The invention also relates to the therapeutic or prophylactic use of such compounds and compositions, and to methods of treating cancer, viral, microbial, and/or parasitic colonization/infection, as well as other disease states associated with unwanted cellular proliferation, by administering effective amounts of such compounds.

BACKGROUND OF THE INVENTION Cell proliferation occurs in response to various stimuli and may stem from de- regulation of the cell division cycle (or cell cycle), the process by which cells multiply and divide. Hyperproliferative disease states, including cancer, are characterized by cells rampantly winding through the cell cycle with uncontrolled vigor due to, for example, damage to the genes that directly or indirectly regulate progression through the cycle. Thus, agents that modulate the cell cycle, and thus hyperproliferation, could be used to treat various disease states associated with uncontrolled or unwanted cell proliferation. In addition to cancer chemotherapeutic agents, cell cycle inhibitors are also proposed as antiparasitics (see Gray et al. , Curr. Med. Chem., 6, 859-875 (1999) ) and recently demonstrated as potential antivirals (see Schang et al. , J. Virol., 74,2107-2120 (2000) ). Moreover, the applicability of antiproliferative agents may be expanded to treating cardiovascular maladies such as arteriosclerosis or restenosis (see Braun-Dullaeus et al., Circulation, 98,82-89 (1998) ), and states of inflammation, such as arthritis (see Taniguchi et al., Nature Med., 5,760-767 (1999) ) or psoriasis.

Mechanisms of cell proliferation are under active investigation at cellular and molecular levels. At the cellular level, deregulation of signaling pathways, loss of cell cycle controls, unbridled angiogenesis and stimulation of inflammatory pathways are under scrutiny, while at the molecular level, these processes are modulated by various proteins, among which

protein kinases are prominent suspects. Overall abatement of proliferation may also result from programmed cell death, or apoptosis, which is also regulated via multiple pathways, some involving proteolytic enzyme proteins.

Among the candidate regulatory proteins, protein kinases are a family of enzymes that catalyze phosphorylation of the hydroxyl group of specific tyrosine, serine or threonine residues in proteins. Typically, such phosphorylation dramatically perturbs the function of the protein, and thus protein kinases are pivotal in the regulation of a wide variety of cellular processes.

Cyclin-dependent kinases (CDKs) are serine-threonine protein kinases that play critical roles in regulating the transitions between different phases of the cell-cycle, such as the progression from a quiescent stage in Gl (the gap between mitosis and the onset of DNA replication for a new round of cell division) to S (the period of active DNA synthesis), or the progression from G2 to M phase, in which active mitosis and cell-division occurs. (See, e. g., the articles compiled in Science, 274,1643-1677 (1996); and Ann. Rev. Cell Dev. Biol., 13, 261-291 (1997)). CDK complexes are formed through association of a regulatory cyclin subunit (e. g. , cyclin A, B1, B2, D1, D2, D3, and E) and a catalytic kinase subunit (e. g., CDK1, CDK2, CDK4, CDK5, and CDK6). As the name implies, the CDKs display an absolute dependence on the cyclin subunit in order to phosphorylate their target substrates, and different kinase/cyclin pairs function to regulate progression through specific phases of the cell-cycle.

Aberrations in this control system, particularly those that affect the function of CDK4 and CDK2, have been implicated in the advancement of cells to the highly proliferative state characteristic of malignancies, particularly familial melanomas, esophageal carcinomas, and pancreatic cancers (see, e. g. , Hall et al., Adv. Cancer Res., 68,67-108 (1996); Kamb, Trends in Genetics, 11,136-140 (1995); Kamb et al., Science, 264,436-440 (1994) ).

Because CDK4 may serve as a general activator of cell division in most cells and complexes of CDK4/cyclin D and CDK2/cyclin E govern the early G1 phase of the cell cycle, CDK4 or CDK2 inhibitors may be used as anti-proliferative agents. Also, the pivotal roles of cyclin E/CDK2 and cyclin B/CDK1 in the G1/S phase and G2/M transitions, respectively, offer additional targets for therapeutic intervention in suppressing deregulated cell cycle progression.

A large number of small molecule ATP-site antagonists have been identified as CDK inhibitors (see, Webster, Exp. Opin. Invest. Drugs, 7, 865-887 (1998); Stover et al., Curr. Opin.

DrugDisc. Dev., 2,274-285 (1999); Gray et al., Curr. Med. Chem., 6,859-875 (1999); Sielecki et al., J Med. Chem., 43,1-18 (2000); Crews et al., Curer. Opin. Chem. Biol., 4,47-53 (2000); Buolamwini, Curr. Pharm. Des., 6, 379-392 (2000); and Rosania et al. , Exp. Opin. Ther. Pat., 10,215-230 (2000) ).

In addition to the protein kinases identified above, many other protein kinases have been considered to be therapeutic targets, and numerous publications disclose inhibitors of kinase activity, as reviewed in the following: McMahon et al., Curer. Opin. Drug Disc. Dev., 1, <BR> <BR> <BR> 131-146 (1998); Strawn et al. , Exp. Opin. Invest. Drugs, 7,553-573 (1998); Adams et al., Curr.

Opin. Drug Disc. Dev., 2,96-109 (1999); Stover et al., Curr. Opin. Drug Disc. Dev. , 2,274- 285 (1999); Toledo et al., Curr. Med. Chem., 6,775-805 (1999); and García-Echeverría et al., Med. Res. Rev., 20,28-57 (2000).

Among others, the following patent publications disclose thiazole compounds: International Publication No. WO 99/21845 discloses certain 2,4-diaminothiazoles as CDK inhibitors; International Publication No. WO 99/62890 discloses certain isothiazoles as anticancer agents; International Publication No. WO 98/04536 describes certain thiazoles as protein kinase C inhibitors; and European Publication No. EP 816362A (1998) discloses certain thiazoles useful as dopamine D4 receptor antagonists. Certain aminothiazoles are reported in International Publication No. WO 99/65844 and International Publication No. WO 99/24416, and certain aminobenzothiazoles are disclosed in International Publication No. WO 99/24035.

International Publication No. WO 00/17175 describes certain other aminothiazoles as p38 mitogen-activated protein (MAP) kinase inhibitors, and International Publication No. WO 00/26202, International Publication No. WO 00/26203, and US Patent No. 6,114, 365 describe certain aminothiazoles and certain ureidothiazoles as anti-tumor agents. International Publication No. WO 99/21845 discloses certain 4-aminothiazole derivatives containing unsubstituted nitrogen or primary benzamides.

There is still a need, however, for more potent inhibitors of protein kinases. Moreover, as is understood by those skilled in the art, it is desirable for kinase inhibitors to possess both high affinity for the target kinase as well as high selectivity versus other protein kinases.

SUMMARY OF THE INVENTION An object of the invention is to discover potent anti-proliferative agents. Another object of the invention is to discover effective inhibitors of protein kinases.

These and other objects of the invention, which will become apparent from the following description, have been achieved through the discovery of 4-aminothiazole compounds with mono-or di-N-substituted benzamides. The invention also relates to pharmaceutically acceptable prodrugs, pharmaceutically active metabolites, and pharmaceutically acceptable salts of such compounds (such compounds, prodrugs, metabolites and salts are collectively referred to as"agents") which modulate and/or inhibit cell growth.

Thus, the inventive agents and pharmaceutical compositions containing such agents are useful in treating various diseases or disorder states associated with uncontrolled or unwanted cellular proliferation, such as cancer, autoimmune diseases, viral diseases, fungal diseases, neurodegenerative disorders, and cardiovascular diseases.

Further, the agents modulate and/or inhibit the activity of protein kinases, for example one or more CDKs, such as CDK1, CDK2, CDK4 and/or CDK6, or cyclin complexes thereof, and/or one or more LCKs, VEGF or FGFs. Thus, the pharmaceutical compositions containing such agents are useful in treating diseases mediated by kinase activity, such as cancer.

In a general aspect, the invention relates to compounds represented by Formula (I): wherein: Rl and RZ are each independently hydrogen, or an alkyl, alkenyl, alkynyl, heteroalkyl, alkoxy, amino alkyl, aryl, heteroaryl, cycloalkyl, or heterocycloalkyl group unsubstituted or substituted with one or more substituents independently selected from the group consisting of alkyl, heteroalkyl, haloalkyl, haloaryl, halocycloalkyl, haloheterocycloalkyl, aryl, cycloalkyl, heterocycloalkyl, heteroaryl,-NO2,-NH2,-N- OH, N-ORC,-CN,- (CH2),-CN where z is 0-4, halogen,-OH,-0-Ra-O-,-ORb,-CO-Rc, -O-CO-Rc, -CO-ORc, -O-CO-ORc, -O-CO-O-CO-Rc, -O-ORc, keto (=O), thioketo (=S), -SO2-Rc, -SO-Rc, -NRdRe, -CO-NRdRe, -O-CO-NRdRe, -NRc-CO-NRdRe, -NRc-CO-Re, <BR> <BR> <BR> - NRc-CO-ORe,-CO-NRc-CO-Rd,-O-SOz-Rc,-0-SO-Rc,-0-S-Rc,-S-CO-R, -SO-CO-<BR> <BR> <BR> <BR> <BR> <BR> ORc,-SO,-CO-ORc,-0-S03,-NRc-SRd,-NRc-SO-Rd, NRc-S02-Rd,-CO-SR,,-CO-SO- Rc, -CO-SO2-Rc, -CS-Rc, -CSO-Rc, -CSO2-Rc, -NRc-CS-Rd, -O-CS-Rc, -O-CSO-Rc, - O-CS02-Rc,-SO2-NRdRe,-SO-NRdRe,-S-NRdRe,-NRd-CSO 2-Rd,-NR-CSO-Rd, -NRC-CS-Rd,-SH,-S-Rb, and-PO2-ORC, where Ra is selected from the group consisting of alkyl, heteroalkyl, alkenyl, and alkynyl, Rb is selected from the group consisting of alkyl, heteroalkyl, haloalkyl, alkenyl, alkynyl, halogen,-CO-Rc,-CO-ORc,-O-CO-O- Rc,-0-CO-Rc,-NRc-CO-Rd,-CO-NRdR,-OH, Ar, heteroaryl, heterocycloalkyl, and cycloalkyl, and Rc, Rd and Re are each independently selected from the group consisting of hydrogen, halogen, alkyl, heteroalkyl, haloalkyl, alkenyl, alkynyl,-CORf, - COORf,-O-CO-O-Rf,-O-CO-Rf,-OH, Ar, heteroaryl, cycloalkyl, and heterocycloalkyl, where Rd and Re can cyclize to form a heteroaryl or heterocycloalkyl

group, and Rfis selected from the group consisting of hydrogen, alkyl, and heteroalkyl, and where any of the alkyl, heteroalkyl, alkylene, aryl, cycloalkyl, heterocycloalkyl, or heteroaryl moieties present in the above substituents may be further substituted with one or more substituents independently selected from the group consisting ofN02,- NH2n-CN-(CH2) z~CN where z is 0-4, halogen, haloalkyl, haloaryl, -OH, keto (=O),- N-OH, N-ORc, -NRdRe, -CO-NRdRe, -CO-ORc, -CO-Rc, -NRc-CO-NRdRe, -C-CO-ORc, NRc-CO-Rd, -O-CO-O-Rc, -O-CO-NRd-Re, -SH, -O-Rb, -O-Ra-O-, -S-Rb, and unsubstituted alkyl, unsubstituted aryl, unsubstituted cycloalkyl, unsubstituted heterocycloalkyl, and unsubstituted heteroaryl, where Ra, Rb, Rc, Rd, and Re are defined above, where R'and W are not both hydrogen, or R1 or R2, together with the and two adjacent carbon atoms of the phenyl ring of Formula (I), forms a 5-or 6-membered ring structure fused to the phenyl ring of Formula (I) and unsubstituted or substituted with one or more substituents independently selected from the group consisting of alkyl, heteroalkyl, haloalkyl, haloaryl, halocycloalkyl, haloheterocycloalkyl, aryl, cycloalkyl, heterocycloalkyl, heteroaryl,-NO2,-NH2,-N-OH,-N-ORc,-CN,- (CH2) z-CN where z is 0-4, halogen,- <BR> <BR> <BR> OH,-O-Ra-O-,-ORb,-CO-Rc,-0-CO-Rc,-CO-ORc,-0-CO-ORc,-O-CO-O-C O-Rc,- O-ORc, keto (=O), thioketo (=S), S02-Rc,-SO-Rc,-NRdRe,-CO-NRdRe,-0-CO-NRdRe, <BR> <BR> <BR> - NRc-CO-NRdRe,-NRc-CO-Re,-NRc-CO-ORe,-CO-NRc-CO-Rd,-O-SO2-Rc, -O-SO-<BR> <BR> <BR> <BR> Rc,-O-S-Rc,-S-CO-R,,-SO-CO-ORc,-SO2-CO-OR,-O-S03,-NRc-SRd,-N Rc-SO-Rd,<BR> <BR> <BR> <BR> <BR> <BR> NRc-S02-Rd,-CO-SRc,-CO-SO-Rc,-CO-s2-Rc,-CS-Rc,-CSO-Rc,-CS02- Rc,-NRc-<BR> <BR> <BR> <BR> <BR> CS-Rd,-O-CS-R,-0-CSO-Rc,-0-CS02-Rc,-SO2-NRdRe,-SO-NRdRe,-S-N RdRe- NRd-CSO2-Rd,-NRc-CSO-Rd,-NRc-CS-Rd,-SH,-S-Rb, and-PO2-ORc, where Ra is selected from the group consisting of alkyl, heteroalkyl, alkenyl, and alkynyl, Rb is selected from the group consisting of alkyl, heteroalkyl, haloalkyl, alkenyl, alkynyl, <BR> <BR> <BR> halogen,-CO-Rc,-CO-ORc,-0-CO-O-Rc,-0-CO-Rc,-NRc-CO-Rd,-CO-NR dRe,-OH, Ar, heteroaryl, heterocycloalkyl, and cycloalkyl, Rcn Rd and Re are each independently selected from the group consisting of hydrogen, halogen, alkyl, heteroalkyl, haloalkyl, alkenyl, alkynyl,-CORf,-COORf,-O-CO-O-Rf,-O-CO-Rf,-OH, Ar, heteroaryl, cycloalkyl, and heterocycloalkyl, where Rd and Re can cyclize to form a heteroaryl or heterocycloalkyl group, and Rf is selected from the group consisting of hydrogen, alkyl, and heteroalkyl, and where any of the alkyl, heteroalkyl, alkylene, aryl, cycloalkyl, heterocycloalkyl, or heteroaryl moieties present in the above substituents may be further substituted with one or more substituents independently selected from the group

consisting of NO2,-NH2,-CN,-(CH2) z-CN where z is 0-4, halogen, haloalkyl, haloaryl, -OH, keto (=O),-N-OH, N-ORc, -NRdRe, -CO-NRdRe, -CO-ORc, -CO-Rc, -NRc-CO- <BR> <BR> <BR> <BR> NRdRe,-C-CO-ORc,-NRc-CO-Rd,-O-CO-O-Rc, O-CO-NRdRe,-SH,-O-Rb,-0-Ra-O-,- S-Rb, and unsubstituted alkyl, unsubstituted aryl, unsubstituted cycloalkyl, unsubstituted heterocycloalkyl, and unsubstituted heteroaryl, where Ra, Rb, Rc, Rd, and Re are defined above ; or Rl and R2, taken together with the nitrogen atom to which they are bonded, form a monocyclic or fused or non-fused polycyclic structure which may contain one to three additional heteroatoms, unsubstituted or substituted with one or more substituents independently selected from the group consisting of hydrogen, alkyl, heteroalkyl, haloalkyl, haloaryl, halocycloalkyl, haloheterocycloalkyl, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, -NO2, -NH2, -N-OH, N-ORc,-CN,- (CHZ) z-CN where z is 0-4, halogen,-OH, O-Ra-O-, -ORb, -CO-Rc, -O-CO-Rc, -CO-ORc, -O-CO-ORc, -O- CO-O-CO-RC,-O-ORcX keto (=O), thioketo (=S),-SO2-Rc,-SO-Rc,-NRdRe,-CO- <BR> <BR> <BR> <BR> NRdRe,-O-CO-NRdRe,-NRc-CO-NRdRe,-NRc-CO-Re,-NR-CO-ORe,-CO-NR c-CO- Rd, -O-SO2-Rc, -O-SORc, -O-S-Rc, -S-CO-Rc, -SO-CO-ORc, -SO2-CO-ORc, -O-SO3, - <BR> <BR> <BR> <BR> NRc-SRd,-NRc-SO-Rd,-NRc-S02-Rd,-CO-SRc,-CO-SO-Rc,-CO-SOz-Rc, -CS-Rc,-<BR> <BR> <BR> <BR> <BR> <BR> <BR> CSO-RC,-CSO2-Rc,-NRc-CS-Rd,-O-CS-Rc,-O-CSO-R,-O-CSO2-Rc,-SO2 -NRdRe,-<BR> <BR> <BR> <BR> <BR> <BR> SO-NRe,-S-NRdRe,-NRd-CS02-Rd,-NRc-CSO-Rd,--CS-Rd,-SH,-S-Rb, and- PO2-ORc, where Ra is selected from the group consisting of alkyl, heteroalkyl, alkenyl, and alkynyl, Rb is selected from the group consisting of alkyl, heteroalkyl, haloalkyl, alkenyl, alkynyl, halogen,-CO-Rc,-CO-ORc,-0-CO-O-Rc,-O-CO-Rc,-NRc-CO-Rd,- CO-NRdRe,-OH, Ar, heteroaryl, heterocycloalkyl, and cycloalkyl, Rc, Rd and Re are each independently selected from the group consisting of hydrogen, halogen, alkyl, heteroalkyl, haloalkyl, alkenyl, alkynyl, -CORf, -COORf, -O-CO-O-Rf, -O-CO-Rf, -OH, Ar, heteroaryl, cycloalkyl, and heterocycloalkyl, where Rd and Re can cyclize to form a heteroaryl or heterocycloalkyl group, and Rf is selected from the group consisting of hydrogen, alkyl, and heteroalkyl, and where any of the alkyl, heteroalkyl, alkylene, aryl, cycloalkyl, heterocycloalkyl, or heteroaryl moieties present in the above substituents may be further substituted with one or more substituents independently selected from the group consisting of NO2,-NH2,-CN,-(CH2) z-CN where z is 0-4, halogen, haloalkyl, haloaryl, -OH, keto (=O),-N-OH,-N-OR,-NRdRe,-CO-NRdRe,- CO-ORc, -CO-Rc, -NRc-CO-NRdRe, -C-CO-ORc, -NRc-CO-Rd, -O-CO-O-Rc, -O-CO- NRdRe,-SH,-O-Rb,-O-Ra-O-,-S-Rb, and unsubstituted alkyl, unsubstituted aryl,

unsubstituted cycloalkyl, unsubstituted heterocycloalkyl, and unsubstituted heteroaryl, where Ra, Rb, Re Rd, and Re are defined above; is an aryl, heteroaryl, alkyl, or cycloalkyl group, unsubstituted or substituted with one or more substituents independently selected from the group consisting of hydrogen, alkyl, heteroalkyl, haloalkyl, haloaryl, halocycloalkyl, haloheterocycloalkyl, aryl, cycloalkyl, heterocycloalkyl, heteroaryl,-NO2,-NH2,-N-OH,-N-ORc,-CN, -(CH2)z-CN where z is 0-4, halogen, -OH, -O-Ra-O-, -ORb, -CO-Rc, -O-CO-Rc, -CO- ORc,-O-CO-ORc,-O-CO-O-CO-Rc,-O-ORc, keto (=O), thioketo (=S),-SO2-Rc,-SO- <BR> <BR> <BR> <BR> Rc,-NRdRe,-CO-NRdRe,-0-CO-NRdRe,-NRc-CO-NRdRe,-NRc-CO-Re,-NR c-CO-<BR> <BR> <BR> <BR> <BR> <BR> ORe,-CO-NRc-CO-Rd,-O-SO2-R,-0-SO-Rc,-O-S-Rc,-S-CO-Rc,-SO-CO- ORc,-SO2- CO-OR,-O-S03,-NRc-SRd,-NRc-SO-Rd, NRc-SO2-Rd, -CO-SRc, -CO-SO-Rc, -CO- SO2-Rc, -CS-Rc, -CSO-Rc, -CSO2-Rc, -NRc-CS-Rd, -O-CS-Rc, -O-CSO-Rc, -O-CSO2- Rc, -SO2-NRdRe, -SO-NRdRe, -S-NRdRE, -NRd-CSO2-Rd, -NRc-CSO-Rd, -NRc-CS-Rd, - SH, -S-Rb, and-PO2-ORc, where Ra is selected from the group consisting of alkyl, heteroalkyl, alkenyl, and alkynyl, Rb is selected from the group consisting of alkyl, heteroalkyl, haloalkyl, alkenyl, alkynyl, halogen,-CO-Rc,-CO-ORc,-O-CO-O-Rc,-O- CO-RC,-NRc-CO-Rd,-CO-NRdRe,-OH, Ar, heteroaryl, heterocycloalkyl, and cycloalkyl, and Rc, Rd and Re are each independently selected from the group consisting of hydrogen, halogen, alkyl, heteroalkyl, haloalkyl, alkenyl, alkynyl,-CORf, -COORf, -O-CO-O-Rf, -O-CO-Rf, -OH, Ar, heteroaryl, cycloalkyl, and heterocycloalkyl, where Rd and Re can cyclize to form a heteroaryl or heterocycloalkyl group, and Rf is selected from the group consisting of hydrogen, alkyl, and heteroalkyl, and where any of the alkyl, heteroalkyl, alkylene, aryl, cycloalkyl, heterocycloalkyl, or heteroaryl moieties present in the above substituents may be further substituted with one or more substituents independently selected from the group consisting of NO2,- NH2,-CN,-(CH2) z-CN where z is 0-4, halogen, haloalkyl, haloaryl, -OH, keto (=O),- N-OH, N-ORc,-NRdRe,-CO-NRdRe,-CO-ORc,-CO-Rc,-NR-CO-NRdRe,-C-CO-ORc , - NRc-CO-Rd,-0-CO-O-R, O-CO-NRdRe,-SH,-O-Rb,-O-Ra-O-,-S-Rb, and unsubstituted alkyl, unsubstituted aryl, unsubstituted cycloalkyl, unsubstituted heterocycloalkyl, and unsubstituted heteroaryl, where Ra, Rb, Rc, Rd, and Re are defined above; and Y is hydrogen, alkyl, heteroalkyl, haloalkyl, halocycloalkyl, haloheterocycloalkyl, cycloalkyl, heterocycloalkyl,-NO2,-NH2,-N-OH, N-ORc, -ON, -(CH2)z-CN where z is 0-4, halogen,-OH,-O-Ra-O-,-ORb,-CO-Rc,-O-CO-Rc,-CO- ORc,-0-CO-ORc,-0-ORc, keto (=O), thioketo (=S),-NRdRe,-CO-NRdRe,-O-CO-

NRdRe,-NRc-CO-Re,-NRc-COz-ORe,-CO-NRe-CO-Rd,-0-S02-Rc,-0-SO- Rc,-0-S- Rc, -S-CO-Rc, -SO-CO-ORc, -SO2-CO-ORc, -O-SO3, -NRc-SRd, -NRc-SO-Rd, NRc-SO2- Rd, -CO-SRc, -CO-SO-Rc, -CO-SO2-Rc, -CS-Rc, -CSO-Rc, -CSO2-Rc, -NRc-CS-Rd, - O-CS-Rc, -O-CSO-Rc, -O-CSO2-Rc, -SO2-NRdRe, -SO-NRdRe, -S-NRdRe, -NRd-CSO2- Rd,-NRc-CSO-Rd,-NRc-CS-Rd,-SH,-S-Rb, and-P02-ORc, where Ra is selected from the group consisting of alkyl, heteroalkyl, alkenyl, and alkynyl, Rb is selected from the group consisting of alkyl, heteroalkyl, haloalkyl, alkenyl, alkynyl, halogen,-CO-Rc,- CO-OR,-O-CO-O-Rc,-O-CO-R,-NRc-CO-Rd,-CO-NRdRe,-OH, heterocycloalkyl, and cycloalkyl, and Rc, Rd and Re are each independently selected from the group consisting of hydrogen, halogen, alkyl, heteroalkyl, haloalkyl, alkenyl, alkynyl,-CORf, - COORf,-O-CO-O-Rf,-O-CO-Rf,-OH, cycloalkyl, and heterocycloalkyl, where Rd and Re can cyclize to form a heteroaryl or heterocycloalkyl group and Rf is selected from the group consisting of hydrogen, alkyl, and heteroalkyl.

The nitrogen-containing ring optionally formed by R1 and R2 may be monocyclic, or fused or un-fused polycyclic (i. e. spiral), and may contain one to three additional heteroatoms selected from N, O or S. Examples of such a ring include and the like. The ring may be substituted

with one or more substituents as described above.

According to one preferred embodiment of the invention, (C (O) N (Rl) (R2)) moiety is connected meta or para to the secondary amine linking the phenyl and thiazole rings, and Y can be at any position on the phenyl ring. More preferably, the (C (O) N (Rl) (ruz)) moiety is para and Y is meta to the secondary amine linking the phenyl and thiazole rings. meta paratOrthO N NH2 N'\ : O R '3 R

In one preferred embodiment of the invention, in the compounds of Formula (I), R3 is an aryl or heteroaryl group having one or more substituents selected from the group consisting of a halogen, alkoxy,-OH, alkyl and-NO2 groups.

