U.S. patent application number 11/537002 was filed with the patent office on 2007-05-17 for pyrazolopyrimidines and related analogs as hsp90-inhibitors.
This patent application is currently assigned to Conforma Therapeutics Corporation. Invention is credited to Marco A. Biamonte, Marcus F. Boehm, Kevin D. Hong, David Hurst, Srinivas Rao Kasibhatla.
Application Number | 20070111996 11/537002 |
Document ID | / |
Family ID | 34381103 |
Filed Date | 2007-05-17 |
United States Patent
Application |
20070111996 |
Kind Code |
A1 |
Kasibhatla; Srinivas Rao ;
et al. |
May 17, 2007 |
Pyrazolopyrimidines and related analogs as HSP90-inhibitors
Abstract
Pyrazolopyrimidines and related analogs are described and
demonstrated or predicted to have utility as Heat Shock Protein 90
(HSP90) inhibiting agents in the treatment and prevention of
various HSP90 mediated disorders, e.g., proliferative disorders.
Method of synthesis and use of such compounds are also described
and claimed.
Inventors: |
Kasibhatla; Srinivas Rao;
(San Diego, CA) ; Biamonte; Marco A.; (San Diego,
CA) ; Hong; Kevin D.; (San Diego, CA) ; Hurst;
David; (San Diego, CA) ; Boehm; Marcus F.;
(San Diego, CA) |
Correspondence
Address: |
WILSON SONSINI GOODRICH & ROSATI
650 PAGE MILL ROAD
PALO ALTO
CA
94304-1050
US
|
Assignee: |
Conforma Therapeutics
Corporation
San Diego
CA
|
Family ID: |
34381103 |
Appl. No.: |
11/537002 |
Filed: |
September 29, 2006 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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10946637 |
Sep 20, 2004 |
7148228 |
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11537002 |
Sep 29, 2006 |
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60504135 |
Sep 18, 2003 |
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60591467 |
Jul 26, 2004 |
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Current U.S.
Class: |
514/227.8 ;
514/234.5; 514/252.16; 514/262.1 |
Current CPC
Class: |
A61P 1/16 20180101; A61P
11/00 20180101; A61P 43/00 20180101; A61P 9/00 20180101; A61P 9/10
20180101; A61P 35/00 20180101; A61P 31/00 20180101; A61P 31/16
20180101; C07D 487/04 20130101; A61P 17/00 20180101; C07D 471/04
20130101; A61P 17/02 20180101; A61P 13/12 20180101; A61P 19/02
20180101; A61P 35/02 20180101; A61P 19/04 20180101; C07D 473/00
20130101; A61P 25/00 20180101; A61P 3/00 20180101; A61P 21/00
20180101; A61P 37/06 20180101; A61P 29/00 20180101; A61P 25/08
20180101; A61P 37/02 20180101 |
Class at
Publication: |
514/227.8 ;
514/234.5; 514/262.1; 514/252.16 |
International
Class: |
A61K 31/541 20060101
A61K031/541; A61K 31/5377 20060101 A61K031/5377; A61K 31/519
20060101 A61K031/519 |
Claims
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44. A method of treating an individual having an HSP90 mediated
disorder comprising administering to said individual a
pharmaceutical composition comprising a pharmaceutically effective
amount of a compound of Formula I: ##STR60## or a polymorph,
solvate, ester, tautomer, pharmaceutically acceptable salt or
prodrug thereof, wherein: R.sup.1 is halogen, --OR.sup.11,
--SR.sup.11 or lower alkyl; R.sup.2 is --NHR.sup.8; R.sup.3 is
selected from the group consisting of hydrogen, halogen,
--SR.sup.8, --OR.sup.8, --CN, --C(O)R.sup.9, --CO.sub.2H,
--NO.sub.2, --NR.sup.8R.sup.10, lower alkyl, lower alkenyl, lower
alkynyl, lower perhaloalkyl, aryl, heteroaryl, alicyclic and
heterocyclic, all optionally substituted, wherein: the aryl,
heteroaryl, alicyclic and heterocyclic groups are optionally mono-,
bi- or tri-cyclic; R.sup.8 and R.sup.10 taken together optionally
form a ring of 3-7 ring atoms and optionally 1-2 of the ring atoms
are heteroatoms selected from the group of O, S and N, and the
optional substituents on R.sup.3 are selected from the group
consisting of halogen, lower alkyl, lower alkenyl, lower alkynyl,
--SR.sup.8, --OR.sup.8, --CN, --C(O)R.sup.9, --C(O)OOH, --NO.sub.2,
--NR.sup.8R.sup.10, lower aryl, lower heteroaryl, lower alicyclic,
lower heterocyclic, arylalkyl, heteroarylalkyl, amino, alkylamino,
dialkylamino, diarylalkylamino, oxo, oxa, perhaloalkyl,
perhaloalkoxy, perhaloacyl, guanidine, pyridinyl, thiophene,
furanyl, indole, indazole, phosphonates, phosphates,
phosphoramides, sulfonates, sulfones, sulfates, sulphonamides,
carbamates, ureas, thioureas and thioamides, wherein R.sup.8 and
R.sup.10 taken together optionally form a ring of 3-7 ring atoms
and optionally 1-3 of the ring atoms are heteroatoms selected from
the group of O, S and N; R.sup.4 is --CHR.sup.12--, --C(O), --C(S),
--S(O)--, or --SO.sub.2--; R.sup.5 is aryl, heteroaryl, alicyclic,
or heterocyclic, wherein the aryl group is substituted with 3 to 5
substituents, the heteroaryl group is substituted with 2 to 5
substituents, the alicyclic group is substituted with 3 to 5
substituents, the heterocyclic group is substituted with 3 to 5
substituents, and the substituents on R.sup.5 are selected from the
group consisting of halogen, lower alkyl, lower alkenyl, lower
alkynyl, --SR.sup.8, --OR.sup.8, --CN, --C(O)OH, --C(O)R.sup.9,
--NO.sub.2 and --NR.sup.8R.sup.10, lower aryl, heteroaryl,
alicyclic, lower heterocyclic, arylalkyl, heteroarylalkyl, amino,
alkylamino, dialkylamino, diarylalkylamino, oxo, oxa, perhaloalkyl,
perhaloalkoxy, perhaloacyl, guanidine, pyridinyl, thiophene,
furanyl, indole, indazole, phosphonates, phosphates,
phosphoramides, sulfonates, sulfones, sulfates, sulphonamides,
carbamates, ureas, thioureas and thioamides, wherein R.sup.8 and
R.sup.10 taken together optionally form a ring of 3-7 ring atoms
and optionally 1-3 of the ring atoms are heteroatoms selected from
the group of O, S and N; R.sup.8 is hydrogen, lower alkyl, lower
alkenyl, lower alkynyl, lower aryl, lower heteroaryl or
--C(O)R.sup.9; R.sup.9 is hydrogen, lower alkyl, lower alkenyl,
lower alkynyl, lower aryl, lower heteroaryl, --NR.sup.10R.sup.10 or
--OR.sup.11, wherein R.sup.10 and R.sup.10 taken together
optionally form a ring of 3-7 ring atoms and optionally 1-3 of the
ring atoms are heteroatoms selected from the group of O, S and N;
R.sup.10 is hydrogen, lower alkyl, lower alkenyl, lower alkynyl,
lower aryl or lower heteroaryl; R.sup.11 is lower alkyl, lower
alkenyl, lower alkynyl, lower aryl or lower heteroaryl; and
R.sup.12 is hydrogen or lower alkyl.
45. The method of claim 44, wherein: R.sup.1 is halogen or lower
alkyl; R.sup.2 is --NHR.sup.8, where R.sup.8 is hydrogen or
--C(O)R.sup.9; and R.sup.5 is aryl or heteroaryl, wherein each of
said aryl and heteroaryl groups is monocyclic or bicyclic.
46. The method of claim 44, wherein: R.sup.2 is --NH.sub.2; R.sup.3
is selected from hydrogen, halogen, --SR.sup.1, --OR.sup.8, --CN,
--NR.sup.8R.sup.10, lower alkyl lower alkenyl, lower alkynyl, lower
perhaloalkyl, lower aryl, lower heteroaryl, lower alicyclic, and
lower heterocyclic, wherein R.sup.8 is hydrogen, lower alkyl, lower
alkenyl, lower alkynyl, lower aryl or lower heteroaryl, and wherein
R.sup.8 and R.sup.10 taken together optionally form a ring of 3-7
ring atoms and optionally 1-3 of the ring atoms are heteroatoms
selected from the group of O, S and N; and R.sup.5 is aryl or
heteroaryl, wherein each of said aryl and heteroaryl groups is
monocyclic or bicyclic.
47. The method of claim 44, wherein: R.sup.1 is halogen or lower
alkyl; R.sup.2 is --NH.sub.2; R.sup.4 is --(CH.sub.2)--; and
R.sup.5 is aryl, heteroaryl, alicyclic or heterocyclic, wherein
each of said aryl, heteroaryl alicyclic or heterocyclic groups is
monocyclic or bicyclic.
48. The method of claim 44, wherein: R.sup.1 is halogen; R.sup.2 is
--NH.sub.2; R.sup.3 is hydrogen, halogen, --SR.sup.8, --OR.sup.8,
lower alkyl, lower alkenyl, lower alkynyl, lower perhaloalkyl,
lower aryl, lower heteroaryl, or --NR.sup.8R.sup.10 wherein R.sup.8
and R.sup.10 when taken together optionally form a ring of 3-7 ring
atoms and optionally 1-3 of the ring atoms are heteroatoms selected
from the group of O, S and N; R.sup.4 is --CH.sub.2--; and R.sup.5
is aryl or heteroaryl, wherein each of said aryl and heteroaryl
groups is monocyclic or bicyclic.
49. The method of claim 48, wherein R.sup.1 is chloro or bromo; and
R.sup.5 is a phenyl having 3 to 5 substituents.
50. The method of claim 48, wherein R.sup.1 is chloro or bromo; and
R.sup.5 is a pyridyl having 3 to 5 substituents.
51. The method of claim 48, wherein R.sup.1 is chloro or bromo; and
R.sup.5 is a 1-oxy-pyridyl(N-oxy-pyridyl) having 3 to 5
substituents.
52. The method of claim 44, wherein the HSP90-mediated disorder is
selected from the group of inflammatory diseases, infections,
autoimmune disorders, stroke, ischemia, cardiac disorders,
neurological disorders, fibrogenetic disorders, proliferative
disorders, tumors, leukemias, neoplasms, cancers, carcinomas,
metabolic diseases, and malignant disease.
53. The method of claim 52 wherein the fibrogenetic disorder is
further selected from the group of scleroderma, polymyositis,
systemic lupus, rheumatoid arthritis, liver cirrhosis, keloid
formation, interstitial nephritis and pulmonary fibrosis.
54. The method of claim 44 further comprising administering at
least one therapeutic agent selected from the group of cytotoxic
agents, anti-angiogenesis agents and anti-neoplastic agents.
55. The method of claim 54 wherein the at least one anti-neoplastic
agent is selected from the group of alkylating agents,
anti-metabolites, epidophyllotoxins; antineoplastic enzymes,
topoisomerase inhibitors, procarbazines, mitoxantrones, platinum
coordination complexes, biological response modifiers and growth
inhibitors, hormonal/anti-hormonal therapeutic agents, and
haematopoietic growth factors.
56. (canceled)
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63. (canceled)
64. A method of treating an individual having an HSP90 mediated
disorder comprising administering to said individual a
pharmaceutical composition comprising a pharmaceutically effective
amount of a compound of Formula II: ##STR61## or a polymorph,
solvate, ester, tautomer, pharmaceutically acceptable salt or
prodrug thereof, wherein: R.sup.1 is halogen, --OR.sup.11,
--SR.sup.11 or lower alkyl; R.sup.2 is --NHR.sup.8; R.sup.4 is
--CHR.sup.12--, --C(O), --C(S), --S(O)--, or --SO.sub.2--; R.sup.5
is aryl, heteroaryl, alicyclic, or heterocyclic, wherein the aryl
group is substituted with 3 to 5 substituents, the heteroaryl group
is substituted with 2 to 5 substituents, the alicyclic group is
substituted with 3 to 5 substituents, the heterocyclic group is
substituted with 3 to 5 substituents, and the substituents on
R.sup.5 are selected from the group consisting of halogen, lower
alkyl, lower alkenyl, lower alkynyl, --SR.sup.8, --OR.sup.8, --CN,
--C(O)OH, --C(O)R.sup.9, --NO.sub.2, --NR.sup.8R.sup.10, lower
aryl, heteroaryl, alicyclic, lower heterocyclic, arylalkyl,
heteroarylalkyl, amino, alkylamino, dialkylamino, diarylalkylamino,
oxo, oxa, perhaloalkyl, perhaloalkoxy, perhaloacyl, guanidine,
pyridinyl, thiophene, furanyl, indole, indazole, phosphonates,
phosphates, phosphoramides, sulfonates, sulfones, sulfates,
sulphonamides, carbamates, ureas, thioureas and thioamides, wherein
R.sup.8 and R.sup.10 taken together optionally form a ring of 3-7
ring atoms and optionally 1-3 of the ring atoms are heteroatoms
selected from the group of O, S and N; R.sup.9 is hydrogen, lower
alkyl, lower alkenyl, lower alkynyl, lower aryl, lower heteroaryl
or --C(O)R.sup.9; R.sup.9 is hydrogen, lower alkyl, lower alkenyl,
lower alkynyl, lower aryl, lower heteroaryl, --NR.sup.10R.sup.10 or
--OR.sup.11, wherein R.sup.10 and R.sup.10 taken together
optionally form a ring of 3-7 ring atoms and optionally 1-3 of the
ring atoms are heteroatoms selected from the group of O, S and N;
R.sup.10 is hydrogen, lower alkyl, lower alkenyl, lower alkynyl,
lower aryl or lower heteroaryl; R.sup.11 is lower alkyl, lower
alkenyl, lower alkynyl, lower aryl or lower heteroaryl; R.sup.12 is
hydrogen or lower alkyl; and R.sup.15 is hydrogen, lower alkyl,
lower alkenyl or lower alkynyl.
65. The method of claim 64, wherein: R.sup.1 is halogen or lower
alkyl; R.sup.2 is --NHR.sup.8, where R.sup.8 is hydrogen or
--C(O)R.sup.9; R.sup.4 is --(CH.sub.2)--; and R.sup.5 is aryl,
heteroaryl, alicyclic, or heterocyclic, all optionally mono-, bi-
or tri-cyclic.
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Description
[0001] This application relates and claims priority to U.S.
application Ser. No. 10/946,637, filed Sep. 20, 2004, and U.S.
Provisional Application Ser. No. 60/504,135, filed Sep. 18, 2003
and U.S. Provisional Application Ser. No. 60/591,467, filed Jul.
26, 2004. This application also relates to three other U.S. Utility
application Ser. Nos. 10/946,645 filed Sep. 20, 2004 (now
Publication No. 20050113340; Ser. No. 10/945,851 filed Sep. 20,
2004 (now Publication No. 20050107343, and Ser. No. 10/946,628
filed Sep. 20, 2004 (now Publication No. 20050113339). This
application further relates to International Application
PCT/US02/35069, filed Oct. 30, 2002, (now Publication No.
WO03/37860). All the above cited U.S. utility applications,
provisional applications and international application are
expressly incorporated herein by reference in their entirety.
FIELD OF THE INVENTION
[0002] The invention relates in general to pyrazolopyrimidines and
their related analogs and their broad-spectrum utility, e.g., in
inhibiting heat shock protein 90 (HSP90) to thereby treat or
prevent HSP90-mediated diseases.
BACKGROUND
[0003] HSP90s are ubiquitous chaperone proteins that are involved
in folding, activation and assembly of a wide range of proteins,
including key proteins involved in signal transduction, cell cycle
control and transcriptional regulation. Researchers have reported
that HSP90 chaperone proteins are associated with important
signaling proteins, such as steroid hormone receptors and protein
kinases, including, e.g., Raf-1, EGFR, v-Src family kinases, Cdk4,
and ErbB-2 (Buchner J. TIBS 1999, 24, 136-141; Stepanova, L. et al.
Genes Dev. 1996, 10, 1491-502; Dai, K. et al. J. Biol. Chem. 1996,
271, 22030-4). Studies further indicate that certain co-chaperones,
e.g., HSP70, p60/Hop/Sti1, Hip, Bag1, HSP40/Hdj2/Hsj1,
immunophilins, p23, and p50, may assist HSP90 in its function (see,
e.g., Caplan, A. Trends in Cell Biol. 1999, 9, 262-68).
[0004] Ansamycin antibiotics, e.g., herbimycin A (HA), geldanamycin
(GM), and 17-allylaminogeldanamycin (17-AAG) are thought to exert
their anticancerous effects by tight binding of the N-terminus
pocket of HSP90, thereby destabilizing substrates that normally
interact with HSP90 (Stebbins, C. et al. Cell 1997, 89, 239-250).
This pocket is highly conserved and has weak homology to the
ATP-binding site of DNA gyrase (Stebbins, C. et al., suprau;
Grenert, J. P. et al. J. Biol. Chem. 1997, 272, 23843-50). Further,
ATP and ADP have both been shown to bind this pocket with low
affinity and to have weak ATPase activity (Proromou, C. et al. Cell
1997, 90, 65-75; Panaretou, B. et al. EMBO J. 1998, 17, 4829-36).
In vitro and in vivo studies have demonstrated that occupancy of
this N-terminal pocket by ansamycins and other HSP90 inhibitors
alters HSP90 function and inhibits protein folding. At high
concentrations, ansamycins and other HSP90 inhibitors have been
shown to prevent binding of protein substrates to HSP90 (Scheibel,
T. H. et al. Proc. Natl. Acad. Sci. USA 1999, 96, 1297-302;
Schulte, T. W. et al. J. Biol. Chem. 1995, 270, 24585-8; Whitesell,
L., et al. Proc. Natl. Acad. Sci. USA 1994, 91, 8324-8328).
Ansamycins have also been demonstrated to inhibit the ATP-dependent
release of chaperone-associated protein substrates (Schneider, C.
L. et al. Proc. Natl. Acad. Sci., USA 1996, 93, 14536-41;
Sepp-Lorenzino et al. J. Biol. Chem. 1995, 270, 16580-16587). In
either event, the substrates are degraded by a ubiquitin-dependent
process in the proteasome (Schneider, C. L., supra; Sepp-Lorenzino,
L., et al. J. Biol. Chem. 1995, 270, 16580-16587; Whitesell, L. et
al. Proc. Natl. Acad. Sci. USA 1994, 91, 8324-8328).
[0005] HSP90 substrate destabilization occurs in tumor and
non-transformed cells alike and has been shown to be especially
effective on a subset of signaling regulators, e.g., Raf (Schulte,
T. W. et al. Biochem. Biophys. Res. Commun. 1997, 239, 655-9;
Schulte, T. W., et al. J. Biol. Chem. 1995, 270, 24585-8), nuclear
steroid receptors (Segnitz, B.; U. Gehring J. Biol. Chem. 1997,
272, 18694-18701; Smith, D. F. et al. Mol. Cell. Biol. 1995, 15,
6804-12), v-Src (Whitesell, L., et al. Proc. Natl. Acad. Sci. USA
1994, 91, 8324-8328) and certain transmembrane tyrosine kinases
(Sepp-Lorenzino, L. et al. J. Biol. Chem. 1995, 270, 16580-16587)
such as EGF receptor (EGFR) and HER2/Neu (Hartmann, F., et al. Int.
J. Cancer 1997, 70, 221-9; Miller, P. et al. Cancer Res. 1994, 54,
2724-2730; Mimnaugh, E. G., et al. J. Biol. Chem. 1996, 271,
22796-801; Schnur, R. et al. J. Med. Chem. 1995, 38, 3806-3812),
CDK4, and mutant p53. Erlichman et al. Proc. AACR 2001, 42,
abstract 4474. The ansamycin-induced loss of these proteins leads
to the selective disruption of certain regulatory pathways and
results in growth arrest at specific phases of the cell cycle
(Muise-Heimericks, R. C. et al. J. Biol. Chem. 1998, 273,
29864-72), and apoptosis, and/or differentiation of cells so
treated (Vasilevskaya, A. et al. Cancer Res., 1999, 59, 3935-40).
Ansamycins thus hold great promise for the treatment and/or
prevention of many types of cancers and proliferative disorders,
and also hold promise as traditional antibiotics. However, their
relative insolubility makes them difficult to formulate and
administer, and they are not easily synthesized and currently must,
at least in part, be generated through fermentation. Further, the
dose limiting toxicity of ansamycins is hepatic.
[0006] In addition to anti-cancer and antitumorgenic activity,
HSP90 inhibitors have also been implicated in a wide variety of
other utilities, including use as anti-inflammation agents,
anti-infectious disease agents, agents for treating autoimmunity,
agents for treating stroke, ischemia, multiple sclerosis, cardiac
disorders, central nervous system related disorders and agents
useful in promoting nerve regeneration (See, e.g., Rosen et al. WO
02/09696 (PCT/US01/23640); Degranco et al. WO 99/51223
(PCT/US99/07242); Gold, U.S. Pat. No. 6,210,974 B1; DeFranco et
al., U.S. Pat. No. 6,174,875. Overlapping somewhat with the above,
there are reports in the literature that fibrogenetic disorders
including but not limited to scleroderma, polymyositis, systemic
lupus, rheumatoid arthritis, liver cirrhosis, keloid formation,
interstitial nephritis, and pulmonary fibrosis also may be
treatable with HSP90 inhibitors. Strehlow, WO 02/02123
(PCT/US01/20578). Still further HSP90 modulation, modulators and
uses thereof are reported in Application Nos. PCT/US03/04283,
PCT/US02/35938, PCT/US02/16287, PCT/US02/06518, PCT/US98/09805,
PCT/US00/09512, PCT/US01/09512, PCT/US01/23640, PCT/US01/46303,
PCT/US01/46304, PCT/US02/06518, PCT/US02/29715, PCT/US02/35069,
PCT/US02/35938, PCT/US02/39993, 60/293,246, 60/371,668, 60/335,391,
60/128,593, 60/337,919, 60/340,762, 60/359,484 and 60/331,893.
[0007] Recently, purine derivatives showing HSP90 inhibitory
activity have been reported, e.g., in PCT/US02/35069 and
PCT/US02/36075. Purine moieties are well accepted bioisosteres for
a variety of ATP-dependent molecular targets, see, JP 10025294;
U.S. Pat. No. 4,748,177; U.S. Pat. No. 4,772,606; U.S. Pat. No.
6,369,092; WO 00/06573; WO 02/055521; WO 02/055082; WO 02/055083;
EP 0178178; Eur. J. Med. Chem. 1994, 29(1), 3-9; and J. Het. Chem.
1990, 27(5), 1409. However, compounds having the desired potency,
selectivity and pharmaceutical properties required for effective
HSP90 inhibition in vivo have not been reported. Therefore, a need
remains for additional novel and potent HSP90 inhibitors that meet
the demanding biological and pharmaceutical criteria required to
proceed towards human clinical trials.
SUMMARY OF THE INVENTION
[0008] The present invention is directed towards heterocyclic
compounds, in particular towards pyrazolopyrimidines and related
compounds that show broad utility, e.g., in inhibiting HSP90 and/or
treating and preventing diseases that are HSP90-dependent.
[0009] In one aspect, the invention comprises the heterocyclic
compounds as specified below in Formulae A, I and II and compounds
that are produced by a synthesis process of the invention. Also
included in the scope of the present invention are stereoisomeric
forms, including the individual enantiomers and diastereomers,
racemic mixtures, and diastereomeric mixtures, as well as
polymorphs, solvates, esters, tautomers, pharmaceutically
acceptable salts and prodrugs of these compounds.
[0010] In one embodiment, the invention provides compounds of
Formula A, or a polymorph, solvate, ester, tautomer, diastereomer,
enantiomer, pharmaceutically acceptable salt or prodrug thereof,
which show utility by inhibiting HSP90 and treating and/or
preventing diseases that are HSP90-dependent. ##STR1## wherein:
[0011] X.sup.1 and X.sup.2 are the same or different and each is
nitrogen or --CR.sup.6; [0012] X.sup.3 is nitrogen or --CR.sup.3
wherein R.sup.3 is hydrogen, OH, a keto tautomer, --OR.sup.8, --CN,
halogen, lower alkyl, or --C(O)R.sup.9; [0013] X.sup.4 is nitrogen
or --CR.sup.6 when X.sup.3 is nitrogen; and X.sup.4 is
--CR.sup.6R.sup.7 when X.sup.3 is --CR.sup.3; [0014] R.sup.1 is
halogen, --OR.sup.8, --SR.sup.8, or lower alkyl; [0015] R.sup.2 is
--NR.sup.8R.sup.10; [0016] R.sup.4 is --(CH.sub.2).sub.n-- wherein
n=0-3, --C(O), --C(S), --SO.sub.2--, or --SO.sub.2N--; and [0017]
R.sup.5 is alkyl, aromatic, heteroaromatic, alicyclic, or
heterocyclic, each of which is optionally bi- or tri-cyclic, and
optionally substituted with H, halogen, lower alkyl, lower alkenyl,
lower alkynyl, lower aryl, lower alicyclic, aralkyl, aryloxyalkyl,
alkoxyalkyl, perhaloalkyl, perhaloalkyloxy, perhaloacyl, --N.sub.3,
--SR.sup.8, --OR.sup.8, --CN, --CO.sub.2R.sup.9, --NO.sub.2, or
--NR.sup.8R.sup.10.
[0018] In certain embodiments, there are exclusionary provisos with
respect to compounds disclosed in JP 10025294; U.S. Pat. No.
4,748,177; U.S. Pat. No. 4,748,177; U.S. Pat. No. 6,369,092; WO
00/06573; WO 02/055521; WO 02/055082; WO 02/055083; Eur. J. Med.
Chem. 1994, 29(1), 3-9; and J. Het. Chem. 1990, 27(5), 1409, which
disclose compounds with --R.sup.4R.sup.5 comprising ribose or a
derivative thereof, or a sugar or derivative thereof; and compounds
where --R.sup.4R.sup.5 is a phosphonate or phosphonic acid, or is
substituted with a phosphonate or phosphonic acid; or compounds
where R.sup.4 is --CH.sub.2-- or --(CH.sub.2).sub.n-- that are
connected through an oxygen atom to another group.
[0019] In another embodiment, the invention provides compounds of
Formula I, or a polymorph, solvate, ester, tautomer, diastereomer,
enantiomer, pharmaceutically acceptable salt or prodrug thereof,
which show utility for inhibiting HSP90 and treating and preventing
diseases that are HSP90-dependent, ##STR2## wherein: [0020] R.sup.1
is halogen, --OR.sup.11, --SR.sup.11 or lower alkyl; [0021] R.sup.2
is --NHR.sup.8; [0022] R.sup.3 is selected from the group
consisting of hydrogen, halogen, --SR.sup.8, --OR.sup.8, --CN,
--C(O)R.sup.9, --CO.sub.2H, --NO.sub.2, --NR.sup.8R.sup.10, lower
alkyl, lower alkenyl, lower alkynyl, lower perhaloalkyl, aryl,
heteroaryl, alicyclic and heterocyclic, all optionally substituted,
wherein: [0023] the aryl, heteroaryl, alicyclic and heterocyclic
groups are optionally mono-, bi- or tri-cyclic; [0024] R.sup.8 and
R.sup.10 taken together optionally form a ring of 3-7 ring atoms
and optionally 1-2 of the ring atoms are heteroatoms selected from
the group of O, S and N, and [0025] the optional substituents on
R.sup.3 are selected from the group consisting of halogen, lower
alkyl, lower alkenyl, lower alkynyl, --SR.sup.8, --OR.sup.8, --CN,
--C(O)R.sup.9, --C(O)OH, --NO.sub.2, --NR.sup.8R.sup.10, lower
aryl, lower heteroaryl, lower alicyclic, lower heterocyclic,
arylalkyl, heteroarylalkyl, amino, alkylamino, dialkylamino,
diarylalkylamino, oxo, oxa, perhaloalkyl, perhaloalkoxy,
perhaloacyl, guanidine, pyridinyl, thiophene, furanyl, indole,
indazole, phosphonates, phosphates, phosphoramides, sulfonates,
sulfones, sulfates, sulphonamides, carbamates, ureas, thioureas and
thioamides, wherein R.sup.8 and R.sup.10 taken together optionally
form a ring of 3-7 ring atoms and optionally 1-3 of the ring atoms
are heteroatoms selected from the group of O, S and N; [0026]
R.sup.4 is --CHR.sup.12--, --C(O), --C(S), --S(O)--, or
--SO.sub.2--; [0027] R.sup.5 is aryl, heteroaryl, alicyclic, or
heterocyclic, wherein [0028] the aryl group is substituted with 3
to 5 substituents, [0029] the heteroaryl group is substituted with
2 to 5 substituents, [0030] the alicyclic group is substituted with
3 to 5 substituents, [0031] the heterocyclic group is substituted
with 3 to 5 substituents, and [0032] the substituents on R.sup.5
are selected from the group consisting of halogen, lower alkyl,
lower alkenyl, lower alkynyl, --SR.sup.8, --OR.sup.8, --CN,
--C(O)OH, --C(O)R.sup.9, --NO.sub.2, --NR.sup.8R.sup.10, lower
aryl, heteroaryl, alicyclic, lower heterocyclic, arylalkyl,
heteroarylalkyl, amino, alkylamino, dialkylamino, diarylalkylamino,
oxo, oxa, perhaloalkyl, perhaloalkoxy, perhaloacyl, guanidine,
pyridinyl, thiophene, furanyl, indole, indazole, phosphonates,
phosphates, phosphoramides, sulfonates, sulfones, sulfates,
sulphonamides, carbamates, ureas, thioureas and thioamides, wherein
R.sup.8 and R.sup.10 taken together optionally form a ring of 3-7
ring atoms and optionally 1-3 of the ring atoms are heteroatoms
selected from the group of O, S and N; [0033] R.sup.8 is hydrogen,
lower alkyl, lower alkenyl, lower alkynyl, lower aryl, lower
heteroaryl or --C(O)R.sup.9; [0034] R.sup.9 is hydrogen, lower
alkyl, lower alkenyl, lower alkynyl, lower aryl, lower heteroaryl,
--NR.sup.10R.sup.10 or --OR.sup.11, wherein R.sup.10 and R.sup.10
taken together optionally form a ring of 3-7 ring atoms and
optionally 1-3 of the ring atoms are heteroatoms selected from the
group of O, S and N; [0035] R.sup.10 is hydrogen, lower alkyl,
lower alkenyl, lower alkynyl, lower aryl or lower heteroaryl;
[0036] R.sup.11 is lower alkyl, lower alkenyl, lower alkynyl, lower
aryl or lower heteroaryl; and [0037] R.sup.12 is hydrogen or lower
alkyl.
[0038] In another embodiment, the invention provides compounds of
Formula II, or a polymorph, solvate, ester, tautomer, diastereomer,
enantiomer, pharmaceutically acceptable salt or prodrug thereof,
which show utility for inhibiting HSP90 and treating and/or
preventing diseases that are HSP90-dependent, ##STR3## wherein:
[0039] R.sup.1 is halogen, --OR.sup.11, --SR.sup.11 or lower alkyl;
[0040] R.sup.2 is --NHR.sup.8; [0041] R.sup.4 is --CHR.sup.12--,
--C(O), --C(S), --S(O)--, or --SO.sub.2--; [0042] R.sup.5 is aryl,
heteroaryl, alicyclic, or heterocyclic, wherein [0043] the aryl
group is substituted with 3 to 5 substituents, [0044] the
heteroaryl group is substituted with 2 to 5 substituents, [0045]
the alicyclic group is substituted with 3 to 5 substituents, [0046]
the heterocyclic group is substituted with 3 to 5 substituents, and
[0047] the substituents on R.sup.5 are selected from the group
consisting of halogen, lower alkyl, lower alkenyl, lower alkynyl,
--SR.sup.8, --OR.sup.8, --CN, --C(O)OH, --C(O)R.sup.9, --NO.sub.2,
--NR.sup.8R.sup.10, lower aryl, heteroaryl, alicyclic, lower
heterocyclic, arylalkyl, heteroarylalkyl, amino, alkylamino,
dialkylamino, diarylalkylamino, oxo, oxa, perhaloalkyl,
perhaloalkoxy, perhaloacyl, guanidine, pyridinyl, thiophene,
furanyl, indole, indazole, phosphonates, phosphates,
phosphoramides, sulfonates, sulfones, sulfates, sulphonamides,
carbamates, ureas, thioureas and thioamides, wherein R.sup.8 and
R.sup.10 taken together optionally form a ring of 3-7 ring atoms
and optionally 1-3 of the ring atoms are heteroatoms selected from
the group of O, S and N; [0048] R.sup.8 is hydrogen, lower alkyl,
lower alkenyl, lower alkynyl, lower aryl, lower heteroaryl or
--C(O)R.sup.9; [0049] R.sup.9 is hydrogen, lower alkyl, lower
alkenyl, lower alkynyl, lower aryl, lower heteroaryl,
--NR.sup.10R.sup.10 or --OR.sup.11, wherein R.sup.10 and R.sup.10
taken together optionally form a ring of 3-7 ring atoms and
optionally 1-3 of the ring atoms are heteroatoms selected from the
group of O, S and N; [0050] R.sup.10 is hydrogen, lower alkyl,
lower alkenyl, lower alkynyl, lower aryl or lower heteroaryl;
[0051] R.sup.11 is lower alkyl, lower alkenyl, lower alkynyl, lower
aryl or lower heteroaryl; and [0052] R.sup.12 is hydrogen or lower
alkyl; and [0053] R.sup.15 is hydrogen, lower alkyl, lower alkenyl
or lower alkynyl.
