U.S. patent application number 12/706551 was filed with the patent office on 2010-06-10 for novel 4-cyano, 4-amino, and 4-aminomethyl derivatives of pyrazolo[1,5-a]pyridines, pyrazolo[1,5-c]pyrimidines and 2h-indazole compounds and 5-cyano, 5-amino, and 5-aminomethyl derivatives of imidazo[1,2-a]pyridines, and imidazo[1,5-a]pyrazines as cyclin dependent kinase inhibitors.
Invention is credited to Vincent S. Madison, Alan K. Mallams, Kamil Paruch.
Application Number | 20100143384 12/706551 |
Document ID | / |
Family ID | 37487994 |
Filed Date | 2010-06-10 |
United States Patent
Application |
20100143384 |
Kind Code |
A1 |
Mallams; Alan K. ; et
al. |
June 10, 2010 |
NOVEL 4-CYANO, 4-AMINO, AND 4-AMINOMETHYL DERIVATIVES OF
PYRAZOLO[1,5-a]PYRIDINES, PYRAZOLO[1,5-c]PYRIMIDINES AND
2H-INDAZOLE COMPOUNDS AND 5-CYANO, 5-AMINO, AND 5-AMINOMETHYL
DERIVATIVES OF IMIDAZO[1,2-a]PYRIDINES, AND IMIDAZO[1,5-a]PYRAZINES
AS CYCLIN DEPENDENT KINASE INHIBITORS
Abstract
In its many embodiments, the present invention provides a novel
class of 4-cyano, 4-amino, and 4-aminomethyl derivatives of
pyrazolo[1,5-a]pyridine, pyrazolo[1,5-c]pyrimidine, and 2H-Indazole
compounds and 5-cyano, 5-amino, and 5-aminomethyl derivatives of
imidazo[1,2-a]pyridine and imidazo[1,5-a]pyrazine compounds as
inhibitors of cyclin dependent kinases, methods of preparing such
compounds, pharmaceutical compositions containing one or more such
compounds, methods of preparing pharmaceutical formulations
comprising one or more such compounds, and methods of treatment,
prevention, inhibition, or amelioration of one or more diseases
associated with the CDKs using such compounds or pharmaceutical
compositions.
Inventors: |
Mallams; Alan K.;
(Hackettstown, NJ) ; Madison; Vincent S.; (Ukiah,
CA) ; Paruch; Kamil; (Tisnov, CZ) |
Correspondence
Address: |
MERCK;PATENT DEPARTMENT (K-6-1, 1990)
2000 GALLOPING HILL ROAD
KENILWORTH
NJ
07033-0530
US
|
Family ID: |
37487994 |
Appl. No.: |
12/706551 |
Filed: |
February 16, 2010 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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11514548 |
Aug 31, 2006 |
7700773 |
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12706551 |
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60715621 |
Sep 9, 2005 |
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Current U.S.
Class: |
424/172.1 ;
424/649; 424/94.6; 514/110; 514/171; 514/19.3; 514/2.4; 514/234.5;
514/245; 514/249; 514/259.3; 514/27; 514/300; 514/338; 514/34;
514/47; 514/49; 544/281; 544/350; 546/121; 546/275.7 |
Current CPC
Class: |
C07D 487/04 20130101;
A61P 35/02 20180101; C07D 401/12 20130101; C07D 231/56 20130101;
A61P 43/00 20180101; A61P 29/00 20180101; A61P 35/00 20180101; A61P
25/28 20180101; C07D 471/04 20130101 |
Class at
Publication: |
424/172.1 ;
424/94.6; 424/649; 514/8; 514/10; 514/15; 514/27; 514/47; 514/49;
514/171; 514/234.5; 514/245; 514/249; 514/300; 514/338; 546/121;
546/275.7; 544/350; 544/281; 514/259.3; 514/34; 514/110 |
International
Class: |
A61K 39/395 20060101
A61K039/395; A61K 38/50 20060101 A61K038/50; A61K 33/24 20060101
A61K033/24; A61K 38/16 20060101 A61K038/16; A61K 38/08 20060101
A61K038/08; A61K 38/09 20060101 A61K038/09; A61K 31/7048 20060101
A61K031/7048; A61K 31/7076 20060101 A61K031/7076; A61K 31/7068
20060101 A61K031/7068; A61K 31/568 20060101 A61K031/568; A61K
31/5377 20060101 A61K031/5377; A61K 31/53 20060101 A61K031/53; A61K
31/4985 20060101 A61K031/4985; A61K 31/437 20060101 A61K031/437;
A61K 31/4439 20060101 A61K031/4439; C07D 471/04 20060101
C07D471/04; C07D 401/12 20060101 C07D401/12; A61K 31/573 20060101
A61K031/573; A61P 35/00 20060101 A61P035/00; C07D 487/04 20060101
C07D487/04; A61K 31/519 20060101 A61K031/519; A61K 31/704 20060101
A61K031/704 |
Claims
1. A compound represented by the structural formula: ##STR00166##
wherein: Y is selected from the group consisting of CN, NH.sub.2,
and CH.sub.2NH.sub.2; R.sup.1 is selected from the group consisting
of H, halogen, R.sup.9, NH.sub.2, CN, alkyl, alkenyl, alkynyl,
aryl, heteroaryl, CF.sub.3, heterocyclylalkyl, arylalkyl,
heteroarylalkyl, heterocyclyalkylalkyl, cycloalkyl,
cycloalkylalkyl, C(O)OR.sup.4, alkyl substituted with 1-6 R.sup.9
groups which can be the same or different and are independently
selected from the list of R.sup.9 shown later below, ##STR00167##
wherein the aryl in the above-noted definitions for R.sup.1 can be
unsubstituted or optionally substituted with one or more moieties
which can be the same or different, each moiety being independently
selected from the group consisting of halogen, CN, NH.sub.2,
--OR.sup.5, SR.sup.S, --CH.sub.2OR.sup.5, --C(O)R.sup.5,
--SO.sub.3H, --S(O.sub.2)R.sup.6, --S(O.sub.2)NR.sup.5R.sup.6,
--NR.sup.5R.sup.6, --C(O)NR.sup.5R.sup.6, --CF.sub.3, and
--OCF.sub.3; R.sup.2 is selected from the group consisting of H,
halogen, --NR.sup.5R.sup.6, --C(O)OR.sup.4, --C(O)NR.sup.5R.sup.6,
alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, aryl,
arylalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl,
##STR00168## wherein each of said alkyl, alkenyl, alkynyl,
cycloalkyl, aryl, arylalkyl, heterocyclylalkyl, heteroaryl and
heteroarylalkyl for R.sup.2 and heterocyclyl moieties whose
structures are shown immediately above for R.sup.2 can be
unsubstituted or optionally independently substituted with one or
more moieties which can be the same or different, each moiety being
independently selected from the group consisting of halogen, alkyl,
alkenyl, alkynyl, aryl, cycloalkyl, CF.sub.3, CN, --OCF.sub.3,
--(CR.sup.4R.sup.5).sub.nOR.sup.5, --OR.sup.5, --R.sup.5OR.sup.5,
--NR.sup.5R.sup.6, --(CR.sup.4R.sup.5).sub.nNR.sup.5R.sup.6,
--C(O.sub.2)R.sup.5, --C(O)R.sup.5, --C(O)NR.sup.5R.sup.6,
--SR.sup.6, --S(O.sub.2)R.sup.6, --S(O.sub.2)NR.sup.5R.sup.6,
--N(R.sup.5)S(O.sub.2)R.sup.7, --N(R.sup.5)C(O)R.sup.7 and
--N(R.sup.5)C(O)NR.sup.5R.sup.6; R.sub.3 is selected from the group
consisting of a halogen, CN, amino, alkylamino, cycloalkylamino,
arylalkylamino, heteroarylamino, heteroarylalkylamino,
hydroxyalkylamino, heterocycloalkylalkylamino, wherein each of said
amino, alkylamino, cycloalkylamino, arylalkylamino,
heteroarylamino, heteroarylalkylamino, hydroxyalkylamino, and
heterocycloalkylalkylamino can be unsubstituted or optionally
independently substituted with one or more moieties, which can be
the same or different, each moiety being independently selected
from the group consisting of halogen, alkyl, aryl, heteroaryl,
cycloalkyl, heterocycloalkyl, heteroarylalkyl,
heterocycloalkylalkyl, cycloalkylalkyl, CF.sub.3, OCF.sub.3, CN,
--OR.sup.5, --NR.sup.5R.sup.6, --C(R.sup.4R.sup.5).sub.nOR.sup.5,
--C(O.sub.2)R.sup.5, --C(O)R.sup.5, --C(O)NR.sup.5R.sup.6,
--SR.sup.6, --S(O.sub.2)R.sup.7, --S(O.sub.2)NR.sup.5R.sup.6,
--N(R.sup.5)S(O.sub.2)R.sup.7, --N(R.sup.5)C(O)R.sup.7 and
--N(R.sup.5)C(O)NR.sup.5R.sup.6; R.sup.4 is H, halogen, CN or
alkyl; R.sup.5 is H or alkyl; R.sup.6 is selected from the group
consisting of H, alkyl, aryl, arylalkyl, cycloalkyl,
heterocycloalkyl, heteroaryl, and heteroarylalkyl, wherein each of
said alkyl, aryl, arylalkyl, cycloalkyl, heterocyclolalkyl,
heteroaryl, and heteroarylalkyl can be unsubstituted or optionally
substituted with one or more moieties which can be the same or
different, each moiety being independently selected from the group
consisting of halogen, alkyl, aryl, cycloalkyl, CF.sub.3,
OCF.sub.3, CN, --OR.sup.5, --NR.sup.5R.sup.10, --N(R.sup.5)Boc,
--(CR.sup.4R.sup.5).sub.nOR.sup.5, --C(O.sub.2)R.sup.5,
--C(O)R.sup.5, --C(O)NR.sup.5R.sup.10, --SO.sub.3H, --SR.sup.10,
--S(O.sub.2)R.sup.7, --S(O.sub.2)NR.sup.5R.sup.10,
--N(R.sup.5)S(O.sub.2)R.sup.7, --N(R.sup.5)C(O)R.sup.7 and
--N(R.sup.5)C(O)NR.sup.5R.sup.10; R.sup.10 is selected from the
group consisting of H, alkyl, aryl, arylalkyl, cycloalkyl,
heterocycloalkyl, heteroaryl, and heteroarylalkyl, wherein each of
said alkyl, aryl, arylalkyl, cycloalkyl, heterocycloalkyl,
heteroaryl, and heteroarylalkyl can be unsubstituted or optionally
substituted with one or more moieties which can be the same or
different, each moiety being independently selected from the group
consisting of halogen, alkyl, aryl, cycloalkyl, CF.sub.3,
OCF.sub.3, CN, --OR.sup.5, --NR.sup.4R.sup.5, --N(R.sup.5)Boc,
--(CR.sup.4R.sup.5).sub.nOR.sup.5, --C(O.sub.2)R.sup.5,
--C(O)NR.sup.4R.sup.5, --C(O)R.sup.5, --SO.sub.3H, --SR.sup.5,
--S(O.sub.2)R.sup.7, --S(O.sub.2)NR.sup.4R.sup.5,
--N(R.sup.5)S(O.sub.2)R.sup.7, --N(R.sup.5)C(O)R.sup.7 and
--N(R.sup.5)C(O)NR.sup.4R.sup.5; optionally (i) R.sup.5 and
R.sup.10 in the moiety --NR.sup.5R.sup.10, or (ii) R.sup.5 and
R.sup.6 in the moiety --NR.sup.5R.sup.6, may be joined together to
form a cycloalkyl or heterocycloalkyl moiety, with each of said
cycloalkyl or heterocycloalkyl moiety being unsubstituted or
optionally independently being substituted with one or more R.sup.9
groups; R.sup.7 is selected from the group consisting of alkyl,
cycloalkyl, aryl, heterocycloalkyl, heteroaryl, arylalkyl and
heteroarylalkyl, wherein each of said alkyl, cycloalkyl, aryl,
heterocycloalkyl, heteroaryl, arylalkyl and heteroarylalkyl, for
R.sup.7 can be unsubstituted or optionally independently
substituted with one or more moieties which can be the same or
different, each moiety being independently selected from the group
consisting of halogen, alkyl, aryl, cycloalkyl, CF.sub.3,
OCF.sub.3, CN, --OR.sup.5, --NR.sup.5R.sup.10, --CH.sub.2OR.sup.5,
--C(O.sub.2)R.sup.5, --C(O)NR.sup.5R.sup.10, --C(O)R.sup.5,
--SR.sup.10, --S(O.sub.2)R.sup.10, --S(O.sub.2)NR.sup.5R.sup.10,
--N(R.sup.5)S(O.sub.2)R.sup.10, --N(R.sup.5)C(O)R.sup.10 and
--N(R.sup.5)C(O)NR.sup.5R.sup.10; R.sup.8 is selected from the
group consisting of R.sup.6, --C(O)NR.sup.5R.sup.10,
--CH.sub.2OR.sup.4, --C(O)OR.sup.6, --C(O)R.sup.7 and
--S(O.sub.2)R.sup.7; R.sup.9 is selected from the group consisting
of halogen, --CN, --NR.sup.5R.sup.6, --(CH.sub.2).sub.nOR.sup.4,
--C(O.sub.2)R.sup.6, --C(O)NR.sup.5R.sup.6, --OR.sup.6, --SR.sup.6,
--S(O.sub.2)R.sup.7, --S(O.sub.2)NR.sup.5R.sup.6,
--N(R.sup.5)S(O.sub.2)R.sup.7, --N(R.sup.5)C(O)R.sup.7 and
--N(R.sup.5)C(O)NR.sup.5R.sup.6; m is 0 to 4; and n is 1 to 4.
2. The compound of claim 1, wherein R.sup.1 is F, Cl, Br, CF.sub.3,
CN, lower alkyl, cycloalkyl or --(CH.sub.2).sub.nOR.sup.6.
3. The compound of claim 1, wherein R.sup.2 is H, lower alkyl,
cycloalkyl, --C(O)OR.sup.4, aryl, heteroaryl, cycloalkylalkyl,
##STR00169## wherein said lower alkyl, aryl, cycloalkyl,
heteroaryl, and the heterocyclyl moieties shown above for R.sup.2
are unsubstituted or optionally independently substituted with one
or more moieties which can be the same or different, each moiety
being independently selected from the group consisting of halogen,
CF.sub.3, lower alkyl, --OCH.sub.3, --CH.sub.2OH,
--CH.sub.2CH.sub.2OH, and CN.
4. The compound of claim 1, wherein R.sup.4 is H or CN.
5. The compound of claim 1, wherein R.sup.3 is selected from the
group consisting of (pyridin-3-ylmethyl)-amino,
(pyridin-2-ylmethyl)-amino, (pyridin-4-ylmethyl)-amino,
isopropylamino, phenylamino, Benzylamino, pyridin-3-ylamino,
pyridin-2-ylamino, pyridin-4-ylamino, 2-amino-ethanol and
1-amino-ethanol.
