Title of Invention	A COMPOUND WHICH IS 1-[5-BROMO-4-METHYL-2-S-(MORPHOLIN-2-YLMETHOXY)-PHENYL]-3-(5-METHYL-PYRAZIN-2-YL)-UREA OR A PHARMACEUTICALLY ACCEPTABLE SALT THEREOF
Abstract	Substituted urea compounds useful in the treatment of diseases and conditions related to DNA damage or lesions in DNA replication are disclosed. Methods of making the compounds, and their use as therapeutic agents, for example, in treating cancer and other diseases characterized by defects in DNA replication, chromosome segregation, or cell division, also are disclosed.

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HETEROARYL UREA DERIVATIVES USEFUL FOR INHIBITING CHK1 FIELD OF THE INVENTION The present invention relates to compounds useful for inhibiting enzymes that maintain and repair the integrity of genetic material. More particularly, the present invention relates to a series of aryl- and heteroaryl-substituted urea compounds, methods of making the compounds, and their use as therapeutic agents, for example, in treating cancer and other diseases characterized by defects in deoxyribonucleic acid replication, chromosome segregation, or cell division. BACKGROUND OF THE INVENTION A large variety of diseases, conditions, and disorders (hereinafter "indications") are characterized as involving aberrantly proliferating cells. As used herein, "aberrantly proliferating cells" (or "aberrant cell proliferation") means cell proliferation that deviates from the normal, proper, or expected course. For example, aberrant cell proliferation includes inappropriate proliferation of cells wherein DNA or other cellular components have become damaged or defective. Aberrant cell proliferation also characterizes clinical indications caused by, mediated by, or resulting in inappropriately high levels of cell division, inappropriately low levels of cell death (e.g., apoptosis), or both. Such indications can be characterized, for example, by single or multiple local abnormal proliferations of cells, groups of cells or tissue(s), and include cancerous (benign or malignant) and noncancerous indications. By definition, all cancers (benign and malignant) involve some form of aberrant cell proliferation. Some noncancerous indications also involve aberrant cell proliferation. Examples of noncancerous indications involving aberrant cell proliferation include rheumatoid arthritis, psoriasis, vitiligo, Wegener's granulomatosis, and systemic lupus. One approach to treating indications involving aberrantly proliferating cells involves the use of DNA damaging agents. These agents are designed to kill aberrantly proliferating cells by disrupting vital cellular processes such as DNA metabolism, DNA synthesis, DNA transcription, and microtubule spindle formation. They also can operate, for example, by introducing lesions into DNA that perturb chromosomal structural integrity. DNA damaging agents are designed and administered in ways that attempt to induce maximum damage and consequent cell death in aberrantly proliferating cells with a minimum damage to normal, healthy cells. A large variety of DNA damaging agents has been developed to date, including chemotherapeutics and radiation, and others are in development. Unfortunately, the effectiveness of DNA damaging agents in treating conditions involving aberrant cell proliferation has been less than desired, particularly in the treatment of cancer. The selectivity of such agents for aberrantly proliferating cells over healthy cells (sometimes referred to as the therapeutic index) often is marginal. Moreover, all cells have sensing and repair mechanisms that can work at cross purposes to DNA damaging agents. Such sensing mechanisms, called cell cycle checkpoints, help to maintain the order of the various cell replication stages and to ensure that each step is executed with high fidelity (Hartwell et al., Science, 246:629-634 (1989); Weinert et al., Genes Dev., 8:652 (1994)). When cells detect DNA damage, including . damage purposefully induced by DNA damaging agents, certain signaling pathways activate cell cycle checkpoints and the cell replication cycle temporarily' ' ceases ("arrests"). This arrest allows cells time to repair their DNA, often to a degree sufficient to allow them to continue to survive and proliferate. In the case of aberrantly proliferating cells, this repair is unwanted, as it may undermine efforts to induce DNA damage sufficient to kill such cells. For example, the chemotherapeutic agent called GEMZAR™ (gemcitabine, or 2',2'-difluoro-2'-deoxycytidine) damages DNA by incorporating itself into DNA during synthesis. Left unrepaired, damaged DNA generally is rendered incapable of sustaining life. In many targeted cells, however, cell cycle checkpoints detect the improperly made (or otherwise damaged) DNA. The activated cell cycle checkpoints trigger cell cycle arrest for a time sufficient to allow damaged DNA to be repaired. This is one way in which aberrantly proliferating cells are theorized to resist the cell- killing effect of DNA-damaging agents such as chemotherapeutics, radiation, and other therapies. Other DNA-damaging agents cause tumor cells to arrest in S-phase. Tumor cells have been observed to resist certain chemotherapeutics simply by arresting in S phase while the chemotherapeutic agent is being administered. Then, as soon as the drug is removed, DNA damage is repaired, cell cycle arrest ceases, and the cells progress through the remainder of the cell cycle (Shi et al., Cancer Res. 61:1065-1012, 2001). Other therapeutics cause cell cycle arrest at other checkpoints, including G1 and G2. Inhibition of various DNA damage checkpoints therefore is expected to assist in preventing cells from repairing therapeutically induced DNA damage and to sensitize targeted cells to DNA damaging agents. Such sensitization is in turn expected to increase the therapeutic index of these therapies. The cell cycle is structurally and functionally the same in its basic process and mode of regulation across all eukaryotic species. The mitotic (somatic) cell cycle consists of four phases: the Gl (gap) phase, the S (synthesis) phase, the G2 (gap) phase, and the M (mitosis) phase. The Gl, S, and G2 phases are collectively referred to as interphase of the cell cycle. During the Gl phase, biosynthetic activities of the cell progress at a high rate. The S phase begins when DNA synthesis starts, and ends when the DNA content of the nucleus of the cell has been replicated and two identical sets of chromosomes are formed. The cell then enters the G2 phase, which continues until mitosis starts. In mitosis, the chromosomes pair and separate, two new nuclei form, and cytokinesis occurs in which the cell splits into two daughter cells each receiving one nucleus containing one of the two sets of chromosomes. Cytokinesis terminates the M phase and marks the beginning of interphase of the next cell cycle. The sequence in which cell cycle events proceed is tightly regulated, such that the initiation of one cell cycle event is dependent on the completion of the prior cell cycle event. This allows fidelity in the duplication and segregation of genetic material from one generation of somatic cells to the next. It has been reported that cell cycle checkpoints comprise at least three distinct classes of polypeptides, which act sequentially in response to cell cycle signals or defects in chromosomal mechanisms (Carr, Science, 271:314-315, 1996). The first class is a family of proteins that detect or sense DNA damage or abnormalities in the cell cycle. These sensors include Ataxia-telangiectasia Mutated protein (Atm) and Ataxia- Telangiectasia Rad-related protein (Atr). The second class of polypeptides amplify and transmit the signal detected by the detector and is exemplified by Rad53 (Alen et al. Genes Dev. 8:2416-2488, 1994) and Chkl. A third class of polypeptides includes cell cycle effectors, such as p53, that mediate a cellular response, for example, arrest of mitosis and apoptosis. Much of the current understanding of the function of cell cycle checkpoints has been derived from the study of tumor derived cell lines. In many cases, tumor cells have lost key cell cycle check points (Hartwell et al., Science 266:1821-28, 1994). It has been reported that a key step in the evolution of cells to a neoplastic state is the acquisition of mutations that inactivate cell cycle checkpoint pathways, such as those involving p53 (Weinberg, Cell 32:323-330, 1995; Levine, Cell 83:3234-331, 1997). Loss of these cell cycle checkpoints results in the replication of tumor cells despite DNA damage. Noncancerous tissue, which has intact cell cycle checkpoints, typically is insulated from temporary disruption of a single checkpoint pathway. Tumor cells, however, have defects in pathways controlling cell cycle progression such that the perturbation of additional checkpoints renders them particularly sensitive to DNA damaging agents. For example, tumor cells that contain mutant p53 are defective both in the Gl DNA damage checkpoint and in the ability to maintain the G2 DNA damage checkpoint (Bunz et al., Science, 282:1491-501, 1998). Checkpoint inhibitors that target initiation of the G2 checkpoint or the S phase checkpoint are expected to further cripple the ability of these tumor cells to repair DNA damage and, therefore, are candidates to enhance the therapeutic index of both radiation and systemic chemotherapy (Gesner, Abstract at SRI Conference: Protein Phosphorylation and Drug Discovery World Summit, March 2003). In the presence of DNA damage or any impediment to DNA replication, the checkpoint proteins Atm and Atr initiate a signal transduction pathway leading to cell cycle arrest. Atm has been shown to play a role in a DNA damage checkpoint in response to ionizing radiation (IR). Atr is stimulated by agents that cause double strand DNA breaks, single strand DNA breaks, and agents that block DNA radiation. Chkl is a protein kinase that lies downstream from Atm and/or Atr in the DNA damage checkpoint signal transduction pathway (Sanchez et al., Science, 277:1497- 1501, 1997; U.S. Patent No. 6,218,109). In mammalian cells, Chkl is phosphorylated in response to agents that cause DNA damage including ionizing radiation (IR), ultraviolet (UV) light, and hydroxyurea (Sanchez et al., supra; Lui et al., Genes Dev., 14:1448-1459, 2000). This phosphorylation which activates Chkl in mammalian cells is dependent on Atm (Chen et al., Oncogene, 18:249-256, 1999) and Atr (Lui et al., supra). Furthermore, Chkl has been shown to phosphorylate both weel (O'Connell et al., EMBO J., 25:545-554, 1997) and Pdsl (Sanchez et al., Science, 286:1166-1171, 1999), gene products known to be important in cell cycle control. These studies demonstrate that mammalian Chkl plays a role in the Atm' dependent DNA damage checkpoint leading to arrest at S phase. A role for Chkl in the S phase mammalian cells has recently been elucidated (Feijoo et al., J. Cell Biol., 254:913-923, 2001; Zhao et al., PNAS U.S.A, 99:14795-800, 2002; Xiao et al., J Biol Chem. , 278 (24) .-21767-21773, 2003; Sorensen et al., Cancer Cell, 3(3):247-58, 2003) highlighting the role of Chkl in monitoring the integrity of DNA synthesis. Chkl invokes an S-phase arrest by phosphorylating Cdc25A, which regulates cyclinA/cdk2 activity (Xiao et al., supra and Sorensen et al./ supra). Chkl also invokes a G2 arrest by phosphorylating and inactivating Cdc25C, the dual specificity phosphatase that normally dephosphorylates cyclin-B/cdc2 (also known as Cdkl) as cells progress from G2 into mitosis (Fernery et al., Science, 277:1495-7, 1997; Sanchez et al., supra; Matsuoka et al., Science, 282:1893-1891, 1998; and Blasina et al., Curr. Biol., 9:1-10, 1999). In both cases, regulation of Cdk activity induces a cell cycle arrest to prevent cells from entering mitosis in the presence of DNA damage or unreplicated DNA. Additional classes of cell cycle checkpoint inhibitors operate at either the G1 or G2/M phase. UCN- 01, or 7-hydroxystaurosporine, originally was isolated as a nonspecific kinase inhibitor having its primary effect on protein kinase C, but recently has been found to inhibit the activity of Chkl and abrogate the G2 cell cycle checkpoint (Shi et al., supra). Thus, because UCN- 01 is a nonselective Chkl inhibitor, it is toxic to cells at high doses. At low doses, it nonspecifically inhibits many cellular kinases and also inhibits the G1 checkpoint (Tenzer et al., Curr. Med Chem. Anticancer Agents, -3:35- 46, 2003) . UCN-01 has been used in conjunction with cancer therapies, such as radiation, the anticancer agent camptothecin (Tenzer et al., supra), and gemcitabine (Shi et al., supra), with limited success. In addition, UCN- 01 has been used to potentiate the effects of temozolomide (TMZ) induced DNA mismatch repair (MMR) in glioblastoma cells (Hirose et al., Cancer Res., 62:5843- 5849, 2001). In the clinic, UCN-01 is not an effective chemotherapeutic as expected, possibly due to a failure in treatment scheduling and a lack of identification of particular key molecular targets (Grant et al., Drug Resistance Updates, 6:15-26, 2003). Thus, Mack et al. report cell cycle-dependent potentiation of cisplatin by UCN-01 in a cultured nonsmall-cell lung carcinoma cell line, but do not identify with specificity the key cell cycle checkpoint (s) targeted by UCN-01. (Mack et al., Cancer Chemother. Pharmacol., 51(4):337-348, 2003). Several other strategies exist for sensitizing tumor cells to treatment with cell cycle affecting chemotherapeutics. For example, administration of 2- aminopurine abrogates multiple cell cycle checkpoint mechanisms, such as mimosine-induced G1 arrest or hydroxyurea-induced S phase arrest, allowing the cell to progress into and through mitosis (Andreassen et al., Proc Natl Acad Sci U.S.A., 86:2212-2216, 1992). Caffeine, a methylxanthine, has also been used to enhance cytotoxicity of DNA-damaging agents, such as cisplatin and ionizing radiation, by mediating progression through the G2 checkpoint and thereby inducing cell death. (Bracey et al., Clin.' Cancer Res., 3:1371-1381, 1997). However, the dose of caffeine used to accomplish the cell cycle abrogation exceeds clinically acceptable levels and is not a viable therapeutic option. Additionally, antisense nucleotides to Chkl kinase have been used to increase sensitivity to the topoisoraerase inhibitor BNP1350 (Yin et al., Biochem. Biophys. Res. Commun., 255:435-44, 2002), but demonstrate problems typically associated with antisense treatment and gene therapy. Chkl inhibitors have been disclosed, including aryl- and heteroaryl-substituted urea compounds described in U.S. Patent Application No. 10/087,715 and U.S. Provisional Patent Application Nos. 60/583,080, 60/585,292, and 60/602,968; diaryl urea compounds described in U.S. Patent Publication No. 2004/0014765, U.S. Patent Publication No. US2003/199511, U.S. Patent Publication No. 2004/0014765, and WO 03/101444; methylxanthines and related compounds described in Fan et al., Cancer Res. 55:1649-54. 