CA2706946A1

CA2706946A1 - 2-fluoropyrazolo[1,5-a]pyrimidines as protein kinase inhibitors

Info

Publication number: CA2706946A1
Application number: CA2706946A
Authority: CA
Inventors: Kamil Paruch; Timothy J. Guzi; Michael P. Dwyer
Original assignee: Individual
Current assignee: Merck Sharp and Dohme LLC
Priority date: 2007-11-28
Filing date: 2008-11-25
Publication date: 2009-06-04
Also published as: EP2225247A1; JP2011504931A; CN101970440A; WO2009070567A1; MX2010005950A

Abstract

Pyrazolo[1,5-a]pyrimidine-based inhibitors of various kinase, compositions including the inhibitors, and methods of using the inhibitors and inhibitor compositions are described. The inhibitors and compositions that contain such inhibitors are useful for treating disease or disease symptoms. The invention also provides for methods of making or CHK-1 inhibitor compounds, methods of inhibiting CDK-2 or CHK-1, and methods for treating disease or disease symptoms.

Description

The present invention relates to novel pyrazolo 1,5-a]pyrimidine 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. The compounds disclosed herein are especially useful as cyclin dependent kinase inhibitors, such as, for example, CDK-1 and CDK-2 inhibitors and Checkpoint inhibitors such as CHK-1 inhibitors.

BACKGROUND OF THE INVENTION
Cell growth and differentiation is a highly controlled process which, when lost, can lead to aberrant cell function, often resulting in a disease state.
Protein phosphorylation is one of the main post translational mechanisms used to control cellular function. Protein kinases catalyze the phosphorylation of serine, threonine and tyrosine residues using either ATP or GTP. An analysis of the human genome has revealed that there are predicted to be - 500 protein kinases (Manning G., Whyte D.B., Martinez R., Hunter T., Sudarsanam S., Science 298, 1912, 2002; Kostich M, English J, Madison V, Gheyas F, Wang L, Qiu P, Greene J, Laz TM., Genome Biol, 3(9), 2002). When phosphorylation regulation by these kinases is lost, a number of diseases may occur, including diabetes, Alzheimer's, inflammation, and cancer (Cohen P., Eur. J. Biochem. 268, 5001-5010, 2001; Cohen P., Nat, Rev. Drug Discovery 1, 309-315, 2002.) g iyk~ `ijfe ..e uÃar si ca ..,l .k ,11 T. '~`'. ~ : ''. `+rr_ :fin a d apop-..
., ..,"Cdr key rll cycle, which division by regulating passage through the G1, S. G2, and M phases of DNA
synthesis and mitosis. Protein kinase inhibitors, regulators or modulators, alter the function of kinases such as cyclin-dependent kinases (CDKs), mitogen activated protein kinase `'. , K ERK , d an s ithase ;ri se 3 '3SK. r a' ..J : -.,':pc f } . `., .,,rHK

Aurora C etc), and the like. Examples of protein kinase inhibitors are described in W002/22610 Al and by Y. Mettey et al in J. Med. Chem., (2003) 46 222-236.
Progression through the eukaryotic cell cycle is controlled by the cyclin dependent kinase (CDK) family of kinases. CDKs are primarily serine/threonine kinases and they bind to several different regulatory subunits called cyclins.
Different CDKfcyclin heterodimers regulate a variety of processes in the cell cycle, thus, it is believed that CDK4/cyclin D and CDK2/cyclin E regulate control through G1 into the onset of the S phase. The down regulation of cyclin D and cyclin E and the up regulation of cyclin A to form heterodimers with CDK2 and CDK1 promotes passage through the S-phase into G2. Finally, activated complexes of CDK1 (Cdc2)/cyclin B
and possibly CDK1 (Cdc2)/cyclin A are thought to promote the transition from G2 into the M-phase. (reviewed by Murray A., Cell 116, 221-234, 2004). Some of the known substrates for the CDKs are the tumor suppressor retinoblastoma protein (RB) and related family members p107 and p130 (Grana X., Garriga J., and Mayol X., Oncogene 17, 3365-3383, 1998). Phosphorylation of RB by CDK4 or CDK2 induces the release of E2F transcription factors which in turn promote the expression of regulatory proteins to stimulate cell cycle progression and cell growth. In human tumors, the control of the RB function has been observed to be disrupted through mutation of the RB gene, CDK4 amplification, cyclin D and cyclin E over expression, inactivation of the CDK4 specific protein inhibitor p16lNK4A and a disruption in the level of the CDK inhibitor p27KIP1 (Sherr, C., Roberts J., Genes Dev. 13, 1501-1512, 1999; Hall M., Peters G., Adv. Cancer Res. 68, 67-108, 1996; Stewart T., Wesfall M., Pietenpol J., Trends Pharmacol. Sci. 24, 139-145, 2003). These functional disruptions are believed to contribute to the development of breast, colon, gastric, prostate, nonsr all cell lure;, ovarian and other human cancers (Tsihiias J., Kapusta .., Slingcri4t -:d J. i . Rev. Med. 50, 401-423, 1999; Lloyd R., Erickson L., Jin L., Kulig E., Qian X., Cheville J., Scheithauser B., Am. J. Patrol. 154(4), 313-323, 1999).
The fact that uncontrolled regulation of the cell cycle pathway is thought to be a source of human cancers leads one to believe that inhibition of unregulated CDK
o ld be r<latment of cancers. A
u lar6 nun, r- torts have bee sward developing CDK c AT ~. t ,, e in out only a few r-.. / .j ales have progressed into human clinical trials. These include flavopiridol, roscovitine (CYC-202) and the 2-aminothiazole derivative BMS-387032 (Zhai, S., Senderowicz A., Sausville E., Figg W., Ann. Pharmacother. 36, 905-911, 2002; McClue S., Blake D., Clarke R., Cummings L., Fischer P., MacKenzie M., Stewart K., Wang S., Zhelev N., Zheleva D., Lane D., Int. J. Cancer 102(5), 463-468, 2002; Misra R., et al., J.Med. Chem.
47, 1719-1728, 2004) Another series of protein kinases are those that play an important role as a checkpoint in cell cycle progression. Checkpoints prevent cell cycle progression at inappropriate times, such as in response to DNA damage, and maintain the metabolic balance of cells while the cell is arrested, and in some instances can induce apoptosis (programmed cell death) when the requirements of the checkpoint have not been met.
Checkpoint control can occur in the G1 phase (prior to DNA synthesis) and in G2, prior to entry into mitosis.
One series of checkpoints monitors the integrity of the genome and, upon sensing DNA damage, these "DNA damage checkpoints" block cell cycle progression in G1 & G2 phases, and slow progression through S phase. This action enables DNA
repair processes to complete their tasks before replication of the genome and subsequent separation of this genetic material into new daughter cells takes place.
Inactivation of CHK1 has been shown to transduce signals from the DNA-damage sensory complex to inhibit activation of the cyclin B/Cdc2 kinase, which promotes mitotic entry, and abrogate G₂ arrest induced by DNA damage inflicted by either anticancer agents or endogenous DNA damage, as well as result in preferential killing of the resulting checkpoint defective cells. See, e.g., Peng et al., Science, 277, 1501-1505 (1997); Sanchez et al., Science, 277, 1497-1501 (1997), Nurse, Cell 91.

867 (1997); Kleinert, Science. 277, 1450-1451 (1997), Walworth et al,, "tip, 363, 368-371 (1993); and Al-Khodairy et al., lolec, BO L Cell., 5, 147-160 (1994).
Selective manipulation of checkpoint control in cancer cells could afford broad utilization in cancer chemotherapeutic and radiotherapy regimens and may, in addition, offer a common hallmark of human cancer "genomic instability" #o be t s~ ~.r born of cancer cells, A n .. f place CHR1 l"A ge cft: ., ., 6troi. The - of 1 of 1 . _.. d k, ;c., as CDDS1/CHK2, a kinase recently discovered to cooperate with CHK1 in regulating S phase progression (see Zeng et al., Nature, 395, 547-510 (1998); Matsuoka, Science, 282, 1893-(1998)), could provide valuable new therapeutic entities for the treatment of cancer.
There is a need to develop CDK and CHK1 inhibitors for the treatment of human diseases, therefore, it is an objective of this invention to describe compounds that would be useful for the prevention or alteration of these diseases.

SUMMARY OF THE INVENTION
The invention relates to novel compounds and compositions containing those compounds as well as methods of using the compounds. The compounds are heterocyclic molecules that are useful in therapeutic applications, including modulation of disease or disease symptoms in a subject (for example, cat, dog, horse, or human).
These diseases include Alzheimer's disease, cancer, diabetes, and inflammation. The compounds (including stereoisomers thereof) are synthesized either singly or in a combinatorial fashion to give structurally and stereochemically diverse libraries of compounds.
In certain embodiments, the compounds are fluoro substituted pyrazolo pyrimidine compounds. In one embodiment, provided herein are compounds of formula (I):

Ni R
F-- Ir N,N R' Formula (I) or a pharraceuticafy acceptable sa't, solvate or ester thereof, wherein.
R`' is hydrogen, alkyl, cycioa k yl, cycienyl, alkynyl, trifluroalkyl, difluroalkyl, monofluroalkyl, heterocyclyl, heterocyclenyl, aryl, heteroaryl, halo, cyano, _0_ trihaloalkyl, NR8R9, COO, CONR8R9, -OR8, -SR8, -S02R9, -S02NR8R9, -NR8S02R9, -NR8COR9, or NR8CONR8R9, wherein each of said alkyl, cycloalkyl, cyclenyl, alkynyl, trif ... ' f , 4 Ik 3 :tern -.. .... qa ..,.$ from ~gp~ the - _C.,.. _.[.. ~..~_ -eleroad the 1, 121 I rc ry alkenyl, cyclenyl, heterocyclenyl, halo, trihaloalkyl, alkoxyl, hydroxyalkyl, trihaloalkoxyl and CN;
R5 and R7 are each selected from the group consisting of hydrogen, alkyl, aminoalkyl, alkenyl, alkenyl, aryl, heterocyclyl, heterocyclenyl, cycloalkyl, cyclenyl, 5 cycloalkylalkyl, cyclenylalkyl, cycloalkylalkenyl, cyclenylalkenyl, heteroaryl, heteroarylalkyl, heteroarylalkenyl, arylalkyl, arylalkenyl, heterocyclylalkyl, heterocycle nylalkyl, heterocyclylalkenyl, heterocyclenylalkenyl, -S-heterocyclyl, -S-aminoalkyl, -S-heterocyclenyl, NR8R9, NRBCOR9, NR"SO2R9, CORI, C02R8, CONRIR9, CH2OR8, ORI, SR8, and S02R8, wherein each of said alkyl, alkenyl, alkynyl, aryl, heterocyclyl, heterocyclenyl, cycloalkyl, cyclenyl, cycl'oalkylalkyl, cyclenylalkyl, cycloalkylalkenyl, cyclenylalkenyl, heteroaryl, heteroarylalkyl, heteroarylalkenyl, arylalkyl, arylalkenyl, heterocyclylalkyl, heterocyclenylalkyl, heterocyclylalkenyl, heterocyclenylaikenyl, -S-heterocyclyl and -S-heterocyclenyl can be unsubstituted or substituted with at least one moiety, which can be the same or different, independently selected from the group consisting of halogen, alkyl, trihaloalkyl, alkenyl, dihaloalkyl, monohaloalkyl, hydroxyalkyl, ORB, -0, NR8R9, SRI, S02R9, CN, S02NR"R9, and NO2;
R6 is hydrogen, halo, trihaloalkyl, alkyl, alkenyl, aryl, cyclenyl, cycloalkyl, heteroaryl, heterocyclenyl, heterocyclyl, heteroarylalkyl, heterocycle nylalkyl, heterocyclyfalkyl, arylalkyl, cyclenylalkyl, cyclylalkyl, NRIR9, NRICOR9, NR8S02R9, COR8, C02R8, CONR8R9, CH2OR8, ORI, SR8, or S02R8, wherein each of said alkyl, alkenyl, aryl, cyclenyl, cycloalkyl, heteroaryl, heterocyclenyl, heterocyclyl, heteroarylalkyl, heterocycienylalkyl, heterocyclylalkyl, arylalkyl, cycienylalkyl, and cyclylalkyl can be unsubstiuted or substituted with one or more moieties independently 2.5 selected from the group consisting of halogen, alkyl, OR8, CN, 02R , CONRIR9, -SR8, S021 8, S02N1 8R5, NO2, NR8S02R~, NRBCORJ, and NRBCONR8R9;
R8 and R9 are each independently selected from the group consisting of hydrogen, trihaloalkyl, dihaloalkyl, monohaloalkyl, alkyl, alkenyl, aryl, heteroar yl, yi, he c. _ c er AR , dies ~.e ji, fr eter'6ocyc c F`Y k :. eterc4.. Y -`C-l F'ke `.)$;
and he eroarylalkyl..r. va ch of said K r , uikenyl, aryl, heteroaryl, arylalkyl, cycloalkyl, cyclenyl, cycloalkylalkyl, cyclenylalkyl, cyclenylalkenyl, heterocyclenyl, heterocyclyl, heterocycle nylalkyl, heterocyclenylalkenyl, heterocyclylalkyl, and heteroarylalkyl can be unsubstituted or substituted with at least one moiety, which can be the same or different, independently selected from the group consisting of halo, alkyl, cycloalkyl, cyclenyl, aryl, heterocyclyl, heterocyclenyl, heteroaryl, trihaloalkyl, CN, hydroxyl, alkoxyl and NO2.
Pharmaceutical compositions formulated for administration by an appropriate route and means containing effective concentrations of one or more of the compounds provided herein, or pharmaceutically acceptable derivatives thereof, that deliver amounts effective for the treatment, prevention, or amelioration of one or more symptoms of diseases or disorders that are modulated or otherwise affected by CDK-2 or CHK-1, are also provided. The effective amounts and concentrations are effective for ameliorating any of the symptoms of any of the diseases or disorders.
Methods of treatment, prevention, or amelioration of one or more symptoms of a disease or disorder that is modulated or otherwise affected by CDK-2 or CHK-1 is implicated, are provided. Such methods include methods of treatment, prevention and amelioration of one or more symptoms of inflammatory disease, neurodegenerative disease, cancer and diabetes using one or more of the compounds provided herein, or pharmaceutically acceptable derivatives thereof. Non-limiting examples of inflammatory disease are acute pancreatitis, chronic pancreatitis, asthma, allergies, and adult respiratory distress syndrome. Non-limiting examples of neurodegenerative disease are acute Alzheimer's disease, Parkinson's disease, cerebral ischemia, and other neurodegenerative diseases. Non-limiting examples of the diabetes are diabetes mellitus and diabetes insipidus, eg., type I diabetes and type 2 diabetes.
F 4 practicing the methods, effective C : r is of the ,car comb _ coruL li "i r g therapeutically effective concentrations of the compounds, which are formulated for systemic delivery, including parenteral, oral, or intravenous delivery, or for local or topical application, for the treatment of CDK-2 or CHK-1 mediated diseases or disorders, including, but not iii,mited to, inflammatory diseases, acute ancreatitis; cfri pancreatitis, E. 't' ~. c? v i u e. t1 disease, P ! son's .-di"- l .~ f i .., :r 5 JC ,~ p di , type 1 diabetes, type 2 diabetes, breast cancer, stomach cancer, cancer of the ovaries, cancer of the colon, lung cancer, brain cancer, cancer of the larynx, cancer of the lymphatic system, cancer of the Benito-urinary tract including the bladder and the prostate, bone cancer and cancer of the pancreas, are administered to an individual exhibiting the symptoms of these diseases or disorders.
The amounts are effective to ameliorate or eliminate one or more symptoms of the diseases or disorders.
Articles of manufacture containing packaging material, a compound or composition, or pharmaceutically acceptable derivative thereof, provided herein, which is effective for modulating the activity of CDK-2 or CHK-1, mediated diseases or disorders are provided, within the packaging material, and a label that indicates that the compound or composition, or pharmaceutically acceptable derivative thereof, is used for modulating the activity of CDK-2 or CHK-1, mediated diseases or disorders, are provided.
The compounds according to the invention can have pharmacological properties; in particular, the compounds of Formula I can be inhibitors of protein kinases such as, for example, CDK1, CDK2, CDK3, CDK4, CDK5, CDK6 and CDK7, CDK8, mitogen activated protein kinase (MAPKIERK), glycogen synthase kinase 3 (GSK3beta), Pim-1 kinases, Chk kinases (such as Chk1 and Chk2), tyrosine kinases, such as the HER subfamily (including, for example, EGFR (HER1), HER2, HER3 and HER4), the insulin subfamily (including, for example, INS-R, IGF-IR, IR, and IR-R), the PDGF subfamily (including, for example, PDGF-alpha and beta receptors, CSFIR, s-kit and FLK-II), the FLK family (including, for example, kinase insert domain receptor (KDR), fetal liver kinase-1 (FLK-1), fetal liver kinase-4 (FLK-4) and the fms-like tyrosine kinase- $ (fit-1)), non-receptor protein tyrosine kinases, for exE F- e g_ CK, Src, Frk, Btk, CSK, Lfap70, Fes/Fps, Fak, Jak, Ack, and LIMK, growth factor receptor tyrosine kinases such as VEGF-R2, FGF-R, TEK, Akt kinases, Aurora kinases (Aurora A, Aurora B, Aurora C) and the like.
The novel compounds of Formula I are expected to be useful in the therapy of uch a ves, fungal ti-p,oliferative (e.g. ,.~ r retinopat~ ,,), 9lopec :ar iiov ,s Disease.