[0054] In another embodiment, the invention provides compounds, or
a polymorph, solvate, ester, tautomer, diastereomer, enantiomer,
pharmaceutically acceptable salt or prodrug thereof, which show
utility for inhibiting HSP90 and treating and/or preventing
diseases that are HSP90-dependent, that are prepared by the process
comprising:
[0055] reacting a compound of Formula Y and a compound of Formula
Z, wherein: [0056] Y is represented by any of the following
formulae: ##STR4## and [0057] Z is L.sup.1-R.sup.4--R.sup.5;
wherein: [0058] L.sub.1 is halogen, NR.sup.8R.sup.10, triflate,
tosylate, or mesylate; [0059] R.sup.4 is --(CHR.sup.12)--, --C(O),
--C(S), --S(O)--, or --SO.sub.2--; [0060] R.sup.5 is aryl,
heteroaryl, alicyclic, or heterocyclic, wherein [0061] the aryl
group is substituted with 3 to 5 substituents, [0062] the
heteroaryl group is substituted with 2 to 5 substituents, [0063]
the alicyclic group is substituted with 3 to 5 substituents, [0064]
the heterocyclic group is substituted with 3 to 5 substituents, and
[0065] the substituents on R.sup.5 are selected from the group
consisting of halogen, lower alkyl, lower alkenyl, lower alkynyl,
--SR.sup.8, --OR.sup.8, --CN, --C(O)OH, --C(O)R.sup.9, --NO.sub.2,
--NR.sup.8R.sup.10, lower aryl, heteroaryl, alicyclic, lower
heterocyclic, arylalkyl, heteroarylalkyl, amino, alkylamino,
dialkylamino, diarylalkylamino, oxo, oxa, perhaloalkyl,
perhaloalkoxy, perhaloacyl, guanidine, pyridinyl, thiophene,
furanyl, indole, indazole, phosphonates, phosphates,
phosphoramides, sulfonates, sulfones, sulfates, sulphonamides,
carbamates, ureas, thioureas and thioamides, wherein R.sup.8 and
R.sup.10 taken together optionally form a ring of 3-7 ring atoms
and optionally 1-3 of the ring atoms are heteroatoms selected from
the group of O, S and N; [0066] R.sup.8 is hydrogen, lower alkyl,
lower alkenyl, lower alkynyl, lower aryl, lower heteroaryl or
--C(O)R.sup.9; [0067] R.sup.9 is hydrogen, lower alkyl, lower
alkenyl, lower alkynyl, lower aryl, lower heteroaryl,
--NR.sup.10R.sup.10, or --OR.sup.11, wherein R.sup.10 and R.sup.10
taken together optionally form a ring of 3-7 ring atoms and
optionally 1-3 of the ring atoms are heteroatoms selected from the
group of O, S and N; [0068] R.sup.10 is hydrogen, lower alkyl,
lower alkenyl, lower alkynyl, lower aryl or lower heteroaryl;
[0069] R.sup.11 is lower alkyl, lower alkenyl, lower alkynyl, lower
aryl or lower heteroaryl; [0070] R.sup.12 is hydrogen or lower
alkyl; [0071] R.sup.21 is halogen, --OR.sup.8, --SR.sup.8 or lower
alkyl; [0072] R.sup.22 is --NR.sup.8R.sup.10; [0073] R.sup.23 is
hydrogen, --OH or its keto tautomer, --OR.sup.8, halogen, --CN,
lower alkyl, lower aryl or --C(O)R.sup.9; [0074] R.sup.24 is --CHO,
--NH.sub.2, --NO.sub.2 or --NO; [0075] R.sup.25 is halogen or --OH;
[0076] R.sup.26 is --C(O)NH.sub.2 or C(O)OEt; and [0077] R.sup.27
is --NH.sub.2, --OH or halogen.
[0078] In another aspect, the present invention is directed to
pharmaceutical compositions comprising the compounds of the
invention, in particular, the compounds of Formulae A, I and II,
and compounds formed by the process of the invention, and their
polymorphs, solvates, esters, tautomers, diastereomer, enantiomers,
pharmaceutically acceptable salts and prodrugs thereof, and one or
more pharmaceutical excipients, for use in treatment or prevention
of diseases that are HSP90-dependent.
[0079] In another aspect, the invention features a method of
treating an individual having an HSP90-mediated disorder by
administering to the individual a pharmaceutical composition that
comprises a pharmaceutically effective amount of a compound of
Formula A, I or II, or a polymorph, solvate, ester, tautomer,
diastereomer, enantiomer, enantiomers pharmaceutically acceptable
salt or prodrug thereof.
[0080] In one embodiment, the invention provides a method for
treating an individual having a disorder selected from the group of
inflammatory diseases, infections, autoimmune disorders, stroke,
ischemia, cardiac disorders, neurological disorders, fibrogenetic
disorders, proliferative disorders, tumors, leukemias, neoplasms,
cancers, carcinomas, metabolic diseases, and malignant disease.
[0081] In yet another embodiment, the invention provides a method
for treating an individual having a fibrogenetic disorder, such as,
for example, scleroderma, polymyositis, systemic lupus, rheumatoid
arthritis, liver cirrhosis, keloid formation, interstitial
nephritis and pulmonary fibrosis.
[0082] In another embodiment, the invention provides a combination
therapy comprising the administration of a pharmaceutically
effective amount of a compound of Formula I or Formula II, or a
polymorph, solvate, ester, tautomer, diastereomer, enantiomer,
pharmaceutically acceptable salt and prodrug thereof, according to
any of the preceding aspects or embodiments, and at least one
therapeutic agent selected from the group of cytotoxic agents,
anti-angiogenesis agents and anti-neoplastic agents. The
anti-neoplastic agent may be selected from the group of alkylating
agents, anti-metabolites, epidophyllotoxins antineoplastic enzymes,
topoisomerase inhibitors, procarbazines, mitoxantrones, platinum
coordination complexes, biological response modifiers and growth
inhibitors, hormonal/anti-hormonal therapeutic agents, and
haematopoietic growth factors.
[0083] Any of the above described aspects and embodiments of the
invention can be combined where practical.
[0084] The individual compounds, methods and compositions
prescribed do not preclude the utilization of other, unspecified
steps and agents, and those of ordinary skill in the art will
appreciate that additional steps and compounds may also be combined
usefully within the spirit of various aspects and embodiments of
the invention.
[0085] Advantages of the invention depend on the specific aspect
and embodiment and may include one or more of: ease of synthesis
and/or formulation, solubility, and IC.sub.50 relative to
previously existing compounds in the same or different classes of
HSP90 inhibitors.
DETAILED DESCRIPTION OF THE INVENTION
I. Definitions
[0086] A "pharmaceutically acceptable derivative or prodrug" means
any pharmaceutically acceptable salt, ester, salt of an ester or
other derivative of a compound of this invention, which, upon
administration to a recipient, is capable of providing, either
directly or indirectly, a compound of this invention or a
pharmaceutically active metabolite or residue thereof. Particularly
favored derivatives or prodrugs are those that increase the
bioavailability of the compounds of this invention when such
compounds are administered to a patient (e.g., by allowing orally
administered compound to be more readily absorbed into blood) or
which enhance delivery of the parent compound to a biological
compartment (e.g., the brain or lymphatic system).
[0087] A "pharmaceutically acceptable salt" may be prepared for any
compound of the invention having a functionality capable of forming
a salt, for example, an acid or base functionality.
Pharmaceutically acceptable salts may be derived from organic or
inorganic acids and bases. Compounds of the invention that contain
one or more basic functional groups, e.g., amino or alkylamino, are
capable of forming pharmaceutically acceptable salts with
pharmaceutically acceptable organic and inorganic acids. These
salts can be prepared in situ during the final isolation and
purification of the compounds of the invention, or by separately
reacting a purified compound of the invention in its free base form
with a suitable organic or inorganic acid, and isolating the salt
thus formed. Examples of suitable acid salts include acetate,
adipate, alginate, aspartate, benzoate, benzenesulfonate,
bisulfate, butyrate, citrate, camphorate, camphorsulfonate,
cyclopentanepropionate, digluconate, dodecylsulfate,
ethanesulfonate, formate, fumarate, glucoheptanoate,
glycerophosphate, glycolate, hemisulfate, heptanoate, hexanoate,
hydrochloride, hydrobromide, hydroiodide, 2-hydroxyethanesulfonate,
lactate, maleate, malonate, methanesulfonate,
2-napthalenesulfonate, nicotinate, nitrate, oxalate, palmoate,
pectinate, persulfate, 3-phenylpropionate, phosphate, picrate,
pivalate, propionate, salicylate, succinate, sulfate, tartrate,
thiocyanate, tosylate and undecampate. Other acids, such as oxalic,
while not in themselves pharmaceutically acceptable, may be
employed in the preparation of salts useful as intermediates in
obtaining the compounds of the invention and their pharmaceutically
acceptable acid addition salts. See, e.g., Berge et al.
"Pharmaceutical Salts", J. Pharm. Sci. 1977, 66:1-19.
[0088] Compounds of the present invention that contain one or more
acidic functional groups are capable of forming pharmaceutically
acceptable salts with pharmaceutically acceptable bases. The term
"pharmaceutically acceptable salts" in these instances refers to
the relatively non-toxic, inorganic and organic base addition salts
of compounds of the present invention. These salts can likewise be
prepared in situ during the final isolation and purification of the
compounds, or by separately reacting the purified compound in its
free acid form with a suitable base, such as the hydroxide,
carbonate or bicarbonate of a pharmaceutically acceptable metal
cation, with ammonia, or with a pharmaceutically acceptable organic
primary, secondary or tertiary amine. Representative alkali or
alkaline earth salts include the lithium, sodium, potassium,
calcium, magnesium, and aluminum salts and the like. Illustrative
examples of some of the bases that can be used include sodium
hydroxide, potassium hydroxide, choline hydroxide, sodium
carbonate, N.sup.+(C.sub.1-4 alkyl).sub.4, and the like.
Representative organic amines useful for the formation of base
addition salts include ethylamine, diethylamine, ethylenediamine,
ethanolamine, diethanolamine, piperazine and the like. This
invention also envisions the quaternization of any basic
nitrogen-containing groups of the compounds disclosed herein. Water
or oil-soluble or dispersible products may be obtained by such
quaternization. See, for example, Berge et al., supra.
[0089] Pharmaceutically acceptable prodrugs of the compounds of
this invention include, but are not limited to, esters, carbonates,
thiocarbonates, N-acyl derivatives, N-acyloxyalkyl derivatives,
quaternary derivatives of tertiary amines, N-Mannich bases, Schiff
bases, aminoacid conjugates, phosphate esters, metal salts and
sulfonate esters.
[0090] Suitable positions for derivatization of the compounds of
the invention to create "prodrugs" include but are not limited,
2-amino substitution. Those of ordinary skill in the art have the
knowledge and means to accomplish this without undue
experimentation. Various forms of prodrugs are well known in the
art. For examples of such prodrug derivatives, see, e.g.,
[0091] a) Design of Prodrugs, Bundgaard, A. Ed., Elseview, 1985 and
Method in Enzymology, Widder, K. et al., Ed.; Academic, 1985, vol.
42, p. 309-396;
[0092] b) Bundgaard, H. "Design and Application of Prodrugs" in A
Textbook of Drug Design and Development, Krosgaard-Larsen and H.
Bundgaard, Ed., 1991, Chapter 5, p. 113-191; and
[0093] c) Bundgaard, H., Advanced Drug Delivery Review, 1992, 8,
1-38.
Each of which is incorporated herein by reference.
[0094] The term "prodrugs" as employed herein includes, but is not
limited to, the following groups and combinations of these
groups:
[0095] Amine Prodrugs: ##STR5##
[0096] Hydroxy Prodrugs:
[0097] Acyloxyalkyl esters;
[0098] Alkoxycarbonyloxyalkyl esters;
[0099] Alkyl esters;
[0100] Aryl esters; and
[0101] Disulfide containing esters.
[0102] The term "alkyl," alone or in combination, refers to an
optionally substituted straight-chain, or optionally substituted
branched-chain saturated hydrocarbon radical having from one to
thirty carbons, more preferably one to twelve carbons. Examples of
alkyl radicals include methyl, ethyl, n-propyl, isopropyl, n-butyl,
isobutyl, sec-butyl, tert-butyl, tert-amyl, pentyl, hexyl, heptyl,
octyl and the like. The term "cycloalkyl" embraces cyclic alkyl
radicals which include monocyclic, bicyclic, tricyclic, and higher
multicyclic alkyl radicals wherein each cyclic moiety has from
three to eight carbon atoms. Examples of cycloalkyl radicals
include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and the
like. A "lower alkyl" is a shorter alkyl, e.g., one containing from
one to six carbon atoms.
[0103] The term "alkenyl," alone or in combination, refers to an
optionally substituted straight-chain, or optionally substituted
branched-chain hydrocarbon radical having one or more carbon-carbon
double-bonds and having from two to thirty carbon atoms, more
preferably two to eighteen carbons. Examples of alkenyl radicals
include ethenyl, propenyl, butenyl, 1,3-butadienyl and the like.
The term "cycloalkenyl" refers to cyclic alkenyl radicals which
include monocyclic, bicyclic, tricyclic, and higher multicyclic
alkenyl radicals wherein each cyclic moiety has from three to eight
carbon atoms. A "lower alkenyl" refers to an alkenyl having from
two to six carbons.
[0104] The term "alkynyl," alone or in combination, refers to an
optionally substituted straight-chain or optionally substituted
branched-chain hydrocarbon radical having one or more carbon-carbon
triple-bonds and having from two to thirty carbon atoms, more
preferably from two to twelve carbon atoms, from two to six carbon
atoms as well as those having from two to four carbon atoms.
Examples of alkynyl radicals include ethynyl, 2-propynyl,
2-butynyl, 1,3-butadiynyl and the like. The term "cycloalkynyl"
refers to cyclic alkynyl radicals which include monocyclic,
bicyclic, tricyclic, and higher multicyclic alkynyl radicals
wherein each cyclic moiety has from three to eight carbon atoms. A
"lower alkynyl" refers to an alkynyl having from two to six
carbons.
[0105] The terms "heteroalkyl, heteroalkenyl and heteroalkynyl"
include optionally substituted alkyl, alkenyl and alkynyl
structures, as described above, and which have one or more skeletal
chain atoms selected from an atom other than carbon, e.g., oxygen,
nitrogen, sulfur, phosphorous or combinations thereof.
[0106] The term "carbon chain" embraces any alkyl, alkenyl,
alkynyl, or heteroalkyl, heteroalkenyl, or heteroalkynyl group,
which are linear, cyclic, or any combination thereof. If the chain
is part of a linker and that linker comprises one or more rings as
part of the core backbone, for purposes of calculating chain
length, the "chain" only includes those carbon atoms that compose
the bottom or top of a given ring and not both, and where the top
and bottom of the ring(s) are not equivalent in length, the shorter
distance shall be used in determining the chain length. If the
chain contains heteroatoms as part of the backbone, those atoms are
not calculated as part of the carbon chain length.
[0107] The term "membered ring" can embrace any cyclic structure,
including aromatic, heteroaromatic, alicyclic, heterocyclic and
polycyclic fused ring systems as described below. The term
"membered" is meant to denote the number of skeletal atoms that
constitute the ring. Thus, for example, pyridine, pyran, and
pyrimidine are six-membered rings and pyrrole, tetrahydrofuran, and
thiophene are five-membered rings.
[0108] The term "aryl," alone or in combination, refers to an
optionally substituted aromatic hydrocarbon radical of six to
twenty ring atoms, and includes mono-aromatic rings and fused
aromatic ring. A fused aromatic ring radical contains from two to
four fused rings where the ring of attachment is an aromatic ring,
and the other individual rings within the fused ring may be
aromatic, heteroaromatic, alicyclic or heterocyclic. Further, the
term aryl includes mono-aromatic ring and fused aromatic rings
containing from six to twelve carbon atoms, as well as those
containing from six to ten carbon atoms. Examples of aryl groups
include, without limitation, phenyl, naphthyl, anthryl, chrysenyl,
and benzopyrenyl ring systems. The term "lower aryl" refers to an
aryl having six to ten skeletal ring carbons, e.g., phenyl and
naphthyl ring systems.
[0109] The term "heteroaryl" refers to optionally substituted
aromatic radicals containing from five to twenty skeletal ring
atoms and where one or more of the ring atoms is a heteroatom such
as, for example, oxygen, nitrogen, sulfur, selenium and phosphorus.
The term heteroaryl includes optionally substituted mono-heteroaryl
radicals and fused heteroaryl radicals having at least one
heteroatom (e.g., quinoline, benzothiazole). A fused heteroaryl
radical may contain from two to four fused rings and where the ring
of attachment is a heteroaromatic ring, the other individual rings
within the fused ring system may be aromatic, heteroaromatic,
alicyclic or heterocyclic. The term heteroaryl also includes
monorheteroaryls or fused heteroaryls having from five to twelve
skeletal ring atoms, as well as those having from five to ten
skeletal ring atoms. Examples of heteroaryls include, without
limitation, furanyl, benzofuranyl, chromenyl, pyridyl, pyrrolyl,
indolyl, quinolinyl, pyridyl-N-oxide, pyrimidyl, pyrazinyl,
imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, benzothiozole,
benzimidazole, benzoxazoles, benzothiadiazole, benzoxadiazole,
benzotriazole, quinolines, isoquinolines, indolyl, purinyl,
indolizinyl, thienyl and the like and their oxides. The term "lower
heteroaryl" refers to a heteroaryl having five to ten skeletal ring
atoms, e.g., pyridyl, thienyl, pyrimidyl, pyrazinyl, pyrrolyl, or
furanyl.
[0110] The term "alicyclic" alone or in combination, refers to an
optionally substituted saturated or unsaturated nonaromatic
hydrocarbon ring system containing from three to twenty ring atoms.
The term alicyclic includes mono-alicyclic and fused alicyclic
radicals. A fused alicyclic may contain from two to four fused
rings where the ring of attachment is an alicyclic ring, and the
other individual rings within the fused-alicyclic radical may be
aromatic, heteroaromatic, alicyclic and heterocyclic. The term
alicyclic also includes mono-alicyclic and fused alicyclic radicals
containing from three to twelve carbon atoms, as well as those
containing from three to ten carbon atoms. Examples of alicyclics
include, without limitation, cyclopropyl, cyclopropenyl,
cyclobutyl, cyclopentyl, cyclodecyl, cyclododecyl,
cyclopentadienyl, indanyl, and cyclooctatetraenyl ring systems. The
term "lower alicyclic" refers to an alicyclic having three to ten
skeletal ring carbons, e.g., cyclopropyl, cyclopropenyl,
cyclobutyl, cyclopentyl, decalinyl, and cyclohexyl.
[0111] The term "heterocyclic" refers to optionally substituted
saturated or unsaturated nonaromatic ring radicals containing from
five to twenty ring atoms where one or more of the ring atoms are
heteroatoms such as, for example, oxygen, nitrogen, sulfur, and
phosphorus. The term alicyclic includes mono-heterocyclic and fused
heterocyclic ring radicals. A fused heterocyclic radical may
contain from two to four fused rings where the attaching ring is a
heterocyclic, and the other individual rings within the fused
heterocyclic radical may be aromatic, heteroaromatic, alicyclic or
heterocyclic. The term heterocyclic also includes mono-heterocyclic
and fused alicyclic radicals having from five to twelve skeletal
ring atoms, as well as those having from five to ten skeletal ring
atoms. Example of heterocyclics include without limitation,
tetrahydrofuranyl, benzodiazepinyl, tetrahydroindazolyl,
dihyroquinolinyl, and the like. The term "lower heterocyclic"
refers to a heterocyclic ring system having five to ten skeletal
ring atoms, e.g., dihydropyranyl, pyrrolidinyl, indolyl,
piperidinyl, piperazinyl, and the like.
[0112] The term "alkylaryl," or "araalkyl," alone or in
combination, refers to an aryl radical as defined above in which
one H atom is replaced by an alkyl radical as defined above, such
as, for example, tolyl, xylyl and the like.
[0113] The term "arylalkyl," alone or in combination, refers to an
alkyl radical as defined above in which one H atom is replaced by
an aryl radical as defined above, such as, for example, benzyl,
2-phenylethyl and the like.
[0114] The term "heteroarylalkyl" refers to an alkyl radical as
defined above in which one H atom is replaced by a heteroaryl
radical as defined above, each of which may be optionally
substituted.
[0115] The term "alkoxy," alone or in combination, refers to an
alkyl ether radical, alkyl-O--, wherein the term alkyl is defined
as above. Examples of alkoxy radicals include methoxy, ethoxy,
n-propoxy, isopropoxy, n-butoxy, iso-butoxy, sec-butoxy,
tert-butoxy and the like.
[0116] The term "aryloxy," alone or in combination, refers to an
aryl ether radical wherein the term aryl is defined as above.
Examples of aryloxy radicals include phenoxy, benzyloxy and the
like.
[0117] The term "alkylthio," alone or in combination, refers to an
alkyl thio radical, alkyl-S--, wherein the term alkyl is as defined
above.
[0118] The term "arylthio," alone or in combination, refers to an
aryl thio radical, aryl-S--, wherein the term aryl is as defined
above.
[0119] The term "heteroarylthio" refers to the group
heteroaryl-S--, wherein the term heteroaryl is as defined
above.
[0120] The term "acyl" refers to a radical --C(O)R where R includes
alkyl, alkenyl, alkynyl, aryl, heteroaryl, alicyclic, heterocyclic,
arylalkyl or heteroarylalkyl wherein the alkyl, alkenyl, alkynyl,
aryl, heteroaryl, alicyclic, heterocyclic, arylalkyl or heteroaryl
alkyl groups may be optionally substituted.
[0121] The term "acyloxy" refers to the ester group --OC(O)R, where
R is H, alkyl, alkenyl, alkynyl, aryl, heteroaryl, alicyclic,
heterocyclic, arylalkyl, or heteroarylalkyl wherein the alkyl,
alkenyl, alkynyl, aryl, heteroaryl, alicyclic, heterocyclic,
arylalkyl or heteroarylalkyl may be optionally substituted.
[0122] The term "carboxy esters" refers to --C(O)OR where R is
alkyl, aryl or arylalkyl, wherein the alkyl, aryl and arylalkyl
groups may be optionally substituted.
[0123] The term "carboxamido" refers to ##STR6##
[0124] where each of R and R' are independently selected from the
group consisting of H, alkyl, aryl, heteroaryl, alicyclic,
heterocyclic, arylalkyl and heteroarylalkyl, wherein the alkyl,
aryl, heteroaryl, alicyclic, heterocyclic, or arylalkyl groups may
be optionally substituted.
[0125] The term "oxo" refers to .dbd.O.
[0126] The term "halogen" includes F, Cl, Br and I.
[0127] The terms "haloalkyl, haloalkenyl, haloalkynyl and
haloalkoxy" include alkyl, alkenyl, alkynyl and alkoxy structures,
as described above, that are substituted with one or more
fluorines, chlorines, bromines or iodines, or with combinations
thereof.
[0128] The terms "perhaloalkyl, perhaloalkyloxy and perhaloacyl"
refer to alkyl, alkyloxy and acyl radicals as described above, that
all the H atoms are substituted with fluorines, chlorines, bromines
or iodines, or combinations thereof.
[0129] The terms "cycloalkyl, arylalkyl, aryl, heteroaryl,
alicyclic, heterocyclic, alkyl, alkynyl, alkenyl, haloalkyl, and
heteroalkyl" include optionally substituted cycloalkyl, arylalkyl,
aryl, heteroaryl, alicyclic, heterocyclic, alkyl, alkynyl, alkenyl,
haloalkyl and heteroalkyl groups.
[0130] The terms "alkylamino", refers to the group --NHR where R is
independently selected from alkyl.
[0131] The terms "dialkylamino", refers to the group --NRR' where R
and R' are alkyls.
[0132] The term "sulfide" refers to a sulfur atom covalently linked
to two atoms; the formal oxidation state of said sulfur is (II).
The term "thioether" may be used interchangeably with the term
"sulfide."
[0133] The term "sulfoxide" refers to a sulfur atom covalently
linked to three atoms, at least one of which is an oxygen atom; the
formal oxidation state of said sulfur atom is (IV).
[0134] The term "sulfone" refers to a sulfur atom covalently linked
to four atoms, at least two of which are oxygen atoms; the formal
oxidation state of said sulfur atom is (VI).
[0135] The terms "optional" or "optionally" mean that the
subsequently described event or circumstance may but need not
occur, and that the description includes instances where the event
or circumstance occurs and instances in which it does not. For
example, "aryl optionally mono- or di-substituted with an alkyl"
means that the alkyl may but need not be present, or either one
alkyl or two may be present, and the description includes
situations where the aryl is substituted with one or two alkyls and
situations where the aryl is not substituted with an alkyl.
[0136] "Optionally substituted" groups may be substituted or
unsubstituted. The substituents of an "optionally substituted"
group may include, without limitation, one or more substituents
independently selected from the following groups or designated
subsets thereof: lower alkyl, lower alkenyl, lower alkynyl, lower
aryl, heteroaryl, alicyclic, heterocyclic, arylalkyl,
heteroarylalkyl, lower alkoxy, lower aryloxy, amino, alkylamino,
dialkylamino, diarylalkylamino, alkylthio, arylthio,
heteroarylthio, oxo, oxa, carbonyl (--C(O)), carboxyesters
(--C(O)OR), carboxamido (--C(O)NH.sub.2), carboxy, acyloxy, --H,
halo, --CN, --NO.sub.2, --N.sub.3, --SH, --OH, --C(O)CH.sub.3,
perhaloalkyl, perhaloalkoxy, perhaloacyl, guanidine, pyridinyl,
thiophene, furanyl, indole, indazole, esters, amides, phosphonates,
phosphonic acid, phosphates, phosphoramides, sulfonates, sulfones,
sulfates, sulphonamides, carbamates, ureas, thioureas, thioamides,
thioalkyls. An optionally substituted group may be unsubstituted
(e.g., --CH.sub.2CH.sub.3), fully substituted (e.g.,
--CF.sub.2CF.sub.3), monosubstituted (e.g., --CH.sub.2CH.sub.2F) or
substituted at a level anywhere in-between fully substituted and
monosubstituted (e.g., --CH.sub.2CF.sub.3).
[0137] The term "pyridine-1-oxy" also means "pyridine-N-oxy."
[0138] Some of the compounds of the present invention may contain
one or more chiral centers and therefore may exist in enantiomeric
and diastereomeric forms. The scope of the present invention is
intended to cover all isomers per se, as well as mixtures of cis
and trans isomers, mixtures of diastereomers and racemic mixtures
of enantiomers (optical isomers) as well. Further, it is possible
using well known techniques to separate the various forms, and some
embodiments of the invention may feature purified or enriched
species of a given enantiomer or diastereomer.
[0139] A "pharmacological composition" refers to a mixture of one
or more of the compounds described herein, or pharmaceutically
acceptable salts thereof, with other chemical components, such as
pharmaceutically acceptable carriers and/or excipients. The purpose
of a pharmacological composition is to facilitate administration of
a compound to an organism.
[0140] The phrase "pharmaceutically acceptable carrier" as used
herein means a pharmaceutically-acceptable material, composition or
vehicle, such as a liquid or solid filler, diluent, excipient,
solvent or encapsulating material, involved in carrying or
transporting the subject agent from one organ, or portion of the
body, to another organ, or portion of the body. Each carrier must
be "acceptable" in the sense of being compatible with the other
ingredients of the formulation and not injurious to the patient.
Some examples of materials which can serve as
pharmaceutically-acceptable carriers include: (1) sugars, such as
lactose, glucose and sucrose; (2) starches, such as corn starch and
potato starch; (3) cellulose, and its derivatives, such as sodium
carboxymethyl cellulose, ethyl cellulose and cellulose acetate; (4)
powdered tragacanth; (5) malt; (6) gelatin; (7) talc; (8)
excipients, such as cocoa butter and suppository waxes; (9) oils,
such as peanut oil, cottonseed oil, safflower oil, sesame oil,
olive oil, corn oil and soybean oil; (10) glycols, such as
propylene glycol; (11) polyols, such as glycerin, sorbitol,
mannitol and polyethylene glycol; (12) esters, such as ethyl oleate
and ethyl laurate; (13) agar; (14) buffering agents, such as
magnesium hydroxide and aluminum hydroxide; (15) alginic acid; (16)
pyrogen-free water; (17) isotonic saline; (18) Ringer's solution;
(19) ethyl alcohol; (20) phosphate buffer solutions; and (21) other
non-toxic compatible substances employed in pharmaceutical
formulations. A physiologically acceptable carrier should not cause
significant irritation to an organism and does not abrogate the
biological activity and properties of the administered
compound.
[0141] An "excipient" refers to an inert substance added to a
pharmacological composition to further facilitate administration of
a compound. Examples of excipients include but are not limited to
calcium carbonate, calcium phosphate, various sugars and types of
starch, cellulose derivatives, gelatin, vegetable oils and
polyethylene glycols.
[0142] A "pharmaceutically effective amount" means an amount which
is capable of providing a therapeutic and/or prophylactic effect.
The specific dose of compound administered according to this
invention to obtain therapeutic and/or prophylactic effect will, of
course, be determined by the particular circumstances surrounding
the case, including, for example, the specific compound
administered, the route of administration, the condition being
treated, and the individual being treated. A typical daily dose
(administered in single or divided doses) will contain a dosage
level of from about 0.01 mg/kg to about 50-100 mg/kg of body weight
of an active compound of the invention. Preferred daily doses
generally will be from about 0.05 mg/kg to about 20 mg/kg and
ideally from about 0.1 mg/kg to about 10 mg/kg. Factors such as
clearance rate, half-life and maximum tolerated dose (MTD) have yet
to be determined but one of ordinary skill in the art can determine
these using standard procedures.
[0143] In some method embodiments, the preferred therapeutic effect
is the inhibition, to some extent, of the growth of cells
characteristic of a proliferative disorder, e.g., breast cancer. A
therapeutic effect will also normally, but need not, relieve to
some extent one or more of the symptoms other than cell growth or
size of cell mass. A therapeutic effect may include, for example,
one or more of 1) a reduction in the number of cells; 2) a
reduction in cell size; 3) inhibition (i.e., slowing to some
extent, preferably stopping) of cell infiltration into peripheral
organs, e.g., in the instance of cancer metastasis; 3) inhibition
(i.e., slowing to some extent, preferably stopping) of tumor
metastasis; 4) inhibition, to some extent, of cell growth; and/or
5) relieving to some extent one or more of the symptoms associated
with the disorder.
[0144] As used herein, the term IC.sub.50 refers to an amount,
concentration or dosage of a particular test compound that achieves
a 50% inhibition of a maximal response in an assay that measures
such response. In some method embodiments of the invention, the
"IC.sub.50" value of a compound of the invention can be greater for
normal cells than for cells exhibiting a proliferative disorder,
e.g., breast cancer cells. The value depends on the assay used.
[0145] By a "standard" is meant a positive or negative control. A
negative control in the context of HER2 expression levels is, e.g.,
a sample possessing an amount of HER2 protein that correlates with
a normal cell. A negative control may also include a sample that
contains no HER2 protein. By contrast, a positive control does
contain HER2 protein, preferably of an amount that correlates with
overexpression as found in proliferative disorders, e.g., breast
cancers. The controls may be from cell or tissue samples, or else
contain purified ligand (or absent ligand), immobilized or
otherwise. In some embodiments, one or more of the controls may be
in the form of a diagnostic "dipstick."
[0146] By "selectively targeting" is meant affecting one type of
cell to a greater extent than another, e.g., in the case of cells
with high as opposed to relatively low or normal HER2 levels.
II. Compounds of the Invention
[0147] Compounds of the invention and their polymorphs, solvates,
esters, tautomers, diastereomers, enantiomers, pharmaceutically
acceptable salts or prodrugs show utility for inhibiting HSP90 and
treating and/or preventing diseases that are HSP90-dependent.
[0148] One embodiment of the compounds of the invention is of
Formula A: ##STR7## or a polymorph, solvate, ester, tautomer,
diastereomer, enantiomer, pharmaceutically acceptable salt or
prodrug thereof, wherein: [0149] X.sup.1 and X.sup.2 are the same
or different and each is nitrogen or --CR.sup.6; [0150] X.sup.3 is
nitrogen or --CR.sup.3 wherein R.sup.3 is hydrogen, OH, a keto
tautomer, --OR.sup.8, --CN, halogen, lower alkyl, or --C(O)R.sup.9;
[0151] X.sup.4 is nitrogen or a group CR.sup.6 when X.sup.3 is
nitrogen, and X.sub.4 is --CR.sup.6R.sup.7 when X.sub.3 is
--CR.sup.3;
[0152] R.sup.1 is halogen, --OR.sup.8, --SR.sup.8, or lower
alkyl;
[0153] R.sup.2 is --NR.sup.8R.sup.10; [0154] R.sup.4 is
--(CH.sub.2).sub.n-- wherein n=0-3, --C(O), --C(S), --SO.sub.2--,
or --SO.sub.2N--; and [0155] R.sup.5 is alkyl, aryl, heteroaryl,
alicyclic, or heterocyclic, each of which is optionally bi- or
tricyclic, and optionally substituted with H, halogen, lower alkyl,
lower alkenyl, lower alkynyl, lower aryl, lower alicyclic,
araalkyl, aryloxyalkyl, alkoxyalkyl, perhaloalkyl, perhaloalkyloxy,
perhaloacyl, --N.sub.3, --SR.sup.8, --OR.sup.8, --CN,
--CO.sub.2R.sup.9, --NO.sub.2, or --NR.sup.8R.sup.10;
[0156] with the provisos that:
[0157] the compound is not one found or described in one or more of
JP 10025294; U.S. Pat. No. 4,748,177; U.S. Pat. No. 4,748,177; U.S.
Pat. No. 6,369,092; WO 00/06573; WO 02/055521; WO 02/055082; WO
02/055083; Eur. J. Med. Chem., 1994, 29(1), 3-9; and J. Het. Chem.
1990, 27(5), 1409;
[0158] --R.sup.4R.sup.5 is not a ribose or derivative thereof, or a
sugar or derivative thereof;
[0159] --R.sup.4R.sup.5 is not a phosphonate or phosphonic acid, or
a group substituted with a phosphonate or phosphonic acid; and
[0160] when R.sup.4 is (CH.sub.2).sub.n where n=0 or 1, then
R.sup.4 and R.sup.5 are not connected with `O`, e.g.,
--CH.sub.2--O--CH.sub.2-- or
--CH.sub.2--CH.sub.2--O--CH.sub.2--.
