WO2011146803A1 - Method of treating lung adenocarcinoma with hsp90 inhibitory compounds - Google Patents

Method of treating lung adenocarcinoma with hsp90 inhibitory compounds Download PDF

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Publication number
WO2011146803A1
WO2011146803A1 PCT/US2011/037285 US2011037285W WO2011146803A1 WO 2011146803 A1 WO2011146803 A1 WO 2011146803A1 US 2011037285 W US2011037285 W US 2011037285W WO 2011146803 A1 WO2011146803 A1 WO 2011146803A1
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Prior art keywords
optionally substituted
indol
triazole
mercapto
phenyl
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PCT/US2011/037285
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French (fr)
Inventor
Vojo Vukovi
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Synta Pharmaceuticals Corp.
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Priority to AU2011255438A priority Critical patent/AU2011255438A1/en
Priority to CA2810254A priority patent/CA2810254A1/en
Priority to JP2013529256A priority patent/JP2013537229A/en
Priority to CN2011800437944A priority patent/CN103269701A/en
Priority to PCT/US2011/051320 priority patent/WO2012037072A1/en
Priority to AU2011302344A priority patent/AU2011302344B2/en
Priority to EP11760643.4A priority patent/EP2616063A1/en
Priority to US13/231,183 priority patent/US20120064175A1/en
Publication of WO2011146803A1 publication Critical patent/WO2011146803A1/en

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A61K31/403—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with carbocyclic rings, e.g. carbazole
    • A61K31/404—Indoles, e.g. pindolol
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/4196—1,2,4-Triazoles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/42—Oxazoles
    • A61K31/423—Oxazoles condensed with carbocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents

Definitions

  • chemotherapeutic agents act on a specific molecular target thought to be involved in the development of the malignant phenotype.
  • a complex network of signaling pathways regulate cell proliferation and the majority of malignant cancers are facilitated by multiple genetic abnormalities in these pathways. Therefore, it is less likely that a therapeutic agent that acts on one molecular target will be fully effective in curing a patient who has cancer.
  • HSPs Heat shock proteins
  • HSPs are a class of chaperone proteins that are up-regulated in response to elevated temperature and other environmental stresses, such as ultraviolet light, nutrient deprivation and oxygen deprivation. HSPs act as chaperones to other cellular proteins (called client proteins), facilitate their proper folding and repair and aid in the refolding of misfolded client proteins.
  • client proteins There are several known families of HSPs, each having its own set of client proteins.
  • the Hsp90 family is one of the most abundant HSP families accounting for about 1-2% of proteins in a cell that is not under stress and increasing to about 4-6% in a cell under stress. Inhibition of Hsp90 results in the degradation of its client proteins via the ubiquitin proteasome pathway.
  • the client proteins of Hsp90 are mostly protein kinases or transcription factors involved in signal transduction, and a number of its client proteins have been shown to be involved in the progression of cancer.
  • Adenocarcinoma account for approximately 40% of lung cancers. Generally, adenocarcinomas grow more slowly and form smaller masses than the other subtypes. However, they tend to form metastases widely at an early stage. Adenocarcinoma is a non-small cell lung carcinoma, and as such, it is not as responsive to radiation therapy as is small cell lung carcinoma, but is rather treated by surgically.
  • the subject has mucinous BAC. In another embodiment, the subject has BAC with a B-raf mutation.
  • the Hsp90 inhibitor is a compound represented in Tables 1 or 2.
  • the lung adenocarcinoma has mutations or translocations in EGFR, K-ras, HER2neu, B-raf, PI3K and/or ALK proteins. In one embodiment, the lung adenocarcinoma has wild type EGFR and K-ras. In one embodiment, the lung adenocarcinoma has mutations in EGFR and wild type K-ras.
  • alkyl means a saturated or unsaturated, straight chain or branched, non-cyclic hydrocarbon having from 1 to 10 carbon atoms.
  • Representative straight chain alkyls include methyl, ethyl, n-propyl, n-butyl, n-pentyl, n-hexyl, n-heptyl, n-octyl, n- nonyl and n-decyl; while representative branched alkyls include isopropyl, sec-butyl, isobutyl, tert-b tyl, isopentyl, 2-methylbutyl, 3-methylbutyl, 2-methylpentyl, 3-methylpentyl, 4- methylpentyl, 2-methylhexyl, 3-methylhexyl, 4-methylhexyl, 5-methylhexyl, 2,3-dimethylbutyl,
  • unsaturated alkyls include vinyl, allyl, 1-butenyl, 2-butenyl, isobutylenyl, 1-pentenyl, 2-pentenyl, 3-methyl-l -butenyl, 2-methyl-2-butenyl, 2,3-dimethyl-2- butenyl, 1-hexenyl, 2-hexenyl, 3-hexenyl, 1-heptenyl, 2-heptenyl, 3-heptenyl, 1-octenyl, 2- octenyl, 3-octenyl, 1-nonenyl, 2-nonenyl, 3-nonenyl, 1-decenyl, 2-decenyl, 3-decenyl, acetylenyl, propynyl, 1-butynyl, 2-butynyl, 1-pentynyl, 2-pentynyl, 3-methyl-l-butynyl, 4- pentynyl, 1-hexy
  • cycloalkyl means a saturated or unsaturated, mono- or polycyclic, non-aromatic hydrocarbon having from 3 to 20 carbon atoms.
  • Representative cycloalkyls include cyclopropyl, 1-methylcyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl, octahydropentalenyl, cyclohexenyl, cyclooctenyl, cyclohexynyl, and the like. Cycloalkyl groups included in the compounds described herein may be optionally substituted with one or more substituents.
  • haloalkoxy is a haloalkyl group which is attached to another moiety via an oxygen linker.
  • substituents for an alkyl, alkylene, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocyclyl, aryl, aralkyl, heteroaryl, and heteroaralkyl include an alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocyclyl, aryl, heteroaryl, aralkyl, heteraralkyl, heteroalkyl, alkoxy, (each of which can be optionally and independently substituted), -C(0)NR 28 R 29 , -C(S)NR 28 R 29 , -C(NR 32 )NR 28 R 29 , -NR 33 C(0)R 31 , -NR 33 C(S)R 31 , -NR 33 C(NR 32 )R 31 , halo, -OR 33 , cyano, nitro, -C(0)R 33 , -C(S)R 33 ,
  • Her2 is a transmembrane tyrosine kinase cell surface growth factor receptor that is expressed in normal epithelial cells. Her2 has an extracellular domain that interacts with extracellular growth factors and an internal tyrosine kinase portion that transmits the external growth signal transduction pathways leading to cell growth and differentiation. Her2 is overexpressed in a significant proportion of malignancies, such as breast cancer, ovarian cancer, prostate cancer and gastric cancers, and is typically associated with a poor prognosis. It is encoded within the genome by HER2/neu, a known proto-oncogene. HER2 is thought to be an orphan receptor, with none of the EGF family of ligands able to activate it.
  • Raf-1 is a MAP 3-kinase (MAP3K) which, when activated, can phosphorylate and activate the serine/threonine specific protein kinases ERK1 and ERK2.
  • MAP3K MAP 3-kinase
  • Activated ERKs play an important role in the control of gene expression involved in the cell division cycle, apoptosis, cell differentiation and cell migration.
  • Epidermal Growth Factor Receptor is a member of the type 1 subgroup of receptor tyrosine kinase family of growth factor receptors which play critical roles in cellular growth, differentiation and survival. Activation of these receptors typically occurs via specific ligand binding which results in hetero- or homodimerization between receptor family members, with subsequent autophosphorylation of the tyrosine kinase domain.
  • Specific ligands which bind to EGFR include epidermal growth factor (EGF), transforming growth factor a (TGFa), amphiregulin and some viral growth factors.
  • pharmaceutically acceptable carriers should be biocompatible, i.e., non-toxic, non-inflammatory, non-immunogenic and devoid of other undesired reactions upon the administration to a subject.
  • Standard pharmaceutical formulation techniques can be employed, such as those described in REMINGTON, J. P., REMINGTON'S PHARMACEUTICAL SCIENCES (Mack Pub. Co., 17 th ed., 1985).
  • Suitable pharmaceutical carriers for parenteral administration include, for example, sterile water, physiological saline, bacteriostatic saline (saline containing about 0.9% mg/ml benzyl alcohol), phosphate-buffered saline, Hank's solution, Ringer's-lactate, and the like.
  • the term "effective amount” refers to an amount of a compound described herein which is sufficient to reduce or ameliorate the severity, duration, progression, or onset of a disease or disorder, delay onset of a disease or disorder, retard or halt the advancement of a disease or disorder, cause the regression of a disease or disorder, prevent or delay the recurrence, development, onset or progression of a symptom associated with a disease or disorder, or enhance or improve the therapeutic effect(s) of another therapy.
  • the disease or disorder is a proliferative disorder.
  • the terms “treat”, “treatment” and “treating” refer to the reduction or amelioration of the progression, severity and/or duration of a disease or disorder or disorder, or the amelioration of one or more symptoms (preferably, one or more discernible symptoms) of a disease or disorder, resulting from the administration of one or more therapies (e.g. , one or more therapeutic agents such as a compound of the invention).
  • therapies e.g. , one or more therapeutic agents such as a compound of the invention.
  • the terms “treat”, “treatment” and “treating” also encompass the delay or inhibition of the recurrence of a disease or disorder.
  • the disease or disorder being treated is a proliferative disorder such as cancer.
  • the term "synergistic” refers to a combination of a compound described herein and another therapeutic agent, which, when taken together, is more effective than the additive effects of the individual therapies.
  • a synergistic effect of a combination of therapies permits the use of lower dosages of one or more of the therapeutic agent(s) and/or less frequent administration of the agent(s) to a subject with a disease or disorder, e.g., a proliferative disorder.
  • the ability to utilize lower the dosage of one or more therapeutic agent and/or to administer the therapeutic agent less frequently reduces the toxicity associated with the administration of the agent to a subject without reducing the efficacy of the therapy in the treatment of a disease or disorder.
  • the term "in combination” refers to the use of more than one therapeutic agent.
  • the use of the term “in combination” does not restrict the order in which the therapeutic agents are administered to a subject with a disease or disorder, e.g., a proliferative disorder.
  • a first therapeutic agent such as a compound described herein, can be administered prior to (e.g. , 5 minutes, 15 minutes, 30 minutes, 45 minutes, 1 hour, 2 hours, 4 hours, 6 hours, 12 hours, 24 hours, 48 hours, 72 hours, 96 hours, 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 8 weeks, or 12 weeks before), concomitantly with, or subsequent to (e.g.
  • the Hsp90 inhibitor and the one or more additional therapeutic agents are dosed on independent schedules. In another embodiment, the Hsp90 inhibitor and the one or more additional therapeutic agents are dosed on approximately the same schedule. In another embodiment, the Hsp90 inhibitor and the one or more additional therapeutic agents are dosed concurrently or sequentially on the same day. In another embodiment, the Hsp90 inhibitor and the one or more additional therapeutic agents are dosed sequentially on different days.
  • the compounds described herein are defined by their chemical structures and/or chemical names. Where a compound is referred to by both a chemical structure and a chemical name, and the chemical structure and the chemical name conflict, the chemical structure is determinative of the compound' s identity.
  • purified means that when isolated, the isolate contains at least 95%, preferably at least 98%, of a compound described herein by weight of the isolate either as a mixture of stereoisomers, or as a diastereomeric or enantiomeric pure isolate.
  • the method includes treating lung adenocarcinoma in a subject in need thereof, comprising administering an effective amount of an Hsp90 inhibitory compound shown in Tables 1 or 2, or according to formula (I) or (la) as set forth below:
  • Z is OH, SH, or NH 2 ;
  • X is CR 4 or N
  • Ri is -H, -OH, -SH, an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, an optionally substituted heteraralkyl, halo, cyano, nitro, guanidino, a haloalkyl, a heteroalkyl, an alkoxy or cycloalkoxy, a haloalkoxy, -NRioRn, -OR 7 , -C(0)R 7 , -C(0)OR 7 , -C(S)R 7 , -C(0)SR 7 , -C(S)SR 7 , -C(S)SR 7 , ,
  • R 3 is -H, an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, an optionally substituted heteraralkyl, hydroxyalkyl, alkoxyalkyl, a haloalkyl, a heteroalkyl, -C(0)R 7 , -(CH 2 ) m C(0)OR 7 , -C(0)OR 7 , -OC(0)R 7 , -C(0)NRioRii, -S(0) p R 7 , -S(0) p OR 7 , or -S(O) p NR 10 Rn;
  • R 4 is -H, -OH, an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, an optionally substituted heteraralkyl, hydroxyalkyl, alkoxyalkyl, halo, cyano, nitro, guanidino, a haloalkyl, a heteroalkyl, -C(0)R 7 , -C(0)OR 7 , -OC(0)R 7 , -C(O)NR 10 Rii, -NR 8 C(0)R 7 , -SR 7 , -S(0) p R 7 , -OS(0) p R 7 , -S(0) p OR 7 , -NR 8 S(0) p R
  • R 7 and R 8 are, independently, -H, an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, or an optionally substituted heteraralkyl;
  • Rio and Rn are independently -H, an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, or an optionally substituted heteraralkyl; or R 10 and R n , taken together with the nitrogen to which they are attached, form an optionally substituted heterocyclyl or an optionally substituted heteroaryl;
  • Ri5 for each occurrence, is independently, a lower alkyl
  • R 4 is selected from the group consisting of -H, methyl, ethyl, propyl, isopropyl or cyclopropyl.
  • R 2 is selected from the group consisting of -H, -OH, methoxy, and ethoxy.
  • Ri is selected from the group consisting of -H, methyl, ethyl, propyl, isopropyl, cyclopropyl, methoxy, ethoxy, propoxy, and cyclopropoxy;
  • R 3 is selected from the group consisting of -H, methyl, ethyl, n-propyl, isopropyl, cyclopropyl, n-butyl, sec-butyl, tert-butyl, n-pentyl, n-hexyl, -C(0)OH, -(CH 2 ) m C(0)OH, -CH 2 OCH 3 , -CH 2 CH 2 OCH 3 , and -C(0)N(CH 3 ) 2 ;
  • R 4 is selected from the group consisting of -H, methyl, ethyl, propyl, isopropyl or cyclopropyl;
  • R 2 is selected from the group consisting of
  • the one or more therapeutic agents described herein can be administered to a subject, preferably a human subject, in the same pharmaceutical composition.
  • a subject preferably a human subject

Abstract

Provided is a method for treating adenocarcinoma, such as bronchioloalveolar carcinoma, by administering to a subject in need thereof, an effective amount of a compound according to the following formula: (l) a tautomer, or a pharmaceutically acceptable salt thereof, wherein the variables in the structural formulae are defined herein.