Many of these diseases and disorders are listed in U.B. 5,413,974 cited earlier, the disclosure of which is incorporated herein.
More specifically, the compounds of Formula I 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; 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;
hematopoietic tumors of myeloid lineage, including acute and chronic myelogenous leukemias, myelodysplastic syndrome and promyelocytic leukemia;
tumors of mesenchymal origin, including fibrosarcoma and rhabdomyosarcoma;
tumors of the central and peripheral nervous system, including astrocytoma, neuroblastoma, glioma and schwannomas; and other tumors, including melanoma, seminoma, teratocarcinoma, osteosarcoma, xenoderoma pigmentosum, keratoctanthoma, thyroid follicular cancer and Kaposi's sarcoma.
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-fi.bromatosis, atherosclerosis, pulmonary fibrosis, arthritis, psoriasis, glomerulonephritis, restenosis following angioplasty or vascular surgery, hyper r ) , '-scar format ^r.
bowel disease, transplantation rejection, endotoxc shock, and fungal infection s.
Compounds of Formula l can 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).
mula l m~ uia.
Th, ~ k c Se:_ .
Cc, - : c u nds of F as r #, . be uuse" ~.., .: .. , ; : 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.
Compounds of Formula 1, 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).
Compounds of Formula I 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.
Compounds of Formula I may also be useful in inhibiting tumor angiogenesis and metastasis.
Cor-, Fo ids of Formula I 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, P13 kinase, weel kinase, Src; Abl and thus be effective in the treatment of diseases associated with other protein kinases, Thu , . 8 a method of treating a m ff -A k human) ring OD.; CHK-1 by a air :}U~ compound of Formula I, or a pharmaceutically acceptable salt or solvate of said compound to the mammal.
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 5 according to the invention and their salts.
This invention is also directed to pharmaceutical compositions which comprise at least one compound of Formula 1, or a pharmaceutically acceptable salt or solvate of said compound and at least one pharmaceutically acceptable carrier.

A. Definitions Unless defined otherwise, all technical and scientific terms used herein have the same meaning as is commonly understood by one of ordinary skill in the art to which this invention belongs. All patents, applications, published applications and other publications are incorporated by reference in their entirety. In the event that there are a plurality of definitions for a term herein, those in this section prevail unless stated otherwise.
As used above, and throughout this disclosure, the following terms, unless otherwise indicated, shall be understood to have the following meanings:
"Patient" includes both human and animals.
"Mammal" means humans and other mammalian animals, "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 to about 12 carbon atoms in the chain. More preferred alkyl groups about 1 to about 3 cart vi 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. "Alkyl" may be unsubstituted or ;_ tiona!ly substituted by one c sub ; =. nick h- the same or ¾i b; sE, each substit ue t being independe4 / ;a led from tie group < -sisting of halo, alkyl, aryl cycf .,:~:J . -:vano, hydroxv, ~.Yy, alkylthio, amino, 1 ., g NH(cycloalkyl), -N(alkyl)2: carboxy and -C(O)O-alkyl. Non-limiting examples of suitable alkyl groups include methyl, ethyl, n-propyl, isopropyl and t-butyl.
"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 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 alkenyl chain. "Lower alkenyl" means about 2 to about 6 carbon atoms in the chain which may be straight or branched. "Alkenyl"
may be unsubstituted or optionally 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, alkoxy and -S(alkyl). Non-limiting examples of suitable alkenyl groups include ethenyl, propenyl, n-butenyl, 3-methylbut-2-enyl, n-pentenyl, octenyl and decenyl.
"Alkylene" means a difunctional group obtained by removal of a hydrogen atom from an alkyl group that is defined above. Non-limiting examples of alkylene include methylene, ethylene and propylene.
"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-:eihy:butynyl. "Alkynyl" may be unsubstituted or optionally 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.
"Aryl" means an aromatic monocyclic or multicyclic ring system comprising about 6 to about 14 carbon atoms; prefe . AD-out 6 to about 10 carbon atoma.
The aryl group can be optionally s _Ibz:...; t ,c or more "ring system subst t '::~

which may be the same or different, and are as defined herein. Non-limiting examples of suitable aryl groups include phenyl and naphthyl.
"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, pyridone (including N-substituted pyridones), isoxazolyl, isothiazolyl, oxazolyl, thiazolyl, pyrazolyl, furazanyl, pyrrolyl, pyrazolyl, triazolyl, 1,2,4-thiadiazolyl, pyrazinyl, pyridazinyl, quinoxalinyl, phthalazinyl, oxindolyl, 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. The term "heteroaryl" also refers to partially saturated heteroaryl moieties such as, for example, tetrahydroisoquinolyi, tetra hydroqui no ly I and the like.
"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 thra;~' ,le alkyl.
"Arylaikenyl" means an aryl group linked to the parent moiety through an alkenyl moiety, defined above.
"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 -.- p#e of = is tolyl. T bond to the parem o f sz ~
tie aryl, "Cycloalkyl" or cyclyl 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 cyclyalkyl 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.
"Cycloalkylalkyl" or cyclylalkyl means a cycloalkyl moiety as defined above linked via an alkyl moiety (defined above) to a parent core. Non-limiting examples of suitable cycloalkylalkyls include cyclohexylmethyl, adamantylmethyl and the like.
"Cycloalkenyl" or cyclenyl 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 which contains at least one carbon-carbon double bond. Preferred cycloalkenyl rings contain about 5 to about 7 ring atoms. The cycloalkenyl 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 cycloalkenyls include cyclopentenyl, cyclohexenyl, cyclohepta-1,3-dienyl, and the like. Non-limiting example of a suitable multicyclic cycloalkenyl is norbornylenyl.
"Cycloalkenylalkyl" or cyclenylalkyl means a cycloalkenyl moiety as defined above linked via an alkyl moiety (defined above) to a parent core. Non-limiting examples of suitable cycloalkenylalkyls include cyclopentenylmethyl, cyclohexenylrethyl and the like.
"CycloalkenylalkenyF" or "Cycloaikylalkenyl" means a cycloa< c fcioalkyi moiety respectively, as defined above, linked via an alkenyl moiety as defined above.
"Halogen" or halo means fluorine, chlorine, bromine, or iodine. Preferred are fluorine, chlorine and bromine.
"Ring system substituent" means a substituent attached to an aromatic or non-0 arc ...g < s h wws a , agent on the P:rq S _ .1 subs t e , same or different, each being pe ;e , w_ ._ , from coo-, e<:.;:irtg of ..' , alkenyl, alkynyl, aryl, heteroaryl, aralkyl, alkylaryl, heteroaralkyl, heteroarylalkenyl, heteroarylalkynyl, alkyiheteroaryl, hydroxy, hydroxyalkyl, alkoxy, aryloxy, aralkoxy, aryl, aroyl, halo, nitro, cyano, carboxy, alkoxycarbonyl, aryloxycarbonyl, a ralkoxycarbonyl, alkylsulfonyl, arylsulfonyl, heteroaryisulfonyl, alkylthio, arylthio, heteroarylthio, aralkylthio, heteroaralkylthio, cycloalkyl, heterocyclyl, -C(=N-CN)-NH2, -C(=NH)-NH2, -C(=NH)-NH(alkyl), Y1Y2N-, Y1Y2N-alkyl-, Y1Y2NC(O)-, Y1Y2NSO2- and -SO2NYIY2, wherein YI
and Y2 can be the same or different and are independently selected from the group consisting of hydrogen, alkyl, aryl, cycloalkyl, and aralkyl. "Ring system substituent"
may also mean a single moiety which simultaneously replaces two available hydrogens on two adjacent carbon atoms (one H on each carbon) on a ring system.
Examples of such moiety are methylene dioxy, ethylenedioxy, -C(CH3)2- and the like which form moieties such as, for example:
ro b n and "Heteroarylalkyl" or heteroarylalkenyl means a heteroaryl moiety as defined above linked via an alkyl or alkenyl moiety respectively (defined above) to a parent core. Non-limiting examples of suitable heteroaryls include 2-pyridinylmethyl, quinolinylmethyl and the like.
"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 contain about 5 to about 6 ring atoms. The prefix aza, oxa or Chia before the heterocyclyi 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 protections are also considered part of this in. Anton. The heterocyclyi can be F s~ E .w d by one 1- r-,-,.e 91rir which may be the same lerert. are as defined herein. J= m of the heterocyclyl can b e c_- ", ona Hy oxidized to the o -: 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, lactam, lactone, and the like.
"Heterocyclyi" may also mean a single moiety (e.g., carbonyl) which simultaneously 5 replaces two available hydrogens on the same carbon atom on a ring system.
Example of such moiety is pyrrolidone:
H
C N

"Heterocyclylalkyl" or heterocycloalkylalkylmeans a heterocyclyl moiety as defined above linked via an alkyl moiety (defined above) to a parent core. Non-limiting 10 examples of suitable heterocyclylalkyls include piperidinylmethyl, piperazinylmethyl and the like.
"Heterocyclenyl" or heterocycloalkenyl means a non-aromatic 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 15 element other than carbon, for example nitrogen, oxygen or sulfur atom, alone or in combination, and which contains at least one carbon-carbon double bond or carbon-nitrogen double bond. There are no adjacent oxygen and/or sulfur atoms present in the ring system. Preferred heterocyclenyl rings contain about 5 to about 6 ring atoms.
The prefix aza, oxa or aria before the heterocyclenyl root name means that at least a nitrogen, oxygen or sulfur atom respectively is present as a ring atom. The heterocyclenyl can be optionally substituted by one or more ring system suV, r , -,Lq,, w e e "ring system substituent" is as defined above, The nitrogen or sulfur atom of the heterocyclenyl can be optionally oxidized to the corresponding N-oxide, S-oxide or S,S-dioxide. Non-limiting examples of suitable heterocyclenyl groups include 1,2,3,4-tetrahydropyridine, 1,24-hydropyridyl, 1,4-d hydropyridyl, 1,2,3,6-tetra hydropyridine, 1, _ . 2 2-pyraz linyl, dihyd:oirie,d z ii i H-p.Y ran, dihyd-,7,f a-dihydrothiophenyl, dihydrothiopyranyl, and the like. "Heterocyclenyl" may also mean a single moiety (e.g., carbonyl) which simultaneously replaces two available hydrogens on the same carbon atom on a ring system. Example of such moiety is pyrrolidinone:
H
N

Q
"Heterocycle nylalkyl" or heterocycloalkenylalkyl means a heterocyclenyl moiety as defined above linked via an alkyl moiety (defined above) to a parent core.
"Heteroalkyl" means is a saturated or unsaturated chain containing carbon and at least one heteroatom, wherein one or more of the chain atoms is an element other than carbon, for example nitrogen, oxygen or sulfur, alone or in combination, wherein no two heteroatoms are adjacent. Heteroalkyl chains contain from 2 to 15 member atoms (carbon and heteroatoms) in the chain, preferably 2 to 10, more preferably 2 to 5. For example, alkoxy (i.e., --O-alkyl or --O-heteroalkyl) radicals are included in heteroalkyl. Heteroalkyl chains may be straight or branched. Preferred branched heteroalkyl have one or two branches, preferably one branch. Preferred heteroalkyl 1.5 are saturated. Unsaturated heteroalkyl have one or more carbon-carbon double bonds and/or one or more carbon-carbon triple bonds. Preferred unsaturated heteroalkyls have one or two double bonds or one triple bond, more preferably one double bond. Heteroalkyl chains may be unsubstituted or substituted with from 1 to 4 substituents. Preferred substituted heteroalkyl are mono-, di-, or tri-substituted.
Heteroalkyl may be substituted with lower alkyl, haloalkyl, halo, hydroxy, aryloxy heteroaryloxy, acyloxy, carboxy, monocyclic aryl, heteroaryl, cycloF 1. hete ;.rl, spirocycle, amino, acylarnino, amido, keto, thioketo, cyano, or any combination thereof.
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, 0 or S, as well as there are no N or on carbon to _ Thus, for example, in the ring:

C>2 N
H
there is no -OH attached directly to carbons marked 2 and 5.
It should also be noted that tautomeric forms such as, for example, the moieties:

5 H and N OH
are considered equivalent in certain embodiments of this invention.
"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.
"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.
"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.
"Aryl" 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. Nona'Fn ing examples of suitable elude formy' , 1 -opanoyl.
"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.
"Alkoxyi or "..X.aaoky' Cra i s ! O c , :n which the alkyl ' , . p is as akKoxy groups incl de methoxy, ethoxy, n-propoxy, isopropoxy and n-butoxy. The bond to the parent moiety is through the ether oxygen.
"Alkoxyoxo" is similar to alkoxycarbonyl (e.g., -CO2R), but the alkoxy group additionally may include polyether functionality.
"Oxaalkynyl" indicates an alkynyl ether (e.g. propargyloxy group) linked to the parent moiety via the oxygen of oxaalkynyl.
"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.
"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.
"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.
"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.
"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.
"Alkoxycarbonyl" means an alkyl-O-CO- group. Non-limiting examples of suitable alkoxycarbonyl groups include methoxycarbonyi and ethoxycarbonyl. The bond to the parent moiety is through the cart r L
"} Aryloxycarbonyl" means an aryl-O-C(C_ group. Non-,-r.ng examples of suitable aryloxycarbonyl groups include phenoxycarbonyl and naphthoxycarbonyl.
The bond to the parent moiety is through the carbonyl.
"Araikoxyca`oonyl" means an aralkyl-O-C(O)- group. Non-limiting example of a . . ; is beFez. -. no Si parent ro gh f' k>.. [_ is "Alkylsulfonyl" means an alkyl-S(02)- group. Preferred groups are those in which the alkyl group is lower alkyl. The bond to the parent moiety is through the sulfonyl.
"Arylsulfonyl" means an aryl-S(02)- group. The bond to the parent moiety is through the sulfonyl.
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.
The term "optionally substituted" means optional substitution with the specified groups, radicals or moieties.
The term "purifiedõ "in purified form" or "in isolated and purified form" for a compound refers to the physical state of said compound after being isolated from a synthetic process or natural source or combination thereof. Thus, the term "purified", "in purified form" or "in isolated and purified form" for a compound refers to the physical state of said compound after being obtained from a purification process or processes described herein or well known to the skilled artisan, in sufficient purity to be characterizable by standard analytical techniques described herein or well known to the skilled artisan.
It should also be noted that any carbon as well as heteroatom with unsatisfied valences in the text, schemes, exa,, - e s and Tables herein is a -` t e,,e the :_ i t n~ m per of hydrogen atar (s) to satisfy the valences.
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 r i :. h; c_:, with ordina, dirt a by reference to stanÃar texib ~ s such as, k - le, T. ` . Greene eta/, Protective Groups in organic Synthesis 0 991). #f v York.