The invention is also directed to pharmaceutically acceptable salts of compounds represented by the Formula (I), pharmaceutically acceptable prodrugs, pharmaceutically active metabolites of compounds represented by the Formula (I), and pharmaceutically acceptable salts of such metabolites. Advantageous methods of making the compounds of the Formula (I) are also described.

In a preferred general embodiment, the invention relates to compounds represented by Formula (II) : wherein: Ri is selected from the group consisting of : alkyl, alyenyl, alkynyl, heteroalkyl, halogen, aryl, heteroaryl, cycloalkyl, and heterocycloalkyl groups unsubstituted or substituted with one or more substituents independently selected from the group consisting of hydrogen, alkyl, heteroalkyl, haloalkyl, haloaryl, halocycloalkyl, haloheterocycloalkyl, aryl, cycloalkyl, heterocycloalkyl, heteroaryl,-NO2,-NH2,-N-OH, N-ORc,-CN,-(CH2) z-CN where z is 0-4, halogen, -OH, -O-Ra-O-, -ORb, -CO-Rc, -O-CO-Rc, -CO-ORc, -O-CO-ORc, -O-CO-O-CO-Rc, -O-ORc, keto (=O), thioketo (=S),-SO2-Rc,-SO-Rc,-NRdRe,-CO-NRdRe,-O-CO-NRdRe,-NRc- CO-NRdRe, -NRc-CO-Re, -NRc-CO2-ORe, -CO-NRc-CO-Rd, -O-SO2-Rc, -O-SO-Rc, -O-S-Rc, - S-CO-Rc, -SO-CO-ORc, -SO2-CO-ORc, -O-SO3, -NRc-SRd, -NRc-SO-Rd, NRc-SO2-Rd, -CO- SRc, -CO-SO-Rc, -CO-SO2-Rc, -CS-Rc, -CSO-Rc, -CSO2-Rc, -NRc-CS-Rd, -O-CS-Rc, -O- <BR> <BR> <BR> <BR> CSO-Rc,-O-CSOz-Rc,-SOz-NRdRe,-SO-NRdR,-S-NRdRe,-NRd-CSOz-Rd, -NR-CSO-Rd,- NRc-CS-Rd,-SH,-S-Rb, and-P02-ORc, where Ra is selected from the group consisting of alkyl, heteroalkyl, alkenyl, and alkynyl, Rb is selected from the group consisting of alkyl, heteroalkyl, haloalkyl, alkenyl, alkynyl, halogen, -CO-Rc, -CO-ORc, -O-CO-O-Rc, -O-CO-Rc, - NRC-CO-Rd,-CO-NRdRef-OH, Ar, heteroaryl, heterocycloalkyl, and cycloalkyl, and Re, Rd and Re are each independently selected from the group consisting of hydrogen, halogen, alkyl, heteroalkyl, haloalkyl, alkenyl, alkynyl,-CORf,-COORf,-O-CO-O-Rf,-O-CO-Rf,-OH, Ar, heteroaryl, cycloalkyl, and heterocycloalkyl, where Rd and Re can cyclize to form a heteroaryl or heterocycloalkyl group, and Rf is selected from the group consisting of hydrogen, alkyl, and heteroalkyl, and where any of the alkyl, heteroalkyl, alkylene, aryl, cycloalkyl,

heterocycloalkyl, or heteroaryl moieties present in the above substituents may be further substituted with one or more substituents independently selected from the group consisting of NO2,-NH2,-CN,- (CH2) z-CN where z is 0-4, halogen, haloalkyl, haloaryl, -OH, keto (=O),-N- OH, N-ORc, -NRdRe, -CO-NRdRe, -CO-ORc, -CO-Rc, -NRc-CO-NRdRe, -C-CO-ORc, -NRc- CO-Rd, -O-CO-O-Rc, O-CO-NRdRe,-SH,-O-Rb,-O-Ra-O-,-S-Rb, and unsubstituted alkyl, unsubstituted aryl, unsubstituted cycloalkyl, unsubstituted heterocycloalkyl, and unsubstituted heteroaryl, where Ra, Rb, Rc, Rd, and Re are defined above; and R4, R5, and R are each independently selected from the group consisting of hydrogen, alkyl, heteroalkyl, haloalkyl, haloaryl, halocycloalkyl, haloheterocycloalkyl, aryl, cycloalkyl, heterocycloalkyl, heteroaryl,-NO2,-NH2,-N-OH, N-ORc,-CN,- (CH2) z-CN where z is 0-4, <BR> <BR> <BR> <BR> halogen,-OH,-0-Ra-O-,-ORb,-CO-Rc,-0-CO-Re,-CO-ORc,-0-CO-ORe, -0-CO-O-CO-Rc, - O-OIZ, keto (=O), thioketo (=S),-SO2-Rc,-SO-R,-NRdRe,-CO-NRdRe,-O-CO-NRdRe, -NRc-CO-NRdRe, -NRc-CO-Re, -NRc-CO2-ORe, -CO-NRc-CO-Rd, -O-SO2-Rc, -O-SO-Rc, -O- <BR> <BR> <BR> <BR> S-R,-S-CO-R,-SO-CO-ORc,-SO2-CO-ORc,-O-S03,-NRc-SRd,-NRc-SO-R d, NRc-S02-Rd,- CO-SRc, -CO-SO-Rc, -CO-SO2-Rc, -CS-Rc, -CSO-Rc, -CSO2-Rc, -NRc-CS-Rd, -O-CS-Rc, -O- <BR> <BR> <BR> <BR> CSO-Rc,-O-CS02-R,-S02-NRdRe,-SO-NRdRe,-S-NRdRe,-NRd-CS02-Rd, -NRc-CSO-Rd,- NRc-CS-Rd,-SH,-S-Rb, and-P02-ORc, where Ra is selected from the group consisting of alkyl, heteroalkyl, alkenyl, and alkynyl, Rb is selected from the group consisting of alkyl, heteroalkyl, haloalkyl, alkenyl, alkynyl, halogen,-CO-Rc,-CO-ORc,-0-CO-O-Rc,-O-CO-Rc, - NRc-CO-Rd,-CO-NRdRe,-OH, Ar, heteroaryl, heterocycloalkyl, and cycloalkyl, and Re, Rd and Re are each independently selected from the group consisting of hydrogen, halogen, alkyl, heteroalkyl, haloalkyl, alkenyl, alkynyl,-CORf,-COORf,-O-CO-O-Rf,-O-CO-Rf,-OH, Ar, heteroaryl, cycloalkyl, and heterocycloalkyl, where Rd and Re can cyclize to form a heteroaryl or heterocycloalkyl group, and Rfis selected from the group consisting of hydrogen, alkyl, and heteroalkyl, and where any of the alkyl, heteroalkyl, alkylene, aryl, cycloalkyl, heterocycloalkyl, or heteroaryl moieties present in the above substituents may be further substituted with one or more substituents independently selected from the group consisting of NO2, -NH2, -CN, -(CH2)z-CN where z is 0-4, halogen, haloalkyl, haloaryl, -OH, keto (=O),-N- OH, N-ORc, -NRdRe, -CO-NRdRe, -CO-ORc, -CO-Rc, -NRc-CO-NRdRe, -C-CO-ORc, -NRc- CO-Rd,-O-CO-O-R,-O-CO-NRdRe,-SH,-O-Rb,-O-Ra-O-,-S-Rb, and unsubstituted alkyl, unsubstituted aryl, unsubstituted cycloalkyl, unsubstituted heterocycloalkyl, and unsubstituted heteroaryl, where Ra, Rb, Re, Rd, and Re are defined above.

Preferred compounds of the invention include those represented by Formula (II) wherein Ru ils an alkyl, heteroalkyl or heterocycloalkyl group substituted with one or more substituents independently selected from the group consisting of hydrogen, alkyl, heteroalkyl,

haloalkyl, haloaryl, halocycloalkyl, haloheterocycloalkyl, aryl, cycloalkyl, heterocycloalkyl, heteroaryl,-NO2,-NH2,-N-OH, N-ORC,-CN,-(CH2) z-CN where z is 0-4, halogen,-OH,-O- Ra-O-, -ORb, -CO-Rc, -O-CO-Rc, -CO-ORc, -O-CO-ORc, -O-CO-O-CO-Rc, -O-ORc, keto (=O), thioketo (=S), -SO2-Rc, -SO-Rc, -NRdRe, -CO-NRdRe, -O-CO-NRdRe, -NRc-CO-NRdRe, -NRc- CO-Re, -NRc-CO2-ORe, -CO-NRc-CO-Rd, -O-SO2-Rc, -O-SO-Rc, -O-S-Rc, -S-CO-Rc, -SO-CO- ORc,-S02-CO-ORc,-O-SOs,-NR-SRd,-NRc-SO-Rd, NRc-S02-Ri,-CO-SRc,-CO-SO-Rc,- CO-SO2-Rc, -CS-Rc, -CSO-Rc, -CSO2-Rc, -NRc-CS-Rd, -O-CS-Rc, -O-CSO-Rc, -O-CSO2-Rc, - SO2-NRdRe, -SO-NRdRe, -S-NRdRe, -NRd-CSO2-Rd, -NRc-CSO-Rd, -NRc-CS-Rd, -SH, -S-Rb, and-PO2-ORc, where Ra is selected from the group consisting of alkyl, heteroalkyl, alkenyl, and alkynyl, Rb is selected from the group consisting of alkyl, heteroalkyl, haloalkyl, alkenyl, alkynyl, halogen,-CO-Rc,-CO-ORc,-O-CO-O-R,-0-CO-Rc,-NRc-CO-Rd,-CO-NRd Re,-OH, Ar, heteroaryl, heterocycloalkyl, and cycloalkyl, and Re, Rd and Re are each independently selected from the group consisting of hydrogen, halogen, alkyl, heteroalkyl, haloalkyl, alkenyl, alkynyl,-CORf,-COORf,-0-CO-O-Rf,-0-CO-Rf,-OH, Ar, heteroaryl, cycloalkyl, and heterocycloalkyl, where Rd and Re can cyclize to form a heteroaryl or heterocycloalkyl group, and Rf is selected from the group consisting of hydrogen, alkyl, and heteroalkyl, and where any of the alkyl, heteroalkyl, alkylene, aryl, cycloalkyl, heterocycloalkyl, or heteroaryl moieties present in the above substituents may be further substituted with one or more substituents independently selected from the group consisting of NO2,-NH2,-CN,-(CH2) z-CN where z is 0- 4, halogen, haloalkyl, haloaryl, -OH, keto (=O),-N-OH, N-ORC,-NRdRe,-CO-NRdRe,-CO- ORc, -CO-Rc, -NRc-CO-NRdRe, -C-CO-ORc, -NRc-CO-Rd, -O-CO-O-Rc, O-CO-NRdRe, SH, - O-Rb, -O-Ra-O-, -S-Rb, and unsubstituted alkyl, unsubstituted aryl, unsubstituted cycloalkyl, unsubstituted heterocycloalkyl, and unsubstituted heteroaryl, where Ra, Rb, Rc, Rd, and Re are defined above. Preferably, the substituted alkyl for R1 is-N (R7) (R8) where R7 and R8 are each independently an alkyl, alkyl- (heterocycloalkyl group unsubstituted or substituted with one or more substituents independently selected from the group consisting of hydrogen, alkyl, heteroalkyl, haloalkyl, haloaryl, halocycloalkyl, haloheterocycloalkyl, aryl, cycloalkyl, heterocycloalkyl, heteroaryl,-NOz,-NH2,-N-OH, N-ORC,-CN,-(CH2) z-CN where z is 0-4, <BR> <BR> <BR> <BR> halogen,-OH,-O-Ra-O-,-ORb,-CO-Rc,-0-CO-Rc,-CO-ORc,-0-CO-ORc, -0-CO-O-CO-Rc,- O-ORc, keto (=O), thioketo (=S), -SO2-Rc, -SO-Rc, -NRdRe, -CO-NRdRe, -O-CO-NRdRe, -NRc- <BR> <BR> <BR> <BR> CO-NRdRe,-NRc-CO-Re,-NRc-CO-ORe,-CO-NR-CO-Rd,-O-SO2-Rc,-0-SO -Rc,-O-S-Rc,- S-CO-Rc, -SO-CO-ORc, -SO2-CO-ORc, -O-SO3, -NRc-SRd, -NRc-SO-Rd, NRc-SO2-Rd, -CO- SRc, -CO-SO-Rc, -CO-SO-Rc, -CS-Rc, -CSO-Rc, -CSO2-Rc, -NRc-CS-Rd, -O-CS-Rc, -O-CSO- Rc, -O-CSO2-Rc, -SO2-NRdRe, -SO-NRdRe,-S-NRdRe, -NRd-CSO2-Rd, -NRc-CSO-Rd, -NRc- CS-Rd,-SH,-S-Rb, and-PO2-ORC, where Ra is selected from the group consisting of alkyl,

heteroalkyl, alkenyl, and alkynyl, Rb is selected from the group consisting of alkyl, heteroalkyl, haloalkyl, alkenyl, alkynyl, halogen,-CO-R,-CO-ORc,-0-CO-O-Rc,-0-CO-Rc,-NRc-CO-Rd, -CO-NRdRe, -OH, Ar, heteroaryl, heterocycloalkyl, and cycloalkyl, and Rc, Rd and Re are each independently selected from the group consisting of hydrogen, halogen, alkyl, heteroalkyl, haloalkyl, alkenyl, alkynyl,-CORf,-COORf,-0-CO-O-Rf,-0-CO-Rf,-OH, Ar, heteroaryl, cycloalkyl, and heterocycloalkyl, where Rd and Re can cyclize to form a heteroaryl or heterocycloalkyl group, and Rfis selected from the group consisting of hydrogen, alkyl, and heteroalkyl, and where any of the alkyl, heteroalkyl, alkylene, aryl, cycloalkyl, heterocycloalkyl, or heteroaryl moieties present in the above substituents may be further substituted with one or more substituents independently selected from the group consisting of NO2, -NH2, -CN, -(CH2)z-CN where z is 0-4, halogen, haloalkyl, haloaryl, -OH, keto (=O),-N- OH, N-ORc, -NRdRe, -CO-NRdRe, -CO-ORc, -CO-Rc, -NRc-CO-NRdRe, -C-CO-ORc, -NRc- CO-Rd,-O-CO-O-RC, O-CO-NRdRe,-SH,-O-Rb,-0-Ra-O-,-S-Rb, and unsubstituted alkyl, unsubstituted aryl, unsubstituted cycloalkyl, unsubstituted heterocycloalkyl, and unsubstituted heteroaryl, where Ra, Rb, Rc, Rd, and Re are defined above, or alkyl- (substituted aryl) group unsubstituted or substituted with one or more substituents independently selected from the group consisting of hydrogen, alkyl, heteroalkyl, haloalkyl, haloaryl, halocycloalkyl, haloheterocycloalkyl, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, -NO2, -NH2, -N-OH, N- ORc, -CN, -(CH2)z-CN where z is 0-4, halogen,-OH,-O-Ra-O-,-ORb,-CO-Rc,-O-CO-R,- CO-OR,-O-CO-ORc,-0-CO-O-CO-Rc,-O-ORc, keto (=O), thioketo (=S),-S02-Rc,-SO-Rc,- <BR> <BR> <BR> <BR> NRdRe,-CO-NRdRe,-0-CO-NRdRe,-NRc-CO-NRdRe,-NRc-CO-Re,-NRc-CO -ORe,-CO-NRc-<BR> <BR> <BR> <BR> <BR> <BR> CO-Rd,-O-SO2-Rc,-O-SO-Rc,-0-S-Rc,-S-CO-Rc,-SO-CO-ORc,-SO2-CO -ORc,-O-S03,- NRc-SRd, -NRc-SO-Rd, NRc-SO-Rd, -CO-SRc, -CO-SO-Rc, -CO-SO-Rc, -CS-Rc, -CSO-Rc, - CSOz-Rc,-NRc-CS-Rd,-0-CS-Rc,-0-CSO-Rc,-O-CSOz-Rc,-SOz-NRdRe, -SO-NRdRe,-S- NRdRe,-NRd-CSO2-Rd,-NR-CSO-Rd,-NRc-CS-Rd,-SH,-S-Rb, and-PO2-ORc, where Ra is selected from the group consisting of alkyl, heteroalkyl, alkenyl, and alkynyl, Rb is selected from the group consisting of alkyl, heteroalkyl, haloalkyl, alkenyl, alkynyl, halogen,-CO-RC,- CO-ORc, -O-CO-O-Rc, -O-CO-Rc, -NRc-CO-Rd, -CO-NRdRe, -OH, Ar, heteroaryl, heterocycloalkyl, and cycloalkyl, and Rc, Rd and Re are each independently selected from the group consisting of hydrogen, halogen, alkyl, heteroalkyl, haloalkyl, alkenyl, alkynyl,-CORf,- COORf,-O-CO-O-Rf,-O-CO-Rf,-OH, Ar, heteroaryl, cycloalkyl, and heterocycloalkyl, where Rd and Re can cyclize to form a heteroaryl or heterocycloalkyl group, and Rfis selected from the group consisting of hydrogen, alkyl, and heteroalkyl, and where any of the alkyl, heteroalkyl, alkylene, aryl, cycloalkyl, heterocycloalkyl, or heteroaryl moieties present in the above substituents may be further substituted with one or more substituents independently

selected from the group consisting of NO2,-NH2,-CN,-(CH2) z-CN where z is 0-4, halogen, haloalkyl, haloaryl, -OH, keto (=O),-N-OH, N-ORC,-NRdRe,-CO-NRdRea-CO-OR^,-CO-R", <BR> <BR> <BR> <BR> -NRC-CO-NRdRe,-C-CO-ORc,-NRc-CO-Rd,-O-CO-O-RC,-O-CO-NRdReS-S H,-ORb,-O-Ra- O-,-S-Rb, and unsubstituted alkyl, unsubstituted aryl, unsubstituted cycloalkyl, unsubstituted heterocycloalkyl, and unsubstituted heteroaryl, where Ra, Rb, Rc, Rd, and Re are defined above ; and R4, Rs and R6 are each independently selected from the group consisting of hydrogen, halogen, -OH, Cl-C3-alkoxy, Cl-C3-alkyl, heteroalkyl, or-N-CORc,-SRc,-SO-Rc,-SO2Rc, and -CO-Rc, where Rc is as defined above.

The invention also relates to methods of treating proliferative diseases such as cancer, autoimmune diseases, viral diseases, fungal diseases, neurodegenerative disorders and cardiovascular diseases, comprising administering effective amounts of a compound of Formula (I) or a pharmaceutically acceptable salt, pharmaceutically acceptable prodrug, pharmaceutically active metabolite, or pharmaceutically acceptable salt of such compound or metabolite to a subject in need of such treatment.

The invention further relates to a method of modulating and/or inhibiting the kinase activity of one or more CDKs such as CDK1, CDK2, CDK4, and/or CDK6 or cyclin complexes thereof, VEGF, FGF and/or LCK by administering a compound of Formula (I) or a pharmaceutically acceptable salt, pharmaceutically acceptable prodrug, or pharmaceutically acceptable salt of such compound or metabolite thereof.

The invention also relates to pharmaceutical compositions, each comprising an effective amount of an agent selected from compounds of Formula (I) and pharmaceutically active metabolites, pharmaceutically acceptable prodrugs, and pharmaceutically acceptable salts of such compounds and metabolites, and a pharmaceutically acceptable carrier or vehicle for such agent.

DETAILED DESCRIPTION OF THE INVENTION AND PREFERRED EMBODIMENTS The inventive compounds of Formula (I) are potent anti-proliferative agents. The compounds are also useful for mediating the activity of protein kinases. More particularly, the compounds are useful as agents for modulating and/or inhibiting the activity of various enzymes, for example protein kinases, thus providing treatments for cancer or other diseases associated with uncontrolled or abnormal cellular proliferation.

The diseases or disorders in association with uncontrolled or abnormal cellular proliferation include the following:

- a variety of cancers, including carcinoma, hematopoietic tumors of lymphoid lineage, hematopoietic tumors of myeloid lineage, tumors of mesenchymal origin, tumors of the central and peripheral nervous system and other tumors including melanoma, seminoma and Kapos's sarcoma and the like.

- a disease process which features abnormal cellular proliferation, e. g. , benign prostatic hyperplasia, familial adenomatosis polyposis, neuro-fibromatosis, atherosclerosis, pulmonary fibrosis, arthritis, psoriasis, glomerulonephritis, restenosis following angioplasty or vascular surgery, hypertrophic scar formation, inflammatory bowel disease, transplantation rejection, endotoxic shock, and fungal infections.

- defective apoptosis-associated conditions, such as cancers (including those types mentioned hereinabove), viral infections (including herpes virus, pox virus, Epstein-Barr virus, Sindbis virus and adenovirus), prevention of AIDS development in HIV-infected individuals, autoimmune diseases (including systemic lupus erythematosus, rheumatoid arthritis, psoriasis, autoimmune mediated glomerulonephritis, inflammatory bowel disease and autoimmune diabetes mellitus), neurodegenerative disorders (including Alzheimer's disease, amyotrophic lateral sclerosis, retinitis pigmentosa, Parkinson's disease, AIDS-related dementia, spinal muscular atrophy and cerebellar degeneration), myelodysplastic syndromes, aplastic anemia, ischemic injury associated with myocardial infarctions, stroke and reperfusion injury, arrhythmia, atherosclerosis, toxin-induced or alcohol related liver diseases, hematological diseases (including chronic anemia and aplastic anemia), degenerative diseases of the musculoskeletal system (including osteroporosis and arthritis), aspirin-sensitive rhinosinusitis, cystic fibrosis, multiple sclerosis, kidney diseases and cancer pain.

The agents of the invention may also be useful in the inhibition of the development of invasive cancer, tumor angiogenesis and metastasis.

Moreover, the agents of the invention, as inhibitors of CDKs, can modulate the level of cellular RNA and DNA synthesis and therefore are useful in the treatment of viral infections such as HIV, human papilloma virus, herpes virus, Epstein-Barr virus, adenovirus, Sindbis virus, pox virus and the like.

The terms"comprising"and"including"are used herein in their open, non-limiting sense.

The term"alkyl"as used herein refers to straight-and branched-chain alkyl groups having from one to twelve carbon atoms. Exemplary alkyl groups include methyl (Me), ethyl, n-propyl,

isopropyl, butyl, isobutyl, sec-butyl, tert-butyl (tBu), pentyl, isopentyl, tert-pentyl, hexyl, isohexyl, and the like.

The term"heteroalkyl"as used herein refers to straight-and branched-chain alkyl groups having from one to twelve atoms containing one or more heteroatoms selected from S, O, and N.

The term"alkenyl"refers to straight-and branched-chain alkenyl groups having from two to twelve carbon atoms. Illustrative alkenyl groups include prop-2-enyl, but-2-enyl, but-3-enyl, 2- methylprop-2-enyl, hex-2-enyl, and the like.

The term"alkynyl"refers to straight-and branched-chain alkynyl groups having from two to twelve carbon atoms. Illustrative alkynyl groups include prop-2-ynyl, but-2-ynyl, but-3-ynyl, 2- methylbut-2-ynyl, hex-2-ynyl, and the like.

The term"aryl" (Ar) refers to monocyclic and polycyclic aromatic ring structures containing only carbon and hydrogen. Illustrative examples of aryl groups include the following moieties: , and the like.

The term"heteroaryl" (heteroAr) refers to monocyclic, or fused polycyclic aromatic ring structures which include one or more heteroatoms selected from nitrogen, oxygen and sulfur and having from 3 to 12 ring atoms per ring. The polycyclic heteroaryl group may be fused or non- fused. More preferably, illustrative examples of heteroaryl groups have from 4 to 7 ring atoms per ring, such as the following moieties: and the like.

The term"cycloalkyl"refers to saturated carbocycles having from three to twelve carbon atoms, including bicyclic and tricyclic cycloalkyl structures. Illustrative examples of cycloalkyl groups include the following moieties: , and compounds of the like.

A"heterocycloalkyl"group refers to a monocyclic or fused or spiro polycyclic ring structure radical which may be saturated or unsaturated and contains from three to twelve ring atoms, selected from carbon and heteroatoms, preferably 4 or 5 ring carbon atoms, and at least one heteroatom selected from nitrogen, oxygen and sulfur. The radicals may be fused with an aryl or heteroaryl. More preferably, illustrative examples of heterocycloalkyl groups have 4 to 7 ring atoms per ring, such as the following moieties, , and the like.

The term"alkoxy"refers to the radical-O-R where R is an alkyl as defined above.

Examples of alkoxy groups include methoxy, ethoxy, propoxy, and the like.

The term"halogen"represents chlorine, fluorine, bromine or iodine. The term"halo" represents chloro, fluoro, bromo or iodo.

The term"alcohol"refers to the radical-R-OH where R is alkyl, alkenyl, alkynyl, Ar, heteroaryl, heterocycloalkyl, or cycloalkyl as defined above. Examples of alcohols include methanol, ethanol, propanol, phenol and the like.

The term"acyl"represents-C (O) R, -C (O) OR, -OC (O) R or-OC (O) OR where R is alkyl, alkenyl, alkynyl, Ar, heteroaryl, heterocycloalkyl, or cycloalkyl as defined as above.

The term"amide"refers to the radical-C (O) N (R') (R") where R'and R"are each independently selected from hydrogen, alkyl, alkenyl, alkynyl, -OH, alkoxy, cycloalkyl, heterocycloalkyl, heteroaryl, aryl as defined above; or R'and R"cyclize together with the nitrogen to form a heterocycloalkyl or heteroaryl as defined above.

