Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
  • C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P17/00—Drugs for dermatological disorders
  • A61P17/14—Drugs for dermatological disorders for baldness or alopecia
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P19/00—Drugs for skeletal disorders
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P25/00—Drugs for disorders of the nervous system
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
  • A61P31/10—Antimycotics
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
  • A61P31/12—Antivirals
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P35/00—Antineoplastic agents
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P35/00—Antineoplastic agents
  • A61P35/02—Antineoplastic agents specific for leukemia
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P9/00—Drugs for disorders of the cardiovascular system
  • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
  • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
  • C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links

Definitions

• the present invention relates to novel Diamido Thiazole Derivatives, compositions comprising the Diamido Thiazoie Derivatives, and methods for using the Diamido Thiazole Derivatives for treating or preventing a proliferative disorder, an antiproliferative disorder, inflammation, arthritis, a central nervous system disorder, a cardiovascular disease, alopecia, a neuronal disease, an ischemic injury, a viral infection, a fungal infection, or a disorder related to the activity of a protein kinase.
• Protein kinases are a family of enzymes that catalyze phosphorylation of proteins, in particular the hydroxy! group of specific tyrosine, serine, or threonine residues in proteins. Protein kinases are pivotal in the regulation of a wide variety of cellular processes, including metabolism, cell proliferation, cell differentiation, and cell survival. Uncontrolled proliferation is a hallmark of cancer cells, and can be manifested by a deregulation of the cell division cycle in one of two ways - making stimulatory genes hyperactive or inhibitory genes inactive.
• Protein kinase inhibitors, regulators or modulators alter the function of kinases such as cyclin-dependent kinases (CDKs), mitogen activated protein kinase (MAPK/ERK), glycogen synthase kinase 3 (GSK3beta), Checkpoint (Chk) (e.g., CHK-1 , CHK-2 etc.) kinases, AKT kinases, JNK, and the like.
• CDKs cyclin-dependent kinases
• MAPK/ERK mitogen activated protein kinase
• GSK3beta glycogen synthase kinase 3
• Checkpoint Chk
• Examples of protein kinase inhibitors are described in WO02/22610 A1 and by Y. Mettey ef a/., in J. Med. Chem., 46:222-236 (2003).
• the cyclin-dependent kinases are serine/threonine protein kinases, which are the driving force behind the cell cycle and cell proliferation. Misreguiation of CDK function occurs with high frequency in many important solid tumors. Individual CDK's, such as, CDK1 , CDK2, CDK3, CDK4, CDK5, CDK6 and CDK7, CDK8 and the like, perform distinct roles in cell cycle progression and can be classified as either G 1S 1 or G2M phase enzymes. CDK2 and CDK4 are of particular interest because their activities are frequently misreguiaied in a wide variety of human cancers. CDK2 activity is required for progression through G1 to the S phase of the cell cycle, and CDK2 is one of the key components of the G1 checkpoint.
• Checkpoints serve to maintain the proper sequence of cell cycle events and allow the eel) to respond to Insults or to proliferative signals, while the loss of proper checkpoint control in cancer cells contributes to tumorgenesis.
• the CDK2 pathway influences tumorgenesis at the level of tumor suppressor function (e.g. p52, RB, and p27) and oncogene activation (cyclin E).
• tumor suppressor function e.g. p52, RB, and p27
• cyclin E oncogene activation
• Both the coactivator, cyclin E, and the inhibitor, p27, of CDK2 are either over- or underexpressed, respectively, in breast, colon, nonsmall cell lung, gastric, prostate, bladder, non-Hodgkin's lymphoma, ovarian, and other cancers. Their altered expression has been shown to correlate with increased CDK2 activity levels and poor overall survival. This observation makes CDK2 and its regulatory pathways compelling targets for the development of cancer treatments.
• adenosine 5'-triphosphate (ATP) competitive small organic molecules as well as peptides have been reported in the literature as CDK inhibitors for the potential treatment of cancers.
• US Patent No. 6,413,974, col. 1, line 23- col. 15, line 10 offers a good description of the various CDKs and their relationship to various types of cancer.
• Flavopiridol (shown below) is a nonselective CDK inhibitor that is currently undergoing human clinical trials, A. M. Sanderowicz etai, J. CHn. Oncol. 16:2986-2999 (1998).
• CDK inhibitors include, for example, oiomoucine (J. Vesely et a/., Eur. J. Biochem., 224:771-786 (1994)) and roscovitine (I. Meijer etai, Eur. J. Biochem., 243:527-536 (1997)).
• US Patent No. 6,107,305 describes certain pyrazoio[3,4-b] pyridine compounds as CDK inhibitors.
• An illustrative compound from the '305 patent is:
• K. S. Kim era/., J. Med. Chem. 45_:3905-3927 (2002) and WO 02/10162 disclose certain aminothiazoie compounds as CDK inhibitors.
• Another series of protein kinases are those that play an important role as a checkpoint in cell cycle progression. Checkpoints prevent cell cycle progression at inappropriate times, such as in response to DNA damage, and maintain the metabolic balance of ceils while the ceil is arrested, and in some instances can induce apoptosis (programmed ceil death) when the requirements of the checkpoint have not been met. Checkpoint control can occur in the G 1 phase (prior to DNA synthesis) and in G2, prior to entry into mitosis.
• Tyrosine kinases can be of the receptor type (having extracellular, transmembrane and intracellular domains) or the non-receptor type (being wholly intracellular).
• Receptor-type tyrosine kinases are comprised of a large number of transmembrane receptors with diverse biological activity. In fact, about 20 different subfamilies of receptor-type tyrosine kinases have been identified.
• One tyrosine kinase subfamily, designated the HER subfamily is comprised of EGFR (HER1 ), HER2, HER3 and HER4.
• Ligands of this subfamily of receptors identified so far include epithelial growth factor, TGF-alpha, amphiregulin, HB-EGF, betacellulin and hereguHn.
• Another subfamily of these receptor-type tyrosine kinases is the insulin subfamily, which includes INS-R, IGF-IR, IR, and IR-R.
• the PDGF subfamily includes the PDGF-alpha and beta receptors, CSFIR, c-kit and FLK-II.
• the FLK family is comprised of the kinase insert domain receptor (KDR), fetal liver kinase-1(FLK-1 ), fetal liver kinase-4 (FLK-4) and the fms-like tyrosine kinase-1 (flt-1).
• KDR kinase insert domain receptor
• FLK-1 fetal liver kinase-1
• FLK-4 fetal liver kinase-4
• flt-1 fms-like tyrosine kinase-1
• At least one of the non-receptor protein tyrosine kinases is believed to mediate the transduction in T-cells of a signal from the interaction of a cell- surface protein (Cd4) with a cross-linked anti-Cd4 antibody.
• Cd4 cell- surface protein
• the non-receptor type of tyrosine kinases is also comprised of numerous subfamilies, including Src, Frk, Btk, Csk, AbI, Zap70, Fes/Fps, Fak, Jak, Ack, and LIMK.
• Src subfamily is one of the largest and includes Src, Yes, Fyn, Lyn, Lck, BIk, Hck, Fgr, and Yrk.
• Src subfamily of enzymes has been linked to oncogenesis.
• angiogenesis is the mechanism by which new capillaries are formed from existing vessels.
• the vascular system has the potential to generate new capillary networks in order to maintain the proper functioning of tissues and organs.
• angiogenesis is fairly limited, occurring only in the process of wound healing and neovascularization of the endometrium during menstruation.
• unwanted angiogenesis is a hallmark of several diseases, such as retinopathies, psoriasis, rheumatoid arthritis, age-related macular degeneration, and cancer (solid tumors).
• Protein kinases which have been shown to be involved in the angiogenic process include three members of the growth factor receptor tyrosine kinase family; VEGF-R2 (vascular endothelial growth factor receptor 2, also known as KDR (kinase insert domain receptor) and as FLK 1); FGF-R (fibroblast growth factor receptor); and TEK (also known as Tie-2).
• VEGF-R2 vascular endothelial growth factor receptor 2, also known as KDR (kinase insert domain receptor) and as FLK 1
• FGF-R fibroblast growth factor receptor
• TEK also known as Tie-2
• VEGF-R2 which is expressed only on endothelial ceils, binds the potent angiogenic growth factor VEGF and mediates the subsequent signal transduction through activation of its intracellular kinase activity.
• VEGF-R2 direct inhibition of the kinase activity of VEGF-R2 will result in the reduction of angiogenesis even in the presence of exogenous VEGF (see Strawn et al, Cancer Res., 56:3540- 3545 (1996)), as has been shown with mutants of VEGF-R2 which fail to mediate signal transduction. Millauer era/, Cancer Res., (56:1615-1620 (1996).
• VEGF-R2 appears to have no function in the adult beyond that of mediating the angiogenic activity of VEGF. Therefore, a selective inhibitor of the kinase activity of VEGF-R2 would be expected to exhibit little toxicity.
• FGFR binds the angiogenic growth factors aFGF and bFGF and mediates subsequent intracellular signal transduction.
• growth factors such as bFGF may play a critical role in inducing angiogenesis in solid tumors that have reached a certain size.
• FGF-R is expressed in a number of different cell types throughout the body and may or may not play important roies in other normal physiological processes in the adult.
• TEK also known as Tie-2
• Tie-2 is another receptor tyrosine kinase expressed only on endothelial cells which has been shown to play a role in angiogenesis.
• the binding of the factor angiopoietin-1 results in autophosphorylation of the kinase domain of TEK and results in a signal transduction process which appears to mediate the interaction of endothelial cells with peri-endothelial support cells, thereby facilitating the maturation of newly formed blood vessels.
• the factor angiopoietin-2 appears to antagonize the action of angiopoietin-1 on TEK and disrupts angiogenesis. Maisonpierre et a/., Science, 277:55-60 (1997).
• JNK The kinase, belongs to the mitogen-activated protein kinase (MAPK) superfamily. JNK plays a crucial role in inflammatory responses, stress responses, cell proliferation, apoptosis, and tumorigenesis. JNK kinase activity can be activated by various stimuli, including the proinflammatory cytokines (TNF-alpha and interleukin- 1), lymphocyte costimulatory receptors (CD28 and CD40), DNA-damaging chemicals, radiation, and Fas signaling. Results from the JNK knockout mice indicate that JNK is involved in apoptosis induction and T helper cell differentiation.
• TNF-alpha and interleukin-1 the proinflammatory cytokines
• CD28 and CD40 lymphocyte costimulatory receptors
• Fas signaling results from the JNK knockout mice indicate that JNK is involved in apoptosis induction and T helper cell differentiation.
• Pim-1 is a small serine/threonine kinase. Elevated expression levels of Pim-1 have been detected in lymphoid and myeloid malignancies, and recently Pim-1 was identified as a prognostic marker in prostate cancer.
• K. Peltola "Signaling in Cancer: Pim-1 Kinase and its Partners", Annales Universitatis Turkuensis, Sarja - Ser, D Osa - Tom. 616, (August 30, 2005), http://kiriasto.utu.fi/iulkaisupatvelut/annaalit/2004/D616.htmi. Pim-1 acts as a cell survival factor and may prevent apoptosis in malignant cells.
• Aurora kinases are serine/threonine protein kinases that have been implicated in human cancer, such as colon, breast and other solid tumors.
• Aurora-A also sometimes referred to as AIK
• Aurora-A is believed to be involved in protein phosphorylation events that regulate the cell cycle.
• Aurora-A may play a role in controlling the accurate segregation of chromosomes during mitosis. Misreguiation of the cell cycle can lead to cellular proliferation and other abnormalities.
• c-Met is a proto-oncogene that encodes for a tyrosine kinase receptor for hepatocyte growth factor/scatter factor (HGF/SF).
• HGF/SF hepatocyte growth factor/scatter factor
• HGF/SF activates c-Met
• the latter in turn may activate a number of kinase pathways, including the pathway from Ras to Raf to Mek to the mitogen-activated protein kinase ERK1 to the transcription factor ETS 1.
• Met signaling has been impiJcated in the etiology and malignant progression of human cancers (see Birchmeier etaL, Nature Reviews Molecular Cell Biology, 4:915-925 (2003); Zhang etaL, Journal of Cellular Biochemistry, 88:408-417 (2003); and PaumeHe etaL, Oncogene, 21:2309-2319 (2002)).
• Mitogen-activated protein kinase-activated protein kinase 2 (MAPKAP K2 or
• MK2 mediates multiple p38 MAPK-dependent cellular responses.
• MK2 is an important intracellular regulator of the production of cytokines, such as tumor necrosis factor alpha (TNFa), interfeukin 6 (IL-6) and interferon gamma (IFNg), that are involved in many acute and chronic inflammatory diseases, e.g. rheumatoid arthritis and inflammatory bowel disease.
• TNFa tumor necrosis factor alpha
• IL-6 interfeukin 6
• IFNg interferon gamma
• MK2 is also implicated in heart failure, brain ischemic injury, the regulation of stress resistance and the production of TNF- ⁇ (see Deak et at., EMBO. 17:4426-4441 (1998); Shi et aL, Biol. Chem. 383:1519-1536 (2002); Staklatvala., Curr. Opin. Pharmacol. 4:372-377 (2004); and Shiroto et aL, J. MoI. Cell Cardiol. 38:93-97 (2005)).
• kinase inhibitors in order to treat or prevent disease states associated with abnormal cell proliferation. Moreover, it is desirable for kinase inhibitors to possess both high affinities for the target kinase as well as high selectivity versus other protein kinases.
• Small-molecule compounds that may be readily synthesized and are potent inhibitors of ceil proliferation are those, for example, that are inhibitors of one or more protein kinases, such as CHK1, CHK2, VEGF (VEGF-R2), Pim-1, CDKs orCDK/cyclin complexes and both receptor and nonreceptor tyrosine kinases.