Description

METHOD OF TREATING LUNG ADENOCARCINOMA WITH HSP90 INHIBITORY
COMPOUNDS
CROSS-REFERENCE TO RELATED PATENT APPLICATIONS This application claims the benefit of U.S. Provisional Application No. 61/346,570, filed on May 20, 2010, the entire disclosure of which is incorporated herein by reference.
BACKGROUND OF THE INVENTION
Although tremendous advances have been made in elucidating the genomic
abnormalities that cause malignant cancer cells, currently available chemotherapy remains unsatisfactory, and the prognosis for the majority of patients diagnosed with cancer remains dismal. Most chemotherapeutic agents act on a specific molecular target thought to be involved in the development of the malignant phenotype. However, a complex network of signaling pathways regulate cell proliferation and the majority of malignant cancers are facilitated by multiple genetic abnormalities in these pathways. Therefore, it is less likely that a therapeutic agent that acts on one molecular target will be fully effective in curing a patient who has cancer.
Heat shock proteins (HSPs) are a class of chaperone proteins that are up-regulated in response to elevated temperature and other environmental stresses, such as ultraviolet light, nutrient deprivation and oxygen deprivation. HSPs act as chaperones to other cellular proteins (called client proteins), facilitate their proper folding and repair and aid in the refolding of misfolded client proteins. There are several known families of HSPs, each having its own set of client proteins. The Hsp90 family is one of the most abundant HSP families accounting for about 1-2% of proteins in a cell that is not under stress and increasing to about 4-6% in a cell under stress. Inhibition of Hsp90 results in the degradation of its client proteins via the ubiquitin proteasome pathway. Unlike other chaperone proteins, the client proteins of Hsp90 are mostly protein kinases or transcription factors involved in signal transduction, and a number of its client proteins have been shown to be involved in the progression of cancer.
The incidence of lung adenocarcinoma has been increasing in many developed Western nations in the past few decades, where it has become the most common major type of lung cancer in smokers and in lifelong nonsmokers. This cancer usually is seen peripherally in the lungs, as opposed to small cell lung cancer and squamous cell lung cancer, which both tend to be more centrally located, although it may also occur as central lesions. By unknown reasons, it often arises in relation to peripheral lung scars. Adenocarcinomas account for approximately 40% of lung cancers. Generally, adenocarcinomas grow more slowly and form smaller masses than the other subtypes. However, they tend to form metastases widely at an early stage. Adenocarcinoma is a non-small cell lung carcinoma, and as such, it is not as responsive to radiation therapy as is small cell lung carcinoma, but is rather treated by surgically.
Adenocarcinomas are highly heterogeneous tumors, and several major histological subtypes are currently recognized:
eke note-who2004-0#eite note-who20()4-0cinar adenocarcinoma; 2) papillary
adenocarcinoma; 3) bronchioloalveolar adenocarcinoma; and 4) solid adenocarcinoma with mucin production.
SUMMARY OF THE INVENTION
It is now found that certain triazolone Hsp90 inhibitors are surprisingly effective at treating subjects with metastatic or unresectable lung adenocarcinoma (a type of non-small cell lung cancer) with a tolerable side effect profile.
The method described herein includes utilizing Hsp90 inhibitors according to formulae (I) or (la), or a compound in Tables 1 or 2, for the treatment of lung adenocarcinoma in a subject in need thereof. The method of treating the subject with adenocarcinoma includes the step of administering to the subject in need thereof, an effective amount of an Hsp90 inhibitor according to formulae (I) or (la) or a compound in Tables 1 or 2. In one embodiment, the Hsp90 inhibitor is administered as a single agent. In another embodiment, the Hsp90 inhibitor is administered in combination with one or more additional therapeutic agents. In one embodiment, the type of adenocarcinoma is BAC. In one embodiment, the subject has non-mucinous BAC. In another embodiment, the subject has mucinous BAC. In another embodiment, the subject has BAC with a B-raf mutation. In any one of these embodiments, the Hsp90 inhibitor is a compound represented in Tables 1 or 2. In one embodiment, the lung adenocarcinoma has mutations or translocations in EGFR, K-ras, HER2neu, B-raf, PI3K and/or ALK proteins. In one embodiment, the lung adenocarcinoma has wild type EGFR and K-ras. In one embodiment, the lung adenocarcinoma has mutations in EGFR and wild type K-ras. In one embodiment, the lung adenocarcinoma has wild type EGFR and mutations in the K-ras protein. In one embodiment, the adenocarcinoma has the ALK-elm4 translocation. In one embodiment, the adenocarcinoma has the HER2neu mutation. In one embodiment, the adenocarcinoma has a mutation in PI3K. In one embodiment, the adenocarcinoma has a mutation in the B-raf protein.
In one embodiment, the method includes the use of an Hsp90 inhibitor according to formulae (I) or (la) or a compound in Tables 1 or 2 for the manufacture of a medicament for treating adenocarcinoma in subjects in need thereof. In another embodiment, the method includes the use of an Hsp90 inhibitor according to formulae (I) or (la) or a compound in Tables 1 or 2 for the manufacture of a medicament for treating BAC in a subject in need thereof. In one embodiment, the method includes the treatment of drug-resistant lung adenocarcinoma in a subject by administering an effective amount of an Hsp90 compound according to formulae (I) or (la) or a compound in Tables 1 or 2. In one embodiment, the method of treatment of a drug-resistant adenocarcinoma may include the administration of one or more therapeutic agents in addition to an Hsp90 compound according to formulae (I) or (la) or a compound in Tables 1 or 2.
DETAILED DESCRIPTION OF THE INVENTION
Definitions
Unless otherwise specified, the below terms used herein are defined as follows:
As used herein, the term "alkyl" means a saturated or unsaturated, straight chain or branched, non-cyclic hydrocarbon having from 1 to 10 carbon atoms. Representative straight chain alkyls include methyl, ethyl, n-propyl, n-butyl, n-pentyl, n-hexyl, n-heptyl, n-octyl, n- nonyl and n-decyl; while representative branched alkyls include isopropyl, sec-butyl, isobutyl, tert-b tyl, isopentyl, 2-methylbutyl, 3-methylbutyl, 2-methylpentyl, 3-methylpentyl, 4- methylpentyl, 2-methylhexyl, 3-methylhexyl, 4-methylhexyl, 5-methylhexyl, 2,3-dimethylbutyl,
2.3- dimethylpentyl, 2,4-dimethylpentyl, 2,3-dimethylhexyl, 2,4-dimethylhexyl, 2,5- dimethylhexyl, 2,2-dimethylpentyl, 2,2-dimethylhexyl, 3,3-dimtheylpentyl, 3,3-dimethylhexyl,
4.4- dimethylhexyl, 2-ethylpentyl, 3-ethylpentyl, 2-ethylhexyl, 3-ethylhexyl, 4-ethylhexyl, 2- methyl-2-ethylpentyl, 2-methyl-3-ethylpentyl, 2-methyl-4-ethylpentyl, 2-methyl-2-ethylhexyl, 2- methyl-3-ethylhexyl, 2-methyl-4-ethylhexyl, 2,2-diethylpentyl, 3,3-diethylhexyl, 2,2- diethylhexyl, 3,3-diethylhexyl, and the like. The term "(Ci-C6)alkyl" means a saturated, straight chain or branched, non-cyclic hydrocarbon having from 1 to 6 carbon atoms. Alkyl groups included in compounds described herein may be optionally substituted with one or more substituents. Examples of unsaturated alkyls include vinyl, allyl, 1-butenyl, 2-butenyl, isobutylenyl, 1-pentenyl, 2-pentenyl, 3-methyl-l -butenyl, 2-methyl-2-butenyl, 2,3-dimethyl-2- butenyl, 1-hexenyl, 2-hexenyl, 3-hexenyl, 1-heptenyl, 2-heptenyl, 3-heptenyl, 1-octenyl, 2- octenyl, 3-octenyl, 1-nonenyl, 2-nonenyl, 3-nonenyl, 1-decenyl, 2-decenyl, 3-decenyl, acetylenyl, propynyl, 1-butynyl, 2-butynyl, 1-pentynyl, 2-pentynyl, 3-methyl-l-butynyl, 4- pentynyl, 1-hexynyl, 2-hexynyl, 5-hexynyl, 1 -heptynyl, 2-heptynyl, 6-heptynyl, 1-octynyl, 2- octynyl, 7-octynyl, 1-nonynyl, 2-nonynyl, 8-nonynyl, 1-decynyl, 2-decynyl, 9-decynyl, and the like. Alkyl groups included in compounds described herein may be optionally substituted with one or more substituents.
As used herein, the term "cycloalkyl" means a saturated or unsaturated, mono- or polycyclic, non-aromatic hydrocarbon having from 3 to 20 carbon atoms. Representative cycloalkyls include cyclopropyl, 1-methylcyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl, octahydropentalenyl, cyclohexenyl, cyclooctenyl, cyclohexynyl, and the like. Cycloalkyl groups included in the compounds described herein may be optionally substituted with one or more substituents.
As used herein, the term "alkylene" refers to an alkyl group that has two points of attachment. The term "(Ci-C6)alkylene" refers to an alkylene group that has from one to six carbon atoms. Straight chain (Ci-C6)alkylene groups are preferred. Non-limiting examples of alkylene groups include methylene (-CH2-), ethylene (-CH2CH2-), n-propylene (-CH2CH2CH2-), isopropylene (-CH2CH(CH3)-), and the like. Alkylene groups may be saturated or unsaturated, and may be optionally substituted with one or more substituents.
As used herein, the term "lower" refers to a group having up to four atoms. For example, a "lower alkyl" refers to an alkyl radical having from 1 to 4 carbon atoms, "lower alkoxy" refers to "-0-(Ci-C4)alkyl.
As used herein, the term "haloalkyl" means an alkyl group, in which one or more, including all, the hydrogen radicals are replaced by a halo group(s), wherein each halo group is independently selected from -F, -CI, -Br, and -I. For example, the term "halomethyl" means a methyl in which one to three hydrogen radical(s) have been replaced by a halo group.
Representative haloalkyl groups include trifluoromethyl, bromomethyl, 1 ,2-dichloroethyl, 4- iodobutyl, 2-fluoropentyl, and the like.
As used herein, an "alkoxy" is an alkyl group which is attached to another moiety via an oxygen linker. Alkoxy groups included in compounds described herein may be optionally substituted with one or more substituents.
As used herein, a "haloalkoxy" is a haloalkyl group which is attached to another moiety via an oxygen linker.
As used herein, the term an "aromatic ring" or "aryl" means a mono- or polycyclic hydrocarbon, containing from 6 to 15 carbon atoms, in which at least one ring is aromatic. Examples of suitable aryl groups include phenyl, tolyl, anthracenyl, fluorenyl, indenyl, azulenyl, and naphthyl, as well as benzo-fused carbocyclic moieties such as 5,6,7, 8-tetrahydronaphthyl. Aryl groups included in compounds described herein may be optionally substituted with one or more substituents. In one embodiment, the aryl group is a monocyclic ring, wherein the ring comprises 6 carbon atoms, referred to herein as "(C6)aryl." As used herein, the term "aralkyl" means an aryl group that is attached to another group by a (Ci-C6)alkylene group. Representative aralkyl groups include benzyl, 2-phenyl-ethyl, naphth-3-yl-methyl and the like. Aralkyl groups included in compounds described herein may be optionally substituted with one or more substituents.
As used herein, the term "heterocyclyl" means a monocyclic or a polycyclic, saturated or unsaturated, non-aromatic ring or ring system which typically contains 5- to 20-members and at least one heteroatom. A heterocyclic ring system can contain saturated ring(s) or unsaturated non-aromatic ring(s), or a mixture thereof. A 3- to 10-membered heterocycle can contain up to 5 heteroatoms, and a 7- to 20-membered heterocycle can contain up to 7 heteroatoms. Typically, a heterocycle has at least one carbon atom ring member. Each heteroatom is independently selected from nitrogen, which can be oxidized (e.g., N(O)) or quaternized, oxygen and sulfur, including sulfoxide and sulfone. The heterocycle may be attached via any heteroatom or carbon atom. Representative heterocycles include morpholinyl, thiomorpholinyl, pyrrolidinonyl, pyrrolidinyl, piperidinyl, piperazinyl, hydantoinyl, valerolactamyl, oxiranyl, oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, tetrahydropyrindinyl, tetrahydropyrimidinyl,
tetrahydrothiophenyl, tetrahydrothiopyranyl, and the like. A heteroatom may be substituted with a protecting group known to those of ordinary skill in the art, for example, a nitrogen atom may be substituted with a tert-butoxycarbonyl group. Furthermore, the heterocyclyl included in compounds described herein may be optionally substituted with one or more substituents. Only stable isomers of such substituted heterocyclic groups are contemplated in this definition.
As used herein, the term "heteroaryl", or like terms, means a monocyclic or a polycyclic, unsaturated radical containing at least one heteroatom, in which at least one ring is aromatic. Polycyclic heteroaryl rings must contain at least one heteroatom, but not all rings of a polycyclic heteroaryl moiety must contain heteroatoms. Each heteroatom is independently selected from nitrogen, which can be oxidized (e.g., N(O)) or quaternized, oxygen and sulfur, including sulfoxide and sulfone. Representative heteroaryl groups include pyridyl, 1-oxo-pyridyl, furanyl, benzo[l ,3]dioxolyl, benzo[l ,4]dioxinyl, thienyl, pyrrolyl, oxazolyl, imidazolyl, thiazolyl, an isoxazolyl, quinolinyl, pyrazolyl, isothiazolyl, pyridazinyl, pyrimidinyl, pyrazinyl, a triazinyl, triazolyl, thiadiazolyl, isoquinolinyl, indazolyl, benzoxazolyl, benzofuryl, indolizinyl, imidazopyridyl, tetrazolyl, benzimidazolyl, benzothiazolyl, benzothiadiazolyl, benzoxadiazolyl, indolyl, tetrahydroindolyl, azaindolyl, imidazopyridyl, quinazolinyl, purinyl,
pyrrolo[2,3]pyrimidinyl, pyrazolo[3,4]pyrimidinyl, imidazo[l ,2-a]pyridyl, and benzothienyl. In one embodiment, the heteroaromatic ring is selected from 5-8 membered monocyclic heteroaryl rings. The point of attachment of a heteroaromatic or heteroaryl ring may be at either a carbon atom or a heteroatom. Heteroaryl groups included in compounds described herein may be optionally substituted with one or more substituents. As used herein, the term "(C5)heteroaryl" means an heteroaromatic ring of 5 members, wherein at least one carbon atom of the ring is replaced with a heteroatom, such as, for example, oxygen, sulfur or nitrogen. Representative (C5)heteroaryls include furanyl, thienyl, pyrrolyl, oxazolyl, imidazolyl, thiazolyl, isoxazolyl, pyrazolyl, isothiazolyl, pyrazinyl, triazolyl, thiadiazolyl, and the like. As used herein, the term "(C6)heteroaryl" means an aromatic heterocyclic ring of 6 members, wherein at least one carbon atom of the ring is replaced with a heteroatom such as, for example, oxygen, nitrogen or sulfur. Representative (C6)heteroaryls include pyridyl, pyridazinyl, pyrazinyl, triazinyl, tetrazinyl, and the like.