[0161] In one embodiment of the compound, tautomer,
pharmaceutically acceptable salt thereof, or prodrug thereof of
Formula A, X.sub.1 and X.sub.2 are the same or different and each
is nitrogen or --CR.sup.6; R.sup.1 is halogen, --OR.sup.8,
--SR.sup.8, or lower alkyl; R.sup.2 is --NR.sup.8R.sup.10; R.sup.3
is hydrogen, --OH or keto tautomer, --OR.sup.8, halogen, --CN,
lower alkyl, or --C(O)R.sup.9; R.sup.4 is --(CH.sub.2).sub.n--
wherein n=0-3, --C(O), --C(S), --SO.sub.2--, or --SO.sub.2N--; and
R.sup.5 is alkyl, aromatic, heteroaromatic, alicyclic,
heterocyclic, each of which is optionally bi- or tricyclic, and
optionally substituted with H, halogen, lower alkyl, --SR.sup.8,
--OR.sup.8, --CN, --CO.sub.2R.sup.9, --NO.sub.2 or
--NR.sup.8R.sup.10; R.sup.8 is hydrogen, lower alkyl, lower aryl or
--(CO)R.sup.9; R.sup.9 is lower alkyl, lower aryl, lower
heteroaryl, --NR.sup.8R.sup.10 or OR.sup.11; R.sup.11 is lower
alkyl or lower aryl; and R.sup.10 is hydrogen or lower alkyl.
[0162] In one embodiment, the compound, tautomer, pharmaceutically
acceptable salt thereof, or prodrug thereof of Formula A, R.sup.1
is selected from halogen, hydroxyl, lower alkoxy, lower thioalkyl
and C.sub.1-4 alkyl; and R.sup.2 is --NH.sub.2; and R.sup.3 is
hydrogen.
[0163] In another embodiment, R.sup.4 is --(CH.sub.2).sub.n--,
where n=0-3.
[0164] In another embodiment, R.sup.1 is selected from halogen,
hydroxyl, lower alkoxy, lower thioalkyl or C.sub.1-4 alkyl;
optionally, R.sup.2 is --NH.sub.2.
[0165] In another embodiment, R.sup.4 is --CH.sub.2--.
[0166] In another embodiment, R.sup.4 is --(CH.sub.2).sub.n--,
wherein n=0-3, R.sup.1 is selected from halogen, hydroxyl, lower
alkoxy, lower thioalkyl, and C.sub.1-4 alkyl, and R.sup.2 is
optionally NH.sub.2.
[0167] In another embodiment, R.sup.1 is halogen, hydroxyl, lower
alkoxy, lower thioalkyl, or C.sub.1-4 alkyl; and R.sup.2 is
optionally NH.sub.2, R.sup.4 is --(CH.sub.2)--, and R.sup.5 is
phenyl, benzyl, or pyridyl, all optionally substituted with H,
halogen, lower alkyl, --SR.sup.8, --OR.sup.8 (or cyclic ethers such
as methylenedioxy), --CN, --CO.sub.2R.sup.9, --NO.sub.2, or
--NR.sup.8R.sup.10; R.sup.8 is hydrogen, lower alkyl, lower aryl or
--(CO)R.sup.9; R.sup.9 is lower alkyl, lower aryl, lower
heteroaryl, --NR.sup.8R.sup.10 or --OR.sup.11; R.sup.11 is lower
alkyl or lower aryl; and R.sup.10 is hydrogen or lower alkyl.
[0168] In another embodiment R.sup.1 is halogen, R.sup.2 is
--NH.sub.2, R.sup.4 is --CH.sub.2--, R.sup.6 is H or halogen, and
R.sup.5 is phenyl optionally substituted with H, halogen, C.sub.1-4
alkyl, C.sub.1-4 alkoxy, C.sub.1-4 alkylthio, perhaloalkyl,
perhaloalkyloxy, --CN, --NO.sub.2, --NH.sub.2 or
--CO.sub.2R.sup.11.
[0169] In another embodiment, R.sup.1 is halogen, R.sup.1 is
--NH.sub.2, R.sup.4 is --CH.sub.2--, R.sup.6 is H, and R.sup.5 is
2-halo-3,5-dimethoxyphenyl optionally substituted with H, halogen,
C.sub.1-4 alkyl, C.sub.1-4 alkoxy, C.sub.1-4 alkylthio,
perhaloalkyl, perhaloalkyloxy, --CN, --NO.sub.2, --NH.sub.2, or
--CO.sub.2R.sup.11 at the para (4-) position.
[0170] In another embodiment, R.sup.1 is chloro, R.sup.2 is
--NH.sub.2, R.sup.4 is --CH.sub.2--, R.sup.6 is H and R.sup.5 is
2-chloro-3,4,5-trimethoxyphenyl.
[0171] In another embodiment, R.sup.1 is chloro, R.sup.2 is
--NH.sub.2, R.sup.4 is --CH.sub.2--, R.sup.6 is H and R.sup.5 is
2-bromo-3,4,5-trimethoxyphenyl. In other embodiments, R.sup.5 is
selected from 2-iodo-3,4,5-trimethoxyphenyl,
2-fluoro-3,4,5-trimethoxyphenyl, or
2-bromo-3,4,5-trimethoxyphenyl.
[0172] Any of the foregoing embodiments can be combined where
feasible and appropriate.
[0173] In another aspect, the invention provides compounds of
Formula A1: ##STR8## or a polymorph, solvate, ester, tautomer,
enantiomer, pharmaceutically acceptable salt or prodrug thereof,
wherein [0174] X.sup.1 and X.sup.2 are the same or different and
each is nitrogen or CR.sup.6;
[0175] R.sup.1 is halogen, --ORS, --SR.sup.8 or lower alkyl; [0176]
R.sup.2 is --NR.sup.8R.sup.10; [0177] R.sup.3 is hydrogen, --OH or
keto tautomer, --OR.sup.8, halogen, --CN, lower alkyl or
--C(O)R.sup.9; [0178] R.sup.4 is --(CH.sub.2).sub.6-- where n=0-3,
--C(O), --C(S), --SO.sub.2-- or --SO.sub.2N--; [0179] R.sup.5 is
alkyl, aryl, heteroaryl, alicyclic, heterocyclic, all optionally
bi- or tricyclic, and all optionally substituted with H, halogen,
lower alkyl, --SR.sup.8, --OR.sup.8, --CN, --CO.sub.2R.sup.9,
--NO.sub.2 or --NR.sup.8R.sup.10; [0180] R.sup.8 is hydrogen, lower
alkyl, lower aryl or --(CO)R.sup.9; [0181] R.sup.9 is lower alkyl,
lower aryl, lower heteroaryl, --NR.sup.8R.sup.10 or OR.sup.11;
[0182] R.sup.11 is lower alkyl or lower aryl; and [0183] R.sup.10
is hydrogen or lower alkyl.
[0184] In one embodiment of the compounds of Formula A1, or a
tautomer, pharmaceutically acceptable salt, or prodrug thereof,
R.sup.1 is halogen, hydroxyl, lower alkoxy, lower thioalkyl, or
C.sub.1-4 alkyl; and R.sup.2 is NH.sub.2.
[0185] In another embodiment of the compounds of Formula A1, or a
tautomer, pharmaceutically acceptable salt, or prodrug thereof,
R.sup.4 is --(CH.sub.2).sub.n--, where n=0-3.
[0186] In another embodiment of the compounds of Formula A1, or a
tautomer, pharmaceutically acceptable salt, or prodrug thereof,
R.sup.1 is halogen, hydroxyl, lower alkoxy, lower thioalkyl, or
C.sub.1-4 alkyl; R.sup.2 is NH.sub.2; and R.sup.4 is
--(CH.sub.2).sub.n--, wherein n=0-3.
[0187] In another embodiment of the compounds of Formula A1, or a
tautomer, pharmaceutically acceptable salt thereof, R.sup.1 is
halogen; R.sup.2 is NH.sub.2; and R.sup.4 is --CH.sub.2--.
[0188] Another embodiment of the compounds of the invention is of
Formula I: ##STR9## or a polymorph, solvate, ester, tautomer,
diastereomer, enantiomer, pharmaceutically acceptable salt or
prodrug thereof, wherein: [0189] R.sup.1 is halogen, --OR.sup.11,
--SR.sup.11 or lower alkyl; [0190] R.sup.2 is --NHR.sup.8; [0191]
R.sup.3 is selected from the group consisting of hydrogen, halogen,
--SR.sup.8, --OR.sup.8, --CN, --C(O)R.sup.9, --CO.sub.2H,
--NO.sub.2, --NR.sup.8R.sup.10, lower alkyl, lower alkenyl, lower
alkynyl, lower perhaloalkyl, aryl, heteroaryl, alicyclic and
heterocyclic, all optionally substituted, wherein: [0192] the aryl,
heteroaryl, alicyclic and heterocyclic groups are optionally mono-,
bi- or tri-cyclic; [0193] R.sup.8 and R.sup.10 taken together
optionally form a ring of 3-7 ring atoms and optionally 1-2 of the
ring atoms are heteroatoms selected from the group of O, S and N,
and [0194] the optional substituents on R.sup.3 are selected from
the group consisting of halogen, lower alkyl, lower alkenyl, lower
alkynyl, --SR.sup.8, --OR.sup.8, --CN, --C(O)R.sup.9, --C(O)OH,
--NO.sub.2, --NR.sup.8R.sup.10, lower aryl, lower heteroaryl, lower
alicyclic, lower heterocyclic, arylalkyl, heteroarylalkyl, amino,
alkylamino, dialkylamino, diarylalkylamino, oxo, oxa, perhaloalkyl,
perhaloalkoxy, perhaloacyl, guanidine, pyridinyl, thiophene,
furanyl, indole, indazole, phosphonates, phosphates,
phosphoramides, sulfonates, sulfones, sulfates, sulphonamides,
carbamates, ureas, thioureas and thioamides, wherein R.sup.8 and
R.sup.10 taken together optionally form a ring of 3-7 ring atoms
and optionally 1-3 of the ring atoms are heteroatoms selected from
the group of O, S and N; [0195] R.sup.4 is --CHR.sup.12--, --C(O),
--C(S), --S(O)--, or --SO.sub.2--; [0196] R.sup.5 is aryl,
heteroaryl, alicyclic, or heterocyclic, wherein [0197] the aryl
group is substituted with 3 to 5 substituents, [0198] the
heteroaryl group is substituted with 2 to 5 substituents, [0199]
the alicyclic group is substituted with 3 to 5 substituents, [0200]
the heterocyclic group is substituted with 3 to 5 substituents, and
[0201] the substituents on R.sup.5 are selected from the group
consisting of halogen, lower alkyl, lower alkenyl, lower alkynyl,
--SR.sup.8, --OR.sup.8, --CN, --C(O)OH, --C(O)R.sup.9, --NO.sub.2,
--NR.sup.8R.sup.10 lower aryl, heteroaryl, alicyclic, lower
heterocyclic, arylalkyl, heteroarylalkyl, amino, alkylamino,
dialkylamino, diarylalkylamino, oxo, oxa, perhaloalkyl,
perhaloalkoxy, perhaloacyl, guanidine, pyridinyl, thiophene,
furanyl, indole, indazole, phosphonates, phosphates,
phosphoramides, sulfonates, sulfones, sulfates, sulphonamides,
carbamates, ureas, thioureas and thioamides, wherein R.sup.8 and
R.sup.10 taken together optionally form a ring of 3-7 ring atoms
and optionally 1-3 of the ring atoms are heteroatoms selected from
the group of O, S and N; [0202] R.sup.8 is hydrogen, lower alkyl,
lower alkenyl, lower alkynyl, lower aryl, lower heteroaryl or
--C(O)R.sup.9; [0203] R.sup.9 is hydrogen, lower alkyl, lower
alkenyl, lower alkynyl, lower aryl, lower heteroaryl,
--NR.sup.10R.sup.10 or --OR.sup.11 wherein R.sup.10 and R.sup.10
taken together optionally form a ring of 3-7 ring atoms and
optionally 1-3 of the ring atoms are heteroatoms selected from the
group of O, S and N; [0204] R.sup.10 is hydrogen, lower alkyl,
lower alkenyl, lower alkynyl, lower aryl or lower heteroaryl;
[0205] R.sup.11 is lower alkyl, lower alkenyl, lower alkynyl, lower
aryl or lower heteroaryl; and [0206] R.sup.12 is hydrogen or lower
alkyl.
[0207] In one embodiment of the compounds of Formula I, or a
polymorph, solvate, ester, tautomer, enantiomer, pharmaceutically
acceptable salt or prodrug thereof, R.sup.1 is halogen or lower
alkyl; R.sup.2 is --NHR.sup.8, where R.sup.8 is hydrogen or
--C(O)R.sup.9; R.sup.5 is aryl or heteroaryl, wherein each of said
aryl and heteroaryl groups is monocyclic or bicyclic.
[0208] In another embodiment of the compounds of Formula I, or a
polymorph, solvate, ester, tautomer, enantiomer, pharmaceutically
acceptable salt or prodrug thereof, R.sup.2 is --NH.sub.2; R.sup.3
is selected from hydrogen, halogen, --SR.sup.8, --OR.sup.8, --CN,
--NR.sup.8R.sup.10, lower alkyl, lower alkenyl, lower alkynyl,
lower perhaloalkyl, lower aryl, lower heteroaryl, lower alicyclic,
and lower heterocyclic, wherein R.sup.8 is hydrogen, lower alkyl,
lower alkenyl, lower alkynyl, lower aryl or lower heteroaryl, and
wherein R.sup.8 and R.sup.10 when taken together optionally form a
ring of 3-7 ring atoms and optionally 1-3 of the ring atoms are
heteroatoms selected from the group of O, S and N; and R.sup.5 is
aryl or heteroaryl, wherein each of said aryl and heteroaryl groups
is monocyclic or bicyclic.
[0209] In another embodiment of the compounds of Formula I, or a
polymorph, solvate, ester, tautomer, enantiomer, pharmaceutically
acceptable salt or prodrug thereof, R.sup.1 is halogen or lower
alkyl; R.sup.2 is --NH.sub.2; R.sup.4 is --(CH.sub.2)--; and
R.sup.5 is aryl, heteroaryl, alicyclic or heterocyclic, wherein
each of said aryl, heteroaryl alicyclic or heterocyclic groups is
monocyclic or bicyclic.
[0210] In another embodiment of the compounds of Formula I, or a
polymorph, solvate, ester, tautomer, enantiomer, pharmaceutically
acceptable salt or prodrug thereof, R.sup.1 is halogen; R.sup.2 is
--NH.sub.2; R.sup.3 is hydrogen, halogen, --SR.sup.8, --OR.sup.8,
lower alkyl, lower alkenyl, lower alkynyl, lower perhaloalkyl,
lower aryl, lower heteroaryl, or --NR.sup.8R.sup.10, wherein
R.sup.8 and R.sup.10 taken together optionally form a ring of 3-7
ring atoms and optionally 1-3 of the ring atoms are heteroatoms
selected from the group of O, S and N; R.sup.4 is --CH.sub.2--; and
R.sup.5 is aryl or heteroaryl, wherein each of said aryl and
heteroaryl groups is monocyclic or bicyclic.
[0211] In another embodiment of the compounds of Formula I, or a
polymorph, solvate, ester, tautomer, enantiomer, pharmaceutically
acceptable salt or prodrug thereof, R.sup.1 is halogen; R.sup.2 is
--NH.sub.2; R.sup.3 is hydrogen, halogen, --SR.sup.8, --OR.sup.8,
lower alkyl, lower aryl, lower heteroaryl, or --NR.sup.8R.sup.10,
wherein R.sup.8 and R.sup.10 taken together optionally form a ring
of 3-7 ring atoms and optionally 1-3 of the ring atoms are
heteroatoms selected from the group of O, S and N; R.sup.4 is
--CH.sub.2--; and R.sup.5 is aryl or heteroaryl, wherein each of
said aryl and heteroaryl groups is monocyclic or bicyclic.
[0212] In another embodiment of the compounds of Formula I, or a
polymorph, solvate, ester, tautomer, enantiomer, pharmaceutically
acceptable salt or prodrug thereof, R.sup.1 is chloro or bromo; and
R.sup.5 is a phenyl having 3 to 5 substituents.
[0213] In another embodiment of the compounds of Formula I, or a
polymorph, solvate, ester, tautomer, enantiomer, pharmaceutically
acceptable salt or prodrug thereof, R.sup.1 is chloro or bromo; and
R.sup.5 is a pyridyl having 3 to 5 substituents.
[0214] In another embodiment of the compounds of Formula I, or a
polymorph, solvate, ester, tautomer, enantiomer, pharmaceutically
acceptable salt or prodrug thereof, R.sup.1 is chloro or bromo; and
R.sup.5 is an 1-oxy-pyridyl (N-oxy-pyridyl) having 3 to 5
substituents.
[0215] It should be understood that any of the foregoing
embodiments can be combined where feasible and appropriate.
[0216] Another embodiment of the compounds of the invention is of
Formula II: ##STR10## or a polymorph, solvate, ester, tautomer,
enantiomer, pharmaceutically acceptable salt or prodrug thereof,
wherein: [0217] R.sup.1 is halogen, --OR.sup.11, --SR.sup.11 or
lower alkyl; [0218] R.sup.2 is --NHR.sup.8; [0219] R.sup.4 is
--CHR.sup.12--, --C(O), --C(S), --S(O)--, or --SO.sub.2--; [0220]
R.sup.5 is aryl, heteroaryl, alicyclic, or heterocyclic, wherein
[0221] the aryl group is substituted with 3 to 5 substituents,
[0222] the heteroaryl group is substituted with 2 to 5
substituents, [0223] the alicyclic group is substituted with 3 to 5
substituents, [0224] the heterocyclic group is substituted with 3
to 5 substituents, and [0225] the substituents on R.sup.5 are
selected from the group consisting of halogen, lower alkyl, lower
alkenyl, lower alkynyl, --SR.sup.8, --OR.sup.8, --CN, --C(O)OH,
--C(O)R.sup.9, --NO.sub.2, --NR.sup.8R.sup.10, lower aryl,
heteroaryl, alicyclic, lower heterocyclic, arylalkyl,
heteroarylalkyl, amino, alkylamino, dialkylamino, diarylalkylamino,
oxo, oxa, perhaloalkyl, perhaloalkoxy, perhaloacyl, guanidine,
pyridinyl, thiophene, furanyl, indole, indazole, phosphonates,
phosphates, phosphoramides, sulfonates, sulfones, sulfates,
sulphonamides, carbamates, ureas, thioureas and thioamides, wherein
R.sub.9 and R.sup.10 taken together optionally form a ring of 3-7
ring atoms and optionally 1-3 of the ring atoms are heteroatoms
selected from the group of O, S and N; [0226] R.sup.8 is hydrogen,
lower alkyl, lower alkenyl, lower alkynyl, lower aryl, lower
heteroaryl or --C(O)R.sup.9; [0227] R.sup.9 is hydrogen, lower
alkyl, lower alkenyl, lower alkynyl, lower aryl, lower heteroaryl,
--NR.sup.10R.sup.10 or --OR.sup.11 wherein R.sup.10 and R.sup.10
taken together optionally form a ring of 3-7 ring atoms and
optionally 1-3 of the ring atoms are heteroatoms selected from the
group of O, S and N; [0228] R.sup.10 is hydrogen, lower alkyl,
lower alkenyl, lower alkynyl, lower aryl or lower heteroaryl;
[0229] R.sup.11 is lower alkyl, lower alkenyl, lower alkynyl, lower
aryl or lower heteroaryl; [0230] R.sup.12 is hydrogen or lower
alkyl; and [0231] R.sup.15 is hydrogen, lower alkyl, lower alkenyl
or lower alkynyl.
[0232] In one embodiment of the compounds of Formula II, or a
polymorph, solvate, ester, tautomer, pharmaceutically acceptable
salt or prodrug thereof, R.sup.2 is --NHR.sup.8, where R.sup.8 is
hydrogen or --C(O)R.sup.9; R.sup.5 is aryl, heteroaryl, alicyclic,
or heterocyclic, all optionally mono-, bi- or tri-cyclic; and
R.sup.9 is lower alkyl, lower alkenyl, lower alkynyl, lower aryl or
lower heteroaryl.
[0233] In another embodiment of the compounds of Formula II, or a
polymorph, solvate, ester, tautomer, pharmaceutically acceptable
salt or prodrug thereof, R.sup.1 is halogen or lower alkyl; R.sup.2
is --NHR.sup.8, where R.sup.8 is hydrogen or --C(O)R.sup.9; R.sup.4
is --(CH.sub.2)--, R.sup.5 is aryl, heteroaryl, alicyclic, or
heterocyclic, all optionally mono-, bi- or tri-cyclic.
[0234] In another embodiment of the compounds of Formula II, or a
polymorph, solvate, ester, tautomer, enantiomer, pharmaceutically
acceptable salt or prodrug thereof, R.sup.1 is chloro or bromo,
R.sup.2 is --NH.sub.2, and R.sup.5 is a phenyl having 3 to 5
substituents.
[0235] In another embodiment of the compounds of Formula II, or a
polymorph, solvate, ester, tautomer, enantiomer, pharmaceutically
acceptable salt or prodrug thereof, R.sup.1 is chloro or bromo,
R.sup.2 is --NH.sub.2, and R.sup.5 is a pyridyl having 3 to 5
substituents.
[0236] In another embodiment of the compounds of Formula II, or a
polymorph, solvate, ester, tautomer, enantiomer, pharmaceutically
acceptable salt or prodrug thereof, R.sup.1 is chloro or bromo,
R.sup.2 is --NH.sub.2, and R.sup.5 is an 1-oxy-pyridyl
(N-oxy-pyridyl) having 3 to 5 substituents.
[0237] It should be understood that any of the foregoing
embodiments can be combined where feasible and appropriate.
[0238] Other embodiment of the compounds of the invention are the
compounds, or polymorphs, solvates, esters, tautomers,
pharmaceutically acceptable salts or prodrugs thereof, prepared by
the process comprising:
[0239] reacting a compound of Formula Y and a compound of a Formula
Z, wherein: [0240] Y is represented by any of the following
formulae: ##STR11## and [0241] Z is L.sup.1-R.sup.4--R.sup.5;
wherein: [0242] L.sup.1 is halogen, NR.sup.8R.sup.10, triflate,
tosylate, or mesylate; [0243] R.sup.4 is --(CHR.sup.12)--, --C(O),
--C(S), --S(O)--, or --SO.sub.2--; [0244] R.sup.5 is aryl,
heteroaryl, alicyclic, or heterocyclic, wherein [0245] the aryl
group is substituted with 3 to 5 substituents, [0246] the
heteroaryl group is substituted with 2 to 5 substituents, [0247]
the alicyclic group is substituted with 3 to 5 substituents, [0248]
the heterocyclic group is substituted with 3 to 5 substituents, and
[0249] the substituents on R.sup.5 are selected from the group
consisting of halogen, lower alkyl, lower alkenyl, lower alkynyl,
--SR.sup.8, --OR.sup.8, --CN, --C(O)OH, --C(O)R.sup.9, --NO.sub.2,
--NR.sup.8R.sup.10, lower aryl, heteroaryl, alicyclic, lower
heterocyclic, arylalkyl, heteroarylalkyl, amino, alkylamino,
dialkylamino, diarylalkylamino, oxo, oxa, perhaloalkyl,
perhaloalkoxy, perhaloacyl, guanidine, pyridinyl, thiophene,
furanyl, indole, indazole, phosphonates, phosphates,
phosphoramides, sulfonates, sulfones, sulfates, sulphonamides,
carbamates, ureas, thioureas and thioamides, wherein R.sup.8 and
R.sup.10 taken together optionally form a ring of 3-7 ring atoms
and optionally 1-3 of the ring atoms are heteroatoms selected from
the group of O, S and N; [0250] R.sup.8 is hydrogen, lower alkyl,
lower alkenyl, lower alkynyl, lower aryl, lower heteroaryl or
--C(O)R.sup.9; [0251] R.sup.9 is hydrogen, lower alkyl, lower
alkenyl, lower alkynyl, lower aryl, lower heteroaryl,
--NR.sup.10R.sup.10 or --OR.sup.11, wherein R.sup.10 and R.sup.10
taken together optionally form a ring of 3-7 ring atoms and
optionally 1-3 of the ring atoms are heteroatoms selected from the
group of O, S and N; [0252] R.sup.10 is hydrogen, lower alkyl,
lower alkenyl, lower alkynyl, lower aryl or lower heteroaryl;
[0253] R.sup.11 is lower alkyl, lower alkenyl, lower alkynyl, lower
aryl or lower heteroaryl; [0254] R.sup.12 is hydrogen or lower
alkyl; [0255] R.sup.21 is halogen, --OR.sup.8, --SR.sup.8 or lower
alkyl; [0256] R.sup.22 is --NR.sup.8R.sup.10; [0257] R.sup.23 is
hydrogen, --OH or its keto tautomer, --OR.sup.8, halogen, --CN,
lower alkyl, lower aryl or --C(O)R.sup.9; [0258] R.sup.24 is --CHO,
--NH.sub.2, --NO.sub.2 or --NO; [0259] R.sup.25 is halogen or --OH;
[0260] R.sup.26 is --C(O)NH.sub.2 or C(O)OEt; and [0261] R.sup.27
is --NH.sub.2, --OH or halogen.
[0262] In one embodiment of the compounds prepared by the process
of the invention, or a polymorph, solvate, ester, tautomer,
pharmaceutically acceptable salt or prodrug thereof, R.sup.5 is
aryl, heteroaryl, alicyclic, or heterocyclic, optionally mono- or
bicyclic.
[0263] In another embodiment of the compounds of the invention
which are prepared by the process of the invention, or a polymorph,
solvate, ester, tautomer, pharmaceutically acceptable salt or
prodrug thereof, L.sup.1 is --Cl, --Br or --NH.sub.2; R.sup.4 is
--CH.sub.2--; and R.sup.5 is aryl or heteroaryl.
[0264] In another embodiment of the compounds of the invention
which are prepared by the process of the invention, or a polymorph,
solvate, ester, tautomer, pharmaceutically acceptable salt or
prodrug thereof, Y is a pyrazolopyrimidine.
[0265] In another embodiment of the compounds of the invention
which are prepared by the process of the invention, or a polymorph,
solvate, ester, tautomer, pharmaceutically acceptable salt or
prodrug thereof, said reaction is performed in a solvent comprising
a member selected from the group of DMF, THF and DMSO.
[0266] In another embodiment of the compounds of the invention
which are prepared by the process of the invention, or a polymorph,
solvate, ester, tautomer, pharmaceutically acceptable salt or
prodrug thereof, said reaction is performed in a solvent that
comprises DMF.
[0267] It should be understood that any of the foregoing
embodiments can be combined where feasible and appropriate.
[0268] Illustrative species of the compounds of the invention that
are based on Formula I, where R.sup.2=--NH.sub.2 are described in
TABLE 1. Prodrugs which can be employed by those compounds include,
but are not limited to, those listed in the Definition section.
