PYRIMIDINE DERIVATIVES FOR THE TREATMENT OF ABNORMAL CELL GROWTH Background of the Invention This invention relates to novel pyrimidine derivatives that are useful in the treatment of abnormal cell growth, such as cancer, in mammals. This invention also relates to a method of using such compounds in the treatment of abnormal cell growth in mammals, especially humans, and to pharmaceutical compositions containing such compounds. It is known that a cell may become cancerous by virtue of the transformation of a portion of its DNA into an oncogene (Le1, a gene which, on activation, leads to the formation of malignant tumor cells). Many oncogenes encode proteins that are aberrant tyrosine kinases capable of causing cell transformation. Alternatively, the overexpression of a normal proto- oncogenic tyrosine kinase may also result in proliferative disorders, sometimes resulting in a malignant phenotype. Receptor tyrosine kinases are enzymes which span the cell membrane and possess an extracellular binding domain for growth factors such as epidermal growth factor, a transmembrane domain, and an intracellular portion which functions as a kinase to phosphorylate specific tyrosine residues in proteins and hence to influence cell proliferation. Other receptor tyrosine kinases include c-erbB-2, c-met, tie-2, PDGFr, FGFr, and VEGFR. It is known that such kinases are frequently aberrantly expressed in common human cancers such as breast cancer, gastrointestinal cancer such as colon, rectal or stomach cancer, leukemia, and ovarian, bronchial or pancreatic cancer. It has also been shown that epidermal growth factor receptor (EGFR), which possesses tyrosine kinase activity, is mutated and/or overexpressed in many human cancers such as brain, lung, squamous cell, bladder, gastric, breast, head and neck, oesophageal, gynecological and thyroid tumors. Accordingly, it has been recognized that inhibitors of receptor tyrosine kinases are useful as selective inhibitors of the growth of mammalian cancer cells. For example, erbstatin, a tyrosine kinase inhibitor, selectively attenuates the growth in athymic nude mice of a transplanted human mammary carcinoma that expresses epidermal growth factor receptor tyrosine kinase (EGFR) but is without effect on the growth of another carcinoma that does not express the EGF receptor. Thus, selective inhibitors of certain receptor tyrosine kinases, are useful in the treatment of abnormal cell growth, in particular cancer, in mammals. In addition to receptor tyrosine kinses, selective inhibitors of certain non-receptor tyrosine kinases, such as FAK (focal adhesion kinase), lck, src, abl or serine/threonine kinases (e.g., cyclin dependent kinases), are useful in the treatment of abnormal cell growth, in particular cancer, in mammals. FAK is also known as the Protein-Tyrosine Kinase 2, PTK2. Convincing evidence suggests that FAK, a cytoplasmic, non-receptor tyrosine kinase, plays an essential role in cell-matrix signal transduction pathways (Clark and Brugge 1995, Science 268: 233-239) and its aberrant activation is associated with an increase in the metastatic potential of tumors (Owens et al. 1995, Cancer Research 55: 2752-2755). FAK was originally identified as a 125 kDa protein highly tyrosine-phosphorylated in cells transformed by v-Src. FAK was subsequently found to be a tyrosine kinase that localizes to focal adhesions, which are contact points between cultured cells and their underlying substratum and sites of intense tyrosine phosphorylation. FAK is phosphorylated and, thus, activated in response to extracellular matrix (ECM)-binding to integrins. Recently, studies have demonstrated that an increase in FAK mRNA levels accompanied invasive transformation of tumors and attenuation of the expression of FAK (through the use of antisense oligonucleotides) induces apoptosis in tumor cells (Xu et al. 1996, Cell Growth and Diff. 7: 413-418). In addition to being expressed in most tissue types, FAK is found at elevated levels in most human cancers, particularly in highly invasive metastases. Various compounds, such as styrene derivatives, have also been shown to possess tyrosine kinase inhibitory properties. Five European patent publications, namely EP 0 566 226 A1 (published October 20, 1993), EP 0 602 851 A1 (published June 22, 1994), EP 0 635 507 A1 (published January 25, 1995), EP 0 635 498 A1 (published January 25, 1995), and EP 0 520 722 A1 (published December 30, 1992), refer to certain bicyclic derivatives, in particular quinazoline derivatives, as possessing anti-cancer properties that result from their tyrosine kinase inhibitory properties. Also, World Patent Application WO 92/20642 (published November 26, 1992), refers to certain bis-mono and bicyclic aryl and heteroaryl compounds as tyrosine kinase inhibitors that are useful in inhibiting abnormal cell proliferation. World Patent Applications WO96/16960 (published June 6, 1996), WO 96/09294 (published March 6, 1996), WO 97/30034 (published August 21, 1997), WO 98/02434 (published January 22, 1998), WO 98/02437 (published January 22, 1998), and WO 98/02438 (published January 22, 1998), also refer to substituted bicyclic heteroaromatic derivatives as tyrosine kinase inhibitors that are useful for the same purpose. In addition, the following list of publications relate to bis-mono and bicyclic aryl and heteroaryl compounds that may optionally be used as tyrosine kinase inhibitors: WO 03/030909, WO 03/032997, US Patent Application No. 2003/0181474, US Patent Application No. 2003/0162802, US Patent No. 5,863,924, WO 03/078404, US Patent No. 4,507146, WO 99/41253, WO 01/72744, WO 02/48133, US Patent Application No. 2002/156087, WO 02/102783, and WO 03/063794. U.S. Patent Application Serial No. 10/734,039, filed December 11 , 2003 (Attorney Docket No. PC25339A) relates to a broad class of novel pyrimidine derivatives that are kinase inhibitors, and more specifically, inhibitors of FAK. Moreover, U.S. Patent Application Serial No. 10/733,215, filed December 11 , 2003 (Attorney Docket No. PC25937A) relate more specifically to a subset of pyrimidine derivatives, i.e., those bearing a 5-aminooxindole, which are tyrosine kinase inhibitors, and more particularly, FAK inhibitors. Compounds such as these are useful in the treatment of abnormal cell growth. Accordingly, a need exists for additional selective inhibitors of certain receptor and non¬ receptor tyrosine kinases, useful in the treatment of abnormal cell growth, such as cancer, in mammals. The present invention provides novel pyrimidine derivatives that are kinase inhibitors and inhibitors of the non-receptor tyrosine kinase, FAK, and are useful in the treatment of abnormal cell growth. Summary of the Invention The present invention relates to a compound of the formula 1

1 or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof, wherein Ar is selected from:

and ring B is selected from the group consisting of:

wherein m is an integer from 0 to 2, Ra is a substituent attached to any aromatic carbon capable of substitution, wherein Ra is selected from the group consisting of hydrogen, halogen, hydroxy, -CF3, -CN, -(C1- Cβ)alkyl, -NR5R5, -OR12, -(C3-C7)cycloalkyl, -(C2-C9)heterocyclyl, -CO2R12, -CONR5R6 and- CONR5R8; Rb is a substituent selected from the group consisting of hydrogen, -(CrCβJalkyl, -(C3-C7)cycloalkyl, -(C2-C9)heterocyclyl, -CO2R12, and -CONR5R6; wherein n is an integer from 1 to 3; each R1 is a substituent independently selected from the group consisting of hydrogen, hydroxy, -(CrC6)alkyI, -(C3-C7)cycloalkyl, -(C2-C9)heterocyclyl, -O(C1-C6)alkyl, -O(C3-C7)cycloaIkyl, -0(C2-C9)heterocyclyl, -NR5R6, -SR7, -SOR7, -SO2R7, -CO2R12, -CONR5R6, -SO2NR5R6, -NHCOR12, -NR12CONR5R6, and -NR12SO2R7; wherein said R1 substituents, -(CrC6)alkyl, -(C3-C7)cycloalkyl, -(C2-C9)heterocyclyl, -O(C1-C6)alkyl, -0(C3- C7)cycloalkyl, -O(C2-C9)heterocyclyl, -NR5R6, -SR7, -SOR7, -SO2R7, -CO2R12, -CONR5R6, -SO2NR5R6, -NHCOR12, -NR12CONR5R6, and -NR12SO2R7, are optionally substituted by one to three moieties independently selected from the group consisting of hydrogen, halogen, hydroxy, -CF3, -CN, -(CrC6)alkyl, -NR5R6, -OR12, -(C3-C7)cycloalkyl, -(C2-C9)heterocyclyl, -CO2R12, -CONR5R6 and-CONR5Rβ; each R2 is a substituent independently selected from the group consisting of hydrogen, -(CrC6)alkyl, -(C2-C6)alkenyl, -(C2-C6)alkynyl, -(C3-C7)cycloalkyl, -(C2- C9)heterocyclyl, -CO2R12, and -CONR5R6; wherein said R2 substituents, -(C1-C6)alkyl, -(C2- C6)alkenyl, -(C2-C6)alkynyl, -(C3-C7)cycloalkyl, -(C2-C9)heterocyclyl, -CO2R12, and -CONR5R6, are optionally substituted by one to three moieties independently selected from the group consisting of hydrogen, halogen, hydroxy, -CF3, -NO2, -CN, -(CrCfOalkyl, -(C2-C6)alkenyl, -(C2-C6)alkynyl, -C=N-OH, -C=N-O((CrC6)alkyl), -NR5R6, -OR12, -(C3-C7)cycloalkyl, -(C2- C9)heterocyclyl, -CO2R12, -CONR5R6, -CONR5R8, -SR7, -SOR7, -SO2R7, -SO2NR5R6, -NHCOR12, -NR12CONR5R6, and -NR12SO2R7, wherein said -(C2-C6)alkenyl and -(C2- C6)alkynyl R2 moieties may be optionally substituted by one to three R12 groups; R1 and R2 may be taken together with the atom(s) to which they are attached to form a cyclic group, -(C3-C10)cycloalkyl or -(C2-C9)heterocyclyl, wherein said cyclic group is optionally substituted by one to three moieties independently selected from the group consisting of hydrogen, halogen, hydroxy, -CF3, -NO2, -CN, -(CrC6)alkyl, -(C2-C6)alkenyl, -(C2-C6)alkynyl, -C=N-OH, -C=N-O((C1-C6)alkyl), -NR5R6, -OR12, -(C3-C7)cycloalkyl, -(C2- C9)heterocyclyl, -CO2R12, -CONR5R6, -CONR5R8, -SR7, -SOR7, -SO2R7, -SO2NR5R6, -NHCOR12, -NR12CONR5R6, and -NR12SO2R7, wherein said -(C2-C6)alkenyl and -(C2- C6)alkynyl moieties of said cyclic group may be optionally substituted by one to three R12 groups, and said cyclic group is optionally interrupted by one to three elements selected from the group consisting of -(C=O), -SO2, -S-, -0-, -N-, -NH- and -NR12; R3 is a substituent selected from the group consisting of: (a) hydrogen; (b) -(C6-C10)aryl or -(C1-C9)HeIeTOaPyI, optionally substituted by one to three moieties independently selected from the group consisting of halogen, hydroxy, -(CrC6)alkyl, -(C1-C6)alkyl-P(O)(O(C1-C6)alkyl)2, -(C3-C10)cycloalkyl, (C6-C10)aryl, (C2-C9)heterocyclyl, -(CrC9)heteroaryl, -NR5R6, -NHSO2(C1- C6)alkyl, -NHSO2(C3-C6)cycloalkyl , -N((C1-C6)alkyl)(SO2-C1-C6)alkyl), -N((Cr C6)alkyl)(SO2(C3-C6)cycloalkyi), -N((C3-C6)cycloalkyl)(SO2-C1-C6)alkyl), -N((C3-C6)cycloalkyl)(SO2(C3-C6)cycloalkyl), -Otd-QOalkyl, -0-SO2(C1- C6)alkyl, -O-SO2(C3-C6)cycloalkyl, -(CO)(C1-C6)alkyl, -(CO)CF3, -(CO)(C3- C10)cycloalkyl, -(CO)(C6-C 10)aryl, -(CO)(C2-C9)heterocyclyl, -(CO)(C1- C9)heteroaryl, -(CO)O(CrC6)alkyl, -(CO)O(C3-C10)cycloalkyl, -(CO)O(C6- C10)aryl, -(CO)O(C2-C9)heterocyclyl, -(CO)0(CrC9)heteroaryl, -(CO)(C1- C6)alkyl-O(CrC6)alkyl, -SO2(CrC6)alkyl, -SO2(C3-C6)cycloalkyl, SO2CF3, SO2NH2, SO2NH(C1-C6)alkyl, -SO2NH(C3-C6)cycloalkyI, -SO2N((CrC6)alkyl)2, SO2N((C1-C6)alkyl)((C3-C6)cycloalkyl), -S02N((C3-C6)cycloalkyl)2 and -SO2NR5R6, wherein said -(C6-C10) aryl or -(C1-C9) heteroaryl are optionally interrupted by one to three elements selected from the group consisting of -S-, -0-, -N-, -NH- and -NR12; (c) -(C3-C10)cycloalkyl, -(C2-C9)heterocyclyl, and -(CrC6)aikyl-(C2-C9) heterocyclyl, optionally substituted by one to three moieties independently selected from the group consisting of halogen, hydroxy, -(C1- C6)alkyl-P(O)(O(C1-C6)alkyl)2, -(C3-C10)cycloalkyl, (C6-C10)aryl, (C2- C9)heterocyclyl, -(CrC9)heteroaryl, -NR5R6, -NSO2(C1-C6)alkyl, -NHSO2(C3- C6)cycloalkyl, -N((C1-C6)alkyl)(SO2-C1-C6)alkyl), -N((CrC6)alkyl)(SO2(C3- C6)cycloalkyl), -N((C3-C6)cycloalkyl)(S02-C1-C6)alkyl), -N((C3- C6)cycIoalkyl)(S02(C3-C6)cycloalkyl), -O(CrC6)alkyl, -O-SO^CrCeJalkyl, -O- SO2(CrC6)alkyl, -O-SO2(C3-C6)cycloalkyl, -(CO)(C1-C6)alkyl, -(CO)CF3, -(CO)(C3-C10)cycloalkyl, -(CO)(C6-C10)aryl, -(CO)(C2-C9)heterocyclyl, -(CO)(CrC9)heteroaryl, -(CO)O(CrC6)alkyl, -(CO)O(C3-C10)cycloalkyl, -(CO)O(C6-C10)aryl, -(CO)O(C2-C9)heterocyclyl, -(CO)O(CrC9)heteroary!, -(CO)(C1-C6)alkyl-O(C1-C6)alkyl, -SO2(C1-C6)alkyl, -SO2(C3-C6)cycloalkyl, SO2CF3, SO2NH2, SO2NH(C1-C6)alkyl, -S02NH(C3-C6)cycloalkyl, -SO2Nt(C1- C6)alkyl)2, SO2N((C1-C6)alkyl)((C3-C6)cycloalkyl), -S02N((C3-C6)cycloaIkyl)2 and -SO2NR5R6,; wherein said -(C3-C10)cycloalkyl, -(C2-C9)heterocyclyl, and -(C1-C6)alkyl-(C2-C9) heterocyclyl are optionally interrupted by one to three elements selected from the group consisting of -(C=O), -SO2, -S-, -0-, -N-, -NH- and -NR12; (d) -(CrC6)aIkyl optionally substituted by one to three moieties selected from the group consisting of halogen, hydroxy, -(Ci-C6)alkyl, -(C1-C6)alkyl-P(O)(O(C1- C6)alkyl)2, -(C3-C10)cycloalkyl, (C6-C10)aryl, (C2-C9)heterocyclyl, -(C1- C9)heteroaryl, -NR5R6, -NHSO2(CrC6)alkyl, -NHS02(C3-C6)cycloalkyl, -N((Cr C6)alkyl)(SO2-CrC6)alkyl), -N((C1-C6)alkyl)(SO2(C3-C6)cycIoalkyl), -N((C3- C6)cycloalkyl)(SO2-CrC6)alkyl), -N((C3-C6)cycloalkyl)(SO2(C3-C6)cycloalkyl), -O(CrC6)alkyl, -O-SO2(C1-C6)alkyl, -O-SO^Cs-^cycloalkyl, -(CO)(C1- C6)alkyl, -(CO)CF3, -(CO)(C3-C10)cycloalkyl, -(CO)(C6-C10)aryl, -(CO)(C2- C9)heterocyclyl, -(CO)(C1 -C9)heteroaryl, -(CO)O(C1-C6)alkyl, -(CO)O(C3- C10)cycloalkyl, -(CO)O(C6-C10)aryl, -(CO)O(C2-C9)heterocyclyl, -(CO)O(C1- C9)heteroaryl, -(CO)(C1-C6)alkyl-O(C1-C6)alkyl, -SO2(CrC6)alkyl, -SO2(C3- C6)cycloalkyl, SO2CF3, SO2NH2, SO2NH(CrC6)alkyl, -SO2NH(C3- C6)cycloalkyl, -SO2N((CrC6)alkyl)2, SO2N((C1-C6)alkyl)((C3-C6)cycloalkyl), -SO2N((C3-C6)cycloalkyl)2 and -SO2NR5R6, wherein said -(C.,-C6)alkyl is optionally interrupted by one to three elements selected from the group consisting Of -(C=O), -SO2, -S-, -0-, -N-, -NH- and -NR12; and wherein each R3 (b)-(d) substituent, moiety, or element is optionally substituted by one to three radicals independently selected from the group consisting of hydrogen, halogen, hydroxy, -CF3, -NO2, -CN, -(CrC6)alkyl, -(C2-C6)alkenyl, -(C2-C6)alkynyl, -(C3- C7)cycloalkyl, -(C2-C9)heterocyclyl, -(C6-C10)aryl, -(CrC9)heteroaryl, -O(CrC6)alkyl, -0(C3- C7)cycloalkyl, -O(C2-C9)heterocyclyl, -C=N-OH, -C=N-O(C1-C6 alkyl), -NR5R6, -SR7, -SOR7, -SO2R7, -CO2R12, -CONR5R6, - SO2NR5R6, -NHCOR5, -NR12CONR5R6, and -NR12SO2R7; and wherein R5 and R6 of said -CONR5R6, -SO2NR5R6, and -NR12CONR5R6 groups may be taken together with the atoms to which they are attached to form a -(C2-C9)heterocyclyl; R4 is a substituent selected from the group consisting of hydrogen, (Ci-C6)alkyl, -(C3- C7)cycloalkyl, and -(C2-C9)heterocyclyl; wherein said (CrC^alkyl, -(C3-C7)cycloalkyl, and -(C2- C9)heterocyclyl R4 substituents are optionally substituted by one to three moieties independently selected from the group consisting of hydrogen, halogen, hydroxyl, -(C1- C6)alkyl, -CN, -NR5R6, -OR5, -(C3-C7)cycloalkyl, -(C2-C9)heterocyclyl, -CO2R12, and -CONR5R8; wherein R5 and R8 of said -CONR5R8 group may be taken together with the atoms to which they are attached to form a -(C2-C9)heterocyclyl; R5 and R6 are each substituents independently selected from the group consisting of hydrogen, -(C1-C6)alkyl, -(C3-C7)cycloalkyl, -(C2-C9)heterocyclyl, -(C6-C10)aryl, and -(C1- C9)heteroaryl; wherein said -(Ci-C6)alkyl, -(C3-C7)cycloalkyl, -(C2-C9)heterocyclyl, -(C6- C10)aryl, and -(CrC9)heteroaryl R5 or R6 substituents are optionally substituted by one to three moieties independently selected from the group consisting of hydrogen, halogen, -CF3, -CN, -(CrCfOalkyl, -NH(C1-C6)alkyl, -NH(C3-C7)cycloalkyl, -NH(C2-C9)heterocyclyl, -NH(C6- C10)aryl, -NH(C1-C9)heteroaryl, -N((C1-C6)alkyl)2, -N((C3-C7)cycloalkyl)2, -N((C2- C9)heterocyclyl)2, -N((C6-C10)aryl)2, -N((C1-C9)heteroaryl)2 , -O(C1-C6)alkyl, -0(C3- C7)cycloalkyl, -O(C2-C9)heterocyclyl, -O(C6-C10)aryl, -O(CrC9)heteroaryl, -(C3-C7)cycloalkyl, -(C2-C9)heterocyclyl, -CO2R7, -CONH2, -CONHR7, and -CONR7R8; wherein R7 and R8 of said -CONR7R8 group may be taken together with the nitrogen atom to which they are attached to form a -(C2-Cg) heterocyclyl; R5 and R6 may be taken together with the atom(s) to which they are attached to form a -(C2-C9)heterocyclyl, wherein said -(C2-C9)heterocyciyl group is optionally substituted by one to three moieties selected from the group consisting of hydrogen, halogen, hydroxy, -CF3, -NO2, -CN, -(d-CβJalkyl, -(C2-C6)alkenyl, -(C2-C6)alkynyl, -C=N-OH, -C=N-0((d- C6)alkyl), -NR7R8, -OR12, -(C3-C7)cycloalkyl, -(C2-C9)heterocyclyl, -CO2R12, -CONR7R8, -CONR5R8, -SR7, -SOR7, -SO2R7, -SO2NR7R8, -NHCOR12, -NR12CONR7R8, and -NR12SO2R7, wherein said -(C2-C6)alkenyl and -(C2-C6)alkynyl moieties of said -(C2-C9)heterocyclyl group may be optionally substituted by one to three R7 groups, and said -(C2-C9)Ii eterocyclyl group is optionally interrupted by one to three elements selected from the group consisting of -(C=O), -SO2, -S-, -O-, -N-, -NH- and -NR12; R7 is a substituent selected from the group consisting of -(d-C^alkyl, -(C3- C7)cycloalkyl, -(C2-C9)heterocyclyl, -(C6-C10)aryl, and -(C1-C9) heteroaryl; wherein said -(C1- C6)alkyl, -(C3-C7)cycloalkyl, -(C2-C9)heterocyclyl, -(C6-C10)aryl, and -(C1-C9) heteroaryl R7 substituents are optionally substituted by one to three moieties independently selected from the group consisting of hydrogen, halogen, hydroxy, -CN, -(CrC6)alkyl, -NR122, and -0(C1- C6)alkyl; R8 is a substituent selected from the group consisting of hydrogen, -(d-CβJalkyl, -(C3- C7)cycloalkyl, -(C2-C9)heterocyclyl, -(C6-C10)aryl, and -(C1-C9) heteroaryl; wherein said -(C1- C6)alkyl, -(C3-C7)cycloalkyl, -(C2-C9)heterocyclyl, -(C6-C10)aryl, and -(C1-C9) heteroaryl R8 radicals are optionally substituted by one to three moieties independently selected from the group consisting of hydrogen, halogen, hydroxy, -CN, -(CrC6)alkyl, -NH2, -NHR9, -NR92, OR9, -(C3-C7)cycloalkyl, -(C2-C9)heterocyclyl, -CO2R10, -CONH2, -CONHR10, and -CONR10R11; wherein R10 and R11 of -CONR10R11 may be taken together with the nitrogen atom to which they are attached to form a -(C2-C9)heterocyclyl; R9 and R10 are each -(d-CfOalkyl; R11 is hydrogen or -(CτC6)alkyl; and R12 is a substituent selected from the group consisting of hydrogen, -(Ci-C6)alkyl, -(C3-C7)cycloalkyl, -(C2-C9)heterocyclyl, -(C6-C10)aryl, and -(CrC9)heteroaryl; wherein said -(CrC6)alkyl, -(C3-C7)cycloalkyl, -(C2-C9)heterocyclyl, -(C6-C10)aryl, and -(CrC9)heteroaryl R12 substituent is optionally substituted by one to three moieties independently selected from the group consisting of hydrogen, halogen, -CF3, -CN, -(d-C^alkyl, -NHζC-pCeJalkyl, -NH(C3- C7)cycloalkyl, -NH(C2-C9)heterocyclyl, -NH(C6-C10)aryl, -NH(C1-C9)heteroaryl, -N(CC1- C6)alkyl)2, -N((C3-C7)cycloalkyl)2> -N((C2-C9)heterocyclyl)2, -N((C6-C10)aryl)2, -N((Cr C9)heteroaryl)2 , -O(CrC6)alkyI, -O(C3-C7)cycloaIkyl, -O(C2-C9)heterocyclyl, -O(C6-C10)aryl, -OCCrCgJheteroaryl, -(C3-C7)cycloalkyl, -(C2-C9)heterocyclyl, -CO2R7, -CONH2, -CONHR7, and -CONR7R8; wherein R7 and R8 of said -CONR7R8 group may be taken together with the atoms to which they are attached to form a -(C2-C9) heterocyclyl. In another embodiment, the present invention relates to a compound of the formula 2