As used herein, the term "heteroaralkyl" means a heteroaryl group that is attached to another group by a (Ci-C6)alkylene. Representative heteroaralkyls include 2-(pyridin-4-yl)- propyl, 2-(thien-3-yl)-ethyl, imidazol-4-yl-methyl, and the like. Heteroaralkyl groups included in compounds described herein may be optionally substituted with one or more substituents.
As used herein, the term "halogen" or "halo" means -F, -CI, -Br or -I.
Suitable substituents for an alkyl, alkylene, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocyclyl, aryl, aralkyl, heteroaryl, and heteroaralkyl groups include are those substituents which form a stable compound described herein without significantly adversely affecting the reactivity or biological activity of the compound described herein. Examples of substituents for an alkyl, alkylene, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocyclyl, aryl, aralkyl, heteroaryl, and heteroaralkyl include an alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocyclyl, aryl, heteroaryl, aralkyl, heteraralkyl, heteroalkyl, alkoxy, (each of which can be optionally and independently substituted), -C(0)NR28R29, -C(S)NR28R29, -C(NR32)NR28R29, -NR33C(0)R31, -NR33C(S)R31, -NR33C(NR32)R31, halo, -OR33, cyano, nitro, -C(0)R33, -C(S)R33, -C(NR32)R33, -NR28R29, -C(0)OR33, -C(S)OR33, -C(NR32)OR33, -OC(0)R33, -OC(S)R33, -OC(NR32)R33, -NR30C(O)NR28R29, -NR33C(S)NR28R29, -NR33C(NR32)NR28R29,
-OC(0)NR28R29, -OC(S)NR28R29, -OC(NR32)NR28R29, -NR33C(0)OR31, -NR33C(S)OR31, -NR33C(NR32)OR31, -S(0)kR33, -OS(0)kR33, -NR33S(0)kR33, -S(0)kNR28R29, -OS(0)kNR28R29, -NR33S(0)kNR28R29, guanidino, -C(0)SR31, -C(S)SR31, -C(NR32)SR31, -OC(0)OR31,
-OC(S)OR31, -OC(NR32)OR31, -SC(0)R33, -SC(0)OR31, -SC(NR32)OR31, -SC(S)R33,
-SC(S)OR31, -SC(0)NR28R29, -SC(NR32)NR28R29, -SC(S)NR28R29, -SC(NR32)R33, -OS(0)kOR31, -S(0)kOR31, -NR30S(O)kOR31, -SS(0)kR33, -SS(0)kOR31, -SS(0)kNR28R29, -OP(0)(OR31)2, or -SP(0)(OR31)2. In addition, any saturated portion of an alkyl, cycloalkyl, alkylene, heterocyclyl, alkenyl, cycloalkenyl, alkynyl, aralkyl and heteroaralkyl groups, may also be substituted with
32 28 29
=0, =S, or =N-R . Each R and R is independently H, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocyclyl, aryl, heteroaryl, aralkyl, or heteraralkyl, wherein each alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocyclyl, aryl, heteroaryl, aralkyl, or heteroalkyl
28 29 30 31 33 represented by R or R is optionally and independently substituted. Each R , R and R is independently H, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocyclyl, aryl, heteroaryl, aralkyl, or heteraralkyl, wherein each alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl,
30 31 33 heterocyclyl, aryl, heteroaryl, aralkyl, and heteraralkyl represented by R or R or R is optionally and independently unsubstituted. Each R32 is independently H, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocyclyl, aryl, heteroaryl, aralkyl, heteraralkyl, -C(0)R33,
-C(0)NR28R29, -S(0)kR33, or -S(0)kNR28R29, wherein each alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocyclyl, aryl, heteroaryl, aralkyl and heteraralkyl represented by R32 is optionally and independently substituted. The variable k is 0, 1 or 2. In some embodiments, suitable substituents include C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 haloalkoxy, C1 -C4 hydroxy alkyl, halo, or hydroxyl.
When a heterocyclyl, heteroaryl or heteroaralkyl group contains a nitrogen atom, it may be substituted or unsubstituted. When a nitrogen atom in the aromatic ring of a heteroaryl group has a substituent, the nitrogen may be oxidized or a quaternary nitrogen.
As used herein, the terms "subject", "patient" and "mammal" are used interchangeably. The terms "subject" and "patient" refer to an animal (e.g. , a bird such as a chicken, quail or turkey, or a mammal), preferably a mammal including a non-primate (e.g. , a cow, pig, horse, sheep, rabbit, guinea pig, rat, cat, dog, and mouse) and a primate (e.g. , a monkey, chimpanzee and a human), and more preferably a human. In one embodiment, the subject is a non-human animal such as a farm animal (e.g. , a horse, cow, pig or sheep), or a pet (e.g. , a dog, cat, guinea pig or rabbit). In another embodiment, the subject is a human.
As used herein, the term "compound(s) described herein" or similar terms refers to a compound of formulae (I), or (la) or a compound in Tables 1 or 2 or a tautomer or
pharmaceutically acceptable salt thereof. Also included in the scope of the embodiments are the anhydrous form, a solvate, clathrate, hydrate, polymorph, prodrug, or protected derivative of a compound of formulae (I), or (la), or a compound in Tables 1 or 2.
The compounds described herein may contain one or more chiral centers and/or double bonds and, therefore, exist as stereoisomers, such as double-bond isomers (i.e. , geometric isomers), enantiomers or diastereomers. Each chemical structure shown herein, including the compounds described herein, encompass all of the corresponding compound' enantiomers, diastereomers and geometric isomers, that is, both the stereochemically pure form (e.g. , geometrically pure, enantiomerically pure, or diastereomerically pure) and isomeric mixtures (e.g., enantiomeric, diastereomeric and geometric isomeric mixtures). In some cases, one enantiomer, diastereomer or geometric isomer will possess superior activity or an improved toxicity or kinetic profile compared to other isomers. In those cases, such enantiomers, diastereomers and geometric isomers of compounds described herein are preferred.
When a disclosed compound is named or depicted by structure, it is to be understood that solvates (e.g. , hydrates) of the compound or a pharmaceutically acceptable salt thereof is also included. "Solvates" refer to crystalline forms wherein solvent molecules are incorporated into the crystal lattice during crystallization. Solvates may include water or nonaqueous solvents such as ethanol, isopropanol, DMSO, acetic acid, ethanolamine and ethyl acetate. When water is the solvent molecule incorporated into the crystal lattice of a solvate, it is typically referred to as a "hydrate". Hydrates include stoichiometric hydrates as well as compositions containing variable amounts of water. Also included are the anhydrous form of the compound, which refers to the corresponding compound without water or solvent incorporated into the crystalline lattice.
When a disclosed compound is named or depicted by structure, it is to be understood that the compound, including solvates thereof, may exist in crystalline forms, non-crystalline forms or a mixture thereof. The compounds or solvates may also exhibit polymorphism (i.e. , the capacity to occur in different crystalline forms). These different crystalline forms are typically known as "polymorphs." It is to be understood that when named or depicted by structure, the disclosed compounds and solvates (e.g., hydrates) also include all polymorphs thereof.
Polymorphs have the same chemical composition but differ in packing, geometrical arrangement and other descriptive properties of the crystalline solid state. Polymorphs, therefore, may have different physical properties such as shape, density, hardness, deformability, stability and dissolution properties. Polymorphs typically exhibit different melting points, IR spectra and X- ray powder diffraction patterns, which may be used for identification. One of ordinary skill in the art will appreciate that different polymorphs may be produced, for example, by changing or adjusting the conditions used in crystallizing the compound. For example, changes in temperature, pressure or solvent may result in different polymorphs. In addition, one polymorph may spontaneously convert to another polymorph under certain conditions.
When a disclosed compound is named or depicted by structure, it is to be understood that clathrates ("inclusion compounds") of the compound or its pharmaceutically acceptable salt, solvate or polymorph, are also included. "Clathrate" means a compound described herein, or a salt thereof, in the form of a crystal lattice that contains spaces (e.g. , channels) that have a guest molecule trapped within (e.g. , a solvent or water). Also included is the compound or its pharmaceutically acceptable salt, solvate or polymorph without the guest compound trapped within spaces in the crystal lattice.
As used herein, and unless otherwise indicated, the term "prodrug" means a derivative of a compound that can hydrolyze, oxidize, or otherwise react under biological conditions (in vitro or in vivo) to provide a compound described herein. Prodrugs may become active upon such reaction under biological conditions, or they may have activity in their unreacted forms. Examples of prodrugs contemplated herein include analogs or derivatives of compounds of formulae (I) or (la) or a compound in Tables 1 or 2 that comprise biohydrolyzable moieties such as biohydrolyzable amides, biohydrolyzable esters, biohydrolyzable carbamates,
biohydrolyzable carbonates, biohydrolyzable ureides and phosphate analogues. Prodrugs can typically be prepared using well-known methods, such as those described by BURGER'S MEDICINAL CHEMISTRY AND DRUG DISCOVERY, (Manfred E. Wolff Ed., 5th ed. (1995)) 172- 178, 949-982.
As used herein, "Hsp90" includes each member of the family of heat shock proteins having a mass of about 90-kiloDaltons. For example, in humans the highly conserved Hsp90 family includes the cytosolic Hsp90a and Hsp90P isoforms, as well as GRP94, which is found in the endoplasmic reticulum, and HSP75/TRAP1, which is found in the mitochondrial matrix.
As used herein, "BAC" refers to bronchioloalveolar carcinoma, a term describing certain variants of lung cancer arising in the distal bronchioles or alveoli that initially exhibit a specific non-invasive growth pattern. BAC is defined as a tumor that grows in a lepidic fashion along pre-existing airway structures, without detectable invasion or destruction of the underlying tissue, blood vessels, or lymphatics. Because invasion must be ruled out, BAC can be diagnosed only after complete sectioning and examination of the entire tumor, not using biopsy or cytology samples. BAC is considered a pre-invasive malignant lesion that, after further mutation and progression, eventually generates an invasive adenocarcinoma. BAC occurs in two major histopathological variants, mucinous BAC (m-BAC, 20 -25 of cases) and non mucinous BAC (nm-BAC, 75 -80 of cases). Non-mucinous BAC's are highly associated with classical EGFR mutations, and thus are often responsive to targeted chemotherapy with erlotinib and gefinitib. K-ras mutations are rare in nm-BAC. Mucinous BAC, in contrast, is much more highly associated with K-ras mutations and wild-type EGFR, and thus is usually insensitive to the EGFR tyrosine kinase inhibitors. Recent research has made it clear that nonmucinous and mucinous BACs are very different types of lung cancer. Mucinous BAC is much more likely to present with multiple unilateral tumors and/or in a unilateral or bilateral pneumonic form than nonmucinous BAC. The overall prognosis for patients with mucinous BAC is significantly worse than patients with nonmucinous BAC. (See Yousem SA, Beasley MB,
Bronchioloalveolar carcinoma: a review of current concepts and evolving issues. Arch Pathol Lab Med 2007; 131: 1027-32).
Her2 is a transmembrane tyrosine kinase cell surface growth factor receptor that is expressed in normal epithelial cells. Her2 has an extracellular domain that interacts with extracellular growth factors and an internal tyrosine kinase portion that transmits the external growth signal transduction pathways leading to cell growth and differentiation. Her2 is overexpressed in a significant proportion of malignancies, such as breast cancer, ovarian cancer, prostate cancer and gastric cancers, and is typically associated with a poor prognosis. It is encoded within the genome by HER2/neu, a known proto-oncogene. HER2 is thought to be an orphan receptor, with none of the EGF family of ligands able to activate it. However, ErbB receptors dimerise on ligand binding, and HER2 is the preferential dimerisation partner of other members of the ErbB family. The HER2 gene is a proto-oncogene located at the long arm of human chromosome 17(17q21-q22). HER2/neu (also known as ErbB-2) stands for "Human Epidermal growth factor Receptor 2" and is a protein giving higher aggressiveness in breast cancers. It is a member of the ErbB protein family, more commonly known as the epidermal growth factor receptor family. HER2/neu has also been designated as CD340 (cluster of differentiation 340) and pl85. Approximately 15-20 percent of breast cancers have an amplification of the HER2/neu gene or overexpression of its protein product. Overexpression of this receptor in breast cancer is associated with increased disease recurrence and worse prognosis.
The Anaplastic Lymphoma Kinase (ALK) tyrosine kinase receptor is an enzyme that in humans is encoded by the ALK gene. The 2;5 chromosomal translocation is frequently associated with anaplastic large cell lymphomas (ALCLs). The translocation creates a fusion gene consisting of the ALK (anaplastic lymphoma kinase) gene and the nucleophosmin (NPM) gene: the 3' half of ALK, derived from chromosome 2, is fused to the 5' portion of NPM from chromosome 5. The product of the NPM-ALK fusion gene is oncogenic. Other possible translocations of the ALK gene, such as the elm4 translocation, are also implicated in cancer.
B-Raf proto-oncogene serine/threonine -protein kinase (B-RAF), also known as V-raf murine sarcoma viral oncogene homolog B 1 , is a protein that in humans is encoded by the BRAF gene. The B-RAF protein is involved in sending signals in cells and in cell growth. The BRAF gene may be mutated, and the B-RAF protein altered, as an inherited mutation which causes birth defects, or as an acquired mutation (oncogene) in adults which causes cancer. Acquired mutations in this gene have also been found in cancers, including non-Hodgkin lymphoma, colorectal cancer, malignant melanoma, papillary thyroid carcinoma, non-small cell lung carcinoma, and adenocarcinoma of lung. More than 30 mutations of the BRAF gene associated with human cancers have been identified. The frequency of BRAF mutations varies widely in human cancers from more than 80% in melanomas, to as little as 0-18% in other tumors, such as 1-3% in lung cancers and 5% in colorectal cancer. In 90% of the cases, a Glu for Val substitution at residue 599 (now referred to as V600E) in the activation segment has been found in human cancers. This mutation has been widely observed in papillary thyroid carcinoma, colorectal cancer and melanomas. Depending on the type of mutation the kinase activity towards MEK may also vary. In the same paper it has been reported that most of the mutants stimulate enhanced B-RAF kinase activity toward MEK. However, a few mutants act through a different mechanism because although their activity toward MEK is reduced, they adopt a conformation that activates wild-type C-RAF, which then signals to ERK.
