)NR10R11, —SC(O)NR10R11, —NR7C(O)NR10R11, —OC(O)R7, —SC(O)R7, —NR7C(O)R7, —OC(O)OR7, —SC(O)OR7, —NR7C(O)OR7, —OCH2C(O)R7, —SCH2C(O)R7, —NR7CH2C(O)R7, —OCH2C(O)OR7, —SCH2C(O)OR7, —NR7CH2C(O)OR7, —OCH2C(O)NR10R11, —SCH2C(O)NR10R11, —NR7CH2C(O)NR10R11, —OS(O)pR7, —SS(O)pR7, —NR7S(O)pR7, —OS(O)pNR10R11, —SS(O)pNR10R11, —NR7S(O)pNR10R11, —OS(O)pOR7, —SS(O)pOR7, —NR7S(O)pOR7, —OC(S)R7, —SC(S)R7, —NR7C(S)R7, —OC(S)OR7, —SC(S)OR7, —NR7C(S)OR7, —OC(S)NR10R11, —SC(S)NR10R11, —NR7C(S)NR10R11, —OC(NR8)R7, —SC(NR8)R7, —NR7C(NR8)R7, —OC(NR8)OR7, —SC(NR8)OR7, —NR7C(NR8)OR7, —OC(NR8)NR10R11, —SC(NR8)NR10R11, —NR7C(NR8)NR10R11, —C(O)R7, —C(O)OR7, —C(O)NR10R11, —C(O)SR7, —C(S)R7, —C(S)OR7, —C(S)NR10R11, —C(S)SR7, —C(NR8)OR7, —C(NR8)R7, —C(NR8)NR10R11, —C(NR8)SR7, —S(O)pOR7, —S(O)pNR10R11, or —S(O)pR7 and R1 and R3 and the remainder of the variables are as described in the second preferred set of values for the variables in structural formulas (LIVa)-(LIVc).
In a fourth preferred set of values for the variables of Structural Formulas (LIVa)-(LIVc):
R1 is —SH or —OH;
R3 and R71 are —OH;
R70 is a C1-C6 alkyl, a C3-C6 cycloalkyl, a C1-C6 alkoxy, a C1-C6 haloalkoxy, a C1-C6 alkyl sulfanyl, or —NR10R11; and
The remainder of the variables are as defined in Structural Formula (VI)-(VIII).
In another preferred embodiment, the Hsp90 inhibitor is represented by a structural formula selected from formulas (LVa)-(LVf):




In formulas (LVa) and (LVb):

R5 is as described for structural formula (VI) or a structural formula from Table 1;
X3′ and X4′ are each, independently, N, N(O), N+(R17), CH or CR70;
X5′ is O, S, NR17, CH2, CH(R70), C(R70)2, CH═CH, CH═CR70, CR70═CH, CR70═CR70, CH═N, CR70═N, CH═N(O), CR70═N(O), N═CH, N═CR70, N(O)═CH, N(O)═CR70, N+(R17)═CH, N+(R17)═CR70, CH═N+(R17), CR70═N+(R17), or N═N, provided that at least one X3′, X4′ or X5′ is a heteroatom;
R70, for each occurrence, is independently an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, an optionally substituted heteraralkyl, halo, cyano, nitro, guanadino, a haloalkyl, a heteroalkyl, alkoxy, haloalkoxy, —NR10R11, —OR7, —C(O)R7, —C(O)OR7, —C(S)R7, —C(O)SR7, —C(S)SR7, —C(S)OR7, —C(S)NR10R11, —C(NR8)OR7, —C(NR8)R7, —C(NR8)NR10R11, —C(NR8)SR7, —OC(O)R7, —OC(O)OR7, —OC(S)OR7, —OC(NR8)OR7, —SC(O)R7, —SC(O)OR7, —SC(NR8)OR7, —OC(S)R7, —SC(S)R7, —SC(S)OR7, —OC(O)NR10R11, —OC(S)NR10R11, —OC(NR8)NR10R11, —SC(O)NR10R11, —SC(NR8)NR10R11, —SC(S)NR10R11, —OC(NR8)R7, —SC(NR8)R7, —C(O)NR10R11, —NR8C(O)R7, —NR7C(S)R7, —NR7C(S)OR7, —NR7C(NR8)R7, —NR7C(O)OR7, —NR7C(NR8)OR7, —NR7C(O)NR10R11, —NR7C(S)NR10R11, —NR7C(NR8)NR10R11, —SR7, —S(O)pR7, —OS(O)pR7, —OS(O)pOR7, —OS(O)pNR10R11, —S(O)pOR7, —NR8S(O)pR7, —NR7S(O)pNR10R11, —NR7S(O)pOR7, —S(O)pNR10R11, —SS(O)pR7, —SS(O)pOR7, —SS(O)pNR10R11, —OP(O)(OR7)2, or —SP(O)(OR7)2;
R17, for each occurrence, is independently an alkyl or an aralkyl; and n is zero or an integer from 1 to 4; and
the remainder of the variables has values defined above with reference to structural formulas (VI), (VII), and (VIII).
Preferably, Hsp90 inhibitor of structural formulas (LVa)-(LVf) are selected from Table 2a-c.










TABLE 2a







Number 
Compound



















1.







 



2.







 



3.







 



4.







 



5.







 



6.







 



7.







 



8.







 



9.







 



10.
























TABLE 2b







Number
Compound



















1







 



2







 



3







 



4







 



5







 



6







 



7







 



8







 



9







 



10
























TABLE 2c







Number
Compound



















1







 



2







 



3







 



4







 



5







 



6







 



7







 



8







 



9







 



10














The values for the variables for the formulas in Tables 2a-c are as defined for structural formulas (LVa)-(LVf). Preferably, R70 is a halo, a haloalkyl, a haloalkoxy, a heteroalkyl, —OH, —SH, —NHR7, —(CH2)kOH, —(CH2)kSH, —(CH2)kNR7H, —OCH3, —SCH3, —NHCH3, —OCH2CH2OH, —OCH2CH2SH, —OCH2CH2NR7H, —SCH2CH2OH, —SCH2CH2SH, —SCH2CH2NR7H, —OC(O)NR10R11, —SC(O)NR10R11, —NR7C(O)NR10R11, —OC(O)R7, —SC(O)R7, —NR7C(O)R7, —OC(O)OR7, —SC(O)OR7, —NR7C(O)OR7, —OCH2C(O)R7, —SCH2C(O)R7, —NR7CH2C(O)R7, —OCH2C(O)OR7, —SCH2C(O)OR7, —NR7CH2C(O)OR7, —OCH2C(O)NR10R11, —SCH2C(O)NR10R11, —NR7CH2C(O)NR10R11, —OS(O)pR7, —SS(O)pR7, —NR7S(O)pR7, —OS(O)pNR10R11, —SS(O)pNR10R11, —NR7S(O)pNR10R11, —OS(O)pOR7, —SS(O)pOR7, —NR7S(O)pOR7, —OC(S)R7, —SC(S)R7, —NR7C(S)R7, —OC(S)OR7, —SC(S)OR7, —NR7C(S)OR7, —OC(S)NR10R11, —SC(S)NR10R11, —NR7C(S)NR10R11, —OC(NR8)R7, —SC(NR8)R7, —NR7C(NR8)R7, —OC(NR8)OR7, —SC(NR8)OR7, —NR7C(NR8)OR7, —OC(NR8)NR10R11, —SC(NR8)NR10R11, —NR7C(NR8)NR10R11, —C(O)R7, —C(O)OR7, —C(O)NR10R11, —C(O)SR7, —C(S)R7, —C(S)OR7, —C(S)NR10R11, —C(S)SR7, —C(NR8)OR7, —C(NR8)R7, —C(NR8)NR10R11, —C(NR8)SR7, —S(O)pOR7, —S(O)pNR10R11, or —S(O)pR7; and

k is 1, 2, 3, or 4.
In another preferred embodiment, the Hsp90 inhibitor of the present invention is represented by structural formula (LVI):




R70 and R71, for each occurrence, are independently an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, an optionally substituted heteraralkyl, halo, cyano, nitro, guanadino, a haloalkyl, a heteroalkyl, alkoxy, haloalkoxy, —NR10R11, —OR7, —C(O)R7, —C(O)OR7, —C(S)R7, —C(O)SR7, —C(S)SR7, —C(S)OR7, —C(S)NR10R11, —C(NR8)OR7, —C(NR8)R7, —C(NR8)NR10R11, —C(NR8)SR7, —OC(O)R7, —OC(O)OR7, —OC(S)OR7, —OC(NR8)OR7, —SC(O)R7, —SC(O)OR7, —SC(NR8)OR7, —OC(S)R7, —SC(S)R7, —SC(S)OR7, —OC(O)NR10R11, —OC(S)NR10R11, —OC(NR8)NR10R11, —SC(O)NR10R11, —SC(NR8)NR10R11, —SC(S)NR10R11, —OC(NR8)R7, —SC(NR8)R7, —C(O)NR10R11, —NR8C(O)R7, —NR7C(S)R7, —NR7C(S)OR7, —NR7C(NR8)R7, —NR7C(O)OR7, —NR7C(NR8)OR7, —NR7C(O)NR10R11, —NR7C(S)NR10R11, —NR7C(NR8)NR10R11, —SR7, —S(O)pR7, —OS(O)pR7, —OS(O)pOR7, —OS(O)pNR10R11, —S(O)pOR7, —NR8S(O)pR7, —NR7S(O)pNR10R11, —NR7S(O)pOR7, —S(O)pNR10R11, —SS(O)pR7, —SS(O)pOR7, —SS(O)pNR10R11, —OP(O)(OR7)2, or —SP(O)(OR7)2. Preferably, R70 is selected from an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, cyano, halo, nitro, an optionally substituted cycloalkyl, haloalkyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, an optionally substituted heteroaralkyl, —OR7, —SR7, —NR10R11, —OC(O)NR10R11, —SC(O)NR10R11, —NR7C(O)NR10R11, —OC(O)R7, —SC(O)R7, —NR7C(O)R7, —OC(O)OR7, —SC(O)OR7, —NR7C(O)OR7, —OCH2C(O)R7, —SCH2C(O)R7, —NR7CH2C(O)R7, —OCH2C(O)OR7, —SCH2C(O)OR7, —NR7CH2C(O)OR7, —OCH2C(O)NR10R11, —SCH2C(O)NR10R11, —NR7CH2C(O)NR10R11, —OS(O)pR7, —SS(O)pR7, —NR7S(O)pR7, —OS(O)pNR10R11, —SS(O)pNR10R11, —NR7S(O)pNR10R11, —OS(O)pOR7, —SS(O)pOR7, —NR7S(O)pOR7, —OC(S)R7, —SC(S)R7, —NR7C(S)R7, —OC(S)OR7, —SC(S)OR7, —NR7C(S)OR7, —OC(S)NR10R11, —SC(S)NR10R11, —NR7C(S)NR10R11, —OC(NR8)R7, —SC(NR8)R7, —NR7C(NR8)R7, —OC(NR8)OR7, —SC(NR8)OR7, —NR7C(NR8)OR7, —OC(NR8)NR10R11, —SC(NR8)NR10R11, —NR7C(NR8)NR10R11, —C(O)R7, —C(O)OR7, —C(O)NR10R11, —C(O)SR7, —C(S)R7, —C(S)OR7, —C(S)NR10R11, —C(S)SR7, —C(NR8)OR7, —C(NR8)R7, —C(NR8)NR10R11, —C(NR8)SR7, —S(O)pOR7, —S(O)pNR10R11, or —S(O)pR7 and R71 is as just described. The values for the remainder of the variables are as described for structural formulas (VI), (VII), and (VIII).
In another preferred embodiment, the Hsp90 inhibitors is represented by structural formula (LVIIa) or (LVIIb):




The variables in formulas (LVIIa) and (LVIIb) are defined above with reference to formula (LVI).

A first preferred set of values for the variables of structural formula (LVIIa) and (LVIIb) is provided in the following paragraph:
R1, R3 or R71 are each independently selected from —OH, —SH, —NHR7, —OC(O)NR10R11, —SC(O)NR10R11, —OC(O)R7, —SC(O)R7, —OC(O)OR7, —SC(O)OR7, —OS(O)pR7, —S(O)pOR7, —SS(O)pR7, —OS(O)pOR7, —SS(O)pOR7, —OC(S)R7, —SC(S)R7, —OC(S)OR7, —SC(S)OR7, —OC(S)NR10R11, —SC(S)NR10R11, —OC(NR8)R7, —SC(NR8)R7, —OC(NR8)OR7, —SC(NR8)OR7, —OP(O)(OR7)2 or —SP(O)(OR7)2, and p, R70, R7, R8, R10, R11 and R30 are as described for structural formula (LVI). Preferably, when R1, R3 and R71 have these values, R10 and R11 are preferably each independently a hydrogen, a C1-C6 straight or branched alkyl, optionally substituted by —OH, —CN, —SH, amino, a C1-C6 alkoxy, alkylsulfanyl, alkylamino, dialkylamino or a cycloalkyl; or R10 and R11 taken together with the nitrogen to which they are attached form a substituted or unsubstituted nonaromatic, nitrogen-containing heterocyclyl; and p, R70, R7, and R30 are as described for structural formula (LVI). More preferably, when R1, R3, R10, R11, and R71 have these values, R70 is preferably a C1-C6 alkyl, a C1-C6 haloalkyl, a C1-C6 alkoxy, a C1-C6 haloalkoxy, a C1-C6 alkyl sulfanyl or a C3-C6 cycloalkyl; and p, R7, R8 and R30 are as described for structural formula (LVI).
A second preferred set of values for the variables of structural formula (LVIIa) and (LVIIb) is provided in the following paragraph:
R1 and R3 are each independently —OH or —SH; R70 is preferably a C1-C6 alkyl, a C1-C6 haloalkyl, a C1-C6 alkoxy, a C1-C6 haloalkoxy, a C1-C6 alkyl sulfanyl or a C3-C6 cycloalkyl; R10 and R11 are preferably each independently a hydrogen, a C1-C6 straight or branched alkyl, optionally substituted by —OH, —CN, —SH, amino, a C1-C6 alkoxy, alkylsulfanyl, alkylamino, dialkylamino or a cycloalkyl; or R10 and R11 taken together with the nitrogen to which they are attached form a substituted or unsubstituted nonaromatic, nitrogen-containing heterocyclyl; R71 is —OH, —SH, —NHR7, —OC(O)NR10R11, —SC(O)NR10R11, —OC(O)R7, —SC(O)R7, —OC(O)OR7, —SC(O)OR7, —OS(O)pR7, —S(O)pOR7, —SS(O)pR7, —OS(O)pOR7, —SS(O)pOR7, —OC(S)R7, —SC(S)R7, —OC(S)OR7, —SC(S)OR7, —OC(S)NR10R11, —SC(S)NR10R11, —OC(NR8)R7, —SC(NR8)R7, —OC(NR8)OR7, —SC(NR8)OR7, —OP(O)(OR7)2 or —SP(O)(OR7)2; and p, R7 R8 and R30 are as described for structural formula (LVI). Preferably, R30 is a —OH, —SH, halogen, cyano, a C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy or C1-C6 alkyl sulfanyl and the remainder of the variables are as just described.
A third preferred set of values for the variables of structural formula (LVIIa) and (LVIIb) is provided in the following paragraph:
R1, R3 and R71 are independently —SH or —OH; R70 is cyclopropyl or isopropyl; R10 and R11 are each independently a hydrogen, a C1-C6 straight or branched alkyl, optionally substituted by —OH, —CN, —SH, amino, a C1-C6 alkoxy, alkylsulfanyl, alkylamino, dialkylamino or a cycloalkyl; or R10 and R11 taken together with the nitrogen to which they are attached form a substituted or unsubstituted nonaromatic, nitrogen-containing heterocyclyl; and R30 is —OH, —SH, halogen, cyano, a C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy or C1-C6 alkyl sulfanyl. Preferably, R30 is a methyl, ethyl, propyl, isopropyl, methoxy or ethoxy. More preferably, R1, R3, R70, R71 and R30 are as just described and R10 and R11 are each independently a hydrogen, methyl, ethyl, propyl, isopropyl, or taken together with the nitrogen to which they are attached, are:




wherein R35 is —H, a C1-C4 alkyl or a C1-C4 acyl.
In another preferred embodiment, the Hsp90 inhibitor is represented by structural formulas (LVIIIa) or (LVIIIb):




The values for the variables in structural formulas (LVIIIa) and (LVIIIb) are as described for structural formulas (LVc) and (LVd). Preferably, R30 is an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, an optionally substituted heteraralkyl, halo, cyano, nitro, guanadino, a haloalkyl, a heteroalkyl, alkoxy, haloalkoxy, —NR10R11, —OR7, —C(O)R7, —C(O)OR7, —C(S)R7, —C(O)SR7, —C(S)SR7, —C(S)OR7, —C(S)NR10R11, —C(NR8)OR7, —C(NR8)R7, —C(NR8)NR10R11, —C(NR8)SR7, —OC(O)R7, —OC(O)OR7, —OC(S)OR7, —OC(NR8)OR7, —SC(O)R7, —SC(O)OR7, —SC(NR8)OR7, —OC(S)R7, —SC(S)R7, —SC(S)OR7, —OC(O)NR10R11, —OC(S)NR10R11, —OC(NR8)NR10R11, —SC(O)NR10R11, —SC(NR8)NR10R11, —SC(S)NR10R11, —OC(NR8)R7, —SC(NR8)R7, —C(O)NR10R11, —NR8C(O)R7, —NR7C(S)R7, —NR7C(S)OR7, —NR7C(NR8)R7, —NR7C(O)OR7, —NR7C(NR8)OR7, —NR7C(O)NR10R11, —NR7C(S)NR10R11, —NR7C(NR8)NR10R11, —SR7, —S(O)pR7, —OS(O)pR7, —OS(O)pOR7, —OS(O)pNR10R11, —S(O)pOR7, —NR8S(O)pR7, —NR7S(O)pNR10R11, —NR7S(O)pOR7, —S(O)pNR10R11, —SS(O)pR7, —SS(O)pOR7, —SS(O)pNR10R11, —OP(O)(OR7)2, or —SP(O)(OR7)2. More preferably, R30 is an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, cyano, halo, nitro, an optionally substituted cycloalkyl, haloalkyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, an optionally substituted heteroaralkyl, —OR7, —SR7, —NR10R11, —OC(O)NR10R11, —SC(O)NR10R11, —NR7C(O)NR10R11, —OC(O)R7, —SC(O)R7, —NR7C(O)R7, —OC(O)OR7, —SC(O)OR7, —NR7C(O)OR7, —OCH2C(O)R7, —SCH2C(O)R7, —NR7CH2C(O)R7, —OCH2C(O)OR7, —SCH2C(O)OR7, —NR7CH2C(O)OR7, —OCH2C(O)NR10R11, —SCH2C(O)NR10R11, —NR7CH2C(O)NR10R11, —OS(O)pR7, —SS(O)pR7, —NR7S(O)pR7, —OS(O)pNR10R11, —SS(O)pNR10R11, —NR7S(O)pNR10R11, —OS(O)pOR7, —SS(O)pOR7, —NR7S(O)pOR7, —OC(S)R7, —SC(S)R7, —NR7C(S)R7, —OC(S)OR7, —SC(S)OR7, —NR7C(S)OR7, —OC(S)NR10R11, —SC(S)NR10R11, —NR7C(S)NR10R11, —OC(NR8)R7, —SC(NR8)R7, —NR7C(NR8)R7, —OC(NR8)OR7, —SC(NR8)OR7, —NR7C(NR8)OR7, —OC(NR8)NR10R11, —SC(NR8)NR10R11, —NR7C(NR8)NR10R11, —C(O)R7, —C(O)OR7, —C(O)NR10R11, —C(O)SR7, —C(S)R7, —C(S)OR7, —C(S)NR10R11, —C(S)SR7, —C(NR8)OR7, —C(NR8)R7, —C(NR8)NR10R11, —C(NR8)SR7, —S(O)pOR7, —S(O)pNR10R11, or —S(O)pR7.
In another preferred embodiment, the Hsp90 inhibitor is represented by a structural formula selected from formulas (LIXa)-(LIXd):




The values of the variables in structural formulas (LIXa)-(LIXd) are defined above with reference to structural formulas (LVIIIa) and (LVIIIb).

A first preferred set of values for the variables in structural formulas (LIXa)-(LIXd) are as described in the following paragraphs:
R1 and R3 are each independently —OH or —SH, —HNR7, —OC(O)NR10R11, —SC(O)NR10R11, —OC(O)R7, —SC(O)R7, —OC(O)OR7, —SC(O)OR7, —OS(O)pR7, —S(O)pOR7, —SS(O)pR7, —OS(O)pOR7, —SS(O)pOR7, —OC(S)R7, —SC(S)R7, —OC(S)OR7, —SC(S)OR7, —OC(S)NR10R11, —SC(S)NR10R11, —OC(NR8)R7, —SC(NR8)R7, —OC(NR8)OR7, —SC(NR8)OR7, —OP(O)(OR7)2 or —SP(O)(OR7)2;
R70, for each occurrence, is independently an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, —OH, —SH, —HNR7, —OC(O)NR10R11, —SC(O)NR10R11, —OC(O)R7, —SC(O)R7, —OC(O)OR7, —SC(O)OR7, —OS(O)pR7, —S(O)pOR7, —SS(O)pR7, —OS(O)pOR7, —SS(O)pOR7, —OC(S)R7, —SC(S)R7, —OC(S)OR7, —SC(S)OR7, —OC(S)NR10R11, —SC(S)NR10R11, —OC(NR8)R7, —SC(NR8)R7, —OC(NR8)OR7, —SC(NR8)OR7, —OP(O)(OR7)2 or —SP(O)(OR7)2. Preferably, R70 is a C1-C6 alkyl, a C1-C6 haloalkyl, a C1-C6 alkoxy, a C1-C6 haloalkoxy, a C1-C6 alkyl sulfanyl or a C3-C6 cycloalkyl; and
R10 and R11 and the remainder of the variables in structural formulas (LIXa)-(LIXd) are as described for structural formulas (LVIIIa) and (LVIIIb). Preferably, R10 and R11 are each independently a hydrogen, a C1-C6 straight or branched alkyl, optionally substituted by —OH, —CN, —SH, amino, a C1-C6 alkoxy, alkylsulfanyl, alkylamino, dialkylamino or a cycloalkyl; or R10 and R11 taken together with the nitrogen to which they are attached form a substituted or unsubstituted nonaromatic, nitrogen-containing heterocyclyl.
In another preferred embodiment, the Hsp90 inhibitor is represented by a structural formula selected from formulas (LXa)-(LXp):










The values of the variables in structural formulas (LXa)-(LXp) are defined above with reference to structural formulas (XIXa)-(XIXd).

A first preferred set of values for the variables in structural formulas (LX) are as described in the following paragraphs:
R1 and R3 are each independently —OH or —SH, or —HNR7;
R70, is a C1-C6 alkyl, a C1-C6 haloalkyl, a C1-C6 alkoxy, a C1-C6 haloalkoxy, a C1-C6 alkyl sulfanyl or a C3-C6 cycloalkyl;
R10 and R11 and the remainder of the variables in structural formulas (LXa)-(LXp) are as described for structural formulas (LVIIIa) and (LVIIIb). Preferably, R10 and R11 are each independently a hydrogen, a C1-C6 straight or branched alkyl, optionally substituted by —OH, —CN, —SH, amino, a C1-C6 alkoxy, alkylsulfanyl, alkylamino, dialkylamino or a cycloalkyl; or R10 and R11 taken together with the nitrogen to which they are attached form a substituted or unsubstituted nonaromatic, nitrogen-containing heterocyclyl; and
R30 and the remainder of the variables in structural formulas (LXa)-(LXp) are as described for structural formulas (LIXa)-(LIXd). Preferably, R30 is —OH, —SH, halogen, cyano, a C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy or C1-C6 alkyl sulfanyl.
A second preferred set of values for the variables in structural formulas (LXa)-(LXp) are as described in the following paragraphs:
R1 and R3 are independently —SH or —OH;
R70 is cyclopropyl or isopropyl;
R10 and R11 are each independently a hydrogen, a C1-C6 straight or branched alkyl, optionally substituted by —OH, —CN, —SH, amino, a C1-C6 alkoxy, alkylsulfanyl, alkylamino, dialkylamino or a cycloalkyl; or R10 and R11 taken together with the nitrogen to which they are attached form a substituted or unsubstituted nonaromatic, nitrogen-containing heterocyclyl;
R30 is —OH, —SH, halogen, cyano, a C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy or C1-C6 alkyl sulfanyl. Preferably, R30 is a methyl, ethyl, propyl, isopropyl, methoxy or ethoxy; and the remainder of the variables are as described for formulas (LVIIIa) and (LVIIIb). More preferably, R10 and R11 are each independently a hydrogen, methyl, ethyl, propyl, isopropyl, or taken together with the nitrogen to which they are attached, are:




    
    
        wherein R35 is —H, a C1-C4 alkyl or a C1-C4 acyl.
    
    


In another embodiment, the Hsp90 inhibitor of the present invention is represented by structural formulas (LXIa) or (LXIb):




In formulas (LXIa) and (LXIb):

X14 is O, S, or NR7. Preferably, X14 is O;
R1 is —OH, —SH, —NR7H, —OR26, —SR26, —NHR26, —O(CH2)mOH, —O(CH2)mSH, —O(CH2)mNR7H, —S(CH2)mOH, —S(CH2)mSH, —S(CH2)mNR7H, —OC(O)NR10R11, —SC(O)NR10R11, —NR7C(O)NR10R11, —OC(O)R7, —SC(O)R7, —NR7C(O)R7, —OC(O)OR7, —SC(O)OR7, —NR7C(O)OR7, —OCH2C(O)R7, —SCH2C(O)R7, —NR7CH2C(O)R7, —OCH2C(O)OR7, —SCH2C(O)OR7, —NR7CH2C(O)OR7, —OCH2C(O)NR10R11, —SCH2C(O)NR10R11, —NR7CH2C(O)NR10R11, —OS(O)pR7, —SS(O)pR7, —S(O)pOR7, —NR7S(O)pR7, —OS(O)pNR10R11, —SS(O)pNR10R11, —NR7S(O)pNR10R11, —OS(O)pOR7, —SS(O)pOR7, —NR7S(O)pOR7, —OC(S)R7, —SC(S)R7, —NR7C(S)R7, —OC(S)OR7, —SC(S)OR7, —NR7C(S)OR7, —OC(S)NR10R11, —SC(S)NR10R11, —NR7C(S)NR10R11, —OC(NR8)R7, —SC(NR8)R7, —NR7C(NR8)R7, —OC(NR8)OR7, —SC(NR8)OR7, —NR7C(NR8)OR7, —OC(NR8)NR10R11, —SC(NR8)NR10R11, —NR7C(NR8)NR10R11, —OP(O)(OR7)2, or —SP(O)(OR7)2. Preferably, R1 is —OH, —SH, or —NHR7;
R3 is —OH, —SH, —NR7H, —OR26, —SR26, —NHR26, —O(CH2)mOH, —O(CH2)mSH, —O(CH2)mNR7H, —S(CH2)mOH, —S(CH2)mSH, —S(CH2)mNR7H, —OC(O)NR10R11, —SC(O)NR10R11, —NR7C(O)NR10R11, —OC(O)R7, —SC(O)R7, —NR7C(O)R7, —OC(O)OR7, —SC(O)OR7, —NR7C(O)OR7, —OCH2C(O)R7, —SCH2C(O)R7, —NR7CH2C(O)R7, —OCH2C(O)OR7, —SCH2C(O)OR7, —NR7CH2C(O)OR7, —OCH2C(O)NR10R11, —SCH2C(O)NR10R11, —NR7CH2C(O)NR10R11, —OS(O)pR7, —SS(O)pR7, —S(O)pOR7, —NR7S(O)pR7, —OS(O)pNR10R11, —SS(O)pNR10R11, —NR7S(O)pNR10R11, —OS(O)pOR7, —SS(O)pOR7, —NR7S(O)pOR7, —OC(S)R7, —SC(S)R7, —NR7C(S)R7, —OC(S)OR7, —SC(S)OR7, —NR7C(S)OR7, —OC(S)NR10R11, —SC(S)NR10R11, —NR7C(S)NR10R11, —OC(NR8)R7, —SC(NR8)R7, —NR7C(NR8)R7, —OC(NR8)OR7, —SC(NR8)OR7, —NR7C(NR8)OR7, —OC(NR8)NR10R11, —SC(NR8)NR10R11, —NR7C(NR8)NR10R11, —C(O)OH, —C(O)NHR8, —C(O)SH, —S(O)OH, —S(O)2OH, —S(O)NHR8, —S(O)2NHR8, —OP(O)(OR7)2, or —SP(O)(OR7)2;
R7 and R8, for each occurrence, are, independently, —H, an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, or an optionally substituted heteraralkyl;
R10 and R11, for each occurrence, are independently —H, an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, or an optionally substituted heteraralkyl; or R10 and R11, taken together with the nitrogen to which they are attached, form an optionally substituted heterocyclyl or an optionally substituted heteroaryl;
R21 is an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, or an optionally substituted heteraralkyl. Preferably, R21 is an optionally substituted alkyl, an optionally substituted cycloalkyl, an optionally substituted aryl or an optionally substituted heteroaryl. Alternatively, R21 is




wherein
R10 and R11 is defined as above; and
R30 is an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, an optionally substituted heteraralkyl, halo, cyano, nitro, guanadino, a haloalkyl, a heteroalkyl, alkoxy, haloalkoxy, —NR10R11, —OR7, —C(O)R7, —C(O)OR7, —C(S)R7, —C(O)SR7, —C(S)SR7, —C(S)OR7, —C(S)NR10R11, —C(NR8)OR7, —C(NR8)R7, —C(NR8)NR10R11, —C(NR8)SR7, —OC(O)R7, —OC(O)OR7, —OC(S)OR7, —OC(NR8)OR7, —SC(O)R7, —SC(O)OR7, —SC(NR8)OR7, —OC(S)R7, —SC(S)R7, —SC(S)OR7, —OC(O)NR10R11, —OC(S)NR10R11, —OC(NR8)NR10R11, —SC(O)NR10R11, —SC(NR8)NR10R11, —SC(S)NR10R11, —OC(NR8)R7, —SC(NR8)R7, —C(O)NR10R11, —NR8C(O)R7, —NR7C(S)R7, —NR7C(S)OR7, —NR7C(NR8)R7, —NR7C(O)OR7, —NR7C(NR8)OR7, —NR7C(O)NR10R11, —NR7C(S)NR10R11, —NR7C(NR8)NR10R11, —SR7, —S(O)pR7, —OS(O)pR7, —OS(O)pOR7, —OS(O)pNR10R11, —S(O)pOR7, —NR8S(O)pR7, —NR7S(O)pNR10R11, —NR7S(O)pOR7, —S(O)pNR10R11, —SS(O)pR7, —SS(O)pOR7, —SS(O)pNR10R11, —OP(O)(OR7)2, or —SP(O)(OR7)2;
z and q are independently an integer from 0 to 4; and
x is 0 or 1, provided that z+x less than or equal to 4.
R22, for each occurrence, is independently a substituent selected from the group consisting of H, an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, or an optionally substituted heteraralkyl, a haloalkyl, —C(O)R7, —C(O)OR7, —OC(O)R7, —C(O)NR10R11, —NR8C(O)R7, —S(O)pR7, —S(O)pOR7, or —S(O)pNR10R11. Preferably, R22 is an alkyl, an aralkyl, —C(O)R7, —C(O)OR7, or —C(O)NR10R11; and
R23 and R24, for each occurrence, are independently a substituent selected from the group consisting of H, an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, or an optionally substituted heteraralkyl, halo, cyano, nitro, guanadino, a haloalkyl, a heteroalkyl, —NR10R11, —OR7, —C(O)R7, —C(O)OR7, —OC(O)R7, —C(O)NR10R11, —NR8C(O)R7, —SR7, —S(O)pR7, —OS(O)pR7, —S(O)pOR7, —NR8S(O)pR7, or —S(O)pNR10R11;
R26 is a lower alkyl;
p, for each occurrence, is, independently, 0, 1 or 2; and
m, for each occurrence, is independently, 1, 2, 3, or 4.
In one embodiment, a compound of the present invention is represented by a structural formula selected from formulas (IX), (X) and (XI):




In formulas (IX)-(XI):

ring A is an aryl or a heteroaryl, optionally further substituted with one or more substituents in addition to R3. Preferably, Ring A is represented one of the following structural formulas:




wherein z is 0, 1, 2, 3 or 4; x is 0 or 1; and z+x is less than or equal to 4.
R1 is —OH, —SH, —NR7H, —OR26, —SR26, —NHR26, —O(CH2)mOH, —O(CH2)mSH, —O(CH2)mNR7H, —S(CH2)mOH, —S(CH2)mSH, —S(CH2)mNR7H, —OC(O)NR10R11, —SC(O)NR10R11, —NR7C(O)NR10R11, —OC(O)R7, —SC(O)R7, —NR7C(O)R7, —OC(O)OR7, —SC(O)OR7, —NR7C(O)OR7, —OCH2C(O)R7, —SCH2C(O)R7, —NR7CH2C(O)R7, —OCH2C(O)OR7, —SCH2C(O)OR7, —NR7CH2C(O)OR7, —OCH2C(O)NR10R11, —SCH2C(O)NR10R11, —NR7CH2C(O)NR10R11, —OS(O)pR7, —SS(O)pR7, —S(O)pOR7, —NR7S(O)pR7, —OS(O)pNR10R11, —SS(O)pNR10R11, —NR7S(O)pNR10R11, —OS(O)pOR7, —SS(O)pOR7, —NR7S(O)pOR7, —OC(S)R7, —SC(S)R7, —NR7C(S)R7, —OC(S)OR7, —SC(S)OR7, —NR7C(S)OR7, —OC(S)NR10R11, —SC(S)NR10R11, —NR7C(S)NR10R11, —OC(NR8)R7, —SC(NR8)R7, —NR7C(NR8)R7, —OC(NR8)OR7, —SC(NR8)OR7, —NR7C(NR8)OR7, —OC(NR8)NR10R11, —SC(NR8)NR10R11, —NR7C(NR8)NR10R11, —OP(O)(OR7)2, or —SP(O)(OR7)2. Preferably, R1 is —OH, —SH, —NHR7, —OC(O)NR10R11, —SC(O)NR10R11, —OC(O)R7, —SC(O)R7, —OC(O)OR7, —SC(O)OR7, —OS(O)pR7, —S(O)pOR7, —SS(O)pR7, —OS(O)pOR7, —SS(O)pOR7, —OC(S)R7, —SC(S)R7, —OC(S)OR7, —SC(S)OR7, —OC(S)NR10R11, —SC(S)NR10R11, —OC(NR8)R7, —SC(NR8)R7, —OC(NR8)OR7, —SC(NR8)OR7, —OP(O)(OR7)2 or —SP(O)(OR7)2. More preferably, R1 is —OH, —SH, or —NHR7. Even more preferably, R1, is —SH or —OH;
R2′ is an optionally substituted phenyl group. Preferably, R2′ is substituted with one or more group represented by R30, wherein R30, for each occurrence, are independently an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, an optionally substituted heteraralkyl, halo, cyano, nitro, guanadino, a haloalkyl, a heteroalkyl, alkoxy, haloalkoxy, —NR10R11, —OR7, —C(O)R7, —C(O)OR7, —C(S)R7, —C(O)SR7, —C(S)SR7, —C(S)OR7, —C(S)NR10R11, —C(NR8)OR7, —C(NR8)R7, —C(NR8)NR10R11, —C(NR8)SR7, —OC(O)R7, —OC(O)OR7, —OC(S)OR7, —OC(NR8)OR7, —SC(O)R7, —SC(O)OR7, —SC(NR8)OR7, —OC(S)R7, —SC(S)R7, —SC(S)OR7, —OC(O)NR10R11, —OC(S)NR10R11, —OC(NR8)NR10R11, —SC(O)NR10R11, —SC(NR8)NR10R11, —SC(S)NR10R11, —OC(NR8)R7, —SC(NR8)R7, —C(O)NR10R11, —NR8C(O)R7, —NR7C(S)R7, —NR7C(S)OR7, —NR7C(NR8)R7, —NR7C(O)OR7, —NR7C(NR8)OR7, —NR7C(O)NR10R11, —NR7C(S)NR10R11, —NR7C(NR8)NR10R11, —SR7, —S(O)pR7, —OS(O)pR7, —OS(O)pOR7, —OS(O)pNR10R11, —S(O)pOR7, —NR8S(O)pR7, —NR7S(O)pNR10R11, —NR7S(O)pOR7, —S(O)pNR10R11, —SS(O)pR7, —SS(O)pOR7, —SS(O)pNR10R11, —OP(O)(OR7)2, or —SP(O)(OR7)2. More preferably, R2′ is an optionally substituted indolyl group or a phenyl group substituted with NR10R11 and optionally with at least one other substitutent represented by R30;
R3 is —OH, —SH, —NR7H, —NHR26, —O(CH2)mOH, —O(CH2)mSH, —O(CH2)mNR7H, —S(CH2)mOH, —S(CH2)mSH, —S(CH2)mNR7H, —OC(O)NR10R11, —SC(O)NR10R11, —NR7C(O)NR10R11, —OC(O)R7, —SC(O)R7, —NR7C(O)R7, —OC(O)OR7, —SC(O)OR7, —NR7C(O)OR7, —OCH2C(O)R7, —SCH2C(O)R7, —NR7CH2C(O)R7, —OCH2C(O)OR7, —SCH2C(O)OR7, —NR7CH2C(O)OR7, —OCH2C(O)NR10R11, —SCH2C(O)NR10R11, —NR7CH2C(O)NR10R11, —OS(O)pR7, —SS(O)pR7, —S(O)pOR7, —NR7S(O)pR7, —OS(O)pNR10R11, —SS(O)pNR10R11, —NR7S(O)pNR10R11, —OS(O)pOR7, —SS(O)pOR7, —NR7S(O)pOR7, —OC(S)R7, —SC(S)R7, —NR7C(S)R7, —OC(S)OR7, —SC(S)OR7, —NR7C(S)OR7, —OC(S)NR10R11, —SC(S)NR10R11, —NR7C(S)NR10R11, —OC(NR8)R7, —SC(NR8)R7, —NR7C(NR8)R7, —OC(NR8)OR7, —SC(NR8)OR7, —NR7C(NR8)OR7, —OC(NR8)NR10R11, —SC(NR8)NR10R11, —NR7C(NR8)NR10R11, —C(O)OH, —C(O)NHR8, —C(O)SH, —S(O)OH, —S(O)2OH, —S(O)NHR8, —S(O)2NHR8, —OP(O)(OR7)2, or —SP(O)(OR7)2. In another embodiment, —OR26 and —SR26, are additional values for R3. Preferably, R3 is —OH, —SH, —NHR7, —OC(O)NR10R11, —SC(O)NR10R11, —OC(O)R7, —SC(O)R7, —OC(O)OR7, —SC(O)OR7, —OS(O)pR7, —S(O)pOR7, —SS(O)pR7, —OS(O)pOR7, —SS(O)pOR7, —OC(S)R7, —SC(S)R7, —OC(S)OR7, —SC(S)OR7, —OC(S)NR10R11, —SC(S)NR10R11, —OC(NR8)R7, —SC(NR8)R7, —OC(NR8)OR7, —SC(NR8)OR7, —OP(O)(OR7)2 or —SP(O)(OR7)2. More preferably, R3 is —OH, —SH, or —NHR7. Even more preferably, R3 is —SH or —OH.
R5 is an optionally substituted heteroaryl; an optionally substituted 6 to 14-membered aryl.
R70, for each occurrence, is independently, an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, an optionally substituted heteraralkyl, halo, cyano, nitro, guanadino, a haloalkyl, a heteroalkyl, an alkoxy or cycloalkoxy, a haloalkoxy, —NR10R11, —OR7, —C(O)R7, —C(O)OR7, —C(S)R7, —C(O)SR7, —C(S)SR7, —C(S)OR7, —C(S)NR10R11, —C(NR8)OR7, —C(NR8)R7, —C(NR8)NR10R11, —C(NR8)SR7, —OC(O)R7, —OC(O)OR7, —OC(S)OR7, —OC(NR8)OR7, —SC(O)R7, —SC(O)OR7, —SC(NR8)OR7, —OC(S)R7, —SC(S)R7, —SC(S)OR7, —OC(O)NR10R11, —OC(S)NR10R11, —OC(NR8)NR10R11, —SC(O)NR10R11, —SC(NR8)NR10R11, —SC(S)NR10R11, —OC(NR8)R7, —SC(NR8)R7, —C(O)NR10R11, —NR8C(O)R7, —NR7C(S)R7, —NR7C(S)OR7, —NR7C(NR8)R7, —NR7C(O)OR7, —NR7C(NR8)OR7, —NR7C(O)NR10R11, —NR7C(S)NR10R11, —NR7C(NR8)NR10R11, —SR7, —S(O)pR7, —OS(O)pR7, —OS(O)pOR7, —OS(O)pNR10R11, —S(O)pOR7, —NR8S(O)pR7, —NR7S(O)pNR10R11, —NR7S(O)pOR7, —S(O)pNR10R11, —SS(O)pR7, —SS(O)pOR7, —SS(O)pNR10R11, —OP(O)(OR7)2, or —SP(O)(OR7)2. Preferably, R70 is selected from the group consisting of —H, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 cycloalkyl, and C1-C6 cycloalkoxy, more preferably from the group consisting of —H, methyl, ethyl, propyl, isopropyl, cyclopropyl, methoxy, ethoxy, propoxy, and cyclopropoxy.
R71, for each occurrence, is independently an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, an optionally substituted heteraralkyl, halo, cyano, nitro, guanadino, a haloalkyl, a heteroalkyl, alkoxy, haloalkoxy, —NR10R11, —OR7, —C(O)R7, —C(O)OR7, —C(S)R7, —C(O)SR7, —C(S)SR7, —C(S)OR7, —C(S)NR10R11, —C(NR8)OR7, —C(NR8)R7, —C(NR8)NR10R11, —C(NR8)SR7, —OC(O)R7, —OC(O)OR7, —OC(S)OR7, —OC(NR8)OR7, —SC(O)R7, —SC(O)OR7, —SC(NR8)OR7, —OC(S)R7, —SC(S)R7, —SC(S)OR7, —OC(O)NR10R11, —OC(S)NR10R11, —OC(NR8)NR10R11, —SC(O)NR10R11, —SC(NR8)NR10R11, —SC(S)NR10R11, —OC(NR8)R7, —SC(NR8)R7, —C(O)NR10R11, —NR8C(O)R7, —NR7C(S)R7, —NR7C(S)OR7, —NR7C(NR8)R7, —NR7C(O)OR7, —NR7C(NR8)OR7, —NR7C(O)NR10R11, —NR7C(S)NR10R11, —NR7C(NR8)NR10R11, —SR7, —S(O)pR7, —OS(O)pR7, —OS(O)pOR7, —OS(O)pNR10R11, —S(O)pOR7, —NR8S(O)pR7, —NR7S(O)pNR10R11, —NR7S(O)pOR7, —S(O)pNR10R11, —SS(O)pR7, —SS(O)pOR7, —SS(O)pNR10R11, —OP(O)(OR7)2, or —SP(O)(OR7)2.
R7 and R8, for each occurrence, are, independently, —H, an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, or an optionally substituted heteraralkyl;
R10 and R11, for each occurrence, are independently —H, an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, or an optionally substituted heteraralkyl; or R10 and R11, taken together with the nitrogen to which they are attached, form an optionally substituted heterocyclyl or an optionally substituted heteroaryl;
R18 is an optionally substituted cycloalkyl, and optionally substituted cycloalkenyl, or a substituted alkyl, wherein the alkyl group is substituted with one or more substituents independently selected from the group consisting of an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heteroaryl, an optionally substituted aralkyl, an optionally substituted heteraralkyl, halo, cyano, nitro, guanadino, a haloalkyl, —NR10R11, —OR7, —C(O)R7, —C(O)OR7, —OC(O)R7, —C(O)NR10R11, —NR8C(O)R7, —SR7, —S(O)pR7, —OS(O)pR7, —S(O)pOR7, —NR8S(O)pR7, or —S(O)pNR10R11;
R26 is a lower alkyl;
p, for each occurrence, is, independently, 0, 1 or 2; and
m, for each occurrence, is independently, 1, 2, 3, or 4.
R5 in structural formula (IX) is preferably represented by the following structural formula:




wherein:
R9, for each occurrence, is independently a substituent selected from the group consisting of an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, an optionally substituted heteraralkyl, hydroxyalkyl, alkoxyalkyl, halo, cyano, nitro, guanadino, a haloalkyl, a heteroalkyl, —NR10R11, —OR7, —C(O)R7, —C(O)OR7, —OC(O)R7, —C(O)NR10R11, —NR8C(O)R7, —SR7, —S(O)pR7, —OS(O)pR7, —S(O)pOR7, —NR8S(O)pR7, or —S(O)pNR10R11; or two R9 groups taken together with the carbon atoms to which they are attached form a fused ring, and m is zero or an integer from 1 to 7. More preferably, substituent R5 is represented by one of the following structural formulas:




wherein:
R9 is as defined as above; q is zero or an integer from 1 to 7; and u is zero or an integer from 1 to 8. The remainder of the variables have values defined above with reference to structural formula (IX).
In another alternative, R5 in structural formula (IX) is represented by the following structural formula:




wherein:
R33 is —H, a halo, lower alkyl, a lower alkoxy, a lower haloalkyl, a lower haloalkoxy, and lower alkyl sulfanyl; R34 is H, a lower alkyl, or a lower alkylcarbonyl; and ring B and ring C are optionally substituted with one or more substituents. The remainder of the variables have values defined above with reference to structural formula (IX).
In another alternative, R5 in structural formula (IX) is selected from a group listed in Table 3.










