HK1237268B - Pyrimidine compounds and methods using the same - Google Patents

Description

Pyrimidine compounds and methods of use thereof

Statement Regarding Federally Funded Research

This invention was made with government support under Grant No. STTR 1R41G042205-01 awarded by the National Institutes of Health. The government has certain rights in this invention.

Field of the Invention

In general, the present invention relates to pyrimidine-based small molecule inhibitors of heat shock protein 90 (Hsp90) and pharmaceutical compositions thereof. The present invention also relates to methods of treating a subject suffering from a neurodegenerative disease.

Background of the Invention

Hsp90 proteins are involved in stabilizing protein conformation, maintaining the function of many cell signaling proteins, and maintaining ATPase activity. Hsp90 activity is also required for the correct folding, stabilization, activation, and localization of oncoproteins involved in tumor progression. The N-terminal ATP-binding domain is responsible for the protein's ATPase activity: this adenine nucleotide-binding pocket is highly conserved in all Hsp90 proteins, from bacteria to mammals, but is not present in other molecular chaperones.

Hsp90 proteins have emerged as important targets in cancer therapy, as many Hsp90 client proteins have themselves been identified as targets for cancer therapy. Exemplary Hsp90 client proteins associated with cancer include HER2 (breast cancer), Raf-1/mutant BRAF (melanoma), mutant EGFR (non-small cell lung cancer, glioblastoma), c-Kit (GIST), c-Met (gastric cancer, lung cancer, glioblastoma), HIF-1α (renal cancer), Zap70 (chronic lymphocytic leukemia), Bcr-Abl (chronic myeloid leukemia), mBcr-Abl (chronic myeloid leukemia), Flt-3 (acute myeloid leukemia), IGF-1R/Akt (myeloma), NMP-ALK (lymphoma), and Akt (small cell lung cancer). Overexpression of mutant Hsp90 clients or amplification of their clients (e.g., HER2) leads to increased reliance of tumor cells on Hsp90 chaperone function. Therefore, Hsp90 provides an imperative target for the treatment of different classes of tumors.

Elevated levels of Hsp90 are also implicated in neurodegenerative disorders, including Alzheimer's disease, Parkinson's disease, Huntington's disease, and tauopathies. Tauopathies are neurodegenerative diseases characterized by abnormal tau protein production, which in turn leads to the accumulation of hyperphosphorylated and aggregated tau protein. It has been proposed that the pathogenic process of hyperphosphorylated tau in Alzheimer's disease is caused by abnormal activation of kinases, particularly cdk5 and GSKβ3. Studies have shown that Hsp90 stabilizes p35, an activator of cdk5, leading to increased tau phosphorylation. It has also been shown that Hsp90 inhibition activates heat shock factor 1 (HSF1), which in turn increases the expression of Hsp70. Increased expression of Hsp70 promotes tau solubility and binding to microtubules, inhibits Aβ peptide aggregation, and enhances Aβ peptide degradation.

Hsp90 has also become a target for the treatment of viral, fungal and bacterial infections. For example, an Hsp90 inhibitor (geldanamycin) has been shown to slow the growth of influenza virus in cell culture. Other viruses that rely on Hsp90-dependent processes include those belonging to the following families: Herpesviridae (e.g., herpes simplex virus-1, herpes simplex virus-2, herpes virus-5, Kaposi's sarcoma-associated herpes virus, varicella-zoster virus or Epstein-Barr virus), Polyomaviridae (e.g., SV40), Poxviridae (e.g., vaccinia virus), Reoviridae (e.g., rotavirus), Biviridae (e.g., infectious bursal disease virus), Picornaviridae (e.g., poliovirus, rhinovirus or coxsackievirus), Flaviviridae (e.g., hepatitis C virus or [0013] In some embodiments, Hsp90 inhibitors are used to treat fungal infections in vivo, such as Candida albicans, Aspergillus fumigatus, or Pneumocystis jiroveci. In some embodiments, Hsp90 inhibitors are used to treat fungal infections in vivo, such as Candida albicans, Aspergillus fumigatus, or Pneumocystis jiroveci. In addition, Hsp90 inhibitors are used to treat bacterial infections, such as mycobacterial disease, anthrax, or bacterial pneumonia.

In view of the above, inhibitors of Hsp90 represent beneficial therapeutic agents for the treatment of diseases, such as cancer, neurodegenerative diseases, and infectious diseases.

SUMMARY OF THE INVENTION

In one aspect, the invention features a compound according to formula (I):

or a pharmaceutically acceptable salt thereof,

in

Z ¹ is -OR ⁷ , -N(R ¹⁰ )R ⁷ , -SR ⁷ , or -C(R ¹⁰ )(R ¹¹ )R ⁷ ;

Z ² is -N= or -C(R ³ )=;

Each R ¹ and R ² is independently H or optionally substituted C _1-3 alkyl (e.g., C _1-3 acyl);

R ³ is H, halogen, cyano, optionally substituted C _1-6 alkyl, optionally substituted C _1-3 alkoxy, or optionally substituted amino, and R ⁴ is halogen, cyano, optionally substituted C _1-6 alkyl, optionally substituted C _1-3 alkoxy, optionally substituted amino, optionally substituted C _1-6 thioalkoxy, or optionally substituted C _6-10 aryl, or R ³ and R ^4, together with the atoms to which they are attached, join to form an optionally substituted five- or six-membered ring optionally including 1 to 3 heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur, wherein the nitrogen is optionally substituted with R ⁹ ;

Each R ⁵ and R ⁶ is independently H, optionally substituted C _1-3 alkyl, optionally substituted C _1-3 alkoxy, halogen or CN;

R ⁷ is optionally substituted C _1-3 alkyl, optionally substituted C _1-3 alkoxycycloalkyl, optionally substituted C _1-3 alkheterocyclyl, or optionally substituted C _1-3 alkaryl, and R ⁸ is H; or R ⁷ and R ^8, together with the atoms to which they are attached, are joined to form an optionally substituted five-, six-, or seven-membered ring, which optionally includes one or two heteroatoms selected from nitrogen, oxygen, and sulfur;

R ⁹ is H, optionally substituted C _1-3 alkyl, optionally substituted C _3-8 cycloalkyl, optionally substituted C _6-10 aryl, optionally substituted C _2-9 heteroaryl, optionally substituted C _{2-9 heterocyclyl, optionally substituted C 1-3 alkoxycycloalkyl, optionally substituted C 1-3 alkheterocyclyl ,} or optionally substituted C _1-3 alkaryl;

R ¹⁰ is H, optionally substituted C _1-3 alkyl, optionally substituted C _3-8 cycloalkyl, optionally substituted C _6-10 aryl, optionally substituted C _2-9 heteroaryl, optionally substituted C _2-9 heterocyclyl, optionally substituted C 1-3 alkoxycycloalkyl, optionally substituted C _1-3 alkheterocyclyl, or optionally substituted C _1-3 alkaryl, and _R ¹¹ is H, optionally substituted C _1-3 alkyl, or R ¹⁰ and R ¹¹ combine to form ═O or ═S; and

R ^m is H, halogen, cyano, optionally substituted C _1-4 alkyl (e.g., C _1-4 acyl), or optionally substituted C _1-3 alkoxy.

In certain embodiments of Formula (I), R ^m is H (e.g., the compound of Formula (I) has the structure:

or a pharmaceutically acceptable salt thereof).

In certain embodiments of formula (I), when Z ² is CR ³ , each of R ¹ and R ² is H, R ³ is H, R ⁴ is methyl or halogen (eg, chlorine), and each of R ⁵ and R ⁶ is halogen (eg, chlorine),

^Z1 is not methoxy.

In certain embodiments of formula (I), when Z ² is CR ³ , R ³ is H, R ⁴ is methyl or halogen (eg, chlorine), and each of R ⁵ and R ⁶ is halogen (eg, chlorine),

Z ² is not unsubstituted C _1-3 alkoxy.

In certain embodiments of formula (I), when Z ² is N, R ³ is H, R ⁴ is optionally substituted C _1-6 thioalkoxy, and each of R ⁵ and R ⁶ is halogen (eg, chlorine),

Z ¹ is not cyanomethoxy or aminomethoxy.

In other embodiments of formula (I), when Z ² is N, R ³ is H, each of R ⁵ and R ⁶ is halogen (eg, chlorine), and R ⁴ is substituted C _1-6 thioalkoxy,

Z ¹ is not cyanomethoxy or aminomethoxy.

In some embodiments of formula (I), when Z ² is N, R ³ is H, and R ⁴ is optionally substituted C _1-6 thioalkoxy,

Z ¹ is not cyanomethoxy or aminomethoxy.

In certain embodiments of formula (I), when Z ² is N, R ³ is H, and R ⁴ is substituted C _1-6 thioalkoxy,

Z ¹ is not cyanomethoxy or aminomethoxy.

In further embodiments of formula (I), when Z ² is N, R ³ is H, and R ⁴ is substituted C _1-6 thioalkoxy,

Z ¹ is not a substituted C ₁ alkoxy group.

In a specific embodiment of formula (I), when Z ² is N, R ³ is H, and R ⁴ is a substituted C _1-6 thioalkoxy group,

Z ¹ is -OR ⁷ , -N(R ⁷ )R ¹⁰ , -SR ⁷ , or -C(R ⁷ )(R ¹⁰ )R ¹¹ , wherein R ⁷ is methyl, dialkylaminoethyl, optionally substituted C _1-3 alkylcycloalkyl, optionally substituted C _1-3 alkylheterocyclyl, or optionally substituted C _1-3 alkylaryl, or R ⁷ and R ^8, together with the atoms to which they are attached, join to form an optionally substituted five- or six-membered ring optionally including one or two heteroatoms selected from nitrogen, oxygen, and sulfur.

In other embodiments of formula (I), when Z ² is CR ³ , each of R ⁵ and R ⁶ is chlorine, R ³ is H, and R ⁴ is halogen (eg, chlorine),

Z ¹ is not 2-amino-2-oxoethoxy, 2-(N,N-diethylamino)ethoxy, methoxy, or benzyloxy.

In still other embodiments of Formula (I), when Z ² is CR ³ , R ³ is H, and R ⁴ is halogen (eg, chlorine),

Z ¹ is not 2-amino-2-oxoethoxy, 2-(N,N-diethylamino)ethoxy, methoxy, or benzyloxy.

In still other embodiments of Formula (I), when Z ² is CR ³ , each of R ⁵ and R ⁶ is chlorine, R ³ is H, and R ⁴ is halogen (e.g., chlorine),

Z ¹ is -OR ⁷ , -N(R ⁷ )R ¹⁰ , -SR ⁷ , or -C(R ⁷ )(R ¹⁰ )R ¹¹ , wherein R ⁷ is dimethylaminoethyl, optionally substituted C _1-3 alkanecycloalkyl, or optionally substituted C _1-3 alkehterocyclyl, or R ⁷ and R ^8, together with the atoms to which they are attached, are joined to form an optionally substituted five- or six-membered ring optionally including one or two heteroatoms selected from nitrogen, oxygen, and sulfur.

In further embodiments of formula (I), when Z ² is CR ³ , each of R ⁵ and R ⁶ is chlorine, R ³ is H, and R ⁴ is halogen (eg, chlorine),

Z ¹ is -OR ⁷ , -N(R ⁷ )R ¹⁰ , -SR ⁷ , or -C(R ⁷ )(R ¹⁰ )R ¹¹ , wherein R ⁷ is optionally substituted C _1-3 alkoxycycloalkyl, or optionally substituted C _1-3 alkoxyheterocyclyl, or R ⁷ and R ⁸ are joined together with the atoms to which they are attached to form an optionally substituted five- or six-membered ring optionally including one or two heteroatoms selected from nitrogen, oxygen, and sulfur.

In particular embodiments of formula (I), when Z ² is CR ³ , R ³ is H, and R ⁴ is halogen (eg, chlorine),

Z ¹ is -OR ⁷ , -N(R ⁷ )R ¹⁰ , -SR ⁷ , or -C(R ⁷ )(R ¹⁰ )R ¹¹ , wherein R ⁷ is optionally substituted C _1-3 alkoxycycloalkyl, or optionally substituted C _1-3 alkoxyheterocyclyl, or R ⁷ and R ⁸ are joined together with the atoms to which they are attached to form an optionally substituted five- or six-membered ring optionally including one or two heteroatoms selected from nitrogen, oxygen, and sulfur.

In some embodiments of formula (I), when R ⁵ is chloro, R ⁶ is bromo, Z ¹ is -OR ⁷ , Z ² is CR ³ , and R ³ and R ⁴ combine to form a group according to formula (IIa):

R ⁷ is not methyl, ethyl, n-propyl, 2-(N-pyrazolyl)ethyl, 2-(N-imidazolyl)ethyl, 3-hydroxypropyl, cyanomethyl, 2-chloroethyl, 2-hydroxyethyl, 2-oxopropyl, 2-(N,N-dimethylamino)ethyl, difluoromethyl or 2-(tert-butylamino)ethyl.

In certain embodiments of formula (I), when R ⁵ is chloro, R ⁶ is bromo, Z ¹ is -OR ⁷ , Z ² is CR ³ , and R ³ and R ⁴ combine to form a group according to formula (IIa),

R ⁷ is not substituted alkyl, unsubstituted alkyl, or unsubstituted C ₂ alkheteroaryl.

In some embodiments of formula (I), when R ⁵ is chloro, R ⁶ is bromo, Z ¹ is -OR ⁷ , Z ² is CR ³ , and R ³ and R ⁴ combine to form a group according to formula (IIa),

R ⁷ is not alkyl or unsubstituted C ₂ alkheteroaryl.

In particular embodiments of formula (I), when R ⁵ is chloro, R ⁶ is bromo, Z ¹ is -OR ⁷ , Z ² is CR ³ , and R ³ and R ⁴ combine to form a group according to formula (IIa),

R ⁷ is not substituted alkyl, unsubstituted alkyl, or unsubstituted C ₂ alkheterocyclyl.

In other embodiments of formula (I), when R ⁵ is chloro, R ⁶ is bromo, Z ¹ is -OR ⁷ , Z ² is CR ³ , and R ³ and R ⁴ combine to form a group according to formula (IIa),

R ⁷ is not an alkyl group or a C ₂ alkaneheterocyclic group.

In still other embodiments of formula (I), when R ⁵ is chloro, R ⁶ is bromo, Z ¹ is -OR ⁷ , Z ² is CR ³ , and R ³ and R ⁴ combine to form a group according to formula (IIa),

R ⁷ and R ⁸ are joined together with the atoms to which they are attached to form an optionally substituted five- or six-membered ring optionally including one or two heteroatoms selected from nitrogen, oxygen, and sulfur.

In still other embodiments of formula (I), when R ⁵ is chloro, R ⁶ is bromo, Z ² is CR ³ , and R ³ and R ⁴ combine to form a group according to formula (IIa),

Z is -OR ⁷ , and R ⁷ and R ⁸ combine to form -CH ₂ -CH ₂ -.

In some embodiments of formula (I), when each R ⁵ and R ⁶ is bromo, Z ¹ is -OR ⁷ , Z ² is CR ³ , and R ³ and R ⁴ combine to form a group according to formula (IIa),

R ⁷ is not methyl.

In specific embodiments of formula (I), when each of R ⁵ and R ⁶ is chloro, Z ¹ is -OR ⁷ , Z ² is CR ³ , and R ³ and R ⁴ combine to form a group according to formula (IIa),

R is not ^methyl , 2-(N-imidazolyl)ethyl, methoxymethyl, 2-(N-pyrazolyl)ethyl, 2-(3-methylpyrazol-1-yl)ethyl, 2-pyridyl-methyl, 1,3-dimethyl-1H-1,2,4-triazol-5-yl-methyl, 2-pyrimidinylmethyl, imidazol-2-yl-methyl, 5-methyl-isoxazol-3-yl-methyl, 4-methyl-imidazol-5-yl-methyl, or 3-methyl-1,2,4-oxadiazol-5-yl-methyl.

In other embodiments of formula (I), when each R ⁵ and R ⁶ is chloro, Z ¹ is -OR ⁷ , Z ² is CR ³ , and R ³ and R ⁴ combine to form a group according to formula (IIa),

R ⁷ is not unsubstituted alkyl, substituted alkyl, unsubstituted alkheteroaryl, or substituted alkheteroaryl.

In other embodiments of formula (I), when each R ⁵ and R ⁶ is chloro, Z ¹ is -OR ⁷ , Z ² is CR ³ , and R ³ and R ⁴ combine to form a group according to formula (IIa),

R ⁷ is not unsubstituted alkyl, substituted alkyl, unsubstituted alkheterocyclyl, or substituted alkheterocyclyl.

In certain embodiments of formula (I), when each R ⁵ and R ⁶ is chloro, Z ¹ is -OR ⁷ , R ⁷ and R ⁸ combine to form -CH ₂ -CH ₂ -, Z ² is CR ³ , and R ³ and R ⁴ combine to form a group according to formula (IIa),

R ⁹ is not ethoxycarbonyl, cyclobutylaminocarbonyl, or cyclobutadienylaminocarbonyl.

In other embodiments of formula (I), when each R ⁵ and R ⁶ is chloro, Z ¹ is -OR ⁷ , R ⁷ and R ⁸ combine to form -CH ₂ -CH ₂ -, Z ² is CR ³ , and R ³ and R ⁴ combine to form a group according to formula (IIa),

^R9 is H or -C(O)-N(H)-(straight chain _C1-3 alkyl).

In specific embodiments of formula (I), when each of R ⁵ and R ⁶ is halogen, Z ² is CR ³ , and R ³ and R ⁴ combine to form a group according to formula (IIa),

Z is -OR ⁷ , R ⁷ is not methyl or 2-chloroethyl, and R ⁹ is H or -C(O)-N(H)-(straight chain C _1-3 alkyl).

In some embodiments of formula (I), when R ⁵ is methoxy, R ⁶ is methyl, Z ¹ is -OR ⁷ , Z ² is CR ³ , and R ³ and R ⁴ combine to form a group according to formula (IIa),

R ⁷ is not methyl.

In certain embodiments of formula (I), when R ⁵ is chloro, R ⁶ is ethyl, Z ¹ is -OR ⁷ , Z ² is CR ³ , and R ³ and R ⁴ combine to form a group according to formula (IIa),

R ⁷ is not methyl.

In some embodiments of formula (I), when each R ⁵ and R ⁶ is chloro, Z ¹ is -OR ⁷ , Z ² is CR ³ , and R ³ and R ⁴ combine to form a group according to formula (IIb) or (IIc),

R ⁷ is not methyl or 2-(N,N-diethylamino)ethyl.

In other embodiments of formula (I), when each R ⁵ and R ⁶ is chloro, Z ¹ is -OR ⁷ , Z ² is CR ³ , and R ³ and R ⁴ combine to form a group according to formula (IIb) or (IIc),

R ⁷ and R ⁸ are joined together with the atoms to which they are attached to form an optionally substituted five- or six-membered ring optionally including one or two heteroatoms selected from nitrogen, oxygen, and sulfur.

In certain embodiments of formula (I), when each R ⁵ and R ⁶ is chloro, Z ² is CR ³ , and R ³ and R ⁴ combine to form a group according to formula (IIb) or (IIc),

Z ¹ is -OR ⁷ , and R ⁷ and R ⁸ combine to form -CH ₂ -CH ₂ -.

In some embodiments of formula (I), when R ⁷ is methyl, R ⁵ is chloro, Z ¹ is -OR ⁷ , Z ² is CR ³ , and R ³ and R ⁴ combine to form a group according to formula (IIIa),

^R6 is not bromine.

In particular embodiments of formula (I), when each R ⁵ and R ⁶ is chloro, Z ¹ is -OR ⁷ , Z ² is CR ³ , and R ³ and R ⁴ combine to form a group according to formula (IIIa),

R ⁷ is not isopropyl, 3,3,3-trifluoropropyl, or 2-(N,N-dimethylamino)ethyl.

In some embodiments of formula (I), when each R ⁵ and R ⁶ is chloro, Z ¹ is -OR ⁷ , Z ² is CR ³ , and R ³ and R ⁴ combine to form a group according to formula (IIIa),

R ⁸ is not H.

In some embodiments of formula (I), when Z ² is CR ³ and R ³ and R ⁴ combine to form a group according to formula (IIIa),

Each of ^R5 and ^R6 is chlorine, and

R ⁷ is methyl and R ⁸ is H, or R ⁷ and R ⁸ , together with the atoms to which they are attached, are joined to form an optionally substituted five- or six-membered ring optionally including one or two heteroatoms selected from nitrogen, oxygen, and sulfur.

In other embodiments of formula (I), when R ⁵ is chloro, R ⁶ is methoxy, Z ¹ is -OR ⁷ , Z ² is CR ³ , and R ³ and R ⁴ combine to form a group according to formula (IIIb):

Neither R ¹ nor R ² is 2-(N,N-diethylamino)ethyl.

In certain embodiments of formula (I), when R ⁵ is chloro, R ⁶ is methoxy, Z ¹ is -OR ⁷ , Z ² is CR ³ , and R ³ and R ⁴ combine to form a group according to formula (IIIb),

Each of ^R1 and ^R2 is H.

In some embodiments of formula (I), when each R ⁵ and R ⁶ is chloro, Z ¹ is -OR ⁷ , Z ² is CR ³ , and R ³ and R ⁴ combine to form a group according to formula (IVa):

R ⁷ is not 3-(N-morpholinyl)propyl, benzyl, 1-ethyl-pyrrolidin-3-yl, 1-methyl-piperidin-4-yl, 2-(1-methyl-pyrrolidin-2-yl)ethyl, or 3-(N,N-diethylamino)propyl.

In specific embodiments of formula (I), when each of R ⁵ and R ⁶ is chloro, Z ¹ is -OR ⁷ , Z ² is CR ³ , and R ³ and R ⁴ combine to form a group according to formula (IVa),

R ⁷ is not a substituted alkyl, heterocyclyl, alkheterocyclyl, or alkaryl group.

In some embodiments of formula (I), when each R ⁵ and R ⁶ is chloro, Z ¹ is -OR ⁷ , Z ² is CR ³ , and R ³ and R ⁴ combine to form a group according to formula (IVb):

c(IVb),

R ⁷ is not 2-methoxyethyl or benzyl.

In certain embodiments of formula (I), when each R ⁵ and R ⁶ is chloro, Z ¹ is -OR ⁷ , Z ² is CR ³ , and R ³ and R ⁴ combine to form a group according to formula (IVb),

R ⁷ is not a substituted alkyl or alkaryl group.

In some embodiments of formula (I), when each R ⁵ and R ⁶ is chloro, Z ¹ is -OR ⁷ , Z ² is CR ³ , and R ³ and R ⁴ combine to form a group according to formula (IVc):

R ⁷ is not 2-(N,N-diethylamino)ethyl or 3-(N,N-dimethylamino)propyl.

In other embodiments of formula (I), when each R ⁵ and R ⁶ is chloro, Z ¹ is -OR ⁷ , Z ² is CR ³ , and R ³ and R ⁴ combine to form a group according to formula (IVc),

R ⁷ is not substituted alkyl.

In particular embodiments of formula (I), when each of R ⁵ and R ⁶ is chloro, Z ¹ is -OR ⁷ , Z ² is CR ³ , and R ³ and R ⁴ combine to form a group according to formula (IVd):

R ⁷ is not 2-(pyrrolidin-1-yl)ethyl or 2-hydroxyethyl.

In certain embodiments of formula (I), when each R ⁵ and R ⁶ is chloro, Z ¹ is -OR ⁷ , Z ² is CR ³ , and R ³ and R ⁴ combine to form a group according to formula (IVd),

R ⁷ is not a substituted alkyl group or an alkaneheterocyclic group.

In some embodiments of formula (I), when each R ⁵ and R ⁶ is chloro, Z ¹ is -OR ⁷ , Z ² is CR ³ , and R ³ and R ⁴ combine to form a group according to formula (IVe) or (IVf):

R ⁷ is not benzyl.

In other embodiments of formula (I), when each R ⁵ and R ⁶ is chloro, Z ¹ is -OR ⁷ , Z ² is CR ³ , and R ³ and R ⁴ combine to form a group according to formula (IVe) or (IVf):

R ⁷ is not an alkaryl group.

In certain embodiments of formula (I), when R ⁵ is chloro, R ⁶ is bromo, Z ¹ is -OR ⁷ , Z ² is CR ³ , and R ³ and R ⁴ combine to form a group according to formula (IVg), (IVh), (IVi), (IVj), or (IVk):

R ⁷ is not methyl.

In certain embodiments of formula (I), when R ⁵ is chloro, R ⁶ is bromo, Z ¹ is -OR ⁷ , Z ² is CR ³ , and R ³ and R ⁴ combine to form a group according to formula (IVg), (IVh), (IVi), (IVj), or (IVk),

^R7 is not an alkyl group.

In some embodiments of formula (I), when R ⁵ is chloro, R ⁶ is bromo, Z ¹ is -OR ⁷ , Z ² is CR ³ , and R ³ and R ⁴ combine to form a group according to formula (IVg), (IVh), (IVi), (IVj), or (IVk),

R ⁷ and R ⁸ are joined together with the atoms to which they are attached to form an optionally substituted five- or six-membered ring optionally including one or two heteroatoms selected from nitrogen, oxygen, and sulfur.

In a specific embodiment of formula (I), when R ⁵ is chloro, R ⁶ is bromo, Z ¹ is -OR ⁷ , and Z ² is CR ³ ,

R ³ and R ⁴ do not combine to form a group according to Formula (IVg), (IVh), (IVi), (IVj), or (IVk).

In a specific embodiment of formula (I), when R ⁶ is methyl,

Each of ^R1 and ^R2 is H.

In certain embodiments of formula (I), when R ³ is H, and each of R ⁵ and R ⁶ is chloro,

R ⁷ is not methyl.

In a specific embodiment, the compound is according to formula (Ia):

or a pharmaceutically acceptable salt thereof,

in

Z ¹ is -OR ⁷ , -N(R ¹⁰ )R ⁷ , -SR ⁷ , or -C(R ¹⁰ )(R ¹¹ )R ⁷ ;

Each R ¹ and R ² is independently H or optionally substituted C _1-3 alkyl;

R ³ is H, halogen, optionally substituted C _1-3 alkyl, or optionally substituted C _1-3 alkoxy, and R ⁴ is halogen, optionally substituted C _1-3 alkyl, optionally substituted C _1-3 alkoxy, optionally substituted amino, optionally substituted C _1-6 sulfanyl, or optionally substituted C _6-10 aryl, or R ³ and R ^4, together with the atoms to which they are attached, join to form an optionally substituted five-membered, six-membered, or seven-membered ring optionally including 1 to 3 heteroatoms selected from nitrogen, oxygen, and sulfur, wherein the nitrogen is optionally substituted with R ⁹ ;

Each R ⁵ and R ⁶ is independently H, optionally substituted C _1-3 alkyl, optionally substituted C _1-3 alkoxy, halogen or CN;

R ⁷ is optionally substituted C _1-3 alkyl, optionally substituted C _1-3 alkoxycycloalkyl, optionally substituted C _1-3 alkheterocyclyl, or optionally substituted C _1-3 alkaryl, and R ⁸ is H; or R ⁷ and R ^8, together with the atoms to which they are attached, are joined to form an optionally substituted five-, six-, or seven-membered ring, which optionally includes one or two heteroatoms selected from nitrogen, oxygen, and sulfur;

R ⁹ is H, optionally substituted C _1-3 alkyl, optionally substituted C _3-8 cycloalkyl, optionally substituted C _6-10 aryl, optionally substituted C _2-9 heteroaryl, optionally substituted C _{2-9 heterocyclyl, optionally substituted C 1-3 alkoxycycloalkyl, optionally substituted C 1-3 alkheterocyclyl ,} or optionally substituted C _1-3 alkaryl;

R ¹⁰ is H, optionally substituted C _1-3 alkyl (e.g., optionally substituted C _1-3 acyl), optionally substituted C _3-8 cycloalkyl, optionally substituted C _6-10 aryl, optionally substituted C _2-9 heteroaryl, optionally substituted C _2-9 heterocyclyl, optionally substituted C _1-3 alkoxycycloalkyl, optionally substituted C _1-3 alkheterocyclyl, or optionally substituted C _1-3 alkaryl, and R ¹¹ is H, optionally substituted C _1-3 alkyl, or R ¹⁰ and R ¹¹ combine to form ═O or ═S.

In other embodiments, when each of R ¹ and R ² is H, R ³ is H, R ⁴ is methyl or chloro, and each of R ⁵ and R ⁶ is chloro,

^Z1 is not methoxy.

In still other embodiments, when R ³ is H, and R ⁴ is halogen (eg, chlorine),

Z ¹ is not 2-amino-2-oxoethoxy, 2-(N,N-diethylamino)ethoxy, methoxy, or benzyloxy.

In still other embodiments, when each of R ⁵ and R ⁶ is chlorine, R ³ is H, and R ⁴ is halogen (e.g., chlorine),

Z ¹ is -OR ⁷ , -N(R ⁷ )R ¹⁰ , -SR ⁷ , or -C(R ⁷ )(R ¹⁰ )R ¹¹ , wherein R ⁷ is dimethylaminoethyl, optionally substituted C _1-3 alkanecycloalkyl, or optionally substituted C _1-3 alkehterocyclyl, or R ⁷ and R ^8, together with the atoms to which they are attached, join to form an optionally substituted five- or six-membered ring optionally including one or two heteroatoms selected from nitrogen, oxygen, and sulfur.

In further embodiments, when each of R ⁵ and R ⁶ is chlorine, R ³ is H, and R ⁴ is halogen (eg, chlorine),

Z ¹ is -OR ⁷ , -N(R ⁷ )R ¹⁰ , -SR ⁷ , or -C(R ⁷ )(R ¹⁰ )R ¹¹ , wherein R ⁷ is optionally substituted C _1-3 alkoxycycloalkyl, or optionally substituted C _1-3 alkoxyheterocyclyl, or R ⁷ and R ⁸ are joined together with the atoms to which they are attached to form an optionally substituted five- or six-membered ring optionally including one or two heteroatoms selected from nitrogen, oxygen, and sulfur.

In specific embodiments, when R ³ is H and R ⁴ is halogen (eg, chlorine),

Z ¹ is -OR ⁷ , -N(R ⁷ )R ¹⁰ , -SR ⁷ , or -C(R ⁷ )(R ¹⁰ )R ¹¹ , wherein R ⁷ is optionally substituted C _1-3 alkoxycycloalkyl, or optionally substituted C _1-3 alkoxyheterocyclyl, or R ⁷ and R ⁸ are joined together with the atoms to which they are attached to form an optionally substituted five- or six-membered ring optionally including one or two heteroatoms selected from nitrogen, oxygen, and sulfur.

In some embodiments, when R ⁵ is chloro, R ⁶ is bromo, Z ¹ is -OR ⁷ , and R ³ and R ⁴ combine to form a group according to formula (IIa):

R ⁷ is not methyl, ethyl, n-propyl, 2-(N-pyrazolyl)ethyl, 2-(N-imidazolyl)ethyl, 3-hydroxypropyl, cyanomethyl, 2-chloroethyl, 2-hydroxyethyl, 2-oxopropyl, 2-(N,N-dimethylamino)ethyl, difluoromethyl or 2-(tert-butylamino)ethyl.

In certain embodiments, when R ⁵ is chloro, R ⁶ is bromo, Z ¹ is -OR ⁷ , and R ³ and R ⁴ combine to form a group according to formula (IIa),

R ⁷ is not substituted alkyl, unsubstituted alkyl, or unsubstituted C ₂ alkheteroaryl.

In some embodiments, when R ⁵ is chloro, R ⁶ is bromo, Z ¹ is -OR ⁷ , and R ³ and R ⁴ combine to form a group according to formula (IIa),

R ⁷ is not alkyl or unsubstituted C ₂ alkheteroaryl.

In a specific embodiment, when R ⁵ is chloro, R ⁶ is bromo, Z ¹ is -OR ⁷ , and R ³ and R ⁴ combine to form a group according to formula (IIa),

R ⁷ is not substituted alkyl, unsubstituted alkyl, or unsubstituted C ₂ alkheterocyclyl.

In other embodiments, when R ⁵ is chloro, R ⁶ is bromo, Z ¹ is -OR ⁷ , and R ³ and R ⁴ combine to form a group according to formula (IIa),

R ⁷ is not an alkyl group or a C ₂ alkaneheterocyclic group.

In still other embodiments, when R ⁵ is chloro, R ⁶ is bromo, Z ¹ is -OR ⁷ , and R ³ and R ⁴ combine to form a group according to formula (IIa),

R ⁷ and R ⁸ are joined together with the atoms to which they are attached to form an optionally substituted five- or six-membered ring optionally including one or two heteroatoms selected from nitrogen, oxygen, and sulfur.

In still other embodiments, when R ⁵ is chloro, R ⁶ is bromo, and R ³ and R ⁴ combine to form a group according to formula (IIa),

Z is -OR ⁷ , and R ⁷ and R ⁸ combine to form -CH ₂ -CH ₂ -.

In some embodiments, when each of R ⁵ and R ⁶ is bromo, Z ¹ is -OR ⁷ , and R ³ and R ⁴ combine to form a group according to formula (IIa),

R ⁷ is not methyl.

In specific embodiments, when each of R ⁵ and R ⁶ is chloro, Z ¹ is -OR ⁷ , and R ³ and R ⁴ combine to form a group according to formula (IIa),

R is not ^methyl , 2-(N-imidazolyl)ethyl, methoxymethyl, 2-(N-pyrazolyl)ethyl, 2-(3-methylpyrazol-1-yl)ethyl, 2-pyridyl-methyl, 1,3-dimethyl-1H-1,2,4-triazol-5-yl-methyl, 2-pyrimidinylmethyl, imidazol-2-yl-methyl, 5-methyl-isoxazol-3-yl-methyl, 4-methyl-imidazol-5-yl-methyl, or 3-methyl-1,2,4-oxadiazol-5-yl-methyl.

In other embodiments, when each of R ⁵ and R ⁶ is chloro, Z ¹ is -OR ⁷ , and R ³ and R ⁴ combine to form a group according to formula (IIa),

R ⁷ is not unsubstituted alkyl, substituted alkyl, unsubstituted alkheteroaryl, or substituted alkheteroaryl.

In other embodiments, when each of R ⁵ and R ⁶ is chloro, Z ¹ is -OR ⁷ , and R ³ and R ⁴ combine to form a group according to formula (IIa),

R ⁷ is not unsubstituted alkyl, substituted alkyl, unsubstituted alkheterocyclyl, or substituted alkheterocyclyl.

In certain embodiments, when each R ⁵ and R ⁶ is chloro, Z ¹ is -OR ⁷ , R ⁷ and R ⁸ combine to form -CH ₂ -CH ₂ -, and R ³ and R ⁴ combine to form a group according to formula (IIa),

R ⁹ is not ethoxycarbonyl, cyclobutylaminocarbonyl, or cyclobutadienylaminocarbonyl.

In other embodiments, when each R ⁵ and R ⁶ is chloro, Z ¹ is -OR ⁷ , R ⁷ and R ⁸ combine to form -CH ₂ -CH ₂ -, and R ³ and R ⁴ combine to form a group according to formula (IIa),

^R9 is H or -C(O)-N(H)-(straight chain _C1-3 alkyl).

In specific embodiments, when each of R ⁵ and R ⁶ is halogen, and R ³ and R ⁴ combine to form a group according to formula (IIa),

Z is -OR ⁷ , R ⁷ is not methyl or 2-chloroethyl, and R ⁹ is H or -C(O)-N(H)-(straight chain C _1-3 alkyl).

In some embodiments, when R ⁵ is methoxy, R ⁶ is methyl, Z ¹ is -OR ⁷ , and R ³ and R ⁴ combine to form a group according to formula (IIa),

R ⁷ is not methyl.

In certain embodiments, when R ⁵ is chloro, R ⁶ is ethyl, Z ¹ is -OR ⁷ , and R ³ and R ⁴ combine to form a group according to formula (IIa),

R ⁷ is not methyl.

In some embodiments, when each of R ⁵ and R ⁶ is chloro, Z ¹ is -OR ⁷ , and R ³ and R ⁴ combine to form a group according to formula (IIb) or (IIc),

R ⁷ is not methyl or 2-(N,N-diethylamino)ethyl.

In other embodiments, when each of R ⁵ and R ⁶ is chloro, Z ¹ is -OR ⁷ , and R ³ and R ⁴ combine to form a group according to formula (IIb) or (IIc),

R ⁷ and R ⁸ are joined together with the atoms to which they are attached to form an optionally substituted five- or six-membered ring optionally including one or two heteroatoms selected from nitrogen, oxygen, and sulfur.

In certain embodiments, when each of R ⁵ and R ⁶ is chloro, and R ³ and R ⁴ combine to form a group according to formula (IIb) or (IIc),

Z ¹ is -OR ⁷ , and R ⁷ and R ⁸ combine to form -CH ₂ -CH ₂ -.

In some embodiments, when R ⁷ is methyl, R ⁵ is chloro, Z ¹ is -OR ⁷ , and R ³ and R ⁴ combine to form a group according to formula (IIIa),

^R6 is not bromine.

In specific embodiments, when each of R ⁵ and R ⁶ is chloro, Z ¹ is -OR ⁷ , and R ³ and R ⁴ combine to form a group according to formula (IIIa),

R ⁷ is not isopropyl, 3,3,3-trifluoropropyl, or 2-(N,N-dimethylamino)ethyl.

In certain embodiments, when each of R ⁵ and R ⁶ is chloro, Z ¹ is -OR ⁷ , and R ³ and R ⁴ combine to form a group according to formula (IIIa),

R ⁸ is not H.

In some embodiments, when R ³ and R ⁴ combine to form a group according to formula (IIIa),

Each of ^R5 and ^R6 is chlorine, and

R ⁷ is methyl and R ⁸ is H, or R ⁷ and R ⁸ , together with the atoms to which they are attached, are joined to form an optionally substituted five- or six-membered ring optionally including one or two heteroatoms selected from nitrogen, oxygen, and sulfur.

In other embodiments, when R ⁵ is chloro, R ⁶ is methoxy, Z ¹ is -OR ⁷ , and R ³ and R ⁴ combine to form a group according to formula (IIIb):

Neither R ¹ nor R ² is 2-(N,N-diethylamino)ethyl.

In certain embodiments, when R ⁵ is chloro, R ⁶ is methoxy, Z ¹ is -OR ⁷ , and R ³ and R ⁴ combine to form a group according to formula (IIIb),

Each of ^R1 and ^R2 is H.

In some embodiments, when each of R ⁵ and R ⁶ is chloro, Z ¹ is -OR ⁷ , and R ³ and R ⁴ combine to form a group according to formula (IVa),

R ⁷ is not 3-(N-morpholinyl)propyl, benzyl, 1-ethyl-pyrrolidin-3-yl, 1-methyl-piperidin-4-yl, 2-(1-methyl-pyrrolidin-2-yl)ethyl, or 3-(N,N-diethylamino)propyl.

In specific embodiments, when each of R ⁵ and R ⁶ is chloro, Z ¹ is -OR ⁷ , and R ³ and R ⁴ combine to form a group according to formula (IVa),

R ⁷ is not a substituted alkyl, heterocyclyl, alkheterocyclyl, or alkaryl group.

In some embodiments, when each of R ⁵ and R ⁶ is chloro, Z ¹ is -OR ⁷ , and R ³ and R ⁴ combine to form a group according to formula (IVb):

R ⁷ is not 2-methoxyethyl or benzyl.

In certain embodiments, when each of R ⁵ and R ⁶ is chloro, Z ¹ is -OR ⁷ , and R ³ and R ⁴ combine to form a group according to formula (IVb),

R ⁷ is not a substituted alkyl or alkaryl group.

In some embodiments, when each of R ⁵ and R ⁶ is chloro, Z ¹ is -OR ⁷ , and R ³ and R ⁴ combine to form a group according to formula (IVc),

R ⁷ is not 2-(N,N-diethylamino)ethyl or 3-(N,N-dimethylamino)propyl.