1995; ureidothiphenes described in WO 03/029241 and WO 03/028731; N- pyrrolopyridinyl carboxamides described in WO 03/028724; antisense Chkl oligonucleotides described in WO 01/57206 and U.S. Patent No. 6,211,164; Chkl receptor antagonists described in WO 00/16781; heteroaroraatic carboxamide derivatives described in WO 03/037886; aminothiophenes described in WO 03/029242; (indazolyl)benzimidazoles described in WO 03/004488; benzimidazole quinolinones described in U.S. Patent Publication No. 2004 0092535 and WO 04/018419; heterocyclic-hydroxyimino-fluorenes described in WO 02/16326; scytoneman derivatives, such as scytonemin, described in U.S. Patent No. 6,495,586; heteroarylbenzamides described in WO 01/53274; indazoles described in WO 01/53268; indolacarbazoles described in Tenzer et al., supra; chromane derivatives described in WO 02/070515; paullones described in Schultz et al., J. Med. Chem., Vol:2909-2919, 1999; indenopyrazoles described in WO 99/17769; flavones described in Sedlacek et al., Int J. Oncol., 5:1143-1168, 1996; peptide derivatives of peptide loop of serine threonine kinases described in WO 98/53050; oxindoles described in WO 03/051838; diazepinoindolones described in WO 2004/063198; pyrimidines described in WO 2004/048343; urea compounds described in WO 2004/014876; and pyrrolocarbazoles, benzofuroisoindoles, and azacyclopentafluorenes described in WO 2003/091255. However, a need remains in the art for effective and selective inhibitors of Chkl. The present invention addresses this and other needs. SUMMARY OF THE INVENTION The present invention relates to potent and selective inhibitors of the checkpoint kinase Chkl that exhibit unexpected properties in biochemical and/or cell-based assays. The present Chkl inhibitors are useful in treating indications involving aberrant cell proliferation, and as chemosensitizing and radiosensitizing agents in the treatment of indications related to DNA damage or lesions in DNA replication. Therefore, one aspect of the present invention is to provide compounds of structural formula (I). Among other things, the compounds are useful in a method of inhibiting Chkl comprising a step of administering an effective amount of a compound of structural formula (I) to an individual in need thereof. Compounds of formula (I) have a structural formula: wherein R1 is halo, C1-3alkyl, CN, or CF3; R2 is hydrogen, C1-3alkyl, CN, OC1-3alkyl, halo, or N(Rb)z, wherein Rb, independently, is hydrogen or C1-3alkyl; R3 is a 6- or 7-membered saturated heterocyclic ring containing one ring N-Ra group and either a second ring N-Ra group, a ring oxygen, or a ring sulfur, wherein Ra, independently, is hydrogen, Chalkyl, CH2CN, or CH2CH2CN, and wherein R3 is optionally substituted with oxo(=O); R4 is hydrogen, C1-3alkyl, 0C1-3alkyl, SC1-3alkyl, N(Rb)2, NRbC(=O)C1-3alkyl, or a 5- or 6-membered saturated heterocyclic ring containing one N-RB group and optionally ring substituted with one to three C1-3alkyl groups; or R2 and R4 are taken together with the carbons to which they are attached to form a 5- to 7- membered saturated carbocyclic ring; and R5 is hydrogen or halo, provided that at least one of R2 and R4 is different from hydrogen, and that when R5 is halo, R2 or R4 is hydrogen, or pharmaceutically acceptable salts, prodrugs, or solvates thereof. Another aspect of the present invention is to provide compounds of structural formula (II), which, among other applications, can be used in a method of inhibiting Chkl. wherein R1 is halo, C1-3alkyl, CN, or CF3; R2 is hydrogen, C^aUcyl, CN, OC!_3alkyl, halo, or N(Rb)2, wherein Rb, independently, is hydrogen or C1-3alkyl; R3 is a 6- or 7-membered saturated heterocyclic ring containing one ring N-Ra group and either a second ring N-Ra group, a ring oxygen, or a ring sulfur, wherein Ra, independently, is hydrogen, C!-3alkyl, or CH2CN, and wherein R3 is optionally substituted with oxo (=O); R4 is hydrogen, C1-3alkyl, 0C1-3alkyl, or halo; or R2 and R4 are taken together with the carbons to which they are attached to form a 5- to 7- membered saturated carbocyclic ring, provided that at least one of R2 and R4 is different from hydrogen, or pharmaceutically acceptable salts, prodrugs, or solvates thereof. Another aspect of the present invention is to provide pharmaceutical compositions comprising one or more compound of structural formula (I) or (II), and use of the compositions in a therapeutic treatment of an indication, wherein inhibition of Chkl, in vivo or ex vivo, provides a therapeutic benefit or is of research or diagnostic interest. Yet another aspect of the present invention is to provide a method of sensitizing cells in a subject undergoing a chemotherapeutic or radiotherapeutic treatment for an indication comprising administration of a compound of structural formula (I) or (II) in combination with a. chemotherapeutic agent, a radiotherapeutic agent, or both, to the individual. A nonlimiting indication treated by this method is a cancer. Another aspect of the present invention is to provide a method of inhibiting or preventing aberrant cell proliferation. In one embodiment, the method comprises contacting a cell population comprising aberrantly proliferating cells with at least one Chkl activator in an amount and for a time sufficient to substantially synchronize cell cycle arrest among the aberrantly proliferating cells. Upon achieving substantial synchronization of cell cycle arrest in the cell population, the cell population is contacted with at least one Chkl inhibitor in an amount and for a time sufficient to substantially abrogate the cell cycle arrest. Another aspect of the present inentionis to provide an article of manufacture for human pharmaceutical use comprising: (a) a pharmaceutical composition comprising a compound of structural formula (I) or (II); (b) a package insert providing that the composition is useful in the treatment of indications involving aberrant cell proliferation; and (c) a container. Another aspecet of the preent invention is to provide: (a) pharmaceutical composition comprising a compound of structural formula (I) or (II) ; (b) a package insert providing that the composition is useful as a chemosensitizer or radiosensitizer in a treatment of an indication related to DNA lesions or DNA replication; (c) a container. These and other aspects of the present invention will become apparent from the following detailed description. DETAILED DESCRIPTION Compounds of the present invention have a structural formula (I): wherein R1 is halo, C1-3alkyl, CN, or CF3; R2 is hydrogen, C1-3alkyl, CN, OC1-3alkyl, halo, or N(Rb)2f wherein Rb, independently, is hydrogen or C1-3alkyl; R3 is a 6- or 7-membered saturated heterocyclic ring containing one ring N-Ra group and either a second ring N-RB group, a ring oxygen, or a ring sulfur, wherein Ra, independently, is hydrogen, C1-3alkyl, CH2CN, or CH2CH2CN, and wherein R3 is optionally substituted with oxo(=O); R4 is hydrogen, C1-3alkyl, OC1-3alkyl, SC1-3alkyl, N(Rb)2, NRbC(=O)C1-3alkyl, or a 5- or 6-membered saturated, heterocyclic ring containing one N-Ra group and optionally ring substituted with one to three C1-3alkyl groups; or R2 and R4 are taken together with the carbons to which they are attached to form a 5- to 7- membered saturated carbocyclic ring; and Rs is hydrogen or halo, provided that at least one of R2 and R4 is different from hydrogen, and that when R5 is halo, R2 or R* is hydrogen, or pharmaceutically acceptable salts, prodrugs, or solvates thereof- In one preferred embodiment, the compounds have a structural formula (II): wherein R1 is halo, C1-3alkyl, CN, or CF3; R2 is hydrogen, C1-3alkyl, CN, OC1-3alkyl, halo, or N(Rb) 2 wherein Rb, independently, is hydrogen or C1-3alkyl; R3 is a 6- or 7-membered saturated heterocyclic ring containing one ring N-Ra group and either a second ring N-R8 group, a ring oxygen, or a ring sulfur, wherein RB, independently, is hydrogen, C1-3alkyl, or CH2CN, and wherein R3 is optionally substituted with oxo (=O); R4 is hydrogen, C1-3alkyl, 0Ci>3alkyl, or halo; or R2 and R4 are taken together with the carbons to which they are attached to form a 5- to 7- membered saturated carbocyclic ring, provided that at least one of R2 and R4 is different from hydrogen, or pharmaceutically acceptable salts, prodrugs, or solvates thereof. In one preferred embodiment of compounds of formulas (I) and (II), R1 is chloro, methyl, CN, or CF3. In another preferred embodiment, R2 is hydrogen, methyl, ethyl, chloro, bromo, dimethylamino, cyano, or methoxy. In more preferred embodiments, R2 is different from hydrogen. In other preferred embodiments of formulas (I) and (II), R4 is methyl, chloro, fluoro, methoxy, isopropoxy, dimethylamino,'~SCH3, -NHC(=O)CH(CH3) 2, -NHC(=O)CH3, pyrrolidinyl, or 3,3-dimethyl- pyrrolidinyl. In more preferred embodiments, R4 is methyl, chloro, or methoxy. in still another preferred embodiment, R2 and R4 are taken together with the carbons to which they are attached to form a five-membered or a six-membered, saturated carbocyclic ring. In still another preferred embodiment of formulas (I) and (II), when R5 is halo, R4 is hydrogen. In a preferred embodiment, R5 is fluoro. In more preferred embodiments, Rs is hydrogen. In one embodiment of formulas (I) and (II), when R1 is cyano, R2 is hydrogen and R4 preferably is chloro or methyl. In another embodiment, R5 is fluoro, R4 is hydrogen, and R2 is methyl, chloro, or bromo. Examples of preferred R3 groups in formulas (I) and (II) include, but are not limited to. As used herein, the term "C1-3alkyl" includes straight chain and branched alkyl groups containing one to three carbon atoms, i.e., methyl, ethyl, n-propyl, and isopropyl. "Halo" is defined herein as fluoro, chloro, bromo, and iodo. "Cyano" is defined as -CN. "Trifluoromethyl" is defined to mean -CF3. The abbreviation "Me" is methyl, i.e., -CH3. DNA-damaging agents that activate cell cycle checkpoints generally are referred to herein as "checkpoint activators." DNA-damaging agents that activate the checkpoint designated "Chkl" (pronounced . "check-one") are referred to herein as "Chkl activators." Likewise, inhibitors of such checkpoints are referred to herein as "checkpoint inhibitors" and "Chkl inhibitors," respectively. As used herein, Chkl inhibitors are compounds that are capable of at least partially abrogating at least one cell cycle checkpoint activity of the Chkl protein. Abrogation of a cell cycle checkpoint is achieved when the cellular checkpoint mechanism is overcome sufficiently to allow the cell to pass from the cell cycle phase in which it is halted to the next phase in the cell cycle or to allow the cell to pass directly to cell death. Abrogation of a cell cycle checkpoint permits cells to carry damaged or imperfect genetic material to subsequent cell cycle phases, thereby inducing or promoting cell death. Cell death can occur by any mechanism, including apoptosis and mitotic catastrophe. The compounds of the invention are Chkl inhibitors. Chkl activator includes any known or after- discovered agent having the ability to activate Chkl kinase activity, and thus induce at least partial cell cycle arrest. Chkl activators include agents capable