TABLE 3







Number
Substituent R5



















1







 



2







 



3







 



4







 



5







 



6







 



7







 



8







 



9







 



10







 



11







 



12







 



13







 



14







 



15







 



16







 



17







 



18







 



19














In the structural formulas of Table 3:

X6, for each occurrence, is independently CH, CR9, N, N(O), N+(R17), provided that at least three X6 groups are independently selected from CH and CR9;
X7, for each occurrence, is independently CH, CR9, N, N(O), N+(R17), provided that at least three X7 groups are independently selected from CH and CR9;
X8, for each occurrence, is independently CH2, CHR9, CR9R9, O, S, S(O)p, NR7, or NR17;
X9, for each occurrence, is independently N or CH;
X10, for each occurrence, is independently CH, CR9, N, N(O), N+(R17), provided that at least one X10 is selected from CH and CR9;
R9, for each occurrence, is independently a substituent selected from the group consisting of an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, an optionally substituted heteraralkyl, hydroxyalkyl, alkoxyalkyl, halo, cyano, nitro, guanadino, a haloalkyl, a heteroalkyl, —NR10R11, —OR7, —C(O)R7, —C(O)OR7, —OC(O)R7, —C(O)NR10R11, —NR8C(O)R7, —SR7, —S(O)pR7, —OS(O)pR7, —S(O)pOR7, —NR8S(O)pR7, or —S(O)pNR10R11; or two R9 groups taken together with the carbon atoms to which they are attached form a fused ring; and
R17, for each occurrence, is independently —H, an alkyl, an aralkyl, —C(O)R7, —C(O)OR7, or —C(O)NR10R11.
Preferred R5 groups from Table 3 are selected from the group consisting of an optionally substituted indolyl, an optionally substituted benzoimidazolyl, an optionally substituted indazolyl, an optionally substituted 3H-indazolyl, an optionally substituted indolizinyl, an optionally substituted quinolinyl, an optionally substituted isoquinolinyl, an optionally substituted benzoxazolyl, an optionally substituted benzo[1,3]dioxolyl, an optionally substituted benzofuryl, an optionally substituted benzothiazolyl, an optionally substituted benzo[d]isoxazolyl, an optionally substituted benzo[d]isothiazolyl, an optionally substituted thiazolo[4,5-c]pylidinyl, an optionally substituted thiazolo[5,4-c]pyridinyl, an optionally substituted thiazolo[4,5-b]pylidinyl, an optionally substituted thiazolo[5,4-b]pyridinyl, an optionally substituted oxazolo[4,5-c]pyridinyl, an optionally substituted oxazolo[5,4-c]pyridinyl, an optionally substituted oxazolo[4,5-b]pylidinyl, an optionally substituted oxazolo[5,4-b]pylidinyl, an optionally substituted imidazopyridinyl, an optionally substituted benzothiadiazolyl, benzoxadiazolyl, an optionally substituted benzotnazolyl, an optionally substituted tetrahydroindolyl, an optionally substituted azaindolyl, an optionally substituted quinazolinyl, an optionally substituted purinyl, an optionally substituted imidazo[4,5-a]pyridinyl, an optionally substituted imidazo[1,2-a]pyridinyl, an optionally substituted 3H-imidazo[4,5-b]pyridinyl, an optionally substituted 1H-imidazo[4,5-b]pyridinyl, an optionally substituted 1H-imidazo[4,5-c]pyridinyl, an optionally substituted 3H-imidazo[4,5-c]pyridinyl, an optionally substituted pyridopyrdazinyl, and optionally substituted pyridopyrimidinyl, an optionally substituted pyrrolo[2,3]pyrimidyl, an optionally substituted pyrazolo[3,4]pylimidyl an optionally substituted cyclopentaimidazolyl, an optionally substituted cyclopentatriazolyl, an optionally substituted pyrrolopyrazolyl, an optionally substituted pyrroloimidazolyl, an optionally substituted pyrrolotriazolyl, or an optionally substituted benzo(b)thienyl.
In another alternative, R5 in structural formula (IX) is selected from the group consisting of:




wherein:
X11, for each occurrence, is independently CH, CR9, N, N(O), or N+(R17), provided that at least one X11 is N, N(O), or N+(R17) and at least two X11 groups are independently selected from CH and CR9;
X12, for each occurrence, is independently CH, CR9, N, N(O), N+(R17), provided that at least one X12 group is independently selected from CH and CR9;
X13, for each occurrence, is independently O, S, S(O)p, NR7, or NR17;
R9, for each occurrence, is independently a substituent selected from the group consisting of an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, an optionally substituted heteraralkyl, halo, cyano, nitro, guanadino, a hydroxyalkyl, alkoxyalkyl, haloalkyl, a heteroalkyl, —NR10R11, —OR7, —C(O)R7, —C(O)OR7, —OC(O)R7, —C(O)NR10R11, —NR8C(O)R7, —SR7, —S(O)pR7, —OS(O)pR7, —S(O)pOR7, —NR8S(O)pR7, or —S(O)pNR10R11; or two R9 groups taken together with the carbon atoms to which they are attached form a fused ring; and R17, for each occurrence, is independently an alkyl or an aralkyl. The remainder of the variables have values defined above with reference to structural formula (IX).
In a preferred embodiment, the compound of the invention is represented by structural formula (LXII):




In structural formula (LXII):

X101 is O, S, or NR102 and X102 is CR104 or N. Preferably, X101 is NR102 and X102 is CR104. Alternatively, X101 is NR102 and X102 is N;
Y, for each occurrence, is independently N or CR103;
Y101 is N or CR105;
Y102 is N, C or CR106;
R1 is OH, SH, or NHR7. Preferably, R1 is —OH or —SH;
R70 is —H, —OH, —SH, an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, an optionally substituted heteraralkyl, halo, cyano, nitro, guanadino, a haloalkyl, a heteroalkyl, an alkoxy or cycloalkoxy, a haloalkoxy, —NR10R11, —OR7, —C(O)R7, —C(O)OR7, —C(S)R7, —C(O)SR7, —C(S)SR7, —C(S)OR7, —C(S)NR10R11, —C(NR8)OR7, —C(NR8)R7, —C(NR8)NR10R11, —C(NR8)SR7, —OC(O)R7, —OC(O)OR7, —OC(S)OR7, —OC(NR8)OR7, —SC(O)R7, —SC(O)OR7, —SC(NR8)OR7, —OC(S)R7, —SC(S)R7, —SC(S)OR7, —OC(O)NR10R11, —OC(S)NR10R11, —OC(NR8)NR10R11, —SC(O)NR10R11, —SC(NR8)NR10R11, —SC(S)NR10R11, —OC(NR8)R7, —SC(NR8)R7, —C(O)NR10R11, —NR8C(O)R7, —NR7C(S)R7, —NR7C(S)OR7, —NR7C(NR8)R7, —NR7C(O)OR7, —NR7C(NR8)OR7, —NR7C(O)NR10R11, —NR7C(S)NR10R11, —NR7C(NR8)NR10R11, —SR7, —S(O)pR7, —OS(O)pR7, —OS(O)pOR7, —OS(O)pNR10R11, —S(O)pOR7, —NR8S(O)pR7, —NR7S(O)pNR10R11, —NR7S(O)pOR7, —S(O)pNR10R11, —SS(O)pR7, —SS(O)pOR7, —SS(O)pNR10R11, —OP(O)(OR7)2, or —SP(O)(OR7)2. Preferably, R70 is selected from the group consisting of —H, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 cycloalkyl, and C1-C6 cycloalkoxy, more preferably from the group consisting of —H, methyl, ethyl, propyl, isopropyl, cyclopropyl, methoxy, ethoxy, propoxy, and cyclopropoxy;
R102 is —H, an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, an optionally substituted heteraralkyl, hydroxyalkyl, alkoxyalkyl, a haloalkyl, a heteroalkyl, —C(O)R7, —(CH2)mC(O)OR7, —C(O)OR7, —OC(O)R7, —C(O)NR10R11, —S(O)pR7, —S(O)pOR7, or —S(O)pNR10R11; preferably, R102 is selected from the group consisting of —H, a C1-C6 alkyl, a C1-C6 cycloalkyl, —C(O)N(R27)2, and —C(O)OH, wherein R27, for each occurrence, is independently is —H or a lower alkyl;
R103 and R104 are, independently, —H, —OH, an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, an optionally substituted heteraralkyl, hydroxyalkyl, alkoxyalkyl, halo, cyano, nitro, guanadino, a haloalkyl, a heteroalkyl, —C(O)R7, —C(O)OR7, —OC(O)R7, —C(O)NR10R11, —NR8C(O)R7, —SR7, —S(O)pR7, —OS(O)pR7, —S(O)pOR7, —NR8S(O)pR7, —S(O)pNR10R11, or R103 and R104 taken together with the carbon atoms to which they are attached form an optionally substituted cycloalkenyl, an optionally substituted aryl, an optionally substituted heterocyclyl, or an optionally substituted heteroaryl; preferably, R103 and R104 are independently, selected from the group consisting of —H, methyl, ethyl, propyl, isopropyl, cyclopropyl, methoxy, ethoxy, propoxy, and cyclopropoxy;
R105 is —H, —OH, —SH, —NR7H, —OR26, —SR26, —NHR26, —O(CH2)mOH, —O(CH2)mSH, —O(CH2)mNR7H, —S(CH2)mOH, —S(CH2)mSH, —S(CH2)mNR7H, —OC(O)NR10R11, —SC(O)NR10R11, —NR7C(O)NR10R11, —OC(O)R7, —SC(O)R7, —NR7C(O)R7, —OC(O)OR7, —SC(O)OR7, —NR7C(O)OR7, —OCH2C(O)R7, —SCH2C(O)R7, —NR7CH2C(O)R7, —OCH2C(O)OR7, —SCH2C(O)OR7, —NR7CH2C(O)OR7, —OCH2C(O)NR10R11, —SCH2C(O)NR10R11, —NR7CH2C(O)NR10R11, —OS(O)pR7, —SS(O)pR7, —NR7S(O)pR7, —OS(O)pNR10R11, —SS(O)pNR10R11, —NR7S(O)pNR10R11, —OS(O)pOR7, —SS(O)pOR7, —NR7S(O)pOR7, —OC(S)R7, —SC(S)R7, —NR7C(S)R7, —OC(S)OR7, —SC(S)OR7, —NR7C(S)OR7, —OC(S)NR10R11, —SC(S)NR10R11, —NR7C(S)NR10R11, —OC(NR8)R7, —SC(NR8)R7, —NR7C(NR8)R7, —OC(NR8)OR7, —SC(NR8)OR7, —NR7C(NR8)OR7, —OC(NR8)NR10R11, —SC(NR8)NR10R11, or —NR7C(NR8)NR10R11; preferably, R105 is selected from the group consisting of —H, —OH, —SH, —NH2, a C1-C6 alkoxy, a C1-C6 alkyl amino, and a C1-C6 dialkyl amino, more preferably from the group consisting of —H, —OH, methoxy and ethoxy; and
R106, for each occurrence, is independently —H, an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, an optionally substituted heteraralkyl, halo, cyano, nitro, guanadino, a haloalkyl, a heteroalkyl, —NR10R11, —OR7, —C(O)R7, —C(O)OR7, —OC(O)R7, —C(O)NR10R11, —NR8C(O)R7, —SR7, —S(O)pR7, —OS(O)pR7, —S(O)pOR7, —NR8S(O)pR7, or —S(O)pNR10R11.
The remainder of the variables of the compounds of structural formula (LXII) has values defined above with reference to structural formula (IX).
In one preferred set of values for the variables of the Hsp90 inhibitor represented by formula (LXII), X101 is NR102, R102 is selected from the group consisting of —H, a C1-C6 alkyl, a C1-C6 cycloalkyl, —C(O)N(R27)2, and —C(O)OH, wherein R27, for each occurrence, is independently is —H or a lower alkyl and the values for the remainder of the variables are as described above for formula (LXII).
In a second preferred set of values for the variables of the Hsp90 inhibitor represented by formula (LXII), X101 is NR102, R102 is selected from the group consisting of —H, methyl, ethyl, n-propyl, isopropyl, cyclopropyl, n-butyl, sec-butyl, tert-butyl, n-pentyl, n-hexyl, —C(O)OH, —(CH2)mC(O)OH, —CH2OCH3, —CH2CH2OCH3, and —C(O)N(CH3)2 and the values for the remainder of the variables are as described above for formula (LXII).
In third preferred set of values for the variables of the Hsp90 inhibitor represented by formula (LXII), X102 is CR104; Y is CR103; and R103 and R104 together with the carbon atoms to which they are attached form a cycloalkenyl, an aryl, heterocyclyl, or heteroaryl ring. Preferably, R103 and R104 together with the carbon atoms to which they are attached form a C5-C8 cycloalkenyl or a C5-C8 aryl and the values for the remainder of the variables are as described above for formula (LXII).
In fourth preferred set of values for the variables of the Hsp90 inhibitor represented by formula (LXII), R1 is —OH or —SH and the values for the remainder of the variables are as described above for formula (LXII).
In another preferred embodiment, the Hsp90 inhibitor of the invention is represented by structural formula (LXIII):




where X103 is CR104 or N and the remainder of the variables is defined above with reference with structural formulas (LXII).

In another preferred embodiment, the Hsp90 inhibitor of the invention is represented by structural formula selected from (LXIVa)-(LXIVi):




The values for the variables in structural formulas (LXIVa)-(LXIVi) are as described in structural formula (IX), (X), and (XI).

In one preferred set of values for the variables of the Hsp90 inhibitor represented by structural formulas (VIa-c)-(VIIIa-c):
R5 is as described for structural formula (IX), (LXII), (LXIII) or a structural formula from Table 1;
R70 and R71, for each occurrence, are independently an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, an optionally substituted heteraralkyl, halo, cyano, nitro, guanadino, a haloalkyl, a heteroalkyl, alkoxy, haloalkoxy, —NR10R11, —OR7, —C(O)R7, —C(O)OR7, —C(S)R7, —C(O)SR7, —C(S)SR7, —C(S)OR7, —C(S)NR7)R11, —C(NR8)OR7, —C(NR8)R7, —C(NR8)NR10R11, —C(NR8)SR7, —OC(O)R7, —OC(O)OR7, —OC(S)OR7, —OC(NR8)OR7, —SC(O)R7, —SC(O)OR7, —SC(NR8)OR7, —OC(S)R7, —SC(S)R7, —SC(S)OR7, —OC(O)NR10R11, —OC(S)NR10R11, —OC(NR8)NR10R11, —SC(O)NR10R11, —SC(NR8)NR10R11, —SC(S)NR10R11, —OC(NR8)R7, —SC(NR8)R7, —C(O)NR10R11, —NR8C(O)R7, —NR7C(S)R7, —NR7C(S)OR7, —NR7C(NR8)R7, —NR7C(O)OR7, —NR7C(NR8)OR7, —NR7C(O)NR10R11, —NR7C(S)NR10R11, —NR7C(NR8)NR10R11, —SR7, —S(O)pR7, —OS(O)pR7, —OS(O)pOR7, —OS(O)pNR10R11, —S(O)pOR7, —NR8S(O)pR7, —NR7S(O)pNR10R11, —NR7S(O)pOR7, —S(O)pNR10R11, —SS(O)pR7, —SS(O)pOR7, —SS(O)pNR10R11, —OP(O)(OR7)2, or —SP(O)(OR7)2;
z in structural formula (VIa-c) is zero or an integer from 1 to 4; z in structural formula (VIIa-c) is zero or an integer from 1 to 3;
x is 0 or 1;
z+x in structural formula (LXIVa)-(LXIVc) is less than or equal to 4; and
the remainder of the variables in formulas (LXIVa)-(LXIVi) have values defined above with reference to structural formula (IX), (X), and (XI).
A second preferred set of values for the variables of the Hsp90 inhibitor represented by structural formula (LXIVa)-(LXIVi) is provided in the following paragraphs:
R71 is a halo, a haloalkyl, a haloalkoxy, a heteroalkyl, —OH, —SH, —NHR7, —(CH2)kOH, —(CH2)kSH, —(CH2)kNR7H, —OCH3, —SCH3, —NHCH3, —OCH2CH2OH, —OCH2CH2SH, —OCH2CH2NR7H, —SCH2CH2OH, —SCH2CH2SH, —SCH2CH2NR7H, —OC(O)NR10R11, —SC(O)NR10R11, —NR7C(O)NR10R11, —OC(O)R7, —SC(O)R7, —NR7C(O)R7, —OC(O)OR7, —SC(O)OR7, —NR7C(O)OR7, —OCH2C(O)R7, —SCH2C(O)R7, —NR7CH2C(O)R7, —OCH2C(O)OR7, —SCH2C(O)OR7, —NR7CH2C(O)OR7, —OCH2C(O)NR10R11, —SCH2C(O)NR10R11, —NR7CH2C(O)NR10R11, —OS(O)pR7, —SS(O)pR7, —NR7S(O)pR7, —OS(O)pNR10R11, —SS(O)pNR10R11, —NR7S(O)pNR10R11, —OS(O)pOR7, —SS(O)pOR7, —NR7S(O)pOR7, —OC(S)R7, —SC(S)R7, —NR7C(S)R7, —OC(S)OR7, —SC(S)OR7, —NR7C(S)OR7, —OC(S)NR10R11, —SC(S)NR10R11, —NR7C(S)NR10R11, —OC(NR8)R7, —SC(NR8)R7, —NR7C(NR8)R7, —OC(NR8)OR7, —SC(NR8)OR7, —NR7C(NR8)OR7, —OC(NR8)NR10R11, —SC(NR8)NR10R11, —NR7C(NR8)NR10R11, —C(O)R7, —C(O)OR7, —C(O)NR10R11, —C(O)SR7, —C(S)R7, —C(S)OR7, —C(S)NR10R11, —C(S)SR7, —C(NR8)OR7, —C(NR8)R7, —C(NR8)NR10R11, —C(NR8)SR7, —S(O)pOR7, —S(O)pNR10R11, or —S(O)pR7; and k is 1, 2, 3, or 4; and R1, R3, R70 and the remainder of the variables are as described in the first preferred set of values for the variables in structural formulas (LXIVa)-(LXIVi). Preferably, R1 and R3 are each, independently, —OH, —SH, or —NHR7.
A third preferred set of values for the variables of the Hsp90 inhibitor represented by formula (LXIVa)-(LXIVi) is provided in the following paragraphs:
R1 and R3 are each, independently, —OH, —SH, or —NHR7;
R70 is an optionally substituted alkyl or cycloalkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, cyano, halo, nitro, an optionally substituted cycloalkyl, haloalkyl, alkoxy, haloalkoxy, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, an optionally substituted heteroaralkyl, —OR7, —SR7, —NR10R11, —OC(O)NR10R11, —SC(O)NR10R11, —NR7C(O)NR10R11, —OC(O)R7, —SC(O)R7, —NR7C(O)R7, —OC(O)OR7, —SC(O)OR7, —NR7C(O)OR7, —OCH2C(O)R7, —SCH2C(O)R7, —NR7CH2C(O)R7, —OCH2C(O)OR7, —SCH2C(O)OR7, —NR7CH2C(O)OR7, —OCH2C(O)NR10R11, —SCH2C(O)NR10R11, —NR7CH2C(O)NR10R11, —OS(O)pR7, —SS(O)pR7, —NR7S(O)pR7, —OS(O)pNR10R11, —SS(O)pNR10R11, —NR7S(O)pNR10R11, —OS(O)pOR7, —SS(O)pOR7, —NR7S(O)pOR7, —OC(S)R7, —SC(S)R7, —NR7C(S)R7, —OC(S)OR7, —SC(S)OR7, —NR7C(S)OR7, —OC(S)NR10R11, —SC(S)NR10R11, —NR7C(S)NR10R11, —OC(NR8)R7, —SC(NR8)R7, —NR7C(NR8)R7, —OC(NR8)OR7, —SC(NR8)OR7, —NR7C(NR8)OR7, —OC(NR8)NR10R11, —SC(NR8)NR10R11, —NR7C(NR8)NR10R11, —C(O)R7, —C(O)OR7, —C(O)NR10R11, —C(O)SR7, —C(S)R7, —C(S)OR7, —C(S)NR10R11, —C(S)SR7, —C(NR8)OR7, —C(NR8)R7, —C(NR8)NR10R11, —C(NR8)SR7, —S(O)pOR7, —S(O)pNR10R11, or —S(O)pR7 and R1 and R3 and the remainder of the variables are as described in the second preferred set of values for the variables in structural formulas (LXIVa)-(LXIVi).
In a fourth preferred set of values for the variables of Structural Formulas (LXIVa)-(LXIVi):
R1 is —SH or —OH;
R3 and R25 are —OH;
R70 is a C1-C6 alkyl, a C3-C6 cycloalkyl, a C1-C6 alkoxy, a C1-C6 haloalkoxy, a C1-C6 alkyl sulfanyl, or —NR10R11; and
The remainder of the variables are as defined in Structural Formula (IX), (X), and (XI).
In another preferred embodiment, the Hsp90 inhibitor is represented by a structural formula selected from (LXVa)-LXVf):




In formulas (LXVa) and (LXVb):

R5 is as described for structural formula (IX), (LXII), or (LXIII), or a structural formula from Table 1;
X3′ and X4′ are each, independently, N, N(O), N+(R17), CH or CR70;
X5′ is O, S, NR17, CH2, CH(R70), C(R70)2, CH═CH, CH═CR70, CR70═CH, CR70═CR70, CH═N, CR70═N, CH═N(O), CR70═N(O), N═CH, N═CR70, N(O)═CH, N(O)═CR70, N+(R17)═CH, N+(R17)═CR70, CH═N+(R17), CR60═N+(R17), or N═N, provided that at least one X3′, X4′ or X5′ is a heteroatom;
R70, for each occurrence, is independently an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, an optionally substituted heteraralkyl, halo, cyano, nitro, guanadino, a haloalkyl, a heteroalkyl, alkoxy, haloalkoxy, —NR10R11, —OR7, —C(O)R7, —C(O)OR7, —C(S)R7, —C(O)SR7, —C(S)SR7, —C(S)OR7, —C(S)NR10R11, —C(NR8)OR7, —C(NR8)R7, —C(NR8)NR10R11, —C(NR8)SR7, —OC(O)R7, —OC(O)OR7, —OC(S)OR7, —OC(NR8)OR7, —SC(O)R7, —SC(O)OR7, —SC(NR8)OR7, —OC(S)R7, —SC(S)R7, —SC(S)OR7, —OC(O)NR10R11, —OC(S)NR10R11, —OC(NR8)NR10R11, —SC(O)NR10R11, —SC(NR8)NR10R11, —SC(S)NR10R11, —OC(NR8)R7, —SC(NR8)R7, —C(O)NR10R11, —NR8C(O)R7, —NR7C(S)R7, —NR7C(S)OR7, —NR7C(NR8)R7, —NR7C(O)OR7, —NR7C(NR8)OR7, —NR7C(O)NR10R11, —NR7C(S)NR10R11, —NR7C(NR8)NR10R11, —SR7, —S(O)pR7, —OS(O)pR7, —OS(O)pOR7, —OS(O)pNR10R11, —S(O)pOR7, —NR8S(O)pR7, —NR7S(O)pNR10R11, —NR7S(O)pOR7, —S(O)pNR10R11, —SS(O)pR7, —SS(O)pOR7, —SS(O)pNR10R11, —OP(O)(OR7)2, or —SP(O)(OR7)2;
R17, for each occurrence, is independently an alkyl or an aralkyl; and n is zero or an integer from 1 to 4; and
the remainder of the variables has values defined above with reference to structural formulas (IX), (X), and (XI).
Preferably, Hsp90 inhibitor of structural formulas (LXVa)-LXVf) are selected from Table 4a-c.










TABLE 4a







Number
Compound



















1.







 



2.







 



3.







 



4.







 



5.







 



6.







 



7.







 



8.







 



9.







 



10.
























TABLE 4b







Number
Compound



















1.







 



2.







 



3.







 



4.







 



5.







 



6.







 



7.







 



8.







 



9.







 



10.
























TABLE 4c







Number
Compound



















1.







 



2.







 



3.







 



4.







 



5.







 



6.







 



7.







 



8.







 



9.







 



10.














The values for the variables for the formulas in Tables 4a-c are as defined for structural formulas (LXVa)-(LXVf). Preferably, R70 is a halo, a haloalkyl, a haloalkoxy, a heteroalkyl, —OH, —SH, —NHR7, —(CH2)kOH, —(CH2)kSH, —(CH2)kNR7H, —OCH3, —SCH3, —NHCH3, —OCH2CH2OH, —OCH2CH2SH, —OCH2CH2NR7H, —SCH2CH2OH, —SCH2CH2SH, —SCH2CH2NR7H, —OC(O)NR10R11, —SC(O)NR10R11, —NR7C(O)NR10R11, —OC(O)R7, —SC(O)R7, —NR7C(O)R7, —OC(O)OR7, —SC(O)OR7, —NR7C(O)OR7, —OCH2C(O)R7, —SCH2C(O)R7, —NR7CH2C(O)R7, —OCH2C(O)OR7, —SCH2C(O)OR7, —NR7CH2C(O)OR7, —OCH2C(O)NR10R11, —SCH2C(O)NR10R11, —NR7CH2C(O)NR10R11, —OS(O)pR7, —SS(O)pR7, —NR7S(O)pR7, —OS(O)pNR10R11, —SS(O)pNR10R11, —NR7S(O)pNR10R11, —OS(O)pOR7, —SS(O)pOR7, —NR7S(O)pOR7, —OC(S)R7, —SC(S)R7, —NR7C(S)R7, —OC(S)OR7, —SC(S)OR7, —NR7C(S)OR7, —OC(S)NR10R11, —SC(S)NR10R11, —NR7C(S)NR10R11, —OC(NR8)R7, —SC(NR8)R7, —NR7C(NR8)R7, —OC(NR8)OR7, —SC(NR8)OR7, —NR7C(NR8)OR7, —OC(NR8)NR10R11, —SC(NR8)NR10R11, —NR7C(NR8)NR10R11, —C(O)R7, —C(O)OR7, —C(O)NR10R11, —C(O)SR7, —C(S)R7, —C(S)OR7, —C(S)NR10R11, —C(S)SR7, —C(NR8)OR7, —C(NR8)R7, —C(NR8)NR10R11, —C(NR8)SR7, —S(O)pOR7, —S(O)pNR10R11, or —S(O)pR7; and

k is 1, 2, 3, or 4.
In another preferred embodiment, the Hsp90 inhibitor of the present invention is represented by structural formula (LXVI):




R70 and R71, for each occurrence, are independently an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, an optionally substituted heteraralkyl, halo, cyano, nitro, guanadino, a haloalkyl, a heteroalkyl, alkoxy, haloalkoxy, —NR10R11, —OR7, —C(O)R7, —C(O)OR7, —C(S)R7, —C(O)SR7, —C(S)SR7, —C(S)OR7, —C(S)NR10R11, —C(NR8)OR7, —C(NR8)R7, —C(NR8)NR10R11, —C(NR8)SR7, —OC(O)R7, —OC(O)OR7, —OC(S)OR7, —OC(NR8)OR7, —SC(O)R7, —SC(O)OR7, —SC(NR8)OR7, —OC(S)R7, —SC(S)R7, —SC(S)OR7, —OC(O)NR10R11, —OC(S)NR10R11, —OC(NR8)NR10R11, —SC(O)NR10R11, —SC(NR8)NR10R11, —SC(S)NR10R11, —OC(NR8)R7, —SC(NR8)R7, —C(O)NR10R11, —NR8C(O)R7, —NR7C(S)R7, —NR7C(S)OR7, —NR7C(NR8)R7, —NR7C(O)OR7, —NR7C(NR8)OR7, —NR7C(O)NR10R11, —NR7C(S)NR10R11, —NR7C(NR8)NR10R11, —SR7, —S(O)pR7, —OS(O)pR7, —OS(O)pOR7, —OS(O)pNR10R11, —S(O)pOR7, —NR8S(O)pR7, —NR7S(O)pNR10R11, —NR7S(O)pOR7, —S(O)pNR10R11, —SS(O)pR7, —SS(O)pOR7, —SS(O)pNR10R11, —OP(O)(OR7)2, or —SP(O)(OR7)2. Preferably, R70 is selected from an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, cyano, halo, nitro, an optionally substituted cycloalkyl, haloalkyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, an optionally substituted heteroaralkyl, —OR7, —SR7, —NR10R11, —OC(O)NR10R11, —SC(O)NR10R11, —NR7C(O)NR10R11, —OC(O)R7, —SC(O)R7, —NR7C(O)R7, —OC(O)OR7, —SC(O)OR7, —NR7C(O)OR7, —OCH2C(O)R7, —SCH2C(O)R7, —NR7CH2C(O)R7, —OCH2C(O)OR7, —SCH2C(O)OR7, —NR7CH2C(O)OR7, —OCH2C(O)NR10R11, —SCH2C(O)NR10R11, —NR7CH2C(O)NR10R11, —OS(O)pR7, —SS(O)pR7, —NR7S(O)pR7, —OS(O)pNR10R11, —SS(O)pNR10R11, —NR7S(O)pNR10R11, —OS(O)pOR7, —SS(O)pOR7, —NR7S(O)pOR7, —OC(S)R7, —SC(S)R7, —NR7C(S)R7, —OC(S)OR7, —SC(S)OR7, —NR7C(S)OR7, —OC(S)NR10R11, —SC(S)NR10R11, —NR7C(S)NR10R11, —OC(NR8)R7, —SC(NR8)R7, —NR7C(NR8)R7, —OC(NR8)OR7, —SC(NR8)OR7, —NR7C(NR8)OR7, —OC(NR8)NR10R11, —SC(NR8)NR10R11, —NR7C(NR8)NR10R11, —C(O)R7, —C(O)OR7, —C(O)NR10R11, —C(O)SR7, —C(S)R7, —C(S)OR7, —C(S)NR10R11, —C(S)SR7, —C(NR8)OR7, —C(NR8)R7, —C(NR8)NR10R11, —C(NR8)SR7, —S(O)pOR7, —S(O)pNR10R11, or —S(O)pR7 and R71 is as just described. The values for the remainder of the variables are as described for structural formulas (IX), (X), and (XI).
In another preferred embodiment, the Hsp90 inhibitors are represented by structural formula (LXVIIa) or (LXVIIb):




The variables in formulas (LXVIIa) and (LXVIIb) are defined above with reference to formula (LXVI).

A first preferred set of values for the variables of structural formula (LXVIIa) and (LXVIIb) is provided in the following paragraph:
R1, R3 or R71 are each independently selected from —OH, —SH, —NHR7, —OC(O)NR10R11, —SC(O)NR10R11, —OC(O)R7, —SC(O)R7, —OC(O)OR7, —SC(O)OR7, —OS(O)pR7, —S(O)pOR7, —SS(O)pR7, —OS(O)pOR7, —SS(O)pOR7, —OC(S)R7, —SC(S)R7, —OC(S)OR7, —SC(S)OR7, —OC(S)NR10R11, —SC(S)NR10R11, —OC(NR8)R7, —SC(NR8)R7, —OC(NR8)OR7, —SC(NR8)OR7, —OP(O)(OR7)2 or —SP(O)(OR7)2, and p, R70, R7, R8, R10, R11 and R30 are as described for structural formula (LXVI). Preferably, when R1, R3 and R71 have these values, R10 and R11 are preferably each independently a hydrogen, a C1-C6 straight or branched alkyl, optionally substituted by —OH, —CN, —SH, amino, a C1-C6 alkoxy, alkylsulfanyl, alkylamino, dialkylamino or a cycloalkyl; or R10 and R11 taken together with the nitrogen to which they are attached form a substituted or unsubstituted nonaromatic, nitrogen-containing heterocyclyl; and p, R70, R7, and R30 are as described for structural formula (LXVI). More preferably, when R1, R3, R10, R11, and R71 have these values, R70 is preferably a C1-C6 alkyl, a C1-C6 haloalkyl, a C1-C6 alkoxy, a C1-C6 haloalkoxy, a C1-C6 alkyl sulfanyl or a C3-C6 cycloalkyl; and p, R7, R8 and R30 are as described for structural formula (LXVI).
A second preferred set of values for the variables of structural formula (LXVIIa) and (LXVIIb) is provided in the following paragraph:
R1 and R3 are each independently —OH, —SH; R70 is preferably a C1-C6 alkyl, a C1-C6 haloalkyl, a C1-C6 alkoxy, a C1-C6 haloalkoxy, a C1-C6 alkyl sulfanyl or a C3-C6 cycloalkyl; R10 and R11 are preferably each independently a hydrogen, a C1-C6 straight or branched alkyl, optionally substituted by —OH, —CN, —SH, amino, a C1-C6 alkoxy, alkylsulfanyl, alkylamino, dialkylamino or a cycloalkyl; or R10 and R11 taken together with the nitrogen to which they are attached form a substituted or unsubstituted nonaromatic, nitrogen-containing heterocyclyl; R71 is —OH, —SH, —NHR7, —OC(O)NR10R11, —SC(O)NR10R11, —OC(O)R7, —SC(O)R7, —OC(O)OR7, —SC(O)OR7, —OS(O)pR7, —S(O)pOR7, —SS(O)pR7, —OS(O)pOR7, —SS(O)pOR7, —OC(S)R7, —SC(S)R7, —OC(S)OR7, —SC(S)OR7, —OC(S)NR10R11, —SC(S)NR10R11, —OC(NR8)R7, —SC(NR8)R7, —OC(NR8)OR7, —SC(NR8)OR7, —OP(O)(OR7)2 or —SP(O)(OR7)2; and p, R7 R8 and R30 are as described for structural formula (LXVI). Preferably, R30 is —OH, —SH, halogen, cyano, a C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy or C1-C6 alkyl sulfanyl and the remainder of the variables are as just described.
A third preferred set of values for the variables of structural formula (LXVIIa) and (LXVIIb) is provided in the following paragraph:
R1, R3 and R71 are independently —SH or —OH; R70 is cyclopropyl or isopropyl; R10 and R11 are each independently a hydrogen, a C1-C6 straight or branched alkyl, optionally substituted by —OH, —CN, —SH, amino, a C1-C6 alkoxy, alkylsulfanyl, alkylamino, dialkylamino or a cycloalkyl; or R10 and R11 taken together with the nitrogen to which they are attached form a substituted or unsubstituted nonaromatic, nitrogen-containing heterocyclyl; and R30 is —OH, —SH, halogen, cyano, a C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy or C1-C6 alkyl sulfanyl. Preferably, R30 is a methyl, ethyl, propyl, isopropyl, methoxy or ethoxy. More preferably, R1, R3, R70, R71 and R30 are as just described and R10 and R11 are each independently a hydrogen, methyl, ethyl, propyl, isopropyl, or taken together with the nitrogen to which they are attached, are:




wherein R35 is —H, a C1-C4 alkyl or a C1-C4 acyl.
In another preferred embodiment, the Hsp90 inhibitor is represented by structural formulas (LXVIIIa) or (LXVIIIb):




The values for the variables in structural formulas (LXVIIIa) and (LXVIIIb) are as described for structural formulas (LXVc) and (LXVd). Preferably, R30 is an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, an optionally substituted heteraralkyl, halo, cyano, nitro, guanadino, a haloalkyl, a heteroalkyl, alkoxy, haloalkoxy, —NR10R11, —OR7, —C(O)R7, —C(O)OR7, —C(S)R7, —C(O)SR7, —C(S)SR7, —C(S)OR7, —C(S)NR10R11, —C(NR8)OR7, —C(NR8)R7, —C(NR8)NR10R11, —C(NR8)SR7, —OC(O)R7, —OC(O)OR7, —OC(S)OR7, —OC(NR8)OR7, —SC(O)R7, —SC(O)OR7, —SC(NR8)OR7, —OC(S)R7, —SC(S)R7, —SC(S)OR7, —OC(O)NR10R11, —OC(S)NR10R11, —OC(NR8)NR10R11, —SC(O)NR10R11, —SC(NR8)NR10R11, —SC(S)NR10R11, —OC(NR8)R7, —SC(NR8)R7, —C(O)NR10R11, —NR8C(O)R7, —NR7C(S)R7, —NR7C(S)OR7, —NR7C(NR8)R7, —NR7C(O)OR7, —NR7C(NR8)OR7, —NR7C(O)NR10R11, —NR7C, (S)NR10R11, —NR7C(NR8)NR10R11, —SR7, —S(O)pR7, —OS(O)pR7, —OS(O)pOR7, —OS(O)pNR10R11, —S(O)pOR7, —NR8S(O)pR7, —NR7S(O)pNR10R11, —NR7S(O)pOR7, —S(O)pNR10R11, —SS(O)pR7, —SS(O)pOR7, —SS(O)pNR10R11, —OP(O)(OR7)2, or —SP(O)(OR7)2. More preferably, R30 is an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, cyano, halo, nitro, an optionally substituted cycloalkyl, haloalkyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, an optionally substituted heteroaralkyl, —OR7, —SR7, —NR10R11, —OC(O)NR10R11, —SC(O)NR10R11, —NR7C(O)NR10R11, —OC(O)R7, —SC(O)R7, —NR7C(O)R7, —OC(O)OR7, —SC(O)OR7, —NR7C(O)OR7, —OCH2C(O)R7, —SCH2C(O)R7, —NR7CH2C(O)R7, —OCH2C(O)OR7, —SCH2C(O)OR7, —NR7CH2C(O)OR7, —OCH2C(O)NR10R11, —SCH2C(O)NR10R11, —NR7CH2C(O)NR10R11, —OS(O)pR7, —SS(O)pR7, —NR7S(O)pR7, —OS(O)pNR10R11, —SS(O)pNR10R11, —NR7S(O)pNR10R11, —OS(O)pOR7, —SS(O)pOR7, —NR7S(O)pOR7, —OC(S)R7, —SC(S)R7, —NR7C(S)R7, —OC(S)OR7, —SC(S)OR7, —NR7C(S)OR7, —OC(S)NR10R11, —SC(S)NR10R11, —NR7C(S)NR10R11, —OC(NR8)R7, —SC(NR8)R7, —NR7C(NR8)R7, —OC(NR8)OR7, —SC(NR8)OR7, —NR7C(NR8)OR7, —OC(NR8)NR10R11, —SC(NR8)NR10R11, —NR7C(NR8)NR10R11, —C(O)R7, —C(O)OR7, —C(O)NR10R11, —C(O)SR7, —C(S)R7, —C(S)OR7, —C(S)NR10R11, —C(S)SR7, —C(NR8)OR7, —C(NR8)R7, —C(NR8)NR10R11, —C(NR8)SR7, —S(O)pOR7, —S(O)pNR10R11, or —S(O)pR7.
In another preferred embodiment, the Hsp90 inhibitor is represented by a structural formula selected from formulas (LXIXa)-(LXIXd):




The values of the variables in structural formulas (LXIXa)-(LXIXd) are defined above with reference to structural formulas (LXVIIIa) and (LXVIIIb).