6. The compound of claim 1, wherein Y is selected from the group
consisting of CN, NH.sub.2, and CH.sub.2NH.sub.2.
7. The compound of claim 1, wherein Y is CN.
8. The compound of claim 1, wherein Y is NH.sub.2.
9. The compound of claim 1, wherein Y is CH.sub.2NH.sub.2.
10. The compound of claim 1, wherein R.sup.3 is
(pyridin-3-ylmethyl)-amino.
11. The compound of claim 1, wherein R.sup.3 is
(pyridin-2-ylmethyl)-amino.
12. The compound of claim 1, wherein R.sup.3 is
(pyridin-4-ylmethyl)-amino.
13. The compound of claim 2, wherein said R.sup.1 is Br or Cl.
14. The compound of claim 2, wherein R.sup.1 is isopropyl or
ethyl.
15. The compound of claim 2, wherein R.sup.1 is CH.sub.2OH or
--CH.sub.2OCH.sub.3.
16. The compound of claim 2, wherein R.sup.1 is CN.
17. The compound of claim 1, wherein R.sup.2 is lower alkyl,
cycloalkyl, cycloalkylalkyl, aryl, --NR.sup.5R.sup.6,
##STR00170##
18. The compound of claim 17, wherein R.sup.2 is ##STR00171##
19. The compound of claim 17, wherein R.sup.2 is unsubstituted
phenyl or phenyl substituted with one or more moieties selected
from the group consisting of F, Br, Cl, OMe, CH.sub.3 and
CF.sub.3.
20. The compound of claim 17, wherein R.sup.2 is
cyclohexylmethyl.
21. A compound selected from the group consisting of: ##STR00172##
##STR00173## or a pharmaceutically acceptable salt or solvate
thereof.
22. A method of inhibiting one or more cyclin dependent kinases,
comprising administering a therapeutically effective amount of at
least one compound of claim 1 to a patient in need of such
inhibition.
23. A method of treating one or more diseases associated with
cyclin dependent kinase, comprising administering a therapeutically
effective amount of at least one compound of claim 1, to a patient
in need of such treatment.
24. The method of claim 22, wherein said cyclin dependent kinase is
CDK2.
25. The method of claim 23 wherein said disease is selected from
the group consisting of: cancer of the bladder, breast, colon,
kidney, liver, lung, small cell lung cancer, esophagus, gall
bladder, ovary, pancreas, stomach, cervix, thyroid, prostate, and
skin, squamous cell carcinoma; leukemia, acute lymphocytic
leukemia, acute lymphoblastic leukemia, B-cell lymphoma, T-cell
lymphoma, Hodgkins lymphoma, non-Hodgkins lymphoma, hairy cell
lymphoma, Burkett's lymphoma; acute and chronic myelogenous
leukemia, myelodysplastic syndrome, promyelocytic leukemia;
fibrosarcoma, rhabdomyosarcoma; astrocytoma, neuroblastoma, glioma
and schwannomas; melanoma, seminoma, teratocarcinoma, osteosarcoma,
xenoderoma pigmentosum, keratoctanthoma, thyroid follicular cancer
and Kaposi's sarcoma.
26. A method of treating one or more diseases associated with
cyclin dependent kinase, comprising administering to a mammal in
need of such treatment an amount of a first compound, which is a
compound of claim 1 or a pharmaceutically acceptable salt or
solvate thereof; and an amount of at least one second compound,
said second compound being an anti-cancer agent; wherein the
amounts of the first compound and said second compound result in a
desired therapeutic effect.
27. The method of claim 26, further comprising radiation
therapy.
28. The method of claim 26, wherein said anti-cancer agent is
selected from the group consisting of a cytostatic agent,
cisplatin, doxorubicin, taxotere, taxol, etoposide, irinotecan (or
CPT-11), camptostar, topotecan, paclitaxel, docetaxel, epothilones,
tamoxifen, 5-fluorouracil, methoxtrexate, 5-Fluorouracil,
temozolomide, cyclophosphamide,
4-[2-[4-[(11R)-3,10-dibromo-8-chloro-6,11-dihydro-5H-benzo[5,6]cyclohepta-
[1,2-b]pyridin-11-yl-]-1-piperidinyl]-2-oxoethyl]-1-piperidinecarboxamide,
tipifarnib, L778,123 (a farnesyl protein transferase inhibitor),
BMS 214662 (a farnesyl protein transferase inhibitor), Iressa,
Tarceva, antibodies to EGFR, Gleevec, intron, ara-C, adriamycin,
cytoxan, gemcitabine, Uracil mustard, Chlormethine, Ifosfamide,
Melphalan, Chlorambucil, Pipobroman, Triethylenemelamine,
Triethylenethiophosphoramine, Busulfan, Carmustine, Lomustine,
Streptozocin, Dacarbazine, Floxuridine, Cytarabine,
6-Mercaptopurine, 6-Thioguanine, Fludarabine phosphate,
oxaliplatin, leucovirin, oxaliplatin, Pentostatine, Vinblastine,
Vincristine, Vindesine, Bleomycin, Dactinomycin, Daunorubicin,
Doxorubicin, Epirubicin, Idarubicin, Mithramycin, Deoxycoformycin,
Mitomycin-C, L-Asparaginase, Teniposide 17.alpha.-Ethinylestradiol,
Diethylstilbestrol, Testosterone, Prednisone, Fluoxymesterone,
Dromostanolone propionate, Testolactone, Megestrolacetate,
Methylprednisolone, Methyltestosterone, Prednisolone,
Triamcinolone, Chlorotrianisene, Hydroxyprogesterone,
Aminoglutethimide, Estramustine, Medroxyprogesteroneacetate,
Leuprolide, Flutamide, Toremifene, goserelin, Cisplatin,
Carboplatin, Hydroxyurea, Amsacrine, Procarbazine, Mitotane,
Mitoxantrone, Levamisole, Navelbene, Anastrazole, Letrazole,
Capecitabine, Reloxafine, Droloxafine, and Hexamethylmelamine.
29. A pharmaceutical composition comprising a therapeutically
effective amount of at least one compound of claim 1 in combination
with at least one pharmaceutically acceptable carrier.
30. The pharmaceutical composition of claim 29, additionally
comprising one or more anti-cancer agents selected from the group
consisting of cytostatic agent, cisplatin, doxorubicin, taxotere,
taxol, etoposide, CPT-11, irinotecan, camptostar, topotecan,
paclitaxel, docetaxel, epothilones, tamoxifen, 5-fluorouracil,
methoxtrexate, 5-fluorouracil, temozolomide, cyclophosphamide,
4-[2-[4-[(11R)-3,10-dibromo-8-chloro-6,11-dihydro-5H-benzo[5,6]cyclohepta-
[1,2-b]pyridin-11-yl-]-1-piperidinyl]-2-oxoethyl]-1-piperidinecarboxamide,
Zarnestra.RTM. (tipifarnib), L778,123 (a farnesyl protein
transferase inhibitor), BMS 214662 (a farnesyl protein transferase
inhibitor), Iressa, Tarceva, antibodies to EGFR, Gleevec, intron,
ara-C, adriamycin, cytoxan, gemcitabine, Uracil mustard,
Chlormethine, Ifosfamide, Melphalan, Chlorambucil, Pipobroman,
Triethylenemelamine, Triethylenethiophosphoramine, Busulfan,
Carmustine, Lomustine, Streptozocin, Dacarbazine, Floxuridine,
Cytarabine, 6-Mercaptopurine, 6-Thioguanine, Fludarabine phosphate,
Pentostatine, Vinblastine, Vincristine, Vindesine, Bleomycin,
Dactinomycin, Daunorubicin, Doxorubicin, Epirubicin, Idarubicin,
Mithramycin, Deoxycoformycin, Mitomycin-C, L-Asparaginase,
Teniposide 171-Ethinylestradiol, Diethylstilbestrol, Testosterone,
Prednisone, Fluoxymesterone, Dromostanolone propionate,
Testolactone, Megestrolacetate, Methylprednisolone,
Methyltestosterone, Prednisolone, Triamcinolone, Chlorotrianisene,
Hydroxyprogesterone, Aminoglutethimide, Estramustine,
Medroxyprogesteroneacetate, Leuprolide, Flutamide, Toremifene,
goserelin, Cisplatin, Carboplatin, Hydroxyurea, Amsacrine,
Procarbazine, Mitotane, Mitoxantrone, Levamisole, Navelbene,
Anastrazole, Letrazole, Capecitabine, Reloxafine, Droloxafine, and
Hexamethylmelamine.
31. A compound of claim 1 in isolated and purified form.
Description
RELATED APPLICATIONS
[0001] The present application is a divisional of co-pending
application U.S. Ser. No. 11/514,548, filed Aug. 31, 2006, which
claims the benefit of priority to U.S. Provisional Application No.
60/715,621, filed Sep. 9, 2005, each of which is incorporated
herein by reference.
FIELD OF THE INVENTION
[0002] The present invention relates to 4-cyano, 4-amino, and
4-aminomethyl derivatives of pyrazolo[1,5-a]pyridine,
pyrazolo[1,5-c]pyrimidine, and 2H-Indazole compounds and 5-cyano,
5-amino, and 5-aminomethyl derivatives of imidazo[1,2-a]pyridine
and imidazo[1,5-a]pyrazine compounds useful as protein kinase
inhibitors, pharmaceutical compositions containing the compounds,
and methods of treatment using the compounds and compositions to
treat diseases such as, for example, cancer, inflammation,
arthritis, viral diseases, neurodegenerative diseases such as
Alzheimer's disease, cardiovascular diseases, and fungal
diseases.
BACKGROUND OF THE INVENTION
[0003] The cyclin-dependent kinases (CDKs) are serine/threonine
protein kinases, which are the driving force behind the cell cycle
and cell proliferation. Individual CDKs, such as, CDK1, CDK2, CDK3,
CDK4, CDK5, CDK6 and CDK7, CDK8 and the like, perform distinct
roles in cell cycle progression and can be classified as either G1,
S, or G2M phase enzymes. Uncontrolled proliferation is a hallmark
of cancer cells, and misregulation of CDK function occurs with high
frequency in many important solid tumors. CDK2 and CDK4 are of
particular interest because their activities are frequently
misregulated in a wide variety of human cancers. CDK2 activity is
required for progression through G1 to the S phase of the cell
cycle, and CDK2 is one of the key components of the G1 checkpoint.
Checkpoints serve to maintain the proper sequence of cell cycle
events and allow the cell to respond to insults or to proliferative
signals, while the loss of proper checkpoint control in cancer
cells contributes to tumorgenesis. The CDK2 pathway influences
tumorgenesis at the level of tumor suppressor function (e.g. p52,
RB, and p27) and oncogene activation (cyclin E). Many reports have
demonstrated that both the coactivator, cyclin E, and the
inhibitor, p27, of CDK2 are either over--or underexpressed,
respectively, in breast, colon, nonsmall cell lung, gastric,
prostate, bladder, non-Hodgkin's lymphoma, ovarian, and other
cancers. Their altered expression has been shown to correlate with
increased CDK2 activity levels and poor overall survival. This
observation makes CDK2 and its regulatory pathways compelling
targets for the development years, a number of adenosine
5'-triphosphate (ATP) competitive small organic molecules as well
as peptides have been reported in the literature as CDK inhibitors
for the potential treatment of cancers. U.S. Pat. No. 6,413,974,
col. 1, line 23-col. 15, line 10 offers a good description of the
various CDKs and their relationship to various types of cancer.
[0004] CDK inhibitors are known. For example, flavopiridol (Formula
I) is a nonselective CDK inhibitor that is currently undergoing
human clinical trials, A. M. Sanderowicz et al, J. Clin. Oncol.
(1998) 16, 2986-2999.
##STR00001##
[0005] Other known inhibitors of the CDKs include, for example,
olomoucine (J. Vesely et al, Eur. J. Biochem., (1994) 224, 771-786)
and roscovitine (I. Meijer et al, Eur. J. Biochem., (1997) 243,
527-536). U.S. Pat. No. 6,107,305 describes certain
pyrazolo[3,4-b]pyridine compounds as CDK inhibitors. An
illustrative compound from the '305 patent has the Formula II:
##STR00002##
[0006] K. S. Kim et al, J. Med. Chem. 45 (2002) 3905-3927 and WO
02/10162 disclose certain aminothiazole compounds as CDK
inhibitors.
[0007] Pyrazolopyrimidines are known. For Example, WO92/18504,
WO02/50079, WO95/35298, WO02/40485, EP94304104.6, EP0628559,
(equivalent to U.S. Pat. Nos. 5,602,136, 5,602,137 and 5,571,813),
U.S. Pat. No. 6,383,790, WO04/022561, WO04/026229, WO04/022559,
WO04/022062, WO04/022560, Chem. Pharm. Bull., (1999) 47 928, J.
Med. Chem., (1977) 20, 296, J. Med. Chem., (1976) 19 517 and Chem.
Pharm. Bull., (1962) 10 620 disclose various
pyrazolopyrimidines.
##STR00003##
[0008] Imidazopyrazines are also known. For Example, WO04/026877
and
[0009] WO04/026310 disclose various imidazopyrazines
##STR00004##
wherein: R.sup.1 is H, halogen, or alkyl.
[0010] Additionally, Imidazopyridines and pyrazolopyridines are
known. For Example, WO04/026867 discloses various imidazopyridines
and WO04/026872 discloses various pyrazolopyridines
##STR00005##
wherein R.sup.4 does not include a cyano or amino substituent.
[0011] Benzimidazoles are known. For example, U.S. Pat. No.
6,897,208 discloses various benzimidazoles.
##STR00006##
[0012] There is a need for new compounds, formulations, treatments
and therapies to treat diseases and disorders associated with CDKs.
It is, therefore, an object of this invention to provide compounds
useful in the treatment or prevention or amelioration of such
diseases and disorders.
SUMMARY OF THE INVENTION
[0013] In its many embodiments, the present invention provides a
novel class of 4-cyano, 4-amino, and 4-aminomethyl derivatives of
pyrazolo[1,5-a]pyridine, pyrazolo[1,5-c]pyrimidine, and 2H-Indazole
compounds and 5-cyano, 5-amino, and 5-aminomethyl derivatives of
imidazo[1,2-a]pyridine and imidazo[1,5-a]pyrazine compounds as
inhibitors of cyclin dependent kinases, methods of preparing such
compounds, pharmaceutical compositions comprising one or more such
compounds, methods of preparing pharmaceutical formulations
comprising one or more such compounds, and methods of treatment,
prevention, inhibition or amelioration of one or more diseases
associated with the CDKs using such compounds or pharmaceutical
compositions.