In other embodiments, when each of R ⁵ and R ⁶ is chloro, Z ¹ is -OR ⁷ , and R ³ and R ⁴ combine to form a group according to formula (IVc),

R ⁷ is not substituted alkyl.

In specific embodiments, when each of R ⁵ and R ⁶ is chloro, Z ¹ is -OR ⁷ , and R ³ and R ⁴ combine to form a group according to formula (IVd):

R ⁷ is not 2-(pyrrolidin-1-yl)ethyl or 2-hydroxyethyl.

In certain embodiments, when each of R ⁵ and R ⁶ is chloro, Z ¹ is -OR ⁷ , and R ³ and R ⁴ combine to form a group according to formula (IVd),

R ⁷ is not a substituted alkyl group or an alkaneheterocyclic group.

In some embodiments, when each of R ⁵ and R ⁶ is chloro, Z ¹ is -OR ⁷ , and R ³ and R ⁴ combine to form a group according to formula (IVe) or (IVf):

R ⁷ is not benzyl.

In other embodiments, when each of R ⁵ and R ⁶ is chloro, Z ¹ is -OR ⁷ , and R ³ and R ⁴ combine to form a group according to formula (IVe) or (IVf),

R ⁷ is not an alkaryl group.

In certain embodiments, when R ⁵ is chloro, R ⁶ is bromo, Z ¹ is -OR ⁷ , and R ³ and R ⁴ combine to form a group according to Formula (IVg), (IVh), (IVi), (IVj), or (IVk):

R ⁷ is not methyl.

In certain embodiments, when R ⁵ is chloro, R ⁶ is bromo, Z ¹ is -OR ⁷ , and R ³ and R ⁴ combine to form a group according to Formula (IVg), (IVh), (IVi), (IVj), or (IVk),

^R7 is not an alkyl group.

In some embodiments, when R ⁵ is chloro, R ⁶ is bromo, Z ¹ is -OR ⁷ , and R ³ and R ⁴ combine to form a group according to Formula (IVg), (IVh), (IVi), (IVj), or (IVk),

R ⁷ and R ⁸ are joined together with the atoms to which they are attached to form an optionally substituted five- or six-membered ring optionally including one or two heteroatoms selected from nitrogen, oxygen, and sulfur.

In a specific embodiment, when R ⁵ is chloro, R ⁶ is bromo, and Z ¹ is -OR ⁷ ,

R ³ and R ⁴ do not combine to form a group according to formula (IVg), (IVh), (IVi), (IVj), or (IVk).

In a specific embodiment, when R ⁶ is methyl,

Each of ^R1 and ^R2 is H.

In certain embodiments, when R ³ is H, and each of R ⁵ and R ⁶ is chloro,

R ⁷ is not methyl.

In certain embodiments, when R ₃ and R ⁴ are joined together with the atoms to which they are attached to form a substituted five-membered ring comprising one nitrogen, the five-membered ring is not substituted with oxygen. In specific embodiments, when R ³ and R ⁴ are joined together with the atoms to which they are attached to form a substituted five-membered ring comprising one sulfur, the five-membered ring is not substituted with hydroxy or C _1-3 alkoxy. In further embodiments, when R ³ and R ⁴ are joined together with the atoms to which they are attached to form an optionally substituted five-membered ring comprising one sulfur, R ⁷ and R ⁸ are joined together with the atoms to which they are attached to form an optionally substituted five- or six-membered ring, the five- or six-membered ring optionally including one or two heteroatoms selected from nitrogen, oxygen, and sulfur.

In a particular embodiment, R ⁷ and R ⁸ are connected together with the atoms to which they are attached to form an optionally substituted five-membered or six-membered ring, the five-membered or six-membered ring optionally including one or two heteroatoms selected from nitrogen, oxygen and sulfur. In other embodiments, R ⁷ and R ⁸ are connected together with the atoms to which they are attached to form an optionally substituted five-membered or six-membered ring, the five-membered or six-membered ring optionally including one or two heteroatoms selected from nitrogen, oxygen and sulfur. In still other embodiments, R ⁷ and R ⁸ are connected together with the atoms to which they are attached to form an optionally substituted five-membered or six-membered ring, the five-membered or six-membered ring optionally including one or two heteroatoms selected from nitrogen and oxygen. In certain embodiments, R ⁷ and R ⁸ are connected together with the atoms to which they are attached to form an optionally substituted five-membered ring.

In some embodiments, the compound is according to Formula (Ib):

or a pharmaceutically acceptable salt thereof,

in

Each R ¹ and R ² is independently H or optionally substituted C _1-3 alkyl;

R ³ is H, halogen, optionally substituted C _1-3 alkyl, or optionally substituted C _1-3 alkoxy, and R ⁴ is halogen, optionally substituted C _1-3 alkyl, optionally substituted C _1-3 alkoxy, optionally substituted amino, optionally substituted C _1-6 thioalkoxy, or optionally substituted C _6-10 aryl, or R ³ and R ^4, together with the atoms to which they are attached, are joined to form an optionally substituted five- or six-membered ring optionally including one nitrogen, one sulfur, or one oxygen, wherein the nitrogen is optionally substituted with R ⁹ ;

each R ⁵ and R ⁶ is independently optionally substituted C _1-3 alkyl (e.g., optionally substituted C _1-3 acyl), optionally substituted C _1-3 alkoxy, halogen, or CN;

R ⁷ is optionally substituted C _1-3 alkyl, optionally substituted C _1-3 alkoxycycloalkyl, optionally substituted C _1-3 alkheterocyclyl, or optionally substituted C _1-3 alkaryl, and R ⁸ is H; or R ⁷ and R ^8, together with the atoms to which they are attached, are joined to form an optionally substituted five-membered or six-membered ring; and

R ⁹ is H, optionally substituted C _1-3 alkyl, optionally substituted C _3-8 cycloalkyl, optionally substituted C _6-10 aryl, optionally substituted C _2-9 heteroaryl, optionally substituted C _{2-9 heterocyclyl, optionally substituted C 1-3 alkoxycycloalkyl, optionally substituted C 1-3 alkheterocyclyl ,} or optionally substituted C _1-3 alkaryl.

In other embodiments, when each of R ¹ and R ² is H, R ³ is H, R ⁴ is methyl or chloro, and each of R ⁵ and R ⁶ is chloro,

R ⁷ is not methyl.

In still other embodiments, when R ³ is H, and R ⁴ is halogen (eg, chlorine),

R ⁷ is not 2-amino-2-oxoethyl, 2-(N,N-diethylamino)ethyl, methyl, or benzyl.

In still other embodiments, when each of R ⁵ and R ⁶ is chlorine, R ³ is H, and R ⁴ is halogen (e.g., chlorine),

R ⁷ is dimethylaminoethyl, optionally substituted C _1-3 alkanecycloalkyl, or optionally substituted C _1-3 alkehterocyclyl, or R ⁷ and R ⁸ , together with the atoms to which they are attached, are joined to form an optionally substituted five- or six-membered ring, which optionally includes one or two heteroatoms selected from nitrogen, oxygen, and sulfur.

In further embodiments, when each of R ⁵ and R ⁶ is chlorine, R ³ is H, and R ⁴ is halogen (e.g., chlorine),

R ⁷ is optionally substituted C _1-3 alkanecycloalkyl, or optionally substituted C _1-3 alkehterocyclyl, or R ⁷ and R ⁸ , together with the atoms to which they are attached, are joined to form an optionally substituted five-membered or six-membered ring, which five-membered or six-membered ring optionally includes one or two heteroatoms selected from nitrogen, oxygen and sulfur.

In specific embodiments, when R ³ is H and R ⁴ is halogen (eg, chlorine),

R ⁷ is optionally substituted C _1-3 alkanecycloalkyl, or optionally substituted C _1-3 alkehterocyclyl, or R ⁷ and R ⁸ , together with the atoms to which they are attached, are joined to form an optionally substituted five-membered or six-membered ring, which five-membered or six-membered ring optionally includes one or two heteroatoms selected from nitrogen, oxygen and sulfur.

In some embodiments, when R ⁵ is chloro, R ⁶ is bromo, and R ³ and R ⁴ combine to form a group according to formula (IIa):

R ⁷ is not methyl, ethyl, n-propyl, 2-(N-pyrazolyl)ethyl, 2-(N-imidazolyl)ethyl, 3-hydroxypropyl, cyanomethyl, 2-chloroethyl, 2-hydroxyethyl, 2-oxopropyl, 2-(N,N-dimethylamino)ethyl, difluoromethyl or 2-(tert-butylamino)ethyl.

In certain embodiments, when R ⁵ is chloro, R ⁶ is bromo, and R ³ and R ⁴ combine to form a group according to formula (IIa),

R ⁷ is not substituted alkyl, unsubstituted alkyl, or unsubstituted C ₂ alkheteroaryl.

In other embodiments, when R ⁵ is chloro, R ⁶ is bromo, and R ³ and R ⁴ combine to form a group according to formula (IIa),

R ⁷ is not alkyl or C ₂ alkheteroaryl.

In a specific embodiment, when R ⁵ is chlorine, R ⁶ is bromine, and R ³ and R ⁴ combine to form a group according to formula (IIa),

R ⁷ is not substituted alkyl, unsubstituted alkyl, or unsubstituted C ₂ alkheterocyclyl.

In some embodiments, when R ⁵ is chloro, R ⁶ is bromo, and R ³ and R ⁴ combine to form a group according to formula (IIa),

R ⁷ is not an alkyl group or a C ₂ alkaneheterocyclic group.

In still other embodiments, when R ⁵ is chloro, R ⁶ is bromo, and R ³ and R ⁴ combine to form a group according to formula (IIa),

R ⁷ and R ⁸ are joined together with the atoms to which they are attached to form an optionally substituted five- or six-membered ring comprising one oxygen atom and optionally including one further heteroatom selected from nitrogen, oxygen and sulfur.

In still other embodiments, when R ⁵ is chloro, R ⁶ is bromo, and R ³ and R ⁴ combine to form a group according to formula (IIa),

R ⁷ and R ⁸ combine to form -CH ₂ -CH ₂ -.

In some embodiments, when each of R ⁵ and R ⁶ is bromo, and R ³ and R ⁴ combine to form a group according to formula (IIa),

R ⁷ is not methyl.

In specific embodiments, when each of R ⁵ and R ⁶ is chlorine, and R ³ and R ⁴ combine to form a group according to formula (IIa),

R is not ^methyl , 2-(N-imidazolyl)ethyl, methoxymethyl, 2-(N-pyrazolyl)ethyl, 2-(3-methylpyrazol-1-yl)ethyl, 2-pyridyl-methyl, 1,3-dimethyl-1H-1,2,4-triazol-5-yl-methyl, 2-pyrimidinylmethyl, imidazol-2-yl-methyl, 5-methyl-isoxazol-3-yl-methyl, 4-methyl-imidazol-5-yl-methyl, or 3-methyl-1,2,4-oxadiazol-5-yl-methyl.

In other embodiments, when each of R ⁵ and R ⁶ is chloro, and R ³ and R ⁴ combine to form a group according to formula (IIa),

R ⁷ is not unsubstituted alkyl, substituted alkyl, unsubstituted alkheteroaryl, or substituted alkheteroaryl.

In other embodiments, when each of R ⁵ and R ⁶ is chloro, and R ³ and R ⁴ combine to form a group according to formula (IIa),

R ⁷ is not unsubstituted alkyl, substituted alkyl, unsubstituted alkheterocyclyl, or substituted alkheterocyclyl.

In certain embodiments, when each of R ⁵ and R ⁶ is chloro, R ⁷ and R ⁸ combine to form -CH ₂ -CH ₂ -, and R ³ and R ⁴ combine to form a group according to formula (IIa),

R ⁹ is not ethoxycarbonyl, cyclobutylaminocarbonyl, or cyclobutadienylaminocarbonyl.

In other embodiments, when each of R ⁵ and R ⁶ is chloro, R ⁷ and R ⁸ combine to form -CH ₂ -CH ₂ -, and R ³ and R ⁴ combine to form a group according to formula (IIa),

^R9 is H or -C(O)-N(H)-(straight chain _C1-3 alkyl).

In specific embodiments, when each of R ⁵ and R ⁶ is halogen, and R ³ and R ⁴ combine to form a group according to formula (IIa),

and R ⁹ is H or -C(O)-N(H)-(straight chain C _1-3 alkyl).

In some embodiments, when R ⁵ is methoxy, R ⁶ is methyl, and R ³ and R ⁴ combine to form a group according to formula (IIa),

R ⁷ is not methyl.

In certain embodiments, when R ⁵ is chloro, R ⁶ is ethyl, and R ³ and R ⁴ combine to form a group according to formula (IIa),

R ⁷ is not methyl.

In some embodiments, when each of R ⁵ and R ⁶ is chloro, and R ³ and R ⁴ combine to form a group according to formula (IIb) or (IIc),

R ⁷ is not methyl or 2-(N,N-diethylamino)ethyl.

In other embodiments, when each of R ⁵ and R ⁶ is chloro and R ³ and R ⁴ combine to form a group according to formula (IIb) or (IIc),

R ⁷ and R ⁸ are joined together with the atoms to which they are attached to form an optionally substituted five- or six-membered ring comprising one oxygen atom and optionally including one further heteroatom selected from nitrogen, oxygen and sulfur.

In certain embodiments, when each of R ⁵ and R ⁶ is chloro and R ³ and R ⁴ combine to form a group according to formula (IIb) or (IIc),

R ⁷ and R ⁸ combine to form -CH ₂ -CH ₂ -.

In some embodiments, when R ⁷ is methyl, R ⁵ is chloro, and R ³ and R ⁴ combine to form a group according to formula (IIIa),

^R6 is not bromine.

In specific embodiments, when each of R ⁵ and R ⁶ is chlorine, and R ³ and R ⁴ combine to form a group according to formula (IIIa),

R ⁷ is not isopropyl, 3,3,3-trifluoropropyl, or 2-(N,N-dimethylamino)ethyl.

In specific embodiments, when each of R ⁵ and R ⁶ is chlorine, and R ³ and R ⁴ combine to form a group according to formula (IIIa),

R ⁸ is not H.

In some embodiments, when R ³ and R ⁴ combine to form a group according to formula (IIIa),

each of ^R5 and ^R6 is chlorine,

R ⁷ is methyl and R ⁸ is H, or R ⁷ and R ⁸ , together with the atoms to which they are attached, are joined to form an optionally substituted five- or six-membered ring containing one oxygen atom and optionally including a further heteroatom selected from nitrogen, oxygen and sulfur.

In other embodiments, when R ⁵ is chloro, R ⁶ is methoxy, and R ³ and R ⁴ combine to form a group according to formula (IIIb):

Neither R ¹ nor R ² is 2-(N,N-diethylamino)ethyl.

In certain embodiments, when R ⁵ is chloro, R ⁶ is methoxy, and R ³ and R ⁴ combine to form a group according to formula (IIIb),

Each of ^R1 and ^R2 is H.

In some embodiments, when each of R ⁵ and R ⁶ is chloro, and R ³ and R ⁴ combine to form a group according to formula (IVa):

R ⁷ is not 3-(N-morpholinyl)propyl, benzyl, 1-ethyl-pyrrolidin-3-yl, 1-methyl-piperidin-4-yl, 2-(1-methyl-pyrrolidin-2-yl)ethyl, or 3-(N,N-diethylamino)propyl.

In specific embodiments, when each of R ⁵ and R ⁶ is chlorine, and R ³ and R ⁴ combine to form a group according to formula (IVa),

R ⁷ is not a substituted alkyl, heterocyclyl, alkheterocyclyl, or alkaryl group.

In some embodiments, when each of R ⁵ and R ⁶ is chloro, and R ³ and R ⁴ combine to form a group according to formula (IVb):

R ⁷ is not 2-methoxyethyl or benzyl.

In certain embodiments, when each of R ⁵ and R ⁶ is chloro, and R ³ and R ⁴ combine to form a group according to formula (IVb),

R ⁷ is not a substituted alkyl or alkaryl group.

In some embodiments, when each of R ⁵ and R ⁶ is chloro, and R ³ and R ⁴ combine to form a group according to formula (IVc):

R ⁷ is not 2-(N,N-diethylamino)ethyl or 3-(N,N-dimethylamino)propyl.

In other embodiments, when each of R ⁵ and R ⁶ is chloro, and R ³ and R ⁴ combine to form a group according to formula (IVc),

R ⁷ is not substituted alkyl.

In specific embodiments, when each of R ⁵ and R ⁶ is chlorine, and R ³ and R ⁴ combine to form a group according to formula (IVd):

R ⁷ is not 2-(pyrrolidin-1-yl)ethyl or 2-hydroxyethyl.

In certain embodiments, when each of R ⁵ and R ⁶ is chloro, and R ³ and R ⁴ combine to form a group according to formula (IVd),

R ⁷ is not a substituted alkyl group or an alkaneheterocyclic group.

In some embodiments, when each of R ⁵ and R ⁶ is chloro, and R ³ and R ⁴ combine to form a group according to formula (IVe) or (IVf):

R ⁷ is not benzyl.

In other embodiments, when each of R ⁵ and R ⁶ is chloro, and R ³ and R ⁴ combine to form a group according to formula (IVe) or (IVf),

R ⁷ is not a substituted alkyl or alkaryl group.

In certain embodiments, when R ⁵ is chloro, R ⁶ is bromo, and R ³ and R ⁴ combine to form a group according to Formula (IVg), (IVh), (IVi), (IVj), or (IVk):

R ⁷ is not methyl.

In some embodiments, when R ⁵ is chloro, R ⁶ is bromo, and R ³ and R ⁴ combine to form a group according to Formula (IVg), (IVh), (IVi), (IVj), or (IVk),

R ⁷ and R ⁸ are joined together with the atoms to which they are attached to form an optionally substituted five- or six-membered ring optionally including one or two heteroatoms selected from nitrogen, oxygen, and sulfur.

In a specific embodiment, when R ⁵ is chlorine and R ⁶ is bromine,

R ³ and R ⁴ do not combine to form a group according to formula (IVg), (IVh), (IVi), (IVj), or (IVk).

In a specific embodiment, when R ⁶ is methoxy,

Each of ^R1 and ^R2 is H.

In certain embodiments, when R ³ is H, and each of R ⁵ and R ⁶ is chloro,

R ⁷ is not methyl.

In some embodiments of Formula (I), (Ia), or (Ib), R ³ is H, halogen, optionally substituted C _1-3 alkyl (e.g., optionally substituted C _1-3 acyl), or optionally substituted C _1-3 alkoxy, and R ⁴ is halogen, optionally substituted C _1-3 alkyl (e.g., optionally substituted C _1-3 acyl), optionally substituted C _1-3 alkoxy, optionally substituted amino, optionally substituted C _1-6 sulfanyl, or optionally substituted C _6-10 aryl, or R ³ and R ^4, together with the atoms to which they are attached, are joined to form an optionally substituted five- or six-membered ring optionally including one nitrogen, one oxygen, or one sulfur, wherein the nitrogen is optionally substituted with R ⁹ .

In further embodiments of Formula (I), (Ia), or (Ib), ^R is optionally substituted _C1-3 alkyl, optionally substituted _C1-3 alkoxycycloalkyl, optionally substituted C1-3 alkheterocyclyl, or optionally substituted _C1-3 alkaryl, and ^R is H; or ^R and ^R, together with the atoms to which they are attached _, are joined to form an optionally substituted five- or six-membered ring optionally including one or two heteroatoms selected from nitrogen, oxygen, and sulfur.

In specific embodiments, when R ³ and R ⁴ combine to form a group according to formula (IIb) or (IIc), the carbonyl group of formula (IIb) or (IIc) is adjacent to C ^6. In other embodiments, when R ³ and R ⁴ combine to form a group according to formula (IIb) or (IIc), the carbonyl group of formula (IIb) or (IIc) is adjacent to C ⁵ or C ⁶ .

In certain embodiments, when R ³ and R ⁴ combine to form a group according to formula (IIIa), the N atom of the group according to formula (IIIa) is adjacent to C ^5. In specific embodiments, when R ³ and R ⁴ combine to form a group according to formula (IIIa), the N atom of the group according to formula (IIIb) is adjacent to C ⁵ or C ⁶ .

In some embodiments, when R ³ and R ⁴ combine to form a group according to formula (IIIb), the N atom of the group according to formula (IIIb) is adjacent to C ^6. In other embodiments, when R ³ and R ⁴ combine to form a group according to formula (IIIb), the N atom of the group according to formula (IIIb) is adjacent to C ⁵ or C ⁶ .

In specific embodiments, when R ³ and R ⁴ combine to form a group according to any one of formulae (IVa)-(IVk), the S atom of the group according to any one of formulae (IVa)-(IVk) is adjacent to C ^6. In specific embodiments, when R ³ and R ⁴ combine to form a group according to any one of formulae (IVa)-(IVk), the S atom of the group according to any one of formulae (IVa)-(IVk) is adjacent to C ⁵ or C ⁶ .

In some embodiments, when R ³ and R ⁴ are joined together with the atoms to which they are attached to form an optionally substituted five-membered ring containing one sulfur, R ⁷ and R ⁸ are joined together with the atoms to which they are attached to form an optionally substituted five-membered ring or six-membered ring. In certain embodiments, when R ³ and R ⁴ are joined together with the atoms to which they are attached to form an optionally substituted five-membered ring containing one sulfur, R ⁷ and R ⁸ are joined together with the atoms to which they are attached to form an optionally substituted five-membered ring. In specific embodiments, when R ³ and R ⁴ are joined together with the atoms to which they are attached to form an optionally substituted five-membered ring containing one sulfur, R ⁷ and R ⁸ are combined to form a -CH ₂ CH ₂ - group.

In other embodiments, R ⁷ and R ^8, together with the atoms to which they are attached, are joined to form a five- or six-membered ring.

In certain embodiments, ^R is optionally substituted C _1-3 alkyl. In other embodiments, ^R is unsubstituted C _1-3 alkyl, C _1-3 alkylamino-C _1-3 alkyl (e.g., C _1-3 haloalkylamino-C _1-3 -alkyl (e.g., C _1-3 fluoroalkylamino-C _1-3 -alkyl)), di-(C _1-3 alkyl)amino-C _1-3 -alkyl (e.g., ^RY1 N( ^RY2 )-(C _1-3 -alkyl)-), wherein each ^RY1 and ^RY2 is independently unsubstituted C _1-3 alkyl or C _1-3 haloalkylamino-C _1-3 -alkyl (e.g., C _1-3 fluoroalkylamino-C _1-3 -alkyl), or C _1-3 haloalkyl (e.g., C _1-3 fluoroalkyl). In specific embodiments, ^R7 is unsubstituted _C1-3 alkyl, _C1-3 alkylamino- _C1-3 -alkyl (e.g., _C1-3 haloalkylamino- _C1-3 -alkyl, such as _C1-3 fluoroalkylamino- _C1-3 -alkyl), or di-( _C1-3 alkyl)amino- _C1-3 -alkyl (e.g., ^RY1 N( ^RY2 )-( _C1-3 alkyl)-, wherein each ^RY1 and ^RY2 is independently unsubstituted _C1-3 alkyl, or _C1-3 haloalkylamino- _C1-3 -alkyl, such as _C1-3 fluoroalkylamino- _C1-3 -alkyl).

In still other embodiments, R ⁷ is optionally substituted C _1-3 alkyl (e.g., R ⁷ is methyl), or R ⁷ is -(CH ₂ ) _k -N(R ²⁴ )R ²⁵ , wherein k is 2 or 3 (e.g., k is 2), and wherein each R ²⁴ and R ²⁵ is independently H or optionally substituted C _1-3 alkyl (e.g., each R ²⁴ and R ²⁵ is independently optionally substituted C _1-3 alkyl, e.g., each R ²⁴ and R ²⁵ is independently C _1-3 haloalkyl (e.g., C _1-3 fluoroalkyl); alternatively, each R ²⁴ and R ²⁵ is independently unsubstituted C _1-3 alkyl, e.g., methyl.

In other embodiments, when R ³ and R ⁴ are joined together with the atoms to which they are attached to form an optionally substituted five-membered ring containing one nitrogen, the optional substituent on the ring is not oxygen. In certain embodiments, when R ³ and R ⁴ are joined together with the atoms to which they are attached to form an optionally substituted five-membered ring containing one sulfur, the optional substituent on the ring is not hydroxy or C _1-3 alkoxy.

In still other embodiments, each R ¹ and R ² is H. In specific embodiments, each R ³ and R ⁴ is independently optionally substituted C _1-3 alkyl or optionally substituted C _1-3 alkoxy; or R ³ and R ⁴ , together with the atoms to which they are attached, are joined to form an optionally substituted five-membered or six-membered ring optionally comprising one nitrogen, one sulfur, or one oxygen, wherein the nitrogen is optionally substituted with R ^9. In some embodiments, R ³ and R ^4, together with the atoms to which they are attached, are joined to form an optionally substituted five-membered ring. In certain embodiments, R ³ and R ⁴ are combined to form -CH ₂ CH ₂ CH ₂ -. In specific embodiments, R ³ and R ^4, together with the atoms to which they are attached, are joined to form an optionally substituted five-membered ring comprising one nitrogen. In some embodiments, R ³ and R ⁴ combine to form -N(R ⁹ )-CH=CH- (e.g., R ⁹ is H or optionally substituted C _1-3 alkyl, e.g., C _1-3 haloalkyl (e.g., C _1-3 fluoroalkyl); alternatively, R ⁹ is H). In certain embodiments, the N atom is adjacent to C ⁵ of Formula (I). In specific embodiments, R ³ and R ^4, together with the atoms to which they are attached, are joined to form an optionally substituted five-membered ring containing one sulfur. In still other embodiments, R ³ and R ⁴ combine to form -C(R ^13A )=C(R ^13B )-S-, wherein R ^13A is H and R ^13B is H or optionally substituted C _1-3 alkyl. In specific embodiments, the S atom is adjacent to C ⁶ of the compounds of the invention. In some embodiments, R ¹³ is optionally substituted C _1-3 alkyl, for example, R ^13B is -C (O) -R ^13C , wherein R ^13C is optionally substituted C ^1-3 alkoxy or optionally substituted amino. In other embodiments, R ⁴ is C _1-3 alkyl. In specific embodiments, R ⁴ is methyl, ethyl or isopropyl. In certain embodiments, R ⁴ is C _1-3 alkoxy (for example, R ⁴ is methoxy). In other embodiments, R ⁴ is optionally substituted C _1-6 thioalkoxy (for example, R ⁴ is 4-amino-4-oxobutyl). In still other embodiments, R ⁴ is optionally substituted amino (for example, R ⁴ is methylamino). In still other embodiments, R ⁴ is halogen (for example, R ⁴ is chlorine). In specific embodiments, R ³ is hydrogen or C _1-3 alkyl (for example, R ³ is hydrogen, methyl or ethyl). In further embodiments, R ³ and R ⁴ combine to form a -C(R ^13A )=C(R ^13B )-S- group, wherein R ^13A is H and R ^13B is H or -C(O)-R ^13C , wherein R ^13C is optionally substituted C _1-3 alkyl, optionally substituted C _1-3 alkoxy, optionally substituted amino, or optionally substituted C _2-9 heterocyclyl.

In some embodiments, R ³ and R ⁴ combine to form -X ¹ -X ² -X ³ -, wherein

X ¹ is -S-, -O-, -(CR ¹⁴ R ¹⁵ )-, -C(R ¹⁶ )=, -N(R ⁹ )-, -N=, H, or optionally substituted C _1-3 alkyl;

^X2 is absent, -( ^CR17R18 ) _n- , -S-, -O-, -N=, -N( ^R9 )-, -C( ^R19 )=, =N-, =C( ^R20 ) ^- , or =C( ^R21 )-C( ^R22 )=;

X ³ is -(CR ¹⁴ R ¹⁵ )-, -S-, -O-, -N(R ⁹ )-, ═N-, ═C(R ²³ )-, halogen, optionally substituted C _1-3 alkyl, optionally substituted C _1-6 thioalkoxy, optionally substituted C _1-3 alkoxy, or optionally substituted C _6-10 aryl;

Each R ¹⁴ and R ¹⁵ is independently H or optionally substituted C _1-3 alkyl, or R ¹⁴ and R ¹⁵ combine to form ═O or ═S;

Each R ¹⁷ and R ¹⁸ is independently H or optionally substituted C _1-3 alkyl, or R ¹⁷ and R ¹⁸ combine to form ═O or ═S;

each R ¹⁶ , R ¹⁹ , R ²⁰ , R ²¹ , R ²² , and R ²³ is independently H, or optionally substituted C _1-3 alkyl; and

n is 1 or 2.

In some embodiments, when X ² is absent,

The chain of atoms -X ¹ -X ² -X ³ - includes not more than one heteroatom selected from nitrogen, oxygen and sulfur.

In specific embodiments, X ¹ is -(CR ¹⁴ R ¹⁵ )-, -C(R ¹⁶ )=, -N(R ⁹ )-, -N=, or optionally substituted C _1-3 alkyl.

In certain embodiments, X ¹ is -(CR ¹⁴ R ¹⁵ )-. In specific embodiments, each of R ¹⁴ and R ¹⁵ is H. In other embodiments, X ¹ is -C(R ¹⁶ )=. In still other embodiments, R ¹⁶ is H. In still other embodiments, X ¹ is -N(R ⁹ )-. In some embodiments, R ⁹ is H or optionally substituted C _1-3 alkyl. In certain embodiments, R ⁹ is halogen, methyl, or ethyl. In specific embodiments, X ¹ is -N=. In other embodiments, X ¹ is optionally substituted C _1-3 alkyl. In still other embodiments, X ² is absent, -(CH ₂ ) _n -, -N(R ⁹ )-, -C(H)=, =C(R ²⁰ )-, or =C(H)-C(H)=. In still other embodiments, X ² is -C(H)=. In further embodiments, X ² is -N(R ⁹ )-. In some embodiments, R ⁹ is H. In certain embodiments, R ⁹ is optionally substituted C _1-3 alkyl (e.g., R ⁹ is -C(O)-N(H)-Et). In specific embodiments, X ² is =C(R ²⁰ )-. In other embodiments, R ²⁰ is optionally substituted C _1-3 alkyl. In still other embodiments, X ² is absent. In still other embodiments, X ³ is -CH ₂ -, -S-, =C(H)-, -N(R ⁹ )-, halogen, optionally substituted C _1-3 alkyl, optionally substituted C _1-3 alkoxy, optionally substituted C _1-6 thioalkoxy, or optionally substituted C _6-10 aryl. In certain embodiments, X ³ is -CH ₂ -. In specific embodiments, X ³ is -S-. In some embodiments, X ³ is =C(H)-. In other embodiments, X ³ is -N(R ⁹ )-. In still other embodiments, X ³ is halogen, optionally substituted C _1-3 alkyl, optionally substituted C _1-3 alkoxy, optionally substituted C _1-6 thioalkoxy, or optionally substituted C _6-10 aryl.

In certain embodiments, Z ¹ and R ⁸ combine to form -Z ³ -Y ¹ -Y ² -, wherein

Z ³ is -O-, -N(R ¹⁰ )-, -N=, -S-, or -(CR ¹¹ R ¹² )-;

Y ¹ is -O-, -N(R ¹⁰ )-, -S-, -(CR ²⁶ R ²⁷ ) _m -, -C(R ²⁰ )＝, ＝C(R ²⁰ )-, ＝C(R ^{21 )-C(R 22 )} ＝, optionally substituted C _1-3 alkyl, optionally substituted C _{1-3 alkheterocyclyl, optionally substituted C 1-3 alkylcycloalkyl} , or optionally substituted C _1-3 alkaryl; and

^Y2 is -O-, -S-, -N( ^R10 )-, ^{-(CR26R27)-, ＝C(R20 ) -} , ＝N-, or H; wherein

Each of R ²⁰ , R ²¹ , and R ²² is independently H or optionally substituted C _1-3 alkyl; and

Each R ²⁶ and R ²⁷ is independently H or optionally substituted C _1-3 alkyl, or R ²⁶ and R ²⁷ combine to form ═O or ═S;

m is 1 or 2; and

Among them, when Y ² is H,

The chain of atoms -Z ³ -Y ¹ -Y ² - includes not more than two heteroatoms selected from nitrogen, oxygen, and sulfur.

In still other embodiments, R ⁷ and R ⁸ form a group -Y ¹ -Y ² -, wherein:

Y ¹ is -(CR ²⁶ R ²⁷ ) _m -, -C(R ²⁰ )=, optionally substituted C _1-3 alkyl, optionally substituted C _1-3 alkheterocyclyl, optionally substituted C _1-3 alkylcycloalkyl, or optionally substituted C _1-3 alkaryl; and

Y ² is -(CR ²⁶ R ²⁷ )-, ＝C(R ²⁰ )-, or H; wherein

Each R ²⁶ and R ²⁷ is independently H or optionally substituted C _1-3 alkyl; and

m is 1 or 2.

In specific embodiments, Z ³ is oxygen. In some embodiments, Y ¹ is -(CR ²⁶ R ²⁷ ) _m -, -C(R ²⁰ ) =, optionally substituted C _1-3 alkyl, optionally substituted C _{1-3 alkheterocyclyl, optionally substituted C 1-3 alkoxycycloalkyl} , or optionally substituted C _1-3 alkaryl. In further embodiments, Y ¹ is -(CR ²⁶ R ²⁷ ) _m - or optionally substituted C _1-3 alkyl. In other embodiments, Y ¹ is -(CR ²⁶ R ²⁷ ) _m -. In other embodiments, Y ¹ is optionally substituted C _1-3 alkyl (e.g., Y ¹ is methyl). In still other embodiments, Y ¹ is -(CH ₂ ) _k -N(R ²⁴ )R ²⁵ , wherein k is 2 or 3, and wherein each R ²⁴ and R ²⁵ is independently H or optionally substituted C _1-3 alkyl. In still other embodiments, k is 2. In further embodiments, each R ²⁴ and R ²⁵ is independently optionally substituted C _1-3 alkyl (e.g., each R ²⁴ and R ²⁵ is methyl). In certain embodiments, Y ² is -(CR ²⁶ R ²⁷ )- or H. In other embodiments, Y ² is -(CR ²⁶ R ²⁷ )-.

In some embodiments of either aspect, each of R ¹ and R ² is H.

In certain embodiments of Formula (I) or (Ia), the compound of the invention has a structure according to Formula (Va):

or a pharmaceutically acceptable salt thereof, wherein all substituents are as defined herein.

In specific embodiments of Formula (I), (Ia), or (Ib), the compound of the present invention has a structure according to Formula (Vb):

or a pharmaceutically acceptable salt thereof,

in

X ¹ is -S-, -O-, -(CR ¹⁴ R ¹⁵ )-, -C(R ¹⁶ )=, -N(R ⁹ )-, -N=, -H, or optionally substituted C _1-3 alkyl;

^X2 is absent, -( ^CR17R18 ) _n- , -S-, -O-, -N=, -N( ^R9 )-, -C( ^R19 )=, =N-, =C( ^R20 ) ^- , or =C( ^R21 )-C( ^R22 )=;

X ³ is -(CR ¹⁴ R ¹⁵ )-, -S-, -O-, -N(R ⁹ )-, ═N-, ═C(R ²³ )-, halogen, optionally substituted C _1-3 alkyl, optionally substituted C _1-6 thioalkoxy, optionally substituted C _1-3 alkoxy, or optionally substituted C _6-10 aryl;

Y ¹ is -(CR ²⁶ R ²⁷ ) _m -, -C(R ²⁰ )=, =C(R ²⁰ )-, =C(R ²¹ )-C(R ²² )=, optionally substituted C _1-3 alkyl, optionally substituted C _1-3 alkheterocyclyl, optionally substituted C _1-3 alkylcycloalkyl, or optionally substituted C _1-3 alkaryl;

Y ² is -O-, -S-, -N(R ¹⁰ )-, -(CR ²⁶ R ²⁷ )-, =C(R ²⁰ )-, =N-, or H;

Each R ¹ and R ² is independently H or optionally substituted C _1-3 alkyl;

Each R ⁵ and R ⁶ is independently optionally substituted C _1-3 alkyl, optionally substituted C _1-3 alkoxy, halogen, or CN;

each R ¹⁴ , R ¹⁵ , R ¹⁶ , R ¹⁷ , R ¹⁷ , R ¹⁸ , R ²⁰ , R ¹⁹ , R ²⁰ , R ²¹ , R ²² , R ²³ , R ²⁶ , and R ²⁷ is independently H or optionally substituted C _1-3 alkyl;

n is 1 or 2; and

m is 1 or 2.

In some embodiments, when R ⁵ is chloro, R ⁶ is bromo, and -X ¹ -X ² -X ³ - forms a group according to formula (IIa):

^Y1 is not methyl, ethyl, n-propyl, 2-(N-pyrazolyl)ethyl, 2-(N-imidazolyl)ethyl, 3-hydroxypropyl, cyanomethyl, 2-chloroethyl, 2-hydroxyethyl, 2-oxopropyl, 2-(N,N-dimethylamino)ethyl, difluoromethyl or 2-(tert-butylamino)ethyl.

In certain embodiments, when R ⁵ is chloro, R ⁶ is bromo, and -X ¹ -X ² -X ³ - forms a group according to formula (IIa),

Y ¹ is not optionally substituted C _1-3 alkyl or optionally substituted C ₂ alkheteroaryl.

In a specific embodiment, when R ⁵ is chloro, R ⁶ is bromo, and -X ¹ -X ² -X ³ - forms a group according to formula (IIa),

Y ¹ is not an optionally substituted C _1-3 alkyl group or an optionally substituted C ₂ alkaneheterocyclyl group.

In still other embodiments, when R ⁵ is chloro, R ⁶ is bromo, and -X ¹ -X ² -X ³ - forms a group according to formula (IIa),

Y ² is not H.

In still other embodiments, when R ⁵ is chloro, R ⁶ is bromo, and -X ¹ -X ² -X ³ - forms a group according to formula (IIa),

Each of Y ¹ and Y ² is -CH ₂ -.

In some embodiments, when each R ⁵ and R ⁶ is bromo, and -X ¹ -X ² -X ³ - forms a group according to formula (IIa),

^Y1 is not a methyl group.

In a specific embodiment, when each of R ⁵ and R ⁶ is chlorine, and -X ¹ -X ² -X ³ - forms a group according to formula (IIa),

^Y1 is not methyl, 2-(N-imidazolyl)ethyl, methoxymethyl, 2-(N-pyrazolyl)ethyl, 2-(3-methylpyrazol-1-yl)ethyl, 2-pyridyl-methyl, 1,3-dimethyl-1H-1,2,4-triazol-5-yl-methyl, 2-pyrimidinylmethyl, imidazol-2-yl-methyl, 5-methyl-isoxazol-3-yl-methyl, 4-methyl-imidazol-5-yl-methyl, or 3-methyl-1,2,4-oxadiazol-5-yl-methyl.

In other embodiments, when each R ⁵ and R ⁶ is chloro, and -X ¹ -X ² -X ³ - forms a group according to formula (IIa),

Y ¹ is not unsubstituted alkyl, substituted alkyl, unsubstituted alkheteroaryl, or substituted alkheteroaryl.

In some embodiments, when each of R ⁵ and R ⁶ is chloro, and -X ¹ -X ² -X ³ - forms a group according to formula (IIa),

Y ¹ is not an unsubstituted alkyl group, a substituted alkyl group, an unsubstituted alkheterocyclyl group, or a substituted alkheterocyclyl group.

In certain embodiments, when each R ⁵ and R ⁶ is chloro, each Y ¹ and Y ² is -CH ₂ -, and -X ¹ -X ² -X ³ - forms a group according to formula (IIa),

R ⁹ is not ethoxycarbonyl, cyclobutylaminocarbonyl, or cyclobutadienylaminocarbonyl.