• the present invention provides compounds of Formula (I):
• M is -C(OK -C(S)-, -S(O)-, -S(O) 2 -, -NHS(O) 2 -, -OC(O)- or -NHC(O)-;
• Q is:
• R 1 is H, alkyl, alkenyl, alkynyl, -(alkyfene) m -aryl, -(alkyiene) m -cycloalkyl, - (alkylene) m -heteroaryi, -(alkylene)nrheterocycioaiky!
• any aryl, cycloalkyl, heteroaryl, heterocycloalkyl or heterocycloalkenyl group can be optionally substituted on a ring carbon or ring nitrogen atom with up to 3 substituents, which may be the same or different, and are selected from halo, alkyl, alkenyl, aikynyl, haloalkyl, hydroxyalkyl, -OR 6 , -(alkylene) m - N(R 6 ) 2 , -C(O)OR 6 , -NHC(O)R 6 , -C(O)N(R 6 ) 2) -S(O) 2 R 7 , -CN 1 -OH, -NO 2 , -(alkylene) m - aryl, -(alkylene) m -cycloalkyl, -(alkylene)m-heteroary
• heterocycloalkenyl group can be optionalty fused to an aryl, cycloalkyl, heteroaryl, heterocycloalkyl or heterocycloalkenyl group; each occurrence of R 2 is independently H, alkyl, haloaikyl, hydroxyalkyl, - (alkylene) m -C(O)N(R 6 ) 2 , -(alkylene) m -NHC(O)R 6 or -(alkylene) m -N(R 6 ) 2 , or R 2 and the ring carbon atom to which it is attached, combine to form a carbonyl group;
• R 3 is H, alkyl, haloalkyl, hydroxyalkyl, -(aikylene) m -C(O)N(R 6 ) 2 , -(alkylene) m - NHC(O)-R 6 or -(alkylene) m -N(R 6 ) 2 , or R 3 and R 3a , together with the common carbon atom to which each are attached, join to form a carbonyl group or a spirocyclic cycloalkyl or heterocycloalkyl group;
• R 3a is H, alkyl, haloalkyl, hydroxyalkyl, -(alkylene) m -C(O)N(R 8 ) 2 , -(alkylene) m - NHC(O)-R 6 or-(alkylene)m-N(R 6 ) 2 ; each occurrence of R 5 is independently H, alkyl, -(alkylene) m -aryl, -(alkylene) m - heteroaryl, -(alkylene) m -heterocycloalkyl, -(alkylene)m-N(R 6 ) 2 , -(alkylene) m -OH, - (alkylene) m -NHC(O)R 6 , hydroxyalkyl, haloalkyl, -C(O)R 6 , -C(O)OR 6 , -C(O)-(alkylene) m - N(R ⁇ )
• R 8 is H, alkyl, -OH, -O-alkyl or haloalkyl
• R 10 is H, alkyl, haloalkyl, hydroxyalkyl, -(alkylene) m -C(O)N(R 6 ) 2 , -(alkylene) m - NHC(O)R 6 or -(alkylene) m -N(R 8 ) 2 , or R 10 and R 10a , together with the common carbon atom to which each are attached, join to form a carbonyl group or a spirocyclic cycloaikyl or heterocycloaJkyl group;
• R 1Oa is H, alkyl, haloalkyl, hydroxyalkyl, -(alkylene) m -C(O)N(R 6 ) 2 , -(alkyiene) m - NHC(O)-R 6 or -(alkylene) m -N(R 6 ) 2 ; each occurrence of R 11 is independently H, alkyi, haloalkyl, hydroxyaikyi, - (alkylene) m -C(O)N(R ⁇ ) 2 , -(alkylene) m -NHC(O)-R 6 or -(alkylene) m -N(R 6 ) 2 , or R 11 and the ring carbon atom to which it is attached, combine to form a carbonyl group; each occurrence of R 12 is independently H, alkyl, -(alkylene) m -aryl, -(alkylene)m- heteroaryl, -(alkyiene
• Ar is arylene or heteroarylene, wherein the arylene or heteroarylene is joined via any 2 of its adjacent ring carbon atoms, and wherein the arylene or heteroarylene group can be optionally substituted with up to 4 substituents, which may be the same or different, and are independently selected from halo, alkyl, alkoxy, aryloxy, -NH 2 ,- NH-alkyl, -N(alkyl) 2) -SR 6 , -S(O)R 7 , -S(O) 2 R 7 , -C(O)R 6 , -C(O)OR 6 , -C(O)N(R 6 ) 2 , - NHC(O)R 6 , haloalkyl, -CN and NO 2 , such that when Ar is tetrahydronaphthylene, R 2 and R 3 are each other than hydrogen;
• W is -N(R 12 ) 2 -, -S-, -O- or -C(R 5 ) 2 -, wherein when W is -C(R 5 ) 2 -, both R 5 groups and the common carbon atom to which they are attached can combine to form a spirocyclic cycloalkyl or heterocycloafkyl group, wherein such a spirocyclic group can be optionally substituted with up to 4 groups, which can be the same or different and are selected from halo, alkyl, alkenyl, alkynyl, haloalkyl, hydroxyalkyl, -OR 6 , -
• Y is H, halo, alkyl or -CN; Z is -C(R 8 )- or -N- when the optional and additional bond is absent, and Z is ⁇
• the compounds of Formula (I) can be useful as protein kinase inhibitors.
• the Diamido Thiazole Derivatives can be useful for treating or preventing a proliferative disorder, an antiproliferative disorder, inflammation, arthritis, a central nervous system disorder, a cardiovascular disease, alopecia, a neuronal disease, an ischemic injury, a viral infection, a fungal infection, or a disorder related to the activity of a protein kinase (each being a "Condition").
• the present invention provides pharmaceutical compositions comprising an effective amount of at least one Diamido Thiazole Derivative and a pharmaceutically acceptable carrier.
• the compositions can be useful for treating or preventing a Condition in a patient.
• the present invention provides methods for treating pr preventing a Condition in a patient, the method comprising administering to the patient an effective amount of at least one Diamido Thiazole Derivative.
• the present invention provides methods for treating a cancer in a patient, the method comprising administering to the patient an effective amount of at least one Diamido Thiazole Derivative.
• the present invention provides methods for treating a cancer in a patient, the method comprising administering to the patient an at least one Diamido Thiazole Derivative and at least one additional anticancer agent which is not a Diamido Thiazole Derivative, wherein the amounts administered are together effective to treat the cancer.
• the present invention provides Diamido Thiazole Derivatives of Formula (I) and or pharmaceutically acceptable salts, solvates, esters and prodrugs thereof.
• the Diamido Thiazoie Derivatives can be useful for treating or preventing a Condition in a patient.
• acyl means an H-C(O)-, alkyl-C(O)- or cycloalkyl-C(O)-, group in which the various groups are as previously described.
• the bond to the parent moiety is through the carbonyl.
• acyls contain a lower alkyl.
• suitable acyl groups include formyl, acetyl and propanoyl.
• Alkoxy * means an alkyl-O- group in which the aikyl group is as previously described.
• suitable alkoxy groups include methoxy, ethoxy, n-propoxy, isopropoxy and n-butoxy.
• the bond to the parent moiety is through the ether oxygen.
• Alkoxycarbonyl means an alkyl-O-CO- group.
• suitable alkoxycarbonyl groups include methoxycarbonyl and ethoxycarbonyl.
• the bond to the parent moiety is through the carbonyl.
• Alky means an aliphatic hydrocarbon group which may be straight or branched and comprising about 1 to about 20 carbon atoms in the chain. In one embodiment, an alkyl group contains from about 1 to about 12 carbon atoms in the chain. In another embodiment, an alkyl group contains from about 1 to about 6 carbon atoms in the chain. Branched means that one or more lower alkyl groups such as methyl, ethyl or propyl, are attached to a linear alkyl chain. Lower alkyl refers to a group having about 1 to about 6 carbon atoms in the chain which may be straight or branched.
• An alkyl group may be unsubstituted or optionally substituted by one or more substituents which may be the same or different, each substituent being independently selected from the group consisting of halo, alkyl, aryl, cycloalkyl, cyano, hydroxy, alkoxy, -S-alkyl, amino, -NH(alkyi), -NH(cycloalkyl), -N(alkyl) 2 , -O-C(O)-alkyl, -O-C(O)-aryl, -O-C(O)-cycloalkyl, carboxy and -C(0)Oalkyl.
• Non-limiting examples of suitable alkyl groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, t-butyl, n-pentyl, isopentyl, neopentyl, n-hexyl, n-heptyl and n-octyl.
• an aikyl group is a "C 1 -C 6 alkyl group,” having from 1 to 6 carbon atoms.
• Alkylaryl means an alkyl-arylene- group in which the alkyl and arylene are as previously described. In one embodiment, alkylaryls comprise a lower alkyl group.
• alkylaryl group is tolyl.
• the bond to the parent moiety is through the arylene group.
• Alkylsuffonyl means an alkyl-S(O2)- group.
• the alkyl moiety of an alkylsulfonyl group is lower alkyl (i.e., C 1 -C 6 alkyl).
• the bond to the parent moiety is through the sulfonyl moiety.
• Alkylthio means an alkyl-S- group in which the alkyl group is as previously described.
• suitable alkylthio groups include methylthio and ethylthio.
• An afkylthio group is bound to the parent moiety via its sulfur atom.
• Alkenyl means an aliphatic hydrocarbon group containing at least one carbon- carbon double bond and which may be straight or branched and comprising about 2 to about 15 carbon atoms in the chain. In one embodiment, an alkenyi group has from about 2 to about 12 carbon atoms in the chain; in another embodiment, an alkenyi group has from about 2 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 alkenyi chain. Lower alkenyi refers to about 2 to about 6 carbon atoms in the chain which may be straight or branched.
• An alkenyi group 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, alky!, aryi, cycloalkyl, cyano, alkoxy and -S(alkyi).
• substituents include ethenyl, propenyl, n-butenyl, 3-methylbut-2-enyl, n-pentenyl, octenyl and decenyl.
• Alkylene means an alkyl group, as defined above, wherein one of the alkyl group's hydrogen atoms has been replaced with a bond.
• alkylene groups include -CH 2 -, -CH 2 CH 2 -, -CH 2 CH 2 CH 2 -, -CH 2 CH 2 CH 2 CH 2 -, - CH(CH 3 )CH 2 CH 2 -, -CH(CH 3 )- and -CH 2 CH(CH 3 )CH 2 -.
• an alkylene group has from 1 to about 6 carbon atoms.
• an alkylene group is branched.
• an alkylene group is linear.
• Alkenylene means a difunctional group obtained by removal of a hydrogen from an alkenyi group that is defined above.
• 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. In one embodiment, an alkynyl group has from about 2 to about 12 carbon atoms in the chain; and in another embodiment, an alkynyl group has from about 2 to about 4 carbon atoms in the chain. Branched means that one or more lower alkyl groups such as methyl, ethyl or propyl, are attached to a linear alkynyl chain. Lower alkynyl refers to about 2 to about 6 carbon atoms in the chain which may be straight or branched.
• alkynyl groups include ethynyl, propynyl, 2-butynyl and 3-methylbutynyl.
• An alkynyl group 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.
• Alkynylalkyl means an alkynyl-alkyl- group in which the alkynyl and alkyl are as previously described. In one embodiment, alkynylalkyls contain a lower alkynyl and a lower alkyl group. The bond to the parent moiety is through the alkyl.
• Non-limiting examples of suitable alkynylalkyl groups include propargylmethyl.
• “Aralkloxy” means an aralkyl-O group in which the aralkyl 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.
• Alkoxycarbonyl means an aralkyl-O-C(O)- group.
• a suitable aralkoxycarbonyl group is benzyloxycarbonyl.
• the bond to the parent moiety is through the carbonyi.
• Aralkyl or “arylalkyl” means an aryl-alkylene- group in which the aryl and alkylene are as previously described. In one embodiment, aralkyls comprise a lower alkylene group. Non-limiting examples of suitable aralkyl groups include benzyl, 2- phenethyl and naphthalenylmethyl. The bond to the parent moiety is through the alkylene group.
• Aralkylthio means an aralkyl-S- group in which the aralkyl group is as previously described. Non-limiting example of a suitable aralkylthio group is benzyfthio. The bond to the parent moiety is through the sulfur.
• Aryl means an aromatic monocyclic or multicyclic ring system comprising about 6 to about 14 carbon atoms, preferably about 6 to about 10 carbon atoms. The aryl group can be optionally substituted with one or more "ring system substituents" which may be the same or different, and are as defined herein. Non-limiting examples of suitable aryl groups include phenyl and naphthyl.
• Arylene means an aryl group, wherein a hydrogen atom connected to one of the aryl group's ring carbon atoms is replaced with a single bond.
• Aryloxy means an aryl-O- group in which the aryl group is as previously described. Non-limiting examples of suitable aryloxy groups include phenoxy and naphthoxy. The bond to the parent moiety is through the ether oxygen.
• Aryloxycarbonyl means an aryi-O-C(O)- group. Non-limiting examples of suitable aryloxycarbonyi groups include phenoxycarbony! and naphthoxycarbonyl. The bond to the parent moiety is through the carbonyi.
• ArylsulfonyP means an aryl-S(O 2 )- group. The bond to the parent moiety is through the sulfonyf.
• 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.
• Benzofused cycloalkyl means a cycloalkyl moiety as defined above which is fused to a benzene ring.
• Non-limiting examples of a benzofused cycloalkyl are indanyl and tetrahydronaphthylenyl.
• Benzofused cycloalkenyl means a cycloalkenyl moiety as defined above which is fused to a benzene ring.