[0014] In one aspect, the present application discloses a compound,
or pharmaceutically acceptable salts or solvates of said compound,
said compound having the general structure shown in anyone of
Formulas III-VII:
##STR00007##
wherein:
[0015] Y is selected from the group consisting of CN, NH.sub.2, and
CH.sub.2NH.sub.2;
[0016] R.sup.1 is selected from the group consisting of H, halogen,
R.sup.9, NH.sub.2, CN, alkyl, alkenyl, alkynyl, aryl, heteroaryl,
CF.sub.3, heterocyclylalkyl, arylalkyl, heteroarylalkyl,
heterocyclyalkylalkyl, cycloalkyl, cycloalkylalkyl, C(O)OR.sup.4,
alkyl substituted with 1-6 R.sup.9 groups which can be the same or
different and are independently selected from the list of R.sup.9
shown later below,
##STR00008##
wherein the aryl in the above-noted definitions for R.sup.1 can be
unsubstituted or optionally substituted with one or more moieties
which can be the same or different, each moiety being independently
selected from the group consisting of halogen, CN, NH.sub.2,
--OR.sup.5, SR.sup.5, --CH.sub.2OR.sup.5, --C(O)R.sup.5,
--SO.sub.3H, --S(O.sub.2)R.sup.6, --S(O.sub.2)NR.sup.5R.sup.6,
--NR.sup.5R.sup.6, --C(O)NR.sup.5R.sup.6, --CF.sub.3, and
--OCF.sub.3;
[0017] R.sup.2 is selected from the group consisting of H, halogen,
--NR.sup.5R.sup.6, --C(O)OR.sup.4, C(O)NR.sup.5R.sup.6, alkyl,
alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl,
heterocyclyl, heterocyclylalkyl, heteroaryl,
##STR00009##
wherein each of said alkyl, alkenyl, alkynyl, cycloalkyl, aryl,
arylalkyl, heterocyclylalkyl, heteroaryl and heteroarylalkyl for
R.sup.2 and heterocyclyl moieties whose structures are shown
immediately above for R.sup.2 can be unsubstituted or optionally
independently substituted with one or more moieties which can be
the same or different, each moiety being independently selected
from the group consisting of halogen, alkyl, alkenyl, alkynyl,
aryl, cycloalkyl, CF.sub.3, CN, --OCF.sub.3,
--(CR.sup.4R.sup.5).sub.nOR.sup.5, --OR.sup.5, --R.sup.5OR.sup.5,
--NR.sup.5R.sup.6, --(CR.sup.4R.sup.5).sub.nNR.sup.5R.sup.6,
--C(O.sub.2)R.sup.5, --C(O)R.sup.5, --C(O)NR.sup.5R.sup.6,
--SR.sup.6, --S(O.sub.2)R.sup.6, --S(O.sub.2)NR.sup.5R.sup.6,
--N(R.sup.5)S(O.sub.2)R.sup.7, --N(R.sup.5)C(O)R.sup.7 and
--N(R.sup.5)C(O)NR.sup.5R.sup.6;
[0018] R.sub.3 is selected from the group consisting of a halogen,
CN, amino, alkylamino, cycloalkylamino, arylalkylamino,
heteroarylamino, heteroarylalkylamino, hydroxyalkylamino,
heterocycloalkylalkylamino, wherein each of said amino, alkylamino,
cycloalkylamino, arylalkylamino, heteroarylamino,
heteroarylalkylamino, hydroxyalkylamino, and
heterocycloalkylalkylamino can be unsubstituted or optionally
independently substituted with one or more moieties, which can be
the same or different, each moiety being independently selected
from the group consisting of halogen, alkyl, aryl, heteroaryl,
cycloalkyl, heterocycloalkyl, heteroarylalkyl,
heterocycloalkylalkyl, cycloalkylalkyl, CF.sub.3, OCF.sub.3, CN,
--OR.sup.5, --NR.sup.5R.sup.6, --C(R.sup.4R.sup.5).sub.nOR.sup.5,
--C(O.sub.2)R.sup.5, --C(O)R.sup.5, --C(O)NR.sup.5R.sup.6,
--SR.sup.6, --S(O.sub.2)R.sup.7, --S(O.sub.2)NR.sup.5R.sup.6,
--N(R.sup.5)S(O.sub.2)R.sup.7, N(R.sup.5)C(O)R.sup.7 and
--N(R.sup.5)C(O)NR.sup.5R.sup.6;
[0019] R.sup.4 is H, halogen, CN or alkyl;
[0020] R.sup.5 is H or alkyl;
[0021] R.sup.6 is selected from the group consisting of H, alkyl,
aryl, arylalkyl, cycloalkyl, heterocycloalkyl, heteroaryl, and
heteroarylalkyl, wherein each of said alkyl, aryl, arylalkyl,
cycloalkyl, heterocyclolalkyl, heteroaryl, and heteroarylalkyl can
be unsubstituted or optionally substituted with one or more
moieties which can be the same or different, each moiety being
independently selected from the group consisting of halogen, alkyl,
aryl, cycloalkyl, CF.sub.3, OCF.sub.3, CN, --OR.sup.5,
--NR.sup.5R.sup.10, --N(R.sup.5)Boc,
--(CR.sup.4R.sup.5).sub.nOR.sup.5, --C(O.sub.2)R.sup.5,
--C(O)R.sup.5, --C(O)NR.sup.5R.sup.10, --SO.sub.3H, --SR.sup.10,
--S(O.sub.2)R.sup.7,
--S(O.sub.2)NR.sup.5R.sup.1--N(R.sup.5)S(O.sub.2)R.sup.7,
--N(R.sup.5)C(O)R.sup.7 and --N(R.sup.5)C(O)NR.sup.5R.sup.10:
[0022] R.sup.10 is selected from the group consisting of H, alkyl,
aryl, arylalkyl, cycloalkyl, heterocycloalkyl, heteroaryl, and
heteroarylalkyl, wherein each of said alkyl, aryl, arylalkyl,
cycloalkyl, heterocycloalkyl, heteroaryl, and heteroarylalkyl can
be unsubstituted or optionally substituted with one or more
moieties which can be the same or different, each moiety being
independently selected from the group consisting of halogen, alkyl,
aryl, cycloalkyl, CF.sub.3, OCF.sub.3, CN, --OR.sup.5,
--NR.sup.4R.sup.5, --N(R.sup.5)Boc,
--(CR.sup.4R.sup.5).sub.nOR.sup.5, --C(O.sub.2)R.sup.5,
--C(O)NR.sup.4R.sup.5, --C(O)R.sup.5, --SO.sub.3H, --SR.sup.5,
--S(O.sub.2)R.sup.7, --S(O.sub.2)NR.sup.4R.sup.5,
--N(R.sup.5)S(O.sub.2)R.sup.7, --N(R.sup.5)C(O)R.sup.7 and
--N(R.sup.5)C(O)NR.sup.4R.sup.5; optionally (i) R.sup.5 and
R.sup.10 in the moiety --NR.sup.5R.sup.10, or (ii) R.sup.5 and
R.sup.6 in the moiety --NR.sup.5R.sup.6, may be joined together to
form a cycloalkyl or heterocycloalkyl moiety, with each of said
cycloalkyl or heterocycloalkyl moiety being unsubstituted or
optionally independently being substituted with one or more R.sup.9
groups;
[0023] R.sup.7 is selected from the group consisting of alkyl,
cycloalkyl, aryl, heterocycloalkyl, heteroaryl, arylalkyl and
heteroarylalkyl, wherein each of said alkyl, cycloalkyl, aryl,
heterocycloalkyl, heteroaryl, arylalkyl and heteroarylalkyl, for
R.sup.7 can be unsubstituted or optionally independently
substituted with one or more moieties which can be the same or
different, each moiety being independently selected from the group
consisting of halogen, alkyl, aryl, cycloalkyl, CF.sub.3,
OCF.sub.3, CN, --OR.sup.5, --NR.sup.5R.sup.10, --CH.sub.2OR.sup.5,
--C(O.sub.2)R.sup.5, --C(O)NR.sup.5R.sup.10, --C(O)R.sup.5,
--SR.sup.10, --S(O.sub.2)R.sup.10, --S(O.sub.2)NR.sup.5R.sup.10,
--N(R.sup.5)S(O.sub.2)R.sup.10, --N(R.sup.5)C(O)R.sup.10 and
--N(R.sup.5)C(O)NR.sup.5R.sup.10;
[0024] R.sup.8 is selected from the group consisting of R.sup.6,
--C(O)NR.sup.5R.sup.10, --CH.sub.2OR.sup.4, --C(O)OR.sup.6,
--C(O)R.sup.7 and --S(O.sub.2)R.sup.7;
[0025] R.sup.9 is selected from the group consisting of halogen,
--CN, --NR.sup.5R.sup.6, --(CH.sub.2).sub.nO.sup.4,
--C(O.sub.2)R.sup.6, --C(O)NR.sup.5R.sup.6, --OR.sup.6, --SR.sup.6,
--S(O.sub.2)R.sup.7, --S(O.sub.2)NR.sup.5R.sup.6,
--N(R.sup.5)S(O.sub.2)R.sup.7, --N(R.sup.5)C(O)R.sup.7 and
--N(R.sup.5)C(O)NR.sup.5R.sup.6;
[0026] m is 0 to 4; and
[0027] n is 1 to 4.
[0028] The compounds of Formulas III-VII can be useful as protein
kinase inhibitors and can be useful in the treatment and prevention
of proliferative diseases, for example, cancer, inflammation and
arthritis. They may also be useful in the treatment of
neurodegenerative diseases such as Alzheimer's disease,
cardiovascular diseases, viral diseases and fungal diseases.
DETAILED DESCRIPTION
[0029] In one embodiment, the present invention discloses
Pyrazolo[1,5-a]pyridine compounds which are represented by
structural Formula III or a pharmaceutically acceptable salt or
solvate thereof, wherein the various moieties are as described
above.
[0030] In another embodiment, the present invention discloses
Pyrazolo[1,5-c]pyrimidine compounds which are represented by
structural Formula IV or a pharmaceutically acceptable salt or
solvate thereof, wherein the various moieties are as described
above.
[0031] In yet another embodiment, the present invention discloses
Imidazo[1,2-a]pyridine compounds which are represented by
structural Formula V or a pharmaceutically acceptable salt or
solvate thereof, wherein the various moieties are as described
above.
[0032] In another embodiment, the present invention discloses
Imidazo[1,5-a]pyrazine compounds, which are represented by
structural Formula VI or a pharmaceutically acceptable salt or
solvate thereof, wherein the various moieties are as described
above.
[0033] In still another embodiment, the present invention discloses
2H-Indazole compounds, which are represented by structural Formula
VII or a pharmaceutically acceptable salt or solvate thereof,
wherein the various moieties are as described above.
[0034] An inventive group of compounds are shown in Table 1.
TABLE-US-00001 TABLE 1 ##STR00010## ##STR00011## ##STR00012##
##STR00013## ##STR00014## ##STR00015## ##STR00016## ##STR00017##
##STR00018## ##STR00019## ##STR00020## ##STR00021## ##STR00022##
##STR00023## ##STR00024## ##STR00025## ##STR00026## ##STR00027##
##STR00028## ##STR00029## ##STR00030## ##STR00031## ##STR00032##
##STR00033## ##STR00034## ##STR00035## ##STR00036## ##STR00037##
##STR00038## ##STR00039## ##STR00040## ##STR00041## ##STR00042##
##STR00043## ##STR00044## ##STR00045## ##STR00046## ##STR00047##
##STR00048## ##STR00049## ##STR00050## ##STR00051## ##STR00052##
##STR00053## ##STR00054## ##STR00055## ##STR00056## ##STR00057##
##STR00058## ##STR00059## ##STR00060## ##STR00061## ##STR00062##
##STR00063## ##STR00064## ##STR00065## ##STR00066##
[0035] As used above, and throughout this disclosure, the following
terms, unless otherwise indicated, shall be understood to have the
following meanings:
[0036] "Patient" includes both human and animals.
[0037] "Mammal" means humans and other mammalian animals.
[0038] "Alkyl" means an aliphatic hydrocarbon group which may be
straight or branched and comprising about 1 to about 20 carbon
atoms in the chain. Preferred alkyl groups contain about 1 to about
12 carbon atoms in the chain. More preferred alkyl groups contain
about 1 to about 6 carbon atoms in the chain. Branched means that
one or more lower alkyl groups such as methyl, ethyl or propyl, are
attached to a linear alkyl chain. "Lower alkyl" means a group
having about 1 to about 6 carbon atoms in the chain which may be
straight or branched. The term "substituted alkyl" means that the
alkyl group may be substituted by one or more substituents which
may be the same or different, each substituent being independently
selected from the group consisting of halo, alkyl, aryl,
cycloalkyl, cyano, hydroxy, alkoxy, alkylthio, amino, --NH(alkyl),
--NH(cycloalkyl), --N(alkyl).sub.2, carboxy and --C(O)O-alkyl.
Non-limiting examples of suitable alkyl groups include methyl,
ethyl, n-propyl, isopropyl and t-butyl.
[0039] "Alkenyl" means an aliphatic hydrocarbon group containing at
least one carbon-carbon double bond and which may be straight or
branched and comprising about 2 to about 15 carbon atoms in the
chain. Preferred alkenyl groups have about 2 to about 12 carbon
atoms in the chain; and more preferably about 2 to about 4 carbon
atoms in the chain. Branched means that one or more lower alkyl
groups such as methyl, ethyl or propyl, are attached to a linear
alkenyl chain. "Lower alkenyl" means about 2 to about 6 carbon
atoms in the chain which may be straight or branched. Non-limiting
examples of suitable alkenyl groups include ethenyl, propenyl,
2-butenyl and 3-methylbutenyl. The term "substituted alkenyl" means
that the alkenyl group may be substituted by one or more
substituents which may be the same or different, each substituent
being independently selected from the group consisting of alkyl,
aryl and cycloalkyl.
[0040] "Alkynyl" means an aliphatic hydrocarbon group containing at
least one carbon-carbon triple bond and which may be straight or
branched and comprising about 2 to about 15 carbon atoms in the
chain. Preferred alkynyl groups have about 2 to about 12 carbon
atoms in the chain; and more preferably about 2 to about 4 carbon
atoms in the chain. Branched means that one or more lower alkyl
groups such as methyl, ethyl or propyl, are attached to a linear
alkynyl chain. "Lower alkynyl" means about 2 to about 6 carbon
atoms in the chain which may be straight or branched. Non-limiting
examples of suitable alkynyl groups include ethynyl, propynyl,
2-butynyl and 3-methylbutynyl. The term "substituted alkynyl" means
that the alkynyl group may be substituted by one or more
substituents which may be the same or different, each substituent
being independently selected from the group consisting of alkyl,
aryl and cycloalkyl.
[0041] "Aryl" means an aromatic monocyclic or multicyclic ring
system comprising about 6 to about 14 carbon atoms, preferably
about 6 to about 10 carbon atoms. The aryl group can be optionally
substituted with one or more "ring system substituents" which may
be the same or different, and are as defined herein. Non-limiting
examples of suitable aryl groups include phenyl and naphthyl.