When any variable (e.g., aryl, heterocycle, R2, etc.) occurs more than one time in any constituent or in Formula 1, its definition on each occurrence is independent of its definition at every other occurrence.
As used herein, the term "composition" is intended to encompass a product 5 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.
Prodrugs and solvates of the compounds of the invention are also contemplated herein. A discussion of prodrugs is provided in T. Higuchi and V.
Stella, 10 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. The term "prodrug" means a compound (e.g, a drug precursor) that is transformed in vivo to yield a compound of Formula (1) or a pharmaceutically acceptable salt, hydrate or solvate of the compound.
15 The transformation may occur by various mechanisms (e.g., by metabolic or chemical processes), such as, for example, through hydrolysis in blood. A discussion of the use of prodrugs is provided by T. Higuchi and W. Stella, "Pro-drugs as Novel Delivery Systems," Vol. 14 of the A.C.S. Symposium Series, and in Bioreversible Carriers in Drug Design, ed. Edward B. Roche, American Pharmaceutical Association and 20 Pergamon Press, 1987.
For example, if a compound of Formula (1) or a pharmaceutically acceptable salt, hydrate or solvate of the compound contains a carboxylic acid functional group, a prodrug can comprise an ester formed by the replacement of the hydrogen atom of the acid group with a group such as, for example, (C1-C8)alkyl, (C2-C12 alkanoyloxymetl yl, 1-(alkanoyloxy ethyl having from 4 to 9 carbon atoms, methyl- l-(alkanoyloxy)-ethyl having from 5 to 10 carbon atoms, alkoxycarbonyloxymethyl having from 3 to 6 carbon atoms, 1 -(a I koxyca rbo nyloxy) ethyl having from 4 to 7 carbon atoms, 1-methyl-1 -(alkoxycarbonyloxy)ethyl having from 5 to 8 carbon atoms, N-(alkoxycarbonyl)aminomethyl having from 3 to 9 carbon atoms, 3t 1 ( `7 having f rom 4 to 10 carbon s, 3 p thalsdyl, 4-crotonoiactonyl, gamma-o , , ...I .cton-4-y l di-N,N-(C C a!k C ; 2-C.w)alkyl (such as j3-dimethylaminoethyl), carbamoyl-(C,-C2)alkyl, N,N-di (C1-C2)alkylcarbamoyl-(C1-C2)alkyl and piperidino-, pyrrolidino- or morpholino(C2-C3)alkyl, and the like.
Similarly, if a compound of Formula (1) contains an alcohol functional group, a prodrug can be formed by the replacement of the hydrogen atom of the alcohol group with a group such as, for example, (C1-C6)alkanoyloxymethyl, 1-((Ci -C6)alkanoyloxy)ethyl, 1-methyl-l-((C,-C6)alkanoyloxy)ethyl, (C,-C6)alkoxycarbonyloxymethyl, N-(C1-C6)alkoxycarbonylaminomethyl, succinoyl, (C,-C6)alkanoyl, u-amino(C1-C4)alkanyl, arylacyl and a-aminoacyl, or u-aminoacyl-a-aminoacyl, where each a-aminoacyl group is independently selected from the naturally occurring L-amino acids, P(O)(OH)2, -P(O)(O(C1-C6)alkyl)2 or glycosyl (the radical resulting from the removal of a hydroxyl group of the hemiacetal form of a carbohydrate), and the like.
If a compound of Formula (l) incorporates an amine functional group, a prodrug can be formed by the replacement of a hydrogen atom in the amine group with a group such as, for example, R-carbonyl, RO-carbonyl, NRR'-carbonyl where R and R' are each independently (C1-C13)alkyl, (C3-C7) cycloalkyl, benzyl, or R-carbonyl is a natural u-aminoacyl or natural cr-aminoacyl, -C(OH)C(O)OY' wherein Y' is H, (C1-C6)alkyl or benzyl, _C(OY2)Y3 wherein Y2 is (C1-C4) alkyl and Y3 is (C1-C6)alkyl, carboxy (C,-C6)alkyl, amino(C1-C4)alkyl or mono-N--or di-N,N-(C1-C6)alkylaminoalkyl, -C(Y4)Y5 wherein Y4 is H or methyl and Y5 is mono-N- or di-N,N-(C,-C6)alkylamino morpholino, piperidin-1-yl or pyrrolidin-l -yl, and the like.
One or more compounds of the invention may exist in unsolvated as well as solvated forms with pharmaceutically acceptable solvents such as water, ethanol, and gthe like, and it is intended that the invention embrace both solvated and unsolvated one or more solvent molecules. "'-"s physical associatcn 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 t s -:phase and isolatadler S y ( ......U `'.anolates, a s ; a. e yyh 5 .. tl Eli One or more compounds of the invention may optionally be converted to a solvate. Preparation of solvates is generally known. Thus, for example, M.
Caira et al, J. Pharmaceutical Sci., 93(3), 601-611 (2004) describe the preparation of the solvates of the antifungal fluconazole in ethyl acetate as well as from water. Similar preparations of solvates, hemisolvate, hydrates and the like are described by E. C.
van Tonder et al, AAPS PharmSciTech., all, article 12 (2004); and A. L.
Bingham et al, Chem. Commur7., 603-604 (2001). A typical, non-limiting, process involves dissolving the inventive compound in desired amounts of the desired solvent (organic or water or mixtures thereof) at a higher than ambient temperature, and cooling the solution at a rate sufficient to form crystals which are then isolated by standard methods. Analytical techniques such as, for example 1. R. spectroscopy, show the presence of the solvent (or water) in the crystals as a solvate (or hydrate).
"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 above-noted diseases and thus producing the desired therapeutic, ameliorative, inhibitory or preventative effect.
The compounds of Formula I can form salts which are also within the scope of this invention. Reference to a compound of Formula I 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 Formula I 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) sans are preferred, although other salts are also useful. Salts of the compounds of the Formula I may be formed, for example, by reacting a compound of Formula I 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, 10 $gq y@ Exer 4 ~+ ascorbates, benzoates.

_::s, camphorates, camphom.3lfonates, furna aces, hy ; b omides, hydroiodides, lactates, maleates, methanesulfonates, naphtha lenesulfonates, nitrates, oxalates, phosphates, propionates, salicylates, succinates, sulfates, tartarates, thiocyanates, toluenesulfonates (also known as tosylates,) and the like. Additionally, acids which are generally considered suitable for the formation of pharmaceutically useful salts from basic pharmaceutical compounds are discussed, for example, by P. Stahl et al, Camille G. (eds.) Handbook of Pharmaceutical Salts. Properties, Selection and Use.
(2002) Zurich: Wiley-VCH; S. Berge et al, Journal of Pharmaceutical Sciences (1977) 66(1) 1-19; P. Gould, International J. of Pharmaceutics (1986) 33 201-217;
Anderson eta!, The Practice of Medicinal Chemistry (1996), Academic Press, New York;
and in The Orange Book (Food & Drug Administration, Washington, D.C. on their website).
These disclosures are incorporated herein by reference thereto.
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, salts with organic bases (for example, organic amines) such as dicyclohexylamines, t-butyl amines, 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, and butyl chlorides, bromides and iodides), dialkyl sulfates (e.g. dimethyl, diethyl, and dibutyl sulfates), long chain halides (e.g. decyl, lauryl, and stearyl chlorides, bromides and iodides), aralkyl halides (e.g. benzyl and phenethyl bromides), and others.
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.
Pharmaceutically acceptable esters of the present compounds include the roiiowing groups: (1) carboxylic acid esters obtained by esterification of the hydroxy groups, in which the non-carbonyl moiety of the carboxylic acid portion of the ester grouping is selected from straight or branched chain alkyl (for example, acetyl, n-propyl, t-butyl, or n-butyl), alkoxyalkyl (for example, methoxymethyl), aralkyl (for ylox ik for ex< . ~ o yl), aryl (for ptk 4 ; ,i X C _4alkytl, t ccxy or a (2) suif for yl (for ;. r r i methanesulfonyl); (3) amino acid esters (for example, L-valyl or L-isoleucyl);
(4) phosphonate esters and (5) mono-, di- or triphosphate esters. The phosphate esters may be further esterified by, for example, a C1-20 alcohol or reactive derivative thereof, or by a 2,3-di (C6-24)acyl glycerol.
Compounds of Formula I, and salts, solvates, esters 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.
The compounds of Formula (1) may contain asymmetric or chiral centers, and, therefore, exist in different stereoisomeric forms. It is intended that all stereoisomeric forms of the compounds of Formula (I) as well as mixtures thereof, including racemic mixtures, form part of the present invention. In addition, the present invention embraces all geometric and positional isomers. For example, if a compound of Formula (1) incorporates a double bond or a fused ring, both the cis- and trans-forms, as well as mixtures, are embraced within the scope of the invention.
Diastereomeric mixtures can be separated into their individual diastereomers on the basis of their physical chemical differences by methods well known to those skilled in the art, such as, for example, by chromatography and/or fractional crystallization. Enantiomers can be separated by converting the enantiomeric mixture into a diastereomeric mixture by reaction with an appropriate optically active compound (e.g., chiral auxiliary such as a chiral alcohol or Mosher's acid chloride), separating the diastereomers and converting (e.g., hydrolyzing) the individual diastereomers to the corresponding pure enantiomers. Also, some of the compounds of Formula (1) may be atropisomers (e.g., substituted biaryls) and are considered as part of this invention. Enantiomers can also be separated by use of chiral HPLC
column.
it is also possible that the compounds of Formula (1) may exist in different tautomeric forms, and all such forms are embraced within the scope of the invention.
Also, for example, all keto-enol and imine-enamine forms of the compounds are included in the invention.

3 p 6a 3 y4 f. e7rQs for b~.isomers . _ t omersygand ~~t,e like) p of L e p rewsent cum pour, s ` i3 e salts, 5 ('.-t.~o_, esters and pro of the compounds as oAj :-1-:E `. d esters cf the prodrugs), r 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, as are positional isomers (such as, for example, 4-pyridyl and 5 3-pyridyl). (For example, if a compound of Formula (l) incorporates a double bond or a fused ring, both the cis- and trans-forms, as well as mixtures, are embraced within the scope of the invention. Also, for example, all keto-enol and imine-enamine forms of the compounds are included in the invention.) Individual stereoisomers of the compounds of the invention may, for example, be substantially free of other isomers, 10 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 1UPAC 1974 Recommendations. The use of the terms "salt", "solvate", "ester", "prodrug" and the like, is intended to equally apply to the salt, solvate, ester and prodrug of enantiomers, stereoisomers, rotamers, tautomers, 15 positional isomers, racemates or prodrugs of the inventive compounds.
The present invention also embraces isotopically-labelled compounds of the present invention which are identical to those recited herein, but for the fact that one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number usually found in nature.
Examples of 20 isotopes that can be incorporated into compounds of the invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine and chlorine, such as 2H, 3H, 13C, 14C, 15N, 180, 170, 3'P, 32P, 35S,'8F, and 36Cl, respectively.
Certain isotopically-labelled compounds of Formula (l) (e.g., those labeled with 3H and 14C) are useful in compound and/or substrate tissue distribution assays.

25 Tritiated (i.e., 3H) and carbon-14 (i,e., 14C isotopes are particularly preferred for their ease of preparation and detectabiiity. Further, substitution with heavier isotopes such as deuterium (i.e., 2H) may afford certain therapeutic advantages resulting from greater metabolic stability (e.g., increased in vivo half-life or reduced dosage requirements) and hence may be preferred it some circumstances. Isotopically $t of F caL be prepared by E ..:''g pa f &s analogous to those disclosed in the Schemes and/or in the Example ; c ~
Jbelow, by substituting an appropriate isotopically labelled reagent for a non-isotopically labelled reagent.
Polymorphic forms of the compounds of Formula 1, and of the salts, solvates, esters and prodrugs of the compounds of Formula 1, are intended to be included in the present invention.
As used herein, amelioration of the symptoms of a particular disorder by administration of a particular compound or pharmaceutical composition refers to any lessening, whether permanent or temporary, lasting or transient that can be attributed to or associated with administration of the composition.
As used herein, IC50 refers to an amount, concentration or dosage of a particular test compound that achieves a 50% inhibition of a maximal response, such as modulation of CDK-2 kinase activity, in an assay that measures such response.
As used herein, EC50 refers to a dosage, concentration or amount of a particular test compound that elicits a dose-dependent response at 50% of maximal expression of a particular response that is induced, provoked or potentiated by the particular test compound.
In the case of amino acid residues, such residues may be of either the L- or D-form. The configuration for naturally occurring amino acid residues is generally L.
When not specified the residue is the L form. As used herein, the term "amino acid"
refers to a-amino acids which are racemic, or of either the D- or L-configuration. The designation "d" preceding an amino acid designation (e.g., dAla, dSer, dVal, etc.) refers to the D-isomer of the amino acid. The designation "dl" preceding an amino acid designation (e.g., d1Pip) refers to a mixture of the L- and D-isomers of the amino acid. it is to be understood that the chiral centers of the compounds provided herein may undergo epimerization in vivo. As such, one of skill in the a s that administration of a compound in its (R) form is equivalent, for compounds that undergo epimerization in vivo, to administration of the compound in its (S) form.
As used herein, substantially pure means sufficiently homogeneous to appear `.,ee of readily detectable impurities as determined bj standard methods of analysis, 3 &
(TLCi nd==ormance liquid ct. ~) ,:uu rY5 C.'. e of skill in the art to assess suc C11 a ion would not detectably alter the physical and chemical properties, such as enzymatic and biological activities, of the substance. Methods for purification of the compounds to produce substantially chemically pure compounds are known to those of skill in the art. A substantially chemically pure compound may, however, be a mixture of stereoisomers. In such instances, further purification might increase the specific activity of the compound.
The term "purified", "in purified form" or "in isolated and purified form" for a compound refers to the physical state of said compound after being isolated from a synthetic process or natural source or combination thereof. Thus, the term "purified", "in purified form" or "in isolated and purified form" for a compound refers to the physical state of said compound after being obtained from a purification process or processes described herein or well known to the skilled artisan, in sufficient purity to be characterizable by standard analytical techniques described herein or well known to the skilled artisan.
As used herein, "haloalkoxy" refers to RO- in which R is a haloalkyl group.
As used herein, "heterocyclyloxy", refers to RO- in which R is a heterocyclyl group, heteroaryloxy refers to RO- in which R is a heteroaryl group.
As used herein, "substituted alkyl," "substituted alkenyl," "substituted alkynyl,"
"substituted cycloalkyl," "substituted cycloalkenyl," "substituted cycloalkynyl,"
"substituted aryl," "substituted heteroaryl," "substituted heterocyclyl,"
"substituted alkylene," "substituted alkenylene," "substituted alkynylene," "substituted cycloalkylene," "substituted cycloalkenylene," "substituted cycloalkynylene,"
"substituted arylene," "substituted heteroarylene" and "substituted heterocyclylene"
refer to alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heteroaryl, heterocyclyl, alkylene, alkenylene, alkynylene, cycloalkylene, cycloalken': ie cycloalkynylene, arylene, heteroarylene and heterocyclylene groups, respectively, that are substituted with one or more substituents, in certain embodiments one, two, three or four substituents, where the substituents are as defined herein, for example, in one embodiment selected from O'.
As herein, "amid." refers _ group - "Thioarn.ido"
refers :r;t refers to the divalent group -%C.1(S)NH
OO(O)NH-, "Thiaamido" refers to the :pup refers G; N

to the divalent group -SC(S)NH-. "Ureido" refers to the divalent group -HNC(O)NH-.
"Thioureido" refers to the divalent group -HNC(S)NH-.
Where the number of any given substituent is not specified (e.g., haloalkyl), there may be one or more substituents present. For example, "haloalkyl" may include one or more of the same or different halogens. As another example, "C1_3alkoxyphenyl" may include one or more of the same or different alkoxy groups containing one, two or three carbons.
As used herein, the abbreviations for any protective groups, amino acids and other compounds, are, unless indicated otherwise, in accord with their common usage, recognized abbreviations, or the IUPAC-IUB Commission on Biochemical Nomenclature (see, (1972) Biochem. 11:942-944). Certain of the abbreviations used herein are listed below.
B. Compounds In one embodiment, the compounds provided herein for use in the compositions and methods provided herein have formula 1, where the variables are as described below. All combinations of such embodiments are within the scope of the instant disclosure.
In one embodiment, provided herein are compounds of formula (1):