or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof, wherein Ar is selected from:

and ring B is selected from the group consisting of:

wherein n is an integer from 1 to 3; each R1 is a substituent independently selected from the group consisting of hydrogen, hydroxy, -(CrC6)alkyl, -(C3-C7)cycloalkyl, -(C2-C9)heterocyclyl, -0[Ct-C6)SAWyI, -O(C3-C7)cycloalkyl, -O(C2-C9)heterocyclyl, -NR5R6, -SR7, -SOR7, -SO2R7, -CO2R12, -CONR5R6, -SO2NR5R6, -NHCOR12, -NR12CONR5R6, and -NR12SO2R7; wherein said R1 substituents, -(C^-C6)a\Wy\, -(C3-C7)cycloalkyl, -(C2-C9)heterocyclyl, -O(CrC6)alkyl, -O(C3- C7)cycloalkyl, -0(C2-C9)heterocyclyl, -NR5R6, -SR7, -SOR7, -SO2R7, -CO2R12, -CONR5R6, -SO2NR5R6, -NHCOR12, -NR12CONR5R6, and -NR12SO2R7, are optionally substituted by one to three moieties independently selected from the group consisting of hydrogen, halogen, hydroxy, -CF3, -CN, -(CrC6)alkyI, -NR5R6, -OR12, -(C3-C7)cycloalkyl, -(C2-C9)heterocyclyl, -CO2R12, -CONR5R6 and-CONR5R8; each R2 is a substituent independently selected from the group consisting of hydrogen, -(CrC6)alkyl, -(C2-C6)alkenyl, -(C2-C6)alkynyl, -(C3-C7)cycloalkyl, -(C2- C9)heterocyclyl, -CO2R12, and -CONR5R6; wherein said R2 substituents, -(CrC6)alkyl, -(C2- C6)alkenyl, -(C2-C6)alkynyl, -(C3-C7)cycloalkyl, -(C2-C9)heterocyclyl, -CO2R12, and -CONR5R6, are optionally substituted by one to three moieties independently selected from the group consisting of hydrogen, halogen, hydroxy, -CF3, -NO2, -CN, -(C1-C6)alkyl, -(C2-C6)alkenyl, -(C2-C6)aikynyl, -C=N-OH, -C=N-O((CrC6)alkyl), -NR5R6, -OR12, -(C3-C7)cycloalkyl, -(C2- C9)heterocyclyl, -CO2R12, -CONR5R6, -CONR5R8, -SR7, -SOR7, -SO2R7, -SO2NR5R6, -NHCOR12, -NR12CONR5R6, and -NR12SO2R7, wherein said -(C2-C6)alkenyl and -(C2- C6)alkynyl R2 moieties may be optionally substituted by one to three R12 groups; R1 and R2 may be taken together with the atom(s) to which they are attached to form a cyclic group, -(C3-C10)cycloalkyl or -(C2-C9)heterocyclyl, wherein said cyclic group is optionally substituted by one to three moieties independently selected from the group consisting of hydrogen, halogen, hydroxy, -CF3, -NO2, -CN, -(CrC^alkyl, -(C2-C6)alkenyl, -(C2-C6)alkynyl, -C=N-OH, -C=N-O((C1-C6)alkyl), -NR5R6, -OR12, -(C3-C7)cycloaikyl, -(C2- C9)heterocyclyl, -CO2R12, -CONR5R6, -CONR5R8, -SR7, -SOR7, -SO2R7, -SO2NR5R6, -NHCOR12, -NR12CONR5R6, and -NR12SO2R7, wherein said -(C2-C6)alkenyl and -(C2- C6)alkynyl moieties of said cyclic group may be optionally substituted by one to three R12 groups, and said cyclic group is optionally interrupted by one to three elements selected from the group consisting Of -(C=O), -SO2, -S-, -0-, -N-, -NH- and -NR12; R3 is a substituent selected from the group consisting of: (a) hydrogen; (c) -(C6-C10)aryl or -(CrCgJheteroaryl, optionally substituted by one to three moieties independently selected from the group consisting of halogen, hydroxy, -(CrC6)alkyl, -(C1-C6)alkyl-P(O)(O(C1-C6)alkyl)2, -(C3-C10)cycloalkyl, (C6-C1o)aryl, (C2-C9)heterocyclyl, -(C1-C9)heteroaryl, -NR5R6, -NHSO2(C1- C6)alkyl, -NHSO2(C3-C6)cycloalkyl , -N((CrC6)alkyl)(SO2-CrC6)alkyl), -N((Cr C6)alkyl)(SO2(C3-C6)cycloalkyl), -N((C3-C6)cycloalkyl)(SO2-CrC6)alkyl), -N((C3-C6)cycloalkyl)(SO2(C3-C6)cycloalkyl), -O(CrC6)alkyl, -0-SO2(C1- C6)alkyl, -O-SO2(C3-C6)cycloalkyl, -(CO)(CrC6)alkyl, -(CO)CF3, -(CO)(C3- C10)cycloalkyl, -(CO)(C6-C10)aryl, -(CO)(C2-C9)heterocyclyl, -(CO)(C1- C9)heteroaryl, -(COPtCrCeJalkyl, -(CO)O(C3-C10)cycloalkyl, -(CO)O(C6- C10)aryl, -(CO)O(C2-C9)heterocyclyl, -(CO)O(C1-C9)heteroaryl, -(CO)(C1- C6)alkyl-O(CrC6)alkyl, -SO2(CrC6)alkyl, -SO2(C3-C6)cycloalkyl, SO2CF3, SO2NH2, SO2NH(CrC6)alkyl, -SO2NH(C3-C6)cycloalkyl, -SO2N((C1-C6)alkyl)2, SO2N((C1-C3)alkyl)((C3-C6)cycloalkyl), -SO2N((C3-C6)cycloalkyl)2 and -SO2NR5R6, wherein said -(C6-C10) aryl or -(C1-C9) heteroaryl are optionally interrupted by one to three elements selected from the group consisting of -S- , -O-, -N-, -NH- and -NR12; (c) -(C3-C10)cycloalkyl, -(C2-C9)heterocyclyl, and -(CrC6)alkyl-(C2-C9) heterocyclyl, optionally substituted by one to three moieties independently selected from the group consisting of halogen, hydroxy, -(C1-C6)alkyl, -(C1- C6)alkyl-P(O)(O(C1-C6)alkyl)2, -(C3-C10)cycloalkyl, (C6-C10)aryl, (C2- C9)heterocyclyl, -(d-C9)heteroaryl, -NR5R6, -NSO2(CrC6)alkyl, -NHSO2(C3- C6)cycloalkyl, -N((C1-Cβ)alkyl)(Sθ2-C1-C6)alkyl), -N((C1-C6)alkyl)(SO2(C3- C6)cycloalkyl), -N((C3-C6)cycloalkyl)(SO2-C1-C6)alkyl), -N((C3- C6)cycloalkyl)(SO2(C3-C6)cycloalkyl), -O(d-C6)alkyl, -O-SO2(C1-C6)alkyl, -O- SO2(C1-C6)alkyl, -0-S02(C3-C6)cycloaikyl, -(CO)(C1-C6)alkyl, -(CO)CF3, -(CO)(C3-C10)cycloalkyl, -(CO)(Cβ-C10)aryl, -(CO)(C2-C9)heterocyclyl, -(CO)(CrC9)heteroaryl, -(CO)O(CrC6)alkyl, -(CO)O(C3-C10)cycloalkyl, -(CO)O(C6-C10)aryl, -(CO)O(C2-C9)heterocyclyl, -(CO)O(C1-C9)heteroaryl, -(CO)(C1-C6)alkyl-O(C1-C6)alkyl, -SO2(C1-C6)alkyl, -SO2(C3-C6)cycloalkyl, SO2CF3, SO2NH2, SO2NH(CrC6)alkyl, -S02NH(C3-C6)cycloalkyl, -SO2N((C1- C6)alkyl)2, SO2N((C1-C6)alkyl)((C3-C6)cycloalkyl), -SO2N((C3-C6)cycloalkyI)2 and -SO2NR5R6,; wherein said -(C3-C10)cycloalkyl, -(C2-C9)heterocyclyl, and -(C1-C6)alkyl-(C2-C9) heterocyclyl are optionally interrupted by one to three elements selected from the group consisting of -(C=O), -SO2, -S-, -O-, -N-, -NH- and -NR12; (d) -(d-C6)alkyl optionally substituted by one to three moieties selected from the group consisting of halogen, hydroxy, -(d-C6)alkyl, -(C1-C6)alkyl-P(O)(O(C1- C6)alkyl)2, -(C3-C10)cycloalkyl, (C6-C10)aryl, (C2-C9)heterocyclyl, -(C1- C9)heteroaryl, -NR5R6, -NHSO2(d-C6)alkyl, -NHSO2(C3-C6)cycloalkyl, -N((Cr C6)alkyl)(SO2-C1-C6)alkyl), -N((CrC6)alkyl)(S02(C3-C6)cycloalkyl), -N((C3- C6)cycloalkyl)(SO2-CrC6)alky!), -N((C3-C6)cycloalkyi)(S02(C3-C6)cycloalkyl), -O(d-C6)alkyl, -O-SO2(d-C6)aIkyl, -0-S02(C3-C6)cycloalkyl, -(CO)(C1- C6)alkyl, -(CO)CF3, -(CO)(C3-C10)cycloalkyl, -(CO)(C6-C10)aryl, -(CO)(C2- C9)heterocyclyl, -(CO)(C1 -C9)heteroaryl, -(CO)O(d-C6)alkyl, -(CO)O(C3- C10)cycloalkyl, -(CO)O(C6-C10)aryl, -(CO)0(C2-C9)heterocyclyl, -(CO)O(C1- C9)heteroaryl, -(CO)(C1-C6)alkyl-O(C1-C6)alkyl, -SO2(C1-C6)alkyl, -SO2(C3- Cs)cycloalkyl, SO2CF3, SO2NH2, SO2NH(CrC6)alkyl, -SO2NH(C3- Cβ)cycloalkyl, -SO2N((C1-C6)alkyl)2, SO2N((C1-C6)alkyl)((C3-C6)cycloalkyl), -SO2N((C3-C6)cycloalkyl)2 and -SO2NR5R6, wherein said -(CrC6)alkyl is optionally interrupted by one to three elements selected from the group consisting Of -(C=O), -SO2, -S-, -0-, -N-, -NH- and -NR12; and wherein each R3 (b)-(d) substituent, moiety, or element is optionally substituted by one to three radicals independently selected from the group consisting of hydrogen, halogen, hydroxy, -CF3, -NO2, -CN, -(CrC6)alkyl, -(C2-C6)alkenyl, -(C2-C6)alkynyl, -(C3- C7)cycloalkyl, -(C2-C9)heterocyclyl, -(C6-C10)aryl, -(CrC9)heteroaryl, -O(CrC6)alkyl, -0(C3- C7)cycloalkyl, -O(C2-C9)heterocyclyl, -C=N-OH, -C=N-O(C1-C6 alkyl), -NR5R6, -SR7, -SOR7, -SO2R7, -CO2R12, -CONR5R6, - O2NR5R6, -NHCOR5, -NR12CONR5R6, and -NR12SO2R7; and wherein R5 and R6 of said -CONR5R6, -SO2NR5R6, and -NR12CONR5R6 groups may be taken together with the atoms to which they are attached to form a -(C2-C8)heterocyclyl; R4 is a substituent selected from the group consisting of hydrogen, (CrC6)alkyl, -(C3- C7)cycloalkyl, and -(C2-C8)heterocyclyl; wherein said (CrC^alkyl, -(C3-C7)cycloalkyl, and -(C2- C9)heterocyclyl R4 substituents are optionally substituted by one to three moieties independently selected from the group consisting of hydrogen, halogen, hydroxyl, -(C1- C6)alkyl, -CN, -NR5R6, -OR5, -(C3-C7)cycloalkyl, -(C2-C9)heterocyclyl, -CO2R12, and -CONR5R8; wherein R5 and R8 of said -CONR5R8 group may be taken together with the atoms to which they are attached to form a -(C2-C9)heterocyclyl; R5 and R6 are each substituents independently selected from the group consisting of hydrogen, -(C-]-CG)a\ky\, -(C3-C7)cycloalkyl, -(C2-C9)heterocyclyl, -(C6-C10)aryl, and -(Cr C9)heteroaryl; wherein said -(C1-C6JaIKyI, -(C3-C7)cycloalkyl, -(C2-Cg)heterocyclyl, -(C6- C10)aryl, and -(CrCgJheteroaryl R5 or R6 substituents are optionally substituted by one to three moieties independently selected from the group consisting of hydrogen, halogen, -CF3, -CN, -(CrCfOalkyl, -NH(CrC6)alkyl, -NH(C3-C7)cycloalkyl, -NH(C2-C9)heterocyclyl, -NH(C6- C10)aryl, -NH(C1-C9)heteroaryl, -N((CrC6)alkyl)2, -N((C3-C7)cycloalkyl)2, -N((C2- C9)heterocyclyl)2, -N((C6-C10)aryl)2, -N((CrC9)heteroaryl)2 , -O(CrC6)alkyl, -O(C3- C7)cycloalkyl, -O(C2-C9)heterocyclyl, -O(C6-C10)aryl, -0(Ci-C9)heteroaryl, -(C3-C7)cycloalkyl, -(C2-C9)heterocyclyl, -CO2R7, -CONH2, -CONHR7, and -CONR7R8; wherein R7 and R8 of said -CONR7R8 group may be taken together with the nitrogen atom to which they are attached to form a -(C2-Cg) heterocyclyl; R5 and R6 may be taken together with the atom(s) to which they are attached to form a -(C2-Cg)heterocyclyl, wherein said -(C2-C9)heterocyclyl group is optionally substituted by one to three moieties selected from the group consisting of hydrogen, halogen, hydroxy, -CF3, -NO2, -CN, -(CrC6)alkyl, -(C2-C6)alkenyl, -(C2-C6)alkynyl, -C=N-OH, -C=N-0((Cr C6)alkyl), -NR7R8, -OR12, -(C3-C7)cycloalkyl, -(C2-C9)heterocyclyl, -CO2R12, -CONR7R8, -CONR5R8, -SR7, -SOR7, -SO2R7, -SO2NR7R8, -NHCOR12, -NR12CONR7R8, and -NR12SO2R7, wherein said -(C2-C6)alkenyl and -(C2-C6)alkynyl moieties of said -(C2-C9)heterocyclyl group may be optionally substituted by one to three R7 groups, and said -(C2-C9)heterocyclyl group is optionally interrupted by one to three elements selected from the group consisting of -(C=O), -SO2, -S-, -0-, -N-, -NH- and -NR12; R7 is a substituent selected from the group consisting of -(Ci-C6)alkyl, -(C3- C7)cycloalkyl, -(C2-C9)heterocyclyl, -(C6-Ci0)aryl, and -(Ci-C9) heteroaryl; wherein said -(C1- C6)alkyl, -(C3-C7)cycloalkyl, -(C2-C9)heterocyclyl, -(C6-C10)aryl, and -(C1-C9) heteroaryl R7 substituents are optionally substituted by one to three moieties independently selected from the group consisting of hydrogen, halogen, hydroxy, -CN, -(C1-C6JaIkVl, -NR122, and -0(C1- C6)alkyl; R8 is a substituent selected from the group consisting of hydrogen, -(C^C^alkyl, -(C3- C7)cycloalkyl, -(C2-C9)heterocyclyl, -(C6-C10)aryl, and -(C1-C9) heteroaryl; wherein said -(C1- C6)alkyl, -(C3-C7)cycloalkyl, -(C2-C9)heterocyclyl, -(C6-C10)aryl, and -(C1-C9) heteroaryl R8 radicals are optionally substituted by one to three moieties independently selected from the group consisting of hydrogen, halogen, hydroxy, -CN, -(CrC^alkyl, -NH2, -NHR9, -NR92, OR9, -(C3-C7)cycloalkyl, -(C2-C9)heterocyclyl, -CO2R10, -CONH2, -CONHR10, and -CONR10R11; wherein R10 and R11 of -CONR10R11 may be taken together with the nitrogen atom to which they are attached to form a -(C2-C9)heterocyclyl; R9 and R10 are each -(C^CeJalkyl; R11 is hydrogen or and R12 is a substituent selected from the group consisting of hydrogen, -(Ci-C6)alkyl,. -(C3-C7)cycloalkyl, -(C2-C9)heterocyclyl, -(C6-C10)aryl, and -(Ci-C9)heteroaryl; wherein said -(Ci-C6)alkyl, -(C3-C7)cycloalkyl, -(C2-C9)heterocyclyl, -(C6-C10)aryl, and -(CrCgJheteroaryl R12 substituent is optionally substituted by one to three moieties independently selected from the group consisting of hydrogen, halogen, -CF3, -CN, -(CrC6)aIkyl, -NH(C1-C6)alkyl, -NH(C3- C7)cycloalkyl, -NH(C2-C9)heterocyclyl, -NH(C6-C10)aryl, -NH(C1-C9)heteroaryI, -N((Ci- C6)alkyl)2, -N((C3-C7)cycloalkyl)2, -N((C2-C9)heterocyclyl)2, -N((C6-C10)aryl)2, -N^C1- C9)heteroaryl)2 , -O(CrC6)alkyl, -O(C3-C7)cycloalkyl, -O(C2-C9)heterocyclyl, -O(C6-C10)aryl, -(C3-C7)cycloalkyl, -(C2-C9)heterocyclyi, -CO2R7, -CONH2, -CONHR7, and -CONR7R8; wherein R7 and R8 of said -CONR7R8 group may be taken together with the atoms to which they are attached to form a -(C2-C9) heterocyclyl. The present invention also includes isotopically-labeled compounds, which are identical to those recited in Formula 1 , but for the fact that one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number usually found in nature. Examples of isotopes that can be incorporated into compounds of the invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorous, fluorine and chlorine, such as 2H, 3H, 13C, 14C, 15N, 18O, 17O, 31P, 32P, 35S, 18F, and 36CI, respectively. Compounds of the present invention, prodrugs thereof, and pharmaceutically acceptable salts of said compounds or of said prodrugs which contain the aforementioned isotopes and/or other isotopes of other atoms are within the scope of this invention. Certain isotopically-Iabelled compounds of the present invention, for example those into which radioactive isotopes such as 3H and 14C are incorporated, are useful in drug and/or substrate tissue distribution assays. Tritiated, i.e., 3H, and carbon-14, i.e., 14C, isotopes are particularly preferred for their ease of preparation and detectability. Further, substitution with heavier isotopes such as deuterium, i.e., 2H, can afford certain therapeutic advantages resulting from greater metabolic stability, for example increased in vivo half-life or reduced dosage requirements and, hence, may be preferred in some circumstances. Isotopically-Iabelled compounds of Formula 1 of this invention and prodrugs thereof can generally be prepared by carrying out the procedures disclosed in the Schemes and/or in the Examples and Preparations below, by substituting a readily available isotopically-Iabelled reagent for a non-isotopically-labelled reagent. The present invention also relates to the pharmaceutically acceptable acid addition salts of compounds of the formula 1. The acids which are used to prepare the pharmaceutically acceptable acid addition salts of the aforementioned base compounds of this invention are those which form non-toxic acid addition salts, i.e., salts containing pharmacologically acceptable anions, such as the chloride, bromide, iodide, nitrate, sulfate, bisulfate, phosphate, acid phosphate, acetate, lactate, citrate, acid citrate, tartrate, bitartrate, succinate, maleate, fumarate, gluconate, saccharate, benzoate, methanesulfonate, ethanesulfonate,, benzenesulfonate, p-toluenesulfonate and pamoate [i-e-. 1,1'-methylene-bis-(2-hydroxy-3- naphthoate)]salts. The invention also relates to base addition salts of formula 1. The chemical bases that may be used as reagents to prepare pharmaceutically acceptable base salts of those compounds of formula 1 that are acidic in nature are those that form non-toxic base salts with such compounds. Such non-toxic base salts include, but are not limited to those derived from such pharmacologically acceptable cations such as alkali metal cations (e.g., potassium and sodium) and alkaline earth metal cations (e.g., calcium and magnesium), ammonium or water- soluble amine addition salts such as N-methylglucamine-(meglumine), and the lower alkanolammonium and other base salts of pharmaceutically acceptable organic amines. The phrase "pharmaceutically acceptable salt(s)", as used herein, unless otherwise indicated, includes salts of acidic or basic groups which may be present in the compounds of the present invention. The compounds of the present invention that are basic in nature are capable of forming a wide variety of salts with various inorganic and organic acids. The acids that may be used to prepare pharmaceutically acceptable acid addition salts of such basic compounds of are those that form non-toxic acid addition salts, Le1, salts containing pharmacologically acceptable anions, such as the hydrochloride, hydrobromide, hydroiodide, nitrate, sulfate, bisulfate, phosphate, acid phosphate, isonicotinate, acetate, lactate, salicylate, citrate, acid citrate, tartrate, pantothenate, bitartrate, ascorbate, succinate, maleate, gentisinate, fumarate, gluconate, glucuronate, saccharate, formate, benzoate, glutamate, methanesulfonate, ethanesulfonate, benzenesulfonate, p-toluenesulfonate and pamoate [Le1, 1 ,1'-methylene-bis- (2-hydroxy-3-naphthoate)] salts. The compounds of the present invention that include a basic moiety, such as an amino group, may form pharmaceutically acceptable salts with various amino acids, in addition to the acids mentioned above. This invention also encompasses pharmaceutical compositions containing prodrugs of compounds of the formula 1. Compounds of formula 1 having free amino, amido, hydroxy or carboxylic groups can be converted into prodrugs. Prodrugs include compounds wherein an amino acid residue, or a polypeptide chain of two or more (e.g., two, three or four) amino acid residues which are covalently joined through peptide bonds to free amino, hydroxy or carboxyiic acid groups of compounds of formula 1. The amino acid residues include the 20 naturally occurring amino acids commonly designated by three letter symbols and also include, 4-hydroxyproline, hydroxylysine, demosine, isodemosine, 3-methylhistidine, norvalin, beta- alanine, gamma-aminobutyric acid, citrulline, homocysteine, homoserine, ornithine and methionine sulfone. Prodrugs also include compounds wherein carbonates, carbamates, amides and alkyl esters that are covalently bonded to the above substituents of formula 1 through the carbonyl carbon prodrug sidechain. This invention also encompasses compounds of formula 1 containing protective groups. One skilled in the art will also appreciate that compounds of the invention can also be prepared with certain protecting groups that are useful for purification or storage and can be removed before administration to a patient. The protection and deprotection of functional groups is described in "Protective Groups in Organic Chemistry", edited by J.W.F. McOmie, Plenum Press (1973) and "Protective Groups in Organic Synthesis", 3rd edition, T.W. Greene and P. G. M. Wuts, Wiley-lnterscience (1999). The compounds of this invention include all stereoisomers (e.g., cis and trans isomers) and all optical isomers of compounds of the formula 1 (e.g., R and S enantiomers), as well as racemic, diastereomeric and other mixtures of such isomers. The compounds, salts and prodrugs of the present invention can exist in several tautomeric forms, including the enol and imine form, and the keto and enamine form and geometric isomers and mixtures thereof. All such tautomeric forms are included within the scope of the present invention. Tautomers exist as mixtures of a tautomeric set in solution. In solid form, usually one tautomer predominates. Even though one tautomer may be described, the present invention includes all tautomers of the present compounds. The present invention also includes atropisomers of the present invention. Atropisomers refer to compounds of formula 1 that can be separated into rotationally restricted isomers. The compounds of this invention may contain olefin-like double bonds. When such bonds are present, the compounds of the invention exist as cis and trans configurations and as mixtures thereof. The term "interrupted by" refers to compounds in which a ring carbon atom is replaced by an element selected from the group consisting of -(C=O), -SO2, -S-, -O-, -N-, -NH-, and -NR12. For example, if a substituent is -(C6-C10)aryl, such as

