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  • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
  • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
  • C07D487/04—Ortho-condensed systems
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Definitions

• the present invention relates to novel py ⁇ az ⁇ lo[1 ,5-a]pyrifmidin ⁇ 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 GDK-2 inhibitors and Checkpoint inhibitors such as CHK- 1 inhibitors.
• Protein phosphorylation is one of the main post translationai mechanisms used to control cellular function. Protein kinases catalyze the phosphorylation of serine, threonine and tyrosine residues using either ATP or GTP.
• MultiplQ cellular signals can stimulate growth, differentiation, and apopt ⁇ sis, and a key mechanism for regulating these processes irwotve-s the cell cycle, which controls ceil 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 cyc ⁇ n-dependent kinases (CDKs), mitogen activated protein kinase (MAPK/ERK), glycogen synthase kinase 3 (GSK3beta).
• CM Checkpoint (e.g., CHK- I 1 CHK-2 etc.) kinases.
• AKT kinases AKT kinases, JNK, Aurora kinases (Aurora A 8 Aurora B, Aurora C etc), and the tike.
• protein kinase inhibitors are described in WO02/22610 A1 and by Y. Mettey et a ⁇ 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 cycfins.
• CDK4/cyclin D and CDK2/cyciin 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.
• activated complexes of CDK1 (Cdc2)/cyclin B and possibly CDK1 (Cdc2)/cyciin A are thought to promote the transition from G2 into the M-phase. (reviewed by Murray A., Cell 116, 221 -234, 2004).
• CDKs 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.
• RB tumor suppressor retinoblastoma protein
• p107 and p130 p107 and p130
• Another series of protein kinases are those that play an important role as a checkpoint in cell cycle progression.
• Checkpoints prevent cefl 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.
• 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, inciuding 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 (inciuding stereoisomers thereof) are synthesized either singly or in a combinatorial fashion to give structurally and stereochemical ⁇ diverse libraries of compounds.
• the compounds are fluoro substituted pyrazolo pyrimidine compounds.
• R 3 is hydrogen, aSkyl, cyctealkyf, cyclenyl, aikynyl, trifluroaiky ⁇ , diffuroaikyi, monofluroalkyl, heterocyclyf, heterocyclenyi, ary ⁇ , heteroaryl, halo, cyano, -O- trihaloalkyl, NR 8 R 9 , CO 2 R 8 , CONR 8 R 9 , -OR 8 , -SR 8 , -SO 2 R 8 , -SO 2 NR 8 R 9 , -NR 8 SO 2 R 9 , - NR 8 COR 3 , or NR 8 CONR 8 R 9 , wherein each of said alkyl, cycloalkyl, cyclenyl, afkynyi, trifluroalkyl, dlfluroafkyi, monofluroaikyi, heterocydyi, heterccyctenyi,
• R 5 and R 7 are each selected from the group consisting of hydrogen, alkyl, arninoalkyl, alkenyl, aSkyny!, aryl, heterocyclyl, heterocycfenyl, cycloalkyl, cycfenyl, cycloalkylalkyi, cycie ⁇ ytalkyl, cycfoalkylalkenyl, cycfenylalkenyl, heteroaryl, heteroaryfalkyl, heteroarylalkenyl, arylalkyl, arylalkenyl, heterocyclyialkyl, h ⁇ terocycl ⁇ nyfatkyl, heterocyclyialkenyl, heterocyclenylaikenyl, -S-heterocyclyi, -S- aminoalkyl, -S-heterocycIeny!, NR 8 R 9 , NR 8 COR 9 , NR 8 SO 2 R 9
• R 6 is hydrogen, halo, trihaloalkyl, alkyl, alkenyl, aryl, cyclenyl, cycloalkyl, heteroaryl, heterocyclenyi, heterocyclyl, heteroarylalkyl, heterocyclenylaikyl, heterocyclyialkyl, arylalkyl, cycienyialkyl, cyclylalkyl, NR 8 R 9 , NR 8 COR 9 , NR 8 SO 2 R 9 , COR 8 , CO 2 R 8 , CONR 8 R 9 , CH 2 OR 8 , OR 8 , SR 8 , or SO 2 R 8 , wherein each of said alkyl, alkenyi, aryl, cyclenyi, cycloalkyl, heteroaryl, heterocyc ⁇ enyl, heterocyciyl, heteroarylalkyl, heterocyclenylaikyl, heterocyclyialkyl, arylalkyl, c
• R 8 and R 9 are each independently selected from the group consisting of hydrogen, trihaloaikyi, dihaioalkyl monohaloalkyl, alky!, alkenyl, aryl, heteroaryl, arylalkyl, cycloaikyl, cyci ⁇ nyi, cycloaikyialkyS, cycle oylalkyt, cycie ⁇ y ⁇ alkenyj, heterocycteny!, heterocycsyf, heter ⁇ cycl ⁇ nylalkyi, heterocyclenylaikenyl. neterocyclyialkyl, and heteroarylalkyi. wherein each of said afkys, alkenyl, aryl.
• heteroaryi arylalkyl, cycloafkyl, cycle ⁇ yl, cycloalkyialkyl, cyclenyialkyl, cyclenylaikenyl, heterocyclenyt r h ⁇ terocyclyl, heterocyclenylalkyi, heterocyclenylalkenyf, h ⁇ terocyclylafkyl, and heteroarylalkyi 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, heteroaryi, trihaloaikyi, CN, hydroxy!, alkoxyf and NO2.
• 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.
• 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-fimiting examples of the diabetes are diabetes meilitus and diabetes insipidus, e.g., type 1 diabetes and type 2 diabetes.
• effective amounts of the compounds or compositions containing therapeutically effective concentrations of the compounds 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 limited to, inflammatory diseases, neurodegenerative diseases, cancer, diabetes, acute pancreatitis, chronic pancreatitis, asthma, allergies, adult respiratory distress syndrome, Alzheimer's disease, Parkinson's disease, cerebral ischemia, diabetes melhtus, diabetes insipidus, 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 genito-urinary tract inc ⁇ uding 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.
• CDK-2 or CHK-1 mediated diseases or disorders including, but not limited to,
• 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 !
• protein kinases such as, for example, CDK1 , CDK2, CDK3, CDK4, CDK5, CDK6 and CDK7, CDK8, mitogen activated protein kinase (MAPK/ERK), 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 1 IR, and IR-R), the PDGF subfamily (including, for example, PDGF-alpha and beta receptors, CSFIR, c- kit and FLK-II), the FLK family (including, for example, kinase insert domain receptor (KDR), fetal iiver kinase-1 (FLK-1 ), mitogen activate
• novel compounds of Formula I are expected to be useful in the therapy of proliferative diseases such as cancer, autoimmune diseases, viral diseases, fungaf diseases, neurotogicaS/neurodege ⁇ erativ ⁇ disorders, arthritis, inflammation, antiproliferative (e.g., ocular retinopathy), neuronal alopecia and cardiovascular disease.
• proliferative diseases such as cancer, autoimmune diseases, viral diseases, fungaf diseases, neurotogicaS/neurodege ⁇ erativ ⁇ disorders, arthritis, inflammation, antiproliferative (e.g., ocular retinopathy), neuronal alopecia and cardiovascular disease.
• proliferative diseases such as cancer, autoimmune diseases, viral diseases, fungaf diseases, neurotogicaS/neurodege ⁇ erativ ⁇ disorders, arthritis, inflammation, antiproliferative (e.g., ocular retinopathy), neuronal alopecia and cardiovascular disease.