TABLE-US-00001 TABLE 1 Exemplary Compounds of Formula I, R.sup.2 is
= NH.sub.2 ##STR12## No. Ex R.sup.1 R.sup.3 R.sup.4 R.sup.5 1 5 Cl
H CH.sub.2 3,4,5-Trimethoxyphenyl 2 6 Cl H CH.sub.2
2-Chloro-3,4,5-trimethoxyphenyl 3 Cl H CH.sub.2
2-Bromo-3,4,5-trimethoxyphenyl 4 Cl H CH.sub.2
2-Iodo-3,4,5-trimethoxyphenyl 5 Cl H CH.sub.2
2-Fluoro-3,4,5-trimethoxyphenyl 6 Cl H CH.sub.2
3,4,5-Trimethylphenyl 7 Cl H CH.sub.2
2-Chloro-3,4,5-trimethylphenyl 8 Cl H CH.sub.2
2-Bromo-3,4,5-trimethylphenyl 9 Cl H CH.sub.2
2-Iodo-3,4,5-trimethylphenyl 10 Cl H CH.sub.2
2-Fluoro-3,4,5-trimethylphenyl 11 Cl H CH.sub.2
3,5-Dimethoxy-4-methylphenyl 12 Cl H CH.sub.2
2-Chloro-3,5-dimethoxy-4-methylphenyl 13 Cl H CH.sub.2
2-Bromo-3,5-dimethoxy-4-methylphenyl 14 Cl H CH.sub.2
2-Iodo-3,5-dimethoxy-4-methylphenyl 15 Cl H CH.sub.2
2-Fluoro-3,5-dimethoxy-4-methylphenyl 16 Cl i-pr CH.sub.2
3,4,5-Trimethoxyphenyl 17 Cl i-pr CH.sub.2
2-Chloro-3,4,5-trimethoxyphenyl 18 Cl i-pr CH.sub.2
2-Bromo-3,4,5-trimethoxyphenyl 19 Cl i-pr CH.sub.2
2-Iodo-3,4,5-trimethoxyphenyl 20 Cl i-pr CH.sub.2
2-Fluoro-3,4,5-trimethoxyphenyl 21 Cl i-pr CH.sub.2
3,4,5-Trimethylphenyl 22 Cl i-pr CH.sub.2
2-Chloro-3,4,5-trimethylphenyl 23 Cl i-pr CH.sub.2
2-Bromo-3,4,5-trimethylphenyl 24 Cl i-pr CH.sub.2
2-Iodo-3,4,5-trimethylphenyl 25 Cl i-pr CH.sub.2
2-Fluoro-3,4,5-trimethylphenyl 26 Cl i-pr CH.sub.2
3,5-Dimethoxy-4-methylphenyl 27 Cl i-pr CH.sub.2
2-Chloro-3,5-dimethoxy-4-methylphenyl 28 Cl i-pr CH.sub.2
2-Bromo-3,5-dimethoxy-4-methylphenyl 29 Cl i-pr CH.sub.2
2-Iodo-3,5-dimethoxy-4-methylphenyl 30 Cl i-pr CH.sub.2
2-Fluoro-3,5-dimethoxy-4-methylphenyl 31 Cl Et CH.sub.2
3,4,5-Trimethoxyphenyl 32 Cl Et CH.sub.2
2-Chloro-3,4,5-trimethoxyphenyl 33 Cl Et CH.sub.2
2-Bromo-3,4,5-trimethoxyphenyl 34 Cl Et CH.sub.2
2-Iodo-3,4,5-trimethoxyphenyl 35 Cl Et CH.sub.2
2-Fluoro-3,4,5-trimethoxyphenyl 36 Cl Et CH.sub.2
3,4,5-Trimethylphenyl 37 Cl Et CH.sub.2
2-Chloro-3,4,5-trimethylphenyl 38 Cl Et CH.sub.2
2-Bromo-3,4,5-trimethylphenyl 39 Cl Et CH.sub.2
2-Iodo-3,4,5-trimethylphenyl 40 Cl Et CH.sub.2
2-Fluoro-3,4,5-trimethylphenyl 41 Cl Et CH.sub.2
3,5-Dimethoxy-4-methylphenyl 42 Cl Et CH.sub.2
2-Chloro-3,5-dimethoxy-4-methylphenyl 43 Cl Et CH.sub.2
2-Bromo-3,5-dimethoxy-4-methylphenyl 44 Cl Et CH.sub.2
2-Iodo-3,5-dimethoxy-4-methylphenyl 45 Cl Et CH.sub.2
2-Fluoro-3,5-dimethoxy-4-methylphenyl 46 27 Cl Me CH.sub.2
3,4,5-Trimethoxyphenyl 47 Cl Me CH.sub.2
2-Chloro-3,4,5-trimethoxyphenyl 48 Cl Me CH.sub.2
2-Bromo-3,4,5-trimethoxyphenyl 49 Cl Me CH.sub.2
2-Iodo-3,4,5-trimethoxyphenyl 50 Cl Me CH.sub.2
2-Fluoro-3,4,5-trimethoxyphenyl 51 Cl Me CH.sub.2
3,4,5-Trimethylphenyl 52 Cl Me CH.sub.2
2-Chloro-3,4,5-trimethylphenyl 53 Cl Me CH.sub.2
2-Bromo-3,4,5-trimethylphenyl 54 Cl Me CH.sub.2
2-Iodo-3,4,5-trimethylphenyl 55 Cl Me CH.sub.2
2-Fluoro-3,4,5-trimethylphenyl 56 Cl Me CH.sub.2
3,5-Dimethoxy-4-methylphenyl 57 Cl Me CH.sub.2
2-Chloro-3,5-dimethoxy-4-methylphenyl 58 Cl Me CH.sub.2
2-Bromo-3,5-dimethoxy-4-methylphenyl 59 Cl Me CH.sub.2
2-Iodo-3,5-dimethoxy-4-methylphenyl 60 Cl Me CH.sub.2
2-Fluoro-3,5-dimethoxy-4-methylphenyl 61 Cl Ph CH.sub.2
3,4,5-Trimethoxyphenyl 62 Cl Ph CH.sub.2
2-Chloro-3,4,5-trimethoxyphenyl 63 Cl Ph CH.sub.2
2-Bromo-3,4,5-trimethoxyphenyl 64 Cl Ph CH.sub.2
2-Iodo-3,4,5-trimethoxyphenyl 65 Cl Ph CH.sub.2
2-Fluoro-3,4,5-trimethoxyphenyl 66 Cl Ph CH.sub.2
3,4,5-Trimethylphenyl 67 Cl Ph CH.sub.2
2-Chloro-3,4,5-trimethylphenyl 68 Cl Ph CH.sub.2
2-Bromo-3,4,5-trimethylphenyl 69 Cl Ph CH.sub.2
2-Iodo-3,4,5-trimethylphenyl 70 Cl Ph CH.sub.2
2-Fluoro-3,4,5-trimethylphenyl 71 Cl Ph CH.sub.2
3,5-Dimethoxy-4-methylphenyl 72 Cl Ph CH.sub.2
2-Chloro-3,5-dimethoxy-4-methylphenyl 73 Cl Ph CH.sub.2
2-Bromo-3,5-dimethoxy-4-methylphenyl 74 Cl Ph CH.sub.2
2-Iodo-3,5-dimethoxy-4-methylphenyl 75 Cl Ph CH.sub.2
2-Fluoro-3,5-dimethoxy-4-methylphenyl 76 Cl 2-Py CH.sub.2
3,4,5-Trimethoxyphenyl 77 Cl 2-Py CH.sub.2
2-Chloro-3,4,5-trimethoxyphenyl 78 Cl 2-Py CH.sub.2
2-Bromo-3,4,5-trimethoxyphenyl 79 Cl 2-Py CH.sub.2
2-Iodo-3,4,5-trimethoxyphenyl 80 Cl 2-Py CH.sub.2
2-Fluoro-3,4,5-trimethoxyphenyl 81 Cl 2-Py CH.sub.2
3,4,5-Trimethylphenyl 82 Cl 2-Py CH.sub.2
2-Chloro-3,4,5-trimethylphenyl 83 Cl 2-Py CH.sub.2
2-Bromo-3,4,5-trimethylphenyl 84 Cl 2-Py CH.sub.2
2-Iodo-3,4,5-trimethylphenyl 85 Cl 2-Py CH.sub.2
2-Fluoro-3,4,5-trimethylphenyl 86 Cl 2-Py CH.sub.2
3,5-Dimethoxy-4-methylphenyl 87 Cl 2-Py CH.sub.2
2-Chloro-3,5-dimethoxy-4-methylphenyl 88 Cl 2-Py CH.sub.2
2-Bromo-3,5-dimethoxy-4-methylphenyl 89 Cl 2-Py CH.sub.2
2-Iodo-3,5-dimethoxy-4-methylphenyl 90 Cl 2-Py CH.sub.2
2-Fluoro-3,5-dimethoxy-4-methylphenyl 91 Cl Me CH.sub.2
3,4,5-Trimethoxyphenyl 92 Cl Me CH.sub.2
2-Chloro-3,4,5-trimethoxyphenyl 93 Cl Me CH.sub.2
2-Bromo-3,4,5-trimethoxyphenyl 94 Cl Me CH.sub.2
2-Iodo-3,4,5-trimethoxyphenyl 95 Cl Me CH.sub.2
2-Fluoro-3,4,5-trimethoxyphenyl 96 Cl Ph CH.sub.2
3,4,5-Trimethylphenyl 97 Cl Ph CH.sub.2
2-Chloro-3,4,5-trimethylphenyl 98 Cl Ph CH.sub.2
2-Bromo-3,4,5-trimethylphenyl 99 Cl Ph CH.sub.2
2-Iodo-3,4,5-trimethylphenyl 100 Cl Ph CH.sub.2
2-Fluoro-3,4,5-trimethylphenyl 101 Cl Ph CH.sub.2
3,5-Dimethoxy-4-methylphenyl 102 Cl Ph CH.sub.2
2-Chloro-3,5-dimethoxy-4-methylphenyl 103 Cl Ph CH.sub.2
2-Bromo-3,5-dimethoxy-4-methylphenyl 104 Cl Ph CH.sub.2
2-Iodo-3,5-dimethoxy-4-methylphenyl 105 Cl Pr CH.sub.2
2-Fluoro-3,5-dimethoxy-4-methylphenyl 106 Cl Pr CH.sub.2
3,5-Dimethoxy-4-methylphenyl 107 Cl Pr CH.sub.2
2-Chloro-3,5-dimethoxy-4-methylphenyl 108 Cl Pr CH.sub.2
2-Bromo-3,5-dimethoxy-4-methylphenyl 109 Cl Pr CH.sub.2
2-Iodo-3,5-dimethoxy-4-methylphenyl 110 Cl Pr CH.sub.2
2-Fluoro-3,5-dimethoxy-4-methylphenyl 111 Cl Pr CH.sub.2
3,4,5-Trimethoxyphenyl 112 Cl Pr CH.sub.2
2-Chloro-3,4,5-trimethoxyphenyl 113 Cl Pr CH.sub.2
2-Bromo-3,4,5-trimethoxyphenyl 114 Cl Pr CH.sub.2
2-Iodo-3,4,5-trimethoxyphenyl 115 Cl Pr CH.sub.2
2-Fluoro-3,4,5-trimethoxyphenyl 116 Cl Pr CH.sub.2
3,4,5-Trimethylphenyl 117 Cl Pr CH.sub.2
2-Chloro-3,4,5-trimethylphenyl 118 Cl Pr CH.sub.2
2-Bromo-3,4,5-trimethylphenyl 119 Cl Pr CH.sub.2
2-Iodo-3,4,5-trimethylphenyl 120 Cl Pr CH.sub.2
2-Fluoro-3,4,5-trimethylphenyl 121 Cl Pr CH.sub.2
3,5-Dimethoxy-4-methylphenyl 122 Cl Pr CH.sub.2
2-Chloro-3,5-dimethoxy-4-methylphenyl 123 Cl Pr CH.sub.2
2-Bromo-3,5-dimethoxy-4-methylphenyl 124 Cl Pr CH.sub.2
2-Iodo-3,5-dimethoxy-4-methylphenyl 125 Cl Pr CH.sub.2
2-Fluoro-3,5-dimethoxy-4-methylphenyl 126 Br H CH.sub.2
3,4,5-Trimethoxyphenyl 127 Br H CH.sub.2
2-Chloro-3,4,5-trimethoxyphenyl 128 Br H CH.sub.2
2-Bromo-3,4,5-trimethoxyphenyl 129 Br H CH.sub.2
2-Iodo-3,4,5-trimethoxyphenyl 130 Br H CH.sub.2
2-Fluoro-3,4,5-trimethoxyphenyl 131 Br H CH.sub.2
3,4,5-Trimethylphenyl 132 Br H CH.sub.2
2-Chloro-3,4,5-trimethylphenyl 133 Br H CH.sub.2
2-Bromo-3,4,5-trimethylphenyl 134 Br H CH.sub.2
2-Iodo-3,4,5-trimethylphenyl 135 Br H CH.sub.2
2-Fluoro-3,4,5-trimethylphenyl 136 Br H CH.sub.2
3,5-Dimethoxy-4-methylphenyl 137 Br H CH.sub.2
2-Chloro-3,5-dimethoxy-4-methylphenyl 138 Br H CH.sub.2
2-Bromo-3,5-dimethoxy-4-methylphenyl 139 Br H CH.sub.2
2-Iodo-3,5-dimethoxy-4-methylphenyl 140 Br H CH.sub.2
2-Fluoro-3,5-dimethoxy-4-methylphenyl 141 Cl i-Bu CH.sub.2
3,4,5-Trimethoxyphenyl 142 Cl i-Bu CH.sub.2
2-Chloro-3,4,5-trimethoxyphenyl 143 Cl i-Bu CH.sub.2
2-Bromo-3,4,5-trimethoxyphenyl 144 Cl i-Bu CH.sub.2
2-Iodo-3,4,5-trimethoxyphenyl 145 Cl i-Bu CH.sub.2
2-Fluoro-3,4,5-trimethoxyphenyl 146 Cl i-Bu CH.sub.2
3,4,5-Trimethylphenyl 147 Cl i-Bu CH.sub.2
2-Chloro-3,4,5-trimethylphenyl 148 Cl i-Bu CH.sub.2
2-Bromo-3,4,5-trimethylphenyl 149 Cl i-Bu CH.sub.2
2-Iodo-3,4,5-trimethylphenyl 150 Cl i-Bu CH.sub.2
2-Fluoro-3,4,5-trimethylphenyl 151 Cl i-Bu CH.sub.2
3,5-Dimethoxy-4-methylphenyl 152 Cl i-Bu CH.sub.2
2-Chloro-3,5-dimethoxy-4-methylphenyl 153 Cl i-Bu CH.sub.2
2-Bromo-3,5-dimethoxy-4-methylphenyl 154 Cl i-Bu CH.sub.2
2-Iodo-3,5-dimethoxy-4-methylphenyl 155 Cl i-Bu CH.sub.2
2-Fluoro-3,5-dimethoxy-4-methylphenyl 156 Cl CN CH.sub.2
3,4,5-Trimethoxyphenyl 157 Cl CN CH.sub.2
2-Chloro-3,4,5-trimethoxyphenyl 158 Cl CN CH.sub.2
2-Bromo-3,4,5-trimethoxyphenyl 159 Cl CN CH.sub.2
2-Iodo-3,4,5-trimethoxyphenyl 160 Cl CN CH.sub.2
3,4,5-Trimethoxyphenyl 161 Cl CN CH.sub.2
2-Chloro-3,4,5-trimethoxyphenyl 162 Cl CN CH.sub.2
2-Bromo-3,4,5-trimethoxyphenyl 163 Cl CN CH.sub.2
2-Iodo-3,4,5-trimethoxyphenyl 164 Cl CN CH.sub.2
2-Fluoro-3,4,5-trimethoxyphenyl 165 Cl CN CH.sub.2
3,4,5-Trimethylphenyl 166 Cl CN CH.sub.2
2-Chloro-3,4,5-trimethylphenyl 167 Cl CN CH.sub.2
2-Bromo-3,4,5-trimethylphenyl 168 Cl CN CH.sub.2
2-Iodo-3,4,5-trimethylphenyl 169 Cl CN CH.sub.2
2-Fluoro-3,4,5-trimethylphenyl 170 Cl CN CH.sub.2
3,5-Dimethoxy-4-methylphenyl 171 Cl CN CH.sub.2
2-Chloro-3,5-dimethoxy-4-methylphenyl 172 Cl CN CH.sub.2
2-Bromo-3,5-dimethoxy-4-methylphenyl 173 Cl CN CH.sub.2
2-Iodo-3,5-dimethoxy-4-methylphenyl 174 Cl CN CH.sub.2
2-Fluoro-3,5-dimethoxy-4-methylphenyl 175 Cl Cl CH.sub.2
3,4,5-Trimethoxyphenyl 176 Cl Cl CH.sub.2
2-Chloro-3,4,5-trimethoxyphenyl 177 Cl Cl CH.sub.2
2-Bromo-3,4,5-trimethoxyphenyl 178 Cl Cl CH.sub.2
2-Iodo-3,4,5-trimethoxyphenyl 179 Cl Cl CH.sub.2
2-Fluoro-3,4,5-trimethoxyphenyl 180 Cl Cl CH.sub.2
3,4,5-Trimethylphenyl 181 Cl Cl CH.sub.2
2-Chloro-3,4,5-trimethylphenyl 182 Cl Cl CH.sub.2
2-Bromo-3,4,5-trimethylphenyl 183 Cl Cl CH.sub.2
2-Iodo-3,4,5-trimethylphenyl 184 Cl Cl CH.sub.2
2-Fluoro-3,4,5-trimethylphenyl 185 Cl Cl CH.sub.2
3,5-Dimethoxy-4-methylphenyl 186 Cl Cl CH.sub.2
2-Chloro-3,5-dimethoxy-4-methylphenyl 187 Cl Cl CH.sub.2
2-Bromo-3,5-dimethoxy-4-methylphenyl 188 Cl Cl CH.sub.2
2-Iodo-3,5-dimethoxy-4-methylphenyl 189 Cl Cl CH.sub.2
2-Fluoro-3,5-dimethoxy-4-methylphenyl 190 Cl Br CH.sub.2
3,4,5-Trimethoxyphenyl 191 Cl Br CH.sub.2
2-Chloro-3,4,5-trimethoxyphenyl 192 Cl Br CH.sub.2
2-Bromo-3,4,5-trimethoxyphenyl 193 Cl Br CH.sub.2
2-Iodo-3,4,5-trimethoxyphenyl 194 Cl Br CH.sub.2
2-Fluoro-3,4,5-trimethoxyphenyl 195 Cl Br CH.sub.2
3,4,5-Trimethylphenyl 196 Cl Br CH.sub.2
2-Chloro-3,4,5-trimethylphenyl 197 Cl Br CH.sub.2
2-Bromo-3,4,5-trimethylphenyl 198 Cl Br CH.sub.2
2-Iodo-3,4,5-trimethylphenyl 199 Cl Br CH.sub.2
2-Fluoro-3,4,5-trimethylphenyl 200 Cl Br CH.sub.2
3,5-Dimethoxy-4-methylphenyl 201 Cl Br CH.sub.2
2-Chloro-3,5-dimethoxy-4-methylphenyl 202 Cl Br CH.sub.2
2-Bromo-3,5-dimethoxy-4-methylphenyl 203 Cl Br CH.sub.2
2-Iodo-3,5-dimethoxy-4-methylphenyl 204 Cl Br CH.sub.2
2-Fluoro-3,5-dimethoxy-4-methylphenyl 205 Cl I CH.sub.2
3,4,5-Trimethoxyphenyl 206 Cl I CH.sub.2
2-Chloro-3,4,5-trimethoxyphenyl 207 Cl I CH.sub.2
2-Bromo-3,4,5-trimethoxyphenyl 208 Cl I CH.sub.2
2-Iodo-3,4,5-trimethoxyphenyl 209 Cl I CH.sub.2
2-Fluoro-3,4,5-trimethoxyphenyl 210 Cl I CH.sub.2
3,4,5-Trimethylphenyl 211 Cl I CH.sub.2
2-Chloro-3,4,5-trimethylphenyl 212 Cl I CH.sub.2
2-Bromo-3,4,5-trimethylphenyl 213 Cl I CH.sub.2
2-Iodo-3,4,5-trimethylphenyl 214 Cl I CH.sub.2
2-Fluoro-3,4,5-trimethylphenyl 215 Cl I CH.sub.2
3,5-Dimethoxy-4-methylphenyl 216 Cl I CH.sub.2
2-Chloro-3,5-dimethoxy-4-methylphenyl 217 Cl I CH.sub.2
2-Bromo-3,5-dimethoxy-4-methylphenyl 218 Cl I CH.sub.2
2-Iodo-3,5-dimethoxy-4-methylphenyl 219 Cl I CH.sub.2
2-Fluoro-3,5-dimethoxy-4-methylphenyl 220 Cl CH.sub.2--NMe.sub.2
CH.sub.2 3,4,5-Trimethoxyphenyl 221 Cl CH.sub.2--NMe.sub.2 CH.sub.2
2-Chloro-3,4,5-trimethoxyphenyl 222 Cl CH.sub.2--NMe.sub.2 CH.sub.2
2-Bromo-3,4,5-trimethoxyphenyl 223 Cl CH.sub.2--NMe.sub.2 CH.sub.2
2-Iodo-3,4,5-trimethoxyphenyl 224 Cl CH.sub.2--NMe.sub.2 CH.sub.2
2-Fluoro-3,4,5-trimethoxyphenyl 225 Cl CH.sub.2--NMe.sub.2 CH.sub.2
3,4,5-Trimethylphenyl 226 Cl CH.sub.2--NMe.sub.2 CH.sub.2
2-Chloro-3,4,5-trimethylphenyl 227 Cl CH.sub.2--NMe.sub.2 CH.sub.2
2-Bromo-3,4,5-trimethylphenyl 228 Cl CH.sub.2--NMe.sub.2 CH.sub.2
2-Iodo-3,4,5-trimethylphenyl 229 Cl CH.sub.2--NMe.sub.2 CH.sub.2
2-Fluoro-3,4,5-trimethylphenyl 230 Cl CH.sub.2--NMe.sub.2 CH.sub.2
3,5-Dimethoxy-4-methylphenyl 231 Cl CH.sub.2--NMe.sub.2 CH.sub.2
2-Chloro-3,5-dimethoxy-4-methylphenyl 232 Cl CH.sub.2--NMe.sub.2
CH.sub.2 2-Bromo-3,5-dimethoxy-4-methylphenyl 233 Cl
CH.sub.2--NMe.sub.2 CH.sub.2 2-Iodo-3,5-dimethoxy-4-methylphenyl
234 Cl CH.sub.2--NMe.sub.2 CH.sub.2
2-Fluoro-3,5-dimethoxy-4-methylphenyl 235 Cl 3-Py CH.sub.2
3,4,5-Trimethoxyphenyl 236 Cl 3-Py CH.sub.2
2-Chloro-3,4,5-trimethoxyphenyl 237 Cl 3-Py CH.sub.2
2-Bromo-3,4,5-trimethoxyphenyl
238 Cl 3-Py CH.sub.2 2-Iodo-3,4,5-trimethoxyphenyl 239 Cl 3-Py
CH.sub.2 2-Fluoro-3,4,5-trimethoxyphenyl 240 7 Cl H CH.sub.2
3,5-Dimethyl-4-methoxypyridin-2-yl 241 10 Cl H CH.sub.2
3,5-Dimethyl-4-methoxy-1-oxypyridin-2-yl 242 Cl H CH.sub.2
6-Bromo-3,5-dimethyl-4-methoxypyridin-2-yl 243 8 Cl H CH.sub.2
6-Chloro-3,5-dimethyl-4-methoxypyridin-2-yl 244 14 Cl H CH.sub.2
3,5-Dimethyl-4-bromopyridin-2-yl 245 15 Cl H CH.sub.2
3,5-Dimethyl-4-bromo-1-oxypyridin-2-yl 246 9 Cl H CH.sub.2
3,5-Dimethyl-4-chloropyridin-2-yl 247 Cl H CH.sub.2
3,5-Dimethyl-4-chloro-1-oxypyridin-2-yl 248 Cl H CH.sub.2
3,5-Dimethyl-4-iodopyridin-2-yl 249 Cl H CH.sub.2
3,5-Dimethyl-4-iodo-1-oxypyridin-2-yl 250 Cl H CH.sub.2
3,5-Dimethyl-4-thiomethyl-pyridin-2-yl 251 Cl H CH.sub.2
3,5-Dimethyl-4-thiomethyl-1-oxypyridin-2-yl 252 Cl H CH.sub.2
3,4,5-Trimethyl-pyridin-2-yl 253 Cl H CH.sub.2
3,4,5-Trimethyl-1-oxypyridin-2-yl 254 Cl H CH.sub.2
4,5,6-Trimethoxypyridin-2-yl 255 Cl H CH.sub.2
4,5,6-Trimethoxy-1-oxypyridin-2-yl 256 Cl H CH.sub.2
3-Bromo-4,5,6-trimethoxypyridin-2-yl 257 Cl H CH.sub.2
3-Chloro-4,5,6-trimethoxypyridin-2-yl 258 Cl H CH.sub.2
3,4,5-Trimethoxy-pyridin-2-yl 259 Cl H CH.sub.2
3,4,5-Trimethoxy-1-oxypyridin-2-yl 260 Cl H CH.sub.2
3-Bromo-3,4,5-trimethoxy-pyridin-2-yl 261 Cl H CH.sub.2
3-Chloro-3,4,5-trimethoxy-pyridin-2-yl 262 Cl H CH.sub.2
4,5,6-Trimethyl-pyridin-2-yl 263 Cl H CH.sub.2
4,5,6-Trimethyl-1-oxypyridin-2-yl 264 Cl H CH.sub.2
4,6-Dimethyl-5-methoxy-pyridin-2-yl 265 Cl H CH.sub.2
4,6-Dimethyl-5-methoxypyridin-3-yl 266 Cl H CH.sub.2
4,6-Dimethyl-5-methoxy-1-oxypyridin-3-yl 267 Cl H CH.sub.2
4,6-Dimethyl-5-bromopyridin-3-yl 268 Cl H CH.sub.2
4,6-Dimethyl-5-chloropyridin-3-yl 269 Cl H CH.sub.2
5,6-Dimethyl-4-bromopyridin-3-yl 270 Cl H CH.sub.2
5,6-Dimethyl-4-chloropyridin-3-yl 271 Cl H CH.sub.2
2,6-Dimethyl-3-methoxypyridin-4-yl 272 Cl H CH.sub.2
2,6-Dimethyl-pyridin-4-yl 273 Cl H CH.sub.2
2,3,6-Trimethyl-pyridin-4-yl 274 Cl H CH.sub.2
2,3,6-Trimethoxy-pyridin-4-yl 275 Cl H CH.sub.2
2,6-Dimethyl-3-bromopyridin-4-yl 276 Cl H CH.sub.2
2,6-Dimethyl-3-chloropyridin-4-yl 277 Cl H CH.sub.2
2,6-Dimethyl-3-methoxy-1-oxy-pyridin-4-yl 278 Cl H CH.sub.2
2,6-Dimethyl-1-oxy-pyridin-4-yl 279 Cl H CH.sub.2
2,3,6-Trimethyl-1-oxy-pyridin-4-yl 280 Cl H CH.sub.2
2,3,6-Trimethoxy-1-oxy-pyridin-4-yl 281 Cl H CH.sub.2
2,6-Dimethyl-3-bromo1-oxy-pyridin-4-yl 282 Cl H CH.sub.2
2,6-Dimethyl-3-chloro1-oxy-pyridin-4-yl 283 Cl H CH.sub.2
4,6-Dimethyl-5-iodopyridin-3-yl 284 Cl H CH.sub.2
3,5-Dimethyl-4-aminopyridin-2-yl 285 31 Cl i-pr CH.sub.2
3,5-Dimethyl-4-methoxypyridin-2-yl 286 Cl i-pr CH.sub.2
3,5-Dimethyl-4-methoxy-1-oxypyridin-2-yl 287 Cl i-pr CH.sub.2
6-Bromo-3,5-dimethyl-4-methoxypyridin-2-yl 288 Cl i-pr CH.sub.2
6-Chloro-3,5-dimethyl-4-methoxypyridin-2-yl 289 Cl i-pr CH.sub.2
3,5-Dimethyl-4-bromopyridin-2-yl 290 Cl i-pr CH.sub.2
3,5-Dimethyl-4-bromo-1-oxypyridin-2-yl 291 Cl i-pr CH.sub.2
3,5-Dimethyl-4-chloropyridin-2-yl 292 Cl i-pr CH.sub.2
3,5-Dimethyl-4-chloro-1-oxypyridin-2-yl 293 Cl i-pr CH.sub.2
3,5-Dimethyl-4-iodopyridin-2-yl 294 Cl i-pr CH.sub.2
3,5-Dimethyl-4-iodo-1-oxypyridin-2-yl 295 Cl i-pr CH.sub.2
3,5-Dimethyl-4-thiomethyl-pyridin-2-yl 296 Cl i-pr CH.sub.2
3,5-Dimethyl-4-thiomethyl-1-oxypyridin-2-yl 297 Cl i-pr CH.sub.2
3,4,5-Trimethyl-pyridin-2-yl 298 Cl i-pr CH.sub.2
3,4,5-Trimethyl-1-oxypyridin-2-yl 299 Cl i-pr CH.sub.2
4,5,6-Trimethoxypyridin-2-yl 300 Cl i-pr CH.sub.2
4,5,6-Trimethoxy-1-oxpyridin-2-yl 301 Cl i-pr CH.sub.2
3-Bromo-4,5,6-trimethoxypyridin-2-yl 302 Cl i-pr CH.sub.2
3-Chloro-4,5,6-trimethoxypyridin-2-yl 303 Cl i-pr CH.sub.2
3,4,5-Trimethoxy-pyridin-2-yl 304 Cl i-pr CH.sub.2
3,4,5-Trimethoxy-1-oxypyridin-2-yl 305 Cl i-pr CH.sub.2
3-Bromo-3,4,5-trimethoxy-pyridin-2-yl 306 Cl i-pr CH.sub.2
3-Chloro-3,4,5-trimethoxy-pyridin-2-yl 307 CI i-pr CH.sub.2
4,5,6-Trimethyl-pyridin-2-yl 308 Cl i-pr CH.sub.2
4,5,6-Trimethyl-1-oxypyridin-2-yl 309 Cl i-pr CH.sub.2
4,6-Dimethyl-5-methoxy-pyridin-2-yl 310 Cl i-pr CH.sub.2
4,6-Dimethyl-5-methoxypyridin-3-yl 311 Cl i-pr CH.sub.2
4,6-Dimethyl-5-methoxy-1-oxypyridin-3-yl 312 Cl i-pr CH.sub.2
4,6-Dimethyl-5-bromopyridin-3-yl 313 Cl i-pr CH.sub.2
4,6-Dimethyl-5-chloropyridin-3 -yl 314 Cl i-pr CH.sub.2
5,6-Dimethyl-4-bromopyridin-3-yl 315 Cl i-pr CH.sub.2
5,6-Dimethyl-4-chloropyridin-3-yl 316 Cl i-pr CH.sub.2
2,6-Dimethyl-3-methoxypyridin-4-yl 317 Cl i-pr CH.sub.2
2,6-Dimethyl-pyridin-4-yl 318 Cl i-pr CH.sub.2
2,3,6-Trimethyl-pyridin-4-yl 319 Cl i-pr CH.sub.2
2,3,6-Trimethoxy-pyridin-4-yl 320 Cl i-pr CH.sub.2
2,6-Dimethyl-3-bromopyridin-4-yl 321 Cl i-pr CH.sub.2
2,6-Dimethyl-3-chloropyridin-4-yl 322 Cl i-pr CH.sub.2
2,6-Dimethyl-3-methoxy-1-oxy-pyridin-4-yl 323 Cl i-pr CH.sub.2
2,6-Dimethyl-1-oxy-pyridin-4-yl 324 Cl i-pr CH.sub.2
2,3,6-Trimethyl-1-oxy-pyridin-4-yl 325 Cl i-pr CH.sub.2
2,3,6-Trimethoxy-1-oxy-pyridin-4-yl 326 Cl i-pr CH.sub.2
2,6-Dimethyl-3-bromo1-oxy-pyridin-4-yl 327 Cl i-pr CH.sub.2
2,6-Dimethyl-3-chloro1-oxy-pyridin-4-yl 328 Cl i-pr CH.sub.2
4,6-Dimethyl-5-iodopyridin-3-yl 329 Cl i-pr CH.sub.2
3,5-Dimethyl-4-aminopyridin-2-yl 330 23 Cl Me CH.sub.2
3,5-Dimethyl-4-methoxypyridin-2-yl 331 Cl Me CH.sub.2
3,5-Dimethyl-4-methoxy-1-oxypyridin-2-yl 332 28 Cl Me CH.sub.2
3,5-Dimethyl-4-bromopyridin-2-yl 333 24 Cl Me CH.sub.2
3,5-Dimethyl-4-bromo-1-oxypyridin-2-yl 334 26 Cl Me CH.sub.2
3,5-Dimethyl-4-chloropyridin-2-yl 335 25 Cl Me CH.sub.2
3,5-Dimethyl-4-chloro-1-oxypyridin-2-yl 336 Cl Me CH.sub.2
3,5-Dimethyl-4-iodopyridin-2-yl 337 Cl Me CH.sub.2
3,5-Dimethyl-4-iodo-1-oxypyridin-2-yl 338 Cl Me CH.sub.2
3,5-Dimethyl-4-thiomethyl-pyridin-2-yl 339 Cl Me CH.sub.2
3,5-Dimethyl-4-thiomethyl-1-oxypyridin-2-yl 340 Cl Me CH.sub.2
3,4,5-Trimethyl-pyridin-2-yl 341 Cl Me CH.sub.2
3,4,5-Trimethyl-1-oxypyridin-2-yl 342 Cl Me CH.sub.2
4,5,6-Trimethoxypyridin-2-yl 343 Cl Me CH.sub.2
4,5,6-Trimethoxy-1-oxypyridin-2-yl 344 Cl Me CH.sub.2
3,4,5-Trimethoxy-pyridin-2-yl 345 Cl Me CH.sub.2
3,4,5-Trimethoxy-1-oxypyridin-2-yl 346 Cl Me CH.sub.2
4,5,6-Trimethyl-pyridin-2-yl 347 Cl Me CH.sub.2
4,5,6-Trimethyl-1-oxypyridin-2-yl 348 Cl Me CH.sub.2
4,6-Dimethyl-5-methoxy-pyridin-2-yl 349 Cl Me CH.sub.2
4,6-Dimethyl-5-methoxypyridin-3-yl 350 Cl Me CH.sub.2
4,6-Dimethyl-5-methoxy-1-oxypyridin-3-yl 351 Cl Me CH.sub.2
4,6-Dimethyl-5-bromopyridin-3-yl 352 Cl Me CH.sub.2
4,6-Dimethyl-5-chloropyridin-3-yl 353 Cl Me CH.sub.2
5,6-Dimethyl-4-bromopyridin-3-yl 354 Cl Me CH.sub.2
5,6-Dimethyl-4-chloropyridin-3-yl 355 Cl Me CH.sub.2
2,6-Dimethyl-3-methoxypyridin-4-yl 356 Cl Me CH.sub.2
2,6-Dimethyl-pyridin-4-yl 357 Cl Me CH.sub.2
2,3,6-Trimethyl-pyridin-4-yl 358 Cl Me CH.sub.2
2,3,6-Trimethoxy-pyridin-4-yl 359 Cl Me CH.sub.2
2,6-Dimethyl-3-bromopyridin-4-yl 360 Cl Me CH.sub.2
2,6-Dimethyl-3-chloropyridin-4-yl 361 Cl Me CH.sub.2
4,6-Dimethyl-5-iodopyridin-3-yl 362 Cl Me CH.sub.2
3,5-Dimethyl-4-aminopyridin-2-yl 363 29 Cl Et CH.sub.2
3,5-Dimethyl-4-methoxypyridin-2-yl 364 Cl Et CH.sub.2
3,5-Dimethyl-4-methoxy-1-oxypyridin-2-yl 365 Cl Et CH.sub.2
3,5-Dimethyl-4-bromopyridin-2-yl 366 Cl Et CH.sub.2
3,5-Dimethyl-4-bromo-1-oxypyridin-2-yl 367 30 Cl Et CH.sub.2
3,5-Dimethyl-4-chloropyridin-2-yl 368 Cl Et CH.sub.2
3,5-Dimethyl-4-chloro-1-oxypyridin-2-yl 369 Cl Et CH.sub.2
3,5-Dimethyl-4-iodopyridin-2-yl 370 Cl Et CH.sub.2
3,5-Dimethyl-4-iodo-1-oxypyridin-2-yl 371 Cl Et CH.sub.2
3,5-Dimethyl-4-thiomethyl-pyridin-2-yl 372 Cl Et CH.sub.2
3,5-Dimethyl-4-thiomethyl-1-oxypyridin-2-yl 373 Cl Et CH.sub.2
3,4,5-Trimethyl-pyridin-2-yl 374 Cl Et CH.sub.2
3,4,5-Trimethyl-1-oxypyridin-2-yl 375 Cl Et CH.sub.2
4,5,6-Trimethoxypyridin-2-yl 376 Cl Et CH.sub.2
4,5,6-Trimethoxy-1-oxypyridin-2-yl 377 Cl Et CH.sub.2
3,4,5-Trimethoxy-pyridin-2-yl 378 Cl Et CH.sub.2
3,4,5-Trimethoxy-1-oxypyridin-2-yl 379 Cl Et CH.sub.2
4,5,6-Trimethyl-pyridin-2-yl 380 Cl Et CH.sub.2
4,5,6-Trimethyl-1-oxypyridin-2-yl 381 Cl Et CH.sub.2
4,6-Dimethyl-5-methoxy-pyridin-2-yl 382 Cl Et CH.sub.2
4,6-Dimethyl-5-methoxypyridin-3-yl 383 Cl Et CH.sub.2
4,6-Dimethyl-5-methoxy-1-oxypyridin-3-yl 384 Cl Et CH.sub.2
4,6-Dimethyl-5-bromopyridin-3-yl 385 Cl Et CH.sub.2
4,6-Dimethyl-5-chloropyridin-3-yl 386 Cl Et CH.sub.2
5,6-Dimethyl-4-bromopyridin-3-yl 387 Cl Et CH.sub.2
5,6-Dimethyl-4-chloropyridin-3-yl 388 Cl Et CH.sub.2
2,6-Dimethyl-3-methoxypyridin-4-yl 389 Cl Et CH.sub.2
2,6-Dimethyl-pyridin-4-yl 390 Cl Et CH.sub.2
2,3,6-Trimethyl-pyridin-4-yl 391 Cl Et CH.sub.2
2,3,6-Trimethoxy-pyridin-4-yl 392 Cl Et CH.sub.2
2,6-Dimethyl-3-bromopyridin-4-yl 393 Cl Et CH.sub.2
2,6-Dimethyl-3-chloropyridin-4-yl 394 Cl Et CH.sub.2
4,6-Dimethyl-5-iodopyridin-3-yl 395 Cl Et CH.sub.2
3,5-Dimethyl-4-aminopyridin-2-yl 396 Cl 2-Py CH.sub.2
3,5-Dimethyl-4-methoxypyridin-2-yl 397 Cl 2-Py CH.sub.2
3,5-Dimethyl-4-methoxy-1-oxypyridin-2-yl 398 Cl 2-Py CH.sub.2
3,5-Dimethyl-4-bromopyridin-2-yl 399 Cl 2-Py CH.sub.2
3,5-Dimethyl-4-bromo-1-oxypyridin-2-yl 400 Cl 2-Py CH.sub.2
3,5-Dimethyl-4-chloropyridin-2-yl 401 Cl 2-Py CH.sub.2
3,5-Dimethyl-4-chloro-1-oxypyridin-2-yl 402 Cl 2-Py CH.sub.2
3,5-Dimethyl-4-iodopyridin-2-yl 403 Cl 2-Py CH.sub.2
3,5-Dimethyl-4-iodo-1-oxypyridin-2-yl 404 Cl 2-Py CH.sub.2
3,5-Dimethyl-4-thiomethyl-pyridin-2-yl 405 Cl 2-Py CH.sub.2
3,5-Dimethyl-4-thiomethyl-1-oxypyridin-2-yl 406 Cl 2-Py CH.sub.2
3,4,5-Trimethyl-pyridin-2-yl 407 Cl 2-Py CH.sub.2
3,4,5-Trimethyl-1-oxypyridin-2-yl 408 Cl 2-Py CH.sub.2
4,5,6-Trimethoxypyridin-2-yl 409 Cl 2-Py CH.sub.2
4,5,6-Trimethoxy-1-oxypyridin-2-yl 410 Cl 2-Py CH.sub.2
3,4,5-Trimethoxy-pyridin-2-yl 411 Cl 2-Py CH.sub.2
3,4,5-Trimethoxy-1-oxypyridin-2-yl 412 Cl 2-Py CH.sub.2