Formula (1) or a pharmaceutically acceptable salts, solvates, esters, prodrugs and stereoisomers thereof, where R3, R5, R6 and R7 are select , wherein:
R3 is hydrogen, alkyl, cycloalkyl, cyclenyl, alkynyl, trifluroalkyl, difluroalkyl, monofluroalkyl, heterocyclyl, heterocyclenyl, aryl, heteroaryl, halo, cyano, -trihaloalkyl, NR8R9, CO:_R8, CONR8R , -OR", -SR", -S02R8, -S02NR8R9, -NR8SC2R9, -R CC , ' 't werein each . z_ . yciÃ ~y1; c e l :; of uroalkyl lY, erocyclyl, ,tE -c e _'l, aryl, 1 .hied or subs sc with ~- c c moieties independently selected from the group consisting of alkyl, cycloalkyl, aryl, heteroaryl, alkenyl, cyclenyl, heterocyclenyl, halo, trihaloalkyl, alkoxyl, hydroxyalkyl, trihaloalkoxyl and CN;
R5 and R7 are each selected from the group consisting of hydrogen, alkyl, aminoalkyl, alkenyl, alkynyl, aryl, heterocyclyl, heterocyclenyl, cycloalkyl, cyclenyl, cycloalkylalkyl, cyclenylalkyl, cycloalkylalkenyl, cyclenylalkenyi, heteroaryl, heteroarylalkyl, heteroarylaikenyl, arylalkyl, arylalkenyl, heterocyclylalkyl, heterocyclenylalkyl, heterocyclylaikenyl, heterocyclenylalkenyl, -S-heterocyclyl, -S-aminoalkyl, -S-heterocyclenyl, NRBR9, NRBCOR9, NR"SO2R9, COR8, C02R8, CONR8R9, CH2OR8, ORB, SR8, and S02R8, wherein each of said alkyl, alkenyl, alkynyl, aryl, heterocyclyl, heterocyclenyl, cycloalkyl, cyclenyl, cycloalkylalkyl, cyclenylalkyl, cycloalkylalkenyl, cyclenylalkenyl, heteroaryl, heteroarylalkyl, heteroarylalkenyl, arylalkyl, arylalkenyl, heterocyclylalkyl, heterocyclenylalkyl, heterocyclylalkenyl, heterocyclenylalkenyl, -S-heterocyclyl and -S-heterocyclenyl can be unsubstituted or substituted with at least one moiety, which can be the same or different, independently selected from the group consisting of halogen, alkyl, trihaloalkyl, alkenyl, dihaloalkyl, monohaloalkyl, hydroxyalkyl, OR8, -0, NR8R9, SR8, S02R9, CN, S02NR"R9, and NO2;
R6 is hydrogen, halo, trihaloalkyl, alkyl, alkenyl, aryl, cyclenyl, cycloalkyl, heteroaryl, heterocyclenyl, heterocyclyl, heteroarylalkyl, heterocycle nylalkyi, heterocyclylalkyl, arylalkyl, cyclenylalkyl, cyclylalkyl, NR8R9, NR8COR9, NR8S02R9, CORE, COO', CONR8R9, CH2OR8, OR8, SR8, or S02R8, wherein each of said alkyl, alkenyl, aryl, cyclenyl, cycloalkyl, heteroaryl, heterocyclenyl, heterocyclyl, heteroarylalkyl, heterocyclenylalkyl, heterocyclylalkyl, arylalkyl, cyclenylalkyl, and cyclylaikyl can be unsubstiuted or substituted with one or more c ieties independently selected fr ~:.<< J Soup consisting of halogen, C~,~y ..ycioalky,, naoalkyl, OR8, CN, NRBR9, C02R8, CONR8R9, -SR8, SO2R8, S02NR8R., NO2, NR8S02R9, NR8COR9, and NRBCONR8R9;
R8 and R9 are each independertly selected from the group consisting of L he { . , l ÃYF _. _ ,e! k('3 a,_ Ja 1r argil cyclc k cycle 9yi, ;.; c alky ti's ;ienylalkyl.
vclenyl h r Oyc; , ,t ycle heterocy. 5 ,. , I
J Y

heterocyclylalkyl, and heteroarylalkyl, wherein each of said alkyl, alkenyl, aryl, heteroaryl, arylalkyl, cycloalkyl, cyclenyl, cycloalkylalkyl, cyclenylalkyl, cyclenylalkenyl, heterocyclenyl, heterocyclyl, heterocyclenylalkyl, heterocyclenylalkenyl, heterocyclylalkyl, and heteroarylalkyl can be unsubstituted or substituted with at least 5 one moiety, which can be the same or different, independently selected from the group consisting of halo, alkyl, cycloalkyl, cyclenyl, aryl, heterocyclyl, heterocyclenyl, heteroaryl, trihaloalkyl, CN, hydroxyl, alkoxyl and NO2.
In one embodiment R3 is selected from the group consisting of heteroaryl, alkyl, halogen and cycloalkyl, wherein said heteroaryl can be unsubstituted or substituted 10 with alkyl.

3 or s In another embodiment, R3 is In yet another embodiment, R3 is N N
=_'N\ ~' N-CH3 t3 \ CH3 'z or In another embodiment, R3 is ethyl.
15 In still another embodiment, R3 is cyclopropyl.
In yet still another embodiment, R3 is bromine.
In another embodiment, R5 is selected from the group consisting of _~_H

/`~/NH
-~-S hater c: aryl, O
[ , or I . ! erc n hoterocyiyi can be unsubstituted or substituted with hydroxyalkyl and said aryt can be 20 unsubstituted or substituted with halogen.

In another embodiment, R5 is or __N

In yet another embodiment, R5 is OH or HO
In another embodiment, R6 is halogen or (C,-C6)alkyl.
In yet another embodiment, R6 is bromine, methyl or ethyl.
In another embodiment, R7 is -NHR8, wherein R6 is selected from the group consisting of hydrogen, heteroaryl and heteroarylalkyl, wherein said heteroarylalkyl can be unsubstituted or substituted with one or more moieties independently selected from the group consisting of hydroxyl, oxo, alkyl, and alkoxyl and said heteroaryl can be unsubstituted or substituted with alkyl.

In another embodiment, R8 is =S
N

In yet another embodiment, R8 is H3C

N
In still yet another embodiment, R8 is N-CH3 or N=OH
C/ N-O
In still another embodiment,, R8 is 0 H3C"/O
In another e,. a rest a o .:x:und having the formula.

N RS
N

NB
or esters, .
h~~.r ,'rugs and stereolsc mers 3l !_. R g'''; 'a :~.+eat ;ted t-r~~ R~, R ~$, R~ i.i .: ;.. ~r ~tra 14+ cr 4av3h i other her wherein:
R3 is selected from the group consisting of heteroaryl, alkyl, halogen and cycloalkyl, wherein said heteroaryl can be unsubstituted or substituted with alkyl;

_~_H
N-P
R5 is selected from the group consisting of heterocyclyl, aryl, OH

5 , or wherein said heterocylyl can be unsubstituted or substituted with hydroxyalkyl and said aryl can be unsubstituted or substituted with halogen;
R6 is halogen or (C,-C6)alkyl;
R8 is selected from the group consisting of hydrogen, heteroaryl and heteroarylalkyl, wherein said heteroarylalkyl can be unsubstituted or substituted with one or more moieties independently selected from the group consisting of hydroxyl, oxo, alkyl, and alkoxyl and said heteroaryl can be unsubstituted or substituted with alkyl.
In another embodiment, a compound having the formula:

NfN R6 or a pharmaceutically acceptable salts, solvates, esters, prodrugs and stereoisomers thereof, where R3, R5, R6 and R7 are selected independently of each other wherein:
R3 is selected from the group consisting of N"'--CHI 0 LCH , ethyl, cyclopropyl, and bromine, R is selected from the group consisting of phenyl, H, N
OH O OH , or NH, wherein said phenyl can be unsubstituted or substituted with fluorine;
R6 is bromine, methyl or ethyl;

R8 is N
N
N
hydrogen, H3C /

s 1 WCH3 or OH
N -OH

Non-limiting examples of compounds of Formula I include:

OH
N-N S
D~N
HN era HN N HN

8r ,N- N Br N
1.0 NH2 o ti H, NHS

N
N
S N

NH.
N/~~" N Br'N
NH2 NH2 NH2 s INH2 -"IH '-'H N

HN 3! e Nht BEd s . V S~iN OH NH
N_ N N_ l3r 1 Lt{ F N Y f N Y #~ \.
NH2 NH2 NH2 NH2 'O
~Br k'~ ~ati H
O., N
Ori l OH Jib OH~-NH OH,, NH (3H~ IH
f 0 0 0 vN'0 N N` N' 6r i NYN , F ,N
4N`N N OH (NH NH
NH (NH
1 ~
N, 0 UN C ~O or or a pharmaceutically acceptable salt, solvate or ester thereof.
In another embodiment a pharmaceutical composition, comprising a compound of Formula 1, and a pharmaceutically acceptable carrier.
In another embodiment the pharmaceutical composition containing the compounds of Formula I that is formulated for single dosage administration.
In another embodiment, use of a compound of Formula I in the preparation of a medicament for the treatment of a CDK-2 mediated disease.
In another embodiment, a method of treatment, prevention, or amelioration of one or more symptoms of a disease or disorder that is modulated or otherwise affected by CDK-2, comprising administering to a patient in need thereof an effective o pound of Formula i ore pharmace :~1 in another embodiment, use of a compound of Formula I in the preparation of a medicament for the treatment of a CHK-1 mediated disease.
In another embodiment, a method of treatment, prevention, or amelioration of on c + r 'c e s r;ptoms of a disease. c disorder tha is . or. uu. ated 0':
an eff , . , .
ou; -Et of a coo,-,;pound of Formuia 1 of a pharmaceuticaily acceptable salt thereof.

In another embodiment, the disease or disorder that is treated is selected from the group inflammatory disease, neurodegenerative disease, cancer and diabetes.
In another embodiment, the disease treated is an inflammatory disease selected from the group consisting of acute pancreatitis, chronic pancreatitis, asthma, 5 allergies, and adult respiratory distress syndrome.
In another embodiment, the disease treated is a neurodegenerative disease selected from the group consisting of acute Alzheimer's disease, Parkinson's disease, cerebral ischemia, and other neurodegenerative diseases.
In another embodiment the disease treated is diabetes selected from diabetes 10 mellitus and diabetes insipidus.
In another embodiment the diabetes treated is selected from type 1 diabetes and type 2 diabetes.
In another embodiment the disease treated is a cancer selected from the group consisting of:
15 tumor of the bladder, breast (including BRCA-mutated breast cancer), colorectal, colon, kidney, liver, lung, small cell lung cancer, non-small cell lung cancer, head and neck, esophagus, bladder, gall bladder, ovary, pancreas, stomach, cervix, thyroid, prostate, and skin, including squamous cell carcinoma;
leukemia, acute lymphocytic leukemia, acute lymphoblastic leukemia, chronic 20 lymphocytic leukemia ("CLL"), acute and chronic myelogenous leukemia, myelodysplastic syndrome and promyelocytic leukemia;
B-cell lymphoma, T- cell lymphoma, Hodgkins lymphoma, nonHodgkins lymphoma, hairy cell lymphoma, mantle cell lymphoma, myeloma and Burkett`s lymphoma;
25 fibrosarcoma, rhabdomyosarcoma;
head and neck. mantle cell lymphoma, myeloma;
astrocytoma, neuroblastoma, glioma, glioblastoma, malignant glial tumors, astrocytoma, hepatocellular carcinoma, gastrointestinal stromal tumors ("GIST") and schwannomas;

30 cart- inrn osteosarcoma, x. urea pigmentosum, sera octanthor - :,:cif follicular cancer and l aposi`s -S C, M a, In another embodiment a method of treating one or more diseases associated with cyclin dependent kinase in a mammal, comprising administering to said mammal an amount of a first compound, which is a compound of Formula I, or a pharmaceutically acceptable salt, solvate, ester or prodrug 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 therapeutic effect.
In another embodiment a method of treatment comprising administering to said mammal an amount of a first compound, which is a compound of Formula I, an amount of at least one second compound, said second compound being an anti-cancer agent and further comprising radiation therapy.
In another embodiment wherein said anti-cancer agent is selected from the group consisting of a cytostatic agent, cytostatic agent, cisplatin, doxorubicin, taxotere, taxol, etoposide, irinotecan, camptostar, topotecan, paclitaxel, docetaxel, epothilones, tamoxifen, 5-fluorouracil, methoxtrexate, temozolomide, cyclophosphamide, SCH 66336, 8115777, L778,123, BMS 214662, Iressa, Tarceva, antibodies to EGFR, Gleevec, intron, ara-C, adriamycin, cytoxan, gemcitabine, Uracil mustard, Chlormethine, Ifosfamide, Melphalan, Chlorambucil, Pipobroma, Triethylenemelamine, Triethylenethiophosphoramine, Busulfan, Carmustine, Lomustine, Streptozocin, Dacarbazine, Floxuridine, Cytarabine, 6-Mercaptopurine, 6-Thioguanine, Fludarabine phosphate, oxaliplatin, leucovirin, ELOXATINTM, Pentostatine, Vinblastine, Vincristine, Vindesine, Bleomycin, Dactinomycin, Daunorubicin, Doxorubicin, Epirubicin, Idarubicin, Mithramycin, Deoxycofor, Mitorycin-C, L-Asparaginase, Teniposide 17a-Ethinylestradiol, Diethylstilbestrol, Testosterone, Prednisone, Fluoxymesterone, Dromostanolone propionate, Testolactone, Megestro I acetate, Methylprednisolone, Methyltestosterone, Prednisolone, Triamcinolone, Chlorotrianisene, Hydroxyprogesterone, Aminoglutetlimid, Estr :: Medroxypro .. u~~eacetate, Leuprolide, `~, 1 v, Tyr E: , goserelin, Cisplatin, Carboplatin, Hydroxyurea, Arnsacr-e, Pry b r Mitoxantrone, Levamisole, Navelbene, Anastrazole, Letrazole, Capecitabine, Reloxafino, Droloxafine, Hexamethylmelamine, Avastin, herceptin, Bexxar, Velcade, Zevalin, Trisenox, Xeloda, Vinoreibine, Porfimer, Erbitux, Liposomal, Thiotepa, Altretamine, Melphalan, Trastuzumab, Lerozole, Fulvestrant, Exemestane, Fulvestrant, lfosfomide, Rituximab, C225, Campath, Clofarabine, cladribino, aphidicolon, rituxan, sunitinib, dasatinib, tezacitabine, SmIl, fludarabine, pentostatin, triapine, didox, trimidox, amidox, 3-AP, and MDL-181,731.
In another embodiment a pharmaceutical composition comprising a therapeutically effective amount of at least one compound of Formula I, or a pharmaceutically acceptable salt, solvate, ester or prodrug thereof, in combination with at least one pharmaceutically acceptable carrier.
in another embodiment, the pharmaceutical composition of containing the compound of Formula I or pharmaceutically acceptable salt, solvate, ester or prodrug thereof, additionally comprising one or more anti-cancer agents selected from the group consisting of cisplatin, doxorubicin, taxotere, taxol, etoposide, irinotecan, camptostar, topotecan, paclitaxel, docetaxel, epothilones, tamoxifen, 5-fluorouracil, methoxtrexate, temozolomide, cyclophosphamide, SCH 66336, R115777, L778,123, BMS 214662, lressa, 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, ELOXATINTM, Pentostatine, Vinblastine, Vincristine, Vindesine, Bleomycin, Dactinomycin, Daunorubicin, Doxorubicin, Epirubicin, Idarubicin, Mithramycin, Deoxycoformycin, Mitomycin-C, L-Asparaginase, Teniposide 17, Ethinylestradioi, Diethyistiibestrol, Testosterone, 'rednisone, =.'`;_,.A-x:ymesterone, Dromostanolone propionate. Testolactone, Megestrolacetate, Methylprednisolone, Methyltestosterone, Prednisolone, Triamcinoione, Chlorotrianisene, Hydroxyprogesterone, Aminoglutethimide, Estramustine, Medro.xyprogesteroneacetate, Leuprolide, Flutamide, Toremifene, goserelin, Cispiatin, m s .: *w g p . S w! Ã ii a,: S P , Lejf .:woe, Naveb L trazole, Cape Relcxa~;Ae, Lk: ~.~ `one, l exa -- . ' r~ ;astir, l e cept r , >.x: tE , Velcad ; Zeval r , Trisenox, Xeloda, Vinorelbine, Porfimer, Erbitux, Liposomal, Thiotepa, Altretamine, ..elphalan, Trastuzumab, Lerozole, Fulvestrant, Exemestane, Fulvestrant, Ifosfomide, Rituximab, C225, Campath, Clofarabine, cladribine, aphidicolon, rituxan, sunitinih, dasatinib, tezacitabine, SmI1, fludarabine, pentostatin, triapine, didox, trimidox, amidox, 3-AP, and MDL-101,731.
In another embodiment, a method of inhibiting one or more cyclin dependent kinases in a patient, comprising administering a therapeutically effective amount of the pharmaceutical composition comprising a therapeutically effective amount of at least one compound of Formula I, or a pharmaceutically acceptable salt, solvate, ester or prodrug thereof, in combination with at least one pharmaceutically acceptable carrier to said patient.
In another embodiment, a method of inhibiting one or more Checkpoint kinases in a patient, comprising administering a therapeutically effective amount of the pharmaceutical composition comprising a therapeutically effective amount of at least 1.5 one compound of Formula I, or a pharmaceutically acceptable salt, solvate, ester or prodrug thereof, in combination with at least one pharmaceutically acceptable carrier to said patient.
A method of treating one or more diseases by inhibiting one or more kinases, wherein said kinases are selected from the group consisting of cyclin dependent kinases, Checkpoint kinases, tyrosine kinases and Pim-1 kinases, comprising administering a therapeutically effective amount of at least one compound of Formula I or a pharmaceutically acceptable salt, solvate, ester or prodrug thereof to a patient in need of such treatment.
In another embodiment, a compound of Formula I in purified form.
C. Preparation of the Compounds The compounds described herein can be obtained from commercial sources or synthesized by convenUional methods as shown below using commercially available F,- t ;,tom, the compounds can be .gig the 1<<: scheme pr be~ow.