the ring may be interrupted or replaced by a nitrogen heteroatom to form the following ring:

such that a ring carbon is replaced by the heteroatom nitrogen. Compounds of the invention can accommodate up to three such replacements or interruptions. The compounds of the invention may contain Ar groups represented by

Compounds represented by this generic formula refer to fused bicyclic ring systems wherein the aromatic ring adjacent to ring B bears one or more nitrogen atoms in the ring. For example, such a structure may refer to one or more of the following ring systems: A "suitable substituent" is intended to mean a chemically and pharmaceutically acceptable functional group i.e., a moiety that does not negate the biological activity of the inventive compounds. Such suitable substituents may be routinely selected by those skilled in the art. Illustrative examples of suitable substituents include, but are not limited to halo groups, perfluoroalkyl groups, perfluoroalkoxy groups, alkyl groups, alkenyl groups, alkynyl groups, hydroxy groups, oxo groups, mercapto groups, alkylthio groups, alkoxy groups, aryl or heteroaryl groups, aryloxy or heteroaryloxy groups, aralkyl or heteroaralkyl groups, aralkoxy or heteroaralkoxy groups, HO-(C=O)- groups, amino groups, alkyl- and dialkylamino groups, carbamoyl groups, alkylcarbonyl groups, alkoxycarbonyl groups, alkylaminocarbonyl groups dialkylamino carbonyl groups, arylcarbonyl groups, aryloxycarbonyl groups, alkylsulfonyl groups, arylsulfonyl groups and the like. Those skilled in the art will appreciate that many substituents can be substituted by additional substituents. Further examples of suitable substituents include those recited in the definition of compounds of Formula 1 , including R1 through R12, as defined hereinabove. As used herein, the term "alkyl," as well as the alkyl moieties of other groups referred to herein (e.g., alkoxy), may be linear or branched (such as methyl, ethyl, n-propyl, /sopropyl, n-butyl, /so-butyl, secondary-butyl, fert/ary-butyl); optionally substituted by 1 to 3 suitable substituents as defined above such as fluoro, chloro, trifluoromethyl, (CrC6)alkoxy, (C6-Cio)aryloxy, trifluoromethoxy, difluoromethoxy or (CrCβJalkyl. The phrase "each of said alkyl" as used herein refers to any of the preceding alkyl moieties within a group such alkoxy, alkenyl or alkylamino. Preferred alkyls include (CrC6)alkyl, more preferred are (C1-C4)alkyl, and most preferred are methyl and ethyl. As used herein, the term "cycloalkyl" refers to a mono, bicyclic or tricyclic carbocyclic ring (e.g., cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, cyclopentenyl, cyclohexenyl, bicyclo[2.2.1]heptanyl, bicyclo[3.2.1]octanyl and bicyclo[5.2.0]nonanyl, etc.); optionally containing 1 or 2 double bonds and optionally substituted by 1 to 3 suitable substituents as defined above such as fluoro, chloro, trifluoromethyl, (C1-CeOaIkOXy, (C6-C10)aryloxy, trifluoromethoxy, difluoromethoxy or (C1- Cβ)alkyl. As used herein, the term "halogen" includes fluoro, chloro, bromo or iodo or fluoride, chloride, bromide or iodide. As used herein, the term "alkenyl" means straight or branched chain unsaturated radicals of 2 to 6 carbon atoms, including, but not limited to ethenyl, 1-propenyl, 2-propenyl (allyl), /so-propenyl, 2-methyl-1-propenyl, 1-butenyl, 2-butenyl, and the like; optionally substituted by 1 to 3 suitable substituents as defined above such as fluoro, chloro, trifluoromethyl, (CrC6)alkoxy, (C6-C10)aryloxy, trifluoromethoxy, difluoromethoxy or (C1- Cβ)alkyl. As used herein, the term "alkynyl" is used herein to mean straight or branched hydrocarbon chain radicals having one triple bond including, but not limited to, ethynyl, propynyl, butynyl, and the like; optionally substituted by 1 to 3 suitable substituents as defined above such as fluoro, chloro, trifluoromethyl, (CrC6)alkoxy, (C6-C10)aryloxy, trifluoromethoxy, difluoromethoxy or (C1-C6)alkyl. As used herein, the term "carbonyl" or "(C=O)" (as used in phrases such as alkylcarbonyl, alkyl-(C=O)- or alkoxycarbonyl) refers to the joinder of the >C=O moiety to a second moiety such as an alkyl or amino group (i.e. an amido group). Alkoxycarbonylamino (i.e. alkoxy(C=O)-NH-) refers to an alkyl carbamate group. The carbonyl group is also equivalently defined herein as (C=O). Alkylcarbonylamino refers to groups such as acetamide. As used herein, the term "aryl" means aromatic radicals such as phenyl, naphthyl, tetrahydronaphthyl, indanyl and the like; optionally substituted by 1 to 3 suitable substituents as defined above. As used herein, the term "heteroaryl" refers to an aromatic heterocyclic group usually with one heteroatom selected from O, S and N in the ring. In addition to said heteroatom, the aromatic group may optionally have up to four N atoms in the ring. For example, heteroaryl group includes pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, thienyl, furyl, imidazolyl, pyrrolyl, oxazolyl (e.g., 1 ,3-oxazolyl, 1,2-oxazolyl), thiazolyl (e.g., 1,2-thiazolyl, 1 ,3-thiazolyl), pyrazolyl, tetrazolyl, triazolyl (e.g., 1 ,2,3-triazolyl, 1 ,2,4-triazolyl), oxadiazolyl (e.g., 1 ,2,3-oxadiazolyl), thiadiazolyl (e.g., 1 ,3,4-thiadiazolyl), quinolyl, isoquinolyl, benzothienyl, benzofuryl, indolyl, and the like; optionally substituted by 1 to 3 suitable substituents as defined above such as fluoro, chloro, trifluoromethyl, (CVCeJalkoxy, (C5-C10)aryloxy, trifluoromethoxy, difluoromethoxy or (Ci-C6)alkyl. The term "heterocyclic" as used herein refers to a cyclic group containing 1-9 carbon atoms and 1 to 4 hetero atoms selected from N, O, S(O)n or NR. Examples of such rings include azetidinyl, tetrahydrofuranyl, imidazolidinyl, pyrrolidinyl, piperidinyl, piperazinyl, oxazolidinyl, thiazolidinyl, pyrazolidinyl, thiomorpholinyl, tetrahydrothiazinyl, tetrahydro- thiadiazinyl, morpholinyl, oxetanyl, tetrahydrodiazinyl, oxazinyl, oxathiazinyl, indolinyl, isoindolinyl, quinuclidinyl, chromanyl, isochromanyl, benzoxazinyl, and the like. Examples of said monocyclic saturated or partially saturated ring systems are tetrahydrofuran-2-yl, tetrahydrofuran-3-yl, imidazolidin-1-yl, imidazoIidin-2-yl, imidazolidin-4-yl, pyrrolidin-1-yl, pyrrol id in-2-yl, pyrrolidin-3-yl, piperidin-1-yl, piperidin-2-yl, piperidin-3-yl, piperazin-1-yl, piperazin-2-yl, piperazin-3-yl, 1 ,3-oxazolidin-3-yl, isothiazolidine, 1 ,3-thiazolidin-3-yl, 1 ,2-pyrazolidin-2-yl, 1 ,3-pyrazolidin-1-yl, thiomorpholin-yl, 1 ,2-tetrahydrothiazin-2-yl, 1 ,3-tetrahydrothiazin-3-yl, tetrahydrothiadiazin-yl, morpholin-yl, 1 ,2-tetrahydrodiazin-2-yl, 1 ,3-tetrahydrodiazin-1-yl, 1 ,4-oxazin-2-yl, 1 ,2,5-oxathiazin-4-yl and the like; optionally containing 1 or 2 double bonds and optionally substituted by 1 to 3 suitable substituents as defined above such as fluoro, chloro, trifluoromethyl, (CrC6)alkoxy, (C6-C10)aryloxy, trifluoromethoxy, difluoromethoxy or (Ci-C6)alkyl. Nitrogen heteroatoms as used herein refers to N=, >N and -NH; wherein -N= refers to a nitrogen double bond; >N refers to a nitrogen containing two bond connections and -N refers to a nitrogen containing one bond. "Embodiment" as used herein refers to specific groupings of compounds or uses into discrete subgenera. Such subgenera may be cognizable according to one particular substituent such as a specific R1 or R3 group. Other subgenera are cognizable according to combinations of various substituents, such as all compounds wherein R2 is hydrogen and R1 is (Ci-C6)alkyl. Therefore, the invention provides a compound of formula 1 wherein Ar is a fused ring system selected from the group consisting of:

Also provided is a compound of formula 1 wherein Ar is a fused heteroaryl ring system selected from the group consisting of:

Further provided is a compound of formula 1 wherein Ar is a fused ring system selected from the group consisting of:

Another embodiment of the invention is a compound of formula 1 wherein Ar is a fused heteroaryl ring system selected from the group consisting of:

A further embodiment of the invention is a compound of formula 1 wherein Ar is a fused ring system selected from the group consisting of:

An additional embodiment of the invention is a compound of formula 1 wherein Ar is a fused heteroaryl ring system selected from the group consisting of:

Another embodiment of the present invention is a compound of formula 1 wherein Ar is a fused ring system selected from the group consisting of:

The invention also contemplates a compound of formula 1 wherein Ar is a fused heteroaryl ring system selected from the group consisting of:

The present invention also contemplates a compound of formula 1 wherein Ar is a heterocyclic fused ring system selected from the group consisting of:

Still further, the invention provides a compound of formula 1 wherein Ar is a heterocyclic fused ring system selected from the group consisting of:

Moreover, another embodiment of the invention is a compound of formula 1 wherein Ar is a heterocyclic fused ring system selected from the group consisting of:

Another embodiment of the present invention is a compound of formula 1 wherein Ar rocyclic fused ring system selected from:

The invention provides a compound of formula 1 wherein R3 is hydrogen. Also provided is a compound of formula 1 wherein R3 is selected from the group consisting of -(C6-C10)aryl and -(CrC9)heteroaryl, optionally substituted by one to three moieties independently selected from the group consisting of halogen, hydroxy, -(Ci-C6)alkyl, -(C1-C6)alkyl-P(O)(O(C1-C6)alkyl)2, -(C3-C10)cycloalkyl, (C6-C10)aryl, (C2-C9)heterocyclyl, -(C1- C9)heteroaryl, -NR5R6, -NHSO2(CrC6)alkyl, -NHSO2(C3-C6)cycloalkyl , -N((CrC6)alkyl)(SO2- d-CeJalkyl), -N((Ci-Cβ)alkyl)(SO2(C3-Cβ)cycloalkyl), -N((C3-C6)cycloalkyl)(S02-C1-C6)alkyl), -N((C3-C6)cycloalkyl)(S02(C3-C6)cycloalkyl), -0(Ci-Cβ)alkyl, -O-SO2(Ci-Cβ)alkyl, -0-SO2(C3- C6)cycloalkyl, -(CO)(CrCβ)alkyl, -(CO)CF3, -(CO)(C3-C10)cycloalkyl, -(CO)(C6-C10)aryl, -(CO)(C2-C9)heterocyclyl, -(CO)(C1 -C9)heteroaryl, -(CO)O(CrC6)alkyl, -(CO)O(C3- C10)cycloalkyl, -(CO)O(C6-C10)aryl, -(CO)0(C2-C9)heterocyclyl, -(CO)0(C1-C9)heteroaryl, -(CO)(CrC6)alkyl-O(C1-C6)alkyl, -SO2(C1-C6)alkyl, -S02(C3-C6)cycloalkyl, SO2CF3, SO2NH2, SO2NH(CrC6)alkyI, -SO2NH(C3-C6)cycloalkyl, -SO2N((C1-C6)alkyl)2, SO2N((C1-C6)alkyl)((C3- C6)cycloalkyl), -SO2N((C3-C6)cycloalkyl)2 and -SO2NR5R6, wherein said -(C6-C10) aryl or -(C1- C9) heteroaryl are optionally interrupted by one to three elements selected from the group consisting of -S-, -0-, -N-, -NH- and -NR12. Still further, the invention provides a compound of formula 1 wherein R3 is selected from the group consisting of -(C3-C10)cycloalkyl, -(C2-C9)heterocyclyl, and -(C.|-C6)alkyl-(C2- C9) heterocyclyl, optionally substituted by one to three moieties independently selected from the group consisting of halogen, hydroxy, -(Ci-C6)alkyl, -(C1-C6)aIkyl-P(O)(O(C1-C6)alkyl)2, -(C3-C10)cycloalkyl, (C6-C10)aryl, (C2-C9)heterocyclyl, -(CrC9)heteroaryl, -NR5R6, -NSO2(C1- C6)alkyl, -NHSO2(C3-C6)CyClOaIkVl1 -N((C1-C6)alkyl)(SO2-C1-C6)alkyl), -N((C1-C6)alkyl)(SO2(C3- C6)cycloalkyl), -N((C3-C6)cycIoalkyl)(SO2-C1-C6)alkyl), -N((C3-C6)cycloalkyl)(SO2(C3- C6)cycloalkyl), -O(CrC6)alkyl, -O-SO2(C1-C8)alkyl, -O-SO2(CrC6)alkyl, -0-SO2(C3- C6)cycloalkyl, -(CO)(C1-C6)alkyl, -(CO)CF3, -(CO)(C3-C10)cycloalkyl, -(CO)(C6-C10)aryl, -(CO)(C2-C9)heterocyclyI, -(CO)(CrC9)heteroaryl, -(CO)O(C1-C6)alkyl, -(CO)O(C3- C10)cycioalkyl, -(CO)O(C6-C10)aryl, -(CO)O(C2-C9)heterocyclyl, -(CO)0(CrC9)heteroaryl, -(CO)(C1-C6)alkyl-O(C1-C6)alkyl, -SO2(C1-Cβ)alkyl, -SO2(C3-C6)cycloalkyl, SO2CF3, SO2NH2, SO2NH(CrC6)alkyl, -SO2NH(C3-C6)cycloalkyl, -SO2N((C1-C6)alkyl)2, SO2N((CrC6)alkyl)((C3- C6)cycloalkyl), -SO2N((C3-C6)cycloalkyl)2 and -SO2NR5R6, wherein said -(C3-C10)cycloalkyl, -(C2-C9)heterocyclyl, and -(C1-C6)alkyl-(C2-C9) heterocyclyl are optionally interrupted by one to three elements selected from the group consisting of -(C=O), -SO2, -S-, -O-, -N-, -NH- and -NR12. In addition, the invention provides a compound of formula 1 wherein R3 is -(C1- C6)alkyl optionally substituted by one to three moieties selected from the group consisting of halogen, hydroxy, -(CrC6)alkyl, -(C1-C6)alkyl-P(O)(O(C1-C6)alkyl)2, -(C3-C10)cycloalkyl, (C6- C10)aryl, (C2-C9)heterocyclyl, -(C1-C9)heteroaryl, -NR5R6, -NHSO2(Ci-C6)alkyl, -NHSO2(C3- C6)cycloalkyl, -N((C1-C6)alkyl)(SO2-C1-C6)alkyl), -N((C1-C6)alkyl)(SO2(C3-C6)cycloaIkyl), -N((C3-C6)cycloalkyl)(SO2-C1-C6)alkyl), -N((C3-C6)cycloalkyl)(S02(C3-C6)cycloalkyl), -0(C1- C6)alkyl, -O-SO^Cr^alkyl, -O-SO2(C3-C6)cycloalkyl, -(CO)(C1-C6)alkyl, -(CO)CF3, -(CO)(C3- C10)cycloalkyl, -(CO)(C6-C10)aryl, -(CO)(C2-C9)heterocyclyl, -(CO)(C1 -C9)heteroaryl, -(CO)O(C.,-C6)alkyl, -(CO)O(C3-C10)cycloalkyl, -(CO)O(C6-C10)aryl, -(CO)O(C2- C9)heterocyclyl, -(CO)O(CrC9)heteroaryI, -(CO)(C1-C6)alkyl-O(C1-C6)alkyl, -SO2(CrC6)alkyl, -SO2(C3-C6)cycloalkyl, SO2CF3, SO2NH2, SO2NH(C1-C6)alkyl, -SO2NH(C3-C6)cycloalkyl, -SO2N((CrC6)alkyl)2, SO2N((CrC6)alkyl)((C3-C6)cycloalkyl), -SO2N((C3-C6)cycloalkyl)2 and -SO2NR5R6, wherein said -(C1-C6)alkyl is optionally interrupted by one to three elements selected from the group consisting Of -(C=O), -SO2, -S-, -0-, -N-, -NH- and -NR12. A further embodiment of the invention is a compound of formula 1 wherein Ra is selected from the group consisting of hydrogen, halogen, hydroxy, -CF3 and -CN. An additional embodiment of the invention is a compound of formula 1 wherein Rb is selected from the group consisting of hydrogen, -(C1-C6)alkyl, -(C3-C7)cycloalkyl and -(C2- C9)heterocyclyl. Further, the invention provides a compound of formula 1 wherein each Rc independently represents a substituent selected from the group consisting of hydrogen, hydroxy, -(CrC6)alkyl, -(C3-C7)cycloalkyl, and -(C2-C9)heterocyclyl, or two Rc substituents may be taken together with the atom(s) to which they are attached to form a cyclic group, -(C3-C10)-cycloalkyl or -(C2-C9)-heterocyclyl. The following is a non-limiting list of compounds according to the present invention: 5-Bromo-N2-[3-(1,2,3,6-tetrahydro-pyridin-4-yl)-1H-indol-5-y l]-N4-p-tolyl-pyrimidine- 2,4-diamine; 5-Bromo-N4-pyridin-2-yl-N2-[3-(1 ,2,3,6-tetrahydro-pyridin-4-yl)-1 H-indol-5-yl]- pyrimidine-2,4-diamine; 5-Bromo-N2-[3-(1 ,2,3,6-tetrahydro-pyridin-4-yl)-1H-indol-5-yl]-N4-(2-trifluo romethyl- benzyl)-pyrimidine-2,4-diamine; N-[2-({5-Bromo-2-[3-(1 ,2,3,6-tetrahydro-pyridin-4-yl)-1 H-indol-5-ylamino]-pyrimidin-4- ylamino}-methyl)-phenyl]-methanesulfonamide; N-[2-({5-Bromo-2-[3-(1 ,2,3,6-tetrahydro-pyridin-4-yl)-1 H-indol-5-ylamino]-pyrimidin-4- ylamino}-methyl)-phenyl]-N-methyl-methanesulfonamide; N-[3-({5-Bromo-2-[3-(1 ,2,3,6-tetrahydro-pyridin-4-yl)-1 H-indol-5-ylamino]-pyrimidin-4- ylamino}-methyl)-pyridin-2-yl]-N-methyl-methanesulfonamide; N-[3-({5-Bromo-2-[3-(1 ,2,3,6-tetrahydro-pyridin-4-yl)-1 H-indol-5-ylamino]-pyrimidin-4- ylamino}-methyl)-phenyl]-methanesulfonamide; N-[3-({5-Bromo-2-[3-(1 ,2,3,6-tetrahydro-pyridin-4-yl)-1 H-indol-5-ylamino]-pyrimidin-4- ylamino}-methyl)-phenyl]-N-methy!-methanesulfonamide; and 5-Bromo-N4-(3-methanesulfonyl-benzyl)-N2-[3-(1 ,2,3,6-tetrahydro-pyridin-4-yl)-1H- indol-5-yl]-pyrimidine-2,4-diamine. Also provided is a compound selected from the group consisting of: N2-[3-(1 ,2,3,6-Tetrahydro-pyridin-4-yl)-1 H-indol-5-yl]-N4-p-tolyl-5-trifluoromethyl- pyrimidine-2,4-diamine; N4-Pyridin-2-yl-N2-[3-(1 ,2,3,6-tetrahydro-pyridin-4-yl)-1 H-indol-5-yl]-5-trifluoromethyl- pyrimidine-2,4-diamine; N2-[3-(1 ,2,3,6-Tetrahydro-pyridin-4-yl)-1 H-indol-5-yl]-5-trifluoromethyl-N4-(2- trifluoromethyl-benzyl)-pyrimidine-2,4-diamine; N-[2-({2-[3-(1 ,2,3,6-Tetrahydro-pyridin-4-yl)-1 H-indol-5-ylamino]-5-trifluoromethyl- pyrimidin-4-ylamino}-methyl)-phenyl]-methanesulfonamide; N-Methyl-N-[2-({2-[3-(1 ,2,3,6-tetrahydro-pyridin-4-yl)-1 H-indol-5-ylamino]-5- trifluoromethyl-pyrimidin-4-ylamino}-methyl)-phenyl]-methane sulfonamide; N-Methyl-N-[3-({2-[3-(1 ,2,3,6-tetrahydro-pyridin-4-yl)-1 H-indol-5-ylamino]-5- trifluoromethyl-pyrimidin-4-ylamino}-methyl)-pyridin-2-yl]-m ethanesulfonamide; N-p-dZ-p-CI^.S.S-Tetrahydro-pyridin^-yO-IH-indol-S-ylaminol- S-trifluoromethyl- pyrimidin-4-ylamino}-methyl)-phenyl]-methanesulfonamide; N-Methyl-N-[3-({2-[3-(1 ,2,3,6-tetrahydro-pyridin-4-yl)-1 H-indol-5-ylamino]-5- trifluoromethyl-pyrimidin-4-ylamino}-methyl)-phenyl]-methane sulfonamide; and N4-(3-Methanesulfonyl-benzyl)-N2-[3-(1 ,2,3,6-tetrahydro-pyridin-4-yI)-1 H-indol-5-yl]- 5-trifluoromethyl-pyrimidine-2,4-diamine. Further provided is a compound selected from the group consisting of: 6-[5-Trifluoromethy!-4-(2-trifluoromethyl-benzylamino)-pyrim idin-2-ylamino]-3,4- dihydro-1 H-quinolin-2-one; N-(2-{[2-(2-Oxo-1 ,2,3,4-tetrahydro-quinolin-6-ylamino)-5-trifluoromethyl-pyri midin-4- ylamino]-methyl}-phenyl)-methanesulfonamide; N-Methyl-N-(2-{[2-(2-oxo-1 ,2,3,4-tetrahydro-quinolin-6-ylamino)-5-trifluoromethyl- pyrimidin-4-ylamino]-methyl}-phenyl)-methanesulfonamide; N-Methyl-N-(3-{[2-(2-oxo-1 ,2,3,4-tetrahydro-quinolin-6-ylamino)-5-trifluoromethyl- pyrimidin-4-ylamino]-methyl}-pyridin-2-yl)-methanesulfonamid e; N-(3-{[2-(2-Oxo-1,2,3,4-tetrahydro-quinolin-6-ylamino)-5-tri fluoromethyl-pyrimidin-4- ylamino]-methyl}-phenyl)-methanesulfonamide; N-Methyl-N-(3-{[2-(2-oxo-1 ,2,3,4-tetrahydro-quinolin-6-ylamino)-5-trifluoromethyl- pyrimidin-4-ylamino]-methyl}-phenyl)-methanesulfonamide; and 6-[4-(3-Methanesulfonyl-benzylamino)-5-trifIuoromethyl-pyrim idin-2-ylamino]-3,4- dihydro-1 H-quinolin-2-one. Still further, the invention provides a compound selected from the group consisting of: 7-[5-Trifluoromethyl-4-(2-trifluoromethyl-benzylamino)-pyrim idin-2-ylamino]-3,4- dihydro-1 H-quinolin-2-one; N-(2-{[2-(2-Oxo-1 ,2,3,4-tetrahydro-quinolin-7-ylamino)-5-trifluoromethyl-pyri midin-4- ylamino]-methyl}-phenyl)-methanesulfonamide; N-Methyl-N-(2-{[2-(2-oxo-1 ,2,3,4-tetrahydro-quinolin-7-ylamino)-5-trifluoromethyl- pyrimidin-4-ylamino]-methyl}-phenyl)-methanesulfonamide; N-Methyl-N-(3-{[2-(2-oxo-1 ,2,3,4-tetrahydro-quinolin-7-ylamino)-5-trifluoromethyl- pyrimidin-4-ylamino]-methyl}-pyridin-2-yl)-methanesulfonamid e; N-(3-{[2-(2-Oxo-1 ,2,3,4-tetrahydro-quinolin-7-ylamino)-5-trifluoromethyl-pyri midin-4- ylamino]-methyl}-phenyl)-methanesulfonamide; N-Methyl-N-(3-{[2-(2-oxo-1 ,2,3,4-tetrahydro-quinolin-7-ylamino)-5-trifluoromethyl- pyrimidin-4-ylamino]-methyl}-phenyl)-methanesuIfonamide; and 7-[4-(3-Methanesulfonyl-benzylamino)-5-trifluoromethyl-pyrim idin-2-ylamino]-3,4- dihydro-1 H-quinolin-2-one. Moreover, the invention also provides a compound selected from: 7-{4-[(Pyridin-2-ylmethyl)-amino]-5-trifluoromethyl-pyrimicl in-2-ylamino}-3,4-dihydro- 1 H-quinoIin-2-one; 6-{4-[(Pyridin-2-ylmethyl)-amino]-5-trifluoromethyl-pyrimidi n-2-ylamino}-3,4-dihydro- 1H-quinolin-2-one; N-Methyl-N-(3-{[2-(2-oxo-1 ,2,3,4-tetrahydro-quinolin-7-ylamino)-5-trifluoromethyl- pyrimidin-4-ylamino]-methyl}-phenyl)-methanesulfonamide; Methanesulfonic acid 3-{[2-(2-oxo-1 ,2,3,4-tetrahydro-quinolin-7-ylamino)-5- trifluoromethyl-pyrimidin-4-ylamino]-methyl}-phenyl ester; 7-(4-Cyclobutylamino-5-trifluoromethyl-pyrimidin-2-ylamino)- 3,4-dihydro-1 H-quinolin- 2-one; 6-[4-(3-Methanesulfonyl-benzylamino)-5-trifluoromethyl-pyrim idin-2-ylamino]-3,4- dihydro-1 H-quinolin-2-one; N-Methyl-N-(3-{[2-(2-oxo-1 ,2,3,4-tetrahydro-quinolin-6-ylamino)-5-trifluoromethyl- pyrimidin-4-ylamino]-methyl}-prienyl)-methanesulfonamide; Methanesulfonic acid 3-{[2-(2-oxo-1,2,3,4-tetrahydro-quinolin-6-ylamino)-5- trifIuoromethyl-pyrimidin-4-ylamino]-methyl}-phenyl ester; 7-[4-(3-Methanesulfonyl-benzylamino)-5-trifluoromethyl-pyrim idin-2-ylamino]-3,4- dihydro-1 H-quinolin-2-one; N-Methyl-N-(2-{[2-(2-oxo-1 ,2,3,4-tetrahydro-quinolin-7-ylamino)-5-trifluoromethyl- pyrimidin-4-ylamino]-methyl}-phenyl)-methanesulfonamide; and N-Methyl-N-(2-{[2-(2-oxo-1 ,2,3,4-tetrahydro-quinolin-6-ylamino)-5-trifluoromethyl- pyrimidin-4-ylamino]-methyl}-phenyl)-methanesulfonamide. This invention also relates to a method for the treatment of abnormal cell growth in a mammal, including a human, comprising administering to said mammal an amount of a compound of the formula 1 , as defined above, or a pharmaceutically acceptable salt, solvate or prodrug thereof, that is effective in treating abnormal cell growth. In one embodiment of this method, the abnormal cell growth is cancer, including, but not limited to, lung cancer, bone cancer, pancreatic cancer, skin cancer, cancer of the head or neck, cutaneous or intraocular melanoma, uterine cancer, ovarian cancer, rectal cancer, cancer of the anal region, stomach cancer, colon cancer, breast cancer, uterine cancer, carcinoma of the fallopian tubes, carcinoma of the endometrium, carcinoma of the cervix, carcinoma of the vagina, carcinoma of the vulva, Hodgkin's Disease, cancer of the esophagus, cancer of the small intestine, cancer of the endocrine system, cancer of the thyroid gland, cancer of the parathyroid gland, cancer of the adrenal gland, sarcoma of soft tissue, cancer of the urethra, cancer of the penis, prostate cancer, chronic or acute leukemia, lymphocytic lymphomas, cancer of the bladder, cancer of the kidney or ureter, renal cell carcinoma, carcinoma of the renal pelvis, neoplasms of the central nervous system (CNS), primary CNS lymphoma, spinal axis tumors, brain stem glioma, pituitary adenoma, or a combination of one or more of the foregoing cancers. In one embodiment the method comprises comprising administering to a mammal an amount of a compound of formula X that is effective in treating said cancer solid tumor. In one preferred embodiment the solid tumor is breast, lung, colon, brain, prostate, stomach, pancreatic, ovarian, skin (melanoma), endocrine, uterine, testicular, and bladder cancer. In another embodiment of said method, said abnormal cell growth is a benign proliferative disease, including, but not limited to, psoriasis, benign prostatic hypertrophy or restinosis. This invention also relates to a method for the treatment of abnormal cell growth in a mammal which comprises administering to said mammal an amount of a compound of formula 1 , or a pharmaceutically acceptable salt, solvate or prodrug thereof, that is effective in treating abnormal cell growth in combination with an anti-tumor agent selected from the group consisting of mitotic inhibitors, alkylating agents, anti-metabolites, intercalating antibiotics, growth factor inhibitors, cell cycle inhibitors, enzymes, topoisomerase inhibitors, biological response modifiers, antibodies, cytotoxics, anti-hormones, and anti-androgens. This invention also relates to a pharmaceutical composition for the treatment of abnormal cell growth in a mammal, including a human, comprising an amount of a compound of the formula 1 , as defined above, or a pharmaceutically acceptable salt, solvate or prodrug thereof, that is effective in treating abnormal cell growth, and a pharmaceutically acceptable carrier. In one embodiment of said composition, said abnormal cell growth is cancer, including, but not limited to, lung cancer, bone cancer, pancreatic cancer, skin cancer, cancer of the head or neck, cutaneous or intraocular melanoma, uterine cancer, ovarian cancer, rectal cancer, cancer of the anal region, stomach cancer, colon cancer, breast cancer, uterine cancer, carcinoma of the fallopian tubes, carcinoma of the endometrium, carcinoma of the cervix, carcinoma of the vagina, carcinoma of the vulva, Hodgkin's Disease, cancer of the esophagus, cancer of the small intestine, cancer of the endocrine system, cancer of the thyroid gland, cancer of the parathyroid gland, cancer of the adrenal gland, sarcoma of soft tissue, cancer of the urethra, cancer of the penis, prostate cancer, chronic or acute leukemia, lymphocytic lymphomas, cancer of the bladder, cancer of the kidney or ureter, renal cell carcinoma, carcinoma of the renal pelvis, neoplasms of the central nervous system (CNS), primary CNS lymphoma, spinal axis tumors, brain stem glioma, pituitary adenoma, or a combination of one or more of the foregoing cancers. In another embodiment of said pharmaceutical composition, said abnormal cell growth is a benign proliferative disease, including, but not limited to, psoriasis, benign prostatic hypertrophy or restinosis. This invention also relates to a method for the treatment of abnormal cell growth in a mammal which comprises administering to said mammal an amount of a compound of formula 1 , or a pharmaceutically acceptable salt, solvate or prodrug thereof, that is effective in treating abnormal cell growth in combination with another anti-tumor agent selected from the group consisting of mitotic inhibitors, alkylating agents, anti-metabolites, intercalating antibiotics, growth factor inhibitors, cell cycle inhibitors, enzymes, topoisomerase inhibitors, biological response modifiers, antibodies, cytotoxics, anti-hormones, and anti-androgens. The invention also contemplates a pharmaceutical composition for treating abnormal cell growth wherein the composition includes a compound of formula 1 , as defined above, or a pharmaceutically acceptable salt, solvate or prodrug thereof, that is effective in treating abnormal cell growth, and another anti-tumor agent selected from the group consisting of mitotic inhibitors, alkylating agents, anti-metabolites, intercalating antibiotics, growth factor inhibitors, cell cycle inhibitors, enzymes, topoisomerase inhibitors, biological response modifiers, antibodies, cytotoxics, anti-hormones, and anti-androgens. This invention also relates to a method for the treatment of a disorder associated with angiogenesis in a mammal, including a human, comprising administering to said mammal an amount of a compound of the formula 1 , as defined above, or a pharmaceutically acceptable salt, solvate or prodrug thereof, that is effective in treating said disorder in combination with one or more anti-tumor agents listed above. Such disorders include cancerous tumors such as melanoma; ocular disorders such as age-related macular degeneration, presumed ocular histoplasmosis syndrome, and retinal neovascularization from proliferative diabetic retinopathy; rheumatoid arthritis; bone loss disorders such as osteoporosis, Paget's disease, humoral hypercalcemia of malignancy, hypercalcemia from tumors metastatic to bone, and osteoporosis induced by glucocorticoid treatment; coronary restenosis; and certain microbial infections including those associated with microbial pathogens selected from adenovirus, hantaviruses, Borrelia burgdorferi, Yersinia spp., Bordetella pertussis, and group A Streptococcus. This invention also relates to a method of (and to a pharmaceutical composition for) treating abnormal cell growth in a mammal which comprise an amount of a compound of formula 1 , or a pharmaceutically acceptable salt, solvate or prodrug thereof, in combination with an amount of one or more substances selected from anti-angiogenesis agents, signal transduction inhibitors, and antiproliferative agents, which amounts are together effective in treating said abnormal cell growth. Anti-angiogenesis agents, such as MMP-2 (matrix-metalloprotienase 2) inhibitors, MMP-9 (matrix-metalloprotienase 9) inhibitors, and COX-II (cyclooxygenase II) inhibitors, can be used in conjunction with a compound of formula 1 in the methods and pharmaceutical compositions described herein. Examples of useful COX-II inhibitors include CELEBREX™ (celecoxib), Bextra (valdecoxib), paracoxib, Vioxx (rofecoxib), and Arcoxia (etoricoxib). Examples of useful matrix metalloproteinase inhibitors are described in WO 96/33172 (published October 24, 1996), WO 96/27583 (published March 7, 1996), European Patent Application No. 97304971.1 (filed July 8, 1997), European Patent Application No. 99308617.2 (filed October 29, 1999), WO 98/07697 (published February 26, 1998), WO 98/03516 (published January 29, 1998), WO 98/34918 (published August 13, 1998), WO 98/34915 (published August 13, 1998), WO 98/33768 (published August 6, 1998), WO 98/30566 (published July 16, 1998), European Patent Publication 606,046 (published July 13, 1994), European Patent Publication 931 ,788 (published July 28, 1999), WO 90/05719 (published May 331 , 1990), WO 99/52910 (published October 21 , 1999), WO 99/52889 (published October 21 , 1999), WO 99/29667 (published June 17, 1999), PCT International Application No. PCT/IB98/01113 (filed July 21 , 1998), European Patent Application No. 99302232.1 (filed March 25, 1999), Great Britain patent application number 9912961.1 (filed June 3, 1999), United States Provisional Application No. 60/148,464 (filed August 12, 1999), United States Patent 5,863,949 (issued January 26, 1999), United States Patent 5,861,510 (issued January 19, 1999), and European Patent Publication 780,386 (published June 25, 1997), all of which are herein incorporated by reference in their entirety. Preferred MMP-2 and MMP-9 inhibitors are those that have little or no activity inhibiting MMP-1. More preferred, are those that selectively inhibit MMP-2 and/or MMP-9 relative to the other matrix-metalloproteinases (i.e. MMP-1 , MMP-3, MMP-4, MMP-5, MMP-6, MMP-7, MMP-8, MMP-10, MMP-11 , MMP-12, and MMP-13). Some specific examples of MMP inhibitors useful in combination with the compounds of the present invention are AG-3340, RO 32-3555, RS 13-0830, and the compounds recited in the following list: 3-[[4-(4-fluoro-phenoxy)-benzenesulfonyl]-(1-hydroxycarbamoy l-cyclopentyl)-amino]- propionic acid; 3-exo-3-[4-(4-fluoro-phenoxy)-benzenesulfonylamino]-8-oxa-bi cyclo[3.2.1]octane-3- carboxylic acid hydroxyamide; (2R, 3R) 1 -[4-(2-chloro-4-fluoro-benzyloxy)-benzenesulfonyl]-3-hydroxy -3-methyl- piperidine-2-carboxylic acid hydroxyamide; 4-[4-(4-fluoro-phenoxy)-benzenesulfonylamino]-tetrahydro-pyr an-4-carboxylic acid hydroxyamide; 3-[[4-(4-fluoro-phenoxy)-benzenesulfonyl]-(1-hydroxycarbamoy l-cyclobutyl)-amino]- propionic acid; 4-[4-(4-chloro-phenoxy)-benzenesulfonylamino]-tetrahydro-pyr an-4-carboxylic acid hydroxyamide; 3-[4-(4-chIoro-phenoxy)-benzenesulfonylamino]-tetrahydro-pyr an-3-carboxylic acid hydroxyamide; (2R, 3R) 1 -[4-(4-fluoro-2-methyI-benzyloxy)-benzenesulfonyl]-3-hydroxy -3-methyl- piperidine-2-carboxylic acid hydroxyamide; 3-[[4-(4-fluoro-phenoxy)-benzenesulfonyl]-(1-hydroxycarbamoy l-1-methyl-ethyl)- amino]-propionic acid; 3-[[4-(4-fluoro-phenoxy)-benzenesulfonyl]-(4-hydroxycarbamoy l-tetrahydro-pyran-4- yl)-amino]-propionic acid; 3-exo-3-[4-(4-chloro-phenoxy)-benzenesulfonylamino]-8-oxa-bi cyclo[3.2.1]octane-3- carboxylic acid hydroxyamide; 3-endo-3-[4-(4-fluoro-phenoxy)-benzenesulfonylamino]-8-oxa-b icyclo[3.2.1]octane-3- carboxylic acid hydroxyamide; and 3-[4-(4-fluoro-phenoxy)-benzenesulfonylamino]-tetrahydro-fur an-3-carboxylic acid hydroxyamide; and pharmaceutically acceptable salts, solvates and prodrugs of said compounds. VEGF inhibitors, for example, SU-11248, SU-5416 and SU-6668 (Sugen Inc. of South San Francisco, California, USA), can also be combined with a compound of formula 1. VEGF inhibitors are described in, for example in WO 99/24440 (published May 20, 1999), PCT International Application PCT/IB99/00797 (filed May 3, 1999), in WO 95/21613 (published August 17, 1995), WO 99/61422 (published December 2, 1999), United States Patent 5,834,504 (issued November 10, 1998), WO 98/50356 (published November 12, 1998), United States Patent 5,883,113 (issued March 16, 1999), United States Patent 5,886,020 (issued March 23, 1999), United States Patent 5,792,783 (issued August 11 , 1998), U.S. Patent No. US 6,653,308 (issued November 25, 2003), WO 99/10349 (published March 4, 1999), WO 97/32856 (published September 12, 1997), WO 97/22596 (published June 26, 1997), WO 98/54093 (published December 3, 1998), WO 98/02438 (published January 22, 1998), WO 99/16755 (published April 8, 1999), and WO 98/02437 (published January 22, 1998), all of which are herein incorporated by reference in their entirety. Other examples of some specific VEGF inhibitors are IM862 (Cytran Inc. of Kirkland, Washington, USA); Avastin, an anti-VEGF monoclonal antibody of Genentech, Inc. of South San Francisco, California; and angiozyme, a synthetic ribozyme from Ribozyme (Boulder, Colorado) and Chiron (Emeryville, California). ErbB2 receptor inhibitors, such as GW-282974 (Glaxo Wellcome pic), and the monoclonal antibodies AR-209 (Aronex Pharmaceuticals Inc. of The Woodlands, Texas, USA) and 2B-1 (Chiron), may be administered in combination with a compound of formula 1. Such erbB2 inhibitors include Herceptin, 2C4, and pertuzumab. Such erbB2 inhibitors include those described in WO 98/02434 (published January 22, 1998), WO 99/35146 (published July 15, 1999), WO 99/35132 (published July 15, 1999), WO 98/02437 (published January 22, 1998), WO 97/13760 (published April 17, 1997), WO 95/19970 (published July 27, 1995), United States Patent 5,587,458 (issued December 24, 1996), and United States Patent 5,877,305 (issued March 2, 1999), each of which is herein incorporated by reference in its entirety. ErbB2 receptor inhibitors useful in the present invention are also described in United States Provisional Application No. 60/117,341 , filed January 27, 1999, and in United States Provisional Application No. 60/117,346, filed January 27, 1999, both of which are herein incorporated by reference in their entirety. Other erbb2 receptor inhibitors include TAK-165 (Takeda) and GW-572016 (Glaxo-Wellcome). Various other compounds, such as styrene derivatives, have also been shown to possess tyrosine kinase inhibitory properties, and some of tyrosine kinase inhibitors have been identified as erbB2 receptor inhibitors. More recently, five European patent publications, namely EP 0 566 226 A1 (published October 20, 1993), EP 0 602 851 A1 (published June 22, 1994), EP 0 635 507 A1 (published January 25, 1995), EP 0 635 498 A1 (published January 25, 1995), and EP 0 520 722 A1 (published December 30, 1992), refer to certain bicyclic derivatives, in particular quinazoline derivatives, as possessing anti-cancer properties that result from their tyrosine kinase inhibitory properties. Also, World Patent Application WO 92/20642 (published November 26, 1992), refers to certain bis-mono and bicyclic aryl and heteroaryl compounds as tyrosine kinase inhibitors that are useful in inhibiting abnormal cell proliferation. World Patent Applications WO96/16960 (published June 6, 1996), WO 96/09294 (published March 6, 1996), WO 97/30034 (published August 21 , 1997), WO 98/02434 (published January 22, 1998), WO 98/02437 (published January 22, 1998), and WO 98/02438 (published January 22, 1998), also refer to substituted bicyclic heteroaromatic derivatives as tyrosine kinase inhibitors that are useful for the same purpose. Other patent applications that refer to anti-cancer compounds are World Patent Application WO00/44728 (published August 3, 2000), EP 1029853A1 (published August 23, 2000), and WO01/98277 (published December 12, 2001) all of which are incorporated herein by reference in their entirety. Other antiproliferative agents that may be used with the compounds of the present invention include inhibitors of the enzyme famesyl protein transferase and inhibitors of the receptor tyrosine kinase PDGFr, including the compounds disclosed and claimed in the following United States patent applications: 09/221946 (filed December 28, 1998); 09/454058 (filed December 2, 1999); 09/501163 (filed February 9, 2000); 09/539930 (filed March 31, 2000); 09/202796 (filed May 22, 1997); 09/384339 (filed August 26, 1999); and 09/383755 (filed August 26, 1999); and the compounds disclosed and claimed in the following United States provisional patent applications: 60/168207 (filed November 30, 1999); 60/170119 (filed December 10, 1999); 60/177718 (filed January 21 , 2000); 60/168217 (filed November 30, 1999), and 60/200834 (filed May 1 , 2000). Each of the foregoing patent applications and provisional patent applications is herein incorporated by reference in their entirety. A compound of formula 1 may also be used with other agents useful in treating abnormal cell growth or cancer, including, but not limited to, agents capable of enhancing antitumor immune responses, such as CTLA4 (cytotoxic lymphocyte antigen 4) antibodies, and other agents capable of blocking CTLA4; and anti-proliferative agents such as other farnesyl protein transferase inhibitors, for example the farnesyl protein transferase inhibitors described in the references cited in the "Background" section, supra. Specific CTLA4 antibodies that can be used in the present invention include those described in United States Provisional Application 60/113,647 (filed December 23, 1998) which is herein incorporated by reference in its entirety. A compound of formula I may be applied as a sole therapy or may involve one or more other anti-tumor substances, for example those selected from, for example, mitotic inhibitors, for example vinblastine; alkylating agents, for example cis-platin, oxaliplatin, carboplatin and cyclophosphamide; anti-metabolites, for example 5-fluorouracil, capecitabine, cytosine arabinoside and hydroxyurea, or, for example, one of the preferred anti-metabolites disclosed in European Patent Application No. 239362 such as N.-(5-[N-(3,4-dihydro-2-methyl- 4-oxoquinazolin-6-ylmethyl)-H-methylamino]-2-thenoyl)-L-glut amic acid; growth factor inhibitors; cell cycle inhibitors; intercalating antibiotics, for example adriamycin and bleomycin; enzymes, for example interferon; and anti-hormones, for example anti-estrogens such as Nolvadex (tamoxifen) or, for example anti-androgens such as Casodex (4'-cyano-3-(4- fluorophenylsulphonyl)-2-hydroxy-2-methyl-3'-(trifluoromethy l)propionanilide). The compounds of the present invention may be used alone or in combination with one or more of a variety of anti-cancer agents or supportive care agents. For example, the compounds of the present invention may be used with cytotoxic agents, e.g., one or more selected from the group consisting of a camptothecin, irinotecan HCI (Camptosar), edotecarin, SU-11248, epirubicin (Ellence), docetaxel (Taxotere), paclitaxel, rituximab (Rituxan) bevacizumab (Avastin), imatinib mesylate (Gleevac), Erbitux, gefitinib (Iressa), and combinations thereof. The invention also contemplates the use of the compounds of the present invention together with hormonal therapy, e.g., exemestane (Aromasin), Lupron, anastrozole (Arimidex), tamoxifen citrate (Nolvadex), Trelstar, and combinations thereof. Further, the invention provides a compound of the present invention alone or in combination with one or more supportive care products, e.g., a product selected from the group consisting of Filgrastim (Neupogen), ondansetron (Zofran), Fragmin, Procrit, Aloxi, Emend, or combinations thereof. Such conjoint treatment may be achieved by way of the simultaneous, sequential or separate dosing of the individual components of the treatment. The compounds of the invention may be used with antitumor agents, alkylating agents, antimetabolites, antibiotics, plant-derived antitumor agents, camptothecin derivatives, tyrosine kinase inhibitors, antibodies, interferons, and/or biological response modifiers. In this regard, the following is a non-limiting list of examples of secondary agents that may be used with the compounds of the invention. • Alkylating agents include, but are not limited to, nitrogen mustard N-oxide, cyclophosphamide, ifosfamide, melphalan, busulfan, mitobronitol, carboquone, thiotepa, ranimustine, nimustine, temozolomide, AMD-473, altretamine, AP-5280, apaziquone, brostallicin, bendamustine, carmustine, estramustine, fotemustine, glufosfamide, ifosfamide, KW-2170, mafosfamide, and mitolactol; platinum- coordinated alkylating compounds include but are not limited to, cisplatin, carboplatin, eptaplatin, lobaplatin, nedaplatin, oxaliplatin or satrplatin; • Antimetabolites include but are not limited to, methotrexate, 6-mercaptopurine riboside, mercaptopurine, 5-fluorouracil (5-FU) alone or in combination with leucovorin, tegafur, UFT, doxifluridine, carmofur, cytarabine, cytarabine ocfosfate, enocitabine, S-1 , gemcitabine, fludarabin, 5-azacitidine, capecitabine, cladribine, clofarabine, decitabine, eflornithine, ethynylcytidine, cytosine arabinoside, hydroxyurea, TS-1 , melphalan, nelarabine, nolatrexed, ocfosfate, disodium premetrexed, pentostatin, pelitrexol, raltitrexed, triapine, trimetrexate, vidarabine, vincristine, vinorelbine; or for example, one of the preferred anti-metabolites disclosed in European Patent Application No. 239362 such as N-(5-[N-(3,4-dihydro-2-methyl-4- oxoquinazolin-6-ylmethyl)-N-methylamino]-2-thenoyl)-L-glutam ic acid; • Antibiotics include but are not limited to: aclarubicin, actinomycin D, amrubicin, annamycin, bleomycin, daunorubicin, doxorubicin, elsamitrucin, epirubicin, galarubicin, idarubicin, mitomycin C, nemorubicin, neocarzinostatin, peplomycin, pirarubicin, rebeccamycin, stimalamer, streptozocin, valrubicin or zinostatin; • Hormonal therapy agents, e.g., exemestane (Aromasin), Lupron, anastrozole (Arimidex), doxercalciferol, fadrozole, formestane, anti-estrogens such as tamoxifen citrate (Nolvadex) and fulvestrant, Trelstar, toremifene, raloxifene, lasofoxifene, letrozole (Femara), or anti-androgens such as bicalutamide, flutamide, mifepristone, nilutamide, Casodex® (4'-cyano-3-(4-fluorophenylsulphonyl)-2-hydroxy-2-methyl-3'- (trifluoromethyl)propionanilide) and combinations thereof; • Plant derived anti-tumor substances include for example those selected from mitotic inhibitors, for example vinblastine, docetaxel (Taxotere) and paclitaxel; • Cytotoxic topoisomerase inhibiting agents include one or more agents selected from the group consisting of aclarubicn, amonafide, belotecan, camptothecin, 10- hydroxycamptothecin, 9-aminocamptothecin, diflomotecan, irinotecan HCI (Camptosar), edotecarin, epirubicin (Ellence), etoposide, exatecan, gimatecan, lurtotecan, mitoxantrone, pirarubicin, pixantrone, rubitecan, sobuzoxane, SN-38, tafluposide, and topotecan, and combinations thereof; • Immunologicals include interferons and numerous other immune enhancing agents. Interferons include interferon alpha, interferon alpha-2a, interferon, alpha-2b, interferon beta, interferon gamma-1a or interferon gamma-n1. Other agents include filgrastim, lentinan, sizofilan, TheraCys, ubenimex, WF-10, aldesleukin, alemtuzumab, BAM-002, dacarbazine, daclizumab, denileukin, gemtuzumab ozogamicin, ibritumomab, imiquimod, lenograstim, lentinan, melanoma vaccine (Corixa), molgramostim, OncoVAX-CL, sargramostim, tasonermin, tecleukin, thymalasin, tositumomab, Virulizin, Z-100, epratuzumab, mitumomab, oregovomab, pemtumomab, Provenge; • Biological response modifiers are agents that modify defense mechanisms of living organisms or biological responses, such as survival, growth, or differentiation of tissue cells to direct them to have anti-tumor activity. Such agents include krestin, lentinan, sizofiran, picibanil, or ubenimex. • Other anticancer agents include alitretinoin, ampligen, atrasentan bexarotene, bortezomib. Bosentan, calcitriol, exisulind, finasteride.fotemustine, ibandronic acid, miltefosine, mitoxantrone, l-asparaginase, procarbazine, dacarbazine, hydroxycarbamide, pegaspargase, pentostatin, tazarotne, TLK-286, Velcade, Tarceva, or tretinoin; • Other anti-angiogenic compounds include acitretin, fenretinide, thalidomide, zoledronic acid, angiostatin, aplidine, cilengtide, combretastatin A-4, endostatin, halofuginone, rebimastat, removab, Revlimid, squalamine, ukrain and Vitaxin; • Platinum-coordinated compounds include but are not limited to, cisplatin, carboplatin, nedaplatin, or oxaliplatin; • Camptothecin derivatives include but are not limited to camptothecin, 10- hydroxycamptothecin, 9-aminocamptothecin, irinotecan, SN-38, edotecarin, and topotecan; • Tyrosine kinase inhibitors are lressa or SU5416; • Antibodies include Herceptin, Erbitux, Avastin, or Rituximab; • Interferons include interferon alpha, interferon alpha-2a, interferon, alpha-2b, interferon beta, interferon gamma-1 a or interferon gamma-n1 ; • Biological response modifiers are agents that modify defense mechanisms of living organisms or biological responses, such as survival, growth, or differentiation of tissue cells to direct them to have anti-tumor activity. Such agents include krestin, lentinan, sizofiran, picibanil, or ubenimex; and Other antitumor agents include mitoxantrone, l-asparaginase, procarbazine, dacarbazine, hydroxycarbamide, pentostatin, or tretinoin. "Abnormal cell growth", as used herein, unless otherwise indicated, refers to cell growth that is independent of normal regulatory mechanisms (e.g., loss of contact inhibition). This includes the abnormal growth of: (1) tumor cells (tumors) that proliferate by expressing a mutated tyrosine kinase or overexpression of a receptor tyrosine kinase; (2) benign and malignant cells of other proliferative diseases in which aberrant tyrosine kinase activation occurs; (4) any tumors that proliferate by receptor tyrosine kinases; (5) any tumors that proliferate by aberrant serine/threonine kinase activation; and (6) benign and malignant cells of other proliferative diseases in which aberrant serine/threonine kinase activation occurs. The compounds of the present invention are potent inhibitors of the FAK protein tyrosine kinases, and thus are all adapted to therapeutic use as antiproliferative agents (e.g., anticancer), antitumor (e.g., effective against solid tumors), antiangiogenesis (e.g., stop or prevent proliferationation of blood vessels) in mammals, particularly in humans. In particular, the compounds of the present invention are useful in the prevention and treatment of a variety of human hyperproliferative disorders such as malignant and benign tumors of the liver, kidney, bladder, breast, gastric, ovarian, colorectal, prostate, pancreatic, lung, vulval, thyroid, hepatic carcinomas, sarcomas, glioblastomas, head and neck, and other hyperplastic conditions such as benign hyperplasia of the skin (e.g., psoriasis) and benign hyperplasia of the prostate (e.g., BPH). It is, in addition, expected that a compound of the present invention may possess activity against a range of leukemias and lymphoid malignancies. In one preferred embodiment of the present invention cancer is selected from lung cancer, bone cancer, pancreatic cancer, gastric, skin cancer, cancer of the head or neck, cutaneous or intraocular melanoma, uterine cancer, ovarian cancer, gynecological, rectal cancer, cancer of the anal region, stomach cancer, colon cancer, breast cancer, uterine cancer, carcinoma of the fallopian tubes, carcinoma of the endometrium, carcinoma of the cervix, carcinoma of the vagina, carcinoma of the vulva, Hodgkin's Disease, cancer of the esophagus, cancer of the small intestine, cancer of the endocrine system, cancer of the thyroid gland, cancer of the parathyroid gland, cancer of the adrenal gland, sarcoma of soft tissue, cancer of the urethra, cancer of the penis, squamous cell, prostate cancer, chronic or acute leukemia, lymphocytic lymphomas, cancer of the bladder, cancer of the kidney or ureter, renal cell carcinoma, carcinoma of the renal pelvis, neoplasms of the central nervous system (CNS), primary CNS lymphoma, spinal axis tumors, brain, pituitary adenoma, or a combination of one or more of the foregoing cancers. In a more preferred embodiment cancer is selected a solid tumor, such as, but not limited to, breast, lung, colon, brain, prostate, stomach, pancreatic, ovarian, skin (melanoma), endocrine, uterine, testicular, and bladder. The compounds of the present invention may also be useful in the treatment of additional disorders in which aberrant expression ligand/receptor interactions or activation or signalling events related to various protein tyrosine kinases, are involved. Such disorders may include those of neuronal, glial, astrocytal, hypothalamic, and other glandular, macrophagal, epithelial, stromal, and blastocoelic nature in which aberrant function, expression, activation or signalling of the erbB tyrosine kinases are involved. In addition, the compounds of the present invention may have therapeutic utility in inflammatory, angiogenic and immunologic disorders involving both identified and as yet unidentified tyrosine kinases that are inhibited by the compounds of the present invention. A particular aspect of this invention is directed to methods for treating or preventing a condition that presents with low bone mass in a mammal (including a human being) which comprise administering to a mammal in need of such treatment a condition that presents with low bone mass treating amount of a Formula I compound or a pharmaceutically acceptable salt of said compound. This invention is particularly directed to such methods wherein the condition that presents with low bone mass is osteoporosis, frailty, an osteoporotic fracture, a bone defect, childhood idiopathic bone loss, alveolar bone loss, mandibular bone loss, bone fracture, osteotomy, periodontitis or prosthetic ingrowth. A particular aspect of this invention is directed to methods for treating osteoporosis in a mammal (including a human being) which comprise administering to a mammal in need of such treatment an osteoporosis treating amount of a Formula I compound or a pharmaceutically acceptable salt of said compound. Another aspect of this invention is directed to methods for treating a bone fracture or an osteoporotic fracture in a mammal which comprise administering to a mammal in need of such treatment a bone fracture treating or an osteoporotic fracture treating amount of a Formula I compound or a pharmaceutically acceptable salt of said compound. The term "osteoporosis" includes primary osteoporosis, such as senile, postmenopausal and juvenile osteoporosis, as well as secondary osteoporosis, such as osteoporosis due to hyperthyroidism or Cushing syndrome (due to corticosteroid use), acromegaly, hypogonadism, dysosteogenesis and hypophospatasemia. The term "treating", as used herein, unless otherwise indicated, means reversing, alleviating, inhibiting the progress of, or preventing the disorder or condition to which such term applies, or one or more symptoms of such disorder or condition. The term "treatment", as used herein, unless otherwise indicated, refers to the act of treating as "treating" is defined immediately above. The present invention also provides a pharmaceutical composition comprising a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, as hereinbefore defined in association with a pharmaceutically acceptable adjuvant, diluent or carrier. The invention further provides a process for the preparation of a pharmaceutical composition of the invention which comprises mixing a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, as hereinbefore defined with a pharmaceutically acceptable adjuvant, diluent or carrier. For the above-mentioned therapeutic uses the dosage administered will, of course, vary with the compound employed, the mode of administration, the treatment desired and the disorder indicated. The daily dosage of the compound of formula (l)/salt/solvate (active ingredient) may be in the range from 1 mg to 1 gram, preferably 1 mg to 250 mg, more preferably 10 mg to 100 mg. The present invention also encompasses sustained release compositions. Detailed Description of the Invention The compounds of formula 1 can be prepared using the synthetic route outlined in Scheme 1. The substituents in Scheme 1 have the same meaning as the substituents defined for formula 1.