In other embodiments, when each of R ⁵ and R ⁶ is chloro, R ⁷ and R ⁸ combine to form -CH ₂ -CH ₂ -, and -X ¹ -X ² -X ³ - forms a group according to formula (IIa),

^R9 is H or -C(O)-N(H)-(straight chain _C1-3 alkyl).

In a specific embodiment, when each of R ⁵ and R ⁶ is halogen, and -X ¹ -X ² -X ³ - forms a group according to formula (IIa),

and R ⁹ is H or -C(O)-N(H)-(straight chain C _1-3 alkyl).

In some embodiments, when R ⁵ is methoxy, R ⁶ is methyl, and -X ¹ -X ² -X ³ - forms a group according to formula (IIa),

^Y1 is not a methyl group.

In certain embodiments, when R ⁵ is chloro, R ⁶ is ethyl, and -X ¹ -X ² -X ³ - forms a group according to formula (IIa),

^Y1 is not a methyl group.

In some embodiments, when each R ⁵ and R ⁶ is chloro, and -X ¹ -X ² -X ³ - forms a group according to formula (IIb) or (IIc),

Y ¹ is not methyl or 2-(N,N-diethylamino)ethyl.

In other embodiments, when each R ⁵ and R ⁶ is chloro and -X ¹ -X ² -X ³ - forms a group according to formula (IIb) or (IIc),

Y ² is not H.

In certain embodiments, when each R ⁵ and R ⁶ is chloro and -X ¹ -X ² -X ³ - forms a group according to formula (IIb) or (IIc),

Each of Y ¹ and Y ² is -CH ₂ -.

In some embodiments, when R ⁷ is methyl, R ⁵ is chloro, and -X ¹ -X ² -X ³ - forms a group according to formula (IIIa),

^R6 is not bromine.

In a specific embodiment, when each of R ⁵ and R ⁶ is chlorine, and -X ¹ -X ² -X ³ - forms a group according to formula (IIIa),

R ⁷ is not isopropyl, 3,3,3-trifluoropropyl, or 2-(N,N-dimethylamino)ethyl.

In some embodiments, when -X ¹ -X ² -X ³ - forms a group according to formula (IIIa),

Each of ^R5 and ^R6 is chlorine, and

^Y1 is methyl and ^Y2 is H, or

^Y1 is -( ^CR26R27 ) _m- , -C( ^R20 )=, =C( ^R20 )-, or =C( ^R21 )-C( ^R22 )=, ^{and Y2} is -O-, -S-, -N( ^R10 )-, -( ^CR26R27 )-, =C ^{(R20 )} -, or =N-.

In some embodiments, when -X ¹ -X ² -X ³ - forms a group according to formula (IIIa),

Each of ^R5 and ^R6 is chlorine, and

Y ² is not H.

In other embodiments, when R ⁵ is chloro, R ⁶ is methoxy, and -X ¹ -X ² -X ³ - forms a group according to formula (IIIb),

Neither R ¹ nor R ² is 2-(N,N-diethylamino)ethyl.

In certain embodiments, when R ⁵ is chloro, R ⁶ is methoxy, and -X ¹ -X ² -X ³ - forms a group according to formula (IIIb),

Each of ^R1 and ^R2 is H.

In some embodiments, when each R ⁵ and R ⁶ is chloro, and -X ¹ -X ² -X ³ - forms a group according to formula (IVa),

Y ¹ is not 3-(N-morpholinyl)propyl, benzyl, 1-ethyl-pyrrolidin-3-yl, 1-methyl-piperidin-4-yl, 2-(1-methyl-pyrrolidin-2-yl)ethyl, or 3-(N,N-diethylamino)propyl.

In a specific embodiment, when each of R ⁵ and R ⁶ is chlorine, and -X ¹ -X ² -X ³ - forms a group according to formula (IVa),

Y ¹ is not a heterocyclic group, an alkheterocyclic group, or an alkaryl group.

In some embodiments, when each of R ⁵ and R ⁶ is chloro, and -X ¹ -X ² -X ³ - forms a group according to formula (IVb),

Y ¹ is not 2-methoxyethyl or benzyl.

In certain embodiments, when each R ⁵ and R ⁶ is chloro, and -X ¹ -X ² -X ³ - forms a group according to formula (IVb),

Y ¹ is not a substituted alkyl or alkaryl group.

In some embodiments, when each of R ⁵ and R ⁶ is chloro, and -X ¹ -X ² -X ³ - forms a group according to formula (IVc),

Y ¹ is not 2-(N,N-diethylamino)ethyl or 3-(N,N-dimethylamino)propyl.

In other embodiments, when each R ⁵ and R ⁶ is chloro, and -X ¹ -X ² -X ³ - forms a group according to formula (IVc),

Y ¹ is not a substituted alkyl group.

In a specific embodiment, when each of R ⁵ and R ⁶ is chloro, and -X ¹ -X ² -X ³ - forms a group according to formula (IVd),

Y ¹ is not 2-(pyrrolidin-1-yl)ethyl or 2-hydroxyethyl.

In certain embodiments, when each of R ⁵ and R ⁶ is chloro, and R ³ and R ⁴ combine to form a group according to formula (IVd),

Y ¹ is not a substituted alkyl group or an alkaneheterocyclic group.

In some embodiments, when each R ⁵ and R ⁶ is chloro, and -X ¹ -X ² -X ³ - forms a group according to formula (IVe) or (IVf),

^Y1 is not benzyl.

In other embodiments, when each R ⁵ and R ⁶ is chloro, and -X ¹ -X ² -X ³ - forms a group according to formula (IVe) or (IVf),

Y ¹ is not an alkaryl group or a substituted alkyl group.

In certain embodiments, when R ⁵ is chloro, R ⁶ is bromo, and -X ¹ -X ² -X ³ - forms a group according to Formula (IVg), (IVh), (IVi), (IVj), or (IVk),

^Y1 is not a methyl group.

In some embodiments, when R ⁵ is chloro, R ⁶ is bromo, and -X ¹ -X ² -X ³ - forms a group according to Formula (IVg), (IVh), (IVi), (IVj), or (IVk),

Y ² is not H.

In a specific embodiment, when R ⁵ is chlorine and R ⁶ is bromine,

R ³ and R ⁴ do not combine to form a group according to formula (IVg), (IVh), (IVi), (IVj), or (IVk).

In a specific embodiment, when R ⁶ is methoxy,

Each of ^R1 and ^R2 is H.

In certain embodiments, when X ¹ is H, and each of R ⁵ and R ⁶ is chloro,

^Y1 is not a methyl group.

In some embodiments, R ¹⁰ is H, optionally substituted C _1-3 alkyl, optionally substituted C _3-8 cycloalkyl, optionally substituted C _1-3 alkanecycloalkyl, optionally substituted C _1-3 alkheterocyclyl, or optionally substituted C _1-3 alkaryl. In other embodiments, R ¹⁰ is H, optionally substituted C _1-3 alkyl, optionally substituted C _1-3 alkanecycloalkyl, optionally substituted C _1-3 alkheterocyclyl, or optionally substituted C _1-3 alkaryl.

In specific embodiments, when ^Xi is - ^{( CR14R15} )-, ^X2 is -N( ^R9 )-, ^X3 is -( ^CR14R15 )-, and each of ^R14 and ^R15 is H, ^R9 is H or -C(O) ^-N (H)-Et, and each of ^Y1 and ^Y2 is _-CH2- . In other embodiments, when ^Xi is -( ^CR14R15 )-, ^X2 is -N( ^R9 )-, and ^X3 is -( ^CR14R15 )-, ^R9 is H or -C(O) ^-N (H)-Et, and each ^{of Y1} and ^Y2 is _-CH2- . In some embodiments, when ^X1 is -N( ^R9 )-, ^X2 is -C( ^R19 )=, ^X3 is =C( ^R23 )-, and each of ^R17 , ^R19 , and ^R23 is H, ^Y1 is - ^{( CR26R27} ) _m- , and ^Y2 is -( ^CR26R27 )-. In other embodiments, when ^X1 is -N( ^R9 ) ^- , ^X2 is -C( ^R19 )=, ^X3 is =C( ^R23 )-, and each of ^R9 , ^R19 , and ^R23 is H, each of ^Y1 and ^Y2 is _-CH2- . In some embodiments, when ^X1 is -N( ^R9 )-, ^X2 is -C( ^R19 )=, ^X3 is =C( ^R23 )-, and each of ^R19 and ^R23 is H, ^Y1 is - ^{( CR26R27} ) _m- , and ^Y2 is -( ^CR26R27 )-. In certain embodiments, when ^X1 is -N( ^R9 )-, ^X2 is -C( ^R19 )=, ^X3 is =C( ^R23 )-, ^Y2 is H, and each of ^R5 and ^R6 is -Cl, ^Y1 is Me. In specific embodiments, when ^X1 is -C( ^R16 )=, ^X2 is =C( ^R20 ) ^- , and ^X3 is -S-, ^R16 is H. In some embodiments, when ^X1 is -C( ^R16 )=, ^X2 is =C( ^R20 )-, and ^X3 is -S-, ^Y1 is -( ^CR26R27 ) _m- , and ^Y2 is -( ^CR26R27 )-. In certain embodiments, when ^X1 is -C( ^{R16 )} =, ^X2 is =C( ^R20 )-, and ^X3 is -S-, each of ^Y1 and ^Y2 is _-CH2- . In some embodiments, when ^X1 is -C( ^R16 )=, ^X2 is =C( ^R20 ) ^- , and ^X3 is -S-, each of ^R5 and ^R6 is -Cl. In certain embodiments, when X ¹ is H and each of R ⁵ and R ⁶ is Cl, Y ¹ is -(CR ²⁶ R ²⁷ ) _m -, and Y ² is -(CR ²⁶ R ²⁷ ) -. In specific embodiments, when X ¹ is H and each of R ⁵ and R ⁶ is halogen, Y ¹ is -(CR ²⁶ R ²⁷ ) _m -, and Y ² is -(CR ²⁶ R ²⁷ ) - (e.g., each of Y ¹ and Y ² is -CH ₂ -). In specific embodiments, when X ¹ is H, Y ¹ is -(CR ²⁶ R ²⁷ ) _m -, and Y ² is -(CR ²⁶ R ²⁷ ) - (e.g., each of Y ¹ and Y ² is -CH ₂ -).

In specific embodiments, X ¹ is -(CR ¹⁴ R ¹⁵ )-, -C(R ¹⁶ )＝, -N(R ⁹ )-, or optionally substituted C _1-3 alkyl (e.g., -CH ₂ -, -C(H)＝, -N＝, optionally substituted C _1-3 alkyl, or -N(R ⁹ )- (e.g., R ¹⁷ is H or optionally substituted C _1-3 alkyl (e.g., R ⁹ is H, -Me, or -Et).

In some embodiments, X ² is absent, -(CH ₂ ) _n -, -N(R ⁹ )-, -C(H)＝, ＝C(R ²⁰ )-, or ＝C(H)-C(H)＝. In certain embodiments, X ² is absent, -C(H)＝, -N(R ⁹ )- (e.g., R ⁹ is H or optionally substituted C _1-3 alkyl (e.g., R ⁹ is C _1-3 haloalkyl, e.g., C _1-3 fluoroalkyl), or R ⁹ is -C(O)-N(H)-Et), or ＝C(R ²⁰ )-, wherein R ²⁰ is, for example, optionally substituted C _1-3 alkyl.

In certain embodiments, X ³ is -CH ₂ -, -S-, =C(H)-, or optionally substituted C _1-3 alkyl.

In some embodiments, each R ⁵ and R ⁶ is independently halogen, or optionally substituted C _1-3 alkyl, for example, each R ⁵ and R ⁶ is halogen (eg, each R ⁵ and R ⁶ is -Cl).

In some embodiments, R ²⁶ is H. In other embodiments, R ²⁷ is H. In certain embodiments, n is 1. In other embodiments, m is 1. In specific embodiments, Y ¹ is optionally substituted C _1-3 alkyl. In other embodiments, Y ^is unsubstituted _C1-3 alkyl, C1-3 alkylamino- _{C1-3 -alkyl} (e.g., _C1-3 haloalkylamino- _C1-3 -alkyl, e.g., _C1-3 fluoroalkylamino- _C1-3 -alkyl), di-( _C1-3 alkyl)amino- _C1-3 -alkyl (e.g., ^RY1 N( ^RY2 )-( _C1-3 alkyl)-, wherein each ^RY1 and ^RY2 is independently unsubstituted _C1-3 alkyl, or _C1-3 haloalkylamino- _C1-3 -alkyl, e.g., _C1-3 fluoroalkylamino- _C1-3 -alkyl), or _C1-3 haloalkyl (e.g., _C1-3 fluoroalkyl). In specific embodiments, ^Y1 is unsubstituted _C1-3 alkyl, _C1-3 alkylamino- _C1-3 -alkyl (e.g., _C1-3 haloalkylamino- _C1-3 -alkyl, e.g., _C1-3 fluoroalkylamino- _C1-3 -alkyl), or di-( _C1-3 alkyl)aminoC1-3 _-alkyl (e.g., ^RY1 N( ^RY2 )-( _C1-3 alkyl)-, wherein each ^RY1 and ^RY2 is independently unsubstituted _C1-3 alkyl, or _C1-3 haloalkylamino- _C1-3 -alkyl, e.g., _C1-3 fluoroalkylamino- _C1-3 -alkyl).

In certain embodiments, the compounds of the present invention have the formula shown in Table 1:

Table 1.

or a pharmaceutically acceptable salt thereof.

In specific embodiments, the compounds of the present invention have the formula:

or a pharmaceutically acceptable salt thereof.

In some embodiments, the compounds of the present invention have the formula:

or a pharmaceutically acceptable salt thereof.

In further embodiments, the compound is not Compound 38 or Compound 39.

In certain embodiments of any of the formulae described herein, each of R ¹ and R ² is H, R ⁵ is Cl, and R ⁶ is F or Cl.

In other embodiments of Formula (I), (Ia), or (Ib), R ³ is H, halogen, optionally substituted C _1-3 alkyl, or optionally substituted C _1-3 alkoxy, and R ⁴ is halogen, optionally substituted C _1-3 alkyl, optionally substituted C _1-3 alkoxy, optionally substituted amino, or optionally substituted C _1-6 thioalkoxy, or R ³ and R ^4, together with the atoms to which they are attached, are joined to form an optionally substituted five- or six-membered ring optionally including one nitrogen, one oxygen, or one sulfur, wherein the nitrogen is optionally substituted with R ⁹ .

In still other embodiments of Formula (I), (Ia), or (Ib), R ³ is H, optionally substituted C _1-3 alkyl, or optionally substituted C _1-3 alkoxy, and R ⁴ is halogen, optionally substituted C _1-3 alkyl, optionally substituted C _1-3 alkoxy, optionally substituted amino, or optionally substituted C _1-6 thioalkoxy, or R ³ and R ^4, together with the atoms to which they are attached, are joined to form an optionally substituted five- or six-membered ring optionally including one nitrogen, one oxygen, or one sulfur, wherein the nitrogen is optionally substituted with R ⁹ .

In still other embodiments of Formula (I), (Ia), or (Ib), ^R is H, optionally substituted _C1-3 alkyl, or optionally substituted _C1-3 alkoxy, and ^R is halogen, optionally substituted _C1-3 alkyl, optionally substituted _C1-3 alkoxy, optionally substituted amino, or optionally substituted _C1-6 thioalkoxy, or ^R and ^R are combined to form one of the following groups:

-N(R ⁹ )-CH=CH-, -CH ₂ CH ₂ CH ₂ -, -CH ₂ CH ₂ CH ₂ CH ₂ -, and -C(R ^13A )=C(R ^13B )-S-,

wherein N is adjacent to position 5 and R ⁹ is H or C _1-3 alkyl.

In certain embodiments of formula (I), Z ² is N, and R ⁴ is halogen, optionally substituted C _1-3 alkyl, optionally substituted C _1-3 alkoxy, optionally substituted amino, or optionally substituted C _1-6 thioalkoxy.

In particular embodiments of formula (I), Z ² is N, and R ⁴ is optionally substituted C _1-3 alkoxy or optionally substituted C _1-6 thioalkoxy.

In other embodiments, X ¹ is -N(R ⁹ )-, -(CR ¹⁴ R ¹⁵ )-, -C(R ¹⁶ )＝, H, or optionally substituted C _1-3 alkyl. In still other embodiments, X ² is absent, -(CR ¹⁷ R ¹⁸ ) _n -, -C(R ¹⁹ )＝, or ＝C(R ²⁰ )-. In still other embodiments, X ³ is -(CR ¹⁴ R ¹⁵ )-, -S-, ＝C(R ²³ )-, halogen, optionally substituted C _1-3 alkyl, optionally substituted C _1-6 thioalkoxy, or optionally substituted C _1-3 alkoxy. In certain embodiments, R ⁹ is H or C _1-3 alkyl.

In certain embodiments, the compounds of the present invention have a molecular weight less than about 500 g/mol (e.g., less than about 450 g/mol, or less than about 400 g/mol). In other embodiments, the compounds of the present invention demonstrate a permeability from the top to substrate (A→B) greater than about 1x 10 ^-7 cm/sec (e.g., greater than about 5x 10 ^-7 cm/sec, greater than about 1x 10 ^-6 cm/sec, or greater than about 3x10 ^-6 cm/sec) in MDR1-MDCK assays. In a particular embodiment, the compounds of the present invention demonstrate a (B→A)/(A→B) ratio less than about 30 (e.g., less than about 10, less than about 5, or less than about 3).

In another aspect, the invention features a pharmaceutical composition comprising a compound of the invention, or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers or excipients. In certain embodiments, the composition is formulated for oral, intradermal, intramuscular, parenteral, intravenous, intraarterial, intracranial, subcutaneous, intraorbital, intraventricular, intraspinal, intraperitoneal, or intranasal administration. Preferably, the composition is formulated for oral administration.

In yet another aspect, the invention features a method of treating a condition in a mammal (e.g., a human) caused by the action of heat shock protein 90 (Hsp90). The method involves administering to the mammal an effective amount of a compound according to formula (I):

or a pharmaceutically acceptable salt thereof,

in

Z ¹ is -OR ⁷ , -N(R ¹⁰ )R ⁷ , -SR ⁷ , or -C(R ¹⁰ )(R ¹¹ )R ⁷ ;

Z ² is -N= or -C(R ³ )=;

Each R ¹ and R ² is independently H or optionally substituted C _1-3 alkyl;

R ³ is H, halogen, cyano, optionally substituted C _1-6 alkyl, optionally substituted C _1-3 alkoxy, or optionally substituted amino, and R ⁴ is halogen, cyano, optionally substituted C _1-6 alkyl, optionally substituted C _1-3 alkoxy, optionally substituted amino, optionally substituted C _1-6 thioalkoxy, or optionally substituted C _6-10 alkyl, or R ³ and R ⁴ , together with the atoms to which they are attached, are joined to form an optionally substituted five- or six-membered ring optionally including one nitrogen, one oxygen, or one sulfur, wherein the nitrogen is optionally substituted with R ⁹ ;

Each R ⁵ and R ⁶ is independently optionally substituted C _1-3 alkyl, optionally substituted C _1-3 alkoxy, halogen, or CN;

R ⁷ is optionally substituted C _1-3 alkyl, optionally substituted C _1-3 alkoxycycloalkyl, optionally substituted C _1-3 alkheterocyclyl, or optionally substituted C _1-3 alkaryl, and R ⁸ is H; or R ⁷ and R ^8, together with the atoms to which they are attached, are joined to form an optionally substituted five- or six-membered ring optionally including one or two heteroatoms selected from nitrogen, oxygen, and sulfur;

R ⁹ is H, optionally substituted C _1-3 alkyl, optionally substituted C _3-8 cycloalkyl, optionally substituted C _6-10 aryl, optionally substituted C _2-9 heteroaryl, optionally substituted C _{2-9 heterocyclyl, optionally substituted C 1-3 alkoxycycloalkyl, optionally substituted C 1-3 alkheterocyclyl ,} or optionally substituted C _1-3 alkaryl;

R ¹⁰ is H, optionally substituted C _1-3 alkyl, optionally substituted C _3-8 cycloalkyl, optionally substituted C _6-10 aryl, optionally substituted C _2-9 heteroaryl, optionally substituted C _2-9 heterocyclyl, optionally substituted C 1-3 alkoxycycloalkyl, optionally substituted C _1-3 alkheterocyclyl, or optionally substituted C _1-3 alkaryl, and _R ¹¹ is H, optionally substituted C _1-3 alkyl, or R ¹⁰ and R ¹¹ combine to form ═O or ═S and

R ^m is H, halogen, optionally substituted C _1-4 alkyl, or optionally substituted C _1-3 alkoxy.

In certain embodiments of formula (I), when Z ² is CR ³ , each of R ¹ and R ² is H, R ³ is H, R ⁴ is methyl or halogen (eg, chlorine), and each of R ⁵ and R ⁶ is halogen (eg, chlorine),

^Z1 is not methoxy.

In certain embodiments of formula (I), when Z ² is CR ³ , R ³ is H, R ⁴ is methyl or halogen (eg, chlorine), and each of R ⁵ and R ⁶ is halogen (eg, chlorine),

Z ² is not unsubstituted C _1-3 alkoxy.

In certain embodiments of formula (I), when Z ² is N, R ³ is H, R ⁴ is optionally substituted C _1-6 thioalkoxy, and each of R ⁵ and R ⁶ is halogen (eg, chlorine),

Z ¹ is not cyanomethoxy or aminomethoxy.

In other embodiments of formula (I), when Z ² is N, R ³ is H, each of R ⁵ and R ⁶ is halogen (eg, chlorine), and R ⁴ is substituted C _1-6 thioalkoxy,

Z ¹ is not cyanomethoxy or aminomethoxy.

In some embodiments of formula (I), when Z ² is N, R ³ is H, and R ⁴ is optionally substituted C _1-6 thioalkoxy,

Z ¹ is not cyanomethoxy or aminomethoxy.

In certain embodiments of formula (I), when Z ² is N, R ³ is H, and R ⁴ is substituted C _1-6 thioalkoxy,

Z ¹ is not cyanomethoxy or aminomethoxy.

In further embodiments of formula (I), when Z ² is N, R ³ is H, and R ⁴ is substituted C _1-6 thioalkoxy,

Z ¹ is not a substituted C ₁ alkoxy group.

In a specific embodiment of formula (I), when Z ² is N, R ³ is H, and R ⁴ is a substituted C _1-6 thioalkoxy group,

Z ¹ is -OR ⁷ , -N(R ⁷ )R ¹⁰ , -SR ⁷ , or -C(R ⁷ )(R ¹⁰ )R ¹¹ , wherein R ⁷ is methyl, dialkylaminoethyl, optionally substituted C _1-3 alkylcycloalkyl, optionally substituted C _1-3 alkylheterocyclyl, or optionally substituted C _1-3 alkylaryl, or R ⁷ and R ^8, together with the atoms to which they are attached, join to form an optionally substituted five- or six-membered ring optionally including one or two heteroatoms selected from nitrogen, oxygen, and sulfur.

In other embodiments of formula (I), when Z ² is CR ³ , each of R ⁵ and R ⁶ is chlorine, R ³ is H, and R ⁴ is halogen (eg, chlorine),

Z ¹ is not 2-amino-2-oxoethoxy, 2-(N,N-diethylamino)ethoxy, methoxy, or benzyloxy.

In still other embodiments of Formula (I), when Z ² is CR ³ , R ³ is H, and R ⁴ is halogen (eg, chlorine),

Z ¹ is not 2-amino-2-oxoethoxy, 2-(N,N-diethylamino)ethoxy, methoxy, or benzyloxy.

In still other embodiments of Formula (I), when Z ² is CR ³ , each of R ⁵ and R ⁶ is chlorine, R ³ is H, and R ⁴ is halogen (e.g., chlorine),

Z ¹ is -OR ⁷ , -N(R ⁷ )R ¹⁰ , -SR ⁷ , or -C(R ⁷ )(R ¹⁰ )R ¹¹ , wherein R ⁷ is dimethylaminoethyl, optionally substituted C _1-3 alkanecycloalkyl, or optionally substituted C _1-3 alkehterocyclyl, or R ⁷ and R ^8, together with the atoms to which they are attached, join to form an optionally substituted five- or six-membered ring optionally including one or two heteroatoms selected from nitrogen, oxygen, and sulfur.

In further embodiments of formula (I), when Z ² is CR ³ , each of R ⁵ and R ⁶ is chlorine, R ³ is H, and R ⁴ is halogen (eg, chlorine),

Z ¹ is -OR ⁷ , -N(R ⁷ )R ¹⁰ , -SR ⁷ , or -C(R ⁷ )(R ¹⁰ )R ¹¹ , wherein R ⁷ is optionally substituted C _1-3 alkoxycycloalkyl, or optionally substituted C _1-3 alkoxyheterocyclyl, or R ⁷ and R ⁸ are joined together with the atoms to which they are attached to form an optionally substituted five- or six-membered ring optionally including one or two heteroatoms selected from nitrogen, oxygen, and sulfur.

In particular embodiments of formula (I), when Z ² is CR ³ , R ³ is H, and R ⁴ is halogen (eg, chlorine),

Z ¹ is -OR ⁷ , -N(R ⁷ )R ¹⁰ , -SR ⁷ , or -C(R ⁷ )(R ¹⁰ )R ¹¹ , wherein R ⁷ is optionally substituted C _1-3 alkoxycycloalkyl, or optionally substituted C _1-3 alkoxyheterocyclyl, or R ⁷ and R ⁸ are joined together with the atoms to which they are attached to form an optionally substituted five- or six-membered ring optionally including one or two heteroatoms selected from nitrogen, oxygen, and sulfur.

In some embodiments of formula (I), when R ⁵ is chloro, R ⁶ is bromo, Z ¹ is -OR ⁷ , Z ² is CR ³ , and R ³ and R ⁴ combine to form a group according to formula (IIa):

R ⁷ is not methyl, ethyl, n-propyl, 2-(N-pyrazolyl)ethyl, 2-(N-imidazolyl)ethyl, 3-hydroxypropyl, cyanomethyl, 2-chloroethyl, 2-hydroxyethyl, 2-oxopropyl, 2-(N,N-dimethylamino)ethyl, difluoromethyl or 2-(tert-butylamino)ethyl.

In certain embodiments of formula (I), when R ⁵ is chloro, R ⁶ is bromo, Z ¹ is -OR ⁷ , Z ² is CR ³ , R ³ and R ⁴ combine to form a group according to formula (IIa),

R ⁷ is not substituted alkyl, unsubstituted alkyl, or unsubstituted C ₂ alkheteroaryl.

In some embodiments of formula (I), when R ⁵ is chloro, R ⁶ is bromo, Z ¹ is -OR ⁷ , Z ² is CR ³ , and R ³ and R ⁴ combine to form a group according to formula (IIa),

R ⁷ is not alkyl or unsubstituted C ₂ alkheteroaryl.

In a specific embodiment of formula (I), when R ⁵ is chloro, R ⁶ is bromo, Z ¹ is -OR ⁷ , Z ² is CR ³ , R ³ and R ⁴ combine to form a group according to formula (IIa),

R ⁷ is not substituted alkyl, unsubstituted alkyl, or unsubstituted C ₂ alkheterocyclyl.

In other embodiments of formula (I), when R ⁵ is chloro, R ⁶ is bromo, Z ¹ is -OR ⁷ , Z ² is CR ³ , and R ³ and R ⁴ combine to form a group according to formula (IIa),

R ⁷ is not an alkyl group or a C ₂ alkaneheterocyclic group.

In still other embodiments of formula (I), when R ⁵ is chloro, R ⁶ is bromo, Z ¹ is -OR ⁷ , Z ² is CR ³ , and R ³ and R ⁴ combine to form a group according to formula (IIa),

R ⁷ and R ⁸ are joined together with the atoms to which they are attached to form an optionally substituted five- or six-membered ring optionally including one or two heteroatoms selected from nitrogen, oxygen, and sulfur.

In still other embodiments of formula (I), when R ⁵ is chloro, R ⁶ is bromo, Z ² is CR ³ , and R ³ and R ⁴ combine to form a group according to formula (IIa),

Z is -OR ⁷ , and R ⁷ and R ⁸ combine to form -CH ₂ -CH ₂ -.

In some embodiments of formula (I), when each R ⁵ and R ⁶ is bromo, Z ¹ is -OR ⁷ , Z ² is CR ³ , and R ³ and R ⁴ combine to form a group according to formula (IIa),

R ⁷ is not methyl.

In specific embodiments of formula (I), when each of R ⁵ and R ⁶ is chloro, Z ¹ is -OR ⁷ , Z ² is CR ³ , and R ³ and R ⁴ combine to form a group according to formula (IIa),

R is not ^methyl , 2-(N-imidazolyl)ethyl, methoxymethyl, 2-(N-pyrazolyl)ethyl, 2-(3-methylpyrazol-1-yl)ethyl, 2-pyridyl-methyl, 1,3-dimethyl-1H-1,2,4-triazol-5-yl-methyl, 2-pyrimidinylmethyl, imidazol-2-yl-methyl, 5-methyl-isoxazol-3-yl-methyl, 4-methyl-imidazol-5-yl-methyl, or 3-methyl-1,2,4-oxadiazol-5-yl-methyl.

In other embodiments of formula (I), when each R ⁵ and R ⁶ is chloro, Z ¹ is -OR ⁷ , Z ² is CR ³ , and R ³ and R ⁴ combine to form a group according to formula (IIa),

R ⁷ is not unsubstituted alkyl, substituted alkyl, unsubstituted alkheteroaryl, or substituted alkheteroaryl.

In other embodiments of formula (I), when each R ⁵ and R ⁶ is chloro, Z ¹ is -OR ⁷ , Z ² is CR ³ , and R ³ and R ⁴ combine to form a group according to formula (IIa),

R ⁷ is not unsubstituted alkyl, substituted alkyl, unsubstituted alkheterocyclyl, or substituted alkheterocyclyl.

In certain embodiments of formula (I), when each R ⁵ and R ⁶ is chloro, Z ¹ is -OR ⁷ , R ⁷ and R ⁸ combine to form -CH ₂ -CH ₂ -, Z ² is CR ³ , and R ³ and R ⁴ combine to form a group according to formula (IIa),

R ⁹ is not ethoxycarbonyl, cyclobutylaminocarbonyl, or cyclobutadienylaminocarbonyl.

In other embodiments of formula (I), when each R ⁵ and R ⁶ is chloro, Z ¹ is -OR ⁷ , R ⁷ and R ⁸ combine to form -CH ₂ -CH ₂ -, Z ² is CR ³ , and R ³ and R ⁴ combine to form a group according to formula (IIa),

^R9 is H or -C(O)-N(H)-(straight chain _C1-3 alkyl).

In specific embodiments of formula (I), when each of R ⁵ and R ⁶ is halogen, Z ² is CR ³ , and R ³ and R ⁴ combine to form a group according to formula (IIa),

Z is -OR ⁷ , R ⁷ is not methyl or 2-chloroethyl, and R ⁹ is H or -C(O)-N(H)-(straight chain C _1-3 alkyl).

In some embodiments of formula (I), when R ⁵ is methoxy, R ⁶ is methyl, Z ¹ is -OR ⁷ , Z ² is CR ³ , and R ³ and R ⁴ combine to form a group according to formula (IIa),

R ⁷ is not methyl.

In certain embodiments of formula (I), when R ⁵ is chloro, R ⁶ is ethyl, Z ¹ is -OR ⁷ , Z ² is CR ³ , and R ³ and R ⁴ combine to form a group according to formula (IIa),

R ⁷ is not methyl.

In some embodiments of formula (I), when each R ⁵ and R ⁶ is chloro, Z ¹ is -OR ⁷ , Z ² is CR ³ , and R ³ and R ⁴ combine to form a group according to formula (IIb) or (IIc),

R ⁷ is not methyl or 2-(N,N-diethylamino)ethyl.

In other embodiments of formula (I), when each R ⁵ and R ⁶ is chloro, Z ¹ is -OR ⁷ , Z ² is CR ³ , and R ³ and R ⁴ combine to form a group according to formula (IIb) or (IIc),

R ⁷ and R ⁸ are joined together with the atoms to which they are attached to form an optionally substituted five- or six-membered ring optionally including one or two heteroatoms selected from nitrogen, oxygen, and sulfur.

In certain embodiments of formula (I), when each R ⁵ and R ⁶ is chloro, Z ² is CR ³ , and R ³ and R ⁴ combine to form a group according to formula (IIb) or (IIc),

Z ¹ is -OR ⁷ , and R ⁷ and R ⁸ combine to form -CH ₂ -CH ₂ -.

In some embodiments of formula (I), when R ⁷ is methyl, R ⁵ is chloro, Z ¹ is -OR ⁷ , Z ² is CR ³ , R ³ and R ⁴ combine to form a group according to formula (IIIa),

^R6 is not bromine.

In particular embodiments of formula (I), when each R ⁵ and R ⁶ is chloro, Z ¹ is -OR ⁷ , Z ² is CR ³ , and R ³ and R ⁴ combine to form a group according to formula (IIIa),

R ⁷ is not isopropyl, 3,3,3-trifluoropropyl, or 2-(N,N-dimethylamino)ethyl.

In some embodiments of formula (I), when each R ⁵ and R ⁶ is chloro, Z ¹ is -OR ⁷ , Z ² is CR ³ , and R ³ and R ⁴ combine to form a group according to formula (IIIa),

R ⁸ is not H.

In some embodiments of formula (I), when Z ² is CR ³ and R ³ and R ⁴ combine to form a group according to formula (IIIa),

Each of ^R5 and ^R6 is chlorine, and

R ⁷ is methyl and R ⁸ is H, or R ⁷ and R ⁸ , together with the atoms to which they are attached, are joined to form an optionally substituted five- or six-membered ring optionally including one or two heteroatoms selected from nitrogen, oxygen, and sulfur.

In other embodiments of formula (I), when R ⁵ is chloro, R ⁶ is methoxy, Z ¹ is -OR ⁷ , Z ² is CR ³ , and R ³ and R ⁴ combine to form a group according to formula (IIIb):

Neither R ¹ nor R ² is 2-(N,N-diethylamino)ethyl.

In certain embodiments of formula (I), when R ⁵ is chloro, R ⁶ is methoxy, Z ¹ is -OR ⁷ , Z ² is CR ³ , and R ³ and R ⁴ combine to form a group according to formula (IIIb):

Each of ^R1 and ^R2 is H.

In some embodiments of formula (I), when each R ⁵ and R ⁶ is chloro, Z ¹ is -OR ⁷ , Z ² is CR ³ , and R ³ and R ⁴ combine to form a group according to formula (IVa),

R ⁷ is not 3-(N-morpholinyl)propyl, benzyl, 1-ethyl-pyrrolidin-3-yl, 1-methyl-piperidin-4-yl, 2-(1-methyl-pyrrolidin-2-yl)ethyl, or 3-(N,N-diethylamino)propyl.

In specific embodiments of formula (I), when each of R ⁵ and R ⁶ is chloro, Z ¹ is -OR ⁷ , Z ² is CR ³ , and R ³ and R ⁴ combine to form a group according to formula (IVa),

R ⁷ is not a substituted alkyl, heterocyclyl, alkheterocyclyl, or alkaryl group.

In some embodiments of formula (I), when each R ⁵ and R ⁶ is chloro, Z ¹ is -OR ⁷ , Z ² is CR ³ , and R ³ and R ⁴ combine to form a group according to formula (IVb):

R ⁷ is not 2-methoxyethyl or benzyl.

In certain embodiments of formula (I), when each R ⁵ and R ⁶ is chloro, Z ¹ is -OR ⁷ , Z ² is CR ³ , and R ³ and R ⁴ combine to form a group according to formula (IVb):

R ⁷ is not a substituted alkyl or alkaryl group.

In some embodiments of formula (I), when each R ⁵ and R ⁶ is chloro, Z ¹ is -OR ⁷ , Z ² is CR ³ , and R ³ and R ⁴ combine to form a group according to formula (IVc):

R ⁷ is not 2-(N,N-diethylamino)ethyl or 3-(N,N-dimethylamino)propyl.

In other embodiments of formula (I), when each R ⁵ and R ⁶ is chloro, Z ¹ is -OR ⁷ , Z ² is CR ³ , and R ³ and R ⁴ combine to form a group according to formula (IVc):

R ⁷ is not substituted alkyl.

In particular embodiments of formula (I), when each of R ⁵ and R ⁶ is chloro, Z ¹ is -OR ⁷ , Z ² is CR ³ , and R ³ and R ⁴ combine to form a group according to formula (IVd):

R ⁷ is not 2-(pyrrolidin-1-yl)ethyl or 2-hydroxyethyl.

In certain embodiments of formula (I), when each R ⁵ and R ⁶ is chloro, Z ¹ is -OR ⁷ , Z ² is CR ³ , and R ³ and R ⁴ combine to form a group according to formula (IVd):

R ⁷ is not a substituted alkyl group or an alkaneheterocyclic group.

In some embodiments of formula (I), when each R ⁵ and R ⁶ is chloro, Z ¹ is -OR ⁷ , Z ² is CR ³ , and R ³ and R ⁴ combine to form a group according to formula (IVe) or (IVf):

R ⁷ is not benzyl.

In other embodiments of formula (I), when each R ⁵ and R ⁶ is chloro, Z ¹ is -OR ⁷ , Z ² is CR ³ , and R ³ and R ⁴ combine to form a group according to formula (IVe) or (IVf):

R ⁷ is not an alkaryl group.

In certain embodiments of formula (I), when R ⁵ is chloro, R ⁶ is bromo, Z ¹ is -OR ⁷ , Z ² is CR ³ , R ³ and R ⁴ combine to form a group according to formula (IVg), (IVh), (IVi), (IVj), or (IVk):

R ⁷ is not methyl.

In certain embodiments of formula (I), when R ⁵ is chloro, R ⁶ is bromo, Z ¹ is -OR ⁷ , Z ² is CR ³ , R ³ and R ⁴ combine to form a group according to formula (IVg), (IVh), (IVi), (IVj), or (IVk),

^R7 is not an alkyl group.

In some embodiments of formula (I), when R ⁵ is chloro, R ⁶ is bromo, Z ¹ is -OR ⁷ , Z ² is CR ³ , R ³ and R ⁴ combine to form a group according to formula (IVg), (IVh), (IVi), (IVj), or (IVk),

R ⁷ and R ⁸ are joined together with the atoms to which they are attached to form an optionally substituted five- or six-membered ring optionally including one or two heteroatoms selected from nitrogen, oxygen, and sulfur.

In a specific embodiment of formula (I), when R ⁵ is chloro, R ⁶ is bromo, Z ¹ is -OR ⁷ , and Z ² is CR ³ ,

R ³ and R ⁴ do not combine to form a group according to Formula (IVg), (IVh), (IVi), (IVj), or (IVk).

In a specific embodiment of formula (I), when R ⁶ is methyl,

Each of ^R1 and ^R2 is H.

In certain embodiments of formula (I), when R ³ is H, and each of R ⁵ and R ⁶ is chloro,

R ⁷ is not methyl.

In certain embodiments of Formula (I), R ^m is H (e.g., the compound of Formula (I) has the structure:

or a pharmaceutically acceptable salt thereof.

In certain embodiments of Formula (I),

In some embodiments of the method of the present invention, substituents are defined as described herein. In a specific embodiment of the method of the present invention, the method includes giving a mammal an effective amount of a compound according to formula (I). In certain embodiments of the method of the present invention, the method includes giving a mammal an effective amount of a compound according to formula (Ib). In other embodiments, the method relates to giving a mammal an effective amount of a compound according to formula (Va). In certain embodiments, the method relates to giving a mammal an effective amount of a compound according to formula (Vb). In a specific embodiment, the compound can be selected from Table 2, (for example, any one of compounds 2, 5-16, 18-27, 29, 33-36, 40-48, and 58-77, or a pharmaceutically acceptable salt thereof). In a further embodiment, the method includes giving a mammal an effective amount of compound 38 or 39 or a pharmaceutically acceptable salt thereof.