[0042] "Heteroaryl" means an aromatic monocyclic or multicyclic
ring system comprising about 5 to about 14 ring atoms, preferably
about 5 to about 10 ring atoms, in which one or more of the ring
atoms is an element other than carbon, for example nitrogen, oxygen
or sulfur, alone or in combination. Preferred heteroaryls contain
about 5 to about 6 ring atoms. The "heteroaryl" can be optionally
substituted by one or more "ring system substituents" which may be
the same or different, and are as defined herein. The prefix aza,
oxa or thia before the heteroaryl root name means that at least a
nitrogen, oxygen or sulfur atom respectively, is present as a ring
atom. A nitrogen atom of a heteroaryl can be optionally oxidized to
the corresponding N-oxide. Non-limiting examples of suitable
heteroaryls include pyridyl, pyrazinyl, furanyl, thienyl,
pyrimidinyl, isoxazolyl, isothiazolyl, oxazolyl, thiazolyl,
pyrazolyl, furazanyl, pyrrolyl, pyrazolyl, triazolyl,
1,2,4-thiadiazolyl, pyrazinyl, pyridazinyl, quinoxalinyl,
phthalazinyl, imidazo[1,2-a]pyridinyl, imidazo[2,1-b]thiazolyl,
benzofurazanyl, indolyl, azaindolyl, benzimidazolyl, benzothienyl,
quinolinyl, imidazolyl, thienopyridyl, quinazolinyl,
thienopyrimidyl, pyrrolopyridyl, imidazopyridyl, isoquinolinyl,
benzoazaindolyl, 1,2,4-triazinyl, benzothiazolyl and the like.
[0043] "Aralkyl" or "arylalkyl" means an aryl-alkyl-group in which
the aryl and alkyl are as previously described. Preferred aralkyls
comprise a lower alkyl group. Non-limiting examples of suitable
aralkyl groups include benzyl, 2-phenethyl and naphthalenylmethyl.
The bond to the parent moiety is through the alkyl.
[0044] "Alkylaryl" means an alkyl-aryl-group in which the alkyl and
aryl are as previously described. Preferred alkylaryls comprise a
lower alkyl group. Non-limiting example of a suitable alkylaryl
group is tolyl. The bond to the parent moiety is through the
aryl.
[0045] "Cycloalkyl" means a non-aromatic mono- or multicyclic ring
system comprising about 3 to about 10 carbon atoms, preferably
about 5 to about 10 carbon atoms. Preferred cycloalkyl rings
contain about 5 to about 7 ring atoms. The cycloalkyl can be
optionally substituted with one or more "ring system substituents"
which may be the same or different, and are as defined above.
Non-limiting examples of suitable monocyclic cycloalkyls include
cyclopropyl, cyclopentyl, cyclohexyl, cycloheptyl and the like.
Non-limiting examples of suitable multicyclic cycloalkyls include
1-decalinyl, norbornyl, adamantyl and the like.
[0046] "Halogen" means fluorine, chlorine, bromine, or iodine.
Preferred are fluorine, chlorine and bromine.
[0047] "Ring system substituent" means a substituent attached to an
aromatic or non-aromatic ring system which, for example, replaces
an available hydrogen on the ring system. Ring system substituents
may be the same or different, each being independently selected
from the group consisting of aryl, heteroaryl, aralkyl, alkylaryl,
heteroaralkyl, alkylheteroaryl, hydroxy, hydroxyalkyl, alkoxy,
aryloxy, aralkoxy, acyl, aroyl, halo, nitro, cyano, carboxy,
alkoxycarbonyl, aryloxycarbonyl, aralkoxycarbonyl, alkylsulfonyl,
arylsulfonyl, heteroarylsulfonyl, alkylthio, arylthio,
heteroarylthio, aralkylthio, heteroaralkylthio, cycloalkyl,
heterocyclyl, Y.sub.1Y.sub.2N-alkyl-, Y.sub.1Y.sub.2--NC(O)-- and
Y.sub.1Y.sub.2NSO.sub.2--, wherein Y.sub.1 and Y.sub.2 may be the
same or different and are independently selected from the group
consisting of hydrogen, alkyl, aryl, and aralkyl.
[0048] "Heterocyclyl" or "Heterocycloalkyl" means a non-aromatic
saturated monocyclic or multicyclic ring system comprising about 3
to about 10 ring atoms, preferably about 5 to about 10 ring atoms,
in which one or more of the atoms in the ring system is an element
other than carbon, for example nitrogen, oxygen or sulfur, alone or
in combination. There are no adjacent oxygen and/or sulfur atoms
present in the ring system. Preferred heterocyclyls or
heterocycloalkyls contain about 5 to about 6 ring atoms. The prefix
aza, oxa or thia before the heterocyclyl or heterocycloalkyl root
name means that at least a nitrogen, oxygen or sulfur atom
respectively is present as a ring atom. Any --NH in a heterocyclyl
ring may exist protected such as, for example, as an --N(Boc),
--N(CBz), --N(Tos) group and the like; such protected moieties are
also considered part of this invention. The heterocyclyl can be
optionally substituted by one or more "ring system substituents"
which may be the same or different, and are as defined herein. The
nitrogen or sulfur atom of the heterocyclyl can be optionally
oxidized to the corresponding N-oxide, S-oxide or S,S-dioxide.
Non-limiting examples of suitable monocyclic heterocyclyl rings
include piperidyl, pyrrolidinyl, piperazinyl, morpholinyl,
thiomorpholinyl, thiazolidinyl, 1,4-dioxanyl, tetrahydrofuranyl,
tetrahydrothiophenyl, and the like.
[0049] It should be noted that in hetero-atom containing ring
systems of this invention, there are no hydroxyl groups on carbon
atoms adjacent to a N, O or S, as well as there are no N or S
groups on carbon adjacent to another heteroatom. Thus, for example,
in the ring:
##STR00067##
there is no --OH attached directly to carbons marked 2 and 5.
[0050] "Alkynylalkyl" means an alkynyl-alkyl-group in which the
alkynyl and alkyl are as previously described. Preferred
alkynylalkyls contain a lower alkynyl and a lower alkyl group. The
bond to the parent moiety is through the alkyl. Non-limiting
examples of suitable alkynylalkyl groups include
propargylmethyl.
[0051] "Heteroaralkyl" means a heteroaryl-alkyl-group in which the
heteroaryl and alkyl are as previously described. Preferred
heteroaralkyls contain a lower alkyl group. Non-limiting examples
of suitable aralkyl groups include pyridylmethyl, and
quinolin-3-ylmethyl. The bond to the parent moiety is through the
alkyl.
[0052] "Hydroxyalkyl" means a HO-alkyl-group in which alkyl is as
previously defined. Preferred hydroxyalkyls contain lower alkyl.
Non-limiting examples of suitable hydroxyalkyl groups include
hydroxymethyl and 2-hydroxyethyl.
[0053] "Acyl" means an H--C(O)--, alkyl-C(O)-- or
cycloalkyl-C(O)--, group in which the various groups are as
previously described. The bond to the parent moiety is through the
carbonyl. Preferred acyls contain a lower alkyl. Non-limiting
examples of suitable acyl groups include formyl, acetyl and
propanoyl.
[0054] "Aroyl" means an aryl-C(O)-- group in which the aryl group
is as previously described. The bond to the parent moiety is
through the carbonyl. Non-limiting examples of suitable groups
include benzoyl and 1-naphthoyl.
[0055] "Alkoxy" means an alkyl-O-- group in which the alkyl group
is as previously described. Non-limiting examples of suitable
alkoxy groups include methoxy, ethoxy, n-propoxy, isopropoxy and
n-butoxy. The bond to the parent moiety is through the ether
oxygen.
[0056] "Aryloxy" means an aryl-O-- group in which the aryl group is
as previously described. Non-limiting examples of suitable aryloxy
groups include phenoxy and naphthoxy. The bond to the parent moiety
is through the ether oxygen.
[0057] "Aralkyloxy" means an aralkyl-O-- group in which the aralkyl
group is as previously described. Non-limiting examples of suitable
aralkyloxy groups include benzyloxy and 1- or 2-naphthalenemethoxy.
The bond to the parent moiety is through the ether oxygen.
[0058] "Alkylthio" means an alkyl-S-- group in which the alkyl
group is as previously described. Non-limiting examples of suitable
alkylthio groups include methylthio and ethylthio. The bond to the
parent moiety is through the sulfur.
[0059] "Arylthio" means an aryl-S-- group in which the aryl group
is as previously described. Non-limiting examples of suitable
arylthio groups include phenylthio and naphthylthio. The bond to
the parent moiety is through the sulfur.
[0060] "Aralkylthio" means an aralkyl-S-- group in which the
aralkyl group is as previously described. Non-limiting example of a
suitable aralkylthio group is benzylthio. The bond to the parent
moiety is through the sulfur.
[0061] "Alkoxycarbonyl" means an alkyl-O--CO-- group. Non-limiting
examples of suitable alkoxycarbonyl groups include methoxycarbonyl
and ethoxycarbonyl. The bond to the parent moiety is through the
carbonyl.
[0062] "Aryloxycarbonyl" means an aryl-O--C(O)-- group.
Non-limiting examples of suitable aryloxycarbonyl groups include
phenoxycarbonyl and naphthoxycarbonyl. The bond to the parent
moiety is through the carbonyl.
[0063] "Aralkoxycarbonyl" means an aralkyl-O--C(O)-- group.
Non-limiting example of a suitable aralkoxycarbonyl group is
benzyloxycarbonyl. The bond to the parent moiety is through the
carbonyl.
[0064] "Alkylsulfonyl" means an alkyl-S(O.sub.2)-- group. Preferred
groups are those in which the alkyl group is lower alkyl. The bond
to the parent moiety is through the sulfonyl.
[0065] "Arylsulfonyl" means an aryl-S(O.sub.2)-- group. The bond to
the parent moiety is through the sulfonyl.
[0066] The term "substituted" means that one or more hydrogens on
the designated atom is replaced with a selection from the indicated
group, provided that the designated atom's normal valency under the
existing circumstances is not exceeded, and that the substitution
results in a stable compound. Combinations of substituents and/or
variables are permissible only if such combinations result in
stable compounds. By "stable compound` or "stable structure" is
meant a compound that is sufficiently robust to survive isolation
to a useful degree of purity from a reaction mixture, and
formulation into an efficacious therapeutic agent.
[0067] The term "optionally substituted" means optional
substitution with the specified groups, radicals or moieties.
[0068] It should also be noted that any heteroatom with unsatisfied
valences in the text, schemes, examples and Tables herein is
assumed to have the hydrogen atom to satisfy the valences.
[0069] When a functional group in a compound is termed "protected",
this means that the group is in modified form to preclude undesired
side reactions at the protected site when the compound is subjected
to a reaction. Suitable protecting groups will be recognized by
those with ordinary skill in the art as well as by reference to
standard textbooks such as, for example, T. W. Greene et al,
Protective Groups in organic Synthesis (1991), Wiley, New York.
[0070] When any variable (e.g., aryl, heterocycle, R.sup.2, etc.)
occurs more than one time in any constituent or Formula of this
invention, its definition on each occurrence is independent of its
definition at every other occurrence.
[0071] As used herein, the term "composition" is intended to
encompass a product comprising the specified ingredients in the
specified amounts, as well as any product which results, directly
or indirectly, from combination of the specified ingredients in the
specified amounts.
[0072] Prodrugs and solvates of the compounds of the invention are
also contemplated herein. The term "prodrug", as employed herein,
denotes a compound that is a drug precursor, which, upon
administration to a subject, undergoes chemical conversion by
metabolic or chemical processes to yield a compound of this
invention or a salt and/or solvate thereof. A discussion of
prodrugs is provided in T. Higuchi and V. Stella, Pro-drugs as
Novel Delivery Systems (1987) 14 of the A.C.S. Symposium Series,
and in Bioreversible Carriers in Drug Design, (1987) Edward B.
Roche, ed., American Pharmaceutical Association and Pergamon Press,
both of which are incorporated herein by reference thereto.
[0073] "Solvate" means a physical association of a compound of this
invention with one or more solvent molecules. This physical
association involves varying degrees of ionic and covalent bonding,
including hydrogen bonding. In certain instances the solvate will
be capable of isolation, for example when one or more solvent
molecules are incorporated in the crystal lattice of the
crystalline solid. "Solvate" encompasses both solution-phase and
isolatable solvates. Non-limiting examples of suitable solvates
include ethanolates, methanolates, and the like. "Hydrate" is a
solvate wherein the solvent molecule is H.sub.2O.
[0074] "Effective amount" or "therapeutically effective amount" is
meant to describe an amount of compound or a composition of the
present invention effective in inhibiting the CDK(s) and thus
producing the desired therapeutic, ameliorative, inhibitory or
preventative effect.
[0075] The compounds of this invention can form salts, which are
also within the scope of this invention. Reference to a compound of
this invention herein is understood to include reference to salts
thereof, unless otherwise indicated. The term "salt(s)", as
employed herein, denotes acidic salts formed with inorganic and/or
organic acids, as well as basic salts formed with inorganic and/or
organic bases. In addition, when a compound of this invention
contains both a basic moiety, such as, but not limited to a
pyridine or imidazole, and an acidic moiety, such as, but not
limited to a carboxylic acid, zwitterions ("inner salts") may be
formed and are included within the term "salt(s)" as used herein.
Pharmaceutically acceptable (i.e., non-toxic, physiologically
acceptable) salts are preferred, although other salts are also
useful. Salts of the compounds of this invention may be formed, for
example, by reacting a compound of this invention with an amount of
acid or base, such as an equivalent amount, in a medium such as one
in which the salt precipitates or in an aqueous medium followed by
lyophilization. Acids (and bases) which are generally considered
suitable for the formation of pharmaceutically useful salts from
basic (or acidic) pharmaceutical compounds are discussed, for
example, by S. Berge et al, Journal of Pharmaceutical Sciences
(1977) 66(1) 1-19; P. Gould, International J. of Pharmaceutics
(1986) 33 201-217; Anderson et al, The Practice of Medicinal
Chemistry (1996), Academic Press, New York; in The Orange Book
(Food & Drug Administration, Washington, D.C. on their
website); and P. Heinrich Stahl, Camille G. Wermuth (Eds.),
Handbook of Pharmaceutical Salts: Properties, Selection, and Use,
(2002) Int'l. Union of Pure and Applied Chemistry, pp. 330-331.
These disclosures are incorporated herein by reference thereto.