KRAS is a protein which in humans is encoded by the KRAS gene. Like other members of the Ras family, the KRAS protein is a GTPase and is an early player in many signal transduction pathways. KRAS is usually tethered to cell membranes because of the presence of an isoprenyl group on its C-terminus. When mutated, KRAS is an oncogene. The protein product of the normal KRAS gene performs an essential function in normal tissue signaling, and the mutation of a KRAS gene is an essential step in the development of many cancers. KRAS acts as a molecular on/off switch, and once it is turned on it recruits and activates proteins necessary for the propagation of growth factor and other receptors' signal, such as c-Raf and PI 3-kinase.
Phosphoinositide 3-kinases (PI 3-kinases or PI3Ks) are a family of enzymes involved in cellular functions such as cell growth, proliferation, differentiation, motility, survival and intracellular trafficking, which in turn are involved in cancer. PI3Ks are a family of related intracellular signal transducer enzymes capable of phosphorylating the 3 position hydroxyl group of the inositol ring of phosphatidylinositol (Ptdlns). They are also known as
phosphatidylinositol-3-kinases. The pathway, with oncogene PIK3CA and tumor suppressor PTEN (gene) is implicated in insensitivity of cancer tumors to insulin and IGF1, in calorie restriction. PI 3-kinases have been linked to an extraordinarily diverse group of cellular functions, including cell growth, proliferation, differentiation, motility, survival and intracellular trafficking. Many of these functions relate to the ability of class I PI 3-kinases to activate protein kinase B (PKB, aka Akt). The class IA PI 3-kinase pi 10a is mutated in many cancers. Many of these mutations cause the kinase to be more active. The PtdIns(3,4,5)P3 phosphatase PTEN that antagonises PI 3-kinase signaling is absent from many tumours. Hence, PI 3-kinase activity contributes significantly to cellular transformation and the development of cancer. AKT protein family, which members are also called protein kinases B (PKB) plays an important role in mammalian cellular signaling. Akt kinase is a serine/threonine kinase which is a downstream effector molecule of phosphoinositide 3 -kinase and is involved in protecting a cell from apoptosis. Akt kinase is thought to be involved in the progression of cancer because it stimulates cell proliferation and suppresses apoptosis. Aktl is involved in cellular survival pathways, by inhibiting apoptotic processes. Aktl is also able to induce protein synthesis pathways, and is therefore a key signaling protein in the cellular pathways that lead to skeletal muscle hypertrophy, and general tissue growth. Since it can block apoptosis, and thereby promote cell survival, Aktl has been implicated as a major factor in many types of cancer. Akt is known to play a role in the cell cycle. Under various circumstances, activation of Akt was shown to overcome cell cycle arrest in Gl and G2 phases. Moreover, activated Akt may enable proliferation and survival of cells that have sustained a potentially mutagenic impact and, therefore, may contribute to acquisition of mutations in other genes.
Cdk4/cyclin D complexes are involved in phosphorylation of the retinoblastoma protein, which is an essential step in progression of a cell through the Gl phase of the cell cycle.
Disruption of Hsp90 activity has been shown to decrease the half life of newly synthesized Cdk4.
Raf-1 is a MAP 3-kinase (MAP3K) which, when activated, can phosphorylate and activate the serine/threonine specific protein kinases ERK1 and ERK2. Activated ERKs play an important role in the control of gene expression involved in the cell division cycle, apoptosis, cell differentiation and cell migration.
The transforming protein of the Rous sarcoma virus, v-src, is a prototype of an oncogene family that induces cellular transformation (i.e., tumorogenesis) by non-regulated kinase activity. Hsp90 has been shown to complex with v-scr and inhibit its degradation. p53 is a tumor suppressor protein that causes cell cycle arrest and apoptosis. Mutation of the p53 gene is found in about half of all human cancers, making it one of the most common genetic alterations found in cancerous cells. In addition, the p53 mutation is associated with a poor prognosis. Wild-type p53 has been shown to interact with Hsp90, but mutated p53 forms a more stable association with Hsp90 than wild-type p53 as a result of its misfolded conformation. A stronger interaction with Hsp90 protects the mutated protein from normal proteolytic degradation and prolongs its half -life. In a cell that is heterozygous for mutated and wild-type p53, inhibition of the stabilizing effect of Hsp90 causes mutant p53 to be degraded and restores the normal transcriptional activity of wild- type p53. There are two classes of protein kinases (PKs): protein tyrosine kinases (PTKs), which catalyze the phosphorylation of tyrosine kinase residues, and the serine -threonine kinases (STKs), which catalyze the phosphorylation of serine or threonine residues. Growth factor receptors with PTK activity are known as receptor tyrosine kinases. Receptor tyrosine kinases are a family of tightly regulated enzymes, and the aberrant activation of various members of the family is one of the hallmarks of cancer. The receptor tyrosine kinase family can be divided into subgroups that have similar structural organization and sequence similarity within the kinase domain.
The members of the type III group of receptor tyrosine kinases include platelet-derived growth factor receptors (PDGF receptors alpha and beta), colony-stimulating factor receptor (CSF-1R, c-Fms), Fms-like tyrosine kinase (FLT3), and stem cell factor receptor (c-Kit). FLT3 is primarily expressed on immature hematopoietic progenitors and regulates their proliferation and survival.
The FLT3-ITD mutation is also present in about 3% of cases of adult myelodysplastic syndrome and some cases of acute lymphocytic leukemia (ALL). Advani, Current
Pharmaceutical Design (2005), ii:3449-3457. FLT3 has been shown to be a client protein of Hsp90, and 17AAG, a benzoquinone ansamycin antibiotic that inhibits Hsp90 activity, has been shown to disrupt the association of FLT3 with Hsp90. The growth of leukemia cells that express either wild type FLT3 or FLT3-ITD mutations was found to be inhibited by treatment with 17AAG. Yao, et al, Clinical Cancer Research (2003), 9:4483-4493. c-Kit is a membrane type III receptor protein tyrosine kinase which binds Stem Cell Factor (SCF) to its extraellular domain. c-Kit has tyrosine kinase activity and is required for normal hematopoiesis. However, mutations in c-Kit can result in ligand-independent tyrosine kinase activity, autophosphorylation and uncontrolled cell proliferation. Aberrant expression and/or activation of c-Kit has been implicated in a variety of pathologic states. For example, there is evidence of a contribution of c-Kit to neoplastic pathology, including its association with leukemias and mast cell tumors, small cell lung cancer, testicular cancer and some cancers of the gastrointestinal tract and central nervous system. In addition, c-Kit has been implicated in carcinogenesis of the female genital tract, sarcomas of neuroectodermal origin, and Schwann cell neoplasia associated with neurofibromatosis. Yang et al., J Clin Invest. (2003), 772: 1851-1861 ; Viskochil, Clin Invest. (2003), 772: 1791-1793. c-Kit has been shown to be a client protein of Hsp90, and Hsp90 inhibitor 17AAG has been shown to induce apoptosis in Kasumi-1 cells, an acute myeloid leukemia cell line that harbors a mutation in c-Kit. c-Met is a receptor tyrosine kinase that is encoded by the Met protooncogene and transduces the biological effects of hepatocyte growth factor (HGF), which is also referred to as scatter factor (SF). Jiang, et al, Crit. Rev. Oncol. Hemtol. (1999), 29: 209-248. c-Met and HGF are expressed in numerous tissues, although their expression is normally predominantly confined to cells of epithelial and mesenchymal origin, respectively. c-Met and HGF are required for normal mammalian development and have been shown to be important in cell migration, cell proliferation, cell survival, morphogenic differentiation and the organization of 3-dimensional tubular structures {e.g. , renal tubular cells, gland formation, etc.). The c-Met receptor has been shown to be expressed in a number of human cancers. c-Met and its ligand, HGF, have also been shown to be co-expressed at elevated levels in a variety of human cancers, particularly sarcomas. However, because the receptor and ligand are usually expressed by different cell types, c-Met signaling is most commonly regulated by tumor-stroma (tumor-host) interactions. Furthermore, c-Met gene amplification, mutation and rearrangement have been observed in a subset of human cancers. Families with germine mutations that activate c-Met kinase are prone to multiple kidney tumors, as well as tumors in other tissues. Numerous studies have correlated the expression of c-Met and/or HGF/SF with the state of disease progression of different types of cancer, including lung, colon, breast, prostate, liver, pancreas, brain, kidney, ovarian, stomach, skin and bone cancers. Furthermore, the overexpression of c-Met or HGF have been shown to correlate with poor prognosis and disease outcome in a number of major human cancers including lung, liver, gastric and breast.
BCR-ABL is an oncoprotein with tyrosine kinase activity that has been associated with chronic myelogenous leukemia (CML), acute lymphocytic leukemia (ALL) in a subset of patients and acute myelogenous leukemia (AML) in a subset of patients. In fact, the BCR-ABL oncogene has been found in at least 90-95% of patients with CML, about 20% of adults with ALL, about 5% of children with ALL and in about 2% of adults with AML. The BCR-ABL oncoprotein is generated by the transloction of gene sequences from the c-ABL protein tyrosine kinase on chromosome 9 into the BCR sequences on chromosome 22, producing the
Philadelphia chromosome. The BCR-ABL gene has been shown to produce at least three alternative chimeric proteins, p230 BCR-ABL, p210 BCR-ABL and pl90 BCR-ABL, which have unregulated tyrosine kinase activity. The p210 BCR-ABL fusion protein is most often associated with CML, while the pl90 BCR-ABL fusion protein is most often associated with ALL. BCR-ABL has also been associated with a variety of additional hematological malignancies including granulocytic hyperplasia, myelomonocytic leukemia, lymphomas and erythroid leukemia. BCR-ABL fusion proteins exist as complexes with Hsp90 and are rapidly degraded when the action of Hsp90 is inhibited. It has been shown that geldanamycin, a benzoquinone ansamycin antibiotic that disrupts the association of BCR-ABL with Hsp90, results in proteasomal degradation of BCR-ABL and induces apoptosis in BCR-ABL leukemia cells.
Epidermal Growth Factor Receptor (EGFR) is a member of the type 1 subgroup of receptor tyrosine kinase family of growth factor receptors which play critical roles in cellular growth, differentiation and survival. Activation of these receptors typically occurs via specific ligand binding which results in hetero- or homodimerization between receptor family members, with subsequent autophosphorylation of the tyrosine kinase domain. Specific ligands which bind to EGFR include epidermal growth factor (EGF), transforming growth factor a (TGFa), amphiregulin and some viral growth factors. Activation of EGFR triggers a cascade of intracellular signaling pathways involved in both cellular proliferation (the ras/raf/MAP kinase pathway) and survival (the PI3 kinase/ Akt pathway). Members of this family, including EGFR and HER2, have been directly implicated in cellular transformation.
A number of human malignancies are associated with aberrant or overexpression of EGFR and/or overexpression of its specific ligands. Gullick, Br. Med. Bull. (1991), 47:87-98; Modijtahedi & Dean, Int. J. Oncol. (1994), 4:277-96; Salomon, et al., Crit. Rev. Oncol.
Hematol. (1995), 79: 183-232. Aberrant or overexpression of EGFR has been associated with an adverse prognosis in a number of human cancers, including head and neck, breast, colon, prostate, lung (e.g., NSCLC, adenocarcinoma and squamous lung cancer), ovarian,
gastrointestinal cancers (gastric, colon, pancreatic), renal cell cancer, bladder cancer, glioma, gynecological carcinomas and prostate cancer. In some instances, overexpression of tumor EGFR has been correlated with both chemoresistance and a poor prognosis. Lei, et al., Anticancer Res. (1999), 79:221-28; Veale, et al, Br. J. Cancer (1993); 68: 162-65. Mutations in EGFR are associated with many types of cancer as well. For example, EGFR mutations are highly prevalent in non-mucinous BAC patients. Finberg, et al., . Mol. Diagnostics (2007) 9(3):320-26.
As used herein, a "proliferative disorder" or a "hyperproliferative disorder," and other equivalent terms, means a disease or medical condition involving pathological growth of cells. Proliferative disorders include cancer, smooth muscle cell proliferation, systemic sclerosis, cirrhosis of the liver, adult respiratory distress syndrome, idiopathic cardiomyopathy, lupus erythematosus, retinopathy, (e.g., diabetic retinopathy or other retinopathies), cardiac hyperplasia, reproductive system associated disorders such as benign prostatic hyperplasia and ovarian cysts, pulmonary fibrosis, endometriosis, fibromatosis, harmatomas,
lymphangiomatosis, sarcoidosis and desmoid tumors. Non-cancerous proliferative disorders also include hyperproliieration of cells in the skin such as psoriasis and its varied clinical forms, Reiter's syndrome, pityriasis rubra pilaris, hyperproliferative variants of disorders of keratinization (e.g., actinic keratosis, senile keratosis), scleroderma, and the like. In one embodiment, the proliferative disorder is a myeloproliferative disorder. In one aspect, the myeloproliferative disorder is polycythemia vera, idiopathic myelofirbrosis, myelodysplastic syndrome, psoriasis or essential thrombocythemia. In one embodiment, the proliferative disorder expresses JAK2V617F mutation of JAK2. In an aspect of this embodiment, the proliferative disorder is polycythemia vera, idiopathic myelofirbrosis, or essential
thrombocythemia. In one aspect, the proliferative disorder is polycythemia vera.
As used herein, the term "pharmaceutically acceptable salt" refers to a salt prepared from a compound of formulae (I) or (la) or a compound in Tables 1 or 2 having an acidic functional group, such as a carboxylic acid functional group, and a pharmaceutically acceptable inorganic or organic base. Suitable bases include hydroxides of alkali metals such as sodium, potassium, and lithium; hydroxides of alkaline earth metal such as calcium and magnesium; hydroxides of other metals, such as aluminum and zinc; ammonia, and organic amines, such as unsubstituted or hydroxy-substituted mono-, di-, or trialkylamines; dicyclohexylamine; tributyl amine; pyridine; N-methyl,N-ethylamine; diethylamine; triethylamine; mono-, bis-, or tris-(2- hydroxy-lower alkyl amines), such as mono-, bis-, or tris-(2-hydroxyethyl)amine, 2-hydroxy- tert-butylamine, or tris-(hydroxymethyl)methylamine, N, N,-di-lower alkyl-N-(hydroxy lower alkyl)-amines, such as N,N-dimethyl-N-(2-hydroxyethyl)amine, or tri-(2-hydroxyethyl)amine; N-methyl-D-glucamine; and amino acids such as arginine, lysine, and the like. The term "pharmaceutically acceptable salt" also refers to a salt prepared from a compound of formulae (I) or (la) or a compound in Tables 1 or 2 having a basic functional group, such as an amine functional group, and a pharmaceutically acceptable inorganic or organic acid. Suitable acids include hydrogen sulfate, citric acid, acetic acid, oxalic acid, hydrochloric acid (HCl), hydrogen bromide (HBr), hydrogen iodide (HI), nitric acid, hydrogen bisulfide, phosphoric acid, isonicotinic acid, oleic acid, tannic acid, pantothenic acid, saccharic acid, lactic acid, salicylic acid, tartaric acid, bitartratic acid, ascorbic acid, succinic acid, maleic acid, besylic acid, fumaric acid, gluconic acid, glucaronic acid, formic acid, benzoic acid, glutamic acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, pamoic acid and p-toluenesulfonic acid.