The term"substituted"as used herein means that the group in question, e. g., alkyl group, etc. , may bear one or more substituents.

The alkyl, cycloalkyl, aryl, heterocycloalkyl and heteroaryl groups and the substituents containing these groups, as defined hereinabove, may be optionally substituted by at least one other substituent. The term"optionally substituted"is intended to expressly indicate that the specified group is unsubstituted or substituted by one or more substituents from the list above. Various groups may be unsubstituted or substituted (i. e. , they are optionally substituted) as indicated.

If the substituents themselves are not compatible with the synthetic methods of this invention, the substituent may be protected with a suitable protecting group that is stable to the reaction conditions used in these methods. The protecting group may be removed at a suitable point in the reaction sequence of the method to provide a desired intermediate or target compound.

Suitable protecting groups and the methods for protecting and de-protecting different substituents using such suitable protecting groups are well known to those skilled in the art; examples of which may be found in T. Greene and P. Wuts, Protecting Groups in Chemical Synthesis (3rd ed. ), John Wiley & Sons, NY (1999), which is incorporated herein by reference in its entirety. In some instances, a substituent may be specifically selected to be reactive under the reaction conditions used in the methods of this invention. Under these circumstances, the reaction conditions convert

the selected substituent into another substituent that is either useful in an intermediate compound in the methods of this invention or is a desired substituent in a target compound.

Some of the inventive compounds may exist in various stereoisomeric or tautomeric forms. The present invention encompasses all such cell proliferation-inhibiting compounds, including active compounds in the form of single pure enantiomers (i. e. , essentially free of other stereoisomers), racemates, mixtures of enantiomers and/or diastereomers, and/or tautomers. Preferably, the inventive compounds that are optically active are used in optically pure form.

As generally understood by those skilled in the art, an optically pure compound having one chiral center (i. e. , one asymmetric carbon atom) is one that consists essentially of one of the two possible enantiomers (i. e. , is enantiomerically pure), and an optically pure compound having more than one chiral center is one that is both diastereomerically pure and enantiomerically pure.

Preferably, the compounds of the present invention are used in a form that is at least 90% optically pure, that is, a form that contains at least 90% of a single isomer (80% enantiomeric excess ("e. e. ") or diastereomeric excess ("d. e. ")), more preferably at least 95% (90% e. e. or d. e.), even more preferably at least 97.5% (95% e. e. or d. e. ), and most preferably at least 99% (98% e. e. or d. e.).

Additionally, the formulae are intended to cover solvated as well as unsolvated forms of the identified structures. For example, Formula I includes compounds of the indicated structure in both hydrated and non-hydrated forms. Additional examples of solvates include the structures in combination with isopropanol, ethanol, methanol, DMSO, ethyl acetate, acetic acid, or ethanolamine.

In addition to compounds of Formula I, the invention includes pharmaceutically acceptable prodrugs, pharmaceutically active metabolites, and pharmaceutically acceptable salts of such compounds and metabolites.

The term"pharmaceutically acceptable"means pharmacologically acceptable and substantially non-toxic to the subject being administered the agent.

"A pharmaceutically acceptable prodrug"is a compound that may be converted under physiological conditions or by solvolysis to the specified compound or to a pharmaceutically acceptable salt of such compound. "A pharmaceutically active metabolite"is intended to mean a pharmacologically active product produced through metabolism in the body of a specified compound or salt thereof. Prodrugs and active metabolites of a compound may be identified using routine techniques known in the art. See, e. g. , Bertolini et al., J. Acted Chem., 40,2011-2016 (1997); Shan et al. , J. Phar77Z. Sci., 86 (7), 765-767; Bagshawe, Drug Dev. Res., 34,220-230 (1995); Bodor, Advances in Drug Res., 13,224-331 (1984); Bundgaard, Design of Prodrugs

(Elsevier Press 1985); and Larsen, Design and Application of Prodrugs, Drug Design and Development (Krogsgaard-Larsen et al. , eds. , Harwood Academic Publishers, 1991).

"A pharmaceutically acceptable salt"is intended to mean a salt that retains the biological effectiveness of the free acids and bases of the specified compound and that is not biologically or otherwise undesirable. A compound of the invention may possess a sufficiently acidic, a sufficiently basic, or both functional groups, and accordingly react with any of a number of inorganic or organic bases, and inorganic and organic acids, to form a pharmaceutically acceptable salt. Exemplary pharmaceutically acceptable salts include those salts prepared by reaction of the compounds of the present invention with a mineral or organic acid or an inorganic base, such as salts including sulfates, pyrosulfates, bisulfates, sulfites, bisulfites, phosphates, monohydrogenphosphates, dihydrogenphosphates, metaphosphates, pyrophosphates, chlorides, bromides, iodides, acetates, propionates, decanoates, caprylates, acrylates, formates, isobutyrates, caproates, heptanoates, propiolates, oxalates, malonates, succinates, suberates, sebacates, fumarates, maleates, butyne-1, 4-dioates, hexyne-1, 6-dioates, benzoates, chlorobenzoates, methylbenzoates, dinitrobenzoates, hydroxybenzoates, methoxybenzoates, phthalates, sulfonates, xylenesulfonates, phenylacetates, phenylpropionates, phenylbutyrates, citrates, lactates, y- hydroxybutyrates, glycolates, tartrates, methane-sulfonates, propanesulfonates, naphthalene-1- sulfonates, naphthalene-2-sulfonates, and mandelates.

If the inventive compound is a base, the desired pharmaceutically acceptable salt may be prepared by any suitable method available in the art, for example, treatment of the free base with an inorganic acid, such as hydrochloric acid, hydrobromic acid, sulfuric acid, sulfamic acid, nitric acid, phosphoric acid and the like, or with an organic acid, such as acetic acid, phenylacetic acid, propionic acid, stearic acid, lactic acid, ascorbic acid, maleic acid, hydroxymaleic acid, isethionic acid, succinic acid, mandelic acid, fumaric acid, malonic acid, pyruvic acid, oxalic acid, glycolic acid, salicylic acid, a pyranosidyl acid, such as glucuronic acid or galacturonic acid, an alpha-hydroxy acid, such as citric acid or tartaric acid, an amino acid, such as aspartic acid or glutamic acid, an aromatic acid, such as benzoic acid, 2- acetoxybenzoic acid or cinnamic acid, a sulfonic acid, such as p-toluenesulfonic acid, methanesulfonic acid or ethanesulfonic acid, or the like.

If the inventive compound is an acid, the desired pharmaceutically acceptable salt may be prepared by any suitable method, for example, treatment of the free acid with an inorganic or organic base, such as an amine (primary, secondary or tertiary), an alkali metal hydroxide or alkaline earth metal hydroxide, or the like. Illustrative examples of suitable salts include organic salts derived from amino acids, such as glycine and arginine, ammonia, carbonates, bicarbonates, primary, secondary, and tertiary amines, and cyclic amines, such as

benzylamines, pyrrolidines, piperidine, morpholine and piperazine, and inorganic salts derived from sodium, calcium, potassium, magnesium, manganese, iron, copper, zinc, aluminum and lithium.

Pharmaceutical compositions according to the invention may, alternatively or in addition to a compound of Formula I, comprise as an active ingredient pharmaceutically acceptable prodrugs, pharmaceutically active metabolites, and pharmaceutically acceptable salts of such compounds and metabolites. Such compounds, prodrugs, multimers, salts, and metabolites are sometimes referred to herein collectively as"active agents"or"agents." In the case of agents that are solids, it is understood by those skilled in the art that the inventive compounds and salts may exist in different crystal or polymorphic forms, all of which are intended to be within the scope of the present invention and specified formulas.

Therapeutically effective amounts of the active agents of the invention may be used to treat diseases mediated by modulation or regulation of protein kinases. An"effective amount"is intended to mean that amount of an agent that significantly inhibits proliferation and/or prevents de-differentiation of a eukaryotic cell, e. g. , a mammalian, insect, plant or fungal cell, and is effective for the indicated utility, e. g. , specific therapeutic treatment.

The amount of a given agent that will correspond to such an amount will vary depending upon factors such as the particular compound, disease condition and its severity, the identity (e. g., weight) of the subject or host in need of treatment, but can nevertheless be routinely determined in a manner known in the art according to the particular circumstances surrounding the case, including, e. g. , the specific agent being administered, the route of administration, the condition being treated, and the subject or host being treated. "Treating"is intended to mean at least the mitigation of a disease condition in a subject such as mammal (e. g. , human), that is affected, at least in part, by the activity of one or more kinases, for example protein kinases such as tyrosine kinases, and includes: preventing the disease condition from occurring in a mammal, particularly when the mammal is found to be predisposed to having the disease condition but has not yet been diagnosed as having it; modulating and/or inhibiting the disease condition ; and/or alleviating the disease condition.

Agents that potently regulate, modulate, or inhibit cell proliferation are preferred. For certain mechanisms, inhibition of the protein kinase activity associated with CDK complexes, among others, and those which inhibit angiogenesis and/or inflammation are preferred. The present invention is further directed to methods of modulating or inhibiting protein kinase activity, for example in mammalian tissue, by administering an inventive agent. The activity of agents as anti-proliferatives is easily measured by known methods, for example by using whole cell cultures in an MTT assay. The activity of the inventive agents as modulators of protein

kinase activity, such as the activity of kinases, may be measured by any of the methods available to those skilled in the art, including in vivo and/or in vitro assays. Examples of suitable assays for activity measurements include those described in International Publication No. WO 99/21845; Parast et al., Biochemistry, 37, 16788-16801 (1998); Connell-Crowley and Harpes, Cell Cycle : Materials and Methods, (Michele Pagano, ed. Springer, Berlin, Germany) (1995) ; International Publication No. WO 97/34876; and International Publication No. WO 96/14843. These properties may be assessed, for example, by using one or more of the biological testing procedures set out in the examples below.

The active agents of the invention may be formulated into pharmaceutical compositions as described below. Pharmaceutical compositions of this invention comprise an effective modulating, regulating, or inhibiting amount of a compound of Formula I or Formula II and an inert, pharmaceutically acceptable carrier or diluent. In one embodiment of the pharmaceutical compositions, efficacious levels of the inventive agents are provided so as to provide therapeutic benefits involving anti-proliferative ability. By"efficacious levels"is meant levels in which proliferation is inhibited, or controlled. These compositions are prepared in unit- dosage form appropriate for the mode of administration, e. g. , parenteral or oral administration.

An inventive agent can be administered in conventional dosage form prepared by combining a therapeutically effective amount of an agent (e. g. , a compound of Formula I) as an active ingredient with appropriate pharmaceutical carriers or diluents according to conventional procedures. These procedures may involve mixing, granulating and compressing or dissolving the ingredients as appropriate to the desired preparation.

The pharmaceutical carrier employed may be either a solid or liquid. Exemplary of solid carriers are lactose, sucrose, talc, gelatin, agar, pectin, acacia, magnesium stearate, stearic acid and the like. Exemplary of liquid carriers are syrup, peanut oil, olive oil, water and the like. Similarly, the carrier or diluent may include time-delay or time-release material known in the art, such as glyceryl monostearate or glyceryl distearate alone or with a wax, ethylcellulose, hydroxypropylmethylcellulose, methylmethacrylate and the like.

A variety of pharmaceutical forms can be employed. Thus, if a solid carrier is used, the preparation can be tableted, placed in a hard gelatin capsule in powder or pellet form or in the form of a troche or lozenge. The amount of solid carrier may vary, but generally will be from about 25 mg to about 1 g. If a liquid carrier is used, the preparation will be in the form of syrup, emulsion, soft gelatin capsule, sterile injectable solution or suspension in an ampoule or vial or non-aqueous liquid suspension.

To obtain a stable water-soluble dose form, a pharmaceutically acceptable salt of an inventive agent can be dissolved in an aqueous solution of an organic or inorganic acid, such as

0.3M solution of succinic acid or citric acid. If a soluble salt form is not available, the agent may be dissolved in a suitable cosolvent or combinations of cosolvents. Examples of suitable cosolvents include, but are not limited to, alcohol, propylene glycol, polyethylene glycol 300, polysorbate 80, glycerin and the like in concentrations ranging from 0-60% of the total volume. In an exemplary embodiment, a compound of Formula I is dissolved in DMSO and diluted with water. The composition may also be in the form of a solution of a salt form of the active ingredient in an appropriate aqueous vehicle such as water or isotonic saline or dextrose solution.

It will be appreciated that the actual dosages of the agents used in the compositions of this invention will vary according to the particular complex being used, the particular composition formulated, the mode of administration and the particular site, host and disease being treated.

Optimal dosages for a given set of conditions can be ascertained by those skilled in the art using conventional dosage-determination tests in view of the experimental data for an agent. For oral administration, an exemplary daily dose generally employed is from about 0.001 to about 1000 mg/kg of body weight, with courses of treatment repeated at appropriate intervals. Administration of prodrugs is typically dosed at weight levels which are chemically equivalent to the weight levels of the fully active form.

The compositions of the invention may be manufactured in manners generally known for preparing pharmaceutical compositions, e. g. , using conventional techniques such as mixing, dissolving, granulating, dragee-making, levigating, emulsifying, encapsulating, entrapping or lyophilizing. Pharmaceutical compositions may be formulated in a conventional manner using one or more physiologically acceptable carriers, which may be selected from excipients and auxiliaries that facilitate processing of the active compounds into preparations which can be used pharmaceutically.

Proper formulation is dependent upon the route of administration chosen. For injection, the agents of the invention may be formulated into aqueous solutions, preferably in physiologically compatible buffers such as Hanks's solution, Ringer's solution, or physiological saline buffer. For transmucosal administration, penetrants appropriate to the barrier to be permeated are used in the formulation. Such penetrants are generally known in the art.

For oral administration, the compounds can be formulated readily by combining the compounds with pharmaceutically acceptable carriers known in the art. Such carriers enable the compounds of the invention to be formulated as tablets, pills, dragees, capsules, liquids, gels, syrups, slurries, suspensions and the like, for oral ingestion by a patient to be treated.

Pharmaceutical preparations for oral use can be obtained using a solid excipient in admixture with the active ingredient (agent), optionally grinding the resulting mixture, and processing the mixture of granules after adding suitable auxiliaries, if desired, to obtain tablets or dragee cores. Suitable

excipients include: fillers such as sugars, including lactose, sucrose, mannitol, or sorbitol ; and cellulose preparations, for example, maize starch, wheat starch, rice starch, potato starch, gelatin, gum, methyl cellulose, hydroxypropylmethyl-cellulose, sodium carboxymethylcellulose, or polyvinylpyrrolidone (PVP). If desired, disintegrating agents may be added, such as crosslinked polyvinylpyrrolidone, agar, or alginic acid or a salt thereof such as sodium alginate.

Dragee cores are provided with suitable coatings. For this purpose, concentrated sugar solutions may be used, which may optionally contain gum arabic, polyvinyl pyrrolidone, Carbopol gel, polyethylene glycol, and/or titanium dioxide, lacquer solutions, and suitable organic solvents or solvent mixtures. Dyestuffs or pigments may be added to the tablets or dragee coatings for identification or to characterize different combinations of agents.

Pharmaceutical preparations which can be used orally include push-fit capsules made of gelatin, as well as soft, sealed capsules made of gelatin and a plasticizer, such as glycerol or sorbitol. The push-fit capsules can contain the agents in admixture with fillers such as lactose, binders such as starches, and/or lubricants such as talc or magnesium stearate, and, optionally, stabilizers. In soft capsules, the agents may be dissolved or suspended in suitable liquids, such as fatty oils, liquid paraffin, or liquid polyethylene glycols. In addition, stabilizers may be added. All formulations for oral administration should be in dosages suitable for such administration. For buccal administration, the compositions take the form of tablets or lozenges formulated in conventional manners.

For administration intranasally or by inhalation, the compounds for use according to the present invention are conveniently delivered in the form of an aerosol spray presentation from pressurized packs or a nebuliser, with the use of a suitable propellant, e. g., dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide or other suitable gas. In the case of a pressurized aerosol the dosage unit may be determined by providing a valve to deliver a metered amount. Capsules and cartridges of gelatin for use in an inhaler or insufflator and the like may be formulated containing a powder mix of the compound and a suitable powder base such as lactose or starch.

The compounds may be formulated for parenteral administration by injection, e. g., by bolus injection or continuous infusion. Formulations for injection may be presented in unit-dosage form, e. g. , in ampoules or in multi-dose containers, with an added preservative. The compositions may take such forms as suspensions, solutions or emulsions in oily or aqueous vehicles, and may contain formulatory agents such as suspending, stabilizing and/or dispersing agents.

Pharmaceutical formulations for parenteral administration include aqueous solutions of the agents in water-soluble form. Additionally, suspensions of the agents may be prepared as appropriate oily injection suspensions. Suitable lipophilic solvents or vehicles include fatty oils

such as sesame oil, or synthetic fatty acid esters, such as ethyl oleate or triglycerides, or liposoms.

Aqueous injection suspensions may contain substances that increase the viscosity of the suspension, such as sodium carboxymethyl cellulose, sorbitol, or dextran. Optionally, the suspension may also contain suitable stabilizers or agents that increase the solubility of the compounds to allow for the preparation of highly concentrated solutions.

For administration to the eye, the agent is delivered in a pharmaceutically acceptable ophthalmic vehicle such that the compound is maintained in contact with the ocular surface for a sufficient time period to allow the compound to penetrate the corneal and internal regions of the eye, for example, the anterior chamber, posterior chamber, vitreous body, aqueous humor, vitreous humor, cornea, iris/ciliary, lens, choroid/retina and sclera. The pharmaceutically acceptable ophthalmic vehicle may be an ointment, vegetable oil, or an encapsulating material. A compound of the invention may also be injected directly into the vitreous and aqueous humor.

Alternatively, the agents may be in powder form for constitution with a suitable vehicle, e. g. , sterile pyrogen-free water, before use. The compounds may also be formulated in rectal compositions such as suppositories or retention enemas, e. g, containing conventional suppository bases such as cocoa butter or other glycerides.

In addition to the formulations described above, the agents may also be formulated as a depot preparation. Such long-acting formulations may be administered by implantation (for example, subcutaneously or intramuscularly) or by intramuscular injection. Thus, for example, the compounds may be formulated with suitable polymeric or hydrophobic materials (for example, as an emulsion in an acceptable oil) or ion-exchange resins, or as sparingly soluble derivatives, for example, as a sparingly soluble salt.

An exemplary pharmaceutical carrier for hydrophobic compounds is a cosolvent system comprising benzyl alcohol, a nonpolar surfactant, a water-miscible organic polymer, and an aqueous phase. The cosolvent system may be a VPD co-solvent system. VPD is a solution of 3% w/v benzyl alcohol, 8% w/v of the nonpolar surfactant polysorbate 80, and 65% w/v polyethylene glycol 300, made up to volume in absolute ethanol. The VPD co-solvent system (VPD: 5W) contains VPD diluted 1 : 1 with a 5% dextrose in water solution. This co-solvent system dissolves hydrophobic compounds well, and itself produces low toxicity upon systemic administration.

Naturally, the proportions of a co-solvent system may be varied considerably without destroying its solubility and toxicity characteristics. Furthermore, the identity of the co-solvent components may be varied: for example, other low-toxicity nonpolar surfactants may be used instead of polysorbate 80; the fraction size of polyethylene glycol may be varied; other biocompatible polymers may replace polyethylene glycol, e. g. polyvinyl pyrrolidone; and other sugars or polysaccharides may be substituted for dextrose.

Alternatively, other delivery systems for hydrophobic pharmaceutical compounds may be employed. Liposomes and emulsions are known examples of delivery vehicles or carriers for hydrophobic drugs. Certain organic solvents such as dimethylsulfoxide also may be employed, although usually at the cost of greater toxicity. Additionally, the compounds may be delivered using a sustained-release system, such as semi-permeable matrices of solid hydrophobic polymers containing the therapeutic agent. Various sustained-release materials have been established and are known by those skilled in the art. Sustained-release capsules may, depending on their chemical nature, release the compounds for a few weeks up to over 100 days. Depending on the chemical nature and the biological stability of the therapeutic reagent, additional strategies for protein stabilization may be employed.

The pharmaceutical compositions also may comprise suitable solid-or gel-phase carriers or excipients. Examples of such carriers or excipients include calcium carbonate, calcium phosphate, sugars, starches, cellulose derivatives, gelatin, and polymers such as polyethylene glycols.

Some of the compounds of the invention may be provided as salts with pharmaceutically compatible counter ions. Pharmaceutically compatible salts may be formed with many acids, including hydrochloric, sulfuric, acetic, lactic, tartaric, malic, succinic, etc. Salts tend to be more soluble in aqueous or other protonic solvents than are the corresponding free-base forms.

The agents of the invention may be useful in combination with known anti-cancer treatments such as: DNA interactive agents such as cisplatin or doxorubicin; topoisomerase II inhibitors such as etoposide; topoisomerase I inhibitors such as CPT-11 or topotecan; tubulin interacting agents such as paclitaxel, docetaxel or the epothilones; hormonal agents such as tamoxifen ; thymidilate synthase inhibitors such as 5-fluorouracil; and anti-metalbolites such as methotrexate. They may be administered together or sequentially, and when administered sequentially, the agents may be administered either prior to or after administration of the known anticancer or cytotoxic agent.

The agents may be prepared using the reaction routes and synthesis schemes as described below, employing the general techniques known in the art using starting materials that are readily available. The preparation of preferred compounds of the present invention is described in detail in the following examples, but the artisan will recognize that the chemical reactions described may be readily adapted to prepare a number of other anti-proliferatives or protein kinase inhibitors of the invention. For example, the synthesis of non-exemplified compounds according to the invention may be successfully performed by modifications apparent to those skilled in the art, e. g. , by appropriately protecting interfering groups, by changing to other suitable reagents known in the art, or by making routine modifications of

reaction conditions. Alternatively, other reactions disclosed herein or generally known in the art will be recognized as having applicability for preparing other compounds of the invention.

EXAMPLES In the examples described below, unless otherwise indicated, all temperatures are set forth in degrees Celsius and all parts and percentages are by weight. Reagents were purchased from commercial suppliers such as Sigma-Aldrich Chemical Company or Lancaster Synthesis Ltd. and were used without further purification unless otherwise indicated. Tetrahydrofuran (THF) and N, N-dimethylformamide (DMF) were purchased from Aldrich in Sure Seal bottles and used as received. All solvents were purified using standard methods known to those skilled in the art, unless otherwise indicated.

The reactions set forth below were done generally under a positive pressure of argon at an ambient temperature (unless otherwise stated) in anhydrous solvents, and the reaction flasks were fitted with rubber septa for the introduction of substrates and reagents via syringe. Glassware was oven dried and/or heat dried. Analytical thin layer chromatography (TLC) was performed on glass-backed silica gel 60 F 254 plates from Analtech (0.25 mm), eluted with the appropriate solvent ratios (v/v), and are denoted where appropriate. The reactions were assayed by TLC, NMR, or analytical HPLC and terminated as judged by the consumption of starting material.

Visualization of the TLC plates was done with iodine vapor, ultraviolet illumination, 2% Ce (NH4) 4 (SO4) 4 in 20% aqueous sulfuric acid, 2% ninhydrin in ethanol, or p-anisaldehyde spray reagent, and activated with heat where appropriate. Work-ups were typically done by doubling the reaction volume with the reaction solvent or extraction solvent and then washing with the indicated aqueous solutions using 25% by volume of the extraction volume unless otherwise indicated. Product solutions were dried over anhydrous Nk,, S04 and/or MgS04 prior to filtration and evaporation of the solvents under reduced pressure on a rotary evaporator and noted as solvents removed in vacuo. Flash column chromatography (Still et al. , J. Org. Chem., 43,2923 (1978) ) was done using Merck silica gel (47-61 urn) with a silica gel crude material ratio of about 20: 1 to 50 : 1, unless otherwise stated. Hydrogenolysis was done at the pressure indicated in the examples or at ambient pressure.

1H-NMR spectra were recorded on a Bruker or Varian instrument operating at 300 MHz and 13C-NMR spectra were recorded operating at 75 MHz. NMR spectra were obtained as CDC13 solutions (reported in ppm), using chloroform as the reference standard (7.27 ppm and 77.00 ppm) unless otherwise noted. When peak multiplicities are reported, the following abbreviations are used: s (singlet), d (doublet), t (triplet), q (quartet), m (multiplet), br (broadened multiplet), bs

(broadened singlet), dd (doublet of doublets), dt (doublet of triplets). Coupling constants, when given, are reported in Hertz (Hz).

Infrared (IR) spectra were recorded on a Perkin-Elmer FT-IR Spectrometer as neat oils, as KBr pellets, or as CDC13 solutions, and when given are reported in wave numbers (cm-1). The mass spectra were obtained using LSIMS, FAB, MALDI, or electrospray (ESIMS). All melting points (mp) are uncorrected.