A first preferred set of values for the variables in structural formulas (LXIXa)-(LXIXd) are as described in the following paragraphs:
R1 and R3 are each independently —OH, —SH, —HNR7, —OC(O)NR10R11, —SC(O)NR10R11, —OC(O)R7, —SC(O)R7, —OC(O)OR7, —SC(O)OR7, —OS(O)pR7, —S(O)pOR7, —SS(O)pR7, —OS(O)pOR7, —SS(O)pOR7, —OC(S)R7, —SC(S)R7, —OC(S)OR7, —SC(S)OR7, —OC(S)NR10R11, —SC(S)NR10R11, —OC(NR8)R7, —SC(NR8)R7, —OC(NR8)OR7, —SC(NR8)OR7, —OP(O)(OR7)2 or —SP(O)(OR7)2;
R70, for each occurrence, is independently an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, —OH, —SH, —HNR7, —OC(O)NR10R11, —SC(O)NR10R11, —OC(O)R7, —SC(O)R7, —OC(O)OR7, —SC(O)OR7, —OS(O)pR7, —S(O)pOR7, —SS(O)pR7, —OS(O)pOR7, —SS(O)pOR7, —OC(S)R7, —SC(S)R7, —OC(S)OR7, —SC(S)OR7, —OC(S)NR10R11, —SC(S)NR10R11, —OC(NR8)R7, —SC(NR8)R7, —OC(NR8)OR7, —SC(NR8)OR7, —OP(O)(OR7)2 or —SP(O)(OR7)2. Preferably, R70 is a C1-C6 alkyl, a C1-C6 haloalkyl, a C1-C6 alkoxy, a C1-C6 haloalkoxy, a C1-C6 alkyl sulfanyl or a C3-C6 cycloalkyl; and
R10 and R11 and the remainder of the variables in structural formulas (LXIXa)-(LXIXd) are as described for structural formulas (LXVIIIa) and (LXVIIIb). Preferably, R10 and R11 are each independently a hydrogen, a C1-C6 straight or branched alkyl, optionally substituted by —OH, —CN, —SH, amino, a C1-C6 alkoxy, alkylsulfanyl, alkylamino, dialkylamino or a cycloalkyl; or R10 and R11 taken together with the nitrogen to which they are attached form a substituted or unsubstituted nonaromatic, nitrogen-containing heterocyclyl.
In another preferred embodiment, the Hsp90 inhibitor is represented by a structural formula selected form formulas (LXXa)-(LXXp):










The values of the variables in structural formulas (LXXa)-(LXXp) are defined above with reference to structural formulas (LXIXa)-(LXIXd).
A first preferred set of values for the variables in structural formulas (XIVa-p) are as described in the following paragraphs:
R1 and R3 are each independently —OH, —SH, —HNR7;
R70, is a C1-C6 alkyl, a C1-C6 haloalkyl, a C1-C6 alkoxy, a C1-C6 haloalkoxy, a C1-C6 alkyl sulfanyl or a C3-C6 cycloalkyl;
R10 and R11 and the remainder of the variables in structural formulas (LXXa)-(LXXp) are as described for structural formulas (LXVIIIa) and (LXVIIIb). Preferably, R10 and R11 are each independently a hydrogen, a C1-C6 straight or branched alkyl, optionally substituted by —OH, —CN, —SH, amino, a C1-C6 alkoxy, alkylsulfanyl, alkylamino, dialkylamino or a cycloalkyl; or R10 and R11 taken together with the nitrogen to which they are attached form a substituted or unsubstituted nonaromatic, nitrogen-containing heterocyclyl; and
R30 and the remainder of the variables in structural formulas (LXXa)-(LXXp) are as described for structural formulas (LXIXa)-(LXIXd). Preferably, R30 is —OH, —SH, halogen, cyano, a C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy or C1-C6 alkyl sulfanyl.
A second preferred set of values for the variables in structural formulas (LXXa)-(LXXp) are as described in the following paragraphs:
R1 and R3 are independently —SH or —OH;
R70 is cyclopropyl or isopropyl;
R10 and R11 are each independently a hydrogen, a C1-C6 straight or branched alkyl, optionally substituted by —OH, —CN, —SH, amino, a C1-C6 alkoxy, alkylsulfanyl, alkylamino, dialkylamino or a cycloalkyl; or R10 and R11 taken together with the nitrogen to which they are attached form a substituted or unsubstituted nonaromatic, nitrogen-containing heterocyclyl;
R30 is —OH, —SH, halogen, cyano, a C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy or C1-C6 alkyl sulfanyl. Preferably, R30 is a methyl, ethyl, propyl, isopropyl, methoxy or ethoxy; and the remainder of the variables are as described for formulas (LXVIIIa) and (LXVIIIb). More preferably, R10 and R11 are each independently a hydrogen, methyl, ethyl, propyl, isopropyl, or taken together with the nitrogen to which they are attached, are:




    
    
        wherein R35 is —H, a C1-C4 alkyl or a C1-C4 acyl.
    
    


In another embodiment, the Hsp90 inhibitor of the present invention is represented by structural formulas (LXXI) and (LXXII):




In formulas (LXXI) and (LXXII):

X14 is O, S, or NR7. Preferably, X14 is O;
R1 is —OH, —SH, —NR7H, —OR26, —SR26, —NHR26, —O(CH2)mOH, —O(CH2)mSH, —O(CH2)mNR7H, —S(CH2)mOH, —S(CH2)mSH, —S(CH2)mNR7H, —OC(O)NR10R11, —SC(O)NR10R11, —NR7C(O)NR10R11, —OC(O)R7, —SC(O)R7, —NR7C(O)R7, —OC(O)OR7, —SC(O)OR7, —NR7C(O)OR7, —OCH2C(O)R7, —SCH2C(O)R7, —NR7CH2C(O)R7, —OCH2C(O)OR7, —SCH2C(O)OR7, —NR7CH2C(O)OR7, —OCH2C(O)NR10R11, —SCH2C(O)NR10R11, —NR7CH2C(O)NR10R11, —OS(O)pR7, —SS(O)pR7, —S(O)pOR7, —NR7S(O)pR7, —OS(O)pNR10R11, —SS(O)pNR10R11, —NR7S(O)pNR10R11, —OS(O)pOR7, —SS(O)pOR7, —NR7S(O)pOR7, —OC(S)R7, —SC(S)R7, —NR7C(S)R7, —OC(S)OR7, —SC(S)OR7, —NR7C(S)OR7, —OC(S)NR10R11, —SC(S)NR10R11, —NR7C(S)NR10R11, —OC(NR8)R7, —SC(NR8)R7, —NR7C(NR8)R7, —OC(NR8)OR7, —SC(NR8)OR7, —NR7C(NR8)OR7, —OC(NR8)NR10R11, —SC(NR8)NR10R11, —NR7C(NR8)NR10R11, —OP(O)(OR7)2, or —SP(O)(OR7)2. Preferably, R1 is —OH, —SH, or —NHR7;
R3 is —OH, —SH, —NR7H, —OR26, —SR26, —NHR26, —O(CH2)mOH, —O(CH2)mSH, —O(CH2)mNR7H, —S(CH2)mOH, —S(CH2)mSH, —S(CH2)mNR7H, —OC(O)NR10R11, —SC(O)NR10R11, —NR7C(O)NR10R11, —OC(O)R7, —SC(O)R7, —NR7C(O)R7, —OC(O)OR7, —SC(O)OR7, —NR7C(O)OR7, —OCH2C(O)R7, —SCH2C(O)R7, —NR7CH2C(O)R7, —OCH2C(O)OR7, —SCH2C(O)OR7, —NR7CH2C(O)OR7, —OCH2C(O)NR10R11, —SCH2C(O)NR10R11, —NR7CH2C(O)NR10R11, —OS(O)pR7, —SS(O)pR7, —S(O)pOR7, —NR7S(O)pR7, —OS(O)pNR10R11, —SS(O)pNR10R11, —NR7S(O)pNR10R11, —OS(O)pOR7, —SS(O)pOR7, —NR7S(O)pOR7, —OC(S)R7, —SC(S)R7, —NR7C(S)R7, —OC(S)OR7, —SC(S)OR7, —NR7C(S)OR7, —OC(S)NR10R11, —SC(S)NR10R11, —NR7C(S)NR10R11, —OC(NR8)R7, —SC(NR8)R7, —NR7C(NR8)R7, —OC(NR8)OR7, —SC(NR8)OR7, —NR7C(NR8)OR7, —OC(NR8)NR10R11, —SC(NR8)NR10R11, —NR7C(NR8)NR10R11, —C(O)OH, —C(O)NHR8, —C(O)SH, —S(O)OH, —S(O)2OH, —S(O)NHR8, —S(O)2NHR8, —OP(O)(OR7)2, or —SP(O)(OR7)2;
R7 and R8, for each occurrence, are, independently, —H, an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, or an optionally substituted heteraralkyl;
R10 and R11, for each occurrence, are independently —H, an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, or an optionally substituted heteraralkyl; or R10 and R11, taken together with the nitrogen to which they are attached, form an optionally substituted heterocyclyl or an optionally substituted heteroaryl;
R21 is an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, or an optionally substituted heteraralkyl. Preferably, R21 is an optionally substituted alkyl, an optionally substituted cycloalkyl, an optionally substituted aryl or an optionally substituted heteroaryl. Alternatively, R21 is




wherein
R10 and R11, for each occurrence, are independently —H, an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aryl or heteroaryl, an optionally substituted aralkyl; or R10 and R11, taken together with the nitrogen to which they are attached, form an optionally substituted heteroaryl or heterocyclyl; and
R30 is an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, an optionally substituted heteraralkyl, halo, cyano, nitro, guanadino, a haloalkyl, a heteroalkyl, alkoxy, haloalkoxy, —NR10R11, —OR7, —C(O)R7, —C(O)OR7, —C(S)R7, —C(O)SR7, —C(S)SR7, —C(S)OR7, —C(S)NR10R11, —C(NR8)OR7, —C(NR8)R7, —C(NR8)NR10R11, —C(NR8)SR7, —OC(O)R7, —OC(O)OR7, —OC(S)OR7, —OC(NR8)OR7, —SC(O)R7, —SC(O)OR7, —SC(NR8)OR7, —OC(S)R7, —SC(S)R7, —SC(S)OR7, —OC(O)NR10R11, —OC(S)NR10R11, —OC(NR8)NR10R11, —SC(O)NR10R11, —SC(NR8)NR10R11, —SC(S)NR10R11, —OC(NR8)R7, —SC(NR8)R7, —C(O)NR10R11, —NR8C(O)R7, —NR7C(S)R7, —NR7C(S)OR7, —NR7C(NR8)R7, —NR7C(O)OR7, —NR7C(NR8)OR7, —NR7C(O)NR10R11, —NR7C(S)NR10R11, —NR7C(NR8)NR10R11, —SR7, —S(O)pR7, —OS(O)pR7, —OS(O)pOR7, —OS(O)pNR10R11, —S(O)pOR7, —NR8S(O)pR7, —NR7S(O)pNR10R11, —NR7S(O)pOR7, —S(O)pNR10R11, —SS(O)pR7, —SS(O)pOR7, —SS(O)pNR10R11, —OP(O)(OR7)2, or —SP(O)(OR7)2;
z and q are independently an integer from 0 to 4; and
x is 0 or 1, provided that z+x less than or equal to 4.
R22, for each occurrence, is independently —H or an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, or an optionally substituted heteraralkyl, a haloalkyl, —C(O)R7, —C(O)OR7, —OC(O)R7, —C(O)NR10R11, —NR8C(O)R7, —S(O)pR7, —S(O)pOR7, or —S(O)pNR10R11. Preferably, R22 is —H, an alkyl, an aralkyl, —C(O)R7, —C(O)OR7, or —C(O)NR10R11; and
R23 and R24, for each occurrence, are independently —H, a substituent selected from the group consisting of an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, or an optionally substituted heteraralkyl, halo, cyano, nitro, guanadino, a haloalkyl, a heteroalkyl, —NR10R11, —OR7, —C(O)R7, —C(O)OR7, —OC(O)R7, —C(O)NR10R11, —NR8C(O)R7, —SR7, —S(O)pR7, —OS(O)pR7, —S(O)pOR7, —NR8S(O)pR7, or —S(O)pNR10R11;
R26 is a lower alkyl;
p, for each occurrence, is, independently, 0, 1 or 2; and
m, for each occurrence, is independently, 1, 2, 3, or 4.
i) Exemplary Compounds of the Invention
Exemplary triazole compounds of the invention are depicted in Table 5 below, including tautomers, pharmaceutically acceptable salts, solvates, clathrates, hydrates, polymorphs or prodrugs thereof.










TABLE 5





No.
Structure
Tautomeric Structure
Name


















1








3-(2- Hydroxyphenyl)-4- (naphthalen-1-yl)-5- mercapto-triazole


 


2








3-(2,4- Dihydroxyphenyl)- 4-[4-(2- methoxyethoxy)- naphthalen-1-yl]-5- mercapto-triazole


 


3








3-(2,4- Dihydroxyphenyl)- 4-(2-methyl-4- bromophenyl)-5- mercapto-triazole


 


4








3-(2,4- Dihydroxyphenyl)- 4-(4-bromophenyl)- 5-mercapto-triazole


 


5








3-(3,4- Dihydroxyphenyl)- 4-(6-methoxy- naphthalen-1-yl)-5- mercapto-triazole


 


6








3-(3,4- Dihydroxyphenyl)- 4-(6-ethoxy- naphthalen-1-yl)-5- mercapto-triazole


 


7








3-(3,4- Dihydroxyphenyl)- 4-(6-propoxy- naphthalen-1-yl)-5- mercapto-triazole


 


8








3-(2,4-Dihydroxy-5- ethyl-phenyl)-4-(5- methoxy- naphthalen-1-yl)-5- mercapto-triazole


 


9








3-(3,4- Dihydroxyphenyl)- 4-(6-isopropoxy- naphthalen-1-yl)-5- mercapto-triazole


 


10








3-(2,4- Dihydroxyphenyl)- 4-(2,6- diethylphenyl)-5- mercapto-triazole


 


11








3-(2,4- Dihydroxyphenyl)- 4-(2-methy-6- ethylphenyl)-5- mercapto-triazole


 


12








3-(2,4- Dihydroxyphenyl)- 4-(2,6- diisopropylphenyl)- 5-mercapto-triazole


 


13








3-(2,4- Dihydroxyphenyl)- 4-(1-ethyl-indol-4- yl)-5-mercapto- triazole


 


14








3-(2,4- Dihydroxyphenyl)- 4-(2,3-dihydro- benzo[1,4]dioxin-5- yl)-5-mercapto- triazole


 


15








3-(2,4- Dihydroxyphenyl)- 4-(3-methylphenyl)- 5-mercapto-triazole


 


16








3-(2,4- Dihydroxyphenyl)- 4-(3-methylphenyl)- 5-mercapto-triazole


 


17








3-(2,4- Dihydroxyphenyl)- 4-(2-chlorophenyl)- 5-mercapto-triazole


 


18








3-(2,4- Dihydroxyphenyl)- 4-(3-chlorophenyl)- 5-mercapto-triazole


 


19








3-(2,4- Dihydroxyphenyl)- 4-(4-chlorophenyl)- 5-mercapto-triazole


 


20








3-(2,4- Dihydroxyphenyl)- 4-(2- methoxyphenyl)-5- mercapto-triazole


 


21








3-(2,4- Dihydroxyphenyl)- 4-(3- methoxyphenyl)-5- mercapto-triazole


 


22








3-(2,4- Dihydroxyphenyl)- 4-(4- methoxyphenyl)-5- mercapto-triazole


 


23








3-(2,4- Dihydroxyphenyl)- 4-(3-fluorophenyl)- 5-mercapto-triazole


 


24








3-(2,4- Dihydroxyphenyl)- 4-(2-ethylphenyl)-5- mercapto-triazole


 


25








3-(2-Hydroxy-4- fluorophenyl)-4- (naphthalen-1-yl)-5- mercapto-triazole


 


26








3-(2-Hydroxy-4- aminophenyl)-4- (naphthalen-1-yl)-5- mercapto-triazole


 


27








3-(2,4- Dihydroxyphenyl)- 4-(2-methyl-4-butyl- phenyl)-5-mercapto- triazole


 


28








3-(2,4- Dihydroxyphenyl)- 4-(2,4-dimethyl- phenyl)-5-mercapto- triazole


 


29








3-(2,4- Dihydroxyphenyl)- 4-(2,6-dimethyl- phenyl)-5-mercapto- triazole


 


30








3-(2,4- Dihydroxyphenyl)- 4-(2,6-dimethyl- phenyl)-5-mercapto- triazole


 


31








3-(2,4- Dihydroxyphenyl)- 4-(4-fluorophenyl)- 5-mercapto-triazole 


 


32








3-(2,4- Dihydroxyphenyl)- 4-(2- methylsulfanylphenyl)- 5-mercapto- triazole


 


33








3-(2,4- Dihydroxyphenyl)- 4-(naphthalene-2- yl)-5-mercapto- triazole


 


34








3-(2,4- Dihydroxyphenyl)- 4-(2,3- dimethylphenyl)-5- mercapto-triazole


 


35








3-(2,4- Dihydroxyphenyl)- 4-(2-methyl-4- fluorophenyl)-5- mercapto-triazole


 


36








3-(2,4- Dihydroxyphenyl)- 4-(acenaphthalen-5- yl)-5-mercapto- triazole


 


37








3-(2-Hydroxy-4- methoxy-phenyl)-4- (naphthalen-1-yl)-5- mercapto-triazole


 


38








3-(2,4- Dihydroxyphenyl)- 4-(2,3- dichlorophenyl)-5- mercapto-triazole


 


39








3-(2,4- Dihydroxyphenyl)- 4-(5- methoxynaphthalen- 1-yl)-5-mercapto- triazole


 


40








3-(2,4- Dihydroxyphenyl)- 4-(pyren-1-yl)-5- mercapto-triazole


 


41








3-(2,4- Dihydroxyphenyl)- 4-(quinolin-5-yl)-5- mercapto-triazole


 


42








3-(2,4- Dihydroxyphenyl)- 4-(1,2,3,4- tetrahydronaphthalen- 5-yl)-5-mercapto- triazole


 


43








3-(2,4- Dihydroxyphenyl)- 4-(anthracen-1-yl)- 5-mercapto-triazole


 


44








3-(2,4- Dihydroxyphenyl)- 4-(biphenyl-2-yl)-5- mercapto-triazole


 


45








3-(2,4-Dihydroxy-6- methyl-phenyl)-4- (naphthalene-1-yl)- 5-mercapto-triazole


 


46








3-(2,4- Dihydroxyphenyl)- 4-(4- pentyloxyphenyl)-5- mercapto-triazole


 


47








3-(2,4- Dihydroxyphenyl)- 4-(4- octyloxyphenyl)-5- mercapto-triazole


 


48








3-(2,4- Dihydroxyphenyl)- 4-(4- chloronaphthalen-1- yl)-5-mercapto- triazole 


 


49








3-(2,4-Dihydroxy-5- ethyl-phenyl)-4- (naphthalen-1-yl)-5- mercapto-triazole


 


50








3-(2,4-Dihydroxy-5- ethyl-phenyl)-4-(7- carboxymethoxy- naphthalen-1-yl)-5- mercapto-triazole


 


51








3-(2,4- Dihydroxyphenyl)- 4-(2-methyl- quinolin-4-yl)-5- mercapto-triazole


 


52








3-(3- Hydroxypyridin-4- yl)-4-(naphthalen-1- yl)-5-mercapto- triazole


 


53








3-(2-Hydroxy-4- acetylamino- phenyl)-4- (naphthalen-1-yl)-5- mercapto-triazole


 


54








3-(2,4-Dihydroxy- phenyl)-4-(1,2,3,4- tetrahydronaphthalen- 1-yl)-5-mercapto- triazole


 


55








3-(2,4-Dihydroxy- phenyl)-4-(2,3- dihydro- benzo[1,4]dioxin-5- yl)-5-mercapto- triazole


 


56








3-(2,4-Dihydroxy- phenyl)-4-(3,5- dimethoxyphenyl)- 5-mercapto-triazole


 


57








3-(2,4-Dihydroxy- phenyl)-4-(2,3- dimethyl-1H-indol- 4-yl)-5-mercapto- triazole


 


58








3-(2,4-Dihydroxy-3- propyl-phenyl)-4- (naphthalen-1-yl)-5- mercapto-triazole


 


59








3-(1-ethyl-4- hydroxy-6-oxo-1,6- dihydro-pyridin-3- yl)-4-(naphthalen-1- yl)-5-mercapto- triazole


 


60








3-(4-hydroxy-6-oxo- pyridin-3-yl)-4- (naphthalen-1-yl)-5- mercapto-triazole


 


61








3-(2,4-Dihydroxy- phenyl)-4-(3,5-di- tert-butylphenyl)-5- mercapto-triazole


 


62








3-(2,6-Dihydroxy5- fluoro-pyridin-3-yl) 4-(naphthalen-1-yl)- 5-mercapto-triazole


 


63








3-(2,4-Dihydroxy-5- methyl-phenyl)-4- (naphthalene-1-yl)- 5-mercapto-triazole


 


64








3-[2,4-Dihydroxy- phenyl]-4-(3- benzoylphenyl)-5- mercapto-triazole


 


65








3-(2,4-Dihydroxy- phenyl)-4-(4- carboxy-naphthalen- 1-yl)-5-mercapto- triazole


 


66








3-(2,4-Dihydroxy- phenyl)-4-[4-(N,N- dimethylcarbamoyl)- naphthalen-1-yl]-5- mercapto-triazole


 


67








3-(2,4-Dihydroxy- phenyl)-4-(4- propoxy-naphthalen- 1-yl)-5-mercapto- triazole


 


68








3-(2,4-Dihydroxy- phenyl)-4-(4- isopropoxy- naphthalen-1-yl)-5- mercapto-triazole


 


69








3-(2,4-Dihydroxy- phenyl)-4-(5- isopropoxy- naphthalen-1-yl)-5- mercapto-triazole


 


70








3-(2,4-Dihydroxy- phenyl)-4- (isoquinolin-5-yl)-5- mercapto-triazole


 


71








3-(2,4-Dihydroxy- phenyl)-4-(5- propoxy-naphthalen- 1-yl)-5-mercapto- triazole


 


72








3-(2-Hydroxy-4- methanesulfonamino- phenyl)-4- (naphthalen-1-yl)-5- mercapto-triazole


 


73








3-(2,4-Dihydroxy- 3,6-dimethyl- phenyl)-4- (naphthalen-1-yl)-5- mercapto-triazole


 


74








3-(2,4-Dihydroxy- phenyl)-4-[7-(2- methoxyethoxy)- naphthalen-1-yl]-5- mercapto-triazole


 


75








3-(2,4-Dihydroxy-5- hexyl-phenyl)-4- (naphthalen-1-yl)-5- mercapto-triazole


 


76








3-(2,4-Dihydroxy-5- ethyl-phenyl)-4-(4- methoxy- naphthalen-1-yl-5- mercapto-triazole


 


77








3-(2,4-Dihydroxy-5- ethyl-phenyl)-4-(6- methoxy-naphthalin- l-yl)-5-mercapto- triazole


 


78








3-(2,4-Dihydroxy-3- chloro-5-ethyl- phenyl)-4- (naphthalen-1-yl)-5- mercapto-triazole


 


79








3-(2,4-Dihydroxy-5- ethyl-phenyl)-4- (2,3-dimethy-4- methoxy-phenyl)-5- mercapto-triazole


 


80








3-(2,4-Dihydroxy- phenyl)-4-(7- isopropoxy- naphthalen-1-yl)-5- mercapto-triazole


 


81








3-(2,4-Dihydroxy- phenyl)-4-(7-ethoxy- naphthalen-1-yl)-5- mercapto-triazole


 


82








3-(2,4-Dihydroxy- phenyl)-4-(7- propoxy-naphthalen- 1-yl)-5-mercapto- triazole


 


83








3-(2-Hydroxy-4- methoxymethyoxy- phenyl)-4- (naphthalen-1-yl)-5- mercapto-triazole


 


84








3-[2-Hydroxy-4-(2- hydroxy-ethoxy)- phenyl]-4- (naphthalen-1-yl)-5- mercapto-triazole


 


85








3-(2,4- Dihydroxyphenyl)- 4-(7-methoxy- naphthalen-1-yl)-5- mercapto-triazole


 


86








3-(2,4- Dihydroxyphenyl)- 4-(5-methoxy- naphthalen-1-yl)-5- mercapto-triazole


 


87








3-(2,4- Dihydroxyphenyl)- 4-(4-hydroxy- naphthalen-1-yl)-5- mercapto-triazole


 


88








3-(2,4- Dihydroxyphenyl)- 4-(1-isopropyl- indol-4-yl)-5- mercapto-triazole


 


89








3-(2,4-Dihydroxy-5- tert-butyl-phenyl)-4- (naphthalen-1-yl)-5- mercapto-triazole


 


90








3-(2,4-Dihydroxy-5- propyl-phenyl)-4- (naphthalen-1-yl)-5- mercapto-triazole


 


91








3-(2,4-Dihydroxy-3- methyl-5-ethyl- phenyl)-4- (naphthalen-1-yl)-5- mercapto-triazole


 


92








3-(2,4-Dihydroxy-5- isobutyl-phenyl)-4- (naphthalen-1-yl)-5- mercapto-triazole


 


93








3-(2,4-Dihydroxy- phenyl)-4-(2,3- dimethoxy-phenyl)- 5-mercapto-triazole


 


94








3-(2,4-Dihydroxy- phenyl)-4-(2- methoxy-3-chloro- phenyl)-5-mercapto- triazole


 


95








3-(2,4-Dihydroxy- phenyl)-4-(indol-4- yl)-5-mercapto- triazole


 


96








3-(2,4-Dihydroxy- phenyl)-4-[1-(2- methoxyethoxy)- indol-4-yl]-5- mercapto-triazole


 


97








3-(2,4-Dihydroxy- phenyl)-4- (naphthalen-1-yl)-5- hydroxy-triazole


 


98








3-(1-Oxo-3- hydroxy-pyridin-4- yl)-4-(naphthalen-1- yl)-5-mercapto- triazole


 


99








3-(2,5-Dihydroxy-4- carboxy)-4- (naphthalen-1-yl)-5- mercapto-triazole


 


100








3-(2,4-Dihydroxy-5- ethyl-phenyl)-4-(1- isopropyl-indol-4- yl)-5-mercapto- triazole


 


101








3-(2,4-Dihydroxy-5- ethyl-phenyl)-4-[1- (dimethyl- carbamoyl)-indol-4- yl]-5-mercapto- triazole


 


102








3-(2,4-Dihydroxy-5- ethyl-phenyl)-4-(1- ethyl-benzoimidazol-4- yl)-5-mercapto- triazole


 


103








3-(2,4-Dihydroxy-5- ethyl-phenyl)-4- (1,2,3-trimethyl- indol-5-yl)-5- mercapto-triazole


 


104








3-(2,5-Dihydroxy-4- hydroxymethyl- phenyl)-4- (naphthalen-1-yl)-5- mercapto-triazole


 


105








3-(2-Hydroxy-4- amino-phenyl)-4- (naphthalen-1-yl)-5- mercapto-triazole


 


106








3-(2-Hydroxy-4- acetylamino- phenyl)-4- (naphthalen-1-yl)-5- mercapto-triazole


 


107








3-(2,4-Dihydroxy-3- chloro-phenyl)-4- (naphthalen-1-yl)-5- mercapto-triazole


 


108








3-(2,4-Dihydroxy-3- phenyl)-4- (naphthalen-1-yl)-5- mercapto-triazole


 


109








3-(2,4-Dihydroxy- phenyl)-4-(2- methyl-phenyl)-5- mercapto-triazole


 


110








3-(2,4-Dihydroxy- phenyl)-4-(2,5- dimethoxy-phenyl)- 5-mercapto-triazole


 


111








3-(2,4-Dihydroxy- phenyl)-4-phenyl-5- mercapto-triazole


 


112








3-(2-Hydroxy- phenyl)-4-(2- methoxy-phenyl)-5- mercapto-triazole


 


113








3-(2-Hydroxy- phenyl)-4-(4- methyl-phenyl)-5- mercapto-triazole


 


114








3-(2-Hydroxy- phenyl)-4-(4-bromo- phenyl)-5-mercapto- triazole


 


115





3-(2,4-Dihydroxy- phenyl)-4- (naphthalen-1-yl)-5- (methyl sulfanyl)- triazole


 


116








3-(2,4-Dimethoxy- phenyl)-4- (naphthalen-1-yl)-5- mercapto-triazole


 


117





3-[2,4-Di-(dimethyl- carbamoyloxy)- phenyl]-4- (naphthalen-1-yl)-5- (dimethyl- carbomoylsulfanyl)- triazole


 


118





3-(2.4-Dihydroxy- phenyl)-4- (naphthalen-1-yl)-5- (dimethylcarbamoyl sulfanyl)-triazole


 


119





3-(2,4- Diethoxycarbonyloxy- phenyl)-4- (naphthalen-1-yl)-5- (ethoxycarbonyl- sulfanyl)-triazole


 


120





3-(2,4-Di- isobutyryloxy- phenyl)-4- (naphthalen-1-yl)-5- (isobutyrylsulfanyl)- triazole


 


121





3-[2,4-Di-(dimethyl- carbamoyloxy)- phenyl]-4-(quinolin- 5-yl)-5-(dimethyl- carbamoylsulfanyl)- triazole


 


122





3-(2,4-Diacetoxy- phenyl)-4- (naphthalen-1-yl)-5- (acetylsulfanyl)- triazole


 


123








3-(2,4-Diacetoxy- phenyl)-4- (naphthalen-1-yl)-5- mercapto-triazole


 


124





3-(2,4- Diethoxycarbonyloxy- phenyl)-4- (naphthalen-1-yl)-5- (ethylcarbamoyl- sulfanyl)-triazole


 


125





3-(2,4-Dihydroxy- phenyl)-4- (naphthalen-1-yl)-5- (2-hydroxyethylsul- fanyl)-triazole


 


126








3-(2,4-Dihydroxy- phenyl)-4-ethyl-5- mercapto-triazole


 


127








3-(2,4-Dihydroxy- phenyl)-4-propyl-5- mercapto-triazole


 


128








3-(2,4-Dihydroxy- phenyl)-4-isopropyl- 5-mercapto-triazole


 


129








3-(2,4-Dihydroxy- phenyl)-4-ethyl-5- mercapto-triazole


 


130








3-(2,4-Dihydroxy- phenyl)-4- cyclopropyl-5- mercapto-triazole


 


131





3-(2,4-Dihydroxy- phenyl)-4- (naphthalen-1-yl)-5- (carboxyethysulfanyl)- triazole


 


132








3-(2,6-Dimethoxy-5- fluoro-pyridin-3-yl)- 4-(naphthalen-1-yl)- 5-mercapto-triazole


 


133








3-(2- Methanesulfonyloxy- 4- methanesulfonyl- amino-phenyl)-4- (naphthalen-1-yl)-5- mercapto-triazole


 


134








3-(2-Methoxy- phenyl)-4-(4- methoxy-phenyl)-5- mercapto-triazole


 


135








3-(3-Hydroxy- naphthalen-2-yl)-4- phenyl-5-mercapto- triazole


 


136








3-(2-Methoxy- phenyl)-4-(4- methyl-phenyl)-5- mercapto-triazole


 


137








3-(2,4-Dihydroxy-5- ethyl-phenyl)-4-(3- methox-phenyl)-5- hydroxy-triazole


 


138








3-(2,4-Dihydroxy-5- ethyl-phenyl)-4- (naphthalen-1-yl)-5- hydroxy-triazole


 


139








3-(2,4-Dihydroxy-5- ethyl-phenyl)-4-(1- isopropyl-indol-3- yl)-5-hydroxy- triazole 


 


140








3-(2,4-Dihydroxy-5- ethyl-phenyl)-4-(1- isopropyl-indol-4- yl)-5-amino-triazole


 


141








3-(2,4-Dihydroxy-5- ethyl-phenyl)-4-(3- methoxy-phenyl)-5- amino-triazole


 


142








3-(2,4-Dihydroxy-5- ethyl-phenyl)-4- (naphthalen-1-yl)-5- amino-triazole


 


143








3-(2-Hydroxy-5- ethyloxy-phenyl)-4- (naphthalen-1-yl)-5- hydroxy-triazole


 


144








3-(2-Hydroxy-5- isopropyl-phenyl)-4- (naphthalen-1-yl)-5- hydroxy-triazole


 


145








3-(2-Dihydroxy- phenyl)-4-(7-fluoro- naphthalen-1-yl)-5- hydroxy-triazole


 


146








3-(2,4-Dihydroxy- phenyl)-4-(2,3- difluorophenyl)-5- hydroxy-triazole


 


147








3-(2,4-Dihydroxy- phenyl)-4-[2-(1H- tetrazol-5-yl)- phenyl]-5-hydroxy- triazole


 


148








3-(2,4-Dihydroxy- phenyl)-4- (benzothiazol-4-yl)- 5-hydroxy-triazole


 


149








3-(2,4-Dihydroxy- phenyl)-4-(9H- purin-6-yl)-5- hydroxy-triazole


 


150








3-(2,4-Dihydroxy- phenyl)-4-{4-[2- (moropholin-1-yl)- ethoxy]-phenyl}-5- hydroxy-triazole


 


151








3-(2,4-Dihydroxy- phenyl)-4- cyclopentyl-5- hydroxy-triazole


 


152





3-(2,4-Dihydroxy- phenyl)-4-phenyl-5- (sulfamoylamino)- triazole


 


153





3-(2,4-Dihydroxy-5- methoxy-phenyl)-4- (naphthalene-1-yl)- 5-ureido-triazole


 


154





3-(2,4-Dihydroxy-5- methoxy-phenyl)-4- (2,3- difluorophenyl)-5- ureido-triazole


 


155





3-(2,4-Dihydroxy-5- ethyl-phenyl)-4-(1- isopropyl-indol-4- yl)-5-ureido-triazole


 


156





3-(2,4-Dihydroxy-5- ethyl-phenyl)-4- (quinolin-5-yl)-5- ureido-triazole


 


157





3-(2,4-Dihydroxy-5- methoxy-phenyl)-4- (naphthalene-1-yl)- 5-carbamoyloxy- triazole


 


158





3-(2,4-Dihydroxy-5- ethyl-phenyl)-4-(3- trifluoromethyl- phenyl)-5- carbamoyloxy- triazole


 


159





3-(2,4-Dihydroxy-5- ethyl-phenyl)-4-(1- methyl-indol-4-yl)- 5-carbamoyloxy- triazole


 


160





3-(2,4-Dihydroxy-5- methoxy-phenyl)-4- (8-methoxy- quinolin-5-yl)-5- carbamoyloxy- triazole


 


161





3-(2,4-Dihydroxy-5- isopropyl-phenyl)-4- (3-methyl-quinolin- 5-yl)-5- carboxyamino- triazole


 


162





3-(2,4-Dihydroxy- phenyl)-4-(1- methyl-2-chloro- indol-4-yl)-5- carbamoyloxy- triazole


 


163





3-(2,4-Dihydroxy-5- methoxy-phenyl)-4- [3,5-di- (trifluoromethyl)- phenyl]-5- carbamoyloxy- triazole


 


164





3-(2,4-Dihydroxy-5- methoxy-phenyl)-4- (3-trifluoromethyl- phenyl)- 5-(sulfamoylamino)- triazole


 


165





3-(2,4-Dihydroxy-5- methoxy-phenyl)-4- (naphthalene-1-yl)- 5-(sulfamoylamino)- triazole


 


166





3-(2,4-Dihydroxy-5- methoxy-phenyl-4- (1-isopropyl- benzoimidazol-4- yl)-5- (sulfamoylamino)- triazole


 


167





3-(2,4-Dihydroxy-5- methoxy-phenyl)-4- (3-isopropylphenyl)- 5- (thiocarboxyamino)- triazole


 


168





3-(2,4-Dihydroxy-5- methoxy-phenyl)-4- (3-isopropyloxy- phenyl)-5- (sulfamoyloxy)- triazole


 


169





3-(2,4-Dihydroxy-5- methoxy-phenyl)-4- (naphthalene-1-yl)- 5-(sulfamoyloxy)- triazole


 


170





3-(2,4-Dihydroxy-5- methoxy-phenyl)-4- (1-isopropyl- benzoimidazol-4- yl)-5- (sulfamoyloxy)- triazole


 


171








3-(2-Hydroxy-4- ethoxycarbonyoxy- 5-methoxy-phenyl)- 4-(1-isopropyl- benzoimidazol-4- yl)-5-hydroxy- triazole


 


172








3-(2-Hydroxy-4- ethoxycarbonyoxy- 5-ethyl-phenyl)-4- (naphthalin-2-yl)-5- hydroxy-triazole


 


173








3-[2-Hydroxy-4- (dimethyl- carbamoyoxy)-5- ethyl-phenyl]-4- (naphthalin-2-yl)-5- hydroxy-triazole


 


174








3-[2-Hydroxy-4- (dimethyl- carbamoyoxy)-5- chloro-phenyl]-4- (quinolin-5-yl)-5- mercapto-triazole


 


175








3-[2-Hydroxy-4- (dimethyl- carbamoyoxy)-5- ethyl-pheny]-4- (2,3-difluoro- phenyl)-5-mercapto- triazole


 


176








3-[2-Hydroxy-4- isobutyryloxy-5- ethyl-phenyl]-4-(1- methyl-benzo- imidazol-4-yl)-5- hydroxy-triazole


 


177








3-(2,4-Dihydroxy-5- methoxy-phenyl)-4- (naphthalen-1-yl)-5- mercapto-triazole


 


178








3-(2,4-Dihydroxy-5- ethyl-phenyl)-4-(5- hydroxy-naphthalen- l-yl)-5-mercapto- triazole


 


179








3-(2,4-Dihydroxy- phenyl)-4- (naphthalen-1- ylmethyl)-5- mercapto-triazole


 


180








3-(2-Hydroxy-4- methoxyphenyl)-4- (naphthalen-1-yl)-5- mercapto-triazole


 