As used herein, the term "pharmaceutically acceptable solvate," is a solvate formed from the association of one or more pharmaceutically acceptable solvent molecules to one of the compounds of formulae (I) or (la) or a compound in Tables 1 or 2. The term "solvate" includes hydrates, e.g. , hemihydrate, monohydrate, dihydrate, trihydrate, tetrahydrate, and the like. A pharmaceutically acceptable carrier may contain inert ingredients which do not unduly inhibit the biological activity of the compound(s) described herein. The
pharmaceutically acceptable carriers should be biocompatible, i.e., non-toxic, non-inflammatory, non-immunogenic and devoid of other undesired reactions upon the administration to a subject. Standard pharmaceutical formulation techniques can be employed, such as those described in REMINGTON, J. P., REMINGTON'S PHARMACEUTICAL SCIENCES (Mack Pub. Co., 17th ed., 1985). Suitable pharmaceutical carriers for parenteral administration include, for example, sterile water, physiological saline, bacteriostatic saline (saline containing about 0.9% mg/ml benzyl alcohol), phosphate-buffered saline, Hank's solution, Ringer's-lactate, and the like. Methods for encapsulating compositions, such as in a coating of hard gelatin or cyclodextran, are known in the art. See BAKER, ETAL., CONTROLLED RELEASE OF BIOLOGICAL ACTIVE AGENTS, (John Wiley and Sons, 1986).
As used herein, the term "effective amount" refers to an amount of a compound described herein which is sufficient to reduce or ameliorate the severity, duration, progression, or onset of a disease or disorder, delay onset of a disease or disorder, retard or halt the advancement of a disease or disorder, cause the regression of a disease or disorder, prevent or delay the recurrence, development, onset or progression of a symptom associated with a disease or disorder, or enhance or improve the therapeutic effect(s) of another therapy. In one embodiment of the invention, the disease or disorder is a proliferative disorder. The precise amount of compound administered to a subject will depend on the mode of administration, the type and severity of the disease or condition and on the characteristics of the subject, such as general health, age, sex, body weight and tolerance to drugs. For example, for a proliferative disease or disorder, determination of an effective amount will also depend on the degree, severity and type of cell proliferation. The skilled artisan will be able to determine appropriate dosages depending on these and other factors. When co-administered with other therapeutic agents, e.g., when co-administered with an anti-cancer agent, an "effective amount" of any additional therapeutic agent(s) will depend on the type of drug used. Suitable dosages are known for approved therapeutic agents and can be adjusted by the skilled artisan according to the condition of the subject, the type of condition(s) being treated and the amount of a compound described herein being used. In cases where no amount is expressly noted, an effective amount should be assumed. Non-limiting examples of an effective amount of a compound described herein are provided herein below. In a specific embodiment, the method includes treating, managing, or ameliorating a disease or disorder, e.g. a proliferative disorder, or one or more symptoms thereof, comprising administering to a subject in need thereof a dose of the Hsp90 inhibitor at least 150 g/kg, at least 250 g/kg, at least 500 g/kg, at least 1 mg/kg, at least 5 mg/kg, at least 10 mg/kg, at least 25 mg/kg, at least 50 mg/kg, at least 75 mg/kg, at least 100 mg/kg, at least 125 mg/kg, at least 150 mg/kg, or at least 200 mg/kg or more of one or more compounds described herein once every day, once every 2 days, once every 3 days, once every 4 days, once every 5 days, once every 6 days, once every 7 days, once every 8 days, once every 10 days, once every two weeks, once every three weeks, or once a month.
As used herein, the terms "treat", "treatment" and "treating" refer to the reduction or amelioration of the progression, severity and/or duration of a disease or disorder or disorder, or the amelioration of one or more symptoms (preferably, one or more discernible symptoms) of a disease or disorder, resulting from the administration of one or more therapies (e.g. , one or more therapeutic agents such as a compound of the invention). The terms "treat", "treatment" and "treating" also encompass the delay or inhibition of the recurrence of a disease or disorder. In one embodiment, the disease or disorder being treated is a proliferative disorder such as cancer. In specific embodiments, the terms "treat", "treatment" and "treating" refer to the amelioration of at least one measurable physical parameter of a disease or disorder, such as growth of a tumor, not necessarily discernible by the patient. In other embodiments the terms "treat", "treatment" and "treating" refer to the inhibition of the progression of a disease or disorder, e.g., a proliferative disorder, either physically by the stabilization of a discernible symptom, physiologically by the stabilization of a physical parameter, or both. In another embodiment, the terms "treat", "treatment" and "treating" of a proliferative disease or disorder refers to the reduction or stabilization of tumor size or cancerous cell count, and/or delay of tumor formation. In another embodiment, the terms "treat", "treating" and "treatment" also encompass the administration of a compound described herein as a prophylactic measure to patients with a predisposition (genetic or environmental) to any disease or disorder described herein.
As used herein, the terms "therapeutic agent" and "therapeutic agents" refer to any agent(s) that can be used in the treatment of a disease or disorder, e.g. a proliferative disorder, or one or more symptoms thereof. In certain embodiments, the term "therapeutic agent" refers to a compound described herein. In certain other embodiments, the term "therapeutic agent" does not refer to a compound described herein. Preferably, a therapeutic agent is an agent that is known to be useful for, or has been or is currently being used for the treatment of a disease or disorder, e.g., a proliferative disorder, or one or more symptoms thereof.
As used herein, the term "synergistic" refers to a combination of a compound described herein and another therapeutic agent, which, when taken together, is more effective than the additive effects of the individual therapies. A synergistic effect of a combination of therapies (e.g. , a combination of therapeutic agents) permits the use of lower dosages of one or more of the therapeutic agent(s) and/or less frequent administration of the agent(s) to a subject with a disease or disorder, e.g., a proliferative disorder. The ability to utilize lower the dosage of one or more therapeutic agent and/or to administer the therapeutic agent less frequently reduces the toxicity associated with the administration of the agent to a subject without reducing the efficacy of the therapy in the treatment of a disease or disorder. In addition, a synergistic effect can result in improved efficacy of agents in the prevention, management or treatment of a disease or disorder, e.g. a proliferative disorder. Finally, a synergistic effect of a combination of therapies may avoid or reduce adverse or unwanted side effects associated with the use of either therapeutic agent alone.
As used herein, the phrase "side effects" encompasses unwanted and adverse effects of a therapeutic agent. Side effects are always unwanted, but unwanted effects are not necessarily adverse. An adverse effect from a therapeutic agent might be harmful or uncomfortable or risky to a subject. Side effects include fever, chills, lethargy, gastrointestinal toxicities (including gastric and intestinal ulcerations and erosions), nausea, vomiting, neurotoxicities,
nephrotoxicities, renal toxicities (including such conditions as papillary necrosis and chronic interstitial nephritis), hepatic toxicities (including elevated serum liver enzyme levels), myelotoxicities (including leukopenia, myelosuppression, thrombocytopenia and anemia), dry mouth, metallic taste, prolongation of gestation, weakness, somnolence, pain (including muscle pain, bone pain and headache), hair loss, asthenia, dizziness, extra-pyramidal symptoms, akathisia, cardiovascular disturbances and sexual dysfunction.
As used herein, the term "in combination" refers to the use of more than one therapeutic agent. The use of the term "in combination" does not restrict the order in which the therapeutic agents are administered to a subject with a disease or disorder, e.g., a proliferative disorder. A first therapeutic agent, such as a compound described herein, can be administered prior to (e.g. , 5 minutes, 15 minutes, 30 minutes, 45 minutes, 1 hour, 2 hours, 4 hours, 6 hours, 12 hours, 24 hours, 48 hours, 72 hours, 96 hours, 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 8 weeks, or 12 weeks before), concomitantly with, or subsequent to (e.g. , 5 minutes, 15 minutes, 30 minutes, 45 minutes, 1 hour, 2 hours, 4 hours, 6 hours, 12 hours, 24 hours, 48 hours, 72 hours, 96 hours, 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 8 weeks, or 12 weeks after) the administration of a second therapeutic agent, such as an anti-cancer agent, to a subject with a disease or disorder, e.g. a proliferative disorder, such as cancer. In one embodiment, the Hsp90 inhibitor and the one or more additional therapeutic agents are dosed on independent schedules. In another embodiment, the Hsp90 inhibitor and the one or more additional therapeutic agents are dosed on approximately the same schedule. In another embodiment, the Hsp90 inhibitor and the one or more additional therapeutic agents are dosed concurrently or sequentially on the same day. In another embodiment, the Hsp90 inhibitor and the one or more additional therapeutic agents are dosed sequentially on different days.
As used herein, the terms "therapies" and "therapy" can refer to any protocol(s), method(s), and/or agent(s) that can be used in the prevention, treatment, management, or amelioration of a disease or disorder, e.g., a. proliferative disorder, or one or more symptoms thereof.
A used herein, a "protocol" includes dosing schedules and dosing regimens. The protocols herein are methods of use and include therapeutic protocols.
As used herein, a composition that "substantially" comprises a compound means that the composition contains more than about 80% by weight, more preferably more than about 90% by weight, even more preferably more than about 95% by weight, and most preferably more than about 97% by weight of the compound.
As used herein, a "racemic mixture" means about 50% of one enantiomer and about 50% of is corresponding enantiomer of the molecule. The combination encompasses all enantiomerically-pure, enantiomerically-enriched, diastereomerically pure, diastereomerically enriched, and racemic mixtures of the compounds described herein. Enantiomeric and diastereomeric mixtures can be resolved into their component enantiomers or diastereomers by well known methods, such as chiral-phase gas chromatography, chiral-phase high performance liquid chromatography, crystallizing the compound as a chiral salt complex, or crystallizing the compound in a chiral solvent. Enantiomers and diastereomers can also be obtained from diastereomerically- or enantiomerically-pure intermediates, reagents, and catalysts by well known asymmetric synthetic methods.
The compounds described herein are defined by their chemical structures and/or chemical names. Where a compound is referred to by both a chemical structure and a chemical name, and the chemical structure and the chemical name conflict, the chemical structure is determinative of the compound' s identity.
When administered to a subject (e.g. , a non-human animal for veterinary use or for improvement of livestock or to a human for clinical use), the compounds described herein are administered in an isolated form, or as the isolated form in a pharmaceutical composition. As used herein, "isolated" means that the compounds described herein are separated from other components of either: (a) a natural source, such as a plant or cell, preferably bacterial culture, or (b) a synthetic organic chemical reaction mixture. Preferably, the compounds described herein are purified via conventional techniques. As used herein, "purified" means that when isolated, the isolate contains at least 95%, preferably at least 98%, of a compound described herein by weight of the isolate either as a mixture of stereoisomers, or as a diastereomeric or enantiomeric pure isolate.
Only those choices and combinations of substituents that result in a stable structure are contemplated. Such choices and combinations will be apparent to those of ordinary skill in the art and may be determined without undue experimentation.
The invention can be understood more fully by reference to the following detailed description and illustrative examples, which are intended to exemplify non-limiting embodiments of the invention.
In one aspect, the method includes treating lung adenocarcinoma in a subject in need thereof, comprising administering an effective amount of an Hsp90 inhibitory compound shown in Tables 1 or 2, or according to formula (I) or (la) as set forth below:
Figure imgf000023_0001
(la)
or a tautomer, or a pharmaceutically acceptable salt thereof, wherein:
Z is OH, SH, or NH2;
X is CR4 or N;
Ri is -H, -OH, -SH, an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, an optionally substituted heteraralkyl, halo, cyano, nitro, guanidino, a haloalkyl, a heteroalkyl, an alkoxy or cycloalkoxy, a haloalkoxy, -NRioRn, -OR7, -C(0)R7, -C(0)OR7, -C(S)R7, -C(0)SR7, -C(S)SR7,
-C(S)OR7, -C(S)NR10Rii, -C(NR8)OR7, -C(NR8)R7, -C(NR8)NR10Rn,
-C(NR8)SR7, -OC(0)R7, -OC(0)OR7, -OC(S)OR7, -OC(NR8)OR7, -SC(0)R7, -SC(0)OR7, -SC(NR8)OR7, -OC(S)R7, -SC(S)R7, -SC(S)OR7, -OC(O)NRi0Rn, -OC(S)NRioRii, -OC(NR8)NRioRii, -SC(O)NRi0Rn, -SC(NR8)NRi0Rn, -SC(S)NRioRii, -OC(NR8)R7, -SC(NR8)R7, -C(O)NRi0Rn, -NR8C(0)R7, -NR7C(S)R7, -NR7C(S)OR7, -NR7C(NR8)R7, -NR7C(0)OR7, -NR7C(NR8)OR7, -NR7C(0)NRioRii, -NR7C(S)NRi0Rn, -NR7C(NR8)NRi0Rn, -SR7, -S(0)pR7, -OS(0)pR7, -OS(0)pOR7, -OS(0)pNRioRn, -S(0)pOR7, -NR8S(0)pR7, -NR7S(0)pNRioRn, -NR7S(0)pOR7, -S(O)pNR10Rn, -SS(0)pR7, -SS(0)pOR7, -SS(0)pNRioRn, -OP(0)(OR7)2, or -SP(0)(OR7)2;
R2 is -H, -OH, -SH, -NR7H, -ORi5, -SRi5, -NHRi5, -0(CH2)mOH, -0(CH2)mSH, -0(CH2)mNR7H, -S(CH2)mOH, -S(CH2)mSH, -S(CH2)mNR7H,
-OC(0)NRioRii, -SC(0)NRioRii, -NR7C(O)NRi0Rn, -OC(0)R7, -SC(0)R7, -NR7C(0)R7, -OC(0)OR7, -SC(0)OR7, -NR7C(0)OR7, -OCH2C(0)R7, -SCH2C(0)R7, -NR7CH2C(0)R7, -OCH2C(0)OR7, -SCH2C(0)OR7,
-NR7CH2C(0)OR7, -OCH2C(0)NRioRii, -SCH2C(O)NRi0Rn,
-NR7CH2C(O)NR10Rii, -OS(0)pR7, -SS(0)pR7, -NR7S(0)pR7,
-OS(O)pNR10Rii, -SS(O)pNR10Rii, -NR7S(O)pNR10Rn, -OS(0)pOR7,
-SS(0)pOR7, -NR7S(0)pOR7, -OC(S)R7, -SC(S)R7, -NR7C(S)R7, -OC(S)OR7, -SC(S)OR7, -NR7C(S)OR7, -OC(S)NRi0Rn, -SC(S)NRi0Rn,
-NR7C(S)NRioRii, -OC(NR8)R7, -SC(NR8)R7, -NR7C(NR8)R7,
-OC(NR8)OR7, -SC(NR8)OR7, -NR7C(NR8)OR7, -OC(NR8)NRi0Rn,
-SC(NR8)NRioRii, or -NR7C(NR8)NRi0Rn;
R3 is -H, an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, an optionally substituted heteraralkyl, hydroxyalkyl, alkoxyalkyl, a haloalkyl, a heteroalkyl, -C(0)R7, -(CH2)mC(0)OR7, -C(0)OR7, -OC(0)R7, -C(0)NRioRii, -S(0)pR7, -S(0)pOR7, or -S(O)pNR10Rn;
R4 is -H, -OH, an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, an optionally substituted heteraralkyl, hydroxyalkyl, alkoxyalkyl, halo, cyano, nitro, guanidino, a haloalkyl, a heteroalkyl, -C(0)R7, -C(0)OR7, -OC(0)R7, -C(O)NR10Rii, -NR8C(0)R7, -SR7, -S(0)pR7, -OS(0)pR7, -S(0)pOR7, -NR8S(0)pR7, -S(O)pNRi0Rn, or R3 and R4 taken together with the carbon atoms to which they are attached form an optionally substituted cycloalkenyl, an optionally substituted aryl, an optionally substituted heterocyclyl, or an optionally substituted heteroaryl;
R7 and R8, for each occurrence, are, independently, -H, an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, or an optionally substituted heteraralkyl;
Rio and Rn, for each occurrence, are independently -H, an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, or an optionally substituted heteraralkyl; or R10 and Rn, taken together with the nitrogen to which they are attached, form an optionally substituted heterocyclyl or an optionally substituted heteroaryl;
Ri5, for each occurrence, is independently, a lower alkyl;
p, for each occurrence, is, independently, 1 or 2; and
m, for each occurrence, is independently, 1, 2, 3, or 4.
