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
  • C07D417/02—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
  • C07D417/04—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 directly linked by a ring-member-to-ring-member bond
• • 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
• • 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
  • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
  • C07D277/02—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings
  • C07D277/20—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
  • C07D277/32—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
  • C07D277/38—Nitrogen atoms
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
  • C07D277/60—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings condensed with carbocyclic rings or ring systems
  • C07D277/62—Benzothiazoles
• • 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
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
  • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
  • C07F9/02—Phosphorus compounds
  • C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
  • C07F9/6536—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having nitrogen and sulfur atoms with or without oxygen atoms, as the only ring hetero atoms
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
  • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
  • C07F9/02—Phosphorus compounds
  • C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
  • C07F9/6536—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having nitrogen and sulfur atoms with or without oxygen atoms, as the only ring hetero atoms
  • C07F9/6539—Five-membered rings
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
  • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
  • C07F9/02—Phosphorus compounds
  • C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
  • C07F9/6558—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing at least two different or differently substituted hetero rings neither condensed among themselves nor condensed with a common carbocyclic ring or ring system
  • C07F9/65583—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing at least two different or differently substituted hetero rings neither condensed among themselves nor condensed with a common carbocyclic ring or ring system each of the hetero rings containing nitrogen as ring hetero atom

Definitions

• This invention is directed to diaminothiazole compounds that modulate and/or inhibit the activity of certain protein kinases, and to pharmaceutical compositions containing such compounds.
• the invention is also directed to the therapeutic or prophylactic use of such compounds and compositions, and to methods of treating cancer as well as other disease states associated with unwanted angiogenesis and/or cellular proliferation, by administering effective amounts of such compounds.
• Protein kinases are a family of enzymes that catalyze phosphorylation of the hydroxy group of specific tyrosine, serine, or threonine residues in proteins. Typically, such phosphorylation dramatically perturbs the function of the protein, and thus protein kinases are pivotal in the regulation of a wide variety of cellular processes, including metabolisim, cell proliferation, cell differentiation, and cell survival. Of the many different cellular functions in which the activity of protein kinases is known to be required, some processes represent attractive targets for therapeutic intervention for certain disease states.
• Angiogenesis is the mechanism by which new capillaries are formed from existing vessels. When required, the vascular system has the potential to generate new capillary networks in order to maintain the proper functioning of tissues and organs. In the adult, however, angiogenesis is fairly limited, occurring only in the process of wound healing and neovascularization of the endometrium during menstruation. See Merenmies et al., Cell Growth & Differentiation, 8, 3-10 (1997).
• 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 cells, 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 NEGF-R2 will result in the reduction of angiogenesis even in the presence of exogenous VEGF (see Strawn et al., Cancer Research, 56, 3540-3545 (1996)), as has been shown with mutants of VEGF-R2 which fail to mediate signal transduction. Millauer et al., Cancer Research, 56, 1615-1620 (1996).
• NEGF-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.
• FGF-R 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.
• bFGF growth factors
• FGF-R is expressed in a number of different cell types throughout the body and may or may not play important roles in other normal physiological processes in the adult. Nonetheless, systemic administration of a small-molecule inhibitor of the kinase activity of FGF-R has been reported to block bFGF-induced angiogenesis in mice without apparent toxicity. Mohammadi et al., EMBO Journal, 17, 5896-5904 (1998).
• 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.
• WO 97/34876 discloses certain cinnoline derivatives that are inhibitors of VEGF- R2, which may be used for the treatment of disease states associated with abnormal angiogenesis and/or increased vascular permeability such as cancer, diabetes, psoriasis, rheumatoid arthritis, Kaposi's sarcoma, haemangioma, acute and chronic nephropathies, atheroma, arterial restinosis, autoimmune diseases, acute inflammation and ocular diseases with retinal vessel proliferation.
• protein kinases also play a crucial role in cell-cycle control. Uncontrolled cell proliferation is the insignia of cancer. Cell proliferation in response to various stimuli is manifested by a de-regulation of the cell division cycle, the process by which cells multiply and divide. Tumor cells typically have damage to the genes that directly or indirectly regulate progression through the cell division cycle.
• CDKs Cyclin-dependent kinases
• a regulatory cyclin subunit e.g., cyclin A, BI, B2, Dl, D2, D3, and E
• a catalytic kinase subunit e.g., cdc2 (CDK1), CDK2, CDK4, CDK5, and CDK6
• CDK1 cdc2
• CDK4 complexed to the D cyclins that plays a critical part in initiating the cell-division cycle from a resting or quiescent stage to one in which cells become committed to cell division. This progression is subject to a variety of growth regulatory mechanisms, both negative and positive. Aberrations in this control system, particularly those that affect the function of CDK4, have been implicated in the advancement of cells to the highly proliferative state characteristic of malignancies, particularly familial melanomas, esophageal carcinomas, and pancreatic cancers. See, e.g., Kamb, Trends in Genetics, 11, 136- 140 (1995); Kamb et al., Science, 264, 436-440 (1994).
• cyclin E/CDK2 and cyclin B/CDK1 kinases in the G_ ⁇ /S phase and G 2 /M transitions, respectively, offer additional targets for therapeutic intervention in suppressing deregulated cell-cycle progression in cancer.
• Another protein kinase, CHK1 plays an important role as a checkpoint in cell-cycle progression. Checkpoints are control systems that coordinate cell-cycle progression by influencing the formation, activation and subsequent inactivation of the cyclin-dependent kinases.
• Checkpoints prevent cell-cycle progression at inappropriate times, maintain the metabolic balance of cells while the cell is arrested, and in some instances can induce apoptosis (programmed cell death) when the requirements of the checkpoint have not been met. See, e.g., O'Connor, Cancer Surveys, 29, 151-182 (1997); Nurse, Cell, 91, 865-867 (1997); Hartwell et al., Science, 266, 1821-1828 (1994); Hartwell et al., Science, 246, 629-634 (1989).