[0076] Exemplary acid addition salts include acetates, adipates,
alginates, ascorbates, aspartates, benzoates, benzenesulfonates,
bisulfates, borates, butyrates, citrates, camphorates,
camphorsulfonates, cyclopentanepropionates, digluconates,
dodecylsulfates, ethanesulfonates, fumarates, glucoheptanoates,
glycerophosphates, hemisulfates, heptanoates, hexanoates,
hydrochlorides, hydrobromides, hydroiodides,
2-hydroxyethanesulfonates, lactates, maleates, methanesulfonates,
methyl sulfates, 2-naphthalenesulfonates, nicotinates, nitrates,
oxalates, pamoates, pectinates, persulfates, 3-phenylpropionates,
phosphates, picrates, pivalates, propionates, salicylates,
succinates, sulfates, sulfonates (such as those mentioned herein),
tartarates, thiocyanates, toluenesulfonates (also known as
tosylates,) undecanoates, and the like.
[0077] Exemplary basic salts include ammonium salts, alkali metal
salts such as sodium, lithium, and potassium salts, alkaline earth
metal salts such as calcium and magnesium salts, aluminum salts,
zinc salts, salts with organic bases (for example, organic amines)
such as benzathines, diethylamine, dicyclohexylamines, hydrabamines
(formed with N,N-bis(dehydroabietyl)ethylenediamine),
N-methyl-D-glucamines, N-methyl-D-glucamides, t-butyl amines,
piperazine, phenylcyclohexylamine, choline, tromethamine, and salts
with amino acids such as arginine, lysine and the like. Basic
nitrogen-containing groups may be quarternized with agents such as
lower alkyl halides (e.g. methyl, ethyl, propyl, and butyl
chlorides, bromides and iodides), dialkyl sulfates (e.g. dimethyl,
diethyl, dibutyl, and diamyl sulfates), long chain halides (e.g.
decyl, lauryl, myristyl and stearyl chlorides, bromides and
iodides), aralkyl halides (e.g. benzyl and phenethyl bromides), and
others.
[0078] All such acid salts and base salts are intended to be
pharmaceutically acceptable salts within the scope of the invention
and all acid and base salts are considered equivalent to the free
forms of the corresponding compounds for purposes of the
invention.
[0079] Compounds of this invention, and salts, solvates and
prodrugs thereof, may exist in their tautomeric form (for example,
as an amide or imino ether). All such tautomeric forms are
contemplated herein as part of the present invention.
[0080] All stereoisomers (for example, geometric isomers, optical
isomers and the like) of the present compounds (including those of
the salts, solvates and prodrugs of the compounds as well as the
salts and solvates of the prodrugs), such as those which may exist
due to asymmetric carbons on various substituents, including
enantiomeric forms (which may exist even in the absence of
asymmetric carbons), rotameric forms, atropisomers, and
diastereomeric forms, are contemplated within the scope of this
invention. Individual stereoisomers of the compounds of the
invention may, for example, be substantially free of other isomers,
or may be admixed, for example, as racemates or with all other, or
other selected, stereoisomers. The chiral centers of the present
invention can have the S or R configuration as defined by the IUPAC
1974 Recommendations. The use of the terms "salt", "solvate"
"prodrug" and the like, is intended to equally apply to the salt,
solvate and prodrug of enantiomers, stereoisomers, rotamers,
tautomers, racemates or prodrugs of the inventive compounds.
[0081] The compounds according to the invention have
pharmacological properties; in particular, the compounds of this
invention can be inhibitors of protein kinases such as the cyclin
dependent kinases (CDKs), for example, CDC2 (CDK1), CDK2, CDK4,
CDK5, CDK6, CDK7 and CDK8. The novel compounds of this invention
are expected to be useful in the therapy of proliferative diseases
such as cancer, autoimmune diseases, viral diseases, fungal
diseases, neurological/neurodegenerative disorders, arthritis,
inflammation, anti-proliferative (e.g., ocular retinopathy),
neuronal, alopecia and cardiovascular disease. Many of these
diseases and disorders are listed in U.S. Pat. No. 6,413,974 cited
earlier, the disclosure of which is incorporated herein.
[0082] More specifically, the compounds of this invention can be
useful in the treatment of a variety of cancers, including (but not
limited to) the following: carcinoma, including that of the
bladder, breast, colon, kidney, liver, lung, including small cell
lung cancer, esophagus, gall bladder, ovary, pancreas, stomach,
cervix, thyroid, prostate, and skin, including squamous cell
carcinoma;
[0083] hematopoietic tumors of lymphoid lineage, including
leukemia, acute lymphocytic leukemia, acute lymphoblastic leukemia,
B-cell lymphoma, T-cell lymphoma, Hodgkins lymphoma, non-Hodgkins
lymphoma, hairy cell lymphoma and Burkett's lymphoma;
[0084] hematopoietic tumors of myeloid lineage, including acute and
chronic myelogenous leukemias, myelodysplastic syndrome and
promyelocytic leukemia;
[0085] tumors of mesenchymal origin, including fibrosarcoma and
rhabdomyosarcoma;
[0086] tumors of the central and peripheral nervous system,
including astrocytoma, neuroblastoma, glioma and schwannomas;
and
[0087] other tumors, including melanoma, seminoma, teratocarcinoma,
osteosarcoma, xenoderoma pigmentosum, keratoctanthoma, thyroid
follicular cancer and Kaposi's sarcoma.
[0088] Due to the key role of CDKs in the regulation of cellular
proliferation in general, inhibitors could act as reversible
cytostatic agents which may be useful in the treatment of any
disease process which features abnormal cellular proliferation,
e.g., benign prostate hyperplasia, familial adenomatosis polyposis,
neuro-fibromatosis, atherosclerosis, pulmonary fibrosis, arthritis,
psoriasis, glomerulonephritis, restenosis following angioplasty or
vascular surgery, hypertrophic scar formation, inflammatory bowel
disease, transplantation rejection, endotoxic shock, and fungal
infections.
[0089] Compounds of this invention may also be useful in the
treatment of Alzheimer's disease, as suggested by the recent
finding that CDK5 is involved in the phosphorylation of tau protein
(J. Biochem, (1995) 117, 741-749).
[0090] Compounds of this invention may induce or inhibit apoptosis.
The apoptotic response is aberrant in a variety of human diseases.
Compounds of this invention, as modulators of apoptosis, will be
useful in the treatment of cancer (including but not limited to
those types mentioned hereinabove), viral infections (including but
not limited to herpevirus, poxvirus, Epstein-Barr virus, Sindbis
virus and adenovirus), prevention of AIDS development in
HIV-infected individuals, autoimmune diseases (including but not
limited to systemic lupus, erythematosus, autoimmune mediated
glomerulonephritis, rheumatoid arthritis, psoriasis, inflammatory
bowel disease, and autoimmune diabetes mellitus), neurodegenerative
disorders (including but not limited to Alzheimer's disease,
AIDS-related dementia, Parkinson's disease, amyotrophic lateral
sclerosis, retinitis pigmentosa, spinal muscular atrophy and
cerebellar degeneration), myelodysplastic syndromes, aplastic
anemia, ischemic injury associated with myocardial infarctions,
stroke and reperfusion injury, arrhythmia, atherosclerosis,
toxin-induced or alcohol related liver diseases, hematological
diseases (including but not limited to chronic anemia and aplastic
anemia), degenerative diseases of the musculoskeletal system
(including but not limited to osteoporosis and arthritis)
aspirin-sensitive rhinosinusitis, cystic fibrosis, multiple
sclerosis, kidney diseases and cancer pain.
[0091] Compounds of this invention, as inhibitors of the CDKs, can
modulate the level of cellular RNA and DNA synthesis. These agents
would therefore be useful in the treatment of viral infections
(including but not limited to HIV, human papilloma virus,
herpesvirus, poxvirus, Epstein-Barr virus, Sindbis virus and
adenovirus).
[0092] Compounds of this invention may also be useful in the
chemoprevention of cancer. Chemoprevention is defined as inhibiting
the development of invasive cancer by either blocking the
initiating mutagenic event or by blocking the progression of
pre-malignant cells that have already suffered an insult or
inhibiting tumor relapse.
[0093] Compounds of this invention may also be useful in inhibiting
tumor angiogenesis and metastasis.
[0094] Compounds of this invention may also act as inhibitors of
other protein kinases, e.g., protein kinase C, her2, raf 1, MEK1,
MAP kinase, EGF receptor, PDGF receptor, IGF receptor, PI3 kinase,
wee1 kinase, Src, Abl and thus be effective in the treatment of
diseases associated with other protein kinases.
[0095] Another aspect of this invention is a method of treating a
mammal (e.g., human) having a disease or condition associated with
the CDKs by administering a therapeutically effective amount of at
least one compound of this invention, or a pharmaceutically
acceptable salt or solvate of said compound to the mammal.
[0096] A preferred dosage is about 0.001 to 500 mg/kg of body
weight/day of the compound of this invention. An especially
preferred dosage is about 0.01 to 25 mg/kg of body weight/day of a
compound of this invention, or a pharmaceutically acceptable salt
or solvate of said compound.
[0097] The compounds of this invention may also be useful in
combination (administered together or sequentially) with one or
more of anti-cancer treatments such as radiation therapy, and/or
one or more anti-cancer agents selected from the group consisting
of cytostatic agents, cytotoxic agents (such as for example, but
not limited to, DNA interactive agents (such as cisplatin or
doxorubicin)); taxanes (e.g. taxotere, taxol); topoisomerase II
inhibitors (such as etoposide); topoisomerase I inhibitors (such as
irinotecan (or CPT-11), camptostar, or topotecan); tubulin
interacting agents (such as paclitaxel, docetaxel or the
epothilones); hormonal agents (such as tamoxifen); thymidilate
synthase inhibitors (such as 5-fluorouracil); anti-metabolites
(such as methoxtrexate); alkylating agents (such as temozolomide
(TEMODAR.TM. from Schering-Plough Corporation, Kenilworth, New
Jersey), cyclophosphamide); Farnesyl protein transferase inhibitors
(such as,
SARASAR.TM.(4-[2-[4-[(11R)-3,10-dibromo-8-chloro-6,1'-dihydro-5H-benzo[5,-
6]cyclohepta[1,2-b]pyridin-11-yl-]-1-piperidinyl]-2-oxoethyl]-1-piperidine-
carboxamide, or SCH 66336 from Schering-Plough Corporation,
Kenilworth, New Jersey), tipifarnib (Zarnestra.RTM. or R115777 from
Janssen Pharmaceuticals), L778,123 (a farnesyl protein transferase
inhibitor from Merck & Company, Whitehouse Station, New
Jersey), BMS 214662 (a farnesyl protein transferase inhibitor from
Bristol-Myers Squibb Pharmaceuticals, Princeton, N.J.); signal
transduction inhibitors (such as, Iressa (from Astra Zeneca
Pharmaceuticals, England), Tarceva (EGFR kinase inhibitors),
antibodies to EGFR (e.g., C225), GLEEVEC.TM. (C-abl kinase
inhibitor from Novartis Pharmaceuticals, East Hanover, N.J.);
interferons such as, for example, intron (from Schering-Plough
Corporation), Peg-Intron (from Schering-Plough Corporation);
hormonal therapy combinations; aromatase combinations; ara-C,
adriamycin, cytoxan, and gemcitabine.
[0098] Other anti-cancer (also known as anti-neoplastic) agents
include but are not limited to Uracil mustard, Chlormethine,
Ifosfamide, Melphalan, Chlorambucil, Pipobroman,
Triethylenemelamine, Triethylenethiophosphoramine, Busulfan,
Carmustine, Lomustine, Streptozocin, Dacarbazine, Floxuridine,
Cytarabine, 6-Mercaptopurine, 6-Thioguanine, Fludarabine phosphate,
oxaliplatin, leucovirin, oxaliplatin (ELOXATIN.TM. from
Sanofi-Synthelabo Pharmaceuticals, France), Pentostatine,
Vinblastine, Vincristine, Vindesine, Bleomycin, Dactinomycin,
Daunorubicin, Doxorubicin, Epirubicin, Idarubicin, Mithramycin,
Deoxycoformycin, Mitomycin-C, L-Asparaginase, Teniposide
17.quadrature.-Ethinylestradiol, Diethylstilbestrol, Testosterone,
Prednisone, Fluoxymesterone, Dromostanolone propionate,
Testolactone, Megestrolacetate, Methylprednisolone,
Methyltestosterone, Prednisolone, Triamcinolone, Chlorotrianisene,
Hydroxyprogesterone, Aminoglutethimide, Estramustine,
Medroxyprogesteroneacetate, Leuprolide, Flutamide, Toremifene,
goserelin, Cisplatin, Carboplatin, Hydroxyurea, Amsacrine,
Procarbazine, Mitotane, Mitoxantrone, Levamisole, Navelbene,
Anastrazole, Letrazole, Capecitabine, Reloxafine, Droloxafine, or
Hexamethylmelamine.
[0099] If formulated as a fixed dose, such combination products
employ the compounds of this invention within the dosage range
described herein and the other pharmaceutically active agent or
treatment within its dosage range. For example, the CDC2 inhibitor
olomucine has been found to act synergistically with known
cytotoxic agents in inducing apoptosis (J. Cell Sci., (1995) 108,
2897. Compounds of this invention may also be administered
sequentially with known anticancer or cytotoxic agents when a
combination formulation is inappropriate. The invention is not
limited in the sequence of administration; compounds of this
invention may be administered either prior to or after
administration of the known anticancer or cytotoxic agent. For
example, the cytotoxic activity of the cyclin-dependent kinase
inhibitor flavopiridol is affected by the sequence of
administration with anticancer agents. Cancer Research, (1997) 57,
3375. Such techniques are within the skills of persons skilled in
the art as well as attending physicians.
[0100] Accordingly, in an aspect, this invention includes
combinations comprising an amount of at least one compound of this
invention, or a pharmaceutically acceptable salt or solvate
thereof, and an amount of one or more anti-cancer treatments and
anti-cancer agents listed above wherein the amounts of the
compounds/treatments result in desired therapeutic effect.
[0101] The pharmacological properties of the compounds of this
invention may be confirmed by a number of pharmacological assays.
The exemplified pharmacological assays, which are described later
have been carried out with the compounds according to the invention
and their salts.
[0102] This invention is also directed to pharmaceutical
compositions, which comprise at least one of the compounds of this
invention, or a pharmaceutically acceptable salt or solvate of said
compound and at least one pharmaceutically acceptable carrier.
[0103] For preparing pharmaceutical compositions from the compounds
described by this invention, inert, pharmaceutically acceptable
carriers can be either solid or liquid. Solid form preparations
include powders, tablets, dispersible granules, capsules, cachets
and suppositories. The powders and tablets may be comprised of from
about 5 to about 95 percent active ingredient. Suitable solid
carriers are known in the art, e.g., magnesium carbonate, magnesium
stearate, talc, sugar or lactose. Tablets, powders, cachets and
capsules can be used as solid dosage forms suitable for oral
administration. Examples of pharmaceutically acceptable carriers
and methods of manufacture for various compositions may be found in
A. Gennaro (ed.), Remington's Pharmaceutical Sciences, 18.sup.th
Edition, (1990), Mack Publishing Co., Easton, Pa.