181








3-(2,4-Dihydroxy- phenyl)-4-(biphenyl- 3-yl)-5-mercapto- triazole


 


182








3-(2,4-Dihydroxy- phenyl)-4-(2- methyl-5- hydroxymethyl- phenyl)-5-mercapto- triazole


 


183








3-(2,4-Dihydroxy- phenyl)-4-(1- dimethylcarbamoyl- indol-4-yl)-5- mercapto-triazole


 


184








3-(2,4,5-Trihydroxy- phenyl)-4- (naphthalene-1-yl)- 5-mercapto-triazole


 


185








3-(2,4-Dihydroxy-5- ethyl-phenyl)-4- (2,3-dimethyl-indol- 5-yl)-5-mercapto- triazole


 


186








3-(2,4-Dihydroxy-5- ethyl-phenyl)-4-(3-t- butyl-4-methoxy- phenyl)-5-mercapto- triazole


 


187








3-(2,4-Dihydroxy-5- ethyl-phenyl)-4-(1- ethyl-1H- benzoimidazol-4- yl)-5-mercapto- triazole, HCl salt


 


188








3-(2,4-Dihydroxy-5- ethyl-phenyl)-4-(1- isopropyl-7- methoxy-indol-4- yl)-5-mercapto- triazole


 


189








3-(2,4-Dihydroxy-5- cyclopropyl- phenyl)-4- (naphthalene-1-yl)- 5-mercapto-triazole


 


190








3-(2,4-dihydroxy-5- ethyl-phenyl)-4-(1- propyl-indol-4-yl)-5- mercapto-[1,2,4] triazole


 


191








3-(2,4-dihydroxy-5- ethyl-phenyl)-4-(1- acetyl-2,3-dimethyl- indol-5-yl)-5- mercapto-[1,2,4] triazole


 


192








3-(2,4-dihydroxy-5- ethyl-phenyl)-4-(2- methyl-3-ethyl- benzimidazol-5-yl)- 5-mercapto-[1,2,4] triazole


 


193








3-(2,4-dihydroxy-5- ethyl-phenyl)-4-(1- ethyl-2-methyl- benzimidazol-5-yl)- 5-mercapto-[1,2,4] triazole


 


194








3-(2,4-dihydroxy-5- ethyl-phenyl)-4-(1- propyl-2,3-dimethyl- indol-5-yl)-5- mercapto-[1,2,4] triazole


 


195








3-(2,4-dihydroxy-5- ethyl-phenyl)-4-(N- methyl- tetrahydrocarbozol- 7-yl)-5-mercapto- [1,2,4] triazole


 


196








3-(2,4-dihydroxy-5- ethyl-phenyl)-4-(N- methyl- cyclononan[a]indol- 5-yl)-5-mercapto- [1,2,4] triazole


 


197








3-(2,4-dihydroxy-5- ethyl-phenyl)-4-(1- n-butyl-indol-4-yl)- 5-mercapto-[1,2,4] triazole


 


198








3-(2,4-dihydroxy-5- ethyl-phenyl)-4-(1- n-pentyl-indol-4-yl)- 5-mercapto-[1,2,4] triazole


 


199








3-(2,4-dihydroxy-5- ethyl-phenyl)-4-(1- n-hexyl-indol-4-yl)- 5-mercapto-[1,2,4] triazole


 


200








3-(2,4-dihydroxy-5- cyclopropyl- phenyl)-4-(1-(1- methylcyclopropyl)- indol-4-yl)-5- mercapto-[1,2,4] triazole


 


201








3-(2,4-dihydroxy-5- cyclopropyl- phenyl)-4-(1- isopropyl-7- methoxy-indol-4- yl)-5-mercapto- [1,2,4] triazole


 


202








3-(2,4-dihydroxy-5- cyclopropyl- phenyl)-4-(1,2,3- trimethyl-indol-5- yl)-5-mercapto- [1,2,4] triazole


 


203





3-(2,4-dihydroxy-5- ethyl-phenyl)-4-(1- isopropyl-7- methoxy-indol-4- yl)-5-mercapto- [1,2,4] triazole disodium salt


 


204








3-(2,4-dihydroxy-5- tert-butyl-phenyl)-4- (1-isopropyl-7- methoxy-indol-4- yl)-5-mercapto- [1,2,4] triazole


 


205








3-(2,4-dihydroxy-5- cyclopropyl- phenyl)-4-(1-propyl- 7-methoxy-indol-4- yl)-5-mercapto- [1,2,4] triazole


 


206








3-(2,4-dihydroxy-5- ethyl-phenyl)-4-(1- methyl-3-ethyl- indol-5-yl)-5- mercapto-[1,2,4] triazole


 


207








3-(2,4-dihydroxy-5- ethyl-phenyl)-4- (1,3-dimethyl-indol- 5-yl)-5-mercapto- [1,2,4] triazole


 


208








3-(2,4-dihydroxy-5- isopropyl-phenyl)-4- (1-isopropyl-7- methoxy-indol-4- yl)-5-mercapto- [1,2,4] triazole


 


209








3-(2,4-dihydroxy-5- ethyl-phenyl)-4-(1- methyl-3-isopropyl- indol-5-yl)-5- mercapto-[1,2,4] triazole


 


210








3-(2,4-dihydroxy-5- ethyl-phenyl)-4-(N- ethyl-carbozol-7-yl)- 5-mercapto-[1,2,4] triazole


 


211








3-(2,4-dihydroxy-5- ethyl-phenyl)-4-(1- isopropyl-7- hydroxy-indol-4-yl)- 5-mercapto-[1,2,4] triazole


 


212








3-(2,4-dihydroxy-5- ethyl-phenyl)-4-(1- isopropyl-7-ethoxy- indol-4-yl)-5- mercapto-[1,2,4] triazole


 


213








3-(2,4-dihydroxy-5- ethyl-phenyl)-4- (1,2-dimethyl-indol- 5-yl)-5-mercapto- [1,2,4] triazole


 


214








3-(2,4-dihydroxy-5- ethyl-phenyl)-4-(N- methyl-indol-5-yl)- 5-mercapto-[1,2,4] triazole


 


215








3-(2,4-dihydroxy-5- ethyl-phenyl)-4-(2- methyl-7-methoxy- benzofuran-4-yl)-5- mercapto-[1,2,4] triazole


 


216








3-(2,4-dihydroxy-5- ethyl-phenyl)-4- (benzofuran-5-yl)-5- mercapto-[1,2,4] triazole


 


217








3-(2,4-dihydroxy-5- ethyl-phenyl)-4-(2- methyl-1,3- benzoxaz-5-yl)-5- mercapto-[1,2,4] triazole


 


218








3-(2,4-dihydroxy-5- isopropyl-phenyl)-4- (1,3-dimethyl-indol- 5-yl)-5-mercapto- [1,2,4] triazole


 


219








3-(2,4-dihydroxy-5- cyclopropyl- phenyl)-4-(1,3- dimethyl-indol-5- yl)-5-mercapto- [1,2,4] triazole


 


220








3-(2,4-dihydroxy-5- ethyl-phenyl)-4- (1,3-dimethyl-indol- 5-yl)-5-hydroxy- [1,2,4] triazole


 


221








3-(2,4-dihydroxy-5- isopropyl-phenyl)-4- (N-methyl-indol-5- yl)-5-mercapto- [1,2,4] triazole


 


222








3-(2,4-dihydroxy-5- isopropyl-phenyl)-4- (1,2-dimethyl-indol- 5-yl)-5-mercapto- [1,2,4] triazole


 


223








3-(2,4-dihydroxy-5- isopropyl-phenyl)-4- (1,3-dimethyl-indol- 5-yl)-5-hydroxy- [1,2,4] triazole


 


224








3-(2,4-dihydroxy-5- cyclopropyl- phenyl)-4-(1- methyl-indol-5-yl)- 5-mercapto-[1,2,4] triazole


 


225








3-(2,4-dihydroxy-5- isopropyl-phenyl)-4- (1H-indol-5-yl)-5- mercapto-[1,2,4] triazole


 


226








3-(2,4-dihydroxy-5- isopropyl-phenyl)-4- (1-methyl-indol-5- yl)-5-hydroxy- [1,2,4] triazole


 


227








3-(2,4-dihydroxy-5- isopropyl-phenyl)-4- (1-ethyl-indol-5-yl)- 5-mercapto-[1,2,4] triazole


 


228








3-(2,4-dihydroxy-5- isopropyl-phenyl)-4- (1-propyl-indol-5- yl)-5-mercapto- [1,2,4] triazole


 


229








3-(2,4-dihydroxy-5- isopropyl-phenyl)-4- (1-methyl-2- trifluoromethyl- benzimidazol-5-yl)- 5-mercapto-[1,2,4] triazole


 


230








3-(2,4-dihydroxy-5- isopropyl-phenyl)-4- (1-methyl-indazol-5- yl)-5-mercapto- [1,2,4] triazole


 


231








3-(2,4-dihydroxy-5- isopropyl-phenyl)-4- (1-methyl-indazol-6- yl)-5-mercapto- [1,2,4] triazole


 


232








3-(2,4-dihydroxy-5- isopropyl-phenyl)-4- (1-isopropyl-indol- 4-yl)-5-hydroxy- [1,2,4] triazole


 


233








3-(2,4-dihydroxy-5- isopropyl-phenyl)-4- (1,3-benzodiaxol-5- yl)-5-mercapto- [1,2,4] triazole


 


234








3-(2,4-dihydroxy-5- isopropyl-phenyl)-4- (indan-5-yl)-5- mercapto-[1,2,4] triazole


 


235








3-(2,4-dihydroxy-5- isopropyl-phenyl)-4- (2-methyl-indazol-6- yl)-5-mercapto- [1,2,4] triazole


 


236








3-(2,4-dihydroxy-5- ethyl-phenyl)-4-(3- oxo- benzo[1,4]oxazin-6- yl)-5-mercapto- [1,2,4] triazole


 


237








3-(2,4-dihydroxy-5- ethyl-phenyl)-4-(2- oxo-1,3-dihydro- benzoimidazol-5- yl)-5-mercapto- [1,2,4] triazole


 


238








3-(2,4-dihydroxy-5- isopropyl-phenyl)-4- (2H- benzo[1,4]oxazin-6- yl)-5-mercapto- [1,2,4] triazole


 


239








4-Ethyl-6-[5- mercapto-4-(1- methyl-2,3-dihydro- 1H-indol-5-yl)-4H- [1,2,4]triazol-3-yl]- benzene-1,3-diol


 


240








5-(3-(5-ethyl-2,4- dihydroxyphenyl)-5- mercapto-4H-1,2,4- triazol-4-yl)indolin- 2-one


 


241








5-(3-(5-ethyl-2,4- dihydroxyphenyl)-5- mercapto-4H-1,2,4- triazol-4-yl)-1H- benzo[d]imidazol- 2(3H)-one


 


242








5-(3-(5-ethyl-2,4- dihydroxyphenyl)-5- mercapto-4H-1,2,4- triazol-4-yl)-1- methylindolin-2-one 


 


243








4-isopropyl-6-(5- mercapto-4-(4- propyl-3,4-dihydro- 2H- benzo[b][1,4]oxazin- 6-yl)-4H-1,2,4- triazol-3-yl)benzene- 1,3-diol


 


244








6-(3-(5-ethyl-2,4- dihydroxyphenyl)-5- mercapto-4H-1,2,4- triazol-4-yl)-2H- benzo[b][1,4]oxazin- 3(4H)-one


 


245








6-(3-(5-ethyl-2,4- dihydroxyphenyl)-5- mercapto-4H-1,2,4- triazol-4-yl)-3- methylbenzo[d]thiazol- 2(3H)-one


 


246








6-(3-(5-ethyl-2,4- dihydroxyphenyl)-5- mercapto-4H-1,2,4- triazol-4- yl)benzo[d]thiazol- 2(3H)-one


 


247








4-(4-(3- (diethylamino)-4- methoxyphenyl)-5- mercapto-4H-1,2,4- triazol-3-yl)-6- ethylbenzene-1,3- diol


 


248








4-(4-(3-(N- isopropyl-N- propylamino)-4- methoxyphenyl)-5- mercapto-4H-1,2,4- triazol-3-yl)-6- ethylbenzene-1,3- diol


 


249








4-(4-(3-(N- isopropyl-N- methylamino)-4- methoxyphenyl)-5- mercapto-4H-1,2,4- triazol-3-yl)-6- ethylbenzene-1,3- diol


 


250








4-(4-(3-(N-ethyl-N- methylamino)-4- methoxyphenyl)-5- mercapto-4H-1,2,4- triazol-3-yl)-6- ethylbenzene-1,3- diol


 


251








4-(4-(3- (dimethylamino)-4- methoxyphenyl)-5- mercapto-4H-1,2,4- triazol-3-yl)-6- ethylbenzene-1,3- diol


 


252








4-(4-(3- (dimethylamino) phenyl)- 5-mercapto-4H- 1,2,4-triazol-3-yl)-6- ethylbenzene-1,3- diol


 


253








4-(4-(3-(N-ethyl-N- isopropylamino)-4- methoxyphenyl)-5- mercapto-4H-1,2,4- triazol-3-yl)-6- ethylbenzene-1,3- diol


 


254








4-ethyl-6-(5- mercapto-4-(3- (pyrrolidin-1- yl)phenyl)-4H-1,2,4- triazol-3-yl)benzene- 1,3-diol


 


255








4-ethyl-6-(5- mercapto-4-(4- methoxy-3- morpholinophenyl)- 4H-1,2,4-triazol-3- yl)benzene-1,3-diol


 


256








4-(4-(3-(N- isopropyl-N- propylamino)-4- methoxyphenyl)-5- mercapto-4H-1,2,4- triazol-3-yl)-6- isopropylbenzene- 1,3-diol


 


257








4-(4-(3-(N-methyl- N-propylamino)-4- methoxyphenyl)-5- mercapto-4H-1,2,4- triazol-3-yl)-6- isopropylbenzene- 1,3-diol


 


258








4-(4-(3-(N-methyl- N-ethylamino)-4- methoxy-phenyl)-5- mercapto-4H-1,2,4- triazol-3-yl)-6- isopropylbenzene- 1,3-diol


 


259








4-(4-(4- (dimethylamino)-3- methoxyphenyl)-5- mercapto-4H-1,2,4- triazol-3-yl)-6- ethylbenzene-1,3- diol


 


260











 


261








4-(4-(3- aminophenyl)-5- mercapto-4H-1,2,4- triazol-3-yl)-6- ethylbenzene-1,3- diol


 


262











 


263








4-(4-(3-(N- isopentyl-N- methylamino)-4- methoxyphenyl)-5- mercapto-4H-1,2,4- triazol-3-yl)-6- isopropylbenzene- 1,3-diol


 


264











 


265








4-(4-(3-(N-(2- (dimethylamino)ethyl)- N-methylamino)- 4-methoxyphenyl)- 5-mercapto-4H- 1,2,4-triazol-3-yl)-6- isopropylbenzene- 1,3-diol


 


266








4-(4-(3-(N-(2- methoxyethyl)-N- methylamino)-4- methoxyphenyl)-5- mercapto-4H-1,2,4- triazol-3-yl)-6- isopropylbenzene- 1,3-diol


 


267








4-(4-(3-(N- (cyclopropylmethyl)- N-methylamino)-4- methoxyphenyl)-5- mercapto-4H-1,2,4- triazol-3-yl)-6- isopropylbenzene- 1,3-diol


 


268








4-(4-(3-(N-butyl-N- methylamino)-4- methoxyphenyl)-5- mercapto-4H-1,2,4- triazol-3-yl)-6- isopropylbenzene- 1,3-diol


 


269








4-(4-(3-(N-isobutyl- N-methylamino)-4- methoxyphenyl)-5- mercapto-4H-1,2,4- triazol-3-yl)-6- isopropylbenzene- 1,3-diol


 


270








4-(4-(3-(N-(2-1H- imidazol-1-yl)ethyl)- N-methylamino)-4- methoxyphenyl)-5- mercapto-4H-1,2,4- triazol-3-yl)-6- isopropylbenzene- 1,3-diol


 


271








4-(4-(3-(N-methyl- N-propylamino)-4- methoxyphenyl)-5- mercapto-4H-1,2,4- triazol-3-yl)-6- isopropylbenzene- 1,3-diol


 


272








4-(4-(3- (dimethylamino)-4- (methylthio)phenyl)- 5-mercapto-4H- 1,2,4-triazol-3-yl)-6- isopropylbenzene- 1,3-diol


 


273








4-(4-(3-(1H-pyrrol- 1-yl)phenyl)-5- hydroxy-4H-1,2,4- triazol-3-yl)-6- ethylbenzene-1,3- diol


 


274








4-(4-(3-(1H- imidazol-1- yl)phenyl)-5- mercapto-4H-1,2,4- triazol-3-yl)-6- isopropylbenzene- 1,3-diol


 


275











 


276











 


277








4-(4-(4- (dimethylamino) phenyl)-5-mercapto- 4H-1,2,4-triazol-3-yl)- 6-ethylbenzene-1,3- diol


 


278








4-(4-(4-(diethylamino) phenyl)-5-mercapto- 4H-1,2,4-triazol-3-yl)- 6-ethylbenzene-1,3- diol


 


279








4-ethyl-6-(5- mercapto-4-(4- morpholinophenyl)- 4H-1,2,4-triazol-3- yl)benzene-1,3-diol


 


280








4-(4-(4-(1H- imidazol-1- yl)phenyl)-5- mercapto-4H-1,2,4- triazol-3-yl)-6- ethylbenzene-1,3- diol


 


281








4-(4-(2,5-diethoxy- 4- morpholinophenyl)- 5-mercapto-4H- 1,2,4-triazol-3-yl)-6- ethylbenzene-1,3- diol


 


282








4-(4-(3-(1H-pyrrol- l-yl)phenyl)-5- mercapto-4H-1,2,4- triazol-3-yl)-6- ethylbenzene-1,3- diol


 


283








4-(4-(4-(1H-pyrazol- 1-yl)phenyl)-5- mercapto-4H-1,2,4- triazol-3-yl)-6- ethylbenzene-1,3- diol


 


284








4-(4-(4-(amino)-3- hydroxyphenyl)-5- mercapto-4H-1,2,4- triazol-3-yl)-6- ethylbenzene-1,3- diol


 


285








4-(4-(4- (methylamino)-3- hydroxyphenyl)-5- mercapto-4H-1,2,4- triazol-3-yl)-6- ethylbenzene-1,3- diol


 


286








4-(4-(4- (dimethylamino)-3- methylphenyl)-5- mercapto-4H-1,2,4- triazol-3-yl)-6- ethylbenzene-1,3- diol









Exemplary pyrazole compounds of the invention are depicted in Table 6 below, including tautomers, pharmaceutically acceptable salts, solvates, clathrates, hydrates, polymorphs or prodrugs thereof.









TABLE 6





No.
Structure
Name







287




4-[3-(N,N-diethylamino)-4-methoxy- phenyl]-3-(5-ethyl-2,4-dihydroxy- phenyl)-5-mercapto-2H-pyrazole 


 


288




4-[3-(isopropyl-propyl-amino)-4- methoxy-phenyl]-3-(5-ethyl-2,4- dihydroxy-phenyl)-5-mercapto-2H- pyrazole 


 


289




4-[3-(isopropyl-methyl-amino)-4- methoxy-phenyl]-3-(5-ethyl-2,4- dihydroxy-phenyl)-5-mercapto-2H- pyrazole 


 


290




4-[3-(ethyl-methyl-amino)-4-methoxy- phenyl]-3-(5-ethyl-2,4-dihydroxy- phenyl)-5-mercapto-2H-pyrazole


 


291




4-[3-(N,N-methylamino)-4-methoxy- phenyl]-3-(5-ethyl-2,4-dihydroxy- phenyl)-5-mercapto-2H-pyrazole 


 


292




4-[3-(N,N-methylamino)-phenyl]-3-(5- ethyl-2,4-dihydroxy-phenyl)-5- mercapto-2H-pyrazole 


 


293




4-[4-(N,N-methylamino)-3-methoxy- phenyl]-3-(5-ethyl-2,4-dihydroxy- phenyl)-5-mercapto-2H-pyrazole 


 


294




4-[3-(isopropyl-ethyl-amino)-4- methoxy-phenyl]-3-(5-ethyl-2,4- dihydroxy-phenyl)-5-mercapto-2H- pyrazole


 


295




4-[3-(pyrrolidin-1-yl)-phenyl]-3-(5- ethyl-2,4-dihydroxy-phenyl)-5- mercapto-2H-pyrazole 


 


296




4-[3-(isopropyl-propyl-amino)-4- methoxy-phenyl]-3-(5-isopropyl-2,4- dihydroxy-phenyl)-5-mercapto-2H- pyrazole 


 


297




4-[3-(methyl-propyl-amino)-4-methoxy- phenyl]-3-(5-isopropyl-2,4-dihydroxy- phenyl)-5-mercapto-2H-pyrazole 


 


298




4-[3-(ethyl-methyl-amino)-4-methoxy- phenyl]-3-(5-isopropyl-2,4-dihydroxy- phenyl)-5-mercapto-2H-pyrazole 


 


299




4-[3-(morpholino-1-yl)-4-methoxy- phenyl]-3-(5-ethyl-2,4-dihydroxy- phenyl)-5-mercapto-2H-pyrazole 


 


300




4-[3-(ethyl-methyl-amino)-4-methoxy- phenyl]-3-(5-isopropyl-2,4-dihydroxy- phenyl)-5-hydroxy-2H-pyrazole 


 


301




4-[3-(N,N-diethyl-amino)-4-methoxy- phenyl]-3-(5-ethyl-2,4-dihydroxy- phenyl)-5-hydroxy-2H-pyrazole 


 


302




4-[3-(pyrrolidin-1-yl)-4-methoxy- phenyl]-3-(5-ethyl-2,4-dihydroxy- phenyl)-5-hydroxy-2H-pyrazole


 


303




4-[3-(ethyl-methyl-amino)-4-methoxy- phenyl]-3-(5-cyclopropyl-2,4- dihydroxy-phenyl)-5-hydroxy-2H- pyrazole 


 


304




4-[3-(ethyl-methyl-amino)-4-methoxy- phenyl]-3-(5-cyclopropyl-2,4- dihydroxy-phenyl)-5-mercapto-2H- pyrazole 


 


305




Phosphoric acid mono {4-[3-(ethyl- methyl-amino)-4-methoxy-phenyl]-3-(5- isopropyl-2,4-dihydroxy-phenyl)-2H- pyrazol-5-yl} ester


 


306




Phosphoric acid {4-[3-(ethyl-methyl- amino)-4-methoxy-phenyl]-3-(5- isopropyl-2,4-dihydroxy-phenyl)-2H- pyrazol-5-yl} ester ethyl ester 


 


307




4-[3-(N,N-methylamino)-4-methoxy- phenyl]-3-(5-isopropyl-2-hydroxy-4- dimethylaminocarbamoyloxy-phenyl)- 5-mercapto-2H-pyrazole 


 


308




4-[3-(pyrrolidin-1-yl)-4-methoxy- phenyl]-3-(5-isopropyl-2-hydroxy-4- dimethylaminocarbamoyloxy-phenyl)- 5-mercapto-2H-pyrazole 


 


309




4-[3-(N,N-methylamino)-4-methoxy- phenyl]-3-(5-isopropyl-2,4-dihydroxy- phenyl)-5-(2-hydroxy-ethylsulfanyl)- 2H-pyrazole


 


310




4-(1-isopropyl-1H-indol-4-yl)-3-(2,4- dihydroxy-phenyl)-5-mercapto-2H- pyrazole 


 


311




4-(1H-indol-4-yl)-3-(2,4-dihydroxy- phenyl)-5-mercapto-2H-pyrazole 


 


312




4-[1-(2-methoxy-ethyl)-1H-indol-4-yl]- 3-(2,4-dihydroxy-phenyl)-5-mercapto- 2H-pyrazole 


 


313




4-(1-isopropyl-1H-indol-4-yl)-3-(5- ethyl-2,4-dihydroxy-phenyl)-5- mercapto-2H-pyrazole


 


314




4-(1-dimethylcarbamoyl-1H-indol-4-yl)- 3-(2,4-dihydroxy-phenyl)-5-mercapto- 2H-pyrazole 


 


315




4-(1-propyl-1H-indol-4-yl)-3-(5-ethyl- 2,4-dihydroxy-phenyl)-5-mercapto-2H- pyrazole 


 


316




4-(1-ethyl-1H-indol-4-yl)-3-(5-ethyl- 2,4-dihydroxy-phenyl)-5-mercapto-2H- pyrazole 


 


317




4-(1,2,3-trimethyl-1H-indol-4-yl)-3-(5- ethyl-2,4-dihydroxy-phenyl)-5- mercapto-2H-pyrazole


 


318




4-(2,3-dimethyl-1H-indol-4-yl)-3-(5- ethyl-2,4-dihydroxy-phenyl)-5- mercapto-2H-pyrazole 


 


319




4-(1-ethyl-1H-benzoimidazol-4-yl)-3- (5-ethyl-2,4-dihydroxy-phenyl)-5- mercapto-2H-pyrazole 


 


320




4-(1-carboxy-2,3-dimethyl-1H-indol-5- yl)-3-(5-ethyl-2,4-dihydroxy-phenyl)-5- mercapto-2H-pyrazole 


 


321




4-(1-ethyl-2-methyl-1H-benzoimidazol- 6-yl)-3-(5-ethyl-2,4-dihydroxy-phenyl)- 5-mercapto-2H-pyrazole


 


322




4-(1-isopropy-7-methoxy-1H-indol-4- yl)-3-(5-ethyl-2,4-dihydroxy-phenyl)- 5-mercapto-2H-pyrazole 


 


323




4-(1-propy-2,3-dimethyl-1H-indol-5- yl)-3-(5-ethyl-2,4-dihydroxy-phenyl)- 5-mercapto-2H-pyrazole 


 


324




4-(1-ethyl-1H-indol-4-yl)-3-(5- isopropyl-2,4-dihydroxy-phenyl)-5- hydroxy-2H-pyrazole


 


325




4-(1-ethyl-1H-indol-4-yl)-3-(5- cyclopropyl-2,4-dihydroxy-phenyl)-5- hydroxy-2H-pyrazole 


 


326




4-(1,2,3-trimethyl-1H-indol-5-yl)-3-(5- ethyl-2,4-dihydroxy-phenyl)-5-amino- 2H-pyrazole  


 


327




4-(1-isopropyl-7-methoxy-1H-indol-4- yl)-3-(5-ethyl-2,4-dihydroxy-phenyl)-5- amino-2H-pyrazole 


 


328




4-(1-isopropyl-7-methoxy-1H-indol-4- yl)-3-(5-isopropyl-2,4-dihydroxy- phenyl)-5-hydroxy-2H-pyrazole


 


329




4-(1,3-dimethyl-1H-indol-5-yl)-3-(5- isopropyl-2,4-dihydroxy-phenyl)-5- hydroxy-2H-pyrazole 


 


330




4-(1-methyl-1H-indol-5-yl)-3-(5- isopropyl-2,4-dihydroxy-phenyl)-5- hydroxy-2H-pyrazole 


 


331




4-(1-methyl-1H-indol-5-yl)-3-(5- isopropyl-2,4-dihydroxy-phenyl)-5- mercapto-2H-pyrazole 


 


332




4-(1-methyl-1H-indol-5-yl)-3-(5- isopropyl-2,4-dihydroxy-phenyl)-5- amino-2H-pyrazole


 


333




4-(7-methoxy-benzofuran-4-yl)-3-(5- isopropyl-2,4-dihydroxy-phenyl)-5- hydroxy-2H-pyrazole 


 


334




4-(5-methoxy-naphthalene-1-yl)-3-(5- isopropyl-2,4-dihydroxy-phenyl)-5- mercapto-2H-pyrazole 


 


335




4-(benzo[l,4]dioxin-5-yl)-3-(5-ethyl- 2,4-dihydroxy-phenyl)-5-mercapto-2H- pyrazole 


 


336




4-(acenaphthen-5-yl)-3-(5-isopropyl- 2,4-dihydroxy-phenyl)-5-hydroxy-2H- pyrazole


 


337




4-(9H-purin-6-yl)-3-(5-isopropyl-2,4- dihydroxy-phenyl)-5-hydroxy-2H- pyrazole


 


338




4-(benzothiazol-4-yl)-3-(5-isopropyl- 2,4-dihydroxy-phenyl)-5-mercapto-2H- pyrazole 


 


339




4-(7-fluoro-naphthylen-1-yl)-3-(5- cyclopropyl-2,4-dihydroxy-phenyl)-5- mercapto-2H-pyrazole 


 


340




4-(quinolin-4-yl)-3-(5-isopropyl-2,4- dihydroxy-phenyl)-5-mercapto-2H- pyrazole


 


341




4-(1-methyl-1H-indol-5-yl)-3-(5- isopropyl-2,4-dihydroxy-phenyl)-5- carbamoyloxy-2H-pyrazole 


 


342




4-(1-methyl-1H-indol-5-yl)-3-(5- cyclopropyl-2,4-dihydroxy-phenyl)-5- carboxyamino-2H-pyrazole 


 


343




4-(1-methyl-1H-indol-5-yl)-3-(5- methoxy-2,4-dihydroxy-phenyl)-5- aminosulfamido-2H-pyrazole


 


344




4-(4-methoxy-naphthalene-1-yl)-3-(5- isopropyl-2-hydroxy-4- ethoxycarbonyloxy-phenyl)-5- mercapto-2H-pyrazole 


 


345




4-(naphthalene-1-yl)-3-(5-isopropyl-2,4- ethylcarbamoyloxy-phenyl)-5-mercapto- 2H-pyrazole 


 


346




4-(1-methyl-1H-indol-4-yl)-3-(5- isopropyl-2,4-ethylcarbamoyloxy- phenyl)-5-dimethylcarbamoylsulfanyl- 2H-pyrazole 


 


347




4-(1,2-dimethyl-1H-indol-4-yl)-3-(5- isopropyl-2,4-ethyloxycarbonyloxy- phenyl)-5-ethoxycarbamoylsulfanyl- 2H- pyrazole


 


348




4-(naphthalen-1-yl)-3-(5-ethyl-2,4- dihydroxy-phenyl)-5-hydroxy-2H- pyrazole 


 


349




4-(2-methyl-4-fluorophenyl)-3-(5-ethyl- 2,4-dihydroxy-phenyl)-5-mercapto-2H- pyrazole 


 


350




4-(3,5-dimethoxyphenyl)-3-(5-ethyl-2,4- dihydroxy-phenyl)-5-amino-2H- pyrazole 


 


351




4-[2-(1H-tetrazol-5-yl)-phenyl]-3-(5- ethyl-2,4-dihydroxy-phenyl)-5-hydroxy- 2H-pyrazole









Exemplary imidazolyl compounds of the invention are depicted in Table 7 below, including tautomers, pharmaceutically acceptable salts, solvates, clathrates, hydrates, polymorphs or prodrugs thereof.









TABLE 7





No.
Structure
Name







352




1-(3-diethylamino-4-methoxy-phenyl)- 2-mercapto-5-(2,4-dihydroxy-5-ethyl- phenyl)-1H-imidazole 


 


353




1-[3-(propyl-isopropylamino)-4- methoxy-phenyl]-2-mercapto-5-(2,4- dihydroxy-5-ethyl-phenyl)-1H- imidazole


 


354




1-[3-(methyl-isopropylamino)-4- methoxy-phenyl]-2-mercapto-5-(2,4- dihydroxy-5-ethyl-phenyl)-1H- imidazole 


 


355




1-[3-(methyl-ethylamino)-4-methoxy- phenyl]-2-mercapto-5-(2,4-dihydroxy-5- ethyl-phenyl)-1H-imidazole 


 


356




l-(3-dimethylamino-4-methoxy- phenyl)-2-mercapto-5-(2,4-dihydroxy-5- ethyl-phenyl)-1H-imidazole 


 


357




1-(3-dimethylamino-phenyl)-2- mercapto-5-(2,4-dihydroxy-5-ethyl- phenyl)-1H-imidazole


 


358




1-(3-methoxy-4-dimethylamino- phenyl)-2-mercapto-5-(2,4-dihydroxy- 5-ethyl-phenyl)-1H-imidazole 


 


360




1-[3-(ethyl-isopropylamino)-4-methoxy- phenyl]-2-mercapto-5-(2,4-dihydroxy-5- ethyl-phenyl)-1H-imidazole 


 


361




1-(3-pyrrolidin-1-yl-phenyl)-2- mercapto-5-(2,4-dihydroxy-5-ethyl- phenyl)-1H-imidazole 


 


362




1-[3-(propyl-isopropylamino)-4- methoxy-phenyl]-2-mercapto-5-(2,4- dihydroxy-5-isopropyl-phenyl)-1H- imidazole


 


363




1-[3-(methyl-propylamino)-4-methoxy- phenyl]-2-mercapto-5-(2,4-dihydroxy-5- isopropyl-phenyl)-1H-imidazole 


 


364




1-[3-(methyl-ethylamino)-4-methoxy- phenyl]-2-mercapto-5-(2,4-dihydroxy-5- isopropyl-phenyl)-1H-imidazole 


 


365




1-[3-(morpholino-1-yl)-4-methoxy- phenyl]-2-mercapto-5-(2,4-dihydroxy-5- ethyl-phenyl)-1H-imidazole 


 


366




1-[3-(methyl-ethylamino)-4-methoxy- phenyl]-2-hydroxy-5-(2,4-dihydroxy-5- isopropyl-phenyl)-1H-imidazole


 


367




1-(3-diethylamino-4-methoxy-phenyl)- 2-hydroxy-5-(2,4-dihydroxy-5-ethyl- phenyl)-1H-imidazole 


 


368




1-[3-(pyrrolidin-1-yl)-4-methoxy- phenyl]-2-hydroxy-5-(2,4-dihydroxy-5- ethyl-phenyl)-1H-imidazole 


 


369




1-[3-(methyl-ethylamino)-4-methoxy- phenyl]-2-hydroxy-5-(2,4-dihydroxy-5- cyclopropyl-phenyl)-1H-imidazole


 


370




1-[3-(methyl-ethylamino)-4-methoxy- phenyl]-2-mercapto-5-(2,4-dihydroxy-5- cyclopropyl-phenyl)-1H-imidazole 


 


371




1-[3-(methyl-ethylamino)-4-methoxy- phenyl]-2-phosphonooxy-5-(2,4- dihydroxy-5-isopropyl-phenyl)-1H- imidazole 


 


372




1-[3-(methyl-ethylamino)-4-methoxy- phenyl]-2-(ethoxy-hydroxy- phosphoryloxy)-5-(2,4-dihydroxy-5- isopropyl-phenyl)-1H-imidazole 


 


373




1-(3-dimethylamino-4-methoxy- phenyl)-2-mercapto-5-(2-hydroxy-4- dimethylcarbamoyloxy-5-isopropyl- phenyl)-1H-imidazole


 


374




1-[3-(pyrrolidin-1-yl)-4-methoxy- phenyl]-2-mercapto-5-(2-hydroxy-4- isobutyryloxy-5-isopropyl-phenyl)-1H- imidazole 


 


375




1-(3-dimethylamino-4-methoxy- phenyl)-2-(2-hydroxy-ethylsulfanyl)-5- (2,4-dihydroxy-5-isopropyl-phenyl)-1H- imidazole 


 


376




1-(1-ethyl-1H-indol-4-yl)-2-mercapto-5- (2,4-dihydroxy-phenyl)-1H-imidazole


 


377




1-(1-isopropyl-1H-indol-4-yl)-2- mercapto-5-(2,4-dihydroxy-phenyl)-1H- imidazole 


 


378




1-(1H-indol-4-yl)-2-mercapto-5-(2,4- dihydroxy-phenyl)-1H-imidazole 


 


379




1-[1-(2-methoxy-ethyl)-1H-indol-4-yl]- 2-mercapto-5-(2,4-dihydroxy-phenyl)- 1H-imidazole 


 


380




1-(1-isopropyl-1H-indol-4-yl)-2- mercapto-5-(2,4-dihydroxy-5-ethyl- phenyl)-1H-imidazole


 


381




1-(1-dimethylcarbamoyl-1H-indol-4-yl)- 2-mercapto-5-(2,4-dihydroxy-phenyl)- 1H-imidazole 


 


382




1-(1-propyl-1H-indol-4-yl)-2-mercapto- 5-(2,4-dihydroxy-5-ethyl-phenyl)-1H- imidazole 


 


383




1-(1-ethyl-1H-indol-4-yl)-2-mercapto-5- (2,4-dihydroxy-5-ethyl-phenyl)-1H- imidazole 


 


384




1-(1,2,3-trimethyl-1H-indol-5-yl)-2- mercapto-5-(2,4-dihydroxy-5-ethyl- phenyl)-1H-imidazole


 


385




1-(2,3-dimethyl-1H-indol-5-yl)-2- mercapto-5-(2,4-dihydroxy-5-ethyl- phenyl)-1H-imidazole 


 


386




1-(1-ethyl-1H-benzoimidazol-4-yl)-2- mercapto-5-(2,4-dihydroxy-5-ethyl- phenyl)-1H-imidazole 


 


387




1-(1-carboxy-2,3-dimethyl-1H-indol-5- yl)-2-mercapto-5-(2,4-dihydroxy-5- ethyl-phenyl)-1H-imidazole 


 


388




1-(1-ethyl-2-methyl-1H-benzoimidazol- 6-yl)-2-mercapto-5-(2,4-dihydroxy-5- ethyl-phenyl)-1H-imidazole


 


389




1-(1-isopropyl-7-methoxy-1H-indol-4- yl)-2-mercapto-5-(2,4-dihydroxy-5- ethyl-phenyl)-1H-imidazole 


 


390




1-(1-propyl-2,3-dimethyl-1H-indol-5- yl)-2-mercapto-5-(2,4-dihydroxy-5- ethyl-phenyl)-1H-imidazole 


 


391




1-(1-ethyl-1H-indol-4-yl)-2-hydroxy-5- (2,4-dihydroxy-5-isopropyl-phenyl)-1H- imidazole 


 


392




1-(1-ethyl-1H-indol-4-yl)-2-hydroxy-5- (2,4-dihydroxy-5-cyclopropyl-phenyl)- 1H-imidazole 


 


393




1-(1,2,3-trimethyl-1H-indol-5-yl)-2- amino-5-(2,4-dihydroxy-5-ethyl- phenyl)-1H-imidazole 


 


394




1-(1-isopropyl-7-methoxy-1H-indol-4- yl)-2-amino-5-(2,4-dihydroxy-5-ethyl- phenyl)-1H-imidazole 


 


395




1-(1-isopropyl-7-methoxy-1H-indol-4- yl)-2-hydroxy-5-(2,4-dihydroxy-5- isopropyl-phenyl)-1H-imidazole


 


396




1-(1,3-dimethyl-1H-indol-5-yl)-2- hydroxy-5-(2,4-dihydroxy-5-isopropyl- phenyl)-1H-imidazole 


 


397




1-(1-methyl-1H-indol-5-yl)-2-hydroxy- 5-(2,4-dihydroxy-5-isopropyl-phenyl)- 1H-imidazole 


 


398




1-(1-methyl-1H-indol-5 -yl)-2-mercapto- 5-(2,4-dihydroxy-5-isopropyl-phenyl)- 1H-imidazole


 


399




1-(9-methyl-6,7,8,9-tetrahydro-5H- carbazol-3-yl)-2-mercapto-5-(2,4- dihydroxy-5-ethyl-phenyl)-1H- imidazole 


 


400




1-(1-methyl-1H-indol-5-yl)-2-amino-5- (2,4-dihydroxy-5-isopropyl-phenyl)-1H- imidazole 


 


401




1-(7-methoxy-benzofuran-4-yl)-2- hydroxy-5-(2,4-dihydroxy-5-isopropyl- phenyl)-1H-imidazole 


 


402




1-(5-methoxy-naphthylen-1-yl)-2- mercapto-5-(2,4-dihydroxy-5-isopropyl- phenyl)-1H-imidazole


 


403




1-(2,3-dihydro-benzo[1,4]dioxin-5-yl)- 2-mercapto-5-(2,4-dihydroxy-5-ethyl- phenyl)-1H-imidazole 


 


404




1-(3-acenaphthylen-5-yl)-2-hydroxy-5- (2,4-dihydroxy-5-isopropyl-phenyl)-1H- imidazole 


 


405




1-(9H-purin-6-yl)-2-hydroxy-5-(2,4- dihydroxy-5-isopropyl-phenyl)-1H- imidazole 


 


406




1-(benzothiazol-4-yl)-2-mercapto-5- (2,4-dihydroxy-5-isopropyl-phenyl)-1H- imidazole


 


407




1-(7-fluoro-naphthylen-1-yl)-2- mercapto-5-(2,4-dihydroxy-5- cyclopropyl-phenyl)-1H-imidazole 


 


408




1-(quinolin-4-yl)-2-mercapto-5-(2,4- dihydroxy-5-isopropyl-phenyl)-1H- imidazole 


 


409




1-(1-methyl-indol-5-yl)-2- carbamoyloxy-5-(2,4-dihydroxy-5- isopropyl-phenyl)-1H-imidazole 


 


410




1-(1-methyl-indol-5-yl)-2- carboxyamino-5-(2,4-dihydroxy-5- cycolpropyl-phenyl)-1H-imidazole


 


411




1-(1-methyl-1H-indol-5-yl)-2- aminosulfamido-5-(5-methoxy-2,4- dihydroxy-phenyl)-1H-imidazole 


 


412




1-(4-methoxy-naphthylen-1-yl)-2- mercapto-5-(2-hydroxy-4- ethoxycarbonyloxy-5-isopropyl- phenyl)-1H-imidazole 


 


413




1-(naphthylen-1-yl)-2-mercapto-5-[2,4- di-(ethoxycarbamoyloxy)-5-isopropyl- phenyl]-1H-imidazole 


 


414




1-(1-methyl-1H-indol-4-yl)-2- dimethylcarbamoylsulfanyl-5-[2,4-di- (ethoxycarbamoyloxy)-5-isopropyl- phenyl]-1H-imidazole 


 


415




1-(1,2-dimethyl-1H-indol-4-yl)-2- ethoxycarbonylsulfanyl-5-[2,4-di- (ethoxycarbonyloxy)-5-isopropyl- phenyl]-1H-imidazole 


 


416




1-(naphthylen-1-yl)-2-hydroxy-5-(2,4- dihydroxy-5-ethyl-phenyl)-1H- imidazole


 


417




1-(2,5-dimethoxyphenyl)-2-amino-5- (2,4-dihydroxy-5-ethyl-phenyl)-1H- imidazole 


 


418




1-(2-methyl-4-fluoro-phenyl)-2- mercapto-5-(2,4-dihydroxy-5-ethyl- phenyl)-1H-imidazole 


 


419




1-[2-(1H-tetrazol-5-yl)-phenyl]-2- hydroxy-5-(2,4-dihydroxy-5-ethyl- phenyl)-1H-imidazole









Preferred triazole compounds of the invention are those compounds that can form a tautomeric structure as shown below and as exemplified by the tautomeric structures shown in Table 5:




Also preferred are compounds which can be metabolized or hydrolyzed in vivo to a compound which can form the tautomeric structure shown above. For example, the following embodiments of a compound of formula (I) can be produced in vivo in the following reaction:





Without wishing to be bound by any theory, it is believed that the compounds of the invention preferentially bind to Hsp90 in the tautomeric form shown above, and thereby inhibit the activity of Hsp90.
It is understood that the pyrazole compounds of the present invention, including compounds of formulas (VI) through (VIII) and Table 6 can be purified, isolated, obtained and used in a form of a pharmaceutically acceptable salt, a solvate, a clathrate, a tautomer or a prodrug.
For example, a compound of formula (VI) can undergo the following tautomerization:




where X0 is O, S, or NR7. It is understood that where a structural formula is depicted, all possible tautomeric forms of the compound are encompassed within that formula.