• One series of checkpoints monitors the integrity of the genome and, upon sensing DNA damage, these "DNA damage checkpoints" block cell-cycle progression in Gj and G 2 phases, and slow progression through S phase.
• CHK1 kinase 1
• CHK1 transduces signals from the DNA-damage sensory complex to inhibit activation of the cyclin B/Cdc2 kinase, which promotes mitotic entry.
• Peng et al. Science, 277, 1501-1505 (1997); Sanchez et al., Science, 277, 1497-1501 (1997).
• Inactivation of CHK1 has been shown to both abrogate G arrest induced by DNA damage inflicted by either anticancer agents or endogenous DNA damage, as well as result in preferential killing of the resulting checkpoint defective cells.
• Cdsl/CHK2 a kinase recently discovered to cooperate with CHKl in regulating S phase progression (see Zeng et al., Nature, 395, 507-510 (1998); Matsuoka, Science, 282, 1893-1897 (1998)), could provide valuable new therapeutic entities for the treatment of cancer. Integrin receptor binding to ECM initiates intracellular signals mediated by
• FAK Fluorescence Activated kinase
• / Tyrosine kinases can be of the receptor type (having extracellular, transmembrane and intracellular domains) or the non-receptor type (being wholly intracellular).
• Cd4 cell- surface protein
• the present invention relates to compounds falling within formula I below which modulate and/or inhibit the activity of protein kinases, as well as to pharmaceutically acceptable prodrugs, pharmaceutically active metabolites, and pharmaceutically acceptable salts thereof (such compounds, prodrugs, metabolites and salts are collectively referred to as "agents").
• the invention is also directed to pharmaceutical compositions containing such agents and their therapeutic use in treating diseases mediated by kinase activity, such as cancer, as well as other disease states associated with unwanted angiogenesis and/or cellular proliferation, such as diabetic retinopathy, neovascular glaucoma, rheumatoid arthritis and psoriasis.
• the invention is related to methods of modulating and/or inhibiting the kinase activity associated with VEGF-R, FGF-R, CDK complexes, TEK, CHKl, LCK, and FAK.
• the invention relates to protein kinase inhibitors of the Formula I:
• R 1 is hydrogen, a substituted or unsubstituted alkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, or a group of the formula R 6 -CO or R 6 -CS where R 6 is substituted or unsubstituted alkyl, cycloalkyl, heterocycloalkyl,
• R R are each independently hydrogen or substituted or unsubstituted alkyl, aryl, or heteroaryl;
• R 2 is hydroxy, halo, cyano, or nitro, or substituted or unsubstituted alkyl, alkenyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, or a group of the formula (A)
• R a is hydrogen, alkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, or a group of the formula (B)
• R a is hydrogen, alkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, or a group of the formula (C)
• R b and R ⁇ are independently hydrogen, alkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, or a group of the formula (D)
• R d is hydrogen, alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, hydroxy, alkoxy, amino, alkylamino, dialkylamino, or acylamino
• R e is hydrogen, alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, amino, alkylamino, or dialkylamino, or a group of the formula (E)
• R f is alkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, or a group of the formula (F)
• R g and R h are each independently hydrogen, alkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, or a group of the formula (G)
• R is alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, or a group of formula (A), formula (B), formula (C), formula (H), or formula (1) as defined herein, or a group of the formula (H) where R j is hydrogen, alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, hydroxy, alkoxy, amino, or a group of formula (A), formula (B), formula (C) or formula (D) as defined herein, and R k is hydrogen, alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, or a group of formula (A), formula (B), formula (C), formula (D), formula (E), or formula (F) as defined herein, or a group of the formula (I)
• R j is hydrogen, alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, or a group of formula (C) as defined herein, or R 2 is a substituted or unsubstituted cycloalkyl, heterocycloalkyl, or aryl that is fused to Q;
• X is C or N
• Q is a divalent radical having 2 or 3 ring atoms (in the ring formed by Q together with X, C* and N* in Formula I) each independently selected from C, N, O, S, C-R 5 and N-R 5 , where R 5 is alkyl, aryl, heteroaryl, alkoxy, hydroxy, halo, cyano, or amino, which together with C* and N* (in Formula I) form a five- or six-membered aromatic or nonaromatic ring.
• the invention is also directed to pharmaceutically acceptable prodrugs, pharmaceutically active metabolites, and pharmaceutically acceptable salts of the compounds of Formula I.
• the invention relates to compounds having the Formula JJ:
• R 1 is substituted or unsubstituted aryl or heteroaryl, or a group of the formula R 6 -CO or R 6 -CS where R 6 is substituted or unsubstituted alkyl, cycloalkyl, heterocycloalkyl alkenyl, aryl, heteroaryl, alkoxy, or N-R 7 R 8 where R 7 R 8 are each independently hydrogen or a substituted or unsubstituted alkyl, aryl, or heteroaryl; R 2 is as defined above;
• X is C or N
• Y and Z are each independently C, N, S, O, C-R 5 or N-R 5 where R 5 is as defined above; and pharmaceutically acceptable prodrugs, pharmaceutically active metabolites, and pharmaceutically acceptable salts thereof.
• Advantageous methods of making the compounds of the Formula II are also described.
• the invention is directed to compounds of Formula II wherein: R l is substituted or unsubstituted aryl or heteroaryl, or R 6 -CO or R 6 -CS where R 6 is substituted or unsubstituted alkyl, cycloalkyl, heterocycloalkyl, alkenyl, aryl, heteroaryl, alkoxy, or N-R 7 R 8 where R 7 R 8 are each independently hydrogen or substituted or unsubstituted alkyl, aryl, or heteroaryl; R 2 is substituted or unsubstituted aryl or heteroaryl; X and Y are each independently C or N; and Z is S or O.
