NZ616890B2 - Hsp90 inhibitors - Google Patents
Hsp90 inhibitors Download PDFInfo
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- NZ616890B2 NZ616890B2 NZ616890A NZ61689012A NZ616890B2 NZ 616890 B2 NZ616890 B2 NZ 616890B2 NZ 616890 A NZ616890 A NZ 616890A NZ 61689012 A NZ61689012 A NZ 61689012A NZ 616890 B2 NZ616890 B2 NZ 616890B2
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- Prior art keywords
- hsp90
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- 235000015097 nutrients Nutrition 0.000 description 1
- 125000002347 octyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 231100000590 oncogenic Toxicity 0.000 description 1
- 230000002246 oncogenic Effects 0.000 description 1
- 108091008124 oncoproteins Proteins 0.000 description 1
- 102000025475 oncoproteins Human genes 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- 210000000056 organs Anatomy 0.000 description 1
- 125000001715 oxadiazolyl group Chemical group 0.000 description 1
- 125000002971 oxazolyl group Chemical group 0.000 description 1
- QVGXLLKOCUKJST-OUBTZVSYSA-N oxygen-17 Chemical compound [17O] QVGXLLKOCUKJST-OUBTZVSYSA-N 0.000 description 1
- 201000002528 pancreatic cancer Diseases 0.000 description 1
- 230000037361 pathway Effects 0.000 description 1
- 230000035515 penetration Effects 0.000 description 1
- 125000001147 pentyl group Chemical group C(CCCC)* 0.000 description 1
- 238000003359 percent control normalization Methods 0.000 description 1
- 125000005561 phenanthryl group Chemical group 0.000 description 1
- 125000001791 phenazinyl group Chemical group C1(=CC=CC2=NC3=CC=CC=C3N=C12)* 0.000 description 1
- 125000001484 phenothiazinyl group Chemical group C1(=CC=CC=2SC3=CC=CC=C3NC12)* 0.000 description 1
- 125000001644 phenoxazinyl group Chemical group C1(=CC=CC=2OC3=CC=CC=C3NC12)* 0.000 description 1
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 1
- 125000004592 phthalazinyl group Chemical group C1(=NN=CC2=CC=CC=C12)* 0.000 description 1
- 125000004591 piperonyl group Chemical group C(C1=CC=2OCOC2C=C1)* 0.000 description 1
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 1
- 239000011591 potassium Substances 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
- 102000003998 progesterone receptors Human genes 0.000 description 1
- 108090000468 progesterone receptors Proteins 0.000 description 1
- 201000002212 progressive supranuclear palsy Diseases 0.000 description 1
- BDERNNFJNOPAEC-UHFFFAOYSA-N propanol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 description 1
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 230000006432 protein unfolding Effects 0.000 description 1
- 201000000196 pseudobulbar palsy Diseases 0.000 description 1
- 125000001042 pteridinyl group Chemical group N1=C(N=CC2=NC=CN=C12)* 0.000 description 1
- GTBORZCYFKUESX-UHFFFAOYSA-N purin-6-amine Chemical compound NC1=NC=NC2=NC=N[C]12 GTBORZCYFKUESX-UHFFFAOYSA-N 0.000 description 1
- 125000000561 purinyl group Chemical group N1=C(N=C2N=CNC2=C1)* 0.000 description 1
- 125000004309 pyranyl group Chemical group O1C(C=CC=C1)* 0.000 description 1
- 125000003373 pyrazinyl group Chemical group 0.000 description 1
- 125000001725 pyrenyl group Chemical group 0.000 description 1
- 125000002098 pyridazinyl group Chemical group 0.000 description 1
- 125000000168 pyrrolyl group Chemical group 0.000 description 1
- 125000002294 quinazolinyl group Chemical group N1=C(N=CC2=CC=CC=C12)* 0.000 description 1
- 125000005493 quinolyl group Chemical group 0.000 description 1
- 125000001567 quinoxalinyl group Chemical group N1=C(C=NC2=CC=CC=C12)* 0.000 description 1
- 230000002285 radioactive Effects 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- 238000000611 regression analysis Methods 0.000 description 1
- 229960004889 salicylic acid Drugs 0.000 description 1
- 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 125000003548 sec-pentyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 101700069804 sec72 Proteins 0.000 description 1
- 230000035939 shock Effects 0.000 description 1
- 231100000486 side effect Toxicity 0.000 description 1
- 229910052709 silver Inorganic materials 0.000 description 1
- 239000004332 silver Substances 0.000 description 1
- BQCADISMDOOEFD-UHFFFAOYSA-N silver Chemical compound [Ag] BQCADISMDOOEFD-UHFFFAOYSA-N 0.000 description 1
- 238000003530 single readout Methods 0.000 description 1
- KEAYESYHFKHZAL-UHFFFAOYSA-N sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 150000003431 steroids Chemical class 0.000 description 1
- 201000011549 stomach cancer Diseases 0.000 description 1
- 125000005017 substituted alkenyl group Chemical group 0.000 description 1
- 125000000547 substituted alkyl group Chemical group 0.000 description 1
- 125000004426 substituted alkynyl group Chemical group 0.000 description 1
- 125000003107 substituted aryl group Chemical group 0.000 description 1
- 125000005346 substituted cycloalkyl group Chemical group 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 239000000758 substrate Substances 0.000 description 1
- 239000001384 succinic acid Substances 0.000 description 1
- LSNNMFCWUKXFEE-UHFFFAOYSA-N sulfonic acid Chemical compound OS(O)=O LSNNMFCWUKXFEE-UHFFFAOYSA-N 0.000 description 1
- NINIDFKCEFEMDL-UHFFFAOYSA-N sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 description 1
- 239000011593 sulfur Substances 0.000 description 1
- 230000001629 suppression Effects 0.000 description 1
- 230000004083 survival Effects 0.000 description 1
- 201000010874 syndrome Diseases 0.000 description 1
- 201000003356 synucleinopathy Diseases 0.000 description 1
- 125000006253 t-butylcarbonyl group Chemical group [H]C([H])([H])C(C(*)=O)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 239000011975 tartaric acid Substances 0.000 description 1
- 235000002906 tartaric acid Nutrition 0.000 description 1
- 229960001367 tartaric acid Drugs 0.000 description 1
- 125000001973 tert-pentyl group Chemical group [H]C([H])([H])C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 150000004685 tetrahydrates Chemical class 0.000 description 1
- 125000001712 tetrahydronaphthyl group Chemical group C1(CCCC2=CC=CC=C12)* 0.000 description 1
- 125000003831 tetrazolyl group Chemical group 0.000 description 1
- 238000002560 therapeutic procedure Methods 0.000 description 1
- 125000004495 thiazol-4-yl group Chemical group S1C=NC(=C1)* 0.000 description 1
- 125000000335 thiazolyl group Chemical group 0.000 description 1
- 125000001544 thienyl group Chemical group 0.000 description 1
- 230000001732 thrombotic Effects 0.000 description 1
- 229910052718 tin Inorganic materials 0.000 description 1
- 239000011135 tin Substances 0.000 description 1
- ATJFFYVFTNAWJD-UHFFFAOYSA-N tin hydride Chemical compound [Sn] ATJFFYVFTNAWJD-UHFFFAOYSA-N 0.000 description 1
- 125000003944 tolyl group Chemical group 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- 125000004306 triazinyl group Chemical group 0.000 description 1
- 125000001425 triazolyl group Chemical group 0.000 description 1
- 125000004953 trihalomethyl group Chemical group 0.000 description 1
- 150000004684 trihydrates Chemical class 0.000 description 1
- 229910052722 tritium Inorganic materials 0.000 description 1
- 201000004810 vascular dementia Diseases 0.000 description 1
- 239000003981 vehicle Substances 0.000 description 1
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 description 1
- 101700042284 yqxD Proteins 0.000 description 1
- HCHKCACWOHOZIP-UHFFFAOYSA-N zinc Chemical compound [Zn] HCHKCACWOHOZIP-UHFFFAOYSA-N 0.000 description 1
- 229910052725 zinc Inorganic materials 0.000 description 1
- 239000011701 zinc Substances 0.000 description 1
Classifications
-
- 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
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
- A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
- A61K31/52—Purines, e.g. adenine
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
- A61P25/16—Anti-Parkinson drugs
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
- A61P35/02—Antineoplastic agents specific for leukemia
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D473/00—Heterocyclic compounds containing purine ring systems
- C07D473/26—Heterocyclic compounds containing purine ring systems with an oxygen, sulphur, or nitrogen atom directly attached in position 2 or 6, but not in both
- C07D473/32—Nitrogen atom
- C07D473/34—Nitrogen atom attached in position 6, e.g. adenine
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D473/00—Heterocyclic compounds containing purine ring systems
- C07D473/40—Heterocyclic compounds containing purine ring systems with halogen atoms or perhalogeno-alkyl radicals directly attached in position 2 or 6
Abstract
The disclosure relates to purine derivative compounds as inhibitors of Heat Shock Protein 90 (HSP90) of general Formula (1), wherein the substituents are as described in the specification. Compositions comprising an effective amount of a Compound of Formula (1) or a pharmaceutically acceptable salt thereof, and methods to treat or prevent a condition, such as cancer which overexpresses Her-kinases, comprising administering to an patient in need thereof a therapeutically effective amount of a Compound of Formula (1) or a pharmaceutically acceptable salt thereof. thereof, and methods to treat or prevent a condition, such as cancer which overexpresses Her-kinases, comprising administering to an patient in need thereof a therapeutically effective amount of a Compound of Formula (1) or a pharmaceutically acceptable salt thereof.