Similarly, prodrugs, i.e. compounds which can be metabolized or hydrolyzed in vivo to a compound of the present invention are encompassed by the present description. For example, the following embodiments of a compound of formula (VI) can be produced in vivo in the following reaction:




One skilled in the art will understand that other hydrolyzable protecting groups can be employed with the compounds of the present invention to obtain prodrugs encompassed by the present description.

It is understood that the compounds of the present invention, including compounds of formulas (IX) through (XI) and Tables 7 can be purified, isolated, obtained and used in a form of a pharmaceutically acceptable salt, a solvate, a clathrate, a tautomer or a prodrug.
For example, a compound of formula (IX) can undergo the following tautomerization:




where X0 is O, S, or NR7. It is understood that where a structural formula is depicted, all possible tautomeric forms of the compound are encompassed within that formula.

Similarly, prodrugs, i.e. compounds which can be metabolized or hydrolyzed in vivo to a compound of the present invention are encompassed by the present description. For example, the following embodiments of a compound of formula (IX) can be produced in vivo in the following reaction:




One skilled in the art will understand that other hydrolyzable protecting groups can be employed with the compounds of the present invention to obtain prodrugs encompassed by the present description.

C. Methods for Making Compounds of the Invention
Methods of making the compounds of the invention are disclosed in U.S. patent application Ser. No. 11/282,119, filed on Nov. 17, 2005; and in U.S. Provisional Patent Application Ser. No. 60/709,310, filed Aug. 18, 2005; U.S. Provisional Patent Application Ser. No. 60/724,105, filed Oct. 6, 2005; U.S. Provisional Patent Application Ser. No. 60/709,358, filed Aug. 18, 2005; U.S. Provisional Patent Application Ser. No. 60/725,044, filed Oct. 6, 2005; U.S. Provisional Patent Application Ser. No. 60/707,836, filed Aug. 12, 2005; U.S. Provisional Patent Application Ser. No. 60/709,228, file Aug. 18, 2005; the entire teachings of each of these patent applications is incorporated herein by reference.
Additional methods of preparing the compounds of the invention can be found in the following U.S. provisional applications: U.S. Provisional patent Application Ser. No. 60/808,376, filed on May 25, 2006; U.S. Provisional patent Application Ser. No. 60/808,342, filed on May 25, 2006; U.S. Provisional patent Application Ser. No. 60/808,375, filed on May 25, 2006; U.S. Provisional patent Application Ser. No. 60/902,031, filed on Feb. 16, 2007; and Attorney Docket No. 3211.1042-002, entitled “Synthesis of Triazole Compounds that Modulate HSP90 Activity,” filed on May 25, 2007, the entire teachings of each of these applications are incorporated herein by reference.
D. Uses of Compounds of the Invention
The present invention is directed to therapies which involve administering one or more compounds of the invention, or compositions comprising said compounds to a subject, preferably a human subject, to inhibit the activity of Hsp90 or to prevent, treat, manage, or ameliorate a proliferative disorder, such as cancer (including c-Met associated cancers), or one or more symptoms thereof.
In another embodiment, the present invention is directed to a method of inducing degradation of c-Met protein in a subject, comprising administering to the subject an effective amount of a compound represented by formula (I) through (LXXII), or any embodiment thereof, or a compound shown in Table 5, 6, or 7. In one embodiment, the subject is a mammal, preferably a human. In another embodiment, the compound is administered with one or more additional therapeutic agents. In a preferred embodiment, the additional therapeutic agent is an anticancer agent.
In one embodiment, the present invention is directed to a method of treating cancer in which dysregulation of c-Met has been implicated as a contributing factor in a subject. The method comprises administering to the subject in need of treatment for such a cancer an effective amount of a compound represented by formula (I) through (LXXII), or any embodiment thereof, or a compound shown in Table 5, 6, or 7. In one embodiment, the subject is a mammal, preferably a human. In another embodiment, the compound is administered with one or more additional therapeutic agents. In a preferred embodiment, the additional therapeutic agent is an anticancer agent.
In another aspect, the invention provides a method for treating a c-Met associated cancer in a mammal, comprising administering to the mammal an effective amount of a compound represented by formula (I) through (LXXII), or any embodiment thereof, or a compound shown in Table 5, 6, or 7. In one embodiment, the subject is a mammal, preferably a human. In another embodiment, the compound is administered with one or more additional therapeutic agents. In a preferred embodiment, the additional therapeutic agent is an anticancer agent.
In one embodiment, the invention provides a method for treating a c-Met associated cancer in a mammal, wherein the c-Met associated cancer has developed a resistance to treatment with a tyrosine kinase inhibitor. This method comprises administering to the mammal an effective amount of a compound represented by formula (I) through (LXXII), or any embodiment thereof, or a compound shown in Table 5, 6, or 7. In one embodiment, the tyrosine kinase inhibitor that the c-Met associate cancer has developed a resistance to inhibits the kinase activity of c-Met. In one embodiment, the tyrosine kinase inhibitor that the c-Met associate cancer has developed a resistance to does not substantially inhibit the kinase activity of c-Met. In another embodiment, the compound is administered with one or more additional therapeutic agents. In a preferred embodiment, the additional therapeutic agent is an anticancer agent.
In another embodiment, the invention provides a method of treating cancer in a subject, comprising:

    a) determining whether the subject has a c-Met associated cancer; and
    b) if the subject has a c-Met associated cancer, administering to the subject an effective amount of a compound of the invention.

In one embodiment, the subject's cancer is determined to be a c-Met associated cancer if the subject's cancer has one or more mutation or deletion in the kinase or juxtamembrane domain of c-Met, amplification of the Met gene, overexpression of c-Met, or a combination thereof.



E. Agents Useful in Combination with the Compounds of the Invention
Without wishing to be bound by theory, it is believed that the compounds of the invention can be particularly effective at treating subjects whose cancer has become multi-drug resistant. Although chemotherapeutic agents initially cause tumor regression, most agents that are currently used to treat cancer target only one pathway to tumor progression. Therefore, in many instances, after treatment with one or more chemotherapeutic agents, a tumor develops multidrug resistance and no longer response positively to treatment. One of the advantages of inhibiting Hsp90 activity is that several of its client proteins, which are mostly protein kinases or transcription factors involved in signal transduction, have been shown to be involved in the progression of cancer. Thus, inhibition of Hsp90 provides a method of short circuiting several pathways for tumor progression simultaneously. Therefore, it is believed that treatment of cancer with an Hsp90 inhibitor of the invention either alone, or in combination with other chemotherapeutic agents, is more likely to result in regression or elimination of the tumor, and less likely to result in the development of more aggressive multidrug resistant tumors than other currently available therapies.
In addition, the compounds of the invention are useful for treating patients with c-Met associated cancers, such as patients with hereditary and sporadic human papillary renal carcinomas, ovarian cancer, hepatocellular carcinoma, metastatic head and neck squamous cell carcinomas, esophageal cancer, gastric cancer, non-small cell lung cancer (NSCLC) and small cell lung cancer (SCLC), colorectal cancer, and osteogenic sarcoma. Such c-Met associated cancers may have become resistant to treatment with a tyrosine kinas inhibitor, such as Gefitinib, Tarceva, Gleevec, or SU11274. Compounds of the invention act by inhibiting the activity of Hsp90 which disrupt c-Met/Hsp90 complexes and causes degradation of c-Met, including c-Met that has a mutation or deletions that makes it constitutively active. Therefore, compounds of the invention are effective in treating c-Met associated cancers that are resistant to treatment with tyrosine kinase inhibitors. Compounds of the invention can be administered alone or with a tyrosine kinase inhibitor in patients who have a c-Met associated cancer that is not resistant to tyrosine kinase inhibitors or to patients whose cancer has become resistant to tyrosine kinase inhibitors.
Other anticancer agents that can be co-administered with the compounds of the invention include TaxolTM, also referred to as “paclitaxel”, is a well-known anti-cancer drug which acts by enhancing and stabilizing microtubule formation, and analogs of TaxolTM, such as TaxotereTM. Compounds that have the basic taxane skeleton as a common structure feature, have also been shown to have the ability to arrest cells in the G2-M phases due to stabilized microtubules.
Other anti-cancer agents that can be employed in combination with the compounds of the invention include Adriamycin, Dactinomycin, Bleomycin, Vinblastine, Cisplatin, acivicin; aclarubicin; acodazole hydrochloride; acronine; adozelesin; aldesleukin; altretamine; ambomycin; ametantrone acetate; aminoglutethimide; amsacrine; anastrozole; anthramycin; asparaginase; asperlin; azacitidine; azetepa; azotomycin; batimastat; benzodepa; bicalutamide; bisantrene hydrochloride; bisnafide dimesylate; bizelesin; bleomycin sulfate; brequinar sodium; bropirimine; busulfan; cactinomycin; calusterone; caracemide; carbetimer; carboplatin; carmustine; carubicin hydrochloride; carzelesin; cedefingol; chlorambucil; cirolemycin; cladribine; crisnatol mesylate; cyclophosphamide; cytarabine; dacarbazine; daunorubicin hydrochloride; decitabine; dexormaplatin; dezaguanine; dezaguanine mesylate; diaziquone; doxorubicin; doxorubicin hydrochloride; droloxifene; droloxifene citrate; dromostanolone propionate; duazomycin; edatrexate; eflornithine hydrochloride; elsamitrucin; enloplatin; enpromate; epipropidine; epirubicin hydrochloride; erbulozole; esorubicin hydrochloride; estramustine; estramustine phosphate sodium; etanidazole; etoposide; etoposide phosphate; etoprine; fadrozole hydrochloride; fazarabine; fenretinide; floxuridine; fludarabine phosphate; fluorouracil; flurocitabine; fosquidone; fostriecin sodium; gemcitabine; gemcitabine hydrochloride; hydroxyurea; idarubicin hydrochloride; ifosfamide; ilmofosine; interleukin II (including recombinant interleukin II, or rIL2), interferon alfa-2a; interferon alfa-2b; interferon alfa-n1; interferon alfa-n3; interferon beta-I a; interferon gamma-I b; iproplatin; irinotecan hydrochloride; lanreotide acetate; letrozole; leuprolide acetate; liarozole hydrochloride; lometrexol sodium; lomustine; losoxantrone hydrochloride; masoprocol; maytansine; mechlorethamine hydrochloride; megestrol acetate; melengestrol acetate; melphalan; menogaril; mercaptopurine; methotrexate; methotrexate sodium; metoprine; meturedepa; mitindomide; mitocarcin; mitocromin; mitogillin; mitomalcin; mitomycin; mitosper; mitotane; mitoxantrone hydrochloride; mycophenolic acid; nocodazole; nogalamycin; ormaplatin; oxisuran; pegaspargase; peliomycin; pentamustine; peplomycin sulfate; perfosfamide; pipobroman; piposulfan; piroxantrone hydrochloride; plicamycin; plomestane; porfimer sodium; porfiromycin; prednimustine; procarbazine hydrochloride; puromycin; puromycin hydrochloride; pyrazofurin; riboprine; rogletimide; safingol; safingol hydrochloride; semustine; simtrazene; sparfosate sodium; sparsomycin; spirogermanium hydrochloride; spiromustine; spiroplatin; streptonigrin; streptozocin; sulofenur; talisomycin; tecogalan sodium; tegafur; teloxantrone hydrochloride; temoporfin; teniposide; teroxirone; testolactone; thiamiprine; thioguanine; thiotepa; tiazofurin; tirapazamine; toremifene citrate; trestolone acetate; triciribine phosphate; trimetrexate; trimetrexate glucuronate; triptorelin; tubulozole hydrochloride; uracil mustard; uredepa; vapreotide; verteporfin; vinblastine sulfate; vincristine sulfate; vindesine; vindesine sulfate; vinepidine sulfate; vinglycinate sulfate; vinleurosine sulfate; vinorelbine tartrate; vinrosidine sulfate; vinzolidine sulfate; vorozole; zeniplatin; zinostatin; zorubicin hydrochloride.
Other anti-cancer drugs that can be employed in combination with the compounds of the invention include: 20-epi-1,25 dihydroxyvitamin D3; 5-ethynyluracil; abiraterone; aclarubicin; acylfulvene; adecypenol; adozelesin; aldesleukin; ALL-TK antagonists; altretamine; ambamustine; amidox; amifostine; aminolevulinic acid; amrubicin; amsacrine; anagrelide; anastrozole; andrographolide; angiogenesis inhibitors; antagonist D; antagonist G; antarelix; anti-dorsalizing morphogenetic protein-1; antiandrogen, prostatic carcinoma; antiestrogen; antineoplaston; antisense oligonucleotides; aphidicolin glycinate; apoptosis gene modulators; apoptosis regulators; apurinic acid; ara-CDP-DL-PTBA; arginine deaminase; asulacrine; atamestane; atrimustine; axinastatin 1; axinastatin 2; axinastatin 3; azasetron; azatoxin; azatyrosine; baccatin III derivatives; balanol; batimastat; BCR/ABL antagonists; benzochlorins; benzoylstaurosporine; beta lactam derivatives; beta-alethine; betaclamycin B; betulinic acid; bFGF inhibitor; bicalutamide; bisantrene; bisaziridinylspermine; bisnafide; bistratene A; bizelesin; breflate; bropirimine; budotitane; buthionine sulfoximine; calcipotriol; calphostin C; camptothecin derivatives; canarypox IL-2; capecitabine; carboxamide-amino-triazole; carboxyamidotriazole; CaRest M3; CARN 700; cartilage derived inhibitor; carzelesin; casein kinase inhibitors (ICOS); castanospermine; cecropin B; cetrorelix; chlorins; chloroquinoxaline sulfonamide; cicaprost; cis-porphyrin; cladribine; clomifene analogues; clotrimazole; collismycin A; collismycin B; combretastatin A4; combretastatin analogue; conagenin; crambescidin 816; crisnatol; cryptophycin 8; cryptophycin A derivatives; curacin A; cyclopentanthraquinones; cycloplatam; cypemycin; cytarabine ocfosfate; cytolytic factor; cytostatin; dacliximab; decitabine; dehydrodidemnin B; deslorelin; dexamethasone; dexifosfamide; dexrazoxane; dexverapamil; diaziquone; didemnin B; didox; diethylnorspermine; dihydro-5-azacytidine; 9-dioxamycin; diphenyl spiromustine; docosanol; dolasetron; doxifluridine; droloxifene; dronabinol; duocarmycin SA; ebselen; ecomustine; edelfosine; edrecolomab; eflornithine; elemene; emitefur; epirubicin; epristeride; estramustine analogue; estrogen agonists; estrogen antagonists; etanidazole; etoposide phosphate; exemestane; fadrozole; fazarabine; fenretinide; filgrastim; finasteride; flavopiridol; flezelastine; fluasterone; fludarabine; fluorodaunorunicin hydrochloride; forfenimex; formestane; fostriecin; fotemustine; gadolinium texaphyrin; gallium nitrate; galocitabine; ganirelix; gelatinase inhibitors; gemcitabine; glutathione inhibitors; hepsulfam; heregulin; hexamethylene bisacetamide; hypericin; ibandronic acid; idarubicin; idoxifene; idramantone; ilmofosine; ilomastat; imidazoacridones; imiquimod; immunostimulant peptides; insulin-like growth factor-1 receptor inhibitor; interferon agonists; interferons; interleukins; iobenguane; iododoxorubicin; ipomeanol, 4-; iroplact; irsogladine; isobengazole; isohomohalicondrin B; itasetron; jasplakinolide; kahalalide F; lamellarin-N triacetate; lanreotide; leinamycin; lenograstim; lentinan sulfate; leptolstatin; letrozole; leukemia inhibiting factor; leukocyte alpha interferon; leuprolide+estrogen+progesterone; leuprorelin; levamisole; liarozole; linear polyamine analogue; lipophilic disaccharide peptide; lipophilic platinum compounds; lissoclinamide 7; lobaplatin; lombricine; lometrexol; lonidamine; losoxantrone; lovastatin; loxoribine; lurtotecan; lutetium texaphyrin; lysofylline; lytic peptides; maitansine; mannostatin A; marimastat; masoprocol; maspin; matrilysin inhibitors; matrix metalloproteinase inhibitors; menogaril; merbarone; meterelin; methioninase; metoclopramide; MIF inhibitor; mifepristone; miltefosine; mirimostim; mismatched double stranded RNA; mitoguazone; mitolactol; mitomycin analogues; mitonafide; mitotoxin fibroblast growth factor-saporin; mitoxantrone; mofarotene; molgramostim; monoclonal antibody, human chorionic gonadotrophin; monophosphoryl lipid A+myobacterium cell wall sk; mopidamol; multiple drug resistance gene inhibitor; multiple tumor suppressor 1-based therapy; mustard anticancer agent; mycaperoxide B; mycobacterial cell wall extract; myriaporone; N-acetyldinaline; N-substituted benzamides; nafarelin; nagrestip; naloxone+pentazocine; napavin; naphterpin; nartograstim; nedaplatin; nemorubicin; neridronic acid; neutral endopeptidase; nilutamide; nisamycin; nitric oxide modulators; nitroxide antioxidant; nitrullyn; O6-benzylguanine; octreotide; okicenone; oligonucleotides; onapristone; ondansetron; ondansetron; oracin; oral cytokine inducer; ormaplatin; osaterone; oxaliplatin; oxaunomycin; palauamine; palmitoylrhizoxin; pamidronic acid; panaxytriol; panomifene; parabactin; pazelliptine; pegaspargase; peldesine; pentosan polysulfate sodium; pentostatin; pentrozole; perflubron; perfosfamide; perillyl alcohol; phenazinomycin; phenylacetate; phosphatase inhibitors; picibanil; pilocarpine hydrochloride; pirarubicin; piritrexim; placetin A; placetin B; plasminogen activator inhibitor; platinum complex; platinum compounds; platinum-triamine complex; porfimer sodium; porfiromycin; prednisone; propyl bis-acridone; prostaglandin J2; proteasome inhibitors; protein A-based immune modulator; protein kinase C inhibitor; protein kinase C inhibitors, microalgal; protein tyrosine phosphatase inhibitors; purine nucleoside phosphorylase inhibitors; purpurins; pyrazoloacridine; pyridoxylated hemoglobin polyoxyethylene conjugate; raf antagonists; raltitrexed; ramosetron; ras farnesyl protein transferase inhibitors; ras inhibitors; ras-GAP inhibitor; retelliptine demethylated; rhenium Re 186 etidronate; rhizoxin; ribozymes; RII retinamide; rogletimide; rohitukine; romurtide; roquinimex; rubiginone B1; ruboxyl; safingol; saintopin; SarCNU; sarcophytol A; sargramostim; Sdi 1 mimetics; semustine; senescence derived inhibitor 1; sense oligonucleotides; signal transduction inhibitors; signal transduction modulators; single chain antigen-binding protein; sizofiran; sobuzoxane; sodium borocaptate; sodium phenylacetate; solverol; somatomedin binding protein; sonermin; sparfosic acid; spicamycin D; spiromustine; splenopentin; spongistatin 1; squalamine; stem cell inhibitor; stem-cell division inhibitors; stipiamide; stromelysin inhibitors; sulfinosine; superactive vasoactive intestinal peptide antagonist; suradista; suramin; swainsonine; synthetic glycosaminoglycans; tallimustine; tamoxifen methiodide; tauromustine; tazarotene; tecogalan sodium; tegafur; tellurapyrylium; telomerase inhibitors; temoporfin; temozolomide; teniposide; tetrachlorodecaoxide; tetrazomine; thaliblastine; thiocoraline; thrombopoietin; thrombopoietin mimetic; thymalfasin; thymopoietin receptor agonist; thymotrinan; thyroid stimulating hormone; tin ethyl etiopurpurin; tirapazamine; titanocene bichloride; topsentin; toremifene; totipotent stem cell factor; translation inhibitors; tretinoin; triacetyluridine; triciribine; trimetrexate; triptorelin; tropisetron; turosteride; tyrosine kinase inhibitors; tyrphostins; UBC inhibitors; ubenimex; urogenital sinus-derived growth inhibitory factor; urokinase receptor antagonists; vapreotide; variolin B; vector system, erythrocyte gene therapy; velaresol; veramine; verdins; verteporfin; vinorelbine; vinxaltine; vitaxin; vorozole; zanoterone; zeniplatin; zilascorb; and zinostatin stimalamer. Preferred anti-cancer drugs are 5-fluorouracil and leucovorin.
Other chemotherapeutic agents that can be employed in combination with the compounds of the invention include but are not limited to alkylating agents, antimetabolites, natural products, or hormones. Examples of alkylating agents useful for the treatment or prevention of T-cell malignancies in the methods and compositions of the invention include but are not limited to, nitrogen mustards (e.g., mechloroethamine, cyclophosphamide, chlorambucil, etc.), alkyl sulfonates (e.g., busulfan), nitrosoureas (e.g., carmustine, lomusitne, etc.), or triazenes (decarbazine, etc.). Examples of antimetabolites useful for the treatment or prevention of T-cell malignancies in the methods and compositions of the invention include but are not limited to folic acid analog (e.g., methotrexate), or pyrimidine analogs (e.g., Cytarabine), purine analogs (e.g., mercaptopurine, thioguanine, pentostatin). Examples of natural products useful for the treatment or prevention of T-cell malignancies in the methods and compositions of the invention include but are not limited to vinca alkaloids (e.g., vinblastin, vincristine), epipodophyllotoxins (e.g., etoposide), antibiotics (e.g., daunorubicin, doxorubicin, bleomycin), enzymes (e.g., L-asparaginase), or biological response modifiers (e.g., interferon alpha).
Examples of alkylating agents that can be employed in combination with the compounds of the invention include but are not limited to, nitrogen mustards (e.g., mechloroethamine, cyclophosphamide, chlorambucil, melphalan, etc.), ethylenimine and methylmelamines (e.g., hexamethlymelamine, thiotepa), alkyl sulfonates (e.g., busulfan), nitrosoureas (e.g., carmustine, lomusitne, semustine, streptozocin, etc.), or triazenes (decarbazine, etc.). Examples of antimetabolites useful for the treatment or prevention of cancer in the methods and compositions of the invention include but are not limited to folic acid analog (e.g., methotrexate), or pyrimidine analogs (e.g., fluorouracil, floxouridine, Cytarabine), purine analogs (e.g., mercaptopurine, thioguanine, pentostatin). Examples of natural products useful for the treatment or prevention of cancer in the methods and compositions of the invention include but are not limited to vinca alkaloids (e.g., vinblastin, vincristine), epipodophyllotoxins (e.g., etoposide, teniposide), antibiotics (e.g., actinomycin D, daunorubicin, doxorubicin, bleomycin, plicamycin, mitomycin), enzymes (e.g., L-asparaginase), or biological response modifiers (e.g., interferon alpha). Examples of hormones and antagonists useful for the treatment or prevention of cancer in the methods and compositions of the invention include but are not limited to adrenocorticosteroids (e.g., prednisone), progestins (e.g., hydroxyprogesterone caproate, megestrol acetate, medroxyprogesterone acetate), estrogens (e.g., diethlystilbestrol, ethinyl estradiol), antiestrogen (e.g., tamoxifen), androgens (e.g., testosterone propionate, fluoxymesterone), antiandrogen (e.g., flutamide), gonadotropin releasing hormone analog (e.g., leuprolide). Other agents that can be used in the methods and compositions of the invention for the treatment or prevention of cancer include platinum coordination complexes (e.g., cisplatin, carboblatin), anthracenedione (e.g., mitoxantrone), substituted urea (e.g., hydroxyurea), methyl hydrazine derivative (e.g., procarbazine), adrenocortical suppressant (e.g., mitotane, aminoglutethimide).
Other examples of anti-cancer agents which act by arresting cells in the G2-M phases due to stabilized microtubules include without limitation the following marketed drugs and drugs in development:
Examples of anti-cancer agents which act by arresting cells in the G2-M phases due to stabilizing or depolymerizing microtubules and which can be used in combination with the compounds of the invention include without limitation the following marketed drugs and drugs in development: Erbulozole (also known as R-55104), Dolastatin 10 (also known as DLS-10 and NSC-376128), Mivobulin isethionate (also known as CI-980), Vincristine, NSC-639829, Discodermolide (also known as NVP-XX-A-296), ABT-751 (Abbott, also known as E-7010), Altorhyrtins (such as Altorhyrtin A and Altorhyrtin C), Spongistatins (such as Spongistatin 1, Spongistatin 2, Spongistatin 3, Spongistatin 4, Spongistatin 5, Spongistatin 6, Spongistatin 7, Spongistatin 8, and Spongistatin 9), Cemadotin hydrochloride (also known as LU-103793 and NSC-D-669356), Epothilones (such as Epothilone A, Epothilone B, Epothilone C (also known as desoxyepothilone A or dEpoA), Epothilone D (also referred to as KOS-862, dEpoB, and desoxyepothilone B), Epothilone E, Epothilone F, Epothilone B N-oxide, Epothilone A N-oxide, 16-aza-epothilone B, 21-aminoepothilone B (also known as BMS-310705), 21-hydroxyepothilone D (also known as Desoxyepothilone F and dEpoF), 26-fluoroepothilone), Auristatin PE (also known as NSC-654663), Soblidotin (also known as TZT-1027), LS-4559-P (Pharmacia, also known as LS-4577), LS-4578 (Pharmacia, also known as LS-477-P), LS-4477 (Pharmacia), LS-4559 (Pharmacia), RPR-112378 (Aventis), Vincristine sulfate, DZ-3358 (Daiichi), FR-182877 (Fujisawa, also known as WS-9885B), GS-164 (Takeda), GS-198 (Takeda), KAR-2 (Hungarian Academy of Sciences), BSF-223651 (BASF, also known as ILX-651 and LU-223651), SAH-49960 (Lilly/Novartis), SDZ-268970 (Lilly/Novartis), AM-97 (Armad/Kyowa Hakko), AM-132 (Armad), AM-138 (Armad/Kyowa Hakko), IDN-5005 (Indena), Cryptophycin 52 (also known as LY-355703), AC-7739 (Ajinomoto, also known as AVE-8063A and CS-39.HCl), AC-7700 (Ajinomoto, also known as AVE-8062, AVE-8062A, CS-39-L-Ser.HCl, and RPR-258062A), Vitilevuamide, Tubulysin A, Canadensol, Centaureidin (also known as NSC-106969), T-138067 (Tularik, also known as T-67, TL-138067 and TI-138067), COBRA-1 (Parker Hughes Institute, also known as DDE-261 and WHI-261), H10 (Kansas State University), H16 (Kansas State University), Oncocidin A1 (also known as BTO-956 and DIME), DDE-313 (Parker Hughes Institute), Fijianolide B, Laulimalide, SPA-2 (Parker Hughes Institute), SPA-1 (Parker Hughes Institute, also known as SPIKET-P), 3-IAABU (Cytoskeleton/Mt. Sinai School of Medicine, also known as MF-569), Narcosine (also known as NSC-5366), Nascapine, D-24851 (Asta Medica), A-105972 (Abbott), Hemiasterlin, 3-BAABU (Cytoskeleton/Mt. Sinai School of Medicine, also known as MF-191), TMPN (Arizona State University), Vanadocene acetylacetonate, T-138026 (Tularik), Monsatrol, Inanocine (also known as NSC-698666), 3-IAABE (Cytoskeleton/Mt. Sinai School of Medicine), A-204197 (Abbott), T-607 (Tularik, also known as T-900607), RPR-115781 (Aventis), Eleutherobins (such as Desmethyleleutherobin, Desaetyleleutherobin, Isoeleutherobin A, and Z-Eleutherobin), Caribaeoside, Caribaeolin, Halichondrin B, D-64131 (Asta Medica), D-68144 (Asta Medica), Diazonamide A, A-293620 (Abbott), NPI-2350 (Nereus), Taccalonolide A, TUB-245 (Aventis), A-259754 (Abbott), Diozostatin, (−)-Phenylahistin (also known as NSCL-96F037), D-68838 (Asta Medica), D-68836 (Asta Medica), Myoseverin B, D-43411 (Zentaris, also known as D-81862), A-289099 (Abbott), A-318315 (Abbott), HTI-286 (also known as SPA-110, trifluoroacetate salt) (Wyeth), D-82317 (Zentaris), D-82318 (Zentaris), SC-12983 (NCB, Resverastatin phosphate sodium, BPR-0Y-007 (National Health Research Institutes), and SSR-250411 (Sanofi).
F. Compositions and Methods for Administering Therapies
The present invention provides compositions for the treatment, prophylaxis, and amelioration of proliferative disorders, such as cancer, including c-Met associated cancers. In one embodiment, a composition for treating a c-Met associated cancer comprises and a pharmaceutically acceptable carrier, diluent or excipient and one or more compound of the invention, or a pharmaceutically acceptable salt, solvate, clathrate, hydrate or prodrug thereof. In another embodiment, a composition for treating a c-Met associated cancer further comprises one or more prophylactic or therapeutic agents other than a compound of the invention. In another embodiment, the composition for treating a c-Met associated cancer further comprises a one or more prophylactic or therapeutic anticancer agent other than a compound of the invention.
In one embodiment, a composition of the invention is a pharmaceutical composition or a single unit dosage form. Pharmaceutical compositions and dosage forms of the invention comprise one or more active ingredients in relative amounts and formulated in such a way that a given pharmaceutical composition or dosage form can be used to treat or prevent proliferative disorders, such as cancer, including a c-Met associated cancers. In one embodiment, pharmaceutical compositions and dosage forms for treating a c-Met associated cancer comprises a compound of formula (I) through (LXXII), or any embodiment thereof, or a compound shown in Table 5, 6, or 7, or a pharmaceutically acceptable prodrug, salt, solvate, clathrate, hydrate, or prodrug thereof, optionally in combination with one or more additional active agents.
A pharmaceutical composition of the invention is formulated to be compatible with its intended route of administration. Examples of routes of administration include, but are not limited to, parenteral, e.g., intravenous, intradermal, subcutaneous, oral (e.g., inhalation), intranasal, transdermal (topical), transmucosal, and rectal administration. In a specific embodiment, the composition is formulated in accordance with routine procedures as a pharmaceutical composition adapted for intravenous, subcutaneous, intramuscular, oral, intranasal or topical administration to human beings. In a preferred embodiment, a pharmaceutical composition is formulated in accordance with routine procedures for subcutaneous administration to human beings.
Single unit dosage forms of the invention are suitable for oral, mucosal (e.g., nasal, sublingual, vaginal, buccal, or rectal), parenteral (e.g., subcutaneous, intravenous, bolus injection, intramuscular, or intraarterial), or transdermal administration to a patient. Examples of dosage forms include, but are not limited to: tablets; caplets; capsules, such as soft elastic gelatin capsules; cachets; troches; lozenges; dispersions; suppositories; ointments; cataplasms (poultices); pastes; powders; dressings; creams; plasters; solutions; patches; aerosols (e.g., nasal sprays or inhalers); gels; liquid dosage forms suitable for oral or mucosal administration to a patient, including suspensions (e.g., aqueous or non-aqueous liquid suspensions, oil-in-water emulsions, or a water-in-oil liquid emulsions), solutions, and elixirs; liquid dosage forms suitable for parenteral administration to a patient; and sterile solids (e.g., crystalline or amorphous solids) that can be reconstituted to provide liquid dosage forms suitable for parenteral administration to a patient.
The composition, shape, and type of dosage forms of the invention will typically vary depending on their use. For example, a dosage form suitable for mucosal administration may contain a smaller amount of active ingredient(s) than an oral dosage form used to treat the same indication. This aspect of the invention will be readily apparent to those skilled in the art. See, e.g., Remington's Pharmaceutical Sciences (1990) 18th ed., Mack Publishing, Easton Pa.
Typical pharmaceutical compositions and dosage forms comprise one or more excipients. Suitable excipients are well known to those skilled in the art of pharmacy, and non-limiting examples of suitable excipients are provided herein. Whether a particular excipient is suitable for incorporation into a pharmaceutical composition or dosage form depends on a variety of factors well known in the art including, but not limited to, the way in which the dosage form will be administered to a patient. For example, oral dosage forms such as tablets may contain excipients not suited for use in parenteral dosage forms.
The suitability of a particular excipient may also depend on the specific active ingredients in the dosage form. For example, the decomposition of some active ingredients can be accelerated by some excipients such as lactose, or when exposed to water. Active ingredients that comprise primary or secondary amines (e.g., N-desmethylvenlafaxine and N,N-didesmethylvenlafaxine) are particularly susceptible to such accelerated decomposition. Consequently, this invention encompasses pharmaceutical compositions and dosage forms that contain little, if any, lactose. As used herein, the term “lactose-free” means that the amount of lactose present, if any, is insufficient to substantially increase the degradation rate of an active ingredient. Lactose-free compositions of the invention can comprise excipients that are well known in the art and are listed, for example, in the U.S. Pharmocopia (USP) SP (XXI)/NF (XVI). In general, lactose-free compositions comprise active ingredients, a binder/filler, and a lubricant in pharmaceutically compatible and pharmaceutically acceptable amounts. Preferred lactose-free dosage forms comprise active ingredients, microcrystalline cellulose, pre-gelatinized starch, and magnesium stearate.
This invention further encompasses anhydrous pharmaceutical compositions and dosage forms comprising active ingredients, since water can facilitate the degradation of some compounds. For example, the addition of water (e.g., 5%) is widely accepted in the pharmaceutical arts as a means of simulating long-term storage in order to determine characteristics such as shelf-life or the stability of formulations over time. See, e.g., Jens T. Carstensen (1995) Drug Stability: Principles & Practice, 2d. Ed., Marcel Dekker, NY, N.Y., 379-80. In effect, water and heat accelerate the decomposition of some compounds. Thus, the effect of water on a formulation can be of great significance since moisture and/or humidity are commonly encountered during manufacture, handling, packaging, storage, shipment, and use of formulations.
Anhydrous pharmaceutical compositions and dosage forms of the invention can be prepared using anhydrous or low moisture containing ingredients and low moisture or low humidity conditions. Pharmaceutical compositions and dosage forms that comprise lactose and at least one active ingredient that comprises a primary or secondary amine are preferably anhydrous if substantial contact with moisture and/or humidity during manufacturing, packaging, and/or storage is expected.
An anhydrous pharmaceutical composition should be prepared and stored such that its anhydrous nature is maintained. Accordingly, anhydrous compositions are preferably packaged using materials known to prevent exposure to water such that they can be included in suitable formulary kits. Examples of suitable packaging include, but are not limited to, hermetically sealed foils, plastics, unit dose containers (e.g., vials), blister packs, and strip packs.
The invention further encompasses pharmaceutical compositions and dosage forms that comprise one or more compounds that reduce the rate by which an active ingredient will decompose. Such compounds, which are referred to herein as “stabilizer” include, but are not limited to, antioxidants such as ascorbic acid, pH buffers, or salt buffers.
i) Oral Dosage Forms
Pharmaceutical compositions of the invention that are suitable for oral administration can be presented as discrete dosage forms, such as, but are not limited to, tablets (e.g., chewable tablets), caplets, capsules, and liquids (e.g., flavored syrups). Such dosage forms contain predetermined amounts of active ingredients, and may be prepared by methods of pharmacy well known to those skilled in the art. See generally, Remington's Pharmaceutical Sciences (1990) 18th ed., Mack Publishing, Easton Pa.
Typical oral dosage forms of the invention are prepared by combining the active ingredient(s) in an admixture with at least one excipient according to conventional pharmaceutical compounding techniques. Excipients can take a wide variety of forms depending on the form of preparation desired for administration. For example, excipients suitable for use in oral liquid or aerosol dosage forms include, but are not limited to, water, glycols, oils, alcohols, flavoring agents, preservatives, and coloring agents. Examples of excipients suitable for use in solid oral dosage forms (e.g., powders, tablets, capsules, and caplets) include, but are not limited to, starches, sugars, micro-crystalline cellulose, diluents, granulating agents, lubricants, binders, and disintegrating agents.
Because of their ease of administration, tablets and capsules represent the most advantageous oral dosage unit forms, in which case solid excipients are employed. If desired, tablets can be coated by standard aqueous or nonaqueous techniques. Such dosage forms can be prepared by any of the methods of pharmacy. In general, pharmaceutical compositions and dosage forms are prepared by uniformly and intimately admixing the active ingredients with liquid carriers, finely divided solid carriers, or both, and then shaping the product into the desired presentation if necessary.
For example, a tablet can be prepared by compression or molding. Compressed tablets can be prepared by compressing in a suitable machine the active ingredients in a free-flowing form such as powder or granules, optionally mixed with an excipient. Molded tablets can be made by molding in a suitable machine a mixture of the powdered compound moistened with an inert liquid diluent.
Examples of excipients that can be used in oral dosage forms of the invention include, but are not limited to, binders, fillers, disintegrants, and lubricants. Binders suitable for use in pharmaceutical compositions and dosage forms include, but are not limited to, corn starch, potato starch, or other starches, gelatin, natural and synthetic gums such as acacia, sodium alginate, alginic acid, other alginates, powdered tragacanth, guar gum, cellulose and its derivatives (e.g., ethyl cellulose, cellulose acetate, carboxymethyl cellulose calcium, sodium carboxymethyl cellulose), polyvinyl pyrrolidone, methyl cellulose, pre-gelatinized starch, hydroxypropyl methyl cellulose, (e.g., Nos. 2208, 2906, 2910), microcrystalline cellulose, and mixtures thereof.
Suitable forms of microcrystalline cellulose include, but are not limited to, the materials sold as AVICEL-PH-101, AVICEL-PH-103 AVICEL RC-581, AVICEL-PH-105 (available from FMC Corporation, American Viscose Division, Avicel Sales, Marcus Hook, Pa.), and mixtures thereof. One specific binder is a mixture of microcrystalline cellulose and sodium carboxymethyl cellulose sold as AVICEL RC-581. Suitable anhydrous or low moisture excipients or additives include AVICEL-PH-103J and Starch 1500 LM.
Examples of fillers suitable for use in the pharmaceutical compositions and dosage forms disclosed herein include, but are not limited to, talc, calcium carbonate (e.g., granules or powder), microcrystalline cellulose, powdered cellulose, dextrates, kaolin, mannitol, silicic acid, sorbitol, starch, pre-gelatinized starch, and mixtures thereof. The binder or filler in pharmaceutical compositions of the invention is typically present in from about 50 to about 99 weight percent of the pharmaceutical composition or dosage form.
Disintegrants are used in the compositions of the invention to provide tablets that disintegrate when exposed to an aqueous environment. Tablets that contain too much disintegrant may disintegrate in storage, while those that contain too little may not disintegrate at a desired rate or under the desired conditions. Thus, a sufficient amount of disintegrant that is neither too much nor too little to detrimentally alter the release of the active ingredients should be used to form solid oral dosage forms of the invention. The amount of disintegrant used varies based upon the type of formulation, and is readily discernible to those of ordinary skill in the art. Typical pharmaceutical compositions comprise from about 0.5 to about 15 weight percent of disintegrant, preferably from about 1 to about 5 weight percent of disintegrant.
Disintegrants that can be used in pharmaceutical compositions and dosage forms of the invention include, but are not limited to, agar-agar, alginic acid, calcium carbonate, microcrystalline cellulose, croscarmellose sodium, crospovidone, polacrilin potassium, sodium starch glycolate, potato or tapioca starch, other starches, pre-gelatinized starch, other starches, clays, other algins, other celluloses, gums, and mixtures thereof.
Lubricants that can be used in pharmaceutical compositions and dosage forms of the invention include, but are not limited to, calcium stearate, magnesium stearate, mineral oil, light mineral oil, glycerin, sorbitol, mannitol, polyethylene glycol, other glycols, stearic acid, sodium lauryl sulfate, talc, hydrogenated vegetable oil (e.g., peanut oil, cottonseed oil, sunflower oil, sesame oil, olive oil, corn oil, and soybean oil), zinc stearate, ethyl oleate, ethyl laureate, agar, and mixtures thereof. Additional lubricants include, for example, a syloid silica gel (AEROSIL 200, manufactured by W.R. Grace Co. of Baltimore, Md.), a coagulated aerosol of synthetic silica (marketed by Degussa Co. of Plano, Tex.), CAB-O-SIL (a pyrogenic silicon dioxide product sold by Cabot Co. of Boston, Mass.), and mixtures thereof. If used at all, lubricants are typically used in an amount of less than about 1 weight percent of the pharmaceutical compositions or dosage forms into which they are incorporated.
ii) Controlled Release Dosage Forms
Active ingredients of the invention can be administered by controlled release means or by delivery devices that are well known to those of ordinary skill in the art. Examples include, but are not limited to, those described in U.S. Pat. Nos. 3,845,770; 3,916,899; 3,536,809; 3,598,123; and 4,008,719, 5,674,533, 5,059,595, 5,591,767, 5,120,548, 5,073,543, 5,639,476, 5,354,556, and 5,733,566, each of which is incorporated herein by reference. Such dosage forms can be used to provide slow or controlled-release of one or more active ingredients using, for example, hydropropylmethyl cellulose, other polymer matrices, gels, permeable membranes, osmotic systems, multilayer coatings, microparticles, liposomes, microspheres, or a combination thereof to provide the desired release profile in varying proportions. Suitable controlled-release formulations known to those of ordinary skill in the art, including those described herein, can be readily selected for use with the active ingredients of the invention. The invention thus encompasses single unit dosage forms suitable for oral administration such as, but not limited to, tablets, capsules, gelcaps, and caplets that are adapted for controlled-release.
All controlled-release pharmaceutical products have a common goal of improving drug therapy over that achieved by their non-controlled counterparts. Ideally, the use of an optimally designed controlled-release preparation in medical treatment is characterized by a minimum of drug substance being employed to cure or control the condition in a minimum amount of time. Advantages of controlled-release formulations include extended activity of the drug, reduced dosage frequency, and increased patient compliance.
Most controlled-release formulations are designed to initially release an amount of drug (active ingredient) that promptly produces the desired therapeutic effect, and gradually and continually release of other amounts of drug to maintain this level of therapeutic or prophylactic effect over an extended period of time. In order to maintain this constant level of drug in the body, the drug must be released from the dosage form at a rate that will replace the amount of drug being metabolized and excreted from the body. Controlled-release of an active ingredient can be stimulated by various conditions including, but not limited to, pH, temperature, enzymes, water, or other physiological conditions or compounds.
A particular extended release formulation of this invention comprises a therapeutically or prophylactically effective amount of a compound of formula (I) through (LXXII), or any embodiment thereof, or a compound shown in Table 5, 6, or 7, or a pharmaceutically acceptable salt, solvate, hydrate, clathrate, or prodrug thereof, in spheroids which further comprise microcrystalline cellulose and, optionally, hydroxypropylmethylcellulose coated with a mixture of ethyl cellulose and hydroxypropylmethylcellulose. Such extended release formulations can be prepared according to U.S. Pat. No. 6,274,171, the entirely of which is incorporated herein by reference.
A specific controlled-release formulation of this invention comprises from about 6% to about 40% a compound of formula (I) through (LXXII), or any embodiment thereof, or a compound shown in Table 5, 6, or 7, or a pharmaceutically acceptable salt, solvate, hydrate, clathrate, or prodrug thereof, by weight, about 50% to about 94% microcrystalline cellulose, NF, by weight, and optionally from about 0.25% to about 1% by weight of hydroxypropylmethylcellulose, USP, wherein the spheroids are coated with a film coating composition comprised of ethyl cellulose and hydroxypropylmethylcellulose.
iii) Parenteral Dosage Forms
Parenteral dosage forms can be administered to patients by various routes including, but not limited to, subcutaneous, intravenous (including bolus injection), intramuscular, and intraarterial. Because their administration typically bypasses patients' natural defenses against contaminants, parenteral dosage forms are preferably sterile or capable of being sterilized prior to administration to a patient. Examples of parenteral dosage forms include, but are not limited to, solutions ready for injection, dry products ready to be dissolved or suspended in a pharmaceutically acceptable vehicle for injection, suspensions ready for injection, and emulsions.
Suitable vehicles that can be used to provide parenteral dosage forms of the invention are well known to those skilled in the art. Examples include, but are not limited to: Water for Injection USP; aqueous vehicles such as, but not limited to, Sodium Chloride Injection, Ringer's Injection, Dextrose Injection, Dextrose and Sodium Chloride Injection, and Lactated Ringer's Injection; water-miscible vehicles such as, but not limited to, ethyl alcohol, polyethylene glycol, and polypropylene glycol; and non-aqueous vehicles such as, but not limited to, corn oil, cottonseed oil, peanut oil, sesame oil, ethyl oleate, isopropyl myristate, and benzyl benzoate.
Compounds that increase the solubility of one or more of the active ingredients disclosed herein can also be incorporated into the parenteral dosage forms of the invention.
iv) Transdermal, Topical, and Mucosal Dosage Forms
Transdermal, topical, and mucosal dosage forms of the invention include, but are not limited to, ophthalmic solutions, sprays, aerosols, creams, lotions, ointments, gels, solutions, emulsions, suspensions, or other forms known to one of skill in the art. See, e.g., Remington's Pharmaceutical Sciences (1980 & 1990) 16th and 18th eds., Mack Publishing, Easton Pa. and Introduction to Pharmaceutical Dosage Forms (1985) 4th ed., Lea & Febiger, Philadelphia. Dosage forms suitable for treating mucosal tissues within the oral cavity can be formulated as mouthwashes or as oral gels. Further, transdermal dosage forms include “reservoir type” or “matrix type” patches, which can be applied to the skin and worn for a specific period of time to permit the penetration of a desired amount of active ingredients.
Suitable excipients (e.g., carriers and diluents) and other materials that can be used to provide transdermal, topical, and mucosal dosage forms encompassed by this invention are well known to those skilled in the pharmaceutical arts, and depend on the particular tissue to which a given pharmaceutical composition or dosage form will be applied. With that fact in mind, typical excipients include, but are not limited to, water, acetone, ethanol, ethylene glycol, propylene glycol, butane-1,3-diol, isopropyl myristate, isopropyl palmitate, mineral oil, and mixtures thereof to form lotions, tinctures, creams, emulsions, gels or ointments, which are non-toxic and pharmaceutically acceptable. Moisturizers or humectants can also be added to pharmaceutical compositions and dosage forms if desired. Examples of such additional ingredients are well known in the art. See, e.g., Remington's Pharmaceutical Sciences (1980 & 1990) 16th and 18th eds., Mack Publishing, Easton Pa.
Depending on the specific tissue to be treated, additional components may be used prior to, in conjunction with, or subsequent to treatment with active ingredients of the invention. For example, penetration enhancers can be used to assist in delivering the active ingredients to the tissue. Suitable penetration enhancers include, but are not limited to: acetone; various alcohols such as ethanol, oleyl, and tetrahydrofuryl; alkyl sulfoxides such as dimethyl sulfoxide; dimethyl acetamide; dimethyl formamide; polyethylene glycol; pyrrolidones such as polyvinylpyrrolidone; Kollidon grades (Povidone, Polyvidone); urea; and various water-soluble or insoluble sugar esters such as Tween 80 (polysorbate 80) and Span 60 (sorbitan monostearate).
The pH of a pharmaceutical composition or dosage form, or of the tissue to which the pharmaceutical composition or dosage form is applied, may also be adjusted to improve delivery of one or more active ingredients. Similarly, the polarity of a solvent carrier, its ionic strength, or tonicity can be adjusted to improve delivery. Compounds such as stearates can also be added to pharmaceutical compositions or dosage forms to advantageously alter the hydrophilicity or lipophilicity of one or more active ingredients so as to improve delivery. In this regard, stearates can serve as a lipid vehicle for the formulation, as an emulsifying agent or surfactant, and as a delivery-enhancing or penetration-enhancing agent. Different salts, hydrates or solvates of the active ingredients can be used to further adjust the properties of the resulting composition.
v) Dosage & Frequency of Administration
The amount of the compound or composition of the invention which will be effective in the prevention, treatment, management, or amelioration of a proliferative disorders, such as a c-Met associated cancer, or one or more symptoms thereof, will vary with the nature and severity of the disease or condition, and the route by which the active ingredient is administered. The frequency and dosage will also vary according to factors specific for each patient depending on the specific therapy (e.g., therapeutic or prophylactic agents) administered, the severity of the disorder, disease, or condition, the route of administration, as well as age, body, weight, response, and the past medical history of the patient. Effective doses may be extrapolated from dose-response curves derived from in vitro or animal model test systems. Suitable regiments can be selected by one skilled in the art by considering such factors and by following, for example, dosages reported in the literature and recommended in the Physician's Desk Reference (57th ed., 2003).
Exemplary doses of a small molecule include milligram or microgram amounts of the small molecule per kilogram of subject or sample weight (e.g., about 1 microgram per kilogram to about 500 milligrams per kilogram, about 100 micrograms per kilogram to about 5 milligrams per kilogram, or about 1 microgram per kilogram to about 50 micrograms per kilogram).
In general, the recommended daily dose range of a compound of the invention for the conditions described herein lie within the range of from about 0.01 mg to about 1000 mg per day, given as a single once-a-day dose preferably as divided doses throughout a day. In one embodiment, the daily dose is administered twice daily in equally divided doses. In another embodiment, the compounds of the invention are administered one to three times a week. Specifically, a dose range should be from about 5 mg to about 500 mg per day, more specifically, between about 10 mg and about 200 mg per day. In managing the patient, the therapy should be initiated at a lower dose, perhaps about 1 mg to about 25 mg, and increased if necessary up to about 200 mg to about 1000 mg per day as either a single dose or divided doses, depending on the patient's global response. It may be necessary to use dosages of the active ingredient outside the ranges disclosed herein in some cases, as will be apparent to those of ordinary skill in the art. Furthermore, it is noted that the clinician or treating physician will know how and when to interrupt, adjust, or terminate therapy in conjunction with individual patient response.
Different therapeutically effective amounts may be applicable for different proliferative disorders, as will be readily known by those of ordinary skill in the art. Similarly, amounts sufficient to prevent, manage, treat or ameliorate such proliferative disorders, but insufficient to cause, or sufficient to reduce, adverse effects associated with the compounds of the invention are also encompassed by the above described dosage amounts and dose frequency schedules. Further, when a patient is administered multiple dosages of a compound of the invention, not all of the dosages need be the same. For example, the dosage administered to the patient may be increased to improve the prophylactic or therapeutic effect of the compound or it may be decreased to reduce one or more side effects that a particular patient is experiencing.
In a specific embodiment, the dosage of the composition of the invention or a compound of the invention administered to prevent, treat, manage, or ameliorate a proliferative disorders, such as a c-Met associated cancer, or one or more symptoms thereof in a patient is 150 μg/kg, preferably 250 μg/kg, 500 μg/kg, 1 mg/kg, 5 mg/kg, 10 mg/kg, 25 mg/kg, 50 mg/kg, 75 mg/kg, 100 mg/kg, 125 mg/kg, 150 mg/kg, or 200 mg/kg or more of a patient's body weight. In another embodiment, the dosage of the composition of the invention or a compound of the invention administered to prevent, treat, manage, or ameliorate a proliferative disorders, such as a c-Met associated cancer, or one or more symptoms thereof in a patient is a unit dose of 0.1 mg to 20 mg, 0.1 mg to 15 mg, 0.1 mg to 12 mg, 0.1 mg to 10 mg, 0.1 mg to 8 mg, 0.1 mg to 7 mg, 0.1 mg to 5 mg, 0.1 to 2.5 mg, 0.25 mg to 20 mg, 0.25 to 15 mg, 0.25 to 12 mg, 0.25 to 10 mg, 0.25 to 8 mg, 0.25 mg to 7 mg, 0.25 mg to 5 mg, 0.5 mg to 2.5 mg, 1 mg to 20 mg, 1 mg to 15 mg, 1 mg to 12 mg, 1 mg to 10 mg, 1 mg to 8 mg, 1 mg to 7 mg, 1 mg to 5 mg, or 1 mg to 2.5 mg.
The dosages of prophylactic or therapeutic agents other than compounds of the invention, which have been or are currently being used to prevent, treat, manage, or proliferative disorders, such as cancer, or one or more symptoms thereof can be used in the combination therapies of the invention. Preferably, dosages lower than those which have been or are currently being used to prevent, treat, manage, or ameliorate a proliferative disorders, or one or more symptoms thereof, are used in the combination therapies of the invention. The recommended dosages of agents currently used for the prevention, treatment, management, or amelioration of a proliferative disorders, such as cancer, or one or more symptoms thereof, can obtained from any reference in the art including, but not limited to, Hardman et al., eds., 1996, Goodman & Gilman's The Pharmacological Basis Of Basis Of Therapeutics 9th Ed, Mc-Graw-Hill, New York; Physician's Desk Reference (PDR) 57th Ed., 2003, Medical Economics Co., Inc., Montvale, N.J., which are incorporated herein by reference in its entirety.
In certain embodiments, when the compounds of the invention are administered in combination with another therapy, the therapies (e.g., prophylactic or therapeutic agents) are administered less than 5 minutes apart, less than 30 minutes apart, 1 hour apart, at about 1 hour apart, at about 1 to about 2 hours apart, at about 2 hours to about 3 hours apart, at about 3 hours to about 4 hours apart, at about 4 hours to about 5 hours apart, at about 5 hours to about 6 hours apart, at about 6 hours to about 7 hours apart, at about 7 hours to about 8 hours apart, at about 8 hours to about 9 hours apart, at about 9 hours to about 10 hours apart, at about 10 hours to about 11 hours apart, at about 11 hours to about 12 hours apart, at about 12 hours to 18 hours apart, 18 hours to 24 hours apart, 24 hours to 36 hours apart, 36 hours to 48 hours apart, 48 hours to 52 hours apart, 52 hours to 60 hours apart, 60 hours to 72 hours apart, 72 hours to 84 hours apart, 84 hours to 96 hours apart, or 96 hours to 120 hours part. In one embodiment, two or more therapies (e.g., prophylactic or therapeutic agents) are administered within the same patient visit.
In certain embodiments, one or more compounds of the invention and one or more other the therapies (e.g., prophylactic or therapeutic agents) are cyclically administered. Cycling therapy involves the administration of a first therapy (e.g., a first prophylactic or therapeutic agents) for a period of time, followed by the administration of a second therapy (e.g., a second prophylactic or therapeutic agents) for a period of time, followed by the administration of a third therapy (e.g., a third prophylactic or therapeutic agents) for a period of time and so forth, and repeating this sequential administration, i.e., the cycle in order to reduce the development of resistance to one of the agents, to avoid or reduce the side effects of one of the agents, and/or to improve the efficacy of the treatment.
In certain embodiments, administration of the same compound of the invention may be repeated and the administrations may be separated by at least 1 day, 2 days, 3 days, 5 days, 10 days, 15 days, 30 days, 45 days, 2 months, 75 days, 3 months, or 6 months. In other embodiments, administration of the same prophylactic or therapeutic agent may be repeated and the administration may be separated by at least at least 1 day, 2 days, 3 days, 5 days, 10 days, 15 days, 30 days, 45 days, 2 months, 75 days, 3 months, or 6 months.
In a specific embodiment, the invention provides a method of preventing, treating, managing, or ameliorating a proliferative disorders, such as c-Met associated cancer, or one or more symptoms thereof, said methods comprising administering to a subject in need thereof a dose of at least 150 μg/kg, preferably at least 250 μg/kg, at least 500 μg/kg, at least 1 mg/kg, at least 5 mg/kg, at least 10 mg/kg, at least 25 mg/kg, at least 50 mg/kg, at least 75 mg/kg, at least 100 mg/kg, at least 125 mg/kg, at least 150 mg/kg, or at least 200 mg/kg or more of one or more compounds of the invention once every day, preferably, once every 2 days, once every 3 days, once every 4 days, once every 5 days, once every 6 days, once every 7 days, once every 8 days, once every 10 days, once every two weeks, once every three weeks, or once a month.
G. Other Embodiments
The compounds of the invention may be used as research tools (for example, to evaluate the mechanism of action of new drug agents, to isolate new drug discovery targets using affinity chromatography, as antigens in an ELISA or ELISA-like assay, or as standards in in vitro or in vivo assays). These and other uses and embodiments of the compounds and compositions of this invention will be apparent to those of ordinary skill in the art.
The invention is further defined by reference to the following examples describing in detail the preparation of compounds of the invention. It will be apparent to those skilled in the art that many modifications, both to materials and methods, may be practiced without departing from the purpose and interest of this invention. The following examples are set forth to assist in understanding the invention and should not be construed as specifically limiting the invention described and claimed herein. Such variations of the invention, including the substitution of all equivalents now known or later developed, which would be within the purview of those skilled in the art, and changes in formulation or minor changes in experimental design, are to be considered to fall within the scope of the invention incorporated herein.
1. EXAMPLES
Reagents and solvents used below can be obtained from commercial sources such as Aldrich Chemical Co. (Milwaukee, Wis., USA). 1H-NMR and 13C-NMR spectra were recorded on a Varian 300 MHz NMR spectrometer. Significant peaks are tabulated in the order: δ (ppm): chemical shift, multiplicity (s, singlet; d, doublet; t, triplet; q, quartet; m, multiplet; br s, broad singlet), coupling constant(s) in Hertz (Hz) and number of protons.
Example 1
Synthesis of Compound 76