In certain embodiments of the methods of the invention, the methods comprise treating a mammal having a neurodegenerative disorder by administering to the mammal a compound having Formula (I) (e.g., Formula (Ia), (Ib), (Va), or (Vb)).

In certain embodiments, the obstacle is a neurodegenerative disorder (for example, tau protein pathology).Neurodegenerative disorder can be Alzheimer's disease, Huntington's chorea, progressive supranuclear palsy, Parkinson's syndrome, Pick's disease, corticobasal degeneration, chronic traumatic encephalopathy, traumatic brain injury or frontotemporal dementia.Preferably, neurodegenerative disorder is Alzheimer's disease.In other embodiments, the obstacle is a proliferative disease (for example cancer, such as acute myeloid leukemia, gastrointestinal stromal tumor, gastric cancer, glioblastoma, lung cancer, lymphoma, melanoma, myeloma, non-small cell lung cancer, renal cancer, small cell lung cancer, blast stage chronic myeloid leukemia, leukemia, lymphoproliferative disorder, metastatic melanoma, relapsed multiple myeloma, refractory multiple myeloma, myeloproliferative disorder, pancreatic cancer, small intestinal cancer or solid tumor).

In specific embodiments, the disorder is an inflammatory or autoimmune disease (e.g., rheumatoid arthritis, systemic lupus erythematosus, or asthma). In certain embodiments, the disorder is a cardiovascular disease (e.g., atherosclerosis or cardiomyopathy). In other embodiments, the disorder is an allergy.

In still another aspect, the invention features a method of treating an infectious disease in a mammal by administering to the mammal an effective amount of a compound of the invention (eg, a compound of the above aspects) or a pharmaceutically acceptable salt thereof.

In some embodiments, the infectious disease is a viral infection. In certain embodiments, the viral infection is a Herpesviridae (e.g., herpes simplex virus-1, herpes simplex virus-2, herpes virus-5, Kaposi's sarcoma-associated herpes virus, varicella-zoster virus, or Epstein-Barr virus), a Polyomaviridae (e.g., SV40), a Poxviridae (e.g., vaccinia virus), a Reoviridae (e.g., rotavirus), a Biviridae (e.g., infectious bursal disease virus), a Picornaviridae (e.g., poliovirus, rhinovirus, or coxsackievirus), a Flaviviridae (e.g., hepatitis C virus or dengue virus), an Arenaviridae Viruses of the family Hepadnaviridae (e.g., lymphocytic choriomeningitis virus), Hepaciviridae (e.g., hepatitis E virus), Rhabdoviridae (e.g., vesicular stomatitis virus), Paratyphiviridae (e.g., human parainfluenza virus 2, human parainfluenza virus 3, SV5, SV41, measles virus, or Sendai virus), Bunyaviridae (e.g., La Crosse virus), Orthoviridae (e.g., influenza A virus), Filoviridae (e.g., Ebola virus), Retroviridae (e.g., HTLV1 or HIV1), or Hepadnaviridae (e.g., hepatitis B virus).

In specific embodiments, the infectious disease is a fungal infection (eg, Candida albicans, Aspergillus fumigatus, or Pneumocystis jiroveci).

In other embodiments, the infectious disease is a bacterial infection (eg, mycobacterium, anthrax, or bacterial pneumonia).

In some embodiments of any aspect of the methods of the invention, the compound is administered orally, sublingually, buccally, transdermally, intradermally, intramuscularly, parenterally, intravenously, intraarterially, intracranially, subcutaneously, intraorbitally, intraventricularly, intraspinally, intraperitoneally, intranasally, by inhalation, and topically. Preferably, the compound is administered orally.

In certain embodiments of any aspect of the methods of the invention, the mammal is a human.

In a further aspect, the invention features a method of inhibiting Hsp90 by contacting a cell with a compound of the invention or a pharmaceutically acceptable salt thereof. In some embodiments, the method is performed in vitro. In other embodiments, the method is performed in vivo.

In another aspect, the invention features a kit comprising:

(i) the pharmaceutical composition of the present invention; and

(ii) instructions for using the pharmaceutical composition of (i) to treat a disorder in a mammal (eg, a human) caused by the action of Hsp90.

In still another aspect, the invention features a compound of the invention for use in treating a disorder caused by the action of heat shock protein 90 (Hsp90). In some embodiments of this aspect, the disorder is any of the disorders described in the characterizing aspects of the methods of the invention. In a related aspect, the invention features a compound of the invention for use in treating an infectious disease. In certain embodiments of this aspect, the infectious disease is any of the infectious diseases described in the characterizing aspects of the methods of the invention.

In yet another aspect, the invention features the use of a compound of the invention for treating a disorder caused by the action of heat shock protein 90 (Hsp90). In some embodiments of this aspect, the disorder can be any of the disorders described in the characterizing aspects of the methods of the invention. In a related aspect, the invention features the use of a compound of the invention for treating an infectious disease. In certain embodiments of this aspect, the infectious disease is any of the infectious diseases described in the characterizing aspects of the methods of the invention.

In a further aspect, the invention features the use of a compound of the invention in the manufacture of a medicament for treating a disorder caused by the action of heat shock protein 90 (Hsp90). In some embodiments of this aspect, the disorder can be any of the disorders described in the characterizing aspects of the methods of the invention. In a related aspect, the invention features the use of a compound of the invention in the manufacture of a medicament for treating an infectious disease. In certain embodiments of this aspect, the infectious disease is any of the infectious diseases described in the characterizing aspects of the methods of the invention.

definition

Chemical substituents

As used herein, the term "about" refers to a value that is ±10% of the recited value.

The terms "acyl" or "alkanoyl," as used interchangeably herein, refer to an alkyl group, as defined herein, or a hydrogen attached to the parent molecular group through a carbonyl group, as defined herein, and are exemplified by formyl, acetyl, propionyl, butyryl, and the like. Exemplary unsubstituted acyl groups contain from 2 to 7 carbon atoms. Acyl groups may be unsubstituted or substituted, as defined for alkyl groups.

The term "alkaryl" as defined herein refers to a chemical substituent of the formula -(alkylene)-(aryl), wherein each group is as defined herein and may be substituted or unsubstituted according to the respective definitions.

The term "alkheterocyclyl" as defined herein refers to a chemical substituent of the formula -(alkylene)-(heterocyclyl), wherein each group is as defined herein and may be substituted or unsubstituted according to the respective definitions.

As used herein, unless otherwise indicated (eg, R is C _1-3 alkyl), the term "alkoxy" refers to a chemical substituent of the formula -OR, wherein R is C _1-6 alkyl. The alkoxy group may be unsubstituted or substituted with one, two, or three substituents independently selected from the group consisting of: (1) alkoxy groups of 1 to 6 carbon atoms; (2) hydroxy groups; (3) amino groups; (4) alkylamino groups of 1 to 6 carbon atoms; (5) dialkylamino groups, wherein each alkyl group is independently 1 to 6 carbon atoms; (6) cycloalkyl groups of 3 to 8 carbon atoms; (7) oxo groups; (8) halogen groups; (9) alkylsulfonyl groups of 1 to 6 carbon atoms; (10) thioalkoxy groups of 1 to 6 carbon atoms; (11) aryl groups; ( ¹² ) _-CO2RA , wherein ^RA is selected from the group consisting of: (a) hydrogen, (b) alkyl, (c) cycloalkyl, (d) alkylcycloalkyl, and (e) alkaryl groups, wherein the alkylene group is 1 to 6 carbon atoms; or (13) -C(O)NR ^{B RC} , wherein each ^RB and R ^C is independently selected from the group consisting of (a) hydrogen, (b) alkyl, (c) cycloalkyl, (d) alkcycloalkyl, and (e) alkaryl, wherein the alkylene group is from 1 to 6 carbon atoms; provided that no more than one substituent (2)-(5) may be attached to a single carbon atom of the alkyl group, and no substituent (2)-(5) may be attached to a carbon atom that is attached to an oxygen atom of an alkoxy group. No more than one oxo substituent may be attached to a single carbon of an alkoxy group, and no more than two oxo substituents may be found in any alkoxy group as defined herein.

As used herein, the term "alkoxyalkyl" refers to an alkyl group substituted with an alkoxy group. Exemplary unsubstituted alkoxyalkyl groups include 2 to 9 carbon atoms. In some embodiments, the alkyl group and the alkoxy group can each be further substituted with 1, 2, 3, 4, or 5 substituents as defined herein for each corresponding group.

Unless otherwise indicated (e.g., 1 to 3 carbons), the term "alkyl" as used herein includes straight and branched chain saturated groups of 1 to 6 carbons. Examples of alkyl groups are methyl, ethyl, n-propyl, and isopropyl, and may be optionally substituted with one, two, three, or, in the case of an alkyl group of two or more carbons, four substituents independently selected from the group consisting of: (1) alkoxy of 1 to 6 carbons; (2) hydroxy; (3) amino; (4) alkylamino of 1 to 6 carbons; (5) dialkylamino, wherein each alkyl group is independently 1 to 6 carbons; (6) cycloalkyl of 3 to 8 carbons; (7) oxo; (8) halogen; (9) alkylsulfonyl of 1 to 6 carbon atoms; (10) thioalkoxy of 1 to 6 carbon atoms; (11) aryl; (12) -CO ₂ R ^A , wherein R ^A is selected from the group consisting of (a) hydrogen, (b) alkyl, (c) cycloalkyl, (d) alkancycloalkyl, and (e) alkaryl, wherein the alkylene group is 1 to 6 carbon atoms; (13) -C(O)NR ^{B RC} , wherein each ^RB and ^RC are independently selected from the group consisting of (a) hydrogen, (b) alkyl, (c) cycloalkyl, (d) alkancycloalkyl, and (e) alkaryl, wherein the alkylene group is 1 to 6 carbon atoms, or ^RB and ^RC are combined to form a C _2-9 heterocyclyl; and (14) cyano; provided that no more than one substituent (2)-(5) may be attached to a single carbon atom of the alkyl group. No more than one oxo substituent may be attached to a single carbon atom of the alkyl group, and no more than two oxo substituents may be found in any alkyl group as defined herein.

As used herein, the term "alkylene" and the prefix "alk-" refer to a saturated divalent _C1-10 hydrocarbon group derived from a straight or branched saturated hydrocarbon by removing two hydrogen atoms, and are exemplified by methylene, ethylene, propylene, isopropylene, and the like. The term " _Cxy alkylene" and the prefix " _Cxy alk-" refer to an alkylene group having between x and y carbon atoms. Exemplary values for x are 1, 2, 3, 4, 5, and 6, and exemplary values for y are 2, 3, 4, 5, 6, 7, 8, 9, or 10. In some embodiments, the alkylene group may be further substituted with 1, 2, 3, or 4 substituent groups as defined herein for an alkyl group.

As used herein, the term "alkylsulfonyl" refers to an alkyl group attached to the parent molecular group through a -S(O) ₂ - group. Exemplary unsubstituted alkylsulfonyl groups have 1 to 6 carbon atoms. In some embodiments, the alkyl group may be further substituted with 1, 2, 3, or 4 substituent groups as defined herein.

As used herein, the term "amino" refers to a chemical substituent of the formula _-NH . Amino groups may be monosubstituted, for example, by alkyl, alkanoyl, aryl, aroyl, cycloalkyl, heterocyclyl, or heterocycloalkylheterocyclyl groups (e.g., "alkylamino" (optionally substituted C _1-6 alkyl) of the formula -NH-, for example, -NH-(unsubstituted C _1-6 alkyl)), or disubstituted, for example, by alkyl, alkanoyl, aryl, aroyl, cycloalkyl, heterocyclyl, or heterocycloalkylheterocyclyl groups (e.g., "dialkylamino" of the formula -NR'R", wherein each R' and R" are independently optionally substituted C _1-6 alkyl, for example, -NR'R", wherein each R' and R" are independently unsubstituted C _1-6 alkyl). Optionally substituted C _1-6 alkyl groups may be C _1-6 haloalkyl, for example, C _1-6 fluoroalkyl.

The term "aminoalkyl" as used herein refers to an alkyl group substituted by an amino group. Each alkyl and amino group may independently be substituted or unsubstituted as defined herein for each corresponding group.

As used herein, the term "aryl" refers to a monocyclic, bicyclic, or polycyclic carbocyclic ring system having three to twelve carbon atoms and one or two aromatic rings. Non-limiting examples of aryl groups include phenyl, naphthyl, 1,2-dihydronaphthyl, 1,2,3,4-tetrahydronaphthyl, fluorenyl, indanyl, indenyl, and the like. The aryl group may be optionally substituted with one, two, three, four, or five substituents independently selected from the group consisting of: (1) alkyl groups of 1 to 6 carbon atoms; (2) alkoxy groups of 1 to 6 carbon atoms; (3) hydroxy groups; (4) amino groups; (5) alkylamino groups of 1 to 6 carbon atoms; (6) dialkylamino groups, wherein each alkyl group is independently 1 to 6 carbon atoms; (7) cycloalkyl groups of 3 to 8 carbon atoms; (8) oxo groups; (9) halogen groups; (10) alkylsulfonyl groups of 1 to 6 carbon atoms; (11) thioalkoxy groups of 1 to 6 carbon atoms; (12) aryl groups; (13) alkaryl groups, wherein the alkylene group is 1 to 6 carbon atoms; (14) -CO ₂ R ^A , wherein R ^A is selected from the group consisting of (a) alkyl, (b) cycloalkyl, (c) alkanecycloalkyl, (d) alkaryl, and (e) halogen, wherein the alkylene group is 1 to 6 carbon atoms; and (15) -C(O)NR ^{B RC} , wherein each ^RB and ^RC is independently selected from the group consisting of (a) alkyl, (b) cycloalkyl, (c) alkanecycloalkyl, (d) alkaryl, and (e) halogen, wherein the alkylene group is 1 to 6 carbon atoms.

The term "aroyl," as used herein, refers to an aryl group attached to the parent molecular group through an alkyl group.

The term "carbonyl" as used herein refers to a C(O) group, which may also be represented as C=O, and results from the combination of a tetravalent carbon atom and an oxo substituent.

The term "cyano" as used herein refers to a -CN group.

As used herein, the term "cyanoalkyl" refers to an alkyl group substituted with a cyano group. Exemplary unsubstituted cyanoalkyl groups include 2 to 9 carbon atoms. In some embodiments, the alkyl group may be further substituted with 1, 2, 3, 4, or 5 substituents as defined herein for each corresponding group.

The term "cycloalkyl" as used herein, unless otherwise specified, means a monovalent saturated or unsaturated non-aromatic cyclic hydrocarbon group of 3 to 8 carbons, and is exemplified by cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, bicyclo[2.2.1.]heptyl and the like. The cycloalkyl group may be optionally substituted with, for example, one, two, three, or four substituents independently selected from: (1) an alkyl group of 1 to 6 carbon atoms; (2) an alkoxy group of 1 to 6 carbon atoms; (3) a hydroxyl group; (4) an amino group; (5) an alkylamino group of 1 to 6 carbon atoms; (6) a dialkylamino group, wherein each alkyl group is independently 1 to 6 carbon atoms; (7) a cycloalkyl group of 3 to 8 carbon atoms; (8) an oxo group; (9) a halogen group; (10) an alkylsulfonyl group of 1 to 6 carbon atoms; (11) a thioalkoxy group of 1 to 6 carbon atoms; (12) an aryl group; (13) an alkaryl group, wherein the alkylene group is 1 to 6 carbon atoms; (14) -CO ₂ R ^A , wherein R ^A is selected from the group consisting of (a) alkyl, (b) cycloalkyl, (c) alkanecycloalkyl, (d) alkaryl, and (e) halogen, wherein the alkylene group is 1 to 6 carbon atoms; or (15) -C(O)NR ^{B RC} , wherein each ^RB and ^RC are independently selected from the group consisting of (a) alkyl, (b) cycloalkyl, (c) alkanecycloalkyl, (d) alkaryl, and (e) halogen, wherein the alkylene group is 1 to 6 carbon atoms, or ^RB and ^RC are combined to form a C _2-9 heterocyclyl.

As used herein, the term "five-membered ring" refers to a saturated or unsaturated aromatic or non-aromatic group having five atoms in a cyclic array, wherein, unless otherwise specified, four atoms are carbon and the remaining atoms are selected from the group consisting of carbon, nitrogen, sulfur and oxygen. The five-membered ring may be fused to another ring group selected from heterocyclyl, heteroaryl, cycloalkyl and aryl. The five-membered ring may be unsubstituted or substituted with, for example, one, two, three, or four substituents independently selected from the group consisting of: (1) alkoxy of 1 to 6 carbon atoms; (2) hydroxy; (3) amino; (4) alkylamino of 1 to 6 carbon atoms; (5) dialkylamino, wherein each alkyl group is independently 1 to 6 carbon atoms; (6) cycloalkyl of 3 to 8 carbon atoms; (7) oxo; (8) alkylsulfonyl of 1 to 6 carbon atoms; (9) thioalkoxy of 1 to 6 carbon atoms; (10) aryl; (11) alkaryl, wherein the alkylene group is 1 to 6 carbon atoms; (12) optionally substituted alkyl of 1 to 6 carbon atoms (e.g., unsubstituted alkyl, alkoxyalkyl, hydroxyalkyl, haloalkyl, or cyanoalkyl); (13) -CO ₂ R ^A , wherein R ^A is selected from the group consisting of (a) alkyl, (b) cycloalkyl, (c) alkancycloalkyl, (d) alkaryl, and (e) halogen, wherein the alkylene group is 1 to 6 carbon atoms; (14) -C(O)NR ^{B RC} , wherein each ^RB and ^RC are independently selected from the group consisting of (a) optionally substituted alkyl (e.g., unsubstituted alkyl, alkoxyalkyl, hydroxyalkyl, haloalkyl, or cyanoalkyl), (b) cycloalkyl, (c) alkancycloalkyl, (d) alkaryl, (e) heterocyclyl, (f) alkheterocyclyl, (g) alkoxy, and (h) halogen, wherein the alkylene group is 1 to 6 carbon atoms, or ^RB and ^RC are combined to form a C _2-9 heterocyclyl; and (15) cyano.

The term "fluoroalkyl" as used herein refers to an alkyl group as defined herein, wherein one or more hydrogen groups (e.g., 1, 2, 3, 4, or 5 or more hydrogen groups) bound to the alkyl group are replaced by a fluoro group. In some embodiments, the fluoroalkyl group can be a perfluoroalkyl group. The prefix "fluoro" indicates that the group is replaced by one or more (e.g., 1, 2, 3, 4, or 5 or more) fluoro groups.

As used herein, the term "haloalkyl" refers to an alkyl group as defined herein that is substituted with a halogen group (i.e., F, Cl, Br, or I). C _1-6 haloalkyl can be substituted with one, two, three, or, in the case of an alkyl group of two or more carbons, four, or five halogens. Haloalkyl groups include perfluoroalkyl groups. In certain embodiments, haloalkyl groups are fluoroalkyl groups. In some embodiments, C _1-6 haloalkyl groups can be further substituted with 1, 2, 3, or 4 substituents as described herein for alkyl groups.

The terms "halogen," "hal," or "halo," used interchangeably herein, refer to a group selected from fluorine (-F), chlorine (-Cl), bromine (-Br), and iodine (-I). The prefix "halogen" indicates that the group is substituted with a halogen group (i.e., F, Cl, Br, or I).

Unless otherwise indicated, the term "heterocyclyl" as used herein refers to a 5-, 6-, or 7-membered ring containing one, two, three, or four heteroatoms independently selected from nitrogen, oxygen, and sulfur. The 5-membered ring has 0 to 2 double bonds, and the 6- and 7-membered rings have 0 to 3 double bonds. The term "heterocyclyl" also refers to a heterocyclic compound having a bridged polycyclic structure in which one or more carbon and/or heteroatoms bridge two non-adjacent members of a monocyclic ring, such as a quinuclidinyl group. The term "heterocyclyl" also includes bicyclic, tricyclic, and tetracyclic groups, wherein any of the above heterocyclic rings is fused to one, two, or three carbocyclic rings, such as an aromatic ring, a cyclohexane ring, a cyclohexene ring, a cyclopentane ring, a cyclopentene ring, or another monocyclic heterocycle, such as an indolyl, quinolyl, isoquinolyl, tetrahydroquinolyl, benzofuranyl, benzothiophenyl, etc. Examples of fused heterocyclic groups include tropane and 1,2,3,5,8,8a-hexahydroindolizine. Heterocyclic rings include pyrrolyl, pyrrolinyl, pyrrolidinyl, pyrazolyl, pyrazolinyl, pyrazolidinyl, imidazolyl, imidazolinyl, imidazolidinyl, pyridinyl, piperidinyl, homopiperidinyl, pyrazinyl, piperazinyl, pyrimidinyl, pyridazinyl, oxazolyl, oxazolidinyl, isoxazolyl, isoxazolidinyl, morpholinyl, thiomorpholinyl, thiazolyl, thiazolidinyl, isothiazolyl, isothiazolidinyl, indolyl, quinolinyl, isoquinolinyl, benzimidazolyl, benzo thiazolyl, benzoxazolyl, furyl, thienyl, thiazolidinyl, isothiazolyl, isoindazoyl, triazolyl, tetrazolyl, oxadiazolyl, uricyl, thiadiazolyl, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothienyl, dihydrothienyl, dihydroindolyl, tetrahydroquinolyl, tetrahydroisoquinolyl, pyranyl, dihydropyranyl, dithiazolyl, benzofuranyl, benzothienyl and the like. The heterocyclic group may be optionally substituted with one, two, three, four, or five substituents independently selected from the group consisting of: (1) alkyl of 1 to 6 carbon atoms; (2) alkoxy of 1 to 6 carbon atoms; (3) hydroxy; (4) amino; (5) alkylamino of 1 to 6 carbon atoms; (6) dialkylamino, wherein each alkyl group is independently 1 to 6 carbon atoms; (7) cycloalkyl of 3 to 8 carbon atoms; (8) oxo; (9) halogen; (10) alkylsulfonyl of 1 to 6 carbon atoms; (11) thioalkoxy of 1 to 6 carbon atoms; (12) aryl; (13) alkaryl; (14) -CO ₂ R ^A , wherein R ^A is selected from the group consisting of (a) alkyl, (b) cycloalkyl, (c) alkanecycloalkyl, (d) alkaryl, and (e) halogen, wherein the alkylene group is 1 to 6 carbon atoms; or (15) -C(O)NR ^{B RC} , wherein each ^RB and ^RC are independently selected from the group consisting of (a) alkyl, (b) cycloalkyl, (c) alkanecycloalkyl, (d) alkaryl, and (e) halogen, wherein the alkylene group is 1 to 6 carbon atoms, or ^RB and ^RC are combined to form a C _2-9 heterocyclyl.

As used herein, the term "heteroaryl" refers to a subset of heterocyclic groups as defined herein that are aromatic: that is, they contain 4n+2 π electrons within a monocyclic or polycyclic ring system. In some embodiments, the heteroaryl group is substituted with, for example, 1, 2, 3, or 4 substituents independently selected from the group consisting of: (1) alkyl of 1 to 6 carbon atoms; (2) alkoxy of 1 to 6 carbon atoms; (3) hydroxy; (4) amino; (5) alkylamino of 1 to 6 carbon atoms; (6) dialkylamino, wherein each alkyl group is independently 1 to 6 carbon atoms; (7) cycloalkyl of 3 to 8 carbon atoms; (8) oxo; (9) halogen; (10) alkylsulfonyl of 1 to 6 carbon atoms; (11) thioalkoxy of 1 to 6 carbon atoms; (12) aryl; (13) alkaryl; (14) -CO ₂ R ^A , wherein R ^A is selected from the group consisting of (a) alkyl, (b) cycloalkyl, (c) alkanecycloalkyl, (d) alkaryl, and (e) halogen, wherein the alkylene group is 1 to 6 carbon atoms; or (15) -C(O)NR ^{B RC} , wherein each ^RB and ^RC are independently selected from the group consisting of (a) alkyl, (b) cycloalkyl, (c) alkanecycloalkyl, (d) alkaryl, and (e) halogen, wherein the alkylene group is 1 to 6 carbon atoms.

As used herein, the term "hydroxy" refers to an -OH group.

The term "hydroxyalkyl" as used herein means an alkyl group as defined herein substituted with one or two hydroxy groups, provided that not more than one hydroxy group may be attached to a single carbon atom of the alkyl group, and is exemplified by hydroxymethyl, dihydroxypropyl, and the like.

The term "N-protected amino" as used herein refers to an amino group, as defined herein, to which is attached an N-protecting group, as defined herein.

As used herein, the term "N-protecting group" refers to those groups intended to protect an amino group from undesirable reactions during synthesis. Commonly used N-protecting groups are disclosed in Greene, Protective Groups in Organic Synthesis, 3rd Edition (John Wiley & Sons, New York, 1999), which is incorporated herein by reference. N-protecting groups include acyl, aroyl or carbamoyl groups, such as formyl, acetyl, propionyl, pivaloyl, tert-butylacetyl, 2-chloroacetyl, 2-bromoacetyl, trifluoroacetyl, trichloroacetyl, phthaloyl, o-nitrophenoxyacetyl, α-chlorobutyryl, benzoyl, 4-chlorobenzoyl, 4-bromobenzoyl, 4-nitrobenzoyl and chiral auxiliaries, such as protected or unprotected D,L or D,L-amino acids, such as alanine, leucine, phenylalanine, etc.; sulfonyl groups, such as benzylsulfonyl, p-toluenesulfonyl, etc.; carbamate-forming groups, such as benzyloxycarbonyl, p-chlorobenzyloxycarbonyl, p-methoxybenzyloxycarbonyl, p-nitrobenzyloxycarbonyl, 2-nitrobenzyloxycarbonyl, p-bromobenzyloxycarbonyl, 3,4-dimethoxybenzyloxycarbonyl, , 3,5-dimethoxybenzyloxycarbonyl, 2,4-dimethoxybenzyloxycarbonyl, 4-methoxybenzyloxycarbonyl, 2-nitro-4,5-dimethoxybenzyloxycarbonyl, 3,4,5-trimethoxybenzyloxycarbonyl, 1-(p-biphenyl)-1-methylethoxycarbonyl, α,α-dimethyl-3,5-dimethoxybenzyloxycarbonyl, benzoyloxycarbonyl, tert-butyloxycarbonyl, diisopropylmethoxycarbonyl, isopropyloxycarbonyl, ethoxycarbonyl, methoxycarbonyl, allyloxycarbonyl, 2,2,2,-trichloroethoxycarbonyl, phenoxycarbonyl, 4-nitrophenoxycarbonyl, fluorenyl-9-methoxycarbonyl, cyclopentyloxycarbonyl, adamantyloxycarbonyl, cyclohexyloxycarbonyl, phenylthiocarbonyl and the like, aralkyl groups such as benzyl, trityl, benzyloxymethyl and the like, and silyl groups such as trimethylsilyl and the like. Preferred N-protecting groups are formyl, acetyl, benzoyl, pivaloyl, tert-butylacetyl, alanyl, phenylsulfonyl, benzyl, tert-butyloxycarbonyl (Boc) and benzyloxycarbonyl (Cbz).

As used herein, the term "six-membered ring" refers to a saturated or unsaturated aromatic or non-aromatic group having six atoms in a cyclic array, wherein, unless otherwise specified, five atoms are carbon and the remaining atoms are selected from the group consisting of carbon, nitrogen, sulfur and oxygen. The six-membered ring may be fused to another cyclic group selected from heterocyclyl, heteroaryl, cycloalkyl and aryl. The six-membered ring may be unsubstituted or substituted with, for example, one, two, three, or four substituents independently selected from the group consisting of: (1) alkyl of 1 to 6 carbon atoms; (2) alkoxy of 1 to 6 carbon atoms; (3) hydroxy; (4) amino; (5) alkylamino of 1 to 6 carbon atoms; (6) dialkylamino, wherein each alkyl group is independently 1 to 6 carbon atoms; (7) carbocycloalkyl of 1 to 8 carbon atoms; (8) oxo; (9) alkylsulfonyl of 1 to 6 carbon atoms; (10) thioalkoxy of 1 to 6 carbon atoms; (11) aryl; (12) alkaryl, wherein the alkylene group is 1 to 6 carbon atoms; (13) -CO ₂ R ^A , wherein R ^A is selected from the group consisting of (a) alkyl, (b) cycloalkyl, (c) alkanecycloalkyl, (d) alkaryl, and (e) halogen, wherein the alkylene group is 1 to 6 carbon atoms; (14) -C(O)NR ^B R ^C , wherein each ^RB and ^RC are independently selected from the group consisting of (a) alkyl, (b) cycloalkyl, (c) alkanecycloalkyl, (d) alkaryl, and (e) halogen, wherein the alkylene group is 1 to 6 carbon atoms, or ^RB and ^RC are combined to form a C _2-9 heterocyclyl; and (15) cyano.

As used herein, the term "thioalkoxy" refers to a chemical substituent of the formula -SR, wherein R is an alkyl group. In some embodiments, the alkyl group may be further substituted with 1, 2, 3, or 4 substituents as described herein for the alkyl group.

As used herein, the term "thiol" refers to a chemical substituent of formula -SH.

When referring to numbered positions in the compounds of the present invention, the following numbering system is used:

For example, the expression " ^R3 and ^R4 combine to form -N( ^R9 )-CH=CH-" means that the nitrogen atom of -N( ^R9 )-CH=CH- can be adjacent to a ^C5 carbon or a ^C6 carbon. The expression " ^R3 and ^R4 combine to form -N( ^R9 )-CH=CH-" combined with "the nitrogen atom of -N( ^R9 )-CH=CH- is adjacent to a ^C5 carbon" represents the following compounds:

Asymmetric or chiral centers may be present in any compound of the invention. The present invention encompasses various stereoisomers and mixtures thereof. Individual stereoisomers of the compounds of the invention are prepared synthetically from commercially available starting materials containing asymmetric or chiral centers, or by preparing mixtures of enantiomeric compounds followed by separation synthesis by methods well known to those of ordinary skill in the art. Examples of such separation methods are as follows: (1) attaching a racemic mixture of enantiomers, designated as (+/-), to a chiral auxiliary, separating the resulting diastereomers by recrystallization or chromatography, and liberating the optically pure product from the auxiliary, or (2) directly separating a mixture of optical enantiomers on a chiral chromatographic column or by chiral HPLC methods. Methods for chiral separation have been described previously (G. B. Cox (ed.) in Preparative Enantioselective Chromatography, 2005, Blackwell Publishing). Alternatively, chiral compounds can be prepared by asymmetric synthesis, which is conducive to preparing a kind of enantiomer rather than another enantiomer. Alternatively, chiral pool synthesis (starting from enantiomerically pure structural units) can be used, wherein the chiral group or center is retained in the intermediate or final product. Enantiomers are represented by the symbol "R" or "S" in this article, depending on the configuration of the substituents around the chiral atom. Alternatively, depending on whether the solution of the enantiomer rotates the plane of polarized light clockwise or counterclockwise respectively, enantiomers are designated as (+) or (-).

Geometric isomers may also exist in the compounds of the present invention. The present invention contemplates various geometric isomers and mixtures thereof arising from the arrangement of substituents around a carbon-carbon double bond, and designates such isomers as Z or E configurations, wherein the term "Z" designates substituents on the same side of the carbon-carbon double bond and the term "E" designates substituents on opposite sides of the carbon-carbon double bond. It is also recognized that for structures in which tautomeric forms are possible, description of one tautomeric form is equivalent to description of both unless otherwise indicated.

Each position in the compounds of the present invention may include an element in its natural isotopic abundance. Alternatively, one or more positions in the compounds of the present invention may include an element enriched in naturally occurring or synthetic isotopes. For example, one or more positions of a compound of the present invention comprising hydrogen may be enriched with, for example, deuterium or tritium. In some embodiments, one or more positions of a compound of the present invention comprising carbon may be enriched with, for example, ¹⁴ C or ¹³ C. In other embodiments, one or more positions of a compound of the present invention comprising nitrogen may be enriched with, for example, ¹⁵ N. In certain embodiments, one or more positions of a compound of the present invention comprising oxygen may be enriched with, for example, ¹⁸ O, ¹⁷ O, or ¹⁵ O. In specific embodiments, one or more positions of a compound of the present invention comprising fluorine may be enriched with, for example, ¹⁸ F. In other embodiments, one or more positions of a compound of the present invention comprising carbon may be enriched with, for example, ³² S, ³³ S, ³⁴ S, ³⁵ S, or ³⁶ S. In still other embodiments, one or more positions of a compound of the present invention comprising chlorine may be enriched with, for example, ³⁵ Cl, ³⁶ Cl, or ³⁷ Cl.

Some abbreviations used here:

BINAP-2,2’-bis(diphenylphosphine)-1,1’-binaphthyl;

t-Bu-tert-butyl or 1,1-dimethylethyl;

cat-catechol;

dppb-bis(diphenylphosphino)butane;

dppf-bis(diphenylphosphino)ferrocene;

Et-ethyl;

Me-methyl;

OAc-acetate;

OMs-methanesulfonic acid or methanesulfonate;

ONf-nonafluorobutanesulfonate or nonafluoro-n-butanesulfonate;

OTf-triflate or triflate;

pin-pinacol;

i-Pr-isopropyl or 1-methylethyl; and

n-Pr-n-propyl;

SIMes-1,3-di(2,4,6-trimethylphenyl)imidazolin-2-ylidene;

SIPr-1,3,-bis(2,6-diisopropylphenyl)imidazolin-2-ylidene; and

THF - tetrahydrofuran.

Other terms

The term "about" is used herein to refer to a value that is ±10% of the stated value.

The term "effective amount" or "amount effective for..." or "therapeutically effective amount" refers to an amount of a compound of the invention sufficient to produce a desired result, such as a decrease in one or more Hsp90 activities (e.g., inhibited Hsp90), an increase in Hsp70 expression, a decrease in Aβ peptide aggregation (e.g., inhibition of Aβ peptide aggregation), an increase in Aβ peptide degradation and a decrease in tau protein phosphorylation, and/or a reduction or improvement in symptoms of a neurodegenerative disease (e.g., Alzheimer's disease) in a subject when administered a composition containing a compound of the invention. Increases and decreases associated with administration of an effective amount of a compound are relative to the level or symptom (if applicable) in a subject not administered a compound of the invention or relative to the subject prior to administration of the compound of the invention.

As used herein, the term "element" refers to a substance composed of a single type of atoms, ie, each nucleus of each atom of a single element contains the same number of protons.

As used herein, the term "neurodegeneration" refers to the progressive loss of neuronal structure or function, including neuronal death. The term "neurodegenerative disease" refers to a disease in which neurodegeneration is at least in part a cause, symptom, or phenotype.

The terms "patient" and "subject" as used interchangeably herein refer to any animal (e.g., a mammal, such as a human). The subject to be treated according to the methods described herein may be a person who has been diagnosed with a neurodegenerative disease, such as a tauopathy (e.g., Alzheimer's disease) or a proliferative disease (e.g., a person having such a condition or being at risk of developing the disease). Diagnosis can be performed by any method or technique known in the art. It will be understood by those skilled in the art that the subject treated according to the present invention may have undergone standard testing, or may have been identified as a high-risk subject without examination due to the presence of one or more risk factors, such as an increase in the total level of tau protein or an increase in the level of phosphorylated tau protein in a sample from the subject (e.g., cerebrospinal fluid) compared to the level in a sample from a healthy subject.

As used herein, the term "pharmaceutical composition" refers to a composition containing a compound described herein, formulated with a pharmaceutically acceptable excipient, and manufactured or sold under approval by a governmental regulatory agency as part of a therapeutic regimen for treating a disease in a mammal. The pharmaceutical composition can be formulated in a unit dosage form for, for example, oral administration (e.g., tablets, capsules, caplets, softgels, or syrups); for topical administration (e.g., as a cream, gel, lotion, or ointment); for intravenous administration (e.g., as a sterile solution without particle plugs and in a solvent system suitable for intravenous use); or any other formulation described herein.

The terms "pharmaceutically acceptable excipient" or "pharmaceutically acceptable carrier" used interchangeably herein refer to any ingredient other than a compound described herein (e.g., a carrier capable of suspending or dissolving the active compound) that is non-toxic and non-inflammatory in the patient. Excipients may include, for example, antiadherents, antioxidants, binders, coatings, compression aids, disintegrants, dyes (pigments), emollients, emulsifiers, fillers (diluents), film formers or coatings, flavors, fragrances, glidants (flow enhancers), lubricants, preservatives, printing inks, adsorbents, suspending or dispersing agents, sweeteners, or water of hydration. Exemplary excipients include, but are not limited to, butylated hydroxytoluene (BHT), calcium carbonate, calcium phosphate (dibasic), calcium stearate, cross-linked carboxymethylcellulose, cross-linked polyvinyl pyrrolidone, citric acid, cross-linked polyvinyl pyrrolidone, cysteine, ethylcellulose, gelatin, hydroxypropyl cellulose, hydroxypropyl methylcellulose, lactose, magnesium stearate, maltitol, mannitol, methionine, methylcellulose, methylparaben, microcrystalline cellulose, polyethylene glycol, polyvinyl pyrrolidone, polyvinyl pyrrolidone, pregelatinized starch, propylparaben, retinyl palmitate, shellac, silicon dioxide, sodium carboxymethylcellulose, sodium citrate, starch glycolate, sorbitol, starch (corn), stearic acid, stearic acid, sucrose, talc, titanium dioxide, vitamin A, vitamin E, vitamin C, and xylitol.

As used herein, the term "pharmaceutically acceptable prodrugs" refers to those prodrugs of the compounds of the present invention that are, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and animals, without undue toxicity, irritation, allergic response, and the like, at a reasonable benefit/risk ratio, and are effective for their intended use.

As used herein, the term "pharmaceutically acceptable salt" means a salt that is, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and animals without undue toxicity, irritation, allergic response, and the like, and commensurate with a reasonable benefit/risk ratio. Pharmaceutically acceptable salts are well known in the art. For example, pharmaceutically acceptable salts are described in: Berge et al., J. Pharmaceutical Sciences 66: 1-19, 1977 and in Pharmaceutical Salts: Properties, Selection, and Use (P. H. Stahl and C. G. Wermuth, eds.), Wiley-VCH, 2008. These salts can be prepared in situ during the final isolation and purification of the compounds as described herein, or separately by reacting the free base group with a suitable organic acid. Representative acid addition salts include acetate, adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentane, digluconate, dodecylsulfate, ethanesulfonate, fumarate, glucoheptonate, glycerophosphate, hemisulfate, heptanoate, hexate, hydrobromide, hydrochloride, hydroiodide, 2-hydroxy-ethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pectinate, persulfate, 3-phenyl, phosphate, picrate, pivalate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, toluenesulfonate, undecanoate, valerate, and the like. Representative alkali metal or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like, as well as non-toxic ammonium, quaternary ammonium, and amine cations, including but not limited to ammonium, tetramethylammonium, tetraethylammonium, methylamine, dimethylamine, trimethylamine, triethylamine, ethylamine, and the like.

The term "pharmaceutically acceptable solvate" as used herein refers to a compound as described herein, wherein molecules of a suitable solvent are incorporated into the crystal lattice. Suitable solvents are physiologically tolerable at the dose administered. For example, solvates can be prepared by crystallization, recrystallization, or precipitation from a solution comprising an organic solvent, water, or a mixture thereof. Examples of suitable solvents are ethanol, water (e.g., monohydrate, dihydrate, and trihydrate), N-methylpyrrolidone (NMP), dimethyl sulfoxide (DMSO), N,N'-dimethylformamide (DMF), N,N'-dimethylacetamide (DMAC), 1,3-dimethyl-2-imidazolidinone (DMEU), 1,3-dimethyl-3,4,5,6-tetrahydro-2-(1H)-pyrimidinone (DMPU), acetonitrile (ACN), propylene glycol, ethyl acetate, benzyl alcohol, 2-pyrrolidone, benzyl benzoate, etc. When water is the solvent, the molecule is referred to as a "hydrate."