• proliferative diseases such as cancer, autoimmune diseases, viral diseases, fung
• 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 fibrosar
• 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, neurofibromatosis, atherosclerosis, pulmonary fibrosis, arthritis, psoriasis, glomerulonephritis, restenosis following angioplasty or vascular surgery, hypertrophic scar formation, inflammatory bowel disease, transplantation rejection, endotoxic shock, and fungal infections.
• any disease process e.g., benign prostate hyperplasia, familial adenomatosis polyposis, neurofibromatosis, atherosclerosis, pulmonary fibrosis, arthritis, psoriasis, glomerulonephritis, restenosis following angioplasty or vascular surgery, hypertrophic scar formation, inflammatory bowel disease, transplantation rejection, endotoxic shock, and fungal infections.
• 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) VU 1 741 -749).
• Compounds of Formula ! may induce or inhibit apopfosis.
• the apoptotte response is aberrant in a variety of human diseases.
• Compounds of Formula ⁇ will be usefu ⁇ in the treatment of cancer (including but not limited to those types mentioned hereinabove), viral infections (including but not limited to herpevirus, poxvirus, Epstein- Barr virus, Sindbis virus and adenovirus), prevention of AIDS development in HIV-infected individuals, autoimmune diseases (including but not limited to systemic lupus, erythematosus, autoimmune mediated glomerulonephritis, rheumatoid arthritis, psoriasis, inflammatory bowel disease, and autoimmune diabetes meliitus), 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), myelodysplasia syndromes, aplastic anemia, ischemic injury associated with myocardial infarctions, stroke and reper
• cancer including but not limited to those types mentioned
• 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.
• viral infections including but not limited to HIV, human papilloma virus, herpesvirus, poxvirus, Epstein-Barr virus, Sindbis virus and adenovirus
• 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 aiso act as inhibitors of other protein kinases, e.g., protein kinase C, her2, rat 1 , MEK1 , MAP kinase, EGF receptor, PDGF receptor, IGF receptor, Pi3 kinase, weel kinase, Src.
• protein kinases e.g., protein kinase C, her2, rat 1 , MEK1 , MAP kinase, EGF receptor, PDGF receptor, IGF receptor, Pi3 kinase, weel kinase, Src.
• another aspect of this invention is a method of treating a mammal (e.g., human) having a disease or condition associated with the CDKs or CHK- 1 by administering a therapeutically effective amount of at least one compound of Formula f, or a pharmaceutically acceptable salt or solvate of said compound to the mammal.
• a mammal e.g., human
• administering a therapeutically effective amount of at least one compound of Formula f, 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 according to the invention and their salts.
• 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.
• “Mammal” means humans and other mammalian animals.
• "Alky! means an aliphatic hydrocarbon group which may be straight or branched and comprising about 1 to about 20 carbon atoms in the chain.
• Preferred alky! groups contain about 1 to about 12 carbon atoms in the chain. More preferred alkyi groups contain about 1 to about 6 carbon atoms in the chain.
• Branched means that one or more lower alkyi groups such as methyl, ethyl or propyl, are attached to a linear alkyi chain.
• “Lower alkyf means a group having about 1 to about 6 carbon atoms in the chain which may be straight or branched. 1!
• Alkyl M may be unsubstifuted or optionally substituted by one or more subststue ⁇ ts which may be the same or different, each substituerst being independently selected from the group consisting of halo, alk ⁇ i, aryl, cycloalkyl, cyano, hydroxy, alkoxy, a ⁇ kySthio, amino, -NH(alkyi), - NH(cycloalkyi), -N(aiky1) 2f carboxy and -C(O)O-alkyl.
• suitable alkyl groups include methyl, ethyl, n-propyl, isopropy! and t-butyl.
• Alkenyt H 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 alkenyf 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 alkenyi” 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, aikyl. aryl, cycloalkyi, cyano, alkoxy and -S(alkyl).
• suitable alkenyl groups include ethenyl, propenyl, n-butenyl, 3-methylbut- 2-enyl, n-pentenyl, octenyl and decenyl.
• Alkyiene means a difunctional group obtained by removal of a hydrogen atom from an alkyi group that is defined above.
• Non- ⁇ rniting 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 aikynyl 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 aikynyl chain. "Lower aikynyl” means about 2 to about 8 carbon atoms in the chain which may be straight or branched.
• Non-iirniting examples of suitable aikynyl groups include ethynyl, propynyl, 2-butyny! and 3- metnyibutynyi, "Alkyny! 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 cycloalkyi.
• Aryl means an aromatic monocyclic or muiticycitc ring system comprising about 6 to about 14 carbon atoms, preferably about 6 to about 10 carbon atoms.
• the aryf group can be optionally substituted with one or more "ring system substituents'' which may be the same or different, and are as defined herein.
• suitable aryl groups include phenyl and naphthyl.
• ⁇ eteroaryf means an aromatic monocyclic or mutticyclic 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 "heteroaryi” 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, pyrazinyi, furanyl, thienyl, pyrimidinyl, pyridone (including N-substituted pyridones), isoxazolyf, isothiazolyi, oxazolyl, thiazolyl, pyrazolyl, furazanyi, pyrrolyl, pyrazolyl, triazolyi, 1 ,2,4- thiadiazoiyi, pyrazinyi, pyridazinyl, quinoxaliny!, phthalazinyl, oxindolyi, imidazo[1 ,2- ajpyridinyl, imidazo[2,1 ⁇ b]thiazoly!, benzofurazanyl, indolyl, azaindoiyl, benzimidazolyl, benzothienyl, quinolinyl, imidazolyl, thieno
• Aralkyr or "aryialkyl” means an aryl-alkyl- group in which the aryl and alkyl are as previously described. Preferred aralkyls comprise a lower alkyl group.
• suitable arafkyf groups include benzyl, 2-phenethyf and naphthaienyfmethyf. The bond to the parent rnoiety is through the alky!.
• Arylalk ⁇ nyf means an aryl group linked to the parent moiety through an alkenyl moiety, defined above.
• Alkylary means an alkyi-aryi- group in which the alkyi and aryl are as previously described.
• Preferred alkylaryls comprise a lower alkyl group.
• Non-limiting example of a suitable alkyiaryl group is toiyl.
• the bond to the parent rnoiety is through the aryi.
• CycloaSkyi 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 cycloalkyi rings contain about 5 to about 7 ring atoms.
• the cycloalkyl can be optionally substituted with one or more "ring system substituents" which may be the same or different, and are as defined above.
• suitable monocyclic cycioafkyfs include cyclopropyt, cyclopentyl, cyclohexyl, cycloheptyl and the like.
• suitable multicyclic cycioalkyls include 1 -decalinyl, norbornyl, adamantyl and the like.
• Cycloalkyiaikyl or cyclylalkyl means a cycfoalkyl moiety as defined above finked via an alkyl moiety (defined above) to a parent core.
• suitable cycloaikylaikyls include cyclohexylmethyi, adamantyl methyl and the like.
• Cycloalkenyl or cyclenyl means a non-aromatic mono or multicyciic 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 cycloafkenyl rings contain about 5 to about 7 ring atoms.
• the cycloalkenyl can be optionally substituted with one or more "ring system substituents 11 which may be the same or different, and are as defined above.
• suitable monocyclic cycioalkenyis include cyclopentenyl, cyclohexenyl, cyclohepta-i ⁇ -dienyl, and the like.
• Non-limiting example of a suitable multicyclic cycioalkenyl is norbornylenyl.
• Cycloalkenylalkyl or cyclenylalkyl means a cycloalkenyl moiety as defined above linked via an alkyl moiety (defined above) to a parent core.
• suitable cycJoalkenyialkyis include cyclopentenylmethyi, cyciohexenylmethyt and the like.