• Non-limiting examples of a benzofused cycloalkyl include indenyl.
• Benzofused hetenocyclyl means a heterocyclyl moiety as defined above which is fused to a benzene ring.
• Non-limiting examples of a benzofused heterocyclyl include indoHnyl and 2,3-dihydrobenzofuran.
• Benzofused heteroaryl means a heteroaryl moiety as defined above which is fused to a benzene ring.
• Non-limiting examples of a benzofused heteroaryl are indolyl, indazolyl, benzofuranyl, quinolinyl, isoquinolinyl, benzthiazolyl, indolyl, benzimidazolyl and benzothiophenyl.
• Composition means 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.
• Cycloalkyl means a non-aromatic mono- or multicyclic ring system comprising about 3 to about 10 carbon atoms, preferably about 5 to about 10 carbon atoms. In one embodiment, cycloalkyl rings contain about 5 to about 7 ring atoms.
• a cycloalkyl group can be optionally substituted with one or more "ring system substituents" which may be the same or different, and are as defined above.
• a cycloalkyl group can be optionally fused to an aryl, heteroaryl or heterocycloalkyl ring.
• a ring carbon atoms of a cycloalkyl group can optionally be double bonded to an oxygen atom to form a carbonyl group and result in a cycloalkanoyl group.
• suitable monocyclic cycloalkyls include cydopropyJ, cyclopentyl, cyclohexyl, cycloheptyl, cyclopentanoyl, cyclohexanoyl, and the like.
• Non-limitrng examples of suitable multicyclic cycloalkyls include 1-decalinyl, norbornyi, adamantyl and the like.
• Cycfoalkylalkyl means a cycloalkyl moiety as defrned above linked via an alkyt moiety (defined above) to a parent core.
• suitable cycloalkylalkyls include cyclohexylmethyl, adamantylmethyl and the like.
• Cycloalkenyt means a non-aromatic mono or multicyclic ring system comprising from 3 to about 10 carbon atoms and having at least one endocyciic carbon-carbon double bond.
• a cycloalkenyl group has from about 5 to about 10 ring carbon atoms.
• a cycloalkenyl group has from about 5 to about 7 ring carbon atoms.
• a cyctoalkenyl group can be optionally substituted with one or more "ring system substituents" which may be the same or different, and are as defined above.
• Non-limiting examples of suitable monocyclic cycloalkenyls include cyclopentenyl, cyclohexenyl, cyclohepta-1,3-dienyl, and the like.
• Non-limiting example of a suitable multicyclic cycloalkenyl is norbornylenyl.
• Cycloalkenylalkyl means a cycloalkenyl moiety as defined above linked via an alkyl moiety (defined above) to a parent core.
• suitable cycloaikenylalkyls include cyclopentenyimethyl, cyclohexenylmethyl and the like.
• Effective amount or “therapeutically effective amount” means an amount of Diamido Thiazole Derivative and/or an additional therapeutic agent, or a composition thereof that is effective in producing the desired therapeutic, ameliorative, inhibitory or preventative effect when administered to a patient suffering from a Condition.
• an effective amount can refer to each individual agent or to the combination as a whole, wherein the amounts of all agents administered are together effective, but wherein the component agent of the combination may not be present individually in an effective amount.
• Halo means -F, -Cl, -Br or -I. In one embodiment, halo refers to -Cl or -Br. In another embodiment, halo refers to -F.
• Haloalkyl means an alkyl group as defined above, wherein one or more of the alkyl group's hydrogen atoms has been replaced with a halogen. In one embodiment, a haloalkyl group has from 1 to 6 carbon atoms. In another embodiment, a haloalkyl group is substituted with from 1 to 3 F atoms. Non-limiting examples of haioaikyi groups include -CH 2 F, -CHF2, -CF 3 , -CH 2 CI and -CCI 3 .
• HeteroaryP means an aromatic monocyclic or muiticyclic ring system comprising about 5 to about 14 ring atoms, wherein from 1 to 4 of the ring atoms is independently O, N or S and the remaining ring atoms are carbon atoms.
• a heteroaryl group has 5 to 10 ring atoms.
• a heteroaryl group is monocyclic and has 5 or 6 ring atoms.
• a heteroaryl group can be optionally substituted by one or more "ring system substituents" which may be the same or different, and are as defined herein below.
• heteroaryP also encompasses a heteroaryl group, as defined above, that is fused to a benzene ring.
• heteroaryls include pyridyl, pyrazinyl, furanyl, thienyl, pyrimidinyl, pyridone (including N-substJtuted pyridones), isoxazolyl, isothiazolyl, oxazolyl, thiazolyl, pyrazolyl, furazanyl, pyrrolyl, triazolyl, 1 ,2,4-thiadiazolyl, pyrazinyl, pyridazinyl, quinoxatinyl, phthalazjnyl, oxindolyl, imidazo[1 ,2-aJpyridinyl, imidazo[2,1-b]thiazolyl, benzofurazanyl, indolyl, azaindolyl, benzimidazolyl, benzothienyl, quinolinyl, imidazolyl, thienopyridyl, qui
• heteroaryl also refers to partially saturated heteroaryl moieties such as, for example, tetrahydroisoquinolyl, tetrahydroquinolyl and the like.
• a heteroaryl group is unsubstituted.
• a heteroaryl group is a 5- membered heteroaryl.
• a heteroaryl group is a 6-membered heteroaryl.
• heteroarylene refers to a heteroaryl group, wherein a hydrogen atom connected to one of the heteroaryl group's ring atoms is replaced with a single bond.
• Heteroarylalkyl means a heteroaryl moiety as defined above linked via an alkyl moiety (defined above) to a parent core.
• suitable heteroaryls include 2-pyridrnylmethyl, quinolinylmethyl and the like.
• Heterocyclyl means a non-aromatic saturated monocyclic or multicyclic ring system comprising 3 to about 10 ring atoms, wherein from 1 to 4 of the ring atoms are independently O, S or N and the remainder of the ring atoms are carbon atoms.
• a heterocyclyl group has from about 5 to about 10 ring atoms.
• a heterocyclyl group has 5 or 6 ring atoms. There are no adjacent oxygen and/or sulfur atoms present in the ring system.
• heterocyclyl any -NH group in a heterocyclyl ring may exist protected such as, for example, as an -N(BOC), -N(Cbz), - N(Tos) group and the like; such protected heterocyclyl groups are considered part of this invention.
• heterocyclyl also encompasses a heterocyclyl group, as defined above, that is fused to an aryJ (e.g., benzene) or heteroaryl ring.
• a heterocyclyl group can be optionally substituted by one or more "ring system substituents" which may be the same or different, and are as defined herein below.
• the nitrogen or sulfur atom of the heterocyclyl can be optionally oxidized to the corresponding N-oxide, S-oxide or S,S-dioxide.
• monocyclic heterocyclyl rings include piperidyl, pyrrolidinyl, piperazinyl, morpholinyi, thiomorpbolinyl, thiazolidinyl, 1,4-dioxanyl, tetrahydrofuranyi, tetrahydrothiophenyl, lactam, lactone, and the like.
• a ring carbon atom of a heterocyclyl group may be functionalized as a carbonyl group.
• An illustrative example of such a heterocyclyl group is pyrrolidonyl:
• a heterocyclyl group is unsubstituted. In another embodiment, a heterocyclyl group is a 5-membered heterocyclyl. In another embodiment, a heterocyclyl group is a 6-membered heterocyclyl.
• Heterocyclylalkyl means a heterocyclyl moiety as defined above linked via an alkyl moiety (defined above) to a parent core.
• suitable heterocycfylalkyls include piperidinylmethyl, piperazinylmethyl and the like.
• HeterocyclenyP means a heterocyclyl group, as defined above, wherein the heterocyclyl group contains from 3 to 10 ring atoms, and at least one endocyclic carbon-carbon or carbon-nitrogen double bond.
• a heterocyclenyl group has from 5 to 10 ring atoms.
• a heterocyclenyl group is monocyclic and has 5 or 6 ring atoms.
• a heterocyclenyl group can optionally substituted by one or more ring system substituents, wherein "ring system substituent” is as defined above.
• the nitrogen or sulfur atom of the heterocyclenyl can be optionally oxidized to the corresponding N-oxide, S-oxide or S,S-dioxide.
• heterocyclenyl groups include 1 ,2,3,4- tetrahydropyridinyi, 1 ,2- dihyclropyricJinyf, 1,4-dihydropyridinyl, 1 ,2,3,6-tetrahydropyridinyi, 1,4,5,6- tetrahydropyrimidinyl, 2-pyrrotinyl, 3-pyrrolinyl, 2-imidazolinyl, 2-pyrazolinyl, dihydroimidazolyl, dihydrooxazolyl, dihydrooxadiazolyl, dihydrothiazolyl, 3,4-dihydro- 2H-pyranyl, dihydrafuranyl, fluoro-substituted dihydrofuranyl, 7- oxabicyclo[2.2.1]hept ⁇ nyl, dihydrothiophenyi, dihydrothiopyranyl, and the like.
• a heterocyclenyl group is unsubstituted. In another embodiment, a heterocyclenyl group is a 5-membered heterocyclenyl.
• Heterocyclenylalkyl means a heterocyclenyl moiety as defined above linked via an alkyl moiety (defined above) to a parent core.
• hetero-atom containing ring systems of this invention there are no hydroxy! groups on carbon atoms adjacent to a N, O or S, as well as there are no N or S groups on carbon adjacent to another heteroatom.
• N, O or S there are no N or S groups on carbon adjacent to another heteroatom.
• Heteroaralkyl means a heteroaryl-aikyi- group in which the heteroary! and alkyl are as previously described.
• heteroaralkyls contain a lower alkyl group.
• suitable aralkyl groups include pyridylmethyl, and quinolin-3-ylmethyl. The bond to the parent moiety is through the alkyl.
• ⁇ ydroxyalkyl means an alkyl group as defined above, wherein one or more of the alkyl group's hydrogen atoms has been replaced with an -OH group.
• a hydroxyalkyl group has from 1 to 6 carbon atoms.
• Non-limiting examples of hydroxyalkyi groups include -CH 2 OH, -CH 2 CH 2 OH, -CH 2 CH 2 CH 2 OH and -CH 2 CH(OH)CH 3 .
• a "patient” is a human or non-human mammal.
• a patient is a human.
• a patient is a non-human mammal, including, but not limited to, a monkey, dog, baboon, rhesus, mouse, rat, horse, cat or rabbit.
• a patient is a companion animal, including but not limited to a dog, cat, rabbit, horse or ferret.
• a patient is a dog.
• a patient is a cat.
• purified refers to the physical state of said compound after being isolated from a synthetic process (e.g. from a reaction mixture), 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 (e.g., chromatography, recrystallization and the like) , in sufficient purity to be characterizable by standard analytical techniques described herein or well known to the skilled artisan.
• Ring system substituent means a substituent group attached to an aromatic or non-aromatic ring system which, for example, replaces an available hydrogen on the ring system.
• Ring system substituents may be the same or different, each being independently selected from the group consisting of alkyl, alkenyl, alkynyl, aryl, heteroaryl, -alkyl-aryl, -aryl-alkyl, -alkylene-heteroaryl, -alkenylene-heteroaryl, - alkynylene-heteroaryl, hydroxy, hydroxyalkyl, haloalkyl, -O-alkyl, -O-haloalkyl, - alkylene-O-alkyl, -O-aryl, aralkoxy, acyl, -C(O)-aryl, halo, nitro, cyano, carboxy, - C(O)O-alkyl, -C(O)O-aryl,
• Ring system substituenf 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 methylenedioxy, ethylenedioxy, -C(CH 3 ) 2 -, -O-alkylene-0-, and the like which form moieties such as, for example:
• 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.
• 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 well as by reference to standard textbooks such as, for example, T. W. Greene et al, Protective Groups in Organic Synthesis (1991 ), Wiley, New York. When any variable (e.g., aryt, heterocycie, R 2 , etc.) occurs more than one time in any constituent or any chemical structure or formula herein, its definition on each occurrence is independent of its definition at every other occurrence.
• any variable e.g., aryt, heterocycie, R 2 , etc.
• 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 Bloreversible Carriers in Drug Design, (1987) Edward B. Roche, ed., American Pharmaceutical Association and Pergamon Press.
• the term "prodrug 11 means a compound (e.g, a drug precursor) that is transformed in vivo to provide a Diamido Thiazole Derivative 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, (C 1 -C 8 )alkyI, (C 2 - C 12 )alkanoyloxymethyl, 1-(alkanoyloxy)ethyl having from 4 to 9 carbon atoms, 1- methyl-1-(alkanoyfoxy)-ethyl having from 5 to 10 carbon atoms, alkoxycarbonyloxymethyl having from 3 to 6 carbon atoms, 1-(alkoxycarbonyloxy)ethyl having from 4 to 7 carbon atoms, 1 -methyl- 1-(alkoxycarbonyloxy)ethyl having from 5 to 8 carbon atoms, N-(alkoxycarbonyl)aminomethyl having from 3 to 9 carbon atoms, 1-(N)alkyI, (C 2 - C 12 )alkanoyloxymethyl, 1-(alkanoyloxy)ethyl having from 4 to 9 carbon
• a prodrug can be formed by the replacement of the hydrogen atom of the alcohol group with a group such as, for example, (C 1 -C 6 )alkanoyloxymethyf, 1-((C 1 - C 6 )alkanoyloxy)ethyl, 1-methyl-1-((C 1 -C 6 )alkanoyloxy)ethyl, (C 1 -
• each ⁇ -aminoacyl group is independently selected from the naturafly occurring L-amino acids, P(OXOH) 2 , -P(O)(O(C 1 -C 6 )alkyl) 2 or glycosyl (the radical resulting from the removal of a hydroxyl group of the hemiacetal form of a carbohydrate), and the like.