4,5,6-Trimethyl-pyridin-2-yl 413 Cl 2-Py CH.sub.2
4,5,6-Trimethyl-1-oxypyridin-2-yl 414 Cl 2-Py CH.sub.2
4,6-Dimethyl-5-methoxy-pyridin-2-yl 415 Cl 2-Py CH.sub.2
4,6-Dimethyl-5-methoxypyridin-3-yl 416 Cl 2-Py CH.sub.2
4,6-Dimethyl-5-methoxy-1-oxypyridin-3-yl 417 Cl 2-Py CH.sub.2
4,6-Dimethyl-5-bromopyridin-3-yl 418 Cl 2-Py CH.sub.2
4,6-Dimethyl-5-chloropyridin-3-yl 419 Cl 2-Py CH.sub.2
5,6-Dimethyl-4-bromopyridin-3-yl 420 Cl 2-Py CH.sub.2
5,6-Dimethyl-4-chloropyridin-3-yl 421 Cl 2-Py CH.sub.2
2,6-Dimethyl-3-methoxypyridin-4-yl 422 Cl 2-Py CH.sub.2
2,6-Dimethyl-pyridin-4-yl 423 Cl 2-Py CH.sub.2
2,3,6-Trimethyl-pyridin-4-yl 424 Cl 2-Py CH.sub.2
2,3,6-Trimethoxy-pyridin-4-yl 425 Cl 2-Py CH.sub.2
2,6-Dimethyl-3-bromopyridin-4-yl 426 Cl 2-Py CH.sub.2
2,6-Dimethyl-3-chloropyridin-4-yl 427 Cl 2-Py CH.sub.2
4,6-Dimethyl-5-iodopyridin-3-yl 428 Cl 2-Py CH.sub.2
3,5-Dimethyl-4-aminopyridin-2-yl 429 32 Cl Ph CH.sub.2
3,5-Dimethyl-4-methoxypyridin-2-yl 430 Cl Ph CH.sub.2
3,5-Dimethyl-4-methoxy-1-oxypyridin-2-yl 431 34 Cl Ph CH.sub.2
3,5-Dimethyl-4-bromopyridin-2-yl 432 Cl Ph CH.sub.2
3,5-Dimethyl-4-bromo-1-oxypyridin-2-yl 433 33 Cl Ph CH.sub.2
3,5-Dimethyl-4-chloropyridin-2-yl 434 35 Cl Ph CH.sub.2
3,5-Dimethyl-4-chloro-1-oxypyridin-2-yl 435 Cl Ph CH.sub.2
3,5-Dimethyl-4-iodopyridin-2-yl 436 Cl Ph CH.sub.2
3,5-Dimethyl-4-iodo-1-oxypyridin-2-yl 437 Cl Ph CH.sub.2
3,5-Dimethyl-4-thiomethyl-pyridin-2-yl 438 Cl Ph CH.sub.2
3,5-Dimethyl-4-thiomethyl-1-oxypyridin-2-yl 439 Cl Ph CH.sub.2
3,4,5-Trimethyl-pyridin-2-yl 440 Cl Ph CH.sub.2
3,4,5-Trimethyl-1-oxypyridin-2-yl 441 Cl Ph CH.sub.2
4,5,6-Trimethoxypyridin-2-yl 442 Cl Ph CH.sub.2
4,5,6-Trimethoxy-1-oxypyridin-2-yl 443 Cl Ph CH.sub.2
3,4,5-Trimethoxy-pyridin-2-yl 444 Cl Ph CH.sub.2
3,4,5-Trimethoxy-1-oxypyridin-2-yl 445 Cl Ph CH.sub.2
4,5,6-Trimethyl-pyridin-2-yl 446 Cl Ph CH.sub.2
4,5,6-Trimethyl-1-oxypyridin-2-yl 447 Cl Ph CH.sub.2
4,6-Dimethyl-5-methoxy-pyridin-2-yl 448 Cl Ph CH.sub.2
4,6-Dimethyl-5-methoxypyridin-3-yl 449 Cl Ph CH.sub.2
4,6-Dimethyl-5-methoxy-1-oxypyridin-3-yl 450 Cl Ph CH.sub.2
4,6-Dimethyl-5-bromopyridin-3-yl 451 Cl Ph CH.sub.2
4,6-Dimethyl-5-chloropyridin-3-yl 452 Cl Ph CH.sub.2
5,6-Dimethyl-4-bromopyridin-3-yl 453 Cl Ph CH.sub.2
5,6-Dimethyl-4-chloropyridin-3-yl 454 Cl Ph CH.sub.2
2,6-Dimethyl-3-methoxypyridin-4-yl 455 Cl Ph CH.sub.2
2,6-Dimethyl-pyridin-4-yl 456 Cl Ph CH.sub.2
2,3,6-Trimethyl-pyridin-4-yl 457 Cl Ph CH.sub.2
2,3,6-Trimethoxy-pyridin-4-yl 458 Cl Ph CH.sub.2
2,6-Dimethyl-3-bromopyridin-4-yl 459 Cl Ph CH.sub.2
2,6-Dimethyl-3-chloropyridin-4-yl 460 Cl Ph CH.sub.2
4,6-Dimethyl-5-iodopyridin-3-yl 461 Cl Ph CH.sub.2
3,5-Dimethyl-4-aminopyridin-2-yl 462 Cl 3-Py CH.sub.2
3,5-Dimethyl-4-methoxypyridin-2-yl 463 Cl 3-Py CH.sub.2
3,5-Dimethyl-4-methoxy-1-oxypyridin-2-yl 464 Cl 3-Py CH.sub.2
3,5-Dimethyl-4-bromopyridin-2-yl 465 Cl 3-Py CH.sub.2
3,5-Dimethyl-4-bromo-1-oxypyridin-2-yl 466 Cl 3-Py CH.sub.2
3,5-Dimethyl-4-chloropyridin-2-yl 467 Cl 3-Py CH.sub.2
3,5-Dimethyl-4-chloro-1-oxypyridin-2-yl 468 Cl 3-Py CH.sub.2
3,5-Dimethyl-4-iodopyridin-2-yl 469 Cl 3-Py CH.sub.2
3,5-Dimethyl-4-iodo-1-oxypyridin-2-yl 470 Cl 3-Py CH.sub.2
3,5-Dimethyl-4-thiomethyl-pyridin-2-yl 471 Cl 3-Py CH.sub.2
3,5-Dimethyl-4-thiomethyl-1-oxypyridin-2-yl 472 Cl 3-Py CH.sub.2
3,4,5-Trimethyl-pyridin-2-yl 473 Cl 3-Py CH.sub.2
3,4,5-Trimethyl-1-oxypyridin-2-yl 474 Cl 3-Py CH.sub.2
4,5,6-Trimethoxypyridin-2-yl 475 Cl 3-Py CH.sub.2
4,5,6-Trimethoxy-1-oxypyridin-2-yl 476 Cl 3-Py CH.sub.2
3,4,5-Trimethoxy-pyridin-2-yl 477 Cl 3-Py CH.sub.2
3,4,5-Trimethoxy-1-oxypyridin-2-yl 478 Cl 3-Py CH.sub.2
4,5,6-Trimethyl-pyridin-2-yl 479 Cl 3-Py CH.sub.2
4,5,6-Trimethyl-1-oxypyridin-2-yl 480 Cl 3-Py CH.sub.2
4,6-Dimethyl-5-methoxy-pyridin-2-yl 481 Cl 3-Py CH.sub.2
4,6-Dimethyl-5-methoxypyridin-3-yl 482 Cl 3-Py CH.sub.2
4,6-Dimethyl-5-methoxy-1-oxypyridin-3-yl 483 Cl 3-Py CH.sub.2
4,6-Dimethyl-5-bromopyridin-3-yl 484 Cl 3-Py CH.sub.2
4,6-Dimethyl-5-chloropyridin-3-yl 485 Cl 3-Py CH.sub.2
5,6-Dimethyl-4-bromopyridin-3-yl 486 Cl 3-Py CH.sub.2
5,6-Dimethyl-4-chloropyridin-3-yl 487 Cl 3-Py CH.sub.2
2,6-Dimethyl-3-methoxypyridin-4-yl 488 Cl 3-Py CH.sub.2
2,6-Dimethyl-pyridin-4-yl
489 Cl 3-Py CH.sub.2 2,3,6-Trimethyl-pyridin-4-yl 490 Cl 3-Py
CH.sub.2 2,3,6-Trimethoxy-pyridin-4-yl 491 Cl 3-Py CH.sub.2
2,6-Dimethyl-3-bromopyridin-4-yl 492 Cl 3-Py CH.sub.2
2,6-Dimethyl-3-chloropyridin-4-yl 493 Cl 3-Py CH.sub.2
4,6-Dimethyl-5-iodopyridin-3-yl 494 Cl 3-Py CH.sub.2
3,5-Dimethyl-4-aminopyridin-2-yl 495 Cl CH.sub.2--NMe.sub.2
CH.sub.2 3,5-Dimethyl-4-methoxypyridin-2-yl 496 Cl
CH.sub.2--NMe.sub.2 CH.sub.2
3,5-Dimethyl-4-methoxy-1-oxypyridin-2-yl 497 Cl CH.sub.2--NMe.sub.2
CH.sub.2 3,5-Dimethyl-4-bromopyridin-2-yl 498 Cl
CH.sub.2--NMe.sub.2 CH.sub.2 3,5-Dimethyl-4-bromo-1-oxypyridin-2-yl
499 Cl CH.sub.2--NMe.sub.2 CH.sub.2
3,5-Dimethyl-4-chloropyridin-2-yl 500 Cl CH.sub.2--NMe.sub.2
CH.sub.2 3,5-Dimethyl-4-chloro-1-oxypyridin-2-yl 501 Cl
CH.sub.2--NMe.sub.2 CH.sub.2 3,5-Dimethyl-4-iodopyridin-2-yl 502 Cl
CH.sub.2--NMe.sub.2 CH.sub.2 3,5-Dimethyl-4-iodo-1-oxypyridin-2-yl
503 Cl CH.sub.2--NMe.sub.2 CH.sub.2
3,5-Dimethyl-4-thiomethyl-pyridin-2-yl 504 Cl CH.sub.2--NMe.sub.2
CH.sub.2 3,5-Dimethyl-4-thiomethyl-1-oxypyridin-2-yl 505 Cl
CH.sub.2--NMe.sub.2 CH.sub.2 3,4,5-Trimethyl-pyridin-2-yl 506 Cl
CH.sub.2--NMe.sub.2 CH.sub.2 3,4,5-Trimethyl-1-oxypyridin-2-yl 507
Cl CH.sub.2--NMe.sub.2 CH.sub.2 4,5,6-Trimethoxypyridin-2-yl 508 Cl
CH.sub.2--NMe.sub.2 CH.sub.2 4,5,6-Trimethoxy-1-oxypyridin-2-yl 509
Cl CH.sub.2--NMe.sub.2 CH.sub.2 3,4,5-Trimethoxy-pyridin-2-yl 510
Cl CH.sub.2--NMe.sub.2 CH.sub.2 3,4,5-Trimethoxy-1-oxypyridin-2-yl
511 Cl CH.sub.2--NMe.sub.2 CH.sub.2 4,5,6-Trimethyl-pyridin-2-yl
512 Cl CH.sub.2--NMe.sub.2 CH.sub.2
4,5,6-Trimethyl-1-oxypyridin-2-yl 513 Cl CH.sub.2--NMe.sub.2
CH.sub.2 4,6-Dimethyl-5-methoxy-pyridin-2-yl 514 Cl
CH.sub.2--NMe.sub.2 CH.sub.2 4,6-Dimethyl-5-methoxypyridin-3-yl 515
Cl CH.sub.2--NMe.sub.2 CH.sub.2
4,6-Dimethyl-5-methoxy-1-oxypyridin-3-yl 516 Cl CH.sub.2--NMe.sub.2
CH.sub.2 4,6-Dimethyl-5-bromopyridin-3-yl 517 Cl
CH.sub.2--NMe.sub.2 CH.sub.2 4,6-Dimethyl-5-chloropyridin-3-yl 518
Cl CH.sub.2--NMe.sub.2 CH.sub.2 5,6-Dimethyl-4-bromopyridin-3-yl
519 Cl CH.sub.2--NMe.sub.2 CH.sub.2
5,6-Dimethyl-4-chloropyridin-3-yl 520 Cl CH.sub.2--NMe.sub.2
CH.sub.2 2,6-Dimethyl-3-methoxypyridin-4-yl 521 Cl
CH.sub.2--NMe.sub.2 CH.sub.2 2,6-Dimethyl-pyridin-4-yl 522 Cl
CH.sub.2--NMe.sub.2 CH.sub.2 2,3,6-Trimethyl-pyridin-4-yl 523 Cl
CH.sub.2--NMe.sub.2 CH.sub.2 2,3,6-Trimethoxy-pyridin-4-yl 524 Cl
CH.sub.2--NMe.sub.2 CH.sub.2 2,6-Dimethyl-3-bromopyridin-4-yl 525
Cl CH.sub.2--NMe.sub.2 CH.sub.2 2,6-Dimethyl-3-chloropyridin-4-yl
526 Cl CH.sub.2--NMe.sub.2 CH.sub.2 4,6-Dimethyl-5-iodopyridin-3-yl
527 Cl CH.sub.2--NMe.sub.2 CH.sub.2
3,5-Dimethyl-4-aminopyridin-2-yl 528 Cl 2-furanyl CH.sub.2
3,5-Dimethyl-4-methoxypyridin-2-yl 529 Cl 2-furanyl CH.sub.2
3,5-Dimethyl-4-methoxy-1-oxypyridin-2-yl 530 Cl 2-furanyl CH.sub.2
3,5-Dimethyl-4-bromopyridin-2-yl 531 Cl 2-furanyl CH.sub.2
3,5-Dimethyl-4-bromo-1-oxypyridin-2-yl 532 Cl 2-furanyl CH.sub.2
3,5-Dimethyl-4-chloropyridin-2-yl 533 Cl 2-furanyl CH.sub.2
3,5-Dimethyl-4-chloro-1-oxypyridin-2-yl 534 Cl 2-furanyl CH.sub.2
3,5-Dimethyl-4-iodopyridin-2-yl 536 Cl 2-furanyl CH.sub.2
3,5-Dimethyl-4-iodo-1-oxypyridin-2-yl 537 Cl 2-furanyl CH.sub.2
3,5-Dimethyl-4-thiomethyl-pyridin-2-yl 538 Cl 2-furanyl CH.sub.2
3,5-Dimethyl-4-thiomethyl-1-oxypyridin-2-yl 539 Cl 2-furanyl
CH.sub.2 3,4,5-Trimethyl-pyridin-2-yl 540 Cl 2-furanyl CH.sub.2
3,4,5-Trimethyl-1-oxypyridin-2-yl 541 Cl 2-furanyl CH.sub.2
4,5,6-Trimethoxypyridin-2-yl 542 Cl 2-furanyl CH.sub.2
4,5,6-Trimethoxy-1-oxypyridin-2-yl 543 Cl 2-furanyl CH.sub.2
3,4,5-Trimethoxy-pyridin-2-yl 544 Cl 2-furanyl CH.sub.2
3,4,5-Trimethoxy-1-oxypyridin-2-yl 545 Cl 2-furanyl CH.sub.2
4,5,6-Trimethyl-pyridin-2-yl 546 Cl 2-furanyl CH.sub.2
4,5,6-Trimethyl-1-oxypyridin-2-yl 547 Cl 2-furanyl CH.sub.2
4,6-Dimethyl-5-methoxy-pyridin-2-yl 548 Cl 2-furanyl CH.sub.2
4,6-Dimethyl-5-methoxypyridin-3-yl 549 Cl 2-furanyl CH.sub.2
4,6-Dimethyl-5-methoxy-1-oxypyridin-3-yl 550 Cl 2-furanyl CH.sub.2
4,6-Dimethyl-5-bromopyridin-3-yl 551 Cl 2-furanyl CH.sub.2
4,6-Dimethyl-5-chloropyridin-3-yl 552 Cl 2-furanyl CH.sub.2
5,6-Dimethyl-4-bromopyridin-3-yl 553 Cl 2-furanyl CH.sub.2
5,6-Dimethyl-4-chloropyridin-3-yl 554 Cl 2-furanyl CH.sub.2
2,6-Dimethyl-3-methoxypyridin-4-yl 555 Cl 2-furanyl CH.sub.2
2,6-Dimethyl-pyridin-4-yl 556 Cl 2-furanyl CH.sub.2
2,3,6-Trimethyl-pyridin-4-yl 557 Cl 2-furanyl CH.sub.2
2,3,6-Trimethoxy-pyridin-4-yl 558 Cl 2-furanyl CH.sub.2
2,6-Dimethyl-3-bromopyridin-4-yl 559 Cl 2-furanyl CH.sub.2
2,6-Dimethyl-3-chloropyridin-4-yl 560 Cl 2-furanyl CH.sub.2
3,5-Dimethyl-4-aminopyridin-2-yl 561 Cl Cl CH.sub.2
3,5-Dimethyl-4-methoxypyridin-2-yl 562 Cl Cl CH.sub.2
3,5-Dimethyl-4-methoxy-1-oxypyridin-2-yl 563 Cl Cl CH.sub.2
3,5-Dimethyl-4-bromopyridin-2-yl 564 Cl Cl CH.sub.2
3,5-Dimethyl-4-bromo-1-oxypyridin-2-yl 565 Cl Cl CH.sub.2
3,5-Dimethyl-4-chloropyridin-2-yl 566 Cl Cl CH.sub.2
3,5-Dimethyl-4-chloro-1-oxypyridin-2-yl 567 Cl Cl CH.sub.2
3,5-Dimethyl-4-iodopyridin-2-yl 568 Cl Cl CH.sub.2
3,5-Dimethyl-4-iodo-1-oxypyridin-2-yl 569 Cl Cl CH.sub.2
3,5-Dimethyl-4-thiomethyl-pyridin-2-yl 570 Cl Cl CH.sub.2
3,5-Dimethyl-4-thiomethyl-1-oxypyridin-2-yl 571 Cl Cl CH.sub.2
3,4,5-Trimethyl-pyridin-2-yl 572 Cl Cl CH.sub.2
3,4,5-Trimethyl-1-oxypyridin-2-yl 573 Cl Cl CH.sub.2
4,6-Dimethyl-5-methoxypyridin-3-yl 574 Cl Cl CH.sub.2
4,6-Dimethyl-5-methoxy-1-oxypyridin-3-yl 575 Cl Cl CH.sub.2
3,5-Dimethyl-4-aminopyridin-2-yl 576 Cl Br CH.sub.2
3,5-Dimethyl-4-methoxypyridin-2-yl 577 Cl Br CH.sub.2
3,5-Dimethyl-4-methoxy-1-oxypyridin-2-yl 578 Cl Br CH.sub.2
3,5-Dimethyl-4-bromopyridin-2-yl 579 Br Br CH.sub.2
3,5-Dimethyl-4-bromo-1-oxypyridin-2-yl 580 Cl Br CH.sub.2
3,5-Dimethyl-4-chloropyridin-2-yl 581 Br Br CH.sub.2
3,5-Dimethyl-4-chloro-1-oxypyridin-2-yl 582 Cl Br CH.sub.2
3,5-Dimethyl-4-iodopyridin-2-yl 583 Br Br CH.sub.2
3,5-Dimethyl-4-iodo-1-oxypyridin-2-yl 584 Cl Br CH.sub.2
3,5-Dimethyl-4-thiomethyl-pyridin-2-yl 585 Br Br CH.sub.2
3,5-Dimethyl-4-thiomethyl-1-oxypyridin-2-yl 586 Cl Br CH.sub.2
3,4,5-Trimethyl-pyridin-2-yl 587 Br Br CH.sub.2
3,4,5-Trimethyl-1-oxypyridin-2-yl 588 Cl Br CH.sub.2
4,6-Dimethyl-5-methoxypyridin-3-yl 589 Cl Br CH.sub.2
4,6-Dimethyl-5-methoxy-1-oxypyridin-3-yl 590 Cl Br CH.sub.2
3,5-Dimethyl-4-aminopyridin-2-yl 591 Cl I CH.sub.2
3,5-Dimethyl-4-methoxypyridin-2-yl 592 Cl I CH.sub.2
3,5-Dimethyl-4-methoxy-1-oxypyridin-2-yl 593 Cl I CH.sub.2
3,5-Dimethyl-4-bromopyridin-2-yl 594 Cl I CH.sub.2
3,5-Dimethyl-4-bromo-1-oxypyridin-2-yl 595 Cl I CH.sub.2
3,5-Dimethyl-4-chloropyridin-2-yl 596 Cl I CH.sub.2
3,5-Dimethyl-4-chloro-1-oxypyridin-2-yl 597 Cl I CH.sub.2
3,5-Dimethyl-4-iodopyridin-2-yl 598 Cl I CH.sub.2
3,5-Dimethyl-4-iodo-1-oxypyridin-2-yl 599 Cl I CH.sub.2
3,5-Dimethyl-4-thiomethyl-pyridin-2-yl 600 Cl I CH.sub.2
3,5-Dimethyl-4-thiomethyl-1-oxypyridin-2-yl 601 Cl I CH.sub.2
3,4,5-Trimethyl-pyridin-2-yl 602 Cl I CH.sub.2
3,4,5-Trimethyl-1-oxypyridin-2-yl 603 Cl I CH.sub.2
4,6-Dimethyl-5-methoxypyridin-3-yl 604 Cl I CH.sub.2
4,6-Dimethyl-5-methoxy-1-oxypyridin-3-yl 605 Cl I CH.sub.2
3,5-Dimethyl-4-aminopyridin-2-yl 606 Cl CN CH.sub.2
3,5-Dimethyl-4-methoxypyridin-2-yl 607 Cl CN CH.sub.2
3,5-Dimethyl-4-methoxy-1-oxypyridin-2-yl 608 Cl CN CH.sub.2
3,5-Dimethyl-4-bromopyridin-2-yl 609 Cl CN CH.sub.2
3,5-Dimethyl-4-bromo-1-oxpyridin-2-yl 610 Cl CN CH.sub.2
3,5-Dimethyl-4-chloropyridin-2-yl 611 Cl CN CH.sub.2
3,5-Dimethyl-4-chloro-1-oxypyridin-2-yl 612 Cl CN CH.sub.2
3,5-Dimethyl-4-iodopyridin-2-yl 613 Cl CN CH.sub.2
3,5-Dimethyl-4-iodo-1-oxypyridin-2-yl 614 Cl CN CH.sub.2
3,5-Dimethyl-4-thiomethyl-pyridin-2-yl 615 Cl CN CH.sub.2
3,5-Dimethyl-4-thiomethyl-1-oxypyridin-2-yl 616 Cl CN CH.sub.2
3,4,5-Trimethyl-pyridin-2-yl 617 Cl CN CH.sub.2
3,4,5-Trimethyl-1-oxypyridin-2-yl 618 Cl CN CH.sub.2
4,6-Dimethyl-5-methoxypyridin-3-yl 619 Cl CN CH.sub.2
4,6-Dimethyl-5-methoxy-1-oxypyridin-3-yl 620 Cl CN CH.sub.2
3,5-Dimethyl-4-aminopyridin-2-yl 621 Cl H C(O)
3,5-Dimethyl-4-methoxypyridin-2-yl 622 Cl H C(O)
3,5-Dimethyl-4-methoxy-1-oxypyridin-2-yl 623 Cl H C(O)
3,5-Dimethyl-4-bromopyridin-2-yl 624 Cl H C(O)
3,5-Dimethyl-4-bromo-1-oxypyridin-2-yl 625 Cl H C(O)
3,5-Dimethyl-4-chloropyridin-2-yl 626 Cl H C(O)
3,5-Dimethyl-4-chloro-1-oxypyridin-2-yl 627 Cl H C(O)
3,5-Dimethyl-4-iodopyridin-2-yl 628 Cl H C(O)
3,5-Dimethyl-4-iodo-1-oxypyridin-2-yl 629 Cl H C(O)
3,5-Dimethyl-4-thiomethyl-pyridin-2-yl 630 Cl H C(O)
3,5-Dimethyl-4-thiomethyl-1-oxypyridin-2-yl 631 Cl H C(O)
3,4,5-Trimethyl-pyridin-2-yl 632 Cl H C(O)
3,4,5-Trimethyl-1-oxypyridin-2-yl 633 Cl H C(O)
4,6-Dimethyl-5-methoxypyridin-3-yl 634 Cl H C(O)
4,6-Dimethyl-5-methoxy-1-oxypyridin-3-yl 635 Cl H C(O)
3,5-Dimethyl-4-aminopyridin-2-yl 636 Cl H S(O)
3,5-Dimethyl-4-methoxypyridin-2-yl 637 Cl H S(O)
3,5-Dimethyl-4-methoxy-1-oxypyridin-2-yl 638 Cl H S(O)
3,5-Dimethyl-4-bromopyndin-2-yl 639 Cl H S(O)
3,5-Dimethyl-4-bromo-1-oxypyridin-2-yl 640 Cl H S(O)
3,5-Dimethyl-4-chloropyridin-2-yl 641 Cl H S(O)
3,5-Dimethyl-4-chloro-1-oxpyridin-2-yl 642 Cl H S(O)
3,5-Dimethyl-4-iodopyridin-2-yl 643 Cl H S(O)
3,5-Dimethyl-4-iodo-1-oxypyridin-2-yl 644 Cl H S(O)
3,5-Dimethyl-4-thiomethyl-pyridin-2-yl 645 Cl H S(O)
3,5-Dimethyl-4-thiomethyl-1-oxypyridin-2-yl 646 Cl Br S(O)
3,4,5-Trimethyl-pyridin-2-yl 647 Cl H S(O)
3,4,5-Trimethyl-1-oxypyridin-2-yl 648 Cl Br S(O)
4,6-Dimethyl-5-methoxypyridin-3-yl 649 Cl H S(O)
4,6-Dimethyl-5-methoxy-1-oxypyridin-3-yl 650 Cl H SO.sub.2
3,5-Dimethyl-4-methoxypyridin-2-yl 651 Cl H SO.sub.2
3,5-Dimethyl-4-methoxy-1-oxypyridin-2-yl 652 Cl H SO.sub.2
3,5-Dimethyl-4-bromopyridin-2-yl 653 Cl H SO.sub.2
3,5-Dimethyl-4-bromo-1-oxypyridin-2-yl 654 Cl Br SO.sub.2
3,5-Dimethyl-4-chloropyridin-2-yl 655 Cl H SO.sub.2
3,5-Dimethyl-4-chloro-1-oxypyridin-2-yl 656 Cl H SO.sub.2
3,5-Dimethyl-4-iodopyridin-2-yl 657 Cl H SO.sub.2
3,5-Dimethyl-4-iodo-1-oxypyridin-2-yl 658 Cl H SO.sub.2
3,5-Dimethyl-4-thiomethyl-pyridin-2-yl 659 Cl H SO.sub.2
3,5-Dimethyl-4-thiomethyl-1-oxypyridin-2-yl 660 Cl H SO.sub.2
3,4,5-Trimethyl-pyridin-2-yl 661 Cl H SO.sub.2
3,4,5-Trimethyl-1-oxypyridin-2-yl 662 Cl H SO.sub.2
4,6-Dimethyl-5-methoxypyridin-3-yl 663 Cl H SO.sub.2
4,6-Dimethyl-5-methoxy-1-oxypyridin-3-yl 664 Cl i-pr C(O)
3,5-Dimethyl-4-methoxypyridin-2-yl 665 Cl i-pr C(O)
3,5-Dimethyl-4-methoxy-1-oxypyridin-2-yl 666 Cl i-pr C(O)
3,5-Dimethyl-4-bromopyridin-2-yl 667 Cl i-pr C(O)
3,5-Dimethyl-4-bromo-1-oxypyridin-2-yl 668 Cl i-pr C(O)
3,5-Dimethyl-4-chloropyridin-2-yl 669 Cl i-pr C(O)
3,5-Dimethyl-4-chloro-1-oxypyridin-2-yl 670 Cl i-pr C(O)
3,5-Dimethyl-4-iodopyridin-2-yl 671 Cl i-pr C(O)
3,5-Dimethyl-4-iodo-1-oxypyridin-2-yl 672 Cl i-pr C(O)
3,5-Dimethyl-4-thiomethyl-pyridin-2-yl 673 Cl i-pr C(O)
3,5-Dimethyl-4-thiomethyl-1-oxypyridin-2-yl 674 Cl i-pr C(O)
3,4,5-Trimethyl-pyridin-2-yl 675 Cl i-pr C(O)
3,4,5-Trimethyl-1-oxypyridin-2-yl 676 Cl i-pr C(O)
4,6-Dimethyl-5-methoxypyridin-3-yl 677 Cl i-pr C(O)
4,6-Dimethyl-5-methoxy-1-oxypyridin-3-yl 678 Cl i-pr C(O)
3,5-Dimethyl-4-aminopyridin-2-yl 679 Cl i-pr S(O)
3,5-Dimethyl-4-methoxypyridin-2-yl 680 Cl i-pr S(O)
3,5-Dimethyl-4-methoxy-1-oxypyridin-2-yl 681 Cl i-pr S(O)
3,5-Dimethyl-4-bromopyridin-2-yl 682 Cl i-pr S(O)
3,5-Dimethyl-4-bromo-1-oxypyridin-2-yl 683 Cl i-pr S(O)
3,5-Dimethyl-4-chloropyridin-2-yl 684 Cl i-pr S(O)
3,5-Dimethyl-4-chloro-1-oxypyridin-2-yl 685 Cl i-pr S(O)
3,5-Dimethyl-4-iodopyridin-2-yl 686 Cl i-pr S(O)
3,5-Dimethyl-4-iodo-1-oxypyridin-2-yl 687 Cl i-pr S(O)
3,5-Dimethyl-4-thiomethyl-pyridin-2-yl 688 Cl i-pr S(O)
3,5-Dimethyl-4-thiomethyl-1-oxypyridin-2-yl 689 Cl i-pr S(O)
3,4,5-Trimethyl-pyridin-2-yl 690 Cl i-pr S(O)
3,4,5-Trimethyl-1-oxypyridin-2-yl 691 Cl i-pr S(O)
4,6-Dimethyl-5-methoxypyridin-3-yl 692 Cl i-pr S(O)
4,6-Dimethyl-5-methoxy-1-oxypyridin-3-yl 693 Cl i-pr SO.sub.2
3,5-Dimethyl-4-methoxypyridin-2-yl 694 Cl i-pr SO.sub.2
3,5-Dimethyl-4-methoxy-1-oxypyridin-2-yl 695 Cl i-pr SO.sub.2
3,5-Dimethyl-4-bromopyridin-2-yl 696 Cl i-pr SO.sub.2
3,5-Dimethyl-4-bromo-1-oxypyridin-2-yl 697 Cl i-pr SO.sub.2
3,5-Dimethyl-4-chloropyridin-2-yl 698 Cl i-pr SO.sub.2
3,5-Dimethyl-4-chloro-1-oxypyridin-2-yl 699 Cl i-pr SO.sub.2
3,5-Dimethyl-4-iodopyridin-2-yl 700 Cl i-pr SO.sub.2
3,5-Dimethyl-4-iodo-1-oxypyridin-2-yl 701 Cl i-pr SO.sub.2
3,5-Dimethyl-4-thiomethyl-pyridin-2-yl 702 Cl i-pr SO.sub.2
3,5-Dimethyl-4-thiomethyl-1-oxypyridin-2-yl 703 Cl i-pr SO.sub.2
3,4,5-Trimethyl-pyridin-2-yl 704 Cl i-pr SO.sub.2
3,4,5-Trimethyl-1-oxypyridin-2-yl 705 Cl i-pr SO.sub.2
4,6-Dimethyl-5-methoxypyridin-3-yl 706 Cl i-pr SO.sub.2
4,6-Dimethyl-5-methoxy-1-oxypyridin-3-yl 707 Cl H C(O)
3,4,5-Trimethoxyphenyl 708 Cl H C(O)
2-Chloro-3,4,5-trimethoxyphenyl 709 Cl H C(O)
2-Bromo-3,4,5-trimethoxyphenyl 710 Cl H C(O)
3,5-Dimethyl-4-methoxyphenyl 711 Cl H C(O)
2-Chloro-3,5-Dimethyl-4-methoxyphenyl 712 Cl H C(O)
2-Bromo-3,5-Dimethyl-4-methoxyphenyl 713 Cl H SO.sub.2
3,4,5-Trimethoxyphenyl 714 Cl H SO.sub.2
2-Chloro-3,4,5-trimethoxyphenyl 715 Cl H SO.sub.2
2-Bromo-3,4,5-trimethoxyphenyl 716 Cl H SO.sub.2
3,5-Dimethyl-4-methoxyphenyl 717 Cl H SO.sub.2
2-Chloro-3,5-Dimethyl-4-methoxyphenyl 718 Cl H SO.sub.2
2-Bromo-3,5-Dimethyl-4-methoxyphenyl 719 Br H CH.sub.2
3,5-Dimethyl-4-methoxypyridin-2-yl 720 Br H CH.sub.2
3,5-Dimethyl-4-methoxy-1-oxypyridin-2-yl 721 Br H CH.sub.2
6-Bromo-3,5-dimethyl-4-methoxypyridin-2-yl 722 Br H CH.sub.2
6-Chloro-3,5-dimethyl-4-methoxypyridin-2-yl 723 Br H CH.sub.2
3,5-Dimethyl-4-bromopyridin-2-yl 724 Br H CH.sub.2
3,5-Dimethyl-4-bromo-1-oxypyridin-2-yl 725 Br H CH.sub.2
3,5-Dimethyl-4-chloropyridin-2-yl 726 Br H CH.sub.2
3,5-Dimethyl-4-chloro-1-oxypyridin-2-yl 727 Br H CH.sub.2
3,5-Dimethyl-4-iodopyridin-2-yl 728 Br H CH.sub.2
3,5-Dimethyl-4-iodo-1-oxypyridin-2-yl 729 Br H CH.sub.2
3,5-Dimethyl-4-thiomethyl-pyridin-2-yl 730 Br H CH.sub.2
3,5-Dimethyl-4-thiomethyl-1-oxypyridin-2-yl 731 Br H CH.sub.2
3,4,5-Trimethyl-pyridin-2-yl 732 Br H CH.sub.2
3,4,5-Trimethyl-1-oxypyridin-2-yl 733 Br H CH.sub.2
4,5,6-Trimethoxypyridin-2-yl
734 Br H CH.sub.2 4,5,6-Trimethoxy-1-oxypyridin-2-yl 735 Br H
CH.sub.2 3-Bromo-4,5,6-trimethoxypyridin-2-yl 736 Br H CH.sub.2
3-Chloro-4,5,6-trimethoxypyridin-2-yl 737 Br H CH.sub.2
3,4,5-Trimethoxy-pyridin-2-yl 738 Br H CH.sub.2
3,4,5-Trimethoxy-1-oxypyridin-2-yl 739 Br H CH.sub.2
3-Bromo-3,4,5-trimethoxy-pyridin-2-yl 740 Br H CH.sub.2
3-Chloro-3,4,5-trimethoxy-pyridin-2-yl 741 Br H CH.sub.2
4,5,6-Trimethyl-pyridin-2-yl 742 Br H CH.sub.2
4,5,6-Trimethyl-1-oxypyridin-2-yl 743 Br H CH.sub.2
4,6-Dimethyl-5-methoxy-pyridin-2-yl 744 Br H CH.sub.2
4,6-Dimethyl-5-methoxypyridin-3-yl 745 Br H CH.sub.2
4,6-Dimethyl-5-methoxy-1-oxypyridin-3-yl 746 Br H CH.sub.2
4,6-Dimethyl-5-bromopyridin-3-yl 747 Br H CH.sub.2
4,6-Dimethyl-5-chloropyridin-3-yl 748 Br H CH.sub.2
5,6-Dimethyl-4-bromopyridin-3-yl 749 Br H CH.sub.2
5,6-Dimethyl-4-chloropyridin-3-yl 750 Br H CH.sub.2
2,6-Dimethyl-3-methoxypyridin-4-yl 751 Br H CH.sub.2
2,6-Dimethyl-pyridin-4-yl 752 Br H CH.sub.2
2,3,6-Trimethyl-pyridin-4-yl 753 Br H CH.sub.2
2,3,6-Trimethoxy-pyridin-4-yl 754 Br H CH.sub.2
2,6-Dimethyl-3-bromopyridin-4-yl 755 Br H CH.sub.2
2,6-Dimethyl-3-chloropyridin-4-yl 756 Br H CH.sub.2
2,6-Dimethyl-3-methoxy-1-oxy-pyridin-4-yl 757 Br H CH.sub.2
2,6-Dimethyl-1-oxy-pyridin-4-yl 758 Br H CH.sub.2
2,3,6-Trimethyl-1-oxy-pyridin-4-yl 759 Br H CH.sub.2
2,3,6-Trimethoxy-1-oxy-pyridin-4-yl 760 Br H CH.sub.2
2,6-Dimethyl-3-bromo1-oxy-pyridin-4-yl 761 Br H CH.sub.2
2,6-Dimethyl-3-chloro1-oxy-pyridin-4-yl 762 Br H CH.sub.2
4,6-Dimethyl-5-iodopyridin-3-yl 763 Br H CH.sub.2
3,5-Dimethyl-4-aminopyridin-2-yl 764 Br i-pr CH.sub.2
3,5-Dimethyl-4-methoxypyridin-2-yl 765 Br i-pr CH.sub.2
3,5-Dimethyl-4-methoxy-1-oxypyridin-2-yl 766 Br i-pr CH.sub.2
6-Bromo-3,5-dimethyl-4-methoxypyridin-2-yl 767 Br i-pr CH.sub.2
6-Chloro-3,5-dimethyl-4-methoxypyridin-2-yl 768 Br i-pr CH.sub.2
3,5-Dimethyl-4-bromopyridin-2-yl 769 Br i-pr CH.sub.2
3,5-Dimethyl-4-bromo-1-oxypyridin-2-yl 770 Br i-pr CH.sub.2
3,5-Dimethyl-4-chloropyridin-2-yl 771 Br i-pr CH.sub.2
3,5-Dimethyl-4-chloro-1-oxypyridin-2-yl 772 Br i-pr CH.sub.2
3,5-Dimethyl-4-iodopyridin-2-yl 773 Br i-pr CH.sub.2
3,5-Dimethyl-4-iodo-1-oxypyridin-2-yl 774 Br i-pr CH.sub.2
3,5-Dimethyl-4-thiomethyl-pyridin-2-yl 775 Br i-pr CH.sub.2
3,5-Dimethyl-4-thiomethyl-1-oxypyridin-2-yl 776 Br i-pr CH.sub.2
3,4,5-Trimethyl-pyridin-2-yl 777 Br i-pr CH.sub.2
3,4,5-Trimethyl-1-oxypyridin-2-yl 778 Br i-pr CH.sub.2
4,5,6-Trimethoxypyridin-2-yl 779 Br i-pr CH.sub.2
4,5,6-Trimethoxy-1-oxypyridin-2-yl 780 Br i-pr CH.sub.2
3-Bromo-4,5,6-trimethoxypyridin-2-yl 781 Br i-pr CH.sub.2
3-Chloro-4,5,6-trimethoxypyridin-2-yl 782 Br i-pr CH.sub.2
3,4,5-Trimethoxy-pyridin-2-yl 783 Br i-pr CH.sub.2
3,4,5-Trimethoxy-1-oxypyridin-2-yl 784 Br i-pr CH.sub.2
3-Bromo-3,4,5-trimethoxy-pyridin-2-yl 785 Br i-pr CH.sub.2
3-Chloro-3,4,5-trimethoxy-pyridin-2-yl 786 Br i-pr CH.sub.2
4,5,6-Trimethyl-pyridin-2-yl 787 Br i-pr CH.sub.2
4,5,6-Trimethyl-1-oxypyridin-2-yl 788 Br i-pr CH.sub.2
4,6-Dimethyl-5-methoxy-pyridin-2-yl 789 Br i-pr CH.sub.2
4,6-Dimethyl-5-methoxypyridin-3-yl 790 Br i-pr CH.sub.2
4,6-Dimethyl-5-methoxy-1-oxypyridin-3-yl 791 Br i-pr CH.sub.2
4,6-Dimethyl-5-bromopyridin-3-yl 792 Br i-pr CH.sub.2
4,6-Dimethyl-5-chloropyridin-3-yl 793 Br i-pr CH.sub.2
5,6-Dimethyl-4-bromopyridin-3-yl 794 Br i-pr CH.sub.2
5,6-Dimethyl-4-chloropyridin-3-yl 795 Br i-pr CH.sub.2
2,6-Dimethyl-3-methoxypyridin-4-yl 796 Br i-pr CH.sub.2
2,6-Dimethyl-pyridin-4-yl 797 Br i-pr CH.sub.2
2,3,6-Trimethyl-pyridin-4-yl 798 Br i-pr CH.sub.2
2,3,6-Trimethoxy-pyridin-4-yl 799 Br i-pr CH.sub.2
2,6-Dimethyl-3-bromopyridin-4-yl 800 Br i-pr CH.sub.2
2,6-Dimethyl-3-chloropyridin-4-yl 801 Br i-pr CH.sub.2
2,6-Dimethyl-3-methoxy-1-oxy-pyridin-4-yl 802 Br i-pr CH.sub.2