Mass spectrometry (MS) was conducted with various techniques. Matrix-Assisted Laser Desorption/Ionization Fourier Transform Mass Spectrometry (MALDI FTMS), was performed on an IonSpec FTMS mass spectrometer. Samples are irradiated with a nitrogen laser (Laser Science Inc. ) operated at 337nm and the laser beam is attenuated by a variable attenuator and focused on the sample target. The ions are then differentiated according to their m/z using an ion cyclotron resonance mass analyzer. The electrospray ionization (ESI) mass spectrometry experiments were performed on an API 100 Perkin Elmer SCIEX single quadrupole mass spectrometer. Electrospray samples are typically introduced into the mass analyzer at a rate of 4. 0 ul/minute. The positive and negative ions, generated by charged droplet evaporation, enter the analyzer through an interface plate and a 100 mm orifice, while the declustering potential is maintained between 50 and 200V to control the collisional energy of the ions entering the mass analyzer. The emitter voltage is typically maintained at 4000V. The liquid chromatography (LC) electrospray ionization (ESI) mass spectrometry experiments are performed on an Hewlett-Packard (HP) 1100 MSD single quadrupole mass spectrometer. Electrospray samples are typically introduced into the mass analyzer at a rate of 100 to 1000 Ill/minute. The positive and negative ions, generated by charged droplet evaporation, enter the analyzer through a heated capillary plate, while the declustering potential is maintained between 100 and 300V to control the collisional energy of the ions entering the mass analyzer. The emitter voltage is typically maintained at 4000V.

Reserved phase preparative HPLC purification was performed on Gilson 321 system, using a C18 reversed phase preparative column (Metasil AQ 10 u, CIS, 120A 250 x 21.2 mm, MetaChem) in a gradient from 0. 1% TFA/5% CH3CN/H20 to 0. 1% TFA/5% H20/CH3CN over 20 minutes at a flow rate of 20ml/min.

In Examples, the compounds may be obtained in the form of salts or free bases. When the compounds are obtained in the form of TFA salts, they were obtained by lyophilizing the HPLC fractions of the corresponding compounds. When the compounds are obtained in the form of the HC1 salts, they were obtained by lyophilizing the HPLC fractions of the corresponding compounds in the presence of excess hydrochloric acid. When the compounds are obtained in the form of the free bases, they were obtained by concentrating ethyl acetate extracts of HPLC fractions, neutralized with Na2CO3.

Compounds in accordance with the invention may be prepared in manners analogous to those specifically described below, with the lettered example prefixes (i. e. , A, B, C, D, E, F and G) designating general synthesis schemes.

Method A F O Br 0 0 O r NH2 NaOH eut0 H2NCN/DBU NCS H S Step 2 O O NH2 R./NHZ Step 1 H F ; F Step 2 H H S PyBop 3 1 Step 3 4 1 The common starting material, 2-bromo-2', 6'-difluoroacetophenone, was prepared as follows.

2-Bromo-2', 6'-difluoroacetophenoze To a mechanically stirring solution of 2', 6'-difluoroacetophenone (100.0 g, 640.0 mmol ; Melford Laboratories, Ltd. ) in ethyl acetate (1300 ml) was added freshly milled copper (II) bromide (300 g, 1.35 mol) and bromine (1.6 ml, 32 mmol). The mixture was heated at reflux for 2.25 hours and allowed to cool to room temperature. The resultant green mixture was filtered and the solids rinsed with ethyl acetate (4x100 ml). The filtrate was concentrated with a rotary evaporator at <40°C under reduced pressure, diluted with methyl t-butyl ether (MTBE ; 650 ml), filtered through a pad of silica gel (230-400 Il, 9.5 cm diam. x 4 cm. ht. ), and solids rinsed with MTBE (5x200 ml).

Concentration of the filtrate gave a pale green oil, which was purified by fractional vacuum distillation to give 117 g of pale yellow oil, bp 88-97°C (2.0 mm Hg) in 78% yield. The results

matched that previously described in PCT Patent Publication W099/21845 (in Example C (79) ) and was used without any further purification or characterization.

1H NMR : 87. 48 (ddd, 1H, J=6.3, 8. 5,14. 8 Hz), 7.01 (ddd, 2H, J=4.6, 5.8, 16.6 Hz), 4. 37 (t, 2H, J=0. 7 Hz).

Step 1. 4-4-Amino-5- (2, 6-difluoro-benzoyl)-thiazol-2-ylaminoJ-benzoic eid Etla, yl Ester ( To a mechanically stirring mixture of 4-ethoxycarbonylphenyl isothiocyanate (1; 25.0 g, 121'mmol ; TransWorld), cyanamide (5.32 g, 127 mmol), and acetonitrile (150 ml) at 2. 6°C was added dropwise over 12 minutes DBU (1,8-diazabicyclo [5.4. 0] -7-undecene; 19.8 ml, 133 mmol).

After 2 hours at 0°C, a solution of 2-bromo-2', 6'-difluoro-acetophenone (29.8 g, 127 mmol) in acetonitrile (25 ml) was added dropwise over 13 minutes. Upon warming to ambient temperature, the resultant mixture turned into a dark red solution, and was allowed to stir overnight. Water (175 ml) was added over 5 minutes, and the resultant yellow suspension stirred for one hour. The yellow solid was rinsed with acetonitrile/water (1/1 ; 3 x 75 ml) and dried under high vacuum at 45°C to give 45.39 g of yellow solid in 93% yield.

1H NMR (DMSO-d6) : 8 11.24 (bs, 1H), 8.30 (br, 1H), 8.06 (d, 2H, J=8.7 Hz), 7.82 (d, 2H, J=8.7 Hz), 7.66 (m, 1H), 7.30 (t, 2H, J=8.7 Hz), 4. 38 (t, 3H, J=5.6 Hz), 1.38 (t, 3H, J=5.6 Hz).

Step 2. 4-[4-Amino-5-(2,6-difluoro-benzoyl)-thiazol-2-ylamino]-benzo ic Acid (3) To a mechanically stirring solution of {4-amino-5- [l- (2, 6-diftuoro-benzoyl)]-thiazol-2- ylamino}-benzoic acid ethyl ester (2, 45.7g, 113 mmol) in methanol (250 ml) was added 3N aqueous NaOH solution (378 ml). An exotherm resulted and the resultant yellow solution at 31°C was allowed to stir at room temperature overnight. The methanol was removed under reduced pressure and the resultant aqueous solution was washed with hexane (2x150 ml). The aqueous layer was cooled to 5°C, adjusted to pH4.0 with 6N HC1 (-200 ml), and diluted with water (100 ml). The bright yellow solid was filtered off, washed with water (3x250 mL), and dried under vacuum at 45°C to provide 38.65 g of canary yellow solid in 91% yield.

'H NMR (DMSO-d6) : 811. 18 (bs, lH), 8.20 (br, 1H), 7.90 (d, 2H, J=8.8Hz), 7.72 (d, 2H, J=8.8Hz), 7.60 (m, lH), 7.24 (t, 2H, J=8.7Hz).

Anal. Calcd. for C17H11F2N3O3S#1.25 H2O : C, 51.32% ; H, 3.42% ; N, 10.56% ; S, 8.06%. Found: C, C, 51.32% ; H, 3.42% ; N, 10.56% ; S, 8.06%.

Step 3. 4- (4-Amino-5- (2, 6-difluoro-benzoyl)-tlziazol-2-ylaminoJ-benzamide () General Method

To a solution of 4- [4-amino-5- (2, 6-difluoro-benzoyl) -thiazol-2-ylamino]-benzoic acid (3 ; 1 eq), appropriate amine (1.2 eq) and DIEA (N, N-diisopropylethylamine; 6 eq) in DMF, PyBop (benzotriazol-1-yl-oxy-tris-pyrrolidino-phosphonium hexafluorophosphate ; 1.1 eq) was added. The reaction mixture was stirred at room temperature for 3 hours.

DMF was removed under reduced pressure and a solution of the resultant residue in ethyl acetate was extracted with saturated aqueous NaHCO3, brine, dried with MgS04, filtered and concentrated to give a crude product that was further purified by either silica gel chromatography or reversed phase preparative HPLC.

Reversed phase preparative HPLC purification was performed on Gilson 321 system, using a C18 reversed phase preparative column (Metasil AQ 10 Li, C18,120A 250 x 21.2 mm, MetaChem) with a gradient from 0. 1% TFA/5% CH3CN/H20 to 0.1% TFA/5% H20/CH3CN over 20 minutes at a flow rate of 20 ml/min.

The TFA salts were obtained by lyophilizing the HPLC fractions of the corresponding compounds.

The HC1 salts were obtained by lyophilizing the HPLC fractions of the corresponding compounds in the presence of excess hydrochloric acid.

The free bases were obtained by concentrating ethyl acetate extracts of HPLC fractions, neutralized with Na2CO3.

The compounds of the following Examples A1-A62 were prepared in a manner similar to Step 3 in Method A from 4- [4-amino-5- (2, 6-difluoro-benzoyl)-thiazol-2-ylamino]-benzoic acid 3 and appropriate amines (R-NH2) with PyBop, HATU [0- (7-azabenzotriazol-1-yl)-N, N, N', N'- tetramethyluronium hexafluoro-phosphate] or other similar coupling reagents.

Example Al : 4- [4-Amino-5- (2, 6-difluoro-benzoyl)-thiazol-2-ylamino]-N- (2-morpholin-4-yl- ethyl)-benzamide 1HNMR (CD30D) : 67. 88 (d, 2H, J=8.9 Hz), 7.76 (d, 2H, J=8.9 Hz), 7.54-7. 43 (m, 1H), 7.08 (m, 2H), 3.84-3. 75 (m, 4H), 3.62 (t, 2H, J=6.4 Hz), 2.98-2. 78 (m, 6H).

HRFABMS : Calcd for C23H23F2NsO3S (M+Na+) : 510.1387. Found: 510.1382.

Anal. Calcd. for C23H23F2N5O3S#0. 82 MeOH#0. 12 CH3CN : C, 55.71% ; H, 5.18% ; N, 13.83% ; S, 6.18%. Found: C, 55.69% ; H, 5.17% ; N, 13.84% ; S, 6. 11%.

Example A2: 4- [4-Amino-5- (2, 6-difluoro-benzoyl)-thiazol-2-ylamino]-N- (2-phenylamino-ethyl)- benzamide

1HNMR (DMSO-d6) : 511. 06 (s, 1H), 8.50 (t, 1H, J=2. 8 Hz), 8.19 (bs, 2H), 7.86 (d, 2H, J=8.7 Hz), 7.68 (d, 2H, J=8.7 Hz), 7.58 (m, 1H), 7.22 (m, 2H), 7.08 (t, 2H, J=7.8 Hz), 6.61 (d, 2H, J=7.8 Hz), 6.52 (t, 1H, J=7.2 Hz), 5.71 (br, 1H), 3.42 (m, 2H), 3.22 (m, 2H).

HRFABMS : Calcd for C25H21F2N502S (M+H+) : 494.1462. Found: 494.1444.

Example A3: 4- [4-Amino-5- (2, 6-difluoro-benzoyl)-thiazol-2-ylamino]-N- (2-dimethylamino- ethyl)-N-methyl-benzamide. HNMR (CD30D) : 87. 74 (d, 2H, J=8.6 Hz), 7.53-7. 39 (m, 3H), 7.07 (t, 2H, J=8.7 Hz), 3.68 (m, 1H), 3.46 (m, 1H), 3.05 (s, 3H), 2.64 (m, 1H), 2.52 (m, 1H), 2.37 (s, 3H), 2.09 (s, 3H).

HRFABMS : Calcd for C22H23F2N502S (M+H)+ : 460.1619. Found: 460.1612.

Example A4: 4- [4-Amino-5- (2, 6-difluoro-benzoyl)-thiazol-2-ylamino]-N- (2-dimethylamino- ethyl) -benzamide Hydrochloride Salt 1H NMR (CD30D) : 57. 84 (d, 2H, J=8.8 Hz), 7.73 (d, 2H, J=8.8 Hz), 7.52-7. 83 (m, 1H), 7.03 (t, 2H, J=7.9 Hz), 3.75 (t, 2H, J=5.8 Hz), 3.38 (t, 2H, J=5.9), 2.98 (s, 6H).

FABMS (M+H+) : 446; (M-H-) : 444.

Anal. Calcd. for C2lH2lF2N502S0. 7 H20O0. 08 EtOAc. 1. 55 HCI : C, 49.09% ; H, 4.75% ; N, 13.43% ; S, 6.15%. Found: C, 49.07% ; H, 4.62% ; N, 13. 43% ; S, 6.15%.

Example A5: 4- [4-Amino-5- (2, 6-difluoro-benzoyl)-thiazol-2-ylamino]-N- (6-hydroxy-6-methyl- hept-2-yl)-benzamide

1HNMR (CD30D) : 67. 82 (d, 2H, J=8.8 Hz), 7.74 (d, 2H, J=8.8 Hz), 7.50 (m, 1H), 7.02-7. 13 (m, 2H), 4.14 (m, 1H), 1.68-1. 37 (m, 6H), 1.23 (d, 3H, J=6.4 Hz), 1.18 (s, 3H), 1. 17 (s, 3H).

FABMS (M+H+) : 503; (M-H-) : 501.

Anal. Calcd. For C25H28F2N4O3S#0. 20 H2O#0. 24 EtOAc: C, 59.13% ; H, 5.80% ; N, 10.63% ; S, 6.08%. Found: C, 59.13% ; H, 5.82% ; N, 10.77% ; S, 6.06%.

Example A6: 4- [4-Amino-5- (2, 6-difluoro-benzoyl)-thiazol-2-ylamino]-N- (5-methyl-furan-2- ylmethyl)-benzamide.

1H NMR (DMSO-d6) : 511. 06 (s, 1H), 8. 83 (br, 1H), 8.22 (bs, 2H), 7.88 (d, 2H, J=8.7 Hz), 7.67 (d, 2H, J=8.7 Hz), 7.55 (m, 1H), 7.21 (t, 2H, J=7.5 Hz), 6.13 (d, 1H, J=3.0 Hz), 5.99 (d, 1H, J=3.0 Hz), 4. 39 (d, 2H, J=5.6 Hz), 2.21 (s, 3H).

FABMS (M+H+) : 469; (M-H-) : 467.

Anal. Calcd. for C23Hl8F2N403S*0-10 H2090. 12 EtOAc: C, 58.65% ; H, 4.02% ; N, 11.65% ; S, 6.67%. Found: C, 58.66% ; H, 4.02% ; N, 11. 85% ; S, 6. 68%.

Example A7: 4- [4-Amino-5- (2, 6-difluoro-benzoyl)-thiazol-2-ylamino]-N- (2-isopropoxy-ethyl)- benzamide.

1H NMR (DMSO-d6) : 8 11.06 (s, 1H), 8.41 (br, 1H), 8.22 (bs, 2H), 7.84 (d, 2H, J=8.7 Hz), 7.64 (d, 2H, J=8.7 Hz), 7.56 (m, 1H), 7.21 (t, 2H, J=8.7 Hz), 3.56 (m, 1H), 3.48 (t, 2H, J=6.0 Hz), 3.35 (m, 2H), 1.09 (d, 6H, J=6. 1 Hz).

FABMS (M+H+) : 461; (M-IT) : 459.

Example A8: 4- [4-Amino-5- (2, 6-difluoro-benzoyl)-thiazol-2-ylamino]-N- (pyrrolidin-2S-yl- methyl)-benzamide.

The intermediate 2S-({[1-(4-{4-amino-5-[1-(2, 6-difluoro-phenyl) -methanoyl]-thiazol- 2-ylamino}-phenyl)-methanoyl]-amino}-methyl)-pyrrolidine-1-c arboxylic acid tert-butyl ester was prepared in a manner similar to Step 3 in Method A from 2S-aminomethyl-pyrrolidine-l- carboxylic acid tert-butyl ester (AstaTech, Inc.).

'H NMR (CDC13) : 8. 45 (br, 1H), 7.84 (d, 2H, J=8.6 Hz), 7.39-7. 24 (m, 3H), 6.95 (m, 2H), 4.20 (m, 1H), 3.54-3. 31 (m, 4H), 2.04-1. 65 (m, 2H) The title compound was prepared by treating the above intermediate with 30 % TFA/CH2C12 in 30 minutes, followed by HPLC purification.

1HNMR (CD30D) : 87. 85 (d, 2H, J=9.0 Hz), 7.74 (d, 2H, J=9.0 Hz), 7.50 (m, 1H), 7.09 (t, 2H, J=8. 0 Hz), 3. 55-3. 38 (m, 3H), 3.12-2. 90 (m, 2H), 2.07-1. 77 (m, 3H), 1.59 (m, 1H).

FABMS (M+H+) : 458; (M-H-): 456.

Anal. Calcd. for C22H2iF2Ns02S'0. 50 H20O0. 06 TFA: C, 56.13% ; H, 4. 70% ; N, 14.80% ; S, 6.77%.

Found: C, 56. 18% ; H, 4.78% ; N, 14.72% ; S, 6. 81%.

Example A9: 4- [4-Amino-5- (2, 6-difluoro-benzoyl)-thiazol-2-ylamino]-N-phenyl-benzamide.

1H NMR (DMSO-d6): 611. 19 (s, 1H), 10.20 (s, 1H), 8.29 (bs, 2H), 8.04 (d, 2H, J=8. 7 Hz), 7.82 (m, 4H), 7.62 (m, 1H), 7.41 (t, 2H, J=7.8 Hz), 7.28 (t, 2H, J=7.9 Hz), 7.17 (t, 1H, J=7.8 Hz).

FABMS (M+H+) : 451; (M-H-): 449.

Anal. Calcd. for C23H16F2N4O2S: C, 61.32% ; H, 3.58% ; N, 12.44% ; S, 7.12%. Found: C, 61. 30% ; H, 3.66% ; N, 12.35% ; S, 7.07%.

Example A10: 4- [4-Amino-5- (2, 6-difluoro-benzoyl)-thiazol-2S-ylamino]-N- (l-Acetyl-pyrrolidin- 2S-ylmethyl)-benzamide.

The title compound was prepared by acylation of the compound of Example A8 with acetic anhydride in CH2Clz, followed by preparative HPLC purification. lHNMR (CD30D) : 8 7.97-7. 71 (u, 4H), 7.47 (m, 1H), 7.08 (t, 2H, J=7.8 Hz), 3.74 (m, 1H), 3.68- 3.40 (m, 4H), 2.95-2. 63 (m, 2H), 2.21 (s, 1H), 2.09 (s, 3H), 1.88 (m, 1H).

HRFABMS : Calcd. For C24H23F2N503S (M+H+) : 500.1568. Found: 500. 1514.

Example All : 4-[4-Amino-5-(2,6-difluoro-benzoyl)-2-ylamino]-N-(1-ethyl-py rrolidin-2RS- ylmethyl)-benzamide.

'H NMR (CDCl3) : 67. 79 (d, 2H, J=8.7 Hz), 7.40 (d, 2H, J=8.7 Hz), 7.33 (m, 1H), 6.94 (t, 2H, J=8.7 Hz), 3.69 (m, 1H), 3.37-3. 17 (m, 2H), 2.85 (m, 1H), 2.72 (m, 1H), 2.26 (m, 2H), 1.94-1. 58 (m, 4H), 1.16 (t, 3H, J=7.1 Hz).

FABMS (M+H+) : 486; (M-H-): 484. Anal. Calcd. for C24H25F2Ns02S0. 2 H2O0. 1 EtOAc: C, 58.85% ; H, 5.19% ; N, 14.06% ; S, 6.44%.

Found: C, 58.84% ; H, 5. 30% ; N, 14.09% ; S, 6.38%.

Example A12: 4- [4-Amino-5- (2, 6-difluoro-benzoyl)-thiazol-2-ylamino]-N- (2-dimethylamino- 2-methyl-propyl)-benzamide.

The starting material 2, N2, N2-trimethyl-propane-1, 2-diamine was prepared according to the literature procedure (Yang et al, Eur J. Med. Chem. Vol 31, pp. 231-239, (1996)).

Coupling as in Step 3 for Method A and column chromatography with 15% MeOH/CHCl3 provided a yellow solid in 25% yield.

1H NMR (DMSO-d6) : # 8.19 (bs, 1H), 7.86 (d, 2H, J=8.7 Hz), 7.66 (d, 2H, J=8.6 Hz), 7.61- 7.48 (m, 1H), 7. 21 (t, 2H, J=7.9 Hz), 2.30 (bs, 2H), 1.02 (s, 6H).

HRFABMS Calcd. for C23H26F2N5O2S (M+H+) : 474.1775. Found: 474.1784.

Anal. Calcd for C23H25F2N5O2S#0. 45 CHC13-0. 15 DMSO: C, 52.93% ; H, 4.93% ; N, 12.99% ; S, 6.84%. Found: C, 52.89% ; H, 5.32% ; N, 12. 61%, S, 6.89%.

Example A13: 4- [4-Amino-5- (2, 6-difluoro-benzoyl)-thiazol-2-ylamino]-N- (l-benzyl-piperidin-4- yl)-benzamide.

'HNMR (DMSO-d6) : 8 11.05 (br, 1H), 8.32-8. 10 (m, 3H), 7.86 (d, 2H, J=8. 7 Hz), 7.65 (d, 2H, J=8.7 Hz), 7.57 (m, 1H), 7.39-7. 18 (m, 7H), 3.78 (m, 1H), 3.49 (s, 2H), 2.85 (m, 2H), 2. 13-1. 98 (m, 2H), 1.80 (m, 2H), 1.68-1. 53 (m, 2H).

FABMS (M+H+) : 548 ; (M-H-): 546.

Anal. Calcd. for C29H27F2N5O2S#0. 25 H2O0. 25 TFA: C, 61.02% ; H, 4.82% ; N, 12.06% ; S, 5.52%.

Found: C, 61.03% ; H, 5.00% ; N, 12.23% ; S, 5.62%.

Example A14: 4- [4-Amino-5- (2, 6-difluoro-benzoyl)-thiazol-2-ylamino]-N- [2- (4-hydroxy- phenyl)-ethyl]-benzamide.

1H NMR (DMSO-d6) : 8 11.04 (s, 1H), 9.12 (s, 1H), 8.40 (t, 1H, J=5.6 Hz), 8.21 (bs, 2H), 7.81 (d, 2H, J=8.7 Hz), 7.67 (d, 2H, J=8. 7 Hz), 7.55 (m, 1H), 7.21 (t, 2H, J=7.8 Hz), 7.02 (d, 2H, J=8.4 Hz), 6.68 (d, 2H, J=8.5 Hz), 3.47-3. 34 (m, 2H), 2.73 (t, 2H, J=7. 4 Hz).

FABMS (M+H)+ : 495, (M-H-) : 493.

Anal. Calcd. for C25H20F2N4O3S#0. 3 H20@D. 04 EtOAc: C, 60.02% ; H, 4. 19% ; N, 11.13% ; S, 6.37%. Found : C, 60.04% ; H, 4. 22% ; N, 11.27% ; S, 6.24%.

Example A15: 4-[4-Amino-5-(2,6-difluoro-benzoyl)-thiazol-2-ylamino]-N-(2- PIPERIDIN-1-YL- ethyl)-benzamide.

'H NMR (CD30D) : # 8.72 (d, 2H, J=8.7 Hz), 7.73 (d, 2H, J=8.7 Hz), 7.47 (m, 1H), 7.05 (t, 2H, J=7.8 Hz), 3.54 (t, 2H, J=6.8 Hz), 2.68-2. 49 (m, 6H), 1.71-1. 58 (m, 4H), 1.56-1. 44 (m, 2H).

FABMS (M+H+) : 486; (M-H-) : 484.

Anal. Calcd. for C24H2sF2Ns0zS0. 4 H20*0. 5 EtOAc: C, 58.17% ; H, 5.60% ; N, 13.05% ; S, 5.97%.

Found: C, 58.34% ; H, 5. 46% ; N, 13.20% ; S, 5.78%.

Example A16: 4- [4-Amino-5- (2, 6-difluoro-benzoyl)-thiazol-2-ylamino]-N- (4-dimethylamino- phenyl)-benzamide.

1H NMR (DMSO-d6) : 8 11.05 (s, 1H), 9.88 (s, 1H), 8.21 (bs, 2H), 7.94 (d, 2H, J=8. 7 Hz), 7.70 (d, 2H, J=8.7 Hz), 7.55 (m, 3H), 7.21 (t, 2H, J=7.9 Hz), 6.86 (d, 2H, J=9.1 Hz), 2.88 (s, 6H).

FABMS (M+H+) : 494; (M+Na+) : 516.

Anal. Calcd. for C25H22F2N5O2S 0. 1 H2O-0. 05 EtOAc: C, 60.56% ; H, 4.36% ; N, 14.01% ; S, 6.42%. Found: C, 60.57% ; H, 4.54% ; N, 14.00% ; S, 6.64%.

Example A17: 4- [4-Amino-5- (2, 6-difluoro-benzoyl)-thiazol-2-ylamino]-N- (2, 3-dihydro-benzo [1, 4] dioxin-6-yl) -benzamide.

1H NMR (DMSO-d6): 5 11. 10 (s, 1H), 9.95 (s, 1H), 8.21 (bs, 2H), 7.92 (d, 2H, J=8. 8 Hz), 7.72 (d, 2H, J=8. 8 Hz), 7.60 (m, 1H), 7.37 (d, 1H, J=2.4 Hz), 7.26-7. 13 (m, 3H), 6.81 (d, 2H, J=8.7 Hz), 4.25-4. 18 (m, 4H).

FABMS (M+H+) : 509; (M-H-) : 507.

Anal. Calcd. for C25H18F2N4O4S#0. 07 H200. 05 EtOAc: C, 58.90% ; H, 3.59% ; N, 10.99% ; S, 6.29%. Found: C, 58.90% ; H, 3.70% ; N. 10.88% ; S, 6.21%.

Example A18 : 4- {4-Amino-5- [1- (2, 6-difluoro-phenyl)-methanoyl]-thiazol-2-ylamino}-N- (2- methyl-2-methylamino-propyl)-benzamide Acetic Acid Salt. The starting material was prepared as follows : 2, N2-Dimethyl-propane-1, 2-diamine.