• 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 (C 1 -C 1 o)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, (d-C ⁇ )alkyl or benzyl, — C(OY 2 )Y 3 wherein Y 2 is (d-C 4 ) alkyl and Y 3 is (C r C 6 )alkyl, carboxy (C 1 -C ⁇ )alkyl, amino(C 1 -C 4 )alkyl or mono-N
• 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 solvated and unsolvated forms.
• “Solvate” means a physical association of a compound of this invention with one or more solvent molecules. This physical association involves varying degrees of ionic and covalent bonding, including hydrogen bonding. In certain instances the solvate will be capable of isolation, for example when one or more solvent molecules are incorporated in the crystal lattice of the crystalline solid. "Solvate” encompasses both solution-phase and isolatable solvates. Non-limiting examples of suitable solvates include ethanolates, methanofates, and the like.
• “Hydrate” is a solvate wherein the solvent 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 a/ J. Pharmaceutical ScL, 93(3). 601-611 (2004) describes the preparation of the solvates of the antifungal fluconazole in ethyl acetate as well as from water.
• Simifar preparations of solvates, hemisoivate, hydrates and the like are described by E. C. van Tonder et al, AAPS PharmSciTech., 5(1), article 12 (2004); and A. L Bingham et a/, Chem, Commun., 603-604 (2001).
• a typical, non-limiting, process involves dissolving the inventive compound in desired amounts of the desired solvent (organic or water or mixtures thereof) at a higher than ambient temperature, and cooling the solution at a rate sufficient to form crystals which are then isolated by standard methods.
• Analytical techniques such as, for example I. R. spectroscopy, show the presence of the solvent (or water) in the crystals as a solvate (or hydrate).
• Diamido Thiazole Derivatives can form salts which are also within the scope of this invention.
• Reference to a Diamido Thiazole Derivative 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.
• Diamido Thiazole Derivative contains both a basic moiety, such as, but not limited to a pyridine or imidazole, and an acidic moiety, such as, but not limited to a carboxylic acid, zwitterions ("inner salts") may be formed and are included within the term " alt(s)" as used herein.
• Pharmaceutically acceptable (i.e., non-toxic, physiologically acceptable) salts are preferred, although other salts are also useful.
• Salts of the compounds of the Formula I may be formed, for example, by reacting a Diamido Thiazoie Derivative with an amount of acid or base, such as an equivalent amount, in a medium such as one in which the salt precipitates or in an aqueous medium followed by lyophilization.
• Exemplary acid addition salts include acetates, ascorbates, benzoates, benzenesulfonates, bisulfates, borates, butyrates, citrates, camphorates, camphorsulfonates, fumarates, hydrochlorides, hydrobromides, hydroiodides, lactates, maieates, methanesulfonates, naphthalenesulfonates, nitrates, oxalates, phosphates, propionates, salicylates, succinates, sulfates, tartarates, thiocyanates, toluenesulfonates (also known as tosyiates,) and the like.
• Exemplary basic salts include ammonium salts, alkali metal salts such as sodium, lithium, and potassium salts, alkaline earth metal salts such as calcium and magnesium salts, salts with organic bases (for example, organic amines) such as dicyclohexylamines, t-butyl amines, and salts with amino acids such as arginine, lysine and the like.
• Basic nitrogen-containing groups may be quarternized with agents such as lower afkyl halides (e.g. methyl, ethyl, and butyl chlorides, 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 following groups: (1 ) carboxylic acid esters obtained by esterification of the hydroxy groups, in which the non-carbonyl moiety of the carboxylic acid portion of the ester grouping is selected from straight or branched chain afkyl (for example, acetyl, n- propyl, t-butyl, or n-butyl), alkoxyalkyl (for example, methoxymethyl), aralkyl (for example, benzyl), aryloxyalkyl (for example, phenoxymethyl), aryl (for example, phenyl optionally substituted with, for example, halogen, C 1-4 alkyl, or C 1-4 alkoxy or amino); (2) sulfonate esters, such as alkyl- or aralkylsulfonyl (for example, methanesulfonyl); (3) amino acid esters (for example, L-valyl or L-isoleucyi);
• Diamido Thiazole Derivatives 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 Diamido ThJazole Derivatives may contain asymmetric or chiral centers, and, therefore, exist in different stereoisomeric forms. It is intended that all stereoisomeric forms of the Diamido Thiazole Derivatives as welt as mixtures thereof, including racemic mixtures, form part of the present invention.
• the present invention embraces all geometric and positional isomers. For example, if a Diamido Thiazole Derivative incorporates a double bond or a fused ring, both the cis- and trans-forms, as well as mixtures, are embraced within the scope of the invention.
• Diastereomeric mixtures can be separated into their individual diastereomers on the basis of their physical chemical differences by methods well known to those skilled in the art, such as, for example, by chromatography and/or fractional crystallization.
• Enantiomers can be separated by converting the enantiomeric mixture into a diastereomeric mixture by reaction with an appropriate optically active compound (e.g., chiral auxiliary such as a chiral alcohol or Moshei ⁇ 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., chiral auxiliary such as a chiral alcohol or Moshei ⁇ s acid chloride
• some of the Diamido Thiazole Derivatives may be atropisomers (e.g., substituted biaryls) and are considered as part of this invention.
• Enantiomers can also be separated by use of
• Diamido Thiazoie Derivatives may exist in different tautomeric forms, and ail such forms are embraced within the scope of the invention. Also, for example, all keto-enol and imine-enamine forms of the compounds are included in the invention.
• All stereoisomers for example, geometric isomers, optical isomers and the like
• of the present compounds including those of the salts, solvates, esters and prodrugs of the compounds as well as the salts, solvates and esters of the prodrugs
• those which may exist due to asymmetric carbons on various substituents including enantiomeric forms (which may exist even in the absence of asymmetric carbons), rotameric forms, atropisomers, and diastereomeric forms, are contemplated within the scope of this invention, as are positional isomers (such as, for example, 4-pyridy! and 3-pyridyl).
• Individual stereoisomers of the compounds of the invention may, for example, be substantially free of other isomers, or may be admixed, for example, as racemates or with all other, or other selected, stereoisomers.
• the chiral centers of the present invention can have the S or R configuration as defined by the IUPAC 1974 Recommendations.
• the use of the terms "salt”, “solvate”, “ester”, “prodrug” and the like, 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 isotopically-labelled compounds of the present invention which are identical to those recited herein, but for the fact that one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number usually found in nature.
• 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 0, 17 O, 31 P, 32 P, 35 S 1 18 F, and 36 CI, respectively.
• Diamido Thiazoie Derivatives e.g., those labeled with 3 H and 14 C are useful in compound and/or substrate tissue distribution assays. Tritiated (i.e., 3 H) and carbon-14 (i.e., 14 C) isotopes are particularly preferred for their ease of preparation and detectability.
• lsotopically labelled Diamido Thiazole Derivatives can generally be prepared by following procedures analogous to those disclosed in the Schemes and/or in the Examples hereinbeiow, by substituting an appropriate isotopically labelled reagent for a non- isotopically labelled reagent.
• Diamido Thiazole Derivatives Polymorphic forms of the Diamido Thiazole Derivatives, and of the salts, solvates, esters, prodrugs and stereoisomers of the Diamido Thiazole Derivatives, are intended to be included in the present invention.
• Boc is tert-butoxycarbonyl
• dba is dibenzyiideneacetone
• DMF is N 1 N - dimethylformamide
• DMSO is dimethylsulfoxide
• EtOAc is ethyl acetate
• LCMS liquid chromatography mass spectrometry
• MeOH is methanol
• NMR nuclear magnetic resonance
• PBS phosphate buffered saline
• SPA scintillation proximity assay
• Tf is trlflate
• TFA trifluoroacetic acid
• Xantphos is 9,9-Dimethyl-4,5- bis(diphenylphosphino)xanthene.
• the present invention provides Diamido Thiazole Derivatives of Formula (I):
• Q is:
• Q is:
• M is -C(O)-.
• M is -C(S)-.
• M is -OC(O)-. In still another embodiment, M is -S(O)-.
• M is -S(0)2-.
• M is -NHS(Ok-
• M is -NHC(O)-.
• R 1 is -H. In another embodiment, R 1 is other than H.
• R 1 is H, alkyl, heteroaryl, aryl, -alkylene-aryl or heterocycloalkyl.
• R 1 is H, alkyl, heteroaryl, aryl, -alkylene-aryl or heterocycloalkyl, wherein a heterocycloalkyl group may be optionally fused to a benzene ring, and wherein any aryl, heteroaryl or heterocycloalkyl group may be optionally substituted with up to 3 groups, each independently selected from heterocycloalkyl, -O-alkyl, -O-haloalkyl and -OH.
• R 1 is phenyl, benzyl, 5 or 6-membered heteroaryl, 5 or 6-membered heterocycloalkyl, cycloalkyl, benzofused heteroaryl or benzofused heterocycloalkyl, each of which can be optionally substituted with up to 3 groups, each independently selected from halo, alkyl, -OH, -NH 2 , heteroaryl, or -O-haloalkyl.
• R 1 is H, methyl, ethyl
• R 1 is alkyl
• R 1 is alkenyl
• R 1 is alkynyl
• R 1 is aryl
• R 1 is phenyl
• R 1 is -alkylene-aryl.
• R 1 is heteroaryl
• R 1 is -alkylene-heteroaryL
• R 1 is pyrazinyl
• R 1 is pyrazolyi.
• R 1 is:
• R 1 is heterocycloalkyl. in one embodiment, R 1 is heterocydoalkenyt.
• R 1 is -alkylene-heterocycloalkyl.
• R 1 is -alkylene-heterocycloalkenyl.
• R 1 is cycloalkyl
• R 1 is -alkyfene-cycioalkyl.
• R 1 is benzofused cycloalkyl.
• R 1 is benzofused heteroaryl. In anotherembodiment, R 1 is benzofused heterocycloalkyl.
• R 1 is benzofused heterocycloalkenyl.
• M is -O- and R 1 is aryl, -alkylene-aryl, cycloalkyl, heteroaryl or heterocycloalkenyl, each of which can be optionally substituted with up to 3 groups, each independently selected from halo, alkyl, -OH, -NH 2 , heteroaryl, or- O-haJoalkyl.
• M is -S- and R 1 is aryl, -alkylene-aryl, cycloalkyl, heteroaryl or heterocycloalkenyl, each of which can be optionally substituted with up to 3 groups, each independently selected from halo, alkyl, -OH, -NH 2 , heteroaryl, or - O-haloalkyl.
• M is -C(O)- and R 1 is H, methyl, ethyl,
• M is -NHC(O)- and R 1 is H, methyl, ethyl,
• R 2 is H.
• R 2 is alkyi. In one embodiment, R 2 is -CH 3 .
• R 2 is - ⁇ -CH 3 .
• R 2 is - ⁇ -CH 3 .
• R 2 is -alkylene-NH 2 . In one embodiment, R 2 is -NH 2 .
• R 2 is - ⁇ -NH 2 .
• R 2 is - ⁇ -NH 2 .
• R 2 is -alkylene-NH 2 .
• R 2 is -CH 2 NH 2 .
• R 3 is -H.
• R 3a is -H.
• R 3 and R 3a are each -H. In still another embodiment, R 3 is alkyl.
• R 3 is haloalkyl
• R 3 is hydroxyalkyl
• R 3 is -(alkylene) m -C(O)N(R 8 ) 2 .
• R 3 is -(alkylene) m -NHC(O)-R 9 . In another embodiment, R 3 is - ⁇ alkylene) m -N(R 9 ) 2 .
• R 3 is -CH 3 .
• R 3 is - ⁇ -CH 3 .
• R 3 is - ⁇ -CH 3 .
• R 3 is -NH 2 . In another embodiment, R 3 is - ⁇ -NH 2 .
• R 3 is - ⁇ -NH 2 .
• R 3 is -alkylene-NH 2 .
• R 3 is -CH 2 NH 2 .
• R 3 and R 3a and the common carbon atom to which they are attached join to form a carbonyl group.
• R 3 and R 3a and the common carbon atom to which they are attached join to form a cycloalkyl group. In another embodiment, R 3 and R 3a and the common carbon atom to which they are attached, join to form a heterocycioalkyl group.
• R 3 and R 3a and the common carbon atom to which they are attached join to form one of the following groups:
• R 2 and R 28 are each H.
• R 2 is alkyl and R 28 is H.
• R 2 is H and R 2 is alkyl.
• R 10 is H.
• R 1Oa is H.
• R 10 and R 1Oa are each H.
• R 10 is alkyl
• R 10 is haloalkyl
• R 10 is hydroxyalkyl
• R 10 is -(alkylene) m -C(O)N(R 8 ) 2 .
• R 10 is -(alkylene) m -NHC(O>-R 9 .
• R 10 is - ⁇ alkylene) m -N(R 9 )2-
• R 10 is -CH 3 .
• R 10 is -01-CH 3 .
• R 10 is ⁇ -CH 3 .
• R 10 is -IMH 2 .
• R 10 is - ⁇ -NH 2 .
• R 10 is - ⁇ -NH 2 .
• R 10 is -alkylene-NHj.
• R 10 is -CH 2 NH 2 .
• R 10 and R 1Oa and the common carbon atom to which they are attached join to form a cycloaikyl group. In another embodiment, R 10 and R 1Oa and the common carbon atom to which they are attached, join to form a heterocycloalkyl group.
• R 11 is H.
• R 11 is afkyl
• R 11 is -CH 3 . In another embodiment, R 11 is - ⁇ -CH 3 .
• R 11 is - ⁇ -CH 3 .