[0104] Liquid form preparations include solutions, suspensions and
emulsions. As an example may be mentioned water or water-propylene
glycol solutions for parenteral injection or addition of sweeteners
and opacifiers for oral solutions, suspensions and emulsions.
Liquid form preparations may also include solutions for intranasal
administration.
[0105] Aerosol preparations suitable for inhalation may include
solutions and solids in powder form, which may be in combination
with a pharmaceutically acceptable carrier, such as an inert
compressed gas, e.g. nitrogen.
[0106] Also included are solid form preparations that are intended
to be converted, shortly before use, to liquid form preparations
for either oral or parenteral administration. Such liquid forms
include solutions, suspensions and emulsions.
[0107] The compounds of the invention may also be deliverable
transdermally. The transdermal compositions can take the form of
creams, lotions, aerosols and/or emulsions and can be included in a
transdermal patch of the matrix or reservoir type as are
conventional in the art for this purpose.
[0108] The compounds of this invention may also be delivered
subcutaneously.
[0109] Preferably the compound is administered orally.
[0110] Preferably, the pharmaceutical preparation is in a unit
dosage form. In such form, the preparation is subdivided into
suitably sized unit doses containing appropriate quantities of the
active component, e.g., an effective amount to achieve the desired
purpose.
[0111] The quantity of active compound in a unit dose of
preparation may be varied or adjusted from about 1 mg to about 100
mg, preferably from about 1 mg to about 50 mg, more preferably from
about 1 mg to about 25 mg, according to the particular
application.
[0112] 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 regimen for a
particular situation is within the skill of the art. For
convenience, the total daily dosage may be divided and administered
in portions during the day as required.
[0113] The amount and frequency of administration of the compounds
of the invention and/or the pharmaceutically acceptable salts
thereof will be regulated according to the judgment of the
attending clinician considering such factors as age, condition and
size of the patient as well as severity of the symptoms being
treated. A typical recommended daily dosage regimen for oral
administration can range from about 1 mg/day to about 500 mg/day,
preferably 1 mg/day to 200 mg/day, in two to four divided
doses.
[0114] Another aspect of this invention is a kit comprising a
therapeutically effective amount of at least one compound of this
invention, or a pharmaceutically acceptable salt or solvate of said
compound and a pharmaceutically acceptable carrier, vehicle or
diluent.
[0115] Yet another aspect of this invention is a kit comprising an
amount of at least one compound of this invention, or a
pharmaceutically acceptable salt or solvate of said compound and an
amount of at least one anticancer therapy and/or anti-cancer agent
listed above, wherein the amounts of the two or more ingredients
result in desired therapeutic effect.
[0116] The invention disclosed herein is exemplified by the
following preparations and examples, which should not be construed
to limit the scope of the disclosure. Alternative mechanistic
pathways and analogous structures will be apparent to those skilled
in the art.
[0117] Where NMR data are presented, .sup.1H spectra were obtained
on either a Varian VXR-200 (200 MHz, .sup.1H), Varian Gemini-300
(300 MHz) or XL-400 (400 MHz) and are reported as ppm down field
from Me.sub.4Si with number of protons, multiplicities, and
coupling constants in Hertz indicated parenthetically. Where LC/MS
data are presented, analyses was performed using an Applied
Biosystems API-100 mass spectrometer and Shimadzu SCL-10A LC
column: Altech platinum C18, 3 micron, 33 mm.times.7 mm ID;
gradient flow: 0 min-10% CH.sub.3CN, 5 min-95% CH.sub.3CN, 7
min-95% CH.sub.3CN, 7.5 min-10% CH.sub.3CN, 9 min-stop. The
retention time and observed parent ion are given.
[0118] The following solvents, reagents, conditions, and techniques
may be referred to by their abbreviations:
Thin layer chromatography: TLC dichloromethane: CH.sub.2Cl.sub.2
ethyl acetate: AcOEt or EtOAc methanol: MeOH trifluoroacetate: TFA
triethylamine: Et.sub.3N or TEA butoxycarbonyl: n-Boc or Boc
nuclear magnetic resonance spectroscopy: NMR liquid chromatography
mass spectrometry: LCMS high resolution mass spectrometry: HRMS
milliliters: mL millimoles: mmol microliters: .mu.l grams: g
milligrams: mg room temperature or rt (ambient): about 25.degree.
C.
[0119] Compounds of this invention can be prepared by known methods
from starting materials either known in the art or prepared by
methods known in the art.
[0120] Compounds of the present invention can be prepared by
several methods. Non-limiting examples of suitable methods are
illustrated in the schemes below.
EXAMPLES
[0121] The compounds of the present invention can be prepared
through the general routes described below.
[0122] Synthesis of pyrazolo[1,5-a]pyridines (Formula III) is
described below in Scheme 1.
##STR00068## ##STR00069##
R is defined above.
[0123] Alternative synthesis of intermediate 2 is illustrated in
Scheme 1a:
##STR00070##
[0124] Generally, one method of preparing a pyrazolo[1,5-a]pyridine
involves combining (1H-Pyrazol-3-yl)-acetonitrile with
2-Benzylidene-malononitrile to form a 7-amino substituted
pyrazolo[1,5-a]pyridine that is further reacted with the
appropriate aldehyde to achieve the target pyrazolo[1,5-a]pyridine
as shown in Schemes 1 and 1a.
[0125] Another method to synthesize a pyrazolo[1,5-a]pyridine is
illustrated in Scheme 1b.
##STR00071## ##STR00072##
[0126] Scheme 1c illustrates an alternative route to intermediate
17, 3-cyano-4-phenyl pyridine.
##STR00073##
[0127] Scheme 1d illustrates a chlorinated form of intermediate 17,
3-cyano-4-phenyl pyridine.
##STR00074##
[0128] An alternative route to target pyrazolo[1,5-a]pyridine is
illustrated in Scheme 1e.
##STR00075## ##STR00076##
[0129] An unsubstituted phenyl pyridine instead of the
3-cyano-4-phenyl pyridine as shown in Schemes 1b-d can be used in
the synthesis of the carbonitrile substituted target
pyrazolo[1,5-a]pyridine. In which case, the cyano group is added
during the last steps of the synthesis by brominating the 4
position then substituting the bromine with a carbonitrile group as
shown in Scheme 1e.
[0130] A 4-methylamino pyrazolo[1,5-a]pyridine derivative is formed
by reducing the 4-cyano group using lithium aluminum hydride as
shown in scheme 1f.
##STR00077##
[0131] Synthesis of other target pyrazolo[1,5-a]pyridine compounds
is illustrated in Scheme 1G.
##STR00078## ##STR00079## ##STR00080##
[0132] Various benzyl derivatives of the target
pyrazolo[1,5-a]pyridine compounds can be prepared by reducing the
3-cyano group of the 3-cyano-4-phenyl pyridine by treating the
compound with lithium aluminum hydride forming the methyl amino
derivative, which is further derivatized as shown in Scheme 1G then
processed using the synthesis described above in Schemes 1b-1d.
[0133] A general, synthesis of imidazo[1,2-a]pyridine (Formula V)
is described below in Scheme 2.
##STR00081## ##STR00082##
[0134] Treatment of the starting 2-amino-5-bromopyridine 86 with
nitric acid and sulfuric acid introduces a nitro group, which is
converted to an amine by a reaction with SnCl.sub.2. Treatment of
this 5-Bromo-4-nitro-pyridin-2-ylamine 90 with
2-Bromo-1,1-diethoxy-ethane 89 in the presence of hydrochloric acid
followed by sodium bicarbonate yields
6-Bromo-imidazo[1,2-a]pyridin-8-ylamine 91. The amino group is
acetylated by treating it with acetyl chloride in the presence of
pyridine, which upon addition of the aromatic boronic acid 93 in
Pd(PPh.sub.3).sub.3, K.sub.3PO.sub.4, and dimethylether-water
furnishes intermediate
N-[6-(2-Chloro-phenyl)-imidazo[1,2-a]pyridin-8-yl]-acetamide 94.
Treatment of compound 94 with NBS gives rise to intermediate
N-[3-Bromo-6-(2-chloro-phenyl)-imidazo[1,2-a]pyridin-8-yl]-acetamide
95, which in the presence of ethanolic hydrochloric acid forms
intermediate
3-Bromo-6-(2-chloro-phenyl)-imidazo[1,2-a]pyridin-8-ylamine 96,
which reacts with the appropriate aldehyde in zinc chloride and
sodium cyanoborohydride to give the desired intermediate amine 97.
Treatment with bromine and acetic acid yields the desired
3,5-Dibromo-6-(2-chloro-phenyl)-imidazo[1,2-a]pyridin-8-ylamine
derivative 98, which is converted to the target compound
8-Amino-3-bromo-6-(2-chloro-phenyl)-imidazo[1,2-a]pyridine-5-carbonitrile
derivative 99.
[0135] An alternative route to synthesize the carbonitrile
derivative of imidazo[1,2-a]pyridine is illustrated in Scheme
2a.
##STR00083##
[0136] Treatment of intermediate
N-[6-(2-Chloro-phenyl)-imidazo[1,2-a]pyridin-8-yl]-acetamide 94
with sodium hydroxide or ethanolic hydrochloric acid converts the
acetamide to its amine, which is then treated with an appropriate
aldehyde in the presence of zinc chloride and
cyanosodiumborohydride giving rise to a derivatized amine
intermediate 102. Intermediate 102 is lithiated and iodated at
position 5 then treated with potassium cyanide to replace the
iodide group with a carbonitrile group in intermediate 104.
Treatment of 104 with NBS yields brominated target compound
8-Amino-3-bromo-6-(2-chloro-phenyl)-imidazo[1,2-a]pyridine-5-carbonitrile
derivative 99.
[0137] A general route to synthesize the amino derivative of
imidazo[1,2-a]pyridine is illustrated in Scheme 2b.
##STR00084##
[0138] The iodated intermediate 103 is converted to an amine by
first treating 103 with benzhydrylideneamine, Pd(OAc).sub.2,
(2,2'-bis(diphenylphosphino)-1,1'-binaphthyl) (BINAP), cesium
carbonate, and toluene to form intermediate 107, which is then
treated with NBS to brominate the imidazo group to form
intermediate 108. Intermediate 108 is converted to the amine by
treatment with ammonia and sodium acetate to yield the amine
derivative of the imidazo[1,2-a]pyridine target compound 109.
[0139] A general route to synthesize the methyl amino derivative of
imidazo[1,2-a]pyridine is illustrated in Scheme 2c.
##STR00085##
[0140] The carbonitrile group of the 8-amino derivative of
imidazo[1,2-a]pyridine-5-carbonitrile is reduced to a methylamino
group using lithium aluminum hydride to yield intermediate 111.
Each of the amino substituents of intermediate 111 are protected
with a tertbutyloxycarbonyl (BOC) protection group by a reaction
with a BOC anhydride reagent. The imidazo ring of the protected
intermediate is brominated with NBS then the compound is
deprotected with sulfuric acid in dioxane to yield target compound
5-aminomethyl-3-bromo-6-(2-chloro-phenyl)-imidazo[1,2-a]pyridine-8-ylamin-
e derivative 114.
[0141] A general, synthesis of imidazo[1,5-a]pyrazine (Formula VI)
is described below in Scheme 3.
##STR00086## ##STR00087##
[0142] Treatment of the commercially available starting compound
3-amino-pyrazine-2-carboxylic acid methyl ester 115 with bromine
provides the 6-bromo derivative of compound 115, which undergoes a
Suzuki coupling reaction by treating compound 115 with an aryl
boronic acid in the presence of the triethyl amine, palladium
diacetate, 1,1-bis(diphenyl-phosphine)ferrocene, dimethyl
formamide, palladium tetra triphenyl phosphate, potassium
phosphate, and benzene forming 3-amino-6-(2
chlorophenyl)-pyrazine-2-carboxylic acid methylester. The methyl
ester is hydrolyzed in aqueous sodium hydroxide leaving the
carboxylic acid 119, which is replaced by a bromine substituent
after treatment with sodium diacetate and bromine in acetic acid it
is combined with 2-bromo-1,1-diethoxy-ethane 121 in aqueous
hydrobromic acid yielding imidopyrazine 122. The imidazo group is
brominated by treatment with NBS in chloroform to yield
intermediate 123. Selective replacement of the bromine with an
amine occurs by treatment of intermediate 123 with ammonium
hydroxide or ammonia in methanol forming intermediate compound 124.
Intermediate 124 is reacted with the appropriate aldehyde in the
presence of zinc chloride followed by cyano sodium borohydride to
give rise to intermediate
3-Bromo-6-(2-chloro-phenyl)-imidazo[1,2-a]pyrazin-8-ylaminederivative
125. Intermediate 125 is further brominated at position 5 by
treatment with bromine in acetic acid to provide intermediate 126.
Intermediate 126 is converted to target compound
8-Aminoderivative-3-bromo-6-(2-chloro-phenyl)-imidazo[1,2-a]pyrazine-5-ca-
rbonitrile 127 after treatment with potassium or copper
cyanide.
[0143] Alternative route to synthesis of intermediate 124 is
illustrated in Scheme 3a.
##STR00088##
[0144] Treatment of compound 122 with benzhydrylideneamine in the
presence of palladium diacetate, BINAP, cesium carbonate, and
toluene yields intermediate 129, which is brominated at its imidazo
ring by treatment with NBS in acetonitrile to yield intermediate
130. Intermediate 130 is aminated by using ammonia in sodium
acetate to form intermediate 124.
[0145] Route to the amino derivative of imidazo[1,5-a]pyrazine is
illustrated in Scheme 3b.
##STR00089##
[0146] Treatment of intermediate 126 with saturated ammonia in
methanol selectively replaces the bromine group of position 5 with
an amino group yielding the target amino substituted
imidazo[1,5-a]pyrazine.
[0147] Route to the methyl amino derivative of
imidazo[1,5-a]pyrazine is illustrated in Scheme 3c.
##STR00090##
[0148] The cyano substituted imidazo[1,5-a]pyrazine 127 is treated
with lithium aluminum hydride which reduces both the carbonitrile
group to the target methyl amino substituted imidazo[1,5-a]pyrazine
and removes the 3-brono groups which is subsequently re-introduced
with NBS to afford 135.
[0149] A general, synthesis of pyrazolo[1,5-c]pyrimidine (Formula
IV) is described below in Scheme 4.