The molecular abbreviation "PSA" and the term "polar surface area," used interchangeably herein, are defined as the surface sum of all polar atoms. The units of PSA are (Angstroms squared).

As used herein, the term "prevention" refers to prophylactic treatment or therapy that prevents one or more symptoms or conditions of a disease, disorder, or condition described herein. Prophylactic treatments comprising administration of a compound described herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, can be acute, short-term, or chronic. The dosage administered can vary during the course of prophylactic treatment.

As used herein, the term "prodrug" refers to a compound that is rapidly converted in vivo to the parent compound of the above formula, for example, by hydrolysis in the blood. Prodrugs of the compounds described herein can be conventional esters. Some common esters that have been used as prodrugs are phenyl esters, aliphatic (C ₁ -C ₈ or C ₈ -C ₂₄ ) esters, cholesterol esters, acyloxymethyl esters, carbamates, and amino acid esters. For example, a compound containing an OH group can be acylated at this position in its prodrug form. A detailed discussion is provided in ACS Symposium Series, Edward B. Roche, ed., Vol. 14, "Pro-drugs as Novel Delivery Systems," in Higuchi and Stella, Bioreversible Carriers in Drug Design, American Pharmaceutical Association and Pergamon Press, 1987, and Judkins et al., Synthetic Communications, 26(23): 4351-4367, 1996, each of which is incorporated herein by reference. Preferably, the prodrugs of the compounds of the invention are suitable for contact with tissues of humans and animals, have undue toxicity, irritation, allergic response, etc., commensurate with a reasonable benefit/risk ratio, and are effective for their intended use.

The term "proliferative disease" as used herein refers to cancer and non-cancer diseases. Proliferative diseases are diseases characterized by the unregulated proliferation of certain types of cells (e.g., astrocytes). Preferably, tumor cells associated with proliferative diseases (e.g., cancer) respond to the inhibition of Hsp90 by apoptosis. Proliferative diseases treated using the compounds of the present invention and according to the methods of the present invention may include gliomas, meningiomas, pituitary adenomas, schwannomas (e.g., schwannomas or neurofibromas). Proliferative diseases within the scope of the present invention may be cancer, e.g., acute myeloid leukemia, gastrointestinal stromal tumors, gastric cancer, lung cancer, lymphoma, melanoma, myeloma, non-small cell lung cancer, renal cancer, small cell lung cancer, embryonic chronic myeloid leukemia, leukemia, lymphoproliferative disorders, metastatic melanoma, relapsed multiple myeloma, refractory multiple myeloma, myeloproliferative disorders, pancreatic cancer, small intestinal cancer, or solid tumors. Preferably, proliferative diseases treated using the compounds of the present invention according to the methods of the present invention may include brain tumors (e.g., malignant brain tumors). For example, a brain tumor that can be treated with the blood-brain barrier permeabilizing agent compounds of the present invention can be a glioma or a meningioma, particularly a glioma (e.g., a glioblastoma) or a malignant form thereof. Cancers that can be treated according to the present invention can also be cancers that have metastasized to the brain (e.g., lung cancer, breast cancer, melanoma, colon cancer, kidney cancer, and thyroid cancer).

As used herein, and as is well understood in the art, "treatment" is an approach for obtaining a beneficial or desired result (e.g., a clinical result). Beneficial or desired results can include, but are not limited to, alleviation or improvement of one or more symptoms or conditions; reduction in the extent of the disease, disorder, or condition; stable state (i.e., not worsening) of the disease, disorder, or condition; prevention of the spread of the disease, disorder, or condition; delay or slowing of the progression of the disease, disorder, or condition; improvement or alleviation of the disease, disorder, or condition; and remission (whether partial or complete), whether detectable or undetectable. To "mitigate" a disease, disorder, or condition means that the extent and/or adverse clinical manifestations of the disease, disorder, or condition are reduced and/or the time course of progression is slowed or prolonged compared to the extent or time course in the absence of treatment.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG1 shows the 500 MHz ¹ H NMR spectrum of compound 20 in CDCl ₃ .

FIG2 shows the 500 MHz ¹ H NMR spectrum of compound 34 in CDCl ₃ .

FIG3 shows the 500 MHz ¹ H NMR spectrum of compound 36 in CDCl ₃ .

4 shows five graphs providing IC ₅₀ data for compounds 20, 36, 37, and 39, as well as known Hsp90 inhibitors, as measured using the fluorescence polarization assay described in Example 2.

FIG5A shows a graph comparing relative association/dissociation rates versus concentration of Compound 20. FIG5A shows a graph comparing relative association/dissociation rates versus concentration of Compound 20.

Figure 5B is a photograph of a gel showing that Hsp70 expression increased at higher concentrations of Compound 20 in a cell-based functional assay. In addition, Figure 5B shows that Hsp90 expression remained unchanged relative to changes in Compound 20 concentration.

Figure 6A shows a histogram comparing the % cell viability of live cells (VC), cells contacted with Compound 20, and cells contacted with a control compound (JNK inhibitor).

Figure 6B shows a graph comparing pTau231 levels in live cells (VC), cells contacted with Compound 20, and cells contacted with a control compound (JNK inhibitor).

Figure 6C shows a graph comparing pTau396 levels in live cells (VC), cells contacted with Compound 20, and cells contacted with a control compound (JNK inhibitor).

Figure 7 shows a graph of the concentration of Compound 20 in mouse plasma. The data in this graph excludes the plasma levels of Compound 20 in animal IRN 12.

Figure 8 shows a graph of the concentration of Compound 20 in mouse plasma. The data in this graph includes all mouse plasma data points.

Figure 9 shows a graph of the concentration of Compound 20 in mouse brain tissue. The data in this graph excludes the plasma levels of Compound 20 in animal IRN 12.

Figure 10 shows a graph of the concentration of Compound 20 in mouse brain tissue. The data in this graph includes all mouse brain tissue data points.

Detailed description

The present invention features novel aminopyrimidines and related compounds having Hsp90 inhibitory activity, pharmaceutical compositions containing them, and their medical uses (e.g., for treating proliferative diseases (e.g., cancer) or neurodegenerative diseases (e.g., tauopathies)). Specifically, the compounds of the invention are able to penetrate the blood-brain barrier. Thus, the medical uses of these compounds include diseases and conditions that afflict the brain of mammals (e.g., humans).

Compounds of the present invention

Table 2 shows exemplary compounds of the present invention.

Table 2.

or a pharmaceutically acceptable salt thereof.

Non-limiting examples of pharmaceutically acceptable salts of the compounds of the present invention are:

Exemplary methods for synthesizing compounds of the invention are described herein.

Methods for preparing the compounds of the present invention

The compounds of the invention can be prepared by methods analogous to those established in the art, for example by the reaction sequence shown in Scheme 1. The numbering system used in the general schemes does not necessarily correspond to the numbering system used elsewhere in the specification or claims.

As shown in Scheme 1, one strategy to obtain compounds (C) of the present invention is to utilize a standard cross-coupling reaction (e.g., Suzuki coupling, Hiyama coupling, Stille coupling, Negishi coupling, Tamao-Kumada coupling, or Murahashi coupling) in which nucleophile A and electrophile B are coupled in the presence of a metal salt such as palladium, copper, iron, or nickel salt (e.g., PdCl2, Pd(OAc) _{2 ,} CuBr, CuI, (CuOTf) ₂ toluene complex, Fe(OTf) ₃ , _FeCl3 , _FeBr3 , _NiCl2 , or _NiBr2 ). Optionally, a ligand such as a phosphine (e.g., PPh ₃ , P(2-furyl) ₃ , P(t-Bu) ₃ , dppf, dppb, or BINAP), an N-heterocyclic carbene (e.g., SIMes or SIPr), or a bipyridine (e.g., 2,2′-bipyridine or 1,10-phenanthroline) may be added to promote the reaction. Alternatively, an organometallic complex such as Pd(PPh ₃ ) ₄ or (dppf)PdCl ₂ may be used directly with or without additional ligands. Additives such as tetrabutylammonium fluoride, LiCl, KOAc, or AgOTf may be added to minimize dehalogenation or promote the cross-coupling reaction. One skilled in the art will be able to determine the appropriate solvent for the reaction by standard screening. Non-limiting examples of solvents for the cross-coupling reaction are water, ethanol, acetone, tetrahydrofuran, toluene, 1,4-dioxane, and mixtures thereof. For non-limiting examples of conditions and catalysts that can be used to prepare compounds of the invention according to Formula C using cross-coupling chemistry, see Miyaura et al., "Cross-Coupling Reactions: A Practical Guide," in Topics in Current Chemistry, Springer, 2002, and Nicolaou et al., Angew. Chem. Int. Ed., 44:4442-4489, 2005, which are incorporated herein by reference. Alternatively, the compound of Formula A can be an electrophile and have a leaving group X instead of M, while the compound of Formula B can be a nucleophile and have a metal or metalloid group M instead of X.

Solution 1.

Compounds of formula A can be prepared according to any method known in the art, for example, metal-halogen (e.g., lithium-halogen) exchange (followed by or without the addition of a boron-, silicon-, tin-, zinc-, or magnesium-based agent), preparation of Grignard reagents, Sandmeyer reaction, or cross-coupling with a dimetallic reagent (e.g., Miyaura borylation reaction). A non-limiting example of the preparation of A (Sandmeyer reaction and lithium halogen exchange to prepare E and Miyaura borylation reaction to prepare G) is shown in Scheme 2.

Scheme 2. Preparation of nucleophile A, such as E or G

Compounds of formula B can be prepared according to any method known in the art, such as the Biginelli reaction followed by oxidation of the resulting 2-aminodihydropyrimidine derivative. Alternatively, the synthetic method outlined in Scheme 3 can be used to obtain compounds of formula B.

Scheme 3. Preparation of electrophile B, such as N-protected B, i.e., L

As shown in Scheme 3, a compound of Formula H can be condensed with a compound of Formula I to give a compound of Formula J. The amino group of the 2-aminopyrimidine derivative J can then be protected (P = a divalent N-protecting group, two monovalent N-protecting groups, or one monovalent N-protecting group and a hydrogen) to give a compound of Formula K. The hydroxyl group in the compound of Formula K can then be converted to the halogen in the compound of Formula L according to any method known in the art, for example, using a dehydration-halogenation reagent (e.g., _POCl3 , _PCl5 , _{SOCl2 , SO2Cl2} , and brominated or iodinated variants thereof). Alternatively, the hydroxyl group in the compound of Formula K can be converted to the pseudohalogen of the compound of Formula L using a reagent such as _Tf2O , _PhNTf2 , _PhNNf2 , or P(O)(OR) _2Cl , and optionally, a base (e.g., _Et3N , (iPr) _2NEt , or pyridine) and/or a catalyst (e.g., 4-dimethylaminopyridine). The N-protecting group P can be removed from compound L before or after the cross-coupling shown in Scheme 1 according to methods known in the art (see, e.g., Greene, Protective Groups in Organic Synthesis, 3rd ed. (John Wiley & Sons, New York, 1999)).

In the above reactions, it may be necessary to protect reactive functional groups (e.g., hydroxyl, amino, thiol, or carboxyl groups) to prevent them from undesirably participating in the reaction. The introduction of these groups and the methods required for their introduction and removal are known to those skilled in the art (e.g., Green, supra). The deprotection step may be the last step in the synthesis, so that removal of the protecting groups can yield compounds of formula (Ia) as disclosed herein. The starting materials used in any of the above schemes can be purchased using methods known to those skilled in the art or prepared by methods described in the chemical literature or by variations thereof. The order in which the steps are performed may vary depending on the groups introduced and the reagents used, but will be apparent to those skilled in the art.

Any compound of formula (I), (Ia), (Ib), (Va), or (Vb) or any intermediate described in the above scheme can be further derivatized by using one or more standard synthetic methods known to those skilled in the art. These methods may include substitution, oxidation or reduction reactions. These methods can also be used to obtain or modify compounds of formula (I), (Ia), (Ib), (Va), or (Vb) or any of the aforementioned intermediates by modifying, introducing or removing appropriate functional groups. Specific substitution methods include alkylation, arylation, heteroarylation, acylation, thioacylation, halogenation, sulfonylation, nitration, formylation, hydrolysis and coupling processes. These steps can be used to introduce functional groups into a parent molecule (e.g., nitration or sulfonylation of an aromatic ring) or to couple two molecules together (e.g., coupling an amine to a carboxylic acid to obtain an amide; or forming a carbon-carbon bond between two heterocycles). For example, an alcohol or phenol group can be converted to an ether group by coupling a phenol with an alcohol in a solvent, for example, tetrahydrofuran, in the presence of a phosphine (e.g., triphenylphosphine) and a dehydrating agent (e.g., diethyl-, diisopropyl-, or dimethyl azodicarboxylate). Alternatively, an ether group can be prepared by deprotonation of the alcohol using a suitable base (e.g., sodium hydride) followed by addition of an alkylating agent (e.g., an alkyl halide or alkyl sulfonate).

In another example, a primary or secondary amine can be alkylated using a reductive alkylation method. For example, the amine can be treated with an aldehyde and a borohydride (e.g., sodium triacetoxyborohydride or sodium cyanoborohydride) in a solvent (e.g., a halogenated hydrocarbon such as dichloromethane or an alcohol such as ethanol) and, if desired, in the presence of an acid such as acetic acid.

In another example, a -OH group can be generated from the corresponding ester, acid, acid chloride, or aldehyde by reduction with a suitable reducing agent, for example, a complex metal hydride, such as lithium aluminum hydride, in a solvent (eg, tetrahydrofuran).

In another example, a hydroxyl group (including a phenolic hydroxyl group) can be converted into a leaving group, for example, a halogen atom or a sulfonyloxy group (for example, an alkylsulfonyloxy group, such as a trifluoromethylsulfonyloxy group or an arylsulfonyl group, such as a p-toluenesulfonyloxy group) using conditions known to those skilled in the art. For example, an aliphatic alcohol can be reacted with thionyl chloride in a halogenated hydrocarbon (for example, dichloromethane) to obtain the corresponding alkyl chloride. A base (for example, triethylamine) can also be used in the reaction.

As another example, an ester group can be converted to the corresponding carboxylic acid by acid- or base-catalyzed hydrolysis, depending on the nature of the ester group. Acid-catalyzed hydrolysis can be achieved by treatment with an organic or inorganic acid (e.g., trifluoroacetic acid in an aqueous solvent, or an inorganic acid such as hydrochloric acid in a solvent such as dioxane). Base-catalyzed hydrolysis can be achieved by treatment with an alkali metal hydroxide (e.g., lithium hydroxide in an aqueous alcohol such as methanol).

In another example, an aromatic halogen substituent in a compound can be treated with a base (e.g., a lithium base, such as n-butyllithium or tert-butyllithium), optionally at low temperature (e.g., -78°C) in a solvent (e.g., tetrahydrofuran), to undergo a halogen-metal exchange, followed by quenching the mixture and introducing the desired substituent in the presence of an electrophile. Thus, for example, a formyl group can be introduced using dimethylformamide as an electrophile. Aromatic halogen substituents can also undergo palladium-catalyzed reactions to introduce groups such as carboxylic acid, ester, cyano, or amino substituents.

In another example, the compound can undergo a series of metal-catalyzed reactions at aromatic halogen substituents to introduce alternative functional groups, such as amines, amides, ethers, thiols, aryls, or heteroaryls.

Specific oxidation methods include dehydrogenation and aromatization and adding oxygen to certain functional groups. For example, aldehyde groups can be prepared by oxidizing corresponding alcohols using conditions well known to those skilled in the art. For example, alcohol can be processed with an oxidant (for example, Dess-Martin reagent) in a solvent (for example, a halogenated hydrocarbon, such as dichloromethane). Alternative oxidation conditions can be used, for example, with oxalyl chloride and an activated amount of dimethyl sulfoxide, followed by quenching with an amine (for example, triethylamine). Such reactions can be carried out in a suitable solvent (for example, a halogenated hydrocarbon, such as dichloromethane) and under suitable conditions (for example, cooled to below room temperature, for example, to -78 ° C, then warming to room temperature). In another example, sulfur atoms can be oxidized to corresponding sulfoxides or sulfones using an oxidant (for example, peroxyacids, such as 3-chloroperoxybenzoic acid) in an inert solvent (for example, a halogenated hydrocarbon, such as dichloromethane) at ambient temperature.

In another example, nitro can be in the presence of a metal catalyst (for example, solid support such as the palladium on carbon) in a solvent (for example, ether, for example tetrahydrofuran, or alcohol, for example methanol) by catalytic hydrogenation, or by using a metal (for example, tin or iron) chemical reduction to be reduced to amine. In a further example, the amine can be obtained by reducing the nitrile, for example, by catalytic hydrogenation in the presence of a metal catalyst (e.g., palladium on a solid support such as carbon), or Raney nickel, in a solvent (e.g., tetrahydrofuran) and under appropriate conditions (e.g., cooling to below room temperature, e.g., to -78°C, or heating to, e.g., reflux).

Pharmaceutical composition

The compounds used in the methods described herein are preferably formulated into pharmaceutical compositions for administration to human subjects in a biocompatible form suitable for in vivo administration.Pharmaceutical compositions generally include a compound described herein and a pharmaceutically acceptable excipient.

The compounds described herein can also be used in the form of free bases, in the form of salts, zwitterions, solvates, or as prodrugs, or pharmaceutical compositions thereof. All forms are within the scope of the present invention. As will be appreciated by those skilled in the art, depending on the selected route of administration, compounds, salts, zwitterions, solvates, prodrugs, or pharmaceutical compositions can be administered to the patient in various forms. The compounds used in the methods described herein can be administered, for example, orally, parenterally, buccal, sublingually, nasally, rectally, by patch, pump, or transdermal administration, as well as with pharmaceutical compositions formulated accordingly. Parenteral administration includes intravenous, intraperitoneal, subcutaneous, intramuscular, transepithelial, nasal, intrapulmonary, intrathecal, rectal, and topical administration. Parenteral administration can be by continuous infusion over a selected time period.

For human use, the compounds of the present invention can be administered alone or in admixture with a pharmaceutical carrier selected according to the intended route of administration and standard pharmaceutical practice. Thus, pharmaceutical compositions for use according to the present invention can be formulated in a conventional manner using one or more physiologically acceptable carriers comprising excipients and adjuvants that assist in converting the compounds of Formula (I), (Ia), (Ib), (Va), or (Vb) into pharmaceutically usable formulations.

The present invention also includes pharmaceutical compositions that can contain one or more pharmaceutically acceptable carriers. When preparing the pharmaceutical compositions of the present invention, the active ingredient is usually mixed with an excipient, diluted with the excipient or encapsulated with such a carrier in the form of a capsule, sachet, paper or other container. When the excipient is used as a diluent, it can be a solid, semisolid or liquid material (e.g., normal saline) that serves as a medium, carrier or vehicle for the active ingredient. Therefore, the composition can be in the form of a tablet, powder, lozenge, sachet, cachet, elixir, suspension, emulsion, solution, syrup and soft and hard gelatin capsule. As known in the art, the type of diluent can vary depending on the intended route of administration. The resulting composition may include additional agents, for example, preservatives.

Excipients or carriers are selected according to the mode of administration and route. Suitable pharmaceutical carriers and pharmaceutical necessities for pharmaceutical preparations are described in Remington: The Science and Practice of Pharmacy, 21st edition, edited by Gennaro, Lippencott Williams & Wilkins (2005), a reference known in the art, and in USP/NF (United States Pharmacopoeia and National Formulary). Examples of suitable excipients are lactose, glucose, sucrose, sorbitol, mannitol, starch, gum arabic, calcium phosphate, alginates, tragacanth gum, gelatin, calcium silicate, microcrystalline cellulose, polyvinylpyrrolidone, cellulose, water, syrup and methylcellulose. These preparations may additionally include: lubricants such as talc, magnesium stearate and mineral oil; wetting agents; emulsifiers and suspending agents; preservatives such as methyl benzoate and propyl hydroxybenzoate; sweeteners; and flavorings. Other exemplary excipients are described in Handbook of Pharmaceutical Excipients, 6th ed., Rowe et al., eds., Pharmaceutical Press (2009).

These pharmaceutical compositions can be produced in a conventional manner, for example, by conventional mixing, dissolving, granulating, making dragees, grinding, emulsifying, encapsulating, embedding or lyophilizing methods. Methods well known in the art for preparing preparations are found in, for example, Remington: The Science and Practice of Pharmacy, 21st edition, edited by Gennaro, Lippencott Williams & Wilkins (2005) and Encyclopedia of Pharmaceutical Technology, edited by J. Swarbrick and J.C. Boylan, 1988-1999, Marcel Dekker, New York. Suitable preparations depend on the selected route of administration. The preparation and preparation of such compositions are well known to those skilled in the art of pharmaceutical preparations. In preparing the preparation, before being combined with other ingredients, the active compound can be ground to provide a suitable particle size. If the active compound is substantially insoluble, it can be milled to a particle size of less than 200 mesh. If the active compound is substantially water soluble, the particle size can be adjusted by milling to provide a substantially uniform distribution in the formulation, e.g., about 40 mesh.

dose

The dosage of the compound used in the methods described herein, or a pharmaceutically acceptable salt or prodrug thereof, or a pharmaceutical composition thereof, can vary depending on many factors, such as the pharmacodynamic properties of the compound, the route of administration, the age, health, and weight of the recipient, the nature and extent of the symptoms, the frequency of treatment, and the type of concurrent treatment (if any), and the clearance rate of the compound in the animal to be treated. One skilled in the art can determine an appropriate dosage based on the above factors. The compound used in the methods described herein can be initially administered at an appropriate dosage, which can be adjusted as needed based on clinical response. Generally, a suitable daily dosage of the compound of the present invention will be the amount of the compound that is the lowest dose effective to produce a therapeutic effect. Generally, such an effective dosage will depend on the factors described above.

The compound of the present invention can be given to the patient with a single dose or multiple doses. When giving multiple dosages, the dosage can be separated from each other, for example 1-24 hours, 1-7 days, 1-4 weeks or 1-12 months. The compound can be given according to a time schedule, or the compound can be given without a predetermined time schedule. For example, every day 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12 times, every 2, 3, 4, 5 or 6 days, weekly 1, 2, 3, 4, 5, 6 or 7 times, monthly 1, 2, 3, 4, 5 or 6 times, or annual 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12 times give active compound. It should be understood that for any specific experimenter, specific dosage regimen should be adjusted over time according to the professional judgment of the people who need to give or supervise the composition to give.

Although the attending physician will ultimately determine the appropriate amount and dosage regimen, the effective amount of the compounds of the present invention can be, for example, a total daily dose of, for example, 0.05 mg to 3000 mg of any compound described herein. Alternatively, the patient's weight can be used to calculate the dosage. Such dosage ranges can include, for example, 10 mg-1000 mg (e.g., 50 mg-800 mg). In some embodiments, 50 mg, 100 mg, 150 mg, 200 mg, 250 mg, 300 mg, 350 mg, 400 mg, 450 mg, 500 mg, 550 mg, 600 mg, 650 mg, 700 mg, 750 mg, 800 mg, 850 mg, 900 mg, 950 mg, or 1000 mg of compound can be administered.

In the method of the present invention, the time period over which multiple doses of the compounds of this invention are administered to a patient can vary. For example, in some embodiments, the dosage of the compounds of this invention is administered to a patient over a period of more than 1-7 days, 1-12 weeks, or 1-3 months. In other embodiments, the compound is administered to a patient over a period of more than, for example, 4-11 months or 1-30 years. In other embodiments, the compound is administered to a patient upon onset of symptoms. In any of these embodiments, the amount of the compound administered can vary over the period administered. When the compound is administered daily, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 times can be administered daily, for example.

preparation

Using any of the methods described herein, compounds identified as being able to treat any of the conditions described herein can be administered to a patient or animal in a unit dosage form with a pharmaceutically acceptable diluent, carrier, or excipient. Compounds for these therapies can be produced and isolated by any standard technique known in the art of pharmaceutical chemistry. Conventional pharmaceutical practices can be used to provide suitable formulations or compositions for administering the identified compounds to a patient suffering from a disease that causes necrosis. Administration can be initiated before the patient becomes symptomatic.

Exemplary routes of administration for the compounds of the present invention (e.g., compounds of Formula (I), (Ia), (Ib), (Va), or (Vb)), or pharmaceutical compositions thereof, include oral, sublingual, buccal, transdermal, intradermal, intramuscular, parenteral, intravenous, intraarterial, intracranial, subcutaneous, intraorbital, intraventricular, intraspinal, intraperitoneal, intranasal, inhalation, and topical administration. Ideally, the compounds are administered with a pharmaceutically acceptable carrier. Pharmaceutical formulations of the compounds described herein formulated for use in treating the conditions described herein are also part of the present invention.

Preparations for oral administration

Pharmaceutical compositions contemplated by the present invention include those formulated for oral administration ("oral dosage forms"). Oral dosage forms can be in the form of, for example, tablets, capsules, liquid solutions or suspensions, powders, or liquid or solid crystals, which contain one or more active ingredients in a mixture with non-toxic pharmaceutically acceptable excipients. These excipients can be, for example, inert diluents or fillers (e.g., sucrose, sorbitol, sugar, mannitol, microcrystalline cellulose, starch including potato starch, calcium carbonate, sodium chloride, lactose, calcium phosphate, calcium sulfate, or sodium phosphate); granulating and disintegrants (e.g., cellulose derivatives including microcrystalline cellulose, starch including potato starch, cross-linked sodium carboxymethyl cellulose, alginate, or alginic acid); binders (e.g., sucrose, glucose, sorbitol, gum arabic, alginic acid, sodium alginate, gelatin, starch, pregelatinized starch, microcrystalline cellulose, magnesium aluminum silicate, sodium carboxymethyl cellulose, methylcellulose, hydroxypropyl methylcellulose, ethylcellulose, polyvinyl pyrrolidone, or polyethylene glycol); and lubricants, glidants, and anti-adherents (e.g., magnesium stearate, zinc stearate, stearic acid, silicon dioxide, hydrogenated vegetable oil, or talc). Other pharmaceutically acceptable excipients can be colorants, flavorings, plasticizers, humectants, buffers, etc.

Formulations for oral administration may also be presented as chewable tablets, as hard gelatin capsules in which the active ingredient is mixed with an inert solid diluent (e.g., potato starch, lactose, microcrystalline cellulose, calcium carbonate, calcium phosphate or kaolin), or as soft gelatin capsules in which the active ingredient is mixed with water or an oil medium (e.g., peanut oil, liquid paraffin, or olive oil). Powders, granules and pills may be prepared in a conventional manner using the ingredients described above for tablets and capsules, for example, using a mixer, fluidized bed equipment or spray drying equipment.

The controlled release composition for oral use can be constructed to release active drug by controlling the dissolution and/or diffusion of active drug substance. Any one of multiple strategies can be carried out to obtain controlled release and target plasma concentration versus time curve. In an example, by appropriately selecting various formulation parameters and composition, for example various types of controlled release composition and coating are obtained. Example includes single or multiple unit tablets or capsule compositions, oil solutions, suspensions, emulsions, microcapsules, microspheres, nanoparticles, plasters and liposomes. In certain embodiments, compositions include biodegradable, pH and/or temperature-sensitive polymer coatings.

Dissolving or diffusion control release can be achieved by tablets, capsules, pills or granular preparations of suitable coating compounds, or by incorporating compound into suitable matrix.Controlled release coating can include one or more above-mentioned coating materials and/or such as shellac, beeswax, polysaccharide wax, castor wax, carnauba wax, stearyl alcohol, glyceryl monostearate, glyceryl distearate, glyceryl palmitostearate, ethylcellulose, acrylic resin, dl-polylactic acid, cellulose acetate butyrate, polyvinyl chloride, polyvinyl acetate, vinyl pyrrolidone, polyethylene, polymethacrylate, methyl methacrylate, 2-hydroxymethylacrylate, methacrylate hydrogel, 1,3-butylene glycol, ethylene glycol methacrylate and/or polyethylene glycol.In controlled release matrix preparation, host material can also include such as, hydrated methylcellulose, carnauba wax and stearyl alcohol, carbopol 934, silicone, tristearin, methyl acrylate-methyl methacrylate, polyvinyl chloride, polyethylene and/or halogenated fluorocarbon.

The compounds and compositions of the present invention can be incorporated into liquid forms for oral administration including aqueous solutions, suitably flavored syrups, aqueous or oily suspensions, and emulsions flavored with edible oils such as cottonseed oil, sesame oil, coconut oil, or peanut oil, as well as elixirs and similar pharmaceutical vehicles.

Formulations for buccal administration

The dosage for buccal or sublingual administration is typically 0.1 mg to 500 mg per single dose, as needed. In practice, the physician determines the actual dosage regimen that best suits the individual patient, and the dosage varies with the age, weight, and response of the particular patient. The above dosages are examples of average conditions, but there are individual instances where higher or lower dosages are desired, and these are within the scope of the present invention.

For buccal administration, the composition can take the form of tablets, lozenges, etc. prepared in a conventional manner. Liquid drug formulations suitable for use with nebulizers and liquid spray devices and electric fluid (EHD) aerosol devices generally include compounds of the present invention with pharmaceutically acceptable carriers. Preferably, pharmaceutically acceptable carriers are liquids, such as alcohol, water, polyethylene glycol, or perfluorocarbons. Optionally, another material can be added to change the aerosol properties of the solution or suspension of the compounds of the present invention. Ideally, the material is a liquid, such as alcohol, ethylene glycol, polyethylene glycol, or fatty acid. Other methods of preparing liquid drug solutions or suspensions suitable for aerosol devices are known to those skilled in the art (see, for example, Biesalski, U.S. Patent number 5,112,598 and Biesalski, U.S. Patent number 5,556,611, each of which is incorporated herein by reference).

Formulations for nasal or inhaled administration

The compound can also be formulated for nasal administration. Compositions for intranasal administration can also be conveniently formulated into aerosols, drops, gels, and powders. The formulations can be provided in single or multiple dose forms. In the case of a dropper or pipette, administration can be achieved by the patient administering a solution or suspension of an appropriate predetermined volume. In the case of a nebulizer, this can be achieved, for example, by means of a metered atomizing spray pump.

The compound can also be formulated for aerosol administration, particularly by inhalation and including intranasal administration to the respiratory tract. The compound typically has a small particle size, for example, about five (5) microns or less. Such particle sizes can be obtained by methods known in the art, for example, by micronization. The active ingredient is provided in a pressurized package with a suitable propellant (for example, a chlorofluorocarbon (CFC), such as dichlorodifluoromethane, trichlorofluoromethane, or dichlorotetrafluoroethane, or carbon dioxide, or other suitable gas). The aerosol can also conveniently contain a surfactant, for example, lecithin. The dose of the drug can be controlled by a metering valve. Alternatively, the active ingredient can be provided in the form of a dry powder, for example, a powder mixture of the compound in a suitable powder matrix (for example, lactose, starch and starch derivatives, for example, hydroxypropyl methylcellulose, and polyvinylpyrrolidone (PVP)). The powder carrier will form a gel in the nasal cavity. The powder composition can be present in unit dose form, for example, in capsules or cartridges such as gelatin or blister packs, from which the powder can be administered by an inhaler.

Aerosol preparations generally comprise solutions or fine suspensions of active substances in physiologically acceptable aqueous or non-aqueous solvents, and are usually present in sealed containers in aseptic form, in single dose or multi-dose form, which can take the form of a tube or refill to use together with atomizing apparatus. Alternatively, sealed containers can be integral dispensing devices, such as single dose nasal inhalers or the aerosol dispenser equipped with a metering valve, which is used for post-use processing. When dosage form comprised an aerosol dispenser, it would comprise a propellant, which could be a compressed gas, such as compressed air or an organic propellant, such as fluorochlorocarbons. Aerosol formulations can also adopt the form of a pump-atomizer.

Preparations for parenteral administration

The compounds described herein for use in the methods of the present invention can be administered in pharmaceutically acceptable parenteral (e.g., intravenous or intramuscular) formulations, as described herein. Pharmaceutical formulations can also be administered parenterally (intravenously, intramuscularly, subcutaneously, etc.) in dosage forms or formulations containing conventional non-toxic pharmaceutically acceptable carriers and adjuvants. Specifically, formulations suitable for parenteral administration include aqueous and non-aqueous sterile injection solutions, which may contain antioxidants, buffers, bacteriostats, and solutes that render the formulation isotonic with the blood of the intended recipient; and aqueous and non-aqueous sterile suspensions (which may include suspending agents and thickening agents). For example, to prepare such compositions, the compounds of the present invention can be dissolved or suspended in a parenterally acceptable liquid carrier. Acceptable carriers and solvents that can be used are water, water adjusted to an appropriate pH by adding an appropriate amount of hydrochloric acid, sodium hydroxide, or a suitable buffer, 1,3-butanediol, Ringer's solution, and isotonic sodium chloride solution. Aqueous formulations may also contain one or more preservatives, for example, methyl, ethyl, or n-propyl paraben. Additional information regarding parenteral formulations can be found, for example, in the United States Pharmacopeia-National Formulary (USP-NF), which is incorporated herein by reference.

A parenteral formulation can be any of five general types of formulations identified by the USP-NF as suitable for parenteral administration:

(1) "Drug injection" means a liquid preparation of a drug substance (e.g., a compound of Formula (I), (Ia), (Ib), (Va), or (Vb)), or a solution thereof;

(2) "Injectable drug": a drug substance (e.g., a compound of Formula (I), (Ia), (Ib), (Va), or (Vb)) as a dry solid to be combined with an appropriate sterile carrier as a pharmaceutical injection for parenteral administration;

(3) “Drug injectable emulsion”: a liquid formulation of a drug substance (e.g., a compound of Formula (I), (Ia), (Ib), (Va), or (Vb)) dissolved or dispersed in a suitable emulsion vehicle;

(4) "Drug injectable suspension": a liquid preparation of a drug substance (e.g., a compound of Formula (I), (Ia), (Ib), (Va), or (Vb)) suspended in a suitable liquid medium; and

(5) "Drug for injectable suspension": a drug substance (e.g., a compound of Formula (I), (Ia), (Ib), (Va) or (Vb)) as a dry solid to be combined with an appropriate sterile vehicle as a pharmaceutical injectable suspension for parenteral administration.

The exemplary preparations for parenteral administration are included in water and are suitably mixed with surfactants such as hydroxypropyl cellulose to prepare a solution of the compound. Colloidal solutions can also be prepared in glycerol, liquid polyethylene glycol, DMSO and mixtures thereof with or without alcohol, and in oil. Under common storage and use conditions, such preparations can contain preservatives to prevent microbial growth. The conventional method and composition for selecting and preparing suitable preparations are described in, for example, Remington: Pharmaceutical Science and Practice (Remington:The Science and Practice ofPharmacy), the 21st edition, edited by Gennaro, Lippencott Williams & Wilkins Publishing Company (Lippencott Williams & Wilkins) (2005) and the United States Pharmacopeia published in 2013: National Formulary (The United States Pharmacopeia:The National Formulary) (USP 36 NF31).

Preparations for parenteral administration can, for example, contain excipients, sterile water or saline, polyalkylene glycols (e.g., polyethylene glycol), oils of plant origin or hydrogenated naphthalene. Biocompatible, biodegradable lactide polymers, lactide/glycolide copolymers or polyoxyethylene-polyoxypropylene copolymers can be used for controlling the release of the compound. For these compounds, other potential useful parenteral delivery systems include ethylene-vinyl acetate copolymer particles, osmotic pumps, implantable infusion systems and liposomes. Preparations for suction can contain excipients, such as lactose, or can be aqueous solutions containing, for example, polyoxyethylene-9-lauryl ether, glycocholate and deoxycholate, or can be oily solutions for use in nasal drops or as a gel.

Parenteral formulations can be formulated for rapid release or sustained/extended release of the compound. Exemplary formulations for parenteral release of the compound include: aqueous solutions, powders for reconstitution, co-solvent solutions, oil/water emulsions, suspensions, oil-based solutions, liposomes, microspheres, and polymer gels.

Treatment

The compounds and compositions described herein are useful for treating disorders and diseases in which Hsp90 is implicated, for example, cell proliferative diseases such as cancer, neurodegenerative diseases such as tauopathies (eg, Alzheimer's disease), and infectious diseases.

Cell proliferative disorders

Because this multi-chaperone complex is involved in various pathogenic cellular processes, Hsp90 has emerged as a key therapeutic target for cancer treatment. Hsp90 client proteins include those involved in acute myeloid leukemia (Flt-3), breast cancer (HER2), chronic lymphocytic leukemia (Zap70), chronic myeloid leukemia (Bcr-Abl or mBcr-Abl), gastrointestinal stromal tumors (c-Kit), gastric cancer (c-Met), glioblastoma (mutated EGFR or c-Met), lung cancer (c-Met), lymphoma (NMP-ALK), melanoma (Raf-1/mutant BRAF), myeloma (IGF-1R/Akt), non-small cell lung cancer (mutated EGFR), renal cancer (HIF-1α), and small cell lung cancer (Akt). The compounds of the present invention are particularly useful in treating brain tumors due to their blood-brain barrier permeability. Brain tumors that can be treated using the compounds of the present invention include gliomas or meningiomas, particularly gliomas (e.g., glioblastomas) or neuroblastomas. Brain tumors (e.g., brain cancers) that can be treated using the compounds of the present invention according to the methods of the present invention can include primary tumors (those that originate in the brain) and metastatic tumors (those that originate in tissues other than brain tissue and spread to the brain). Other cell proliferative diseases that can be treated by inhibiting Hsp90 include: embryonic chronic myeloid leukemia, leukemias, lymphoproliferative disorders, metastatic melanoma, multiple myeloma (e.g., relapsed or refractory multiple myeloma), myeloproliferative diseases, pancreatic cancer, small intestinal cancer, and solid tumors. In addition, cancer cells have been shown to be more sensitive to Hsp90 inhibition than non-pathogenic cells. Therefore, the compounds described herein can be used to treat cell proliferative diseases.

neurodegenerative diseases

Increased Hsp90 levels have been implicated in neurodegenerative disorders. For example, aberrant Hsp90 activity has been shown in tauopathies, which are disorders characterized by the accumulation of abnormal Tau protein (e.g., hyperphosphorylated and aggregated Tau). Thus, the compounds and compositions described herein can be used to treat neurodegenerative diseases and tauopathies, including Alzheimer's disease (AD), argyrophilic grain dementia, amyotrophic lateral sclerosis, corticobasal degeneration, dementia pugislistica, Down syndrome, familial British dementia, frontal lobe degeneration (dementia lacking characteristic histopathological features), chronic traumatic encephalopathy, traumatic brain injury, frontotemporal dementia (FTD; frontotemporal dementia with parkinsonism associated with chromosome 17 (FTDP-17)), hippocampal tauopathy in the aging brain, myotonic dystrophy type I, Niemann-Pick disease type C, Parkinson's disease (e.g., Parkinson's disease of Guam, Parkinson's syndrome associated with Guadeloupe dementia, or postencephalitis parkinsonism), Pick's disease (PiD), and progressive supranuclear palsy. Thus, the compounds described herein are useful for treating neurodegenerative disorders, such as, for example, tauopathies (eg, Alzheimer's disease).

infectious disease

Hsp90 has emerged as a therapeutic target for treating infectious diseases such as viral, fungal, and bacterial infections. Many pathogens (e.g., viruses, fungi, and bacteria) rely on Hsp90-dependent processes (see, e.g., Geller et al., Biochim. Biophys. Acta-Mol. Cell Res., 1823: 698-706, 2012; the entire disclosure of this disclosure is incorporated herein). Therefore, inhibition of Hsp90 provides therapeutic benefits to patients with infections that rely on Hsp90 activity. For example, the Hsp90 inhibitor (geldanamycin) has been shown to delay the growth of influenza virus in cell culture. Other viruses that rely on Hsp90-dependent processes include those belonging to the following families: Herpesviridae (e.g., herpes simplex virus-1, herpes simplex virus-2, herpes virus-5, Kaposi's sarcoma-associated herpesvirus, varicella-zoster virus, or Epstein-Barr virus), Polyomaviridae (e.g., SV40), Poxviridae (e.g., vaccinia virus), Reoviridae (e.g., rotavirus), Bitrnaviridae (e.g., infectious bursal disease virus), Picornaviridae (e.g., poliovirus, rhinovirus, or coxsackievirus), Flaviviridae (e.g., hepatitis C virus, or dengue virus), In some embodiments, Hsp90 inhibitors are used to treat fungal infections in vivo, such as Candida albicans, Aspergillus fumigatus, or Pneumocystis jiroveci. In some embodiments, Hsp90 inhibitors are used to treat fungal infections in vivo, such as Candida albicans, Aspergillus fumigatus, or Pneumocystis jiroveci. In addition, Hsp90 inhibitors are used to treat bacterial infections, such as mycobacterial disease, anthrax, or bacterial pneumonia. A discussion of diseases that can be treated with Hsp90 inhibitors is provided in U.S. Patent Application Publication No. 2011/0201587, the disclosure of which is incorporated herein by reference in its entirety. Thus, the compounds of the present invention can be used in accordance with the methods of the present invention to treat infectious diseases, e.g., viral infections, fungal infections, or bacterial infections.