• R 11 is -alkylene-NH 2 .
• R 11 is -NH 2 .
• R 11 is - ⁇ -NH 2 . In another embodiment, R 11 is - ⁇ -NH 2 .
• R 11 is -alkylene-NH 2 .
• R 11 is -CH 2 NH 2 .
• R 11 and the carbon atom to which it is attached form a carbonyl group.
• R 2 , R 3 , R 3a , R 10 , R 1Oa and R 11 are each H.
• R 2 , R 3 , R 10 , R 1Oa and R 11 are each H.
• R 2 , R 10 , R 1Oa and R 11 are each H.
• R 3 , R 3a , R 10 , R 1Oa and R 11 are each H.
• Ar is -arylene-. in another embodiment, Ar is -heteroarylene-.
• Ar is:
• Ar is:
• Ar is:
• Ar is:
• Ar is:
• Ar is: In one embodiment, Ar is: ;Z is -N- and W is -N(FT 12 ⁇ ).
• Ar is: ;Z is -N- and W is -C(FT 12 ⁇ ) In one embodiment, W is -C(NH 2 KC(O)NH 2 )-.
• W is ⁇ C(NH 2 )(alkyl)-.
• W is -C(NH 2 KCH 3 )-.
• W is -C(NH 2 K-C(O)NHOH)-. In one embodiment, W is -CH(-NC(O)CF 3 )-.
• W is -CH(-NS(O) 2 alkyl)-.
• W is -C(NH 2 K-C(O)NHOH)-.
• W is -CH(-CH 2 NH 2 )-.
• W is -C(-C(O)NH 2 K-NHalkyl)-. In another embodiment, W is -CH(-C(O)NH 2 )-.
• W is -CH 2 -.
• W is -NH-.
• W is -C(R 5 ) 2 -.
• W is -CH(OH)-. In a further embodiment, W is -CH(NH 2 )-.
• W is -CH(CH 3 )-.
• W is -CH(-C(O)CH 3 )-.
• W is -C(OH)(aIkyl)-.
• W is -C(OH)(-alkylene ⁇ OH)-. In another embodiment, W is -N(R 12 )-,
• W is -0-.
• W is -S-.
• W is -C(R 5 ) 2 - and both R 5 groups, together with the common carbon atom to which they are attached, join to form a cycloalkyl group.
• W is -C(R 5 ) 2 - and both R 5 groups, together with the common carbon atom to which they are attached, join to form a heterocycloalkyi group.
• W is -C(R 5 ) 2 - and both R 5 groups, together with the common carbon atom to which they are attached, join to form a group having the formula:
• W is -C(R 5 ) 2 - and each R 5 group is independently selected from H, -(alkylene) m -NH 2 , -NH-alkyl, -N(alkyl) 2) -C(O)NH 2 , -OH 1 -C(O)O-alkyl, 5 or 6 membered heteroaryl or hydroxyalkyl.
• W is -C(R 5 ) 2 - and each R 5 group is independently selected from H, -(alkylene) m -NH 2 , -NH-alkyl, -N ⁇ alkyl) 2 Or-C(O)NH 2 .
• Y is -H.
• Y is -halo, alkyl or -CN.
• Y is methyl. In another embodiment, Z is -CR 8 -.
• Z is -CH-.
• Z is -C(alkyl)-.
• Z is -C(OH)-.
• Z is -C(-O-alkyl)-. In still another embodiment, Z is -C(CFs)-.
• Z is -N-.
• the optional double bond is present and Z is -C-.
• n O.
• n is 1. In another embodiment, n is 2.
• p is O.
• p is 1.
• n and p are each 1.
• n is O and p is 1. In another embodiment, n is 2 and p is 1.
• p is 1 and R 2 , R 3 , R 3a , R 10 , R 1Oa and R 11 are each H. In another embodiment, p is 1 and R 2 , R 10 , R 1Oa and R 11 are each H.
• p is 1 and R 3 , R 3a , R 10 , R 1Oa and R 11 are each H.
• Z is -N-; p is 1; and R 2 , R 3 , R 3a , R 10 , R 1Oa and R 11 are each H. In another embodiment, Z is -N-; p is 1 ; and R 2 , R 10 , R 1Oa and R 11 are each H.
• Z is -N-; p is 1 ; and R 3 , R 3a , R 10 , R 1Oa and R 11 are each H.
• n and p are each 1 and R 2 , R 3 , R 3a , R 10 , R 1Oa and R 11 are each H. In another embodiment, n and p are each 1 and R 2 , R 10 , R 1Oa and R 11 are each
• n and p are each 1 and R 3 , R 3a , R 10 , R 1Oa and R 11 are each H.
• W is -C(R 5 )2- and Z is -N-. In another embodiment, W is -N(R 12 )- and Z is -N-.
• W is -C(R 5 )2- and Z is -CH-.
• W is -N(R 12 )- and Z is -CH-.
• W is -CH(NH 2 K -CH(OH)- or CH(NHSO 2 CH 3 ), and Z is -N-.
• W is -CH(NH 2 )-, -CH(OH)- or CH(NHSO 2 CH 3 ), and Z is -CH-.
• W is -N(R 12 )- and Z is -N-.
• W is -NH- and Z is -N-.
• Ar is phenyl
• W is -C(R 5 ) 2 - and Z is -N-.
• Ar is phenyf, W is -N(R 12 )- and Z is -N-.
• Ar is phenyl
• W is -C(R 8 ) 2 - and Z is -CH-.
• Ar is phenyl
• W is -N(R 12 )- and Z is -CH-.
• Ar is pyridyl
• W is -C(R 5 ) 2 - and Z is -N-.
• Ar is pyridyl
• W is -N(R 12 )- and Z is -N-.
• Ar is pyridyl, W is -C(R 5 ) 2 - and Z is -CH-.
• Ar is pyridyl
• W is -N(R 12 )- and Z is -CH-.
• R 1 is H, methyl, ethyl, and the group is: or
• the present invention provides a compound of formula (I) or a pharmaceutically acceptable salt, solvate, ester, prodrug or stereoisomer thereof, wherein R 1 , R 2 , R 3 , R 3a ,R 10 , R 1Oa , R 11 , Ar 1 n, p, M, W, Y and Z are selected independently of each other in one embodiment, the Diamido Thiazole Derivatives have the formula (IA):
• X is -N- or -CH-
• M is -C(O)- or -NHC(OK and
• R 1 is H, alkyl, heteroaryl, aryl, -alkylene-aryl or heterocycloalkyl.
• the Diamido Thiazole Derivatives have the formula (IA) and R 1 is H, methyl, ethyl,
• the Oiamido Thiazole Derivatives have the formula (IA) and X is N.
• Diamido Thiazole Derivatives have the formula (IA) and X is CH.
• Diamido Thiazole Derivatives have the formula (IA) and M is -C(O)-.
• Diamido Thiazole Derivatives have the formula (IA) and M is -NHC(O)-.
• the Diamido Thiazole Derivatives have the formula (IA) wherein X is -N- and R 1 is H, methyl, ethyl,
• Diamido Thiazole Derivatives have the formula (IA) wherein X is -CH- and R 1 is H 1 methyl, ethyl,
• the Diamiclo Thiazole Derivatives have the formula (IA) wherein M is -C(O)- and R 1 is H, methyl, ethyl,
• the Oiamido Thiazole Derivatives have the formula (IA) wherein M is -NHC(O)- and R 1 is H, methyl, ethyl,
• the present invention provides a compound of formula (IA) or a pharmaceutically acceptable salt, solvate, ester, prodrug or stereoisomer thereof, wherein R 1 , M and X are selected independently of each other.
• the Diamido Thiazole Derivatives have the formula (IB):
• X is -N- or -CHs
• M is -C(O)- or -NHC(O)-;
• R 1 is H, alkyl, heteroaryl, aryl, -alkylene-aryl or heterocycloalkyl.
• the Diamido Thiazole Derivatives have the formula (IB) and R 1 is H, methyl, ethyl,
• Diamido Thiazole Derivatives have the formula (IB) and X is N. In another embodiment, the Diamido Thiazole Derivatives have the formula (IB) and X is CH.
• Diamido Thiazole Derivatives have the formula (IB) and M is -C(O)-.
• Diamido Thiazole Derivatives have the formula (IB) and M is -NHC(O)-.
• the Diamido Thiazole Derivatives have the formula (IB) wherein X is -N- and R 1 is H, methyl, ethyl,
• Diamido Thiazole Derivatives have the formula (IB) wherein X is -CH- and R 1 is H, methyl, ethyl,
• the Diamido Thiazole Derivatives have the formula (IB) wherein M is -C(O)- and R 1 is H, methyl, ethyl,
• the Oiamido Thiazole Derivatives have the formula (IB) wherein M is -NHC(O)- and R 1 is H, methyl, ethyl,
• the present invention provides a compound of formula (IB) or a pharmaceutically acceptable salt, solvate, ester, prodrug or stereoisomer thereof, wherein R 1 , M and X are selected independently of each other.
• variables R 1 , R 2 , R 3 , R 3a , R 10 , R 1Oa , R 11 , Ar, M, Q, W, Y, Z, n and p are selected independently of each other.
• the compounds of formula (I) are in purified form.
• Non-limiting, illustrative examples of the Diamido Thiazole Derivatives of formula (I) include compounds 1-16, listed below:
• Diamido Thiazole Derivatives of formula (I) include compounds 17-26, as depicted in the Examples section below, and pharmaceutically acceptable salts, solvates, esters, prodrugs and stereoisomers thereof.
• Scheme 1 illustrates a method for making the compounds of formula iv, which is a useful intermediate for making the compounds of formula (I), wherein Z is -N- and W iS -N(R 12 )-.
• a nitro-substituted aryl or heteroaryl derivative of formula i can be coupled with a piperizine compound of formula Ii in the presence of diisopropylethylamine (DIEA) using a microwave-assisted process to provide the coupled compound iii.
• DIEA diisopropylethylamine
• the nitro group of a compound of formula Hi can then be reduced using an appropriate method to provide the intermediate amine compounds of formula iv.
• Scheme 2 illustrates a method for making the compounds of formula vii, which is a useful intermediate for making the compounds of formula (I), wherein Z is -N- and
• W is other than -N(R 12 K
• X a is F or Cl
• R 2 , R 3 , W 1 Ar and n are as defined above for the compounds of formula (I).
• a nitro-substituted aryl or heteroaryl derivative of formula i can be coupled with a cyclic amine of formula v to provide the coupled compound vi, using the DIEA coupling method described in Scheme 1.
• the nitro group of a compound of formula vi can then be reduced using an appropriate method to provide the intermediate amine compounds of formula vii.
• Scheme 3 illustrates a method for making the compounds of formula x, which is a useful intermediate for making the compounds of formula (I), wherein 2 is carbon and W is -N(R 12 )-.
• X is Cl, Br or -OTf
• M is B(OH) 2 , ZnX or SnBu 3 i and R 2 , R 3 , Ar and n are as defined above for the compounds of formula (I).
• a nitro-substituted aryl or heteroaryl derivative of formula i can be coupled with a piperidine compound of formula viii using a Pd-catalyzed coupling method ⁇ e.g., a Suzuki coupling, a Negishi coupling or a StHIe coupling) to provide the coupled compound ix.
• the nitro group of a compound of formula ix can then be reduced using an appropriate reduction method to provide the intermediate amine compounds of formula x.
• Scheme 4 illustrates a method for making the compounds of formula xiii, which is a useful intermediate for making the compounds of formula (I), wherein Z is carbon and W is other than -N(R 12 )-.
• X is -Cl, -Br or -OTf
• M is B(OH) 2 , ZnX or SnBu 3
• R 2 , R 3 , W, Ar and n are as defined above for the compounds of formula (I).
• a nitro-substituted aryl or heteroaryl derivative of formula viii can be coupled with a compound of formula xii to provide a compound of formula xiii, using the Pd coupling method described in Scheme 3.
• the nitro group of a compound of formula xiii can then be reduced using an appropriate method to provide the intermediate amine compounds of formula xiv.
• Scheme 5 illustrates a method for making the Diamido Thiazole Derivatives of formula (I) 1 wherein M is -OC(O)-.
• a 2-carbethoxy-thiazole-4-carboxylic acid compound of formula xiv can be coupled with an amine compound of formula xv (which represents compounds iv, vii, x or xiii) using 2-(1H-7-azabenzotriazol-1-yl)-1,1 ,3,3-tetramethyl uranium hexafluorophosphate (HATU) in the presence of N,N -diisopropylethylamine to provide the intermediates of formula xvi, which can be deprotected and further elaborated using well-known methods to provide the compounds of formula (I), wherein M is - OC(O)-.
• HATU 2-(1H-7-azabenzotriazol-1-yl)-1,1 ,3,3-tetramethyl uranium hexafluorophosphate
• Scheme 6 illustrates a method for making the Diamido Thiazoie Derivatives of formula (I), wherein M is -NHC(O)-.
• R 2 , R 2 , R 3 , W, Y, Z and Ar are as defined above for the compounds of formula (I).
• An carboxylic acid compound of formula xvii can be coupled with an amine of formula NH 2 R 2 using conditions described in the scheme 5 to provide the compounds of xviii, which correspond to the compounds of formula (I) wherein M is -NHC(O)-.
• Scheme 7 illustrates a method for making the Diamido Thiazoie Derivatives of formula (I), wherein M is -C(O)-.
• R 1 , R 2 , R 3 , W, Y, Z and Ar are as defined above for the compounds of formula (I).
• An carboxylic acid compound of formula xvii can be reacted with thionyl chloride to provide the acid chloride compounds of xix.
• the compounds of formula xix can then be reacted with with a compound of formula R 1 Li to provide the compounds of formula xx, which correspond to the compounds of formula (I) wherein M is -C(O)-.