of arresting the cell cycle at any phase of the cell cycle, which phase may be referred to herein as the "target phase" for that activator. Target phases include any of the cell cycle phases except mitosis, i.e., any of the Gl, S, and G2 phases. Chkl activators useful in the invention include DNA damaging agents, such as chemotherapeutic agents and/or radiation. Radiation Chkl activators include, but are not limited to, ionizing radiation. Ionizing radiation includes elctromgnetic or particulate radiation capable of producing ion pairs by interacting with matter. Ionizing radiation includes x and gamma rays, alpha and beta particles, neutrons and charged nuclei. Radioation includes ultraviolet light-, visible light, infrared radiation, microwave radiation, and mixtures thereof. Assays such as that described in Example 8 can be used to determine whether an agent is a Chkl activator. "Inhibiting aberrant cell proliferation" means retarding the rate at which aberrantly proliferating cells proliferate or eliminating such proliferation altogether. This inhibition can result either from a decreased rate of replication, an increased rate of cell death, or both. Cell death can occur by any mechanism, including apoptosis and mitotic catastrophe. "Preventing aberrant cell proliferation" means inhibiting aberrant cell proliferation prior to occurrence, or inhibiting the recurrence thereof. "In vivo" means within a living subject, as within an animal or human. In this context, agents can be used therapeutically in vivo to retard or eliminate the proliferation of aberrantly replicating cells. The agents also can be used in vivo as a prophylactic to prevent aberrant cell proliferation or the manifestation of symptoms associated therewith. "Ex vivo" means outside a living subject. Examples of ex vivo cell populations include cell cultures and biological samples such as fluid or tissue samples from humans or animals. Such samples can be obtained by methods well known in the art. Exemplary biological fluid samples include blood, cerebrospinal fluid, urine, saliva. Exemplary tissue samples include tumors and biopsies. In this context; the present compounds can be in numerous applications, both therapeutic and experimental. "Radiosensitizer," as used herein, means a compound, administered to a human or other animal in a therapeutically effective amount to increase the sensitivity of cells to electromagnetic radiation and/or to promote the treatment of diseases treatable with electromagnetic radiation. "Radiation" as used herein includes/ but is not limited to, radiation having wavelengths in the range of 10"20 to 100 meters. The term "container" means any receptacle and closure therefor suitable for storing, shipping, dispensing, and/or handling a pharmaceutical product. The term "package insert" means information accompanying the product that provides a description of how to administer the product, along with the safety and efficacy data required to allow the physician, pharmacist, and patient to make an informed decision regarding use of the product. The package insert generally is regarded as the "label" for a pharmaceutical product. The present invention includes all possible stereoisomers and geometric isomers of the compounds of structural formula (I) or (II) . The present invention includes not only racemic compounds, but optically active isomers as well. When a compound of structural formula (I) or (II) is desired as a single enantiomer, it can be obtained either by resolution of the final product or by stereospecific synthesis from either isomerically pure starting material or use of a chiral auxiliary reagent, for example, see Z. Ma et al., Tetrahedron: Asymmetry, 8(6), 883-888 (1997). Resolution of the final product, an intermediate, or a starting material can be achieved by any suitable method known in the art. Additionally, in situations where tautomers of the compounds of structural formula (I) or (II) are possible, the present invention is intended to include all tautomeric forms of the compounds. As demonstrated below, specific stereoisomers can exhibit an exceptional ability to inhibit Chkl in combination with chemotherapeutic or radiotherapeutic treatments. Prodrugs of compounds of structural formula (I) or (II) also can be used as the compound in a method of the present invention. It is well established that a prodrug approach, wherein a compound is derivatized into a form suitable for formulation and/or administration, then released as a drug in vivo, has been successfully employed to transiently (e.g., bioreversibly) alter the physicochemical properties of the compound (see, H. Bundgaard, Ed., "Design of Prodrugs," Elsevier, Amsterdam, (1985); R.B. Silverman, "The Organic Chemistry of Drug Design and Drug Action," Academic Press, San Diego, chapter 8, (1992); K.M-. Hillgren et al., Med. Res. Rev., 15, 83 (1995)) . Compounds of the present invention contain one or more functional groups. The functional groups, if desired or necessary, can be modified to provide a prodrug. Suitable prodrugs include, for example, acid derivatives, such as amides and esters. It also is appreciated by those skilled in the art that N-oxides can be used as a prodrug. Compounds of the invention can exist as salts. Pharmaceutically acceptable salts of the compounds of the invention generally are preferred in the methods of the invention. As used herein, the term "pharmaceutically acceptable salts" refers to salts or zwitterionic forms of the compounds of structural formula (I) or (II). Salts of compounds of formula (I) or (II) can be prepared during the final isolation and purification of the compounds or separately by reacting the compound with an acid having a suitable cation. Suitable pharmaceutically acceptable cations include alkali metal (e.g., sodium or potassium) and alkaline earth metal (e.g., calcium or magnesium) cations. In addition, the pharmaceutically acceptable salts of compounds of structural formula (I) or (II) that contain a basic center are acid addition salts formed with pharmaceutically acceptable acids. Examples of acids which can be employed to form pharmaceutically acceptable salts include inorganic acids such as hydrochloric, hydrobromic,sulfuric, and phosphoric, and organic acids such as oxalic, maleic, succinic, malonic, and citric. Nonlimiting examples of salts of compounds of the invention include, but are not limited to, hydrochloride, hydrobromide, hydroiodide, sulfate, bisulfate, 2-hydroxyethansulfonate, phosphate, hydrogen phosphate, acetate, adipate, alginate, aspartate, benzoate, butyrate, camphorate, camphorsulfonate, citrate, digluconate, glycerolphsphate, hemisulfate, heptanoate, hexanoate, formate, succinate, malonate, fumarate, maleate, methanesulfonate, mesitylenesulfonate, naphthylenesulfonate, nicotinate, 2- naphthalenesulfonate, oxalate, pamoate, pectinate, persulfate, 3-phenylproprionate, picrate, pivalate, propionate, trichloroacetate, trifluoroacetate, glutamate, bicarbonate, paratoluenesulfonate, undecanoate, lactate, citrate, tartrate, gluconate, benzene sulphonate, and p-toluenesulphonate salts. In addition, available amino groups present' in the compounds of the invention can be quaternized with methyl, ethyl, propyl, and butyl chlorides, bromides, and iodides; dimethyl, diethyl, dibutyl, and diamyl sulfates; decyl, lauryl, myristyl, and steryl chlorides, bromides, and iodides; and benzyl and phenethyl bromides. In light of the foregoing, any reference to compounds of the present invention appearing herein is intended to include compounds of structural formula (I) or (II) as well as pharmaceutically acceptable salts, solvates, or prodrugs thereof. Nonlimiting examples of compounds of the present invention are: 37 9* - NH N H H Y G CI NH H H S> ° V^ xr ^ CI WO 2006/105262 q-0 - -as PCTYUS2006/011584 H H V N Cl H3C H H H3C Y 0 ci NH 1-[5-methyl-2-(4-methyl-morpholin-2-ylmethoxy)-phenyl]-3- (5-methylpyrazin-2-yl)-urea (LRMS (ES, positive) m/e - 372.4) 1-[5-chloro-2-(4-methyl-morpholin-2-ylmethoxy)-phenyl]-3- (5-methyl-pyrazin-2-yl)-urea (LRMS (ES, positive) m/e - 392.4) 1-(5-cyano-pyrazin-2-yl)-3-[2-{l,4-dimethyl-piperazin-2- ylmethoxy)-5-methyl-phenyl]-urea (LRMS (ES, positive) m/e - 396.4) 1-[5-chloro-2-R-(1-methyl-piperazin-2-ylmethoxy)-phenyl]- 3-(5-methyl-pyrazin-2-yl)-urea (LRMS (ES, positive) m/e - 391.3) l-[5-bromo-2-R-(4-methyl-morpholin-2-ylmethoxy)-phenyl]- 3-(5-methyl-pyrazin-2-yl)-urea (LRMS (ES, positive) m/e - 438.0) l-(5-cyano-pyrazin-2-yl)-3-[5-methyl-2-R-(4-methyl- morpholin-2-ylmethoxy)-phenyl]-urea (LRMS (ES, positive) in/e - 383.0) 1-[5-chloro-2-(4-methyl-[1,4]oxazepan-2-ylmethoxy)- phenyl]-3-(5-methyl-pyrazin-2-yl)-urea (LRMS (ES, positive) m/e - 406.0) 1-[5-chloro-2-S-(5-oxo-morpholin-2-ylmethoxy)-phenyl]-3- (5-methyl-pyrazin~2-yl)-urea (LRMS (ES, positive) m/e - 392.2) w N-[2-chloro-4-[3-(5-methyl-pyrazin-2-yl)-ureido]-5-(S- morpholin-2-ylmethoxy)-phenyl]-acetamide (LRMS (ES, positive) m/e - 435.0) 1-[5-chloro-3-fluoro-2-(S-morpholin-2-ylmethoxy)-phenyl]- 3-(5-methyl-pyrazin-2-yl)-urea (LRMS (ES, positive) m/e - 396.3) 1-[5-methoxy-2-(S-morpholin-2-ylmethoxy)-phenyl]-3-(5- methyl-pyrazin-2-yl)-urea (LRMS (ES, positive) m/e - 374.3) 1-[5-methoxy-2-(S-morpholin-2-ylmethoxy)-phenyl]-3-(5- methyl-pyrazin-2-yl)-urea (LRMS (ES, positive) m/e - 358.3) l-[4-chloro-2-(S-morpholin-2-ylmethoxy)-phenyl]-3-(5- methyl-pyrazin-2-yl)-urea (LRMS (ES, positive) m/e - 378.3) 1-[5-chloro-4-fluoro-2-(S-morpholin-2-ylmethoxy)-phenyl]- 3-(5-methyl-pyrazin-2-yl)-urea (LRMS (ES, positive) m/e - 396.1) l-[5-cyano-4-methyl-2-(S-morpholin-2-ylmethoxy)-phenyl]-: 3-(5-methyl-pyrazin-2-yl)-urea (LRMS (ES, positive) m/e - 383.3) r 1-[5-chloro-4-dimethylamino-2-(S~morpholin-2-ylmethoxy)- phenyl]-3-{5-methyl-pyrazin-2-yl)-urea (LRMS (ES, positive) m/e - 421.2) N-[2-chloro-4-[3-(5-methyl-pyrazin-2-yl)-ureido]-5-(S- morpholin-2-ylraethoxy)-phenyl]-isobutyramide (LRMS (ES, positive) m/e - 463.2) 1-(5-methyl-pyrazin-2-yl)-3-[6-(S-morpholin-2-ylmethoxy)- indan-5-yl]-urea (LRMS (ES, positive) m/e - 384.3) 1~[5-chloro-2-(4~cyanomethyl-thiomorpholin-2-ylmethoxy)- phenyl]-3-(5-methyl-pyrazin-2-yl)-urea (LRMS (ES, positive) iri/e - 433.0) l-{5-chloro-2-[4-(2-cyano-ethyl)-S-morpholin-2- ylmethoxy]-phenyl)-3-(5-methyl-pyrazin-2~yl)-urea (LRMS (ES, positive) m/e - 431.0) 1-[5-chloro-2- (S-morpholin-2~ylmethoxy)-4-pyrrolidin-l- yl-phenyl]-3-(5-methyl-pyrazin-2-yl)-urea (LRMS (ES, positive) m/e - 447.2) and or salts, solvates (e.g., hydrates), or prodrugs thereof. The compounds of the present invention can be therapeutically administered as the neat chemical, but it is preferable to administer the compounds as a pharmaceutical composition or formulation. Thus, the present invention provides a pharmaceutical composition comprising a compound of the formula (I) or (II) together with a pharmaceutically acceptable diluent or carrier therefor. Also provided is a process of preparing a pharmaceutical composition comprising admixing a compound of formula (I) or (II) with a pharmaceutically acceptable diluent or carrier therefor. Accordingly, the present invention further provides pharmaceutical formulations comprising a compound of structural formula (I) or (II), or a pharmaceutically acceptable salt, prodrug, or solvate thereof, together with one or more pharmaceutically acceptable carriers and, optionally, other therapeutic and/or prophylactic ingredients. The carriers are "acceptable" in the sense of being compatible with the other ingredients of the formulation and not deleterious to the recipient thereof. Compounds of the invention exhibit unexpectedly high potency. Potency typically is expressed as the concentration of a compound required to achieve a certain result. The greater the potency, the less compound required to perform its intended function. In vitro potency typically is expressed in terras of IC50 values and measured using a dose-response assay. IC50 values can be measured by contacting a sensitive assay system with a compound of interest over a range of concentrations, including concentrations at which no or minimal effect is observed, through higher concentrations at which partial effect is observed, to saturating concentrations at which a maximum effect is observed. Theoretically, such assays of the dose-response effect of inhibitor compounds can be described as a sigmoidal curve expressing a degree of inhibition as a function of concentration when plotted on a log scale. The curve also theoretically passes through a point at which the concentration is sufficient to reduce activity of the checkpoint enzyme to a level that is 50% that of the difference between minimal and maximal enzyme activity observed in the assay. This concentration is defined as the Inhibitory Concentration at 50% inhibition or IC50 value. ICS0 values can be determined using conventional biochemical (acellular) assay techniques or cell-based assay techniques well known to those of ordinary skill in the art. An example of such an assay is provided in Example 1 below. Preferably, IC5o values are obtained by performing the relevant assay at