Crude 2-methyl-2-methylamino-propionitrile (2.00 g, 20.4 mmol; Gabriel, Chemin. Ber., 47, 2922-2925 (1914) and 1HNMR matched Stork et al. , J. Am. Chem. Soc. ; 96; 1974; 5787-5791 (1974) ) was added to a suspension of LiAlH4 (1.55 g, 20.38 mmol) in ether (40 mL) at 0°C. The resultant mixture was heated at reflux for 3 hours, then cooled to 0°C, and quenched with Hz0 (4

mL) and 2N NaOH (3 mL). After a few minutes of stirring, the granular white solids were filtered off. The filtrate was dried over Na2S04, filtered, and concentrated in vacuo to afford 1.5 g of a colorless oil in 72% yield, which was used without further purification.

'H NMR (CDCl3) : 8 2.47 (2H, s), 2.22 (3H, s), 0.94 (6H, s).

The title compound was prepared in a manner similar to Step 2 in Method A from 2, N2- dimethyl-propane-1, 2-diamine, and purified via column chromatography with 2% HOAc/10% MeOH/ CHC13 as eluant.

'H NMR (DMSO-d6): 8 8.28 (bs, 1H), 8. 15 (bs, 1H), 7.87 (d, 2H, J = 8.7 Hz), 7.62 (d, 2H, J = 8.5 Hz), 7.60-7. 48 (m, 1H), 7.20 (t, 2H, J = 7.9 Hz), 3.32 (d, 2H, J = 6.0 Hz), 2. 28 (s, 3H), 1.02 (s, 6H).

HRFABMS Calcd. for C22H24F2N502S (M+H") : 460.1619. Found: 460.1612.

Anal. Calcd. for C22H23F2N502S2 HOAc0. 4 CHC13 : C, 50. 54% ; H, 5.04% ; N, 11.16% ; S, 5. 11%. Found: C, 50. 31% ; H, 5.20% ; N, 10. 88% ; S, 5.03%.

Example A19 : 4- [4-Amino-5- (2, 6-difluoro-benzoyl)-thiazol-2-ylamino]-N- (5-methoxy-2-methyl- phenyl)-benzamide

'H NMR (DMSO-d6) : 8 11.11 (br, 1H), 9.70 (s, 1H), 8.21 (bs, 2H), 7.98 (d, 2H, J=8.8 Hz), 7.73 (d, 2H, J=8.8 Hz), 7.56 (m, 1H), 7.29-7. 13 (m, 3H), 7.01 (d, 1H, J=2.7 Hz), 6.75 (dd, 1H, J=2.7, 5.6 Hz), 3.73 (s, 3H), 2.17 (s, 3H).

FABMS (M+H+) : 495; (M-H-) : 493.

Anal. Calcd. for C25H20F2N4O3S#0.19 H2O#0. 15 EtOAc: C, 60.15% ; H, 4. 26% ; N, 10. 96% ; S, 6.27%. Found: C, 60.03% ; H, 4.21% ; N, 10.91% ; S, 6.33.

Example A20: 4- [4-Amino-5- (2, 6-difluoro-benzoyl)-thiazol-2-ylamino]-N- (2-dimethylamino- lRS-methyl-ethyl)-benzamide Hydrochloride Salt

1H NMR (DMSO-d6) : 8 11. 02 (br, 1H), 8.18 (bs, 2H), 8.03 (d, 1H, J=8.1 Hz), 7.82 (d, 2H, J=8.8 Hz), 7.68 (d, 2H, J=8. 8 Hz), 7.55 (m, 1H), 7.26-7. 14 (t, 2H, J=8.7 Hz), 4.16 (m, 1H), 2.42 (m, 1H), 2.28 (m, 1H), 2.21 (s, 6H), 1.14 (d, 3H, J=4.5 Hz).

FABMS (M+H+) : 460; (M-H-): 458.

Anal. Calcd. for C22H23F2N5O2S#0. 80 HCl#0. 4 EtOAc: C, 54.10% ; H, 5.19% ; N, 13.37% ; S, 6.12%. Found: C, 53.97% ; H, 5.10% ; N, 13.49% ; S, 6.16%.

Example A21 : 4- [4-Amino-5- (2, 6-difluoro-benzoyl)-thiazol-2-ylamino]-N- (4-morpholin-4-yl- phenyl)-benzamide.

1H NMR (DMSO-d6) : 8 11. 10 (s, 1H), 9.94 (s, 1H), 8.21 (bs, 2H), 7.95 (d, 2H, J=8. 7 Hz), 7. 71 (d, 2H, J=8.7 Hz), 7.56 (m, 3H), 7.22 (t, 2H, J=7. 8 Hz), 6.94 (d, 2H, J=9.1 Hz), 3.84 (t, 2H, J=4.7 Hz), 3.08 (t, 2H, J=4.7 Hz).

FABMS (M+H+) : 536; (M-H-) : 534.

Anal. Calcd. for C27H23F2NsO3S-1. 25 H20 : C, 58.11% ; H, 4.61% ; N, 12.55% ; S, 5.75%. Found: C, 58.11% ; H, 4.48% ; N, 12.58% ; S, 5.79%.

Example A22: 4- [4-Amino-5- (2, 6-difluoro-benzoyl)-thiazol-2-ylamino]-N-indan-2-yl-benzamid e.

1H NMR (DMSO-d6) : 8 11.05 (s, 1H), 8.54 (d, 1H, J=7.0 Hz), 8.20 (bs, 2H), 7.87 (d, 2H, J=8.7 Hz), 7.64 (d, 2H, J=8.7 Hz), 7.55 (m, 1H), 7.28-7. 12 (m, 6H), 4.68 (m, 1H), 3.24-3. 19 (m, 2H), 3.01-2. 89 (m, 2H).

FABMS (M+H) : 548; (M-H-) : 546.

Anal. Calcd. for C26H20F2N402Stl. 00 CHC13 : C, 53.17% ; H, 3.47% ; N, 9.19% ; S, 5.26%. Found: C, 52.95% ; H, 3. 38% ; N, 9.45% ; S, 5.54%. Example A23: 4- [4-Amino-5- (2, 6-difluoro-benzoyl)-thiazol-2-ylamino]-N- (2-diisopropylamino- ethyl)-benzamide.

'H NMR (CD30D) : 6 8.83 (d, 2H, J=8. 9 Hz), 7.76 (d, 2H, J=8. 9 Hz), 7.48 (m, 1H), 7. 08 (t, 2H, J=7.1 Hz), 3.42 (t, 2H, J=7.1), 3.18 (m, 2H), 2. 85 (m, 2H), 1.12 (d, 6H, J=6.5 Hz).

FABMS (M+H+) : 515; (M-H-) : 513.

Anal. Calcd. For C25H29F2N5O2S#0.12 H2O : C, 59.60% ; H, 5.85% ; N, 13.90% ; S, 6.37%. Found: C, 59.60% ; H, 5.82% ; N, 13.80% ; S, 6.34%.

Example A24: 4- [4-Amino-5- (2, 6-difluoro-benzoyl)-thiazol-2-ylamino]-N- [4- (2-hydroxy-ethyl)- phenyl]-benzamide. lH NMR (DMSO-d6) : # 11.12 (s, 1H), 10.15 (s, 1H), 8.21 (bs, 2H), 7.94 (d, 2H, J=8. 7 Hz), 7.84 (d, 2H, J=8.7 Hz), 7.64 (d, 2H, J=8. 7 Hz), 7.55 (m, 1H), 7.30-7. 12 (m, 4H), 4.60 (t, 1H, J=5.2 Hz), 3.40 (dd, 2H, J=5.2, 7.1 Hz), 2.71 (t, 2H, J=7.1 Hz).

FABMS (M+H+) : 495; (M-H-): 493.

Anal. Calcd. For C25H20F2N4O3S#0. 25 H2O : C, 60.17% ; H, 4.14% ; N, 11.23% ; S, 6. 43%. Found: C, 60.26% ; H, 4.22% ; N, 11. 14% ; S, 6. 36%.

Example A25 : 4- [4-Amino-5- (2, 6-difluoro-benzoyl)-thiazol-2-ylamino]-N- [4- (acetyl-methyl- amino)-phenyl]-benzamide.

'H NMR (DMSO-d6): 8 11.12 (s, 1H), 10. 25 (s, 1H), 8.21 (bs, 2H), 7.96 (d, 2H, J=8. 8 Hz), 7.82 (d, 2H, J=8.7 Hz), 7.75 (d, 2H, J=8.9 Hz), 7.56 (m, 1H), 7.31 (d, 2H, J=8.8 Hz), 7.21 (t, 2H, J=7.8 Hz), 3.16 (s, 3H), 1.88 (s, 3H).

LCMS (M+H+) : 522 Example A26: 4- [4-Amino-5- (2, 6-difluoro-benzoyl)-thiazol-2-ylamino]-N- (2-thiophen-2-yl- ethyl)-benzamide.

1H NMR (DMSO-d6) : 11. 05 (s, 1H), 8.54 (br, 1H), 8.21 (bs, 2H), 7.84 (d, 2H, J=8.8 Hz), 7.67 (d, 2H, J=8. 8 Hz), 7.55 (m, 1H), 7. 34 (dd, 1H, J=1.2, 5.4 Hz), 7.22 (t, 2H, J=7.8 Hz), 6.98-6. 90 (m, 2H), 3.21 (m, 2H), 3.08 (t, 2H, J=7.2 Hz).

FABMS (M+H+) : 485; (M-H-): 483.

Anal. Calcd. For C23H18F2N4O2S2#0.18 H20: C, 59.63% ; H, 3.79% ; N, 11.49% ; S, 13.15%. Found: C, 59.80% ; H, 3.96% ; N, 11.39% ; S, 13.09%.

Example A27: 4- [4-Amino-5- (2, 6-difluoro-benzoyl)-thiazol-2-ylamino]-N- (pyridin-3-yl)- benzamide 1H NMR (CD30D) : # 8. 90 (s, 1H), 8.28 (m, 2H), 8.04 (d, 2H, J=8.8Hz), 7.82 (d, 2H, J=8.8 Hz), 7.44 (m, 2H), 7.75 (d, 2H, J=8. 9 Hz), 7.08 (t, 2H, J=8.7 Hz).

Anal. Calcd. For C22H15F2N502S0. 5 Ho : C, 57. 38% ; H, 3.50% ; N, 15.21% ; S, 6.96%. Found: C, 57.49% ; H, 3.75% ; N, 15.09% ; S, 6.82%.

Example A28: 4-{[4-Amino-5-(2, 6-diiluoro-benzoyl)-thiazol-2-ylamino]-N-(4-cyanomethyl- benzyl)-benzamide.

'H NMR (DMSO-d6): # 11.10 (br, 1H), 10.20 (s, 1H), 8.21 (bs, 2H), 7.98 (d, 2H, J=8. 8 Hz), 7.86- 7.71 (m, 4H), 7.57 (m, 1H), 7. 35 (d, 2H, J=8. 6 Hz), 7.22 (t, 2H, J=7.9 Hz), 3.18 (d, 2H, J=5.2 Hz), 2.09 (s, 2H).

FABMS (M+H+) : 490; (M-H-): 488.

Anal. Calcd. For C23H18F2N402S20. 20 H20-0. 20 EtOAc: C, 60.67% ; H, 3.75% ; N, 13.71% ; S, 6.28%. Found: C, 60.50% ; H, 3.89% ; N, 13.72% ; S, 6.29%.

Example A29: 4- [4-Amino-5- (2, 6-difluoro-benzoyl)-thiazol-2-ylamino]-N- (2-pyridin-4-yl-ethyl)- benzamide.

1H NMR (DMSO-d6) : 8 11. 08 (br, 1H), 8.52-8. 45 (m, 3H), 8.24 (bs, 2H), 7.84 (d, 2H, J=8.7 Hz), 7.69 (d, 2H, J=8.7 Hz), 7.57 (m, 1H), 7.31-7. 18 (m, 4H), 3.55 (m, 2H), 2.92 (t, 2H, J=7.1 Hz).

FABMS (M+H+) : 480; (M-H-): 478.

Anal. Calcd. For C23Hl8F2N402S20. 70 H2O#0. 14 EtOAc: C, 58.70% ; H, 4.37% ; N, 13. 94%; S, 6.38%. Found: C, 58.77% ; H, 4.15% ; N, 14.10%, S, 6.29%.

Example A30: 4- [4-Amino-5- (2, 6-difluoro-benzoyl)-thiazol-2-ylamino]-N- (l-methyl-pyrrolidin- 3R-yl)-benzamide.

The starting material, 1-methyl-pyrrolidin-3R-ylamine trifluoroacetic acid salt, was prepared as follows :

A mixture of 3R-(t-Boc-amino)pyrrolidine (0.38 g, 2.0 mmol; TCT) and paraformaldehyde (0.06 g, 2.2 mmol) in MeOH (15 ml) was hydrogenated at 60 psi with 10% Pd/C for 16 hours.

Catalyst was filtered off and the filtrate concentrated. A solution of the resultant residue in ethyl acetate was washed with sat. NaHC03, dried over MgS04, filtered, and concentrated to give 0.27 g of (1-methyl-pyrrolidin-3R-yl)-carbamic acid tert-butyl ester as a clear oil in 67% yield, which was used without further purification.

1H NMR : 5 4.80 (m, 1H), 4.10 (m, 1H), 2.74 (m, 1H), 2.50 (m, 2H), 2.30 (s, 3H), 2.22 (m, 1H), 1.40 (s, 9H).

(l-Methyl-pyrrolidin-3R-yl)-carbamic acid ter-butyl ester (0.20 g, 1.0 mmol) in 30% TFA/CH2Cl2 (10 ml) was stirred at room temperature for 30 minutes. The solvent was removed and the residue was dried under vacuum to give 1-methyl-pyrrolidin-3R-ylamine trifluoroacetic acid salt as a clear oil in 100% yield which was used directly in the next step.

The title compound was prepared in a manner similar to Step 3 in Method A. lH NMR (DMSO-d6) : 8 11.05 (br, 1H), 8. 35 (d, 1H, J=7.0 Hz), 8.20 (br, 2H), 7.86 (d, 2H, J=8.7 Hz), 8.64 (d, 2H, J=8.7 Hz), 7.56 (m, 1H), 7.19 (t, 2H, J=7. 9 Hz), 4.38 (m, 1H), 2.71 (m, 1H), 2.58 (m, 1H), 2.48-2. 37 (m, 2H), 2.27 (s, 3H), 2.15 (m, 1H), 1.76 (m, 1H).

FABMS (M+H) : 458 ; (M-H-) : 456.

Anal. Calcd. For C22H2lF2Ns02S : C, 57. 76% ; H, 4. 63% ; N, 15. 31% ; S, 7. 01%. Found: C, 57. 76% ; H, 4.79% ; N, 15. 05%; S, 6.90%.

Example A31: 4- [4-Amino-5- (2, 6-difluoro-benzoyl)-thiazol-2-ylamino]-N- (l-methyl-pyrrolidin- 2S-yl-methyl)-benzamide Dihydrochloride.

4-[4-Amino-5-(2, 6-difluoro-benzoyl-thiazol)-2-ylamino]-N-(1-methyl-pyrrolidi n-2S-yl- methyl)-benzamide To a solution of (l-methyl-pyrrolidin-2S-yl)-methylamine (3.04 g, 26.6 mmol; Sassaman et al., Bioorg. Med. Clam., 6,1759-1766 (1998) ) in DMF (70 ml) was added 4- [4- amino-5- (2, 6-difluoro-benzoyl)-thiazol-2-ylamino]-benzoic acid (3 ; 9.08 g, 24.2 mmol). The resultant yellow solution was cooled to 4. 7°C, PyBOP (13.2 g, 25.4 mmol) and diisopropylethylamine (10.5 ml, 60.5 mmol) were sequentially added (slight exotherm

observed after each), and allowed to warm to room temperature overnight. Most of the DMF was removed in vacuo, and the resultant liquid diluted with ethyl acetate (1.2 L). The solution was washed with 5% aq Na2C03 (4 x 350 ml) and sat. NaCI (250 ml), dried over MgS04, and concentrated to give a yellow solid, typically used without any further purification. An analytically pure sample was available via preparative HPLC.

1H NMR (DMSO-d6): 8 11.04 (br, 1H), 8.34-8. 05 (m, 3H), 7.84 (d, 2H, J=8.8 Hz), 7.66 (d, 2H, J=8.8 Hz), 7.56 (m, 1H), 7.22 (t, 2H, J=7.8 Hz), 3.46 (m, 1H), 3.15 (m, 1H), 2.94 (m, 1H), 2. 38 (m, 1H), 2.35 (s, 3H), 2.17 (m, 1H), 1.84 (m, 1H), 1.72-1. 51 (m, 3H).

FABMS (M+H+) : 472. (M-H-) : 470.

Anal. Calcd. For C23H23F2N502S : C, 58.00% ; H, 5.13% ; N, 14.16% ; S, 6.48%. Found: C, 57.98% ; H, 5. 13% ; N, 14.03% ; S, 6.32%.

The title compound was prepared as follows. Through a solution of crude 4- [4-amino-5- (2, 6-difluoro-benzoyl)-thiazol-2-ylamino]-N- (1-methyl-pyrrolidin-2S-yl-methyl)-benzamide (theoretical 24.2 mmol) in CH2C12 (170 ml) at 0°C was passed HCl gas for a few minutes. The resultant suspension was allowed to warm and stir for 2 hours. The yellow solid was filtered off, rinsed with CH2C12 (3 x 100 ml), and dried under vacuum to obtain 10.54 g in 80% yield from 4- [4-amino-5- (2, 6-difluoro-benzoyl) -thiazol-2-ylamino]-benzoic acid [2] D =-20. 2° (MeOH). lH NMR (DMSO-d6) : 8 7.93 (d, 2H, J=8.5 Hz), 7. 72 (d, 2H, J=8.5 Hz), 7.54 (m, 1H), 7.20 (m, 2H), 3.82-3. 43 (m, 4H), 3.08 (m, 1H), 2.48 (s, 3H), 2. 11 (m, 1H), 1.96 (m, 1H).

Anal. Calcd for C23H23F2N502S2. 25 HC1 : C, 49.90 ; H, 4.60 ; N, 12.65 ; S, 5.79. Found: C, 49.75 ; H, 4.88 ; N, 12.50 ; S, 5.77.

Example A32: 4-[4-Amino-5-(2, 6-difluoro-benzoyl)-thiazol-2-ylamino]-N-(1-methyl-pyrrolidi n- 3 S-yl)-benzamide.

The starting material, 1-methyl-pyrrolidin-3S-ylamine trifluoroacetic acid salt, was prepared in a route similar to that for Example A30 from 3R- (t-Boc-amino) pyrrolidine.

The title compound was prepared in a manner similar to Step 3 in Method A.

Spectral data are identical to Example A30.

Anal. Calcd. For C22H2lF2N502S0. 90 H20@0. 08 EtOAc0. 09 CHCl3 : C, 54. 76% ; H, 4. 83% ; N, 14.25% ; S, 6.52%. Found: C, 54.69% ; H, 4.68% ; N, 14.12% ; S, 6.41%.

Example A33 : 4- [4-Amino-5- (2, 6-difluoro-benzoyl)-thiazol-2-ylamino]-N- (piperidin-2RS- ylmethyl) -benzamide Trifluoroacetate Salt.

The intermediate 2-({[1-(4-{4-Amino-5-[1-(2, 6-difluoro-phenyl) -methanoyl]-thiazol-2- ylamino}-phenyl)-methanoyl]-amino}-methyl)-piperidine-l-carb oxylic acid tert-butyl ester was prepared in a manner similar to Step 3 in Method A from 2-aminomethyl-piperidine-1-carboxylic acid tert-butyl ester.

The title compound was prepared by treating the above intermediate with 30% TFA/CH2Cl2 for 30 minutes, followed by HPLC purification.

H NMR (DMSO-d6) : 8 11.04 (br, 1H), 8. 15 (bs, 2H), 7.82 (m, 2H), 7.66 (d, 2H, J=8.7 Hz), 7.54 (m, 1H), 7.43 (d, 2H, J=8.7 Hz), 7.21 (t, 2H, J=7.8 Hz), 3.68-3. 21 (m, 5H), 1.82-1. 25 (m, 6H).

FABMS (M+H) : 472; (M-H-): 470.

Anal. Calcd. For C23H23F2NsO2S0. 60 H20ol. 32 TFA: C, 48.66% ; H, 4.06% ; N, 11.07% ; S, 4.83%. Found: C, 48.55% ; H, 4.03% ; N, 11.24% ; S, 4.83%.

Example A34: 4- [4-Amino-5- (2, 6-difluoro-benzoyl)-thiazol-2-ylamino]-N- (l-methyl-pyrrolidin- 2R-ylmethyl)-benzamide

The starting material (l-methyl-pyrrolidin-2R-yl)-methylamine was prepared in analogous fashion to that for the (S) isomer (Sassaman et al. Bioorg. Med. Chem. Vol. 6, pp. 1759-1766, (1998)).

The title compound was prepared in a manner similar to Step 3 in Method A.

Spectra data are identical to Example 31.

Anal. Calcd. For C23H23F2N502S0. 52 H2O#0.18 EtOAc: C, 57.35% ; H, 5.17% ; N, 14.10% ; S, 6.45%. Found: C, 57.40% ; H, 4. 98% ; N, 14.04% ; S, 6. 31%.

Example A35: 4- [4-Amino-5- (2, 6-difluoro-benzoyl)-thiazol-2-ylamino]-N- (2-pyrrolidin-1-yl- ethyl)-benzamide.

'H NMR (CD30D) : 8 7.88 (8, 2H, J=8. 7 Hz), 7.74 (d, 2H, J=8.7 Hz), 7.49 (m, 1H), 7. 10 (t, 2H, J=7.8 Hz), 3.59 (t, 2H, J=6.7 Hz), 2.82 (t, 2H, J=6.7 Hz), 2.73 (bs, 4H), 1.88 (bs, 4H).

FABMS (M+H+) : 472; (M-H-): 470.

Anal. Calcd. For C23H23F2N5O2S#0. 60 H2O-0. 20 EtOAc#0. 10 CHC13 : C, 56.08% ; H, 5.10% ; N, 13.68% ; S, 6.26%. Found: C, 56. 11% ; H, 4.98% ; N, 13.63% ; S, 6.34.

Example A36 : 4-[4-Amino-5-(2,6-difluoro-benzoyl)-thiazol-2-ylamino]-N-(2- dimethylamino-1S- methyl-ethyl)-N-methyl-benzamide.

The starting material, (S)-Nl, N, N2-trimethyl-propane-1, 2-diamine, was prepared as follows: To a solution of N-(tert-butoxyvarbonyl)-L-alanine (1.5 g, 8.0 mmol) in DMF (100 ml), were added PyBop (5. 0g, 9.6 mmol), DIEA (5.0 ml, 28.0 mmol), and dimethyl-amine hydrochloride salt (0.98 g, 12 mmol). The mixture was stirred at room temperature for 3 hours.

The solvent was evaporated under reduced pressure and a solution of the resultant residue in ethyl acetate was washed with sat. Na2C03 and brine, dried over MgS04, filtered, and concentrated to a syrup. Column chromatography (hexane/ethyl acetate=1/1) afforded 1.50 g of (lys- dimethylcarbamoyl-ethyl)-carbamic acid tert-butyl ester in 87% yield, which was used without further purification.

To a solution of 1.0 M LiAlH4 (5.6 mmol, 5.6 ml) in 50% THF/Et2O (50 ml), (1S- dimethylcarbamoyl-ethyl) -carbamic acid tert-butyl ester (0.60 g, 2.8 mmol) in THF (12 ml)

was added dropwise over 30 minutes. The reaction mixture was stirred at room temperature for 60 minutes and then refluxed for 18 hours. The resulting opaque milky-white solution was cooled to room temperature and quenched with careful addition of sat. Na2SO4 (1.0 ml). The mixture was filtered and the filtrate was carefully concentrated below 50°C under reduced pressure to give the desired amine as a clear oil in 56 % yield, which was used without further purification.

The title compound was prepared in a manner similar to Step 3 in Method A.

IHNMR (CD30D) : # 7.74 (8, 2H, J=8.5 Hz), 7.58-7. 39 (m, 3H), 7.08 (t, 3H, J=7.8 Hz), 2.91 (m, 3H), 2.80-2. 52 (m, 2H), 2.38 (bs, 3H), 2.28 (m, 1H), 2.07 (bs, 3H), 1.23 (d, 3H, J=6.7 Hz).

FABMS (M+H+) : 474; (M-H-): 472.

Anal. Calcd. For C23H2sF2NsO2S0. 40 H2O0. 20 EtOAc#0. 50 CHC13 : C, 52.30% ; H, 5.04% ; N, 12.55% ; S, 5.75%. Found: C, 52.24% ; H, 5.26% ; N, 12.53% ; S, 5.73%.

Example A37: 4-[4-Amino-5-(2,6-difluoro-benzoyl)-thiazol-2-ylamino]-N-[2- dimethylamino-1R- methyl-ethyl]-N-methyl-benzamide.

The starting material (R)-NI, N, N2-trimethyl-propane-1, 2-diamine was prepared with a route similar to that for Example 36 from 2R-tert-butoxycarbonylamino-propionic acid.

The title compound was prepared in a manner similar to Step 3 in Method A.

Spectral data are identical to Example A36.