Compounds of Formula l where R5 is a C-linked substituent (e.g. compound 1a), can be prepared as illustrated in Scheme 1, starting from 2-fluoro-5-aminopyrazole (J.
Heterocyclic Chem, 1978, 15, 1447. and Tetrahedron Letters 1979, 34, 3179.) and the corresponding beta-ketoester:

Scheme 1 H2N j F AEQH ~/~ R
F
H Fib Q N-N reflex N /--N PQCl, H
0 N,N-dÃrnethylanil ie 1 . NBS, CH3CN N RBr N RS 2. E+eleQNa,MeC}H N!N Re Ci NN i Rs We 5 1 . Suzuki coupling N- N

N NH (Z= NH00, S) N R5 F \ N F \
N- Br NBS N-N Rs 1. R ,=H NH2 Rf,_Br 1,0 R~
la (Fi, =NHFi, OR, 5R) Compounds of Formula l where R5 is a N-linked substituent (e.g. compound 1 b), can be prepared as illustrated in Scheme 2 from 2-fluoro-5-aminopyrazole and appropriately substituted dimethyl malonate:

Scheme 2 + f #. re#lux N` OH PQCi3 C3 N-N McUNa N'N R6 N,N dimethylaniline R6 R6 H McOr H cl RZH
H [ (z= NH, 0, S) N N Br 1. NBS
F N,N Br Suzuki N;`R6 R5 CH3CN /`~~NJ CC
Fes`
NH C-linked N N~2. NaHCO3 N"N Rs lb substituent R7 NMP 9 R7 I 1.0 (R7 =NHR, OR, SR) R R`NH (R7 =NHR, OR, SR) N (R5 = NHR.R") 5 The compounds described herein can be separated from a. reaction mixture and further purified by a method such as column chromatography, high-pressure liquid chromatography, or recrystallization. As can be appreciated by the skilled artisan, further methods of synthesizing the compounds of the formulae herein will be evident to those of ordinary skill in the art. Additionally, the various synthetic steps may be 10 performed in an alternate sequence or order to give the desired compounds.
Synthetic chemistry transformations and protecting group methodologies (protection and deprotection) useful in synthesizing the compounds described herein are known in the art and include, for example, those such as described in R. Larock, Comprehensive Organic Transformations, VCH Publishers (1989); T.W. Greene and 15 P.G.M. Wuts, Protective Groups in Organic Synthesis, 2d. Ed., John Wiley and Sons 11991); L. Fieser and M. Fieser, Pieser and Fieser's Reagents for Organic Synthesis, John Wiley and Sons (12 L. F' r c c _ Y. f R for Organic Synthesis, John Wiley and Sons ( 995), and subsequent editions thereof.
The compounds according to the invention can have pharmacological 20 properties; in particular, the compounds of Formula l can be inhibitors of protein kinases such as, for example, the inhibitors of the cyclin-dependent kinases, Checkpoint kinase, r itog -; Vated protein k; P 'ER gll tease kinasc: GSK beta) and' 'he ; W. The cyclirt depe 1r:eE:i _~ kinases (C s) 'nc!
ode, for exam p e, C D02 (..Cf K1), C K2, CDK4, CDK5, CDK6, COK7 and CDK8. One such Checkpoint kinase is CHK-1. The novel compounds of Formula I 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.
6,413,974 cited earlier, the disclosure of which is incorporated herein.
More specifically, the compounds of Formula I 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; 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;
hematopoietic tumors of myeloid lineage, including acute and chronic myelogenous leukemias, myelodysplastic syndrome and promyelocytic leukemia;
tumors of mesenchymal origin, including fibrosarcoma and rhabdomyosarcoma;
tumors of the central and peripheral nervous system, including astrocytoma, neuroblastoma, glioma and schwannomas; and other tumors, including melanoma, seminoma, teratocarcinoma, osteosarcoma, xenoderoma pigmentosum, keratoctanthoma, thyroid follicular cancer and Kaposi's sarcoma.
Due to the key role of CDKs in the regulation of cellular proliferation in general, 23 inhibitors could act as revs .,; h`e -yttosta.ti = t . may be 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 cease tr f. f ation ~~ er~c otoxic sl ocl , aid f n ` g_ One series of checkpoints Ã. 4 he integrity of the =e an~
sensing DNA damage, these "DNA d; i:;a checkpoints" block ccH cycle progression in G, & G2 phases, and slow progression through S phase. This action enables DNA
repair processes to complete their tasks before replication of the genome and subsequent separation of this genetic material into new daughter cells takes place.
Inactivation of CHK1 has been shown to transduce signals from the DNA-damage sensory complex to inhibit activation of the cyclin B/Cdc2 kinase, which promotes mitotic entry, and abrogate G₂ arrest induced by DNA damage inflicted by either anticancer agents or endogenous DNA damage, as well as result in preferential killing of the resulting checkpoint defective cells. See, e.g., Peng et al., Science, 277, 1501-1505 (1997); Sanchez et al., Science, 277, 1497-1501 (1997), Nurse, Cell, 91, 867 (1997); Weinert, Science, 277, 1450-1451 (1997); Walworth et al., Nature, 363, 368-371 (1993); and Al-Khodairy et al., Mo/ec. Biol. Cell., 5, 147-160 (1994).
Selective manipulation of checkpoint control in cancer cells could afford broad utilization in cancer chemotherapeutic and radiotherapy regimens and may, in addition, offer a common hallmark of human cancer "genomic instability" to be exploited as the selective basis for the destruction of cancer cells. A number of factors place CHK1 as a pivotal target in DNA-damage checkpoint control. The elucidation of inhibitors of this and functionally related kinases such as CDS1/CHK2, a kinase recently discovered to cooperate with CHK1 in regulating S phase progression (see Zeng et al., Nature, 395, 507-510 (1998); Matsuoka, Science, 282, 1893-(1998)), could provide valuable new therapeutic entities for the treatment of cancer.
Compounds of Formula I can 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), Compounds of Formula I may induce or inhibit apoptosis. The apoptotic response is aberrant in a variety of human diseases, Compounds of Fora `
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 Hl infected individuals, autoimmune diseases tC:._ lupus, m., ~r': osus, a..1 hne me an i o m e r u I o n meumatcsd a hritis, psoriasis, infian d sease autoimmune d (-:betes rnellitu:), Jrc-=degenerative disorders c! ;c;i;~:g but not ,.. ., &