In one embodiment, in formula (I) or (la), X is CR4.
In another embodiment, in formula (I) or (la), X is N.
In another embodiment, in formula (I) or (la), Ri is selected from the group consisting of -H, lower alkyl, lower alkoxy, lower cycloalkyl, and lower cycloalkoxy.
In another embodiment, in formula (I) or (la), Ri is selected from the group consisting of -H, methyl, ethyl, propyl, isopropyl, cyclopropyl, methoxy, ethoxy, propoxy, and cyclopropoxy. In another embodiment, in formula (I) or (la), R3 is selected from the group consisting of -H, a lower alkyl, a lower cycloalkyl, -C(0)N(R27)2, and -C(0)OH, wherein R27 is -H or a lower alkyl.
In another embodiment, in formula (I) or (la), R3 is selected from the group consisting of -H, methyl, ethyl, n-propyl, isopropyl, cyclopropyl, n-butyl, sec-butyl, tert-butyl, n-pentyl, n- hexyl, -C(0)OH, -(CH2)mC(0)OH, -CH2OCH3, -CH2CH2OCH3, and -C(0)N(CH3)2.
In one embodiment, R4 is H or a lower alkyl.
In another embodiment, in formula (I) or (la), R4 is selected from the group consisting of -H, methyl, ethyl, propyl, isopropyl or cyclopropyl.
In another embodiment, in formula (I) or (la), Ri is selected from the group consisting of -H, -OH, -SH, -NH2, a lower alkoxy and a lower alkyl amino.
In another embodiment, in formula (I) or (la), Ri is selected from the group consisting of -H, -OH, methoxy and ethoxy.
In another embodiment, in formula (I) or (la), Z is -OH.
In another embodiment, in formula (I) or (la), Z is -SH.
In another embodiment, in formula (I) or (la), R2 is selected from the group consisting of -H, -OH, -SH, -NH2, a lower alkoxy and a lower alkyl amino.
In another embodiment, in formula (I) or (la), R2 is selected from the group consisting of -H, -OH, methoxy, and ethoxy.
In another embodiment, in formula (I) or (la), Ri is selected from the group consisting of -H, methyl, ethyl, propyl, isopropyl, cyclopropyl, methoxy, ethoxy, propoxy, and cyclopropoxy; R3 is selected from the group consisting of -H, methyl, ethyl, n-propyl, isopropyl, cyclopropyl, n-butyl, sec-butyl, tert-butyl, n-pentyl, n-hexyl, -C(0)OH, -(CH2)mC(0)OH, -CH2OCH3, -CH2CH2OCH3, and -C(0)N(CH3)2; R4 is selected from the group consisting of -H, methyl, ethyl, propyl, isopropyl or cyclopropyl; R2 is selected from the group consisting of -H, -OH, -SH, -NH2, a lower alkoxy and a lower alkyl amino; and Z is OH.
In another embodiment, in formula (I) or (la), Ri is selected from the group consisting of -H, methyl, ethyl, propyl, isopropyl, cyclopropyl, methoxy, ethoxy, propoxy, and cyclopropoxy; R3 is selected from the group consisting of -H, methyl, ethyl, n-propyl, isopropyl, cyclopropyl, n-butyl, sec-butyl, tert-butyl, n-pentyl, n-hexyl, -C(0)OH, -(CH2)mC(0)OH, -CH2OCH3, -CH2CH2OCH3, and -C(0)N(CH3)2; R4 is selected from the group consisting of -H, methyl, ethyl, propyl, isopropyl or cyclopropyl; R2 is selected from the group consisting of -H, -OH, -SH, -NH2, a lower alkoxy and a lower alkyl amino; and Z is SH. In another embodiment, the compound is selected from the group consisting of:
3-(2,4-dihydroxy-5-ethyl-phenyl)-4-(l,3-dimethyl-indol-5-yl)-5-hydroxy-[l,2,4]triazole,
3-(2,4-dihydroxy-5-isopropyl-phenyl)-4-(l,3-dimethyl-indol-5-yl)-5-hydroxy- [l,2,4]triazole,
3-(2,4-dihydroxy-5-isopropyl-phenyl)-4-(l -methyl -indol-5-yl)-5-hydroxy- [l,2,4]triazole,
3-(2,4-dihydroxy-5-isopropyl-phenyl)-4-(l-isopropyl-indol-4-yl)-5-hydroxy- [l,2,4]triazole,
3-(2,4-dihydroxy-5-isopropyl-phenyl)-4-(l -methyl -indazol-5-yl)-5-mercapto- [l,2,4]triazole,
3-(2,4-dihydroxy-5-isopropyl-phenyl)-4-(l -methyl -indazol-6-yl)-5-mercapto- [l,2,4]triazole,
3-(2,4-dihydroxyphenyl)-4-(l-ethyl-indol-4-yl)-5-mercapto-[l,2,4]triazole,
3-(2,4-dihydroxyphenyl)-4-(l-isopropyl-indol-4-yl)-5-mercapto-[l,2,4]triazole,
3-(2,4-dihydroxyphenyl)-4-(indol-4-yl)-5-mercapto-[l,2,4]triazole,
3-(2,4-dihydroxyphenyl)-4-(l-methoxyethyl-indol-4-yl)-5-mercapto-[l,2,4]triazole,
3-(2,4-dihydroxy-5-ethyl-phenyl)-4-(l-isopropyl-indol-4-yl)-5-mercapto-[l,2,4]triazole,
3-(2,4-dihydroxyphenyl)-4-(l-dimethylcarbamoyl-indol-4-yl)-5-mercapto- [l,2,4]triazole,
3-(2,4-dihydroxy-5-ethyl-phenyl)-4-(l-propyl-indol-4-yl)-5-mercapto-[l,2,4]triazole,
3-(2,4-dihydroxy-5-ethyl-phenyl)-4-(l,2,3-trimethyl-indol-5-yl)-5-mercapto- [l,2,4]triazole,
3-(2,4-dihydroxy-5-ethyl-phenyl)-4-(2,3-dimethyl-indol-5-yl)-5-mercapto- [l,2,4]triazole,
3-(2,4-dihydroxy-5-ethyl-phenyl)-4-(l-acetyl-2,3-dimethyl-indol-5-yl)-5-mercapto- [l,2,4]triazole,
3-(2,4-dihydroxy-5-ethyl-phenyl)-4-(l-propyl-2,3-dimethyl-indol-5-yl)-5-mercapto- [l,2,4]triazole,
3-(2,4-dihydroxy-5-ethyl-phenyl)-4-(l-n-butyl-indol-4-yl)-5-mercapto-[l,2,4]triazole, 3-(2,4-dihydroxy-5-ethyl-phenyl)-4-(l-n-pentyl-indol-4-yl)-5-mercapto-[l,2,4]triazole, 3-(2,4-dihydroxy-5-ethyl-phenyl)-4-(l-n-hexyl-indol-4-yl)-5-mercapto-[l,2,4]triazole,
3-(2,4-dihydroxy-5-cyclopropyl-phenyl)-4-(l-(l-methylcyclopropyl)-indol-4-yl)-5- mercapto- [1,2,4] triazole ,
3-(2,4-dihydroxy-5-cyclopropyl-phenyl)-4-(l,2,3-trimethyl-indol-5-yl)-5-mercapto- [l,2,4]triazole,
3-(2,4-dihydroxy-5-ethyl-phenyl)-4-(l-methyl-3-ethyl-indol-5-yl)-5-mercapto- [l,2,4]triazole,
3-(2,4-dihydroxy-5-ethyl-phenyl)-4-(l,3-dimethyl-indol-5-yl)-5-mercapto- [l,2,4]triazole,
3-(2,4-dihydroxy-5-ethyl-phenyl)-4-(l-methyl-3-isopropyl-indol-5-yl)-5-mercapto- [l,2,4]triazole,
3-(2,4-dihydroxy-5-ethyl-phenyl)-4-(l,2-dimethyl-indol-5-yl)-5-mercapto- [l,2,4]triazole,
3-(2,4-dihydroxy-5-ethyl-phenyl)-4-(N-methyl-indol-5-yl)-5-mercapto-[l,2,4]triazole,
3-(2,4-dihydroxy-5-isopropyl-phenyl)-4-(l,3-dimethyl-indol-5-yl)-5-mercapto- [l,2,4]triazole,
3-(2,4-dihydroxy-5-cyclopropyl-phenyl)-4-(l,3-dimethyl-indol-5-yl)-5-mercapto- [l,2,4]triazole,
3-(2,4-dihydroxy-5-cyclopropyl-phenyl)-4-(l -methyl -indol-5-yl)-5-mercapto- [l,2,4]triazole,
3-(2,4-dihydroxy-5-isopropyl-phenyl)-4-(lH-indol-5-yl)-5-mercapto-[l,2,4]triazole,
3-(2,4-dihydroxy-5-ethyl-phenyl)-4-(l,2-dimethyl-indol-5-yl)-5-mercapto- [l,2,4]triazole,
3-(2,4-dihydroxy-5-isopropyl-phenyl)-4-(l -ethyl -indol-5-yl)-5-mercapto-[l,2,4]triazole,
3-(2,4-dihydroxy-5-isopropyl-phenyl)-4-(l-propyl-indol-5-yl)-5-mercapto- [l,2,4]triazole, or a tautomer, or a pharmaceutically acceptable salt thereof.
In another embodiment, the compound is selected from the group consisting of
3-(2,4-dihydroxy-5-ethyl-phenyl)-4-(l-ethyl-benzimidazol-4-yl)-5-mercapto- [l,2,4]triazole,
3-(2,4-dihydroxy-5-ethyl-phenyl)-4-(l-ethyl-benzimidazol -4-yl)-5-mercapto- [l,2,4]triazole HCL salt, 3-(2,4-dihydroxy-5-ethyl^henyl)-4-(2-methyl-3-ethyl-benzimidazol-5-yl)-5-mercapto- [l,2,4]triazole,
3-(2,4-dihydroxy-5-ethyl^henyl)-4-(l-ethyl-2-methyl-benzimidazol-5-yl)-5-mercapto- [l,2,4]triazole,
3- (2,4-dihydroxy-5-isopropyl-phenyl)-4-(l -methyl -2-trifluoromethyl-benzimidazol-5- yl)-5-mercapto-[l,2,4]triazole, or a tautomer, or a pharmaceutically acceptable salt thereof.
In another embodiment, the compound is selected from the group consisting of 5-hydroxy-4-(5-hydroxy-4-( 1 -methyl- 1 H-indol-5 -yl)-4H- 1 ,2,4-triazol-3 -yl)-2- isopropylphenyl dihydrogen phosphate,
sodium 5-hydroxy-4-(5 -hydroxy-4-( 1 -methyl- 1 H-indol-5 -yl)-4H- 1 ,2,4-triazol-3 -yl)-2- isopropylphenyl phosphate,
2-(3,4-dimethoxyphenethyl)-5-hydroxy-4-(5-hydroxy-4-(l-methyl-lH-indol-5-yl)-4H- l,2,4-triazol-3-yl)phenyl dihydrogen phosphate,
5-hydroxy-2-isopropyl-4-(5-mercapto-4-(4-methoxybenzyl)-4H-l,2,4-triazol-3- yl)phenyl dihydrogen phosphate,
5-hydroxy-4-(5-hydroxy-4-(4-methoxybenzyl)-4H-l,2,4-triazol-3-yl)-2-isopropylphenyl dihydrogen phosphate,
4- (4-(l,3-dimethyl-lH-indol-5-yl)-5-hydroxy-4H-l,2,4-triazol-3-yl)-2-ethyl-5- hydroxyphenyl dihydrogen phosphate, or a tautomer, or a pharmaceutically acceptable salt thereof.
Hsp90 inhibitory compounds, as well as tautomers or pharmaceutically acceptable salts thereof, that may be used in the methods described herein are depicted in Tables 1 or 2.
Table 1
Figure imgf000029_0001
Figure imgf000030_0001
Figure imgf000031_0001
Figure imgf000032_0001
Figure imgf000034_0001
Figure imgf000035_0001
Figure imgf000036_0001
Figure imgf000037_0001
Figure imgf000038_0001
Table 2: Compounds according to Formula (la)
Figure imgf000039_0002
The Hsp90 inhibitory compounds used in the disclosed methods can be prepared according to the procedures disclosed in U.S. Patent Publication No. 2006/0167070, and WO2009/023211.
These triazolone compounds typically can form a tautomeric structure as shown below and as exemplified by the tautomeric structures shown in Tables 1 and 2:
Figure imgf000039_0001
The method described herein includes treating lung adenocarcinoma in a subject in need thereof, comprising administering to a subject an Hsp90 inhibitor according to formulae (I) or (la) or a compound in Tables 1 or 2. The method further comprises administering one or more other therapies to the subject in need thereof (e.g. , one or more therapeutic agents that are currently being used, have been used, are known to be useful or in development for use in the treatment or amelioration of a proliferative disorder, such as cancer, or one or more symptoms associated with said proliferative disorder).