Inflammatory and autoimmune diseases, allergies

Hsp90 has been shown to play a role in antigen presentation, activation of lymphocytes and macrophages, maturation of dendritic cells, and induction of potentiome-mediated inflammation. Hsp90 inhibition is associated with blockade of inflammatory components, such as reduced cytokine and NO production, and blockade of NFκB nuclear translocation. Furthermore, extensive work suggests that molecular chaperones, such as Hsp90, may be able to induce the production of proinflammatory cytokines by the monocyte-macrophage system and induce dendritic cell activation and maturation via the TLR2 and 4 signaling pathways. Thus, Hsp90 clearly functions as a potent activator of the innate immune system. Indeed, elevated levels of Hsp90 have been detected in the serum of patients with systemic lupus erythematosus. Autoantibodies and cells reactive to Hsp90 have been detected in patients with rheumatoid arthritis. The anti-inflammatory effects of Hsp90 inhibition have also been observed to reduce airway inflammation in a murine model of asthma. The compounds of the present invention may be useful in treating inflammatory or autoimmune diseases in patients. Furthermore, the anti-inflammatory effects of Hsp90 inhibition may have therapeutic applications in the treatment of allergies. Therefore, the compounds of the present invention are useful in the treatment of allergies.

cardiovascular disease

Hsp90 has recently been implicated in the etiology of cardiovascular diseases, such as atherosclerosis and cardiomyopathy. Therefore, the compounds of the present invention may be useful in the treatment of cardiovascular diseases (eg, atherosclerosis or cardiomyopathy).

Kit of the present invention

The present invention also provides a kit comprising (i) a pharmaceutical composition of the present invention, and (ii) instructions for using the pharmaceutical composition as described herein to treat a mammalian disease caused by the action of Hsp90 (e.g., a neurodegenerative disorder, a proliferative disease, or an infectious disease). The kit of the present invention may include instructions explaining how a practitioner (e.g., a doctor, nurse, caregiver, or patient) administers the composition contained therein. The pharmaceutical composition within the kit of the present invention may be provided in a container (e.g., a bottle, an ampoule, a tube, or a blister pack). In addition, the kit may further include additional components, for example, instructions or a dosing regimen for a patient suffering from a neurodegenerative disease or a proliferative disease, and optionally, a device for administering the pharmaceutical composition (e.g., a syringe).

The following examples are intended to illustrate the present invention. These examples are not intended to limit the present invention in any way.

Examples

Example 1 Synthesis of the compounds of the present invention

Scheme 1. Reagents and conditions: (a) Pd(PPh ₃ ) ₄ , Na ₂ CO ₃ , dioxane/H ₂ O (9/5), 90° C., 72%.

4-(5,7-dichloro-2,3-benzodihydrofuran-4-yl)-5H-pyrrolo[3,2-d]pyrimidin-2-amine (20). A mixture of 5,7-dichloro-2,3-dihydro-1-benzofuran-4-ylboronic acid (233 mg, 1.0 mmol), 4-chloro-5H-pyrrolo[3,2-d]pyrimidin-2-amine (219 mg, 1.3 mmol), sodium carbonate (318 mg, 3.0 mmol), palladium tetrakis(triphenylphosphine) and dioxane/water (9/5, 14 ml) was stirred at 90° C. under argon for 20 hours, then cooled to room temperature, quenched with brine (25 ml), and extracted with ethyl acetate (30 ml×2). The combined organic layers were dried over sodium sulfate and concentrated. The residue was purified by silica gel chromatography on silica gel using cyclohexane/ethyl acetate (100/0 to 30/70, 15 min) to give the product as a white solid (230 mg, 72%). ¹ H NMR (500 MHz, CDCl ₃ ): δ 8.01 (s, 1H), 7.45 (t, J=3 Hz, 1H), 7.34 (s, 1H), 6.46 (m, 1H), 4.83 (s, 2H), 4.71 (m, 2H), 3.60 (m, 1H), 2.94 (m, 1H); LCMS [M+H] ⁺ : 321.0 (calculated for [C ₁₄ H ₁₀ Cl ₂ N ₄ O+H] ⁺ : 321.0).

The following compounds of the present invention have been prepared according to the methods described herein.

4-(5,7-Dichloro-2,3-benzodihydrofuran-4-yl)-N,6-dimethylpyrimidin-2-amine (3). ¹ H NMR (500 MHz, CDCl ₃ ): δ 7.25 (s, 1H), 6.57 (s, 1H), 5.07 (d, J=10 Hz, 1H), 4.68 (t, J=9 Hz, 2H), 3.29 (t, J=9 Hz, 2H), 3.02 (d, J=10 Hz, 3H), 2.40 (s, 3H).

4-(5,7-Dichloro-2,3-benzodihydrofuran-4-yl)-N,N,6-trimethylpyrimidin-2-amine (4). ¹ H NMR (500 MHz, CDCl ₃ ): δ 7.25 (s, 1H), 6.51 (s, 1H), 4.67 (t, J=9 Hz, 2H), 3.30 (t, J=9 Hz, 2H), 3.20 (s, 6H), 2.40 (s, 3H).

4-(5,7-Dichloro-2,3-benzodihydrofuran-4-yl)-6-methylpyrimidin-2-amine (5). ¹ H NMR (500 MHz, CDCl ₃ ): δ 7.27 (s, 1H), 6.64 (s, 1H), 5.04 (s, 2H), 4.68 (t, J=9 Hz, 2H), 3.25 (t, J=9 Hz, 2H), 2.42 (s, 3H).

4-(5,7-Dichloro-2,3-benzodihydrofuran-4-yl)-6-ethylpyrimidin-2-amine (6). ¹ H NMR (500 MHz, CDCl ₃ ): δ 7.27 (s, 1H), 6.65 (s, 1H), 5.05 (s, 2H), 4.68 (t, J=9 Hz, 2H), 3.26 (t, J=8.5 Hz, 2H), 2.68 (q, J=8 Hz, 2H), 1.29 (t, J=7.5 Hz, 3H); LCMS [M+H] ⁺ : 310.1 (calculated for [C14H13Cl2N3O+H] ⁺ : 310.04).

4-(5,7-Dichloro-2,3-benzodihydrofuran-4-yl)-6-isopropylpyrimidin-2-amine (7). ¹ H NMR (500 MHz, CDCl ₃ ): δ 7.28 (s, 1H), 6.66 (s, 1H), 5.04 (s, 2H), 4.69 (t, J=9 Hz, 2H), 3.27 (t, J=9 Hz, 2H), 2.87 (m, 1H), 1.28 (d, J=7 Hz, 6H); LCMS [M+H] ⁺ : 324.02 (calculated for [C15H15Cl2N3O+H] ⁺ : 324.06).

4-(5,7-Dichloro-2,3-benzodihydrofuran-4-yl)-6-methoxypyrimidin-2-amine (8). ¹ H NMR (500 MHz, CDCl ₃ ): δ 7.28 (s, 1H), 6.19 (s, 1H), 4.98 (s, 2H), 4.68 (t, J=8.5 Hz, 2H), 3.94 (s, 3H), 3.25 (t, J=9 Hz, 2H); LCMS [M+H] ⁺ : 311.87 (calculated for [C13H11Cl2N3O2+H] ⁺ : 312.02).

4-(2,4-Dichloro-5-methoxyphenyl)-5,6-dimethylpyrimidin-2-amine (9). ¹ H NMR (500 MHz, CDCl ₃ ): δ 7.47 (s, 1H), 6.83 (s, 1H), 4.88 (s, 2H), 3.90 (s, 3H), 2.42 (s, 3H), 1.95 (s, 3H).

4-(5,7-Dichloro-2,3-benzodihydrofuran-4-yl)-5,6-dimethylpyrimidin-2-amine (10). ¹ H NMR (500 MHz, CDCl ₃ ): δ 7.25 (s, 1H), 4.89 (s, 2H), 4.69 (t, J=9 Hz, 2H), 3.25 (m, 1H), 2.88 (m, 1H), 2.42 (s, 3H), 1.93 (s, 3H).

4-(2-Chloro-4-fluoro-5-methoxyphenyl)-6,7-dihydro-5H-cyclopentadieno[d]pyrimidin-2-amine (11). ¹ H NMR (500 MHz, CDCl ₃ ): δ 7.20 (d, J = 10.5 Hz, 1H), 6.94 (d, J = 9 Hz, 1H), 4.99 (s, 2H), 3.90 (s, 3H), 2.91 (t, J = 8 Hz, 2H), 2.72 (t, J = 7.5 Hz, 2H), 2.08 (m, 2H); LCMS [M+H] ⁺ : 294.2 (calculated for [C14H13ClFN3O+H] ⁺ : 294.07).

4-(2,4-Dichloro-5-methoxyphenyl)-6,7-dihydro-5H-cyclopentadieno[d]pyrimidin-2-amine (12). ¹ H NMR (500 MHz, CDCl ₃ ): δ 7.47 (s, 1H), 6.90 (s, 1H), 4.98 (s, 2H), 3.91 (s, 3H), 2.92 (t, J=7.5 Hz, 2H), 2.72 (t, J=7.5 Hz, 2H), 2.08 (m, 2H).

4-(5,7-Dichloro-2,3-benzodihydrofuran-4-yl)-6,7-dihydro-5H-cyclopentadieno[d]pyrimidin-2-amine (13). ¹ H NMR (500 MHz, CDCl ₃ ): δ 7.25 (s, 1H), 4.69 (m, 2H), 3.38 (m, 1H), 2.99-2.81 (m, 4H), 2.49 (m, 1H), 2.17-2.00 (m, 2H).

4-(2,4-Dichloro-5-(2-(dimethylamino)ethoxy)phenyl)-6,7-dihydro-5H-cyclopentadieno[d]pyrimidin-2-amine (14). ¹ H NMR (500 MHz, CDCl ₃ ): δ 7.46 (s, 1H), 6.90 (s, 1H), 4.97 (s, 2H), 4.13 (t, J=6 Hz, 2H), 2.91 (t, J=8 Hz, 2H), 2.80 (t, J=6 Hz, 2H), 2.71 (t, J=7.5 Hz, 2H), 2.36 (s, 6H), 2.08 (m, 2H); LCMS [M+H] ⁺ : 367.1 (calcd for [C17H20Cl2N4O+H] ⁺ : 367.10).

4-(5,7-Dichloro-2,3-benzodihydrofuran-4-yl)-5,6,7,8-tetrahydroquinazolin-2-amine (15). ¹ H NMR (500 MHz, CDCl ₃ ): δ 7.28 (s, 1H), 4.88 (s, 2H), 4.69 (t, J=9 Hz, 2H), 3.21 (m, 1H), 2.89 (m, 1H), 2.78 (m, 2H), 2.44 (m, 1H), 2.15 (m, 1H), 1.86 (m, 2H), 1.72 (m, 2H); LCMS [M+H] ⁺ : 336.1 (calcd. for [C16H15Cl2N3O+H] ⁺ : 336.06).

4-(2,4-Dichloro-5-methoxyphenyl)-5H-pyrrolo[3,2-d]pyrimidin-2-amine (19). ¹ H NMR (500 MHz, CDCl ₃ ): δ 8.15 (s, 1H), 7.54 (s, 1H), 7.46 (m, 1H), 7.15 (s, 1H), 6.45 (m, 1H), 4.86 (s, 2H), 3.94 (s, 3H).

4-(5,7-Dichloro-2,3-benzodihydrofuran-4-yl)-5H-pyrrolo[3,2-d]pyrimidin-2-amine (20). ¹ H NMR (500 MHz, CDCl ₃ ): δ 8.01 (s, 1H), 7.45 (t, J=3 Hz, 1H), 7.34 (s, 1H), 6.46 (m, 1H), 4.83 (s, 2H), 4.71 (m, 2H), 3.60 (m, 1H), 2.94 (m, 1H); LCMS [M+H] ⁺ : 321.0 (calcd for [C ₁₄ H ₁₀ Cl ₂ N ₄ O+H] ⁺ : 321.0). The ¹ H NMR spectrum is shown in FIG1 .

4-(5,7-Dichloro-2,3-benzodihydrofuran-4-yl)-5-methyl-5H-pyrrolo[3,2-d]pyrimidin-2-amine (21). ¹ H NMR (500 MHz, CDCl ₃ ): δ 7.32 (s, 1H), 7.22 (d, J=3 Hz, 1H), 6.36 (d, J=3 Hz, 1H), 4.81 (s, 2H), 4.72 (m, 2H), 3.40 (s, 3H), 3.34 (m, 1H), 2.91 (m, 1H); LCMS [M+H] ⁺ : 335.0 (calculated for [C15H12Cl2N4O+H] ⁺ : 335.04).

4-(5,7-Dichloro-2,3-benzodihydrofuran-4-yl)-5-ethyl-5H-pyrrolo[3,2-d]pyrimidin-2-amine (22). ¹ H NMR (500 MHz, CDCl ₃ ): δ 7.33 (m, 2H), 6.40 (d, J=2.5 Hz, 1H), 4.80 (s, 2H), 4.70 (m, 2H), 3.72 (d, J=7 Hz, 2H), 3.33 (m, 1H), 2.91 (m, 1H), 1.14 (t, J=7.5 Hz, 3H); LCMS [M+H] ⁺ : 349.1 (calcd. for [C16H14Cl2N4O+H] ⁺ : 349.05).

Ethyl-2-amino-4-(5,7-dichloro-2,3-benzodihydrofuran-4-yl)thieno[2,3-d]pyrimidine-6-carboxylate (23). ¹ H NMR (500 MHz, CDCl ₃ ): δ 7.54 (s, 1H), 7.35 (s, 1H), 5.32 (s, 2H), 4.70 (m, 2H), 4.37 (m, 2H), 3.35 (m, 1H), 2.92 (m, 1H), 1.38 (t, J=7 Hz, 3H); LCMS [M+H] ⁺ : 410.0 (calcd. for [C17H13Cl2N3O3S+H] ⁺ : 410.01).

2-Amino-4-(5,7-dichloro-2,3-benzodihydrofuran-4-yl)-N-ethylthieno[2,3-d]pyrimidine-6-carboxamide (24). ¹ H NMR (500 MHz, CDCl ₃ ): δ 7.34 (s, 1H), 7.21 (s, 1H), 5.91 (s, 1H), 5.28 (s, 2H), 4.70 (m, 2H), 4.48 (m, 2H), 3.36 (m, 1H), 2.91 (m, 1H), 1.26 (t, J=3.5 Hz, 3H); LCMS [M+H] ⁺ : 409.0 (calcd. for [C17H14Cl2N4O2S+H] ⁺ : 409.02).

Compounds 34 and 36 were prepared according to methods known in the art, such as those described herein. ¹ H NMR spectra (CDCl ₃ ) of compounds 34 and 36 are provided in Figures 2 and 3 , respectively.

Compounds 40-48 can be prepared according to methods known in the art, such as those described herein.

4-Chloro-6-(5,7-dichloro-2,3-benzodihydrofuran-4-yl)pyrimidin-2-amine (49). ^1H NMR (400 MHz, DMSO-d6): δ = 7.48 (s, 1H), 7.30 (s, 2H), 6.78 (s, 1H), 4.64 (t, J = 8.8 Hz, 2H), 3.20 (t, J = _{8.8 Hz} , 2H). LCMS: m/z calculated for _C12H8Cl3N3O [M+H] ⁺ : _316.0 ; found: 316.0.

4-Trifluoromethyl-6-(5,7-dichloro-2,3-benzodihydrofuran-4-yl)pyrimidin-2-amine (50). ¹ H NMR (400 MHz, DMSO-d6): δ 7.520 (br s, 2H, NH ₂ ), 7.093 (s, 1H), 4.655 ( _t , 2H, J=8.8 Hz), 3.547 (s, 1H), 3.221 (t, _2H , _{J=8.8 Hz). LCMS: m/z calculated for Ci3H8Cl2F3N3O [ M} +H] ⁺ : 350.1; found: 350.0.

4-Thioxomethyl-6-(5,7-dichloro-2,3-benzodihydrofuran-4-yl)pyrimidin-2-amine (51). ¹ H NMR (400 MHz, DMSO-d6): δ 7.438 (s, 1H), 6.815 (br s, 2H, NH ₂ ), 6.549 (s, 1H), 4.633 (t, 2H, J=8.8 Hz), 3.178 (t, _2H , J=8.8 Hz), 2.453 (s, _{3H). LCMS: m/z calculated for Ci3HiCl2N3OS [ M} +H] ⁺ : 328.2; found: 328.1.

4-Chloro-6-(5,7-dichloro-2,3-benzodihydrofuran-4-yl)pyrimidine-2,5-diamine (52). ^1H NMR (400 MHz, DMSO-d6): δ = 7.46 (s, 1H), 6.25 (s, 2H), 4.67 (t, J = 8.8 Hz, 2H), 4.30 (s, 2H), 3.15-3.07 _m , _{2H )} . HPLC/MS: m/z calculated for _C12H9Cl3N4O [M+H] ⁺ : 331.0; found: 331.1.

2-Amino-6-(5,7-dichloro-2,3-dihydrobenzofuran-4-yl)pyrimidin-4-ol (53). To a flask containing dioxane:1N NaOH aqueous solution (50:50; 1 mL:1 mL) was added 4-chloro-6-(5,7-dichloro-2,3-dihydrobenzofuran-4-yl)pyrimidin-2-amine (49) (20 mg, 0.063 mmol) and DABCO (8 mg, 0.069 mmol) at room temperature. The reaction was then heated at 80°C. The reaction was cooled, acidified by the addition of 1N HCl aqueous solution (2 mL), dissolved in ethyl acetate (5 mL), and washed with brine (3×5 mL). The organic layer was dried over Na ₂ SO ₄ , filtered, and the volatiles were evaporated. The residue was purified by silica gel chromatography using a gradient of DCM:MeOH (100:0 to 90:10). The product was obtained as a white solid in 77% yield.

¹ H NMR (400 MHz, DMSO-d6): δ = 7.39 (s, 1H), 5.57 (s, 1H), 4.62 (t, J = 8.8 Hz, 2H), 3.20 (t, J = 8.8 Hz, 2H). HPLC/MS: m/z calcd for C ₁₂ H ₉ Cl ₂ N ₃ O ₂ [M+H] ⁺ : 298.0; found: 298.1.

Methyl 2-amino-4-(5,7-dichloro-2,3-benzodihydrofuran-4-yl)-5H-pyrrolo[3,2-d]pyrimidine-5-carboxylate (54). To a flask containing 4-(5,7-dichloro-2,3-dihydrobenzofuran-4-yl)-5H-pyrrolo[3,2-d]pyrimidin-2-amine (20) (20 mg, 0.062 mmol) in DCM (1 mL) was added dry K ₂ CO ₃ (30 mg, 0.22 mmol) and methyl chloroformate (0.014 mL, 0.186 mmol) at 0°C. The reaction was stirred at room temperature for 8 hours. The reaction was then quenched by the addition of 1N NaOH aqueous solution (1 mL) and stirred at room temperature for 1 hour. The reactants were dissolved in DCM (10 mL) and washed with saturated NaHCO ₃ aqueous solution (10 mL). The organic layer was dried over Na ₂ SO ₄ , filtered, and the volatiles were evaporated. The residue was purified by silica gel chromatography using a gradient of DCM:MeOH (100:0 to 90:10). The product was obtained as a yellow solid in 66% yield.

¹ H NMR (400 MHz, CDCl 3 ): δ=7.61 (s, 1H), 7.23 (s, 1H), 6.51 (s, 1H), 4.63 (br s, 2H), 3.77 (s, 3H), 3.65 (br s, 1H), 2.85 (br s, 1H). HPLC/MS: m/z calculated for C ₁₆ H ₁₂ Cl ₂ N ₄ O ₃ [M+H] ⁺ : 379.0; found: 379.1.

1-(2-Amino-4-(5,7-dichloro-2,3-dihydrobenzofuran-4-yl)-5H-pyrrolo[3,2-d]pyrimidin-5-yl)ethan-1-one (55). To a flask containing 4-(5,7-dichloro-2,3-dihydrobenzofuran-4-yl)-5H-pyrrolo[3,2-d]pyrimidin-2-amine (20 mg, 0.062 mmol) in DCM (1 mL) was added dry K ₂ CO ₃ (30 mg, 0.22 mmol) and acetyl chloride (0.006 mL, 0.074 mmol) at 0°C. The reaction was stirred at room temperature for 8 hours. The reaction was then quenched by the addition of 1 N NaOH aqueous solution (1 mL) and stirred at room temperature for 1 hour. The reactants were dissolved in DCM (10 mL) and washed with saturated NaHCO ₃ aqueous solution (10 mL). The organic layer was dried _{over Na2SO4} , filtered, and the volatiles were evaporated. The residue was purified by silica gel chromatography using a gradient of DCM:MeOH (100:0 to 90:10). The product was obtained as a yellow solid in 81% yield.

¹ H NMR (400 MHz, CDCl 3 ): δ=7.57 (s, 1H), 7.23 (s, 1H), 6.55 (s, 1H), 4.63 (br s, 2H), 3.45 (br s, 1H), 3.35 (s, 3H), 2.85 (br s, 1H). HPLC/MS: m/z calculated for C ₁₆ H ₁₂ Cl ₂ N ₄ O ₂ [M+H] ⁺ : 363.0; found: 363.1.

2-Amino-4-(5,7-dichloro-2,3-dihydrobenzofuran-4-yl)-5H-pyrrolo[3,2-d]pyrimidine-7-carbaldehyde (56). To a flask containing dry THF (2 mL) at 0°C was added anhydrous DMF (0.1 mL) and _POCl3 (0.015 mL, 0.16 mmol). The reaction was stirred at 0°C under argon for 30 minutes, then 4-(5,7-dichloro-2,3-dihydrobenzofuran-4-yl)-5H-pyrrolo[3,2-d]pyrimidin-2-amine (20 mg, 0.062 mmol) in THF (1 mL) was added dropwise. The reaction was stirred for 8 hours and warmed to room temperature. 1N aqueous NaOH solution (2 mL) was then added to the reaction and heated to 80°C for 1 hour. The reaction was cooled to room temperature and dissolved in EtOAc (20 mL) and washed with saturated NaHCO ₃ aqueous solution (20 mL). The organic layer was dried over Na ₂ SO ₄ , filtered, and the volatiles were evaporated. The residue was purified by silica gel chromatography using a gradient of DCM: MeOH (100: 0 to 90: 10). The product was obtained as a white solid in 58% yield.

¹ H NMR (400 MHz, CDCl 3 ): δ=10.05 (s, 1H), 7.96 (s, 1H), 7.24 (s, 1H), 4.63 (br s, 2H), 3.31 (br s, 1H), 2.85 (br s, 1H). HPLC/MS: m/z calculated for C ₁₅ H ₁₀ Cl ₂ N ₄ O ₂ [M+H] ⁺ : 349.0; found: 349.1.

7-Bromo-4-(2,4-dichloro-5-methoxyphenyl)-5H-pyrrolo[3,2-d]pyrimidin-2-amine (57). To a flask containing 4-(2,4-dichloro-5-methoxyphenyl)-5H-pyrrolo[3,2-d]pyrimidin-2-amine (20 mg, 0.065 mmol) in AcOH:tBuOH (50:50, 0.5 mL:0.5 mL) was added LiBr (18 mg, 0.22 mmol) and Br ₂ (0.011 mL, 0.22 mmol) at 0°C. The reaction was stirred at room temperature for 8 hours. The reactant was then dissolved in EtOAc (20 mL) and washed with saturated aqueous NaHCO ₃ solution (3×20 mL) and Na ₂ S ₂ O ₃ (10% wt. aqueous solution, 20 mL). The organic layer was dried over Na ₂ SO ₄ , filtered, and the volatiles were evaporated. The residue was purified by silica gel chromatography using a gradient of DCM:MeOH (100:0 to 90:10). The product was obtained as a yellow solid in 56% yield.

¹ H NMR (400 MHz, DMSO-d6): δ=7.75 (s, 1H), 7.72 (s, 1H), 7.26 (s, 1H), 6.24 (s, 2H), 3.86 (s, 3H). HPLC/MS: m/z calculated for C ₁₃ H ₉ BrCl ₂ N ₄ O [M+H] ⁺ : 386.9; found: 387.0.

2-Amino-4-(5,7-dichloro-2,3-benzodihydrofuran-4-yl)thieno[2,3-d]pyrimidine-6-carboxamide General synthesis method:

Step 1: Synthesis of the precursor 2,5-dioxopyrrolidin-1-yl 2-amino-4-(5,7-dichloro-2,3-benzodihydrofuran-4-yl)thieno[2,3-d]pyrimidine-6-carboxylate. To a flask containing degassed DMF: _H₂O (50:50; 2 mL:2 mL) was added ethyl 2-amino-4-chlorothieno[2,3-d]pyrimidine-6-carboxylate (100 mg, 0.39 mmol), (5,7-dichloro-2,3-dihydrobenzofuran-4-yl)boronic acid (91 mg, 0.39 mmol), _NaHCO₃ (82 mg, 0.98 mmol), and Pd( _PPh₃ ) _₄ (22 mg, 0.02 mmol) at room temperature. The reaction was then heated at 80°C under argon for 8 hours. The reaction was cooled, dissolved in ethyl acetate (20 mL), and washed with brine (3 × 20 mL). The organic layer was dried over Na ₂ SO ₄ , filtered, and the volatiles were evaporated. The residue was purified by silica gel chromatography using a gradient of DCM:MeOH (100:0 to 90:10). The product, ethyl 2-amino-4-(5,7-dichloro-2,3-dihydrobenzofuran-4-yl)thieno[2,3-d]pyrimidine-6-carboxylate, was obtained in a yield of 38% as a yellow solid.

Ethyl 2-amino-4-(5,7-dichloro-2,3-dihydrobenzofuran-4-yl)thieno[2,3-d]pyrimidine-6-carboxylate (60 mg, 0.15 mmol) was dissolved in THF (1 mL) and a 1N aqueous NaOH solution (1 mL) was added to the flask. The reaction was stirred at room temperature for 8 hours. Subsequently, the solution was cooled to 0°C and acidified by the addition of a 1N aqueous HCl solution (2 mL), resulting in the formation of a white precipitate, which was filtered and dried to afford 2-amino-4-(5,7-dichloro-2,3-dihydrobenzofuran-4-yl)thieno[2,3-d]pyrimidine-6-carboxylic acid in quantitative yield without further purification. The filtrate (57 mg, 0.15 mmol) was dissolved in dry DMF (1 mL) and cooled to 0°C. N-hydroxysuccinimide (23 mg, 0.2 mmol) and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide HCl (38 mg, 0.2 mmol) were added to the reaction vessel. The reaction was heated to room temperature with stirring for more than 8 hours. The solution was dissolved in DCM (20 mL) and washed with saturated aqueous _NH4Cl (3 x 20 mL). The organic layer was dried _{over Na2SO4} , filtered, and the volatiles were evaporated. The residue was purified by silica gel chromatography using a gradient of DCM:MeOH (100:0 to 90:10). The product, 2,5-dioxopyrrolidin-1-yl 2-amino-4-(5,7-dichloro-2,3-dihydrobenzofuran-4-yl)thieno[2,3-d]pyrimidine-6-carboxylate, was obtained as a white solid in 88% yield.

Step 2: General procedure for amide formation:

To a flask containing 2,5-dioxopyrrolidin-1-yl 2-amino-4-(5,7-dichloro-2,3-dihydrobenzofuran-4-yl)thieno[2,3-d]pyrimidine-6-carboxylate (10 mg, 0.02 mmol) was added dry DMF (0.5 mL) followed by an amine (3 equivalents, 0.06 mmol) (e.g., ammonia, a primary amine, or a secondary amine). The reaction was stirred at room temperature for 12 hours before being dissolved in DCM (5 mL) and washed with saturated aqueous _NH₄Cl (3 x 5 mL). The organic layer was dried _{over Na₂SO₄} , filtered, and the volatiles evaporated. The residue was purified by silica gel chromatography using a gradient of DCM:MeOH (100:0 to 90:10). The resulting amide was obtained in good to excellent yields.

2-Amino-4-(5,7-dichloro-2,3-benzodihydrofuran-4-yl)-N-(2-(pyrrolidin-1-yl)ethyl)thieno[2,3-d]pyrimidine-6-carboxamide (58). ^1H NMR (400 MHz, DMSO-d6): δ = 8.79 (s, 1H), 7.61 (s, 1H), 7.58 (s, 1H), 7.28 (s, 2H), 4.67 (t, J = 8.8 Hz, 2H), 3.44-3.11 (m, 6H), 2.90-2.75 (m, _4H ), _1.77-1.73 (m, _{4H )} . HPLC/MS: m/z calculated for _{C21H21Cl2N5O2S} [M+H] ⁺ : 478.1; found: 478.1

2-Amino-N-(2-cyanoethyl)-4-(5,7-dichloro-2,3-benzodihydrofuran-4-yl)thieno[2,3-d]pyrimidine-6-carboxamide (59). ¹ H NMR (400 MHz, DMSO-d6): δ = 8.94 (t, J = 5.6 Hz, 1H), 7.63 (s, 1H), 7.60 (s, 1H), 7.34 (s, 2H), 4.69 (t, J = 8.8 Hz, 2H), 3.46-3.41 (m, 2H), 3.23-3.15 (m, 1H), 3.03-2.97 (m, 1H), 2.76 (t, J = 6.4 Hz, 2H). HPLC/MS: m/ _z calcd for _{Ci8H13Cl2N5O2S} [M+H] ⁺ : _434.0 ; found _{: 434.1} .

2-Amino-4-(5,7-dichloro-2,3-benzodihydrofuran-4-yl)-N-(2-hydroxyethyl)thieno[2,3-d]pyrimidine-6-carboxamide (60). ¹ H NMR (400 MHz, DMSO-d6): δ = 8.57 (t, J = 5.6 Hz, 1H), 7.59 (s, 2H), 7.26 (s, 2H), 4.73 (t, J = 5.6 Hz, 1H), 4.67 (t, J = 8.8 Hz, 2H), 3.46-3.41 (m, 2H), 3.26-3.12 (m, 3H), 3.03-2.94 (m, 1H). HPLC/MS: m/ _z calcd for _{Ci7H14Cl2N4O3S} [M+H] ⁺ : _425.0 ; found _{: 425.1} .

2-Amino-4-(5,7-dichloro-2,3-benzodihydrofuran-4-yl)-N-(2,2,2-trifluoroethyl)thieno[2,3-d]pyrimidine-6-carboxamide (61). ¹ H NMR (400 MHz, DMSO-d6): δ = 9.18 (t, J = 6.0 Hz, 1H), 7.72 (s, 1H), 7.63 (s, 1H), 7.38 (s, 2H), 4.69 (t, J = 8.8 Hz, 2H), 4.12-4.03 (m, 2H), 3.26-3.18 (m, 1H), 3.03-2.94 (m, 1H). HPLC/MS: m/z calcd for _{Ci7H11Cl2F3N4O2S} [M _{+ H} ] ⁺ : _463.0 ; found _{: 463.1} .

2-Amino-N-cyclopropyl-4-(5,7-dichloro-2,3-benzodihydrofuran-4-yl)thieno[2,3-d]pyrimidine-6-carboxamide (62). ¹ H NMR (400 MHz, DMSO-d6): δ = 8.54 (s, 1H), 7.61 (s, 1H), 7.53 (s, 1H), 7.29 (s, 2H), 4.68 (t, J = 8.8 Hz, 2H), 3.26-3.18 (m, 1H), 3.03-2.94 (m, 1H), 2.81-2.71 (m, 1H), 0.75-0.61 (m, 2H), 0.55-0.40 (m, 2H). HPLC/MS: m/ _z calcd for _{Ci8H14Cl2N4O2S} [M+H] ⁺ : _421.0 ; found _{: 421.1} .

2-Amino-4-(5,7-dichloro-2,3-benzodihydrofuran-4-yl)-N-methylthieno[2,3-d]pyrimidine-6-carboxamide (63). ^1H NMR (400 MHz, DMSO-d6): δ = 8.62-8.59 (m, 1H), 7.61 (s, 2H), 7.27 (s, 2H), 4.64 ₍ t _, J = 8.8 Hz, 2H), 3.24 (s, 3H), 3.23-3.18 (m, 1H), 3.03-2.91 (m, 1H) _{. HPLC/MS: m/z calculated for Ci6Hi2Cl2N4O2S [} M+H] ⁺ : _395.0 ; found: 395.1.

2-Amino-4-(5,7-dichloro-2,3-benzodihydrofuran-4-yl)-N-(2-methoxyethyl)thieno[2,3-d]pyrimidine-6-carboxamide (64). ^1H NMR (400 MHz, DMSO-d6): δ = 8.51-8.41 (m, 1H), 7.59 (s, 1H), 7.50 (s _, 1H), 7.26 (s, 2H), 4.67 (t, J = 8.8 Hz, 2H), _3.23-3.10 (m, 4H), 3.03-2.91 (m, 2H), _2.72-2.67 (m, _3H ). HPLC/MS: m/z calculated for _{Ci8Hi6Cl2N4O3S} [M+H] ⁺ : 439.0; found: 439.1.

2-Amino-N-cyclobutyl-4-(5,7-dichloro-2,3-benzodihydrofuran-4-yl)thieno[2,3-d]pyrimidine-6-carboxamide (65). ¹ H NMR (400 MHz, DMSO-d6): δ = 8.68 (d, J = 6.8 Hz, 1H), 7.61 (s, 1H), 7.56 (s, 1H), 7.26 (s, 2H), 4.67 (t, J = 8.8 Hz, 2H), 4.33-4.26 (m, 1H), 3.23-3.18 (m, 1H), 3.03-2.91 (m, 1H), 2.16-1.92 (m, 2H), 1.70-1.60 (m, 1H), 1.33-1.20 (m, 2H), 0.90-0.78 (m, 1H). HPLC/MS: m/ _{z calcd for C19H16Cl2N4O2S [} M+H] ⁺ : _435.0 ; found _{: 435.1} .

2-Amino-4-(5,7-dichloro-2,3-benzodihydrofuran-4-yl)-N,N-dimethylthieno[2,3-d]pyrimidine-6-carboxamide (66). ^1H NMR (400 MHz, DMSO-d6): δ = 7.54 (s, 1H), 7.23 (s, 2H), 7.15 (s, 1H), 4.66 ( _t , J = 8.8 Hz, 2H), 3.31 (s, 3H), _3.23-2.90 (m, _5H ). _HPLC /MS: m/z calculated for _{Ci7H14Cl2N4O2S} [M+H] ⁺ : 409.0; found: 409.1.

2-Amino-4-(5,7-dichloro-2,3-benzodihydrofuran-4-yl)-N-(oxetan-3-yl)thieno[2,3-d]pyrimidine-6-carboxamide (67). ¹ H NMR (400 MHz, DMSO-d6): δ = 9.17 (d, J = 6.8 Hz, 1H), 7.64 (s, 1H), 7.62 (s, 1H), 7.31 (s, 2H), 4.97-4.90 (m, 1H), 4.75-4.65 (m, 4H), 4.55-4.45 (m, 2H), 3.20-3.11 (m, 1H), 3.02-2.92 (m, 1H). HPLC/MS: m/ _z calcd for _{Ci8H14Cl2N4O3S} [M+H] ⁺ : _437.0 ; found _{: 437.1} .

(2-Amino-4-(5,7-dichloro-2,3-benzodihydrofuran-4-yl)thieno[2,3-d]pyrimidin-6-yl)(morpholino)methanone (68). ^1H NMR (400 MHz, DMSO-d6): δ = 7.54 (s, 1H), 7.23 (s, 2H), 7.12 (s _, 1H), 4.66 ( _t , J = 8.8 _Hz , 2H), 3.59 (br s, 8H), 3.26-3.21 (m, 1H), _3.02-2.92 (m, 1H). HPLC/MS: m/z calculated for _{Ci9Hi6Cl2N4O3S} [M+H] ⁺ : 451.0; found: 451.1.

(2-Amino-4-(5,7-dichloro-2,3-benzodihydrofuran-4-yl)thieno[2,3-d]pyrimidin-6-yl)(pyrrolidin-1-yl)methanone (69). ¹ H NMR (400 MHz, DMSO-d6): δ = 7.54 (s, 1H), 7.23 (s, 2H), 7.21 (s, 1H), 4.66 (t, J = 8.8 Hz, 2H), 3.68-3.64 (m, 2H), 3.44 (br s, 2H), 3.26-3.16 (m, 1H), 3.02-2.92 (m, 1H), 1.91-1.76 (m, 4H). HPLC/MS: m/ _{z calcd for C19H16Cl2N4O2S [} M+H] ⁺ : _435.0 ; found _{: 435.1} .

2-Amino-4-(5,7-dichloro-2,3-benzodihydrofuran-4-yl)-N-methyl-N-(2,2,2-trifluoroethyl)thieno[2,3-d]pyrimidine-6-carboxamide (70). ^1H NMR (400 MHz, DMSO-d6): δ = 7.54 (s, 1H), 7.33 (s, 3H) _, 4.66 (t, J ₌ 8.8 Hz, 2H), 4.41-4.28 (m, 2H), 3.27 (s, 3H), 3.26-3.16 (m, 1H), _3.02-2.92 (m, _1H ). _HPLC /MS: m/z calculated for _{Ci8Hi3Cl2F3N4O2S} [M+H] ⁺ : 477.0; found: 477.1.

2-Amino-N-(2-cyanoethyl)-4-(5,7-dichloro-2,3-benzodihydrofuran-4-yl)-N-methylthieno[2,3-d]pyrimidine-6-carboxamide (71). ^1H NMR (400 MHz, DMSO-d6): δ = 7.54 (s, 1H), 7.28 (s, 2H), 7.20 (s, 1H), 4.66 (t, J = 8.8 Hz, 2H), 3.69 (br s, 2H), 3.26-3.16 (m, 4H), 3.02-2.92 (m, 1H) _{, 2.82-2.70 (m, 2H). HPLC/MS: m/z calculated for Ci9Hi5Cl2N5O2S [ M +} H] ⁺ : 448.0; found: 448.1.

2-Amino-4-(5,7-dichloro-2,3-benzodihydrofuran-4-yl)-N-methyl-N-(oxetan-3-yl)thieno[2,3-d]pyrimidine-6-carboxamide (72). ^1H NMR (400 MHz, DMSO-d6): δ = 7.55 (s, 1H), 7.26 (s, 2H), 7.16 (s _{, 1H), 5.21-5.16 (m, 1H), 4.69-4.60 (m, 6H), 3.26-3.14 (m, 4H), 3.02-2.92 (m, 1H). HPLC/MS: m/z calculated for Ci9Hi6Cl2N4O3S [ M + H} ] ⁺ : 451.0; found: 451.1.