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.
Compounds of Formula I, 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).
Compounds of Formula I may also be useful in the chemoprevention of cancer.
.1.5 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.
Compounds of Formula I may also be useful in inhibiting tumor angiogenesis and metastasis.
Compounds of Formula I 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, P13 kinase, weel kinase, Src, Abl and thus be effective in the treatment of diseases associated with other protein kinases.
Thus, another aspect of this invention is a method of treating a mammal (e.g., human) having a disease or condition assoc -e with the CDKs by administ ~~
therapeutically effective amount of at least one compound of Formula 1, or a pharmaceutically acceptable salt or solvate of said compound to the mammal.
The compounds of this invention may also be useful in combination with one or more of anti-cancer treatments such as radiation therapy, and/or one or more anti-_:c '-gym the group consisting of cy: agents, cytotoxic age; is (suc..n as for example, but not limited to, DNA interactive ctggents (such as _ rit ? or doxorubicin))= taxanes (e.g. taxotere, taxoi); topois4 -:e ii inhibitors (such as etoposide); topoisomerase I inhibitors (such as irinotecan (or CPT-1 1), 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 (TEMODARTM from Schering-Plough Corporation, Kenilworth, New Jersey), cyclophosphamide); Farnesyl protein transferase inhibitors (such as, TM (4-[2-[4-[(11 R)-3,10-dibromo-8-chloro-6,11-dihydro-5H-benzo[5,6]cyclohepta[1,2-b]pyridin-11-y1-]-1-pipe ridinyl]-2-oxoehtyl]-1-pipe ridinecarboxamide, or SCH 66336 from Schering-Plough Corporation, Kenilworth, New Jersey), tipifarnib (Zarnestrao~ or R115777 from Janssen Pharmaceuticals), L778,123 (a farnesyl protein transferase inhibitor from Merck & Company, Whitehouse Station, New Jersey), BUS 214662 (a farnesyl protein transferase inhibitor from Bristol-Myers Squibb Pharmaceuticals, Princeton, New Jersey); signal transduction inhibitors (such as, Iressa (from Astra Zeneca Pharmaceuticals, England), Tarceva (EGFR kinase inhibitors), antibodies to EGFR (e.g., C225), GLEEVECTM (C-abl kinase inhibitor from Novartis Pharmaceuticals, East Hanover, New Jersey);
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.
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, oxaiiplatin (ELOXATINT' from Sanofi-Synthelabo Pharmaeuticals, France), Pentostatine, Vinblastine, Vincristine, Vindesine, Bleomycin, Dactinomycin, Daunorubicin. Doxorubicin, Epirubicin, idarubicin, Mithramycin, Deoxycoformycin, Mitomycin-C, L-Asparaginase, Teniposide 17(x-Ethinylestradiol, Diethylstilbestrol, Testosterone, Predniysone~,gFluoxymesterone, DromostanoionepropioYnyate, tor `, n. ', ~' 9rthaC at . M _. ``-}9 ate, a4 t 9L s o E ¾e¾on, Pretartisc' ~G~ r e, Chior r sene; Hydroxyprogesterone, Amin glute , Es[ramustinc 'E rccgxyprogesteroneacetate, Leuprolide, Flutamide, Toremifene, goserelin, Cisplatin, Carboplatin, Hydroxyurea, Amsacrine, Procarbazine, Mitotane, Mitoxantrone, Levamisole, Navelbene, Anastrazole, Letrazole, Capecitabine, Reloxafine, Droloxafine, or Hexamethylmelamine, Avastin, herceptin, Bexxar, Velcade, Zevalin, Trisenox, Xeloda, Vinoreibine, Porfimer, Erbitux, 5 Liposomal, Thiotepa, Altretamine, Melphalan, Trastuzumab, Lerozole, Fulvestrant, Exemestane, Fulvestrant, Ifosfomide, Rituximab, C225, Campath, Clofarabine, cladribine, aphidicolon, rituxan, sunitinib, dasatinib, tezacitabine, SmI1, fludarabine, pentostatin, triapine, didox, trimidox, amidox, 3-AP, and MDL-101,731.
When administering a combination therapy to a patient in need of such 10 administration, the therapeutic agents in the combination, or a pharmaceutical composition or compositions comprising the therapeutic agents, may be administered in any order such as, for example, sequentially, concurrently, together, simultaneously and the like. The amounts of the various actives in such combination therapy may be different amounts (different dosage amounts) or same amounts (same dosage 15 amounts). Thus, for non-limiting illustration purposes, a compound of Formula I and an additional therapeutic agent may be present in fixed amounts (dosage amounts) in a single dosage unit (e.g., a capsule, a tablet and the like). A commercial example of such single dosage unit containing fixed amounts of two different active compounds for oral administration is VYTORINe (available from Merck Schering-Plough 20 Pharmaceuticals, Kenilworth, New Jersey).
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 25 agents in inducing apoptosis (J. Ce// Sci., (1995) 108, 2897. Compounds of Formula i 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 Formula I may be administered either prior to or after administration of the known anticancer or cytotoxic agent. For example, the 3c cy' of he c~,,:oe gas.. is ; o tc . lfeced by the setae aye c 0i :6 .listration with anticancer gc-7_}_s. Dancer Research, 11997) 57_ 3375. Such techniques are within the skills of persons skilled in the art as well as attending physicians.
Accordingly, in an aspect, this invention includes combinations comprising an amount of at least one compound of Formula 1, 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.
The pharmacological properties of the compounds of this invention may be confirmed by a number of pharmacological assays.
I[l This invention is also directed to pharmaceutical compositions which comprise at least one compound of Formula I, or a pharmaceutically acceptable salt or solvate of said compound and at least one pharmaceutically acceptable carrier.
D. Formulation of pharmaceutical compositions The pharmaceutical compositions provided herein contain therapeutically effective amounts of one or more of the compounds provided herein that are useful in the prevention, treatment, or amelioration of one or more of the symptoms of diseases or disorders associated with CDK-2 or CHK-1, in a pharmaceutically acceptable carrier. Diseases or disorders associated with CDK-2 or CHK-1 include, but are not limited to, inflammatory diseases, neurodegenerative diseases, cancer and diabetes.
Pharmaceutical carriers suitable for administration of the compounds provided herein include any such carriers known to those skilled in the art to be suitable for the particular mode of administration.
In addition, the compounds may be formulated as the sole pharmaceutically active ingredient in the composition or may be combined with other active ingredients.
The compositions contain one or more compounds ;r ed herein. The compounds are, in one embodiment, formulated into suitable pharmaceutical preparations such as solutions, suspensions, tablets, dispersible tablets, pills, capsules, powders, sustained release formulations or elixirs, for oral administration or in sterile solutions or suspensions for parenteral administration, as well as transdermal ep '~ inhalers. In one the c , desc'ibed above are formulated into compositions t._ dues and procedures well known in the art (see, e.g., Ansel introduction to Pharmaceutical Dosage Forms, Fourth Edition 1985, 126).
In the compositions, effective concentrations of one or more compounds or pharmaceutically acceptable derivatives thereof is (are) mixed with a suitable pharmaceutical carrier. The compounds may be derivatized as the corresponding salts, esters, enol ethers or esters, acetals, ketals, orthoesters, hemiacetals, hemiketals, acids, bases, solvates, hydrates or prodrugs prior to formulation, as described above. The concentrations of the compounds in the compositions are effective for delivery of an amount, upon administration, that treats, prevents, or ameliorates one or more of the symptoms of diseases or disorders associated with CDK-2 or CHK-1 activity or in which CDK-2 or CHK-1 activity is implicated.
In one embodiment, the compositions are formulated for single dosage administration. To formulate a composition, the weight fraction of compound is dissolved, suspended, dispersed or otherwise mixed in a selected carrier at an effective concentration such that the treated condition is relieved, prevented, or one or more symptoms are ameliorated.
The active compound is included in the pharmaceutically acceptable carrier in an amount sufficient to exert a therapeutically useful effect in the absence of undesirable side effects on the patient treated. The therapeutically effective concentration may be determined empirically by testing the compounds using in vitro and in vivo systems described herein and then extrapolated therefrom for dosages for humans.
The concentration of active compound in the pharmaceutical composition will depend on absorption, inactivation and excretion rates of the active compound, the physicochemical characteristics of the compound, the dosage schedule, and amount administered as well as other factors known to those of skill in the art. For example, the amount that is delivered is sufficient to ameliorate one or more of the symptoms of diseases or disorders associated with CDK-2 or CHK-1 activity or in which CDK-2 or CHK-1 activity is implicated, as described herein.
n or:c r t, a osa void produce a serum cotave ingredieni of from j;..1 to about 5 10 pg, m;. Ã he ph t' , =a l Om positions, in anoth, r tiao me should provide a dosage of from about 0.001 mg to about 2000 mg of compound per kilogram of body weight per day. Pharmaceutical dosage unit forms are prepared to provide from about 0.01 mg, 0.1 mg or 1 mg to about 500mg, 1000 mg or 2000 mg, and in one embodiment from about 10 mg to about 500 mg of the active ingredient or a combination of essential ingredients per dosage unit form.
The active ingredient may be administered at once, or may be divided into a number of smaller doses to be administered at intervals of time. It is understood that the precise dosage and duration of treatment is a function of the disease being treated and may be determined empirically using known testing protocols or by extrapolation from in vivo or in vitro test data. It is to be noted that concentrations and dosage values may also vary with the severity of the condition to be alleviated. It is to be further understood that for any particular subject, specific dosage regimens should be adjusted over time according to the individual need and the professional judgment of the person administering or supervising the administration of the compositions, and that the concentration ranges set forth herein are exemplary only and are not intended to limit the scope or practice of the claimed compositions.
In instances in which the compounds exhibit insufficient solubility, methods for solubilizing compounds may be used. Such methods are known to those of skill in this art, and include, but are not limited to, using cosolvents, such as dimethylsulfoxide (DMSO), using surfactants, such as TWEEN , or dissolution in aqueous sodium bicarbonate. Derivatives of the compounds, such as prodrugs of the compounds may also be used in formulating effective pharmaceutical compositions.
Upon mixing or addition of the compound(s), the resulting mixture may be a solution, suspension, emulsion or the like. The form of the resulting mixture depends upon a number of factors, including the intended mode of administration and the solubility of the compound in the selected carrier or vehicle. The effective concentration is sufficient for ameliorating the symptoms of the disease, disorder or condition treated and may be empirically determined.
The pharmaceutical compositions are provided for administration to humans r: s dosage forms; such as tablets, _ ses pills granules, ><T ntE g o LS ,aL~
pdwe on or sLÃ gs pe}ye 7:~ _-~. -d oral .lions, :nd oil-t=r emulsions c! ; . ~g suitable the co . rn~ _ _ y acceptable derivatives thereof. The pharmaceutically therapeutically active compounds and derivatives thereof are, in one embodiment, formulated and administered in unit-dosage forms or multiple-dosage forms. Unit-dose forms as used herein refers to physically discrete units suitable for human and animal subjects and packaged individually as is known in the art. Each unit-dose contains a predetermined quantity of the therapeutically active compound sufficient to produce the desired therapeutic effect, in association with the required pharmaceutical carrier, vehicle or diluent. Examples of unit-dose forms include ampoules and syringes and individually packaged tablets or capsules. Unit-dose forms may be administered in fractions or multiples thereof. A multiple-dose form is a plurality of identical unit-dosage forms packaged in a single container to be administered in segregated unit-dose form.
Examples of multiple-dose forms include vials, bottles of tablets or capsules or bottles of pints or gallons. Hence, multiple dose form is a multiple of unit-doses which are not segregated in packaging.
Liquid pharmaceutically administrable compositions can, for example, be prepared by dissolving, dispersing, or otherwise mixing an active compound as defined above and optional pharmaceutical adjuvants in a carrier, such as, for example, water, saline, aqueous dextrose, glycerol, glycols, ethanol, and the like, to thereby form a solution or suspension. If desired, the pharmaceutical composition to be administered may also contain minor amounts of nontoxic auxiliary substances such as wetting agents, emulsifying agents, solubilizing agents, pH buffering agents and the like, for example, acetate, sodium citrate, cyclodextrine derivatives, sorbitan monolaurate, triethanolamine sodium acetate, triethanolamine oleate, and other such agents.
Actual methods of preparing s dosage ` re known. be .pparent, to those skilled in this art; for example, see Remington's Pharmaceutical Sciences, Mack Publishing Company, Easton, Pa., 15th Edition, 1975.
Dosage forms or compositions containing active ingredient in the range of 0.005% to 100% with the balance made up from non-toxic carrier may be prepared.
3 E ..5 mrs are known a the art.
plated ... : i ,3n s i 3.001%-1001:- . _~ m::ve ingredient, in one 1. Compositions for oral administration Oral pharmaceutical dosage forms are either solid, gel or liquid. The solid dosage forms are tablets, capsules, granules, and bulk powders. Types of oral tablets include compressed, chewable lozenges and tablets which may be enteric-coated, 5 sugar-coated or film-coated. Capsules may be hard or soft gelatin capsules, while granules and powders may be provided in non-effervescent or effervescent form with the combination of other ingredients known to those skilled in the art.
a. Solid compositions for oral administration In certain embodiments, the formulations are solid dosage forms, in one 10 embodiment, capsules or tablets. The tablets, pills, capsules, troches and the like can contain one or more of the following ingredients, or compounds of a similar nature: a binder; a lubricant; a diluent; a glidant; a disintegrating agent; a coloring agent; a sweetening agent; a flavoring agent; a wetting agent; an emetic coating; and a film coating. Examples of binders include microcrystalline cellulose, gum tragacanth, 15 glucose solution, acacia mucilage, gelatin solution, molasses, polvinylpyrrolidine, povidone, crospovidones, sucrose and starch paste. Lubricants include talc, starch, magnesium or calcium stearate, lycopodium and stearic acid. Diluents include, for example, lactose, sucrose, starch, kaolin, salt, mannitol and dicalcium phosphate.
Glidants include, but are not limited to, colloidal silicon dioxide.
Disintegrating agents 20 include crosscarmellose sodium, sodium starch glycolate, alginic acid, corn starch, potato starch, bentonite, methylcellulose, agar and carboxymethylcellulose.
Coloring agents include, for example, any of the approved certified water soluble FD
and C
dyes, mixtures thereof; and water insoluble FD and C dyes suspended on alumina hydrate. Sweetening agents include sucrose, lactose, mannitol and artificial 25 sweetening agents such as saccharin, and any number of spry dried flavors.
Flavoring agents include natural flavors extracted from plants such as fruits and synthetic blends of compounds which produce a pleasant sensation, such as, but not limited to peppermint and methyl salicylate. Wetting agents include propylene glycol monostearate, sorbitan monooleate, diethylene glycol monolaurate and 30 polyoxyeti=yler c- .: e'-ie,. Ernetic-coatin'- uc e fatty. ; fats, waxes.
a t. d shellac; and ce !'.use aceta0 ;: : tes. coatings include hydroxyethylcelIulose, sodium ca rboxymethylceliulose, polyethylene glycol 4000 and cellulose acetate phthalate.
The compound, or pharmaceutically acceptable derivative thereof, could be provided in a composition that protects it from the acidic environment of the stomach.
For example, the composition can be formulated in an enteric coating that maintains its integrity in the stomach and releases the active compound in the intestine. The composition may also be formulated in combination with an antacid or other such ingredient.
When the dosage unit form is a capsule, it can contain, in addition to material of the above type, a liquid carrier such as a fatty oil. In addition, dosage unit forms can contain various other materials which modify the physical form of the dosage unit, for example, coatings of sugar and other enteric agents. The compounds can also be administered as a component of an elixir, suspension, syrup, wafer, sprinkle, chewing gum or the like. A syrup may contain, in addition to the active compounds, sucrose as a sweetening agent and certain preservatives, dyes and colorings and flavors.
The active materials can also be mixed with other active materials which do not impair the desired action, or with materials that supplement the desired action, such as antacids, H2 blockers, and diuretics. The active ingredient is a compound or pharmaceutically acceptable derivative thereof as described herein. Higher concentrations, up to about 98% by weight of the active ingredient may be included.
In all embodiments, tablets and capsules formulations may be coated as known by those of skill in the art in order to modify or sustain dissolution of the active ingredient. Thus, for example, they may be coated with a conventional enterically digestible coating, such as phenylsalicylate, waxes and cellulose acetate phthalate.
b. Liquid compositions for oral administration Liquid oral dosage forms include aqueous solutions, emulsions, suspensions, solutions and/or suspensions reconstituted from non-effervescent granules and effervescent preparations reconstituted from effervescent granules. Aqueous solutions include, for example, elixirs and syrups. Emulsions are either oil-in-water or water-in-oil, E x;rc- are clear, sweetened, hyorca b ;c Filarmaceutica,`6y to ors 'ri elixirs include so r;s concentrated a ,.4 s solutions of a sugar, for example, sucrose, and may contain a preservative. An emulsion is a two-phase system in which one liquid is dispersed in the form of small globules throughout another liquid. Pharmaceutically acceptable carriers used in emulsions are non-aqueous liquids, emulsifying agents and preservatives.
Suspensions use pharmaceutically acceptable suspending agents and preservatives.
Pharmaceutically acceptable substances used in non-effervescent granules, to be reconstituted into a liquid oral dosage form, include diluents, sweeteners and wetting agents. Pharmaceutically acceptable substances used in effervescent granules, to be reconstituted into a liquid oral dosage form, include organic acids and a source of carbon dioxide. Coloring and flavoring agents are used in all of the above dosage forms.
Solvents include glycerin, sorbitol, ethyl alcohol and syrup. Examples of preservatives include glycerin, methyl and propylparaben, benzoic acid, sodium benzoate and alcohol. Examples of non-aqueous liquids utilized in emulsions include mineral oil and cottonseed oil. Examples of emulsifying agents include gelatin, acacia, tragacanth, bentonite, and surfactants such as polyoxyethylene sorbitan monooleate.
Suspending agents include sodium carboxymethylcellulose, pectin, tragacanth, Veegum and acacia. Sweetening agents include sucrose, syrups, glycerin and artificial sweetening agents such as saccharin. Wetting agents include propylene glycol monostearate, sorbitan monooleate, diethylene glycol monolaurate and polyoxyethylene lauryl ether. Organic acids include citric and tartaric acid.
Sources of carbon dioxide include sodium bicarbonate and sodium carbonate. Coloring agents include any of the approved certified water soluble FD and C dyes, and mixtures thereof. Flavoring agents include natural flavors extracted from plants such fruits, and synthetic blends of compounds which produce a pleasant taste sensation, For a solid dosage form, the solution or suspension, in for example propylene carbonate, vegetable oils or triglycerides, is in one embodiment encapsulated in a gelatin capsule. For a liquid dosage form, the solution, e.g., for example, in a polyethylene glycol, may be diluted with a sufficient quantity of a pharmaceutically accepta carrier, e.
g ., ~ ate r. to ~. _sas_. _ do ... ..
Alternatively, liquid or semi-solid oral fo , may be prepared oy dispersing the active compound or sa in vegetable oils, glycols, triglycerides, propylene glycol esters (e.g., propylene carbonate) and other such carriers, and encapsulating these solutions or suspensions in hard or soft gelatin capsule shells. Briefly, such formulations include, but are not limited to, those containing a compound provided herein, a dialkylated mono- or poly-alkylene glycol, including, but not limited to, 1,2-dimeth.oxymethane, diglyme, triglyrne, tetraglyme, polyethylene glycol-350-dimethyl ether, polyethylene glycol-550-dimethyl ether, polyethylene glycol-750-dimethyl ether wherein 350, 550 and 750 refer to the approximate average molecular weight of the polyethylene glycol, and one or more antioxidants, such as butylated hydroxytolueno (BHT), butylated hydroxyanisole (BHA), propyl gallate, vitamin E, hydroquinone, hydroxycoumarins, ethanolamine, lecithin, cephalin, ascorbic acid, malic acid, sorbitol, phosphoric acid, thiodipropionic acid and its esters, and dithiocarbamates.
Other formulations include, but are not limited to, aqueous alcoholic solutions including a pharmaceutically acceptable acetal. Alcohols used in these formulations are any pharmaceutically acceptable water-miscible solvents having one or more hydroxyl groups, including, but not limited to, propylene glycol and ethanol.
Acetals include, but are not limited to, di(lower alkyl) acetals of lower alkyl aldehydes such as acetaldehyde diethyl acetal.
2. Injectables, solutions and emulsions Parenteral administration, in one embodiment characterized by injection, either subcutaneously, intramuscularly or intravenously is also contemplated herein.
Injectables can be prepared in conventional forms, either as liquid solutions or suspensions, solid forms suitable for solution or suspension in liquid prior to injection, or as emulsions. The injectables, solutions and emulsions also contain one or more excipients, Suitable excipients are, for example, water, saline, dextrose, c 1viceroi or e r iol. In addition, if desired, the pharmaceutical compositions to be adrn.;nistered may also contain minor amounts of non-toxic auxiliary substances such as wetting or emulsifying agents, pH buffering agents, stabilizers, solubility enhancers, and other such agents, such as for example, sodium acetate, sorbitan monolaurate, L 1 ... 5, i..` _ . kxt7 in , n o a slow-release or sus ~i . t ; ' : 's that a col ~t v:, of dosage is maintained is alo ;pit t.;d Briefly, a compound provided herein is dispersed in a solid inner matrix, e.g., polymethylmethacrylate, polybutylmethacrylate, plasticized or unplasticized polyvinylchloride, plasticized nylon, plasticized polyethyleneterephthalate, natural rubber, polyisoprene, polyisobutylene, polybutadiene, polyethylene, ethylene-vinylacetate copolymers, silicone rubbers, polydimethylsiloxanes, silicone carbonate copolymers, hydrophilic polymers such as hydrogels of esters of acrylic and methacrylic acid, collagen, cross-linked polyvinylalcohol and cross-linked partially hydrolyzed polyvinyl acetate, that is surrounded by an outer polymeric membrane, e.g., polyethylene, polypropylene, ethylene/propylene copolymers, ethylene/ethyl acrylate copolymers, ethylene/vinylacetate copolymers, silicone rubbers, polydimethyl siloxanes, neoprene rubber, chlorinated polyethylene, polyvinylchloride, vinylchloride copolymers with vinyl acetate, vinylidene chloride, ethylene and propylene, ionomer polyethylene terephthalate, butyl rubber epichlorohydrin rubbers, ethylene/vinyl alcohol copolymer, ethylene/vinyl acetate/vinyl alcohol terpolymer, and 1.5 ethylene/vinyloxyethanol copolymer, that is insoluble in body fluids. The compound diffuses through the outer polymeric membrane in a release rate controlling step. The percentage of active compound contained in such parenteral compositions is highly dependent on the specific nature thereof, as well as the activity of the compound and the needs of the subject.
Parenteral administration of the compositions includes intravenous, subcutaneous and intramuscular administrations. Preparations for parenteral administration include sterile solutions ready for injection, sterile dry soluble products, such as lyophilized powders, ready to be combined with a solvent just prior to use, including hypodermic tablets, sterile suspensions ready for injection, sterile dry -,5 insoluble products ready to be combined with a vehicle just prior to use and sterile emulsions. The solutions may be either aqueous or nonaqueous.
If administered intravenously, suitable carriers include physiological saline or phosphate buffered saline (PBS), and solutions containing thickening and solubilizing agents, such as glucose, polyethylene glycol, and polypropylene glycol and mixtures thereof.
Pharm:-, .. 'y a ,., .r ,aL used z w t p j- parations include aqueous `.onaquec .......,.:`, c agents, buffers, antioxidants, local anesthetics, suspending and dispersing agents, emulsifying agents, sequestering or chelating agents and other pharmaceutically acceptable substances.
Examples of aqueous vehicles include Sodium Chloride Injection, Ringers 5 Injection, Isotonic Dextrose Injection, Sterile Water Injection, Dextrose and Lactated Ringers Injection. Nortaqueous parenteral vehicles include fixed oils of vegetable origin, cottonseed oil, corn oil, sesame oil and peanut oil. Antimicrobial agents in bacteriostatic or fungistatic concentrations must be added to parenteral preparations packaged in multiple-dose containers which include phenols or cresols, mercurials, 10 benzyl alcohol, chlorobutanol, methyl and propyl p-hydroxybenzoic acid esters, thimerosal, benzalkonium chloride and benzethonium chloride. Isotonic agents include sodium chloride and dextrose. Buffers include phosphate and citrate.
Antioxidants include sodium bisulfate. Local anesthetics include procaine hydrochloride.
Suspending and dispersing agents include sodium carboxymethylcelluose, 15 hydroxypropyl methylcellulose and pofyvinylpyrrolidone. Emulsifying agents include Polysorbate 80 (TWEEN`" 80). A sequestering or chelating agent of metal ions include EDTA. Pharmaceutical carriers also include ethyl alcohol, polyethylene glycol and propylene glycol for water miscible vehicles; and sodium hydroxide, hydrochloric acid, citric acid or lactic acid for pH adjustment.
20 The concentration of the pharmaceutically active compound is adjusted so that an injection provides an effective amount to produce the desired pharmacological effect. The exact dose depends on the age, weight and condition of the patient or animal as is known in the art.
The unit-dose parenteral preparations are packaged in an ampoule, a vial or a 25 syringe with a needle. All preparations for par= r f , be sterile, as is known and practiced in the art.
Illustratively, intravenous or intraarterial infusion of a sterile aqueous solution containing an active compound is an effective mode of administration. Another embodiment is a sterile aqueous or oily solution or suspension containing an active material injected as necessary to produce the ~ c > '~ l gicai effect.
Injectabies are designed for local and sy 'emic ads,: ,F~tr '. n. in one embodiment, a therapeutically effective dcs-~ e s formulated to ,: ntair a concentration of at least about 0.1 % w/w up to about 90% w/w or more, in certain embodiments more than 1 % w/w of the active compound to the treated tissue(s).
The compound may be suspended in micronized or other suitable form or may be derivatized to produce a more soluble active product or to produce a prodrug. The form of the resulting mixture depends upon a number of factors, including the intended mode of administration and the solubility of the compound in the selected carrier or vehicle. The effective concentration is sufficient for ameliorating the symptoms of the condition and may be empirically determined.
3. Lyophilized powders Of interest herein are also lyophilized powders, which can be reconstituted for administration as solutions, emulsions and other mixtures. They may also be reconstituted and formulated as solids or gels.
The sterile, lyophilized powder is prepared by dissolving a compound provided herein, or a pharmaceutically acceptable derivative thereof, in a suitable solvent. The solvent may contain an excipient which improves the stability or other pharmacological component of the powder or reconstituted solution, prepared from the powder.
Excipients that may be used include, but are not limited to, dextrose, sorbital, fructose, corn syrup, xylitol, glycerin, glucose, sucrose or other suitable agent. The solvent may also contain a buffer, such as citrate, sodium or potassium phosphate or other such buffer known to those of skill in the art at, in one embodiment, about neutral pH.
Subsequent sterile filtration of the solution followed by lyophilization under standard conditions known to those of skill in the art provides the desired formulation. In one embodiment, the resulting solution will be apportioned into vials for lyophilization.
Each vial will contain a single dosage or multiple dosages of the compound.
The iyophilized powder can be stored under appropriate conditions, such as at about 4 "C
to room temperature.
Reconstitution of this lyophilized powder with water for injection provides a formulation for use in parenteral administration. For reconstitution, the lyophilized powder is addedq to sterile water or other suitable carrier.
y ~The precise amount :T _ _ p^ `mod c.7 a pon tb Ã,_, -) .,. f..j L,:: ..a ,,.y. :.Sir. x V-i-r+ 6t an be Topical administration Topical mixtures are prepared as described for the local and systemic administration. The resulting mixture may be a solution, suspension, emulsions or the like and are formulated as creams, gels, ointments, emulsions, solutions, elixirs, lotions, suspensions, tinctures, pastes, foams, aerosols, irrigations, sprays, suppositories, bandages, dermal patches or any other formulations suitable for topical administration.
The compounds or pharmaceutically acceptable derivatives thereof may be formulated as aerosols for topical application, such as by inhalation. These formulations for administration to the respiratory tract can be in the form of an aerosol or solution for a nebulizer, or as a microfine powder for insuff lation, alone or in combination with an inert carrier such as lactose. In such a case, the particles of the formulation will, in one embodiment, have diameters of less than 50 microns, in one embodiment less than 10 microns.
The compounds may be formulated for local or topical application, such as for topical application to the skin and mucous membranes, such as in the eye, in the form of gels, creams, and lotions and for application to the eye or for intracisternal or intraspinal application. Topical administration is contemplated for transdermal delivery and also for administration to the eyes or mucosa, or for inhalation therapies. Nasal solutions of the active compound alone or in combination with other pharmaceutically acceptable excipients can also be administered.
These solutions, particularly those intended for ophthalmic use, may be formulated as 0.01 % - 10% isotonic solutions, pH about 5-7, with appropriate salts.
5. Compositions for other routes of administration Other routes of administration, such as transdermal patches, including iontophoretic and electrophoretic devices, and rectal administration, are also contemplated herein.
Transdermal patches, including iotophoretic and electrophoretic devices, are well known to those of skill in the art.
For example, pharmaceutical dosage forms for rectal administration are rectal suppositories, cad. _. a rtd herein mean solid bodies for ins ini.o the rer en at body temperature releasing one or m l-IF
macobQ , o y active ingredients. Pharmaceutically acceptable substances utilized in rectal suppositories are bases or vehicles and agents to raise the melting point. Examples of bases include cocoa butter (theobroma oil), glycerin-gelatin, carbowax (polyoxyethylene glycol) and appropriate mixtures of mono-, di- and triglycerides of fatty acids.
Combinations of the various bases may be used. Agents to raise the melting point of suppositories include spermaceti and wax. Rectal suppositories may be prepared either by the compressed method or by molding. The weight of a rectal suppository, in one embodiment, is about 2 to 3 gm.
Tablets and capsules for rectal administration are manufactured using the same pharmaceutically acceptable substance and by the same methods as for formulations for oral administration.
6. Targeted Formulations The compounds provided herein, or pharmaceutically acceptable derivatives thereof, may also be formulated to be targeted to a particular tissue, receptor, or other area of the body of the subject to be treated. Many such targeting methods are well known to those of skill in the art. All such targeting methods are contemplated herein for use in the instant compositions.
In one embodiment, liposomal suspensions, including tissue-targeted liposomes, such as tumor-targeted liposomes, may also be suitable as pharmaceutically acceptable carriers. These may be prepared according to methods known to those skilled in the art. Briefly, liposomes such as multilamellar vesicles (MLV's) may be formed by drying down egg phosphatidyl choline and brain phosphatidyl serine (7:3 molar ratio) on the inside of a flask. A solution of a compound provided herein in phosphate buffered saline lacking divalent cations (PBS) is added and the flask shaken until the lipid film is dispersed. The res asides are washed to remove unencapsulated compound, pelleted by centrifugation, and then resuspended in PBS.
7. Articles of manufacture The compounds or pharmaceutically acceptable derivatives may be packaged 30, c r r aging material, a compound oe Pharr _.ceptubie de,uca:~).. le'f provided herein, fy;, active for mods il y CE K-2 or CHK-1 , or for treatment, prever W ; ;; F.