In one embodiment, the one or more therapeutic agents described herein can be administered sequentially or concurrently. In certain embodiments, the one or more therapeutic agents described herein improve therapeutic effect of one or more compounds described herein by functioning together with the compounds to have an additive or synergistic effect. In certain embodiments, the one or more therapeutic agents described herein reduce the side effects associated with the therapies (e.g. , therapeutic agents). In certain embodiments, the one or more therapeutic agents described herein reduce the effective dosage of one or more of the therapies.
The one or more therapeutic agents described herein can be administered to a subject, preferably a human subject, in the same pharmaceutical composition. In alternative
embodiments, the one or more therapeutic agents described herein can be administered concurrently to a subject in separate pharmaceutical compositions. The therapeutic agents may be administered to a subject by the same or different routes of administration.
The therapeutic agents described herein can be administered to a subject by any route known to one of skill in the art. Examples of routes of administration include, but are not limited to, parenteral, e.g. , intravenous, intradermal, subcutaneous, oral (e.g. , inhalation), intranasal, transdermal (topical), transmucosal, and rectal administration.
The present invention provides pharmaceutical formulations for the treatment, prophylaxis, and amelioration of proliferative disorders, such as cancer. The pharmaceutical formulations described herein are formulated to be compatible with its intended route of administration. Examples of routes of administration include parenteral, e.g. , intravenous, intradermal, subcutaneous, oral, intranasal (e.g. , inhalation), transdermal (topical), transmucosal, and rectal administration. In a specific embodiment, the formulation is formulated in accordance with routine procedures as a pharmaceutical composition adapted for intravenous, subcutaneous, intramuscular, oral, intranasal or topical administration to human beings. In one embodiment, the formulation is formulated in accordance with routine procedures for subcutaneous administration to human beings.
Suitable formulation for the the triazolone compounds described herein can be found in U.S. Patent No. 7,825,148 and co-pending PCT Application Serial Number PCT/US11/37283, filed May 20, 2011 and entitled FORMULATION AND DOSING OF HSP90 INHIBITORY COMPOUNDS. The entire teachings of both of these documents are incorporated herein by reference. The triazolone compounds described herein can be formulated into or administered by controlled release means or by delivery devices that are well known to those of ordinary skill in the art. Examples include those described in U.S. Patent Nos.: 3,845,770; 3,916,899; 3,536,809; 3,598,123; and 4,008,719, 5,674,533, 5,059,595, 5,591,767, 5,120,548, 5,073,543, 5,639,476,
5,354,556, and 5,733,566.
Other anti-proliferative or anti-cancer therapies may be combined with the compounds described herein to treat proliferative diseases and cancer. Other therapies or anti-cancer agents that may be used in combination with the inventive anti-cancer agents described herein include surgery, radiotherapy (including gamma-radiation, neutron beam radiotherapy, electron beam radiotherapy, proton therapy, brachytherapy, and systemic radioactive isotopes), endocrine therapy, biologic response modifiers (including interferons, interleukins, and tumor necrosis factor (TNF)), hyperthermia and cryotherapy, agents to attenuate any adverse effects (e.g., antiemetics), and other approved chemotherapeutic drugs.
In one embodiment, the method of treating a subject with cancer includes administering to the subject an effective amount of a triazolone compound of 3-(2,4-dihydroxy-5-isopropyl- phenyl)-4-(l -methyl-indol-5-yl)-5-hydroxy-[l ,2,4]triazole, or a tautomer, or a pharmaceutically acceptable salt thereof.
In another embodiment, the method of treating a subject with cancer includes administering to the subject an effective amount of a triazolone compound of 5-hydroxy-4-(5- hydroxy-4-(l-methyl-lH-indol-5-yl)-4H-l ,2,4-triazol-3-yl)-2-isopropylphenyl dihydrogen phosphate, or a tautomer, or a pharmaceutically acceptable salt thereof.
In general, the recommended daily dose range of a triazolone compound for the conditions described herein lie within the range of from about 0.01 mg to about 1000 mg per day, given as a single once-a-day dose preferably as divided doses throughout a day. In one embodiment, the daily dose is administered twice daily in equally divided doses. Specifically, a daily dose range should be from about 5 mg to about 500 mg per day, more specifically, between about 10 mg and about 200 mg per day. In managing the patient, the therapy should be initiated at a lower dose, perhaps about 1 mg to about 25 mg, and increased if necessary up to about 200 mg to about 1000 mg per day as either a single dose or divided doses, depending on the patient's global response. It may be necessary to use dosages of the active ingredient outside the ranges disclosed herein in some cases, as will be apparent to those of ordinary skill in the art.
Furthermore, it is noted that the clinician or treating physician will know how and when to interrupt, adjust, or terminate therapy in conjunction with individual patient response.
Different therapeutically effective amounts may be applicable for different cancers, as will be readily known by those of ordinary skill in the art. Similarly, amounts sufficient to prevent, manage, treat or ameliorate such cancers, but insufficient to cause, or sufficient to reduce, adverse effects associated with the triazolone compounds described herein are also encompassed by the above described dosage amounts and dose frequency schedules. Further, when a patient is administered multiple dosages of a triazolone compound described herein, not all of the dosages need be the same. For example, the dosage administered to the patient may be increased to improve the prophylactic or therapeutic effect of the compound or it may be decreased to reduce one or more side effects that a particular patient is experiencing.
In a specific embodiment, the dosage of the composition comprising a triazolone compound described herein administered to prevent, treat, manage, or ameliorate cancer, or one or more symptoms thereof in a patient is 150 g/kg, preferably 250 g/kg, 500 g/kg, 1 mg/kg, 5 mg/kg, 10 mg/kg, 25 mg/kg, 50 mg/kg, 75 mg/kg, 100 mg/kg, 125 mg/kg, 150 mg/kg, or 200 mg/kg or more of a patient's body weight. In another embodiment, the dosage of the composition comprising a compound described herein administered to prevent, treat, manage, or ameliorate cancer, or one or more symptoms thereof in a patient is a unit dose of 0.1 mg to 20 mg, 0.1 mg to 15 mg, 0.1 mg to 12 mg, 0.1 mg to 10 mg, 0.1 mg to 8 mg, 0.1 mg to 7 mg, 0.1 mg to 5 mg, 0.1 to 2.5 mg, 0.25 mg to 20 mg, 0.25 to 15 mg, 0.25 to 12 mg, 0.25 to 10 mg, 0.25 to 8 mg, 0.25 mg to 7m g, 0.25 mg to 5 mg, 0.5 mg to 2.5 mg, 1 mg to 200 mg, 1 mg to 175 mg, 1 mg to 150 mg, 1 mg to 125 mg, 1 mg to 100 mg, 1 mg to 75 mg, 1 mg to 50 mg, 1 mg to 20 mg, 1 mg to 15 mg, 1 mg to 12 mg, 1 mg to 10 mg, 1 mg to 8 mg, 1 mg to 7 mg, 1 mg to 5 mg, or 1 mg to 2.5 mg. The unit dose can be administered 1 , 2, 3, 4 or more times daily, or once every 2, 3, 4, 5, 6 or 7 days, or once weekly, once every two weeks, once every three weeks or once monthly.
In certain embodiments, one or more compounds described herein and one or more other the therapies (e.g. , therapeutic agents) are cyclically administered. Cycling therapy involves the administration of a first therapy (e.g. , a first prophylactic or therapeutic agents) for a period of time, followed by the administration of a second therapy (e.g. , a second prophylactic or therapeutic agents) for a period of time, followed by the administration of a third therapy (e.g. , a third prophylactic or therapeutic agents) for a period of time and so forth, and repeating this sequential administration, i.e. , the cycle in order to reduce the development of resistance to one of the agents, to avoid or reduce the side effects of one of the agents, and/or to improve the efficacy of the treatment.
In certain embodiments, administration of the same compound described herein may be repeated and the administrations may be separated by at least 1 day, 2 days, 3 days, 5 days, 10 days, 15 days, 30 days, 45 days, 2 months, 75 days, 3 months, or 6 months. In other embodiments, administration of the same prophylactic or therapeutic agent may be repeated and the administration may be separated by at least at least 1 day, 2 days, 3 days, 5 days, 10 days, 15 days, 30 days, 45 days, 2 months, 75 days, 3 months, or 6 months.
In a specific embodiment, the method includes preventing, treating, managing, or ameliorating a proliferative disorders, such as cancer, or one or more symptoms thereof, comprising administering to a subject in need thereof a dose of at least 150 g/kg, preferably at least 250 g/kg, at least 500 g/kg, at least 1 mg/kg, at least 5 mg/kg, at least 10 mg/kg, at least 25 mg/kg, at least 50 mg/kg, at least 75 mg/kg, at least 100 mg/kg, at least 125 mg/kg, at least 150 mg/kg, or at least 200 mg/kg or more of one or more compounds described herein once every day, preferably, once every 2 days, once every 3 days, once every 4 days, once every 5 days, once every 6 days, once every 7 days, once every 8 days, once every 10 days, once every two weeks, once every three weeks, or once a month. Alternatively, the dose can be divided into portions (typically equal portions) administered two, three, four or more times a day.
EXAMPLES
Example 1: Synthesis of HSP90 Inhibitory Compounds
The Hsp90 inhibitory compounds used in the disclosed pharmaceutical compositions and methods herein can be prepared according to the procedures disclosed in U.S. Patent Publication No. 2006/0167070, and WO2009/023211.
Example 2: Once Weekly Administration of Compound 1
Study protocol:
This was an open-label Phase 1 dose-escalation study in subjects with solid tumors. The subject received 150 mg/m2 of compound 1 during a 1-hour infusion 1 time per week for three consecutive weeks followed by a 1 week dose-free interval. Each four week period of treatment is considered one cycle. The subjects in this study had histologically- or cytologically- confirmed non-hematological malignancy that was metastatic or unresectable. The subjects were documented to be refractory to, or were not candidates for, current standard therapy. Subjects were assessed for response rate (CR, PR, SD) based on the Response Evaluation Criteria in Solid Tumors (RECIST). Durability of response was also measured.
This subject entered the study with stage IV mucinous BAC, with target lesions in the subcarinal lymph node and the right paratracheal lymph node. Additional lesions were in the mediastinal lymph nodes and diffuse lung lesions. The patient was diagnosed with BAC in 2006. Molecular profiling showed wild type KRAS and EGFR, and EGFR was not amplified on FISH testing. This subject stayed on study for thirteen complete cycles. Response and progression were evaluated in this study using the international criteria proposed by the RECIST Committee. Changes in only the largest diameter (unidimensional measurement) of the tumor lesions were used in the RECIST criteria. The RECIST criteria specify:
Complete Response (CR): Disappearance of all target lesions
Partial Response (PR): At least a 30% decrease in the sum of the longest diameter (LD) of target lesions, taking as reference the baseline sum LD.
Progressive Disease (PD): At least a 20% increase in the sum of the LD of target lesions, taking as reference the smallest sum LD recorded since the treatment started or the appearance of one or more new lesions.
Stable Disease (SD): Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, taking as reference the smallest sum LD since the treatment started. Stable disease was measured from the start of the treatment until the criteria for progression were met, taking as reference the smallest measurements recorded since the treatment started.
The best overall response was the best response recorded from the start of the treatment until disease progression/recurrence (taking as reference for progressive disease the smallest measurements recorded since the treatment started). The subject's best response assignment would depend on the achievement of both measurement and confirmation criteria. Past Chemotherapy Treatments:
Figure imgf000045_0001
Other Treatments: Surgery - once in 2004, twice in 2005
Treatment with compound 1:
Dosage: 150 mg/m2, once a week
Figure imgf000045_0002
Number of cycles initiated: 13
Overall duration of stable disease: 344 days
Reason for discontinuing study: death from pneumonia (not treatment related)
As shown above, this was the seventh chemotherapeutic treatment that the subject tried. During treatment, the subject had diarrhea (grade 1) that was associated with treatment and also experienced some intermittent shortness of breath (grade 1) that was potentially associated with treatment with compound 1.
Example 3: Twice Weekly Administration of Compound 1
Study protocol:
This was an open-label Phase 1 dose-escalation study in subjects with solid tumors. The subject received 14 mg/m2 of compound 1 during a 1-hour infusion 2 times per week for three consecutive weeks followed by a 1 week dose-free interval. Each four week period of treatment is considered one cycle. The subjects in this study had histologically- or cytologically- confirmed non-hematological malignancy that was metastatic or unresectable. The subjects were documented to be refractory to, or were not candidates for, current standard therapy.
This subject entered the study with stage IV BAC, with target lesions in the mediastinal lymph node and the right hepatic lobe. The subject also had multiple attenuated lesions in the liver. This subject stayed on study for three complete cycles. Response and progression were evaluated in this study using the international criteria proposed by the RECIST Committee. Durability of response was also measured. Changes in only the largest diameter
(unidimensional measurement) of the tumor lesions are used in the RECIST criteria described in Example 3.
Past Chemotherapy Treatments:
Figure imgf000046_0001
Other Treatments: Surgery - once in 2006, once in 2008
Treatment with compound 1:
Dosage: 14 mg/m2, twice a week
Figure imgf000046_0002
Number of cycles initiated: 3
Overall duration of stable disease: 93 days
Reason for discontinuing study: symptomatic deterioration
As detailed above, this was the seventh chemotherapeutic treatment that the subject tried. During treatment, the subject had some adverse events that were potentially associated with treatment, including weight loss, elevated aspartate aminotransferase levels (grade 1), and fatigue (grade 2 and 3). All publications, patent applications, patents, and other documents cited herein are incorporated by reference in their entirety. In case of conflict, the present specification, including definitions, will control. In addition, the materials, methods, and examples throughout the specification are illustrative only and not intended to be limiting in any way.