Description
This application claims the benefit of and priority from US provisional application no.
61/472,061, filed April 5, 2011, the contents of which are incorporated herein by reference.
1. BACKGROUND
This application relates to compounds that inhibit heat shock n 90 (Hsp90).
The Hsp90 family of proteins has four recognized members in ian cells: Hsp90 CL
and B, Grp94 and Trap—l. Hsp90 CL and [3 exist in the cytosol and the nucleus in association with a
number of other proteins. Hsp90 in its various forms is the most abundant cellular chaperone, and
has been shown in experimental systems to be required for ATP-dependent refolding of denatured
or ded'I proteins. It has therefore been proposed to function as part of the cellular defense
against stress. When cells are exposed to heat or other environmental stresses, the aggregation of
unfolded proteins is prevented by pathways that catalyze their refolding or degradation. This
s s on the association of the unfolded protein in an ordered fashion with multiple
chaperones (Hsp60, Hsp90, Hsp70 and p23), forming a "refoldosome" and ultimately the ATP—
dependent release of the chaperones from the refolded protein.
Hsp90 can also play a role in maintaining the stability and function of mutated proteins. It
seems to be required for expression of mutated p53 and V—src to a much r extent than for their
2O Wild—type counterparts. It has been suggested that this occurs as a result of Hsp90—mediated
suppression of the phenotypes of mutations that lead to protein unfolding.
Hsp90 is also necessary to the mational maturation of several key proteins involved
in the growth response of the cell to extracellular factors. These include the steroid receptors as
well as certain kinases (i.e., Raf serine kinase, V—src and Her2). The mechanism whereby Hsp90
affects these proteins is not fully understood, but appears to be similar to its role in protein
ing. In the case of the progesterone receptor, it has been shown that binding and e of
Hsp90 from the receptor occurs in a cyclic fashion in concert with release of other chaperones and
immunophilins and is ed for high affinity binding of the steroid to the receptor. Thus, Hsp90
could function as a physiologic regulator of signaling pathways, even in the absence of stress.
Hsp90 has been shown to be overexpressed in multiple tumor types and as a function of
oncogenic transformation. Whether it plays a ary role in maintaining ormation is
unknown, but it could have at least three ons in this regard. Cancer cells grow in an
environment of hypoxia, low pH and low nutrient tration. They also rapidly adapt to or are
selected to become resistant to radiation and cytotoxic chemotherapeutic agents. Thus, the general
role of Hsp90 in maintaining the stability of ns under stress may be necessary for cell viability
under these conditions. Secondly, cancer cells harbor mutated oncogenic proteins. Some of these
are gain—of-function mutations which are necessary for the transformed phenotype. Hsp90 may be
required for ining the folded, functionally-active conformation of these proteins. y,
tion of signaling pathways mediated by steroid receptors, Raf and other Hsp90 targets is
necessary for the growth and survival of many tumors which thus probably also require onal
Hsp90.
Hsp90 has been recognized as a viable target for eutic agents. Hsp90 family
members possess a unique pocket in their N—terminal region that is specific to and conserved
among all Hsp905 from bacteria to mammals, but which is not t in other molecular
chaperones. The endogenous ligand for this pocket is not known, but it binds ATP and ADP with
low affinity and has weak ATPase activity. The ansamycin antibiotics geldanamycin (GM) and
herbimycin (HA) have been shown to bind to this conserved pocket, and this binding ty has
been shown for all members of the Hsp90 . International Patent Publication No.
WO98/51702 discloses the use of ansamycin antibiotics coupled to a targeting moiety to provide
targeted delivery of the ansamycin leading to the degradation of proteins in and death of the
targeted cells. International Patent Publication No, WOOO/61578 s to bifunctional molecules
having two moieties which interact with the chaperone protein Hsp90, including in particular
homo- and heterodimers of ansamycin antibiotics. These bifunctional molecules act to promote
ation and/or inhibition of HER—family tyrosine kinases and are effective for treatment of
cancers which press Her—kinases.
Exemplary small molecule therapeutics that bind to the same binding pocket of Hsp90 as
ATP and the ansamycin antibiotics are disclosed in PCT Publication Nos. W002/36075,
W02006/084030, W02009/042646, W02009/065035, and W02011/044394; US. Patent No.
7,834,181; and US. Patent Publication Nos. 2005/0113339, 2005/0004026, 2005/0049263,
2005/0256183, 2005/0119292, 2005/0113340, 2005/0107343, 2008/0096903, 234297,
2008/0234314, 2008/0253 865, and 2009/0298857, all of which are incorporated herein by
reference.
In particular, certain small molecule therapeutics that bind to the same binding pocket of
Hsp90 can be described by the following general ural formula where Z1, 22, and Z3 are
selected from CH and N:
NH2 X2 Xd
AerY >33
R Xe Xb
While these compounds can be active as inhibitors of Hsp90, their level of activity is extremely
variable with measured values for ECso and IC50 being reported in anywhere from the micromolar
to nanomolar ranges.
2. SUMlVIARY
In one aspect of the disclosure, new compounds that inhibit Hsp90 are described.
A compound of a (1):
NH2 X2
21 \ Z\
A / Y >58
X4 Z2 N :Xc
. R Xb (1)
or a pharmaceutically able salt thereof, wherein:
(a) each of 21, Z2 and 23 is independently CH or N;
(b) Y is S;
(c) Xa and Xb are 0;
(d) Xc is —CH2-;
(e) X2 is -NR1R2, wherein R1 and R2 are each independently H, C1-C6 alkyl, C2-C6 alkenyl,
C2-C6 alkynyl, cycloalkyl, heteroalkyl, heterocycloalkyl, aryl, aryl, alkylaryl,
arylalkyl, alkylheteroaryl, heteroarylalkyl, or alkylheteroarylalkyl;
(i) X; is hydrogen or halogen; and
(g) R is Rlo-NH-RH wherein R10 is ethylene or ene, and R11 is a branched alkyl.
The compounds are useful in ceutical compositions for the treatment of
cancer and neurodegenerativer diseases through their activity as Hsp90 inhibitors and can
be used in a method of treating cancer or neurodegenerative diseases.
3. DETAILED DESCRIPTION
The invention includes the following:
(1) A Compound of Formula (1):
NH2 x2
Z1 \ \
A / Y )sa
X4 Z2 N
\ 'Xc
R Xb (1)
or a pharrnaceutically able salt thereof, wherein:
(a) each of Z], Zz and Z3 is independently CH or N;
(b) Y is S;
(c) Xa and Xb are 0;
(d) X is —CH2.;
(e) X2 is -NR1R2, n R1 and R2 are each independently H, C1-C6 alkyl, C2-C6 alkenyl, C2-
C5 alkynyl, cycloalkyl, heteroalkyl, heterocycloalkyl, aryl, heteroaryl, alkylaryl, kyl,
alkylheteroaryl, heteroarylalkyl, or alkylheteroarylalkyl, or a protonated form thereof;
(f) X4 is hydrogen or halogen; and
(g) R is -R10-NH-R11 n R10 is ethylene or propylene, and R11 is a branched alkyl.
(2) Compounds of (1) in which Z1, 22 and Z3 are all N as shown in formula (2)
)L / N\: Y
X4 N N\ J
R o
or a pharmaceutically acceptable salt thereof,.
(3) Compounds of (1) or (2) or a phannaceutically acceptable salt thereof in which R11 is
neopentyl, isopropyl or l.
(4) Compounds of one of the above (1) to (3) or a pharmaceutically acceptable salt thereof
in which X2 is dimethylamine.
(5) A pharmaceutical composition comprising the compound as in one of the above (1) to
(5) or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.
(6) A method for treating or preventing cancer or a neurodegenerative disorder, comprising
stering to a patient in need thereof a therapeutically effective amount of a compound as in one of
the above (1) to (5) or a pharmaceutically acceptable salt thereof.
(7) Use of a compound as in one of the above (1) to (5) or a pharmaceutically acceptable salt
thereof in ating a ceutical ition for the treatment or prevention of cancer or a
neurodegenerative disorder.
(8) A method for the inhibition of Hsp90, comprising contacting Hsp90 with an Hsp90
function inhibiting amount of a compound as in one of the above (1) to (5) or a pharmaceutically
acceptable salt thereof.