• Cycioalkenylaikenyi or “CydoaikySalkenyi” means a cycfoa ⁇ k ⁇ nyl or cycloalkyl moiety respectively, as defined above, isnked via an aikenyi moiety as defined above.
• Halogen or halo means fluorine, chlorine, bromine, or iodine. Preferred are fluorine, chlorine and bromine.
• Ring system substituent means a subst ⁇ tuent attached to an aromatic or non- aromatic ring system which, for example, replaces an available hydrogen on the ring system.
• Ring system substituents may be the same or different, each being Independently s ⁇ f ⁇ cted from the group consisting of alkyi aikenyl, alkynyf, ary ⁇ , heteroary), arafkyl, alkylaryl, heteroaralkyl, heteroarylalkenyi, heteroarylafkynyl, aikylheteroaryl, hydroxy, hydroxyalkyi, aikoxy, aryloxy, aralkoxy, acyl, aroyi s halo, nitro, cyano, carboxy, aikoxycarbonyf, aryloxycarbonyl, aralkoxycarbonyl, alkylsulfonyl, aryisuffonyl, heteroarytsulfonyi, aikylthio, ary
• Y 1 Y 2 NSO 2 - and -SO 2 NY 1 Y 2 wherein Y 1 and Y 2 can be the same or different and are independently selected from the group consisting of hydrogen, alkyl, aryl, cycioalkyi, 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(CH 3 V and the like which form moieties such as, for example:
• ⁇ eteroarylaikyi or heteroarylaikenyl means a heteroaryl moiety as defined above linked via an alky I or alkenyl moiety respectively (defined above) to a parent core.
• suitable heteroaryls include 2-pyridinylmethyl, quinolinylmethy! and the like.
• Heterocyciyl or heterocycloalky! 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 h ⁇ terocyclyis contain about 5 to about 6 ring atoms.
• the prefix aza ; oxa or thia ⁇ efore the h ⁇ terocyciyi root name means that at feast a nitrogen, oxygen or sulfur atom respectively is present as a ring atom.
• Any -NH in a heterocyciyl 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 invention.
• the heterocyclyi can be optionally substituted by one or more "ring system substituenfs" which may be the same or different, and are as defined herein.
• the nrtrogen or sulfur atom of the heterocyciyl can be optionally oxidized to the corresponding N-oxide, S-o ⁇ sde or S,S- dioxide.
• suitable monocyclic heterocyclyl rings include piperidyl, pyrrolidinyi, piperazinyi, morpholinyf, thiornorpholinyl, thiazolidinyf, 1 ,4- dioxanyl, tetrahydrofuranyl, tetrahydrothiophenyf, lactam, lactone, and the like.
• Heterocyclyl may also mean a singfe moiety (e.g., carbonyl) which simultaneously replaces two available hydrogens on the same carbon atom on a ring system.
• a singfe moiety e.g., carbonyl
• Example of such moiety is pyrroiidone:
• heterocyclylalkyj or heterocycloalkylalkylrneans a heterocyclyl moiety as defined above linked via an alkyl moiety (defined above) to a parent core.
• suitable heterocyclylalkyls include piperidinylmethyl, piperazinylmethyl and the like.
• ⁇ eterocyclenyl 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 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 thia before the heterocyclenyl root name means that at least a nitrogen, oxygen or sulfur atom respectively is present as a ring atom.
• the heterocvcfenyf can be optionally substituted by one or more ring system subsfttuents, wherein "ring system substftue ⁇ f is as defined above.
• the nitrogen or sulfur atom of the heterocyclenyf 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 ,2-dihydropyridyl, 1 ,4-dfhydropyridyl, 1 ,2,3,6-tetrahydropyridine, 1 ,4,5,6-tetrahycfropyrimidine, 2-pyrroliny!, 3-pyr ⁇ oli ⁇ yi, 2-smkJazolinyJL 2 ⁇ pyrazoil ⁇ y!, d ⁇ hydroimidazoSe, dihydrooxazote, dihydrooxad ⁇ azo ⁇ e, dshydrottiiazoie, 3 ⁇ 4"dshydro-2H- pyran, dihydrofuranyi, fluorodihydrofuranyi, 7-oxabseydiQ[2, 2.I]HePIeOyI, dihydrothiopheny!, dihydrothiopyranyl.
• ⁇ eterocyclenyf may also mean a single moiety (e.g., carbonyi) which simultaneously replaces two available hydrogens on the same carbon atom on a ring system.
• a single moiety e.g., carbonyi
• Example of such moiety is pyrroiidinone:
• Heterocyclenylalky or heterocycloalkenylaikyi means a heterocyclenyl moiety as defined above linked via an alkyl moiety (defined above) to a parent core,
• Heteroaikyl 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.
• Heteroaikyl chains contain from 2 to 15 member atoms (carbon and heteroatoms) in the chain, preferably 2 to 10, more preferably 2 to 5.
• alkoxy (i.e., ⁇ O-a!kyi or -O-heteroalkyl) radicals are included in heteroaikyl.
• Heteroaikyl chains may be straight or branched.
• Preferred branched heteroaikyl have one or two branches, preferably one branch.
• Preferred heteroaikyl are saturated. Unsaturated heteroalky! 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, Heteroaikyl chains may be unsubstituted or substituted with from 1 to 4 substituents, Preferred substituted heteroafkyl are mono-, di-, or tri-substituted. Heteroalky] may be substituted with lower alkyl, haioalkyi, haio s hydroxy, arytoxy, heteroarytoxy, acyloxy. carboxy, monocyclic aryl. heteroary!. cycloaikyi, heterocyciy!. spirocycle, amino, acyiamino, am MG, keto, thioketo, cyano ; or any combination thereof.
• Alkynylalkyl means an alkynyl-aikyl- group in which the alkynyi and alkyl are as previously described.
• Preferred alkynylaikyis contain a lower alkynyi and a lower alkyi group.
• the bond to the parent moiety is through the aikyl.
• suitable aikynylalkyl groups include propargylmethyl.
• ⁇ eteroaralkyl means a heteroaryl-aikyl- group in which the heteroaryl and alkyl are as previously described.
• Preferred heteroaralkyls contain a lower aikyl group.
• suitable aralkyi groups include pyridyimethyi, and quinofin-3- ylmethyl.
• the bond to the parent moiety is through the alkyl.
• “Hydroxyalkyl” means a HO-alkyl- group in which alkyi is as previously defined.
• Preferred hydroxyalkyls contain lower a!kyl.
• suitable hydroxyalkyl groups include hydroxymethyl and 2-hydroxyethyl,
• acyl means an H-C(O)-, aikyi-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 tower alkyi. No ⁇ -iirniting examples of suitable acy ⁇ groups include forr ⁇ yl. acetyl and propanoyf.
• “Aroyi” means an aryl-C(O)- group in which the aryi group is as previously described.
• the bond to the parent moiety is through the carbonyl.
• suitable groups include benzoyl and 1 - naphthoyl.
• “Alkoxy * or "oxaalky! means an alkyi-G- group in which the alkyl group is as previously described,
• Non-Iimltmg examples of suitable aikoxy groups include methoxy, ethoxy, n-propoxy, isopropoxy and ⁇ -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 alkyny! ether (e.g. propargyl ⁇ xy group) linked to the parent moiety via the oxygen of oxaalkynyi.
• Aryloxy means an aryl-O- group in which the aryl group is as previously described.
• suitable aryioxy groups include phenoxy and naphthoxy.
• the bond to the parent moiety is through the ether oxygen.
• Aralkyloxy means an ara!ky!-O- group in which the araikyi group is as previously described.
• 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 aikyl group is as previously described.
• 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.
• suitable arylthio groups include phenylthio and naphthylthio.