2,6-Dimethyl-1-oxy-pyridin-4-yl 803 Br i-pr CH.sub.2
2,3,6-Trimethyl-1-oxy-pyridin-4-yl 804 Br i-pr CH.sub.2
2,3,6-Trimethoxy-1-oxy-pyridin-4-yl 805 Br i-pr CH.sub.2
2,6-Dimethyl-3-bromo1-oxy-pyridin-4-yl 806 Br i-pr CH.sub.2
2,6-Dimethyl-3-chloro1-oxy-pyridin-4-yl 807 Br i-pr CH.sub.2
4,6-Dimethyl-5-iodopyridin-3-yl 808 Br i-pr CH.sub.2
3,5-Dimethyl-4-aminopyridin-2-yl 809 Br Ph CH.sub.2
3,5-Dimethyl-4-methoxypyridin-2-yl 810 Br Ph CH.sub.2
3,5-Dimethyl-4-methoxy-1-oxypyridin-2-yl 811 Br Ph CH.sub.2
3,5-Dimethyl-4-bromopyridin-2-yl 812 Br Ph CH.sub.2
3,5-Dimethyl-4-bromo-1-oxypyridin-2-yl 813 Br Ph CH.sub.2
3,5-Dimethyl-4-chloropyridin-2-yl 814 Br Ph CH.sub.2
3,5-Dimethyl-4-chloro-1-oxypyridin-2-yl 815 Br Ph CH.sub.2
3,5-Dimethyl-4-iodopyridin-2-yl 816 Br Ph CH.sub.2
3,5-Dimethyl-4-iodo-1-oxypyridin-2-yl 817 Br Ph CH.sub.2
3,5-Dimethyl-4-thiomethyl-pyridin-2-yl 818 Br Ph CH.sub.2
3,5-Dimethyl-4-thiomethyl-1-oxypyridin-2-yl 819 Br Ph CH.sub.2
3-Bromo-4,5,6-trimethoxypyridin-2-yl 820 Br Ph CH.sub.2
3-Chloro-4,5,6-trimethoxypyridin-2-yl 821 Br Ph CH.sub.2
4,6-Dimethyl-5-methoxypyridin-3-yl 822 Br Ph CH.sub.2
4,6-Dimethyl-5-methoxy-1-oxypyridin-3-yl 823 Br Et CH.sub.2
3,5-Dimethyl-4-methoxypyridin-2-yl 824 Br Et CH.sub.2
3,5-Dimethyl-4-methoxy-1-oxypyridin-2-yl 825 Br Et CH.sub.2
3,5-Dimethyl-4-bromopyridin-2-yl 826 Br Et CH.sub.2
3,5-Dimethyl-4-bromo-1-oxypyridin-2-yl 827 Br Et CH.sub.2
3,5-Dimethyl-4-chloropyridin-2-yl 828 Br Et CH.sub.2
3,5-Dimethyl-4-chloro-1-oxypyridin-2-yl 829 Br Et CH.sub.2
3,5-Dimethyl-4-iodopyridin-2-yl 830 Br Et CH.sub.2
3,5-Dimethyl-4-iodo-1-oxypyridin-2-yl 831 Br Et CH.sub.2
3,5-Dimethyl-4-thiomethyl-pyridin-2-yl 832 Br Et CH.sub.2
3,5-Dimethyl-4-thiomethyl-1-oxypyridin-2-yl 833 Br Et CH.sub.2
3-Bromo-4,5,6-trimethoxypyridin-2-yl 834 Br Et CH.sub.2
3-Chloro-4,5,6-trimethoxypyridin-2-yl 835 Br Et CH.sub.2
4,6-Dimethyl-5-methoxypyridin-3-yl 836 Br Et CH.sub.2
4,6-Dimethyl-5-methoxy-1-oxypyridin-3-yl 837 Br Me CH.sub.2
3,5-Dimethyl-4-methoxypyridin-2-yl 838 Br Me CH.sub.2
3,5-Dimethyl-4-methoxy-1-oxypyridin-2-yl 839 Br Me CH.sub.2
3,5-Dimethyl-4-bromopyridin-2-yl 840 Br Me CH.sub.2
3,5-Dimethyl-4-bromo-1-oxypyridin-2-yl 841 Br Me CH.sub.2
3,5-Dimethyl-4-chloropyridin-2-yl 842 Br Me CH.sub.2
3,5-Dimethyl-4-chloro-1-oxypyridin-2-yl 843 Br Me CH.sub.2
3,5-Dimethyl-4-iodopyridin-2-yl 844 Br Me CH.sub.2
3,5-Dimethyl-4-iodo-1-oxypyridin-2-yl 845 Br Me CH.sub.2
3,5-Dimethyl-4-thiomethyl-pyridin-2-yl 846 Br Me CH.sub.2
3,5-Dimethyl-4-thiomethyl-1-oxypyridin-2-yl 847 Br Me CH.sub.2
3-Bromo-4,5,6-trimethoxypyridin-2-yl 848 Br Me CH.sub.2
3-Chloro-4,5,6-trimethoxypyridin-2-yl 849 Br Me CH.sub.2
4,6-Dimethyl-5-methoxypyridin-3-yl 850 Br Me CH.sub.2
4,6-Dimethyl-5-methoxy-1-oxypyridin-3-yl 851 Br 2-Py CH.sub.2
3,5-Dimethyl-4-methoxypyridin-2-yl 852 Br 2-Py CH.sub.2
3,5-Dimethyl-4-methoxy-1-oxypyridin-2-yl 853 Br 2-Py CH.sub.2
3,5-Dimethyl-4-bromopyridin-2-yl 854 Br 2-Py CH.sub.2
3,5-Dimethyl-4-bromo-1-oxypyridin-2-yl 855 Br 2-Py CH.sub.2
3,5-Dimethyl-4-chloropyridin-2-yl 856 Br 2-Py CH.sub.2
3,5-Dimethyl-4-chloro-1-oxypyridin-2-yl 857 Br 2-Py CH.sub.2
3,5-Dimethyl-4-iodopyridin-2-yl 858 Br 2-Py CH.sub.2
3,5-Dimethyl-4-iodo-1-oxypyridin-2-yl 859 Br 2-Py CH.sub.2
3,5-Dimethyl-4-thiomethyl-pyridin-2-yl 860 Br 2-Py CH.sub.2
3,5-Dimethyl-4-thiomethyl-1-oxypyridin-2-yl 861 Br 2-Py CH.sub.2
3-Bromo-4,5,6-trimethoxypyridin-2-yl 862 Br 2-Py CH.sub.2
3-Chloro-4,5,6-trimethoxypyridin-2-yl 863 Br 2-Py CH.sub.2
4,6-Dimethyl-5-methoxypyridin-3-yl 864 Br 2-Py CH.sub.2
4,6-Dimethyl-5-methoxy-1-oxypyridin-3-yl 865 Br 3-Py CH.sub.2
3,5-Dimethyl-4-methoxypyridin-2-yl 866 Br 3-Py CH.sub.2
3,5-Dimethyl-4-methoxy-1-oxypyridin-2-yl 867 Br 3-Py CH.sub.2
3,5-Dimethyl-4-bromopyridin-2-yl 868 Br 3-Py CH.sub.2
3,5-Dimethyl-4-bromo-1-oxypyridin-2-yl 869 Br 3-Py CH.sub.2
3,5-Dimethyl-4-chloropyridin-2-yl 870 Br 3-Py CH.sub.2
3,5-Dimethyl-4-chloro-1-oxypyridin-2-yl 871 Br 3-Py CH.sub.2
3,5-Dimethyl-4-iodopyridin-2-yl 872 Br 3-Py CH.sub.2
3,5-Dimethyl-4-iodo-1-oxypyridin-2-yl 873 Br 3-Py CH.sub.2
3,5-Dimethyl-4-thiomethyl-pyridin-2-yl 874 Br 3-Py CH.sub.2
3,5-Dimethyl-4-thiomethyl-1-oxypyridin-2-yl 875 Br 3-Py CH.sub.2
3-Bromo-4,5,6-trimethoxypyridin-2-yl 876 Br 3-Py CH.sub.2
3-Chloro-4,5,6-trimethoxypyridin-2-yl 877 Br 3-Py CH.sub.2
4,6-Dimethyl-5-methoxypyridin-3-yl 878 Br 3-Py CH.sub.2
4,6-Dimethyl-5-methoxy-1-oxypyridin-3-yl
Particularly preferred compounds in Table 1 are 1, 2, 3 16, 17, 18,
27, 28, 47, 48, 62, 63, 77, 78, 92, 93, 97, 98, 129, 130, 242, 243,
245, 246, 247, 248, 249, 250, 251, 252, 253, 267, 268, 287, 288,
289, 290, 291, 292, 293, 294, 295, 296, 297, 298, 312, 313, 332,
333, 334, 335, 336, 337, 338, 339, 351, 352, 365, 366, 367, 368,
369, 370, 384, 385, 398, 399, 400, 401, 417, 418, 431, 432, 433,
434, 435, 436, 437, 438, 439, 440, 450, 451, 464, 465, 466, 466,
467, 468, 469, 470, 471, 433, 484, 497, 498, 530, 531, 550, 551,
563, 564, 575, 576, 578, 579, 590, 591, 593, 594, 605, 606, 608,
609, 620, 621, 721, 722, 725, 726, 727, 728, 729, 730, 746, 747,
766, 767, 791, 792, 811, 812, 823, 824, 825, 826, 839, 840, 853,
854, 867, and 868. The more preferred compounds are 242, 243, 245,
246, 247, 248, 267, 268, 287, 288, 312, 313, 332, 333, 334, 335,
336, 337, 338, 339, 365, 369, 398, 417, 431, 432, 433, 434, 435,
436, 437, 438, 450, 451, 464, 465, 483, and 484. III. Synthesis of
the Compounds of the Invention
[0269] The compounds the present invention may be synthesized by
various methods known in the art, including those described in, for
example, Gillespie, WO 02/055082; Dempcy, US Publication No. U.S.
2003/0078413. For the synthesis of compounds of Formulae I and II,
a general strategy is outlined in Scheme 1 and consists of three
parts: (1) constructing the bicyclic system, starting from either a
pyridine or a pyrazole, (2) appending the --R.sup.4--R.sup.5 group,
and (3) further elaborating the ring systems.
[0270] Importantly, one skilled in the art will recognize that the
sequence of events is not necessarily (1)-(2)-(3), and that these
events may be interchanged, provided there is no incompatibility
between the reagents and the functional groups specific to the
point in case. ##STR13##
[0271] Also, the starting materials and the intermediates of the
Formula 1, 2, 3, or 4 can exist in tautomeric forms as shown in the
following examples, and both forms are indiscriminately used in
this patent. ##STR14## 1. Assembly of the
Pyrazolo[3,4-d]pyrimidine
[0272] 1.1 Assembly of the Pyrazolo[3,4-d]pyrimidine Starting from
a Pyrimidine ##STR15##
[0273] The compounds of Formula 3 can be prepared from pyrimidines
as outlined in Scheme 2. For instance:
[0274] Method 1.1.1
[0275] The compound of Formula 3, wherein R.sup.6 is --Cl, R.sup.7
is --NH.sub.2, and R.sup.3 is --H, is readily prepared by treating
2-amino-4,6-dichloro-pyrimidine-5-carbaldehyde (Formula 1) with
hydrazine, see, F. Seela, Heterocycles 1985, 23, 2521; F. Seela,
Helv. Chim. Acta 1986, 69, 1602; and R. O. Dempcy, WO
03/022859.
[0276] Method 1.1.2
[0277] The compounds of Formula 3, wherein R.sup.6 is Cl, R.sup.7
is NH.sub.2 and R.sup.3 is alkyl, aryl, or heteroaryl have not been
previously reported. They can be made by converting a compound of
Formula 1 to a compound of Formula 5 in two steps: i) Nucleophilic
addition to the carbonyl group; and ii) Oxidation of the resulting
alcohol. In a subsequent step, the compound of Formula 5 is
converted to the compound of Formula 3 by reaction with hydrazine,
or an equivalent thereof.
[0278] Method 1.1.3
[0279] The compounds of Formula 3 wherein R.sup.3 is NH.sub.2 can
be obtained by treatment of a nitrile of Formula 6 with hydrazine
(See, A. M. El-Reedy, Phosphorus, Sulfur, Silicon, Relat. Elem.
1989, 42, 231).
[0280] The compounds of Formula 3 wherein R.sup.3 is OH can be
obtained by treatment of a nitrile of Formula 6 with hydrazine
followed by hydrolysis (See, Ciba, Patent No. UK 884,151
(1961)).
[0281] Method 1.1.4
[0282] The compounds of Formula 3 wherein R.sup.3 is OH can be
obtained by treatment of an acid, ester, or activated ester (or
equivalent thereof) of Formula 7 with hydrazine (Ciba, Patent No.
UK 884,151 (1961)).
[0283] 1.2. Assembly of the Pyrazolo[3,4-d]pyrimidine Starting from
a Pyrazole
[0284] The compounds of Formula 3 can also be made from pyrazoles
of Formula 2 (Scheme 3). There are a variety of methods by which
the 6-membered ring can be formed (e.g. R. J. Bontems, J. Med.
Chem, 1990, 33, 2174 and references therein). For instance:
##STR16##
[0285] Compounds of Formula 2 wherein R.sup.13 is --CONH.sub.2 and
R.sup.14 is NH.sub.2 can be treated with Ph--CO--NCS to give
compounds of Formula 3 in which R.sup.6 is OH and R.sup.7 is
NH.sub.2 (F. Babin, J. Heterocycl. Chem. 1983, 20, 1169.)
[0286] Compounds of Formula 2 wherein R.sup.13 is --CN and R.sup.14
is NH.sub.2 can be treated with thiourea or guanidine to give
compounds of Formula 3 in which R.sup.6 is NH.sub.2 and R.sup.7 is
NH.sub.2 (H. Kosaku, Heterocycles, 2001, 55, 2279).
[0287] Compounds of Formula 2 wherein R.sup.13 is --CONH.sub.2 and
R.sup.14 is NH.sub.2 can be treated with CS.sub.2 or EtOCS.sub.2K
to give compounds of Formula 3 in which R.sup.6 is OH and R.sup.7
is SH (S. M. Bennett, J. Med. Chem. 1990, 33, 2162).
2. Incorporation of the --R.sup.4--R.sup.5 Fragment.
[0288] 2.1. Alkylation of Compounds of Formula 3
[0289] Compounds of Formula 3 can be alkylated in the presence of a
base such as K.sub.2CO.sub.3, NaH, Cs.sub.2CO.sub.3, DBU etc.
with/without the presence of a catalyst such as NaI, KI,
(Bu).sub.3NI etc., and in a polar solvent such as DMF, THF, DMSO
etc. using electrophiles such as L.sub.1-R.sup.4--R.sup.5 where
L.sub.1 is a leaving group. Leaving groups include but are not
limited to, e.g., halogen, triflate, tosylate, mesylate,
triphenylphosphonium (generated under Mitsunobu conditions, e.g.
PPh.sub.3/DEAD) etc. (See Kasibhatla, WO 03/037860) ##STR17##
[0290] 2.2. Preparation of Electrophiles L.sub.1-R.sup.4--R.sup.5
wherein L.sub.1 is a Leaving Group and of Nucleophiles
NH.sub.2--R.sup.4--R.sup.5.
[0291] 2.2.1. Synthesis of Benzyl Type Electrophiles: ##STR18##
[0292] The electrophiles can be prepared from the substituted
benzene derivatives using various methods reported in the
literature, see Jerry March, Advanced Organic Chemistry, 4.sup.th
edition; Larock, Comprehensive Organic Transformations, 1989, VCH,
New York. For example the compounds wherein L.sub.1 is Br can be
prepared by reduction of the corresponding benzoic acid or
benzaldehyde, followed by halogenation. These benzyl derivatives
can also be prepared by benzylic oxidation or benzylic
halogenation. Further modification of the benzyl ring can be done
before or after the pyrazolo[3,4-d]pyrimidine alkylation step. The
corresponding amines where L.sub.1 is NH.sub.2 can be prepared by a
variety of methods, for instance from compounds where L.sub.1 is
leaving group such as chloride, bromide, tosylate, mesylate etc.
using ammonia, or with sodium azide followed by hydrogenation.
[0293] 2.2.2. Synthesis of Pyridyl Methyl Type Electrophile:
##STR19##
[0294] These compounds can be prepared from many methods reported
in the literature. Morisawa, J. Med. Chem. 1974, 17, 1083; Klaus,
W., J. Med. Chem. 1992, 35, 438; Abramovitch, R. A.; Smith, E. M.
"Pyridine-1-oxide in Pyridine and its Derivatives" in The Chemistry
of Heterocyclic Compounds; Weissberger, A., Taylor, E. C., Eds.;
John Wiley, New York, 1974, Pt. 2, pp 1-261; Jeromin, G. E., Chem.
Ber. 1987, 120, 649. Blanz, E. J., J. Med. Chem. 1970, 13, 1124;
Smith, Kline and French, EP 0184322, 1986; Abblard, J., Bull. Soc.
Chim. Fr. 1972, 2466; Fisher, B. E., "The Structure of Isomaltol"
J. Org. Chem. 1964, 29, 776. De Cat, A., Bull. Soc. Chim. Belg.
1965, 74, 270; Looker, J. H., J. Org. Chem. 1979, 44, 3407.
Ackerman, J. F. Ph.D. Dissertation, University of Notre Dame, June,
1949. These methods can be applied to the synthesis of quinoline
and isoquinolines type compounds.
3. Further Elaboration of the Ring Systems.
[0295] 3.1. Functional Group Interconversions of R.sup.1:
[0296] Compounds of Formula I, wherein R.sup.1 is --OH, can be
converted to halides using standard conditions POCl.sub.3,
POBr.sub.3 etc. with/without the presence of base such as
Et.sub.3N, N,N-dimethylaniline, (i-Pr).sub.2NEt etc. and
with/without a catalyst such as BnEt.sub.3N.sup.+Cl.sup.-, in polar
solvents such as CH.sub.3CN, CH.sub.2Cl.sub.2 etc. Related methods
include, but are not limited to, SOCl.sub.2/DMF (M. J. Robins, Can.
J. Chem. 1973, 12, 3161), PPh.sub.3/CCl.sub.4 (L. De Napoli, J.
Chem. Soc. Perkin Trans 1, 1994, 923), HMPT/CCl.sub.4 or HMPT/NBS
(E. A. Veliz, Tetrahedron Lett, 2000, 41, 1695) or
PPh.sub.3/I.sub.2 (X. Lin, Org. Letters, 2000, 2, 3497).
[0297] Compounds of Formula I, wherein R.sup.1 is --NH.sub.2, can
be converted to halides by a Balz-Schiemann (F) or Sandmeyer
reaction (Cl, Br, I) by means of a nitrosylating agent (e.g.
NaNO.sub.2/H.sup.+, NOBF.sub.4, RONO) and a halogen donor (e.g.
BF.sub.4.sup.-, CuX.sub.2, SbX.sub.3, where X is a halogen).
[0298] Compounds of Formula I, wherein R.sup.1 is alkyl can be
prepared from compounds of Formula 3 where R.sup.1 is halogen and
trialkyl aluminum or dialkyl zinc (A. Holy, J. Med. Chem. 1999, 42,
2064).
[0299] Compounds of Formula I, wherein R.sup.1 is a halide can be
converted to compounds wherein [0300] R.sup.1 is --NH.sub.2, --OH,
--SH, --OR, --SR with standard reagents, e.g. NH.sub.3, NaOH,
thiourea, RO.sup.-, RS.sup.-, with or without a catalyst (e.g. Pd,
Ni, Cu, Lewis acid, H.sup.+), wherein R is lower alkyl.
[0301] 3.2. Functional Group Interconversions of R.sup.2:
[0302] Compounds of Formula I, wherein R.sup.1 is --NH.sub.2 can be
temporarily protected, e.g. as an amide (Ac.sub.2O, PivCl,
(tBoc).sub.2O) or a formamidine (DMF-DMA).
[0303] Compounds of Formula I, wherein R.sup.2 is NH.sub.2 can be
converted to halides by a Balz-Schiemann (F) or Sandmeyer reaction
(Cl, Br, I) by means of a nitrosylating agent (e.g.
NaNO.sub.2/H.sup.+, NOBF.sub.4, RONO) and a halogen donor (e.g.
BF.sub.4.sup.-, CuX.sub.2, SbX.sub.3) where X is a halogen.
[0304] Compounds of Formula I, wherein R.sup.2 is a halide can be
converted to compounds wherein R.sup.2 is NH.sub.2, OH, SH,
OR.sup.8, SR.sup.8 with standard reagents, e.g. NH.sub.3, NaOH,
thiourea, R.sup.8O.sup.-, R.sup.8S.sup.-, with or without a
catalyst (e.g. Pd, Ni, Cu, Lewis acid, H.sup.+).
[0305] Compounds of Formula I, wherein R.sup.2 is SH can be
converted to halides (Br.sub.2). They can also be oxidized (e.g.
H.sub.2O.sub.2) and treated with ammonia to give a NH.sub.2 group
(S. M. Bennett, J. Med. Chem. 1990, 33, 2162).
[0306] Compounds of Formula I, wherein R.sup.2 is a sulfide, e.g.
MeS--, can be converted to a sulfone, e.g. MeSO.sub.2.sup.-, and
displaced with a nucleophile, e.g. NH.sub.3 or NH.sub.2--NH.sub.2,
N.sub.3.sup.-, CN.sup.-.
[0307] 3.3. Functional Group Interconversions of R.sup.3:
[0308] Compounds of Formula I, wherein R.sup.3 is H can be
converted to compounds of Formula I wherein R.sup.3 is a halogen
(e.g. NCS, NBS, NIS, Br.sub.2, ICl, I.sub.2/KOH. F. Seela et al,
Helv. Chim. Acta 1999, 82, 105).
[0309] Compounds of Formula I wherein R.sup.3 is a halogen can be
functionalized by Pd-catalyzed reactions ((a) Sonogashira coupling:
E. C. Taylor et al, Tetrahedron, 1992, 48, 8089. (b) carboxylation:
J. W. Pawlik, J. Heterocycl. Chem. 1992, 29, 1357 (c) Suzuki
coupling (T. Y. I Wu, Org. Lett., 2003, 5, 3587) or by addition of
nucleophiles (e.g. hydrazine, B. M. Lynch, Can. J. Chem. 1988, 66,
420).
[0310] Compounds of Formula I, wherein R.sup.3 is a halide can be
converted to compounds wherein [0311] R.sup.3 is NH.sub.2, OH, SH,
OR.sup.8, SR.sup.8 with standard reagents, e.g. NH.sub.3, NaOH,
thiourea, R.sup.8O.sup.-, R.sup.8S.sup.-, with or without a
catalyst (e.g. Pd, Ni, Cu, Lewis acid, H.sup.+).
[0312] Compounds of Formula I, wherein R.sup.3 is MeO can be
demethylated to provide compounds of Formula I, wherein R.sup.3 is
OH (J. D. Anderson, J. Heterocycl. Chem., 1990 27, 439).
[0313] 3.4. Further Elaboration of R.sup.5:
[0314] R.sup.5 especially when it is aryl or heteroaryl, can be
further modified as needed, for example by halogenation, nitration,
palladium coupling of halogen, Friedel-Crafts alkylation/acylation,
etc. or these modifications can also be done before alkylation, see
Jerry March, Advanced Organic Chemistry. The heteroaromatic rings
can also be oxidized to their corresponding N-oxides using various
oxidizing agents such as H.sub.2O.sub.2, O.sub.3, MCPBA etc. in
polar solvents such as CH.sub.2Cl.sub.2, CHCl.sub.3, CF.sub.3COOH
etc. See Jerry March, Advanced Organic Chemistry, 4th edition,
Chapter 19. Examples of modifications are suggested in Scheme 5.
##STR20## ##STR21## 4. Permutations of the Order of Events
[0315] As mentioned above, the events (1) assembly of the bicyclic
system (2) appendage of the R.sup.5--R.sup.4-- moiety, and (3)
further elaboration of the ring systems do not necessarily have to
be made in the sequence of (1)-(2)-(3), and it may be beneficial to
proceed in a different sequence.
[0316] For illustrative purposes, Scheme 6 shows a putative
synthesis in which the order of events is not (1)-(2)-(3), but is
(1)-(3)-(2).
[0317] First the bicyclic system is prepared, then it is
elaborated, and finally R.sup.5 is appended via an alkylation.
##STR22##
[0318] For illustrative purposes, Scheme 7 shows a putative
synthesis in which the order of events is not (1)-(2)-(3), but is
(2)-(1)-(3). First the R group is appended to a pyrimidine via an
aromatic nucleophilic substitution, then the bicyclic ring system
is constructed, and finally a series of functional group
interconversions yields the compound of Formula I. ##STR23##
[0319] Also, if R.sup.5 is, for instance, a pyridine, it can be
converted to a N-oxide either before or after alkylation.
IV. Pharmaceutical Compositions, Dosing, and Modes of
Administration
[0320] The present invention is directed to the clinical use of the
heterocyclics, in particular, the pyrazolopyrimidines and their
related analogs of Formulae A, I and II, and their polymorphs,
solvates, esters, tautomers, diastereomers, enantiomers,
pharmaceutically acceptable salts and prodrugs thereof, for use in
treatment or prevention of diseases that are HSP90-dependent. For
example, a disorder such as inflammatory diseases, infections,
autoimmune disorders, stroke, ischemia, cardiac disorder,
neurological disorders, fibrogenetic disorders, proliferative
disorders, tumors, leukemias, neoplasms, cancers, carcinomas,
metabolic diseases, and malignant disease. The fibrogenetic
disorders include but are not limited to scleroderma, polymyositis,
systemic lupus, rheumatoid arthritis, liver cirrhosis, keloid
formation, interstitial nephritis and pulmonary fibrosis.
[0321] The present invention features pharmaceutical compositions
comprising the compound of Formulae A, I and II, or a polymorph,
solvate, ester, tautomer, enantiomer, diastereomer,
pharmaceutically acceptable salt thereof, or prodrug thereof, of
any of the preceding aspect and embodiments and one or more
pharmaceutical excipients.
[0322] Those of ordinary skill in the art are familiar with
formulation and administration techniques that can be employed with
the compounds and methods of the invention, e.g., as discussed in
Goodman and Gilman, The Pharmacological Basis of Therapeutics,
(current edition), Pergamon; and Remington's, Pharmaceutical
Sciences (current edition), Mack Publishing Co., Easton, Pa.
[0323] The compounds utilized in the methods of the instant
invention may be administered either alone or in combination with
pharmaceutically acceptable carriers, excipients or diluents, in a
pharmaceutical composition, according to standard pharmaceutical
practices. The compounds can be administered orally or
parenterally, including the intravenous, intramuscular,
intraperitoneal, subcutaneous, rectal and topical routes of
administration.
[0324] For example, the therapeutic or pharmaceutical compositions
of the invention can be administered locally to the area in need of
treatment. This may be achieved by, for example, but not limited
to, local infusion during surgery, topical application, e.g.,
cream, ointment, injection, catheter, or implant, said implant
made, e.g., out of a porous, non-porous, or gelatinous material,
including membranes, such as sialastic membranes, or fibers. The
administration can also be by direct injection at the site (or
former site) of a tumor or neoplastic or pre-neoplastic tissue.
[0325] Still further, the compounds or compositions of the
invention can be delivered in a vesicle, e.g., a liposome (see, for
example, Langer, Science 1990, 249, 1527-1533; Treat et al.,
Liposomes in the Therapy of Infectious Disease and Cancer,
Lopez-Bernstein and Fidler, Ed., Liss, N.Y., pp. 353-365,
1989).
[0326] The compounds and pharmaceutical compositions used in the
methods of the present invention can also be delivered in a
controlled release system. In one embodiment, a pump may be used
(see, Sefton, 1987, CRC Crit. Ref. Biomed. Eng. 14:201; Buchwald et
al. Surgery, 1980, 88, 507; Saudek et al. N. Engl. J. Med. 1989,
321, (574). Additionally, a controlled release system can be placed
in proximity of the therapeutic target. (See, Goodson, Medical
Applications of Controlled Release, 1984, 2, 115-138).
[0327] The pharmaceutical compositions used in the methods of the
instant invention can also contain the active ingredient in a form
suitable for oral use, for example, as tablets, troches, lozenges,
aqueous or oily suspensions, dispersible powders or granules,
emulsions, hard or soft capsules, or syrups or elixirs.