(9) Use of a compound as in one of the above (1) t0 (5) or a pharmaceutically acceptable salt
thereof in formulating a pharmaceutical composition for the inhibition of Hsp90.
As stated above, the disclosure encompasses Compounds of Formula (1):
NH2 x2
Z1 \ \
A / Y
N )\(a
X4 22 \ IXC
R Xb (1)
or a pharmaceutically acceptable salt thereof, wherein:
(a) each of 21, Zz and Z3 is independently CH or N;
(b) Y is S;
(c) Xa and Xb are 0;
(d) X0 is —CH2.
(e) X2 is —NR1R2, wherein R1 and R2 are each independently H, C1-C6 alkyl, C2-C6 l, C2-
C6 alkynyl, cycloalkyl, alkyl, heterocycloalkyl, aryl, heteroaryl, alkylaryl, ary1a1ky1,
alkylheteroaryl, arylalkyl, or alkylheteroarylalkyl, or a protonated form thereof;
(f) X4 is hydrogen or halogen; and
(g) R is -R10—NH-R11 wherein R10 is ne or propylene, and R11 is a branched alkyl.
ions
As used in tion with the present disclosure, the terms used herein have the ing
meaning:
The terms "alkyl" and "substituted alkyl" are interchangeable unless otherwise ically
noted and refer to substituted and unsubstituted CFC“) straight-chain saturated aliphatic hydrocarbon
groups, i.e., groups having 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 carbon atoms, and substituted and unsubstituted
C3—C10 branched saturated aliphatic hydrocarbon groups, i. 6., groups having 3, 4, 5, 6, 7, 8, 9, or 10
carbon atoms. For example, "alkyl" includes but is not limited to: methyl (Me), ethyl (Et), propyl (Pr),
isopropyl, butyl (Bu), tert-butyl, pentyl, hexyl, heptyl, octyl, nonyl, decyl, and the like. In one
embodiment, an alkyl is a C1—C6 alkyl, i.e., a group having 1, 2, 3, 4, 5, or 6 carbon atoms. An alkyl
can be substituted with 1, 2, 0r 3 substituents or optionally substituted with l, 2, or 3 substituents.
Illustrative es of tuted C1—C6 alkyl groups include -CHZOH, -CFZOH, —
CH2C(CH3)2C(O)OCH3, —CF3, F3, -C(O)CH3, —(CH2)4SCH3, -
CH(C(O)OH)CH2CH2C(O)N(CH3)2, —(CH2)5NHC(O)NH2, —CH2CH2~(4-fluorophenyl), —
CH(OCH3)CH2CH3, -CH2802NH2, and ~CH(CH3)CH2CHZOC(O)CH3. The term “branched alkyl”
encompasses alkyl groups that are linear alkyl groups attached through a non-terminal carbon atom as
well as alkyl groups that include a defined branch point. Illustrative examples of ed alkyl groups
thus include isopropyl, isobutyl, sec—butyl, l, isopentyl, sec-pentyl, t-pentyl, and neopentyl
groups. The terms "alkenyl" and ”substituted alkenyl" are interchangeable unless otherwise specifically
noted and refer to substituted and unsubstituted QC ,0 straight—chain aliphatic hydrocarbon groups
having 1, 2, or 3 carbon-carbon double bonds, 1'. 6., groups having 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 carbon
atoms, and substituted and unsubstituted C3—C 10 branched aliphatic hydrocarbon groups having 1, 2, or
3 carbon-carbon double bonds, Le.
, groups having 3, 4, 5, 6, 7, 8, 9, or 10 carbon atoms. For example,
"alkenyl" includes but is not limited to: ethenyl, l—prop—l-enyl, 1—prop—2-enyl, 2—prop—l—enyl, l—but-3—
enyl, 2-pentenyl, l-hexenyl, l-heptenyl, l-octenyl, and the like. In one embodiment, an
alkenyl is a C2-C6 alkenyl, i.e., a group having 2, 3, 4, 5, or 6 carbon atoms and 1 or 2 carbon-carbon
double bonds. An l can be substituted with 1, 2, or 3 substituents or optionally substituted with
1, 2, or 3 substituents. rative examples of substituted C2-C6 l groups include —
C(H)=CHCHZOH, -C(H)=CF2, -CH2C(H)=CH(CH2)2CF20H, —CH2C(=CH2)C(O)OCH3, —
C(H)=CHCF3, -CH2CH2C(H):CHC(O)CH3, -C(H)=C(CH3)SCH3, —C(H)=CHC(H)=C(CH3)C(O)OCH3,
and C=CHOC(O)CH3.
The terms "alkynyl" and "substituted alkynyl“ are interchangeable unless otherwise specifically
noted and refer to substituted and tituted C2—C10 straight-chain aliphatic hydrocarbon groups
having I, 2, or 3 carbon-carbon triple bonds, i.e., groups having 1,2, 3, 4, 5, 6, 7, 8, 9, or 10 carbon
atoms, and tuted and unsubstituted C3—C10 branched aliphatic hydrocarbon groups having 1, 2, or
3 carbon-carbon triple bonds, i.e., groups having 3, 4, 5, 6, 7, 8, 9, or 10 carbon atoms. For example,
"alkynyl" includes but is not limited to: ethynyl, 1—prop-l-ynyl, 1-propynyl, 2-propynyl, 3-prop-
1-ynyl, l—but—3—ynyl, 2—pent-2—ynyl, 6—ynyl, l-hept—7-ynyl, 1—oct-8ynyl, and the like. In one
embodiment, an alkynyl is a C2-C6 alkynyl, i.e., a group having 2, 3, 4, 5, or 6 carbon atoms and 1 or 2
-carbon triple bonds. An alkynyl can be substituted with l, 2, or 3 substituents or optionally
substituted with 1, 2, or 3 substituents. Illustrative examples of substituted C2-C6 alkynyl groups
include -CECCH20H, —CECF, -CH2CEC(CH2)2CFZOH, —CECCH2C(O)OCH3, -CH2CECCF3, —
CH2CH2CECC(O)CH3, —CECSCH3, and -CECC(O)OC(O)CH3.
The terms "cycloalkyl" and "substituted cycloalkyl" are interchangeable unless ise
specifically noted and refer to a mono- or multi-ringed carboeycle wherein each ring contains 3, 4, 5, 6,
7, 8, 9, or 10 carbon atoms, and wherein any ring can contain 1, 2, or 3 carbon—carbon double or triple
bonds. For example, "cycloalkyl" includes but is not limited to: cyclopropyl, cyclobutyl, cyclopentyl,
cyclohexyl, cycloalkenyl, cycloalkynyl, and cycloheptyl. A lkyl can be tuted with l, 2, or
3 substituents or optionally substituted with 1, 2, or 3 tuents.
The terms "ary " and "substituted aryl" are interchangeable unless otherwise specifically noted
and refer to a monocyclic, clic, biaryl aromatic groups covalently attached at any ring position
capable of forming a stable covalent bond, certain red points of attachment being apparent to
those in the art (e.g., 3-phenyl, 4-naphthyl, and the like). An aryl can be substituted with l, 2, or 3
substituents or ally substituted With l, 2, or 3 substituents. The definition of "aryl“ includes but
is not limited to heteroaryl. Illustrative examples of aryl groups include phenyl, biphenyl, naphthyl,
onaphthyl, tetrahydronaphthyl, indenyl, indanyl, azulenyl, anthryl, phenanthryl, fluorenyl,
pyrenyl, anthracenyl, pyridyl, pyrimidyl, pyridizinyl, thiadiazolyl, and the like.
The term "heteroalkyl" refers to an alkyl group where one or more of the carbon atoms or
hydrogen atoms present is replaced, independently, with a nitrogen, oxygen, , or halogen
heteroatom. If the heteroatom does not have the same number of valence sites as the carbon atom it
replaces, the number of ens bonded to the replacement heteroatom may need to be sed or
decreased to match the number of valence sites of the heteroatom. For example, if a carbon atom (with
a valence of four) is replaced by a en atom (valence of three), one of the hydrogen atoms
formerly attached to the replaced carbon is deleted. Likewise, if a carbon atom is replaced by a
halogen atom (valence of one), three of the hydrogen atoms formerly attached to the replaced carbon is
deleted. The term "heteroalkyl" also refers to (I) an alkyl group where at least one of the hydrogen
atoms attached to a carbon or (2) to a heteroalkyl group where at least one of the hydrogen atoms
attached to a heteroatom of the heteroalkyl can be substituted with at least one of the following: alkyl,
aryl, and alkyl.