• the bond to the parent moiety is through the sulfur.
• “Araikylthso” 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.
• uAlkoxycarbony! means an alkyl-O-CO- group.
• suitable aikoxycarbonyl groups include methoxycarbonyf and ethoxycarbonyi, The bond to the parent moiety is through the carbonyl.
• Ary!oxycarbony! Si means an aryS-0-C ⁇ O) ⁇ group.
• suitable aryioxycarbonyi groups include phenoxycarbonyl and naphthoxycarbonyi. The bond to the parent moiety is through the carbonyl.
• Araikoxycarbonyl means an ara!kyl-O-C(O)- group.
• Non-limiting example of a suitable araikoxycarbonyl group is benzyloxycarbonyl.
• the bond to the parent moiety is through the carbonyi.
• Aikylsulfonyl means an alkyl-S(t>2)- group. Preferred groups are those in which the alkyl group is lower alkyl. The bond to the parent moiety is through the sulfonyl.
• Aljsulfonyl means an aryl-S(O 2 )- group. The bond to the parent moiety is through the suifonyl.
• 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.
• 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.
• purified refers to the physical state of said compound after being isolated from a synthetic process or natural source or combination thereof.
• purified 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.
• protecting groups When a functional group in a compound is termed "protected”, this means that the group is in modified form to preclude undesired side reactions at the protected site when the compound is subjected to a reaction. Suitable protecting groups will be recognized by those with ordinary skill in the art as we!! as by reference to standard textbooks such as, for exampte, T. W, Greene et a/. Protective Groups in organic Synthesis (1991), Wiley, New York. When any variable (e.g., aryt, heterocycle, R 2 , etc.) occurs more than one time in any constituent or in Formula i, its definition on each occurrence is independent of its definition at every other occurrence.
• any variable e.g., aryt, heterocycle, R 2 , etc.
• composition is intended to encompass a product comprising the specified ingredients in the specified amounts, as well as any product which results, directly or indirectly, from combination of the specified ingredients in the specified amounts.
• 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, Pro-drugs as Novel Delivery Systems ( 1987) 14 of the A. C. S. Symposium Series, and in Bioreversibte 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 (I) or a pharmaceutically acceptable salt, hydrate or solvate of the compound. The transformation may occur by various mechanisms (e.g., by metabolic or chemical processes), such as, for example, through hydrolysis in blood.
• 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, (d-Caiaikyf, (C 2 - Ci 2 )alkanoytexymethyf. 1 -(a!kanoy!oxy)ethy!
• a prodrug can be formed by the replacement of the hydrogen atom of the alcohol group with a group such as, for example, (Ci-Cejalkanoyloxymethyl, 1 -((Cr C 6 )alkanoy!oxy)ethyi, 1 -methyi-1-((Ci-Ce)alkanoyloxy)ethyl, (Cr C e )alkoxycarbonyloxymethyi, N-tCrCeJalkoxycarbonyiaminomethyl, succinoyl, (Cr C 6 )alkanoyl, u-arninotCrC ⁇ alkanyi, arylacyl and ⁇ -aminoacyl, or ⁇ -aminoacyl- ⁇ - aminoacyi, where each ⁇ -aminoacyl group is independently selected from the naturally occurring L-amino acids, P(O)(OH) 2 , -
• 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 (CrCio)alkyl, (C 3 -C 7 ) cycloalkyl, benzyl, or R-carbonyl is a natural ⁇ -aminoacyl or natural ⁇ -aminoacyl, -C(OH)C(O)OY 1 wherein Y 1 is H, (Cr C e )aikyl or benzyl, — C(OY 2 ) Y 3 wherein Y 2 is (C 1 -C 4 ) alkyl and Y 3 is (CrC 6 )a!kyl, carboxy (Ci-C 6 )alkyl, am!no(C r C 4 )alkyl or mono-
• R-carbonyl RO-carbonyl
• 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 the like, and it is intended that the invention embrace both soivated and unsoivated forms.
• “Solvate” means a phystea ⁇ association of a compound of this invention with one or more solvent mofec ⁇ ies. This physical association involves varying degrees of ionic and covalent bonding, including hydrogen bonding. In certain instances the solvate will be capable of isolation, for example when one or more solvent molecules are incorporated in the crystal lattice of the crystalline solid.
• Solvate encompasses both soiution-phase and isofatabfe solvates.
• solvates include ethan ⁇ laies, methanoiates. and the like, "Hydrate * is a solvate wherein the soiv ⁇ nt molecule is H 2 O.
• One or more compounds of the invention may optionally be converted to a solvate.
• Preparation of solvates is generally known.
• M. Caira et al, J. Pharmaceutical ScL, 93(3), 601-61 1 (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.
• 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 I. 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.
• zwitterions inner salts may be formed and are included within the term "salt(s)" as used herein.
• 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 iyophitization.
• exemplary/ acid addition safe include acetates, ascorbates, be ⁇ zoates. benzenesulfonates * bisuffates, borates, butyrat ⁇ s, citrates, camphorates, camphorsuifo ⁇ ates, fumarates.
• acids which are generally considered suitable for the formation of pharmaceutically useful salts from basic pharmaceutical compounds are discussed, for example, by P. Stah! et ai, Camrite G. (eds.) Handbook of Pharmaceutical Salts. Properties, Selection and Use.
• 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-butyi 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 chiorides, bromides and iodides), dialkyl sulfates (e.g.
• dimethyl, diethyl, and dibutyl sulfates 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
• esters of the present compounds include the fofiowing groups: (1 ) carboxyhc acid esters obtained by ester ⁇ ficat ⁇ on of the hydroxy groups, in which the non-carbonyf moiety of the carboxylic acid portion of the ester grouping is selected from straight or branched chain alkyl (for example, acetyl, n- propyi, t-butyi, or rvbutyl), alkoxyalkyi (for example, methoxymethyl), aralkyl (for example, benzyl), aryfoxyaikyi (for example, phe ⁇ oxymetnyl), aryl (for example, phenyl optionally substituted with, for example, halogen, or d- 4 a!koxy or amsno); (2) sulf
• the phosphate esters may be further esterified by, for example, a Ci -20 alcohof or reactive derivative thereof, or by a 2,3-di (C 6 -24)acyI 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 (I) 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.
• the present invention embraces alt geometric and positional isomers. For example, if a compound of Formula (I) 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., chira! auxiliary such as a chiral alcoho! or Mosher's acid chloride), separating the diastereomers and converting (e.g., hydrolyzing) the individual diastereomers to the corresponding pure enantiomers.
• an appropriate optically active compound e.g., chira! auxiliary such as a chiral alcoho! or Mosher's acid chloride
• converting e.g., hydrolyzing
• some of the compounds of Formula (I) may be atropisomers (e.g., substituted biaryls) and are considered as part
• All stereoisomers (for example, geometric isomers, optical isomers and the like) of the present compounds including those of the sails, solvates, esters and prodrugs of the compounds as well as the salts, solvates and esters of the prodrugs), such as those which may exist due to asymmetric carbons on various substttuents, including enantiomeric forms (which may exist even in the absence of asymmetric carbons), rctameric forms, atropisomers, and diastereomeric forms, are contemplated within the scope of this invention, as are positional isomers (such as, for example, 4-pyridyl and 3-pyridyi).
• a compound of Formula (I) 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.
• ad 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, or may be admixed, for example, as racemates or with all other, or other selected, stereoisomers.
• the chiral centers of the present invention can have the S or R configuration as defined by the IUPAC 1974 Recommendations.
• salt is intended to equally apply to the salt, solvate, ester and prodrug of enantiomers, stereoisomers, rotamers, tautomers, positional isomers, racemates or prodrugs of the inventive compounds.