• R 1 and R 2 are each independently substituted aryl, X is C, Y is C or N, and Z is S or O. More preferably, R 1 is a substituted or unsubstituted alkyl, R 2 is a substituted aryl, X is C, Y is C or N, and Z is S or O.
• the invention relates to compounds of Formula HI:
• R 1 is substituted or unsubstituted aryl or heteroaryl, or R 6 -CO or R 6 -CS where R 6 is a substituted or unsubstituted alkyl, alkenyl, aryl, heteroaryl, alkoxy, or N-R 7 R 8 where R 7 R 8 are each independently hydrogen, alkyl, aryl, or heteroaryl; R 3 is substituted or unsubstituted alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, alkoxy, aryloxy, or N-R 7 R 8 where R 7 R 8 are each independently hydrogen, alkyl, aryl, or heteroaryl; R 4 is hydrogen, hydroxy, lower alkyl, halo, lower alkoxy, amino, nitro, or
• Y and Z are each independently C, N, S, O, C-R 5 or N-R 5 where R 5 is unsubstituted or substituted alkyl or aryl; as well as pharmaceutically acceptable prodrugs, pharmaceutically acceptable metabolites, and pharmaceutically acceptable salts thereof.
• R 1 is substituted or unsubstituted aryl or heteroaryl, or R 6 -CO where R 6 is a substituted or unsubstituted alkyl, alkenyl, aryl, heteroaryl, alkoxy, cycloalkyl, heterocycloalkyl, or N-R 7 R 8 where R 7 R 8 are each independently hydrogen, alkyl, aryl, or heteroaryl;
• R 3 is substituted or unsubstituted alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, alkoxy, aryloxy, or N-R 7 R 8 where R 7 R 8 are each independently hydrogen, alkyl, aryl, or heteroaryl;
• R 4 is independently selected from hydrogen, hydroxy, lower alkyl, halo, lower alkoxy, amino, nitro, and trifluoromethyl;
• Y is C or N; and Z is S or O; as well as pharmaceutically acceptable prodrugs, pharmaceutically acceptable metabolites, and pharmaceutically acceptable salts thereof.
• R 1 is substituted or unsubstituted aryl or heteroaryl, or R 6 -CO where R 6 is N-R 7 R 8 where R 7 R 8 are each independently hydrogen, alkyl, aryl, or heteroaryl; R 3 is substituted or unsubstituted alkyl, aryl, heteroaryl, or alkoxy; R 4(a and R 4(b are independently hydrogen, lower alkyl, or halo; Y is C or N; and Z is S or O.
• R 1 is substituted or unsubstituted aryl or heteroaryl, or R 6 -CO where R 6 is N-R 7 R 8 where R 7 R 8 are each independently hydrogen, alkyl, aryl, or heteroaryl; R 3 is substituted or unsubstituted aryl, heteroaryl, or alkoxy; R 4 a) is chloro, fluoro, or methyl; R (b) is fluoro; Y is N; and Z is O.
• the invention also relates to a method of modulating and/or inhibiting the kinase activity of VEGF-R, FGF-R, TEK, a CDK complex, CHKl, TEK, LCK, and/or FAK by administering a compound of the formula I or a pharmaceutically acceptable prodrug, pharmaceutically active metabolites, or pharmaceutically acceptable salt thereof.
• compounds of the present invention that have selective kinase activity — i.e., they possess significant activity against one specific kinase while possessing less or minimal activity against a different kinase.
• compounds of the present invention are those of Formula I possessing substantially higher potency against VEGF receptor tyrosine kinase than against FGF-R 1 receptor tyrosine kinase.
• the invention is also directed to methods of modulating VEGF receptor tyrosine kinase activity without significantly modulating FGF receptor tyrosine kinase activity.
• the invention also relates to pharmaceutical compositions each comprising: an effective amount of an agent selected from compounds of Formula I and pharmaceutically acceptable salts, pharmaceutically active metabolites, and pharmaceutically acceptable prodrugs thereof; and a pharmaceutically acceptable carrier or vehicle for such agent.
• the invention further provides methods of treating cancer as well as other disease states associated with unwanted angiogenesis and/or cellular proliferation, comprising administering effective amounts of such agents to a patient in need of such treatment.
• inventive compounds of the Formula I, ⁇ , HI, and IV are useful for mediating the activity of protein kinases. More particularly, the compounds are useful as anti-angiogenesis agents and as agents for modulating and/or inhibiting the activity of protein kinases, thus providing treatments for cancer or other diseases associated with cellular proliferation mediated by protein kinases.
• alkyl refers to straight- and branched-chain alkyl groups having one to twelve carbon atoms.
• Exemplary alkyl groups include methyl (Me), ethyl, n-propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl (t-Bu), pentyl, isopentyl, tert-pentyl, hexyl, isohexyl, and the like.
• the term "lower alkyl” designates an alkyl having from 1 to 8 carbon atoms (a C 1-8 -alkyl).
• Suitable substituted alkyls include fluoromethyl, difluoromethyl, trifluoromethyl, 2-fluoroethyl, 3-fluoropropyl, hydroxymethyl, 2-hydroxyethyl, 3-hydroxypropyl, and the like.
• alkenyl refers to straight- and branched-chain alkenyl groups having from two to twelve carbon atoms.
• Illustrative alkenyl groups include prop-2- enyl, but-2-enyl, but-3-enyl, 2-methylprop-2-enyl, hex-2-enyl, and the like.
• cycloalkyl refers to partially saturated or unsaturated carbocycles having from three to twelve carbon atoms, including bicyclic and tricyclic cycloalkyl structures. Suitable cycloalkyls include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and the like.