The terms "heteroaryl" and "substituted heteroaryl" are interchangeable unless ise
specifically noted and the terms "heterocyclo" and "substituted heterocyclo" are hangeable unless
otherwise specifically noted and these terms refer to a monovalent unsaturated group having a single
ring or multiple condensed rings, from 1 to 8 carbon atoms, and from 1 to 4 heteroatoms within the
ring, each heteroatom being independently selected from nitrogen, sulfur, or oxygen. In either
heteroaryl or heterocyclo, the point of attachment to the molecule can be at a heteroatom or ere
Within the ring. A heteroaryl or heterocyclo can be substituted with l, 2, or 3 substituents or optionally
substituted with l, 2, or 3 substituents,
Illustrative examples of heteroaryl groups include thienyl, benzothienyl, isobenzothienyl, 2,3—
dihydrobenzothienyl, furyl, pyranyl, benzofuranyl, isobenzofuranyl, 2,3-dihydrobenzofuranyl, yl,
pyrrolyl, pyrrol-l-yl, indolyl, isoindolyl, 3H-indolyl, indolinyl, indolizinyl, indazolyl, imidazolyl,
imidazol—4-yl, 2H—imidazolinyl, benzimidazolyl, pyridyl, pyrazinyl, pyradazinyl, pyrimidinyl,
din—Z-yl, triazinyl, quinolyl, isoquinolyl, 4H—quinolizinyl, inyl, phthalazinyl, quinazolinyl,
quinoxalinyl, 1,8—naphthyridinyl, pteridinyl, carbazolyl, nyl, phenazinyl, phenothiazinyl,
phenoxazinyl, chromanyl, benzodioxolyl, piperonyl, purinyl, pyrazolyl, pyrazolyl, triazolyl, 1,2,4—
triazol— l -yl, tetrazolyl, tetrazol-l -yl, thiazolyl, thiazol—4—yl, azolyl, benzthiazolyl, oxazolyl,
oxazol—Z—yl, isoxazolyl, isoxazol-3—yl, benzoxazolyl, oxadiazolyl, 1,2,4-oxadiazol-3—yl, thiadiazolyl,
pyridazinyl, pyrazin—Z—yl, thiophen—Z-yl, furan—Z—yl, n—Z—yl, n—4—yl, pyrimidin—Z—yl, and
the like.
When any group is substituted with l, 2, or 3 substituents or optionally substituted with l, 2, or
3 substituents, each tuent is independently selected from the group comprising halo, —OH, —SH, —
CN, —NOz,—NH2, trihalomethyl, pentahaloethyl, C1—C10alkyl, arleO—Cloalkyl, C0-CloalkyloxyC0—
Cloalkyl, arleo-C loalkyloxyCo-Cmalkyl, alkylthioCo-Cmalkyl, arleo-C loalkylthioCo-C loalkyl,
Co-CmalkylaminoCO—Cloalkyl, arleo—C1oalkylaminoCO-Cmalkyl, N—aryl—N—Co—CIoalkylarninoCo-
Cloalkyl, C1—Cwalkylcarbonleo-Cwalkyl, arle1—C10alkylcarbonleo—Cloalkyl, C1-C10alkylcarboxyCo-
Cloalkyl, arle1—C10alkylearboxyCO—C malkyl, C1-CmalkylcarbonylaminoCO-Cloalkyl, arle1~
CloalkylcarbonylaminoCo-Cmalkyl, ~Co-C10alkle(O)ORX, and -CO—C10alkle(O)NRsz wherein Rx,
Ry and Rz are independently selected from en, alkyl, and aryl or RY and RZ are taken together
with the nitrogen to which they are attached to form a saturated cyclic or unsaturated cyclic system
having 3, 4, 5, 6, 7, or 8 carbon atoms with at least one substituent as defined above. A "Coalkyl," as in
C0—C10alkyl, is a covalent bond.
The term "Co—Cloalkyloxy" refers to an alkyl group having the indicated number of carbon
atoms and attached to the molecule through an oxygen atom. In one embodiment, a C0—C10alkyloxy is a
lkyloxy, i.e., a group having 1, 2, 3, 4, 5, or 6 carbon atoms. Illustrative examples of alkyloxy
groups include methoxy, ethoxy, n—propyloxy, and isopropyloxy. Thus, the term "C0—C10alkyloxyC0-
Cloalkyl" refers to a C0—C10alkyloxy attached through an oxygen atom to a C0-C10alky1 which is
ed to the molecule. Likewise, the term "arleg—CwalkyloxyCO—Cmalkyl" refers to a C0-
Cloalkyloxy, which is substituted by aryl, attached through an oxygen atom to a C0—Cmalkyl which is
attached to the molecule. A "Coalkyloxy" is -OH.
The term "Co-Cloalkylthio" refers to an alkyl group having the indicated number of carbon
atoms and attached to the molecule through a sulfur atom. In one embodiment, a C0-C10alkylthio is a
C1—C6alkylthio, i.e., a group having 1, 2, 3, 4, 5, or 6 carbon atoms. Illustrative examples of alkyloxy
groups include methylthio, ethylthio, n-propylthio, and isopropylthio. Thus, the term "C0-
lthioCO—Cloalkyl" refers to a C0—C10alkylthio attached through a sulfur atom to a C0—C10alkyl
which is attached to the molecule. Likewise, the term —Cwall<ylthioCo-C10alkyl" refers to a CO—
Cmalkylthio, which is substituted by aryl, attached through a sulfur atom to a C0-C10alkyl which is
attached to the molecule. A "Coalkylthio" is —SH.
The term "C1—C10alkylcarbonyl" refers to an alkyl group having the indicated number of carbon
atoms and attached to the molecule through the carbon atom of a yl group. In one embodiment,
a C1—C10alkylcarbonyl is a C1-C6alkylcarbonyl, i.e., a group having 1, 2, 3, 4, 5, or 6 carbon atoms,
including the carbonyl carbon atom. Thus, the term "C1~Cloalkylcarbonle0-Cloalkyl" refers to a C]—
Cloalkylcarbonyl attached through the carbon atom of a yl group to a C0—C10alkyl which is
ed to the molecule. Likewise, the term "arle1-C10alkylcarbonleo—Cloalkyl" refers to a C1-
Cloalkylcarbonyl, which is tuted by aryl, ed through the carbon atom of a carbonyl group to
a C0-C10alkyl which is attached to the molecule.
The term "C1—C10alkylcarboxy" refers to an alkyl group having the indicated number of carbon
atoms, including the carboxy's carbon atom, and attached to the molecule through the carboxy group,
wherein the y group has either a —O- or a —O-C(=O)- orientation. In one embodiment, a
C1-C10alkylcarboxy is a C1—C6alkylcarboxy, 126., a group having 2, 3, 4, 5, or 6 carbon atoms, including
the carboxy's carbon atom. Thus, the term "CI-CloalkylcarboxyCO-Cwalkyl" refers to a C1-
Cmalkylcarboxy attached through the y group to a C0—C10alky1 which is attached to the molecule.
se, the term "arle1-C1oalkylcarboxyCo—Cwalkyl" refers to a C1-Cmalkylcarboxy, which is
substituted by aryl, ed through the carboxy group to a C0—C10a1kyl which is attached to the
molecule.
The term "Co—Cmalkylamino” refers to an alkyl group having the indicated number of carbon
atoms and attached to the molecule through the nitrogen atom of the amino group -N(Rw)—, wherein Rw
is H, C1-C6alkyl, or aryl. A "Coalkylamino" is -NHRW. In one embodiment, a C0-C10alkylamino is a
C1-C6alkylamino, i.e., a group having 1, 2, 3, 4, 5, or 6 carbon atoms in the alkyl group and O, 1, 2, 3, 4,
, or 6 carbon atoms in the Rw group. Thus, the term "CO-CmalkylaminoCO—Cmalkyl" refers to a CO-
Cloalkylamino attached through the nitrogen atom of an amino group to a C0—C10alkyl which is attached
to the molecule. Likewise, the term "arleo-CloalkylaminoCo-Cloalkyl" refers to a C0—C10alkylamino,
which is substituted by aryl, attached through the nitrogen atom of an amino group to a C0-C10alky1
which is attached to the molecule. The term "N—aryl—N—Co-CloalkylaminoCo—Cloalkyl" refers to an
amine nitrogen atom substituted by aryl and C0-Cloa1kyl, that nitrogen atom being further attached to a
C0—Cloalkyl which is attached to the molecule.
The term "C1-C10alkylcarbonylamino" refers to an alkyl group having the indicated number of
carbon atoms, including the carbonylamino's (i.e., s) carbon atom, and attached to the molecule
through the amide, group, wherein the amide group has either a -C(=O)N(RV)- or a C(=O)-
orientation and n RV is H or C1—C6alkyl. In one embodiment, a alkylcarbonylamino is a
C1—C6alkylcarbonylamino, i.e., a group having 2, 3, 4, 5, or 6 carbon atoms, including the amide's
carbon atom, in the alkyl group and 0, 1, 2, 3, 4, 5, or 6 carbon atoms in the RV group. Thus, the term
"C1-CloalkylcarbonylaminoCo—Cloalkyl" refers to a C1-Cloalkylcarbonylamino attached h the
amide group to a C0-C10alkyl which is attached to the molecule. Likewise, the term "arlel—
CloalkylcarbonylaminoCo—Cloalky " refers to a C1—C10alkylcarbonylamino, which is tuted by aryl,
attached through the amide group to a C0-C10alkyl which is attached to the molecule.