• the present invention also embraces isotopicaily- ⁇ abefied 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.
• isotopes that can be incorporated into compounds of the invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine and chlorine, such as 2 H, 3 H, 13 C, 14 C, 15 N, 18 O 5 17 O, 31 P, 32 P, 35 S, 18 F, and 36 CI, respectively.
• Certain isotopically-iabeiled compounds of Formula (I) are useful in compound and/or substrate tissue distribution assays. Tril ⁇ afed (i.e., 3 H) and carbon- 14 ⁇ i.e., 14 C) isotopes are particularly preferred for their ease of preparation and detectability.
• isotopically labelled compounds of Formula (!) can generally be prepared by following procedures analogous to those disclosed in the Schemes and/or in the Examples hereinbefow, by substituting an appropriate isotopically labelled reagent for a ⁇ on-isotopicalty labelled reagent.
• 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.
• IC 5 O 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.
• EC 5 O 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.
• 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.
• the residue is the L form.
• amino acid refers to ⁇ -amino acids which are racemic, or of either the D- or (--configuration.
• the designation "d” preceding an amino acid designation e.g., dAla, dSer, dVal, etc.
• the designation ! 'dl preceding an amino acid designation (e.g., dlPip) refers to a mixture of the L- and D-isomers of the amino acid.
• substantially pure means sufficiently homogeneous to appear free of readily detectable impurities as determined by standard methods of analysis. such as thin [aver chromatography (TLC), gel eiectrophoresis, high performance liquid chromatography (HPLC) and mass spectrometry (MS), used by those of skill in the art to assess such purity, or sufficiently pure such that further purification would not detectably alter the physical and chemical properties, such as enzymatic and biological activities, of the substance.
• TLC trans chromatography
• HPLC high performance liquid chromatography
• MS mass spectrometry
• purified refers to the physical state of said compound after being isolated from a synthetic process or natural source or combination thereof.
• purified 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,
• haloalkoxy refers to RO- in which R is a haloalkyl group.
• heterocyclyioxy refers to RO- in which R is a heterocyclyl group
• heteroaryloxy refers to RO- in which R is a heteroaryl group
• substituted alkyl refers to alky!, alkenyt alkynyl, cycfoalkyS, cyclo
• amldo refers to the divalent group -C(O)NH-.
• Thioamido refers to the divalent group -C(S)NH-.
• Oxyamido iS refers to the dsvatent group - OC(O)NH-.
• Thiaamicfo refers to the divatenf group -SC(O)NH-.
• Dithiaamido refers 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-.
• haloalkyi may include one or more of the same or different halogens.
• haloalkyi may include one or more of the same or different halogens.
• Ci-aalkoxyphenyr 1 may include one or more of the same or different alkoxy groups containing one, two or three carbons.
• the compounds provided herein for use in the compositions and methods provided herein have formula I 1 where the variables are as described below. Al! combinations of such embodiments are within the scope of the instant disclosure.
• R 3 is hydrogen, alkyf, cycioalkyl, cycienyi, alkynyi, trifluroalkyi, difiuroalkyl, monofluroalkyl, heterocyclyl, heterocyclenyf, aryl, heteroaryl, halo, cyano, -O- trihaloalkyl, NR 8 R 9 5 CO 2 R 8 , CONR 8 R 9 , -OR 8 , -SR 8 , -SO 2 R 8 , -SO 2 NR 8 R 9 , -NR 8 SO 2 R 9 , - NR 8 COR 3 , or NR 8 CONR 8 R 9 , wherein each of said alkyl, cycioalkyl, cycienyi, alkynyi, tfifluroaikyi, difluroalkyl.
• R 5 and R 7 are each selected from the group consisting of hydrogen, alkyf, aminoalkyl, alkenyl, alkynyl, aryl, heterocyclyi, heterocycienyl, cycloalkyi, cyclenyl, cycfoalkySaikyl, cyclenylalkyl, cycioalkylalkenyl, cyclenylalkenyl, heteroaryi, heteroarylalkyl, heteroaryialkenyl, arylalkyl, arylalkenyl, heterocyclylalkyl, heterocyclenylalkyl, heterocyclylaikenyf, heterocyclenylaikenyl, -S-heterocycfyl, -S- aminoalkyl, -S-heterocycienyl, NR 8 R 9 , NR 8 COR 9 , NR 8 SO 2 R 9 , COR 8 , CO 2 R 8 , CONR
• -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, alky!, trihaloalkyl, alkenyi, dihaloalkyl, monohaloalkyl, hydroxyalkyl, OR 8 , -O, NR 8 R 9 , SR 8 , SO 2 R 9 , CN, SO 2 NR 8 R 9 , and NO 2 ;
• R 6 is hydrogen, halo, trihaloalkyl, alkyl, alkenyi, aryl, cyclenyl, cycloalkyi, heteroaryi, heterocycienyi, heterocyclyi, heteroarylalkyl, heterocycienylalkyl, heterocyclylalkyl, arylalkyl, cyclenylalkyl, cydylalkyl, NR 8 R 9 , NR 8 COR 9 , NR 8 SO 2 R 9 , COR 8 , CO 2 R 8 , CONR 8 R 9 , CH 2 OR 8 , OR 8 , SR 8 , or SO 2 R 6 , wherein each of said alkyl, alkenyi, aryl, cyclenyl, cycloalkyi, heteroaryi, heterocycienyi, heterocydyl, heteroarylalkyl, heterocyclenylalkyl, heterocyclylalkyl , aryiaikyl
• NR 8 R 9 CO 2 R 8 , CONR 8 R 3 , -SR 8 , SO 2 R 6 , SO 2 NR 8 R 9 , NO 2 , NR 8 SO 2 R 9 , NR 8 COR 9 , and NR 8 CONR 8 R 9 ;
• R e and R 9 are each independently selected from the group consisting of hydrogen, trihafoaikyf, dihaloa ⁇ kyi, monohai ⁇ aikyi, aSkyf, a ⁇ k ⁇ nyi, aryl heteroaryi, arylalkyi, cyctoalky!, cycienyi, cycloaSkyialkyi, cyclenylalkyl, cyclenylaikenyl, heterocycienyl, heterocyciyi, heterocycte ⁇ ylaikyl, heterocyc! ⁇ nyja!kenyl, heterocyclylalkyl, and heteroarylaikyl, wherein each of said alky!, alk ⁇ yi, aryl, heteroaryi, arylalky!, cycloalkyl, cyclenyl, cycloatkylafkyl, cyclenylalkyl, cyclenylalkenyl, heterocycfenyl
• R 3 is selected from the group consisting of heteroaryi, alkyl, halogen and cycloalkyl, wherein said heteroaryl can be unsubstituted or substituted with alkyl.
• R 3 is In another embodiment, R 3 is In yet another embodiment, R 3 is
• R 3 is ethyl
• R 3 is cyclopropyl. in yet still another embodiment, R 3 is bromine.
• R 5 is selected from the group consisting of
• heterocylyi can be unsubstituted or substituted with hydroxyalkyf and said aryl can be unsubstituted or substituted with halogen.
• R 5 is or In yet another embodiment, R is
• R 6 is halogen or (d-C 6 )a!kyI.
• R 6 is bromine, methyl or ethyl.
• R 7 is -NHR 8 , wherein R 8 is selected from the group consisting of hydrogen, heteroaryl and heteroarylalkyl, wherein said heteroaryiaikyl can be unsubstituted or substituted with one or more moieties independently selected from the group consisting of hydroxy!, oxo, alkyl, and alkoxyl and said heteroary! can be unsubstituted or substituted with alkyl.