The hydrazide (M) (1.45 g, 7.39 mmol) and the isothiocyanate (N) (1.59 g, 7.39 mmol) were dissolved in ethanol (20 ml) with heating. When the starting materials were dissolved the solution was allowed to cool to room temperature and a precipitate formed. This precipitate was filtered then washed with ether to provide the intermediate (P) as a white solid (2.85 g, 97%). The intermediate (VII) (1.89 g, 4.77 mmol) was heated in a solution of sodium hydroxide (0.38 g, 9.54 mmol) in water (20 mL) at 110° C. for 2 hours. The solution was allowed to cool to room temperature then acidified with conc. HCl. The resulting precipitate was filtered then washed with water (100 mL) and dried. The crude product was recrystallized from ethanol to produce compound 76 as a white solid (1.4 g, 75%).
1H NMR (DMSO-d6) δ 9.43-9.53 (bs, 2H), 8.11-8.16 (m, 1H), 7.47-7.55 (m, 2H), 7.38 (d, J=8.1 Hz, 1H), 7.31-7.36 (m, 1H), 6.98 (d, J=8.1 Hz, 1H), 6.71 (s, 1H), 6.17 (s, 1H), 3.98 (s, 3H), 2.17 (q, J=7.5 Hz, 2H), 0.73 (t, J=7.5 Hz, 3H);
ESMS calculated for (C21H19N3O3S) 393.11. Found 394.1 (M+1)+.
Example 2
Synthesis of Compound 124
3-(2,4-Dihydroxy-phenyl)-4-(naphthalen-1-yl)-5-mercapto-triazole (505 mg, 1.5 mmol), which is commercially available from Scientific Exchange, Inc., Center Ossipee, N.H. 03814, and Et3N (0.84 ml, 6.0 mmol) in 15 ml CH2Cl2 were treated dropwise with ethyl isocyanate (360 mg, 5.0 mmol) at 0° C. The mixture was then warmed to room temperature and stirred for 3 h. The reaction mixture was diluted with CH2Cl2, washed with H2O and saturated brine, dried with Na2SO4, and concentrated in vacuo. The residue was chromatographed (Hexane/EtOAc 3:1) to give Compound 124 as a white solid (480 mg, 58%).
1H-NMR (CDCl3) δ 10.13 (s, 1H), 7.96 (d, J=9.0 Hz, 2H), 7.61-7.57 (m, 3H), 7.49-7.36(m, 2H), 7.01(s, 1H), 6.88 (d, J=8.4 Hz, 1H), 6.70 (d, J=8.4 Hz, 1H), 4.98-4.96(m, 2H), 3.56(q, J=7.2 Hz, J=12.6 Hz, 2H), 3.28-3.10(m, 4H), 1.33(t, J=7.2 Hz, 3H), 1.13 (q, J=15.0 Hz, J=7.2 Hz, 6H);
ESMS calculated for C2H28N6O5S: 548.18. Found: 549.1 (M+1)+.
Example 3
Synthesis of Compound 188




1-Benzenesulfonyl-7-methoxy-1H-indole (Q)
To a solution of 7-methoxyindole (1 eq) in DMF cooled in an ice bath was added NaH (60% dispersion in oil, 1.2 eq). The reaction was stirred for 1 hr at room temperature then recooled in an ice bath. Benzenesulfonyl chloride (1.1 eq) was added then the reaction was stirred for 2 hrs at room temperature. Water/ethyl acetate were added and the ethyl acetate layer was washed repeatedly (3×) with water. The ethyl acetate layer was concentrated and evaporated to dryness.
1-Benzenesulfonyl-7-methoxy-4-nitro-1H-indole (R)
To a solution of 1-benzenesulfonyl-7-methoxy-1H-indole (Q) (1 eq) in dichloromethane cooled in an ice bath was added SiO2—HNO3 (2 wt eq) in small portions. The reaction was stirred for 1 hr at room temperature. Activated carbon (2 wt eq) was added then the entire mixture was stirred for 1 hr. The mixture was then filtered and evaporated to dryness. Separation of the isomers was achieved by column chromatography.
7-Methoxy-4-nitro-1H-indole (S)
To a solution of 1-benzenesulfonyl-7-methoxy-4-nitro-1H-indole (R) (1 eq) in methanol was added a solution of sodium hydroxide (5 eq) in water. The solution was heated to reflux for 3 hrs. Methanol was removed under reduced pressure then water and ethyl acetate were added. The ethyl acetate layer separated and washed repeatedly (3×) with water. The ethyl acetate layer was concentrated and evaporated to dryness to produce the desired product.
1-Isopropyl-7-methoxy-4-nitro-1H-indole (T)
To a solution of 7-methoxy-4-nitro-1H-indole (S) (1 eq) in DMF cooled in an ice bath was added NaH (60% dispersion in oil, 1.2 eq). The reaction was stirred for 1 hr at room temperature then recooled in an ice bath. 2-Iodopropane (1.1 eq) was added then the reaction was stirred for 2 hrs at room temperature. Water and ethyl acetate were added. The ethyl acetate layer was separated and washed repeatedly (3×) with water. The ethyl acetate layer was concentrated then evaporated to dryness. Further purification by column chromatography produced the pure desired product.
1-Isopropyl-7-methoxy-1H-indol-4-ylamine (U)
A solution of 1-isopropyl-7-methoxy-4-nitro-1H-indole (T) (1 eq) and palladium 10% on activated carbon (0.1 wt eq) in methanol/ethyl acetate (1:1) was shaken on a Parr hydrogenation apparatus under hydrogen for 1 hr. The reaction was then filtered through Celite and evaporated to dryness to produce the desired product.
1-Isopropyl-4-isothiocyanato-7-methoxy-1H-indole (V)
To a solution of 1-isopropyl-7-methoxy-1H-indol-4-ylamine (U) (1 eq) in dichloromethane was added 1,1′-thiocarbonyldiimidazole (1.2 eq). The reaction was stirred for 2 hrs at room temperature then evaporated to dryness. Further purification by column chromatography produced the pure desired product.
3-(2,4-Dihydroxy-5-ethyl-phenyl)-4-(1-isopropyl-7-methoxy-indol-4-yl)-5-mercapto-[1,2,4]triazole (Compound 188)
5-Ethyl-2,4-dihydroxy-benzoic acid hydrazide (W) (1 eq) and 1-isopropyl-4-isothiocyanato-7-methoxy-1H-indole (V) (1.01 eq) were heated in ethanol (0.02 M based on isothiocyante) at 80° C. for 1 hr. The solution was allowed to cool to room temperature overnight. The resulting precipitate was filtered, washed with ether, dried and used without further purification (yield 80%). The precipitate was suspended in aqueous NaOH solution (2 eq NaOH) and nitrogen was bubbled through this suspension for 10 min. The reaction was then heated to 110° C. for 1 hr under a nitrogen atmosphere then allowed to cool to room temperature. Neutralisation with conc. HCl produced a white precipiate which was filtered and washed with water. Repeated recrystallisation from EtOH/water produced the desired product (purity>95%, yield 50-70%)
1H-NMR (DMSO-d6) δ (ppm), 9.52 (s, 1H), 9.42 (s, 1H), 7.40 (d, J=3.3 Hz, 1H), 6.82 (d, J=8.4 Hz, 1H), 6.61 (s, 1H), 6.20 (s, 1H), 6.05 (d, J=3.3 Hz, 1H), 5.30 (qn, J=6.6 Hz, 1H), 3.89 (s, 3H), 2.14 (q, J=7.5 Hz, 2H), 1.41-1.47 (m, 6H), 0.68 (t, J=7.5 Hz, 3H);
2. ESMS Calculated. for C22H24N4O3S: 424.16. Found: 425.1 (M+1)+
Example 4
Synthesis of Compound 223