Anal. Calcd. For C23H2sF2Nso2s-0. 40 H20e0. 28 EtOAc0. 39 CHC13 : C, 53. 33% ; H, 5.19% ; N, 12.69% ; S, 5. 81%. Found: C, 53.32% ; H, 5.19% ; N, 12.69% ; S, 5. 81%.

Example A38 : 4- [4-Amino-5- (2, 6-difluoro-benzoyl)-thiazol-2-ylamino]-N- (l-ethyl-pyrrolidin-2S- yl-methyl)-benzamide.

Starting material, S-(-)-2aminoemthyl-1-ethyl-pyrrolidine, is available from TCT.

The title compound was prepared in a manner similar to Step 3 in Method A.

Spectra data are identical to Example Al 1.

Anal. Calcd. For C24H2sF2Nso2s0. 10 H20-0. 25 EtOAc0. 17 CHC13 : C, 57.07% ; H, 5. 21% ; N, 13.22% ; S, 6.05%. Found: C, 56.93% ; H, 5.21% ; N, 13.20% ; S, 6.05%.

Example A39: 4- [4-Amino-5- (2, 6-difluoro-benzoyl)-thiazol-2-ylamino}-N-2- (cyclopropylmethyl-methyl-amino)-2-methyl-propyl]-benzamide The starting materials were prepared as follows : Step 1. 2-(Cyclopropylmethyl-met12yl-amino)-2-methyl-propionitrile.

To a solution of 0.262 M of cyclopropylmethyl-methyl-amine in ether (39. 0 mL, 10.1 mmol; Grotjahn, J. Het. Cam., 20,1031-1036 (1983) ) at ambient temperature was added 2- hydroxy-2-methyl-propionitrile (922 pL, 10.1 mmol) and 10% HCl (20 mL). After 12 hours, the mixture was brought to pH8 with 10% NaOH and extracted with ether (2 x 25 mL). The combined organic layers were dried over Na2SO4, filtered, and carefully concentrated under aspirator pressure below 50°C to provide 1.49 g of a volatile colorless oil in 97% yield, which was used without further purification.

'H NMR : 8 2.30 (s, 3H), 1.35 (s, 6H).

Step 2. N2-Cyclopropylmethyl-2, N2-dimethyl-propane-1, 2-diamine.

To a suspension of LiAlH4 (749 mg, 19.72 mmol) in ether (40 mL) at 0°C was added crude 2- (cyclopropylmethyl-methyl-amino)-2-methyl-propionitrile (1.50 g, 9.86 mmol). The resultant mixture was heated at reflux for 3 hours, then cooled to 0°C, and carefully quenched with H20 (4 mL) and 2N NaOH (3 mL). After a few minutes of stirring, the granular white solids were filtered

off. The filtrate was dried over Na2S04, filtered, and carefully concentrated under aspirator pressure below 50°C to afford 995 mg of a volatile colorless oil in 65% yield, which was used without further purification.

'H NMR: 8 2.45 (s, 2H), 2.19 (s, 3H), 2.12 (d, 2H, J=6.4 Hz), 0.88 (s, 6H).

The title compound was prepared in a manner similar to Step 3 in Method A.

1H NMR (DMSO-d6) : 8 7. 80 (d, 2H, J=8.8 Hz), 7.64 (d, 2H, J=8.7 Hz), 7.60-7. 50 (m, 1H), 7.20 (dd, 2H, J=7.7, 8.2 Hz), 2.50 (s, 3H), 1.00 (s, 6H), 0.88-0. 78 (m, 1H), 0.48-0. 40 (m, 2H), 0.09 (d, 2H, J=4.2 Hz).

Anal. Calcd. for C26H29F2N502S0. 4 H20 : C, 59. 96% ; H, 5.77% ; N, 13.45% ; S, 6.16%. Found: C, 59.66% ; H, 5.82% ; N, 13.40% ; S, 6.06%.

Example A40: 4- [4-Amino-5- (2, 6-difluoro-benzoyl)-thiazol-2-ylamino]-N- (2-dimethylamino-lR- methyl-ethyl)-benzamide Dihydrochloride

The starting material, (R)-N, N-dimethyl-propane-1, 2-diamine dihydrochloride salt was prepared as follows: Step 1: (1R-Dimethylcarbamoyl-ethyl)-carbamic Acid Benzyl Ester

To a solution of N-benzyloxycarbonyl-D-alanine (11.1 g, 50.0 mmol), dimethylamine hydrochloride salt (8.10 g, 100 mmol) and DIEA (13.0 g, 100 mmol) in CH3CN (200 ml) at 0°C was added dicyclohexyl-carbodiimide (10. 3 g, 50.0 mmol). The mixture was stirred for 2 hours and filtered. The filtrate was concentrated and a solution of the resultant residue in ethyl acetate was washed with 0.1 N HCI, 0.1 N NaOH, dried over MgSO4, filtered, and concentrated. Column chromatography (hexane/ethyl acetate=1/1) afforded 14.1 g of desired product in 98% yield, which

displayed an'H NMR that matched literature (Isogai et al, J. Chemin. Soc. Perkin Trans. 1,1405- 1411 (1984) ) and used without further purification.

Step 2: (2-Dimetlaylamino-IR-methyl-ethyl)-carbamic Acid Benzyl Ester To a solution of (lR-dimethylcarbamoyl-ethyl)-carbamic acid benzyl ester (14.0 g, 56.0 mmol) in THF (200 ml), was added dropwise over 30 minutes 1.0 M borane/THF (9.7 mmol, 9.7 ml). The reaction mixture was stirred at room temperature for 18 hours then quenched with conc.

HCl (5ml). Solvent was evaporated under reduced pressure. The residue was dissolved in water and extracted with ethyl ether. The aqueous layer was separated, neutralized with 1M NaOH and extracted with ethyl acetate three times. The organic layers were combined, dried over MgSO4, filtered and concentrated to give 6.2 g of clear oil in 50% yield, which was used without further purification.

1H NMR (CDCl3) : # 7.34 (m, 5H), 5.12 (m, 2H), 3.72 (m, 1H), 2.32 (m, 1H), 2.24 (s, 6H), 2.16 (m, 1H), 1.20 (d, 3H, J=5. 0 Hz).

Step 3: (R)-N, N-Dimethyl-propane-l, 2-diamine Dihydrochloride Salt

A solution of above intermediate (6.0 g, 25 mmol) in 50% MeOH/H20 (250 ml), conc. HCl (2 ml), and 10% Pd/C (0.5 g) was shaken under hydrogen at 30 psi for 1 hour. The catalyst was filtered off and the filtrate was lyophilized to give 5.4 g of white hydroscopic amorphous solid in 90% yield, which was used without further purification. lH NMR (CD30D) : 83. 82 (m, 1H), 3.46-3. 28 (m, 2H), 2.90 (s, 3H), 1. 38 (d, 3H, J=5.0 Hz).

Step 4: 4-[4-Amino-5-(2,6-difluoro-benzoyl)-thiazol2-ylamino]-N-(2-d imethylamino-1R- methyl-ethyl)-benzamide

To a mixture of (R)-N, N-dimethylpropane-1, 2-diamine dihydrochloride salt (8.42 g, 48. 1 mmol) and 4- [4-amino-5- (2, 6-difluoro-benzoyl)-thiazol-2-ylamino]-benzoic acid (3 ; 16.4 g, 43.7 mmol) in DMF (125 ml) at 2. 5°C was added PyBOP (23.9 g, 45.9 mmol). Diisopropylethyl-amine

(26.6 ml, 153 mmol) was added dropwise over 12 minutes. The resultant bright yellow-orange mixture stirred at 0°C for 30 minutes, then allowed to warm to room temperature overnight. The DMF was removed under reduced pressure, and the resultant oil partitioned with ethyl acetate (600 ml) and 5% aq Na2CO3 (300 ml). The organic layer was separated, washed with 5% aq Na2C03 (2 x 300 ml) and sat. NaCI (250 ml), dried over MgS04, and concentrated to give a bright yellow solid, which was used without any further purification.

1H NMR spectral data are identical to that for Example A20.

HRFABMS Calcd. For C22H24F2N502S (M+H+) : 460.1613. Found: 460.1628.

Anal. Calcd. For C23H23F2N502S : C, 58.00% ; H, 5.13% ; N, 14.16% ; S, 6.48%. Found: C, 57.98% ; H, 5.13% ; N, 14.03% ; S, 6.32%.

The title compound was prepared as follows. Through a solution of crude 4- [4-amino-5- (2, 6-difluoro-benzoyl)-thiazol-2-ylamino]-N-(1-methyl-pyrrolidi n-2S-yl-methyl)-benzamide (theoretical 43.7 mmol) in CH2C12 (375 ml) at 0°C was passed HCl gas for a few minutes. The resultant suspension was allowed to warm and stir overnight. The yellow solid was filtered off, rinsed with CH2C12 (3 x 150 ml), and dried under vacuum. The solid was suspended in CH2C12 (150 ml) and MeOH (0.75 ml), stirred 24 hours, filtered off, rinsed with CH2C12 (2 x 100 ml), and dried under vacuum to obtain 17.92 g of bright yellow solid in 77% yield from 4- [4-amino-5- (2, 6- difluoro-benzoyl)-thiazol-2-ylamino]-benzoic acid (O.

'H NMR (CD30D) : 87. 90 (d, 2H, J=8.8 Hz), 7.78 (d, 2H, J=8.8 Hz), 7.52 (m, 1H), 7.08 (t, 2H, J=7.9 Hz), 4.62 (m, 1H), 3.04 (s, 3H), 2.95 (s, 3H), 1. 38 (d, 2H, J=6.8 Hz).

Anal. Calcd. For C22H23F2N502S*1. 88 HC1 : C, 50.04% ; H, 4.75% ; N, 13.26% ; S, 6.07%. Found: C, 50.04% ; H, 5.93% ; N, 13.21% ; S, 6.05%.

Chiral HPLC : Retention time 13.9 min. with Chiralcel OD-R 250 x 4.6 mm column, 0 to 30% acetonitrile/0.5 M NaC104 gradient over 20 min, flow rate 0.8 mL/min.

Example A41: 4- [4-Amino-5- (2, 6-difluoro-phenyl)-methanoyl]-thiazol-2-ylamino}-N- (2- dimethylamino-1 S-methyl-ethyl)-benzamide.

The starting material (S)-N, N-dimethyl-propane-1, 2-diamine dihydrochloride salt was prepared in a route similar to that in Example A40 from 2S-benzyloxycarbonylamino-propionic acid.

The title compound was prepared in a manner similar to Step 3 in Method A.

Spectral data are identical to Example A40.

HRFABMS Calcd. for C22H23F2N5O2SNa (M+Na+) : 482.1433. Found: 482.1436.

Chiral HPLC : Retention time 16.6 min. with Chiralcel OD-R 250 x 4.6 cm column, 0 to 30% acetonitrile/0. 5 M NaClO4 gradient over 20 min, flow rate 0.8 mL/min.

Example A42: 4- [4-Amino-5- (2, 6-difluoro-benzoyl)-thiazol-2-ylamino]-N- (2S-dimethylamino- propyl)-benzamide The starting material was prepared as follows: Step 1. (S)-2-Dimethylamino-propionamide Hydrochloride Salt

According to a procedure from Dallavalle et al, Helv. Chim. Acta ; Vol. 72, pp. 1479- 1486 (1989), (S)-2-amino-propionamide hydrochloride (1.0 g, 8.0 mmol; Advanced ChemTech) and formaldehyde (37% aq. soln. , 662 juL, 8.8 mmol) in MeOH (15 mL) were stirred in the presence of 10% Pd/C (320 mg) at 40°C under hydrogen for 5 hours. Catalyst was filtered off, and the filtrate was acidified to pH 3 with 1N HCl in MeOH. The solvent was removed and the resultant slurry was crystallized from MeOH/acetone to give a white solid, which was used without further purification.

1H NMR (DMSO-d6) : 8 3.90 (m, 1H), 2.77 (d, 3H, J=4.9 Hz), 2.74 (d, 3H, J=4.9 Hz), 1.44 (d, 3H, J=7.0 Hz).

Step 2. (S)-N2, 1f-Dimethyl-propa7le-1, 2-diamine Dihydrochloride Salt

To the above intermediate in THF (10 ml) at 0°C under argon, was added dropwise 1M LiAlH4 in THF (16 ml). The mixture was stirred at room temperature for one hour, then refluxed for 5 hours, cooled, and quenched with sat. Na2S04 (1 ml). The mixture was diluted with ethyl ether, and stirred another 10 minutes, filtered, acidified with 4N HCl/dioxane, and evaporated to dryness to afford 0.70 g of white solid in 61% yield from (S)-2-amino- propionamide hydrochloride, which was used without further purification.

1H NMR (DMSO-d6) : 8 3.80 (m, 1H), 3. 55 (dd, 2H, J=5. 4,13. 6 Hz), 3.17 (dd, 1H, J=7. 0,13. 6 Hz), 1.49 (d, 3H, J=6.8 Hz).

The title compound was prepared in a manner similar to Step 3 in Method A.

1H NMR (CD30D) : 67. 88 (d, 2H, J=8.8 Hz), 7.75 (d, 2H, J=8.8 Hz), 7.49 (m, 1H), 7.08 (t, 2H, J=7.8 Hz), 3.51 (dd, 1H, J=6.5, 13.6 Hz), 3.39 (dd, 1H, J=6.5, 13.6 Hz), 2.89 (sextet, 1H, J=6.6 Hz), 2.35 (s, 6H), 1.08 (d, 3H, J=6.0 Hz).

13C NMR (DMSO-d6): 8 11. 3,40. 3,42. 1,57. 8,96. 3,112. 1, 118. 3, 119.2, 128.3, 129.4, 131.6, 141.7, 164.6, 165.3, 167.2, 172.8.

Anal. Calcd. For C22H23F2N502S : C, 57. 50% ; H, 5. 05% ; N, 15.24% ; S, 6.98%. Found: C, 57.50% ; H, 5.06% ; N, 15. 23% ; S, 6.93%.

Example A43: 4- [4-Amino-5- (2, 6-difluoro-benzoyl)-thiazol-2-ylamino]-N- (l-methyl-piperidin- 2 S-yl-methyl)-benzamide The starting material was prepared as follows : (1-Methyl piperidin-2S-yl)-methylamine Anhydrous ammonia gas was bubbled through a solution of (S)-(-)-l-(tert- butoxycarbonyl) -2-piperidine carboxylic acid (500 mg, 2.18 mmol) in DMF (50 ml) for 15 minutes. PyBop (1.25 g, 2.40 mmol) was added. After 5 hours, solvent was evaporated under reduced pressure. A solution of the resultant residue in ethyl acetate was washed with 5% citric acid (50 ml x 3), 1 N NaOH (50 ml x 3), dried with MgS04, filtered, and concentrated to give 450

mg of (S)-2-carbamoyl-piperidine-l-carboxylic acid tert-butyl ester as a clear oil in 95% yield, which was used without further purification.

(1-Methyl-piperidin-2S-yl)-methylamine was prepared in a manner similar to the production step of (S)-N1, Ni, N2-trimethyl-propane-1, 2-diamine in Example A36 from (S) -2- carbamoyl-piperidine-1-carboxylic acid tert-butyl ester in 56% yield.

HNMR (CD30D) : 63. 58-3.49 (m, 1H), 3. 48-3.36 (m, 1H), 3.13-3. 02 (m, 1H), 2.81 (s, 3H), 2.16- 1.60 (m, 7H).

The title compound was prepared in a manner similar to Step 3 in Method A.

1H NMR (acetone-d6): 87. 71 (m, 2H), 7.54. (m, 3H), 7.11 (m, 2H), 4.06 (m, 1H), 3.81-3. 52 (m, 3H), 3.18 (s, 3H), 2.97 (m, 2H), 2.00-1. 61 (m, 5H).

HRMALDIMS Calcd for C24H25F2N502S (M+H+) : 486.1770. Found: 486.1761 Example A44: 4- [4-Amino-5- (2, 6-difluoro-benzoyl)-thiazol-2-ylamino]-N- (2R-dimethylamino- propyl)-benzamide

The starting material (R)-N2, N2-dimethyl-propane-1, 2-diamine hydrochloride was prepared with a route similar to that for Example A42, from (L) -2-amino-propionamide hydrochloride.

The title compound was prepared in a manner similar to Step 3 in Method A.

Spectral data are identical to Example A42.

Anal. Calcd. For C22H23F2NsO2S : C, 57.50% ; H, 5.05% ; N, 15.24% ; S, 6.98%. Found: C, 57.72% ; H, 5.68% ; N, 15.31% ; S, 7. 1-2%.

Example A45: 4- [4-Amino-5- (2, 6-difluoro-benzoyl)-thiazol-2-ylamino]-N- [2- (2, 5-dihydro- pyrrol-l-yl)-ethyl]-benzamide Dihydrochloride Salt

The starting material was prepared as follows: Step 1. [2-(2,5-Dihydro-pyrrol-1-yl)-2-oxo-ethyl]-carbamic Acit tert-butyl Ester

To a solution of N-tert-butoxycarbonyl glycine (1.4 g, 5.0 mmol), DIEA (2.6 ml, 15 mmol) and 2, 5-dihydro-lH-pyrrole (0.51 g, 7.5 mmol) in DMF (15 ml), was added PyBop (2.7 g, 5.25 mmol). The reaction solution was stirred at room temperature for 3 hours. Solvent was removed under reduced pressure and a solution of resultant residue in ethyl acetate was extracted with sat. NaHCO3, brine, dried with MgS04, filtered and concentrated to a syrup.

Chromatography on silica (hexane/ethyl acetate=1/2) afforded 1.05 g of desired product in 93% yield, which was used without further purification.

IH NMR (CDC13) : 65. 88-5. 72 (m, 2H), 4.24-4. 10 (m, 4H), 3.82 (s, 2H), 1.4 (s, 9H).

Step 2. 2-Amino-1-(2,5-dihydro-pyrrol-1-yl)-ethanone A solution of above intermediate (1.0 g, 4.6 mmol) in 30% TFA/CH2C12 (20 ml) was stirred at room temperature for 30 min. Solvent was removed and a solution of resultant residue in ethyl acetate was extracted with sat. NaHCO3, dried with MgS04, filtered and concentrated to give 0.5 g of product as a clear oil in 95% yield, which was used without further purification. lH NMR (CDCI3) : 6 5.80 (m, 2H), 4.20 (m, 4H), 3.45 (s, 2H).

Step 3. 2- (2, 5-Dihydro-pyrrol-l-yl)-ethylamine Dilzydrochloride Salt The desired amine was obtained after LiAlH4 reduction of the above intermediate as described in Step 2 in Example A42 in 50% yield and used as crude.

The title compound was prepared in a manner similar to Step 3 in Method A.

'H NMR (CD30D) : 87. 92 (d, 2H, J=8. 8 Hz), 7.78 (d, 2H, J=8.8 Hz), 7.50 (m, 1H), 7. 08 (t, 2H, J=15.9 Hz), 5.98 (s, 2H), 4.49 (d, 2H, J=12. 4 Hz), 4.12 (d, 2H, J=12.4 Hz), 3.78 (t, 2H, J=6.1 Hz), 3.58 (t, 2H, J=5.6 Hz).

LCMS (M+H+) : 470; (M-H-) : 468.

Anal. Calcd. for C23H2lF2N502S2. 05 Hic151. 10 H20 : C, 48. 97% ; H, 4.51% ; N, 12.42% ; S, 5.68%.

Found: C, 49.13% ; H, 4.71% ; N, 12.29% ; S, 5.37%. Example A46: 4-[4-Amino-5-(2,6-difluoro-benzoyl)-thiazol-2-ylamino]-N-(1R -methyl-2- piperidin-1-yl-ethyl)-benzamide Trifluoroacetate Salt

The starting material lR-methyl-2-piperidin-1-yl-ethylamine was prepared in a route similar to that for Example A45 from N-tert-butoxycarbonyl D-alanine and piperidine in 43% overall yield and used without further purification.

The title compound was prepared in a manner similar to Step 3 in Method A.

IH NMR (CD30D) : 810. 08 (d, 2H, J=8.8 Hz), 7.68 (d, 2H, J=8.8 Hz), 7.48 (m, 1H), 6.96 (t, 2H, J=15.9 Hz), 4.54 (m, 1H), 3.86 (m, 1H), 3.38 (m, 1H), 3. 18 (m 2H), 2.90 (m, 2H), 1.95-1. 40 (m, 6H), 1.27 (d, 2H, J=6. 8 Hz).

MALDIMS (M+H~) : 500.

Anal. Calcd. for C25H27F2N502S1. 50 TFA. 0. 60 H20 : C, 49.35% ; H, 4.39% ; N, 10. 28%; S, 4.71%.

Found: C, 49. 29% ; H, 4.42% ; N, 10. 38% ; S, 4.63%.

Example A47: 4- [4-Amino-5- (2, 6-difluoro-benzoyl)-thiazol-2-ylamino]-N- (lR- dimethylaminomethyl-2-methyl-propyl)-benzamide.

The starting material (R)-3, N9, Nl-trimethyl-butane-1, 2-diamine was prepared in a route similar to that in Example45 from N-tert-butoxycarbonyl D-valine and dimethylamine and used without further purification.

The title compound was prepared in a manner similar to Step 3 in Method A.

'H NMR (DMSO-d6): # 11. 10 (br, IH), 8.22 (br, 2H), 8.01-7. 89 (m, 3H), 7.72 (d, 2H, J=8. 6 Hz), 7.62 (m, 1H), 7.26 (t, 2H, J=7. 8 Hz), 4.11 (m, lH), 2.50 (m, 1H), 2.34 (br, 6H), 1.88 (m, 1H), 0.99- 0.88 (m, 7H).

FABMS (MH) : 488; (M-H-) : 486.

Anal. Calcd. For C24H27F2N502S1. 08 H20O0. 35 EtOAc: C, 56.72% ; H, 5.99% ; N, 13.02% ; S, 5.96%. Found: C, 56.66% ; H, 5.77% ; N, 13.03% ; S, 5.93%.

Example A48: 4- [4-Amino-5- (2, 6-difluoro-benzoyl)-thiazol-2-ylamino]-N- (5, 5-dimethyl- pyrrolidin-2RS-yl-methyl) -benzamide Hydrochloride Salt

The starting material 5-aminomethyl-2, 2-dimethyl-pyrrolidin-1-ol was prepared according to the literature procedure (Zhong et al., Bioorg. Med Chem. Vol. 6, pp. 2405-2419, (1998) ) from 5, 5-dimethyl-1-pyrroline N-oxide.

The intermediate 4- [4-amino-5- (2, 6-difluoro-benzoyl)-thiazol-2-ylamino]-N- (l-hydroxy- 5,5-dimethyl-pyrrolidin-2-ylmethyl)-benzamide was prepared in a manner similar to Step 3 in Method A from the above amine.

1HNMR (CDC13) : 8 8.14 (d, 2H, J=8. 9 Hz), 7.95 (d, 2H, J=8.9), 7.68 (m, 1H), 7.25 (t, 2H, J=9. 0, Hz), 4.20 (m, 2H), 3.85 (m, 1H), 2.56-2. 08 (m, 4H), 1.68 (s, 3H), 1.58 (s, 3H).

The title compound was prepared as follows: A solution of above intermediate in MeOH was hydrogenated on 10% Pd/C at 30 psi for 3 hours. The catalyst was filtered off and the filtrate was concentrated. Preparative HPLC purification afforded a white solid in 25% yield. tH NMR (CD30D) : 87. 84 (d, 2H, J=8.8 Hz), 7.73 (d, 2H, J=8.8 Hz), 7.42 (m, 1H), 6.98 (t, 2H, J=15.9 Hz), 3.92 (m, 1H), 3.62 (d, 2H, J=5. 5 Hz), 2.22 (m, 1H), 1.94-1. 81 (m, 3H), 1.40 (s, 6H).

LC-MS (M+H+) : 486 ; (M-H-) : 484.

Example A49: 4- [4-Amino-5- (2, 6-difluoro-benzoyl)-thiazol-2-ylamino]-N- (thiazol-2-yl-methyl)- benzamide Hydrochloride The starting material, C-thiazol-2-yl-methylamine, was prepared as follows.

According to a procedure from Kuo et al, Chem. Pharm. Bull., 39,181-183 (1991), to a solution of 2-tliiazolecarboxaldehyde (1.52 g, 13.4 mmol) in ethanol (16 ml) and H20 (3.3 ml) were added hydroxylamine hydrochloride (1.40 g, 20.1 mmol) and NaOH (1.61 g, 40.3 mmol).

The mixture was heated at reflux for 0.5 h, allowed to cool to ambient temperature, and acidified to pH4 with 2N HC1. The aqueous layer was extracted with ether (100 ml x 2). The combined organic layers were dried over Na2S04, filtered, and concentrated to give a white solid, which was placed in a mixture of ethanol (30 ml) and conc. aq. NH40H (67 ml). Zn dust (6.58 g, 101 mmol) and ammonium acetate (0. 826 g, 10.7 mmol) were added. The mixture was heated at reflux for 0.5 hour, allowed to cool to ambient temperature, and filtered. The filtrate was diluted with H2O (25 ml) and extracted with 10% MeOH/CHC13 (50 ml). The organic layer was separated, dried over MgS04, and concentrated to afford 998 mg of yellow oil in 65% yield, which displayed an'H NMR that matched previously reported (Dondoni et al. , Synthesis, 641-646 (1996) ) and was used without further purification.

The title compound was prepared in a manner similar to Step 3 in Method A.