• R 8 is
• R 8 is
• R 3 , R " 5 R 6 and R 7 are selected independently of each other wherein:
• R 3 is selected from the group consisting of heteroaryl, alkyl, halogen and cycfoalkyl, wherein said heteroaryl can be unsubstituted or substituted with alkyl;
• R 5 is selected from the group consisting of heterocycly!, aryl, OH , wherein said heterocyly! can be unsubstituted or substituted with hydroxyalky! and said aryl can be unsubstituted or substituted with halogen;
• R 6 is halogen or (Ci-C ⁇ )alkyl
• R 8 is selected from the group consisting of hydrogen, heteroaryl and heteroarylaikyl, wherein said heteroarylaikyl can be unsubstituted or substituted with one or more moieties independently selected from the group consisting of hydroxyl, oxo, alkyl, and aikoxyl and said heteroaryl can be unsubstituted or substituted with alkyl.
• R 3 , R 5 , R 6 and R 7 are selected independently of each other wherein:
• R 3 is selected from the group consisting of
• R 5 is selected from the group consisting of . , wherein said phenyl can be unsubstituted or substituted w ith fluorine; R 6 is bromine, methyl or ethyl; R 8 is
• a pharmaceutical composition comprising a compound of Formula 1 , and a pharmaceutically acceptable carrier.
• composition containing the compounds of Formula I that is formulated for single dosage administration.
• 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 amount of a compound of Formula i or a pharmaceutically acceptable salt thereof, Sn another embodiment, use of a compound of Formula I in the preparation of a medicament for the treatment of a CHK- 1 mediated disease.
• a method of treatment, prevention, or amelioration of one or more symptoms of a disease or disorder that is modutated or otherwise affected by CHK-I comprising administering to a patient in need thereof an effective amount of a compound of Formula 1 or a pharmaceutically acceptable salt thereof.
• the disease or disorder that is treated is selected from the group inflammatory disease, neurodegenerative disease, cancer and diabetes.
• the disease treated is an inflammatory disease selected from the group consisting of acute pancreatitis, chronic pancreatitis, asthma, allergies, and adult respiratory distress syndrome.
• 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.
• the disease treated is diabetes selected from diabetes meflitus and diabetes insipidus.
• the diabetes treated is selected from type 1 diabetes and type 2 diabetes.
• the disease treated is a cancer 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, myelodyspiastic syndrome and promyeiocytic leukemia;
• CLL chronic lymphocytic leukemia
• B-cell lymphoma T- cell lymphoma, Hodgkins lymphoma, non-Hodgkins lymphoma, hairy cell lymphoma, mantle ce ⁇ l lymphoma, myeloma and Burkett's lymphoma; fibrosarcoma, rhabdomyosarcoma; hea ⁇ and neck, mantle cell lymphoma, myeloma; astrocytoma, neuroblastoma, glioma, glioblastoma, malignant glial tumors, astrocytoma, hepatocellular carcinoma, gastrointestinal stromal tumors ("GIST”) and schwannomas; inesa ⁇ oma, rnultipte myeloma, seminoma, teratocarcinoma, osteosarcoma, xenoderoma pigmentosum, keratoctanthoma, thyroid follicular cancer and Kaposi's sarcoma
• said anti-cancer agent is selected from the group consisting of a cytostatic agent, cytostatic agent, cisplatin, doxorubicin, taxotere, taxol, etoposide, irinotecan, camptostar, topotecan, paciitaxe!, docetaxel, epoth ⁇ ones, tamoxifen, 5-fluorouracil, methoxtrexate, temozolomide, cyclophosphamide, SCH 66336, R115777, L778 5 123, BMS 214662, Iressa, Tarceva, antibodies to EGFR, Gieevec, intron, ara-C, adriamycin, Cytoxan, gemcitabine, Uracil mustard, Chlormethine, Ifosfamide, Melphalan, Chlorambucil, Pipobroman, Triethylenemelamine, Triethylenethiophosphoramine, Busulfan, Carmustine,
• 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.
• 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.
• 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 one compound of Formula I 1 or a pharmaceutically acceptable salt, solvate, ester or prodrug thereof, in combination with at least one pharmaceutically acceptable carrier to said patient.
• SR SR
• 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 recrystaliization.
• a method such as column chromatography, high-pressure liquid chromatography, or recrystaliization.
• 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 performed in an alternate sequence or order to give the desired compounds.
• Synthetic chemistry transformations and protecting group methodologies 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 P. G. M. Wuts, Protective Groups in Organic Synthesis, 2d. Ed., John Wiley and Sons (1991 ); L Fieser and M, Fieser, Fieser and Fieser's Reagents for Organic Synthesis, John Wiley and Sons (1994); and L Paquette, ed. ; Encyclopedia of Reagents for Organic Synthesis, John Wiley and Sons (1995), and subsequent editions thereof.
• 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 s for example, the inhibitors of the cycl ⁇ n-dependent kinases, Checkpoint kinase, mitogen-activated protein kinase (MAPKZERK) 5 glycogen synthase kinase 3(GSK3beta) and the like,
• the cyc ⁇ in dependent kinases (CDKs) include, for example, CDC2 (CDK1), CDK2 : GDK4, CDKS, CDKS, CDK7 and CDK8.
• One such Checkpoint kinase is CHK-1.
• 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.
• 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.
• 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.
• 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, myeiodysplastic syndrome and promyeiocytic leukemia; tumors of mesenchymal origin, including fibro
• inhibitors could act as reversible cytostatic agents which may be us ⁇ fti in the treatment of any disease process which features abnormal cellular proliferation, e.g., benign prostate hyperplasia, familial adenomatosis polyposis, neurofibromatosis, atherosclerosis, pulmonary fibrosis, arthritis, psoriasis, glomerulonephritis, restenosis following angioplasty or vascular surgery, hypertrophic scar formation, inflammatory bowei disease, transplantation rejection, e ⁇ dotoxic shock, and fungai infections.
• One series of checkpoints monitors the integrity of the genome and.
• 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 Formula I, as modulators of apoptosis, will be useful in the treatment of cancer (including but not limited to those types mentioned hereinabove), viral infections (including but not limited to herpevirus, poxvirus, Epstein- Barr virus, Sindbis virus and adenovirus), prevention of AIDS development in HIV-infected individuals, autoimmune diseases (including but not limited to systemic lupus, erythematosus, autoimmune mediated glomerulonephritis; rheumatoid arthritis, psoriasis, inflammatory bowel disease, and autoimmune diabetes meliitus), neurodegenerative disorders (including but not limited to Alzheimer's disease, AIDS-refated dementia, Parkinson's disease, amyotrophic lateral sclerosis, retinitis pigmentosa, spinal muscular atrophy and cerebellar degeneration
• Compounds of Formula I 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 HlV 1 human papilloma virus, herpesvirus, poxvirus, Epstein-Barr virus, Sindbis virus and adenovirus).
• viral infections including but not limited to HlV 1 human papilloma virus, herpesvirus, poxvirus, Epstein-Barr virus, Sindbis virus and adenovirus.
• 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, PI3 kinase, weel kinase, Src, AbI and thus be effective in the treatment of diseases associated with other protein kinases.
• another aspect of this invention is a method of treating a mamma! (e.g., human) having a disease or condition associated with the CDKs by administering a therapeutically effective amount of at least one compound of Formula ⁇ , or a pharmaceutically acceptable salt or solvate of said compound to the mammal.
• a mamma! e.g., human
• 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- cancer agents selected from the group consisting of cytostatic agents, cytotoxic agents (such as for example, but not limited to, DNA interactive agents (such as dsp ⁇ at ⁇ n or doxorubicin)); taxanes (e.g. taxotere, taxoi); topoisomerase (I inhibitors (such as ⁇ toposide); topotsomerase !