The term "alkylaryl" refers to an aryl group as defined above that is substituted with l, 2, or 3
alkyl groups as defined above; a tolyl group is an exemplary ryl. In one embodiment, an
alkylaryl group is a "lower alkylaryl" group having 1, 2, or 3 alkyl groups attached to an aryl group,
each alkyl group having, independently, l, 2, 3, 4, 5, or 6 carbon atoms.
The term "arylalkyl" refers to an alkyl group as defined above that is substituted with l, 2, or 3
aryl groups as defined above; a benzyl group is an exemplary arylalkyl. In one embodiment, an
arylalkyl group is a "lower arylalkyl" group having 1, 2, or 3 aryl groups attached to an alkyl group
having 1, 2, 3, 4, 5, or 6 carbon atoms.
The term "heterocycloalkyl" refers to an alkyl group as defined above that is substituted with 1,
2, or 3 heterocyclo groups as defined above. In one embodiment, a heterocycloalkyl group is a "lower
heterccycloalkyl" group having 1, 2, or 3 heterocyclo groups attached to an alkyl group having 1, 2, 3,
4, 5, or 6 carbon atoms.
The term heteroaryl" refers to a heteroaryl group as defined above that is substituted with
l, 2, or 3 alkyl groups as defined above. In one embodiment, a alkylheteroaryl group is a "lower
alkylheteroaryl" group having 1, 2, or 3 alkyl groups attached to a heteroaryl group, each alkyl group
having, independently, l, 2, 3, 4, 5, or 6 carbon atoms.
The term "heteroarylalkyl" refers to an alkyl group as defined above that is substituted with 1,
2, or 3 heteroaryl groups as defined above. In one embodiment, a heteroarylalkyl group is a "lower
heteroarylalkyl" group having 1, 2, or 3 heteroaryl groups attached to an alkyl group having 1, 2, 3, 4,
, or 6 carbon atoms.
The term "alkylheteroarylalkyl" refers to a arylalkyl group as defined above that is
substituted With 1, 2, or 3 alkyl groups as defined above. In one embodiment, an alkylheteroarylalkyl
group is a "lower alkylheteroarylalkyl" group with each alkyl portion having, independently, 1, 2, 3, 4,
, or 6 carbon atoms.
The terms "halogen" and "halo" refer to fluorine, chlorine, bromine, and iodine.
Should there be doubt as to the agreement of a depicted chemical ure and a chemical
name, the depicted chemical structure governs.
The term "pharmaceutically acceptable salt" refers to those salts which retain the biological
effectiveness and properties of the "free" compounds of Formula ( 1)
. A ceutically acceptable
salt can be obtained from the on of the free base of a Compound of a (1) with an nic
acid, for example, hloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and
the like, or an organic acid, for example, sulfonic acid, carboxylic acid, organic phosphoric acid,
methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, citric acid, fumaric acid, maleic acid,
succinic acid, benzoic acid, salicylic acid, lactic acid, tartaric acid (e.g., (+)-tartaric acid or (—)—tartaric
acid or es thereof), and the like. Certain compounds of Formula (1) have acidic substituents and
can exist as pharmaceutically acceptable salts with pharmaceutically acceptable bases. The present
disclosure includes such salts. Examples of such salts include metal counterion salts, such as sodium,
potassium, lithium, magnesium, calcium, iron, copper, zinc, tin, silver, or aluminum salts, and c
amine salts, such as methylamine, dimethylamine, hylamine, lamine, triethylamine, n—
propylamine, 2—propylamine, or dimethylisopropylamine salts, and the like. The term
"pharmaceutically able salt" includes mono-salts and compounds in which a plurality of salts is
present, e.g., di-salts and/or tri—salts. Pharmaceutically acceptable salts can be prepared by methods
known to those in the art.
Certain compounds of Formula (1) and/or their pharmaceutically acceptable salts can exist in
more than one crystal form and the t disclosure encompasses each crystal form and es
thereof. These crystal forms can be prepared by methods known to those in the art.
The term "solvate" refers to a complex or aggregate formed by one or more molecules of a
solute, e.g., a Compound of Formula (1) or its ceutically acceptable salt, and one or more
molecules of a solvent, which is present in stoichiometric or non-stoichiometric amount. Suitable
solvents include but are not limited to water, acetic acid, ethanol, methanol, isopropanol, and n-
propanol. Where the solvent is water, the solvate is a hydrate. Exemplary hydrates include but are not
limited to a hemihydrate, a monohydrate, a dihydrate, a trihydrate, and a tetrahydrate. In one
embodiment, the solvent is pharmaceutically able. In another embodiment, the complex or
ate is in a crystalline form. In another ment, the complex or ate is in a
stalline form. The present disclosure encompasses each solvate and mixtures thereof. These
solvates can be prepared by methods known to those in the art.
Certain compounds of a (1) may exist in different tautomeric forms or as different
geometric isomers, and the t disclosure es each tautomer and/or geometric isomer of
compounds of Formula (1) and es thereof.
2O Certain compounds of Formula (I) may contain one or more chiral centers and exist in
different optically active forms, and the present disclosure includes each lly active form of
compounds of Formula (1) and mixtures thereof. When compounds of Formula (1) n one chiral
center, the compounds exist in two enantiomeric forms and the present disclosure includes both
enantiomers and mixtures of enantiomers, such as racemic mixtures. The enantiomers may be resolved
by methods known to the art, for example, by formation of diastereoisomeric salts which may be
separated, e.g., by crystallization or liquid chromatography. Alternatively, specific enantiomers may be
synthesized by asymmetric synthesis using optically active reagents, substrates, catalysts or solvents, or
by converting one enantiomer into the other by asymmetric transformation. When a Compound of
Formula (1) contains more than one chiral center, it may exist in reoisomeric forms. The
diastereoisomeric compounds may be separated by methods known to the art, for example, by
chromatography or crystallization, and the individual enantiomers may be separated as described
above, The present disclosure includes each diastereoisomer of compounds of Formula ( 1) and
mixtures thereof.
The term "isotopically enriched" refers to a Compound of Formula (1) that contains an
unnatural proportion of an e at one or more of the atoms constituting the compound, and the
present disclosure includes each isotopically enriched form of compounds of Formula (1) and mixtures
thereof. In certain embodiments, an ically enriched compound ns unnatural tions of
one or more isotopes, including but not limited to hydrogen (II-I), deuterium (2H), tritium (3H), carbon—
11 (11C), carbon—12 (‘20), carbon—13 (13C), carbon-l4 (14(3), nitrogen-13 (13N),nitrogen-14 (MN),
nitrogen-15 (UN), oxygen—14 (HO), oxygen—15 (150), oxygen-16 (160), oxygen-17 (”0), oxygen—18
(180), fluorine—17 (17F), fluorine—l8 (18F), —32 (328), sulfur—33 (33S), sulfur-34 (34S), sulfur—35
(35$), sulfur-36 (368), chlorine—35 , chlorine-36 (36Cl), chlorine-37 , bromine—79 (79Br),
bromine-81 (81Br), iodine—123 (ml), —125 (1251), iodine-127 (ml), —129 (12991), and iodine-
131 (1311). In another embodiment, an isotopically enriched compound contains ral proportions
of one or more isotopes, including but not limited to 1H, 2H, 12C, 13C, 14N, 15N, 16O, 17O, 18O, 17F, 328,
33S, 34S, 368, 35C1, 37Cl, 79Br, 81Br, and 127I. In another embodiment, an isotopically enriched compound
is radioactive. In another embodiment, an isotopically enriched compound contains unnatural
proportions of one or more isotopes, including but not limited to 3H, “C, 4C, 13 N, 14O, 15O, 18F, 35 S,
36Cl, 123I, 1251, 1291, and 1311. In r embodiment, an isotopically enriched compound contains
unnatural proportions of 1231, 1241, or 1311 and r isotope selected from 3H, 11C, 4C, 13N, 14O, 15O,
18F, 35S, and 36Cl. In another embodiment, an isotopically enriched compound ns an unnatural
proportion of 1231, 1241, and/or 1311. In another ment, an isotopically enriched compound contains
an unnatural proportion of 123I. In another embodiment, an ically enriched compound contains an
unnatural proportion of 1241. In another embodiment, an isotopically enriched compound contains an
unnatural proportion of 131I.
The term "isotopically enriched" refers to the percentage of incorporation of a less prevalent
isotope (e. g., deuterium for hydrogen) of an element at a given location in a molecule in place of a
more prevalent isotope (e. g. 1H for hydrogen) of that element. When an atom at a particular location
in a molecule is designated as a ular less prevalent isotope, it is understood that the abundance of
that isotope at that location is substantially r than its natural abundance.