2,4-Dimethoxy-5-isopropylbenzoic acid (2.24 g, 10.0 mmol, 1.00 equiv.) in 50 mL CH2Cl2 at room temperature was treated with (COCl)2 (1.40 g, 11.0 mmol, 1.10 equiv.) and catalytic amount of DMF (0.1 mL) for 1 hour. Solvent and excess (COCl)2 were removed in vacuo. The residue was dissolved in 100 mL CH2Cl2, and treated with 1,3-dimethyl-5-aminoindole (1.60 g, 10.0 mmol, 1.00 equiv.) and triethylamine (1.55 g, 15.0 mmol, 1.50 equiv.) at 0° C. for one hour. Aqueous workup and removal of solvent gave a light brown solid which was washed with ether to yield off-white solid (2.28 g, 6.22 mmol, 62%).
1H NMR (CDCl3) δ (ppm) 9.78 (br s, 1H), 8.21 (s, 1H), 8.09 (d, J=2.1 Hz, 1H), 7.31 (dd, J=8.7 Hz, 2.1 Hz, 1H), 7.22 (d, J=8.7 Hz, 1H), 6.82 (s, 1H), 6.50 (s, 1H), 4.09 (s, 3H), 3.92 (s, 3H), 3.73 (s, 3H), 3.26 (hept, J=6.9 Hz, 1H), 2.32 (s, 3H), 1.24 (d, J=6.9 Hz, 6H).
The off-white solid obtained above was treated with Lawesson's reagent (1.51 g, 3.74 mmol, 0.6 equiv.) in 50 mL toluene at 110° C. for three hours. Toluene was removed on rotary evaporator and vacuum pump, and the residue was treated with hydrazine (anhydrous, 3.0 g, 94 mmol, 15.0 equiv.) in 20 mL dioxane at 80° C. for 30 minutes. The reaction mixture was extracted with ethyl acetate and water to remove excess hydrazine. The organic layer was dried over MgSO4, and filtered to remove drying agent. Carbodiimidazole (CDI)(3.02 g, 18.7 mmol, 3.00 equiv.) was added to the solution, and the solution was refluxed (65° C.) for 2 hours. Solvent was removed, and the residue was treated with 20 mL THF and 10 mL NaOH (2M) to destroy excess CDI. Extraction with ethyl acetate (EtOAc) and water, followed by chromatography purification gave the desired product 3-(2,4-methoxy-5-isopropyl-phenyl)-4-(1,3-dimethyl-indol-5-yl)-5-hydroxy-[1,2,4]triazole as light brown solid (2.20 g, 5.42 mmol, 87%).
1H NMR (CDCl3), δ (ppm) 9.63 (br s, 1H), 7.34 (d, J=2.1 Hz, 1H), 7.20 (s, 1H), 7.18 (d, J=8.4 Hz, 1H), 7.00 (dd, J=8.4 Hz, 2.1 Hz, 1H), 6.80 (s, 1H), 6.19 (s, 1H), 3.76 (s, 3H), 3.69 (s, 3H), 3.40 (s, 3H), 3.15 (hept, J=6.9 Hz, 1H), 2.20 (s, 3H), 1.10 (d, J=6.9 Hz, 6H).
3-(2,4-methoxy-5-isopropyl-phenyl)-4-(1,3-dimethyl-indol-5-yl)-5-hydroxy-[1,2,4]triazole obtained above was treated with pyridine hydrochloride (12.53 g, 108.3 mmol, 20.0 equiv.), NaI (0.812 g, 5.42 mmol, 1.0 equiv.) and 0.5 mL water at 205° C. under nitrogen protection for 1 hour. The reaction mixture was treated with 200 mL water. The solid was collected by filtration, washed with 3×20 mL water, and dissolved in 50 mL 2M NaOH solution. The aqueous solution was extracted with 100 mL EtOAc, and the EtOAc layer was extracted with 2×20 mL 0.5M NaOH. EtOAc layer was discarded. The aqueous layer were combined, neutralized with HCl to PH around 5, and extracted with 3×100 mL EtOAc. The combined EtOAc layer was diluted with 50 mL THF, dried over MgSO4, and filtered through silica gel plug. Most of solvents were removed to form a slurry with around 2 mL of solvent left. Solid was collected by filtration, washed with 2 mL EtOAc, and dried. The desired product 3-(2,4-dihydroxy-5-isopropyl-phenyl)-4-(1,3-dimethyl-indol-5-yl)-5-hydroxy-[1,2,4]triazole (Compound 223) was obtained as an off-white solid (1.75 g, 4.63 mmol, 85%).
1H NMR (CD3OD), δ (ppm) 7.46 (d, J=1.8 Hz, 1H), 7.41 (d, J=8.4 Hz, 1H), 7.04 (dd, J=8.4 Hz, 1.8 Hz, 1H), 7.02 (s, 1H), 6.53 (s, 1H), 6.26 (s, 1H), 3.74 (s, 3H), 2.88 (sept, J=6.9 Hz, 1H), 2.24 (s, 3H), 0.62 (d, J=6.9 Hz, 6H);
ESMS calculated. for C21H23N4O3 378.1. Found: 379.1 (M+1)+.
The following compounds were prepared as described above in the section entitled “Methods of Making the Compounds of the Invention” and as exemplified in Examples 1 through 4.
Example 5
Compound 1
ESMS calcd for C18H13N3OS: 319.1. Found: 320.0 (M+1)+.
Example 6
Compound 2
ESMS calcd for C21H19N3O4S: 409.11. Found: 410.0 (M+H)+.
Example 7
Compound 5
ESMS calcd for C19H15N3O2S: 365.08. Found: 266.0 (M+H)+.
Example 8
Compound 6
ESMS calcd for C20H17N3O2S: 379.10. Found: 380.0 (M+H)+.
Example 9
Compound 7
ESMS calcd for C21H19N3O2S: 393.11. Found: 394.0 (M+H)+.
Example 10
Compound 8
ESMS calcd for C21H19N3O3S: 393.11. Found: 394.0(M+H)+.
Example 11
Compound 9
ESMS calcd for C21H19N3O2S: 393.11. Found: 394.0 (M+H)+.
Example 12
Compound 13
1H-NMR (DMSO-d6) δ 9.65 (s, 1H), 9.57 (s, 1H), 7.50 (d, J=8.1 Hz, 1H), 7.35 (d, J=3.3 Hz, 1H), 7.14 (t, J=7.8 Hz, 1H), 6.96 (d, J=7.5 Hz, 1H), 6.88 (d, J=8.1 Hz, 1H), 6.09-6.11 (m, 2H), 6.01 (dd, J1=2.1 Hz, J2=8.1 Hz, 1H), 4.13-4.22 (m, 2H), 1.36 (t, J=7.2 Hz, 3H);
ESMS calcd for C18H16N4O2S: 352.10. Found: 353.1 (M+1)+.
Example 13
Compound 14
1H NMR (DMSO-d6) δ 9.72(s, 1H), 9.67(s, 1H), 7.04-7.01(m, 1H), 6.83-6.78(m, 2H), 6.66-6.63(m, 1H), 6.20-6.19(m, 2H), 4.22(s, 4H);
ESMS calcd for C16H13N3O4S: 343.06. Found: 344.0 (M+1)+.
Example 14
Compound 15
ESMS calcd for C15H13N3O2S: 299.07. Found: 300.0 (M+H)+.
Example 15
Compound 16
ESMS calcd for C15H13N3O2S: 299.07. Found: 300.0 (M+H)+.
Example 16
Compound 17
ESMS calcd for C14H10ClN3O2S: 319.02. Found: 320.0 (M+H)+.
Example 17
Compound 18
ESMS calcd for C14H10ClN3O2S: 319.02. Found: 320.0 (M+H)+.
Example 18
Compound 19
ESMS calcd for C14H10ClN3O2S: 319.02. Found: 320.1 (M+H)+.
Example 19
Compound 20
ESMS calcd for C15H13N3O3S: 315.07. Found: 316.0 (M+H)+.
Example 20
Compound 21
ESMS calcd for C15H13N3O3S: 315.07. Found: 316.0 (M+H)+.
Example 21
Compound 22
ESMS calcd for C15H13N3O3S: 315.07. Found: 316.0 (M+H)+.
Example 22
Compound 23
ESMS calcd for C14H10FN3O2S: 303.05. Found: 304.0 (M+H)+.
Example 23
Compound 23
1H NMR (DMSO-d6) δ 9.69 (s, 1H), 9.65 (s, 1H), 7.16 (d, J=7.2 Hz, 1H), 7.05 (t, J=7.2 Hz, 1H), 6.93 (d, J=8.1 Hz, 2H), 6.11-6.16 (m, 2H), 2.21 (s, 3H), 1.89 (s, 3H);
ESMS Calcd C16H15N3O2S: 313.09. Found 314.1 (M+1)+.
Example 24
Compound 24
ESMS calcd for C16H15N3O2S: 313.09. Found: 314.0 (M+H)+.
Example 25
Compound 25
1H NMR (DMSO-d6) δ 10.44 (m, 1H), 8.00-7.95 (m, 2H), 7.55-7.37 (m, 5H), 6.61 (d, J=7.8 and 1.8 Hz, 1H), 6.51 (t, J=8.6 Hz, 1H), 6.41 (d, J=10.8 Hz, 1H);
ESMS calcd for C18H12FN3OS: 337.07. Found: 338.0 (M+1)+.
Example 26
Compound 26
1H NMR (DMSO-d6) δ 9.57 (s, 1H), 7.99 (d, J=8.4 Hz, 1H), 7.96 (d, J=6.9 Hz, 1H), 7.55-7.37 (m, 5H), 6.61 (d, J=8.1 Hz, 1H), 5.83 (d, J=2.1 Hz, 1H), 5.73(dd, J=8.1 and 1.8 Hz, 1H), 5.24 (s, 2H);
ESMS calcd for C18H14N4OS: 334.09. Found: 335.0 (M+1)+.
Example 27
Compound 27
ESMS calcd for C18H19N3O2S: 341.12. Found: 342.0 (M+H)+.
Example 28
Compound 28
ESMS calcd for C16H15N3O2S: 313.09. Found: 314.0 (M+H)+.
Example 29
Compound 29
ESMS calcd for C16H15N3O2S: 313.09. Found: 314.0 (M+H)+.
Example 30
Compound 30
ESMS calcd for C16H15N3O2S: 313.09. Found: 314.0 (M+H)+.
Example 31
Compound 31
ESMS calcd for C14H10FN3O2S: 303.05. Found: 304.0 (M+H)+.
Example 32
Compound 32
ESMS calcd for C15H13N3O2S: 331.04. Found: 332.0 (M+H)+.
Example 33
Compound 33
ESMS calcd for C18H13N3O2S: 335.07. Found: 336.0 (M+H)+.
Example 34
Compound 34
ESMS calcd for C16H15N3O2S: 313.09. Found: 314.0 (M+H)+.
Example 35
Compound 35
ESMS calcd for C15H12FN3O2S: 317.06. Found: 317.0 (M+H)+.
Example 36
Compound 36
ESMS calcd for C20H15N3O2S: 361.1. Found: 362.0 (M+1)+.
Example 37
Compound 37
1H NMR (DMSO-d6) δ 10.03 (s, 1H), 8.00-7.96 (m, 2H), 7.55-7.37 (m, 5H), 7.00 (d, J=8.1 Hz, 1H), 6.20 (m, 2H), 3.57 (s, 3H);
ESMS calcd for C19H15N3O2S: 349.09. Found: 350.0 (M+1)+.
Example 38
Compound 38
ESMS calcd for C14H9Cl2N3O2S: 352.98. Found: 353.9 (M+H)+.
Example 39
Compound 39
1H NMR (DMSO-d6) δ 9.74 (s, 1H), 9.63 (s, 1H), 8.14 (m, 1H), 7.52-7.48 (m, 2H), 7.37 (d, J=8.4 Hz, 1H), 7.32 (m, 1H), 6.96 (d, =8.1 Hz, 1H), 6.90 (d, =8.4 Hz, 1H), 6.08 (d, =1.9 Hz, 1H), 6.01 (d, =8.4 Hz, 1H), 3.98 (s, 3H);
ESMS calcd for C19H15N3O3S: 365.08. Found: 366.0 (M+1)+.
Example 40
Compound 40
ESMS calcd for C25H16N3O2S: 409.09. Found: 410.0 (M+1)+.
Example 41
Compound 42
1H NMR (DMSO-d6) δ 9.75 (s, 1H), 9.67(s, 1H), 7.08(s, 2H), 6.96-6.94(m, 2H), 6.18-6.13(m, 2H), 2.72-2.50(m, 3H), 2.35-2.28(m, 1H), 1.64-1.60(m, 4H);
ESMS calcd for C18H17N3O2S: 339.10. Found: 340.0 (M+1)+.
Example 42
Compound 43
ESMS calcd for C22H15N3O2S: 385.09. Found: 386.0 (M+1)+.
Example 43
Compound 44
ESMS calcd for C20H15N3O2S: 361.09. Found: 362.0 (M+1)+.
Example 44
Compound 45
ESMS calcd for C19H15N3O2S: 349.09. Found: 350.0 (M+1)+.
Example 45
Compound 46
ESMS calcd for C19H21N3O3S: 371.13. Found: 372.0 (M+1)+.
Example 46
Compound 47
ESMS calcd for C22H27N3O3S: 413.18. Found: 414.1 (M+1)+.
Example 47
Compound 48
ESMS calcd for C18H12ClN3O2S: 369.03. Found: 370.0 (M+H)+.
Example 48
Compound 49
1H NMR (DMSO-d6) δ 9.49 (s, 1H), 9.40 (s, 1H), 7.94-7.99 (m, 2H), 7.38-7.56 (m, 5H), 6.70 (s, 1H), 6.13 (s, 1H), 2.12 (q, J=7.2 Hz, 2H), 0.71 (t, J=7.2 Hz, 3H);
ESMS Calcd for C20H17N3O2S: 363.10. Found 364.1 (M+1)+.
Example 49
Compound 50
ESMS calcd for C20H15N3O5S: 409.07. Found: 410.0 (M+H)+.
Example 50
Compound 51
ESMS calcd for C18H14N4O2S: 350.08. Found: 351.0 (M+H)+.
Example 51
Compound 52
ESMS calcd for C17H12N4OS: 320.07. Found: 320.9 (M+H)+.
Example 52
Compound 53
1H NMR (CDCl3) δ 12.0 (br s, 1H), 9.87 (br s, 1H), 9.83 (br s, 1H), 7.97 (d, J=8.1 Hz, 2H), 7.41-7.56 (m, 5H), 7.13 (d, J=1.5 Hz, 1H), 7.07 (d, J=8.7 Hz, 1H), 6.71 (dd, J=1.8 Hz, 8.1 Hz, 1H), 1.93 (s, 3H);
ESMS calcd for C20H17N4O2S: 376.1. Found: 377.0 (M+1)+.
Example 53
Compound 56
ESMS calcd for C16H15N3O4S: 345.08. Found: 346.0 (M+1)+.
Example 54
Compound 57
ESMS calcd for C18H16N4O2S: 352.10. Found: 353.0 (M+1)+.
Example 55
Compound 61
1H NMR (DMSO-d6) δ 9.66(s, 1H), 9.60(s, 1H), 7.29-7.27(m, 1H), 7.12-7-10(m, 2H), 7.03-7.00(m, 1H), 6.19-6.17(m, 2H), 1.18(s, 18H);
ESMS calcd for C22H27N3O2S: 397.18. Found: 398.1 (M+1)+.
Example 56
Compound 64
ESMS calcd for C21H15N3O3S: 389.08. Found: 390.0 (M+H)+.
Example 57
Compound 65
ESMS calcd for C19H13N3O4S: 379.06. Found: 380.0 (M+1)+.
Example 58
Compound 66
ESMS calcd for C21H18N4O3S: 406.11. Found: 407.0 (M+1)+.
Example 59
Compound 67
ESMS calcd for C21H19N3O3S: 393.11. Found: 394.0 (M+1)+.
Example 60
Compound 68
ESMS calcd for C21H19N3O3S: 393.11. Found: 394.0 (M+1)+.
Example 61
Compound 69
ESMS calcd for C21H19N3O3S: 393.11. Found: 394.0 (M+1)+.
Example 62
Compound 70
ESMS calcd for C17H12N4O2S: 336.07. Found: 337.0 (M+H)+.
Example 63
Compound 71
ESMS calcd for C21H19N3O3S: 393.11. Found: 394.0 (M+1)+.
Example 64
Compound 72
1H NMR (DMSO-d6) δ 10.3 (br s, 1H), 7.95-8.19 (m, 2H), 7.48-7.72 (m, 5H), 7.17 (d, J=8.4 Hz, 1H), 6.44 (d, J=8.4 Hz, 1H), 5.95 (d, J=2.1 Hz, 1H), 5.73 (dd, J=2.1 Hz, 8.4 Hz, 1H), 5.47 (br s, 1H), 3.62 (s, 3H);
ESMS calcd for C19H17N4O2S2: 412.1. Found: 413.0 (M+1)+.
Example 65
Compound 73
1H NMR (DMSO-d6) δ 9.37 (s, 1H), 8.94 (s, 1H), 7.94-7.98 (m, 2H), 7.43-7.60 (m, 5H), 5.97 (s, 1H), 1.85 (s, 3H), 1.81 (s, 3H);
ESMS calcd for C20H18N3O2S: 363.1. Found: 364.0 (M+1)+.
Example 66
Compound 74
ESMS calcd for C21H19N3O4S: 409.11. Found: 410.0 (M+H)+.
Example 67
Compound 75
1H NMR (DMSO-d6) δ 9.46 (s, 1H), 9.45 (s, 1H), 7.95-8.00 (m, 2H), 7.38-7.56 (m, 5H), 6.65 (s, 1H), 6.15 (s, 1H), 2.07-2.14 (m, 2H), 081-1.18 (m, 11H);
ESMS calcd for C24H26N3O2S: 419.1. Found: 420.1 (M+1)+.
Example 68
Compound 76
ESMS calcd for C21H19N3O3S: 393.11. Found: 394.0 (M+H)+.
Example 69
Compound 77
ESMS calcd for C21H19N3O3S: 393.11. Found: 394.0 (M+H)+.
Example 70
Compound 78
1H NMR (DMSO-d6) δ 9.71 (s, 1H), 9.35 (s, 1H), 7.98-8.04 (m, 2H), 7.50-7.62 (m, 5H), 6.58 (s, 1H), 2.15 (q, J=7.5 Hz, 2H), 0.58 (t, J=7.5 Hz, 3H);
ESMS calcd for C20H17C1N3O2S: 397.0. Found: 398.0 (M+1)+.
Example 71
Compound 79
ESMS calcd for C19H21N3O3S: 371.13. Found: 372.0 (M+H)+.
Example 72
Compound 80
ESMS calcd for C21H19N3O2S: 393.11. Found: 394.0 (M+H)+.
Example 73
Compound 81
ESMS calcd for C20H17N3O2S: 379.10. Found: 380.0 (M+H)+.
Example 74
Compound 82
ESMS calcd for C21H19N3O2S: 393.11. Found: 394.0 (M+H)+.
Example 75
Compound 83
ESMS calcd for C20H17N3O3S: 379.10. Found: 380.0 (M+H)+.
Example 76
Compound 84
ESMS calcd for C20H17N3O3S: 379.10. Found: 380.0 (M+H)+.
Example 77
Compound 85
ESMS calcd for C19H15N3O2S: 365.08. Found: 266.0 (M+H)+.
Example 78
Compound 86
1H NMR (DMSO-d6) δ 9.68 (s, 1H), 9.58 (s, 1H), 8.2 (dd, J=7.0 and 2.4 Hz, 1H), 7.50 (m, 2H), 7.40 (tr, J=8.1 Hz, 1H), 7.32 (m, 1H), 6.97 (d, J=7.5 Hz, 1H), 6.95 (m, 1H), 6.89 (d, =8.4 Hz, 1H), 6.08 (d, =2.1 Hz, 1H), 6.0 (dd, =7.4 and 2.1 Hz, 1H), 3.96 (s, 3H);
ESMS calcd for C19H15N3O3S: 365.08. Found: 366.0 (M+1)+.
Example 79
Compound 87
1H NMR (MeOH-d4) δ 8.25 (m, 1H), 7.96 (s, 1H), 7.46-7.44 (m, 2H), 7.26 (d, J=8.4 Hz, 1H), 6.83 (d, J=8.1 Hz, 1H), 6.70 (d, J=8.7 Hz, 1H), 6.17 (d, J=2.1 Hz, 1H), 5.98 (dd, J=8.4 and 2.4 Hz, 1H);
ESMS calcd for C18H13N3O3S: 351.07. Found: 352.0 (M+1)+.
Example 80
Compound 88
1H-NMR (DMSO-d6) δ 9.69 (s, 1H), 9.59 (s, 1H), 7.54 (d, J=8.1 Hz, 1H), 7.46 (d, J=3 Hz, 1H), 7.14 (t, J=7.8 Hz, 1H), 6.97 (d, J=7.2 Hz, 1H), 6.89 (d, J=8.7 Hz, 1H), 6.12-6.13 (m, 2H), 6.02 (dd, J1=2.4 Hz, J2=8.4 Hz, 1H), 4.74 (qn, J=6.6 Hz, 1H), 1.40-1.46 (m, 6H);
ESMS calcd for C19H18N4O2S: 366.12. Found: 367.1 (M+1)+.
Example 81
Compound 89
ESMS calcd for C22H21N3O2S: 391.14. Found: 392.0 (M+H)+.
Example 82
Compound 90
1H NMR (DMSO-d6) δ 9.47 (s, 1H), 9.43 (s, 1H), 7.94-8.00 (m, 2H), 7.39-7.57 (m, 5H), 6.68 (s, 1H), 6.15 (s, 1H), 2.05-2.15 (m, 2H), 1.05-1.17 (m, 2H), 0.50 (t, J=7.5 Hz, 3H); ESMS calcd for C21H20N3O2S: 377.1. Found: 378.0 (M+1)+.
Example 83
Compound 91
1H NMR (DMSO-d6) δ 9.15 (s, 1H), 8.50 (s, 1H), 8.00-8.07 (m, 2H), 7.47-7.63 (m, 5H), 6.27 (s, 1H), 2.06 (q, J=7.5 Hz, 2H), 1.93 (s, 3H), 0.45 (t, J=7.5 Hz, 3H);
ESMS calcd for C21H20N3O2S: 377.1. Found: 378.0 (M+1)+.
Example 84
Compound 93
ESMS calcd for C16H15N3O4S: 345.08. Found: 346.0 (M+H)+.
Example 85
Compound 95
ESMS calcd for C16H12N4O2S: 324.07. Found: 325.0 (M+H)+.
Example 86
Compound 96
ESMS calcd for C19H18N4O3S: 382.11. Found: 383.0 (M+H)+.
Example 87
Compound 98
ESMS calcd for C17H12N4O2S: 336.07. Found: 337.0 (M+H)+.
Example 88
Compound 99
ESMS calcd for C19H13N3O4S: 379.06. Found: 379.9 (M+H)+.
Example 89
Compound 100
1H-NMR (DMSO-d6) δ 9.52 (s, 1H), 9.42 (s, 1H), 7.56 (d, J=8.7 Hz, 1H), 7.49 (d, J=3.3 Hz, 1H), 7.14 (t, J=7.5 Hz, 1H), 6.95 (d, J=8.4 Hz, 1H), 6.61 (s, 1H), 6.21 (s, 1H), 6.14 (dd, J=3.3 Hz, 1H), 4.76 (qn, J=6.6 Hz, 1H), 2.14 (q, J=7.5 Hz, 2H), 1.41-1.47 (m, 6H), 0.66 (t, J=7.5 Hz, 3H);
ESMS calcd for C21H22N4O2S: 394.15. Found: 395.1 (M+1)+.
Example 90
Compound 101
ESMS calcd for C19H17N5O3S: 395.11. Found: 396.0 (M+H)+.
Example 91
Compound 102
ESMS calcd. for C19H20N5O2S: 381.1. Found: 382.0 (M+1)+.
Example 92
Compound 103
1H NMR (DMSO-d6) δ 9.48 (s, 1H), 9.38 (s, 1H), 7.29(d, J=8.4 Hz, 1H), 7.25(d, J=1.8 Hz, 1H), 6.85-6.89 (m, 2H), 6.18 (s, 1H), 3.61 (s, 3H), 2.30 (s, 3H), 2.29 (q, J=7.5 Hz, 2H), 2.09 (s, 3H), 0.94 (t, J=7.5 Hz, 3H);
ESMS calcd for C21H23N4O2S: 394.1. Found: 395.0(M+1)+.
Example 93
Compound 104
ESMS calcd for C19H15N3O3S: 365.08. Found: 366.0 (M+H)+.
Example 94
Compound 106
ESMS calcd for C20H17N4O2S: 377.1. Found: 378.0 (M+H)+.
Example 95
Compound 107
ESMS calcd for C18H13ClN3O2S: 369.0. Found: 370.0 (M+H)+.
Example 96
Compound 116
1H NMR (DMSO-d6) δ 7.98-7.56 (m, 2H), 7.55-7.30 (m, 6H), 6.43 (dd, J=8.1 and 1.8 Hz, 1H), 6.29 (m, 1H), 3.65 (s, 3H), 3.16 (s, 3H);
ESMS calcd for C20H17N3O2S: 363.10. Found: 364.0 (M+1)+.
Example 97
Compound 117
1H-NMR (CDCl3) δ 7.83(d, J=8.1 Hz, 2H), 7.48-7.34(m, 4H), 7.28-7.20(m, 1H), 6.99 (d, J=1.8 Hz, 1H), 6.80(d, J=8.7 Hz, 1H), 6.62-6.58(m, 1H), 2.94(s, 3H), 2.89(s, 3H), 2.84(s, 3H), 2.81(s, 3H), 2.75-2.69(m, 6H);
ESMS calcd for C27H28N6O5S: 548.18. Found: 549.2 (M+1)+.
Example 98
Compound 122
1H-NMR (CDCl3) δ 7.98(m, 2H), 7.60-7.55(m, 3H), 7.51-7.45(m, 1H), 7.36-7.33(m, 1H), 6.98-6.97(m, 1H), 6.86(d, J=9.9 Hz, 1H), 6.70-6.67(m, 1H), 2.86(s, 3H), 2.26(s, 3H), 2.21(s, 3H);
ESMS calcd for C24H19N3O5S: 461.10. Found: 462.0 (M+1)+.
Example 99
Compound 125
ESMS calcd for C20H17N3O3S: 379.10. Found: 380.0 (M+H)+.
Example 100
Compound 126
ESMS calcd for C10H11N3O2S: 237.06. Found: 238.0 (M+H)+.
Example 101
Compound 127
ESMS calcd for C11H13N3O2S: 251.07. Found: 252.0 (M+H)+.
Example 102
Compound 128
ESMS calcd for C11H13N3O2S: 251.07. Found: 252.0 (M+H)+.
Example 103
Compound 129
ESMS calcd for C11H11N3O2S: 249.06. Found: 250.0 (M+H)+.
Example 104
Compound 130
ESMS calcd for C12H15N3O2S: 265.09. Found: 266.0 (M+H)+.
Example 105
Compound 131
ESMS calcd for C20H15N3O4S: 393.08. Found: 394.1 (M+H)+.
Example 106
Compound 177
1H NMR (DMSO-d6) δ 9.34(s, 1H), 9.22(s, 1H), 8.01-7.96 (m, 2H), 7.58-7.44 (m,
ESMS calcd for C19H15N3O3S: 365.08. Found: 366.0 (M+1)+.
Example 107
Compound 178
1H NMR (DMSO-d6) δ 10.29 (s, 1H), 9.49 (s, 1H), 9.42 (s, 1H), 8.16 (t, J=5.1 Hz, 1H), 7.45-7.43 (m, 2H), 7.26 (t, J=8.0 Hz, 1H), 6.84 (d, J=7.8 Hz, 1H), 6.75 (d, J=8.7 Hz, 1H), 6.66 (s, 1H), 6.14 (s, 1H), 2.12 (q, J=7.5 Hz, 2H), 0.70 (t, J=7.2 Hz, 3H);
ESMS calcd for C20H17N3O3S: 379.10. Found: 379.9 (M+1)+.
Example 108
Compound 179
ESMS calcd for C19H15N3O2S: 349.09. Found: 350.0 (M+1)+.
Example 109
Compound 180
ESMS calcd for C19H15N3O2S: 349.09. Found: 350.0 (M+H)+.
Example 110
Compound 181
ESMS calcd for C20H15N3O2S: 361.09. Found: 362.0 (M+H)+.
Example 111
Compound 182
ESMS calcd for C16H15N3O3S: 329.08. Found: 330.0 (M+H)+.
Example 112
Compound 183
ESMS calcd for C20H17N3O2S: 363.10. Found: 364.0 (M+H)+.
Example 113
Compound 184
ESMS calcd for C18H13N3O3S: 350.38. Found: 351.9 (M+H)+.
Example 114
Compound 185
ESMS calcd. for C20H21N4O2S: 380.1. Found: 381.0 (M+1)+.
Example 115
Compound 187
3. ESMS calcd. for C19H20N5O2S: 381.1. Found: 382.0 (M+1)+.
Example 116
Compound 190
4. ESMS Calcd. for C21H22N4O2S: 394.15. FOUND: 395.0 (M+1)+.
Example 117
Compound 191
ESMS calcd. for C22H23N4O4S: 438.1. Found: 439.0 (M+1)+.
Example 118
Compound 192
ESMS calcd. for C20H22N5O2S: 395.1. Found: 396.0 (M+1)+.
Example 119
Compound 193
ESMS calcd. for C20H22N5O2S: 395.1. Found: 396.0 (M+1)+.
Example 120
Compound 194
ESMS calcd. for C23H27N4O2S: 422.1. Found: 423.0 (M+1)+.
Example 121
Compound 195
ESMS calcd. for C23H25N4O2S: 420.1. Found: 421.0 (M+1)+.
Example 122
Compound 196
ESMS calcd. for C25H29N4O2S: 448.1. Found: 449.3 (M+1)+.
Example 123
Compound 197
ESMS calcd. for C22H24N4O2S: 408.16. Found: 409.2 (M+1)+.
Example 124
Compound 198
ESMS calcd. for C23H26N4O2S: 422.18. Found: 423.3 (M+1)+.
Example 125
Compound 199
ESMS calcd. for C24H28N4O2S: 436.19. Found: 437.3 (M+1)+.
Example 126
Compound 200
ESMS calcd. for C22H22N4O2S: .406.15. Found: 407.2 (M+1)+.
Example 127
Compound 201
ESMS calcd. for C23H24N4O3S: 436.16. Found: 437.3 (M+1)+.
Example 128
Compound 202
ESMS calcd. for C22H23N4O2S: 406.1. Found: 407.0 (M+H)+.
Example 129
Compound 204
ESMS calcd. for C24H28N4O3S: .452.19. Found: 453.2 (M+1)+.
Example 130
Compound 205
ESMS calcd. for C23H24N4O3S: 436.16. Found: 437.1 (M+1)+.
Example 131
Compound 206
ESMS calcd. for C21H23N4O2S: 394.1. Found: 395.1 (M+1)+.
Example 132
Compound 207
ESMS calcd. for C20H21N4O2S: 380.1. Found: 381.1 (M+1)+.
Example 133
Compound 208
ESMS calcd. for C23H26N4O3S: 438.17. Found: 439.1 (M+1)+.
Example 134
Compound 209
ESMS calcd. for C22H24N4O2S: 408.1. Found: 409.1 (M+1)+.
Example 135
Compound 210
ESMS calcd. for C24H23N4O2S: 430.1. Found: 431.1 (M+1)+.
Example 136
Compound 211
ESMS calcd. for C21H22N4O3S: 410.14. Found: 411.1 (M+1)+.
Example 137
Compound 212
ESMS calcd. for C23H26N4O3S: 438.17. Found: 439.1 (M+1)+.
Example 138
Compound 213
ESMS calcd. for C20H2)N4O2S: 380.1. Found: 381.1 (M+1)+.
Example 139
Compound 214
ESMS calcd. for C19H19N4O2S: 366.1. Found: 367.1 (M+1)+.
Example 140
Compound 215
ESMS calcd. for C20H19N3O4S: 397.1. Found: 398.1 (M+1)+.
Example 141
Compound 216
1H NMR (DMSO-d6): δ (ppm) 9.56 (s, 1H), 9.40 (s, 1H), 8.03 (d, J=2.4 Hz, 1H), 7.58 (d, J=8.4 Hz, 1H), 7.54 (d, J=2.1 Hz, 1H), 7.11 (dd, J=8.4, 2.1 Hz, 1H), 6.97 (d, J=2.4 Hz, 1H), 6.89 (s, 1H), 6.17 (s, 1H), 2.23 (q, J=7.2 Hz, 2H), 0.93 (t, J=7.2 Hz, 3H);
ESMS calcd. for C18H15N3O3S: 353.08. Found: 354.0 (M+1)+.
Example 142
Compound 217
1H NMR (DMSO-d6): δ (ppm) 9.59 (s, 1H), 9.43 (s, 1H), 7.67 (d, J=8.7 Hz, 1H), 7.54 (d, J=2.1 Hz, 1H), 7.20 (dd, J=8.4, 2.1 Hz, 1H), 6.96 (s, 1H), 6.18 (s, 1H), 2.60 (s, 3H), 2.34 (q, J=7.2 Hz, 2H), 0.98 (t, J=7.2 Hz, 3H);
ESMS calcd. for C18H16N4O3S: 368.09. Found: 369.0 (M+1)+.
Example 143
Compound 218
ESMS calcd. for C21H23N4O2S: 394.1. Found: 395.1 (M+1)+.
Example 144
Compound 219
ESMS calcd. for C21H21N4O2S: 392.1. Found: 393.1 (M+1)+.
Example 145
Compound 220
ESMS calcd. for C20H21N4O3: 364.1. Found: 365.1 (M+1)+.
Example 146
Compound 221
ESMS calcd. for C20H21N4O2S: 379.1. Found: 381.1 (M+1)+.
Example 147
Compound 222
ESMS calcd. for C21H23N4O2S: 394.1. Found: 395.1 (M+1)+.
Example 148
Compound 224
ESMS calcd. for C19H21N4O2S: 368.1. Found: 369.1 (M+1)+.
Example 149
Compound 225
ESMS calcd. for C19H19N4O2S: 366.1. Found: 367.1(M+1)+.
Example 150
Compound 226
ESMS calcd. for C20H21N4O3: 364.1. Found: 365.1 (M+1)+.
Example 151
Compound 227
ESMS calcd. for C21H22N4O2S: 394.15. Found: 395.1 (M+1)+.
Example 152
Compound 228
ESMS calcd. for C22H24N4O2S: 408.16. Found: 409.1 (M+1)+.
Example 153
Compound 229
ESMS calcd. for C20H18F3N5O2S: 449.11. Found: 450.1 (M+1)+.
Example 154
Compound 230
ESMS calcd. for C19H19N5O2S: 381.13. Found: 382.1 (M+1)+.
Example 155
Compound 231
ESMS calcd. for C19H19N5O2S: 381.13. Found: 382.1 (M+1)+.
Example 156
Compound 232
ESMS calcd. for C22H24N4O3S: 392.18. Found: 393.1 (M+1)+.
Example 157
Compound 233
ESMS calcd. for C18H17N3O4S: 371.09. Found: 372.1 (M+1)+.
Example 158
Compound 234
ESMS calcd. for C20H21N3O2S: 367.14. Found: 368.1 (M+1)+.
Example 159
Compound 235
ESMS calcd. for C19H19N5O2S: 381.13. Found: 382.1 (M+1)+.
Example 160
Compound 239
ESMS clcd for C19H21N4O2S: 368.1. Found: 369.1 (M+H)+.
Example 161
Compound 240
ESMS clcd for C18H16N4O3S: 368.09.10. Found: 369.1 (M+H)+.
Example 162
Compound 241
ESMS clcd for C17H15N5O3S: 369.09. Found: 370.1 (M+H)+.
Example 163
Compound 242
ESMS clcd for C19H18N4O3S: 382.11. Found: 383.1 (M+H)+.
Example 164
Compound 243
ESMS clcd for C22H26N4O3S: 426.17. Found: 427.1 (M+H)+.
Example 165
Compound 244
ESMS clcd for C18H16N4O4S: 384.09. Found: 385.1 (M+H)+
Example 166
Compound 245
ESMS clcd for C18H16N4O3S2: 400.07. Found: 401.1 (M+H)+
Example 167
Compound 245
ESMS clcd for C17H14N4O3S2: 386.05. Found: 387.0 (M+H)+.
Example 168
4-{5-Hydroxy-4-[4-methoxy-3-(methylpropylamino)phenyl]-4H-[1,2,4]triazol-3-yl}-6-isopropyl-benzene-1,3-diol








To a solution of 2,4-dihydroxy-5-isopropylbenzoic acid methyl ester (1.63 g, 7.75 mmol) in dimethylformamide (DMF) (100 mL) was added potassium carbonate (3.21 g, 23 mmol) then benzyl chloride (1.95 ml, 17 mmol). The suspension was heated to 80° C. for 16 hrs under a nitrogen atmosphere. Ethyl acetate (100 ml) and water (100 ml) were added, and then the ethyl acetate layer was washed with water (3×50 mL), and then dried over magnesium sulfate, filtered and evaporated to dryness to produce the desired compound as brown oil (2.9 g, 97%).
2,4-Bis-benzyloxy-5-isopropylbenzoic acid methyl ester (3.23 g, 8.27 mmol) and LiOH (1.0 g, 24.8 mmol) were heated in a mixture of tetrahydrofuranyl (THF)/methanol/water (100 mL, 3:1:1) for 16 hrs. Ethyl acetate (100 mL) and water (100 ml) were added, then the ethyl acetate layer was washed with water (3×50 mL), dried over magnesium sulfate, filtered and evaporated to dryness to produce the desired compound as a yellow solid (2.6 g, 83%).
2,4-Bis-benzyloxy-5-isopropylbenzoic acid (1.25 g, 3.32 mmol) was dissolved in dichloromethane (50 mL) and cooled in an ice bath. Oxalyl chloride (0.32 mL, 3.65 mmol) was added followed by the dropwise addition of DMF (0.1 mL). The reaction was stirred at room temperature for 1 hr then evaporated to dryness under reduced pressure to produce a brown solid. This solid was dissolved in THF (50 mL) and cooled in an ice bath. A solution of 4-Methoxy-N3-methyl-N3-propyl-benzene-1,3-diamine (0.71 g, 3.65 mmol) in THF (20 mL) was added dropwisely followed by the triethylamine (1.6 mL) and the reaction was stirred at room temperature for 16 hrs. Ethyl acetate (50 mL) and water (100 mL) were added. The ethyl acetate layer was washed with water (3×50 mL), dried over magnesium sulfate, filtered and evaporated to dryness to produce the crude product as a brown solid. Purification by silicagel chromatography (elution with 25% ethyl acetate/hexane) provided the desired compound as a white solid (1.8 g, 93%).
2,4-Bis-benzyloxy-5-isopropyl-N-[4-methoxy-3-(methylpropylamino)phenyl]benzamide (700 mg, 1.27 mmol) and Lawesson's reagent (0.31 g, 0.76 mmol) were dissolved in toluene (20 mL) and heated to 110° C. for 3 hrs then evaporated to dryness under reduced pressure to produce a yellow oil. This crude product was dissolved in dioxane (10 mL), anhydrous hydrazine (0.6 mL) was added and the reaction was heated to 80° C. for 30 min. After cooling, ethyl acetate (50 mL) and water (50 mL) were added. The ethyl acetate layer was washed with water (3×50 mL), dried over magnesium sulfate, filtered and evaporated to dryness to produce the crude product as a brown solid. This solid was dissolved in ethyl acetate (50 mL), CDI (0.66 g, 4.08 mmol) was added then the reaction was heated to reflux for 3 hrs. Removal of the solvent under reduced pressure followed by purification by silicagel chromatography (elution with 50% ethyl acetate/hexane) provided the desired compound as a white solid (250 mg, 33% over 3 steps).
5-(2,4-Bis-benzyloxy-5-isopropyl-phenyl)-4-[4-methoxy-3-(methylpropylamino)phenyl]-4H-[1,2,4]triazol-3-ol (240 mg, 0.4 mmol) was dissolved in methanol (10 mL) then 10% palladium on charcoal (200 mg) was added and the reaction was stirred under an atmosphere of hydrogen for 16 hrs. Filtration was carried out through a silca gel plug and removal of the solvent under reduced pressure produced the desired compound as a white solid (150 mg, 94%).
1H NMR (300 MHz, DMSO-d6), δ (ppm): 11.8 (s, 1H), 9.55 (s, 1H), 9.39 (s, 1H), 6.88 (d, J=8.7 Hz, 1H), 6.77-6.79 (m, 2H), 6.5 (s, 1H), 6.24 (s, 1H), 3.73 (s, 3H), 2.97 (qn, J=6.9 Hz, 1H), 2.79 (t, J=7.5 Hz, 2H), 2.48 (s, 3H), 1.30 (m, 2H), 0.97 (d, J=6.9 Hz, 6H), 0.73 (t, J=7.5 Hz, 3H).
ESMS clcd for C22H28N4O4: 412.21. Found: 413.2 (M+H)+.
Example 169
4-Isopropyl-6-{5-mercapto-4-[4-methoxy-3-(methyl-propyl-amino)-phenyl]-4H-[1,2,4]triazol-3-yl}-benzene-1,3-diol











2-methoxy-5-nitroaniline (1) (10.1 g, 60.0 mmol) in 250 mL dichloromethane at 0°-5° C. was treated with triethylamine (10.0 g, 100.0 mmol) and propionyl chloride (6.7 g, 6.3 mL, 72.0 mmol) for 1 hour and 0.5 h at room temperature (RT). Normal aqueous workup and removal of solvent gave a light yellow solid which was washed with hexane/EtOAc (9:1) to yield solid N-(2-Methoxy-5-nitro-phenyl)-propionamide (2) (13.2 g, 98%).
To a stirred solution of 11.2 g (50.0 mmol) of (2) in 150 mL of anhydrous THF at 0° C. under the nitrogen, was added 3.0 g (75 mmol) of NaH (60% in oil). The suspension was stirred for 0.5 h at 0° C. and 10 mL (150 mmol) of iodomethane was added at 0° C. After the mixture warmed to room temperature and stirred for 3 h, the reaction was quenched by ice brine and extracted with EtOAc (200 mL). The organic phase was washed with brine, dried (Na2SO4), filtered, evaporated in vacuo and the solid was washed with hexane/EtOAc (9:1) to give pure product N-(2-Methoxy-5-nitro-phenyl)-N-methyl-propionamide (3) as a light yellow solid (11.3 g, 95% yield).
N-(2-Methoxy-5-nitro-phenyl)-N-methyl-propionamide (3) (10.0 g 42 mmol) and borane-methyl sulfide complex (21 mL of 2.0M solution in tetrahydrofurane) in 50 mL THF were heated unter reflux for 30 min, cooled and quenched by ice-water (slowly). Extraction with EtOAc and the organic layer washed with brine dried (Na2SO4), filtered and evaporated in vacuo to give (9.1 g, 96%) (2-Methoxy-5-nitro-phenyl)-methyl-propyl-amine (4) as a yellow oil.
A solution of 9.0 g (40.1 mmol) of (2-Methoxy-5-nitro-phenyl)-methyl-propyl-amine (4) in 200 mL of MeOH/EtOAc (1:1) containing 5% w/w of Pd—C (10%) was subjected to hydrogenation (1 atm, balloon) overnight. The contents of the flask were passed through a short pad of celite and washed with EtOAc. The filtrate was evaporated under reduced pressure to give 7.7 g (92%) of crude amine 4-Methoxy-N3-methyl-N3-propyl-benzene-1,3-diamine (5) of an oil.
To a stirred solution of 6.8 g (35.0 mmol) of (5) in 150 mL of CH2Cl2 at RT was added 6.4 g (35 mmol) of 1,1′-thiocarbonyldiimidazole. The mixture was stirred at room temperature for 15 minutes and then evaporated under reduced pressure and the residue was passed through a short pad of silica gel, eluting with a gradient of hexane/EtOAc, which gave (5-Isothiocyanato-2-methoxy-phenyl)-methyl-propyl-amine (6) (7.85 g, 95%) as a colorless oil.
To a stirred solution of 4.5 g (19.0 mmol) of the isothiocyanate (6) in 60 mL of ethanol was added 4.0 g (19.0 mmol) of the hydrazide (7) portion wise. The resultant mixture was then heated at 70° C. for 1 h, then cooled. Solvent was removed on rotary evaporator and the residue was treated with hexane/EtoAc (9:1). The white precipitate thus obtained was filtered, washed with ether (2×50 mL) and vacuum dried to 7.6 g (90%) of (8) as white solid.
To a solution of 1.36 g (34 mmol) of NaOH in 80 mL of water was added 7.5 g (16.8 mmol) of the intermediate (8) portion-wise. After the dissolution of the solid (1-2 min), the flask was flushed with nitrogen and heated to 110° C. for 3 h. The reaction mixture was cooled, an additional 100 mL of water was added and the whole mixture was acidified with conc. HCl to pH 7. The white precipitate thus obtained was filtered, washed with water (3×75 mL) and dried. The crude product was then re-dissolved in a mixture of 200 mL of ethyl acetate, dried over anhydrous Na2SO4 and passed through a short pad of silica gel with an additional 150 mL of ethyl acetate as eluent. The filtrates were concentrated and crude product was re-precipitated in 3:1 hexane/ethyl acetate to give 6.83 g (95%) of 4-isopropyl-6-{5-mercapto-4-[4-methoxy-3-(methyl-propyl-amino)-phenyl]-4H-[1,2,4]triazol-3-yl}-benzene-1,3-diol as white solid.
1H NMR (300 MHz, DMSO-d6), (ppm): 9.58 (s, 1H); 9.39 (s, 1H); 6.92-6.83 (m, 3H); 6.56(d, J=1.8 Hz, 1H); 6.23 (s, 1H); 3.74 (s, 3H); 3.0-2.93(m, 1H); 2.81(t, J=6.9 Hz, 2H); 2.48(s, 3H); 1.31-1.24 (m, 2H); 0.96 (d, J=6.9 Hz, 6H); 0.72 (t, J=7.2 Hz, 3H);
ESMS clcd for C22H28N4O3S: 428.19. Found: 429.2 (M+H)+.
Example 170
4-(4-{3-[(2-Dimethylamino-ethyl)-methyl-amino]-4-methoxy-phenyl}-5-mercapto-4H-[1,2,4]triazol-3-yl)-6-isopropyl-benzene-1,3-diol








An oven-dried flask was charged with cesium carbonate (2.28 g, 7 mmol, 1.4 eq), Pd(OAc)2 (79 mg, 0.35 mmol, 0.07 eq), and X-phos (238 mg, 0.5 mmol, 0.1 eq) under nitrogen. 2-bromo-1-methoxy-4-nitrobenzene (1.16 g, 5 mmol, 1 eq), N1,N2,N2-trimethylethane-1,2-diamine (613 mg, 6 mmol, 1.2 eq) and toluene (20 mL, 0.25 M) were added, and the mixture was heated to 100° C. with stiffing overnight. The reaction mixture was cooled to room temperature and concentrated. The crude product was then purified by flash chromatography on silica gel to give N1-(2-methoxy-5-nitrophenyl)-N1, N2, N2-trimethylethane-1,2-diamine(2) (340 mg, 1.34 mmol, 27%).
A solution of 340 mg of N1-(2-methoxy-5-nitrophenyl)-N1, N2, N2-trimethylethane-1,2-diamine (2) in 20 mL of ethanol containing 5% w/w of Pd—C (10%) was subjected to hydrogenation (1 atm, balloon) for 1.5 h. The contents of the flask were passed through a short pad of celite and washed with MeOH. The filtrate was evaporated under reduced pressure and crude amine obtained was carried over to the next reaction without further purification. Thiocarbodiimidazole (260 mg, 1.46 mmol) was added to the crude amine in dichloromethane (10 mL) at room temperature. The reaction mixture was stirred at room temperature for 1 h, and concentrated. The crude product was then purified by flash chromatography on silica gel to give N1-(5-isothiocyanato-2-methoxyphenyl)-)-N1, N2, N2-trimethylethane-1,2-diamine (3) (110 mg, 0.42 mmol, 31%).
To a stirred solution of 110 mg (0.54 mmol) of the isothiocyanate (3) in 5 mL of ethanol was added 105 mg (0.54 mmol) of 2,4-dihydroxy-5-isopropyl-benzoic acid hydrazide portion wise. The resultant mixture was then heated at 80° C. for 1 h, and then cooled. Solvent was removed on rotary evaporator and the residue was treated with hexane/EtOAc (9:1). The white precipitate thus obtained was filtered, washed with ether (2×20 mL) and vacuum dried to crude product as white solid. This solid was added to a solution of 44 mg (1.08 mmol) of NaOH in 5 mL of water portion-wise. After the dissolution of the solid (1-2 min), the flask was flushed with nitrogen and heated to 110° C. for 1.5 h. The reaction mixture was cooled, an additional 20 mL of water was added and the whole mixture was acidified with conc. HCl to pH 7. The white precipitate thus obtained was filtered, washed with water (3×20 mL) and dried. The crude product was then re-dissolved in a mixture of 20 mL of ethyl acetate, dried over anhydrous Na2SO4 and passed through a short pad of silica gel with an additional 15 mL of ethyl acetate as eluent. The filtrates were concentrated and crude product was re-precipitated in 3:1 hexane/ethyl acetate to give 97 mg of 4-(4-(3-((2-(dimethylamino)ethyl)(methyl)amino)-4-methoxyphenyl)-5-mercapto-4H-1,2,4-triazol-3-yl)-6-isopropylbenzene-1,3-diol (4) as white solid.
1H-NMR300 MHz, DMSO-d6) δ (ppm): 9.80 (s, 1H), 9.62 (br s, 1H), 6.85 (m. 3H), 6.63 (m, 1H), 6.41 (s, 1H), 3.78 (s, 3H), 3.06 (m, 2H), 2.97 (q, J=6.9 Hz, 1H), 2.55 (s, 3H), 2.47 (m, 2H), 2.24 (s, 6H), 0.99 (s, 3H), 0.97 (s, 3H).
ESMS clcd for C23H31N5O3S: 457.21. Found: 458.2 (M+H)+.
Example 171
4-Isopropyl-6-(5-mercapto-4-{4-methoxy-3-[(2-methoxy-ethyl)methylamino]phenyl}-4H-[1,2,4]triazol-3-yl)-benzene-1,3-diol




1H NMR (300 MHz, DMSO-d6) δ (ppm): 9.57 (s, 1H), 9.39 (s, 1H), 6.83-6.90 (m, 3H), 6.59 (d, J=2.1 Hz, 1H), 6.23 (s, 1H), 3.74 (s, 3H), 3.39 (t, J=6 Hz, 2H), 3.14 (s, 3H), 3.07 (t, J=6 Hz, 2H), 2.96 (qn, J=6.9 Hz, 1H), 2.54 (s, 3H), 0.97 (d, J=6.9 Hz, 6H). ESMS clcd for C22H28N4O4S: 444.18. Found: 445.2 (M+H)+.
Example 172
4-{4-[3-(Cyclopropylmethylmethylamino)-4-methoxy-phenyl]-5-mercapto-4H-[1,2,4]triazol-3-yl}-6-isopropylbenzene-1,3-diol




1H NMR (300 MHz, DMSO-d6) δ (ppm): 9.56 (s, 1H), 9.39 (s, 1H), 6.85-6.90 (m, 3H), 6.58 (d, J=2.1 Hz, 1H), 6.23 (s, 1H), 3.76 (s, 3H), 2.96 (qn, J=6.9 Hz, 1H), 2.76 (d, J=6.3 Hz, 2H), 2.57 (s, 3H), 0.99 (d, J=6.9 Hz, 6H), 0.58-0.64 (m, 1H), 0.32-0.34 (m, 2H), −0.03-0.01 (m, 2H).
ESMS clcd for C23H28N4O3S: 440.19. Found: 441.1 (M+H)+.
Example 173
N-{4-[3-(5-Ethyl-2,4-dihydroxy-phenyl)-5-mercapto-[1,2,4]triazol-4-yl]-phenyl}-N-methyl-acetamide




ESMS clcd for C19H20N4O3S: 384.13. Found: 385.1 (M+H)+.
Example 174
N-Ethyl-N-{5-[3-(5-ethyl-2,4-dihydroxy-phenyl)-5-mercapto-[1,2,4]triazol-4-yl]-2-methoxy-phenyl}-acetamide




ESMS clcd for C21H24N4O4S: 428.15. Found: 429.2 (M+H)+.
Example 175
4-[4-(3-Diethylamino-4-methoxy-phenyl)-5-mercapto-4H-[1,2,4]triazol-3-yl]-6-ethyl-benzene-1,3-diol




ESMS clcd for C21H26N4O3S: 414.17. Found: 415.2 (M+H)+.
Example 176
4-[4-(4-Dimethylamino-phenyl)-5-mercapto-4H-[1,2,4]triazol-3-yl]-6-ethyl-benzene-1,3-diol




ESMS clcd for C18H20N4O2S: 356.13. Found: 357.2 (M+H)+.
Example 177
4-[4-(4-Diethylamino-phenyl)-5-mercapto-4H-[1,2,4]triazol-3-yl]-6-ethyl-benzene-1,3-diol




ESMS clcd for C20H24N4O2S: 384.16. Found: 385.2 (M+H)+.
Example 178
4-Ethyl-6-[5-mercapto-4-(4-morpholin-4-yl-phenyl)-4H-[1,2,4]triazol-3-yl]-benzene-1,3-diol




ESMS clcd for C20H22N4O3S: 398.14. Found: 399.2 (M+H)+.
Example 179
4-Ethyl-6-[4-(4-imidazol-1-yl-phenyl)-5-mercapto-4H-[1,2,4]triazol-3-yl]-benzene-1,3-diol




ESMS clcd for C19H17N5O2S: 379.11. Found: 380.2 (M+H)+.
Example 180
4-[4-(2,5-Diethoxy-4-morpholin-4-yl-phenyl)-5-mercapto-4H-[1,2,4]triazol-3-yl]-6-ethyl-benzene-1,3-diol




ESMS clcd for C24H30N4O5S: 486.19. Found: 487.3 (M+H)+.
Example 181
4-Ethyl-6-{4-[3-(isopropyl-propyl-amino)-4-methoxy-phenyl]-5-mercapto-4H-[1,2,4]triazol-3-yl}-benzene-1,3-diol




ESMS clcd for C23H30N4O3S: 442.20. Found: 443.3 (M+H)+.
Example 182
4-[4-(4-Dimethylamino-3-methoxy-phenyl)-5-mercapto-4H-[1,2,4]triazol-3-yl]-6-ethyl-benzene-1,3-diol




ESMS clcd for C19H22N4O3S: 386.14. Found: 387.2 (M+H)+.
Example 183
4-Ethyl-6-[5-mercapto-4-(3-pyrrolidin-1-yl-phenyl)-4H-[1,2,4]triazol-3-yl]-benzene-1,3-diol