least twice, with the IC50 value expressed as the average (arithmetic mean, or "mean") of the individual values obtained. More preferably, the assay is repeated from 3 to 10 (or more) times, with the IC50 value expressed as the mean of the values obtained. Most preferably, the assay is performed a number of times sufficient to generate a statistically reliable mean IC50 value, using statistical methods known to those of ordinary skill in the art. Compounds of the invention 'exhibit unexpectedly low IC50 values, corresponding to unexpectedly high in vitro potency. Compounds of the invention, when assayed as described in Example 1 below, exhibit IC50 values of less than about 200 nM, in some embodiments less than about 150 nM, in other embodiments less than about 100 nM, in others less than about 50 nM, in others less than about 10 nM, and in others less than about 5 nM. In other embodiments, the compounds of the invention exhibit IC50 values from about 0.1 nM to about 5 nM. Compounds of the invention exhibit selectivity for inhibiting Chkl over other protein kinases. Selectivity may be advantageous in reducing adverse side effects and/or increasing therapeutic index. "Selectivity" is expressed herein as "fold selectivity." In general, fold selectivity, as used herein, is the IC50 of a test compound for a comparison enzyme divided by the IC50 of a comparator enzyme. In particular, fold selectivity for a Chkl inhibitor, as used herein, is the IC50 of a Chkl inhibitor (a test compound) for Chkl (the comparison enzyme) divided by the ICso for a comparator enzyme. Comparator enzymes against which compounds of the invention may be measured include at least the following protein kinases: Cdc2, Chk2, CTAK, EphAl, EphA2, Erkl, FGFR1, FGFR4, IR, JNKl, c-Kit, p38alpha, p38beta, p38delta, Ros, Rse, Rsk2, TrkA, TrkB, protein kinas A, protein kinas C, pp60v-src, protein kinase B/Akt-1, p38MapK, p70S6K, calcium calmodulin- dependent kinase II, and abl tyrosine kinase. Assays for determining ICS0 values for a test compound against a comparator enzyme are described in Example 2 and are well known to those of ordinary skill in the art. Compounds of the invention exhibit at least about 20-fold selectivity over the aforementioned protein kinases tested, in some embodiments, Chkl inhibitors of the present invention exhibit at least about 50-fold selectivity, in other embodiments at least about 75-fold . selectivity, in other embodiments at least about 100-fold selectivity in inhibiting Chkl over the aforementioned protein kinases tested. The compounds of the invention exhibit unexpectedly high potency in a cell-based assay. To measure cell-based potency of a Chkl inhibitor, an assay was developed that allows one to measure the concentration of Chkl inhibitor required to increase the growth-inhibiting effects of a DNA damaging agent in a cell-based model involving aberrantly proliferating cells." This measure of cell-based potency, is expressed herein as an "ECTrs" value, where "ECTFS" is the Effective Concentration of Chkl inhibitor that produces a Two-Fold Sensitization of a population of aberrantly proliferating cells to the growth-inhibiting effects of a DNA damaging agent. ECTFs is calculated to be the concentration of Chkl inhibitor that reduces the amount of DNA damaging agent required for 90% inhibition of cell growth by half. Applicants have found that the compounds of the invention exhibit unexpectedly low ECTFS values, corresponding to unexpectedly high cell-based potency. Another parameter that may be measured is the the fold sensitization achieved at the LD50 (the dose of compound alone that' inhibits growth of 50% of cells) for the Chkl inhibitor compound. These two values, BCTFS and fold sensitization at the LD50, allow direct ranking of both the potency and toxicity of Chkl inhibitors with respect to one another. An example of an assay useful to measure ECTFS values is described in Example 3 below. Briefly, this assay uses. HT29 human colon carcinoma cells as the population of aberrantly proliferating cells, gemcitabine as the DNA damaging agent/Chkl activator, and a compound of the invention as the Chkl inhibitor. The population of aberrantly proliferating cells is cultured and allowed to grow in a suitable growth medium. Subsequently, the cells are subjected to the DNA damaging agent over a range of concentrations. After a predetermined amount of time, the DNA damaging agent is removed, and the cells are subjected to a Chkl inhibitor over a range of concentrations and for a predetermined period of time. The plates of cultured cells then are harvested and the relative number of surviving cells is counted.- The data is normalized against Chkl inhibitor alone as control, and then plotted on a log/log graph of DNA damaging agent concentration vs. relative cell survival (100% equaling 1.0). The fold sensitization is derived from the difference between the amount of DNA damaging agent required to achieve 90% growth inhibition with and without Chkl inhibitor for each concentration of Chkl inhibitor used. These data then are plotted on a graph of Chkl inhibitor concentration vs. fold sensitization, from which ECTFs is calculated. Preferably ECTFs values are obtained by performing the assay at least twice, with the ECTFS value expressed as the mean of the individual values obtained. More preferably, the assay is repeated from 3 to 10 (or more) times, with the ECTFS value expressed as the mean of the values obtained. Most preferably, the assay is performed a number of times necessary to generate a statistically reliable mean ECTFS value, using statistical methods known to those of ordinary skill in the art. All compounds that were subject to an ECTFS assay exhibited ECTFS values of less than about 1000 nM. In contrast, structurally similar compounds that are previously known exhibit ECTFS values of about 11,000 nM. In some embodiments, compounds of the present invention exhibit ECTFS values of less than about 500 nM, in others less than about 300 nM, in others less than about 200 nM, in others less than about 150nM, in others less than about 100 nM, in others less than abut 50 nM, in others less than about 30 nM, and in others less than about 20 nM, or less than about 10 nM, or in other embodiments less than about 5 nM. Compounds and pharmaceutical compositions suitable for use in the present invention include those wherein the active ingredient is administered in an effective amount to achieve its intended purpose. More specifically, a "therapeutically effective amount" means an amount sufficient to treat an individual suffering an indication, or to alleviate the existing symptoms of the indication. Determination of a therapeutically effective amount is well within the capability of those skilled in the art, especially in light of the detailed disclosure provided herein. In addition to the Chkl inhibitor, pharmaceutical compositions of the invention can be formulated to include biologically active agents, such as cytokines, lymphokines, growth factors, other hematopoietic factors, or mixtures thereof, to reduce adverse side effects that can arise from, or be associated with, administration of the pharmaceutical composition alone. Alternatively, such biologically active agents may be included in the pharmaceutical composition of the invention to promote a desired therapeutic effect. Adjuvant biologically active agents useful in pharmaceutical compositions of the invention include, but are not limited to, M-CSF, -GM-CSF, TNF, II- 1, IL-2, IL-3, IL-4, IL-5, IL-6, IL-7, IL-8, IL-9, IL-10, 1L-11, 1L-12, 1L-13, 1L-14, 1L-15, 1L-16, 1L-17, 1L-18, IFN, TNF, G-CSF, Meg-CSF, GM-CSF, thrombopoietin, stem cell factor, erythropoietin, angiopoietins, including Ang-1, Ang-2, Ang-4, Ang-Y, and/or the human angiopoietin-like polypeptide, vascular endothelial growth factor (VEGF), angiogenin, bone morphogenic protein-1 (BMP-1), BMP-2, BMP-3, BMP-4, BMP-5, BMP-6, BMP-7, BMP-8, BMP-9, BMP-10, BMP-11, BMP-12, BMP-13, BMP- 14, BMP-15, BMP receptor IA, BMP receptor IB, brain derived neurotrophic factor, ciliary neutrophic factor, ciliary neutrophic factor receptor cytokine-induced neutrophil chemotactic factor 1, cytokine-induced neutrophil chemotactic factor 2, cytokine-induced neutrophil chemotactic factor 2, endothelial cell growth factor, endothelin 1, epidermal growth factor, epithelial-derived neutrophil attractant, fibroblast growth factor (FGF) 4, FGF 5, FGF 6, FGF 7, FGF 8, FGF 8b, FGF 8c, FGF 9, FGF 10, FGF acidic, FGF basic, glial cell line-derived neutrophic factor receptor 1, glial cell line-derived neutrophic factor receptor 2, growth related protein, growth related protein, growth related protein, growth related protein, heparin binding epidermal growth factor, hepatocyte growth factor, hepatocyte growth factor receptor, insulin-like growth factor I, insulin-like growth factor receptor, insulin- like growth factor II, insulin-like growth factor binding protein, keratinocyte growth factor, leukemia inhibitory factor, leukemia inhibitory factor receptor, nerve growth factor nerve growth factor receptor, neurotrophin-3, neurotrophin-4, placenta growth factor, placenta growth factor 2, platelet-derived endothelial cell growth factor, platelet derived growth factor, platelet derived growth factor A chain, platelet derived growth factor AA, platelet derived growth factor AB, platelet derived growth factor B chain, platelet derived growth factor BB, platelet derived growth factor receptor, platelet derived growth factor receptor, pre-B cell growth stimulating factor, stem cell factor, stem cell factor receptor, transforming growth factor (TGF) , TGF, TGF 1, TGF 1.2, TGF 2, TGF 3, TGF 5, latent TGF 1, TGF, binding protein I, TGF binding protein II, TGF binding protein III, tumor necrosis factor receptor type I, tumor necrosis factor receptor type II, urokinase-type plasminogen activator receptor, vascular endothelial growth factor, and chimeric proteins and biologically or immunologically active fragments thereof. The compounds of structural formulae (I) and (II) also can be conjugated or linked to auxiliary moieties that promote a beneficial property (or mitigate an undesirable property) of the compounds in a method of therapeutic use. Such conjugates can enhance delivery of the compounds to a particular anatomical site or region (for example, lactose, sugar, raicrocrystalline cellulose, maize-starch, calcium phosphate, or sorbitol), lubricants (for example, magnesium stearate, stearic acid, talc, polyethylene glycol or silica), disintegrants (for example, potato starch or sodium starch glycolate), or wetting agents (for example, sodium lauryl sulfate). The tablets can be coated according to methods well known in the art. Alternatively, compounds of the present invention can be incorporated into oral liquid preparations such'as aqueous or oily suspensions, solutions, emulsions, syrups, or elixirs, for example. Moreover, formulations containing these compounds can be presented as a dry product for constitution with water or other suitable vehicle before use. Such liquid preparations can contain conventional additives, for example suspending agents, such as sorbitol syrup, methyl cellulose, glucose/sugar syrup, gelatin, hydroxyethylcellulose, hydroxypropylmethylcellulose, carboxymethylcellulose, aluminum stearate gel, and hydrogenated edible fats; emulsifying agents, such as lecithin, sorbitan monooleate, or acacia; nonaqueous vehicles (which can include edible oils), such as almond oil, fractionated coconut oil, oily esters, propylene glycol, and ethyl alcohol; and preservatives, such as methyl or propyl p-hydroxybenzoate and sorbic acid. Preparations also can' be formulated as suppositories, e.g., containing conventional suppository bases, such as cocoa butter or other glycerides. Compositions for inhalation typically can be provided in the form of a solution, suspension, or emulsion that can be administered as a dry powder or in the form of an aerosol using a conventional propellant, such as dichlorodifluoromethane or trichloroflu'oromethane. Topical and transdermal formulations comprise conventional aqueous or nonaqueous vehicles, such as eye drops, creams, ointments, lotions, and pastes, or are in the form of a medicated plaster, patch, or membrane. Additionally, compositions of the present invention can be formulated for administration by injection or continuous infusion. Formulations for injection can be in the form of suspensions, solutions, or emulsions in oily or aqueous vehicles, and can contain formulation agents, such as suspending, stabilizing, and/or dispersing agents. Alternatively, the active ingredient can be in powder form for constitution with a suitable vehicle (e.g., sterile, pyrogen-free water) before use. A composition, of the present invention also can be formulated as a depot preparation. Such long acting formulations can be administered by implantation (for example, subcutaneously or intramuscularly) or by intramuscular injection. Accordingly, the compounds of the invention can be formulated with suitable polymeric materials (e.g., water-soluble polymers) hydrophobic materials (e.g., an emulsion in an acceptable oil), ion exchange resins, or sparingly soluble derivatives (e.g., a sparingly soluble salt). For veterinary use, a compound of formula (I) or (II), or a pharmaceutically acceptable salt, prodrug, or solvate thereof, is administered as a suitably acceptable formulation in accordance with normal veterinary practice. The veterinarian can readily determine the dosing regimen and route of administration that is most appropriate for a particular animal. Animals treatable by the present compounds and methods include, but are not limited to, pets, livestock, show animals, and zoo specimens. SYNTHETIC METHODS The compounds of the present invention can be prepared by the following synthetic schemes. First, the alkoxyarylamines used to prepare the Chkl inhibitors described herein can be prepared by different general synthetic schemes. For example, General Scheme 1 summarizes the reaction of a nitrophenol with an activated form of an alcohol, formed in situ or prepared and isolated independently, to provide a nitrophenyl ether product. Reduction of the ether under standard conditions provides an arylamine that is used to produce a compound of the invention. General Scheme 1 Alternatively, reaction of a halo nitrobenzene with an alcohol in the presence of a strong base, such as sodium hydride or potassium bis (trirmethylsilyl) amide, also affords nitroaryl ethers, as illustrated in General Scheme 2. These ethers then are reduced as indicated in General Scheme 1. General Scheme 2 Conversion of an arylamine to a urea can be achieved by one of several synthetic schemes. For example, an arylamine can be reacted with a pyrazine carbamate to yield a urea as illustrated in General Scheme 3. General Scheme 3 Alternatively, as outlined in General Scheme 4, heat induced decomposition of an acyl azide produces a reactive aryl isocyanate which then is allowed to react with an arylamine to yield the desired urea. General Scheme 4 Another approach, illustrated in General Scheme 5, utilizes phosgene or a phosgene equivalent to couple two arylamines and provide a urea. General Scheme 5 Abbreviations used in the syntheses described herein are: h (h) , rain (min), pound per square inch (psi), saturated (sat'd), water (H2O), deionized (DI), isopropyl alcohol (iPrOH), platinum on carbon (Pt/C), nitrogen (N2), hydrogen (H2), palladium on carbon (Pd/C), platinum oxide (Pt2O) , magnesium sulfate (MgSO4) , hydrochloric acid (HC1), diisopropyl azodicarboxylate (DIAD), methylene chloride (CH2C12), chloroform (CHC13), methanol (MeOH), ammonium hydroxide (NH4OH), tetrahydrofuran (THF), N-methylpyrrolidone (NMP), acetic acid (AcOH), NaOH (NaQH), EtOAc (EtOAc), ethanol (EtOH), dimethyl sulfoxide (DMSO), deuterated dimethyl sulfoxide (d6-DMSO), sodium carbonate (Na2CC>3) , deuterated chloroform (CDC13), sodium bicarbonate (NaHC03) , sodium hydride (NaH), TEA (TEA), cesium carbonate (CSSC03) , carbon dioxide (C02), palladium hydroxide (Pd(OH)2), sulfuric acid (H2SO«) , nitric acid (HN03) , sodium chloride (NaCl), sodium sulfate (Na2SO4) , and dimethylformamide (DMF). Preparation of Compounds The following compounds of the present invention were prepared using the general schemes disclosed above. Additional compounds of the invention can be prepared using the above general schemes, and the following specific syntheses, by a judicious selection of starting materials. Compound 1 1- [5-Chloro-2-S- ([1,4] oxazepan-2-ylmethoxy) -phenyl]-3-(5- methyl-pyrazin-2-yl)-urea Step 1: 2-Amino-5~methylpyrazine. Aminomalononitrile p-toluenesulfonate salt (20.0 g, 79 mmol) and pyruvaldehyde 1-oxime (6.88 g, 79 mmol) were combined in a flask. iPrOH (140 mL) was added, and the resulting yellow slurry was allowed to stir at room temperature for 18 h, during which time a yellow precipitate accumulated. The mixture was filtered and the precipitate was washed with iPrOH (2 x 50 mL) and DI H20 (20 mL), then lyophilized to give 2-amino-3-cyano-5- methypyrazine N-oxide (10.7 g). The pyrazine N-oxide was suspended in MeOH (22 mL) and AcOH (5 mL). To this, 5% Pt/C (1.6 g) and Darco KB-B (8 g) were carefully added. The mixture was allowed to absorb H2 at 60 psi for 18 h. The reaction was quenched with 25% NaOH (34 mL) and purged with N2 for 30 min. The mixture was filtered through a bed of wet celite and washed with MeOH (4 x 100 mL). The filtrate was concentrated in vacuo to a quarter volume. The filtrate was diluted with EtOAc (150 mL) and washed with 5% NaOH (30 mL) and back extracted with EtOAc (2 x 70 mL). The organic layers were combined and washed with sat'd NaCl (20 mL), filtered, and concentrated in vacuo to give an orange sticky solid (5.16 g). Step 2: (5-Methylpyrazin~2-yl) carbamic acid phenyl ester. 2-And.no-5-methylpyrazi.ne (5.16 g, 47 mmol) was dissolved in CHZC12 (52 mL) , stirred and cooled to 0°C under N2. To this, pyridine (4.8 mL, 59 mmol) was added followed by phenyl chloroformate (6.2 mL, 59 mmol) , dropwise, over 15 min, causing a precipitate to form. The mixture was stirred at 0°C for 1 h. Then the reaction was quenched with 0.25 M HCl (40 mL) and anhydrous ether (50 mL), and stirred at 0°C, for 30 min. The precipitate was isolated by filtration, washed with DI H20 (20 mL) and ether (2 x 25 mL) , and dried under vacuum to give the product (7.4 g) as a white fluffy powder. Step 3: (5)-2-Hydroxymethyl-[l,4]oxazepane-4- carboxylic acid tert-butyl ester. To a 250 mL round bottom flask were added (S)-(+)-benzyl glycidyl ether, (1.31 g, 7.9 mmol), 3-benzylamino-propan-l-ol (1.3 g, 7.9 mmol) and 10 mL EtOH. The mixture was heated to 40°C for 15 h. The reaction was cooled and concentrated in vacuo and the resulting oily product was used without further purification. The diol was placed in a 250 mL round bottom flask and dissolved in 75 mL dry pyridine. The solution was cooled to 0°C and toluene sulfonyl chloride (5.27 g, 27.7 mmol) was added in one portion. The mixture was stirred for 6 h, carefully maintaining the reaction temperature at 0°C. The cold reaction was quenched with 50 mL sat'd aqueous NaHC03 solution. An additional 20 mL of water was added and the mixture was extracted three times with 100 mL portions of EtOAc. The combined organics were dried over Na2SO4 and concentrated in vacuo. The alcohol then was purified by column chromatography using a 25-50% gradient of EtOAc and hexanes as the eluent. This yielded 1.39 g of tosyl alcohol as a yellow oil. The alcohol was dissolved in 50 mL DMF and cooled to 0CC. To the cold, stirred mixture was carefully added 95% wt. NaH (0.29 g, 11.5 mmol) . The reaction was stirred at 0°C for 15 min, then allowed to slowly warm to room temperature and stirred 6 h. The reaction was carefully quenched with 50 mL of water and extracted three times with 50 mL portions of EtOAc. The combined organics were dried over Na2SO4 and concentrated under vacuum. The crude product was taken up in EtOH and placed in a Parr hydrogenation apparatus. Also added to the solution were 10% wt. Pd/C (0.426 g, 0.30 mmol) and 2M HC1 (2.1 mL). The hydrogenation was run at 50 psi for 2 days at which point the reaction was deemed to be done by LCMS analysis. The solution was neutralized with sat'd aqueous NaHC03 solution and extracted using a 3:1 mixture of CHCl3:iPrOH. The combined organics were concentrated under vacuum and the crude product was taken on to the next step. The crude amino alcohol was dissolved in 100 mL dry CH2C12. To this solution were added TEA (1.59 mL, 11.5 mmol) and di-tert-butyl dicarbonate (5.74 g, 5.74 mmol). The solution was stirred at room temperature for 18 h, then quenched with sat'd aqueous NaHC03 solution and extracted three times using 50 mL portions of CH2CI2. The combined organics were dried over Na2SO4 and concentrated in vacuo. The product was purified by column chromatography using a 25-50% gradient of EtOAc/hexanes. This yielded 0.240 g of the oxazapane alcohol as a yellow oil. Step 4: (S)-2-(4-Chloro-2-nitro- phenoxymethyl)-[1,4]oxazepane-4-carboxylic acid tert- butyl ester. To a 50 mL round bottom were added oxazapane alcohol (0.240 g, 1.03 mmol), TEA (0.21 mL, 1.545 mmol), and 10 ml dry CH2C12. The solution was cooled to 0°C and methane sulfonyl chloride (0.10 mL) was added dropwise. The mixture was stirred for 1.5 h at 0°C and then quenched, cold, with water. The layers were separated and the aqueous layer was extracted once with 20 mL CH2C12. The combined organics were dried over Na2SO« and concentrated under vacuum. The crude mesylate then was dissolved' in 5 mL dry DMF. To this solution was added Cs2C03 (0.671 g, 2.06 mmol) and 4-chloro-2-nitro- phenol (0.215 g, 1.24 mmol). This bright yellow solution then was heated to 100°C overnight. The reaction was cooled to room temperature, quenched with 50 mL of water, and extracted three times with 50 mL portions of EtOAc. The product was purified by flash chromatography using a 10-35% gradient of EtOAc/hexanes. This sequence of steps yielded 0.120 g of the nitrophenyl oxazapane as a bright yellow oil. Step 5: l-[5-Chloro-2-([l,4)oxazepan-2-(S)- ylmethoxy)-phenyl]-3-(5-methyl-pyrazin-2-yl)-urea. In a 25 mL round bottom were placed nitrophenyl oxazapane (0.120 g, 0.31 mmol) and Pt20 (0.007 g, 0.03 mmol) in 5 mL MeOH. A helium balloon was attached, the flask was evacuated using an aspirator, and backfilled with H2 three times, then allowed to stir under H2 for 2 h. The reaction was filtered through celite, washing the celite pad twice with 20 mL portions of MeOH. The solution was concentrated in vacuo. The crude aniline was dissolved in 5 mL of dry DMF. To this solution were added TEA (0.005 mL, 0.34 mmol) and (5-methylpyrazin-2-yl) carbamic acid phenyl ester (0.07 g, 0.31 mmol). This mixture was stirred 18 h at room temperature. The solvent was removed under vacuum and the residue was redissolved in 10 mL EtOAc and washed with sat'd aqueous NaHC03 solution. The organics were dried over Na2SO« and concentrated at reduced pressure. The gray/brown residue was covered with 3 raL CH2C12 and to this was added 1 mL concentrated trifluoroacetic acid. Upon addition of acid all solids dissolved. The reaction was stirred at room temperature for 4 h at which time sat'd aqueous NaHC03 solution is added until solution reaches pH 8. The mixture was extracted three times with 10 mL portions of a 3:1 mixture of CHCl3:iPrOH. The combined organics were then dried over NazSO4 and concentrated under vacuum. The off white solids then were trituated in EtOAc and filtered through a medium fritted filter, washing with 50 mL of EtOAc. The white solid was thoroughly dried under vacuum. This sequence yielded 0.020 g of the desired urea as a fine white powder. ^-NMR (300 MHz, d6-DMSO) 5 10.83 (br s, 1H), 8.39 (dd, 1H), 8.18 (s, 1H) 8.04 (br s, 1H), 6.99 (dd, 1H), 6.82 (d, 1H), 4.25-3.98 (m, 2H), 3.90-3.76 (m, 1H), 3.38 (d, 1H), 3.13-3.06 (m, 2H), 3.00 (dd, 1H), 2.54 (s, 3H), 2.06-1.89 (m, 3H). LCMS (ES, positive) m/e 392.3 (M+l). Compound. 2 1-[5-Chloro-2- (i?-morpholin-3-ylmethoxy) -phenyl] -3- (5- methyl-pyrazin-2-yl)-urea Step 1: 3-Hydroxymethyl-S-morpholine-4- carboxylic acid tert-butyl ester. To a cooled solution of morpholine-3-R-4-dicarboxylic acid 4-tert- butyl ester (1.00 g, 4.32 mmol) in dry THF (40 mL) was added borane (4.76 mL of 1M solution in THF, 4.7 6 mmol) dropwise over 15 min under a nitrogen atmosphere . After stirring for 1 h, the bath was removed and stirring continued for an additional 3 h at ambient temperature. Acetic acid (14.3 mL of 1M aqueous solution, 14.3 mmol) then was added. After stirring for 1 h, the solution was neutralized by the addition of excess aqueous saturated sodium bicarbonate. Dichloromethane (20 mL) was added and the solution was stirred for 15 min, then the layers were separated. The aqueous layer was extracted with CH2C12 (3 x 20 mL), and the combined organic layers were dried (MgSO4), and filtered. The filtered solution was concentrated to a white solid (0.46 g). Step 2: 3- (4-Chloro-2-nitro-phenoxymethyl)-R- morpholine-4-carboxylic acid tert-butyl ester. To a cooled (-78°C bath) stirred solution of 3-hydroxymethyl- S-morpholine-4-carboxylic acid tert-butyl ester (0.13 g, 0.60 mmol) and 5-chloro-2-fluoronitrobenzene (0.11 g, 0.66 mmol) in dry THF (40 mL) was added potassium bis (trimethylsilyl)amide (2.4 mL of 0.5M solution in THF, 1.2 mmol) dropwise over 15 min under a nitrogen atmosphere. After stirring an additional 15 min, aqueous saturated ammonium chloride (10 mL) was added and the bath removed to allow the solution to warm to ambient temperature. After stirring for 1 hour, water (15 mL) and CH2C12 (10 mL) were added and stirred for 5 min and the layers were separated. The aqueous layer was extracted with CH2C12 (2 x 10 mL) and the combined organic layers were dried (MgSO4), and filtered. The filtered solution was concentrated to a yellow oil (0.26 g) that was purified by column chromatography eluting with hexanes/EtOAc (1:1) to afford a light yellow oil (0.195 g). Step 3: 3-(2-Amino-4-chloro-phenoxymethyl) -R-' morpholine-4-carboxylic acid tert-butyl ester. To a stirred