• cytostatic agents such as for example, but not limited to, DNA interactive agents (such as dsp ⁇ at ⁇ n or doxorubicin)
• taxanes e.g. taxotere, taxoi
• topoisomerase I inhibitors (such as ⁇ toposide); topotsomerase !
• inhibitors such as irinotecan (or CPT-11 ), carnptostar, or topotecan); tubulin interacting agents (such as paclitaxel, docetaxel or the epothilones); hormonal agents (such as tamoxifen); thymidilate synthase inhibitors (such as 5-ffuorouraciI); 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, SARASARTM(4-[2-[4-[(11 R)-3,10-dibromo-8-chloro-6,11 -dihydro-5H- benzo[5,6]cyclohepta[1 ,2-b]pyridin-11 -yl-]-1 -piperidinyi]-2-oxoeh
• L778 t 123 (a farnesyl protein transferase inhibitor from Merck & Company, Whitehouse Station, New Jersey), BMS 214662 (a farnesyl protein transferase inhibitor from Bristol-Myers Squibb Pharmaceuticals, Princeton, New Jersey); signal transduction inhibitors (such as, lressa (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-lntron (from Schering-Plough Corporation); hormonal therapy combinations; aromatase combinations; ara-C, adriamycin, Cytoxan, and gemcitabine.
• signal transduction inhibitors such as, lressa (from Astra Zeneca Pharmaceuticals, England), Tarceva (EGFR
• anti-cancer also known as antineoplastic
• anti-cancer 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, Ffudarabine phosphate, oxaliplatin, leucovirin, oxalip ⁇ atin (ELOXATfN l ' M from Sanofi-Synthelabo Pharmaeutfca ⁇ s, France), Pentostafine, Vinblastine.
• Vincristine, Vindesine, Bleomycin, Dactinomyci ⁇ , Daunorubicin s Doxorubicin, Epirubicin, idarubicin, Mithramycin, Deoxycoformycin, Mitomyci ⁇ -C, L-Asparaginase, Teniposid ⁇ 17 ⁇ -Ethinylestradiol, Dietnyfstilbestrol, Testosterone, Prednisone, Fluoxymesterone, Dromostanoione propionate, T ⁇ stOsacfone, Megestroiacetate, Methyfprednisolo ⁇ e, Methyltestosterone, Prednisolone, Triamcinolone, Chlorotrianisene, Hydroxyprogesterone, Aminoglutethisnide, Estramustine, Medroxyprogesteroneacetate.
• rituxan sunitinib, dasatinib, tezacitabin ⁇ , SmH , fludarabine, pentostatin, triapine, didox, trimidox, amidox, 3-AP, and MDL-101 ,731 .
• the therapeutic agents in the combination 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 amounts).
• 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 ⁇ ke).
• a commercial example of such single dosage unit containing fixed amounts of two different active compounds for oral administration is VYTORi N ® (available from Merck Schering-Plough Pharmaceuticals, Kenilworth, New Jersey).
• 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.
• the CDC2 inhibitor olomucine has been found to act synergisticafiy with known cytotoxic agents in inducing apoptosis (J, Cell ScL, (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.
• the cytotoxic activity of the cyci ⁇ n-dependerrt kinase inhibitor ftevopirido( is affected by the sequence of administration with anticancer agents. Cancer Research, ⁇ 1997 ⁇ 57. 3375. Such techniques are within the skills of persons skilled in the art as well as attending physicians.
• this invention includes combinations comprising an amount of at least one compound of Formula I, or a pharmaceutically acceptable salt or solvate thereof, and an amount of one or more anti-cancer treatments and anticancer agents listed above wherein the amounts of the compounds/ treatments result in desired therapeutic effect.
• 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.
• 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 iimited 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.
• 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 provided herein.
• the compounds are, in one embodiment formulated into suitable pharmaceutical preparations such as solutions, suspensions, tablets, dispersibte 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 patch preparation and dry powder inhaters.
• the compounds described above are formulated into pharmaceutical composrttons using techniques and procedures well known in the art (see, e.g., Ansel Introduction to Pharmaceutical Dosage Forms, Fourth Edition 1985, 126).
• 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 derivat ⁇ zed as the corresponding salts, esters, enol ethers or esters, acetals, ketais, orthoesters, hemiacetais, hemiketals, acids, bases, solvates, hydrates or prodrugs prior to formulation, as described above.
• 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.
• the compositions are formulated for single dosage administration.
• 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.
• a therapeutically effective dosage shouW produce a serum concentration of active ingredient of from about 0,1 ng/ml to about 50- 100 ⁇ g/ml.
• compositions in another embodiment, 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 rng s 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 5 ingredients per dosage unit form.
• the active ingredient may be administered at once, or may be divided into a number of smalier 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
• 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
• 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 0 (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.
• cosolvents such as dimethylsulfoxide 0 (DMSO)
• surfactants such as TWEEN ®
• dissolution in aqueous sodium bicarbonate such as sodium bicarbonate
• the resulting mixture may be a solution, suspension, emulsion or the like.
• the form of the resulting mixture depends 5 upon a number of factors, including the intended mode of administration and the solubility of the compound in the sefected 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 0 and animals in unit dosage forms, such as tablets, capsules, pi ⁇ s powders, granules, ste ⁇ le parenteral solutions or suspensions, and oral solutions or suspensions, and oil- water emulsions containing suitable quantities of the compounds or pharmaceutically 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.
• 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.
• muitiple-dose forms include vials, bottles of tablets or capsules or bottles of pints or gallons.
• 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.
• a carrier such as, for example, water, saline, aqueous dextrose, glycerol, glycols, ethanol, and the like, to thereby form a solution or suspension.
• 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, cyciodextrine derivatives, sorbitan monofaurate, triethanolamine sodium acetate, triethanolamine oleate, and other such agents,
• auxiliary substances such as wetting agents, emulsifying agents, solubilizing agents, pH buffering agents and the like, for example, acetate, sodium citrate, cyciodextrine derivatives, sorbitan monofaurate, triethanolamine sodium acetate, triethanolamine oleate, and other such agents.
• compositions containing active ingredient in the range of 0.005% to 100% with the balance made up from non-toxic carrier may be prepared, Methods for preparation of these compositions are known to those skived the art.
• the contemplated compositions may contain 0,001 %- 100% active ingredient, in one embodiment 0,1 -95%, in another embodiment 75-85%.
• 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, sugar-coated or film-coated.
• Capsules may be hard or soft gelatin capsules, white granules and powders may be provided in non-effervescent or effervescent form with the combination of other ingredients known to those skilled ⁇ n the art.
• Solid compositions for oral administration In certain embodiments, the formulations are solid dosage forms, in one embodiment, capsuies 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 diiuent; a glidant; a disintegrating agent; a coloring agent; a sweetening agent; a flavoring agent; a wetting agent; an emetic coating; and a film coating.
• binders include microcrystaUine cellulose, gum tragacanth, 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 dicalctum phosphate.
• Glidants include, but are not limited to, colloidal silicon dioxide.
• Disintegrating agents include crosscarmellose sodium, sodium starch giycolate, alginic acid, corn starch, potato starch, bentonite, rnethyfceilulose, 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, mannitoS and artificial sweetening agents such as saccharin, and any number of spray dried flavors- Flavoring agents include natural flavors extracted from piants 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 rnonostearate, sorbitan monooleate, diethylene glycol rnonolaurate and polyoxyethylene ⁇ aura ⁇ ether.
• Eme ⁇ c-coatings Jn clude fatty acids ; fats, waxes, shellac, ammomafed shellac and cellulose acetate phthalates.