• heterocycloalkyl is intended to mean a partially saturated or unsaturated monocycUc radical containing carbon atoms, preferably 4 or 5 ring carbon atoms, and at least one heteroatom selected from nitrogen, oxygen and sulfur.
• aryl (Ar) and “heteroaryl” refer to monocycUc and polycyclic unsaturated or aromatic ring structures, with “aryl” referring to those that are carbocycles and “heteroaryl” referring to those that are heterocycles.
• aromatic ring structures include phenyl, naphthyl, 1,2,3,4-tetrahydronaphthyl, furyl, thienyl, pyrrolyl, pyridyl, pyridinyl, pyrazolyl, imidazolyl, pyrazinyl, pyridazinyl, 1,2,3-triazinyl, 1 ,2,4-oxadiazolyl, 1,3,4-oxadiazolyl, l-H-tetrazol-5-yl, indolyl, quinoUnyl, benzofuranyl, benzothiophenyl (thianaphthenyl), and the like.
• Such moieties may be optionally substituted by one or more suitable substituents, for example, a substituent selected from a halogen (F, Cl, Br or I); lower alkyl; OH; NO 2 ; CN; CO 2 H; O-lower alkyl; aryl; aryl-lower alkyl; CO 2 CH 3 ; CONH 2 ; OCH 2 CONH 2 ; NH 2 ; SO 2 NH 2 ; OCHF 2 ; CF 3 ; OCF 3 ; and the like.
• Such moieties may also be optionally substituted by a fused-ring structure or bridge, for example OCH -O.
• alkoxy is intended to mean the radical -O-alkyl. Illustrative examples include methoxy, ethoxy, propoxy, and the like.
• lower alkoxy designates an alkoxy having from 1 to 8 carbon atoms
• aryloxy represents -O— aryl, where aryl is defined above.
• halogen represents chlorine, fluorine, bromine or iodine.
• halo represents chloro, fluoro, bromo or iodo.
• substituents include a halogen (F, Cl, Br, or I), lower alkyl, -OH, -NO , - CN, -CO 2 H, -O-lower alkyl,
• -CF 3 e.g., -CF 3 , -CH 2 CF 3
• -O-haloalkyl e.g., -OCF 3 , -OCHF 2
• Formula I depicts a double bond between C* and N*, the artisan will understand that when Q together with C* and N* form a five- or six-membered aromatic ring, the presence of the double bond is not necessarily between C* and N*, as other canonical forms of the aromatic ring exist. It is therefore understood that all possible canonical forms of the aromatic ring formed by Q together with C* and N* are also intended to be covered by Formula I.
• the compounds of the invention are preferably those of the Formula ⁇ , more preferably those of the Formula Dl, and even more preferably those of the Formula IV.
• inventive compounds may exist as single stereoisomers (i.e., essentiaUy free of other stereoisomers), racemates, and/or mixtures of enantiomers and/or diastereomers. All such single stereoisomers, racemates and mixtures thereof are intended to be within the scope of the present invention.
• inventive compounds that are optically active are used in optically pure form.
• an optically pure compound having one chiral center is one that consists essentially of one of the two possible enantiomers (i.e., is enantiomerically pure), and an optically pure compound having more than one chiral center is one that is both diastereomerically pure and enantiomerically pure.
• the compounds of the present invention are used in a form that is at least 90% optically pure, that is, a form that contains at least 90% of a single isomer (80% enantiomeric excess ("e.e.") or diastereomeric excess (“d.e.”)), more preferably at least 95% (90% e.e. or d.e.), even more preferably at least 97.5% (95% e.e. or d.e.), and most preferably at least 99% (98% e.e. or d.e.).
• Formula I includes compounds of the indicated structure in both hydrated and non-hydrated forms.
• Other examples of solvates include the structures in combination with isopropanol, ethanol, methanol, DMSO, ethyl acetate, acetic acid, or ethanolamine.
• the invention includes pharmaceutically acceptable prodrugs, pharmaceutically active metabolites, and pharmaceutically acceptable salts of such compounds.
• a "pharmaceutically acceptable prodrug” is a compound that may be converted under physiological conditions or by solvolysis to the specified compound or to a pharmaceutically acceptable salt of such compound.
• a "pharmaceuticaUy active metaboUte” is intended to mean a pharmacologically active product produced through metabolism in the body of a specified compound or salt thereof. Metabolites of compound may be identified using routine techniques known in the art and their activities determined using tests such as those described herein.
• a “pharmaceutically acceptable salt” is intended to mean a salt that retains the biological effectiveness of the free acids and bases of the specified compound and that is not biologically or otherwise undesirable.
• a compound of the invention may possess a sufficiently acidic, a sufficiently basic, or both functional groups, and accordingly react with any of a number of inorganic or organic bases, and inorganic and organic acids, to form a pharmaceutically acceptable salt.
• Exemplary pharmaceutically acceptable salts include those salts prepared by reaction of the compounds of the present invention with a mineral or organic acid or an inorganic base, such as salts including sulfates, pyrosulfates, bisulfates, sulfites, bisulfites, phosphates, monohydrogenphosphates, dihydrogenphosphates, metaphosphates, pyrophosphates, chlorides, bromides, iodides, acetates, propionates, decanoates, caprylates, acrylates, formates, isobutyrates, caproates, heptanoates, propiolates, oxalates, malonates, succinates, suberates, sebacates, fumarates, maleates, butyne-1,4- dioates, hexyne-l,6-dioates, benzoates, chlorobenzoates, methylbenzoates, dinitrobenzoates, hydroxybenzoates, methoxybenzoates
• lactates ⁇ -hydroxybutyrates, glycollates, tartrates, methane-sulfonates,
• the desired pharmaceutically acceptable salt may be prepared by any suitable method available in the art, for example, treatment of the free base with an inorganic acid, such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid and the like, or with an organic acid , such as acetic acid, maleic acid, succinic acid, mandelic acid, fumaric acid, malonic acid, pyrovic acid, oxaUc acid, glycolic acid, salicylic acid, a pyranosidyl acid, such as glucuronic acid or galacturonic acid, an alpha- hydrozy acid, such as citric acid or tartaric acid, an amino acid, such as aspartic acid or glutamic acid, an aromatic acid, such as benzoic acid or cinnamic acid, a sulfonic acid, such as p-toluenesulfonic acid or ethanesulfonic acid, or the like.