The term "therapeutically effective amount" refers to an amount of a Compound of Formula (1)
or a combination of two or more such compounds that inhibits, totally or partially, the ssion of
the treated condition or alleviates, at least partially, one or more ms of the condition. A
therapeutically effective amount can also be an amount which is prophylactically effective. The
amount which is therapeutically effective s on the patient’s gender and size, the condition to be
treated, the condition's ty, and the result sought. For a given t, a therapeutically effective
amount can be ined by methods known to those in the art.
The term n " refers to an animal, including but not d to a mammal, a primate (e.g., a
human), cow, pig, sheep, goat, horse, dog, cat, rabbit, rat, or mouse.
The term "cancer" or "neoplastic disorder" refers to a tumor resulting from al or
uncontrolled ar growth. Examples of cancers include but are not limited to breast cancers, colon
cancers, colorectal cancers, te cancers, ovarian cancers, pancreatic cancers, lung cancers, gastric
cancers, esophageal cancers, glioma cancers, and hematologic malignancies. Examples of neoplastic
disorders include but are not limited to hematopoietic disorders, such as the myeloproliferative
disorders, essential thrombocytosis, thrombocythemia, angiogenic d metaplasia, polycythemia
vera, myelofibrcsis, myelofibrosis with myeloid metaplasia, chronic idiopathic myelofibrosis, the
cytopenias, and pre-malignant myelodysplastic syndromes.
The term "hematologic malignancy" refers to cancer of the bone marrow and lymphatic tissue —
body's forming and immune system. Examples of hematological malignancies e but are
not limited to ysplasia, lymphomas, leukemias, lymphomas (non—Hodgkin’s lymphoma),
Hodgkin's disease (also known as Hodgkin's ma), and myeloma, such as acute lymphocytic
leukemia (ALL), adult T-cell ALL, acute myeloid leukemia (AML), AML with trilineage
myelodysplasia, acute promyelocytic leukemia, acute undifferentiated leukemia, anaplastic large-cell
lymphoma, chronic lymphocytic leukemia, chronic myeloid leukemia, chronic neutrophilic leukemia,
juvenile myelomonocyctic leukemia, mixed lineage leukemia, myeloproliferative disorders,
myelodysplastic mes, multiple myeloma, and prolymphocytic leukemia.
The term "leukemia" refers to malignant neoplasms of the blood-forming tissues including but
not d to acute lyrnphoblastic leukemia, acute myeloid leukemia, acute myeloblastic leukemia,
chronic lymphocytic ia, and chronic myelocytic leukemia. The leukemia can be relapsed,
refractory, or resistant to conventional therapy.
The term "neurodegenerative disorder" refers to a disorder in which progressive loss of neurons
occurs either in the eral nervous system or in the central nervous system. Examples of
neurodegenerative disorders include but are not limited to chronic neurodegenerative diseases such as
diabetic peripheral neuropathy, Alzheimer's disease, Pick's disease, diffuse Lewy body e,
progressive supranuclear palsy (Steel-Richardson syndrome), multisystem degeneration (Shy—Drager
syndrome), motor neuron diseases including amyotrophic lateral sclerosis ("ALS"), degenerative
ataxias, cortical basal degeneration, ALS-Parkinson's—Dementia complex of Guam, subacute sclerosing
panencephalitis, Huntington's disease, son's disease, multiple sclerosis, synucleinopathies,
primary progressive aphasia, striatonigral degeneration, Machado-Joseph e/spinocerebellar ataxia
type 3 and olivopontocerebellar degenerations, Gilles De La Tourette's disease, bulbar and
pseudobulbar palsy, spinal and spinobulbar muscular atrophy (Kennedy's disease), primary lateral
sclerosis, familial spastic egia, Wernicke-Korsakoff‘s related dementia (alcohol induced
dementia), Werdnig—Hoffmann disease, Kugelberg—Welander disease, Tay—Sach's disease, Sandhoff
disease, familial spastic e, Wohifart—Kugelberg—Welander disease, spastic paraparesis,
progressive ocal leukoencephalopathy, and prion diseases (including feldt—Jakob,
ann—Straussler—Scheinker disease, Kuru and fatal familial insomnia). Other conditions also
included Within the methods of the present disclosure include age—related dementia and other
dementias, and conditions with memory loss including vascular dementia, e White matter disease
(Binswanger's disease), dementia of endocrine or metabolic origin, dementia of head trauma and
diffuse brain , dementia pugilistica, and frontal lobe dementia. Also other neurodegenerative
disorders resulting from cerebral ischemia or infarction including embolic occlusion and thrombotic
occlusion as well as intracranial hage of any type (including but not limited to epidural,
al, subarachnoid, and intracerebral), and intracranial and intravertebral lesions (including but not
limited to contusion, penetration, shear, compression, and laceration). Thus, the term
"neurodegenerative disorder" also encompasses acute neurodegenerative disorders such as those
involving stroke, traumatic brain injury, phrenia, eral nerve damage, hypoglycemia, spinal
cord injury, epilepsy, anoxia, and hypoxia.
In certain embodiments, the egenerative disorder is selected from Alzheimer's disease,
Parkinson’s disease, amyotrophic lateral sclerosis, age—related memory loss, senility, and age—related
ia. In another embodiment, the neurodegenerative disorder is Alzheimer’s disease, also
characterized as an amyloidosis. Thus, other embodiments of the disclosure relate to the treatment or
prevention of other amyloidosis disorders which share features, includin, but not limited to, hereditary
cerebral angiopathy, ropathic hereditary amyloid, Down's syndrome, macroglobulinemia,
secondary al Mediterranean fever, Muckle-Wells me, multiple a, pancreatic- and
cardiac-related amyloidosis, chronic hemodialysis arthropathy, Finnish amyloidosis, and Iowa
amyloidosis.
The term "pharmaceutically acceptable carrier" refers to a pharmaceutically—acceptable
material, composition, or vehicle, such as a liquid or solid filler, diluent, solvent, or ulating
al. In one embodiment, each component is "pharmaceutically acceptable" in the sense of being
compatible with the other ingredients of a pharmaceutical formulation, and suitable for use in contact
with the tissue or an organ of a patient without excessive toxicity, irritation, allergic response,
immunogenicity, or other ms or complications, commensurate with a reasonable t/risk
ratio. Pharmaceutically acceptable carriers are known in the art; see, e.g, Pharmaceutical
mulation and Formulation (Gibson, ed., 2‘1d Ed, CRC Press, Boca Raton, FL, 2009); Handbook
ofPharmaceutical Additives (Ash and Ash, eds., 3rd Ed, Gower Publishing Co., Aldershot, UK, 2007);
Remington’s Pharmaceutical Sciences (Gennaro, ed., l9th Ed., Mack Publishing, Easton, PA, 1995);
and Handbook ofPharmaceutical Excipients (Amer. Pharmaceutical Ass'n, gton, DC, 1986).
In another embodiment, a pharmaceutical composition is formed from a Compound of Formula
(1) and a pharmaceutically acceptable carrier by a method known in the art. Thus, another
embodiment s to a pharmaceutical composition comprising a Compound of a (1) and a
pharmaceutically acceptable carrier. Such a composition is useful for ng or preventing cancer or a
neurodegenerative disorder, e.g, in a patient in need thereof.
Another embodiment relates to a method for treating or preventing cancer or a
neurodegenerative disorder, comprising administering to a patient in need f a therapeutically
effective amount of a Compound of Formula (1) . Another embodiment relates to a method for treating
or preventing cancer or a neurodegenerative er, comprising administering to a patient in need
thereof a therapeutically effective amount of a pharmaceutical ition comprising a Compound of
Formula (1) . Another ment relates to a method for treating cancer or a egenerative
disorder, comprising administering to a patient in need thereof a therapeutically effective amount of a
Compound of Formula (1) . Another embodiment relates to a method for treating cancer or a
neurodegenerative disorder, comprising administering to a t in need thereof a therapeutically
effective amount of a pharmaceutical composition comprising a Compound of Formula (1)
. Another
embodiment relates to a method for preventing cancer or a neurodegenerative disorder, comprising
administering to a patient in need thereof a therapeutically effective amount of a Compound of Formula
(1) .
Another embodiment relates to a method for preventing cancer or a neurodegenerative disorder,
comprising administering to a patient in need f a therapeutically effective amount of a
pharmaceutical composition comprising a Compound of Formula (1) . Another embodiment relates to
the use of a Compound of Formula (1) in the manufacture of a ment useful for treating cancer
or a neurodegenerative disorder or for preventing cancer or a neurodegenerative disorder.
r embodiment relates to a method for the inhibition of Hsp90, comprising contacting
Hsp90 with an Hsp90 on inhibiting amount of a Compound of a (1) . An exemplary
determination of an Hsp90 function inhibiting amount is provided in the example below entitled
"Hsp90 Binding " In one embodiment, the ICSO determined by the "Hsp90 Binding Assay"
provided herein is less than 10 uM. In r embodiment, the IC50 determined by the "Hsp90
Binding Assay" provided herein is less than 1 uM. In another embodiment, the IC50 determined by the
"Hsp90 Binding Assay" ed herein is 50.1 uM. r embodiment relates to the use of a
Compound of Formula (1) in formulating a pharmaceutical composition for the inhibition of Hsp90.