2-Amino-4-(5,7-dichloro-2,3-benzodihydrofuran-4-yl)-N-(2-hydroxy-2-methylpropyl)thieno[2,3-d]pyrimidine-6-carboxamide (73). ^1H NMR (400 MHz, DMSO-d6): δ = 8.44 (s, 1H), 7.69 (s, 1H), 7.59 (s, 1H), 7.23 (s, 2H), 4.67 (t, J = 8.8 Hz, 2H), 4.45 (s, 1H), 3.21-3.12 (m, 3H), _3.02-2.92 (m, 1H), 1.04 (s, _6H ). _HPLC /MS: m/ _z calculated for _{C19H18Cl2N4O3S} [M+H] ⁺ : 453.0; found: 453.1.

2-Amino-N-cyclopropyl-4-(5,7-dichloro-2,3-benzodihydrofuran-4-yl)-N-methylthieno[2,3-d]pyrimidine-6-carboxamide (74). ^1H NMR (400 MHz, DMSO-d6): δ = 7.55 (s, 1H), 7.36 (s, 1H), 7.28 (s _, 2H), 4.70-4.62 (m, 2H), 3.13-3.06 (m, 1H), 3.00-2.91 (m, 4H), 0.80-0.72 (m, 2H), _0.68-0.63 (m, _2H ). _HPLC /MS: m/z calculated for _{Ci9Hi6Cl2N4O2S} [M+H] ⁺ : 435.0; found: 435.1.

2-Amino-4-(5,7-dichloro-2,3-benzodihydrofuran-4-yl)-N-methoxy-N-methylthieno[2,3-d]pyrimidine-6-carboxamide (75). ^1H NMR (400 MHz, DMSO-d6): δ = 7.57 (s, 1H), 7.47 (s, 1H), 7.37 (s, 2H), 4.70-4.62 (m, 2H), 3.74 (s, 3H), 3.27-3.19 (m, 4H), _3.00-2.91 (m, _1H ). HPLC/MS: m/z calculated for _{Ci7H14Cl2N4O3S} [M+H] ⁺ : 425.0; found _{: 425.1} .

1-(2-Amino-4-(5,7-dichloro-2,3-dihydrobenzofuran-4-yl)thieno[2,3-d]pyrimidin-6-yl)propan-1-one (76). To a beaker containing 2-amino-4-(5,7-dichloro-2,3-dihydrobenzofuran-4-yl)-N-methoxy-N-methylthieno[2,3-d]pyrimidine-6-carboxamide (20 mg, 0.048 mmol) in dry THF (1 mL) was added EtMgBr (2.0 M in THF; 0.029 mL, 0.057 mmol) at 0°C. The reaction was stirred for 8 hours and then quenched by the addition of saturated aqueous _NH4Cl solution (1 mL). The aqueous layer was extracted with EtOAc (3×2 mL), dried _{over Na2SO4} , filtered, and the volatiles evaporated. The residue was purified by silica gel chromatography using a gradient of DCM:MeOH (100:0 to 90:10). The product was obtained as a white solid in 91% yield.

¹ H NMR (400 MHz, CDCl ₃ ): δ=7.41 (s, 1H), 7.34 (s _, 1H), 5.84 (br s, 2H), 4.74-4.64 (m, 2H), 3.87-3.76 (m, 1H), 3.30-3.10 (m, 3H), _1.50-1.41 (m, 3H). _HPLC /MS: m/z calcd for _{Ci7Hi3Cl2N3O2S} [ _M +H] ⁺ : 394.0; found: 394.1.

2-(2-Amino-4-(5,7-dichloro-2,3-dihydrobenzofuran-4-yl)thieno[2,3-d]pyrimidin-6-yl)propan-2-ol (77). To a beaker containing ethyl 2-amino-4-(5,7-dichloro-2,3-dihydrobenzofuran-4-yl)thieno[2,3-d]pyrimidine-6-carboxylate (20 mg, 0.048 mmol) in dry THF (1 mL) was added MeMgBr (2.0 M in THF; 0.072 mL, 0.144 mmol) at 0°C. The reaction was stirred for 8 hours and then quenched by the addition of saturated aqueous _NH4Cl (1 mL). The aqueous layer was extracted with EtOAc (3 x 2 mL), _dried over _Na2SO4 , filtered, and the volatiles evaporated. The residue was purified by silica gel chromatography using a gradient of DCM:MeOH (100:0 to 90:10). The product was obtained as a white solid in 78% yield.

^1H NMR (400 MHz, DMSO-d6): δ = 7.53 (s, 1H), 6.85 (s, 2H), 6.54 (s, 1H), 5.95 (s, 1H), 4.64 (t, J = 8.8 Hz, 2H), 3.20-3.12 (m, 1H), 3.00-2.90 (m, 1H), 1.46 (s, 3H), _1.44 ( _s , _{3H). HPLC/MS: m/z calcd for Ci7H15Cl2N3O2S [} M+H] ⁺ : 396.0; found _: 396.1.

Example 2. In vitro assay of the compounds of the present invention

Hsp90 biochemical assay (fluorescence polarization)

The Hsp90 inhibitory activity of the compounds of the present invention was assessed using fluorescence polarization (FP) assays using FITC-labeled geldanamycin and truncated α-Hsp90 proteins. Binding activity was measured on a BMG reader (BMG Labtech, Ortenberg, Germany). The assay was homogeneous and performed in 384-well plates, consistent with known standards. The assay was validated with known Hsp90 inhibitors, such as PU-H71 (IC ₅₀ = 60 nM), which is consistent with the reported IC ₅₀ (Luo et al., supra). The results of this assay for compounds 20, 36, 37, and 39 and known Hsp90 inhibitors are shown in Figure 4.

Hsp90 biochemical assay (AlphaLISA)

A robust and reproducible assay based on the AlphaLISA format developed by PerkinElmer, Inc., Waltham, MA, was used to evaluate the Hsp90 inhibitory activity of compounds of the invention (the format of the assay is described, for example, in the "ELISA to AlphaLISA Conversion Guide," published by PerkinElmer, Inc., August 2012). The assay uses biotinylated geldanamycin, His-tagged Hsp90, and Ni ⁺² -coated beads. The assay is homogeneous and miniaturized to 384-well plates. Binding activity is measured on an Envision instrument. The assay is validated with known Hsp90 inhibitors, including PU-H71 ( _IC50 = 60 nM), which is consistent with the reported _IC50 (Luo et al., supra). This assay is the primary assay for evaluating compounds of the invention. In this assay, compound 20 showed Hsp90 inhibitory activity (IC50 = 60 nM). ₅₀ was 0.74±0.1 μM; see FIG5A ).

Hsp90 cell-based functional assays

Cells were treated with compounds of the invention for 24 hours and then lysed in a buffer containing NP-40, orthovanadate, and protease inhibitors. Western blotting was performed using antibodies specific for Hsp70, Hsp90, or actin (as a control). Tau phosphorylation was determined using the SHSY5Y-hTau441V337M/R406W cell line (Loeffler et al., J. Mol. Neurosci., 47: 192-203, 2012) using methods such as Liu et al., Biochemistry, 49: 4921-4929, 2010. This cell line represents a stably transfected cell line that has been shown to have hyperphosphorylated tau by overexpressing the longest human tau isoform hTAU441 with two mutations: V337M and R406W. The functional assays described herein provide an in vitro model of tauopathy and can be used to evaluate the effects of Hsp90 inhibitors on phosphorylated tau (p-Tau). In these assays, compound 20 showed increased expression of Hsp70 (see Figure 5B), a significant decrease in pTau231 levels at 0.1 μM and 0.5 μM (see Figure 6B), and a significant decrease in pTau396 levels at 0.05 μM, 0.1 μM, and 0.5 μM (see Figure 6C).

Cytotoxicity assay

SH-SY5Y-hTAU441 cell viability was determined using the MTT assay. As shown in Figure 6A, compound 20 did not affect the cell viability of SH-SY5Y-hTAU441 cells. SH-SY5Y cell viability can also be measured after 24 and 48 hours along with an assay that measures ATP levels. In addition, a variety of results can be measured using a GE InCell Analyzer 2000 with live cell microscopy imaging, including apoptosis markers, membrane permeability, and mitochondrial activity to measure cytotoxicity.

Mouse liver microsome stability

The metabolic stability of the compounds of the invention was evaluated by monitoring their degradation in mouse liver microsomes. Compound 20 showed good microsomal stability (T _1/2 =26 min).

Solubility

Compound solubility was determined in a buffer solution at pH 7.4. A water solubility of greater than or equal to about 0.5 μM (e.g., greater than or equal to about 1 μM, greater than or equal to about 2 μM, greater than or equal to about 5 μM, greater than or equal to about 10 μM, greater than or equal to about 20 μM, or greater than or equal to about 30 μM) can indicate a compound with acceptable solubility for medical use (e.g., for the treatment of neurodegenerative disorders). At pH 7.4, compound 20 had an aqueous solubility of 30 μM.

Cell permeability

Compounds can be evaluated in the MDR1-MDCK permeability assay or the Caco-2 permeability assay to determine their permeability. A compound with an apical (A) to basal (B) permeability > 3 × ^10-6 cm/sec and a B→A/A→B asymmetry < 3 is considered an acceptable predictor of brain penetration, and compounds with this property are unlikely to be P-glycoprotein (P-gp) substrates. Compound 20 showed excellent permeability in the MDR1-MDCK assay (AB = 28 × ^10-6 cm/s) and had low asymmetry (B→A/A→B asymmetry = 0.9).

The results of the above assays for certain compounds of the present invention are summarized in Table 3.

Table 3.

In Table 3, "Hsp90 Inhibitory Activity" provides an assessment of the ability of exemplary compounds to inhibit Hsp90. Specifically, "-" indicates that the compound has an _IC50 greater than about 10 μM, "+" indicates that the compound has an _IC50 in the range of about 4 μM to about 10 μM, "++" indicates that the compound has an _IC50 in the range of about 1 μM to about 4 μM, and "+++" indicates that the compound has an _IC50 less than about 1 μM. "Hsp70 Agonist Activity" indicates the _EC50 (μM) of the exemplary compound that increases Hsp70 by two-fold, unless otherwise indicated; "-" indicates the lack of an observable effect at concentrations exceeding 10 μM. (1) Based on data from the AlphaLISA assay, FP assay results: >10 μM. (2) Based on data from the AlphaLISA assay, FP assay results: 5.5 μM and 6.2 μM. (3) Based on data from the AlphaLISA assay, FP assay results: 1 μM and 1.4 μM. (4) Based on the data of AlphaLISA, the FP determination results were: 2.3μM and 2.4μM. (5) Based on the data of AlphaLISA, the FP determination results were: 1.7μM. (6) Based on the data of AlphaLISA, the FP determination results were: 1.8μM. (7) Based on the data of AlphaLISA, the FP determination results were: 11.1μM. (8) Based on the data of AlphaLISA, the FP determination results were: 12.1μM and 19.3μM. (9) Based on the data of AlphaLISA, the FP determination results were: 8.5μM and 11.2μM.

Example 3. Pharmacokinetic properties of the compounds of the present invention

The preclinical study included 85 mice distributed in 6 groups; a summary of the treatment groups is given in Table 4.

Table 4.

Plasma and brain samples were taken before dosing, at 15 and 30 minutes, 1 hour, 2 hours, and 8 hours post-dose time points. The pre-dose group was represented by 5 animals, while the post-dose group was represented by 3 animals.

Bioanalytical methods

Bioanalysis of mouse plasma samples of compound 20 was performed by protein precipitation and LC-MS/MS with compound 22 as an internal standard. The method was based on the 'generic assay', and some method development was performed to customize the assay for specific compounds and internal standards. The final non-GLP assay was first tested by analyzing the bioanalytical activity with spiked mouse plasma samples. The run acceptance criteria (see below) passed the quantitative run. Plasma sample extracts and brain sample homogenate extracts were then bioanalyzed using calibration and quality control samples spiked in mouse plasma. The assay is described below.

Determination of plasma levels of compound 20 in mice

Sample processing

Compound 20 and compound 22 were extracted from mouse plasma matrix by protein precipitation. 10.0 μL of internal standard working solution (1000 ng/mL in MeOH) and 200 μL of MeCN were added to 20.0 μL samples. The mixture was vortexed (approximately 5 seconds) and centrifuged (14000 rpm, 5 minutes). The supernatant was then recovered and evaporated to dryness. The residue was redissolved in 100 μL of redissolution solution (80:20 v:v mobile phase A:B). For analysis, 20.0 μL was injected into the LC-MS/MS system.

Chromatography

All chromatography was performed using an Agilent 1100 liquid chromatograph equipped with an autoinjector. The analytical column was an Xbridge C18 3.5 μm 2.1 × 50 mm (Waters) column, operated at 50°C. The mobile phase was a gradient consisting of solvent A: 1 g/L ammonium acetate in Milli-Q water and solvent B: MeCN. The gradient is shown in Table 5.

Table 5.

Mass spectrometry

All experiments were performed on an API 3000 triple quadrupole instrument (AB Sciex) operating in positive turbo ion spray mode (‘TIS+’). Instrument parameters were optimized during method development. The MS/MS transitions used are shown in Table 6.

Table 6.

Description of bioanalytical experiments and acceptance criteria

The calibration range for compound 20 was set to cover concentrations between 0.988 ng/mL and 20,000 ng/mL. Two sets of calibration samples were used, one before the study samples and the other after the study samples. In addition, five levels of QC samples (two samples per level) were included in the run as performance indicators and run acceptance.

Acceptance criteria for applied calibration and QC samples are as follows:

The absolute %RE (|%RE|) relative to the nominal concentration of individual calibration and QC samples should be within 20% (or 25% of the LLOQ);

A calibration level is considered a valid standard when at least one calibration sample at that concentration level is accepted by the above |%RE|;

• A QC level is considered a valid standard when at least one QC sample at that concentration level is accepted by the above |%RE|.

The lowest and highest accepted calibration concentration levels were used as the lower and upper limits of quantitation, LLOQ and HLOQ, respectively.

Bioanalysis results

For compound 20, the highest calibration level (STD L, 20000ng/mL) does not pass acceptance criteria, because two calibration samples have demonstrated too high deviation (referring to Table 7).Single sample demonstrates too high deviation in STD C and STD G, and compound 20, all other calibration levels of STD A to STD K are accepted.As a result, adopt lowest level (STD A, 0.988ng/mL) as LLOQ, and adopt next higher level (STD K, 8000ng/mL) as HLOQ.One of QC LLOQ and QC Med sample result has too high deviation.Compound 20 accepts the overall method performance in bioanalysis operation.

The calibration and QC concentration levels used are shown in Table 7:

Table 7.

The bioanalytical results of plasma and brain samples are shown in Tables 8 and 9.

Table 8.

(a) “0.00” means “below the limit of quantification” (LLOQ; LLOQ is 0.988 ng/mL).

(b) Values were out of range (0.988–8000 ng/mL); both calibrators at 20,000 ng/mL were rejected, but the one at 14,000 ng/mL showed an average level of response.

Table 9.

In plasma samples, the following observations were made:

A minor reaction was observed in a predose sample (one A_0 sample; found at 2.16 ng/mL). This reaction may be due to minor contamination or assay interference. Although LC-MS/MS methods are generally highly selective, selectivity for compound 20 in plasma was not tested. Conclusions can only be drawn after more complex method characterization or even validation. At less than 3 times the LLOQ, this predose response is considered negligible.

The results for most measurements at time point B_0.25 and all measurements at time point C_0.5 were above the upper limit of quantitation (ULOQ, at 8000 ng/mL). To obtain more reliable results, these samples must be diluted prior to analysis. It should be noted that the highest calibrant of 20,000 ng/mL was included in the run, but failed on bias. The average back-calculated concentration for 20,000 ng/mL was 14,000 ng/mL, indicating a bias of -30% at this level. The above ULOQ results are included in this example as indicative values to support the PK evaluation. However, the results for the B_0.25 and C_0.5 time points should be treated with caution.

The result from the first subject at time point B_0.25 (IRN 12) is unlikely to be close to the observed 2.66 ng/mL because it does not match the relatively high concentrations observed in the other two subjects at time points after this first dose (IRN 14 and 16). Tentatively, the PK evaluation for this time point was performed for two scenarios: (1) a mean of 3, and (2) excluding the BLOQ result, a mean of 2.

In the brain (homogenate) sample, a different result than expected was observed:

The result from the first subject at time point B_0.25 (IRN 12) is unlikely to be below LLOQ because it does not match the relatively high concentrations observed in the other two subjects at this first post-dose time point (IRNs 14 and 16). Note that this is similar to the findings in plasma from subject (IRN 12). Tentatively, the PK evaluation for this time point was performed for two scenarios: (1) with a mean of 3, and (2) excluding the BLOQ result, with a mean of 2.

Pharmacokinetic evaluation

Evaluation of pharmacokinetic parameters was performed by calculation from the mean concentration at each time point (n=5 before administration, n=3 after administration).The pharmacokinetic results are summarized below.

Mouse plasma

The results of the pharmacokinetic evaluations are presented in Tables 10-12 and Figures 7 and 8. No correction was made for results exceeding the ULOQ or for the inclusion of the results for animal IRN12 in Group B_0.25.

Table 10.

(a) Excluding IRN 12 results: 14950 ng/mL

Tables 11 and 12 provide the plasma pharmacokinetic profiles of Compound 20.

Table 11. ^(a)

(a) Excluding IRN12 results.

Table 12. ^{(a) {}

(a) Including IRN12 results.

Mouse brain tissue

The results of the brain tissue pharmacokinetic evaluation are presented in Figures 9 and 10 and Tables 13 to 15. No correction was made for the inclusion of additional results for IRN12 of animals in the B_0.25 group.

Table 13.

(a) Excluding IRN 12 results: 15772 ng/g.

Tables 14 and 15 provide the brain tissue pharmacokinetic profiles of Compound 20.

Table 14. ^(a)

(a) Excluding IRN 12 results.

Table 15. ^(a)

(a) Including IRN 12 results.

Example 4. Effects of the Compounds of the Invention on Total Tau and p-Tau Levels in Cerebrospinal Fluid (CSF) and Brain in a Tau Transgenic Mouse Model (hTAU441)

To evaluate the effect of the compounds of the present invention on p-tau accumulation, age-matched (e.g., 5-month-old) transgenic mice with humanized tau protein genes (hTAU mice) can be treated with low or high doses of the compounds of the present invention or vehicle by intraperitoneal administration for 7 days (N=6 per arm). The dose of the compound of the present invention can be calculated based on the PK results. hTAU transgenic mice (C57BL/6 background) overexpress TAU441 carrying missense mutations V337M and R406W under the control of the brain-specific mouse Thy-1 promoter. This human mutant tau isomer is expressed at high levels, and symptoms are visible early, starting at 4 months of age. The severity of brain disorders is associated with increasing age and behavioral deficits, however, no motor deficits occur. All animals can be sacrificed and soluble and insoluble tau and p-tau brain (hippocampus and cortex) can be quantified using the MSD multi-array p-tau (ThR ²¹ 1) immunosorbent assay (Meso Scale Discovery, Rockville, MD) to establish total tau and p-tau levels in CSF and Hsp70 levels in brain extracts. Specifically, animals can be anesthetized with a ketamine/xylazine mixture (note: isoflurane is known to affect p-tau levels) before and during CSF collection, kept warm and in a horizontal position, and then blood can be collected. The volume of CSF collected in hTAU441 is only 2-6 μL/mouse, compared to some strains (2-15 μL/mouse). p-Tau (ThR ²¹ 1) and total tau levels can be assessed using the Phospho-PHF-Tau pThR ²¹ 1 (MSD Dual Kit, Meso Discovery, Rockville, MD).

Administration of a compound of the invention can result in a decrease in p-tau levels in mice treated with the compound of the invention relative to p-tau levels in mice administered vehicle.

Example 5. Effects of the compounds of the present invention on memory and learning in the hTAU441 transgenic mouse model

Five-month-old transgenic hTAU mice described in Example 3 can be intraperitoneally administered a low or high dose of a compound of the present invention or vehicle daily for 12 weeks (N=15 per arm). The corresponding untreated group of mice is analyzed as a baseline. Behavioral tests, such as exploration tests, nose stimulation interest and activity tests, and Morris water maze tasks, can be performed. After completion of the study, CSF can be collected and brain tissue can be harvested from these animals. Total tau levels and p-tau levels in CSF and brain can be assessed. In addition, immunohistochemical assays for tau pathology can be performed. Tau deposition can be measured using monoclonal antibodies AT180 (Thermo Scientific Pierce Antibodies, Rockford, IL) and HT7 (Thermo Scientific Pierce Antibodies, Rockford, IL). Sodium selenate, a PP2A phosphatase activator that dephosphorylates tau and reverses memory deficits is effective in the TMHT tau model (Corcoran et al., J. Clin. Neuroscience, 17: 1025-1033, 2010).

If chronic treatment with the compounds of the invention is associated with a general improvement in memory function as measured by the Morris maze, a reduction in p-tau levels in the brain may be observed.

Other embodiments

The present invention is further described by the following numbered embodiments:

1. A compound according to formula (I):

or a pharmaceutically acceptable salt thereof,

in

Z ¹ is -OR ⁷ , -N(R ¹⁰ )R ⁷ , -SR ⁷ , or -C(R ¹⁰ )(R ¹¹ )R ⁷ ;

Z ² is -N= or -C(R ³ )=;

Each R ¹ and R ² is independently H or optionally substituted C _1-3 alkyl;

R ³ is H, halogen, cyano, optionally substituted C _1-6 alkyl, optionally substituted C _1-3 alkoxy, or optionally substituted amino, and R ⁴ is halogen, cyano, optionally substituted C _1-6 alkyl, optionally substituted C _1-3 alkoxy, optionally substituted amino, optionally substituted C _1-6 thioalkoxy, or optionally substituted C _6-10 aryl, or R ³ and R ^4, together with the atoms to which they are attached, join to form an optionally substituted five- or six-membered ring optionally including one nitrogen, one oxygen, or one sulfur, wherein the nitrogen is optionally substituted with R ⁹ ;

Each R ⁵ and R ⁶ is independently H, optionally substituted C _1-3 alkyl, optionally substituted C _1-3 alkoxy, halogen, or CN;

R ⁷ is optionally substituted C _1-3 alkyl, optionally substituted C _1-3 alkoxycycloalkyl, optionally substituted C _1-3 alkheterocyclyl, or optionally substituted C _1-3 alkaryl, and R ⁸ is H; or R ⁷ and R ^8, together with the atoms to which they are attached, are joined to form an optionally substituted five- or six-membered ring optionally including one or two heteroatoms selected from nitrogen, oxygen, and sulfur;

R ⁹ is H, optionally substituted C _1-3 alkyl, optionally substituted C _3-8 cycloalkyl, optionally substituted C _6-10 aryl, optionally substituted C _2-9 heteroaryl, optionally substituted C _{2-9 heterocyclyl, optionally substituted C 1-3 alkoxycycloalkyl, optionally substituted C 1-3 alkheterocyclyl ,} or optionally substituted C _1-3 alkaryl;

R ¹⁰ is H, optionally substituted C _1-3 alkyl, optionally substituted C _3-8 cycloalkyl, optionally substituted C _6-10 aryl, optionally substituted C _2-9 heteroaryl, optionally substituted C _2-9 heterocyclyl, optionally substituted C 1-3 alkoxycycloalkyl, optionally substituted C _1-3 alkheterocyclyl, or optionally substituted C _1-3 alkaryl, and R ¹¹ is H, optionally substituted C _1-3 alkyl, or R ¹⁰ and R ¹¹ combine to form ═O or ═S _;

R ^m is H, halogen, optionally substituted C _1-4 alkyl, or optionally substituted C _1-3 alkoxy;

in,

When ^Z2 is ^CR3 , each of ^R1 and ^R2 is H, ^R3 is H, ^R4 is methyl or chlorine, and each of ^R5 and ^R6 is chlorine,

Z ¹ is not methoxy;

When ^Z2 is N, each of ^R5 and ^R6 is chlorine, ^R3 is H, and ^R4 is substituted _{C1-6thioalkoxy} ,

Z ¹ is not cyanomethoxy or aminomethoxy;

When Z ² is CR ³ , each of R ⁵ and R ⁶ is chlorine, R ³ is H, and R ⁴ is halogen,

Z ¹ is not 2-amino-2-oxoethoxy, 2-(N,N-diethylamino)ethoxy, methoxy, or benzyloxy;

When R ⁵ is chlorine, R ⁶ is bromine, Z ¹ is -OR ⁷ , and R ³ and R ⁴ combine to form a group according to formula (IIa):

R ⁷ is not methyl, ethyl, n-propyl, 2-(N-pyrazolyl)ethyl, 2-(N-imidazolyl)ethyl, 3-hydroxypropyl, cyanomethyl, 2-chloroethyl, 2-hydroxyethyl, 2-oxopropyl, 2-(N,N-dimethylamino)ethyl, difluoromethyl or 2-(tert-butylamino)ethyl;

When each of R ⁵ and R ⁶ is bromine, Z ¹ is -OR ⁷ , and R ³ and R ⁴ combine to form a group according to formula (IIa),

^R7 is not a methyl group;

When each of R ⁵ and R ⁶ is chlorine, Z ¹ is -OR ⁷ , and R ³ and R ⁴ combine to form a group according to formula (IIa),

R is not ^methyl , 2-(N-imidazolyl)ethyl, methoxymethyl, 2-(N-pyrazolyl)ethyl, 2-(3-methylpyrazol-1-yl)ethyl, 2-pyridyl-methyl, 1,3-dimethyl-1H-1,2,4-triazol-5-yl-methyl, 2-pyrimidinylmethyl, imidazol-2-yl-methyl, 5-methyl-isoxazol-3-yl-methyl, 4-methyl-imidazol-5-yl-methyl, or 3-methyl-1,2,4-oxadiazol-5-yl-methyl;

When each of R ⁵ and R ⁶ is chlorine, Z ¹ is -OR ⁷ , R ⁷ and R ⁸ combine to form -CH ₂ -CH ₂ -, and R ³ and R ⁴ combine to form a group according to formula (IIa),

R ⁹ is not ethoxycarbonyl, cyclobutylaminocarbonyl, or cyclobutadienylaminocarbonyl;

When R ⁵ is methoxy, R ⁶ is methyl, Z ¹ is -OR ⁷ , and R ³ and R ⁴ combine to form a group according to formula (IIa),

^R7 is not a methyl group;

When R ⁵ is chloro, R ⁶ is ethyl, Z ¹ is -OR ⁷ , and R ³ and R ⁴ combine to form a group according to formula (IIa),

^R7 is not a methyl group;

When each of R ⁵ and R ⁶ is chlorine, Z ¹ is -OR ⁷ , and R ³ and R ⁴ combine to form a group according to formula (IIb) or (IIc),

R ⁷ is not methyl or 2-(N,N-diethylamino)ethyl;

When R ⁷ is methyl, R ⁵ is chloro, Z ¹ is -OR ⁷ , and R ³ and R ⁴ combine to form a group according to formula (IIIa),

R ⁶ is not bromine;

When R ⁵ is chloro, R ⁶ is methoxy, Z ¹ is -OR ⁷ , and R ³ and R ⁴ combine to form a group according to formula (IIIb):

R ¹ and R ² are not 2-(N,N-diethylamino)ethyl;

When each of R ⁵ and R ⁶ is chlorine, Z ¹ is -OR ⁷ , and R ³ and R ⁴ combine to form a group according to formula (IVa):

R ⁷ is not 3-(N-morpholinyl)propyl, benzyl, 1-ethyl-pyrrolidin-3-yl, 1-methyl-piperidin-4-yl, 2-(1-methyl-pyrrolidin-2-yl)ethyl, or 3-(N,N-diethylamino)propyl;

When each of R ⁵ and R ⁶ is chlorine, Z ¹ is -OR ⁷ , and R ³ and R ⁴ combine to form a group according to formula (IVb):

^R7 is not 2-methoxyethyl or benzyl;

When each of R ⁵ and R ⁶ is chlorine, Z ¹ is -OR ⁷ , and R ³ and R ⁴ combine to form a group according to formula (IVc):

^R7 is not 2-(N,N-diethylamino)ethyl or 3-(N,N-dimethylamino)propyl;

When each of R ⁵ and R ⁶ is chloro, Z ¹ is -OR ⁷ , and R ³ and R ⁴ combine to form a group according to formula (IVd):

^R7 is not 2-(pyrrolidin-1-yl)ethyl or 2-hydroxyethyl;

When each of R ⁵ and R ⁶ is chloro, Z ¹ is -OR ⁷ , and R ³ and R ⁴ combine to form a group according to formula (IVe) or (IVf):

^R7 is not benzyl;

When R ⁵ is chloro, R ⁶ is bromo, Z ¹ is -OR ⁷ , and R ³ and R ⁴ combine to form a group according to formula (IVg), (IVh), (IVi), (IVj), or (IVk):

^R7 is not a methyl group;

When R ⁶ is methyl,

each of ^R1 and ^R2 is H; and

When R ³ is H, Z ¹ is -OR ⁷ , and each of R ⁵ and R ⁶ is chlorine,

R ⁷ is not methyl.

2. The compound of embodiment 1, wherein R ^m is H.

3. A compound according to formula (Ia):

or a pharmaceutically acceptable salt thereof,

in

Each R ¹ and R ² is independently H or optionally substituted C _1-3 alkyl;

R ³ is H, halogen, cyano, optionally substituted C _1-6 alkyl, optionally substituted C _1-3 alkoxy, or optionally substituted amino, and R ⁴ is halogen, cyano, optionally substituted C _1-6 alkyl, optionally substituted C _1-3 alkoxy, optionally substituted amino, optionally substituted C _1-6 sulfanyl, or optionally substituted C _6-10 aryl, or R ³ and R ⁴ , together with the atoms to which they are attached, join to form an optionally substituted five- or six-membered ring optionally including one nitrogen, one oxygen, or one sulfur, wherein the nitrogen is optionally substituted with R ⁹ ;

Each R ⁵ and R ⁶ is independently H, optionally substituted C _1-3 alkyl, optionally substituted C _1-3 alkoxy, halogen, or CN;

R ⁷ is optionally substituted C _1-3 alkyl, optionally substituted C _1-3 alkoxycycloalkyl, optionally substituted C _1-3 alkheterocyclyl, or optionally substituted C _1-3 alkaryl, and R ⁸ is H; or R ⁷ and R ^8, together with the atoms to which they are attached, are joined to form an optionally substituted five- or six-membered ring optionally including one or two heteroatoms selected from nitrogen, oxygen, and sulfur;

R ⁹ is H, optionally substituted C _1-3 alkyl, optionally substituted C _3-8 cycloalkyl, optionally substituted C _6-10 aryl, optionally substituted C _2-9 heteroaryl, optionally substituted C _{2-9 heterocyclyl, optionally substituted C 1-3 alkoxycycloalkyl, optionally substituted C 1-3 alkheterocyclyl ,} or optionally substituted C _1-3 alkaryl;

Z ¹ is -OR ⁷ , -N(R ¹⁰ )R ⁷ , -SR ⁷ , or -C(R ¹⁰ )(R ¹¹ )R ⁷ ; and

R ¹⁰ is H, optionally substituted C _1-3 alkyl, optionally substituted C _3-8 cycloalkyl, optionally substituted C _6-10 aryl, optionally substituted C _2-9 heteroaryl, optionally substituted C _2-9 heterocyclyl, optionally substituted C 1-3 alkoxycycloalkyl, optionally substituted C _1-3 alkheterocyclyl, or optionally substituted C _1-3 alkaryl, and R ¹¹ is H, optionally substituted C _1-3 alkyl, or R ¹⁰ and R ¹¹ combine to form ═O or ═S _;

in,

When each of ^R1 and ^R2 is H, ^R3 is H, ^R4 is methyl or chlorine, and each of ^R5 and ^R6 is chlorine,

Z ¹ is not methoxy;

When each of ^R5 and ^R6 is chlorine, ^R3 is H, and ^R4 is halogen,

Z ¹ is not 2-amino-2-oxoethoxy, 2-(N,N-diethylamino)ethoxy, methoxy, or benzyloxy;

When R ⁵ is chlorine, R ⁶ is bromine, Z ¹ is -OR ⁷ , and R ³ and R ⁴ combine to form a group according to formula (IIa):

R ⁷ is not methyl, ethyl, n-propyl, 2-(N-pyrazolyl)ethyl, 2-(N-imidazolyl)ethyl, 3-hydroxypropyl, cyanomethyl, 2-chloroethyl, 2-hydroxyethyl, 2-oxopropyl, 2-(N,N-dimethylamino)ethyl, difluoromethyl or 2-(tert-butylamino)ethyl;

When each of R ⁵ and R ⁶ is bromine, Z ¹ is -OR ⁷ , and R ³ and R ⁴ combine to form a group according to formula (IIa),

^R7 is not a methyl group;

When each of R ⁵ and R ⁶ is chlorine, Z ¹ is -OR ⁷ , and R ³ and R ⁴ combine to form a group according to formula (IIa),

R is not ^methyl , 2-(N-imidazolyl)ethyl, methoxymethyl, 2-(N-pyrazolyl)ethyl, 2-(3-methylpyrazol-1-yl)ethyl, 2-pyridyl-methyl, 1,3-dimethyl-1H-1,2,4-triazol-5-yl-methyl, 2-pyrimidinylmethyl, imidazol-2-yl-methyl, 5-methyl-isoxazol-3-yl-methyl, 4-methyl-imidazol-5-yl-methyl, or 3-methyl-1,2,4-oxadiazol-5-yl-methyl;

When each of R ⁵ and R ⁶ is chlorine, Z ¹ is -OR ⁷ , R ⁷ and R ⁸ combine to form -CH ₂ -CH ₂ -, and R ³ and R ⁴ combine to form a group according to formula (IIa),

R ⁹ is not ethoxycarbonyl, cyclobutylaminocarbonyl, or cyclobutadienylaminocarbonyl;

When R ⁵ is methoxy, R ⁶ is methyl, Z ¹ is -OR ⁷ , and R ³ and R ⁴ combine to form a group according to formula (IIa),

^R7 is not a methyl group;

When R ⁵ is chloro, R ⁶ is ethyl, Z ¹ is -OR ⁷ , and R ³ and R ⁴ combine to form a group according to formula (IIa),

^R7 is not a methyl group;

When each of R ⁵ and R ⁶ is chlorine, Z ¹ is -OR ⁷ , and R ³ and R ⁴ combine to form a group according to formula (IIb) or (IIc),

R ⁷ is not methyl or 2-(N,N-diethylamino)ethyl;

When R ⁷ is methyl, R ⁵ is chloro, Z ¹ is -OR ⁷ , and R ³ and R ⁴ combine to form a group according to formula (IIIa),

R ⁶ is not bromine;

When R ⁵ is chloro, R ⁶ is methoxy, Z ¹ is -OR ⁷ , and R ³ and R ⁴ combine to form a group according to formula (IIIb):

R ¹ and R ² are not 2-(N,N-diethylamino)ethyl;

When each of R ⁵ and R ⁶ is chlorine, Z ¹ is -OR ⁷ , and R ³ and R ⁴ combine to form a group according to formula (IVa):

R ⁷ is not 3-(N-morpholinyl)propyl, benzyl, 1-ethyl-pyrrolidin-3-yl, 1-methyl-piperidin-4-yl, 2-(1-methyl-pyrrolidin-2-yl)ethyl, or 3-(N,N-diethylamino)propyl;

When each of R ⁵ and R ⁶ is chlorine, Z ¹ is -OR ⁷ , and R ³ and R ⁴ combine to form a group according to formula (IVb):

^R7 is not 2-methoxyethyl or benzyl;

When each of R ⁵ and R ⁶ is chlorine, Z ¹ is -OR ⁷ , and R ³ and R ⁴ combine to form a group according to formula (IVc):

^R7 is not 2-(N,N-diethylamino)ethyl or 3-(N,N-dimethylamino)propyl;

When each of R ⁵ and R ⁶ is chloro, Z ¹ is -OR ⁷ , and R ³ and R ⁴ combine to form a group according to formula (IVd):

^R7 is not 2-(pyrrolidin-1-yl)ethyl or 2-hydroxyethyl;

When each of R ⁵ and R ⁶ is chloro, Z ¹ is -OR ⁷ , and R ³ and R ⁴ combine to form a group according to formula (IVe) or (IVf):

^R7 is not benzyl;

When R ⁵ is chloro, R ⁶ is bromo, Z ¹ is -OR ⁷ , and R ³ and R ⁴ combine to form a group according to formula (IVg), (IVh), (IVi), (IVj), or (IVk):

^R7 is not a methyl group;

When R ⁶ is methyl,

each of ^R1 and ^R2 is H; and

When R ³ is H, Z ¹ is -OR ⁷ , and each of R ⁵ and R ⁶ is chlorine,

R ⁷ is not methyl.

4. A compound according to formula (Ib):

or a pharmaceutically acceptable salt thereof,

in

Each R ¹ and R ² is independently H or optionally substituted C _1-3 alkyl;

R ³ is H, halogen, cyano, optionally substituted C _1-6 alkyl, optionally substituted C _1-3 alkoxy, or optionally substituted amino, and R ⁴ is halogen, cyano, optionally substituted C _1-6 alkyl, optionally substituted C _1-3 alkoxy, optionally substituted amino, optionally substituted C _1-6 thioalkoxy, or optionally substituted C _6-10 aryl, or R ³ and R ^4, together with the atoms to which they are attached, are joined to form an optionally substituted five- or six-membered ring optionally including one nitrogen, one sulfur, or one oxygen, wherein the nitrogen is optionally substituted with R ⁹ ;

Each R ⁵ and R ⁶ is independently H, optionally substituted C _1-3 alkyl, optionally substituted C _1-3 alkoxy, halogen, or CN;

R ⁷ is optionally substituted C _1-3 alkyl, optionally substituted C _1-3 alkoxycycloalkyl, optionally substituted C _1-3 alkheterocyclyl, or optionally substituted C _1-3 alkaryl, and R ⁸ is H; or R ⁷ and R ^8, together with the atoms to which they are attached, are joined to form an optionally substituted five-membered or six-membered ring; and

R ⁹ is H, optionally substituted C _1-3 alkyl, optionally substituted C _3-8 cycloalkyl, optionally substituted C _6-10 aryl, optionally substituted C _2-9 heteroaryl, optionally substituted C _{2-9 heterocyclyl, optionally substituted C 1-3 alkoxycycloalkyl, optionally substituted C 1-3 alkheterocyclyl ,} or optionally substituted C _1-3 alkaryl;

in,

When each of ^R1 and ^R2 is H, ^R3 is H, ^R4 is methyl or chlorine, and each of ^R5 and ^R6 is chlorine,

^R7 is not a methyl group;

When each of R ⁵ and R ⁶ is chlorine, R ³ is H, and R ⁴ is halogen,

R ⁷ is not 2-amino-2-oxoethyl, 2-(N,N-diethylamino)ethyl, methyl, or benzyl;

When R ⁵ is chlorine, R ⁶ is bromine, and R ³ and R ⁴ combine to form a group according to formula (IIa):

R ⁷ is not methyl, ethyl, n-propyl, 2-(N-pyrazolyl)ethyl, 2-(N-imidazolyl)ethyl, 3-hydroxypropyl, cyanomethyl, 2-chloroethyl, 2-hydroxyethyl, 2-oxopropyl, 2-(N,N-dimethylamino)ethyl, difluoromethyl or 2-(tert-butylamino)ethyl;

When each of R ⁵ and R ⁶ is bromine, and R ³ and R ⁴ combine to form a group according to formula (IIa),

^R7 is not a methyl group;

When each of R ⁵ and R ⁶ is chlorine, R ⁸ is H, and R ³ and R ⁴ combine to form a group according to formula (IIa),

R is not ^methyl , 2-(N-imidazolyl)ethyl, methoxymethyl, 2-(N-pyrazolyl)ethyl, 2-(3-methylpyrazol-1-yl)ethyl, 2-pyridyl-methyl, 1,3-dimethyl-1H-1,2,4-triazol-5-yl-methyl, 2-pyrimidinylmethyl, imidazol-2-yl-methyl, 5-methyl-isoxazol-3-yl-methyl, 4-methyl-imidazol-5-yl-methyl, or 3-methyl-1,2,4-oxadiazol-5-yl-methyl;

When each of R ⁵ and R ⁶ is chlorine, R ⁷ and R ⁸ combine to form -CH ₂ -CH ₂ -, and R ³ and R ⁴ combine to form a group according to formula (IIa),

R ⁹ is not ethoxycarbonyl, cyclobutylaminocarbonyl, or cyclobutadienylaminocarbonyl;

When R ⁵ is methoxy, R ⁶ is methyl, and R ³ and R ⁴ combine to form a group according to formula (IIa),

^R7 is not a methyl group;

When R ⁵ is chlorine, R ⁶ is ethyl, and R ³ and R ⁴ combine to form a group according to formula (IIa),

^R7 is not a methyl group;

When each of R ⁵ and R ⁶ is chlorine, and R ³ and R ⁴ combine to form a group according to formula (IIb) or (IIc),

R ⁷ is not methyl or 2-(N,N-diethylamino)ethyl;

When ^R7 is methyl, ^R5 is chlorine, and ^R3 and ^R4 combine to form a group according to formula (IIIa),

R ⁶ is not bromine;

When R ⁵ is chloro, R ⁶ is methoxy, and R ³ and R ⁴ combine to form a group according to formula (IIIb):

R ¹ and R ² are not 2-(N,N-diethylamino)ethyl;

When each of R ⁵ and R ⁶ is chlorine, and R ³ and R ⁴ combine to form a group according to formula (IVa):

R ⁷ is not 3-(N-morpholinyl)propyl, benzyl, 1-ethyl-pyrrolidin-3-yl, 1-methyl-piperidin-4-yl, 2-(1-methyl-pyrrolidin-2-yl)ethyl, or 3-(N,N-diethylamino)propyl;

When each of R ⁵ and R ⁶ is chlorine, and R ³ and R ⁴ combine to form a group according to formula (IVb):

^R7 is not 2-methoxyethyl or benzyl;

When each of R ⁵ and R ⁶ is chlorine, and R ³ and R ⁴ combine to form a group according to formula (IVc):

^R7 is not 2-(N,N-diethylamino)ethyl or 3-(N,N-dimethylamino)propyl;

When each of R ⁵ and R ⁶ is chlorine, and R ³ and R ⁴ combine to form a group according to formula (IVd):

^R7 is not 2-(pyrrolidin-1-yl)ethyl or 2-hydroxyethyl;

When each of R ⁵ and R ⁶ is chlorine, and R ³ and R ⁴ combine to form a group according to formula (Ive) or (IVf):

^R7 is not benzyl;

When R ⁵ is chloro, R ⁶ is bromo, and R ³ and R ⁴ combine to form a group according to formula (IVg), (IVh), (IVi), (IVj), or (IVk):

^R7 is not a methyl group;

When R ⁶ is methyl,

each of ^R1 and ^R2 is H; and

When ^R3 is H, and each of ^R5 and ^R6 is chlorine,

R ⁷ is not methyl.