• Film coatings Include hydroxyethylceliulose, sodium carboxyrrt ⁇ thylcetlutose, 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.
• 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.
• the dosage unit form 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.
• 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.
• 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.
• they may be coated with a conventional enterically digestible coating, such as phenylsalicylate, waxes and cellulose acetate phthalate.
• enterically digestible coating such as phenylsalicylate, waxes and cellulose acetate phthalate.
• Liquid oraf 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 osl-in-water or water- ⁇ n- oil
• Elixirs are ctear, sweetened, hydroalcoho ⁇ c preparations.
• Pharmaceutically acceptable carriers used in elixirs include solvents. Syrups are concentrated aqueous 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.
• preservatives include glycerin, methyl and propylparaben, benzoic acid, sodium benzoate and alcohol.
• non-aqueous liquids utilized in emulsions include mineral oil and cottonseed oil.
• 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 fauryl 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.
• the solution or suspension in for example propylene carbonate, vegetable oils or triglycerides, is in one embodiment encapsulated in a gelatin capsule.
• the solution e.g., for example, in a polyethylene glycol
• a pharmaceutically acceptable liquid carrier e.g., water
• liquid or semi-solid orai formulations may be prepared by dissolving or dispersing the active compound or salt in vegetable oils, glycate, 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.
• 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-dimethoxymethane, diglyme, trigfyme, tetraglyme, polyethylene glycol-350-dimethyl ether, polyethylene giycol-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 hydroxytoluene (BHT), butyiated hydroxyanisoie (BHA), propyl gallate, vitamin E, hydroquinone, hydroxycoumarins, ethanoiamtne, lecithin, cephalin, ascorbic acid, malic acid, sorbitol, phosphoric acid, thiod ⁇ propionic acid and its esters
• 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 iimited to, propylene glycol and ethanol.
• Acetals include, but are not limited to, di(lower alky!) acetais of lower alkyl aldehydes such as acetaldehyde diethyl acetai. 2, Injectables, solutions and emulsions
• Parenteral administration in one embodiment characterized by injection, either subcutaneousiy, 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 excipie ⁇ ts. Suitable exctpients are, for exampfe, water, saline, dextrose, glycerol or ethanol.
• the pharmaceutical compositions to be administered 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 monot ⁇ urate, triethanolamin ⁇ ofeafe and cyclodextrins implantation of a slow-release or sustained-r ⁇ fease system, such that a constant level of dosage is maintained is aiso contemplated herein.
• 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 monot ⁇ urate, triethanolamin ⁇ ofeafe and cyclodextrins implantation of a slow-release or sustained-r ⁇ fease system, such that a constant level of dosage is maintained is aiso contemplated herein.
• a compound provided herein is dispersed in a solid inner matrix, e.g., polymethylmethacrylate, polybutylmethacrylate, pfasticized or unplasticized polyvinylchloride, piasticized nyion, plasticized polyethyieneterephthafate, natural rubber, poiyisoprene, polyisobutytene, polybutadiene, polyethylene, ethylene- vinytacetate 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-finked partially hydroiyzed polyvinyl acetate, that is surrounded by an outer polymeric membrane, e.g., polyethylene, polypropylene, ethylene/propylene copolymers, ethylene/ethyl acrylate copolymers, e
• 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 iyophilized powders, ready to be combined with a solvent just prior to use, including hypodermic tablets, sterile suspensions ready for injection, sterile dry insoluble products ready to be combined with a vehicle just prior to use and sterile emulsions.
• the solutions may be either aqueous or nonaqueous,
• suitable carriers include physiological saline or phosphate buffered saline (PBS), and solutions containing thickening and solub ⁇ lizing agents, such as glucose, polyethylene glycol, and polypropylene glycol and mixtures thereof.
• PBS physiological saline or phosphate buffered saline
• thickening and solub ⁇ lizing agents such as glucose, polyethylene glycol, and polypropylene glycol and mixtures thereof.
• Pharmaceutically acceptable carriers used in parenteral preparations include aqueous vehicles, nonaqueous vehicles, a ⁇ timicrobiai agents, isotonic agents. buffers, antioxidants, local anesthetics, suspending and dispersing agents, emulsifying agents, sequestering or chelating agents and other pharmaceutically acceptable substances.
• aqueous vehicles examples include Sodium Chloride Injection, Ringers Injection, Isotonic Dextrose Injection, Sterile Water Injection, Dextrose and Lactated Ringers injection.
• Nonaqueous 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 cresofs, mercurials, 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, hydroxypropyl methylcellulose and polyvinylpyrrolidone. Emulsifying agents include Polysorbate 80 (TWEEFvP 80). A sequestering or chelating agent of metal ions include EDTA.
• Pharmaceutica! carriers also include ethyl alcohol, polyethylene glycol and propylene glycol for water mtscible vehicles; and sodium hydroxide, hydrochloric acid, citric acid or lactic acid for pH adjustment. 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 syringe with a needle, All. preparations for parenteral administration must be sterile, as is known and practiced in the art.
• 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 desired pharmacological ef%ct
• Injectabies are designed for focai and systemic administration.
• a therapeutically effective dosage is formulated to contain 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 mieronized or other suitabfe 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.
• Lyophiiized powders Of interest herein are also lyophiiized 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, lyophiiized 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.
• the resulting solution will be apportioned into vials for lyophilization.
• Each vial will contain a single dosage or multiple dosages of the compound.
• the lyophjiized powder can be stored under appropriate conditions; such as at about 4 0 C to room temperature.
• Reconstitution of this lyophiiized powder with water for injection provides a formulation for use in parenteral administration.
• the iyophilized powder is added to sterile water or other suitable carrier. The precise amount depends upon the selected compound. Such amount cars be empirically determined,
• 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 insufflation, alone or in combination with an inert carrier such as lactose.
• 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.
• compositions for other routes of administration may be formulated as 0.01 % - 10% isotonic solutions, pH about 5-7, with appropriate salts. 5, Compositions for other routes of administration
• transdermal patches including io ⁇ tophoretfe and eiectrophoretic devices, and rectal administration, are also contemplated herein.
• Transdermal patches including iotophoretic and eiectrophoretic devices, are well known to those of skill in the art.
• Recta! suppositories are used herein mean solid bodies for insertion into the rectum whscn melt or soften at body temperature releasing one or more pharmacologically or therapeutically active ingredients.
• Pharmaceutically acceptable substances utilized in recta! suppositories are bases or vehicles and agents to raise the melting point. Examples of bases include cocoa butter (theobroma oil), glycerin-gelatin, carbowax (polyoxyethyfene glycol) and appropriate mixtures of mono-, di- and triglycerides of fatty acids. Combinations of the various bases may be used.
• spermaceti and wax 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.
• 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. Ail such targeting methods are contemplated herein for use in the instant compositions.
• liposomal suspensions including tissue-targeted liposomes, such as tumor-targeted liposomes, may also be suitable as pharmaceutically acceptable carriers.
• liposomes such as multilamellar vesicles (MLV y 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 fesk shaken until the lipid film is dispersed. The resulting vesicles are washed to remove unencapsulated compound, pelleted by centrifugatton, and then resuspended in PBS.
• PBS phosphate buffered saline lacking divalent cations
• the compounds or pharmaceutically acceptable derivatives may be packaged as articles of manufacture containing packaging material, a compound or pharmaceutically acceptable derivative thereof provided herein, which is effective for moduiating 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 activity, is implicated, within the packaging material, and a label that indicates that the compound or composition, or pharmaceuticaf ⁇ y 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.
• 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.

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  • 2008-11-25 WO PCT/US2008/084643 patent/WO2009070567A1/en active Application Filing
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