• the mobile phase A is composed of 0.1 % TFA in H 2 O and the mobile phase B is composed of CH 3 CN (95%) / H 2 O (5%) / TFA (0.1%).
• the mixture of mobile phase A and B was eluted through the column at a flow rate of 20 m ⁇ min at room temperature.
• the purity of ail the final discrete compounds was checked by LCMS using a Higgins Haisil HL C18 5 ⁇ m 15O x 4.6 mm column and an eluent mixture of mobile phase A and B, wherein mobile phase A is composed of 0.1 % TFA in H 2 O and the mobile phase B is composed of CH 3 CN (95%) / H 2 O (5%) / TFA (0.1 %).
• the column was eluted at a flow rate of 3 mL/min at a temperature of 60 °C.
• intermediate compounds were characterized by LCMS using a Higgins Haisil HL C18 5 ⁇ m 50 x 4.6 mm column and an eluent mixture of mobile phase A and B, wherein mobile phase A is composed of 0.1% TFA in H 2 O and the mobile phase B is composed of CH 3 CN (95%) / H 2 O (5%) / TFA (0.1 %).
• the column was etuted at a flow rate of 3 mL/min at a column temperature of 60 °C.
• aqueous layer was then acidified to pH 2 with 21 mL of concentrated aqueous HCI, resulting in a change to a dark red color and the formation of a heavy precipitate.
• This suspension was then extracted with ethyl acetate (5 x 500 mL). These extracts were combined, dried over sodium sutfate, filtered and concentrated in vacuo to provide Compound 3A as a red-brown solid (14.4 g, 73%).
• This in vitro assay utilizes recombinant His-CHK1 expressed in the baculovirus expression system as an enzyme source and a biotinylated peptide based on CDC25C as substrate (biotin-RSGLYRSPSMPENLNRPR).
• Staurosporine 100 ⁇ g: CALBIOCHEM, Cat. # 569397
• 6 nM is required to yield positive controls of -5,000 CPM.
• Wash buffer 1 2 M NaCI
• Wash buffer 2 2 M NaCI, 1 % H3PO4
• Radio nuclide Manual SPA:P33 Scintillator: Liq/plast Energy Range: Low
• ICfin DETERMINATIONS Dose-response curves were plotted from inhibition data generated, each in duplicate, from 8 point serial dilutions of inhibitory compounds.
• Concentration of compound was plotted against % kinase activity, calculated by CPM of treated samples divided by CPM of untreated samples. To generate IC 50 values, the dose-response curves were then fitted to a standard sigmoidal curve and ICso values were derived by nonlinear regression analysis. Selected Heterocyclic Ether or Thioether Derivatives of the present invention were tested using this assay and provided IC 50 values ranging from about 1 nM to about 10 ⁇ M.
• BACULQVIRUS CONSTRUCTIONS Cyclin E was cloned into pVL1393 (Pharmingen, La JoIIa, California) by PCR, with the addition of 5 histidine residues at the amino-terminal end to allow purification on nickel resin. The expressed protein was approximately 45kDa. CDK2 was cloned into pVL1393 by PCR, with the addition of a haemaglutintn epitope tag at the carboxy-terminal end (YDVPDYAS). The expressed protein was approximately 34kDa in size.
• MOI multiplicity of infection
• Cyclin E/CDK2 kinase assays can be performed as described below in low protein binding 96-well plates (Corning Inc, Corning, New York).
• Enzyme is diluted to a final concentration of 50 ⁇ g/mL in kinase buffer containing 5OmM Tris pH 8.0, 10 mM MgCI 2 I mM DTT, and 0.1 mM sodium orthovanadate.
• the substrate used in these reactions is a biotinylated peptide derived from Histone H1 (from Amersham, UK). The substrate is thawed on ice and diluted to 2 ⁇ M in kinase buffer. Test compounds are diluted in 10% DMSO to desirable concentrations.
• kinase reaction For each kinase reaction, 20 ⁇ l_ of the 50 ⁇ g/mL enzyme solution (1 ⁇ g of enzyme) and 20 ⁇ l of the 2 ⁇ M substrate solution are mixed, then combined with 10 ⁇ L of diluted compound in each well for testing.
• the kinase reaction is initiated by addition of 50 ⁇ L of 2 ⁇ M ATP and 0.1 ⁇ CI of 33P-ATP (from Amersham, UK). The reaction iss allowed to run for 1 hour at room temperature, then is stopped by adding 200 ⁇ L of stop buffer containing 0.1% Triton X-100, 1 mM ATP, 5mM EDTA, and 5 mg/mL streptavidine coated SPA beads (from Amersham, UK) for 15 minutes.
• the SPA beads are then captured onto a 96-well GF/B filter plate (Packard/Perkin Elmer Life Sciences) using a Filtermate universal harvester (Packard/Perkin Elmer Life Sciences.). Non-specific signals are eliminated by washing the beads twice with 2M NaCI then twice with 2 M NaCI with 1% phosphoric acid. The radioactive signal can then be measured using, for example, a TopCount 96 well liquid scintillation counter (from Packard/Perkin Elmer Life Sciences).
• IC ⁇ DETERMINATIONS Dose-response curves are plotted from inhibition data generated, each in duplicate, from 8 point serial dilutions of inhibitory compounds. Concentration of compound is plotted against % kinase activity, calculated by CPM of treated samples divided by CPM of untreated samples. To generate IC 50 values, the dose-response curves are then fitted to a standard sigmoidal curve and IC 50 values can be derived using nonlinear regression analysis.
• Full-length active phosphorylated MEK1 was expressed as a 6X histidine tagged protein (HiS 6 -MEKI) by baculovirus infection of Hi-Five cells co-infected with a baculovirus expressing untagged constitutiveiy active RaM .
• HiS 6 -MEKI 6X histidine tagged protein
• Several milligrams of active His ⁇ -MEK1 was then purified by Ni-NTA affinity chromatography followed by gel filtration chromatography.
• Full-length murine catalytically inactive ERK2KR which had the lysine in subdomain Il mutated to arginine was used as a substrate.
• ERK2KR was expressed from vector pET32aRC in IPTG-induced BL21D3 £ coli as a biotinylated, 6X histidine and thbredoxin tagged fusion protein and purified by Ni-NTA affinity chromatography followed by Mono Q ion exchange chromatography.
• Kinase reactions were performed in duplicate in a 96-well plate, 33 ⁇ L per well at 25 °C for 15 mins, and consisted of 20 nM HiS 6 -MEKI , 2 ⁇ M ERK2KR, 2 ⁇ M ATP, 10 ⁇ CI/ ⁇ L [ ⁇ - 33 P]-ATP 1 10 mM MgCI 2 , 0.01% ⁇ -octylgiucoside t 1 mM DTT, 20 mM HEPES pH 7.5, 3% DMSO and test compounds ranging from 20 ⁇ M down to 0.08 nM.
• Selected Heterocyclic Ether or Thioether Derivatives of the present invention were tested using this assay and provided IC50 values ranging from about 10 nM to about 100 ⁇ M.
• 1 ⁇ M protein was mixed with micromolar concentrations (usually 1-50 ⁇ M) of compounds in 20 ⁇ l of assay buffer (25 mM HEPES, pH 7.4, 300 mM NaCI, 1 mM
• the inhibitory effect of compounds was determined with a DELFIA (Perkin- Elmer) based enzyme assay in which both compound individual percent inhibitions and dose response curves (IC50 determinations) were run.
• Activated recombinant human MEK1 (5 nanomolar final concentration) in buffer containing Hepes, magnesium chloride, dithiothreitol and ATP (2 micromolar final concentration) was preincubated for 10 minutes, before starting the reaction by addition of the recombinant MEK1 substrate ERK (1 micromolar final concentration), which contains a biotin label.
• reaction was run at 20 degrees centigrade for 60 minutes, at which time the reaction was stopped by transfer of reaction aliquots to ROCHE streptavkJin microplates (Perkin-Elmer #11734776001 ) containing DELFIA assay buffer (Perkin- Elmer #4002-0010). After one hour of binding at room temperature with agitation the plates were washed with DELFIA wash buffer (Perkin-Elmer #4010-0010) following which DELFIA assay buffer containing a phosphotyrosine specific antibody (Perkin Elmer #AD0040) was added to the plate and incubated as above for one hour.
• DELFIA wash buffer Perkin-Elmer #4010-0010
• Selected Heterocyclic Ether or Thioether Derivatives of the present invention were tested using this assay and provided IC 50 values ranging from about 10 nM to about 100 ⁇ M.
• Aurora A kinase assays were performed in low protein binding 384-well plates (Corning Inc). Ail reagents were thawed on ice. Test compounds were diluted in 100% DMSO to desirable concentrations. Each reaction consisted of 8 nM enzyme (Aurora A, Upstate cat#14-511), 100 nM Tamra-PKAtide (Molecular Devices, 5TAMRA-GRTGRRNSICOOH ), 25 ⁇ M ATP (Roche), 1 mM DTT (Pierce), and kinase buffer (10 mM Tris, 10 mM MgCI2, 0.01% Tween 20).
• Aurora A kinase assays were performed in low protein binding 384-well plates (Corning tnc). All reagents were thawed on ice. Compounds were diluted in 100% DMSO to desirable concentrations. Each reaction consisted of 26 nM enzyme (Aurora B, Invitrogen cat#pv3970), 100 nM Tamra-PKAtide (Molecular Devices,
• 5TAMRA-GRTGRRNSICOOH 50 ⁇ M ATP (Roche), 1 mM DTT (Pierce), and kinase buffer (10 mM Tris, 10 mM MgCI2, 0.01% Tween 20).
• 14 ⁇ l containing TAMRA-PKAtide, ATP, DTT and kianse buffer were combined with 1 ⁇ l diluted compound.
• the kinase reaction was started by the addition of 5 ⁇ l diluted enzyme. The reaction was allowed to run for 2 hours at room temperature. The reaction was stopped by adding 60 ⁇ l IMAP beads (1 :400 beads in progressive (94.7% buffer A: 5.3% buffer B) 1X buffer, 24 mM NaCI). After an additional 2 hours, fluorescent polarization was measured using an Analyst AD (Molecular devices).
• Dose-response curves were plotted from inhibition data generated each in duplicate, from 8-point serial dilutions of test compounds. Concentration of compound was plotted against kinase activity, calculated by degree of fluorescent polarization. To generate IC 5 0 values, the dose-response curves were then fitted to a standard sigmoidal curve and IC 50 values were derived by nonlinear regression analysis.
• Diamido Thiazole Derivatives can be useful for treating or preventing a Condition in a patient.
• Diamido Thiazole Derivative include, but are not limited to, those disclosed in US Patent No. 6,413,974, which is incorporated by reference herein. Treatment or Prevention of a Cardiovascular Disease
• Diamido Thiazole Derivatives are useful for treating or preventing a cardiovascular disease in a patient.
• the present invention provides a method for treating a cardiovascular disease in a patient, comprising administering to the patient an effective amount of one or more Diamido Thiazole Derivatives.
• cardiovascular diseases treatable or preventable using the present methods include, but are not limited to atherosclerosis, congestive heart failure, cardiac arrhythmia, myocardial infarction, atrial fibrillation, atrial flutter, circulatory shock, left ventricular hypertrophy, ventricular tachycardia, supraventricular tachycardia, coronary artery disease, angina, infective endocarditis, non-infective endocarditis, cardiomyopathy, peripheral artery disease, Reynaud's phenomenon, deep venous thrombosis, aortic stenosis, mitral stenosis, pulmonic stenosis and tricuspid stenosis.
• the cardiovascular disease is atherosclerosis.
• the cardiovascular disease is congestive heart failure.
• the cardiovascular disease is coronary artery disease.
• Diamido Thiazole Derivatives are useful for treating or preventing a central nervous system (CNS) disorder in a patient.
• the present invention provides a method for treating a CNS disorder in a patient, comprising administering to the patient an effective amount of one or more Diamido Thiazole Derivatives.
• CNS disorders treatable or preventable using the present methods include, but are not limited to hypoactivity of the central nervous system, hyperactivity of the central nervous system, a neurodegenerative disease, Alzheimer's disease, amyotrophic lateral sclerosis (ALS), Creutzfeldt-Jakob disease, Huntingdon disease, multiple sclerosis, Lewy body disorder, a tic disorder, Tourette's Syndrome, Parkinson disease, Pick's disease, a prion disease or schizophrenia, epilepsy, migraine, anxiety, bipolar disorder, depression, attention deficit hyperactivity disorder (ADHD) and dementia.
• the CNS disorder is Alzheimer's disease.
• the CNS disorder is Parkinson disease.
• the CNS disorder is ALS.
• Diamido Thiazole Derivatives are useful for treating or preventing a viral infection in a patient.
• the present invention provides a method for treating a viral infection in a patient, comprising administering to the patient an effective amount of one or more Diamido Thiazole Derivatives.
• viral infections treatable or preventable using the present methods include, but are not limited to, HIV, human papilloma virus (HPV), herpesvirus, poxvirus, Epstein-Barr virus, Sindbis virus and adenovirus.
• HPV human papilloma virus
• herpesvirus herpesvirus
• poxvirus Epstein-Barr virus
• Sindbis virus Sindbis virus
• adenovirus adenovirus
• the viral infection is HIV. In another embodiment the viral infection is HPV.
• the Diamido Thiazole Derivatives are useful for treating or preventing a fungal infection in a patient. Accordingly, in one embodiment, the present invention provides a method for treating a fungal infection in a patient, comprising administering to the patient an effective amount of one or more Diamido Thiazole Derivatives.