The following examples are set forth to assist in understanding the invention and should not be
construed as specifically limiting the invention as described and claimed herein. Variations of the
invention, including the substitution of all equivalents now known or later developed, that would be
within the purview of those in the art, and changes in formulation or changes in experimental design,
are to be considered to fall within the scope of the invention orated herein.
4. EXAMPLES
Certain examples below relate to the synthesis of illustrative compounds of the disclosure.
Scheme 1. Synthesis of DZ4-132, DZ4-134, DZ4—l35, and Related Compounds
HZN AcHN o bAcHN o c
(1%» UV»o a H2N o d
O O | O
|U>——»O
A' 'B C D
.11? —~ mama —‘+ 1 $1jS
F §) G, n =1
n —_1 2
Br ’ H, n = 2
NH2 ——N NH2 —N/
N \ >‘3 O N
t / )
.k >\_s
N N O )
N/ N O
i) t)
HN\ "=12
HN n=1,2
R \R
R = rtT-fltit‘figfilsrgfigi‘yl
n = 1, R = peopentyl, 024-132
i—propylsulfonyl, n f 2, R :- l-propyL [324.134
n - 2, R — l, DZ4-135
acetyl,
t—butylcarbonyl, etc
Reagents and conditions: (a) A020, AcOH, rt; (b) 1C1, CH2C12, AcOH, rt; (c) NaOH, EtOH, H20,
reflux; (d) paraformaldehyde, NaBH3CN, MeOH, 50°C; (e) aptoadenine, neocuproine, Cul,
NaOtBu, DMF, 115°C; (f) 1,2—dibromoethane / 1,3 ~dibromopropane or corresponding bromides,
CSZCO3, DMF,’ rt; (g) amines, DMF, rt
N—(benzo[d][1,3]dioxol—5—yl)acetamide (B):
To a solution of 3,4-(methylenedioxy)aniline (5.0 g, 36.5 mmol) in AcOH (75 mL) was added
acetic anhydride (30 mL). The reaction mixture was stirred at a temperature of about 25°C for about
16 hours, then poured into a saturated NaHCO3 solution and d. The filtrate was extracted with
ethyl acetate to provide B in quantitative yield which was used t further purification.
‘H NMR (500 MHz, DMSO-d6, 5): 9.82 (s, 1H), 7.29 (d, J: 1.4 Hz, 1H), 6.93 (dd, J: 8.3, 1.4
Hz, 1H), 6.83 (d,J= 8.3 Hz, 1H), 5.97 (s, 2H), 1.99 (s, 3H).
): m/z = 180.1 [M+H]+.
N-(6—iodobenzo[d][l ,3]dioxol—5—yl)acetamide (C):
A 1.0 M on of iodine monochloride in methylene de (46.5 mL) was added dropwise
to a solution of B (6.4 g, 35.8 mmol) in methylene chloride (42 mL) and acetic acid (7 mL). The
reaction mixture was stirred for about 16 hours then washed with saturated sodium thiosulfate and
brine. The methylene chloride solution was dried over MgSO4, filtered and concentrated under reduced
pressure to provide a residue which was purified by chromatography (CHzClzzEtOAc, 20:1) to provide
C (6.0 g, 55% yield).
‘H NMR (500 MHz, DMSO-dg, 5); 9.33 (s, 1H), 7.37 (s, 1H), 6.96 (s, 1H), 6.07 (s, 2H), 2.01
(s, 3H).
MS (ESI): m/z = 328.0 [M+Na]+.
6-lodobenzo[d][1,3]dioxol-5—amine (D):
A solution of C (3.2 g, 10.5 mmol) and NaOH (21 g, 525 mmol) in ethanol (420 mL) and water
(96 mL) was refluxed for 4 h. The reaction mixture was cooled and concentrated under reduced
pressure to provide a residue that was partitioned between methylene chloride and water. The c
layer was washed with water, dried over MgSO4, filtered and concentrated under reduced pressure to
provide a e which was purified by chromatography (hexanezCHzClz, 7:3) to provide D (2.1 g,
76% yield).
1H NMR (500 MHZ, CDCl}, 5): 7.05 (s, 1H), 6.38 (s, 1H), 5.87 (s, 2H), 3.85 (br s, 2H).
MS (ESI): m/z = 264.0 [M+H]+.
6—Iodo-N,N-dirnethylbenzo[d][1,3]dioxolamine (E):
To a mixture ofD (200 mg, 0.7604 mmol), paraformaldehyde (228 mg, 7.604 mmol), and
molecular sieves (2 g) in methylene chloride (4 ml) and AcOH (0.435 mL, 7.604 mmol) was added
N. The mixture was heated to 50°C for 2 h. To the reaction e was added water and the
organic layer was separated and the aqueous layer was further extracted with methylene chloride a few
times. The organic layers were combined and washed with brine, dried over MgSO4, filtered and
concentrated under d pressure to provide E (181 mg, 82% yield) which was used without further
purification.
1H NMR (500 MHZ, CDC13, 5): 7.25 (s, 1H), 6.74 (s, 1H), 5.95 (s, 2H), 2.65 (s, 6H).
MS (ESI): m/z = 292.1 [M+H]+.
8—(6—(Dimethy1amino)benzo[d] [1 ,3]dioxol—S—y1thio)—9H—purin—6—amine (F):
A e of 8-mercaptoadenine (160 mg, 0.978 rnmol), neocuproine hydrate (40.7 mg, 0.196
mmol), CuI (36.4 mg, 0.196 mmol), sodium tert-butoxide (0.184 mg, 1.91 mmol), E (370 mg, 1.27
mmol) and DMF (4 mL) were heated at 115°C for 32 h. The solvent was removed under reduced
re and the residue was purified by preparatory TLC (CH2C122MeOH—NH3 (7N), 10:1) to provide
F (123 mg, 39% .
1H NMR (500 MHz, CDC13/MeOH—d4, a): 8.15 (s, 1H), 6.86 (s, 1H), 6.81 (s, 1H), 5.97 (s, 2H),
2.72 (s, 6H).
MS (ESI): m/z = 331.3 [M+H]+.
9-(2-Bromoethy1)—8—(6—(dimethy1amino)benzo[d] [1 ,3]dioxol-5—y1thio)—9H—purin—6-amine (G):
F (29 mg, 0.0878 mrnol), Cs2C03 (42.9 mg, 0.1317 mmol), bromoethane (82.5 mg, 37.8
uL, 0.439 mmol) in DMF (0.6 mL) was stirred for 1.5 h at a temperature of about 25°C. Then
additional Cs2C03 (14 mg, 0.043 mmol) was added and the mixture stirred for an onal 20 min.
The mixture was dried under reduced pressure and the residue purified by preparatory TLC
(CH2C12zMeOH:AcOH, 15:1 :0.5) to e G (24 mg, 63% yield).
1H NMR (500 MHz, CDC13/MeOH—d4, 5): 8.24 (s, 1H), 6.81 (s, 1H), 6.68 (s, 1H), 5.96 (s, 2H),
4.62 (t, J= 6.9 Hz, 2H), 3.68 (t, J: 6.9 Hz, 2H), 2.70 (s, 6H).
MS (ESI): m/z = 4372/4391 [M+H]+.
8—(6—(Dimethy1arnino)benzo [d] [1 ,3 ]dioxol—S—y1thio)—9-(2-(neopenty1amino)ethy1)~9H—purin—6—amine
(DZ4— 1 32):
G (24 mg, 0.0549 mmol) and neopentylamine (239 mg, 2.7 mmol) in DMF (0.50 mL) was
stirred at a temperature of about 25°C for about 16 hours. Solvent was removed under reduced
pressure and the resulting residue was purified by preparatory TLC (CH2C12:MeOH~NH3 (7N), 20:1) to
provide 20.6 mg (85% yield) of DZ4-132.
1H NMR (500 MHz, CDC13/MeOH—d4, 8); 8.16 (s, 1H), 6.73 (s, 1H), 6.55 (s, 1H), 5.88 (s, 2H),
4.27 (t, J: 6.4 Hz, 2H), 2.91 (t, J: 6.4 Hz, 2H), 2.61 (s, 6H), 2.28 (5,211), 0.79 (s, 9H).
13C NMR (125 MHZ, CDC13/MeOH-d4, 5): 154.8, 152.9, 151.8, 149.4, 149.2, 148.7, 145.2,
120.0, 118.7, 111.6, 102.9, 102.3, 62.4, 50.1, 45.7, 44.1, 31.9, 28.1.