##STR00091## ##STR00092## ##STR00093##
[0150] Combination of the starting Benzyl-hydrazine 136 with
Oxo-acetic acid ethyl ester 137 gives rise to intermediate
(Benzyl-hydrazono)-acetic acid ethyl ester 138, which is
chlorinated by treatment with N-chloromethyl succinamide or
tertiarybutoxy chloride to form intermediate 139. The combination
of Intermediate 139 with vinyl benzene 140 forms the ester
intermediate 1-Benzyl-5-phenyl-4,5-dihydro-1H-pyrazole-3-carboxylic
acid ethyl ester 141. Saponification of the ester intermediate 141
gives rise to intermediate
1-Benzyl-5-phenyl-4,5-dihydro-1H-pyrazole-3-carboxylic acid 142
that gives rise to the cyanoamine intermediate 143 when heated to
high temperatures in anhydrous dimethylformamide. Upon further
reaction of intermediate 143 with diethyl oxalate 144 affords the
intermediate 2,3-dioxo-4-cyanopyrrolidine 145, which forms
intermediate
1-Benzyl-4-hydroxy-5-oxo-2-phenyl-2,5-dihydro-1H-pyrrole-3-carboxylic
acid amide 146 under acidic conditions and an amino group replaces
the OH group forming intermediate
4-Amino-1-benzyl-5-oxo-2-phenyl-2,5-dihydro-1H-pyrrole-3-carboxylic
acid amide 147. Treatment of Intermediate 147 with
dimethylformamide and sodium nitrite forms intermediate
1-Benzyl-4-imino-5-oxo-2-phenyl-4,5-dihydro-1H-pyrrole-3-carboxylic
acid amide 148 and a combination with compound But-2-ynedioic acid
diethyl ester 149 forms an intermediate
7-Benzyl-9-carbamoyl-6-oxo-8-phenyl-1,2,7-triaza-spiro[4.4]nona-1,3,8-tri-
ene-3,4-dicarboxylic acid diethyl ester 150, which converts to
intermediate
6-Benzyl-4-carbamoyl-7-oxo-5-phenyl-6,7-dihydro-pyrazolo[1,5-c]pyrimidine-
-2,3-dicarboxylic acid diethyl ester 151. Reflux of intermediate
151 in the presence of the acid gives rise to intermediate
6-Benzyl-7-oxo-5-phenyl-6,7-dihydro-pyrazolo[1,5-c]pyrimidine-4-carboxyli-
c acid amide 152. Heating formic acid and ammonium ion mixture in
methanol and 10% Pd--C to reflux eliminates the benzyl group
forming intermediate
7-Oxo-5-phenyl-6,7-dihydro-pyrazolo[1,5-c]pyrimidine-4-carboxylic
acid amide 153. Reflux of 153 in phosphorous oxychloride forms
intermediate
7-Chloro-5-phenyl-pyrazolo[1,5-c]pyrimidine-4-carbonitrile 154 and
treatment with the appropriate amine represented as Y--NH.sub.2
results in a substitution of the chloride ion of 154 with the
described amine derivative intermediate 155. Treatment of 155 with
NBS forms target compound 7-Amino
derivative-3-bromo-5-phenyl-pyrazolo[1,5-c]pyrimidine-4-carbonitrile
156.
[0151] A route to the synthesis of a methyl amino
pyrazolo[1,5-c]pyrimidine is described below in Scheme 4a.
##STR00094##
[0152] Treatment of intermediate 157 with lithium aluminum hydride
followed by NBS forms target compound
4-Aminomethyl-3-bromo-5-phenyl-pyrazolo[1,5-c]pyrimidin-7-ylamine
derivative 159.
[0153] A general, synthesis of 2H-indazoles (Formula VII) is
described below in Scheme 5.
##STR00095##
[0154] Reflux of a combination of starting compounds
4-Bromo-2-methyl-6-nitro-phenylamine 160 and aromatic boronic acid
161 in the presence of Pd(Ph.sub.3P).sub.4, K.sub.3PO.sub.4,
Benzene, dimethylformamide gives rise to intermediate
2'-Fluoro-5-methyl-3-nitro-biphenyl-4-ylamine 162. Tricyclic
intermediate 5-(2-Fluoro-phenyl)-7-nitro-2H-indazole 165 is formed
from intermediate 162 by using one of two reactions. One reaction
involves treating intermediate 162 with sodium nitrite, acetic
acid, and hydrochloric acid to form intermediate
N-(2'-Fluoro-5-methyl-3-nitro-biphenyl-4-yl)-hydroxylamine 163 then
refluxing intermediate 163 in benzene to form intermediate 165. The
second reaction involves treating intermediate 162 with HBF.sub.4
and sodium nitrite forming intermediate
2'-Fluoro-5-methyl-3-nitro-biphenyl-4-diazonium.sup.+
BF.sub.4.sup.31 164 then treating intermediate 164 with potassium
acetate and 18-Crown-6 in chloroform to form intermediate 165.
Intermediate 165 is treated with Pd--C in ethanol and hydrogen,
which reduces the nitro substituent of intermediate 165 to an amine
forming intermediate 5-(2-Fluoro-phenyl)-2H-indazol-7-ylamine 166.
Treatment of intermediate 166 with Bu.sub.4NBr.sub.3 (TBATB) and
DMF-H.sub.2O brominated intermediate 166 to form intermediate
4-Bromo-5-(2-fluoro-phenyl)-2H-indazol-7-ylamine 167. The bromine
of intermediate 167 is replaced with a carbonitrile group by
refluxing in coppercyanide in pyridine forming intermediate
7-Amino-5-(2-fluoro-phenyl)-2H-indazole-4-carbonitrile 168.
Reductive alkylation of intermediate 168 is accomplished by
treating intermediate 168 with the appropriate aldehyde in the
presence of zinc chloride and sodium cyano borohydride forming
intermediate 169, which is brominated by treatment with
Bu.sub.4NBr.sub.3 (TBATB) in DMF-H.sub.2O forming target compound
7-Amino-3-bromo-5-(2-fluoro-phenyl)-2H-indazole-4-carbonitrile
derivative 170
[0155] Route to the amino methyl 2H-indazole derivative is
illustrated in Scheme 5a.
##STR00096##
[0156] The carbonitrile group of Intermediate 169 is reduced with
lithium aluminum hydride yielding the methylamino substituent group
of intermediate 171. Intermediate 171 is brominated by treatment
with Bu.sub.4NBr.sub.3 (TBATB) and DMF-H.sub.2O to form target
compound
4-Aminomethyl-3-bromo-5-(2-fluoro-phenyl)-2H-indazol-7-ylamine
172.
[0157] Route to the amino 2H-indazole derivative is illustrated in
Scheme 5b.
##STR00097##
[0158] Intermediate 167 undergoes reductive alkylation to form
compound intermediate 173. The bromine group is replaced with an
amine substitutent by refluxing in ammonia and methanol to form
intermediate 174. The imidazo ring of intermediate 174 is
bromintated by treatment with TBATB and dimethylformamide in water
to form target compound
3-Bromo-5-(2-fluoro-phenyl)-2H-indazole-4,7-diamine derivative
175.
Preparative Examples
Preparative Example 1
##STR00098##
[0159] Step A:
##STR00099##
[0161] A mixture of the starting material prepared as in
WO2004/026877 (640 mg, 2.78 mmol), 3-(aminomethyl)pyridine (360 mg,
3.34 mmol), diisopropylethylamine (3.2 mL), and anhydrous dioxane
(8 mL) was stirred at 90.degree. C. under N.sub.2 for 72 hr. The
solvent was evaporated and the residue was purified by column
chromatography on silica gel with CH.sub.2Cl.sub.2/7N NH.sub.3 in
MeOH (40:1). White solid (720 mg, 86%) was obtained. LCMS:
MH.sup.+=302.
Step B
[0162] A solution of N-bromosuccinimide ("NBS") (424 mg, 2.36 mmol)
in anhydrous
[0163] CH.sub.3CN (20 mL) was added under N.sub.2 to a stirred
solution of the product of Step A (710 mg, 2.36 mmol) in anhydrous
CH.sub.3CN (20 mL) and CH.sub.2Cl.sub.2 (20 mL). The mixture was
stirred at 25.degree. C. for 2 hr and the solvent was then
evaporated. Chromatography on silica gel with EtOAc/MeOH (20:1)
afforded a white solid (710 mg, 79%). LCMS: M.sup.+=380,
M.P.=169-170.degree. C.
##STR00100##
Step C:
[0164] A mixture of the product from Step B (500 mg, 1.31 mmol
mmol), Zn(CN).sub.2 (300 mg, 2.56 mmol),
tris(dibenzylideneacetone)dipalladium (150 mg, 0.16 mmol), and
bis(tri-t-butylphosphine)palladium (150 mg, 0.29 mmol) in anhydrous
DMF (10 mL) was stirred at 140.degree. C. under N.sub.2 for 20 hr.
The solvent was evaporated and the residue was purified by column
chromatography and then by preparative TLC on silica gel with
PhCH.sub.3/MeOH (10:1). A Pale orange solid (9 mg, 2%) was
obtained. LCMS: MH.sup.+=327.
Preparative Example 2
##STR00101##
[0166] A solution of N-bromosuccinimide ("NBS") (2.7 mg, 0.015
mmol) in anhydrous CH.sub.3CN (0.2 mL) was added under N.sub.2 to a
stirred solution of the product from Preparative Example 1, Step C
(5.0 mg, 0.015 mmol) in anhydrous CH.sub.3CN (0.5 mL). The mixture
was stirred at 25.degree. C. for 24 hr and the solvent was then
evaporated. Chromatography on silica gel with PhCH.sub.3/MeOH (7:1)
afforded a colorless solid (3 mg, 48%). LCMS: M.sup.+=405.
Preparative Example 3
##STR00102##
[0167] Step A:
##STR00103##
[0169] Propargyl alcohol (10.0 g, 78 mM) was added under argon to a
stirred solution of 2.0 M Trimethylsilyl diazomethane in hexanes
(89 mL, 178 mM) in anhydrous Et.sub.2O (200 mL). The solution
stirred for 11 days at 25.degree. C. and the solvent then
evaporated. Chromatography on silica gel (30.times.5 cm) with
CH.sub.2Cl.sub.2/MeOH (10:1) afforded the product (3.15 g, 18%).
(Jones, Reuben, JACS, 71, 3994-4000. 1949)
Step B:
##STR00104##
[0171] SOCl.sub.2 (3.45 mL, 47.3 mM) was added to a vigorously
stirring biphasic mixture of (1H-Pyrazol-3-yl)-methanol (2.59 g,
26.4 mM) from Step A in anhydrous CH.sub.2Cl.sub.2 at 0.degree. C.
The mixture was stirred at 0.degree. C. for 0.5 hr and then the
solvent and excess SOCl.sub.2 were evaporated, forming
3-Chloromethyl-1H-pyrazole. The 3-Chloromethyl-1H-pyrazole was used
without purification for Step C. (Jones, Reuben, JACS, 71,
3994-400, 1949)
Step C:
##STR00105##
[0173] To a stirred solution of KCN (15.86 g, 243 mM) in H.sub.2O
(30 mL) at 0.degree. C. was added dropwise over 0.33 hr, a solution
of 3-Chloromethyl-1H-pyrazole (3.08 g, 26.4 mM) from Step B in
absolute EtOH (62 mL). After 2.5 hours, the reaction mixture was
filtered, the solids were washed with absolute EtOH (2.times.50
mL), and the filtrate was evaporated. Chromatography on silica gel
(30.times.5 cm) with CH.sub.2Cl.sub.2/MeOH (97.5:2.5) afforded
(1H-Pyrazol-3-yl)-acetonitrile (1.93 g, 68%). (Jones, Reuben, JACS,
71, 3994-4000, 1949)
Preparative Example 4
##STR00106##
[0175] To a stirred solution of (1H-Pyrazol-3-yl)-acetonitrile (100
mg, 0.93 mM) from Step C of Preparative Example 3, in absolute EtOH
(4.7 mL) at 25.degree. C. was added benzylidene malononitrile (144
mg, 0.93 mM) and piperidine (0.009 mL, 0.09 mM). The mixture then
refluxed for 1.0 hr. The solvent evaporated. Chromatography on
silica gel (60.times.2.5 cm) with CH.sub.2Cl.sub.2 afforded
7-Amino-5-phenyl-pyrazolo[1,5-a]pyridine-4,6-dicarbonitrile (34.6
mg, 14%) LCMS: MH.sup.+=260; HRMS: m/z 260.0938 (MH.sup.+), Calcd.
C.sub.15H.sub.9N.sub.15: m/z 260.0936; .delta..sub.C (DMSO) CH:
99.0, 128.5, 128.5, 128.8, 128.8, 129.8, 145.4; C: 75.4, 86.9,
115.5, 116.0, 134.8, 138.9, 148.1, 149.4.
Preparative example 5
##STR00107##
[0177] To a stirred solution of (1H-Pyrazol-3-yl)-acetonitrile
(1.56 g, 14.5 mM) from Preparative Example 3 Step C in absolute
EtOH (73 mL) at 25.degree. C. was added o-chlorobenzylidene
malononitrile (2.74 g, 14.5 mM) and piperidine (0.14 mL, 1.45 mM).
The mixture then refluxed for 1.75 hr. The solvent evaporated.
Chromatography on silica gel (30.times.5 cm) with CH.sub.2Cl.sub.2
afforded
7-Amino-5-(2-chloro-phenyl)-pyrazolo[1,5-a]pyridine-4,6-dicarbonitrile
(0.62 g, 15%). HRMS: m/z 293.0472 (M.sup.+), Calcd.
C.sub.15H.sub.8N.sub.5Cl.sub.1: m/z 293.0468; .delta..sub.C
(CDCl.sub.3) CH: 99.3, 127.6, 129.6, 130.8, 131.6, 145.5; C: 75.7,
86.9, 114.8, 115.1, 131.5, 133.8, 138.4, 145.6, 149.2.
Preparative Example 6
##STR00108##
[0179] NaH (52 mg, 2 mM) was added to a stirred solution of
7-Amino-5-(2-chloro-phenyl)-pyrazolo[1,5-a]pyridine-4,6-dicarbonitrile
(0.30 g, 1 mM) from Preparative Example 5 in anhydrous DMF (6 mL)
at 25.degree. C. After 0.5 hr, 3-Picolinyl chloride hydrochloride
(167 mg, 1 mM) was added. The mixture was stirred at 25.degree. C.
for 0.5 hr and then at 60.degree. C. for 17 hr. The mixture was
added to CH.sub.2Cl.sub.2 (400 mL) and washed with saturated
NaHCO.sub.3 (60 mL). Chromatography on silica gel (15.times.5 cm)
afforded unreacted starting material (121 mg, 41%) and
5-(2-Chloro-phenyl)-7-[(pyridin-3-ylmethyl)-amino]-pyrazolo[1,5-a]pyridin-
e-4,6-dicarbonitrile 147 mg, 37%). LCMS:
[0180] MH.sup.+=385; HRMS: m/z 385.0967 (MH.sup.+) Calcd.
C.sub.21H.sub.4N.sub.6Cl.sub.1: m/z 385.0968; .delta..sub.C
(CDCl.sub.3) CH.sub.2: 45.5; CH: 100.8, 124.1, 127.5, 130.3, 130.5,
131.7, 135.7, 144.8, 149.4, 150.2; C: 76.6, 91.7, 114.5, 115.8,
133.0, 133.5, 138.4, 146.5, 146.7.