• Illustrative examples of fungal infections treatable or preventable using the present methods include, but are not limited to, aspergillosis, blastomycosis, candidiasis, coccidioidomycosis, cryptococcosis, histomplamosis, an opportunistic fungi (including yeasts and molds), mucormycosis, mycetoma, paracoccidioidomycosis and sporotrichosis.
• the fungal infection is candidiasis. Treating or Preventing a Disease Related to the Activity of a Protein Kinase
• the Diamido Thiazole Derivatives can be inibitors, regulators or modulators of protein kinases and are useful for treating or preventing a disease related to the activity of a protein kinase in a patient. Accordingly, in one embodiment, the present invention provides a method for treating a disease related to the activity of a protein kinase in a patient, comprising administering to the patient an effective amount of one or more Diamido Thiazole Derivatives.
• CDKs cyclin-dependent kinases
• aurora kinases such as Aurora-A, Aurora-B and Aurora-C
• mitogen activated protein kinase MAPK/ERK
• GSK3beta mitogen activated protein kinase
• c- Met kinases such as c-Met
• Pim-1 kinases Pim-1 kinases
• checkpoint kinases such as Chk1 and Chk2
• tyrosine kinases such as the HER subfamily (including, for example, EGFR (HER1), HER2, HER3 and HER4), the insulin subfamily (including, for example, INS- R, IGF-IR, IR, and IR-R), the PDGF sub
• HER subfamily including, for example, EGFR (HER1), HER2, HER3 and HER4
• the insulin subfamily including, for example, INS- R, IGF-IR, IR, and IR-R
• the present invention provides a method of inhibiting one or more Checkpoint kinases in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of at least one Diamido Thiazole Derivative or a pharmaceutically acceptable salt, solvate, ester, prodrug or stereoisomer thereof.
• the present invention provides a method of treating, or slowing the progression of, a disease associated with one or more Checkpoint kinases in a patient in need thereof, comprising administering a therapeutically effective amount of at least one Diamido Thiazoie Derivative or a pharmaceutically acceptable salt, solvate, ester, prodrug or stereoisomer thereof.
• the present invention provides a method of treating one or more diseases associated with Checkpoint kinase, comprising administering to a patient in need of such treatment at least one Diamido Thiazoie Derivative, or a pharmaceutically acceptable salt, solvate, ester, prodrug or stereoisomer thereof; and at least one additional anticancer agent, wherein the amounts of the at least one Diamido Thiazoie Derivative and the at least one anticancer agent result in a therapeutic effect.
• the present invention provides a method of treating, or slowing the progression of, a disease associated with one or more Checkpoint kinases in a patient in need thereof, comprising administering a therapeutically effective amount of a pharmaceutical composition comprising in combination at least one pharmaceutically acceptable carrier and at least one Diamido Thiazoie Derivative, or a pharmaceutically acceptable salt, solvate, ester, prodrug or stereoisomer thereof.
• the checkpoint kinase to be inhibited, modulated or regulated is Chk1. In another embodiment, the checkpoint kinase to be inhibited, modulated or regulated is Chk2. In one embodiment, the present invention provides a method of inhibiting one or more tyrosine kinases in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of at least one Diamido Thiazoie Derivative or a pharmaceutically acceptable salt, solvate, ester, prodrug or stereoisomer thereof.
• the present invention provides a method of treating, or slowing the progression of, a disease associated with one or more tyrosine kinases in a patient in need thereof, comprising administering a therapeutically effective amount of at least one Diamido Thiazoie Derivative or a pharmaceutically acceptable salt, solvate, ester, prodrug or stereoisomer thereof.
• the present invention provides a method of treating one or more diseases associated with tyrosine kinase, comprising administering to a patient in need of such treatment at least one Diamido Thiazoie Derivative, or a pharmaceutically acceptable salt, solvate, ester, prodrug or stereoisomer thereof; and at least one additional anticancer agent, wherein the amounts of the at least one Diamido Thiazole Derivative and the at least one anticancer agent result in a therapeutic effect.
• the present invention provides a method of treating, or slowing the progression of, a disease associated with one or more tyrosine kinases in a patient in need thereof, comprising administering a therapeutically effective amount of a pharmaceutical composition comprising in combination at least one pharmaceutically acceptable carrier and at least one Diamido Thiazole Derivative or a pharmaceutically acceptable saft, solvate, ester, prodrug or stereoisomer thereof.
• a pharmaceutical composition comprising in combination at least one pharmaceutically acceptable carrier and at least one Diamido Thiazole Derivative or a pharmaceutically acceptable saft, solvate, ester, prodrug or stereoisomer thereof.
• the tyrosine kinase being inhibited, modulated or regulated is VEGFR (VEGF-R2), EGFR, HER2, SRC 1 JAK or TEK, or a combination thereof.
• the present invention provides a method of inhibiting one or more Pim-1 kinases in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of at least one Diamido Thiazole Derivative or a pharmaceutically acceptable salt, solvate, ester, prodrug or stereoisomer thereof.
• the present invention provides a method of treating, or slowing the progression of, a disease associated with one or more Pim-1 kinases in a patient in need thereof, comprising administering a therapeutically effective amount of at least one Diamido Thiazote Derivative or a pharmaceutically acceptable salt, solvate, ester, prodrug or stereoisomer thereof.
• the present invention provides a method of treating one or more diseases associated with Pim-1 kinase, comprising administering to a patient in need of such treatment at least one Diamido Thiazole Derivative, or a pharmaceutically acceptable salt, solvate, ester, prodrug or stereoisomer thereof; and at least one additional anticancer agent, wherein the amounts of the at least one Diamido Thiazole Derivative and the at least one anticancer agent result in a therapeutic effect.
• the present invention provides a method of treating, or slowing the progression of, a disease associated with one or more Pim-1 kinases in a patient in need thereof, comprising administering a therapeutically effective amount of a pharmaceutical composition comprising in combination at least one pharmaceutically acceptable carrier and at least one Diamido Thiazole Derivative or a pharmaceutically acceptable salt, solvate, ester, prodrug or stereoisomer thereof.
• the present invention provides a method of treating one or more diseases associated with an Aurora kinase, comprising administering to a patient in need of such treatment at least one Diamido Thiazole Derivative, or a pharmaceutically acceptable salt, solvate, ester, prodrug or stereoisomer thereof; and at least one additional anticancer agent, wherein the amounts of the at least one Diamido Thiazoie Derivative and the at least one anticancer agent result in a therapeutic effect.
• the present invention provides a method of treating, or slowing the progression of, a disease associated with one or more Aurora kinases in a patient in need thereof, comprising administering a therapeutically effective amount of a pharmaceutical composition comprising in combination at least one pharmaceutically acceptable carrier and at least one Diamido Thiazole Derivative or a pharmaceutically acceptable salt, solvate, ester, prodrug or stereoisomer thereof.
• the present invention provides a method of treating one or more diseases associated with a cyclin dependent kinase, comprising administering to a patient in need of such treatment an amount of a first compound, which is a Diamido Thiazole Derivative, or a pharmaceutically acceptable salt, solvate, ester, prodrug or stereoisomer thereof; and an amount of at least one second compound, the second compound being an anticancer agent different from the Diamido Thiazoie Derivative, wherein the amounts of the first compound and the second compound result in a therapeutic effect.
• a first compound which is a Diamido Thiazole Derivative, or a pharmaceutically acceptable salt, solvate, ester, prodrug or stereoisomer thereof
• an amount of at least one second compound the second compound being an anticancer agent different from the Diamido Thiazoie Derivative, wherein the amounts of the first compound and the second compound result in a therapeutic effect.
• Diamido Thiazole Derivatives can also be useful for inhibiting oncogenes that encode for protein kinases.
• oncogenes include C- Met.
• the Diamido Thiazole Derivatives are useful for treating or preventing a proliferative disorder in a patient. Accordingly, in one embodiment, the present invention provides a method for treating a proliferative disorder in a patient, comprising administering to the patient an effective amount of one or more Diamido Thiazole Derivatives.
• proliferative disorders treatable or preventable using the present methods include, but are not limited to, cancer, atherosclerosis, benign prostate hyperplasia, familial adenomatosis polyposis, neuro-fibromatosis, atherosclerosis, pulmonary fibrosis, arthritis, psoriasis, glomerulonephritis, restenosis following angioplasty or vascular surgery, hypertrophic scar formation, inflammatory bowel disease, transplantation rejection, endotoxic shock, idiopathic pulmonary fibrosis, scleroderma and cirrhosis of the liver.
• the Diamido Thiazole Derivatives are useful for inducing or inhibiting apoptosis in a patient. Accordingly, in one embodiment, the present invention provides a method for inducing or inhibiting apoptosis in a patient, comprising administering to the patient an effective amount of one or more Diamido Thiazole Derivatives.
• the apoptotic response is aberrant in a variety of human diseases and the Diamido Thiazole Derivatives, as modulators of apoptosis, can be useful for the treatment of cancer, a viral infection, prevention of AIDS development in HIV-infected individuals, an autoimmune disease (including but not limited to systemic lupus, erythematosus, autoimmune mediated glomerulonephritis, rheumatoid arthritis, psoriasis, inflammatory bowel disease, and autoimmune diabetes mellitus), a 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), a myeiodyspiastic syndrome, aplastic anemia, an ischemic injury associated with myocardial infarction, stroke and reperfusion injury, arrhythmia, atherosclerosis, toxin-induced or
• the Diamido Thiazole Derivatives are useful for treating or preventing cancer in a patient. Accordingly, in one embodiment, the present invention provides a method for treating cancer in a patient, comprising administering to the patient an effective amount of one or more Diamido Thiazole Derivatives.
• cancers treatable or preventable using the present methods include, but are not limited to cancers of the bladder, breast, colon, rectum, kidney, liver, lung (including small cell lung cancer, non-small cell lung cancer, mesothelioma, and giant cell cancer), head and neck, esophagus, gall bladder, ovary, pancreas, stomach, cervix, thyroid, prostate or skin (including squamous cell carcinoma and melanoma); hematopoietic tumors of lymphoid lineage (including but not limited to, a leukemia such as acute lymphocytic leukemia, chronic lymphocytic leukemia or acute lymphoblastic leukemia; a lymphoma, such as B-cell lymphoma, T- cell lymphoma, Hodgkins lymphoma, non-Hodgkins lymphoma, hairy cell lymphoma, mantle cell lymphoma, myeloma or Burkett's lymph
• Diamido Thiazole Derivatives may also be useful in the chemoprevention of cancer.
• Chemoprevention is defined as inhibiting the development of invasive cancer by either blocking the initiating mutagenic event or by blocking the progression of pre-maiignant cells that have already suffered an insult or inhibiting tumor relapse.
• the Diamido Thiazole Derivatives may also be useful in inhibiting tumor angiogenesis and metastasis.
• the cancer treated or prevented is selected from: breast cancer, colorectal cancer, lung cancer, prostate cancer, ovarian cancer, pancreatic cancer, skin cancer, a leukemia and a lymphoma.
• the cancer treated or prevented is selected from: breast cancer, colorectal cancer, lung cancer and prostate cancer.
• the cancer treated or prevented is breast cancer.
• the cancer treated or prevented is lung cancer.
• the cancer treated or prevented is colorectal cancer.
• the cancer treated or prevented is prostate cancer. In still another embodiment, the cancer treated or prevented is a leukemia.
• the cancer treated or prevented is a lymphoma.
• the cancer treated or prevented is a solid tumor. In another embodiment, the cancer treated or prevented is a cancer of the blood or lymph. In one embodiment, the cancer treated or prevented is a primary cancer.
• the cancer treated or prevented is a metastatic cancer.
• the patient is being treated for both primary and metastatic cancer.
• the present invention provides methods for treating a Condition in a patient, the method comprising administering to the patient one or more Diamido Thiazoie Derivatives, or a pharmaceutically acceptable salt, solvate, ester or prodrug thereof and at least one additional therapeutic agent that is not a Diamido Thiazoie Derivative, wherein the amounts administered are together effective to treat or prevent a Condition.
• Additional therapeutic agents useful in the present methods include, but are not limited to, an anticancer agent, an agent useful for treating a cardiovascular disease, an agent useful for treating a CNS disorder, an antiviral agent, an antifungal agent, an anti-proliferative agent, an anti-alopecia agent, an anti-inflammatory agent, an agent useful for the treatment of a protein kinase-related disorder, an anti-ischemic agent or any combination of two or more of these agents.
• the other therapeutic agent is an agent useful for reducing any potential side effect of a Diamido Thiazole Derivative.
• Such potential side effects include, but are not limited to, nausea, vomiting, headache, fever, lethargy, muscle aches, diarrhea, general pain, and pain at an injection site.
• 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).
• the one or more Diamido Thiazole Derivatives are administered during a time when the additional therapeutic agent(s) exert their prophylactic or therapeutic effect, or wee versa.
• the one or more Diamido Thiazole Derivatives and the additional therapeutic agent(s) are administered in doses commonly employed when such agents are used as monotherapy for treating a Condition.
• the one or more Diamido Thiazole Derivatives and the additional therapeutic agent(s) are administered in doses lower than the doses commonly employed when such agents are used as monotherapy for treating a Condition.
• the one or more Diamido Thiazole Derivatives and the additional therapeutic agent(s) act synergistically and are administered in doses lower than the doses commonly employed when such agents are used as monotherapy for treating a Condition.
• the one or more Diamido Thiazole Derivatives and the additional therapeutic agent(s) are present in the same composition.
• this composition is suitable for oral administration.
• this composition is suitable for intravenous administration.
• the one or more Diamido Thiazoie Derivatives and the additional therapeutic agent(s) can act additively or synergistically.
• a synergistic combination may allow the use of lower dosages of one or more agents and/or less frequent administration of one or more agents of a combination therapy.