Claims

CLAIMS What is claimed is:
1. A method of treating lung adenocarcinoma in a subject in need thereof, comprising administering to the subject an effective amount of an Hsp90 inhibitor according to the following formulae:
Figure imgf000048_0001
Figure imgf000048_0002
(la) or a tautomer, or a pharmaceutically acceptable salt thereof, wherein: Z is OH, SH, or NH2; X is CR4 or N;
Ri is -H, -OH, -SH, an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, an optionally substituted heteraralkyl, halo, cyano, nitro, guanidino, a haloalkyl, a heteroalkyl, an alkoxy or cycloalkoxy, a haloalkoxy, -NRioRn, -OR7, -C(0)R7, -C(0)OR7, -C(S)R7, -C(0)SR7, -C(S)SR7, -C(S)OR7, -C(S)NRioRii, -C(NR8)OR7, -C(NR8)R7, -C(NR8)NRi0Rn, -C(NR8)SR7, -OC(0)R7, -OC(0)OR7, -OC(S)OR7, -OC(NR8)OR7, -SC(0)R7, -SC(0)OR7, -SC(NR8)OR7, -OC(S)R7, -SC(S)R7, -SC(S)OR7, -OC(O)NRi0Rn, -OC(S)NRioRii, -OC(NR8)NRioRii, -SC(O)NR10Rn, -SC(NR8)NR10Rn, -SC(S)NRioRii, -OC(NR8)R7, -SC(NR8)R7, -C(O)NR10Rn, -NR8C(0)R7, -NR7C(S)R7, -NR7C(S)OR7, -NR7C(NR8)R7, -NR7C(0)OR7, -NR7C(NR8)OR7, -NR7C(O)NR10Rii, -NR7C(S)NR10Rn, -NR7C(NR8)NR10Rn, -SR7, -S(0)pR7, -OS(0)pR7, -OS(0)pOR7, -OS(0)pNRioRn, -S(0)pOR7, -NR8S(0)PR7, -NR7S(0)pNRioRn, -NR7S(0)pOR7, -S(O)pNR10Rn, -SS(0)pR7, -SS(0)pOR7, -SS(0)pNRioRn, -OP(0)(OR7)2, or -SP(0)(OR7)2;
R2 is -H, -OH, -SH, -NR7H, -ORi5, -SRi5, -NHRi5, -0(CH2)mOH, -0(CH2)mSH, -0(CH2)mNR7H, -S(CH2)mOH, -S(CH2)mSH, -S(CH2)mNR7H,
-OC(0)NRioRii, -SC(0)NRioRii, -NR7C(O)NRi0Rn, -OC(0)R7, -SC(0)R7, -NR7C(0)R7, -OC(0)OR7, -SC(0)OR7, -NR7C(0)OR7, -OCH2C(0)R7, -SCH2C(0)R7, -NR7CH2C(0)R7, -OCH2C(0)OR7, -SCH2C(0)OR7,
-NR7CH2C(0)OR7, -OCH2C(0)NRioRii, -SCH2C(O)NRi0Rn,
-NR7CH2C(0)NRioRii, -OS(0)pR7, -SS(0)pR7, -NR7S(0)pR7,
-OS(0)pNRioRn, -SS(0)pNRioRn, -NR7S(O)pNR10Rn, -OS(0)pOR7,
-SS(0)pOR7, -NR7S(0)pOR7, -OC(S)R7, -SC(S)R7, -NR7C(S)R7, -OC(S)OR7, -SC(S)OR7, -NR7C(S)OR7, -OC(S)NRi0Rn, -SC(S)NRi0Rn,
-NR7C(S)NRioRii, -OC(NR8)R7, -SC(NR8)R7, -NR7C(NR8)R7,
-OC(NR8)OR7, -SC(NR8)OR7, -NR7C(NR8)OR7, -OC(NR8)NRi0Rn,
-SC(NR8)NR10Rii, or -NR7C(NR8)NR10Rn;
R3 is -H, an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, an optionally substituted heteraralkyl, hydroxyalkyl, alkoxyalkyl, a haloalkyl, a heteroalkyl, -C(0)R7, -(CH2)mC(0)OR7, -C(0)OR7, -OC(0)R7, -C(0)NRioRii, -S(0)pR7, -S(0)pOR7, or -S(O)pNR10Rn;
R4 is -H, -OH, an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, an optionally substituted heteraralkyl, hydroxyalkyl, alkoxyalkyl, halo, cyano, nitro, guanidino, a haloalkyl, a heteroalkyl, -C(0)R7, -C(0)OR7, -OC(0)R7, -C(O)NR10Rii, -NR8C(0)R7, -SR7, -S(0)pR7, -OS(0)pR7, -S(0)pOR7, -NR8S(0)pR7, -S(O)pNRi0Rn, or R3 and R4 taken together with the carbon atoms to which they are attached form an optionally substituted cycloalkenyl, an optionally substituted aryl, an optionally substituted heterocyclyl, or an optionally substituted heteroaryl;
R7 and R8, for each occurrence, are, independently, -H, an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, or an optionally substituted heteraralkyl;
Rio and Rn, for each occurrence, are independently -H, an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, or an optionally substituted heteraralkyl; or Ri0 and Rn, taken together with the nitrogen to which they are attached, form an optionally substituted heterocyclyl or an optionally substituted heteroaryl;
Ri5, for each occurrence, is independently, a lower alkyl;
p, for each occurrence, is, independently, 1 or 2; and
m, for each occurrence, is independently, 1, 2, 3, or 4.
2. The method of claim 1 , wherein the Hsp90 inhibitor is selected from the group
consisting of:
3-(2,4-dihydroxyphenyl)-4-(l-ethyl-indol-4-yl)-5-mercapto-[l,2,4]triazole,
3-(2,4-dihydroxyphenyl)-4-(l-isopropyl-indol-4-yl)-5-mercapto-[l,2,4]triazole,
3-(2,4-dihydroxyphenyl)-4-(indol-4-yl)-5-mercapto-[l,2,4]triazole,
3-(2,4-dihydroxyphenyl)-4-(l-methoxyethyl-indol-4-yl)-5-mercapto-[l,2,4]triazole,
3-(2,4-dihydroxy-5-ethyl-phenyl)-4-(l-isopropyl-indol-4-yl)-5-mercapto-[l,2,4]triazole,
3-(2,4-dihydroxyphenyl)-4-(l-dimethylcarbamoyl-indol-4-yl)-5-mercapto-
[l,2,4]triazole,
3-(2,4-dihydroxy-5-ethyl-phenyl)-4-(l-propyl-indol-4-yl)-5-mercapto-[l,2,4]triazole,
3-(2,4-dihydroxy-5-ethyl-phenyl)-4-(l,2,3-trimethyl-indol-5-yl)-5-mercapto-
[l,2,4]triazole,
3-(2,4-dihydroxy-5-ethyl-phenyl)-4-(2,3-dimethyl-indol-5-yl)-5-mercapto- [l,2,4]triazole, 3-(2,4-dihydroxy-5-ethyl-phenyl)-4-(l-acetyl-2 -dimethyl-indol-5-yl)-5-mercapto- [l,2,4]triazole,
3-(2,4-dihydroxy-5-ethyl-phenyl)-4-(l-propyl-2,3-dimethyl-indol-5-yl)-5-mercapto- [l,2,4]triazole,
3-(2,4-dihydroxy-5-ethyl-phenyl)-4-(l-n-butyl-indol-4-yl)-5-mercapto-[l,2,4]triazole, 3-(2,4-dihydroxy-5-ethyl-phenyl)-4-(l-n-pentyl-indol-4-yl)-5-mercapto-[l,2,4]triazole, 3-(2,4-dihydroxy-5-ethyl-phenyl)-4-(l-n-hexyl-indol-4-yl)-5-mercapto-[l,2,4]triazole, 3-(2,4-dihydroxy-5-cyclopropyl-phenyl)-4-(l-(l-methylcyclopropyl)-indol-4-yl)-5- mercapto- [1,2,4] triazole ,
3-(2,4-dihydroxy-5-cyclopropyl-phenyl)-4-(l,2,3-trimethyl-indol-5-yl)-5-mercapto- [l,2,4]triazole,
3-(2,4-dihydroxy-5-ethyl-phenyl)-4-(l-methyl-3-ethyl-indol-5-yl)-5-mercapto- [l,2,4]triazole,
3-(2,4-dihydroxy-5-ethyl-phenyl)-4-(l,3-dimethyl-indol-5-yl)-5-mercapto- [l,2,4]triazole,
3-(2,4-dihydroxy-5-ethyl-phenyl)-4-(l-methyl-3-isopropyl-indol-5-yl)-5-mercapto- [l,2,4]triazole,
3-(2,4-dihydroxy-5-ethyl-phenyl)-4-(l,2-dimethyl-indol-5-yl)-5-mercapto- [l,2,4]triazole,
3-(2,4-dihydroxy-5-ethyl-phenyl)-4-(N-methyl-indol-5-yl)-5-mercapto-[l,2,4]triazole, 3 -(2,4-dihydroxy-5 -isopropyl-phenyl)-4-( 1 , 3 -dimethyl-indol-5 -yl) -5 -mercapto- [l,2,4]triazole,
3-(2,4-dihydroxy-5-cyclopropyl-phenyl)-4-(l,3-dimethyl-indol-5-yl)-5-mercapto- [l,2,4]triazole,
3-(2,4-dihydroxy-5-cyclopropyl-phenyl)-4-(l-methyl-indol-5-yl)-5-mercapto- [l,2,4]triazole,
3-(2,4-dihydroxy-5-isopropyl-phenyl)-4-(lH-indol-5-yl)-5-mercapto-[l,2,4]triazole,
3-(2,4-dihydroxy-5-ethyl-phenyl)-4-(l,2-dimethyl-indol-5-yl)-5-mercapto-
[l,2,4]triazole,
3-(2,4-dihydroxy-5-isopropyl-phenyl)-4-(l -ethyl -indol-5-yl)-5-mercapto-[l,2,4]triazole, and
3-(2,4-dihydroxy-5-isopropyl-phenyl)-4-(l-propyl-indol-5-yl)-5-mercapto- [l,2,4]triazole,
5-hydroxy-4-(5-hydroxy-4-( 1 -methyl- 1 H-indol-5 -yl)-4H- 1 ,2,4-triazol-3 -yl)-2- isopropylphenyl dihydrogen phosphate, sodium 5-hydroxy-4-(5 -hydroxy-4-( 1 -methyl- 1 H-indol-5 -yl)-4H- 1 ,2,4-triazol-3 -yl)-2- isopropylphenyl phosphate,
2-(3,4-dimethoxyphenethyl)-5-hydroxy-4-(5-hydroxy-4-(l-methyl-lH-indol-5-yl)-4H- l,2,4-triazol-3-yl)phenyl dihydrogen phosphate,
5-hydroxy-2-isopropyl-4-(5-mercapto-4-(4-methoxybenzyl)-4H-l,2,4-triazol-3- yl)phenyl dihydrogen phosphate,
5-hydroxy-4-(5-hydroxy-4-(4-methoxybenzyl)-4H-l,2,4-triazol-3-yl)-2-isopropylphenyl dihydrogen phosphate,
4-(4-(l,3-dimethyl-lH-indol-5-yl)-5-hydroxy-4H-l,2,4-triazol-3-yl)-2-ethyl-5- hydroxyphenyl dihydrogen phosphate,
or a tautomer, or a pharmaceutically acceptable salt thereof.
The method of claim 1 , wherein the Hsp90 inhibitor is selected from the group consisting of:
3-(2,4-dihydroxy-5-ethyl-phenyl)-4-(l-isopropyl-7-methoxy-indol-4-yl)-5- mercapto-[ 1,2,4] triazole;
3-(2,4-dihydroxy-5-isopropyl-phenyl)-4-(N-methyl-indol-5-yl)-5-mercapto- [1,2,4] triazole;
3-(2,4-dihydroxy-5-isopropyl-phenyl)-4-(l -methyl -indol-5-yl)-5-hydroxy- [1,2,4] triazole; or a tautomer or pharmaceutically acceptable salt thereof.
The method of claim 1, wherein the Hsp90 inhibitor is 3-(2,4-dihydroxy-5-isopropyl- phenyl)-4-(l-methyl-indol-5-yl)-5-hydroxy-[l,2,4] triazole or a tautomer or a pharmaceutically acceptable salt thereof.
The method of claim 1, wherein the Hsp90 inhibitor is 5-hydroxy-4-(5-hydroxy-4-(l- methyl-lH-indol-5-yl)-4H-l,2,4-triazol-3-yl)-2-isopropylphenyl dihydrogen phosphate, or a tautomer, or a pharmaceutically acceptable salt thereof.
The method of any one of the preceding claims, wherein the subject is human.
The method of any of claims 1-6, wherein the lung adenocarcinoma has an EGFR mutation.
8 The method of any of claims 1-6, wherein the lung adenocarcinoma has a K-ras mutation.
9. The method of any of claims 1-6, wherein the lung adenocarcinoma has an ALK-elm4 translocation.
10. The method of any of claims 1-6, wherein the lung adenocarcinoma has the HER2neu mutation.
11. The method of any of claims 1-6, wherein the lung adenocarcinoma has a B-raf
mutation.
12. The method of any of claims 1-6, wherein the lung adenocarcinoma has a PI3K
mutation.
13. The method of any one of claims 1-6, wherein the lung adenocarcinoma is
bronchioloalveolar carcinoma.
14. The method of claim 13, wherein the brochioloalveolar carcinoma is non-mucinous.
15. The method of claim 13, wherein the brochioloalveolar carcinoma is mucinous.
16. The method of claim 13, wherein the brochioloalveolar carcinoma has a B-raf mutation
17. The method of any of the preceding claims, wherein the lung adenocarcinoma has metastatized or is unresectable.
18. The method of any of the preceding claims, wherein the lung adenocarcinoma is drug resistant.
19. The method of any of the preceding claims, wherein the Hsp90 inhibitor is administered in combination with one or more additional therapeutic agents.
20. The method of claim 19, wherein the one or more therapeutic agents is erlotinib,
bevacizumab, paclitaxel, docetaxel, cisplatin, carboplatin, Abraxane®, pemetrexed, bortezomib, topotecan, cetuximab, gemcitabine and/or tetracycline.
21. The method of claim 20, wherein the one or more therapeutic agents is erlotinib or bevacizumab.
22. The method of claim 20, wherein the one or more therapeutic agents is docetaxel, paclitaxel or Abraxane®.
PCT/US2011/037285 2010-05-20 2011-05-20 Method of treating lung adenocarcinoma with hsp90 inhibitory compounds WO2011146803A1 (en)

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AU2011255438A AU2011255438A1 (en) 2010-05-20 2011-05-20 Method of treating lung adenocarcinoma with Hsp90 inhibitory compounds
CA2810254A CA2810254A1 (en) 2010-09-13 2011-09-13 Hsp90 inhibitors for treating non-small cell lung cancers in wild-type egfr and/or kras patients
JP2013529256A JP2013537229A (en) 2010-09-13 2011-09-13 HSP90 inhibitors for treating non-small cell lung cancer in patients with wild type EGFR and / or KRAS
CN2011800437944A CN103269701A (en) 2010-09-13 2011-09-13 Hsp90 inhibitors for treating non-mall cell lung cancers in wild-<wbr/>type egfr and/or kras patients
PCT/US2011/051320 WO2012037072A1 (en) 2010-09-13 2011-09-13 Hsp90 inhibitors for treating non-small cell lung cancers in wild-type egfr and/or kras patients
AU2011302344A AU2011302344B2 (en) 2010-09-13 2011-09-13 HSP90 inhibitors for treating non-small cell lung cancers in wild-type EGFR and/or KRAS patients
EP11760643.4A EP2616063A1 (en) 2010-09-13 2011-09-13 Hsp90 inhibitors for treating non-small cell lung cancers in wild-type egfr and/or kras patients
US13/231,183 US20120064175A1 (en) 2010-05-20 2011-09-13 HSP90 Inhibitors for Treating Non-Small Cell Lung Cancer in Wild-Type EGFR and/or KRAS Patients

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