H R4^(CR1R2X1R3

Scheme 1 Compounds of formula 1 can be prepared starting from the fused aromatic amine (2) and pyrimidine (3). Combining 3 with a Lewis Acid at temperatures ranging from -15 to 450C for a time period of 10-60 minutes in an inert solvent (or solvent mixture) followed by addition of 2a and a suitable base provides after the period of 1-24 h the intermediate 4- chloropyrimidine (4) in high yields. Examples of inert solvents include but are not limited to THF, 1 ,4-dioxane, n-BuOH, i-PrOH, dichloromethane and 1 ,2-dichloroethane. Examples of suitable bases employed may include but are not limited to (i) non-nucleophilic organic bases for example triethylamine or diisopropylethylamine (ii) inorganic bases such as potassium carbonate or cesium carbonate or (iii) resin bound bases such as MP-carbonate. Examples of Lewis Acids include but are not limited to halide salts of magnesium, copper, zinc, tin or titanium. In the next reaction, intermediate 4 is reacted with an amine of the formula 5 either neat or in the presence of an inert solvent (or solvent mixture) at temperatures ranging from 0 to 15O0C to provide the compounds of formula 1. Optionally this reaction can be run in the presence of a suitable base. Examples of suitable solvents for this reaction include but are not limited to THF, 1 ,4-dioxane, DMF, N-methyl-pyrrolidinone, EtOH, n-BuOH, i-PrOH, dichloromethane, 1 ,2-dichloroethane, DMSO or acetonitrile. Suitable bases are as outlined above. With respect to the preparation of bromo-substituted pyrimidines of the present invention, as identified above in formula 2, reference is made to U.S. Patent Application Serial No. 10/734,039, filed December 11 , 2003 (Attorney Docket No. PC25339A), and in particular to the description at pages 32-33 of the specification, as well as the general methods and examples provided therein. Compounds of the present invention may be synthetically transformed into other compounds of the invention by techniques known to those skilled in the art. Simply for illustrative purposes and without limitation, such methods include: a) removal of a protecting group by methods outlined in T. W. Greene and P. G. M. Wuts, "Protective Groups in Organic Synthesis", Second Edition, John Wiley and Sons, New York, 1991 ; e.g., emoval of a BOC protecting group with an acid source such as HCI or trifluoroacetic acid; b) displacement of a leaving group (halide, mesylate, tosylate, etc) with functional groups such as but not limited to a primary or secondary amine, thiol or alcohol to form a secondary or tertiary amine, thioether or ether, respectively; c) treatment of phenyl (or substituted phenyl) carbamates with primary of secondary amines to form the corresponding ureas as in Thavonekham, B et. al. Synthesis (1997), 10. p1189; d) reduction of propargyl or homopropargyl alcohols or N-BOC protected primary amines to the corresponding E-allylic or E-homoallylic derivatives by treatment with sodium bis(2-methoxyethoxy)aluminum hydride (Red-AI) as in Denmark, S. E.; Jones, T. K. J. Org. Chem. (1982) 47, 4595-4597 or van Benthem, R. A. T. M.; Michels, J. J.; Speckamp, W. N. Synlett (1994), 368-370; e) reduction of alkynes to the corresponding Z-alkene derivatives by treatment hydrogen gas and a Pd catalyst as in Tomassy, B. et. al. Synth. Commun. (1998), 28, p1201 ; f) treatment of primary and secondary amines with an isocyanate, acid chloride (or other activated carboxylic acid derivative), alkyl/aryl chloroformate or sulfonyl chloride to provide the corresponding urea, amide, carbamate or sulfonamide; g) reductive amination of a primary or secondary amine using an aldehyde or ketone and an appropriate reducing reagent; h) treatment of alcohols with an isocyanate, acid chloride (or other activated carboxylic acid derivative), alkyl/aryl chloroformate or sulfonyl chloride to provide the corresponding carbamate, ester, carbonate or sulfonic acid ester. Amines of the formula 5 may be purchased and used directly or alternatively be prepared by one skilled in the art using ordinary chemical transformations. For example; arylalkylamines or heteroarylalkylamines may be prepared from the corresponding nitrile by catalytic hydrogenation using catalysts such as Pd/C or Raney Nickel or by lithium aluminum hydride reduction, (see Rylander, Catalytic Hydrogenation in Organic Synthesis, Academic Press, 1979).