Preparative Example 7
##STR00109##
[0182] N-Bromosuccinimde (64 mg, 0.34 mM) was added to a stirred
solution of Preparative Example
6,5-(2-Chloro-phenyl)-7-[(pyridin-3-ylmethyl)-amino]-pyrazolo[1,5-a]pyrid-
ine-4,6-dicarbonitrile, (140 mg, 0.34 mM) in anhydrous
CH.sub.2Cl.sub.2 (7 mL) and CH.sub.3CN (7 mL) at 25.degree. C. The
mixture stirred at 25.degree. C. for 90 hr. The mixture was
filtered through a medium sintered glass filter and the solid
washed with CH.sub.2Cl.sub.2 (3.times.25 mL). The filtrate was
evaporated and the residue was chromatographed on silica gel
(15.times.2.5 cm) with CH.sub.2Cl.sub.2 and then a 0.5% solution of
(10% NH.sub.4OH in MeOH) in CH.sub.2Cl.sub.2 to afford crude
3-Bromo-5-(2-chloro-phenyl)-7-[(pyridin-3-ylmethyl)-amino]-pyrazolo[1,5-a-
]pyridine-4,6-dicarbonitrile (59.5 mgs). This sample was further
purified by a CH.sub.2Cl.sub.2/saturated aq. NaHCO.sub.3 extraction
and chromatographed on silica gel (15.times.2 cm) with 0.5%
solution of (10% NH.sub.4OH in MeOH) in CH.sub.2Cl.sub.2, followed
by an Et.sub.2O/H.sub.2O extraction, and finally a Prep TLC on four
20.times.20 cm 250 micron silica gel plates developed in 2.0%
solution of (10% NH.sub.4OH in MeOH) in CH.sub.2Cl.sub.2. This
afforded
3-Bromo-5-(2-chloro-phenyl)-7-[(pyridin-3-ylmethyl)-amino]-pyrazolo[1,5-a-
]pyridine-4,6-dicarbonitrile. LCMS: MH.sup.+=465; .delta..sub.c
(DMSO)CH.sub.2: 43.7; CH: 123.5, 127.6, 129.6, 130.7, 131.7, 134.8,
145.6, 147.7, 148.0; C: 75.9, 86.3, 87.7, 113.4, 115.6, 131.5,
133.3, 133.7, 147.0, 148.6.
Example 1
Step A
##STR00110##
[0184] A mixture of the starting material prepared as in
WO2004/026877 (640 mg, 2.78 mmol), 3-(aminomethyl)pyridine (360 mg,
3.34 mmol), diisopropylethylamine (3.2 mL), and anhydrous dioxane
(8 mL) was stirred at 90.degree. C. under N.sub.2 for 72 hr. The
solvent was evaporated and the residue was purified by column
chromatography on silica gel with CH.sub.2Cl.sub.2/7N NH.sub.3 in
MeOH (40:1). White solid (720 mg, 86%) was obtained. LCMS:
MH.sup.+=302.
Step B
[0185] A solution of N-bromosuccinimide ("NBS") (424 mg, 2.36 mmol)
in anhydrous CH.sub.3CN (20 mL) was added under N.sub.2 to a
stirred solution of the starting material from Step A (710 mg, 2.36
mmol) in anhydrous CH.sub.3CN (20 mL) and CH.sub.2Cl.sub.2 (20 mL).
The mixture was stirred at 25.degree. C. for 2 hr and the solvent
was then evaporated. Chromatography on silica gel with EtOAc/MeOH
(20:1) afforded white solid (710 mg, 79%). LCMS: M.sup.+380,
M.P.=169-170.degree. C.
Step C
##STR00111##
[0187] A mixture of the product from Step B (500 mg, 1.31 mmol
mmol), Zn(CN).sub.2 (300 mg, 2.56 mmol),
tris(dibenzylideneacetone)dipalladium (150 mg, 0.16 mmol), and
bis(tri-t-butylphosphine)palladium (150 mg, 0.29 mmol) in anhydrous
DMF (10 mL) was stirred at 140.degree. C. under N.sub.2 for 20 hr.
The solvent was evaporated and the residue was purified by column
chromatography and then by preparative TLC on silica gel with
PhCH.sub.3/MeOH (10:1). Pale orange solid (9 mg, 2%) was obtained.
LCMS: MH.sup.+=327.
Examples 2-6
[0188] The compounds of column 4 shown in Table 2 are prepared by
essentially the same procedure set forth in Example 1, only
substituting the compound shown in Column 2 and the amine shown in
column 3. The cyano substituent of the products shown in column 4
are reduced to a methylamino group as shown in column 5 using
lithium aluminum anhydride as illustrated in scheme if above.
Example 6 is the product of Example 1 that also has been reduced in
lithium aluminum anhydride.
TABLE-US-00002 TABLE 2 Example Column 2 Column 3 Column 4 Column 5
2 ##STR00112## ##STR00113## ##STR00114## ##STR00115## 3
##STR00116## ##STR00117## ##STR00118## ##STR00119## 4 ##STR00120##
##STR00121## ##STR00122## ##STR00123## 5 ##STR00124## ##STR00125##
##STR00126## ##STR00127## 6 ##STR00128## ##STR00129##
Example 7
##STR00130##
[0190] A solution of N-bromosuccinimide ("NBS") (2.7 mg, 0.015
mmol) in anhydrous CH.sub.3CN (0.2 mL) was added under N.sub.2 to a
stirred solution of the product from Preparative Example 1, Step C
(5.0 mg, 0.015 mmol) in anhydrous CH.sub.3CN (0.5 mL). The mixture
was stirred at 25.degree. C. for 24 hr and the solvent was then
evaporated. Chromatography on silica gel with PhCH.sub.3/MeOH (7:1)
afforded a colorless solid (3 mg, 48%). LCMS: M.sup.+=405.
Examples 8-11
[0191] The compounds of column 3 shown in Table 3 are prepared by
essentially the same procedure set forth in Example 7, only
substituting the compound shown in Column 2. Again, the cyano
substituent of the products shown in column 3 are reduced to a
methylamino group as shown in column 4 using lithium aluminum
anhydride as illustrated in scheme if above. Example 11 is the
methylamino substituted version of Example 7 above:
TABLE-US-00003 TABLE 3 Examples Column 2 Column 3 Column 4 8
##STR00131## ##STR00132## ##STR00133## 9 ##STR00134## ##STR00135##
##STR00136## 10 ##STR00137## ##STR00138## ##STR00139## 11
##STR00140##
Example 12
##STR00141##
[0193] To a stirred solution of (1H-Pyrazol-3-yl)-acetonitrile (100
mg, 0.93 mM) in absolute EtOH (4.7 mL) at 25.degree. C. was added
benzylidene malononitrile (144 mg, 0.93 mM) and piperidine (0.009
mL, 0.09 mM). The mixture then refluxed for 1.0 hr. The solvent
evaporated. Chromatography done on silica gel (60.times.2.5 cm)
with CH.sub.2Cl.sub.2 afforded
7-Amino-5-phenyl-pyrazolo[1,5-a]pyridine-4,6-dicarbonitrile (34.6
mg, 14%) LCMS: MH.sup.+=260; HRMS: m/z 260.0938 (MH.sup.+), Calcd.
C.sub.15H.sub.9N.sub.5: m/z 260.0936; .delta..sub.C (DMSO) CH:
99.0, 128.5, 128.5, 128.8, 128.8, 129.8, 145.4; C: 75.4, 86.9,
115.5, 116.0, 134.8, 138.9, 148.1, 149.4.
Example 13
##STR00142##
[0195] Boc-anhydride and NaOH was added to the product of Example
12 in order to protect its amine as an N-Boc derivative. A solution
of N-bromosuccinimide ("NBS") in anhydrous CH.sub.3CN is added and
stirred under N.sub.2 in anhydrous CH.sub.3CN. The mixture is
stirred at 25.degree. C. for 24 hr and the solvent is then
evaporated. The Boc group may be removed from the amine by stirring
with sulfuric acid in dioxane to yield the product
7-Amino-5-phenyl-pyrazolo[1,5-a]pyridine-4,6-dicarbonitrile.
Examples 14-20
[0196] The free amine of the product of Example 13 is stirred in
the presence of ZnCl.sub.2 and NaBH.sub.3CN with the appropriate
aldehyde as shown in Column 2 of Table 4 below to produce the
various amino derivatives illustrated in column 3:
TABLE-US-00004 TABLE 4 Examples: Column 2 Column 3 14 ##STR00143##
##STR00144## 15 ##STR00145## ##STR00146## 16 ##STR00147##
##STR00148## 17 ##STR00149## ##STR00150## 18 ##STR00151##
##STR00152## 19 ##STR00153## ##STR00154## 20 ##STR00155##
##STR00156##
Example 21-27
[0197] The amine derivatives of the compounds of this invention are
prepared by following a series of reactions in the order described
below. The starting material is the same as that of Scheme 2 above
(compound 86). The series of reactions illustrated in Scheme 2 from
compound 86 to compound 94 are followed. Next, compound 94 is used
according to the series of reactions illustrated in Scheme 2a,
beginning with compound 94 to compound 103. Finally, compound 103
is used according to the series of reactions illustrated in Scheme
2b. The series of reactions of Scheme 2b are also illustrated and
described below:
##STR00157##
[0198] The iodated intermediate is converted to an amine by first
treating it with benzhydrylideneamine, Pd(OAc).sub.2,
(2,2'-bis(diphenylphosphino)-1,1'-binaphthyl) (BINAP), cesium
carbonate, and toluene to form the 5,8-diamine intermediate, which
is then treated with NBS to brominate the imidazo group. The
brominated 5,8-diamine intermediate is converted to the amine by
treatment with NH.sub.2OH and NaOAc to yield the amine derivative
of the imidazo[1,2-a]pyridine target compounds.
[0199] Alternatively, the amine derivatives are formed by following
essentially the same procedure described in Scheme 3b wherein
intermediates that correspond to intermediate 126 for each compound
of this invention are treated with saturated ammonia in methanol,
which selectively replaces the bromine group with an amino group
yielding the target amino substituted compound as illustrated
below:
##STR00158##
[0200] Some representative examples are illustrated in column 2 of
Table 5 below:
TABLE-US-00005 TABLE 5 Examples Column 2 21 ##STR00159## 22
##STR00160## 23 ##STR00161## 24 ##STR00162## 25 ##STR00163## 26
##STR00164## 27 ##STR00165##
ASSAY: The assay on the compounds of the present invention may be
performed as follows.
[0201] BACULOVIRUS CONSTRUCTIONS: Cyclin E is cloned into pVL1393
(Pharmingen, La Jolla, Calif.) by PCR, with the addition of 5
histidine residues at the amino-terminal end to allow purification
on nickel resin. The expressed protein is approximately 45 kDa.
CDK2 is cloned into pVL1393 by PCR, with the addition of a
haemaglutinin epitope tag at the carboxy-terminal end (YDVPDYAS).
The expressed protein is approximately 34 kDa in size.
[0202] ENZYME PRODUCTION: Recombinant baculoviruses expressing
cyclin E and CDK2 are co-infected into SF9 cells at an equal
multiplicity of infection (MOI=5), for 48 hrs. Cells are harvested
by centrifugation at 1000 RPM for 10 minutes, then pellets lysed on
ice for 30 minutes in five times the pellet volume of lysis buffer
containing 50 mM Tris pH 8.0, 150 mM NaCl, 1% NP40, 1 mM DTT and
protease inhibitors (Roche Diagnostics GmbH, Mannheim, Germany).
Lysates are spun down at 15000 RPM for 10 minutes and the
supernatant retained. 5 ml of nickel beads (for one liter of SF9
cells) are washed three times in lysis buffer (Qiagen GmbH,
Germany). Imidazole is added to the baculovirus supernatant to a
final concentration of 20 mM, then incubated with the nickel beads
for 45 minutes at 4.degree. C. Proteins are eluted with lysis
buffer containing 250 mM imidazole. Eluate is dialyzed overnight in
2 liters of kinase buffer containing 50 mM Tris pH 8.0, 1 mM DTT,
10 mM MgCl.sub.2, 100 uM sodium orthovanadate and 20% glycerol.
Enzyme is stored in aliquots at -70.degree. C.
[0203] IN VITRO KINASE ASSAY: Cyclin E/CDK2 kinase assays are
performed in low protein binding 96-well plates (Corning Inc,
Corning, N.Y.). Enzyme is diluted to a final concentration of 50
.quadrature.g/ml in kinase buffer containing 50 mM Tris pH 8.0, 10
mM MgCl.sub.2,1 mM DTT, and 0.1 mM sodium orthovanadate. The
substrate used in these reactions is a biotinylated peptide derived
from Histone H1 (from Amersham, UK). The substrate is thawed on ice
and diluted to 2 .mu.M in kinase buffer. Compounds are diluted in
10% DMSO to desirable concentrations. For each kinase reaction, 20
.mu.l of the 50 .mu.g/ml enzyme solution (1 .quadrature.g of
enzyme) and 20 .mu.l of the 2 .mu.M substrate solution are mixed,
then combined with 10 .mu.l of diluted compound in each well for
testing. The kinase reaction is started by addition of 50 .mu.l of
2 .mu.M ATP and 0.1 .mu.Ci of 33P-ATP (from Amersham, UK). The
reaction is allowed to run for 1 hour at room temperature. The
reaction is stopped by adding 200 .mu.l of stop buffer containing
0.1% Triton X-100, 1 mM ATP, 5 mM EDTA, and 5 mg/ml streptavidine
coated SPA beads (from Amersham, UK) for 15 minutes. The SPA beads
are then captured onto a 96-well GF/B filter plate (Packard/Perkin
Elmer Life Sciences) using a Filtermate universal harvester
(Packard/Perkin Elmer Life Sciences.). Non-specific signals are
eliminated by washing the beads twice with 2M NaCl then twice with
2 M NaCl with 1% phosphoric acid. The radioactive signal is then
measured using a TopCount 96 well liquid scintillation counter
(from Packard/Perkin Elmer Life Sciences).
[0204] IC.sub.50 DETERMINATION: Dose-response curves are be plotted
from inhibition data generated, each in duplicate, from 8 point
serial dilutions of inhibitory compounds. Concentration of compound
is plotted against % kinase activity, calculated by CPM of treated
samples divided by CPM of untreated samples. To generate IC.sub.50
values, the dose-response curves are then fitted to a standard
sigmoidal curve and IC.sub.50 values are derived by nonlinear
regression analysis.
[0205] While the present invention has been described with in
conjunction with the specific embodiments set forth above, many
alternatives, modifications and other variations thereof will be
apparent to those of ordinary skill in the art. All such
alternatives, modifications and variations are intended to fall
within the spirit and scope of the present invention.
* * * * *