1H NMR (DMSO-d6) : 8 10.96 (s, 1H), 9.10 (t, 1H, J=5.9 Hz), 8. 05 (br, 2H), 7.72 (d, 2H, J=8.8 Hz), 7.55 (d, 1H, J=3. 3 Hz), 7.53 (d, 2H, J=8. 8. Hz), 7.44 (d, 1H, J=3.3 Hz), 7.37 (m, 1H), 7.03 (dd, 2H, J=7.8, 8.0 Hz), 4.56 (d, 2H, J=5.9 Hz).

Anal. Calcd. for C21H15F2N5O2S2#1.4 HCl#1. 0 H20 : C, 46.66% ; H, 3.43% ; N, 12. 96%; S, 11.86%.

Found: C, 46.77% ; H, 3. 51% ; N, 13.02% ; S, 11. 81%.

Example A50: 4- [4-Amino-5- (2, 6-difluoro-benzoyl)-thiazol-2-ylamino]-N- (l-methyl-lH- imidazol-2-ylmethyl)-benzamide Hydrochloride Salt

The starting material was prepared as follows: C- (1-Methyl-lH-irnidazol-2-yl)-methylamine.

According to a procedure from Kruse et al, J. Med. Chem. Vol. 33, pp. 781-789 (1990), hydroxylamine hydrochloride (3.78 g, 54.5 mmol) and sodium acetate (9.38 g, 114 mmol) were added to a solution of l-methyl-2-imidazolecarboxaldehyde (2.00 g, 18.2 mmol) in H2O (90 ml). After one hour, the resultant mixture was filtered. The white solid was washed with a small amount of water and dried under vacuum to give 1. 01 g of a colorless solid in 44% yield.

This presumed 1-methyl-lH-imidazole-2-carboxaldehyde (E/Z)-oxime was submitted to the

conditions described for thiazol-2-yl-methylamine in Example A49 to give 643 mg of yellow oil in 72% yield, which was used without any further purification.

'H NMR (CDC13) : 8 6.94 (d, 1H, J=1.2 Hz), 6.82 (d, 1H, J=1. 2 Hz), 3.91 (s, 2H), 3.64 (s, 3H).

The title compound was prepared in a manner similar to Step 3 in Method A.

1H NMR (DMSO-d6) : 8 14.22 (br, 1H), 11.20 (s, 1H), 9.21 (t, 1H, J=5.2 Hz), 8.11 (br, 2H), 7.82 (d, 2H, J=8. 8. Hz), 7.64 (d, 2H, J=8.8 Hz), 7.55 (d, 1H, J=1. 9 Hz), 7.49 (d, 1H, J=1.9 Hz), 7. 45 (m, 1H), 7.11 (dd, 2H, J=7.7, 8.2 Hz), 4.64 (d, 2H, J=5.2 Hz).

Anal. Calcd. for C22Hl8F2N602S'1. 6 HCl-l. l H20 : C, 48. 34%; H, 4.02% ; N, 15.37% ; S, 5.87%.

Found: C, 48.23% ; H, 4. 29% ; N, 15.27% ; S, 5.86%.

Example A51: 4- [4-Amino-5-2, 6-difluoro-benzoyl)-thiazol-2-ylamino]-N- [2- (cis-2, 6-dimethyl- piperidin-1-yl)-ethyl]-benzamide The starting material 1- (2-aminoethyl)-2, 6-dimethylpiperidine was prepared in a route similar to that for N2-cyclopropylmethyl-2, N2-dimethylpropane-1, 2-diamine in Example A39 from glycolonitrile and 2,6-dimethylpiperidine.

IHNMR (CDC13) 6 : 2.76-2. 65 (m, 4H), 2.56-2. 41 (m, 2H), 1.77-1. 48 (m, 5H), 1. 38- 1.19 (m, 3H), 1.14 (d, 6H, J=6.3Hz).

The title compound was prepared in a manner similar to Step 3 in Method A.

1H NMR (DMSO-d6) : 510. 85 (br, 1H), 8. 3 (m, 3H), 7.65 (d, 2H, J=8.8 Hz), 7.49 (d, 2H, J=8.8 Hz), 7.40 (m, 1H), 7.05 (t, 2H, J=7.7 Hz), 3.10 (m, 2H), 2.6-2. 4 (m, 4H), 1.5-1. 2 (m, 6H), 0.95 (d, 6H, J= 6. 1 Hz).

Anal. Calcd for C26H29F2N502S1. 0 H2O : C, H, N. Example A52: 4- [4-Amino-5- (2, 6-difluoro-benzoyl)-thiazol-2-ylamino]-N- (2-methyl-2- piperidin-1-yl-propyl)-benzamide

The starting material 1- (2-amino-l, 1-dimethylethyl) piperidine was prepared in a route similar to that in Example 39 from 2-hydroxy-2-methyl-propionitrile and piperidine.

'H NMR (CDC13) : 8 2.56 (s, 2H), 2.52-2. 41 (m, 4H), 1.87 (br, 2H), 1.61-1. 49 (m, 4H), 1.46- 1.35 (m, 2H), 0.97 (s, 6H).

The title compound was prepared in manner similar to Step 3 in Method A.

1H NMR (DMSO-d6) : 68. 18 (br, 2H), 7.8 (d, 2H, J= 8.7 Hz), 7.67 (d, 2H, J=8.7 Hz), 7.56 (m, 1H), 7.20 (t, 1H, J=7.8 Hz), 3.45 (m, 2H), 1.7-1. 4 (m, 10H), 1.00 (s, 6H).

Anal. Calcd For C26H29F2NsO2S0. 5 H20: C, H, N.

Example A53 : 4- [4-Amino-5- (2, 6-difluoro-benzoyl)-thiazol-2-ylamino]-N- [2- (2, 2,6, 6- tetramethyl-piperidin-1-yl)-ethyl]-benzamide The starting material 1- (2-aminoethyl)-2, 2,6, 6-tetramethylpiperidine was prepared in a route similar to that of Example A39 from 2,2, 6, 6-tetramethylpiperidine and glycolonitrile.

'H NMR (DMSO-d6) : 62. 46-2.26 (m, 4H), 1.52-1. 40 (m, 2H), 1.35-1. 25 (m, 4H), 0.97 (s, 12H).

The title compound was prepared in a manner similar to Step 3 in Method A.

1H NMR (DMSO-d6) : 88. 4 (m, 3H), 7.85 (d, 2H, J=8.7 Hz), 7. 65 (d, 2H, J=8.7 Hz), 7.59 (m, 1H), 7.22 (m, 2H), 3.2 (m, 2H), 3.16 (m, 1H), 1.7 (m, 1H), 1.4-1. 2 (m, 6H), 1.06 (s, 12H) Anal. Calcd For C28H33F2N502S*1. 0 H20: C, H, N.

Example A54: 4- {4-Amino-5- (2, 6-difluoro-benzoyl)-thiazol-2-ylamino]-N- (4R-hydroxy-1- methyl-pyrrolidin-2S-yl-methyl)-benzamide The starting material was prepared as follows : Step1. [45, 2Sy-2-Carbamoyl-4-hydroxy-pyrrolidine-1-carboxylicAcidBenzyl Ester

4S-Hydroxy-pyrrolidine-1, 2S-dicarboxylic acid 1-benzyl ester (Bachem, 5.00 g, 18.8 mmol) in THF (25 ml) was cooled to 0°C. Pyridine (892 mg, 11.3 mmol), NH4HC03 (1. 93 g, 24.4 mmol) and di-tert-butyl dicarbonate (5. 3 g, 24.4 mmol) were added. The reaction was allowed to reach 25°C over 1 h and was stirred an additional 24 h. The mixture was diluted with EtOAc, washed with saturated aqueous NaHCO3, 0.4 N NaHSO4, brine, dried over Na2S04 and concentrated to a syrup. Chromatography on silica (3%-12% MeOH-CH2Cl2) afforded 1.79 g of amide as a white foam in 38% yield, which was used without further purification.

Rf=0. 22 (10% MeOH-CH2C12). tH NMR (CDC13) 6 7.32 (s, 5H), 6.72, 5.97 (two bs, 1H), 5.53 (two bs, 1H), 5.13 (m, 2H), 4.45 (bs, 2H), 3.58 (bs, 2H), 2.38 (bm, 2H), 2.11 (bs, 1H).

LCMS (M+H+) : 265; (M+Na+) : 287.

Step 2. [5R,3S]-5-Aminomethyl-1-methyl-pyrrolidin-3-ol To the above amide (1.7g, 6.43 mmol) in THF (30 ml) at 0°C was added lithium aluminum hydride (1.22 g, 32.2 mmol) in 15 mL THF. The mixture was refluxed for 12 hours. The reaction was cooled to 0°C and treated with solid Na2S04'10H20 until gas evolution ceased. The whole was filtered and concentrated to yield 1.2 g of desired amine as a clear oil which was used directly in the next step.

The title compound was prepared in a manner similar to Step 3 in Method A.

'H NMR (CDCl3-acetone-d6) : 8 7. 58 (d, 2H, J=8. 6 Hz), 7. 38 (d, 2H, J=8.6 Hz), 7.17 (m, 1H), 6.74 (t, 3H, J=8.1 Hz), 4.14 (m, 1H), 3.82 (m, 1H), 3.54 (m, 1H), 3.20 (dd, 1H, J=9. 9 Hz, 13. 1Hz), 3.07 (bd, 1 H, J=13.1 Hz), 2.65 (m, 1H), 2.19 (s, 3H), 1.72 (m, 2H).

LCMS (M+H+) : 488.

Anal. Calcd For C23H23F2N503S : C, H, N.

Example A55 : 4- [4-Amino-5- (2, 6-difluoro-benzoyl)-thiazol-2-ylamino]-N- [2- (imidazol-1-yl)- ethyl]-benzamide Dihydrochloride Salt The starting material 2-imidazol-1-yl-ethylamine was prepared according to the literature procedure (Hay et al., J. Med. Chem., 37; pp. 381-391 (1994)).

The title compound was prepared in a manner similar to Step 3 in Method A.

1H NMR (DMSO-d6): 8 14.48 (bs, 1H), 11.40 (bs, 1H), 9.15 (s, 1H), 8. 69 (t, 1H, J=5. 4 Hz), 8. 18 (bs, 2H), 7.80 (d, 2H, J=8.8 Hz), 7.75 (t, 1H, J=1.5 Hz), 7.69 (d, 2H, J=8.8 Hz), 7.63 (t, 1H, J=1.5 Hz), 7.52 (m, 1H), 7.17 (dd, 2H, J=7.7, 8.1 Hz), 4.37 (t, 2H, J=5.4 Hz), 3.67 (q, 2H, J=5.4 Hz).

LCMS: (M+H4) : 469.

Anal. Calcd. for C22HI8F2N602S2. 5 Cl'1. 0 H20 : C, 45.74% ; H, 3.93% ; N, 14.55% ; S, 5.55%.

Found: C, 45.45% ; H, 4.16% ; N, 14. 55% ; S, 5.57%.

Example A56: 4- [4-Amino-5- (2, 6-difluoro-benzoyl)-thiazol-2-ylamino]-N- (2, 2,5, 5-tetramethyl- pyrrolidin-3R, S-ylmethyl)-benzamide Dihydrochloride Salt

The intermediate 4- [4-amino-5- [1- (2, 6-difluoro-benzoyl)-thiazol-2-ylamino]-N- (1- hydroxy-2,2, 5, 5-tetramethyl-pyrrolidin-3R, S-ylmethyl)-benzamide was prepared in a manner similar to Step 3 in Method A, from 3R, S-aminomethyl-2, 2,5, 5-tetramethyl-1-pyrrolidinyloxy.

The title compound was prepared in a manner similar to that for Example A48 in 30% yield after HPLC purification.

'H NMR (CD30D): 8 7.88 (d, 2H, J=8.8 Hz), 7.88 (d, 2H, J=8.8 Hz), 7.58 (m, 1H), 7.13 (t, 2H, J=8.7 Hz), 2.67 (m, 1H), 2.22-2. 00 (m, 2H), 1. 58 (s, 6H), 1.47 (d, 6H, J=9.4 Hz), 1.20 (m, 2H).

LCMS (M+H+) : 514.

Anal. Calcd. For C26H29F2N5O2S#2 HCl#1. 60 H20 : C, 50.75% ; H, 5.60% ; N, 11.38% ; S, 5. 21%.

Found: C, 50. 75% ; H, 5.74% ; N, 11.35% ; S, 5. 21%.

Example A57: 4- [4-Amino-5- (2, 6-difluoro-benzoyl)-thiazol-2-ylamino}-N-2- (cis-3, 5- dimethyl-piperazin-1-yl)-ethyl3-benzamide

The starting materials were prepared as follows: Step 1. cis-3, 5-Dimethyl-pìperazine-l-earbonitrile To a solution of cis-3, 5-dimethyl-piperazine (1.5 g, 13.13 mmol) in CH3CN (10 ml) were added K2CO3 (8.70 g, 63.02 mmol) and chloroacetonitrile (0.90 ml, 14.44 mmol). The mixture

was stirred for 12 h, filtered, and concentrated to afford the desired product as a brown solid in 78% yield, which was used without further purification.

H NMR (CDC13): 6 1.08 (3H, s), 3.00-2. 88 (2H, m), 1.94 (2H, dd, J = 10. 4,10. 5 Hz), 1.08 (3H, s), 1.06 (3H, s).

Step 2. 5-Dimethyl-piperazin-l-yl)-ethylamine The title amine was prepared according to the procedure described in Step 2 in Example A39 and used as crude.

The title compound was prepared in a manner similar to Step 3 in Method A.

'H NMR (CD30D) : 8 7. 83 (d, 2H, J = 8.9 Hz), 7.72 (d, 2H, J = 8.7 Hz), 7.52-7. 42 (m, 1H), 7.06 (dd, 2H, J = 7.9, 8.0 Hz), 3.54 (dd, 2H, J = 6.6, 6.8 Hz), 2. 61 (dd, 2H, J = 6.4, 7.2 Hz), 1.76 (dd, 2H, J= 10. 8,11. 2 Hz), 1. 18 (dd, 2H, J= 6.9, 7.1 Hz), 1.08 (s, 3H), 1.06 (s, 3H).

Anal. Calcd. for C2sH2sF2N602S'1. 5 H20 : C, 55.44% ; H, 5.77% ; N, 15.52% ; S, 5.92%. Found: C, 55.31% ; H, 5.47% ; N, 15.35% ; S, 5. 96%.

Example A58 : 4- [5- (l-Adamantan-1-yl-methanoyl)-4-amino-thiazol-2-ylamino]-N- (2- dimethylamino-ethyl)-benzamide The title compound was prepared from 1-adamantyl bromomethyl ketone in a route similar to that of Method A.

1H NMR (DMSO-d6): 8 11.00 (bs, 1H), 8.30 (bs, 1H), 8.10 (br, 2H), 7.88 (d, 2H, J=6.5 Hz), 7.74 (d, 2H, J=6.5 Hz), 2.40 (m, 2H), 2.20 (s, 6H), 2.05 (m, 3H), 1.92 (m, 6H), 1.70 (m, 6H).

ESIMS (M+H+) : 468 Example A59: 4- {4-Amino-5- [1- (4-methyl-pyridin-3-yl) methanoyl]-thiazol-2-ylamino}-N- (1- methyl-pyrrolidin-2S-ylmethyl) -benzamide Hydrochloride Salt. The starting materials were prepared as follows: Step 1. 3-(1-Ethoxy-vinyl)-4-methyl-pyridine

3-Bromo-4-methyl-pyridine (2.46 g, 14. 3 mmol; Emka Chemie), tributyl-(1-ethyoxyvinyl)- stannane (6.20 g, 17.2 mmol), and tetrakis (triphenylphosphine)-palladium (0) (1.32 g, 1.14 mmol) stirred in dry toluene (50 ml) at reflux under argon for 4 hours. The mixture was concentrated in vacuo and purified by column chromatography (25% EtOAc/hexanes) to give 2.12 g of a clear oil in 91% yield, which was used without any further purification.

1H NMR : 8 8.50 (s, 1H), 8.40 (d, 1H, J=5.1 Hz), 7.08 (s, 1H, J=5.1 Hz), 4.38 (d, 1H, J=2.4 Hz), 4.24 (d, 1H, J=2.4 Hz), 3.91 (q, 2H, J=7.2 Hz), 2.37 (s, 3H), 1. 38 (t, 3H, J=7.2 Hz).

Step 2. 1-(4-Methyl-pyridin-3-yl)-ethanone.

3-(1-Ethoxy-vinyl)-4-methyl-pyridine stirred in a mixture of toluene (150 ml), water (30 ml), and concentrated HCl (30 ml) for 2 hours. The solution was concentrated to-40 ml in vacuo, made basic with sat. NaHCO3, and extracted with EtOAc. Organic layers were washed with brine, dried over Na2S04, and concentrated in vacuo. Purification by column chromatography (75% EtOAc/hexanes) gave 1. 7 g of a clear oil in 96% yield, which was used without any further purification.

1H NMR : 8 8.95 (s, 1H), 8.54 (d, 1H, J=5.1 Hz), 7.19 (d, 1H, J=5. 1 Hz), 2.64 (s, 3H), 2. 56 (s, 3H).

Step 3. 2-Bronao-1- (4-naetlayl-pyridin-3-yl)-etlzanone Hydrobromide Salt

Bromine (0.66 ml, 12.7 mmol) in acetic acid (2.5 ml) was added slowly to a stirred solution of 1- (4-methyl-pyridin-3-yl)-ethanone (1.68 g, 12.4 mmol) in acetic acid (2.5 ml) and 48% aqueous HBr (2.5 ml) at 0°C. The reaction mixture was stirred for 16 hours at room temperature and then diluted with ether (50 ml) to form a precipitate. The white solid was collected by filtration and washed with ether and acetone to give 2. 59 g of white solid in 71% yield, which was used without any further purification.

IHNMR (DMSO-d6) : 8 9.24 (s, 1H), 8.83 (d, 1H, J=5.7 Hz), 7.86 (d, 1H, J=5.7 Hz), 5.02 (s, 2H), 2.58 (s, 3H).

Step 4. 4-{4-Amino-5-[1-(4-methyl-pyridin-3-yl)-methanoyl]-thiazol-2 -ylamino}-benzoic acid Ethyl Ester

The title compound was prepared in a manner similar to that for Step 1 in Method A from ethoxycarbonylphenyl isothiocyanate (700 mg, 3.40 mmol) and 2-bromo-l- (4-methyl-pyridin-3- yl) -ethanone hydrobromide (1.0 g, 3.4 mmol) and purified by silica gel chromatography (7: 2: 1 EtOAc/THF/hexanes) to provide 967 mg of a yellow solid in 75% yield.

1H NMR (DMSO-d6) : 8 11. 11 (s, 1H), 8.47-8. 50 (m, 2H), 8.20 (br s, 2H), 7.93 (d, 2H, J=8.7 Hz), 7.73 (d, 2H, J=8. 7 Hz), 7.32 (d, 1H, J=5.1 Hz), 4.27 (q, 2H, J=7.2 Hz), 2.30 (s, 3H), 1.30 (t, 3H, J=7.2 Hz).

Anal. (Cl9Hl8N403S) C, H, N, S.

Step 5. 4-{4-Amino-5-[1-(4-methyl-pyridin-3-yl)-methanoyl]-thiazol-2 -ylamino}-benzoic Acid

4-f 4-Amino-5- [1- (4-methyl-pyridin-3-yl)-methanoyl]-thiazol-2-ylamino-benzoic acid ethyl ester was hydrolyzed by refluxing for 5 hours with lithium hydroxide in water/THF (1/1) to give the title compound in a quantitative yield, which was used without any further purification.

'H NMR (DMSO-d6) : 8 11.37 (br, 1H), 8.47 (bd, 2H, J=5.1 Hz), 8.19 (br, 2H), 7.80 (d, 2H, J=8.7 Hz), 7.74 (d, 2H, J=8. 7 Hz), 7.32 (d, 1H, J=5.1 Hz), 2.29 (s, 3H).

ESIMS (M+H+) : 355. Step 6. 4-{4-Amino-5-[1-(4-methyl-pyridin-3-yl)methanoyl]-thiazol-2- ylamino}-N-(1-methyl- pyrrolidin-2S'ylrnethyl)-benzamide

The title compound was prepared in a manner similar to that of Step 3 in Method A from 4- {4-amino-5- [l- (4-methyl-pyridin-3-yl)-methanoyl]-thiazol-2-ylamino}-benzoi c acid (420 mg, 1.19 mmol) and (l-methyl-pyrrolidin-2S-yl)-methylamine (from Example A31 ; 150 mg, 1.32 mmol) as a bright yellow solid (320 mg) in 51% yield, which was used without any further purification.

IHNMR (DMSO-d6) 6 11. 01 (br s, 1H), 8.45-8. 48 (m, 2H), 8.24 (t, 1H, J=6.0 Hz), 8.17 (br s, 2H), 7.80 (d, 2H, J=8.7 Hz), 7.61 (d, 2H, J=8.7 Hz), 7.31 (d, 1H, J=5.1 Hz), 3.38-3. 46 (m, 1H), 3.07- 3.14 (m, 1H), 2.87-2. 93 (m, 1H), 2.28-2. 34 (m, 7H), 2.10 (q, 1H, J=8.4 Hz), 1.78-1. 82 (m, 1H), 1.52-1. 62 (m, 3H).

ESIMS (M+H+) : 451.

For the title compound, a solution of 4-f 4-amino-5- [1- (4-methyl-pyridin-3-yl) methanoyl] - thiazol-2-ylamino}-N-(1-methyl-pyrrolidin-2S-ylmethyl)-benza mide was dissolved in 1 N HCl, washed with EtOAc, and concentrated in vacuo to give a yellow solid.

1H NMR (DMSO-d6) : 6 11. 88 (s, 1H), 10.79 (s, 1H), 8.98-9. 04 (m, 2H), 8.83 (d, 1H, J=6.0 Hz), 8.40 (bs, 2H), 8.03 (s, 1H), 7.99 (d, 2H, J=8.7 Hz), 7.82 (d, 2H, J=8.7 Hz), 3.50-3. 82 (m, 4H), 3.00-3. 07 (m, 1H), 2.84 (d, 3H, J=5.1 Hz), 2.54 (s, 3H), 1.77-2. 12 (m, 4H), 124-1.31 (m, 1H).

Anal. For Cz3H26N602S. 2.0 Hic1. 2.0 H20 : C, H, N, S.

Example A60: 4- [4-Amino-5- (2, 6-difluoro-benzoyl)-thiazol-2-ylamino]-N- (2RS-dimethylamino- 1-methyl-ethyl)-2-methoxy-benzamide The title compound was prepared starting from 4-amino-2-methoxy-benzoic acid methyl ester and 2-bromo-2', 6'-difluoro-acetophenone in a route similar to that of Method A.

1H NMR : 8 7.92 (d, 1H, J=8.8 Hz), 7.28 (m, 1H), 7.12 (s, 1H), 6.88 (t, 2H, J=8.7 Hz), 6.72 (d, 1H, J=8.8 Hz), 4.24 (m, 1H), 3.86 (s, 3H), 2.50 (m, 1H), 2.28 (s, 6H), 1.22 (d, 3H, J=6.5 Hz).

HRFABMS Calcd for C23H25F2N503S (M+H+) : 490.1724. Found: 490.1722.

Example A61: 4- [4-Amino-5- (2, 6-difluoro-benzoyl)-thiazol-2-ylamino]-N- (2- dimethylamino-l, 1-dimethyl-ethyl)-benzamide Dihydrochloride The title compound was prepared in a manner analogous to Step 3 of Method A, from 4- [4- amino-5- (2, 6-difluoro-benzoyl) -thiazol-2-ylamino] -benzoic acid (3) and 2, Nl, Nl-trimethyl- propane-1, 2-diamine (Tsuji, et al Chem. Pharm. Bull. Vol. 12, pp. 946-950 (1964) ). Radial chromatography with 0.5% (58% NH40H)/5% MeOH/CHCl3 gave a yellow oil, which was placed in CHC13, treated with 4M HCI in dioxane (2.2equiv), and azeotroped from CHC13 in succession to provide 100 mg of yellow powder in 23% yield, mp 275-290°C (decomp).

'H NMR (CD30D) : 8 8. 16 (bs, 1H), 7.91 (s, 1H), 7.90 (d, 2H, J=6.8 Hz), 7.77 (d, 2H, J=6.8 Hz), 7.51 (ddd, 1H, J=6.4, 8. 4, 15. 1 Hz), 7.08 (dd, 2H, J=7.6, 8.3 Hz), 3.66 (s, 2H), 3.00 (s, 6H), 1.58 (s, 6H).

FTIR (KBr): 1602,1610, 1543,1524, 1464,1426 cm-1.

HRESIMS. Calcd for C23H26F2NsO2S (M+H+) : 474.1775. Found: 474.1793.

Anal. Calcd. for C23H2sF2N502S'2. 0 HCl#0. 3 CHCl3 0. 9 H20: C, 46.76% ; H, 4.90% ; N, 11.70% ; Cl, 17.18% ; S, 5.36%. Found: C, 46.77% ; H, 4.66% ; N, 11.34% ; Cl, 17.19% ; S, 5.28%.