ESMS clcd for C20H22N4O2S: 382.15. Found: 383.2 (M+H)+.
Example 184
4-[4-(3-Dimethylamino-phenyl)-5-mercapto-4H-[1,2,4]triazol-3-yl]-6-ethyl-benzene-1,3-diol




ESMS clcd for C18H20N4O2S: 356.13. Found: 357.2 (M+H)+.
Example 185
4-Ethyl-6-{4-[3-(isopropyl-methyl-amino)-4-methoxy-phenyl]-5-mercapto-4H-[1,2,4]triazol-3-yl}-benzene-1,3-diol




ESMS clcd for C21H26N4O3S: 414.17. Found: 415.2 (M+H)+.
Example 186
4-[4-(3-Dimethylamino-4-methoxy-phenyl)-5-mercapto-4H-[1,2,4]triazol-3-yl]-6-ethyl-benzene-1,3-diol




ESMS clcd for C19H22N4O3S: 386.14. Found: 387.2 (M+H)+.
Example 187
4-Ethyl-6-{4-[3-(ethyl-methyl-amino)-4-methoxy-phenyl]-5-mercapto-4H-[1,2,4]triazol-3-yl}-benzene-1,3-diol




ESMS clcd for C20H24N4O3S: 400.16. Found: 401.2 (M+H)+.
Example 188
4-Isopropyl-6-{4-[3-(isopropyl-propyl-amino)-4-methoxy-phenyl]-5-mercapto-4H-[1,2,4]triazol-3-yl}-benzene-1,3-diol




ESMS clcd for C24H32N4O3S: 456.22. Found: 457.3 (M+H)+.
Example 189
4-Ethyl-6-{4-[3-(ethyl-isopropyl-amino)-4-methoxy-phenyl]-5-mercapto-4H-[1,2,4]triazol-3-yl}-benzene-1,3-diol




ESMS clcd for C22H28N4O3S: 428.19. Found: 429.3 (M+H)+.
Example 190
4-Ethyl-6-[5-mercapto-4-(4-methoxy-3-morpholin-4-yl-phenyl)-4H-[1,2,4]triazol-3-yl]-benzene-1,3-diol




ESMS clcd for C21H24N4O4S: 428.15. Found: 429.2 (M+H)+.
Example 191
4-Isopropyl-6-{5-mercapto-4-[4-methoxy-3-(methyl-propyl-amino)-phenyl]-4H-[1,2,4]triazol-3-yl}-benzene-1,3-diol




1H NMR (300 MHz, DMSO-d6) δ (ppm): 9.58 (s, 1H); 9.39 (s, 1H); 6.92-6.83 (m, 3H); 6.56(d, J=1.8 Hz, 1H); 6.23 (s, 1H); 3.74 (s, 3H); 3.0-2.93(m, 1H); 2.81(t, J=6.9 Hz, 2H); 2.48(s, 3H); 1.31-1.24 (m, 2H); 0.96 (d, J=6.9 Hz, 6H); 0.72 (t, J=7.2 Hz, 3H);
ESMS clcd for C22H28N4O3S: 428.19. Found: 429.2 (M+H)+.
Example 192
4-{4-[3-(Ethyl-methyl-amino)-4-methoxy-phenyl]-5-mercapto-4H-[1,2,4]triazol-3-yl}-6-isopropyl-benzene-1,3-diol




1H NMR (300 MHz, DMSO-d6) δ (ppm): 9.58 (s, 1H); 9.40 (s, 1H); 6.92-6.85 (m, 3H); 6.58 (d, J=1.8 Hz, 1H); 6.24 (s, 1H); 3.76 (s, 3H); 3.02-2.90 (m, 3H); 2.49 (s, 3H) 0.99 (d, J=6.9 Hz, 6H); 0.86 (t, J=7.2 Hz, 3H).
ESMS clcd for C21H26N4O3S: 414.17. Found: 415.1 (M+H)+.
Example 193
4-Isopropyl-6-(5-mercapto-4-{4-methoxy-3-[methyl-(3-methyl-butyl)-amino]-phenyl}-4H-[1,2,4]triazol-3-yl)-benzene-1,3-diol




ESMS clcd for C24H32N4O3S: 456.22. Found: 457.2 (M+H)+.
Example 194
4-Isopropyl-6-{5-mercapto-4-[4-methoxy-3-(methyl-propyl-amino)-phenyl]-4H-[1,2,4]triazol-3-yl}-benzene-1,3-diol; compound with hydrogen chloride




ESMS clcd for C22H29ClN4O3S: 464.16. Found: 429.3 (M+H)+.
Example 195
4-{4-[3-(Butyl-methyl-amino)-4-methoxy-phenyl]-5-mercapto-4H-[1,2,4]triazol-3-yl}-6-isopropyl-benzene-1,3-diol




ESMS clcd for C23H30N4O3S: 442.20. Found: 443.3 (M+H)+.
Example 196
4-{4-[3-(Isobutyl-methyl-amino)-4-methoxy-phenyl]-5-mercapto-4H-[1,2,4]triazol-3-yl}-6-isopropyl-benzene-1,3-diol




ESMS clcd for C23H30N4O3S: 442.20. Found: 443.1 (M+H)+.
Example 197
4-(4-{3-[(2-Imidazol-1-yl-ethyl)-methyl-amino]-4-methoxy-phenyl}-5-mercapto-4H-[1,2,4]triazol-3-yl)-6-isopropyl-benzene-1,3-diol




ESMS clcd for C24H28N6O3S: 480.19. Found: 481.1 (M+H)+.
Example 198
4-(4-(3-(1H-pyrrol-1-yl)phenyl)-5-mercapto-4H-1,2,4-triazol-3-yl)-6-ethylbenzene-1,3-diol




ESMS clcd for C20H18N4O2S: 378.12. Found: 379.1 (M+H)+.
Example 199
4-(4-(4-(1H-pyrazol-1-yl)phenyl)-5-mercapto-4H-1,2,4-triazol-3-yl)-6-ethylbenzene-1,3-diol




ESMS clcd for C19H17N5O2S: 379.11. Found: 380.1 (M+H)+.
Example 200
4-(4-(3-(dimethylamino)-4-(methylthio)phenyl)-5-mercapto-4H-1,2,4-triazol-3-yl)-6-isopropylbenzene-1,3-diol




ESMS clcd for C20H24N4O2S2: 416.13. Found: 417.1 (M+H)+.
Example 201
4-isopropyl-6-(5-mercapto-4-(4-methoxy-3-(propylamino)phenyl)-4H-1,2,4-triazol-3-yl)benzene-1,3-diol




ESMS clcd for C21H26N4O3S: 414.17. Found: 415.1 (M+H)+.
Example 202
4-[4-(4-Amino-3-hydroxy-phenyl)-5-mercapto-4H-[1,2,4]triazol-3-yl]-6-ethyl-benzene-1,3-diol




ESMS clcd for C16H16N4O3S: 344.09. Found: 345.1 (M+H)+.
Example 203
4-ethyl-6-(4-(3-hydroxy-4-(methylamino)phenyl)-5-mercapto-4H-1,2,4-triazol-3-yl)benzene-1,3-diol




ESMS clcd for C17H18N4O3S: 358.11. Found: 359.1 (M+H)+
Example 204
4-(4-(3-aminophenyl)-5-mercapto-4H-1,2,4-triazol-3-yl)-6-ethylbenzene-1,3-diol




ESMS clcd for C16H16N4O2S: 328.10. Found: 329.1 (M+H)+.
Example 205
4-[4-(4-Dimethylamino-3-methyl-phenyl)-5-mercapto-4H-[1,2,4]triazol-3-yl]-6-ethyl-benzene-1,3-diol




ESMS clcd for C19H23N4O2S: 371.1. Found: 371.1 (M+H)+.
Example 206
4-[4-(3-Imidazol-1-yl-phenyl)-5-mercapto-4H-[1,2,4]triazol-3-yl]-6-isopropyl-benzene-1,3-diol




ESMS clcd. for C20H20N5O2S: 394.1. Found: 394.1 (M+H)+.
Example 207
4-[4-(3-Imidazol-1-yl-phenyl)-5-mercapto-4H-[1,2,4]triazol-3-yl]-6-isopropyl-benzene-1,3-diol




2-{3-[3-(2,4-Dihydroxy-5-isopropyl-phenyl)-5-mercapto-[1,2,4]triazol-4-yl]-phenyl}-5-methyl-2,4-dihydro-pyrazol-3-one
1H NMR (300 MHz, DMSO-d6) δ (ppm): 9.63 (br s, 1H); 7.70-7.80 (m, 2H); 7.37-7.43 (m, 1H); 6.99-7.02 (m, 1H); 6.91 (s, 1H); 6.25 (s, 1H); 5.35 (s, 1H); 3.70 (s, 2H); 2.96 (hept, J=6.9 Hz, 1H); 2.09 (s, 3H); 0.99 (d, J=6.9 Hz, 6H);
ESMS clcd. for C21H22N5O3S: 424.1. Found: 424.1 (M+H)+.
Example 208
Inhibition of Hsp90
Hsp90 protein was obtained from Stressgen (Cat#SPP-770). Assay buffer: 100 mM Tris-HCl, Ph7.4, 20 mM KCl, 6 mM MgCl2. Malachite green (0.0812% w/v) (M9636) and polyviny alcohol USP (2.32% w/v) (P1097) were obtained from Sigma. A Malachite Green Assay (see Methods Mol Med, 2003, 85:149 for method details) was used for examination of ATPase activity of Hsp90 protein. Briefly, Hsp90 protein in assay buffer (100 mM Tris-HCl, Ph7.4, 20 mM KCl, 6 mM MgCl2) was mixed with ATP alone (negative control) or in the presence of Geldanamycin (a positive control) or Compound 108 in a 96-well plate. Malachite green reagent was added to the reaction. The mixtures were incubated at 37° C. for 4 hours and sodium citrate buffer (34% w/v sodium citrate) was added to the reaction. The plate was read by an ELISA reader with an absorbance at 620 nm.
As can be seen in FIG. 1, 40 μM of geldanamycin, a natural product known to inhibit Hsp90 activity, the ATPase activity of Hsp90 was only slightly higher than background. 40 μM Compound 108 showed an even greater inhibition of ATPase activity of Hsp90 than geldanamycin, and even at 4 μM Compound 108 showed significant inhibition of ATPase activity of Hsp90 protein.
Example 209
Degradation of Client Proteins Via Inhibition of Hsp90 Activity
A. Cells and Cell Culture
Human high-Her2 breast carcinoma BT474 (HTB-20), SK-BR-3 (HTB-30) and MCF-7 breast carcinoma (HTB-22) from American Type Culture Collection, VA, USA were grown in Dulbecco's modified Eagle's medium with 4 mM L-glutamine and antibiotics (100 IU/ml penicillin and 100 ug/ml streptomycine; GibcoBRL). To obtain exponential cell growth, cells were trypsinized, counted and seeded at a cell density of 0.5×106 cells/ml regularly, every 3 days. All experiments were performed on day 1 after cell passage.
B. Degradation of Her2 in Cells after Treatment with a Compound of the Invention

    
    
        1. Method 1
    
    


BT-474 cells were treated with 0.5 μM, 2 μM, or 5 μM of 17AAG (a positive control) or 0.5 μM, 2 μM, or 5 μM of Compound 108 or Compound 49 overnight in DMEM medium. After treatment, each cytoplasmic sample was prepared from 1×106 cells by incubation of cell lysis buffer (#9803, cell Signaling Technology) on ice for 10 minutes. The resulting supernatant used as the cytosol fractions were dissolved with sample buffer for SDS-PAGE and run on a SDS-PAGE gel, blotted onto a nitrocellulose membrane by using semi-dry transfer. Non-specific binding to nitrocellulose was blocked with 5% skim milk in TBS with 0.5% Tween at room temperature for 1 hour, then probed with anti-Her2/ErB2 mAb (rabbit IgG, #2242, Cell Signaling) and anti-Tubulin (T9026, Sigma) as housekeeping control protein. HRP-conjugated goat antirabbit IgG (H+L) and HRP-conjugated horse anti-mouse IgG (H+L) were used as secondary Ab (#7074, #7076, Cell Signaling) and LumiGLO reagent, 20× Peroxide (#7003, Cell Signaling) was used for visualization.
As can be seen from FIG. 2, Her2, an Hsp90 client protein, is almost completely degraded when cells are treated with 5 μM of Compound 108 and partially degradated when cells are treated with 2 μM and 0.5 μM of Compound 108. Compound 49 which is even more active than Compound 108 causes complete degradation of Her2 when cells are treated with 2 μM and 5 μM and causes partial degradated when cells are treated with 0.5 μM 17AAG is a known Hsp90 inhibitor and is used as a positive control.
2. Method 2
MV-4-11 cells (20,000 cells/well) are cultured in 96-well plates and maintained at 37° C. for several hours. The cells are treated with a compound of the invention or 17AAG (a positive control) at various concentrations and incubated at 37° C. for 72 hours. Cell survival is measured with Cell Counting Kit-8 (Dojindo Laboratories, Cat. #CK04).







TABLE 8







IC50 range of compounds of the invention


for inhibition of Her2 degradation








IC50 Range
Compound Number





<3 μM
8, 13, 39, 49, 63, 76, 77, 79, 87, 88, 95, 96,



100, 103, 177, 178, 185, 188, 189, 247, 248,



249, 250, 251, 252, 259


3 μM to 10 μM
2, 5, 6, 7, 9, 14, 27, 28, 34, 36, 38, 42, 48,



64, 70, 93, 97, 108, 122, 183, 184


10 μM to 100 μM
21, 22, 30, 51, 59, 60, 61, 62, 94, 98, 99, 102,



104, 123, 181, 182, 186, 187, 348









C. Fluorescent Staining of Her2 on the Surface of Cells Treated with a Compound of the Invention
After treatment with a compound of the invention, cells were washed twice with 1×PBS/1% FBS, and then stained with anti-Her2-FITC (#340553, BD) for 30 min at 4° C. Cells were then washed three times in FACS buffer before the fixation in 0.5 ml 1% paraformadehydrede. Data was acquired on a FACSCalibur system. Isotype-matched controls were used to establish the non-specific staining of samples and to set the fluorescent markers. A total 10,000 events were recorded from each sample. Data were analysed by using CellQuest software (BD Biosciences). The IC50 range for Hsp90 inhibition by compounds of the invention are listed below in Table 2.
D. Apoptosis Analysis
After treatment with the compounds of the invention, cells were washed once with 1×PBS/1% FBS, and then stained in binding buffer with FITC-conjugated Annexin V and Propidium iodide (PI) (all obtained from BD Biosciences) for 30 min at 4° C. Flow cytometric analysis was performed with FACSCalibur (BD Biosciences) and a total 10,000 events were recorded from each sample. Data were analyzed by using CellQuest software (BD Biosciences). The relative fluorescence was calculated after subtraction of the fluorescence of control.
E. Degradation of c-Met in NCI-H1993 Cells after Treatment with a Compound of the Invention
We examined the ability of the Hsp90 inhibitors of the invention to induce the degradation of c-Met, an Hsp90 client protein that is expressed at high levels in several types of cancer. A non-small cell lung cancer cell line, NCI-H1993 (ATCC, cat#CRL-5909), which expresses c-met at high levels, was seeded in 6-well plates at 5×105 cells/well. The cells were either untreated (lane 2), treated with STA-4783, a compound that does not inhibit Hsp90 (control, lane 3), or treated with 17AAG (400 nM (lane 4) or 100 nM (lane 5), Compound 221 (400 nM (lane 6) or 100 nM (lane 7)), Compound 257 (400 nM (lane 8) or 100 nM (lane 9)) or Compound 258 (400 nM (lane 10) or 100 nM (lane 11)). After 24 hours, the cells were lysed and an equal amount of protein from each treatment group was used for Western blot analysis. The Western blot shown in FIG. 3 indicates that compounds of the invention potently induced degradation of c-Met due to inhibition.
F. Degradation of c-Met in ACHN and MKN-45 Cells after Treatment with a Compound of the Invention
Flow cytometric analysis was used to monitor the degradation of c-Met over-expressed on the surface of the ACHN human renal cell carcinoma cell line which contains the juxtamembrane domain mutation (C3223T: T1010I) and is constitutively active, and the MKN45 which is a c-Met amplified human gastric carcinoma cell line. ACHN and MKN45 cells (5×105 cells) were treated with Compound 226, 17-AAG or 17-DMAG for 18 hours. After treatment the cells were stained with FITC conjugated c-MET antibody. The expression of the c-Met cell surface proteins was measured by flow cytometry analysis (see FIG. 4 for ACHN cells and FIG. 5 for MKN45 cells). The IC50 value was determined by XLfit software. Compound 226 potently induced the degradation of mutant c-Met with an IC50 value of 18 nM. In contrast, 17-AAG was about ten folds less affective at induce c-Met degradation (IC50 value of 244 nM), and 17-DMAG was about five folds less affective (IC50 value of 95 nM). In the MKN-45 cell line, Compound 226 induced the degradation of c-Met (26 nM) with a greater potency than 17-AAG (202 nM IC50) and 17-DMAG (70 nM).
Example 210
Evaluation of IC50 for Cell Survival in Cells Treated with Hsp90 Inhibitors
MNK45 cell line, (DSMZ #ACC 409), which is a c-Met amplified human gastric carcinoma cell line, was obtained from the Deutsche Sammlung von Mikroorganismen and Zellkulturen GmbH (DSMZ; Braunschweig, Germany). Growth of this tumor cell line is dependent upon the expression of an amplified c-Met locus (G. A. Smolen et al., Proc. Natl. Acad. Sci. USA 103:2316-2321, 2006). MNK45 cells (20,000 cells/well) were cultured in 96-well plates and maintained at 37° C. for several hours. The cells were incubated at 37° C. for 72 hours with various concentrations of compound 226 of the invention, 17AAG, or DMAG. 17AAG and 17DMAG are Hsp90 inhibitors that are currently in clinical trials and are used here as positive controls for Hsp90 inhibition. Cell survival was measured with Cell Counting Kit-8 (Dojindo Laboratories, Cat # CK04). As can be seen from FIG. 6, compound 226 of the invention had a lower IC50 for cell survival than either 17AAG or DMAG. The IC50 values are shown in the table below:














Compound
IC50 (μM)









17AAG
0.045



DMAG
0.014



Compound 226
0.008










Example 211
Compound 49 Displays Anti-Tumor Activity Against the Human Tumor Cell Line MDA-MB-435S in a Nude Mouse Xenograft Model
The human tumor cell line, MDA-MB-435S (ATCC #HTB-129; G. Ellison, et al., Mol. Pathol. 55:294-299, 2002), was obtained from the American Type Culture Collection (Manassas, Va., USA). The cell line was cultured in growth media prepared from 50% Dulbecco's Modified Eagle Medium (high glucose), 50% RPMI Media 1640, 10% fetal bovine serum (FBS), 1% 100× L-glutamine, 1% 100× Penicillin-Streptomycin, 1% 100× sodium pyruvate and 1% 100× MEM non-essential amino acids. FBS was obtained from Sigma-Aldrich Corp. (St. Louis, Mo., USA), and all other reagents were obtained from Invitrogen Corp. (Carlsbad, Calif., USA). Approximately 4-5×10(6) cells that had been cryopreserved in liquid nitrogen were rapidly thawed at 37° C. and transferred to a 175 cm2 tissue culture flask containing 50 ml of growth media and then incubated at 37° C. in a 5% CO2 incubator. The growth media was replaced every 2-3 days until the flask became 90% confluent, typically in 5-7 days. To passage and expand the cell line, a 90% confluent flask was washed with 10 ml of room temperature phosphate buffered saline (PBS) and the cells were disassociated by adding 5 ml 1× Trypsin-EDTA (Invitrogen) and incubating at 37° C. until the cells detached from the surface of the flask. To inactivate the trypsin, 5 ml of growth media was added and then the contents of the flask were centrifuged to pellet the cells. The supernatant was aspirated and the cell pellet was resuspended in 10 ml of growth media and the cell number determined using a hemocytometer. Approximately 1-3×10(6) cells per flask were seeded into 175 cm2 flasks containing 50 ml of growth media and incubated at 37° C. in a 5% CO2 incubator. When the flasks reached 90% confluence, the above passaging process was repeated until sufficient cells had been obtained for implantation into mice.
Six to eight week old, female Crl:CD-1-nuBR (nude) mice were obtained from Charles River Laboratories (Wilmington, Mass., USA). Animals were housed 4-5/cage in micro-isolators, with a 12 hr/12 hr light/dark cycle, acclimated for at least 1 week prior to use and fed normal laboratory chow ad libitum. Studies were conducted on animals between 7 and 12 weeks of age at implantation. To implant tumor cells into nude mice, the cells were trypsinized as above, washed in PBS and resusupended at a concentration of 50×10(6) cells/ml in PBS. Using a 27 gauge needle and 1 cc syringe, 0.1 ml of the cell suspension was injected into the corpus adiposum of nude mice. The corpus adiposum is a fat body located in the ventral abdominal vicera in the right quadrant of the abdomen at the juncture of the os coxae (pelvic bone) and the os femoris (femur). Tumors were then permitted to develop in vivo until they reached approximately 150 mm3 in volume, which typically required 2-3 weeks following implantation. Tumor volumes (V) were calculated by caliper measurement of the width (W), length (L) and thickness (T) of tumors using the following formula: V=0.5326×(L×W×T) Animals were randomized into treatment groups so that the average tumor volumes of each group were similar at the start of dosing.
Sock solutions of test compounds were prepared by dissolving the appropriate amounts of each compound in dimethyl sulfoxide (DMSO) by sonication in an ultrasonic water bath. Stock solutions were prepared at the start of the study, stored at −20° C. and diluted fresh each day for dosing. A solution of 20% Cremophore RH40 (polyoxyl 40 hydrogenated castor oil; BASF Corp., Aktiengesellschaft, Ludwigshafen, Germany) in 80% D5W (5% dextrose in water; Abbott Laboratories, North Chicago, Ill., USA) was also prepared by first heating 100% Cremophore RH40 at 50-60° C. until liquefied and clear, diluting 1:5 with 100% D5W, reheating again until clear and then mixing well. This solution was stored at room temperature for up to 3 months prior to use. To prepare formulations for daily dosing, DMSO stock solutions were diluted 1:10 with 20% Cremophore RH40. The final formulation for dosing contained 10% DMSO, 18% Cremophore RH40, 3.6% dextrose and 68.4% water and the appropriate amount of test article. Animals were intraperitoneal (IP) injected with this solution at 10 ml per kg body weight on a schedule of 5 days per week (Monday thru Friday, with no dosing on Saturday and Sunday) for 3 weeks.
As shown in FIG. 4, treatment with 300 mg/kg body weight of Compound 49 decreased the growth rate of MDA-MB-435S cells in nude mice to a greater extent than did a dose of 100 mg/kg body weight of the Hsp90 inhibitor 17-AAG. This effect was not associated with significant toxicity, as shown by the lack of an effect on body weights (FIG. 5).
Example 212
Compound #226 Displays Anti-Tumor Activity Against Human Tumor Cells Having an Amplified c-MET Locus in a Mouse Xenograft Model
The human gastric carcinoma cell line, MKN-45 (DSMZ #ACC 409), was obtained from the Deutsche Sammlung von Mikroorganismen and Zellkulturen GmbH (DSMZ; Braunschweig, Germany). Growth of this tumor cell line is dependent upon the expression of an amplified c-Met locus (G. A. Smolen et al., Proc. Natl. Acad. Sci. USA 103:2316-2321, 2006). The cells were cultured in growth media prepared with RPMI Media 1640 (high glucose), 20% fetal bovine serum (FBS), 1% 100× Penicillin-Streptomycin, 1% 100× sodium pyruvate and 1% 100× MEM non-essential amino acids. FBS was obtained from ATCC and all other reagents were obtained from Invitrogen Corp. (Carlsbad, Calif., USA). Cells that had been cryopreserved in liquid nitrogen were rapidly thawed at 37° C. and transferred to a tissue culture flask containing growth media and then incubated at 37° C. in a 5% CO2 incubator. To expand the cell line, growth media was replaced every 2-3 days until the flask became 90% confluent, typically in 5-10 days. Cultures were passaged by washing with 10 mL of room temperature phosphate buffered saline (PBS) and then disassociating cells by adding 5 mL 1× trypsin-EDTA and incubating at 37° C. until the cells detached from the surface of the flask. To inactivate the trypsin, 5 mL of growth media was added and then the contents of the flask were centrifuged to pellet the cells. The supernatant was aspirated and the cell pellet was resuspended in 10 mL of growth media and the cell number determined using a hemocytometer. Approximately 3-6×10(6) cells per flask were seeded into 175 cm2 flasks containing 50 mL of growth media and incubated at 37° C. in a 5% CO2 incubator. When the flasks reached 90% confluence, the above passaging process was repeated until sufficient cells had been obtained for implantation into mice.
Seven to eight week old, female Crl:CD-1-Foxn1nu (nude) mice were obtained from Charles River Laboratories (Wilmington, Mass., USA) Animals were housed 4-5/cage in micro-isolators, with a 12 hr/12 hr light/dark cycle, acclimated for at least 1 week prior to use and fed normal laboratory chow ad libitum. Animals were between 18 and 19 weeks of age at implantation. To implant MKN-45 tumor cells into nude mice, cell cultures were trypsinized as above, washed in PBS and resusupended at a concentration of  ̃5-10×10(7) cells/mL in 50% non-supplemented RPMI Media 1640 (high glucose) and 50% Matrigel Basement Membrane Matrix (#354234; BD Biosciences; Bedford, Mass., USA). Using a 27 gauge needle and 1 cc syringe, 0.1 mL of the cell suspension was injected subcutaneously into the flanks of nude mice.
Tumors were then permitted to develop in vivo until the majority reached 100-200 mm3 in tumor volume, which required  ̃2 weeks following implantation. Animals with oblong, very small or large tumors were discarded and only animals carrying tumors that displayed consistent growth rates were selected for studies. Tumor volumes (V) were calculated by caliper measurement of the width (W), length (L) and thickness (T) of tumors using the following formula: V=0.5236×(L×W×T). Animals were randomized into treatment groups so that the average tumor volumes of each group were similar at the start of dosing. % T/C values, as a measure of efficacy, were determined as follows:

    
    
        (i) If ΔT>0: % T/C=(ΔT/ΔC)×100
        (ii) If ΔT<0: % T/C=(ΔT/T0)×100
        (iii) ΔT=Change in average tumor volume between start of dosing and the end of study.
        (iv) ΔC=Change in average tumor volume between start of dosing and the end of study.
        (v) T0=Average tumor volume at start of dosing.
    
    


To formulate Compound #226 in DRD, stock solutions of the test article were prepared by dissolving the appropriate amounts of the compound in dimethyl sulfoxide (DMSO) by sonication in an ultrasonic water bath. Stock solutions were prepared weekly, stored at −20° C. and diluted fresh each day for dosing. A solution of 20% Cremophore RH40 (polyoxyl 40 hydrogenated castor oil; BASF Corp., Aktiengesellschaft, Ludwigshafen, Germany) in 5% dextrose in water (Abbott Laboratories, North Chicago, Ill., USA) was also prepared by first heating 100% Cremophore RH40 at 50-60° C. until liquefied and clear, diluting 1:5 with 100% D5W, reheating again until clear and then mixing well. This solution can be stored at room temperature for up to 3 months prior to use. To prepare DRD formulations for daily dosing, DMSO stock solutions were diluted 1:10 with 20% Cremophore RH40. The final DRD formulation for dosing contained 10% DMSO, 18% Cremophore RH40, 3.6% dextrose, 68.4% water and the appropriate amount of test article. Animals were intravenously (i.v.) injected with this formulation at 10 mL per kg body weight on three days each week (Monday, Wednesday, Friday) for a total of 9 doses.
As shown in FIG. 7, treatment 3 times per week with a dose of 50 mg/kg body weight of Compound #226 substantially decreased the growth rate of MKN-45 cells in nude mice, with a % T/C value of 8. This effect was not associated with excessive toxicity, as dose group treated with 50 mg/kg Compound #226 had an average body weight loss of −3.5% (+/−0.8 SEM) over the course of the study.
All publications, patent applications, patents, and other documents cited herein are incorporated by reference in their entirety. In case of conflict, the present specification, including definitions, will control. In addition, the materials, methods, and examples are illustrative only and not intended to be limiting.

## Claims

1. A method of treating a c-Met associated cancer in a subject, comprising administering to the subject an effective amount of a compound represented by formula (XVIII):



or a tautomer or pharmaceutically acceptable salt thereof, wherein:
R1 is —OH, —SH, —NR7H, —OR26, —SR26, —NHR26, —O(CH2)mOH, —O(CH2)mSH, —O(CH2)mNR7H, —S(CH2)mOH, —S(CH2)mSH, —S(CH2)mNR7H, —OC(O)NR10R11, —SC(O)NR10R11, —NR7C(O)NR10R11, —OC(O)R7, —SC(O)R7, —NR7C(O)R7, —OC(O)OR7, —SC(O)OR7, —NR7C(O)OR7, —OCH2C(O)R7, —SCH2C(O)R7, —NR7CH2C(O)R7, —OCH2C(O)OR7, —SCH2C(O)OR7, —NR7CH2C(O)OR7, —OCH2C(O)NR10R11, —SCH2C(O)NR10R11, —NR7CH2C(O)NR10R11, —OS(O)pR7, —SS(O)pR7, —S(O)pOR7, —NR7S(O)pR7, —OS(O)pNR10R11, —SS(O)pNR10R11, —NR7S(O)pNR10R11, —OS(O)pOR7, —SS(O)pOR7, —NR7S(O)pOR7, —OC(S)R7, —SC(S)R7, —NR7C(S)R7, —OC(S)OR7, —SC(S)OR7, —NR7C(S)OR7, —OC(S)NR10R11, —SC(S)NR10R11, —NR7C(S)NR10R11, —OC(NR8)R7, —SC(NR8)R7, —NR7C(NR8)R7, —OC(NR8)OR7, —SC(NR8)OR7, —NR7C(NR8)OR7, —OC(NR8)NR10R11, —SC(NR8)NR10R11, —NR7C(NR8)NR10R11, —OP(O)(OR7)2, or —SP(O)(OR7)2;
R3 is —OH, —SH, —NR7H, —OR26, —SR26, —NHR26, —O(CH2)mOH, —O(CH2)mSH, —O(CH2)mNR7H, —S(CH2)mOH, —S(CH2)mSH, —S(CH2)mNR7H, —OC(O)NR10R11, —SC(O)NR10R11, —NR7C(O)NR10R11, —OC(O)R7, —SC(O)R7, —NR7C(O)R7, —OC(O)OR7, —SC(O)OR7, —NR7C(O)OR7, —OCH2C(O)R7, —SCH2C(O)R7, —NR7CH2C(O)R7, —OCH2C(O)OR7, —SCH2C(O)OR7, —NR7CH2C(O)OR7, —OCH2C(O)NR10R11, —SCH2C(O)NR10R11, —NR7CH2C(O)NR10R11, —OS(O)pR7, —SS(O)pR7, —S(O)pOR7, —NR7S(O)pR7, —OS(O)pNR10R11, —SS(O)pNR10R11, —NR7S(O)pNR10R11, —OS(O)pOR7, —SS(O)pOR7, —NR7S(O)pOR7, —NR7S(O)pR7, —OS(O)pNR10R11, —SS(O)pNR10R11, —NR7S(O)pNR10R11, —OS(O)pOR7, —SS(O)pOR7, —NR7S(O)pOR7, —OC(S)R7, —SC(S)R7, —NR7C(S)R7, —OC(S)OR7, —SC(S)OR7, —NR7C(S)OR7, —OC(S)NR10R11, —SC(S)NR10R11, —NR7C(S)NR10R11, —OC(NR8)R7, —SC(NR8)R7, —NR7C(NR8)R7, —OC(NR8)OR7, —SC(NR8)OR7, —NR7C(NR8)OR7, —OC(NR8)NR10R11, —SC(NR8)NR10R11, —NR7C(NR8)NR10R11, —C(O)OH, —C(O)NHR8, —C(O)SH, —S(O)OH, —S(O)2OH, —S(O)NHR8, —S(O)2NHR8, —OP(O)(OR7)2, or —SP(O)(OR7)2;
R2 is a substituted phenyl, wherein the phenyl group is substituted with:
i) one substituent selected from nitro, cyano, a haloalkoxy, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, an optionally substituted heteraralkyl, hydroxylalkyl, alkoxyalkyl, guanadino, —NR10R11, —O—R20, —C(O)R7, —C(O)OR20, —OC(O)R7, —C(O)NR10R11, —NR8C(O)R7, —SR7, —S(O)pR7, —OS(O)pR7, —S(O)pOR7, —NR8S(O)pR7, or —S(O)pNR10R11, or
ii) two to five substituents selected from the group consisting of an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, an optionally substituted heteraralkyl, hydroxyalkyl, alkoxyalkyl, —F, —Br, —I, cyano, nitro, guanadino, a haloalkyl, a heteroalkyl, —NR10R11, —OR7, —C(O)R7, —C(O)OR7, —OC(O)R7, —C(O)NR10R11, —NR8C(O)R7, —SR7, —S(O)pR7, —OS(O)pR7, —S(O)pOR7, —NR8S(O)pR7, or —S(O)pNR10R11; and
R6, for each occurrence, is independently a substituent selected from the group consisting of an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, an optionally substituted heteraralkyl, halo, cyano, nitro, guanadino, a haloalkyl, a heteroalkyl, —NR10R11, —OR7, —C(O)R7, —C(O)OR7, —OC(O)R7, —C(O)NR10R11, —NR8C(O)R7, —SR7, —S(O)pR7, —OS(O)pR7, —S(O)pOR7, —NR8S(O)pR7, or —S(O)pNR10R11;
R7 and R8, for each occurrence, are, independently, —H, an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, or an optionally substituted heteraralkyl;
R10 and R11, for each occurrence, are independently —H, an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, or an optionally substituted heteraralkyl; or R10 and R11, taken together with the nitrogen to which they are attached, form an optionally substituted heterocyclyl or an optionally substituted heteroaryl;
R20, for each occurrence, is independently an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, or an optionally substituted heteraralkyl;
R26 is a lower alkyl;
p, for each occurrence, is, independently, 0, 1 or 2;
n is zero of an interger from 1 to 4; and
m, for each occurrence, is independently, 1, 2, 3, or 4,
wherein the c-Met associated cancer has developed a resistance to treatment with a tyrosine kinase inhibitor.

2. The method of claim 1, wherein the tyrosine kinase inhibitor inhibits the kinase activity of c-Met.

3. The method of claim 1, wherein the tyrosine kinase inhibitor does not substantially inhibit the kinase activity of c-Met.

4. A method of treating a c-Met associated cancer in a subject, comprising administering to the subject an effective amount of a compound represented by formula (XVIII):



or a tautomer or pharmaceutically acceptable salt thereof, wherein:
R1 is —OH, —SH, —NR7H, —OR26, —SR26, —NHR26, —O(CH2)mOH, —O(CH2)mSH, —O(CH2)mNR7H, —S(CH2)mOH, —S(CH2)mSH, —S(CH2)mNR7H, —OC(O)NR10R11, —SC(O)NR10R11, —NR7C(O)NR10R11, —OC(O)R7, —SC(O)R7, —NR7C(O)R7, —OC(O)OR7, —SC(O)OR7, —NR7C(O)OR7, —OCH2C(O)R7, —SCH2C(O)R7, —NR7CH2C(O)R7, —OCH2C(O)OR7, —SCH2C(O)OR7, —NR7CH2C(O)OR7, —OCH2C(O)NR10R11, —SCH2C(O)NR10R11, —NR7CH2C(O)NR10R11, —OS(O)pR7, —SS(O)pR7, —S(O)pOR7, —NR7S(O)pR7, —OS(O)pNR10R11, —SS(O)pNR10R11, —NR7S(O)pNR10R11, —OS(O)pOR7, —SS(O)pOR7, —NR7S(O)pOR7, —OC(S)R7, —SC(S)R7, —NR7C(S)R7, —OC(S)OR7, —SC(S)OR7, —NR7C(S)OR7, —OC(S)NR10R11, —SC(S)NR10R11, —NR7C(S)NR10R11, —OC(NR8)R7, —SC(NR8)R7, —NR7C(NR8)R7, —OC(NR8)OR7, —SC(NR8)OR7, —NR7C(NR8)OR7, —OC(NR8)NR10R11, —SC(NR8)NR10R11, —NR7C(NR8)NR10R11, —OP(O)(OR7)2, or —SP(O)(OR7)2;
R3 is —OH, —SH, —NR7H, —OR26, —SR26, —NHR26, —O(CH2)mOH, —O(CH2)mSH, —O(CH2)mNR7H, —S(CH2)mOH, —S(CH2)mSH, —S(CH2)mNR7H, —OC(O)NR10R11, —SC(O)NR10R11, —NR7C(O)NR10R11, —OC(O)R7, —SC(O)R7, —NR7C(O)R7, —OC(O)OR7, —SC(O)OR7, —NR7C(O)OR7, —OCH2C(O)R7, —SCH2C(O)R7, —NR7CH2C(O)R7, —OCH2C(O)OR7, —SCH2C(O)OR7, —NR7CH2C(O)OR7, —OCH2C(O)NR10R11, —SCH2C(O)NR10R11, —NR7CH2C(O)NR10R11, —OS(O)pR7, —SS(O)pR7, —S(O)pOR7, —NR7S(O)pR7, —OS(O)pNR10R11, —SS(O)pNR10R11, —NR7S(O)pNR10R11, —OS(O)pOR7, —SS(O)pOR7, —NR7S(O)pOR7, —NR7S(O)pR7, —OS(O)pNR10R11, —SS(O)pNR10R11, —NR7S(O)pNR10R11, —OS(O)pOR7, —SS(O)pOR7, —NR7S(O)pOR7, —OC(S)R7, —SC(S)R7, —NR7C(S)R7, —OC(S)OR7, —SC(S)OR7, —NR7C(S)OR7, —OC(S)NR10R11, —SC(S)NR10R11, —NR7C(S)NR10R11, —OC(NR8)R7, —SC(NR8)R7, —NR7C(NR8)R7, —OC(NR8)OR7, —SC(NR8)OR7, —NR7C(NR8)OR7, —OC(NR8)NR10R11, —SC(NR8)NR10R11, —NR7C(NR8)NR10R11, —C(O)OH, —C(O)NHR8, —C(O)SH, —S(O)OH, —S(O)2OH, —S(O)NHR8, —S(O)2NHR8, —OP(O)(OR7)2, or —SP(O)(OR7)2;
R2 is a substituted phenyl, wherein the phenyl group is substituted with:
i) one substituent selected from nitro, cyano, a haloalkoxy, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, an optionally substituted heteraralkyl, hydroxylalkyl, alkoxyalkyl, guanadino, —NR10R11, —O—R20, —C(O)R7, —C(O)OR20, —OC(O)R7, —C(O)NR10R11, —NR8C(O)R7, —SR7, —S(O)pR7, —OS(O)pR7, —S(O)pOR7, —NR8S(O)pR7, or —S(O)pNR10R11, or
ii) two to five substituents selected from the group consisting of an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, an optionally substituted heteraralkyl, hydroxyalkyl, alkoxyalkyl, —F, —Br, —I, cyano, nitro, guanadino, a haloalkyl, a heteroalkyl, —NR10R11, —OR7, —C(O)R7, —C(O)OR7, —OC(O)R7, —C(O)NR10R11, —NR8C(O)R7, —SR7, —S(O)pR7, —OS(O)pR7, —S(O)pOR7, —NR8S(O)pR7, or —S(O)pNR10R11; and
R6 , for each occurrence, is independently a substituent selected from the group consisting of an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, an optionally substituted heteraralkyl, halo, cyano, nitro, guanadino, a haloalkyl, a heteroalkyl, —NR10R11, —OR7, —C(O)R7, —C(O)OR7, —OC(O)R7, —C(O)NR10R11, —NR8C(O)R7, —SR7, —S(O)pR7, —OS(O)pR7, —S(O)pOR7, —NR8S(O)pR7, or —S(O)pNR10R11; and
R7 and R8, for each occurrence, are, independently, —H, an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, or an optionally substituted heteraralkyl;
R10 and R11, for each occurrence, are independently —H, an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, or an optionally substituted heteraralkyl; or R10 and R11, taken together with the nitrogen to which they are attached, form an optionally substituted heterocyclyl or an optionally substituted heteroaryl;
R20, for each occurrence, is independently an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, or an optionally substituted heteraralkyl;
R26 is a lower alkyl;
p, for each occurrence, is, independently, 0, 1 or 2;
n is zero of integer from 1 to 4; and
m, for each occurrence, is independently, 1, 2, 3, or 4,
wherein the cancer has mutations or deletions in the kinase or juxtamembrane domain of c-Met, amplification of the Met gene, or overexpression of c-Met.