The nitrile starting materials can be either purchased or prepared from the corresponding aryl/heteroaryl bromide, iodide or triflate and Zn(CN)2 using Pd coupling conditions found in Tschaen, D. M., et. al Synthetic Communications (1994), 24, 6, pp 887- 890.

Heteroaryl nitriles can be prepared by nucleophilic addition of an alkali metal cyanide to an alkylsulfonylated heteroaromatic system in an inert solvent at temperatures ranging from 22-1000C.

Alternatively, nitriles can be prepared by dehydration of the corresponding primary amide derivative using trifluoroacetic anhydride and pyridine in an inert solvent.

Benzyl or heteroarylmethylamines can be prepared by reacting the appropriate arylalkyl or heteroarylalkyl halide and the potassium salt of (BOC)2NH and subsequent removal of the BOC groups with acid.

Amines, protected forms of amines, precursors to amines and precursors to the protected forms of amines of formula 5 can be prepared by combining the appropriate alkyne, or alkenyl stannane, alkenyl borane, alkenyl boronic acid, boronic ester with the appropriate aryl or heteroaryl bromide, iodide or triflate using Pd coupling conditions as found in Tsuji, J.; Palladium Reagents and Catalysis, John Wiley and Sons 1999 and references cited therein.

Appropriately protected amines of formula 5 may be converted to different amines of formula 5 according to methods familiar to those skilled in the art for exampleas but limited to: (a) oxidation of a thioether to a sulfoxide or sulfone.

(b) N-alkylation of a sulfanilide can be achieved under phase transfer using conditions described by Brehme, R. "Synthesis", (1976), pp113-114.

Inert Solvent

N-aryl sulfonamides may be prepared by the reaction of an appropriately substituted 2-fluorobenzylnitrile with a sulfonamide using cesium carbonate or potassium carbonate in an inert solvent at a temperature of 22 - 1000C.

N-heteroaryl sulfonamides may be prepared by the reaction of the appropriately substituted halogenated pyridine, pyrimidine or pyrazine with a sulfonamide using cesium carbonate in an inert solvent at a termperature of 22 - 100° C.

Alternatively, N-heteroaryl sulfonamides may be prepared from heteroaromaic N- oxides by displacement of a halogen with a sulfonamide anion using cesium carbonate in an inert solvent in a sealed tube at a temperature of 70°C.

As understood by those skilled in the art, the chemical transformation to convert an aryl halide or triflate or heteroaryl halide or triflate to an aromatic or heteroaromatic amine may be carried out using conditions currently outlined in the literature, see Hartwig, J. F.: "Angew. Chem. Int. Ed." (1998), 37, pp. 2046-2067, Wolfe, J. P.; Wagaw, S.; Marcoux, J. F.; Buchwald, S.L.; "Ace. Chem. Res.", (1998), 31 , pp 805-818, Wolfe, J. P.; Buchwald, S.L.; "J. Org. Chem.", (2000), 65, pp 1144-1157, Muci, A. R.; Buchwald, S. L.; "Topics in Current Chemistry" (2002), pp131-209 and references cited therein. Further, as understood by those skilled in the art, these same aryl or heteroaryl aminatiion chemical transformations may alternatively be carried out on nitrile (or primary amide) precursors which provide amines of the formula 5 after nitrile (or amide) reduction. Protected amines of formula 5 may be further converted to different amines of formula 5 according to methods familiar to those skilled in the art.