5. The compound of any one of embodiments 1 to 4, wherein R is ^H , halogen, optionally substituted _C1-3 alkyl, or optionally substituted _C1-3 alkoxy, ^R is halogen, optionally substituted _C1-3 alkyl, optionally substituted _C1-3 alkoxy, optionally substituted amino, optionally substituted _C1-6 sulfanyl, or optionally substituted _C6-10 aryl, or ^R and ^R, together with the atoms to which they are attached, are joined to form an optionally substituted five- or six-membered ring optionally including one nitrogen, one oxygen, or one sulfur, wherein the nitrogen is optionally substituted with ^R.

6. The compound of any one of embodiments 1 to 5, wherein R ³ and R ⁴ , together with the atoms to which they are attached, are joined to form an optionally substituted five-membered ring.

7. The compound of any one of embodiments 1 to 5, wherein R ³ and R ⁴ combine to form a -CH ₂ CH ₂ CH ₂ - group.

8. The compound of any one of embodiments 1 to 5, wherein R ³ and R ^{4 ,} together with the atoms to which they are attached, are joined to form an optionally substituted five-membered ring including one nitrogen.

9. The compound of embodiment 8, wherein R ³ and R ⁴ combine to form a -N(R ⁹ )-CH=CH- group.

10. The compound of embodiment 9, wherein R ⁹ is H.

11. The compound of any one of embodiments 1 to 5, wherein R ³ and R ^{4 ,} together with the atoms to which they are attached, are joined to form an optionally substituted five-membered ring including one sulfur.

12. The compound of any one of embodiments 1 to 5, wherein R ³ and R ⁴ combine to form a -C(R ^13A )=C(R ^13B )-S- group, wherein R ^13A is H and R ^13B is H or optionally substituted C _1-3 alkyl.

13. The compound of embodiment 12, wherein R ^13B is optionally substituted C _1-3 alkyl.

14. The compound of embodiment 13, wherein R ^13B is -C(O)-R ^13C , wherein R ^13C is optionally substituted C _1-3 alkoxy or optionally substituted amino.

15. A compound as described in any one of embodiments 1 to 5, wherein R ³ and R ⁴ combine to form a -C(R ^13A )═C(R ^13B )—S— group, wherein R ^13A is H and R ^13B is H or -C(O)—R ^13C , wherein R ^13C is optionally substituted C _1-3 alkyl, optionally substituted C _1-3 alkoxy, optionally substituted amino, or optionally substituted C _2-9 heterocyclyl.

16. The compound of any one of embodiments 1 to 5, wherein R ⁴ is C _1-3 alkyl.

17. The compound of embodiment 16, wherein R ⁴ is methyl, ethyl, or isopropyl.

18. The compound of any one of embodiments 1 to 5, wherein R ⁴ is C _1-3 alkoxy.

19. The compound of embodiment 18, wherein R ⁴ is methoxy.

20. The compound of any one of embodiments 1 to 5, wherein R ⁴ is optionally substituted C _1-6 thioalkoxy.

21. The compound of embodiment 20, wherein R ⁴ is 4-amino-4-oxobutyl.

22. The compound of any one of embodiments 1 to 5, wherein R ⁴ is optionally substituted amino.

23. The compound of embodiment 22, wherein R ⁴ is methylamino.

24. The compound of any one of embodiments 1 to 5, wherein R ⁴ is halogen.

25. The compound of embodiment 24, wherein R ⁴ is chloro.

26. The compound of any one of embodiments 1-5 and 15-25, wherein R ³ is hydrogen or C _1-3 alkyl.

27. The compound of embodiment 26, wherein R ³ is halogen, methyl, or ethyl.

28. The compound of any one of embodiments 1 to 5, wherein R ³ and R ⁴ combine to form -X ¹ -X ² -X ³ -, wherein

X ¹ is -S-, -O-, -(CR ¹⁴ R ¹⁵ )-, -C(R ¹⁶ )=, -N(R ⁹ )-, -N=, H, or optionally substituted C _1-3 alkyl;

^X2 is absent, -( ^CR17R18 ) _n- , -S-, -O-, -N=, -N( ^R9 )-, -C( ^R19 )=, =N-, =C( ^R20 ) ^- , or =C( ^R21 )-C( ^R22 )=;

X ³ is -(CR ¹⁴ R ¹⁵ )-, -S-, -O-, -N(R ⁹ )-, ═N-, ═C(R ²³ )-, halogen, optionally substituted C _1-3 alkyl, optionally substituted C _1-6 thioalkoxy, optionally substituted C _1-3 alkoxy, or optionally substituted C _6-10 aryl;

Each R ¹⁴ and R ¹⁵ is independently H or optionally substituted C _1-3 alkyl, or R ¹⁴ and R ¹⁵ combine to form ═O or ═S;

Each R ¹⁷ and R ¹⁸ is independently H or optionally substituted C _1-3 alkyl, or R ¹⁷ and R ¹⁸ combine to form ═O or ═S;

each R ¹⁶ , R ¹⁹ , R ²⁰ , R ²¹ , R ²² , and R ²³ is independently H, or optionally substituted C _1-3 alkyl; and

n is 1 or 2; and

Among them, when X ² is not absent,

The chain of atoms -X ¹ -X ² -X ³ - includes not more than one heteroatom selected from the group consisting of nitrogen, oxygen and sulfur.

29. The compound of embodiment 28, wherein X ¹ is -(CR ¹⁴ R ¹⁵ )-, -C(R ¹⁶ )=, -N(R ⁹ )-, -N=, or optionally substituted C _1-3 alkyl.

30. The compound of embodiment 29, wherein X ¹ is -(CR ¹⁴ R ¹⁵ )-.

31. The compound of embodiment 30, wherein each of R ¹⁴ and R ¹⁵ is H.

32. The compound of embodiment 29, wherein X ¹ is -C(R ¹⁶ )=.

33. The compound of embodiment 32, wherein R ¹⁶ is H.

34. The compound of embodiment 29, wherein X ¹ is -N(R ⁹ )-.

35. The compound of embodiment 34, wherein R ⁹ is H or optionally substituted C _1-3 alkyl.

36. The compound of embodiment 35, wherein R ⁹ is halogen, methyl, or ethyl.

37. The compound of embodiment 29, wherein X ¹ is -N=.

38. The compound of embodiment 29, wherein X ¹ is optionally substituted C _1-3 alkyl.

39. The compound of any one of embodiments 28 to 37, wherein ^X2 is absent, -( _CH2 ) _n- , -N( ^R9 )-, -C(H)=, =C( ^R20 )-, or =C(H)-C(H)=.

40. The compound of embodiment 39, wherein ^X2 is -C(H)=.

41. The compound of embodiment 39, wherein X ² is -N(R ⁹ )-.

42. The compound of embodiment 41, wherein R ⁹ is H.

43. The compound of embodiment 41, wherein R ⁹ is optionally substituted C _1-3 alkyl.

44. The compound of embodiment 43, wherein R ⁹ is -C(O)-N(H)-Et.

45. The compound of embodiment 39, wherein ^X2 is =C( ^R20 )-.

46. The compound of embodiment 45, wherein R ²⁰ is optionally substituted C _1-3 alkyl.

47. The compound of embodiment 39, wherein ^X2 is absent.

48. The compound of any one of embodiments 28-37 and 39-47, wherein X ³ is -CH ₂ -, -S-, =C(H)-, -N(R ⁹ )-, halogen, optionally substituted C _1-3 alkyl, optionally substituted C _1-3 alkoxy, optionally substituted C _1-6 thioalkoxy, or optionally substituted C _6-10 aryl.

49. The compound of embodiment 48, wherein X ³ is -CH ₂ -.

50. The compound of embodiment 48, wherein X ³ is -S-.

51. The compound of embodiment 48, wherein X ³ is ═C(H)—.

52. The compound of embodiment 48, wherein X ³ is -N(R ⁹ )-.

53. The compound of embodiment 48, wherein X ³ is halogen, optionally substituted C _1-3 alkyl, optionally substituted C _1-3 alkoxy, optionally substituted C _1-6 thioalkoxy, or optionally substituted C _6-10 aryl.

54. The compound of any one of embodiments 1-53, wherein each R ⁵ and R ⁶ is independently halogen or optionally substituted C _1-3 alkyl.

55. The compound of embodiment 54, wherein each of R ⁵ and R ⁶ is halogen.

56. The compound of embodiment 55, wherein each of R ⁵ and R ⁶ is chloro.

57. The compound of any one of embodiments 1 to 56, wherein R ⁷ and R ^8, together with the atoms to which they are attached, are joined to form an optionally substituted five- or six-membered ring optionally including one or two heteroatoms selected from nitrogen, oxygen, and sulfur.

58. The compound of any one of embodiments 1 to 56, wherein R ⁷ and R ^8, together with the atoms to which they are attached, are joined to form an optionally substituted five- or six-membered saturated ring optionally including one or two heteroatoms selected from nitrogen, oxygen, and sulfur.

59. The compound of any one of embodiments 1 to 56, wherein R ⁷ and R ^8, together with the atoms to which they are attached, are joined to form an optionally substituted five- or six-membered ring optionally including one or two heteroatoms selected from nitrogen and oxygen.

60. The compound of any one of embodiments 1 to 56, wherein R ⁷ and R ⁸ , together with the atoms to which they are attached, are joined to form an optionally substituted five-membered ring.

61. The compound of any one of embodiments 1 to 56, wherein R ⁷ and R ⁸ , together with the atoms to which they are attached, are joined to form an optionally substituted saturated five-membered ring.

62. The compound of any one of embodiments 1 to 56, wherein R ⁷ and R ⁸ are combined to form a -CH ₂ CH ₂ - group.

63. A compound as described in any one of embodiments 1 to 56, wherein R ⁷ is optionally substituted C _1-3 alkyl.

64. The compound of embodiment 63, wherein R ⁷ is methyl.

65. The compound of embodiment 63, wherein ^R7 is -( _CH2 ) _k -N( ^R24 ) ^R25 , wherein k is 2 or 3, and each ^R24 and ^R25 is independently H or optionally substituted _C1-3 alkyl.

66. The compound of embodiment 65, wherein k is 2.

67. The compound of embodiment 65 or 66, wherein each R ²⁴ and R ²⁵ is independently optionally substituted C _1-3 alkyl.

68. The compound of any one of embodiments 65 to 67, wherein each R ²⁴ and R ²⁵ is methyl.

69. The compound of any one of embodiments 1 to 56, wherein R ⁷ and R ⁸ form a group -Y ¹ -Y ² -, wherein:

Y ¹ is -(CR ²⁶ R ²⁷ ) _m - or optionally substituted C _1-3 alkyl, optionally substituted C _1-3 alkheterocyclyl, optionally substituted C _1-3 alkylcycloalkyl, or optionally substituted C _1-3 alkaryl; and

Y ² is -(CR ²⁶ R ²⁷ )- or H; wherein

Each R ²⁶ and R ²⁷ is independently H or optionally substituted C _1-3 alkyl; and

m is 1 or 2.

70. The compound of any one of embodiments 1 to 5, wherein Z ¹ and R ⁸ combine to form

-Z ³ -Y ¹ -Y ² -, where

Z ³ is -O-, -N(R ¹⁰ )-, -N=, -S-, or -(CR ¹⁴ R ¹⁵ )-;

Y ¹ is -O-, -N(R ¹⁰ )-, -S-, -(CR ²⁶ R ²⁷ ) _m -, -C(R ²⁰ )＝, ＝C(R ²⁰ )-, ＝C(R ^{21 )-C(R 22 )} ＝, optionally substituted C _1-3 alkyl, optionally substituted C _{1-3 alkheterocyclyl, optionally substituted C 1-3 alkylcycloalkyl} , or optionally substituted C _1-3 alkaryl; and

Y ² is -O-, -S-, -N(R ¹⁰ )-, -(CR ²⁶ R ²⁷ )-, =C(R ²⁰ )-, =N-, or H;

in

Each of R ²⁰ , R ²¹ , and R ²² is independently H or optionally substituted C _1-3 alkyl; and

Each R ²⁶ and R ²⁷ is independently H or optionally substituted C _1-3 alkyl, or R ²⁶ and R ²⁷ combine to form ═O or ═S;

m is 1 or 2; and

Among them, when Y ² is H,

The chain of atoms -Z ³ -Y ¹ -Y ² - includes not more than two heteroatoms selected from nitrogen, oxygen, and sulfur.

71. The compound of embodiment 70, wherein Z ³ is -O-.

72. The compound of embodiment 69 or 71, wherein Y ¹ is -(CR ²⁶ R ²⁷ ) _m - or optionally substituted C _1-3 alkyl, optionally substituted C _1-3 alkheterocyclyl, optionally substituted C _1-3 alkylcycloalkyl, or optionally substituted C _1-3 alkaryl.

73. The compound of any one of embodiments 69 to 72, wherein Y ¹ is -(CR ²⁶ R ²⁷ ) _m - or optionally substituted C _1-3 alkyl.

74. The compound of any one of embodiments 69 to 73, wherein Y ² is -(CR ²⁶ R ²⁷ )- or H.

75. The compound of any one of embodiments 69 to 74, wherein Y ² is -(CR ²⁶ R ²⁷ )-.

76. The compound of any one of embodiments 69 to 75, wherein R ²⁶ is H.

77. The compound of any one of embodiments 69 to 76, wherein R ²⁷ is H.

78. The compound of any one of embodiments 69 to 77, wherein m is 1.

79. The compound of any one of embodiments 69 to 78, wherein Y ¹ is optionally substituted C _1-3 alkyl.

80. The compound of embodiment 79, wherein Y ¹ is methyl.

81. The compound of embodiment 80, wherein Y ¹ is -(CH ₂ ) _k -N(R ²⁴ )R ²⁵ , wherein k is 2 or 3, and wherein each R ²⁴ and R ²⁵ is independently H or optionally substituted C _1-3 alkyl.

82. The compound of embodiment 81, wherein k is 2.

83. The compound of embodiment 81 or 82, wherein each R ²⁴ and R ²⁵ is independently optionally substituted C _1-3 alkyl.

84. The compound of any one of embodiments 81 to 83, wherein each R ²⁴ and R ²⁵ is methyl.

85. The compound of any one of embodiments 1 to 84, wherein each R ¹ and R ² is H.

86. A compound:

or a pharmaceutically acceptable salt thereof.

87. The compound of embodiment 84, having the formula:

or a pharmaceutically acceptable salt thereof.

88. A pharmaceutical composition comprising a compound as described in any one of Examples 1 to 87, or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers or excipients.

89. The pharmaceutical composition of embodiment 88, wherein the composition is formulated for oral, sublingual, buccal, transdermal, intradermal, intramuscular, parenteral, intravenous, intraarterial, intracranial, subcutaneous, intraorbital, intraventricular, intraspinal, intraperitoneal, intranasal, by inhalation, and topical administration.

90. The pharmaceutical composition of embodiment 89, wherein the composition is formulated for oral administration.

91. A method of treating a disorder caused by the action of heat shock protein 90 (Hsp90) in a mammal, the method comprising administering to the mammal an effective amount of a compound of any one of embodiments 1 to 87 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of embodiment 88.

92. The method of embodiment 91, wherein the disorder is a neurodegenerative disorder.

93. The method of embodiment 92, wherein the neurodegenerative disorder is tauopathy.

94. The method of embodiment 92 or 93, wherein the neurodegenerative disorder is Alzheimer's disease, Huntington's disease, progressive supranuclear palsy, Parkinson's disease, Pick's disease, corticobasal degeneration, chronic traumatic encephalopathy, traumatic brain injury, or frontotemporal dementia.

95. The method of embodiment 94, wherein the neurodegenerative disorder is Alzheimer's disease.

96. The method of embodiment 91, wherein the disorder is a proliferative disease.

97. The method of embodiment 96, wherein the proliferative disease is cancer.

98. The method of embodiment 97, wherein the cancer is acute myeloid leukemia, gastrointestinal stromal tumor, gastric cancer, glioma, neuroblastoma, glioblastoma, lung cancer, lymphoma, melanoma, myeloma, non-small cell lung cancer, renal cancer, small cell lung cancer, embryonic chronic myeloid leukemia, leukemia, lymphoproliferative disorder, metastatic melanoma, relapsed multiple myeloma, refractory multiple myeloma, myeloproliferative disorder, pancreatic cancer, small intestinal cancer, or a solid tumor.

99. A method of treating an infectious disease in a mammal, comprising administering to the mammal an effective amount of the compound of any one of Examples 1 to 87 or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition of Example 88.

100. The method of embodiment 99, wherein the infectious disease is a viral infection.

101. The method of embodiment 100, wherein the viral infection is an infection caused by a virus of a family selected from the group consisting of Herpesviridae, Polyomaviridae, Poxviridae, Reoviridae, Birnaviridae, Picornaviridae, Flaviviridae, Arenaviridae, Hepaciviridae, Rhabdoviridae, Paramyxoviridae, Bunyaviridae, Orthomyxoviridae, Filoviridae, Retroviridae, and Hepadnaviridae.

102. The method of embodiment 101, wherein the virus of the Herpesviridae family is herpes simplex virus-1, herpes simplex virus-2, herpes virus-5, Kaposi's sarcoma-associated herpes virus, varicella-zoster virus, or Epstein-Barr virus.

103. The method of embodiment 101, wherein the virus of the Polyomaviridae family is SV40.

104. The method of embodiment 101, wherein the virus of the Poxviridae family is vaccinia virus.

105. The method of embodiment 101, wherein the virus of the Reoviridae family is a rotavirus.

106. The method of embodiment 101, wherein the virus of the Birnaviridae family is infectious bursal disease virus.

107. The method of embodiment 101, wherein the Picornaviridae virus is a poliovirus, a rhinovirus, or a coxsackievirus.

108. The method of embodiment 101, wherein the virus of the Flaviviridae family is hepatitis C virus or dengue virus.

109. The method of embodiment 101, wherein the virus of the Arenaviridae family is lymphocytic choriomeningitis virus.

110. The method of embodiment 101, wherein the virus of the Hepaciviridae family is Hepatitis E virus.

111. The method of embodiment 101, wherein the virus of the Rhabdoviridae family is vesicular stomatitis virus.

112. The method of embodiment 101, wherein the virus of the Paramyxoviridae family is human parainfluenza virus 2, human parainfluenza virus 3, SV5, SV41, measles virus, or Sendai virus.

113. The method of embodiment 101, wherein the virus of the Bunyaviridae family is La Crosse virus.

114. The method of embodiment 101, wherein the virus of the Orthomyxoviridae family is influenza A virus.

115. The method of embodiment 101, wherein the virus of the Filoviridae family is Ebola virus.

116. The method of embodiment 101, wherein the virus of the Retroviridae family is HTLV1 or HIV1.

117. The method of embodiment 101, wherein the virus of the Hepadnaviridae family is hepatitis B virus.

118. The method of embodiment 99, wherein the infectious disease is a fungal infection.

119. The method of embodiment 118, wherein the fungal infection is a Candida albicans infection, an Aspergillus fumigatus infection, or a Pneumocystis infection.

120. The method of embodiment 99, wherein the infectious disease is a bacterial infection.

121. The method of embodiment 120, wherein the bacterial infection is a mycobacterial infection or an anthrax infection.

122. The method of embodiment 120, wherein the bacterial infection is bacterial pneumonia.

123. The method of embodiment 91, wherein the disorder is an inflammatory or autoimmune disease.

124. The method of embodiment 123, wherein the inflammatory or autoimmune disease is rheumatoid arthritis, systemic lupus erythematosus, or asthma.

125. The method of embodiment 91, wherein the disorder is cardiovascular disease.

126. The method of embodiment 125, wherein the cardiovascular disease is atherosclerosis or cardiomyopathy.

127. The method of embodiment 91, wherein the disorder is allergy.

128. The method of any one of embodiments 91 to 127, wherein the compound is administered orally, sublingually, buccally, transdermally, intradermally, intramuscularly, parenterally, intravenously, intraarterially, intracranially, subcutaneously, intraorbitally, intraventricularly, intraspinally, intraperitoneally, intranasally, by inhalation, and topically.

129. The method of embodiment 128, wherein the compound is administered orally.

130. The method of any one of embodiments 91 to 129, wherein the mammal is a human.

131. The method of any one of embodiments 91 to 130, wherein the compound is administered orally, sublingually, buccally, transdermally, intradermally, intramuscularly, parenterally, intravenously, intraarterially, intracranially, subcutaneously, intraorbitally, intraventricularly, intraspinally, intraperitoneally, intranasally, by inhalation, and topically.

132. The method of embodiment 131, wherein the compound is administered orally.

133. The method of any one of embodiments 91 to 132, wherein the mammal is a human.

134. A compound for use in treating a disorder caused by the action of heat shock protein 90 (Hsp90) in a mammal, wherein the compound is a compound of any one of embodiments 1 to 87, or a pharmaceutically acceptable salt thereof.

135. The compound of embodiment 134, wherein the disorder is a neurodegenerative disorder.

136. The compound of embodiment 135, wherein the neurodegenerative disorder is a tauopathy.

137. The compound of embodiment 134 or 135, wherein the neurodegenerative disorder is Alzheimer's disease, Huntington's disease, progressive supranuclear palsy, Parkinson's disease, Pick's disease, corticobasal degeneration, chronic traumatic encephalopathy, traumatic brain injury, or frontotemporal dementia.

138. The compound of embodiment 137, wherein the neurodegenerative disorder is Alzheimer's disease.

139. The compound of embodiment 134, wherein the disorder is a proliferative disease.

140. The compound of embodiment 139, wherein the proliferative disease is cancer.

141. The compound of embodiment 140, wherein the cancer is acute myeloid leukemia, gastrointestinal stromal tumor, gastric cancer, glioblastoma, lung cancer, lymphoma, melanoma, myeloma, non-small cell lung cancer, renal cancer, small cell lung cancer, embryonic chronic myeloid leukemia, leukemia, lymphoproliferative disorder, metastatic melanoma, relapsed multiple myeloma, refractory multiple myeloma, myeloproliferative disorder, pancreatic cancer, small intestinal cancer, or a solid tumor.

142. The compound of embodiment 134, wherein the disorder is an infectious disease.

143. The compound of embodiment 142, wherein the infectious disease is a viral infection.

144. The compound of embodiment 143, wherein the viral infection is an infection caused by a virus of a family selected from the group consisting of Herpesviridae, Polyomaviridae, Poxviridae, Reoviridae, Birnaviridae, Picornaviridae, Flaviviridae, Arenaviridae, Hepaciviridae, Rhabdoviridae, Paramyxoviridae, Bunyaviridae, Orthomyxoviridae, Filoviridae, Retroviridae, and Hepadnaviridae.

145. The compound of embodiment 144, wherein the virus of the Herpesviridae family is herpes simplex virus-1, herpes simplex virus-2, herpes virus-5, Kaposi's sarcoma-associated herpes virus, varicella-zoster virus, or Epstein-Barr virus.

146. The compound of embodiment 144, wherein the virus of the Polyomaviridae family is SV40.

147. The compound of embodiment 144, wherein the virus of the Poxviridae family is vaccinia virus.

148. The compound of embodiment 144, wherein the virus of the Reoviridae family is a rotavirus.

149. The compound of embodiment 144, wherein the virus of the Birnaviridae family is infectious bursal disease virus.

150. The compound of embodiment 144, wherein the Picornaviridae virus is a poliovirus, a rhinovirus, or a coxsackievirus.

141. The compound of embodiment 144, wherein the virus of the Flaviviridae family is hepatitis C virus or dengue virus.

152. The compound of embodiment 144, wherein the virus of the Arenaviridae family is lymphocytic choriomeningitis virus.

153. The compound of embodiment 144, wherein the virus of the Hepaciviridae family is Hepatitis E virus.

154. The compound of embodiment 144, wherein the virus of the Rhabdoviridae family is vesicular stomatitis virus.

155. The compound of embodiment 144, wherein the virus of the Paramyxoviridae family is human parainfluenza virus 2, human parainfluenza virus 3, SV5, SV41, measles virus, or Sendai virus.

156. The compound of embodiment 144, wherein the virus of the Bunyaviridae family is La Crosse virus.

157. The compound of embodiment 144, wherein the virus of the Orthomyxoviridae family is influenza A virus.

158. The compound of embodiment 144, wherein the virus of the Filoviridae family is Ebola virus.

159. The compound of embodiment 144, wherein the virus of the Retroviridae family is HTLV1 or HIV1.

160. The compound of embodiment 144, wherein the virus of the Hepadnaviridae family is hepatitis B virus.

161. The compound of embodiment 134, wherein the infectious disease is a fungal infection.

162. The compound of embodiment 161, wherein the fungal infection is a Candida albicans infection, an Aspergillus fumigatus infection, or a Pneumocystis infection.

163. The compound of embodiment 134, wherein the infectious disease is a bacterial infection.

165. The compound of embodiment 163, wherein the bacterial infection is a mycobacterial infection or an anthrax infection.

166. The compound of embodiment 163, wherein the bacterial infection is bacterial pneumonia.

167. The compound of embodiment 134, wherein the disorder is an inflammatory or autoimmune disease.

168. The compound of embodiment 167, wherein the inflammatory or autoimmune disease is rheumatoid arthritis, systemic lupus erythematosus, or asthma.

169. The compound of embodiment 134, wherein the disorder is cardiovascular disease.

170. The compound of embodiment 169, wherein the cardiovascular disease is atherosclerosis or cardiomyopathy.

171. The compound of embodiment 170, wherein the disorder is allergy.

172. Use of a compound in the manufacture of a medicament for treating a disorder caused by the action of heat shock protein 90 (Hsp90) in a mammal, wherein the compound is a compound of any one of embodiments 1 to 87, or a pharmaceutically acceptable salt thereof.

173. Use of a compound for treating a disorder caused by the action of heat shock protein 90 (Hsp90) in a mammal, wherein the compound is a compound of any one of embodiments 1 to 87, or a pharmaceutically acceptable salt thereof.

174. The use of embodiment 172 or 173, wherein the disorder is a neurodegenerative disorder.

175. The use of embodiment 174, wherein the neurodegenerative disorder is tauopathy.

176. The use of embodiment 174 or 175, wherein the neurodegenerative disorder is Alzheimer's disease, Huntington's disease, progressive supranuclear palsy, Parkinson's disease, Pick's disease, corticobasal degeneration, chronic traumatic encephalopathy, traumatic brain injury, or frontotemporal dementia.

177. The use of embodiment 176, wherein the neurodegenerative disorder is Alzheimer's disease.

178. The use of embodiment 172 or 173, wherein the disorder is a proliferative disease.

179. The use of embodiment 178, wherein the proliferative disease is cancer.

180. The use of embodiment 179, wherein the cancer is acute myeloid leukemia, gastrointestinal stromal tumor, gastric cancer, glioblastoma, lung cancer, lymphoma, melanoma, myeloma, non-small cell lung cancer, renal cancer, small cell lung cancer, embryonic chronic myeloid leukemia, leukemia, lymphoproliferative disorder, metastatic melanoma, relapsed multiple myeloma, refractory multiple myeloma, myeloproliferative disorder, pancreatic cancer, small intestinal cancer, or a solid tumor.

181. Use of a compound for treating an infectious disease, or in the manufacture of a medicament for treating an infectious disease, wherein the compound is a compound of any one of embodiments 1 to 87.

182. The use of embodiment 181, wherein the infectious disease is a viral infection.

183. The use of embodiment 182, wherein the viral infection is an infection caused by a virus of a family selected from the group consisting of Herpesviridae, Polyomaviridae, Poxviridae, Reoviridae, Birnaviridae, Picornaviridae, Flaviviridae, Arenaviridae, Hepaciviridae, Rhabdoviridae, Paramyxoviridae, Bunyaviridae, Orthomyxoviridae, Filoviridae, Retroviridae, and Hepadnaviridae.

184. The use of embodiment 183, wherein the virus of the Herpesviridae family is herpes simplex virus-1, herpes simplex virus-2, herpes virus-5, Kaposi's sarcoma-associated herpes virus, varicella-zoster virus, or Epstein-Barr virus.

185. The use of embodiment 183, wherein the virus of the Polyomaviridae family is SV40.

186. The use of embodiment 183, wherein the virus of the Poxviridae family is vaccinia virus.

187. The use of embodiment 183, wherein the virus of the Reoviridae family is a rotavirus.

188. The use of embodiment 183, wherein the virus of the Birnaviridae family is infectious bursal disease virus.

189. The use of embodiment 183, wherein the virus of the Picornaviridae family is a poliovirus, a rhinovirus, or a coxsackievirus.

190. The use of embodiment 183, wherein the virus of the Flaviviridae family is hepatitis C virus or dengue virus.

191. The use of embodiment 183, wherein the virus of the Arenaviridae family is lymphocytic choriomeningitis virus.

192. The use of embodiment 183, wherein the virus of the Hepaciviridae family is Hepatitis E virus.

193. The use of embodiment 183, wherein the virus of the Rhabdoviridae family is vesicular stomatitis virus.

194. The use of embodiment 183, wherein the virus of the Paramyxoviridae family is human parainfluenza virus 2, human parainfluenza virus 3, SV5, SV41, measles virus, or Sendai virus.

195. The use of embodiment 183, wherein the virus of the Bunyaviridae family is La Crosse virus.

196. The use of embodiment 183, wherein the virus of the Orthomyxoviridae family is influenza A virus.

197. The use of embodiment 183, wherein the virus of the Filoviridae family is Ebola virus.

198. The use of embodiment 183, wherein the virus of the Retroviridae family is HTLV1 or HIV1.

199. The use of embodiment 183, wherein the virus of the Hepadnaviridae family is hepatitis B virus.

200. The use of embodiment 172 or 173, wherein the infectious disease is a fungal infection.

201. The use of embodiment 200, wherein the fungal infection is Candida albicans infection, Aspergillus fumigatus infection, or Pneumocystis infection.

202. The use of embodiment 172 or 173, wherein the infectious disease is a bacterial infection.

203. The use of embodiment 202, wherein the bacterial infection is a mycobacterial infection or an anthrax infection.

204. The use of embodiment 203, wherein the bacterial infection is bacterial pneumonia.

205. The use of embodiment 172 or 173, wherein the disorder is an inflammatory or autoimmune disease.

206. The use of embodiment 205, wherein the inflammatory or autoimmune disease is rheumatoid arthritis, systemic lupus erythematosus, or asthma.

207. The use of embodiment 172 or 173, wherein the disorder is cardiovascular disease.

208. The use of embodiment 207, wherein the cardiovascular disease is atherosclerosis or cardiomyopathy.

209. The use of embodiment 172 or 173, wherein the disorder is allergy.

210. The compound of any one of embodiments 134 to 171 or the use of any one of embodiments 172 to 209, wherein the compound is formulated for administration by a route selected from the group consisting of oral, sublingual, buccal, transdermal, intradermal, intramuscular, parenteral, intravenous, intraarterial, intracranial, subcutaneous, intraorbital, intraventricular, intraspinal, intraperitoneal, intranasal, by inhalation, and topical.

211. The compound or use of embodiment 128, wherein the compound is formulated for oral administration.

212. A method of inhibiting Hsp90, the method comprising contacting a cell with a compound of any one of embodiments 1 to 87, or a pharmaceutically acceptable salt thereof.

213. The method of embodiment 212, wherein the cell is in vitro.

214. A compound for use in inhibiting Hsp90, wherein the compound is the compound of any one of embodiments 1 to 87 or a pharmaceutically acceptable salt thereof.

215. Use of a compound for inhibiting Hsp90, wherein the compound is the compound of any one of Embodiments 1 to 87 or a pharmaceutically acceptable salt thereof.

216. A kit comprising:

(i) the pharmaceutical composition of any one of Examples 88 to 90; and

(ii) instructions for using the pharmaceutical composition of (i) to treat a disorder caused by the action of Hsp90 in a mammal.

All publications, patents, and patent applications mentioned in this specification are herein incorporated by reference to the same extent as if each individual publication or patent application was specifically and individually indicated to be incorporated by reference.

While the invention has been described with reference to particular embodiments thereof, it will be understood that it is capable of further modifications, and this application is intended to cover any variations, uses, or adaptations of the invention which generally follow the principles of the invention and which involve departures from the invention which come within the known or customary practice of the art to which the invention pertains and which are applicable to the essential characteristics as set forth above and appear within the scope of the claims.

Other embodiments are within the claims.

Claims (35)

1. The following compound: 61. 62. 49. 5. 6. 7. 8. 10. 12. 13. 14. 20. twenty four, 29. 34. 60. 51. 52. 58. 59. 63. 64. 65. 66. 67. 71. 73. 75, or 76. Or its pharmaceutically acceptable salt. 2. The compound of claim 1, having the following formula: 61. 62. 49. 14. 20. 12. 7. 10. 13. 5. 6. 8. twenty four, 34. 60. 51 63. 64. 65. 66. 67. 71. 73. 75, or 76. Or its pharmaceutically acceptable salt. 3. The compound of claim 2, wherein the compound is: 61. 62, or 49, Or its pharmaceutically acceptable salt. 4. A pharmaceutical composition comprising the compound of any one of claims 1 to 3 or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers or excipients. 5. The pharmaceutical composition of claim 4, wherein the composition is formulated for parenteral administration. 6. The pharmaceutical composition of claim 4, wherein the composition is formulated for administration via sublingual, buccal, transcutaneous, intramuscular, intravenous, intraarterial, intracranial, intraorbital, intravenous, intraspinal, intraperitoneal, intranasal, or inhalation. 7. The pharmaceutical composition of claim 4, wherein the composition is formulated for intradermal or subcutaneous administration. 8. The pharmaceutical composition of claim 4, wherein the composition is formulated for oral administration. 9. The pharmaceutical composition of claim 4, wherein the composition is formulated for topical administration. 10. Use of the compound in the preparation of a medicament for treating disorders in mammals caused by the action of heat shock protein 90 (Hsp90), wherein said compound is the compound of any one of claims 1 to 3 or a pharmaceutically acceptable salt thereof. 11. The use as claimed in claim 10, wherein the disorder is a neurodegenerative disorder. 12. The use as claimed in claim 11, wherein the neurodegenerative disorder is a tau protein lesion. 13. The use as described in claim 11, wherein the neurodegenerative disorder is Alzheimer's disease, Huntington's disease, progressive supranuclear palsy, Parkinson's disease, Pick's disease, corticobasal degeneration, chronic traumatic encephalopathy, traumatic brain injury, or frontotemporal dementia. 14. The use as described in claim 13, wherein the neurodegenerative disorder is Alzheimer's disease. 15. The use as claimed in claim 10, wherein the disorder is a proliferative disease. 16. The use as described in claim 15, wherein the proliferative disease is cancer. 17. Use of a compound in the preparation of a medicament for treating infectious diseases in mammals, wherein said compound is a compound as claimed in any one of claims 1 to 3 or a pharmaceutically acceptable salt thereof. 18. The use as described in claim 17, wherein the infectious disease is a viral infection. 19. The use as claimed in claim 18, wherein the viral infection is an infection caused by a virus selected from the family Herpesviridae, Polyomaviridae, Poxviridae, Reoviridae, DiRNAviridae, Picornaviridae, Flaviviridae, Arenaviridae, Hepatitis Eviridae, Rhabdoviridae, Paramyxoviridae, Bunyaviridae, Orthomyxoviridae, Filoviridae, Retroviridae, and Hepatoviridae. 20. The use as claimed in claim 17, wherein the infectious disease is a fungal infection. 21. The use as claimed in claim 17, wherein the infectious disease is a bacterial infection. 22. The use as described in claim 10, wherein the obstacle is an inflammatory or autoimmune disease. 23. The use as described in claim 22, wherein the inflammatory or autoimmune disease is rheumatoid arthritis, systemic lupus erythematosus, or asthma. 24. The use as claimed in claim 10, wherein the obstacle is a cardiovascular disease. 25. The use as claimed in claim 24, wherein the cardiovascular disease is atherosclerosis. 26. The use as claimed in claim 10, wherein the barrier is an allergy. 27. The use as described in claim 10, wherein the compound is administered parenterally. 28. The use as claimed in claim 10, wherein the compound is administered sublingually, buccally, percutaneously, intramuscularly, intravenously, intraarterially, intracranially, intraorbitally, intravenously, intraspinally, intraperitoneally, intranasally, or by inhalation. 29. The use as described in claim 10, wherein the compound is administered intradermally or subcutaneously. 30. The use as described in claim 10, wherein the compound is administered locally. 31. The use as described in claim 10, wherein the compound is administered orally. 32. The use as claimed in claim 10, wherein the mammal is a human. 33. Use of the compound in the preparation of a medicament for inhibiting Hsp90 in cells, wherein the compound is the compound of any one of claims 1 to 3 or a pharmaceutically acceptable salt thereof. 34. The use as described in claim 33, wherein the cells are in vitro. 35. A reagent kit comprising: (i) the pharmaceutical composition as claimed in claim 4; and (ii) Instructions for use of the pharmaceutical composition of (i) to treat disorders in mammals caused by the action of Hsp90.