• an inorganic acid such as hydrochlor
• the desired pharmaceutically acceptable salt may be prepared by any suitable method, for example, treatment of the free acid with an inorganic or organic base, such as an amine (primary, secondary or tertiary), an alkali metal hydroxide or alkaline earth metal hydroxide, or the like.
• an inorganic or organic base such as an amine (primary, secondary or tertiary), an alkali metal hydroxide or alkaline earth metal hydroxide, or the like.
• suita'ble salts include organic salts derived from amino acids, such as giycine and arginine, ammonia, primary, secondary, and tertiary amines, and cyclic amines, such as piperidine, morpholine and piperazine, and inorganic salts derived from sodium, calcium, potassium, magnesium, manganese, iron, copper, zinc, aluminum and lithium.
• Therapeutically effective amounts of the agents of the invention may be used to treat diseases mediated by modulation or regulation of protein kinases.
• An "effective amount" is intended to mean that amount of an agent that, when administered to a mammal in need of such treatment, is sufficient to effect treatment for a disease mediated by the activity of one or more protein kinases, such as tryosine kinases.
• a therapeutically effective amount of a compound of the Formula I, salt, active metabolite or prodrug thereof is a quantity sufficient to modulate, regulate, or inhibit the activity of one or more protein kinases such that a disease condition which is mediated by that activity is reduced or alleviated.
• the amount of a given agent that will correspond to such an amount will vary depending upon factors such as the particular compound, disease condition and its severity, the identity (e.g., weight) of the mammal in need of treatment, but can nevertheless be routinely determined by one skilled in the art.
• Treating is intended to mean at least the mitigation of a disease condition in a mammal, such as a human, that is affected, at least in part, by the activity of one or more protein kinases, such as tyrosine kinases, and includes: preventing the disease condition from occurring in a mammal, particularly when the mammal is found to be predisposed to having the disease condition but has not yet been diagnosed as having it; modulating and/or inhibiting the disease condition; and/or alleviating the disease condition.
• inventive agents may be prepared using the reaction routes and synthesis schemes as described below, employing the techniques available in the art using starting materials that are readily available.
• the compound of Formula VII is not isolated, but is directly converted to the compound of Formula I by continued reaction at a temperature between room temperature and 80 °C, preferably 50 °C, for 1 to 24 h. Conventional work-up and purification yields final compound I.
• a compound of Formula VII is isolated and purified, and then is converted to a compound of Formula I by treatment with a suitable base, such as potassium t- butoxide, lithium hexamethyldisilazide, or lithium diisopropylamide, in an appropriate solvent, such as THF, for 0.5 to 24 h at a temperature between -78 °C and room temperature.
• a suitable base such as potassium t- butoxide, lithium hexamethyldisilazide, or lithium diisopropylamide
• Compounds of Formula VI may also be prepared by methods known to those skilled in the art. See, e.g., Mylari et al., J. Med. Chem., 35, 457-465 (1992); Baiocchi et al., Heterocyclic Chem., 16, 1469-1474 (1979), which are incorporated by reference herein.
• a compound of Formula V ⁇ i may be prepared by conventional acylation of 3-aminobenzonitrile, followed by heating at 60-100 °C with hydroxylamine in a suitable solvent, such as ethanol or isopropanol, for 1 to 24 hours.
• a compound of Formula VI(a) may be prepared by treatment of a compound of Formula VIE with chloroacetyl chloride and a suitable base, such as diispropylethylamine (“DDEA”), in an appropriate solvent, such as dichloromethane.
• DDEA diispropylethylamine
• aqueous work- up provides a crude intermediate, which is further heated at 100 °C in a suitable solvent, such as dioxane, for 0.5 to 4 hours, to yield, after conventional isolation and purification, a compound of Formula VI(a).
• a suitable solvent such as dioxane
• Inventive compounds of Formulas H , HI, and IV may also be prepared by other processes, including the general procedure shown in the following reaction scheme.
• a compound of Formula D where X and Y are C and Z is S, may be prepared by adding DBU to a solution of R'-isothiocyanato and cyanamide in a suitable solvent at an appropriate temperature, preferably acetonitrile at room temperature for approximately 40-80 minutes. To this reaction mixture is added bromo-acetonitrile and additional DBU, to yield, after conventional work-up and purification, an intermediate 2-R 1 -amino-4-amino-thiazole-5-carbonitrile intermediate IX.
• the reaction of intermediate DC with dihydrogen sulfide in triethylamine/pyridine at about 0 °C provides intermediate X.
• a compound of Formula ⁇ (d) is produced after standard acid work-up and purification by silica chromatography.
• Compounds of Formula D(e) may also be prepared from compounds DC by refluxing in a suitable aprotic solvent, such as toluene, a solution of DC, TMSN 3 , and a catalytic amount of Bu 2 SnO. After refluxing, the solvent is removed and the residue is redissolved in ethyl acetate, washed with a appropriate aqueous acid solution, and dried over a suitable drying agent. After the removal of the solvent, the residue is triturated in ethyl ether and compound 11(e) is collected by filtration.
• Compounds of Formula HI may also be prepared directly from compound H(b) where R 2 is 3-nitrophenyl by reducing the nitro group with a suitable reducing agent to form the amino substituted phenyl (H(f)).
• a suitable reducing agent to form the amino substituted phenyl (H(f)).