solution of 3- (4-chloro-2-nitro-phenoxymethyl) -R- morpholine-4-carboxylic acid tert-butyl ester (0.17 g, 0.46 mmol) in MeOH (4 mL) was added Pt20 (0.020 g, 0.088 mmol). The flask was evacuated, then backfilled with H2 for three iterations. After stirring for 4.h, the solution was filtered over a pad of Celite and the filtrate was concentrated to give the product as a yellow oil. Step 4: 3-{4-Chloro-2-[3-(5-methyl-pyrazin-2- yl) -ureido]-phenoxymethyl}-R-morpholine-4-carboxylic acid tert-butyl ester . A solution of the yellow oil and (5- methyl-pyrazin-2-yl)-carbamic acid phenyl ester (0.13 g, 0.57 mmol) in dry DMP (2 mL) was prepared and TEA (0.074 mL, 0.53 mmol) was added. After stirring for 24 h, the reaction was concentrated under reduced pressure, then redissolved in water (10 mL) and EtOAc (10 mL). After stirring for 15 min, the layers were separated and the aqueous layer was extracted with EtOAc (2 x 10 mL) and combined organic layers were washed with brine (10 mL), then dried (Na2SO4) and filtered. The filtered solution was concentrated, then purified by column chromatography eluting with EtOAc/CH2Cl2 (1:1) to afford a yellow oil (0.8 g) . Step 5: l-[5-Chloro-2-(R-morpholin-3- ylmethoxy)-phenyl]-3- (5-methyl-pyrazin-2-yl)-urea. To a stirred solution of 3-{4-chloro-2-[3-(5-methyl-pyrazin-2- yl)-ureido]-phenoxymethyl}-R-morpholine-4-carboxylic acid tert-butyl ester (0.8 g) in CH2C12 (6 mL) was added trifluoroacetic acid (3 mL) . After stirring 5 h, the solution was treated with aqueous potassium carbonate solution (1M) until basic, then stirred for 30 min. The layers were separated and the aqueous layer was extracted with CH2C12 (3 x 10 mL) . The combined organic layers were dried (MgSOj) , and filtered. The filtered solution was concentrated, then purified by column chromatography, eluting with MeOH/CH2Cl2 (1:9), to afford a pale yellow solid (0.0523 g) . ^-NMR (300 MHz, d6-DMSO) 5 10.22 (s, 1H), 9.96 (br s, 1H), 8.74 (s, 1H) , 8.28 (d, 1H) , 8.18 (s, 1H), 7.04 (dd, 2H), 3..94 (m, 3H), 3.71 (br d, 1H) , 3.43 (m, 1H) , 3.23 (m, 2H), 3.34 (br m, 2H) , 2.66 (br m, 1H) , 2.43 (s, 3H) . LRMS (es, positive) m/e 378.3 (M+l) . Compound 3 l-[2- (1, 4-Dimethyl-piperazin-2-ylraethoxy)-5-methyl~ phenyl]-3-(5-methyl-pyrazin-2-yl)-urea Step 1: l,4-Dimethyl-2-(4-methyl-2-nitro- phenoxymethyl)-piperazine. 4-Methyl-2-nitro-phenol (0.95 g, 6.20 mmol), (1,4-dimethyl-piperazin-2-ylj-MeOH (0.98 g, 6.82 mmol), and triphenylphosphine (1.79 g, 6.82 mmol) were combined in THF, stirred for 5 min, then treated with DIAD (1-38 g, 6.82 mmol). The reaction was allowed to stir overnight. Concentration under vacuum afforded an orange oil which was dissolved in EtOAc and extracted with 2M aqueous HC1 solution. The aqueous washes were combined, washed with EtOAc, and treated with solid NaOH until basic. The resulting aqueous mixture was extracted with EtOAc and the combined organic extracts were dried over Na2SO4, filtered and concentrated in vacuo to give a brown oil. Flash chromatography (1% MeOH in CH2Cl2) gave 1.0 g of the desired aryl ether.- Step 2: 2- (1,-J-Dimethyl-piperazin-^- ylmethoxy)-5-methyl-phenylaraine. 1,4-Dimethyl-2- (4- methyl-2-nitro-phenoxymethyl) -piperazine (1.02 g, 3.65 mmol) was dissolved in MeOH (75 mL) and treated with sat'd aqueous ammonium chloride solution until the mixture became turbid. Zinc (0.24 g, 3.65 mmol) was added. The resulting warm reaction mixture was allowed to stir for an additional 30 min at which time LCMS indicate that starting material had been consumed. The reaction was diluted with EtOAc and aqueous Na2C03 and the layers were separated. The organic layer was washed with saturated NaCl solution and dried over solid anhydrous Na2SO4. The mixture was filtered and concentrated in vacuo to afford the desired aniline. Step 3: l-[2-(l,4-Dimethyl-piperazin-2- ylmethoxy)-5-methyl-phenyl]-3-(5-methyl~pyrazin-2-yl)- urea. 5-Methyl-pyrazine-2-carboxylic acid (691 mg, 5 mmol) was stirred in toluene (15 mL) and treated with TEA (765 mL, 5.5 mmol) followed by diphenylphosphoryl azide (1.0 mL, 5.0 mmol). The resulting solution was stirred for 30 min, then used directly. A solution of 5-methyl-pyrazine-2-carbonyl azide (1.0 mmol) in toluene was heated at 90°C for 10 min. The reaction flask was removed from the heating bath and the brown solution was treated with 2-(1,4- dimethyl-piperazin-2-ylmethoxy)-5-methyl-phenylamine (0.25 g, 1.0 nunol) . The flask was returned to the heating bath and heated at 40°C for 4 h. The mixture was allowed to cool, then filtered to give the product as a tan powder. XH-NMR (400 MHz, CDC13) 5 10.90 (s, 1, H) , 8.4 (s, 1, H), 8.2 (m, 3, H), 6.8 (m, 2, H), 4.2 (-dd, 1, H) , 3.9 (t, 1, H), 3.1 (d, 1, H)f 2.8 (br d, 1, H) , 2.6 (m, 2, H) , 2.5 (s, 3, H), 2.4 (m, 1, H), 2.4 (s, 3, H), 2.3 (s, 3, H), 2.25 (m, 1, H), 2.2 (s, 3, H), 2.1 (m, 1, H) . LRMS (esi, positive) m/e 385.30 (M+l). Compound 4 1- [4, 5-Dichloro-2- (S-morpholin-2-ylmethoxy) -phenyl] -3- (5- methyl-pyrazin-2-yl)-urea Step 1: (S)-2-Hydroxyinethyl-morpholine-4- carboxylic acid tert-butyl ester. In a 500 mL flask were combined (S)-benzyl glycidyl ether (15g, 91.4 mmol),' MeOH (10 mL) , and 50% wt. NaOH (30 mL, 365 mmol). To this mixture was added 2-aminoethylsulfate (25,8 g, 183 mmol) in portions. This heterogeneous mixture was heated to 4 0°C at which point the solution becomes homogenous. The temperature was maintained at 40°C for 4 h. The reaction was cooled slightly and additional solid NaOH (14.6 g, 365 mmol) was added along with 50 mL toluene. The biphasic solution then was heated to 65°C for 12 h. The reaction was cooled to room temperature, the layers were separated and the aqueous layer was extracted once with 75 mL of toluene. The combined organic layers were washed three times with 75 mL portions of 1M HC1. The pH of the combined aqueous layers was adjusted to pH 12 with. aqueous NaOH solution and extracted four times with 70 mL portions of EtOAc. The combined organics were dried over Na2SO4 and concentrated in vacuo to yield 10.084 g of the desired morpholine as an opaque oil. The crude morpholine product was dissolved in CH2C12 (100 mL) and TEA (12.1 mL, 87.5 mmol) and di-tert- butyl dicarbonate (15.9 g, 73 mmol) was added accompanied by the generation of C02 gas. The reaction was stirred at room temperature for 18 h, then quenched with 35 mL sat'd aqueous NaHCOa solution. An additional 50 mL water was added and the layers were separated. The organic layer was dried over anhydrous Na2SO«, concentrated in vacuo and purified by flash chromatography (20% EtOAc/hexane) to give the desired N-Boc-O-benzyl morpholine as a pale yellow oil (5.536 g) . The purified diprotected morpholine was dissolved in 50 L absolute EtOH and Pd(OH)2 (1.26 g, 20%wt, 1.8 mmol) was added. A hydrogen balloon was attached and the flask was evacuated using an aspirator and backfilled with H2 three times. The reaction was stirred under H2 for 30 h. The mixture was filtered over celite, rinsing the celite pad thoroughly with EtOH. The filtered solution was concentrated down under vacuum to yield of the desired N-boc-raorpholine alcohol as a pale white solid (3.918 g). Step 2: 4,5-Dichloro-2-nitro-phenol. A 250 mL roundbottom flask charged with 3, 4-dichlorophenol (3.053 g, 18.7 mmol) in 50 mL CH2C12 was cooled to 0°C in an ice bath. To the stirred solution was added concentrated H2SO4 (1.56 mL, 28.1 mmol). The solution became turbid. To this mixture was added concentrated HN03 (1.2 ml, 18.7 mmol)/ dropwise and carefully to maintain a temperature below 5°C. The reaction was stirred for 30 min at 0°C, then cooled with an ice bath and quenched with 150 mL H20. The layers were separated and the aqueous layer was extracted once with 35 mL CH2Cl2. The combined organics . were dried over anhydrous Na2SO4, concentrated under vacuum and purified using flash chroraatrography (10% EtOAc/hexanes as eluent) to yield the desired nitrophenol as a bright yellow solid (1.793 g) . Step 3: 1-[4,5-Dichloro~2-(S-morpholin-2- ylmethoxy) -phenyl] -3- (5-methyl-pyrazin-2-yl) -urea. Prepared according to the procedure for Compound 1, Steps 4 and 5, using 4,5-dichloro-2-nitro-phenol and (S)-2- benzyloxymethyl-morpholine-4-carbbxylic acid tert-butyl ester. ^-NMR (300 MHz, d€-DMSO) 6 10.42 (s, 1H) , 10.29 (s, 1H), 8.93 (s, 1H), 8.42 (s, 1H) , 8.21 (s, 1H), 7.32 (s, 1H), 4.18-3.41 (m, 5H), 3.03-2.66 (m, 4H) , 2.38 (s, 3H) LRMS (ES, positive) m/e 412.2 (M+l). Compound 5 1-(5-Cyano-pyrazin-2-yl)-3-[5-methyl-2-(4-methyl- morpholin-2-ylmethoxy)-phenyl]-urea Step 1: 5-Bromo-pyrazin-2-ylamine. A solution of pyrazin-2-ylamine (6.66 g, 70 mmol) in CH2C12 (200 mL) was cooled to 0°C, treated with N-bromosuccinamide (12.5 g, 70 mmol) and allowed to warm to room temperature. The resulting reaction mixture was stirred overnight, then diluted with additional CH2C12 (200 mL) and washed with 10% aqueous Na2C03 solution. The layers were separated, and the organic layer washed with sat'd aqueous NaCl solution, then dried over anhydrous MgSO4 filtered, and concentrated under reduced pressure. The residue was taken up in EtOAc (50 mL) and the product was precipitated by the addition of hexane (300 mL) . The precipitate was dried under vacuum to yield 5.57 g of a tan solid. Step 2: 5-Amino-pyrazine-2-carbonitrile. 5- Bromo-pyrazin-2-ylamine was combined with copper (I) iodide (1.3 g, 6.9 mmol), potassium cyanide (0.44 g, 6.8 mmol), tetrakis (triphenylphosphine)palladium(O) (0.95 g, 0.83 mmol), and 18-crown-6 (0.058 g, 0.22 mmol) in DMF (15 mL). The resulting mixture was stirred for 40 min, then heated at reflux (155°C) for 2 h. The reaction was cooled to room temperature, then allowed to stand overnight. The precipitate was separated by filtration and the filtrate was concentrated to dryness in vacuo. The orange-colored residue was taken up in EtOAc and hexanes and an initial precipitate was formed, then separated by filtration. Upon standing, additional precipitate formed in the mother liquor and was collected by filtration. The solids were combined to yield 0.10 g of a bright orange solid. Step 3: 2-{2-[3-(5-Cyano-pyrazin-2-yl)- ureido]-4-methyl-phenoxymethyl}-morpholine-4-carboxylic acid tert-butyl ester. 2-(2-Amino-4-methyl- phenoxymethyl)-morpholine-4-carboxylic acid tert-butyl ester (0.087 g, 0.270 mmol) was prepared from 2-amino-4- methyl-phenol according to methods of Compound 3, steps 1 and 2 using 2-hydroxymethyl~morpholine-4-carboxylic acid tert-butyl ester (prepared according to the procedure for Compound 2, Step 1 using the corresponding acid) and 4- methyl-2-nitro-phenol. It was combined with tr±phosgene (0.029 g, 0.10 mmol), toluene (2 mL) and Hunig's base (0.15 mL, 0.86 mmol), and stirred at room temperature for 25 min. The suspension then was transferred through a cannula to a cold solution (-78°C) containing 5—amino- pyrazine-2-carbonitrile (0.032 g, 0.27 mmol), and lithium bis (trimethylsilyl) amide (0.27 mmol) in THF (1 mL) , which had been stirring at -78°C for 30 min. The reaction was allowed to warm, then was stirred for 16 h at room temperature. A precipitate formed and was collected by filtration to yield the desired product (0.043 g). Step 4: 1- (5-Cyano-pyrazin-2-yl)-3- [5-methyl- 2- (morpholin-2-ylraethoxy) -phenyl] -urea. A slurry of 2- (2-[3-(5-cyano-pyrazin-2-yl)-ureido]-4-methyl- phenoxymethyl}-morpholine-4-carboxylic acid tert-butyl ester (0.043 g, 0.0918 mmol) in THF'(2 mL) was treated with HC1 in dioxane (4M, 0.11 mL) and stirred for 20 h. Additional HC1 in dioxane (4M, 0.25 mL) was added and the reaction was heated to 50°C for 18 h. The reaction was cooled and concentrated. The resulting solid was suspended in ether, and the suspension filtered and air dried to afford the desired product as the HC1 salt (0.042 g). Step 5: l-(5-Cyano-pyrazin-2-yl)-3-[5-methyl- 2-(4-methyl-morpholin-2-ylmethoxy)-phenyl]-urea. A solution of 1-(5-cyano-pyrazin-2-yl)-3-[S-methyl-^- ^orpholin^-ylmethoxy) -phenyl] -urea hydrochloride salt (0.0104 g, 0.129 mmol) in MeOH (1 mL) was cooled to 0°c and treated with an aqueous solution of formaldehyde (0.12 mmol) followed by sodium triacetoxy borohydride (0.06 g, 0.292 mmol) . The reaction was stirred for 12 h, then concentrated in vacuo. The residue was chromatographed on silica (2% MeOH in CH2C12) to give the product as a white solid (0.014 g) . ^-NMR (400 MHz, d6- DMSO) 5 10.90 (s, 1, H), 10 (br s, 1, H), 8.9 (s, 1, H), 8.8 (s, 1, H), 8 (s, 1, H), 6.9 (m, 1, H) , 6.8 3.8 (m, 4, H) , 3.6 (t, 1, H), 2.9 (d, 1, H), 2.7 (d, 1, H) , 2.2 (s, 3, H), 2.1 (s, 3, H), 2 (t, 1, H), 1.8 (t, 1, H) . LRMS (esi, positive) m/e 383.40 (M+l) . Compound 6 1- [5-Chloro-2- ( [ 1,4] oxazepan-2-ylmethoxy).