The in vitro activity of the compounds of formula 1. may be determined by the following procedure. More particularly, the following assay provides a method to determine whether compounds of the formula 1_ inhibit the tyrosine kinase activity of the catalytic construct FAK(410-689). The assay is an ELISA-based format, measuring the inhibition of poly-glu-tyr phosphorylation by FAK(410-689). The assay protocol has three parts: I. Purification and cleavage of His-FAK(410-689) II. FAK410-689 (a.k.a. FAKcd) Activation III. FAKcd Kinase ELISA Materials: -Ni-NTA agarose (Qiagen) -XK-16 column (Amersham-Pharmacia) -300 mM Imidizole -Superdex 200 HiLoad 16/60 prep grade column (Amersham Biotech.) -Antibody: Anti-Phosphotyrosine HRP-Conjugated Py20 (Transduction labs). -FAKcd: Purified and activated in house -TMB Microwell Peroxidase Substrate (Oncogene Research Products #CL07) -BSA: Sigma #A3294 -Tween-20: Sigma #P1379 -DMSO: Sigma #D-5879 -D-PBS: Gibco #14190-037. Reaqents for Purification: -Buffer A: 5OmM HEPES pH 7.0, 50OmM NaCI, 0.1 mM TCEP CompIeteTM protease inhibitor cocktail tablets (Roche) -Buffer B: 25mM HEPES pH 7.0, 40OmM NaCI, 0.1 mM TCEP. -Buffer C: 1OmM HEPES pH 7.5, 20OmM Ammonium Sulfate, 0.1 mM TCEP. Reagents for Activation -FAK(410-689): 3 tubes of frozen aliquots at 150ul/tube for a total of 45OuI at 1.48 mg/ml (660ug) -His-Src(249-524): -0.74 mg/ml stock in 1OmM HEPES, 20OmM (NH4)2SO4 -Src reaction buffer (Upstate Biotech): 100 mM Tris-HCI pH7.2, 125mM MgCI2, 25 mM MnCI2, 2mM EDTA, 250 uM Na3VO4, 2 mM DTT -Mn2+/ATP cocktail (Upstate Biotech) 75mM MnCI2 500 uM ATP 2OmM MOPS pH 7.2 1mM Na3VO4 25mM D-glycerol phosphate 5mM EGTA 1mM DTT -ATP: 150mM stock -MgCI2: 1 M Stock -DTT: 1 M stock Reagents for FAKcd Kinase ELISA -Phosphorylation Buffer: 5OmM HEPES, pH 7.5, 125mM NaCI, 48mM MgCI2 -Wash Buffer: TBS + 0.1 % Tween-20. -Blocking Buffer: Tris Buffer Saline, 3% BSA, 0.05% Tween-20, filtered. -Plate Coating Buffer: 50mg/ml Poly-Glu-Tyr (Sigma #P0275) in Phosphate buffer Saline (DPBS). -ATP: 0.1 M ATP in H2O or HEPES, pH7. Note: ATP Assay Buffer: Make up as 75 uM ATP in PBS, so that 80 ul in 120 ul reaction volume=50uM final ATP concentration. I. Purification of His-FAKcd(410-689) 1. Resuspend 13O g baculovirus cell paste containing the over expressed His- FAKcd410-689 recombinant protein in 3 volumes (400ml) of Buffer A. 2. Lyse cells with one pass on a microfluidizer. 3. Remove cell debris by centrifugation at 4OC for 35 minutes at 14,000 rpm in a Sorval SLA-1500 rotor. 4. Transfer the supernatant to a clean tube and add 6.0 ml of Ni-NTA agarose (Qiagen). 5. Incubate the suspension with gentle rocking at 4OC for 1 hour. 6. Centrifuge suspension at 700 x g in a swinging bucket rotor. 7. Discard the supernatant and resuspend the agarose beads in 20.0 ml of Buffer A. 8. Transfer the beads to an XK-16 column (Amersham-Pharmacia) connected to a FPLCTM. 9. Wash the agarose-beads with 5 column volumes of Buffer A and elute off the column with a step gradient of Buffer A containing 30OmM Imidizole. 10. Perform a buffer exchange of the eluted fractions into Buffer B. 11. Following buffer exchange, pool the fractions and add thrombin at a 1 :300 (w/w) ratio and incubated overnight at 130C to remove the N-terminal His-tag (His-FAK410- 698 -» FAK410-689 (a.k.a. FAKcd)). 12. Add the reaction mixture back onto the Ni-NTA column equilibrated with Buffer A and collect the flow-through. 13. Concentrate the flow-through down to 1.7 ml and load directly onto a Superdex 200 HiLoad 16/60 prep grade column equilibrated with Buffer C. The desired protein elutes between 85 - 95 ml. 14. Aliquot the FAKcd protein and store frozen at -800C. II. FAK activation 1. To 45OuI of FAK(410-689) at 1.48 mg/ml (660ug) add the following: 3OuI of 0.037 mg/ml (1 uM) His-Src(249-524) 3OuI of 7.5 mM ATP 12ul of 20 mM MgCI2 1OuI Mn2+/ATP cocktail (UpState Biotech.) 4ul of 6.7mM DTT 6OuI Src Reaction Buffer (UpState Biotech.) 2. Incubate Reaction for at least 3 hours at room temperature At time t0, almost all of the FAK(410-689) is singly phosphorylated. The second phosphorylation is slow. At t120 (t = 120 minutes), add 10ul of 150 mM ATP. T0 = (Start) 90% singly phosphorylated FAK(410-689) (1 PO4) T43 = (43 min) 65% singly phosphorylated (1 PO4), 35% doubly phosphorylated (2 PO4) T90 = (90 min) 45% 1 PO4, 55% 2 PO4 T150 = 15% 1 PO4, 85% 2 PO4 T2io = <10% 1 PO4, >90% 2 PO4 desalted sample 3. Add 180 ul aliquots of the desalted material to NiNTA spin column and incubate on spin column 4. Spin at 10k rpm (microfuge), for 5 min to isolate and collect flow through (Activated FAK(410-689)) and remove His-Src (captured on column) III. FAKcd Kinase ELISA 1. Coat 96-well Nunc MaxiSorp plates with poly-glu-tyr (pGT) at 10 ug/well: Prepare 10 ug/ml of pGT in PBS and aliquot 100 ul/well. Incubate the plates at 37°C overnight, aspirate the supernatant, wash the plates 3 times with Wash Buffer, and flick to dry before storing at 4°C. 2. Prepare compound stock solutions of 2.5 mM in 100% DMSO. The stocks are subsequently diluted to 6OX of the final concentration in 100% DMSO, and diluted 1 :5 in Kinase Phosphorylation Buffer. 3. Prepare a 75 uM working ATP solution in Kinase phosphorylation buffer. Add 80 ul to each well for a final ATP concentration of 50 uM. 4. Transfer 10 ul of the diluted compounds (O.δlog serial dilutions) to each well of the pGT assay plate, running each compound in triplicates on the same plate. 5. Dilute on ice, FAKcd protein to 1 :1000 in Kinase Phosphorylation Buffer. Dispense 30 ul per well. 6. Note: Linearity and the appropriate dilution must be pre-determined for each batch of protein. The enzyme concentration selected should be such that quantitation of the assay signal will be approximately 0.8-1.0 at OD450, and in the linear range of the reaction rate. 7. Prepare both a No ATP control (noise) and a No Compound Control (Signal). 8. (Noise) One blank row of wells receives 10 ul of 1 :5 diluted compounds in DMSO, 8OuI of Phosphorylation buffer (minus ATP), and 30 ul FAKcd solution. 9. (Siganl) Control wells receive 10 ul of 1 :5 diluted DMSO (minus Compound) in Kinase phosphorylation buffer, 80 ul of 75 u M ATP, and 30 ul of 1 :1000 FAKcd enzyme. 10. Incubate reaction at room temperature for 15 minutes with gentle shaking on a plate shaker. 11. Terminate the reaction by aspirating off the reaction mixture and washing 3 times with wash buffer. 12. Dilute phospho-tyrosine HRP-conjugated (pY20HRP) antibody to 0.250ug/ml (1 :1000 of Stock) in blocking buffer. Dispense 100 ul per well, and incubate with shaking for 30 minutes at room temperature. 13. Aspirate the supernatant and wash the plate 3 times with wash buffer. 14. Add 100 ul per well of room temperature TMB solution to initiate color development. Color development is terminated after approximately 15-30 sec. by the addition of 10Oul of 0.09M H2SO4 per well. 15. The signal is quantitated by measurement of absorbance at 450nm on the BioRad microplate reader or a microplate reader capable of reading at OD450. 16. Inhibition of tyrosine kinase activity would result in a reduced absorbance signal. The signal is typically 0.8-1.0 OD units. The values are reported as IC50s, uM concentration. FAK Inducible cell-based ELISA: Final Protocol Materials: Reacti-Bind Goat Anti-Rabbit Plates 96-well (Pierce Product#15135ZZ @115.00 USD) FAKpY397 rabbit polyclonal antibody (Biosource #44624 @315.00 USD) ChromePure Rabbit IgG, whole molecule (Jackson Laboratories #001-000-003 @60/25mg USD) UBI ccFAK clone 2A7 mouse monoclonal antibody (Upstate#05-182 @ 289.00 USD) Peroxidase-conjugated AffiniPure Goat Anti-Mouse IgG (Jackson Labs #115-035-146 @95/1.5ml USD) SuperBlock TBS (Pierce Product#37535ZZ @99 USD) Bovine Serum Albumin (Sigma #A-9647 @117.95/100 g USD) TMB Peroxidase substrate (Oncogene Research Products #CL07-1 OfJmI @40.00 USD) Na3VO4 Sodium Orthovanadate (Sigma #S6508 @43.95/50g USD) MTT substrate (Sigma # M-2128 @25.95/500mg USD) Growth Media: DMEM+10%FBS, P/S, GIu, 750 ug/ml Zeocin and 50 ug/ml Hygromycin (Zeocin InVitrogen #R250-05 @ 725 USD and Hygromycon InVitrogen #R220-05 @ 150 USD) Mifepristone InVitrogen # H110-01 @ 125 USD CompleteTM EDTA-free Protease Inhibitor pellet Boehringer Mannheim #1873580 FAK cell-based Protocol for selectivity of kinase-dependent phosphoFAKY397 Procedure: An inducible FAK cell-based assay in ELISA format for the screening of chemical matter to identify tyrosine kinase specific inhibitors was developed. The cell-based assay exploits the mechanism of the GeneSwitchTM system (InVitrogen) to exogenously control the expression and phosphorylation of FAK and the kinase-dependent autophosphorylation site at residue Y397. Inhibition of the kinase-dependent autophosphorylation at Y397 results in a reduced absorbance signal at OD450. The signal is typically 0.9 to 1.5 OD450 units with the noise falling in the range of 0.08 to 0.1 OD450 units. The values are reported as IC50s, uM concentration. On day 1 , grow A431»FAKwt in T175 flasks. On the day prior to running the FAK cell-assay, seed A431»FAKwt cells in growth media on 96-well U-bottom plates. Allow cells to sit at 37oC, 5% CO2 for 6 to 8 hours prior to FAK induction. Prepare Mifepristone stock solution of 10 uM in 100% Ethanol. The stock solution is subsequently diluted to 10 X of the final concentration in Growth Media. Transfer 10 ul of this dilution (final concentration of 0.1 nM Mifepristone) into each well. Allow cells to sit at 37°C, 5% CO2 overnight (12 to 16 hours). Also, prepare control wells without Mifepristone induction of FAK expression and phosphorylation. On day 2, coat Goat Anti-Rabbit plate(s) with 3.5 ug/ml of phosphospecific FAKp Y397 polyclonal antibody prepared in SuperBlock TBS buffer, and allow plate(s) to shake on a plate shaker at room temperature for 2 hours. Optionally, control wells may be coated with 3.5 ug/ml of control Capture antibody (Whole Rabbit IgG molecules) prepared in SuperBlock TBS. Wash off excess FAKpY397 antibody 3 times using buffer. Block Anti-FAKpY397 coated plate(s) with 200 ul per well of 3%BSA/0.5%Tween Blocking buffer for 1 hour at room temperature on the plate shaker. While the plate(s) are blocking, prepare compound stock solutions of 5 mM in 100% DMSO. The stock solutions are subsequently serially diluted to 100X of the final concentration in 100% DMSO. Make a 1 :10 dilution using the 100X solution into growth media and transfer 10 ul of the appropriate compound dilutions to each well containing either the FAK induced or uninduced control A431 cells for 30 minutes at 37°C, 5% CO2. Prepare RIPA lysis buffer (50 mM Tris-HCI, pH7.4, 1% NP-40, 0.25% Na-deoxycholate, 150 mM NaCI, 1 mM EDTA, 1 mM Na3VO4, 1 mM NaF, and one CompleteTM EDTA-free protease inhibitor pellet per 50 ml solution). At the end of 30 minutes compound treatment, wash off compound 3 times using TBS-T wash buffer. Lyse cells with 100 ul/well of RIPA buffer. To the coated plate, remove blocking buffer and wash 3 times using TBS-T wash buffer. Using a 96-well automated microdispenser, transfer 100 ul of whole cell-lysate (from step 6) to the Goat Anti-Rabbit FAKp Y397 coated plate(s) to capture phosphoFAKY397 proteins. Shake at room temperature for 2 hours. Wash off unbound proteins 3 times using TBS-T wash buffer. Prepare 0.5 ug/ml (1 :2000 dilution) of UBI αFAK detection antibody in 3%BSA/0.5% Tween blocking buffer. Dispense 100 ul of UBI αFAK solution per well and shake for 30 minutes at room temperature. Wash off excess UBI αFAK antibody 3 times using TBS-T wash buffer. Prepare 0.08 ug/ml (1 :5000 dilution) of secondary Anti-Mouse Peroxidase (Anti-2MHRP) conjugated antibody. Dispense 100 ui per well of the Anti-2MHRP solution and shake for 30 minutes at room temperature. Wash off excess Anti-2MHRP antibody 3 times using TBS-T wash buffer. Add 100 ul per well of room temperature TMB substrate solution to allow for color development. Terminate the TMB reaction with 100 ul per well of TMB stop solution (0.09M H2SO4) and quantitate the signal by measurement of absorbance at 450 nm on the BioRad microplate reader. Additional FAK cell assays are hereby incorporated by reference from Pfizer Attorney Docket No. PC11699 entitled "INDUCIBLE FOCAL ADHESION KINASE CELL ASSAY". In a preferred embodiment, the compounds of the present invention have an in vitro activity as determined by a kinase assay, e.g., such as that described herein, of less than 500 nM. Preferably, the compounds have an IC50 of less than 25 nM in the kinase assay, and more preferably less than 10 nM. In a further preferred embodiment, the compounds exhibit an IC50 in a FAK cell based assay, e.g., such as that described herein, of less than 1 μM, more preferably less than 100 nM, and most preferably less than 25 nM. Administration of the compounds of the present invention (hereinafter the "active compound(s)") can be effected by any method that enables delivery of the compounds to the site of action. These methods include oral routes, intraduodenal routes, parenteral injection (including intravenous, subcutaneous, intramuscular, intravascular or infusion), topical, and rectal administration. The amount of the active compound administered will be dependent on the subject being treated, the severity of the disorder or condition, the rate of administration, the disposition of the compound and the discretion of the prescribing physician. However, an effective dosage is in the range of about 0.001 to about 100 mg per kg body weight per day, preferably about 1 to about 35 mg/kg/day, in single or divided doses. For a 70 kg human, this would amount to about 0.05 to about 7 g/day, preferably about 0.2 to about 2.5 g/day. In some instances, dosage levels below the lower limit of the aforesaid range may be more than adequate, while in other cases still larger doses may be employed without causing any harmful side effect, provided that such larger doses are first divided into several small doses for administration throughout the day. The active compound may be applied as a sole therapy or may involve one or more other anti-tumour substances, for example those selected from, for example, mitotic inhibitors, for example vinblastine; alkylating agents, for example cis-platin, carboplatin and cyclophosphamide; anti-metabolites, for example 5-fluorouracil, cytosine arabinoside and hydroxyurea, or, for example, one of the preferred anti-metabolites disclosed in European Patent Application No. 239362 such as N-(5-[N-(3,4-dihydro-2-methyl-4-oxoquinazolin-6- ylmethyl)-N.-methylamino]-2-thenoyl)-L-glutamic acid; growth factor inhibitors; cell cycle inhibitors; intercalating antibiotics, for example adriamycin and bleomycin; enzymes, for example interferon; and anti-hormones, for example anti-estrogens such as NolvadexD (tamoxifen) or, for example anti-androgens such as CasodexD (4'-cyano-3-(4- fluorophenylsulphonyl)-2-hydroxy-2-methyl-3'-(trifIuoromethy l)propionanilide). Such conjoint treatment may be achieved by way of the simultaneous, sequential or separate dosing of the individual components of the treatment. The pharmaceutical composition may, for example, be in a form suitable for oral administration as a tablet, capsule, pill, powder, sustained release formulations, solution, suspension, for parenteral injection as a sterile solution, suspension or emulsion, for topical administration as an ointment or cream or for rectal administration as a suppository. The pharmaceutical composition may be in unit dosage forms suitable for single administration of precise dosages. The pharmaceutical composition will include a conventional pharmaceutical carrier or excipient and a compound according to the invention as an active ingredient. In addition, it may include other medicinal or pharmaceutical agents, carriers, adjuvants, etc. Exemplary parenteral administration forms include solutions or suspensions of active compounds in sterile aqueous solutions, for example, aqueous propylene glycol or dextrose solutions. Such dosage forms can be suitably buffered, if desired. Suitable pharmaceutical carriers include inert diluents or fillers, water and various organic solvents. The pharmaceutical compositions may, if desired, contain additional ingredients such as flavorings, binders, excipients and the like. Thus for oral administration, tablets containing various excipients, such as citric acid may be employed together with various disintegrants such as starch, alginic acid and certain complex silicates and with binding agents such as sucrose, gelatin and acacia. Additionally, lubricating agents such as magnesium stearate, sodium lauryl sulfate and talc are often useful for tableting purposes. Solid compositions of a similar type may also be employed in soft and hard filled gelatin capsules. Preferred materials, therefor, include lactose or milk sugar and high molecular weight polyethylene glycols. When aqueous suspensions or elixirs are desired for oral administration the active compound therein may be combined with various sweetening or flavoring agents, coloring matters or dyes and, if desired, emulsifying agents or suspending agents, together with diluents such as water, ethanol, propylene glycol, glycerin, or combinations thereof. Methods of preparing various pharmaceutical compositions with a specific amount of active compound are known, or will be apparent, to those skilled in this art. For examples, see Remington's Pharmaceutical Sciences, Mack Publishing Company, Easter, Pa., 15th Edition (1975). The examples and preparations provided below further illustrate and exemplify the compounds of the present invention and methods of preparing such compounds. It is to be understood that the scope of the present invention is not limited in any way by the scope of the following examples and preparations. In the following examples molecules with a single chiral center, unless otherwise noted, exist as a racemic mixture. Those molecules with two or more chiral centers, unless otherwise noted, exist as a racemic mixture of diastereomers. Single enantiomers/diastereomers may be obtained by methods known to those skilled in the art. Where HPLC chromatography is referred to in the preparations and examples below, the general conditions used, unless otherwise indicated, are as follows. The column used is a ZORBAXD RXC18 column (manufactured by Hewlett Packard) of 150 mm distance and 4.6 mm interior diameter. The samples are run on a Hewlett Packard-1100 system. A gradient solvent method is used running 100 percent ammonium acetate / acetic acid buffer (0.2 M) to 100 percent acetonitrile over 10 minutes. The system then proceeds on a wash cycle with 100 percent acetonitrile for 1.5 minutes and then 100 percent buffer solution for 3 minutes. The flow rate over this period is a constant 3 ml / minute. In the following examples and preparations, "Et" means ethyl, "Ac" means acetyl, "Me" means methyl, and "Bu" means butyl. Examples General Methods: Preparation of 6-(4-Chloro-5-trifluoromethyl-pyrimidin-2-ylamino)-3,4-dihyd ro- 1H-quinolin-2-one To a solution of 2,4-Dichloro-5-trifluoromethyl-pyrimidine (963mg, 4.43 mmol) in 30 ml_ of 50/50 mixture of t-BuOH/DCE was added a solution of ZnCI2 (1M in THF;4.43mL). After one hour 6-Amino-3,4-dihydro-1 H-quinolin-2-one (480mg;2.95 mmol) was added followed by the dropwise addition of triethylamine (0.617 ml, 4.43 mmol) in 2 ml_ t- BUOH/DCE. Following removal of the solvent under reduced pressure, the crude reaction was triturated from methanol and the product filtered off as a yellow solid 723 mg (72 % yield). 1 H NMR (DMSO-d6, 400 MHz) δ 2.39 (t, J = 12Hz; 2H), 2.80 (t, J = 8 Hz; 2H), 6.78 (d, J = 8 Hz; 1H), 7.35 (d, J = 8 Hz; 1 H), 7.40 (br s, 1 H), 8.70 (s, 1 H), 10.02 (s, 1 H), 10.48 (s, 1 H). HPLC ret. time: 6.074 (96% purity), LRMS (M+) 343.2/345.2. Example 1 Preparation of 6-[4-(3-Methanesulfonyl-benzylamino)-5-trifluoromethyl- pyrimidin-2-ylamino1-3,4-dihvdro-1H-quinolin-2-one: 6-(4-Chloro-5-trifluoromethyl-pyrimidin-2-ylamino)-3,4-dihyd ro-1 H-quinolin-2-one ( 50 mg, 0.145 mmol) was added to 0.5 ml NMP and 3-Methanesulfonyl-benzylamine mono hydrochloride salt (32 mg, 0.145 mmoles) and triethylamine (0.060 ml, 0.435 mmoles) were added the reaction was heated to 1000C for one hour. The reaction was cooled to room temperature and 0.5 mL NMP was added. The reaction was then filtered and purify by preparative reverse phase HPLC 30X50 mm XTerra C18 prep column, fifteen minute gradient 15-60% (0.1% NH4OH in Acetonitrile) and (0.1% NH4OH in water)), flow rate 40 mL/min. The desired product eluted (retention time 8.41 minutes) and was concentrated to a solid (38 mg, 54% yield). 1 H NMR (Methanol-d4, 400 MHz) δ 2.52 ( m, 2H), 2.80 (m, 2H), 2.99 (s, 3H), 4.80 (s, 2H), 6.73 (d, J = 9 Hz; 1 H), 7.22 (d, J = 9 Hz; 1 H), 7.37 (s, 1 H), 7.57 (t, J = 8 Hz; 1 H), 7.64 (d, J = 8 Hz;1 H), 7.80 (m, 1 H), 7.90 (s, 1 H), 8.12 (s, 1 H). HPLC ret. time: 5.390, LRMS (M+) 492.12. Other compounds prepared by the method of Example 1 include, but are not limited to the following: N2-[3-(1 ,2,3,6-Tetrahydro-pyridin-4-yl)-1 H-indol-5-yl]-N4-p-tolyl-5-trifluoromethyl- pyrimidine-2,4-diamine; N4-Pyridin-2-yl-N2-[3-(1 ,2,3,6-tetrahydro-pyridin-4-yl)-1 H-indol-5-yl]-5-trifluoromethyI- pyrimidine-2,4-diamine; N2-[3-(1 ,2,3,6-Tetrahydro-pyridin-4-yl)-1H-indol-5-yl]-5-trifluorome thyl-N4-(2- trifluoromethyl-benzyl)-pyrimidine-2,4-diamine; N-[2-({2-[3-(1 ,2,3,6-Tetrahydro-pyridin-4-yl)-1 H-indol-5-ylamino]-5-trifluoromethyl- pyrimidin-4-ylamino}-methyl)-phenyl]-methanesulfonamide; N-Methyl-N-[2-({2-[3-(1 ,2,3,6-tetrahydro-pyridin-4-yl)-1 H-indol-5-ylamino]-5- trifluoromethyl-pyrimidin-4-ylamino}-methyl)-phenyl]-methane sulfonamide; N-Methyl-N-[3-({2-[3-(1 ,2,3,6-tetrahydro-pyridin-4-yl)-1 H-indol-5-ylamino]-5- trifluoromethyl-pyrimidin-4-ylamino}-methyl)-pyridin-2-yl]-m ethanesulfonamide; N-[3-({2-[3-(1 ,2,3,6-Tetrahydro-pyridin-4-yl)-1 H-indol-5-ylamino]-5-trifluoromethyl- pyrimidin-4-ylamino}-methyl)-phenyl]-methanesulfonamide; N-Methyl-N-[3-({2-[3-(1 ,2,3,6-tetrahydro-pyridin-4-yl)-1 H-indol-5-ylamino]-5- trifluoromethyl-pyrimidin-4-ylamino}-methyl)-phenyl]-methane sulfonamide; N4-(3-MethanesuIfonyl-benzyl)-N2-[3-(1 ,2,3,6-tetrahydro-pyridin-4-yl)-1 H-indol-5-yl]- 5-trifluoromethyl-pyrimidine-2,4-diamine; 6-[5-Trifluoromethyl-4-(2-trifluoromethyl-benzylamino)-pyrim idin-2-yiamino]-3,4- dihydro-1 H-quinolin-2-one; N-(2-{[2-(2-Oxo-1,2,3,4-tetrahydro-quinolin-6-ylamino)-5-tri fluoromethyl-pyrimidin-4- ylamino]-methyl}-phenyl)-methanesulfonamide; N-Methyl-N-(2-{[2-(2-oxo-1 ,2,3,4-tetrahydro-quinolin-6-ylamino)-5-trifluoromethyl- pyrimidin-4-ylamino]-methyl}-phenyl)-methanesulfonamide; N-Methyl-N-(3-{[2-(2-oxo-1 ,2,3,4-tetrahydro-quinolin-6-ylamino)-5-trifluoromethyl- pyrimidin-4-ylamino]-methyl}-pyridin-2-yl)-methanesulfonamid e; N-(3-{[2-(2-Oxo-1 ,2,3,4-tetrahydro-quinolin-6-ylamino)-5-trifluoromethyi-pyri midin-4- ylamino]-methyl}-phenyl)-methanesulfonamide; N-Methyl-N-(3-{[2-(2-oxo-1 ,2,3,4-tetrahydro-quinolin-6-ylamino)-5-trifluoromethyl- pyrimidin-4-ylamino]-methyl}-phenyl)-methanesulfonamide; 6-[4-(3-Methanesulfonyl-ben2ylamino)-5-trifluoromethyl-pyrim idin-2-ylamino]-3,4- dihydro-1 H-quinolin-2-one; 7-[5-Trifluoromethyl-4-(2-trifluoromethyl-benzylamino)-pyrim idin-2-ylamino]-3,4- dihydro-1 H-quinolin-2-one; N-(2-{[2-(2-Oxo-1 ,2,3,4-tetrahydro-quinolin-7-ylamino)-5-trifluoromethyl-pyri midin-4- ylamino]-methyl}-phenyl)-methanesulfonamide; N-Methyl-N-(2-{[2-(2-oxo-1 ,2,3,4-tetrahydro-quinolin-7-ylamino)-5-trifluoromethyl- pyrimidin-4-ylamino]-methyl}-phenyl)-methanesulfonamide; N-Methyl-N-(3-{[2-(2-oxo-1 ,2,3,4-tetrahydro-quinolin-7-ylamino)-5-trifluoromethyl- pyrimidin-4-ylamino]-methyl}-pyridin-2-yl)-methanesulfonamid e; N-(3-{[2-(2-Oxo-1 ,2,3,4-tetrahydro-quinoIin-7-ylamino)-5-trifluoromethyl-pyri midin-4- ylamino]-methyl}-phenyl)-methanesulfonamide; N-Methyl-N-(3-{[2-(2-oxo-1 ,2,3,4-tetrahydro-quinolin-7-ylamino)-5-trifluoromethyl- pyrimidin-4-ylamino]-methyl}-phenyl)-methanesulfonamide; 7-[4-(3-Methanesulfonyl-benzylamino)-5-trifluoromethyl-pyrim idin-2-ylamino]-3,4- dihydro-1 H-quinolin-2-one; 7-{4-[(Pyridin-2-ylmethyl)-amino]-5-trifluoromethyl-pyrimidi n-2-ylamino}-3,4-dihydro- 1 H-quinolin-2-one; 6-{4-[(Pyridin-2-ylmethyl)-amino]-5-trifluoromethyl-pyrimidi n-2-ylamino}-3,4-dihydro- 1 H-quinolin-2-one; N-Methyl-N-(3-{[2-(2-oxo-1 ,2,3,4-tetrahydro-quinolin-7-ylamino)-5-trifluoromethyl- pyrimidin-4-ylamino]-methyl}-phenyl)-methanesulfonamide; Methanesulfonic acid 3-{[2-(2-oxo-1 ,2,3,4-tetrahydro-quinolin-7-ylamino)-5- trifluoromethyl-pyrimidin-4-ylannino]-methyl}-phenyl ester; 7-(4-Cyclobutylamino-5-trifluoromethyl-pyrimidin-2-ylamino)- 3,4-dihydro-1 H-quinolin- 2-one; 6-[4-(3-Methanesulfonyl-benzylamino)-5-trifluoromethyl-pyrim idin-2-ylamino]-3,4- dihydro-1 H-quinolin-2-one; N-Methyl-N-(3-{[2-(2-oxo-1 ,2,3,4-tetrahydro-quinolin-6-ylamino)-5-trifluoromethyl- pyrimidin-4-ylamino]-methyl}-phenyl)-methanesulfonamide; Methanesulfonic acid 3-{[2-(2-oxo-1 ,2,3,4-tetrahydro-quinolin-6-ylamino)-5- trifluoromethyl-pyrimidin-4-ylamino]-methyl}-phenyl ester; 7-[4-(3-MethanesuIfonyl-benzylamino)-5-trifluoromethyl-pyrim idin-2-ylamino]-3,4- dihydro-1 H-quinolin-2-one; N-Methyl-N-(2-{[2-(2-oxo-1 ,2,3,4-tetrahydro-quinolin-7-ylamino)-5-trifluoromethyl- pyrimidin-4-ylamino]-methyl}-phenyl)-methanesulfonamide; N-Methyl-N-(2-{[2-(2-oxo-1 ,2,3,4-tetrahydro-quinolin-6-ylamino)-5-trifluoromethyl- pyrimidin-4-ylamino]-methyl}-phenyl)-methanesulfonamide,; 7-{4-[(Pyridin-2-ylmethyl)-amino]-5-trifluoromethyl-pyrimidi n-2-ylamino}-3,4-dihydro- 1 H-quinolin-2-one; 6-{4-[(Pyridin-2-ylmethyl)-amino]-5-trifluoromethyl-pyrimidi n-2-ylamino}-3,4-dihydro- 1 H-quinolin-2-one; N-Methyl-N-(3-{[2-(2-oxo-1 ,2,3,4-tetrahydro-quinolin-7-ylamino)-5-trifluoromethyl- pyrimidin-4-ylamino]-methyl}-phenyl)-methanesulfonamide; Methanesulfonic acid 3-{[2-(2-oxo-1 ,2,3,4-tetrahydro-quinoIin-7-ylamino)-5- trifluoromethyl-pyrimidin-4-ylamino]-methyl}-phenyl ester; 7-(4-Cyclobutylamino-5-trifluoromethyl-pyrimidin-2-ylamino)- 3,4-dihydro-1H-quinolin- 2-one; 6-[4-(3-Methanesulfonyl-benzylamino)-5-trifluoromethyI-pyrim idin-2-ylamino]-3,4- dihydro-1 H-quinolin-2-one; N-Methyl-N-(3-{[2-(2-oxo-1 ,2,3,4-tetrahydro-quinolin-6-ylamino)-5-trifluoromethyl- pyrimidin-4-ylamino]-methyl}-phenyl)-methanesulfonamide; Methanesulfonic acid 3-{[2-(2-oxo-1 ,2,3,4-tetrahydro-quinolin-6-ylamino)-5- trifluoromethyl-pyrimidin-4-ylamino]-methyl}-phenyl ester; 7-[4-(3-Methanesulfonyl-benzylamino)-5-trifluoromethyl-pyrim idin-2-ylamino]-3,4- dihydro-1 H-quinolin-2-one; N-Methyl-N-(2-{[2-(2-oxo-1 ,2,3,4-tetrahydro-quinolin-7-ylamino)-5-trifluoromethyl- pyrimidin-4-yIamino]-methyl}-phenyl)-methanesulfonamide; and N-Methyl-N-(2-{[2-(2-oxo-1 ,2,3,4-tetrahydro-quinolin-6-ylamino)-5-trifluoromethyl- pyrimidin-4-ylamino]-nnethyl}-phenyl)-methanesulfonamide. * * * The present invention is not to be limited in scope by the specific embodiments described herein. Indeed, various modifications of the invention in addition to those described herein will become apparent to those skilled in the art from the foregoing description and the accompanying figures. Such modifications are intended to fall within the scope of the appended claims. All patents, applications, publications, test methods, literature, and other materials cited herein are hereby incorporated herein by reference in their entireties.