• a solution of compound H(b) where R 2 is 3-nitrophenyl and stannous chloride is dissolved in dimethylformamide ("DMF') under inert atmosphere conditions and stirred at between 40-60 °C until H(f) is formed.
• DMF' dimethylformamide
• the intermediate H(f) may be reacted with a suitable acylating agent under standard acylating conditions to form a compound of the Formula IH(a).
• a preferable acylating procedure involves dissolving compound D(f) in DMF and tetrahydrofuran ("THF') and adding pyridine and a suitable acid chloride or acyl chloroformate at -30 to 0 °C. The reaction is quenched with a proton source (e.g., methanol) and purified by preparative C-18 reverse phase HPLC to provide compound IH(a).
• a proton source e.g., methanol
• Other compounds of Formula I may be prepared in manners analogous to the general procedures described above or the detailed procedures described in the examples herein.
• the affinity of the compounds of the invention for a receptor may be enhanced by providing multiple copies of the Ugand in close proximity, preferably using a scaffolding provided by a carrier moiety. It has been shown that provision of such multiple valence compounds with optimal spacing between the moieties dramatically improves binding to a receptor. See for example, Lee et al., Biochem, 23, 4255 (1984).
• the multivalency and spacing can be controlled by selection of a suitable carrier moiety or linker units.
• Such moieties include molecular supports which contain a multiplicity of functional groups that can be reacted with functional groups associated with the compounds of the invention.
• a variety of carriers can be used, including proteins such as BSA or HAS, a multiplicity of peptides including, for example, pentapeptides, decapeptides, pentadecapeptides, and the like.
• the peptides or proteins can contain the desired number of amino acid residues having free amino groups in their side chains; however, other functional groups, such as sulfhydryl groups or hydroxyl groups, can also be used to obtain stable linkages.
• the present invention is further directed to methods of modulating or inhibiting protein kinase activity, for example in mammalian tissue, by administering an inventive agent.
• the activity of the inventive compounds as modulators of protein kinase activity such as the activity of kinases, may be measured by any of the methods available to those skiUed in the art, including in vivo and/or in vitro assays.
• Suitable assays for activity measurements include those described in Parast C. et al., Biochemistry, 37, 16788-16801 (1998); Jeffrey et al., Nature, 376, 313-320 (July 27, 1995); WIPO International Publication No. WO 97/34876; and WIPO International Publication No. WO 96/14843. These properties may be assessed, for example, by using one or more of the biological testing procedures set out in the examples below.
• compositions of this invention comprise an effective modulating, regulating, or inhibiting amount of a compound of Formula I, H , HI or IV and an inert, pharmaceutically acceptable carrier or diluent.
• efficacious levels of the inventive agents are provided so as to provide therapeutic benefits involving modulation of protein kinases.
• efficacious levels is meant levels in which the effects of protein kinases are, at a minimum, regulated.
• An inventive agent is administered in conventional dosage form prepared by combining a therapeutically effective amount of an agent (e.g., a compound of Formula I) as an active ingredient with appropriate pharmaceutical carriers or diluents according to conventional procedures. These procedures may involve mixing, granulating and compressing or dissolving the ingredients as appropriate to the desired preparation.
• an agent e.g., a compound of Formula I
• the pharmaceutical carrier employed may be either a solid or liquid.
• soUd carriers are lactose, sucrose, talc, gelatin, agar, pectin, acacia, magnesium stearate, stearic acid and the like.
• liquid carriers are syrup, peanut oil, olive oil, water and the like.
• the carrier or diluent may include time-delay or time-release material known in the art, such as glyceryl monostearate or glyceryl distearate alone or with a wax, ethylcellulose, hydroxypropylmethylcellulose,
• a soUd carrier used, the preparation can be tableted, placed in a hard gelatin capsule in powder or pellet form or in the form of a troche or lozenge.
• the amount of solid carrier may vary, but generally will be from about 25 mg to about 1 g.
• a liquid carrier is used, the preparation will be in the form of syrup, emulsion, soft gelatin capsule, sterile injectable solution or suspension in an ampoule or vial or non-aqueous liquid suspension.
• a pharmaceutically acceptable salt of an inventive agent is dissolved in an aqueous solution of an organic or inorganic acid, such as 0.3M solution of succinic acid or citric acid.
• the agent may be dissolved in a suitable cosolvent or combinations of cosolvents.
• suitable cosolvents include, but are not limited to, alcohol, propylene glycol, polyethylene glycol 300, polysorbate 80, gylcerin and the like in concentrations ranging from 0-60% of the total volume.
• a compound of Formula I is dissolved in DMSO and diluted with water.
• the composition may also be in the form of a solution of a salt form of the active ingredient in an appropriate aqueous vehicle such as water or isotonic saline or dextrose solution.
• an exemplary daily dose generally employed is from about 0.001 to about 1000 mg/kg of body weight, with courses of treatment repeated at appropriate intervals.
• Administration of prodrugs are typically dosed at weight levels which are chemically equivalent to the weight levels of the fully active form.
• compositions of the invention may be manufactured in manners generally known for preparing pharmaceutical compositions, e.g., using conventional techniques such as mixing, dissolving, granulating, dragee-making, levigating, emulsifying, encapsulating, entrapping or lyophilizing.
• Pharmaceutical compositions may be formulated in a conventional manner using one or more physiologically acceptable carriers, which may be selected from excipients and auxiliaries that facilitate processing of the active compounds into preparations which can be used pharmaceutically.
• the agents of the invention may be formulated into aqueous solutions, preferably in physiologically compatible buffers such as Hanks 's solution, Ringer's solution, or physiological saline buffer.
• physiologically compatible buffers such as Hanks 's solution, Ringer's solution, or physiological saline buffer.
• penetrants appropriate to the barrier to be permeated are used in the formulation. Such penetrants are generally known in the art.