-phenyl ] -3- (5- methyl-pyrazin-2-yl)-urea Step 1: 3-Benzyl-2-chloromethyl- [l,3]oxaze'pane. A solution of 3-benzylamino-propan-l-ol (14 g, 88.0 mmol) and epichlorohydrin (81.4 g, 8 80 ramol) was heated to 40°C. After stirring for 3 h the reaction was cooled and excess epichlorohydrin was removed by evaporation in vacuo. Sulfuric acid 410 mL) was added slowly, then the reaction flask was placed in a preheated oil bath at 150°C. Stirring proceeded for 1 h, then the reaction was allowed to cool to room temperature and quenched with the addition of ice. The mixture was adjusted to a basic pH with 10% aqueous Na2C03 solution and extracted with EtOAc (3 x 300 mL) . The combined organic layers were dried over anhydrous MgSO4, filtered, and dried under reduced pressure. The resulting residue was purified by flash chromatography (70:28:2 hexanes/CH2Cl2/2M NH,OH aq) to afford 5 g of a light yellow oil. Step 2: 2- (4-Chloro~2-nitro-phenoxymethyl)- [1,3]oxazepane-3-carboxylic acid tert-butyl ester. To a stirred solution of 4-bromo-2-nitro-phenol (1.39 g, 8.0 mmol) in DMSO (30 mL) .was added potassium carbonate (2.76 g, 20.0 mmol) followed by 3-benzyl-2-chloromethyl- [l,3]oxazepane. The reaction was stirred at 60°C for 12 h then allowed to cool to room temperature and diluted with EtOAc (200 mL) and 10% aqueous Na2C03 solution (200 mL) . The layers were separated and the organic layer was washed with brine, dried over anhydrous MgSO* anci concentrated in vacuo. The crude product was purified by flash chromatography (70:30 hexanes/EtOAc) to gi~ve 480 mg of a light orange oil. The oil was taken up in CH2C12 (5 mL) and cooled in an ice bath. The alpha chloro ethyl chloroformate (0.18 mL, 1.65 mmol) was added. The reaction was stirred for 2 h, then 2N aqueous HC1 solution was added. Stirring was continued for 10 min, then the mixture was concentrated to dryness. Trie resulting residue was taken up in MeOH and refluxed for 2 h. The reaction was concentrated under reduced pressure and the residue was taken up in 2N aqueous HC1 solution (75 mL) and washed with EtOAc (2 x 50 mL) . The pH of the • aqueous layer was adjusted to a pH of 11 by the addition of solid NaOH. The resulting basic solution was extracted with EtOAc (2 x 50 mL) and the combined organic layers were washed with brine and dried over MgSO«. Filtration and concentration in vacuo afforded 2 4 0 mg of product as a light yellow oil. The oil was dissolved in CH2C12 (3 mL) , then treated with TEA (0.116 mL, 0.831 mmol) and di-tert-butyl dicarbonate (0.181 g, 0.831 mmol). The reaction was allowed to stir at room temperature for 1 h then diluted with additional CH2Cl2 (100 mL) and washed with 10% aqueous Na2C03 solution (100 mL) . The organic layer was dried over MgSO«, filtered and concentrated under reduced pressure. Purification was achieved using flash chromatography (7:3 hexane/EtOAc) to give 252 mg of the product as of a white foam. Step 3: 2- (2~Amino-4-chloro-phenoxymethyl) - [l,3]oxazepane-3-carboxylic acid tert-butyl ester. Prepared from 2-(4-chloro-2-nitro-phenoxymethyl) - [1,3]oxazepane~3-carboxylic acid tert-butyl ester (0.252 g, 0.65 mmol) according to the procedure for Compound 3," Step 2 to give 150 mg of the product as a clear oil. Step 4: l-[5-Chloro-2-([l,4]oxazepan-2- ylmethoxy)-phenyl]-3-(5-methyl-pyrazin-2-yl)-urea. Prepared from 2-(2-amino-4-bromo-phenoxvmethyl)- [l,3]oxazepane-3-carboxylic acid tert-butyl ester using according to the procedure for Compound 2, Step 4 and Compound 5, Step 4, to give 0.175 g of product. *H-NMR (400 MHz, CDC13), 5 8.65 (br s, 1, H), 8.3 (s, 1, H) , 8.25 (s, 1, H), 6.98 (dd, 1, H), 6.8 (d, 1, H), 4.08 (m, 3, H), 3.8 (m, 1, H), 3.35 (s, 1, H), 3.25 (d, 1, H), 3 (m, 3, H), 2.5 (s, 3, H), 1.98 (m, 2, H) . LRMS (esi, positive) m/e 391.90 (M+l). Compound 7 1-[5-Methyl-2- (1 -methyl-piperazin-2-ylmethoxy) -phenyl]-3- (5-methyl-pyrazin-2-yl) -urea Step 1: 3-Hydroxymethyl-4-methyl-piperazine- 1-carboxylic acid tert-butyl ester. Piperazine-2- carboxylic acid (20 g, 154 iranol) in a slurry with 200 mL of 1:1 H20/dioxane was cooled in an ice bath and treated with solid NaOH (11 g) followed by a solution of di-tert- butyl dicarbonate (21.6 g, 99 mmole) in dioxane added dropwise from an addition funnel. The reaction pH was adjusted to pH>10 as needed during the course of the reaction. The resulting mixture was allowed to stir for 3 h, then diluted with water until homogeneous and acidified with concentrated aqueous HC1 until the pH was between 2 and 3. The solution was washed with ether then the pH was adjusted with NaOH until pH was 6.5 to 7. The solution was allowed to stand several days and the resulting precipitate was collected by filtration to give piperazine-1,3-dicarboxylic acid 1-tert-butyl ester as a white solid (9.7 g). A slurry of piperazine-1,3-dicarboxylic acid 1-tert-butyl ester (4.62 g, 20.0 mmol) in CH3OH (100 mL) was treated with aqueous formaldehyde (40 mmol) and formic acid (70 mmol), then heated at 65CC for several hours. Upon completion by HPLC, the reaction was allowed to cool and was concentrated in vacuo. The residue was taken up in THF and cooled in an ice bath, then treated with a solution of lithium aluminum hydride in THF (19.0 mmol) . After 1 h, the reaction was allowed to warm to room temperature and stired for an additional 30 min. The reaction then was cooled in an ice bath and quenched with H20 (0.7 5 mL) and 15% aqueous NaOH solution (0.75 mL) , and H20 again (3 x 0.75 mL) . The salts were removed by filtration and the filtrate concentrated under vacuum to' give the crude product. Chromatography over silica gel (2.5% MeOH in CH2C12) gave the product as a yellow oil (0.70 g) . Step 2: 1- [ 5-Methyl-2- (l-methyl-piperazin-2- ylmethoxy) -phenyl] -3- (5-methyl-pyrazin-2-yl) -urea. Prepared according to the procedure for Compound 3 using 3-hydroxymethyl-4-methyl-piperazine-1-carboxylic acid tert-butyl ester, and the procedure, for Compound 5, Step 4. ^-NMR (400 MHz, d6-DMSO) 6 10.24 (br s, 1, H) , 10.1 (s, 1, H), 9.7 (br s, 1, H), 9.42 (s, 1, H) , 9.12 (s, 1, H), 8.2 (s, 1, H) , 8.08 (s, 1, H), 6.91 (d, 1, H) , 6.82 (d, 1, H) , 4.6 (d, 1, H), 4.4 (m, 1, H), 4.1 (m, 1, H) , 3.6 (m, 6, H), 3 (s, 3, H), 2.4 (s, 3, H), 2.2 (s, 3, H). LRMS (esi, positive) m/e 371.40 (M+l). Compound 8 l-(5-Cyano-pyrazin-2-yl)-3-[5-methyl-2-(morpholin-2- ylmethoxy)-phenyl]-urea Prepared according to the procedures for Compound 5, Steps 1 through 4, using 4-methyl-2-nit ro- phenol. aH-NMR (400 MHz, CD30D), 5 8.80 (s, 1, H) , 8.7 (s, 1, H) , 7.9 (s, 1, H), 6.8 (m, 2, H), 4.2 (m, 3.8 (m, 1/ H), 3.6 (m, 1, H), 3.5 (m, 1, H) , 3.2 (m, 2, H) , 2.3 (s, 3, H) . LRMS (esi, positive) m/e 369.30 (M+1). Compound 9 1- [5-Chloro-4-methyl-2- (S-morpholin-2-ylmethoxy) -phenyl] - 3- (5-methyl-pyrazin-2-yl) -urea Prepared according to the procedure fox- Compound 1/ Steps 4 and 5 using 2-hydroxymethyl-S- morpholine-4-carboxylic acid tert-butyl ester, prepared using the procedure for Compound 4, Step 1 and 4-chloro- 5-methyl-2-nitro-phenol, prepared according to the procedure for Compound 4, Step 2. 1H-NMR (300 MHz, d6- DMSO) 6 10.32 (s, 1H) , 10.21 (s, 1H) , 8.75 (s, 1H) , 8.29- 8.10 (m, 2H)r 7.06 (d, 1H), 7.18 (d, 1H), 4.12-3.42 (m, 5H), 3.29-2.63 (m, 4H), 2.48 (s, 3H) , 2.25 (s, 3H) . LRMS (ES, positive) m/e 392.2 (M+l). Compound 10 l-[5-Chloro-4-methyl-2-(R-morpholin-2-ylmethoxy) -phenyl]- 3-(5-methyl-pyrazin-2-yl)-urea Prepared according to the procedure for Compound 1, Steps 4 and 5 using 2-hydroxymethyl-R- morpholine-4-carboxylic, prepared from (R)-benzyl glycidyl ether acid tert-butyl ester, using the procedure for Compound 4, Step 1, and 4-chloro~5-methyl-2-nitro- phenol, prepared according to the procedure for Compound 4, Step 2. :H-NMR (300 MHz., d6-DMSO) 8 10.32 (s, 1H) , 10.21 (s, 1H), 8.75 (s, 1H), 8.29-8.10 (m, 2H) , 7.06 (d, 1H), 7.18 (d, 1H), 4.12-3.42 (m, 5H), 3.29-2.63 (m, 4H), 2.48 (s, 3H), 2.25 (s, 3H). LRMS (ES, positive)•m/e 392.3 (M+l). Compound 11 1-[4,5-Dichloro-2-(R-morpholin-2-ylmethoxy)-phenyl]-3-(5- methyl-pyrazin-2-yl)-urea Prepared according to the procedure for Compound 1, Steps 4 and 5 using 2-hydroxymethyl-S- morpholine-4-carboxylic acid tert-butyl ester and 4,5- dichloro-2-nitro-phenol, prepared according to the procedure for Compound 4, Step 2. 1H-NMR (300 MHz, d6- DMSO) 6 10.42 (s, 1H), 10.29 (s, 1H), 8.93 (s, 1H), 8.42, (s, 1H), 8.21 (s, 1H), 7.32 (s, 1H), 4.18-3.41 (m, 5H), 3.03-2.66 412.2 (M+l). Compound 12 1- [4, 5-Dimethyl-2- (morpholin-2-ylmethoxy) -phenyl] -3- (5- methyl-pyrazin-2-yl)-urea Prepared according to the procedures for Compound 1, Steps 4 and 5 using 2-hydroxymethyl-S- morpholine-4-carboxylic acid tert-butyl ester and 4,5- dimethyl-2-nitro-phenol, prepared according to the procedure for Compound 4, Step 2. 1H-NMR (300 MHz, d6- DMSO) 6 10.02 (s, 1H), 9.89 (br s, 1H), 8.85 (br s, 1H), 8.27 (s, 1H), 8.91 (s, 1H), 6.84 (s, 1H) , 4.18-3.97 (m, 3H) , 3.69 (t, 1H), 3.43-3.26 (m, 2H), 2.97 (t, 2H), 2.33 (s, 3H), 2.18 (s, 2H), 2.12 (s, 3H). LRMS (ES, positive) m/e 372.3 (M+l). Compound 13 1- [4-Chloro-5-methyl-2- (S-morpholin-2-ylmethoxy) -phenyl]- 3-(5-methyl-pyrazin-2-yl)-urea Prepared according to the procedures for Compound 1, Steps 4 and 5 using 2-hydroxymethyl-S- morpholine-4-carboxylic acid tert-butyl ester and 5- chloro-4-itiethyl-2-nitro-phenol, prepar-ed according to the procedure for Compound 4, Step 2. XH-NMR (300 MHz, d€- DMSO) 6 10.26 (s, 1H), 8.82 (s, 1H), 8.19 (s, 1H), 8.17 (s, 1H), 7.10 (s, 1H), 4.21-3.96 (ra, 2H), 3.90-3.86 (m, 2H), 3.54 (dt, 1H), 2.98 (d, 1H), 2.84 (t, 2H), 2.36 (s, 3H), 2.21 (s, 3H). LRMS Compound 14 l-l5-Cyano-2-(S-morpholin-2-ylmethoxy)-phenyl]-3- (5- methyl-pyrazin-2-yl)-urea Prepared according to the procedure for Compound 1, Steps 4 and 5 using 2-hydroxymethyl-S- morpholine-4-carboxylic acid tert-butyl ester and 4- Compound 16 1- [5~Chloro-4-methoxy-2- (S-morpholin-2-ylraethoxy) - phenyl] -3- (5-methyl-pyrazin-2-yl) -urea Prepared according to the procedures for Compound 1, Steps 4 and 5 using 2-hydroxymethyl-S- morpholine-4-carboxylic acid tert-butyl ester and 4- chloro-5-methoxy-2-nitro-phenol, prepared according to the procedure for Compound 4, Step 2. XH-NMR (300 MHz, de-DMSO) 6 10.11 (s, 1H), 10.05 (br s, 1H) , 8.64 (s, 1H), 8.19 (s, 2H), 6.91 (s, 1H), 4.29 (s, 2H), 4.16 (m, 1H), 4.09 (d, 1H), 3.87 (s, 3H), 3.75 (t, 1H), 3.44-3.17 (m, 2H), 3.01 (t, 2H), 2.39 (s, 3H). LRMS (ES, positive) m/e 408.0 (M+l). Compound 17 1-[5-Dimethylamino-2-(S-morpholin-2-ylmethoxy)-phenyl]-3- (5-methyl-pyrazin-2-yl)-urea Prepared according to the procedure for . Compound 1, Steps 4 and 5 using 2-hydroxymethyl-S- roorpholine-4-carboxylic acid tert-butyl ester and 4- dimethylamino-2-nitro-phenol, prepared according to the procedure for Compound 4, Step 2. JH-NMR (300 MHz, d6- DMSO) 6 10.11 (s, 1H), 10.05 (br s, 1H) , 8.69 (s , 1H), 8.19- (s, 1H), 7.75 (s, 1H), 6.90 (d, 1H) , 6.34 (dd, 1H), 4.05-3.81 (m, 4H), 3.56 (t, 1H), 3.14 (d, 1H), 2.93 (d, 1H) , 2.80 (s, 6H), 2.76-2.63 (m, 2H), 2.41 (s, 3H). LRMS (ES, positive) m/e 387.4 (M+l). Compound 18 1- [5-Bromo-4-methyl-2-S- (morpholin-2-ylmethoxyJ -phenyl] - 3-(5-methyl-pyrazin~2-yl)-urea Prepared according to the procedure for Compound 4, using 4-bromo-5-methyl-2-nitro-phenol, • prepared using the procedure for Compound 4, Step 2. 1H- NMR (300 MHz, d6-DMSO) 6 10.31 (br s, 1H), 10.19 (s, 1H), 8.63 (s, 1H), 8.41 (s, 1H), 8.20 (s, 1H), 7.07 (s, 1H), 4.13-3.94 (m, 3H), 3.87-3.74 (m, 2H), 6 3.52 (td, 1H) , 3.00 (d, 1H), 2.69 (t, 2H), 2.42 (s, 1H), 2.25 (s, 1H) . LRMS (ES, positive) m/e 438.2.0 (M+l). Compound 19 1-[5-Methyl-2- (morpholin-2-ylrnethoxy)-phenyl]-3- (5- methyl-pyrazin-2-yl)-urea Prepared according to the procedure for Compound 3 using 2-hydroxyroethyl-morpholine-4-carboxylic acid tert-butyl ester which was prepared from the corresponding acid according to the procedure for Compound 2, Step 1. :H-NMR (400 MHz, CD3OD) , 8 8.90 (s, 1, H), 8.6 (s, 1, H) , 7.9 is, 1, H), 6.9 (m, 2, H) , 4.2 (m, 4, H), 3.8 (t, 1, H) , 3.7 (s, 2, H) , 3.5 (d, 1, H) , 3.2 (m, 1, H), 2.6 (s, 3, H), 2.3 (s, 3, H) . LRMS (esi, positive) m/e 358.20 (M+l). Compound 20 1-[5-Chloro-2-(morpholin-2-ylmethoxy)-phenyl]-3-(5- methyl-pyrazin-2-yl)-urea Prepared according to the procedure for Compound 3 using 4-chloro-2-nitro-phenol and 2- hydroxymethyl-morpholine-4-carboxylic acid tert-butyl ester which was prepared from the corresponding acid according to the procedure for Compound 2, Step 1. 1H- NMR (400 MHz, CD3OD), 6 8.70 (s, 1, H) , 8.5 (s, 1, H) , 8.4. (s, 1, H), 7.05 (m, 1, H) , 4.2 (m, 4, H) , 3.8 (t, 1, H), 3.5 (d, 1, H), 3.2 (m, 2, H), 2.6 (s, 3, H). LRMS (esi, positive) m/e 378.50 (M+l). Compound 21 1-[5-Chloro-2- (S-morpholin-2-ylmethoxy)-phenyl]-3- (5- methyl-pyrazin-2-yl)-urea Prepared according to the procedure for Compound 4 using 4-chloro-2-nitro-phenol. 