amelioration of one or more symptoms of CDK-2 or CHK-1 mediated diseases or disorders, or diseases or disorders in which CDK-2 or CHK-1 activity, is implicated, within the packaging material, and a label that indicates that the compound or composition, or pharmaceutically acceptable derivative thereof, is used for modulating the activity of CDK-2 or CHK-1, or for treatment, prevention or amelioration of one or more symptoms of CDK-2 or CHK-1 mediated diseases or disorders, or diseases or disorders in which CDK-2 or CHK-1 is implicated.
The articles of manufacture provided herein contain packaging materials.
Packaging materials for use in packaging pharmaceutical products are well known to those of skill in the art. Examples of pharmaceutical packaging materials include, but are not limited to, blister packs, bottles, tubes, inhalers, pumps, bags, vials, containers, syringes, bottles, and any packaging material suitable for a selected formulation and intended mode of administration and treatment. A wide array of formulations of the compounds and compositions provided herein are contemplated as are a variety of treatments for any disease or disorder in which CDK-2 or CHK-1 is implicated as a mediator or contributor to the symptoms or cause.

EXAMPLES
Normal phase silica gel chromatography on a Biotage instrument was accomplished using a Quad UV System (PIN 07052) utilizing KP-SIL 32-63 um columns, 60A with flash cartridges 12+M or 25+M.

Commonly used abbreviations AcOH Acetic acid (Boc)20 1-tent-butyl-dicarbonate DMAP 4-Dimethylaminopyridine Et20 Diethyl ether EtOAc Ethyl acetate EtOH Ethanol ÃCPBA meta-Chlorope ro:rf z,:ic acid MeOH Methanol NBS N-bromosuccinimide NMP 1 -methyl-2-pyrrolid i none Pd(OAc)2 Palladium acetate POCK Phosphorus oxychloride 5 RT Room temperature SEMCL 2-(Trimethylsilyl)ethoxymethyl chloride Si02 Silica gel BocN OH BocN O~

SOCl2 (18.5 ml-) was added slowly under N2 to a stirred mixture of the acid 15 (50.0 g, 218 mmol) and pyridine (44.0 ml-) in anhydrous CH2CI2 (300 mL).
The mixture was stirred at 25 C for 20 min, then Meldrum's acid (35.0 g, 243 mmol) and DMAP (66.6 g, 546 mmol) were added and the mixture was stirred under N2 for 1 hr.
Then Et20 (2 L) was added, the mixture was washed with 1 M HCI (3x500 mL), brine (500 mL), and the organic layer was dried over Na2SO4, flitered, and the solvent was 20 evaporated. The residue was dissolved in MeOH (580 mL), and the mixture was refluxed for 4 hr. The solvent was evaporated and the residue was purified by column chromatography on silica gel with 10:1 CH2CI2/EtOAc as eluent. Pale yellow oil (26.5 g, 43 %) was obtained.

H2N BocNN
BocN O -N-NN`N

A mixture of the beta-ketoester from Preparative Example 1 (1.1 eq.) and 2-fluoro-5-aminopyrazole (J. Heterocyclic Chem. 1978, 15, 1447. and Tetrahedron Letters 1979, 34, 3179.) (1.0 eq.) in anhydrous toluene is stirred and refluxed under N2. The solvent is evaporated and the residue is purified by column chromatography on silica gel with CH2CI2/MeOH as eluent.

i BocN N ~~ - BocN _N

"Y N- N N- N
OH Cl A mixture of the product from Preparative Example 2 , N,N-dimethylaniline , and POCI3 is stirred at 25 C. Excess of POCI3 is evaporated and the residue is poured into saturated aqueous NaHCO3. The mixture is extracted with CH2CI2 (3x200 mL), the combined extracts are dried over Na2SO4, filtered, and the solvent is evaporated. The residue is purified by column chromatography on silica gel with CH2CI2/EtOAc as eluent.

BocN,,,-',Y N BocN N

N-N
N-N

A mixture of the product from Preparative Example 3, 2.0 M NH3 in 2-propanol, and conc. aqueous NH4OH is stirred in a closed pressure vessel at 70 C. The solvents are evaporated and the residue is purified by column chromatography on BOON N ocN __N
NH2 SEM"N,SEM
A mixture of the product from Preparative Example 4 (1.0 eq.), SEMCI (3.5 eq.), and diisopropylethylamine (7.0 eq.) in dry 1,2-dichloroethane is stirred and refluxed under N2. The mixture is then poured into saturated aqueous NaHCO3 solution, extracted with CH2CI2, dried over Na2SO4, and filtered. The solvents are evaporated and the residue is purified by column chromatography on silica gel with CH2CI2/EtOAc as eluent.

Br BocN rN BocN N,' N F - F

N N
SEM"N'SEM SEM"N'SEM
A solution of NBS (0.9 eq.) in anhydrous CH3CN is added under N2 to a stirred solution of the product from Preparative Example 5 (1.0 eq.) in anhydrous CH3CN .
Th 4 x _ the .. >. _ dv ~r a,.
column chromatography on silica gel with hexane/EtOAc as eluent.

N N

BocNCI_ _N BC BocN N , N; tjt / F -`~ -N
N
SEM"N,SEM SEM"'SEM

A mixture of the product from Preparative Example 6 (1.0 eq.), 1-methyl-4-(4,4,5,5-tetramethyl- 1,3,2-dioxaborolan-2-yl)-1 H-pyrazole (1.4 eq.), Pd[PPh3]4 (0.10 eq.), and Na2CO3 (3.0 eq.) in 1,2-dirnethoxyethane and H2O is stirred and refluxed under N2. The solvents are evaporated and the residue is purified by column chromatography on silica gel with hexane/EtOAc as eluent.

V, N
N-- N.
BOCK N HN N
N-N F N-N

A mixture of the product from Preparative Example 7 and 3N aqueous HCI
plus EtOH is stirred at 60 C. The solvents are evaporated, Na2CO3 and 6:1 mixture of CH2Cl2/MeOH are added to the residue and the mixture is stirred under N2 for 15 min.
Then it is loaded onto a column and it is purified by column chromatography on silica gel with CH2C12/7N NH3 in MeOH as eluerlt.

KN,N~ N

A solution of Br2 (1.0 eq.) in dry CH2CI2 is added dropwise to a stirred solution of the amine from Preparative Example 8 (1.0 eq.) in tert-BuNH2 and CH2CI2.
The mixture is stirred at 25 C, the solvents are evaporated and the residue is purified by column chromatography on silica gel with CH2CI2/MeOH as eluent.

Y YDu` H2N HO TN
HN- N F r.
O O
OBI
A mixture of diethyl malonate (2.0 eq.) and 2-fluoro-5-aminopyrazole (J.
Heterocyclic Chem. 1978, 15, 1447. and Tetrahedron Letters 1979, 34, 3179.) (1.0 eq.) is stirred and refluxed under N2. MeONa in MeOH is then added to the residue and the mixture is refluxed under N2. The mixture is then acidified, the precipitate is filtered, washed with H2O, then with CH2CI2, and dried in a vacuum.

HOB N - C rN
N-N
OH CI

A mixture from Preparative Example 10, N,N
and POC13 is stirred at 100 C. Excess of POCK is evaporated and the residue is poured into saturated aqueous NaHCO3. The mixture is extracted with CH2CI2 (3x200 mL), the combined extracts are dried over Na2SO4. filtered, and the solvent is evaporated. The residue is purified by cc;,, -.i chromatography on i~ . gel with CH

CI Qr N -C ~N
F F
CI HN
\.-N

5 A mixture of the product from Preparative Example 11, 3-aminomethylpyridine, and triethylamine in dioxane is stirred at 100 C. The residue is poured into saturated aqueous NaHCO3 and the mixture is extracted with CH2CI2 (3x200 mL). The combined extracts are dried over Na2SO4, filtered, and the solvent is evaporated. The residue is purified by column chromatography on silica gel with CH2CI2/EtOAc as 10 eluent.

CI N~-- CI N
N F \,F
HN SEW N

N N
A mixture of the product from Preparative Example 12 (1.0 eq.), SEMCI (3.5 (7 in Jr is stirred and ,;7 1 reflu>.ed under N2.le mixture is then poured into saturated aqueous NaHCO3 solution, extracted with CH2Cl2, dried over Na2SO4, and filtered, The solvents are evaporated and the residue is purified by column chromatography on silica gel with CH2CI2/EtOAc as eluent.