• the compounds can be formulated readily by combining the active compounds with pharmaceutically acceptable carriers known in the art.
• Such carriers enable the compounds of the invention to be formulated as tablets, pills, dragees, capsules, liquids, gels, syrups, slurries, suspensions and the like, for oral ingestion by a patient to be treated.
• Pharmaceutical preparations for oral use can be obtained using a solid excipient in admixture with the active ingredient (agent), optionally grinding the resulting mixture, and processing the mixture of granules after adding suitable auxiliaries, if desired, to obtain tablets or dragee cores.
• Suitable excipients include: fillers such as sugars, including lactose, sucrose, mannitol, or sorbitol; and cellulose preparations, for example, maize starch, wheat starch, rice starch, potato starch, gelatin, gum, methyl cellulose, hydroxypropylmethyl-cellulose, sodium carboxymethylcellulose, or polyvinylpyrroUdone (PVP).
• disintegrating agents may be added, such as crosslinked polyvinyl pyrrolidone, agar, or alginic acid or a salt thereof such as sodium alginate.
• Dragee cores are provided with suitable coatings.
• suitable coatings For this purpose, concentrated sugar solutions may be used, which may optionally contain gum arabic, polyvinyl pyrrolidone, Carbopol gel, polyethylene glycol, and/or titanium dioxide, lacquer solutions, and suitable organic solvents or solvent mixtures.
• Dyestuffs or pigments may be added to the tablets or dragee coatings for identification or to characterize different combinations of active agents.
• compositions which can be used orally include push-fit capsules made of gelatin, as well as soft, sealed capsules made of gelatin and a plasticizer, such as glycerol or sorbitol.
• the push-fit capsules can contain the active ingredients in admixture with fillers such as lactose, binders such as starches, and/or lubricants such as talc or magnesium stearate, and, optionally, stabilizers.
• the active agents may be dissolved or suspended in suitable liquids, such as fatty oils, liquid paraffin, or liquid polyethylene glycols.
• stabilizers may be added. All formulations for oral administration should be in dosages suitable for such administration.
• the compositions may take the form of tablets or lozenges formulated in conventional manner.
• the compounds for use according to the present invention are conveniently deUvered in the form of an aerosol spray presentation from pressurized packs or a nebuliser, with the use of a suitable propellant, e.g., dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide or other suitable gas.
• a suitable propellant e.g., dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide or other suitable gas.
• the dosage unit may be determined by providing a valve to deliver a metered amount.
• Capsules and cartridges of gelatin for use in an inhaler or insufflator and the like may be formulated containing a powder mix of the compound and a suitable powder base such as lactose or starch.
• the compounds may be formulated for parenteral administration by injection, e.g., by bolus injection or continuous infusion.
• Formulations for injection may be presented in unit-dosage form, e.g., in ampoules or in multi-dose containers, with an added preservative.
• the compositions may take such forms as suspensions, solutions or emulsions in oily or aqueous vehicles, and may contain formulatory agents such as suspending, stabilizing and/or dispersing agents.
• compositions for parenteral administration include aqueous solutions of the active compounds in water-soluble form. Additionally, suspensions of the active agents may be prepared as appropriate oily injection suspensions. Suitable lipophilic solvents or vehicles include fatty oils such as sesame oil, or synthetic fatty acid esters, such as ethyl oleate or triglycerides, or liposomes. Aqueous injection suspensions may contain substances which increase the viscosity of the suspension, such as sodium carboxymethyl cellulose, sorbitol, or dextran. Optionally, the suspension may also contain suitable stabilizers or agents which increase the solubility of the compounds to allow for the preparation of highly concentrated solutions.
• a compound of the Formula I, H, HI, or IV is delivered in a pharmaceutically acceptable ophthalmic vehicle such that the compound is maintained in contact with the ocular surface for a sufficient time period to allow the compound to penetrate the corneal and internal regions of the eye, including, for example, the anterior chamber, posterior chamber, vitreous body, aqueous humor, vitreous humor, cornea, iris/cilary, lens, choroid/retina and selera.
• the pharmaceutically acceptable ophthalmic vehicle may be an ointment, vegetable oil, or an encapsulating material.
• a compound of the invention may also be injected directly into the vitreous and aqueous humor.
• the active ingredient may be in powder form for constitution with a suitable vehicle, e.g., sterile pyrogen-free water, before use.
• a suitable vehicle e.g., sterile pyrogen-free water
• the compounds may also be formulated in rectal compositions such as suppositories or retention enemas, e.g, containing conventional suppository bases such as cocoa butter or other glycerides.
• the compounds may also be formulated as a depot preparation. Such long-acting formulations may be administered by implantation (for example, subcutaneously, intramuscularly, or intraocularly) or by intramuscular injection.
• the compounds may be formulated with suitable polymeric or hydrophobic materials (for example, as an emulsion in an acceptable oil) or ion-exchange resins, or as sparingly soluble derivatives, for example, as a sparingly soluble salt.
• a pharmaceutical carrier for hydrophobic compounds is a cosolvent system comprising benzyl alcohol, a nonpolar surfactant, a water-miscible organic polymer, and an aqueous phase.
• the cosolvent system may be a VPD co-solvent system.
• VPD is a solution of 3% w/v benzyl alcohol, 8% w/v of the nonpolar surfactant polysorbate 80, and 65% w/v polyethylene glycol 300, made up to volume in absolute ethanol.
• the VPD co-solvent system (VPD:5W) cotains VPD diluted 1:1 with a 5% dextrose in water solution. This co-solvent system dissolves hydrophobic compounds well, and itself produces low toxicity upon systemic administration. Naturally, the proportions of a co-solvent system may be varied considerably without destroying its solubility and toxicity characteristics.