• a lower dosage or less frequent administration of one or more agents may lower toxicity of the therapy without reducing the efficacy of the therapy.
• the administration of one or more Diamido Thiazofe Derivatives and the additional therapeutic agent(s) may inhibit the resistance of a Condition to one or more of these agents.
• the additional therapeutic agent is used at its known therapeutically effective dose. In another embodiment, the additional therapeutic agent is used at its normally prescribed dosage. In another embodiment, the additional therapeutic agent is used at less than its normally prescribed dosage or its known therapeutically effective dose.
• the doses and dosage regimen of the other agents used in the combination therapies of the present invention for the treatment or prevention of a Condition can be determined by the attending clinician, taking into consideration the the approved doses and dosage regimen in the package insert; the age, sex and general health of the patient; and the type and severity of the viral infection or related disease or disorder.
• the Diamido Thiazofe Derivative(s) and the other agent(s) for treating diseases or conditions listed above can be administered simultaneously or sequentially. This particularly useful when the components of the combination are given on different dosing schedules, e.g., one component is administered once daily and another every six hours, or when the compositions are different, e.g. one is a tablet and one is a capsule.
• a kit comprising the separate dosage forms is therefore advantageous.
• a total daily dosage of the one or more Diamido Thiazole Derivatives and the additional therapeutic agent(s)can when administered as combination therapy range from about 0.1 to about 2000 mg per day, although variations will necessarily occur depending on the target of the therapy, the patient and the route of administration.
• the dosage is from about 0.2 to about 100 mg/day, administered in a single dose or in 2-4 divided doses.
• the dosage is from about 1 to about 500 mg/day, administered in a single dose or in 2-4 divided doses.
• the dosage is from about 1 to about 200 mg/day, administered in a single dose or in 2-4 divided doses.
• the dosage is from about 1 to about 100 mg/day, administered in a single dose or in 2-4 divided doses. In yet another embodiment, the dosage is from about 1 to about 50 mg/day, administered in a single dose or in 2-4 divided doses. In a further embodiment, the dosage is from about 1 to about 20 mg/day, administered in a single dose or in 2-4 divided doses.
• the compounds of this invention may also be useful in combination (administered together or sequentially in any order) with one or more separate anticancer treatments such as surgery, radiation therapy, biological therapy (e.g., anticancer vaccine therapy) and/or the administration of at least one additional anticancer agent different from the Diamido Thiazole Derivatives, in order to treat or prevent cancer in a patient.
• the compounds of the present invention can be present in the same dosage unit as the additional anticancer agent(s) or in separate dosage units.
• Non-limiting examples of additional anticancer agents suitable for use in combination with the compounds of the present invention include cytostatic agents, cytotoxic agents (such as for example, but not limited to, DNA interactive agents (such as cisplatin or doxorubicin)); taxanes (e.g.
• topoisomerase Il inhibitors such as etoposide orteniposide
• topoisomerase I inhibitors such as irinotecan (or CPT-11 ), camptostar, or topotecan
• tubulin interacting agents such as paclitaxel, docetaxel or the epothilones
• hormonal agents such as tamoxifen
• thymidilate synthase inhibitors such as 5-fluorouracil
• anti-metabolites such as methotrexate
• alkylating agents such as temozotomide (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
• Additional anticancer agents include but are not limited to Uracil mustard, Chlormethine, Ifosfamide, Melphalan, Chlorambucil, Pipobroman, Triethylenemelamine, ara-C, adriamycin, Cytoxan, Clofarabine (Clolar ® from Genzyme Oncology, Cambridge, Massachusetts), cladribine (Leustat ® from Janssen-CIlag Ltd.), aphidicolon, rituxan (from Genentech/Biogen pi), sunitinib (Sutent ® from Pfizer), dasatinib (or BMS-354825 from Bristol-Myers Squibb), tezacitabine (from Aventis Pharma), SmH , fludarabine (from Trigan Oncology Associates), pentostatin (from BC Cancer Agency), triapine (from Vion Pharmaceuticals), didox (from Bioseeker Group), trimidox (from ALS Therapy Development Foundation), amidox, 3-AP (3- amino
• Additional anticancer agents include but are not limited to Triethylenethiophosphoramine, Busulfan, Carmustine, Lomustine, Streptozocin, dacarbazine, Floxuridine, Cytarabine, 6-Mercaptopurine, 6-Thioguanine, Fiudarabine phosphate, oxaliplatin, leucovirin, oxaliplatin (ELOXATINTM from Sanoft-Synthelabo Pharmaceuticals, France), Pentostatine, Vinblastine, Vincristine, Vindesine, Bleomycin, Dactinomycin, Daunorubicin, Doxorubicin, Epirubicin, Idarubicin, Mithramycin, Deoxycoformycin, Mitomycin-C, L-Asparaginase, Teniposide 17 ⁇ - Ethinyiestradiol, Diethylstilbestrol, Testosterone, Prednisone, Fiuoxymesterone,
• Dromostanolone propionate Testolactone, Megestrolacetate, Methylprednisoi ⁇ ne, Methyltestosterone, Prednisolone, Triamcinolone, Chlorotrianisene, Hydroxyprogesterone, Aminoglutethimide, Estramustine, Medroxyprogester ⁇ neacetate, Leuprolide, Fiutam ⁇ de, Toremifene, goserelin, CIsplatin, Carboplatin, OxaHplatin, Aroplatin, Hydroxyurea, Amsacrine, Procarbazine, Mitotane, Mitoxantrone, Levamisole, Navelbene, Anastrazoie, Letrazole, Capecitabine, Reloxafine, Droloxafine, Hexamethylrnelamine, Avastin, Herceptin, Bexxar, Velcade, Zevalin, Trisenox, Xeloda,
• the other anticancer agent is selected from: a cytostatic agent, cisplatin, doxorubicin, taxotere, taxol, etoposide, irinotecan, camptostar, topotecan, paclitaxel, docetaxel, epothUones, tamoxifen, 5-fluorouracil, methoxtrexate, temozolomide, cyclophosphamide, SCH 66336, R115777, L778.123, BMS 214662, Iressa, Tarceva, antibodies to EGFR, Gleevec, intron, ara-C, adriamycin, Cytoxan, gemcitabine, Uracil mustard, Chlormethine, Ifosfamide, Melphalan, Chlorambucil, Pipobroman, Triethylenemelamine, Triethylenethiophosphoramine, Busulfan, Carmustine, Lomustine, Streptozocin, dacarb
• the other anticancer agent is a platinum-based agent, such as cispiatin, carboplatin or oxaliplatin.
• the other anticancer agent is an alkylating agent.
• the other anticancer agent is a vinca alkaloid, such as vincristine or vinblastine.
• the other anticancer agent is a topoisomerase I inhibitor.
• the other anticancer agent is a topoisomerase Il inhibitor. In a further embodiment, the other anticancer agent is an antimetabolite.
• the other anticancer agent is a spindle poison. In another embodiment, the other anticancer agent is an antitumor antibiotic. If formulated as a fixed dose, such combination products employ the compounds of this invention within the dosage range described herein and the other pharmaceutically active agent or treatment within its dosage range.
• the CDC2 inhibitor olomucine has been found to act synergistically with known cytotoxic agents in inducing apoptosis (J. Ce// ScL, (1995) 108, 2897. Diamido Thiazole Derivatives may also be administered sequentially with known anticancer or cytotoxic agents when a combination formulation is inappropriate.
• Diamido Thiazole Derivatives may be administered either prior to or after administration of the known anticancer or cytotoxic agent.
• the cytotoxic activity of the cyclin-dependent kinase inhibitor flavopiridol is affected by the sequence of administration with anticancer agents. Cancer Research, (1997) 57, 3375. Such techniques are within the skills of persons skilled in the art as well as attending physicians.
• this invention includes methods for treating cancer in a patient, comprising administering to the patient an amount of at least one Diamido Thiazole Derivative, or a pharmaceutically acceptable salt, solvate, ester, prodrug or stereoisomer thereof, and one or more other anticancer treatment modalities, wherein the amounts of the Diamido Thiazole Derivative(s)/ other treatment modality result in the desired therapeutic effect.
• the at least one Diamido Thiazole Derivative and the one or more other treatment modalities act synergistically.
• the at least one Diamido Thiazole Derivative and the one or more other treatment modalities act additively.
• the other treatment modality is surgery.
• the other treatment modality is radiation therapy.
• the other treatment modality is biological therapy, such as hormonal therapy or anticancer vaccine therapy.
• 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 herein below have been carried out with compounds according to the invention and their salts, solvates, esters or prodrugs.
• compositions which comprise at least one Diamido Thiazole Derivative, or a pharmaceutically acceptable salt, solvate, ester or prodrug of said compound and at least one pharmaceutically acceptable carrier.
• inert, pharmaceutically acceptable carriers can be either solid or liquid.
• Solid form preparations include powders, tablets, dispersible granules, capsules, cachets and suppositories.
• the powders and tablets may be comprised of from about 5 to about 95 percent active ingredient.
• Suitable solid carriers are known ⁇ n the art, e.g., magnesium carbonate, magnesium stearate, talc, sugar or lactose. Tablets, powders, cachets and capsules can be used as solid dosage forms suitable for oral administration. Examples of pharmaceutically acceptable carriers and methods of manufacture for various compositions may be found in A. Gennaro (ed.), Remington's Pharmaceutical Sciences, 18 th Edition, (1990), Mack Publishing Co., Easton, Pennsylvania.
• Liquid form preparations include solutions, suspensions and emulsions. As an example may be mentioned water or water-propylene glycol solutions for parenteral injection or addition of sweeteners and opacifiers for oral solutions, suspensions and emulsions. Liquid form preparations may also include solutions for intranasal administration.
• Aerosol preparations suitable for inhalation may include solutions and solids in powder form, which may be in combination with a pharmaceutically acceptable carrier, such as an inert compressed gas, e.g. nitrogen. Also included are solid form preparations that are intended to be converted, shortly before use, to liquid form preparations for either oral or parenteral administration. Such liquid forms include solutions, suspensions and emulsions.
• the compounds of the invention may also be deliverable transdermally.
• the transdermal compositions can take the form of creams, lotions, aerosols and/or emulsions and can be included in a transdermal patch of the matrix or reservoir type as are conventional in the art for this purpose.
• the compounds of this invention may also be delivered subcutaneously.
• the compound is administered orally or intravenously or intrathecal ⁇ or some suitable combinatron(s) thereof.
• the pharmaceutical preparation is in a unit dosage form.
• the preparation is subdivided into suitably sized unit doses containing appropriate quantities of the active component, e.g., an effective amount to achieve the desired purpose.
• the quantity of active compound in a unit dose of preparation may be varied or adjusted from about 0.001 mg to about 500 mg.
• the quantity of active compound in a unit dose of preparation is from about 0.01 mg to about 250 mg.
• the quantity of active compound in a unit dose of preparation is from about 0.1 mg to about 100 mg.
• the quantity of active compound in a unit dose of preparation is from about 1.0 mg to about 100 mg, In another embodiment, the quantity of active compound in a unit dose of preparation is from about 1.0 mg to about 50 mg. In still another embodiment, the quantity of active compound in a unit dose of preparation is from about 1.0 mg to about 25 mg.
• the actual dosage employed may be varied depending upon the requirements of the patient and the severity of the condition being treated. Determination of the proper dosage regimen for a particular situation is within the skill of the art. For convenience, the total daily dosage may be divided and administered in portions during the day as required.
• a typical 88 recommended daily dosage regimen for oral administration can range from about 0.01 mg/day to about 2000 mg/day of the Diamido Thiazole Derivatives.
• a daily dosage regimen for oral administration is from about 1 mg/day to 1000 mg/day.
• a daily dosage regimen for oral administration is from about 1 mg/day to 500 mg/day.
• a daily dosage regimen for oral administration is from about 100 mg/day to 500 mg/day.
• a daily dosage regimen for oral administration is from about 1 mg/day to 250 mg/day. in another embodiment, a daily dosage regimen for oral administration is from about 100 mg/day to 250 mg/day. In still another embodiment, a daily dosage regimen for oral administration is from about 1 mg/day to 100 mg/day. In still another embodiment, a daily dosage regimen for oral administration is from about 50 mg/day to 100 mg/day. In a further embodiment, a daily dosage regimen for oral administration is from about 1 mg/day to 50 mg/day. In another embodiment, a daily dosage regimen for oral administration is from about 25 mg/day to 50 mg/day. In a further embodiment, a daily dosage regimen for oral administration is from about 1 mg/day to 25 mg/day. The daily dosage may be administered in a single dosage or can be divided into from two to four divided doses.
• kits in one aspect, the present invention provides a kit comprising an effective amount of one or more Diamido Thiazole Derivatives, or a pharmaceutically acceptable salt, solvate, ester or prodrug thereof, and a pharmaceutically acceptable carrier.
• the present invention provides a kit comprising an amount of one or more Diamido Thiazole Derivatives, or a pharmaceutically acceptable salt, solvate, ester or prodrug thereof, and an amount of at least one additional therapeutic agent listed above, wherein the combined amounts are effective for treating or preventing a Condition in a patient.
• kits comprising a single package containing one or more containers, wherein one container contains one or more Diamido Thiazole Derivatives m a pharmaceutically acceptable carrier, and a second, separate container comprises an additional therapeutic agent in a pharmaceutically acceptable carrier, with the active components of each composition being present in amounts such that the combination is therapeutically effective.
• the present invention provides a kit comprising an amount of at least one Diamido Thiazole Derivative, or a pharmaceutically acceptable salt, solvate, ester or prodrug of said compound and an amount of at least one anticancer therapy and/or additional anticancer agent listed above, wherein the amounts of the two or more ingredients result in the desired therapeutic effect.

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