OH
"Nnl -F F
_N N-N
,N
SEM SEWN
i i N N

A mixture of the product from Preparative Example 13, 2-hydroxyethylpiperidine, and triethylamine in dioxane is stirred at 100 C. The residue is poured into saturated aqueous NaHCO3 and the mixture is extracted with (3x240 mL). The combined extracts are dried over Na2SO4, filtered, and the solvent is evaporated. The residue is purified by column chromatography on silica gel with CH2CI2/MeOH as eluent.

OH OH
Br =NN CN N
Fj F
N N
Sf`M`N SEM`N

~ 1 Ff l A solution of NBS (0.9 eq.) in anhydrous CH3CN is added under N2 to a stirred solution of the product from Preparative Example 14 (1.0 eq.) in anhydrous CH3CN.
The mixture is stirred, the solvents are evaporated, and the residue is purified by column chromatography on silica gel with CH2C121EtOAc as eluent.

OH OH A
NN N N N --~ ~ N N

SEW N SEM`N
N

A mixture of the product from Preparative Example 15 (1.0 eq.), tributylethynyltin (1.4 eq.) and Pd[PPh3 4 (0.10 eq.) in dioxane is stirred and refluxed under N2. The solvents are evaporated and the residue is purified by column chromatography on silica gel with CH2CI2/EtOAc as eluent.

Uri A
N N N
CNT

N N EN'N
SEW N SEM"N

N

A mixture of the product from Preparative Example 16 and Pd/C in EtOAc is stirred under H2. The solvents are evaporated and the residue is purified by column chromatography on silica gel with CH2CI2/EtOAc as eluent.

OH OH
N N N N
s i N-N N-SEMN SEWN

O

A mixture of the product from Preparative Example 17 and MCPBA in CH2CI2 is stirred under N2. The mixture is poured into saturated aqueous NaHCO3 and extracted with CH2CI2 (3x200 mL). The combined extracts are dried over Na2SO4, filtered, and the solvent is evaporated. The residue is purified by column chromatography on silica gel with CH2CI2/MeOH as eluent.

OH OH
~N'r N N N

SEM"N~ HNC
N,O N O

A mixture of the product from Preparative Example 18 and 3N aqueous HCI
plus EtOH is stirred at 60 C. The solvents are evaporated, Na2CO3 and 6:1 mixture of CH2CI2/MeOH are added to the residue and the mixture is stirred under N2 for 15 min.
Then is loaded onto a column and it is purified by column chromatography on silica ge v H as eiuent, All references cited herein, whether in print, electronic, computer readable storage media or other form, are expressly incorporated by reference in their entirety, including but not limited to, abstracts, articles, journals, publications, texts, treatises, internet web sites, databases, software packages, patents, and patent publications. A
number of embodiments of the invention have been described. Nevertheless, it will be understood that various modifications may be made without departing from the spirit and scope of the invention. These modifications specifically include but are not limited to the addition of substituents to carbon or nitrogen atoms, or as otherwise appropriate, as envisioned by and described in the specification; the resulting molecules are within the spirit and scope of the invention. Accordingly, other embodiments are within the scope of the following claims and the Summary (above).

Claims

1. A compound of the formula (I) or a pharmaceutically acceptable salt, solvate, ester, prodrug or stereoisomer thereof, wherein:
R3 is hydrogen, alkyl, cycloalkyl, cyclenyl, alkynyl, trifluroalkyl, difluroalkyl, monofluroalkyl, heterocyclyl, heterocyclenyl, aryl, heteroaryl, halo, cyano, -O-trihaloalkyl, NR8R9, CO2R8, CONR8R9, -OR8, -SR8, -SO2R8, -SO2NR8R9, -NR8SO2R9, -NR8COR9, or NR8CONR8R9, wherein each of said alkyl, cycloalkyl, cyclenyl, alkynyl, trifluroalkyl, difluroalkyl, monofluroalkyl, heterocyclyl, heterocyclenyl, aryl, heteroaryl,can be unsubstituted or substituted with one or more moieties independently selected from the group consisting of alkyl, cycloalkyl, aryl, heteroaryl, alkenyl, cyclenyl, heterocyclenyl, halo, trihaloalkyl, alkoxyl, hydroxyalkyl, trihaloalkoxyl and CN;
R5 and R7 are each selected from the group consisting of hydrogen, alkyl, aminoalkyl, alkenyl, alkynyl, aryl, heterocyclyl, heterocyclenyl, cycloalkyl, cyclenyl, cycloalkylalkyl, cyclenylalkyl, cycloalkylalkenyl, cyclenylalkenyl, heteroaryl, heteroarylalkyl, heteroarylalkenyl, arylalkyl, arylalkenyl, heterocyclylalkyl, heterocyclenylalkyl, heterocyclylalkenyl, heterocyclenylalkenyl, -S-heterocyclyl, -S-aminoalkyl, -S-heterocyclenyl, NR8R9, NR8COR9, NR8SO2R9, COR8, CO2R8, CONR8R9, CH2OR8, OR8, SR8, and SO2R8, wherein each of said alkyl, alkenyl, alkynyl, aryl, heterocyclyl, heterocyclenyl, cyccloalkyl, cyclenyl, cycloalkylalkyl, cyclenylalkyl, cycroalkylalkenyl, cyclenylalkenyl, heteroaryl, heteroarylalkyl, heteroarylalkenyl, arylalkyl, arylalkenyl, heterocyclylalkyl, heterocyclenylalkyl, heterocyclylalkenyl, heterocyclenylalkenyl, -S-heterocyclyl and -S-heterocyclenyl can be unsubstituted or substituted with at least one moiety which can be the same or different independently selected from the group consisting of halogen, alkyl, trihaloalkyl, alkenyl, dihaloalkyl, monohaloalkyl, hydroxyalkyl, OR8, -O, NR8R9, SR8, SO2R9, CN, SO2NR8R9, and NO2;

R6 is hydrogen, halo, trihaloalkyl, alkyl, alkenyl, aryl, cyclenyl, cycloalkyl, heteroaryl, heterocyclenyl, heterocyclyl, heteroarylalkyl, heterocyclenylalkyl, heterocyclylalkyl, arylalkyl, cyclenylalkyl, cyclylalkyl, NR8R9, NR8COR9, NR8SO2R9, COR8, CO2R8, CONR8R9, CH2OR8, OR8, SR8, or SO2R8, wherein each of said alkyl, alkenyl, aryl, cyclenyl, cycloalkyl, heteroaryl, heterocyclenyl, heterocyclyl, heteroarylalkyl, heterocyclenylalkyl, heterocyclylalkyl, arylalkyl, cyclenylalkyl, and cyclylalkyl can be unsubstiuted or substituted with one or more moieties independently selected from the group consisting of halogen, alkyl, cycloalkyl, trihaloalkyl, OR8, CN, NR8R9, CO2R8, CONR8R9, -SR8, SO2R8, SO2NR8R9, NO2, NR8SO2R9, NR8COR9, and NR8CONR8R9;
R8 and R9 are each independently selected from the group consisting of hydrogen, trihaloalkyl, dihaloalkyl, monohaloalkyl, alkyl, alkenyl, aryl, heteroaryl, arylalkyl, cycloalkyl, cyclenyl, cycloalkylalkyl, cyclenylalkyl, cyclenylalkenyl, heterocyclenyl, heterocyclyl, heterocyclenylalkyl, aminoalkyl, heterocyclenylalkenyl, heterocyclylalkyl, and heteroarylalkyl, wherein each of said alkyl, alkenyl, aryl, heteroaryl, arylalkyl, cycloalkyl, cyclenyl, cycloalkylalkyl, cyclenylalkyl, cyclenylalkenyl, heterocyclenyl, heterocyclyl, heterocyclenylalkyl, aminoalkyl, heterocyclenylalkenyl, heterocyclylalkyl, and heteroarylalkyl can be unsubstituted or substituted with at least one moiety, which can be the same or different, independently selected from the group consisting of halo, alkyl, cycloalkyl, cyclenyl, aryl, heterocyclyl, heterocyclenyl, heteroaryl, trihaloalkyl, CN, hydroxyl, alkoxyl and NO2.

2. The compound of claim 1, wherein R3 is selected from the group consisting of heteroaryl, alkyl, halogen and cycloalkyl, wherein said heteroaryl can be unsubstituted or substituted with alkyl.

3. The compound of claim 2, wherein said heteroaryl is

4. The compound of claim 3, wherein said substituted heteroaryl is

5. The compound of claim 2, wherein said alkyl is ethyl.

6. The compound of claim 2, wherein said cycloalkyl is cyclopropyl.

7. The compound of claim 2, wherein said halogen is bromine.

8. The compound of claim 1, wherein R'5 is selected from the group consisting of heterocyclyl, aryl, wherein said heterocylyl can be unsubstituted or substituted with hydroxyalkyl and said aryl can be unsubstituted or substituted with halogen.

9. The compound of claim 8, wherein said heterocyclyl is or

10. The compound of claim 8, wherein said substituted heterocyclyl is

11. The compound of claim 1, wherein R6 is halogen or (C1-C6)alkyl.

12. The compound of claim 11, wherein said halogen is bromine and said alkyl is methyl or ethyl.

13. The compound of claim 1, wherein R7 is -NHR8, wherein R8 is selected from the group consisting of hydrogen, heteroaryl and heteroarylalkyl, wherein said heteroarylalkyl can be unsubstituted or substituted with one or more moieties independently selected from the group consisting of hydroxyl, oxo, alkyl, and alkoxyl and said heteroaryl can be unsubstituted or substituted with alkyl.

14. The compound of claim 13, wherein said heteroaryl is

15. The compound of claim 14, wherein said substituted heteroaryl is

16. The compound of claim 13, wherein said heteroarylalkyl is

17. The compound of claim 16, wherein said substituted heteroarylallkyl is

18. The compound of claim 1, having the formula:
wherein R3 is selected from the group consisting of heteroaryl, alkyl, halogen and cycloalkyl, wherein said heteroaryl can be unsubstituted or substituted with alkyl;
R5 is selected from the group consisting of heterocyclyl, aryl, wherein said heterocylyl can be unsubstituted or substituted with hydroxyalkyl and said aryl can be unsubstituted or substituted with halogen;
R6 is halogen or (C1-C6)alkyl;
R8 is selected from the group consisting of hydrogen, heteroaryl and heteroarylalkyl, wherein said heteroarylalkyl can be unsubstituted or substituted with one or more moieties independently selected from the group of hydroxyl, oxo, alkyl, and alkoxyl and said heteroaryl can be unsubstituted or substituted with alkyl.

19. A compound having the structure:

or a pharmaceutically acceptable salt, solvate, ester, prodrug or stereoisomer thereof.

20. A pharmaceutical composition, comprising a compound of claim 1, and a pharmaceutically acceptable carrier.

21. The pharmaceutical composition of claim 20 that is formulated for single dosage administration.

22. Use of a compound of claim 1 in the preparation of a medicament for the treatment of a CDK-2 or CHK-1 mediated disease.

23. A method of treatment, prevention or amelioration of one or more symptoms of a disease or disorder that is modulated or otherwise affected by CDK-2 or CHK-1, comprising administering to a patient in need thereof an effective amount of a compound of claim 1 or a pharmaceutically acceptable salt thereof.

24. The method of claim 23, wherein the disease or disorder is selected from the group consisting of inflammatory disease, neurodegenerative disease, cancer and diabetes.

25. The method of claim 24, wherein the inflammatory disease is selected from the group consisting of acute pancreatitis, chronic pancreatitis, asthma, allergies, and adult respiratory distress syndrome.

26. The method of claim 24, wherein the neurodegenerative disease is selected from the group consisting of acute Alzheimer's disease, Parkinson's disease, cerebral ischemia, and other neurodegenerative diseases.

27. The method of claim 24, wherein the diabetes is selected from the group consisting of diabetes mellitus and diabetes insipidus.

28. The method of claim 27, wherein the diabetes is selected from type 1 diabetes and type 2 diabetes.

29. The method of claim 24, wherein said cancer is selected from the group consisting of:
tumor of the bladder, breast (including BRCA-mutated breast cancer), colorectal, colon, kidney, liver, lung, small cell lung cancer, non-small cell lung cancer, head and neck, esophagus, bladder, gall bladder, ovary, pancreas, stomach, cervix, thyroid, prostate, and skin, including squamous cell carcinoma;
leukemia, acute lymphocytic leukemia, acute lymphoblastic leukemia, chronic lymphocytic leukemia ("CLL"), acute and chronic myelogenous leukemia, myelodysplastic syndrome and promyelocytic leukemia;
B-cell lymphoma, T- cell lymphoma, Hodgkins lymphoma, non-Hodgkins lymphoma, hairy cell lymphoma, mantle cell lymphoma, myeloma and Burkett's lymphoma;
fibrosarcoma, rhabdomyosarcoma;

head and neck, mantle cell lymphoma, myeloma;
astrocytoma, neuroblastoma, glioma, glioblastoma, malignant glial tumors, astrocytoma, hepatocellular carcinoma, gastrointestinal stromal tumors ("GIST") and schwannomas;

melanoma, multiple myeloma, seminoma, teratocarcinoma, osteosarcoma, xenoderoma pigmentosum, keratoctanthoma, thyroid follicular cancer and Kaposi's sarcoma.

30. A method of treating one or more diseases associated with cyclin dependent kinase or Checkpoint kinase 1 in a mammal, comprising administering to said mammal an amount of a first compound, which is a compound of claim 1, or a pharmaceutically acceptable salt, solvate, ester or prodrug 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 therapeutic effect.

31. The method of claim 30, further comprising radiation therapy.

32. The method of claim 30, wherein said anti-cancer agent is selected from the group consisting of a cytostatic agent, cisplatin, doxorubicin, taxotere, taxol, etoposide, irinotecan, camptostar, topotecan, paclitaxel, docetaxel, epothilones, tamoxifen, 5-fluorouracil, methoxtrexate, temozolomide, cyclophosphamide, SCH
66336, R115777, L778,123, BMS 214662, 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, ELOXATIN.TM., 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, or Hexamethylmelamine..

33. A pharmaceutical composition comprising a therapeutically effective amount of at least one compound of claim 1, or a pharmaceutically acceptable salt, solvate, ester or prodrug thereof, in combination with at least one pharmaceutically acceptable carrier.

34. The pharmaceutical composition of claim 33, additionally comprising one or more anti-cancer agents selected from the group consisting of cytostatic agent, cisplatin, doxorubicin, taxotere, taxol, etoposide, irinotecan, camptostar, topotecan, paclitaxel, docetaxel, epothilones, tamoxifen, 5-fluorouracil, methoxtrexate, temozolomide, cyclophosphamide, SCH 66336, R115777, L778,123, BMS 214662, 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 17.alpha.-Ethinylestradiol, Diethylstilbestrol, Testosterone, Prednisone, Fluoxymesterone, Dromostanolone propionate, Testolactone, Megestrolacetate, Methylprednisolone, Methyltestosterone, Prednisolone, Triamcinolone, Chlorotrianisene, Hydroxyprogesterone, Aminoglutethimide, Estramustine, Medroxyprogosteroneacetate, Leuprolide, Flutamide, Toremifene, goserelin, Cisplatin, Carboplatin, Hydroxyurea, Amsacrine, Procarbazine, Mitotane, Mitoxantrone, Levamisole, Navelbene, Anastrazole, Letrazole, Capecitabine, Reloxafine, Droloxafine, or Hexamethylmelamine.

35. A method of inhibiting one or more cyclin dependent kinases in a patient, comprising administering a therapeutically effective amount of the pharmaceutical composition of claim 33 to said patient.

36. A method of treating one or more diseases by inhibiting one or more kinases, wherein said kinases are selected from the group consisting of cyclin dependent kinases, Checkpoint kinases, tyrosine kinases and Pim-1 kinases, comprising administering a therapeutically effective amount of at least one compound of claim 1 or a pharmaceutically acceptable salt, solvate, ester or prodrug thereof to a patient in need of such treatment.

37. A method of treating one or more diseases by inhibiting one or more kinases, wherein said kinases are selected from the group consisting of cyclin dependent kinase 2 and Checkpoint kinase 1, comprising administering a therapeutically effective amount of at least one compound of claim 1 or a pharmaceutically acceptable salt, solvate, ester or prodrug thereof to a patient in need of such treatment.

38. A compound of claim 1 in purified form.