• co-solvent components may be varied: for example, other low-toxicity nonpolar surfactants may be used instead of polysorbate 80; the fraction size of polyethylene glycol may be varied; other biocompatible polymers may replace polyethylene glycol, e.g. polyvinyl pyrroUdone; and other sugars or polysaccharides may be substituted for dextrose.
• hydrophobic pharmaceutical compounds may be employed.
• Liposomes and emulsions are known examples of delivery vehicles or carriers for hydrophobic drugs.
• Certain organic solvents such as dimethylsulfoxide also may be employed, although usually at the cost of greater toxicity.
• the compounds may be delivered using a sustained-release system, such as semipermeable matrices of solid hydrophobic polymers containing the therapeutic agent.
• sustained-release materials have been estabUshed and are known by those skilled in the art. Sustained-release capsules may, depending on their chemical nature, release the compounds for a few weeks up to over 100 days.
• additional strategies for protein stabilization may be employed.
• compositions also may comprise suitable solid- or gel- phase carriers or excipients.
• suitable solid- or gel- phase carriers or excipients include calcium carbonate, calcium phosphate, sugars, starches, cellulose derivatives, gelatin, and polymers such as polyethylene glycols.
• Some of the compounds of the invention may be provided as salts with pharmaceutically compatible counter ions.
• PharmaceuticaUy compatible salts may be formed with many acids, including hydrochloric, sulfuric, acetic, lactic, tartaric, malic, succinic, etc. Salts tend to be more soluble in aqueous or other protonic solvents than are the conesponding free-base forms.
• the reactions set forth below were done generally under a positive pressure of nitrogen or with a drying tube, at ambient temperature (unless otherwise stated), in anhydrous solvents, and the reaction flasks were fitted with rubber septa for the introduction of substrates and reagents via syringe. Glassware was oven dried and/or heat dried. Analytical thin layer chromatography (TLC) was performed on glass- backed silica gel 60 F 254 plates Analtech (0.25 mm) and eluted with the appropriate solvent ratios (v/v), and are denoted where appropriate. The reactions were assayed by TLC and terminated as judged by the consumption of starting material.
• TLC thin layer chromatography
• Visualization of the tip plates was done with a p-anisaldehyde spray reagent or phosphomolybdic acid reagent (Aldrich Chemical 20 wt% in ethanol) and activated with heat. Work-ups were typically done by doubling the reaction volume with the reaction solvent or extraction solvent and then washing with the indicated aqueous solutions using 25% by volume of the extraction volume unless otherwise indicated.
• Hydrogenolysis was done at the pressure indicated in the examples or at ambient pressure.
• NMR spectra were recorded on a Bruker instrument operating at 300 MHz and 13 C-NMR spectra were recorded operating at 75 MHz. NMR spectra were obtained as CDC1 3 solutions (reported in ppm), using chloroform as the reference standard (7.25 ppm and 77.00 ppm) or CD 3 OD (3.4 and 4.8 ppm and 49.3 ppm), or internally tetramethylsilane (0.00 ppm) when appropriate. Other NMR solvents were used as needed.
• IR Infrared
• Example A(l) the following Examples A(2) through A(71) were prepared.
• the title compound was prepared as follows. To a solution of tritylisothiocyanate (5.0 mmol) and cyanamide (5.5 mmol) dissolved in anhydrous THF (10 mL) was added 1,8-diazabicyclo [5.4.0]undec-7-ene (5.5 mmol). After stirring for 2 hours, the reaction was diluted with acetonitrile (15 mL) and then treated with 5-chloromethyl-3-(3-(t-butoxy-carbamoyl)phenyl)-[l,2,4]-oxadiazole (2.5 mmol) and 1,8-diazabicyclo [5.4.0]undec-7-ene (2.75 mmol). The product was isolated after 1 hour by concentrating the crude reaction in vacuo, and chromatographing the resulting oil (gradient elution, 20% EtOAc/hexane to 40%
• Example B (6) 3 -(2-methyl-5 -(tert-butyloxy carboxy amino)-phenyl)- - [2- [(3 ,4,5 trimethoxyphenyl)-amino] -4-amino-5-thiazolyl] - 1 ,2,4-oxadiazole
• Example B(12)N (3- ⁇ 5-[ 4-Amino-2-(3,4,5-trimethoxy-phenylamino)-thiazol-5-yl]- [l,2,4]oxadiazoyl ⁇ -4-chloro-phenyl)-carbamic acid tert-butyl ester
• Example B ( 14) (5 - ⁇ 5 - [4- Amino-2-(3 ,4,5 -trimethoxy-phenylamino)-thiazol-5 -yl] - [l,2,4]oxadiazol-3-yl ⁇ -4-chloro-2-fluoro-phenyl)-carbamic acid tert-butyl ester
• Example B ( 19) : N- ⁇ 5 - [5 -(4- Amino-2-isopropylamino-thiazol-5 -yl)- [1,2,4] oxadiazol- 3-yl] -2,4-difluoro-phenyl ⁇ -3 -methoxy-benzamide
• Example B (21 ) ⁇ 5 - [5 -(4- Amino-2-isopropylamino-thiazol-5 -yl)- [ 1 ,2 ,4] oxadiazol-3 - yl]-2,4-difluoro-phenyl ⁇ -carbamic acid tert-butyl ester
• Example B (22) : N- ⁇ 3 - [5 -(4- Amino-2-isopropylamino-thiazol-5 -yl)- [ 1 ,2 ,4] oxadiazol- 3 -yl] -4-methyl-phenyl ⁇ -3 -methoxy-benzamide
• Examples B(38) and B(39) are formed in a similar manner to the procedure described in B(37).
• Example C(6) 3-(3-amino-6-methyl-phenyl)-5-[2-[(3,4,5 trimethoxyphenyl)-amino]- 4-amino-5 -thiazoly 1] -1,2 ,4-oxadiazole

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