Compositions intended for oral use may be prepared according to any
method known to the art for the manufacture of pharmaceutical
compositions, and such compositions may contain one or more agents
selected from the group consisting of sweetening agents, flavoring
agents, coloring agents and preserving agents in order to provide
pharmaceutically elegant and palatable preparations. Tablets
contain the active ingredient in admixture with non-toxic
pharmaceutically acceptable excipients which are suitable for the
manufacture of tablets. These excipients may be, for example, inert
diluents, such as calcium carbonate, sodium carbonate, lactose,
calcium phosphate or sodium phosphate; granulating and
disintegrating agents, such as microcrystalline cellulose, sodium
crosscarmellose, corn starch, or alginic acid; binding agents, for
example starch, gelatin, polyvinyl-pyrrolidone or acacia, and
lubricating agents, for example, magnesium stearate, stearic acid
or talc. The tablets may be un-coated or coated by known techniques
to mask the taste of the drug or delay disintegration and
absorption in the gastrointestinal tract and thereby provide a
sustained action over a longer period. For example, a water soluble
taste masking material such as hydroxypropylmethyl-cellulose or
hydroxypropylcellulose, or a time delay material such as ethyl
cellulose, or cellulose acetate butyrate may be employed as
appropriate.
[0328] Formulations for oral use may also be presented as hard
gelatin capsules wherein the active ingredient is mixed with an
inert solid diluent, for example, calcium carbonate, calcium
phosphate or kaolin, or as soft gelatin capsules wherein the active
ingredient is mixed with water soluble carrier such as
polyethyleneglycol or an oil medium, for example peanut oil, liquid
paraffin, or olive oil.
[0329] Aqueous suspensions contain the active material in admixture
with excipients suitable for the manufacture of aqueous
suspensions. Such excipients are suspending agents, for example
sodium carboxymethylcellulose, methylcellulose,
hydroxypropylmethyl-cellulose, sodium alginate,
polyvinyl-pyrrolidone, gum tragacanth and gum acacia; dispersing or
wetting agents may be a naturally-occurring phosphatide, for
example lecithin, or condensation products of an alkylene oxide
with fatty acids, for example polyoxyethylene stearate, or
condensation products of ethylene oxide with long chain aliphatic
alcohols, for example heptadecaethylene-oxycetanol, or condensation
products of ethylene oxide with partial esters derived from fatty
acids and a hexitol such as polyoxyethylene sorbitol monooleate, or
condensation products of ethylene oxide with partial esters derived
from fatty acids and hexitol anhydrides, for example polyethylene
sorbitan monooleate. The aqueous suspensions may also contain one
or more preservatives, for example ethyl, or n-propyl
p-hydroxybenzoate, one or more coloring agents, one or more
flavoring agents, and one or more sweetening agents, such as
sucrose, saccharin or aspartame.
[0330] Oily suspensions may be formulated by suspending the active
ingredient in a vegetable oil, for example arachisd oil, olive oil,
sesame oil or coconut oil, or in mineral oil such as liquid
paraffin. The oily suspensions may contain a thickening agent, for
example beeswax, hard paraffin or cetyl alcohol. Sweetening agents
such as those set forth above, and flavoring agents may be added to
provide a palatable oral preparation. These compositions may be
preserved by the addition of an anti-oxidant such as butylated
hydroxyanisol or alpha-tocopherol.
[0331] Dispersible powders and granules suitable for preparation of
an aqueous suspension by the addition of water provide the active
ingredient in admixture with a dispersing or wetting agent,
suspending agent and one or more preservatives. Suitable dispersing
or wetting agents and suspending agents are exemplified by those
already mentioned above. Additional excipients, for example
sweetening, flavoring and coloring agents, may also be present.
These compositions may be preserved by the addition of an
anti-oxidant such as ascorbic acid.
[0332] The compounds and pharmaceutical compositions used in the
methods of the instant invention may also be in the form of an
oil-in-water emulsions. The oily phase may be a vegetable oil, for
example olive oil or arachis oil, or a mineral oil, for example
liquid paraffin or mixtures of these. Suitable emulsifying agents
may be naturally-occurring phosphatides, for example soy bean
lecithin, and esters or partial esters derived from fatty acids and
hexitol anhydrides, for example sorbitan monooleate, and
condensation products of the said partial esters with ethylene
oxide, for example polyoxyethylene sorbitan monooleate. The
emulsions may also contain sweetening agents, flavoring agents,
preservatives and antioxidants.
[0333] Syrups and elixirs may be formulated with sweetening agents,
for example glycerol, propylene glycol, sorbitol or sucrose. Such
formulations may also contain a demulcent, a preservative,
flavoring and coloring agents and antioxidant.
[0334] The pharmaceutical compositions may be in the form of a
sterile injectable aqueous solution. Among the acceptable vehicles
and solvents that may be employed are water, Ringer's solution and
isotonic sodium chloride solution.
[0335] The sterile injectable preparation may also be a sterile
injectable oil-in-water microemulsion where the active ingredient
is dissolved in the oily phase. For example, the active ingredient
may be first dissolved in a mixture of soybean oil and lecithin.
The oil solution then introduced into a water and glycerol mixture
and processed to form a microemulsion.
[0336] The injectable solutions or microemulsions may be introduced
into a patient's blood-stream by local bolus injection.
Alternatively, it may be advantageous to administer the solution or
microemulsion in such a way as to maintain a constant circulating
concentration of the instant compound. In order to maintain such a
constant concentration, a continuous intravenous delivery device
may be utilized. An example of such a device is the Deltec
CADD-PLUS.TM. model 5400 intravenous pump.
[0337] The pharmaceutical compositions may be in the form of a
sterile injectable aqueous or oleagenous suspension for
intramuscular and subcutaneous administration. This suspension may
be formulated according to the known art using those suitable
dispersing or wetting agents and suspending agents which have been
mentioned above. The sterile injectable preparation may also be a
sterile injectable solution or suspension in a non-toxic
parenterally-acceptable diluent or solvent, for example as a
solution in 1,3-butane diol. In addition, sterile, fixed oils are
conventionally employed as a solvent or suspending medium. For this
purpose any bland fixed oil may be employed including synthetic
mono- or diglycerides. In addition, fatty acids such as oleic acid
find use in the preparation of injectables.
[0338] The compounds of the present invention used in the methods
of the present invention may also be administered in the form of
suppositories for rectal administration of the drug. These
compositions can be prepared by mixing the inhibitors with a
suitable non-irritating excipient which is solid at ordinary
temperatures but liquid at the rectal temperature and will
therefore melt in the rectum to release the drug. Such materials
include cocoa butter, glycerinated gelatin, hydrogenated vegetable
oils, mixtures of polyethylene glycols of various molecular weights
and fatty acid esters of polyethylene glycol.
[0339] For topical use, creams, ointments, jellies, solutions or
suspensions, etc., containing a compound or composition of the
invention can be used. As used herein, topical application can
include mouth washes and gargles.
[0340] The compounds used in the methods of the present invention
can be administered in intranasal form via topical use of suitable
intranasal vehicles and delivery devices, or via transdermal
routes, using those forms of transdermal skin patches well known to
those of ordinary skill in the art. To be administered in the form
of a transdermal delivery system, the dosage administration will,
of course, be continuous rather than intermittent throughout the
dosage regimen.
[0341] The methods, compounds and compositions of the instant
invention may also be used in conjunction with other well known
therapeutic agents that are selected for their particular
usefulness against the condition that is being treated. For
example, the instant compounds may be useful in combination with
known anti-cancer and cytotoxic agents. Further, the instant
methods and compounds may also be useful in combination with other
inhibitors of parts of the signaling pathway that links cell
surface growth factor receptors to nuclear signals initiating
cellular proliferation.
[0342] The methods of the present invention may also be useful with
other agents that inhibit angiogenesis and thereby inhibit the
growth and invasiveness of tumor cells, including, but not limited
to VEGF receptor inhibitors, including ribozymes and antisense
targeted to VEGF receptors, angiostatin and endostatin.
[0343] Examples of antineoplastic agents that can be used in
combination with the compounds and methods of the present invention
include, in general, and as appropriate, alkylating agents,
anti-metabolites, epidophyllotoxins, antineoplastic enzymes,
topoisomerase inhibitors, procarbazines, mitoxantrones, platinum
coordination complexes, biological response modifiers and growth
inhibitors, hormonal/anti-hormonal therapeutic agents and
haematopoietic growth factors. Exemplary classes of antineoplastic
include the anthracyclines, vinca drugs, mitomycins, bleomycins,
cytotoxic nucleosides, epothilones, discodermolides, pteridines,
diynenes and podophyllotoxins. Particularly useful members of those
classes include, for example, carminomycin, daunorubicin,
aminopterin, methotrexate, methopterin, dichloromethotrexate,
mitomycin C, porfiromycin, 5-fluorouracil, 6-mercaptopurine,
gemcitabine, cytosine arabinoside, podophyllotoxin or
podo-phyllotoxin derivatives such as etoposide, etoposide phosphate
or teniposide, melphalan, vinblastine, vincristine, leurosidine,
vindesine, leurosine, paclitaxel and the like. Other useful
antineoplastic agents include estramustine, carboplatin,
cyclophosphamide, bleomycin, gemcitibine, ifosamide, melphalan,
hexamethyl melamine, thiotepa, cytarabin, idatrexate, trimetrexate,
dacarbazine, L-asparaginase, camptothecin, CPT-11, topotecan,
ara-C, bicalutamide, flutamide, leuprolide, pyridobenzoindole
derivatives, interferons and interleukins.
[0344] When a compound or composition of the invention is
administered into a human subject, the daily dosage will normally
be determined by the prescribing physician with the dosage
generally varying according to the age, weight, and response of the
individual patient, as well as the severity of the patient's
symptoms.
[0345] In one exemplary application, a suitable amount of compound
is administered to a mammal undergoing treatment for cancer, for
example, breast cancer. Administration typically occurs in an
amount of between about 0.01 mg/kg of body weight to about 100
mg/kg of body weight per day (administered in single or divided
doses), more preferably at least about 0.1 mg/kg of body weight per
day. A particular therapeutic dosage can include, e.g., from about
0.01 mg to about 1000 mg of compound, and preferably includes,
e.g., from about 1 mg to about 1000 mg. The quantity of active
compound in a unit dose of preparation may be varied or adjusted
from about 0.1 mg to 1000 mg, preferably from about 1 mg to 300 mg,
more preferably 10 mg to 200 mg, according to the particular
application. The amount administered will vary depending on the
particular IC.sub.50 value of the compound used and the judgment of
the attending clinician taking into consideration factors such as
health, weight, and age. In combinational applications in which the
compound is not the sole active ingredient, it may be possible to
administer lesser amounts of compound and still have therapeutic or
prophylactic effect.
[0346] Preferably, the pharmaceutical preparation is in unit dosage
form. In such form, the preparation is subdivided into unit doses
containing appropriate quantities of the active component, e.g., an
effective amount to achieve the desired purpose.
[0347] The actual dosage employed may be varied depending upon the
requirements of the patient and the severity of the condition being
treated. Determination of the proper dosage for a particular
situation is within the skill of the art. Generally, treatment is
initiated with smaller dosages which are less than the optimum dose
of the compound. Thereafter, the dosage is increased by small
amounts until the optimum effect under the circumstances is
reached. For convenience, the total daily dosage may be divided and
administered in portions during the day if desired.
[0348] The amount and frequency of administration of the compounds
and compositions of the present invention used in the methods of
the present invention, and if applicable other chemotherapeutic
agents and/or radiation therapy, will be regulated according to the
judgment of the attending clinician (physician) considering such
factors as age, condition and size of the patient as well as
severity of the disease being treated.
[0349] The chemotherapeutic agent and/or radiation therapy can be
administered according to therapeutic protocols well known in the
art. It will be apparent to those skilled in the art that the
administration of the chemotherapeutic agent and/or radiation
therapy can be varied depending on the disease being treated and
the known effects of the chemotherapeutic agent and/or radiation
therapy on that disease. Also, in accordance with the knowledge of
the skilled clinician, the therapeutic protocols (e.g., dosage
amounts and times of administration) can be varied in view of the
observed effects of the administered therapeutic agents (i.e.,
antineoplastic agent or radiation) on the patient, and in view of
the observed responses of the disease to the administered
therapeutic agents.
[0350] Also, in general, the compounds of the invention need not be
administered in the same pharmaceutical composition as a
chemotherapeutic agent, and may, because of different physical and
chemical characteristics, be administered by a different route. For
example, the compounds/compositions may be administered orally to
generate and maintain good blood levels thereof, while the
chemotherapeutic agent may be administered intravenously. The
determination of the mode of administration and the advisability of
administration, where possible, in the same pharmaceutical
composition, is well within the knowledge of the skilled clinician.
The initial administration can be made according to established
protocols known in the art, and then, based upon the observed
effects, the dosage, modes of administration and times of
administration can be modified by the skilled clinician.
[0351] The particular choice of compound (and where appropriate,
chemotherapeutic agent and/or radiation) will depend upon the
diagnosis of the attending physicians and their judgment of the
condition of the patient and the appropriate treatment
protocol.
[0352] The compounds/compositions of the invention (and where
appropriate chemotherapeutic agent and/or radiation) may be
administered concurrently (e.g., simultaneously, essentially
simultaneously or within the same treatment protocol) or
sequentially, depending upon the nature of the proliferative
disease, the condition of the patient, and the actual choice of
chemotherapeutic agent and/or radiation to be administered in
conjunction (i.e., within a single treatment protocol) with the
compound/composition.
[0353] In combinational applications and uses, the
compound/composition and the chemotherapeutic agent and/or
radiation need not be administered simultaneously or essentially
simultaneously, and the initial order of administration of the
compound/composition, and the chemotherapeutic agent and/or
radiation, may not be important. Thus, the compounds/compositions
of the invention may be administered first followed by the
administration of the chemotherapeutic agent and/or radiation; or
the chemotherapeutic agent and/or radiation may be administered
first followed by the administration of the compounds/compositions
of the invention. This alternate administration may be repeated
during a single treatment protocol. The determination of the order
of administration, and the number of repetitions of administration
of each therapeutic agent during a treatment protocol, is well
within the knowledge of the skilled physician after evaluation of
the disease being treated and the condition of the patient. For
example, the chemotherapeutic agent and/or radiation may be
administered first, especially if it is a cytotoxic agent, and then
the treatment continued with the administration of the
compounds/compositions of the invention followed, where determined
advantageous, by the administration of the chemotherapeutic agent
and/or radiation, and so on until the treatment protocol is
complete.
[0354] Thus, in accordance with experience and knowledge, the
practicing physician can modify each protocol for the
administration of a compound/composition for treatment according to
the individual patient's needs, as the treatment proceeds.
[0355] The attending clinician, in judging whether treatment is
effective at the dosage administered, will consider the general
well-being of the patient as well as more definite signs such as
relief of disease-related symptoms, inhibition of tumor growth,
actual shrinkage of the tumor, or inhibition of metastasis. Size of
the tumor can be measured by standard methods such as radiological
studies, e.g., CAT or MRI scan, and successive measurements can be
used to judge whether or not growth of the tumor has been retarded
or even reversed. Relief of disease-related symptoms such as pain,
and improvement in overall condition can also be used to help judge
effectiveness of treatment.
V. Assays for Determining HSP90 Binding and Downstream Effect
[0356] A variety of in vitro and in vivo assays are available to
test the effect of the compounds of the invention on HSP90. HSP90
competitive binding assays and functional assays can be performed
as known in the art substituting in the compounds of the invention.
Chiosis et al. Chemistry & Biology 2001, 8, 289-299, describe
some of the known ways in which this can be done. For example,
competition binding assays using, e.g., geldanamycin or 17-AAG as a
competitive binding inhibitor of HSP90 can be used to determine
relative HSP90 affinity of the compounds of the invention by
immobilizing the compound of interest or other competitive
inhibitor on a gel or solid matrix, preincubatirg HSP90 with the
other inhibitor, passing the preincubated mix over the gel or
matrix, and then measuring the amount of HSP90 that retains or does
not retain on the gel or matrix.
[0357] Downstream effects can also be evaluated based on the known
effect of HSP90 inhibition on function and stability of various
steroid receptors and signaling proteins including, e.g., Raf1 and
HER2. Compounds of the present invention induce dose-dependent
degradation of these molecules, which can be measured using
standard techniques. Inhibition of HSP90 also results in
up-regulation of HSP90 and related chaperone proteins that can
similarly be measured. Antiproliferative activity on various cancer
cell lines can also be measured, as can morphological and
functional differentiation related to HSP90 inhibition.
[0358] Many different types of methods are known in the art for
determining protein concentrations and measuring or predicting the
level of proteins within cells and in fluid samples. Indirect
techniques include nucleic acid hybridization and amplification
using, e.g., polymerase chain reaction (PCR). These techniques are
known to the person of skill and are discussed, e.g., in Sambrook,
Fritsch & Maniatis Molecular Cloning: A Laboratory Manual, 2nd
ed., Cold Spring Harbor Laboratory, Cold Spring Harbor, N.Y., 1989;
Ausubel, et al. Current Protocols in Molecular Biology, John Wiley
& Sons, NY, 1994, and, as specifically applied to the
quantification, detection, and relative activity of HER2/Neu in
patient samples, e.g., in U.S. Pat. Nos. 4,699,877, 4,918,162,
4,968,603, and 5,846,749. A brief discussion of two generic
techniques that can be used follows.
[0359] The determination of whether cells overexpress or contain
elevated levels of HER2 can be determined using well known antibody
techniques such as immunoblotting, radioimmunoassays, western
blotting, immunoprecipitation, enzyme-linked immunosorbant assays
(ELISA), and derivative techniques that make use of antibodies
directed against HER2. As an example, HER2 expression in breast
cancer cells can be determined with the use of an
immunohistochemical assay, such as the Dako Hercep.TM. test (Dako
Corp., Carpinteria, Calif.). The Hercep.TM. test is an antibody
staining assay designed to detect HER2 overexpression in tumor
tissue specimens. This particular assay grades HER2 expression into
four levels: 0, 1, 2, and 3, with level 3 representing the highest
level of HER2 expression. Accurate quantitation can be enhanced by
employing an Automated Cellular Imaging System (ACIS) as described,
e.g. by Press, M. et al. Modern Pathology 2000, 13, 225A.
[0360] Antibodies, polyclonal or monoclonal, can be purchased from
a variety of commercial suppliers, or may be manufactured using
well-known methods, e.g., as described in Harlow et al. Antibodies:
A Laboratory Manual, 2nd ed; Cold Spring Harbor Laboratory, Cold
Spring Harbor, N.Y., 1988.
[0361] HER2 overexpression can also be determined at the nucleic
acid level since there is a reported high correlation between
overexpression of the HER2 protein and amplification of the gene
that codes for it. One way to test this is by using RT-PCR. The
genomic and cDNA sequences for HER2 are known. Specific DNA primers
can be generated using standard, well-known techniques, and can
then be used to amplify template already present in the cell. An
example of this is described in Kurokawa, H. et al. Cancer Res.
2000, 60, 5887-5894. PCR can be standardized such that quantitative
differences are observed as between normal and abnormal cells,
e.g., cancerous and noncancerous cells. Well known methods
employing, e.g., densitometry, can be used to quantitate and/or
compare nucleic acid levels amplified using PCR.
[0362] Similarly, fluorescent in situ hybridization (FISH) assays
and other assays can be used, e.g., Northern and/or Southern
blotting. These rely on nucleic acid hybridization between the HER2
gene or mRNA and a corresponding nucleic acid probe that can be
designed in the same or a similar way as for PCR primers, above.
See, e.g., Mitchell M S, and Press M. F. Oncol., Suppl. 1999, 12,
108-116. For FISH, this nucleic acid probe can be conjugated to a
fluorescent molecule, e.g., fluorescein and/or rhodamine, that
preferably does not interfere with hybridization, and which
fluorescence can later be measured following hybridization. See,
e.g., Kurokawa, H et al, Cancer Res. 2000, 60, 5887-5894
(describing a specific nucleic acid probe having sequence
5'-FAM-NucleicAcid-TAMRA-p-3' sequence). ACIS-based approaches as
described above can be employed to make the assay more quantitative
(de la Torre-Bueno, J., et al. Modern Pathology 2000, 13,
221A).
[0363] Immuno and nucleic acid detection can also be directed
against proteins other than HSP90 and HER2, which proteins are
nevertheless affected in response to HSP90 inhibition.
[0364] The following examples are offered by way of illustration
only and are not intended to be limiting of the full scope and
spirit of the invention.
EXAMPLES
I. Materials and Methods
[0365] The chemical reagents used to create the novel products of
the invention below are all available commercially, e.g., from
Aldrich Chemical Co., Milwaukee, Wis., USA. Otherwise their
preparation is facile and known to one of ordinary skill in the
art, or it is referenced or described herein.
[0366] The final compounds were usually purified by preparative TLC
(silica gel 60 .ANG., Whatman Partisil PK6F) or flash
chromatography (silica gel 60 .ANG., EMD Chemicals) using
EtOAc/hexane or MeOH/CH.sub.2Cl.sub.2 as eluents. Rf's were
measured using silica gel TLC plates (silica gel 60 .ANG., EMD
Chemicals). Analytical HPLC chromatograms were obtained using a C18
column (Agilent Zorbax 300SB-C18; 5 microns; 4.6 mm.times.150 mm).
A gradient was applied between solvent A (0.1% TFA in H.sub.2O) and
solvent B (0.5% TFA in CH.sub.3CN) increasing the proportion of A
linearly from 5% (t=0) to 100% (t=7.00 min), with a constant flow
rate of 1 mL/min. The samples were diluted to typically 0.1-1 mg/mL
in MeOH or CH.sub.3CN and the injection volumes were typically 10
.mu.L. The column was not heated, and UV detection was effected at
254 nm. .sup.1H-NMR spectra were recorded on a Bruker Avance 400
MHz spectrometer.
[0367] The chemical names were generated using the Beilstein
Autonom 2.1 software.
II. General Procedures
[0368] 1. General Procedures to Prepare and Manipulate the
pyrazolo[3,4-d]pyrimidine Ring
[0369] General procedure 1.1: Alkylation of
pyrazolo[3,4-d]-pyrimidines at N-1 ##STR24##
[0370] 4-Chloro-1H-pyrazolo[3,4-d]pyrimidin-6-ylamine was prepared
as described in Seela, F.; Stecker, H. Helv. Chim. Acta 1986, 69,
1602-1613. A suspension of the
4-Chloro-1H-pyrazolo[3,4-d]pyrimidin-6-ylamine (1 mmol), benzyl
halide (1 mmol) and K.sub.2CO.sub.3 (1-3 mmol) in dry DMF (5 mL)
was stirred at 22-70.degree. C. for 0.5-16 h. Work-up (EtOAc) and
purification by preparative TLC or flash chromatography
(EtOAc/hexane or MeOH/CH.sub.2Cl.sub.2) yielded the pure N-1
alkylated product.
[0371] General Procedure 1.2: Preparation of 3-alkyl
pyrazolo[3,4-d]pyrimidines
Step 1: 1-(2-Amino-4,6-dichloro-pyrimidin-5-yl)-ethanol
[0372] A fine suspension of
2-amino-4,6-dichloro-pyrimidine-5-carbaldehyde (3.0 g, 15 mmol);
(Seela, F.; Stecker, H. Helv. Chim. Acta 1986, 69, 1602) in THF was
cooled to -78.degree. C. A 3M solution of MeMgBr in THF (25 mL, 75
mmol, 5 equiv.) was added over 3 h, keeping the internal
temperature at -78.degree. C. The mixture was stirred for a further
0.5 h, quenched with 100 ml H.sub.2O, and neutralized with aw. HCl.
Extraction (EtOAc) gave
1-(2-amino-4,6-dichloro-pyrimidin-5-yl)-ethanol as a pale yellow
solid (2.5 g, 76%) which was used without further purification.
Step 2: 1-(2-Amino-4,6-dichloro-pyrimidin-5-yl)-ethanone
[0373] 1-(2-Amino-4,6-dichloro-pyrimidin-5-yl)-ethanol (2.0 g, 9.6
mmol) was treated with MnO.sub.2 (20 g, 229 mmol, 24 equiv.) in
1,2-dichloroethane for 16 h at 70.degree. C. Filtration over celite
and concentration gave
1-(2-Amino-4,6-dichloro-pyrimidin-5-yl)-ethanone as a pale orange
solid (1.4 g, 6.7 mmol, 71%), which was used without further
purification.
Step 3: 4-Chloro-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-6-ylamine
[0374] 1-(2-Amino-4,6-dichloro-pyrimidin-5-yl)-ethanone (200 mg,
0.97 mmol) was dissolved in CH.sub.2Cl.sub.2 and treated with
anhydrous hydrazine (31 mg, 0.97 mmol, 1 equiv.) at r.t. overnight.
The precipitate was collected by filtration, washed with
CH.sub.2Cl.sub.2, dissolved in DMSO (0.5 mL), and partitioned
between EtOAc (100 mL) and water (25 mL). The organic layer was
dried (brine, Na.sub.2SO.sub.4) and concentrated to afford the
title compound as a white solid (95 mg, 0.52 mmol, 53%).
[0375] 2. General Procedures to Manipulate the Pyridine Ring
[0376] General Procedure 2.1: Preparation of Pyridine N-oxides
[0377] A solution of the pyridine derivative (1.0 mmol) in
dichloromethane or chloroform (5 mL) was cooled by means of an
ice-bath, treated with m-CPBA (1.1 to 3 mmol) in three portions,
and allowed to warm to r.t. The mixture was extracted with
dichloromethane and washed with aqueous NaOH, followed by water.
Drying (Na.sub.2SO.sub.4) and concentration afforded the pyridine
N-oxide.
[0378] General procedure 2.2: Preparation of
2-(acetoxymethyl)-pyridines
[0379] A solution of the 2-methylpyridine N-oxide (1.0 mmol) in
acetic anhydride (5 mL) was heated to reflux for 0.5 h. Work-up
(EtOAc), drying (MgSO.sub.4), evaporation and purification by
preparative TLC or flash chromatography afforded the
2-(acetoxymethyl)-pyridine.
[0380] General procedure 2.3: Preparation of
2-(hydroxymethyl)-pyridines A suspension of
2-acetoxymethyl-pyridine derivative and solid K.sub.2CO.sub.3 in
methanol was heated to 50.degree. C. for 5-30 min. Evaporation,
work-up (EtOAc), and drying (MgSO.sub.4) afforded the
2-hydroxymethylpyridine.
[0381] General procedure 2.4: Preparation of
2-(bromomethyl)-pyridines
[0382] A solution of 2-(hydroxymethyl)-pyridine (1.0 mmol) and
triphenyl phosphine (1.2 mmol) in dichloromethane or chloroform (5
mL) was cooled to 0.degree. C. A solution of CBr.sub.4 (1.5 mmol)
in dichloromethane or chloroform was added dropwise, and the
resulting mixture was stirred at 0.degree. C. for 0.5-1 h. Work-up
followed and purification by flash chromatography afforded the
2-(bromomethyl)-pyridine.
[0383] General Procedure 2.5: Preparation of 2-chloropyridines
[0384] A suspension of 2-(hydroxymethyl)-pyridine (10 g) in
POCl.sub.3 (30 mL) was stirred at 110.degree. C. for 1.5 h. The
resulting viscous oil was cooled to r.t. and poured onto ice water
(500 g). The pH was adjusted to 10 with solid KOH. Work-up
(CHCl.sub.3), drying (MgSO.sub.4) and evaporation gave the
2-(chloromethyl)-pyridine, usually as a purple oil or solid, which
was used without purification.
[0385] General Procedure 2.6: Preparation of Pyridinium Salts
[0386] A solution of pyridine was heated in MeOH until it
dissolved. A methanolic solution of acid (1.0 equiv of e.g. HCl,
MeOH) was added, and the solvent was evaporated to give the
pyridinium salt.
[0387] 3. General Procedure to Manipulate Benzene Rings
[0388] General procedure 3.1: Halogenation of Benzene Rings.
[0389] Variant 1: A solution of the aromatic compound in
MeOH/THF/acetate buffer (1N in each AcOH and AcONa) was treated
with Br.sub.2 (1.3 equiv) at r.t. for 5 min. The excess bromine and
solvent were removed on a rotary evaporator. Work-up (CHCl.sub.3)
and flash chromatography afforded the desired bromobenzene.
[0390] Variant 2: A solution of the aromatic compound (7 mmol) and
n-halosuccinimide (NCS, NBS, or NIS, 1.06 equiv) in acetic acid (40
mL) was heated to 40-90.degree. C. for 0.3-1 h. Evaporation,
work-up (EtOAc) and flash chromatography afforded the desired
halogenated benzene.
III. Preparation Of Intermediates
Example 1
2-Chloro-1-chloromethyl-3,4,5-trimethoxy-benzene
[0391] The title compound was obtained by chlorination of
5-chloromethyl-1,2,3-trimethoxy-benzene with NCS according to the
general procedure 3.1. .sup.1H-NMR (CDCl.sub.3): .delta. 6.82 (s,
1H), 4.70 (s, 1H), 3.93 (s, 3H), 3.90 (s, 3H) 3.87 (s, 3H).
Example 2
2-Chloro-6-chloromethyl-4-methoxy-3,5-dimethyl-pyridine
[0392] ##STR25##
Step 1: 2-Chloromethyl-4-methoxy-3,5-dim ethylpyridine-1-oxide
[0393] The title compound was obtained by oxidation of
2-chloromethyl-4-methoxy-3,5-dimethyl-pyridine according to the
general procedure 2.1. R.t.: 4.46 min. .sup.1H-NMR (CDCl.sub.3):
.delta. 8.05 (s, 1H), 4.93 (s, 2H), 3.77 (s, 3H), 2.37 (s, 3H),
2.24 (s, 3H).
Step 2: 2-Chloro-6-chloromethyl-4-methoxy-3,5-dimethylpyridine
[0394] The title compound was obtained by treating
2-chloromethyl-4-methoxy-3,5-dimethylpyridine-1-oxide with
POCl.sub.3 according to the general procedure 2.5. R.t.: 6.757 min.
1H-NMR (CDCl.sub.3): .delta. 4.64 (s, 2H), 3.79 (s, 3H), 2.35 (s,
3H), 2.33 (s, 3H).
Example 3
4-Chloro-2-chloromethyl-3,5-dimethyl-pyridine
[0395] The title compound was obtained by treating
2-chloromethyl-3,5-dimethyl-pyridin-4-ol (Tarbit, et al. WO
99/10326) with POCl.sub.3 according in the same manner as the
general procedure 2.5 (74% yield). R.t.: 5.54 min. .sup.1H-NMR
(CDCl.sub.3): 8.24 (s, 1H), 4.71 (s, 2H), 2.48 (s, 3H), 2.36 (s,
3H).
Example 4
4-Bromo-2-bromomethyl-3,5-dimethyl-pyridine
[0396] 4-Bromo-2-bromomethyl-3,5-dimethyl-pyridine was prepared by
any of the following three methods:
[0397] Method 1
Step 1: 2,3,5-Collidine-N-oxide
[0398] 2,3,5-Collidine-N-oxide was obtained by oxidation of
2,3,5-collidine according to the general procedure 2.1 in 70%
yield. R.t.: 3.96 min. .sup.1H-NMR (CDCl.sub.3): .delta. 8.03 (s,
1H), 6.90 (s, 1H), 2.47 (s, 3H), 2.31 (s, 3H), 2.24 (s, 3H). m/z
(%) 138.2 (M+1, 100%). Rf (20% MeOH/EtOAc): 0.35.
Step 2: 4-Bromo-2,3,5-collidine-N-oxide
[0399] 2,3,5-collidine-N-oxide (1.3 g, 10 mmol) and K.sub.2CO.sub.3
(2.9 g, 20 mmol) were suspended in 10 mL of CCl.sub.4. Bromine (1
mL, 20 mmol) was added dropwise, and the reaction mixture was
heated to reflux for 2 h. Work-up (EtOAc) and flash chromatography
(10% MeOH/EtOAc) afforded the title compound as a solid (1.05 g,
51% yield). R.t.: 5.24 min. .sup.1H-NMR (CDCl.sub.3): .delta. 8.06
(s, 1H), 2.56 (s, 3H), 2.43 (s, 3H), 2.31 (s, 3H). m/z (%) 216.2
(M+1, 100%), 218.2 (M+3, 100%). Rf (20% MeOH/EtOAc): 0.45.
Step 3: Acetic acid 4-bromo-3,5-dimethyl-pyridin-2-yl methyl
ester
[0400] 4-Bromo-2,3,5-collidine-N-oxide (0.25 g, 11 mmol) was
dissolved in acetic anhydride (5 mL) and the solution was heated to
reflux for 30 min. Work-up and flash chromatography (50%
Hexane/EtOAc) afforded the title compound (0.27 g, 96% yield). Rf
(50% Hexane/EtOAc): 0.70. R.t.: 4.76 min. .sup.1H-NMR (CDCl.sub.3):
.delta. 8.26 (s, 1H), 5.27 (s, 2H), 2.46 (s, 3H), 2.41 (s, 3H),
2.14 (s, 3H).
Step 4: 4-Bromo-3,5-dimethyl-pyridin-2-yl methanol
[0401] A suspension of acetic acid
4-bromo-3,5-dimethyl-pyridin-2-yl methyl ester (0.26 g, 1.0 mmol)
and K.sub.2CO.sub.3 (excess) in MeOH (5 mL) was heated to
50.degree. C. for 15 min. Work-up (CHCl.sub.3), evaporation, and
filtration through a silica gel pad (eluent: 100% EtOAc) gave the
title compound as a white solid (0.19 g, 88% yield). Rf (50%
Hexane/EtOAc): 0.5. R.t.: 3.80 min. .sup.1H-NMR (CDCl.sub.3):
.delta. 8.23 (s, 1H), 4.70 (s, 2H), 2.46 (s, 3H), 2.30 (s, 3H).
[0402] Step 5: 4-Bromo-2-bromomethyl-3,5-dimethyl-pyridine
[0403] The title compound was obtained from
4-bromo-3,5-dimethyl-pyridin-2-yl methanol according to the general
procedure 2.4. R.t.: 6.32 min. .sup.1H-NMR (CDCl.sub.3): .delta.
8.22 (s, 1H), 4.63 (s, 2H), 2.52 (s, 3H), 2.40 (s, 3H).
[0404] Method 2:
Step 1: 2-chloromethyl-3,5-dimethyl-pyridin-4-ol
[0405] The title compound was obtained by heating
2-chloromethyl-4-methoxy-3,5-dimethyl-pyridine hydrochloride in
toluene as described by Tarbit, et al. WO 99/10326.