1H-NMR (400 MHz, d6-DMSO) 5 10.35 (s, 1, H) , 9.4 (br s, 1, H) , 8.55 (br s, 1, H), 8.25 (m, .2, H), 7.22 (m, 2, H) , 4.2 (m, 3, H), 4 (d, 1, H), 3.8 (t, 1, H), 3.4 (d, 1, H), 3.2 (d, 1, H) , 2.8 (m, 1, H), 2.45 (s, 3, H). LRMS (esi, positive) m/e 378.30 (M+l). Compound 22 l-[5-Methyl-2- (S-morpholin-2-ylmethoxy) -phenyl]-3- (5- methyl-pyrazin-2-yl)-urea Prepared according to the procedure for Compound 4 using (R)-benzyl glycidyl ether and 4-methyl- 2-nitro-phenol. ^-NMR (400 MHz, d6-DMSO) 6 10.20 (s, 1, H) , 10.1 (br s, 1, H), 9.89 (br s, 1, H) , 9.5 (br s, 1, H) , 8.7 (s, 1, H), 8.3 (s, 1,H), 7.98 (s, 1, H), 6.9 (m, 1, H) , 6.8 (m, 1, H) , 4 (m, 3, H), 3.42 (m, 2, H) , 3.19 (m, 2, H), 3 (m, 2, H), 2.43 (s, 3, H) , 2.25 (s, 3, H) . LRMS (esi, positive) ra/e 358.30 (M+l). Compound 23 1-[5-Chloro-2-(R-raorpholin-2-ylmethoxy)-phenyl]-3-(5- methyl-pyrazin-2-yl)-urea Prepared according to the procedure for Compound 4 using (R)-benzyl glycidyl ether and 4-chloro- 2-nitro-phenol. ^-NMR (400 MHz, d6-DMSO) 6 10.45 (s, 1, H), 9.6 (br s, 1, H), 9.3 (br s-, 1, H), 8.7 (-br s, 1, H), 8.3 (s, 1, H), 7.19 (m, 2, ), 4.2 (m, 2, H), 4 (d, 1, H), 3.84 (t, 1, H), 3.41 (d, 1, H) , 3.21 (d, 1, H), 3.02 (nt, 2, H), 2.5 (s, 3, H) LRMS (esi, positive) m/e 378.30 (M+l). Compound 24 1- [5-Chloro-2-R- ([1, 4]oxazepan-2-ylmethoxy) -phenyl] -3- (5- methyl-pyrazin-2-yl)-urea Prepared according to the procedure for Compound 1 using (JR) -2-hydroxymethyl- [1, 4)oxazepane-4- carboxylic acid tert-butyl ester. *H-NMR (300 MHz, d6- DMSO) 5 10.83 (br s, 1H), 8.39 (dd, 1H), 8.18 8.04 (br s, 1H), 6.99 (dd, 1H), 6.82 (d, 1H), 4.25-3.98 (a, 2H), 3.90-3.76 (m, 1H), 3.38 (d, 1H) , 3.13-3.06 (m, 2H), 3.00 (dd, 1H), 2^54 (s, 3H), 2.06-1.89 (m, 3H) . LRMS (ES, positive) m/e 392.3 (M+l). Compound 25 l-[5-Chloro-2-(l-methyl-piperazin-2-ylmethoxy)-phenyl]-3- (5-raethyl-pyrazin-2-yl)-urea Prepared according to the procedure for Compound 7 using 4-chloro-2-nitro-phenol. ^-NMR (400 MHz, ds-DMSO) 5 10.35 (br s, 1, H), 10.2 (s, 1, H), 9.84 (br s, 1, H), 9.6 (s, 1, H>, 8.31 (s, 1, H) , 8.21 (s, 1, H) , 7.08 (m, 2, H), 4.58 (d, 1, H), 4.42 (d, 1, H) , 3.7 (m, 6, H), 3 (s, 3, H), 2.44 (s, 3, H). LRMS (esi, positive) m/e 391.40 (M+l). Compound 26 1-[5-Chloro-2-S-(1-methyl-piperazin-2 -ylmethoxy)- phenyl]-3-(5-methyl-pyrazin-2-yl)-urea Prepared according to the procedure for Compound 7 using S-piperazine-2-carboxylic acid and 4- chloro-2-nitro-phenol. ^-NMR (400 MHz, CD3OD) 5 8.80 (s, 1, H), 8.28 (d, 2, H), 6.99 (s, 2, H), 4.17 (in, 3, H), 3.1 (d, 1, H), 2.92 (d, 2, H), 2.84 (t, 1, H) , 2.5 (s, 3, H) , 2.45 (m, 2, H), 2.42 (s, 3, H). LRMS (esi, positive) m/e 391.30 (M+l). Compound 27 l-[5-Chloro~4-methyl-2-S-( [1,4]-oxazepan-2-ylmethoxy)- phenyl]-3-(5-methyl-pyrazin-2-yl)-urea Prepared according to the procedure for Compound 1 using 4-chloro-5-methyl-2-nitro-phenol which was prepared according to the procedure for Compound 4, Step 2. :H-NMR (300 MHz, d6-DMSO) 5 10.2 (s, 1H) , 8.62 (s, 1H), 8.27 (s, 1H), 8.24 (s, 1H), 7.32 (s, 1H),' 4.09-3.91 (m, 3H), 3.90-3.79 (m, 1H) , 3.77-3.62 (m, 1H), 3.14 (d, 1H), 2.85 (m, 1H), 2.73 (s, 2H), 2.39 (s, 3H), 2.27 (s, 1H), 1.82-1.67 (m, 2H). LRMS (ES, positive) m/e 406.2 (M+l). Compound 28 1- [5-Bromo-2- (S-morpholin-2-ylmethoxy) -phenyl] -3- (5- methyl-pyra zin-2-yl)-urea Prepared according to the procedure for Compound 4 using 4-bromo-2-nitro-phenol. aH-NMR {400 MHz, de-DMSO), 6 10.30 (s, 1, H), 8.63 (br s, 1, H), 8.43 (s, 1, H), 8.22 (s, 1, H), 7.15 (m, 1, H) , 7.05 (d, 1, H), 4.08 (m, 3, H), 3.82 (m, 2, H), 3.47 (t, 1, H), 3.17 (s, 2, H) , 3 (d, 1, H), 3.07 (s, 3, H), 2.68 (ra, 2, H) . LRMS (esi, positive) m/e 423.90 (M+l). Compound 29 1- [5-Bromo-2-R- (R-morpholin-2-ylmethoxy) -phenyl] -3- (5- methyl-pyrazin-2-yl)-urea Prepared according to the procedure for Compound 4 using (R)-benzyl glycidyl ether and 4-brorao-2- nitro-phenol. JH~NMR {400 MHz, d6-DMSO), 5 10.30 (br s, 1, H) , 8.65 (br s, 1, H), 8.43 (s, 1, H), 8.25 (s, 1, H), 7.18 (dd, 1, H), 7.03 (d, 1, H), 4.03 2, H), 3.52 (t, 2, H), 3.19 (d, 1, H) , 3 (d, 1, H) , 2.76 (ra, 2, H), 2.43 (s, 3, H). LRMS (esi, positive) m/e 443.90 (M+l). Compound 30 1-[5-Bromo-2-S- (4-methyl-morpholin-2-ylmethoxy)-phenyl]- 3-(5-methyl-pyrazin-2-yl)-urea Prepared according to the procedure for Compound 4 using 4-bromo-2-nitro-phenol and the procedures for Compound 2, Step 4 and Compound 5, Steps 4 and 5. *H-NMR (400 MHz, CDC13) , 5 11.43 (br s, 1, H), 9.02 (s, 1, H), 8.6 H), 7.12 (d, 1, H), 6.76 (d, 1, H), 4 (m, 3, H) , 3.8 (t, 1, H) , 3.02 (d, 1, H), 2.73 (d, 1, H), 2.51 (s, 3, H), 2.3 (t, 1, H), 2.22 (s, 3, H), 2.08 (t, 1, H) . Compound 31 1- [5-Bromo-2- ([1, 4] oxazepan-2-ylmethoxy)-phenyl] -3-(5- methyl-pyrazin-2-yl)-urea Prepared according to the procedure for Compound 6 using 4-bromo-2-nitro-phenol, which was prepared according to the procedure for Compound 4, Step 2. ^-NMR (400 MHz, CDC13), 5 8.72 (br s, 1, H) , 8.48 (s, 1, H), 8.45 (s, 1, H), 7.11 (d, 1, H), 6.75 (d, 1, H) , 4.02 (m, 3, H), 3.8 (m, 1, H), 3.21 2, H), 2.51 (s, 3, H), 1.92 (br m, 2, H) . LRMS -(esi, positive) m/e 436.00 (M+l). Compound 32 l-[5-Bromo-2- {4-methyl- [1, 4]oxazepan-2-ylmethoxy) - phenyl] -3- (5-methyl-pyrazin-2-yl) -urea Prepared according to the procedure for Compound 6, using 4-bromo-2-nitro-phenol, and by the procedure for Compound 5, Step 5. ^-NMR (400 MHz, CDC13) , 5 8.25 (s, 1, H), 8.23 (s, 1, H), 7.1 6.72 (d, 1, H) , 4.19 (m, 1, H), 4 (m, 1, H) , 3.95 (m, 2, H) , 3.42 (br s, 1, H) , 3.02 (df 1, H), 2.84 (m, 1, H), 2.62 (t, .1, H) , 2.5 (s, 3, H), 2.4 (s, 3, H), 2 (m, 2, H). LRMS (esi, positive) m/e 451.90 (M+l). Compound. 33 1- [5-Chloro-2-S- (4-cyanomethyl-morpholin-2-ylmethoxy) - phenyl]-3-(5-methyl-pyrazin-2-yl)-urea 1-[5-Chloro-2-(S-morpholin-2-ylmethoxy) - phenyl]-3-(5-methyl-pyrazin-2-yl)-urea (0.189 g, 0.5 mmol) was suspended in DMF (2 mL) . Potassium -carbonate (0.104 g, 0.75 mmol) and bromoacetonitrile (0.035 mL, 0.5 mmol) were added and the reaction mixture was heated to 80°C for 8 h. The reaction mixture was allowed to cool to room temperature and quenched by addition of HzO (10 mL). The resulting solid was collected by filtration and recrystallized from MeOH to give the product as a white powder (0.072 g) . ^-NMR (400 MHz, d6-DMSO) 6 10.4€ (br s, 1H), 10.26 (br s, 1H), 8.63 (br s, 1H) , 8.31 (d, 1H), 8.17 (s, 1H), 7.10 (d, 1H), 7.03 (dd, 1H) , 4.14 (dd, 1H), 4.09 (dd, 1H), 3.96-4.01 (m, 1H) , 3.91-3.95 (m, 1H). 3.81 (d, 1H) , 3.72 (d, 1H), 3.64 (td, 1H) , 2.95 2.72 (br d,■1H), 2.43 (s, 3H), 2.32 (td, 1H), 2.18 (t, 1H) . LRMS (esi, positive) m/e 417 (M+l). Compound 34 l-[5-Chloro-2-(thiomorpholin-2-ylmethoxy)-phenyl]-3-(5- methyl-pyrazin-2-yl)-urea Prepared according to the procedure for Compound 2, Step 2 (using 2-hydroxymethyl-thiomorpholine- 4-carboxylic acid tert-butyl ester obtained from thiomorpholine-2,4-dicarboxylic acid 4-tert-butyl ester according to the procedure for Compound 2, Step 1), and the procedures for Compound 3, Step 2 and Compound 2, Steps 4 and 5. lH-NMR (400 MHz, d6-DMSO) 6 10.48 (br s, 1H), 10.27 (br s, 1H), 8.62 (br s, 1H), 8.31 (d, 1H), 8.21 (s, 1H), 7.12 (d, 1H), 7.03 (dd, 1H), 4.36 (t, 1H), 4.12 (dd, 1H), 3.24 (dd, 1H), 3.10-3.17 (m, 1H), 2.99 (dd, 1H), 2.94-2.98 (m, 1H) , 2.89 (ddd, 1H) , 2.71 -(ddd, 1H), 2.46-2.48 (m, 1H), 2.44 (s, 3H). LRMS (esi, positive) m/e 394 (M+l). Compound 35 1- (5-Methyl-pyrazin-2~yl) -3- [3-S- (morpholin-2-ylmethoxy) - 5,6,7, 8-tetrahydro-naphthalen-2-yl]-urea Prepared according to the procedure for Compound 3, Step 1 (using (S)-2-hydroxymethyl-morpholine- 4-carboxylic acid tert-butyl ester prepared from S- morpholine-2,4-dicarboxylic acid 4-tert-butyl ester according to the procedure for Compound 2, Step 1 and 3- nitro-5, 6,7,8-tetrahydro-naphthalen-2-ol, prepared according to the procedure for Compound 4, Step 2, and the procedure for Compound 1, Step 5. 1H-NMR (4 00 MHz, d6-DMSO) 6 10.09 (br,l,H), 10.05 (s,l,H), 8.60 (br s,l,H), 8.17 (s,l,H), 7.86 (s,l,H), 6.68 (s,l,H), 3.97 (m,l,H), 3.89 (m,l,H), 3.78 (m,2,H), 3.31 (t,l,H), 2.98 (d,l,H), 2.63 (m,6,H), 2.44 (m,l,H), 2.41 (s,3,H), 1.68 (m,4,H). Compound. 36 l-[5-Chloro-2-S-(morpholin-3-ylmethoxy)-phenyl]-3-(5- methyl-pyrazin-2-yl)-urea Prepared according to the procedure for Compound 2 using morpholine-3-S-4--dicarboxylic acid 4- tert-butyl ester. ^-NMR (400 MHz, d6-DMSO) 5 10.22 (s,l,H), 9.96 (s,l,H), 7.04 (m,2,H), 3.94 (m,3,H) 3.70 (br d, 1,H), 3.42 (m,l,H), 3.23 (m,2,H), 2.83 (brs,2,H), 2.43 (s,3rH). Compound 37 l-[5-Methyl-2-R- (niorpholin-3-ylmethoxy) -phenyl]-3- (5- methyl-pyrazin-2-yl)-urea Prepared according to the procedure for Compound 2 using 4-methyl-2-nitro-phenol. 1H-NMR (400 MHz, de-DMSO) 5 10.08 (br s,l,H), 9.76 (s,l,H), 8.03 (d,l,H), 6.90 (d,l,H), 6.80 (d,l,H), 3.88 (m,3,H), 3.70 (brd,2,H), 3.41 (m,l,H), 3.20 (m,2,H), 2.82 (m,2,H), 2.43 (s,3,H), 2.24 (s,3,H). Compound 38 1- [5-Chloro-2-S- (morpholin-2-ylmethoxy) -phenyl] -3- (5- trifluororaethyl-pyrazin-2-yl) -urea Prepared according to the procedure for Compound 1, Steps 2 through 5, using 5-trifluoromethyl- pyrazin-2-ylamine prepared according to the method of Miesel U.S. Patent No. 4,293,552 and (S)-2-hydroxymethyl- morpholine-4-carboxylic acid tert-butyl ester. IH-NMR (d6-DMSO) 6 10.85 (bs, 1H), 9.97 (bs, 1H) , 9.11 (bs, 1H), 8.98 (bs, 1H) , 8.73 (bs, 1H), 8.22 (bs, 1H) , 7.08 (bs, 1H), 4.19-3.73 (m, 6H), 3.32-2.98 (m, 4H) . LRMS (esi, positive) m/e 432 (M+l). Compound 39 l-[4-Chloro-5-methyl-2-S-(morpholin-2-ylmethoxy)-phenyl]- 3-(5-cyano-pyrazih-2-yl)-urea Prepared according to the procedures for Compound 5, Steps 1 through 4 using 5-chloro-4-methyl-2- nitro-phenol prepared from 3-chloro-4-methyl-phenol according to the procedure for Compound 4, Step 2. 1H- NMR (300 MHz, CDC13) 6 10.39 (br s, 1H) , 9.05 (br s, 1H), 8.74 (s, 1H), 8.68 (s, 1H), 8.18 (s, 1H), 6.91 {s, 1H), 4.04 (m, 4H), 3.78 (m, 1H), 3.19 (d, 1H) , 2.97 (m, 2H), 2.78 (m, 1H), 2.36 (s, 3H). LCMS (esi, positive) m/z 403.16 (M+l). Compound 40 1-[5-Chloro-4-methoxy-2-(S-morpholin-2-ylmethoxy)- phenyl]-3-(5-cyano-pyrazin-2-yl)-urea Prepared according to the procedure for Compound 1, Step 2 (using 5-amino-pyrazine-2-carbonitrile prepared according to the procedures for Compound 5, Steps 1 and 2) and the procedures for Compound 1, Steps 4 and 5 (using 2-hydroxymethyl-S-morpholine-4-carboxylic acid tert-butyl ester- and 4-chloro-5-raethoxy-2-nitro- phenol, prepared according to the procedure for Compound 4, Step 2). ^-NMR (300 MHz, d6-DMSO) 6 10.82 (s, 1H) , 9.93 (s, 1H) , 8.95 (s, 1H) , 8.81 (s, 1H) , 8.14 (s, 1H), 6.93 (s, 1H) , 4.25 (s, 2H), 4.13-3.98 (m, 2H), 3.83 (s, 3H), 3.61 (t, 1H), 3.41-3.19 LRMS (ES, positive) m/e 419.1 (M+l). Compound 41 1-[5-Chloro-2-S-(morpholin-2-ylmethoxy)-phenyl]-3-(5- cyano-pyrazin-2-yl)-urea Prepared according to the procedure for Compound 1, Step 2 (using 5-amino-pyrazine-2-carbonitrile prepared according to the procedures for Compound 5, Steps 1 and 2) and the procedures for Compound 1, Steps 4 and 5 (using 2-hydroxymethyl-S-morpholine-4-carboxylic acid tert-butyl ester and 4-chloro-2-nitro-phenol) . *H- NMR (d6-DMSO) 5 10.97 (bs, 1H), 10.02 (bs, 1H), 9.05 (bs, 1H), 8.95 (s, 1H), 8.85 (s, 1H), 8.2 (s, 1H), 7.10 (m, 1H), 3.96-4.24 (m, 4H)-, 3.68-3.78 (m, 2H), 3.3 (m, 2H) , 3.0 (m, 2H) . LKMS (esi, positive) m/e 388 (M+l) . Compound 42 1- [5-Chloro-2-S- (4-methyl-morpholin-2-ylmethoxy) -phenyl] - 3-(5-cyano-pyrazin-2-yl)-urea Step 1: l-[5-Chloro-2~(morpholin-2- ylmethoxy) -phenyl ] -3- (5-cyano-pyrazin-2-yl) -urea. Prepared according to the procedure for Compound 1, Step 2 (using 5-amino-pyrazine-2-carbonitrile prepared according to the procedures,for Compound 5, Steps 1 and 2) and the procedures for Compound 1, Steps 4 and 5 (using 2-hydroxymethyl-S-morpholine-4-carboxylic acid tert-butyl ester and 4-chloro-2-nitro-phenol) to give 0.27 g of product. Step 2: l-(5-Chloro~2-(morpholin-2- ylmethoxy)-phenyl]-3-(5-cyano-pyrazin-2-yl)-urea (0.276 g, 0.73 mmol) was suspended in DMF (5 ml) and treated with potassium carbonate (0.15 g, 1.1 mmol) and methyl iodide (0.046 mL, 0.73 mmol). The mixture became homogeneous and was stirred at room temperature for 4 h. The reaction was quenched with the addition of water (20 mL) and extracted with a 3:1 mixture of CHCl3:iPrOH (3 x 25 mL) . The combined organic layers were concentrated • under reduced pressure and the residue was triturated with EtOAc. Filtration provided 0.214 g of the product as a white solid. ^-NMR (300 MHz, d«-DMSO) 6 11.01 (s, 1H) , 10.16 (s, 1H), 8.86 (d, 2H) , 8.27 (d, 1H) , 8.17 (s, 1H) , 7.18 (m, 2H), 4.25-4.06 (m, 2H), 3.95 (m, 1H) , 3.83 (d, 1H), 3.61 (t, 1H), 2.89 (d, 1H) , 2.65 (d, 1H), 2.18 (s, 3H) , 2.02 (td, 1H), 1.83 (t, 1H). LRMS (ES, positive) m/e 403.0 (M+l). Compound 43 1- [5-Chloro-2- (S-4-methyl-morpholin-2-ylmethoxy) -phenyl]- 3-(5-methyl-pyrazin-2-yl)-urea Prepared according to the procedure for Compound 42, Step 2 using 1-[5-chloro-2- morpholin-2-ylmethoxy)-phenyl]-3- urea. *H-NMR (300 MHz, d€-DMSO) 6 10.54 (br s, 1H), 10.24 (s, 1H), 8.73 (s, 1H), 8.30 (s, 1H), 8.27 (s, 1H), 7.12- 6.93 (m, 2H), 4.17-3.81 (m, 4H), 3.59 (t, 1H), 3.91 (d, 1H) , 2.64 (d, 1H), 2.43 (s, 3H), 2.18 (s, 3H), 2.03

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3561-KOLNP-2007-(05-08-2013)-ABSTRACT.pdf

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3561-KOLNP-2007-(05-08-2013)-CLAIMS.pdf

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3561-KOLNP-2007-(05-08-2013)-PETITION UNDER RULE 137-1.pdf

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3561-KOLNP-2007-(18-02-2013)-CORRESPONDENCE.pdf

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3561-KOLNP-2007-(25-02-2014)-ASSIGNMENT.pdf

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3561-KOLNP-2007-EXAMINATION REPORT.pdf

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3561-KOLNP-2007-INTERNATIONAL PUBLICATION.pdf

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