MS (ESI): m/z = 444.3 [M+H]+.
9-(3-Bromopropyl)(6-(dimethy1amino)benzo[d] [1 ,3]diox01—5-y1thio)—9H-purin—6-amine (H):
F (60 mg, 0.1818 mmol), Cs2CO3 (88.8 mg, 0.2727 mmol), 1,3—dibromopropane (184 mg, 93
11L, 0.909 mmol) in DMF (2 mL) was stirred for 40 min. at a temperature of about 25°C. The mixture
was dried under reduced pressure and the residue purified by preparatory TLC (CH2C1zzMeOHzAcOH,
1521105) to e H (60 mg, 73% yield).
1H NMR (500 MHz, CDC13, 5): 8.26 (s, 1H), 6.84 (br s, 2H), 6.77 (s, 1H), 6.50 (s, 1H), 5.92
(s, 2H), 4.35 (t, J: 7.0 Hz, 2H), 3.37 (t, J: 6.6 Hz, 2H), 2.68 (s, 6H), 2.34 (m, 2H).
MS (E31): m/z = 4511/4531 [M+H]+.
8-(6-(Dimethylamino)benzo[d] [1 ,3]dioxolylthio)(3-(isopropylamino)propyl)-9H—purin—6-amine
(DZ4— 1 34):
H (30 mg, 0.0665 mmol) and isopropylamine (196 mg, 283 uL, 3.3 mmol) in DMF (1 mL) was
stirred at a ature of about 25°C for about 16 hours. Solvent was removed under reduced
pressure and the resulting residue was purified by preparatory TLC (CH2C122MeOH-NH3 (7N), 20:1) to
provide 21.8 mg (78% yield) of DZ4-134.
1H NMR (500 MHZ, CDC13, 6): 8.24 (s, 1H), 6.69 (s, 1H), 6.39 (s, 1H), 5.98 (br s, 2H), 5.83
(s, 2H), 4.23 (t, J: 6.9 Hz, 2H), 2.68 (septet, J: 6.3 Hz, 1H), 2.61 (s, 6H), 2.48 (t, J: 6.8 Hz, 2H),
1.95 (m, 2H), 0.99 (d, J: 6.3 Hz, 6H).
l3CNMR (125 MHZ, CDC13, 6): 153.6,152.3, 148.7, 147.7, 147.0,145.4,121.1, 120.8,
109.7,103.1,102.3, 49.6, 45.9, 44.2, 42.1, 30.5, 23.1.
MS (ESI): m/z = 430.2 [M+H]+.
9—(3—(tert-Butylamino)propyl)—8-(6—(dimethy1amino)benzo[d][1,3]dioxol~5~ylthio)—9H—purin—6—amine
(DZ4- 1 3 5):
H (30 mg, 0.0665 mmol) and tert—butylamine (243 mg, 350 11L, 3.3 mmol) in DMF (1 mL) was
stirred at a temperature of about 25°C for about 16 hours. Solvent was removed under reduced
pressure and the resulting e was purified by preparatory TLC 2:MeOH-NH3 (7N), 20: 1) to
provide 18.5 mg (63% yield) of DZ4-l35.
1H NMR (500 MHz, CDC13, 5): 8.25 (s, 1H), 6.69 (s, 1H), 6.40 (s, 1H), 5.88 (br s, 2H), 5.83
(s, 2H), 4.23 (t, J: 7.0 Hz, 2H), 2.62 (s, 6H), 2.43 (t, J: 6.8 Hz, 2H), 1.91 (m, 2H), 0.98 (s, 9H).
MS (ESI): m/z = 444.2 [M+H]+.
Hsp90 Binding Assay:
For the binding s, fluorescence polarization (PP) assays were performed similarly as was
previously reported [Du et al. (2007) "High-throughput screening fluorescence polarization assay for
tumor—specific Hsp90" J Biomol. Screen Qz9lS—924]. Briefly, FP measurements were performed on
an Analyst GT ment (Molecular Devices, Sunnyvale, CA). Measurements were taken in black
96-well microtiter plates (Corning # 3650) where both the excitation and the emission occurred from
the top of the well. A stock of 10 uM cy3B-GM was prepared in DMSO and diluted with HFB buffer
(20 mM Hepes (K), pH 7.3, 50 mM KCl, 2 mM DTT, 5 mM MgClz, 20 mM NazMoO4, and 0.01%
NP40 with 0.1 mg/mL BGG). The test compounds were dissolved in DMSO and added at several
trations to the HFB assay buffer containing both 6 nM cy3B-GM and transgenic mouse brain
lysate (6 ug INPL3 lysate) or human cancer cell lysate (3 pg SKBr3 lysate) in a final volume of 100
uL. Drugs were added to triplicate wells. Free cy3B—GM (6 nM cy3B—GM), bound cy3B-GM (6 nM
cy3B—GM + lysate, as indicated above) and buffer only containing wells round) were included as
controls in each plate. Plates were incubated on a shaker at 4°C, and polarization values measured at
24 h. Percentage inhibition was calculated as follows: (% Control) = 100 — ((mPc - H1Pf)/(me - mPf)) x
100, where mPc is the ed mP from compound wells, mPf is the average recorded mP from cy3B—
GM-only wells, and me is the e recorded mP from wells containing both cy3B—GM and lysate,
and plotted against values of competitor concentrations. The inhibitor concentration at which 50% of
bound M was ced was obtained by fitting the data using a nonlinear regression analysis as
implemented in Prism 4.0 Pad Software).
In these assays, the following simplified Hsp90 g grading was used: I 210 uM; 10 uM
> H > 1 uM; 1 uM > 111 > 0.1 uM; IV $0.1 uM for C50. As shown, each of the compounds tested
showed an IC50 of less than or equal to 0.1 M which is a high level of activity.
Table 1 shows results of testing for Compounds DZ4—132, DZ4—l34, and DZ4—135, and a
comparison compound (PU—H71) of the formula
NH2 l
litiji—SQ‘S
l...
In interpreting these test results, it will be appreciated that binding to Hsp90 for activity in the
treatment of cancer or neurodegenerative disorders is desirable. In contrast, it is generally
undersirable to have binding to hERG since binding to hERG can result in undesirable cardiac
side effects. Therefore, having a low value for binding to Hsp90 and a high value for binding
to hERG is desirable, bearing in mind that the units for the two measurement are different.
Table l
SKBr3 Binding Affinity (nM) hERG binding (uM)
DZ4—132
DZ4—l 34
DZ4— 1 3 5
PU—H71
The invention is not to be limited in scope by the c embodiments sed in the
examples that are intended as illustrations of a few aspects of the invention and any embodiments that
are functionally equivalent are within the scope of this invention. Indeed, various modifications of the
invention in addition to those shown and described herein will become nt to those in the art and
are intended to fall within the scope of the appended . A number of references have been cited,
the entire sures of which are incorporated herein by reference for all purposes.
Claims (3)
1. A compound of Formula (1): NH2 X2 Y Xa X4 Z2 N R Xb (1) or a pharmaceutically acceptable salt thereof, wherein: (a) each of Z1, Z2 and Z3 is independently CH or N; (b) Y is S; (c) Xa and Xb are O; (d) Xc is -CH2-; (e) X2 is -NR1R2, wherein R1 and R2 are each independently H, C1-C6 alkyl, C2- C6 alkenyl, C2-C6 alkynyl, cycloalkyl, heteroalkyl, heterocycloalkyl, aryl, heteroaryl, alkylaryl, arylalkyl, alkylheteroaryl, heteroarylalkyl, or alkylheteroarylalkyl; (f) X4 is hydrogen or halogen; (g) R is H-R11, wherein R10 is ethylene or ene, and (i) R11 is isopropyl or t-butyl, or (ii) R11 is a branched alkyl, Z1, Z2 and Z3 are each N, and R1 and R2 are each independently C1-6 alkyl, C2 -C6 l, C2-6 alkynyl, cycloalkyl, heteroalkyl, heterocycloalkyl, aryl, aryl, alkylaryl, arylalkyl, alkylheteroaryl, heteroarylalkyl, or alkylheteroarylalkyl.
2. A compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein X2 is ylamine.
3. A compound ing to claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein R11 is neopentyl. H:\ACG\Interwoven\NRPortbl\DCC\ACG\9188654_1.docx-24/
Applications Claiming Priority (3)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US201161472061P | 2011-04-05 | 2011-04-05 | |
US61/472,061 | 2011-04-05 | ||
PCT/US2012/032373 WO2012138896A1 (en) | 2011-04-05 | 2012-04-05 | Hsp90 inhibitors |
Publications (2)
Publication Number | Publication Date |
---|---|
NZ616890A NZ616890A (en) | 2016-01-29 |
NZ616890B2 true NZ616890B2 (en) | 2016-05-03 |
Family
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