Step 2: 4-bromo-2-chloromethyl-3,5-dimethyl pyridine
[0406] A mixture of 2-chloromethyl-3,5-dimethyl-pyridin-4-ol (8.2
g, 47.8 mmol) and POBr.sub.3 (60 g, 209 mmol) was stirred at
130.degree. C. for 3 h. The resulting viscous oil was cooled to
r.t. and poured onto ice water. The pH was adjusted to 10 with
solid KOH. Work-up (CHCl.sub.3), drying (MgSO.sub.4) and
evaporation afforded the title compound as a purple solid (8.7 g,
78% yield) which was used without purification. R.t.: 6.03 min.
.sup.1H-NMR (CDCl.sub.3): 8.20 (s, 1H), 4.62 (s, 2H), 2.50 (s, 3H),
2.38 (s, 3H).
[0407] Method 3:
4-bromo-2-chloromethyl-3,5-dimethylpyridine
[0408] A suspension of
2-chloromethyl-4-methoxy-3,5-dimethyl-pyridine (3.24 g, 14.6 mmol)
in PBr.sub.3 (8.0 ml, 85.1 mmol, 5.8 equiv.) was heated to
80.degree. C. under nitrogen. A catalytic amount of DMF (0.50 ml,
6.4 mmol, 0.44 equiv.) was added, whereupon the suspension rapidly
turned into an orange solution. After 40 min., the reaction was
still incomplete as judged by HPLC. The temperature was raised to
110.degree. C. and the reaction was prolonged for 30 min, at which
point it was complete. The mixture was poured over ice, made basic
with conc. aq. NH.sub.4OH and extracted into EtOAc. Washing with
water, drying (brine, MgSO.sub.4) and concentration gave the title
compound as a pink solid (1.51 g, 44%) containing 10% of an
impurity by .sup.1H-NMR. The crude was used without further
purification. .sup.1H-NMR (CDCl.sub.3) .delta. 8.19 (s, 1H), 4.59
(s, 2H), 2.48 (s, 3H), 2.37 (s, 3H).
IV. Preparation of Final Compounds
Example 5
4-Chloro-1-(3,4,5-trimethoxy-benzyl)-1H-pyrazolo[3,4-d]pyrimidin-6-ylamine
[0409] The title compound was obtained by alkylation of
4-chloro-1H-pyrazolo[3,4-d]pyrimidin-6-ylamine (See F. Seela,
Heterocycles 1985, 23, 2521; F. Seela, Helv. Chim. Acta 1986, 69,
1602; R. O. Dempcy, WO 03/022859) with
5-chloromethyl-1,2,3-trimethoxy-benzene according to the general
procedure 1.1. R.t. 5.68 min. .sup.1H-NMR (CDCl.sub.3) .delta. 7.93
(s, 1H), 6.59 (s, 2H), 5.37 (br. s., 4H), 3.84 (s, 6H), 3.82 (s,
3H).
Example 6
4-Chloro-1-(2-chloro-3,4,5-trimethoxy-benzyl)-1H-pyrazolo[3,4-d]pyrimidin--
6-ylamine
[0410] The title compound was obtained by alkylation of
4-chloro-1H-pyrazolo[3,4-d]pyrimidin-6-ylamine with
2-chloro-1-chloromethyl-3,4,5-trimethoxy-benzene according to the
general procedure 1.1. R.t. 6.44 min. .sup.1H-NMR (CDCl.sub.3)
.delta. 7.95 (s, 1H), 6.36 (s, 1H), 5.51 (s, 2H), 5.24 (br. s, 2H),
3.90 (s, 3H), 3.86 (s, 3H), 3.70 (s, 3H).
Example 7
4-Chloro-1-(4-methoxy-3,5-dimethyl-pyridin-2-ylmethyl)-1H-pyrazolo[3,4-d]p-
yrimidin-6-ylamine
[0411] A mixture of 4-chloro-1H-pyrazolo[3,4-d]pyrimidin-6-ylamine
(1.76 g), 2-chloromethyl-4-methoxy-3,5-dimethyl-pyridine
hydrochloride (3.70 g), K.sub.2CO.sub.3 (5.17 g), and DMF (20 ml)
was heated to 80.degree. C. for 30 min, diluted with EtOAc, washed
with water and brine, concentrated, and purified by flash
chromatography to give the title compound as a white solid (0.57
g). R.t. 4.46 min. .sup.1H-NMR (CDCl.sub.3) .delta. 8.10 (s, 1H),
7.89 (s, 1H), 5.53 (2H), 5.24 (br. s, 2H), 3.74 (s, 3H), 2.27 (s,
3H), 2.22 (s, 3H).
Example 8
4-Chloro-1-(6-chloro-4-methoxy-3,5-dimethyl-pyridin-2-ylmethyl)-1H-pyrazol-
o[3,4-d]pyrimidin-6-ylamine
[0412] A mixture of 4-chloro-1H-pyrazolo[3,4-d]pyrimidin-6-ylamine
(124 mg), Cs.sub.2CO.sub.3 (392 mg) and crude
2-chloro-6-chloromethyl-4-methoxy-3,5-dimethyl-pyridine (200 mg) in
DMF (2 ml) was heated to 80.degree. C. for 1 h, diluted with EtOAc
and washed with water. Concentration and purification by
preparative TLC (EtOAc) gave the title compound. R.t. 6.43 min.
.sup.1H-NMR (CDCl.sub.3) .delta. 7.86 (s, 1H), 5.48 (s, 2H), 5.37
(s, 2H), 3.71 (s, 3H), 2.27 (s, 3H), 2.15 (s, 3H).
Example 9
4-Chloro-1-(4-chloro-3,5-dimethyl-pyridin-2-ylmethyl)-1H-pyrazolo[3,4-d]py-
rimidin-6-ylamine
[0413] A mixture of 4-chloro-1H-pyrazolo[3,4-d]pyrimidin-6-ylamine
(158 mg), crude 4-chloro-2-chloromethyl-3,5-dimethyl-pyridine (204
mg), Cs.sub.2CO.sub.3 (660 mg) and DMF was heated to 80.degree. C.
for 1.5 h, diluted with EtOAc and washed with water. The crude
material was concentrated and suspended in MeOH/DCM. Filtration
gave a 2:1 mixture of regioisomers which was further purified by
preparative silica gel plate (EtOAc 100%). The major (less polar)
isomer corresponded to the title compound. R.t. 5.45 min.
.sup.1H-NMR (CDCl.sub.3) .delta. 8.22 (s, 1H), 7.90 (s, 1H), 5.57
(s, 2H), 5.28 (s, 2H), 2.43 (s, 3H), 2.31 (s, 3H).
Example 10
4-Chloro-1-(4-methoxy-3,5-dimethyl-1-oxy-pyridin-2-ylmethyl)-1H-pyrazolo[3-
,4-d]pyrimidin-6-ylamine
[0414] A solution of
4-chloro-1-(4-methoxy-3,5-dimethyl-pyridin-2-ylmethyl)-1H-pyrazolo[3,4-d]-
pyrimidin-6-ylamine (50 mg) in CH.sub.2Cl.sub.2 (2 ml) was treated
with m-CPBA (90 mg) for 10 min, diluted with CH.sub.2Cl.sub.2,
washed with sat. aq. NaHCO.sub.3, concentrated and re-crystallized
from CHCl.sub.3/MeOH to give the title compound as a white solid.
R.t. 4.87 min. .sup.1H-NMR (DMSO-d.sub.6) .delta. 8.06 (s, 1H),
7.89 (s, 1H), 7.36 (s, 2H), 5.55 (s, 2H), 3.72 (s, 3H), 2.30 (s,
3H), 2.18 (s, 3H).
Example 11
4-Chloro-1-(3,4-dichloro-benzyl)-1H-pyrazolo[3,4-d]pyrimidin-6-ylamine
[0415] The title compound was obtained by alkylation of
4-chloro-1H-pyrazolo[3,4-d]pyrimidin-6-ylamine with
4-bromomethyl-1,2-dichloro-benzene according to general procedure
1.1. R.t. 6.89 min. .sup.1H-NMR (CDCl.sub.3) .delta. 7.90 (s, 1H),
7.39-7.37 (m, 2H), 7.26 (dd, 1H), 5.37 (s, 2H), 5.20 (br. s,
2H).
Example 12
4-Chloro-1-(2,5-dimethoxy-benzyl)-1H-pyrazolo[3,4-d]pyrimidin-6-ylamine
[0416] The title compound was obtained by alkylation of
4-chloro-1H-pyrazolo[3,4-d]pyrimidin-6-ylamine with
2-chloromethyl-1,4-dimethoxy-benzene according to general procedure
1.1. R.t. 6.06 min. .sup.1H-NMR (CDCl.sub.3) .delta. 7.94 (s, 1H),
6.85 (d, 1H), 6.75 (dd, 1H), 6.42 (dd, 1H), 5.48 (s, 2H), 5.24 (s,
2H), 3.82 (s, 3H), 3.70 (s, 3H).
Example 13
4-Chloro-1-(4,5-dimethoxy-2-nitro-benzyl)-1H-pyrazolo[3,4-d]pyrimidin-6-yl-
amine
[0417] The title compound was obtained by alkylation of
4-chloro-1H-pyrazolo[3,4-d]pyrimidin-6-ylamine with
1-bromomethyl-4,5-dimethoxy-2-nitro-benzene according to general
procedure 1.1. R.t. 5.99 min. .sup.1H-NMR (DMSO-d.sub.6) .delta.
8.06 (s, 1H), 7.71 (s, 1H), 7.38 (br. s, 2H), 6.57 (s, 1H), 5.71
(s, 2H), 3.86 (s, 3H), 3.68 (s, 3H).
Example 14
1-(4-Bromo-3,5-dimethyl-pyridin-2-ylmethyl)-4-chloro-1H-pyrazolo[3,4-d]pyr-
imidin-6-ylamine
[0418] The title compound was obtained by alkylation of
4-chloro-1H-pyrazolo[3,4-d]pyrimidin-6-ylamine with
4-bromo-2-chloromethyl-3,5-dimethyl-pyridine according to general
procedure 1.1. R.t. 5.64 min. .sup.1H-NMR (CDCl.sub.3) .delta. 8.20
(s, 1H), 7.92 (s, 1H), 5.61 (s, 2H), 5.21 (br. s, 2H), 2.50 (s,
3H), 2.37 (s, 3H).
Example 15
1-(4-Bromo-3,5-dimethyl-1-oxy-pyridin-2-ylmethyl)-4-chloro-1H-pyrazolo[3,4-
-d]pyrimidin-6-ylamine
[0419] The title compound was obtained by oxidation of
1-(4-bromo-3,5-dimethyl-pyridin-2-ylmethyl)-4-chloro-1H-pyrazolo[3,4-d]py-
rimidin-6-ylamine with m-CPBA according to general procedure 2.1.
R.t. 5.57 min. .sup.1H-NMR (CDCl.sub.3) .delta. 8.23 (s, 1H), 7.90
(s, 1H), 7.38 (s, 2H), 5.64 (s, 2H), 2.50 (s, 3H), 2.30 (s,
3H).
Example 16
4-Chloro-1-(2,3,6-trifluoro-benzyl)-1H-pyrazolo[3,4-d]pyrimidin-6-ylamine
[0420] The title compound was obtained by alkylation of
4-chloro-1H-pyrazolo[3,4-d]pyrimidin-6-ylamine with
2-bromomethyl-1,3,4-trifluoro-benzene according to general
procedure 1.1. R.t. 7.12 min. .sup.1H-NMR (CDCl.sub.3) .delta.
7.89(s, 1H), 7.25-7.05 (m, 1H), 6.95-6.85 (m, 1H), 5.53 (s, 2H),
5.49 (br. s, 2H).
Example 17
1-(2-Amino-4,6-dichloro-pyrimidin-5-yl)-ethanol
[0421] The title compound was obtained by treatment of
2-Amino-4-chloro-pyrimidine-5-carbaldehyde with MeMgBr according to
general procedure 1.2. R.t. 4.19 min. .sup.1H-NMR (DMSO-d.sub.6)
.delta. 7.38 (s, 1H), 5.18 (bs, 2H), 5.15 (m, 1H), 3.56 (d,
3H).
Example 18
1-(2-Amino-4,6-dichloro-pyrimidin-5-yl)-ethanone
[0422] ##STR26##
[0423] The title compound was obtained by treatment of
1-(2-Amino-4,6-dichloro-pyrimidin-5-yl)-ethanol with MnO.sub.2
according to general procedure 1.2. R.t. 5.23 min. .sup.1H-NMR
(DMSO-d.sub.6) .delta. 7.90 (s, 2H), 2.52 (s, 3H).
Example 19
4-Chloro-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-6-ylamine
[0424] ##STR27##
[0425] The title compound was obtained by treatment of
1-(2-Amino-4,6-dichloro-pyrimidin-5-yl)-ethanone with hydrazine
according to general procedure 1.2. R.t. 4.61 min. .sup.1H-NMR
(DMSO-d.sub.6) .delta. 11.82 (s, 1H), 8.16 (bs, 2H), 2.46 (s,
3H).
Example 20
4-Chloro-3-ethyl-1H-pyrazolo[3,4-d]pyrimidin-6-ylamine
[0426] The title compound was obtained by treating
2-amino-4,6-dichloro-pyrimidine-5-carbaldehyde by sequentially with
EtMgCl, MnO.sub.2, and hydrazine according to general procedure
1.2. R.t. 4.55 min. .sup.1H-NMR (DMSO-d.sub.6) .delta. 12.84 (s,
1H), 7.07 (s, 2H), 2.85 (m, 2H), 1.27-1.23 (m, 3H).
Example 21
4-Chloro-3-isopropyl-1H-pyrazolo[3,4-d]pyrimidin-6-ylamine
[0427] ##STR28##
[0428] The title compound was obtained by treating
2-amino-4,6-dichloro-pyrimidine-5-carbaldehyde sequentially with
i-PrMgCl, MnO.sub.2 and hydrazine according to general procedure
1.2. R.t. 6.10 min. .sup.1H-NMR (DMSO-d.sub.6) .delta. 12.86 (s,
1H), 7.06 (s, 2H), 1.29 (d, 6H).
Example 22
4-Chloro-3-phenyl-1H-pyrazolo[3,4-d]pyrimidin-6-ylamine
[0429] ##STR29##
[0430] The title compound was obtained by treating
2-amino-4,6-dichloro-pyrimidine-5-carbaldehyde sequentially with
PhMgCl, MnO.sub.2 and hydrazine according to general procedure 1.2.
R.t. 6.04 min. .sup.1H-NMR (DMSO-d.sub.6) .delta. 13.04 (s, 1H),
7.70 (m, 2H), 7.46 (m, 3H), 7.19 (bs, 2H).
Example 23
4-Chloro-1-(4-methoxy-3,5-dimethyl-pyridin-2-ylmethyl)-3-methyl-1H-pyrazol-
o[3,4-d]pyrimidin-6-ylamine
[0431] ##STR30##
[0432] The title compound was obtained by alkylation of
4-chloro-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-6-ylamine with
2-chloromethyl-4-methoxy-3,5-dimethyl-pyridine according to general
procedure 1.1. R.t. 6.72 min. .sup.1H-NMR (CDCl.sub.3) .delta. 8.20
(s, 1H), 5.47 (s, 2H), 5.26 (s, 2H), 3.76 (s, 2H), 2.58 (s, 3H),
2.30 (s, 3H), 2.23 (s, 3H).
Example 24
1-(4-Bromo-3,5-dimethyl-1-oxy-pyridin-2-ylmethyl)-4-chloro-3-methyl-1H-pyr-
azolo[3,4-d]pyrimidin-6-ylamine
[0433] ##STR31##
[0434] The title compound was obtained by alkylation of
4-chloro-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-6-ylamine with
4-bromo-2-chloromethyl-3,5-dimethyl-pyridine 1-oxide according to
general procedure 1.1. R.t. 5.90 min. .sup.1H-NMR (DMSO-d.sub.6)
.delta. 8.25 (s, 1H), 7.29 (s, 2H), 5.53 (s, 2H), 2.45 (s, 3H),
2.36 (s, 3H), 2.28 (s, 3H).
Example 25
4-Chloro-(4-chloro-3,5-dimethyl-1-oxy-pyridin-2-ylmethyl)-3-methyl-1H-pyra-
zolo[3,4-d]pyrimidin-6-ylamine
[0435] ##STR32##
[0436] The title compound was obtained by alkylation of
4-chloro-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-6-ylamine with
4-chloro-2-chloromethyl-3,5-dimethyl-pyridine 1-oxide according to
general procedure 1.1. R.t. 5.90 min. .sup.1H-NMR (DMSO-d.sub.6)
.delta. 8.25 (s, 1H), 7.30 (s, 2H), 5.54 (s, 2H), 2.45 (s, 3H),
2.36 (s, 3H), 2.28 (s, 3H).
Example 26
4-Chloro-1-(4-chloro-3,5-dimethyl-pyridin-2-ylmethyl)-3-methyl-1H-pyrazolo-
[3,4-d]pyrimidin-6-ylamine
[0437] ##STR33##
[0438] The title compound was obtained by alkylation of
4-chloro-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-6-ylamine with
4-chloro-2-chloromethyl-3,5-dimethyl-pyridine according to general
procedure 1.1. R.t. 5.63 min. .sup.1H-NMR (CDCl.sub.3) .delta. 8.23
(s, 1H), 5.51 (s, 2H), 5.28 (br.s 2H), 2.57 (s, 3H), 2.45 (s, 3H),
2.33 (s, 3H).
Example 27
4-Chloro-3-methyl-1-(3,4,5-trimethoxy-benzyl)-1H-pyrazolo[3,4-d]pyrimidin--
6-ylamine
[0439] ##STR34##
[0440] The title compound was obtained by alkylation of
4-chloro-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-6-ylamine with
5-chloromethyl-1,2,3-trimethoxy-benzene according to general
procedure 1.1. R.t. 6.72 min. .sup.1H-NMR (DMSO-d.sub.6) .delta.
7.30 (s, 2H), 6.57 (s, 2H), 5.22 (s, 2H), 3.71 (s, 6H), 3.62 (s,
3H), 2.47(s, 3H), 2.29 (s, 3H).
Example 28
1-(4-Bromo-3,5-dimethyl-pyridin-2-ylmethyl)-4-chloro-3-methyl-1H-pyrazolo[-
3,4-d]pyrimidin-6-ylamine
[0441] ##STR35##
[0442] The title compound was obtained by alkylation of
4-chloro-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-6-ylamine with
4-bromo-2-chloromethyl-3,5-dimethyl-pyridine according to general
procedure 1.1. R.t. 5.90 min. .sup.1H-NMR (DMSO-d.sub.6) .delta.
8.15 (s, 1H), 7.22 (s, 1H), 5.46 (s, 2H), 2.42 (s, 6H), 2.30 (s,
3H).
Example 29
4-Chloro-3-ethyl-1-(4-methoxy-3,5-dimethyl-pyridin-2-ylmethyl)-1H-pyrazolo-
[3,4-d]pyrimidin-6-ylamine
[0443] ##STR36##
[0444] The title compound was obtained by alkylation of
4-chloro-3-ethyl-1H-pyrazolo[3,4-d]pyrimidin-6-ylamine with
2-chloromethyl-4-methoxy-3,5-dimethyl-pyridine according to general
procedure 1.1. R.t. 6.02 min. .sup.1H-NMR (DMSO) .delta. 8.04
(s,1H), 7.19 (br. s, 2H), 5.39 (s, 2H), 3.71(s, 3H), 2.87-2.81 (m,
2H), 2.22 (s, 3H), 2.16 (s, 3H), 1.21(m, 3H).
Example 30
4-Chloro-1-(4-chloro-3,5-dimethyl-pyridin-2-ylmethyl)-3-ethyl-1H-pyrazolo[-
3,4-d]pyrimidin-6-ylamine
[0445] ##STR37##
[0446] The title compound was obtained by alkylation of
4-chloro-3-ethyl-1H-pyrazolo[3,4-d]pyrimidin-6-ylamine with
4-chloro-2-chloromethyl-3,5-dimethyl-pyridine according to general
procedure 1.1. R.t. 6.90 min. .sup.1H-NMR (DMSO-d.sub.6) .delta.
8.18 (s 1H), 7.21 (s, 1H), 5.47 (s, 2H), 2.87-2.81 (m, 2H), 2.39
(s, 3H), 2.27 (s, 3H), 1.21 (m, 3H).
Example 31
4-Chloro-3-isopropyl-1-(4-methoxy-3,5-dimethyl-pyridin-2-ylmethyl)-1H-pyra-
zolo[3,4-d]pyrimidin-6-ylamine
[0447] ##STR38##
[0448] The title compound was obtained by alkylation of
4-chloro-3-isopropyl-1-(4-methoxy-3,5-dimethyl-pyridin-2-ylmethyl)-1H-pyr-
azolo[3,4-d]pyrimidin-6-ylamine with
2-chloromethyl-4-methoxy-3,5-dimethyl-pyridine according to the
general procedure 1.1. R.t. 5.75 min. .sup.1H-NMR (DMSO-d.sub.6)
.delta. 8.02 (s, 1H), 7.17 (br. s, 1H), 5.40 (s, 2H), 3.71 (s, 3H),
2.23 (s, 3H), 2.16 (s, 3H), 1.26 (d, 6H).
Example 32
4-Chloro-1-(4-methoxy-3,5-dimethyl-pyridin-2-ylmethyl)-3-phenyl-1H-pyrazol-
o[3,4-d]pyrimidin-6-ylamine
[0449] ##STR39##
[0450] The title compound was obtained by alkylation of
4-chloro-3-phenyl-1H-pyrazolo[3,4-d]pyrimidin-6-ylamine with
2-chloromethyl-4-methoxy-3,5-dimethyl-pyridine according to general
procedure 1.1. R.t. 5.89 min. .sup.1H-NMR (DMSO-d.sub.6) .delta.
8.06 (s, 1H), 7.68-7.66 (m, 2H), 7.47-7.45 (m, 3H), 7.32 (br.s,
2H), 5.52 (s, 2H), 3.72 (s, 3H), 2.27 (s, 3H), 2.16 (s, 3H).
Example 33
4-Chloro-1-(4-chloro-3,5-dimethyl-pyridin-2-ylmethyl)-3-phenyl-1H-pyrazolo-
[3,4-d]pyrimidin-6-ylamine
[0451] ##STR40##
[0452] The title compound was obtained by alkylation of
4-chloro-3-phenyl-1H-pyrazolo[3,4-d]pyrimidin-6-ylamine with
2-chloromethyl-4-methoxy-3,5-dimethyl-pyridine according to general
procedure 1.1. R.t. 6.80 min. .sup.1H-NMR (DMSO-d.sub.6) .delta.
8.20 (s, 1H), 7.67-7.65 (m, 2H), 7.47-7.45 (m, 3H), 7.34 (br.s,
2H), 5.61 (s, 2H), 2.43 (s, 3H), 2.27 (s, 3H).
Example 34
1-(4-Bromo-3,5-dimethyl-pyridin-2-ylmethyl)-4-chloro-3-phenyl-1H-pyrazolo[-
3,4-d]pyrimidin-6-ylamine
[0453] ##STR41##
[0454] The title compound was obtained by alkylation of
4-chloro-3-phenyl-1H-pyrazolo[3,4-d]pyrimidin-6-ylamine with
4-bromo-2-chloromethyl-3,5-dimethyl-pyridine according to general
procedure 1.1. R.t. 7.41 min. .sup.1H-NMR (DMSO-d.sub.6) .delta.
8.15 (s, 1H), 7.67 (m, 2H), 7.46 (m, 3H), 7.34 (br. s, 2H), 5.62
(s, 2H), 2.4 (s, 3H), 2.3 (s, 3H).
Example 35
4-Chloro-1-(4-chloro-3,5-dimethyl-1-oxy-pyridin-2-ylmethyl)-3-phenyl-1H-py-
razolo[3,4-d]pyrimidin-6-ylamine
[0455] The title compound was obtained by alkylation of
4-chloro-3-phenyl-1H-pyrazolo[3,4-d]pyrimidin-6-ylamine with
4-chloro-2-chloromethyl-3,5-dimethyl-pyridine 1-oxide according to
general procedure 1.1. R.t. 7.50 min. .sup.1H-NMR (DMSO-d.sub.6)
.delta. 8.25 (s, 1H), 7.57 (s, 2H), 7.42 (m, 5H), 5.67 (s, 2H),
2.49 (s, 3H), 2.26 (s, 3H).
Biology Examples
Example A
rHSP90 Competitive Binding Assay
[0456] Five microgram of purified rHSP90 protein (Stressgen, BC,
Canada, #SPP-770) in phosphated buffered saline (PBS) was coated on
96 well plates by incubating overnight at 4.degree. C. Unbound
protein was removed and the coated wells were washed twice with 200
.mu.L PBS. DMSO controls (considered as untreated samples) or test
compounds were then added at 100-30-10-3-1-0.3 .mu.M dilutions (in
PBS), the plates mixed for 30 seconds on the plate shaker, and then
incubated for 60 min. at 37.degree. C. The wells were washed twice
with 200 .mu.L PBS, and 10 .mu.M biotinylated-geldanamycin
(biotin-GM) was added and incubated for 60 min. at 37.degree. C.
The wells were washed again twice with 200 .mu.L PBS, before the
addition of 20 .mu.g/mL streptavidin-phycoerythrin
(streptavidin-PE) (Molecular Probes, Eugene, Oreg.) and incubation
for 60 min. at 37.degree. C. The wells were washed again twice with
200 .mu.L PBS. Relative fluorescence units (RFU) was measured using
a SpectraMax Gemini XS Spectrofluorometer (Molecular Devices,
Sunnyvale, Calif.) with an excitation at 485 nm and emission at 580
nm; data was acquired using SOFTmax.RTM. PRO software (Molecular
Devices Corporation, Sunnyvale, Calif.). The background was defined
as the RFU generated from wells that were not coated with HSP90 but
were treated with the biotin-GM and streptavidin-PE. The background
measurements were substrated from each sample treated with
biotin-GM and streptavidin-PE measurements before other
computation. Percent inhibition of binding for each sample was
calculated from the background subtracted values as follows:
%binding inhibition=[RFU untreated-RFU treated]/RFU
untreated].times.100.
Example B
Cell Lysate Binding Assay
[0457] MCF7 breast carcinoma cell lysates were prepared by douncing
in lysing buffer (20 mM HEPES, pH 7.3, 1 mM EDTA, 5 mM MgCl.sub.2,
100 mM KCl), and then incubated with or without test compound for
30 mins at 4.degree. C., followed by incubation with biotin-GM
linked to BioMag.TM. streptavidin magnetic beads (Qiagen) for 1 hr
at 4.degree. C. The tubes were placed on a magnetic rack, and the
unbound supernatant removed. The magnetic beads were washed three
times in lysis buffer and boiled for 5 mins at 95.degree. C. in
SDS-PAGE sample buffer. Samples were analyzed on SDS protein gels,
and Western blots done for rHSP90. Bands in the Western Blots were
quantitated using the Bio-rad Fluor-S MultiImager, and the %
inhibition of binding of rHSP90 to the biotin-GM was
calculated.
[0458] The lysate binding ability of selected compounds of the
invention based on the above assay is summarized in Table 2. The
IC.sub.50 reported is the concentration of test compound needed to
achieve 30% inhibition of the biotin-GM binding to rHSP90 in the
MCF7 cell lysates.
Example C
HER2 Degradation Assay
[0459] MCF7 breast carcinoma cells (ATCC) were grown in Dulbecco's
modified Eagle's medium (DMEM) containing 10% fetal bovine serum
(FBS) and 10 mM HEPES, and plated in 24 well plates (50%
confluent). Twenty-four hrs later (cells are 65-70% confluent),
test compounds were added and incubated overnight for 16 h. For the
less potent compounds, the amounts added were 100 .mu.M, 30 .mu.M,
10 .mu.M and 1 .mu.M, and for more potent compounds, the amounts
added were 1 .mu.M, 0.3 .mu.M, 0.1 .mu.M, 0.03 .mu.M, 0.01 .mu.M
and 0.003 .mu.M. The wells were washed with 1 mL phosphate buffered
saline (PBS), and 200 .mu.L trypsin was added to each well. After
trypsinization was complete, 50 .mu.L of FBS was added to each
well. Then 200 .mu.L cells was transferred to 96 well plates. The
cells were pipetted up and down to obtain a single cell suspension.
The plates were centrifuged at 2,500 rpm for 1 min using a Sorvall
Legend RT.TM. tabletop centrifuge (Kendro Laboratory Products,
Asheville, N.C.). The cells were then washed once in PBS containing
0.2% BSA and 0.2% sodium azide (BA buffer). Phycoerythrin (PE)
conjugated anti HER2/Neu antibody (Becton Dickinson, #340552), or
PE conjugated anti-keyhole limpet hemacyanin [KLH] (Becton
Dickinson, #340761) control antibody was added at a dilution of
1:20 and 1:40 respectively (final concentration was 1 .mu.g/mL) and
the cells were pipetted up and down to form a single cell
suspension, and incubated for 15 mins. The cells were washed twice
with 200 .mu.L BA buffer, and resuspended in 200 .mu.L BA buffer,
and transferred to FACSCAN tubes with an additional 250 .mu.L BA
buffer. Samples were analyzed using a FACSCalibur.TM. flow
cytometer (Becton Dickinson, San Jose, Calif.) equipped with
Argon-ion laser that emits 15 mW of 488 nm light for excitation of
the PE fluorochrome. 10,000 events were collected per sample. A
fluorescence histogram was generated and the mean fluorescence
intensity (MFI) of each sample was determined using Cellquest
software. The background was defined as the MFI generated from
cells incubated with control IgG-PE, and was subtracted from each
sample stained with the HER2/Neu antibody. Cells incubated with
DMSO was always done as untreated controls since the compounds were
resuspended in DMSO. Percent degradation of HER2 was calculated as
follows: %HER2 degraded=[(MFl untreated cells-MFl treated
cells)/MFl untreated cell].times.100
[0460] The HER2 degradation ability of selected compounds of the
invention based on this assay is summarized in Table 2. IC.sub.50
is defined as the concentration at which there was 50% degradation
of the HER2/Neu protein.
Example D
MTS Assay
[0461] MTS assays measures the cytotoxicity of geldanamycin
derivatives. MTS
(3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfoph-
enyl)-2H-tetrazolium is a tetrazolium dye that is converted to a
formazan product by dehydrogenase enzymes of metabolically active
cells (Corey, A. et al. "Use of an aqueous soluble
tetrazolium/formazan assay for cell growth assays in culture,"
Cancer Commun. 1991, 3, 207-212). Cells were seeded in 96 well
plates at 2000 cells/well and allowed to adhere overnight in
Dulbecco's modified Eagle's medium supplemented with 10% fetal
bovine serum. The final culture volume was 100 .mu.l. Viable cell
number was determined by using the Celltiter 96 AQ.sub.ueous
Non-radioactive Cell Proliferation Assay (Promega, Madison Wis.).
The MTS/PMS (phenazine methosulfate) solution was mixed at a ratio
of 20:1, and 20 .mu.L was added per well to 100 .mu.l of culture
medium. After 2-4 hours, the formation of the formazan product was
measured at 490 nm absorbance using a multiwell plate
spectrophotometer. Background was determined by measuring the Abs
490 nm of cell culture medium and MTS-PMS in the absence of cells
and was subtracted from all values. Percent viable cells was
calculated as follows: %viable cells=(Abs at 490 nm treated
cells/Abs at 490 nm untreated cells).times.100
[0462] The effect of selected compounds of the invention on MCF7
breast carcinoma cells according to the MTS assay is summarized in
Table 2. IC.sub.50 was defined as the concentration of the compound
which gave rise to 50% viable cell number. TABLE-US-00002 TABLE 2
Biological Activities of Selected Compounds of the Invention Lysate
HER2 MTS Ex binding IC.sub.50 IC.sub.50 S.No # Structure (.mu.M)
(.mu.M) (.mu.M) 1 7 ##STR42## 0.14 0.05 0.13 2 8 ##STR43## ND 0.14
0.5 3 9 ##STR44## ND 0.09 0.3 4 31 ##STR45## ND 0.05 0.3 5 32
##STR46## ND 0.04 0.08 6 33 ##STR47## ND 0.16 0.6 7 34 ##STR48## ND
0.12 1.0 8 30 ##STR49## ND 0.11 1.0 9 29 ##STR50## 0.1 0.85 1.0 10
35 ##STR51## 0.08 0.02 1.0 11 10 ##STR52## 0.06 0.03 0.7 12 23
##STR53## ND 0.04 0.1 13 14 ##STR54## 0.11 0.09 1.0 14 26 ##STR55##
0.09 0.05 ND 15 15 ##STR56## ND 0.9 ND 16 25 ##STR57## ND 0.03 0.3
17 28 ##STR58## ND 0.04 1.0 18 24 ##STR59## ND 0.03 1.0 ND = not
determined
[0463] The foregoing examples are not limiting and are merely
illustrative of various aspects and embodiments of the present
invention. All documents cited herein are indicative of the levels
of skill in the art to which the invention pertains and are
incorporated by reference herein in their entireties. None,
however, is admitted to be prior art.
[0464] One skilled in the art will readily appreciate that the
present invention is well adapted to carry out the objects and
obtain the ends and advantages mentioned, as well as those inherent
therein. The methods and compositions described illustrate
preferred embodiments, are exemplary, and are not intended as
limitations on the scope of the invention. Certain modification and
other uses will occur to those skilled in the art, and are
encompassed within the spirit of the invention, as defined by the
scope of the claims.
[0465] The invention illustratively described herein suitably may
be practiced in the absence of any element or elements, limitation
or limitations which is not specifically disclosed herein. The
terms and expressions which have been employed are used as terms of
description and not of limitation, and there is no intention in the
use of such terms and expressions of excluding any equivalents of
the features shown and described, or portions thereof. It is
recognized that various modifications are possible within the scope
of the invention claimed. Thus, it should be understood that
although the present invention has been specifically disclosed by
preferred embodiments, optional features, modifications and
variations of the concepts herein disclosed may be resorted to by
those skilled in the art, and that such modifications and
variations are considered to be within the scope of this invention
as defined by the description and the appended claims.
[0466] In addition, where features or aspects of the invention are
described in terms of Markush groups or other grouping of
alternatives, e.g., genuses, those skilled in the art will
recognize that the invention is also thereby described in terms of
any individual member or subgroup of members of the Markush group
or subgenus, and exclusions of individual members as appropriate,
e.g., by proviso.
[0467] Other embodiments are within the following claims.
* * * * *