Example A62: 4- {4-Amino-5- [1- (3-methyl-thiophen-2-yl)-methanoyl]-thiazol-2- ylamino}-N-(2-dimethylamino-lR-methyl-ethyl)-benzamide Trifluoroacetic Acid Salt Starting materials were prepared as follows: Step 1. 4-{4-Amino-5-[1-(3-methyl-thiophen-2-yl)-methanoyl]-thiazol- 2-ylamino}-benzoic Acid Ethyl Ester

Prepared in a manner analogous to Step 1 of Method A. To 4-ethoxycarbonyl- phenylisothiocyanate (0.930 g, 4.48 mmol) in CH3CN (5 ml) were sequentially added cyanamide (0.207 g, 4.92 mmol) and a solution of potassium t-butoxide (0.552 g, 4.92 mmol) in t-butanol (5 ml). The resultant mixture stirred for 0.5 h, then 2-bromoacetyl-3- methyl-thiophene (1.00 g, 4.56 mmol; PCT Patent Publication WO 99/21845) was added.

The mixture stirred for 3 h, was diluted with 10% MeOH/CHC13 (100 ml), and washed with H20 (25 ml X 2). The organic layer was dried over Na2S04 and concentrated to a brown solid, which recrystallized from hot EtOAc to give 1.1 g of a yellow solid in 65% yield, which was used without any further purification.

1H NMR : 8 8.18 (2H, d, J=8. 8 Hz), 7. 56 (2H, d, J=8.8 Hz), 7.42 (1H, d, J=5.0 Hz), 7.04 (1H, d, J=5.0 Hz), 4.49 (2H, q, J=7.1 Hz), 2.60 (3H, s), 1.50 (3H, t, J=7.1 Hz).

Step 2. 4-{4-Amino-5-[1-(3-methyl-thiophen-2-yl)-methanoyl7-thiazol- 2-ylamino}-benzoic Acid Prepared in a manner analogous to Step 2 of Method A. To a suspension of 4-{4- amino-5- [1- (3-methyl-thiophen-2-yl)-methanoyl]-thiazol-2-ylamino}-benzo ic acid ethyl ester (1.00 g, 2.58 mmol) in MeOH (6 ml) was added 3N NaOH (8.60 ml, 25.8 mmol). The resultant solution stirred at ambient temperature for 18 h. The methanol was removed in vacuo and the aqueous layer adjusted to pH 3 with 10% HC1 to give 0.80 g of a yellow solid in 90% yield, which was used without further purification.

1H NMR (DMSO-d6) : 8 11.02 (1H, s), 8.02 (1H, bs), 7.90 (2H, d, J=8. 7 Hz), 7.74 (2H, d, J=8.7 Hz), 7.61 (1H, d, J=4.9 Hz), 7.00 (1H, d, J=4.9 Hz), 2.4 (3H, s).

The title compound was prepared in a manner similar to Step 3 in Method A, from 4-f 4- amino-5- [l- (3-methyl-thiophen-2-yl)-methanoyl]-thiazol-2-ylamino}-benzo ic acid and (R)-

N, N-dimethyl-propane-1, 2-diamine dihydrochloride salt (from Step 3 of Example A40) to provide a yellow foam in 62% yield.

'H NMR (CD30D) : 8 7.88 (2H, d, J=8.7 Hz), 7.76 (2H, d, J=8.7 Hz), 7.42 (1H, d, J=5.1 Hz), 6.98 (1H, d, J=4. 8 Hz), 2.56 (6H, s), 2.42 (3H, s), 1.28 (3H, d, J=6.6 Hz).

Anal. Calcd. for C21H25N5O2S2#0. 6 CF3CO2H : C, 52.08% ; H, 5.04% ; N, 13. 68% ; S, 12.53%. Found : C, 52. 28% ; H, 5.22% ; N, 13. 34% ; S, 12.29%.

Example A63: 4- [4-Amino-5- (2, 6-difluoro-benzoyl)-thiazol-2-ylamino]-N- (l-methyl- imidazol-4-yl-methyl)-benzamide Trifluoroacetic Acid Salt Step 1. 1-Methyl-lH-imidazole-4-carboxylic acid amide Prepared according to a procedure described by Piotrovskii, et al, Chem.

Heterocycl. Compo. (Eng. Transi.), 26,4, 407-409 (1990).

1H NMR (DMSO-d6) : 8 7.68 (s, 1H), 7.64 (s, 1H), 7.23 (bs, 1H), 7.04 (bs, 1H), 3.28 (s, 3H).

Step 2. C-1-Methyl-IH-imidazol-4-yl)-methylamine To a solution of 1-methyl-lH-imidazole-4-carboxylic acid amide (0.80 g, 6.4 mmol) in THF (15 ml) at 0°C was added LiAlH4 (486 mg, 12.8 mmol). The mixture was refluxed for 24 h, cooled to 0°C, then carefully quenched with sat NaHCO3 (2 ml), diluted with ether (80 ml), and filtered through a pad of Celite. The filtrate was dried over Na2SO4 and concentrated to give 476 mg of yellow oil in 67% yield and was used without any further purification.

1H NMR (CDC13) : 8 7.35 (s, 1H), 6.73 (s, 1H), 3.78 (s, 2H), 3.64 (s, 3H).

The title compound was prepared in a manner analogous to Step 3 of Method A, from 4- [4- amino-5- (2, 6-difluoro-benzoyl) -thiazol-2-ylamino] -benzoic acid (3) and C-1-methyl-lH- imidazol-4-yl) -methylamine. Purified via preparative HPLC.

1H NMR (DMSO-d6): 8 11.07 (s, 1H), 8.99 (t, 1H, J=5.3 Hz), 8.94 (s, 1H), 8.19 (bs, 2H), 7.88 (d, 2H, J=8. 7 Hz), 7.69 (d, 2H, J=8.7 Hz), 7.56 (s, 1H), 7.54 (m, 1H), 7.21 (dd, 2H, J=8.0, 8.0 Hz), 4.47 (d, 2H, J=5.3 Hz), 3.83 (s, 3H).

ESMS (M+H+) : 469.

Anal. Calcd. for C22H18F2N602S 2. 3 TFA 1.0 H20 : C, 42.67% ; H, 3.00% ; N, 11. 22% ; S, 4.28%. Found: C, 42.40% ; H, 3.14% ; N, 11.17% ; S, 4.30%.

Example A64: 4- [4-Amino-5- (2, 6-difluoro-benzoyl)-thiazol-2-ylamino]-N- (l- methylimidazol-5-yl-methyl)-benzamide.

Step 1. C-(3-Methyl-3H-imidazol-4-yl)-methylami7te

Prepared in a manner analogous to Step 2 of Example A63, from 1- methylimidazole-5-carboxamide (Apollo Scientific, Ltd) to give a yellow oil in 86% yield, which was used without any further purification.

1H NMR (CDC13) : 5 7.39 (s, 1H), 6.89 (s, 1H), 3.85 (d, 2H, J=0.6 Hz), 3.66 (s, 3H).

The title compound was prepared in a manner analogous to Step 3 of Method A, from 4- [4- amino-5- (2, 6-difluoro-benzoyl) -thiazol-2-ylamino] -benzoic acid (3) and C- (3-methyl-3H- imidazol-4-yl)-methylamine. Purified via preparative HPLC.

1H NMR (DMSO-d6) : 8 11.00 (s, 1H), 8.93 (s, 1H), 8.85 (t, 1H, J=5. 8 Hz), 8.11 (bs, 2H), 7.79 (d, 2H, J=8.7 Hz), 7.60 (d, 2H, J=8.7 Hz), 7.51 (s, 1H), 7.47 (m, 1H), 7.14 (dd, 2H, J=7.8, 8.0 Hz), 4.48 (d, 2H, J=5.5 Hz), 3.80 (s, 3H).

ESMS (M+H+) : 469.

Anal. Calcd. for C22HisF2N602S'1. 5 TFA 1.0 H20 : C, 45. 67% ; H, 3.30% ; N, 12.78% ; S, 4.88%. Found: C, 45.66% ; H, 3.44% ; N, 12.96% ; S, 4.89%.

Example A65: 2R-{4-L4-Amino-5-(2, 6-difluoro-benzoyl)-thiazol-2-ylamino]-benzoyl}- amino}-propionic Acid Trifluoroacetic Acid Salt The starting material was prepared as follows: 2R-{4-[4-Amino-5-(2,6-difluoro-benzoyl)-thiazol-2-ylamino]-b enzoyl}amino-propionic Acid tert-Butyl Ester Prepared in a manner similar to Step 3 in Method A from D-alanine tert-butyl ester hydrochloride (Novabiochem). Column chromatography with 10% MeOH/CHCl3 provided a yellow powder in 98% yield, which was used without any further purification.

1H NMR (CD30D): # 7.86 (d, 2H, J=8.9 Hz), 7.74 (d, 2H, J=8.8 Hz), 7.52-7. 42 (m, 1H), 7.06 (dd, 2H, J=7.5, 7.5 Hz), 2.98 (s, 3H), 1.48 (s, 9H).

The title Example was prepared as follows. A solution of 2R-4- [4-amino-5- (2, 6- difluoro-benzoyl)-thiazol-2-ylamino]-benzoyl} amino-propionic acid tert-butyl ester (350 mg, 0.696 mmol) in TFA (2 ml) stirred for 0.5 h. Ether was added to the solution until a yellow precipitate formed, which was filtered and dried under high vacuum to afford 150 mg of yellow powder in 49% yield.

1H NMR (CD30D) : 8 7.89 (d, 2H, J=8.8 Hz), 7.76 (d, 2H, J=8.7 Hz), 7. 58-7. 46 (1H, m), 7.06 (dd, 2H, J=7.7, 8.1 Hz), 1.54 (d, 3H, J=7.3 Hz).

LC-MS (M+H+) : 447; (M-H-): 445.

Anal. Calcd. for C20Hl6F2N404SelH2On0. 5TFA : C, 48.37% ; H, 3.58% ; N, 10.74% ; S, 6.15%. Found: C, 48.68% ; H, 3.58% ; N, 10.45% ; S, 5.94%.

Example A66: 4- {4-Amino-5- (2-fluoro-benzoyl)-thiazol-2-ylamino}-N-dimethylamino-lR- (methyl-ethyl)-benzamide Trifluoroacetic Acid Salt Starting materials were prepared as follows: Step 1. 2-Bromo-2'-fluoro-acetophefzone.

The above intermediate was prepared in a manner similar to that for 2-bromo-2', 6'- difluoro-acetophenone as described in Method A and used without any further purification.

The 1H NMR spectrum matched that described previously in C. Giuseppe et. al. J. Med.

Chem., 20,3763-3772 (1998).

Step 2. 4-[4-Amino-5-(2-fluoro-benzoyl)-thiazol-2-ylamino]-benzoic Acid Ethyl Ester

As described in Step 1 in Method A, 4-ethoxycarbonylphenyl isothiocyanate and 2- bromo-2'-fluoro-acetophenone provided a yellow solid in 99% yield, which was used without any further purification.

1H NMR (DMSO-d6): 5 11.09 (s, 1H), 8.15 (br, 2H), 7.94 (d, 2H, J=8.6 Hz), 7.75 (d, 2H, J=8.6 Hz), 7.55 (d, 1H, J=7.2 Hz), 7.50 (d, 1H, J=7. 0 Hz), 4.30 (q, 2H, J=7.1 Hz), 1.31 (t, 3H, J=7.1 Hz).

ESIMS (M+H+) : 386.

Step 3. 4-[4-Amino-5-(2-fluoro-benzoyl)-thiazol2-ylamino]-benzoic Acid

Prepared as described in Step 2 of Method A from 4- [4-amino-5- (2-fluoro- benzoyl) -thiazol-2-ylamino] -benzoic acid ethyl ester to give a yellow solid in 90% yield, which was used without any further purification.

1H NMR (DMSO-d6) : 8 12.88 (br, 1H), 11.25 (s, 1H), 8.32 (br, 2H), 8.09 (d, 2H, J=8.7 Hz), 7.89 (d, 2H, J=8.. 7 Hz), 7.72 (d, 1H, J=7.1 Hz), 7.66 (d, 1H, J=6.7 Hz).

ESIMS (M+H+) : 358.

The title compound was prepared in a manner analogous to Step 3 in Method A from 4- [4- amino-5- (2-fluoro-benzoyl)-thiazol-2-ylamino]-benzoic acid and (R)-N, N-dimethyl- propane-1, 2-diamine dihydrochloride salt (from Step 3 of Example A40).

1H NMR (DMSO-d6) : 8 10.81 (s, 1H), 8. 87 (br, 1H), 8.12 (d, 1H, J=8. 6 Hz), 7.92 (br, 2H), 7.65 (d, 2H, J=8.7 Hz), 7.45 (d, 2H, J=8.7 Hz), 4.23 (sextet, 1H, J=6.3 Hz), 2.61 (d, 3H, J=4.7 Hz), 2.56 (d, 3H, J=4.7 Hz), 0.96 (d, 3H, J=6.7 Hz).

ESIMS (M+H+) : 442.

Anal. Calcd. for C22H24FNs02S'0. 9 H20 1. 9 TFA: C, 45. 95% ; H, 4.14% ; N, 10.38% ; S, 4.75%. Found: C, 45.76% ; H, 4.10% ; N, 10.67% ; S, 4.95%.

Example A67: 4-{4-Amino-5-(2-fluoro-benzoyl)-thiazol-2-ylamino}-N-(l-meth yl-pyrrolidin- 2S-ylmethyl) -benzamide Trifluoroacetic Acid Salt The title compound was prepared in a manner analogous to Step 3 in Method A, from 4- [4- amino-5- (2-fluoro-benzoyl)-thiazol-2-ylamino]-benzoic acid (from Step 3 in Example A66) and (1-methyl-pyrrolidin-2S-yl)-methylamine (Sassaman, et al., Bioorg. Med. Chem., 6,1759-1766 (1998) ), and purified via preparative HPLC.

1H NMR (DMSO-d6) : 8 11.10 (s, 1H), 9.40 (br, 1H), 8.78 (t, 1H, J=5.6 Hz), 8.21 (br, 2H), 7.95 (d, 2H, J=8.7 Hz), 7.79 (d, 2H, J=8.7 Hz), 3.18 (m, 1H), 3.03 (d, 3H, J=4.7 Hz).

ESIMS (M+H+) : 454.

Anal. Calcd. for C23H24FN502S'1. 6 H20 0.2 CH3CN 2. 0 TFA: C, 45.80% ; H, 4.18% ; N, 10.14% ; S, 4.46%. Found : C, 45.50% ; H, 4.03% ; N, 10.48% ; S, 4.80%.

Example A68: 4- {4-Amino-5- (2, 6-difluoro-4-methyl-benzoyl)-thiazol-2-ylamino}-N- (l- methyl-pyrrolidin-2S-ylmethyl)-benzamide The starting materials were prepared as follows: Step 1. (4-Bronao-2, 6-difluoro-phenyl) triffaethylsilane.

To diisopropylamine (1.73 ml, 12.4 mmol) in THF (30 ml) at-78°C was added slowly n-butyllithium (7.73 ml of 1.6 M in hex). The mixture stirred at 0°C for 20 min and then was recooled to-100°C with a liquid nitrogen/ether slush bath, whereupon 1-bromo- 3,5-difluorobenzene (2.17 g, 11.2 mmol) was added at such a rate that the temperature never exceeded-90°C. After 2h at-100°C, chlorotrimethylsilane (1.86 ml, 14.6 mmol) was added dropwise at such a rate that the temperature kept below-85gC. The resultant mixture was allowed to warm to ambient temperature overnight, then quenched with water (2 ml), and extracted with ether. The separated organic layer was washed with brine and carefully concentrated below 30°C under reduced pressure on a rotary evaporator to give 2.97 g (100%) of a colorless oil, which was used in the next step without any further purification.

1H NMR: 8 7.00 (ddd, 2H, , J=2.6, 2.6, 7.9 Hz), 0.36 (dd, 9H, J=1.4, 1.4 Hz).

Step 2. (2, 6-Difluoro-4-methyl-phenyl)-trimethyl-silane To a solution of (4-bromo-2,6-difluoro-phenyl) trimethylsilane (2.52 g, 9.50 mmol) in ether (25 ml) at-60°C was added n-butyllithium (7.1 ml of 1.6 M in THF) and the cooling bath removed. After a half-hour, the temperature rose to 0°C, recooled to-60°C, and iodomethane (0.89 ml, 14.3 mmol) was added. The mixture was allowed to warm over one hour, quenched with water, and extracted with ether. The organic layer was washed with water and brine, dried over dry MgS04, and concentrated to give a yellow oil, which was used immediately without any further purification.

1H NMR: 8 6.61 (d, 2H, J=8.1 Hz), 2.31 (s, 3H), 0.34 (t, 9H, J=1.3 Hz).

Step 3. 2, 6-Difluoro-4-methyl-acetophenone

According to a procedure described by Bennetau, et al., Tetrahedron, 49,10843- 10845 (1993), a mixture of AlCl3 (1.58 g, 11.9 mmol) in CH2C12 (17 ml) was cooled to 0°C, and acetyl chloride (0.84 ml, 12 mmol) was added. The resultant suspension stirred at 0°C for 15 min, and a solution of (2, 6-difluoro-4-methyl-phenyl)-trimethylsilane (9.50 mmol) in CH2C12 (15 ml) was added dropwise. The mixture was allowed to warm over one hour, recooled to 0°C, quenched with 1N HC1, and extracted with ether. The organic layer was washed with 1N HC1 and brine, dried over MgS04, and concentrated to give 1.56 g of a brown oil in 97% yield for two steps from 4-bromo-2,6-difluoro-phenyl) trimethylsilane, and was used without any further purification.

1H NMR : 5 6.76 (d, 2H, J=9.3 Hz), 2.56 (t 3H, J=1. 9 Hz), 2.37 (s, 3H).

Step 4. 2-Bromo-2', 6'-difluoro-4'-rraethyl-acetophenone.

Prepared in a manner similar to that for 2-bromo-2', 6'-difluoro-acetophenone in Method A, and used without any further purification.

1H NMR : 5 6.81 (d, 2H, J=9.4 Hz), 4.35 (s 2H), 2.40 (s, 3H).

Step 5. 4-[4-Amino-5-(2,6-difluoro-4-methyl-benzoyl)-thiazol-2-ylami no]-benzoic Acid

As described in Step 1 in Method A, 4-ethoxycarbonyl-phenylisothiocyanate and 2- bromo-2', 6'-difluoro-4'-methyl-acetophenone provided a yellow solid in 92% crude yield, which displayed a MS consistent for desired 4- [4-amino-5- (2, 6-difluoro-4-methyl- benzoyl) -thiazol-2-ylamino] -benzoic acid ethyl ester (ESIMS (M+H+) : 418) and was treated as described in Step 2 in Method A to furnish a yellow solid in 88% yield, which was used without any further purification.

1H NMR (DMSO-d6): 8 12.77 (br, 1H), 11.17 (s, 1H), 8. 20 (br, 2H), 7.92 (d, 2H, J=8.7 Hz), 7.71 (d, 2H, J=8.7 Hz), 7.04 (d, 2H, J=8.6 Hz), 2.37 (s, 3H).

ESIMS (M+H+) : 390.

The title compound was prepared in a manner analogous to Step 3 in Method A from 4- [4- amino-5- (2, 6-difluoro-4-methyl-benzoyl)-thiazol-2-ylamino]-benzoic acid and (1-methyl- pyrrolidin-2S-yl) -methylamine (Sassaman, et al., Bioorg. Med. Chem., 6,1759-1766 (1998)).

1H NMR (DMSO-d6): 6 10.99 (br, 1H), 8.32 (t, 1H, J=5.9 Hz), 8.20 (br, 2H), 7.83 (d, 2H, J=8. 7 Hz), 7.65 (d, 2H, J=8.7 Hz), 7.04 (d, 2H, J=8.5 Hz), 3.17 (m, 1H), 2.99 (m, 1H), 2.37 (s, 3H), 2.35 (s, 3H).

ESIMS (M+H+) : 486.

Anal. Calcd. for C24H2sF2Ns02S'1. 3 MeOH : C, 57.64% ; H, 5.77% ; N, 13.28% ; S, 6.08%.

Found: C, 57.59% ; H, 5.44% ; N, 12. 90% ; S, 6.22%.

Example A69: 4- [4-Amino-5- (2, 6-difluoro-benzoyl)-thiazol-2-ylamino-N- [lS- (l-methyl- pyrrolidin-2S-yl)-ethyl]-benzamide The starting materials were prepared as follows: Step 1. 2S-(l S-Amino-ethyl)-pyrrolidine-1-carboxylic Acid tert-Butyl Ester To a solution of 2S-[lS-(benzyl-hydroxyamino)-ethyl]-pyrrolidine-l-carboxylic acid tert-butyl ester (0.500 g, 1.56 mmol; Merino, et al., Tetrahedron : Asymmetry, 10, 1861-1865 (1999); Merino, et al., Tetrahedron : AsymmelYy, 10, 1867-1871 (1999) ) in MeOH (10 ml) was added 20% palladium hydroxide on activated charcoal (0.2 g). The resultant mixture stirred under a hydrogen balloon at ambient temperature for 2 days. The

catalyst was filtered off through a plug of Celite and rinsed with MeOH. The filtrate was concentrated in vacuo to afford 0.33 g of a colorless oil in 99% yield, which was used without further purification.

1H NMR: 8 3.71 (bs, 1H), 3.49 (s, 2H), 3.32-3. 24 (m, 1H), 3.00 (m, 1H, J=6.6 Hz), 1.46 (s, 9H), 1.05 (d, 3H, J=6.5 Hz).

Step 2. (IS-Methyl-pyrrolidin-2S-yl)-ethylamine Hydrochloride Prepared in a manner similar to Step 2 of Example A39: 2S- (1S-amino-ethyl)- pyrrolidine-1-carboxylic acid tert-butyl ester (0.760 g, 3.54 mmol) was reduced with LiAlH4 and the crude filtrate treated with 4N HCl in dioxane (1 ml). The resultant solution was concentrated in vacuo to provide 0.70 g of a gummy oil in 99% yield, which was used without further purification.

1H NMR: 6 3.94 (ddd, 1H, J=2.5, 7.1, 9. 5 Hz), 3.74-3. 68 (m, 1H), 3.42-3. 32 (m, 1H), 2.79 (s, 3H), 2. 28-2.18 (m, 1H), 1.42 (d, 3H, J=6.6 Hz).

The title Example was prepared in a manner similar to that for Step 3 in Method A from 4- [4-amino-5- (2, 6-difluoro-benzoyl) -thiazol-2-ylamino] -benzoic acid (3) and (IS-methyl- pyrrolidin-2S-yl) -ethylamine (Sassaman, et al., Bioorg Med. Chem., 6,1759-1766 (1998) ).

1H NMR (CD30D) : 6 7.73 (d, 2H, J=8.7 Hz), 7.57 (d, 2H, J=8. 5 Hz), 7.52-7. 44 (m, 1H), 7.06 (dd, 2H, J=7.5, 8.3 Hz), 4.50-4. 44 (m, 1H), 2. 48 (s, 3H), 1.10 (d, 3H, J=6.3 Hz).

LC-MS (M+H+) : 486 ; (M-H-): 484.

Anal. Calcd. for C24H25F2N5O2S#1.3H2O#0.2CHCl3 : C, 54.55% ; H, 5.03% ; N, 13.14% ; S, 6.02%. Found: C, 54.71% ; H, 5.03% ; N, 13.08% ; S, 5.89%.

Example A70: 4- {4-Amino-5- [l- (3-methyl-thiophen-2-yl)-methanoyl]-thiazol-2- ylamino}-N- (l-methyl-pyrrolidin-2S-ylmethyl)-benzamide

The title Example was prepared in a manner similar to Step 3 in Method A from 4- {4- amino-5-[1-(3-methyl-thiophen-2-yl)-methanoyl]-thiazol-2-yla mino}-benzoic acid (Example A62 Step 2) and (R)-N, N-dimethyl-propane-1, 2-diamine dihydrochloride salt (from Example A33).

1H NMR (CD30D) : 8 7.85 (d, 2H, J=8. 8 Hz), 7.76 (d, 2H, J=8.8 Hz), 7.43 (d, 1H, J=5.0 Hz), 6.94 (d, 1H, J=5.0 Hz), 3.68 (1H, dd, J=4.3, 13.9 Hz), 2.40 (s, 3H).

Anal. Calcd. for C22H2sNs02S20. 35Hexane#0. 3CHCl3 : C, 56.19% ; H, 5.84% ; N, 13.43% ; S, 12.30%. Found: C, 56.54% ; H, 5.84% ; N, 13.79% ; S, 11.92%.

LC-MS (M+H+) : 456; (M-H-): 454.

Example A71: 4- [4-Amino-5- (2-chloro-6-fluoro-benzoyl)-thiazol-2-ylamino]-N- (l- methyl-pyrrolidin-2S-ylmethyl)-benzamide The starting materials were prepared as follows: Step 1. 2-Bromo-Z- (2-chloro-6-fluoro-phefayl)-ethanone Prepared in a manner similar to that for 2-bromo-2', 6'-difluoro-acetophenone in Method A, and used without any further purification.

1HNMR : 8 7.45-7. 32 (m, 1H), 7.12 (d, 1H, J=8.8 Hz), 7.07 (dd, 1H, J=4.2, 8.7 Hz), 4.38 (s, 2H).

Step 2. 4-[4-Amino-5-(2-chloro-6-fluoro-benzoyl)-thiazol-2-ylamino]- benzoic Acif Ethyl Ester Prepared in a manner analogous to Step 1 of Method A and used without any further purification.

1H NMR (CD30D) : 8 8.00 (d, 2H, J=8.8 Hz), 7.77 (d, 2H, J=8.8 Hz), 7.50-7. 42 (m, 1H), 7.34 (d, 1H, J=8.1 Hz), 7.18 (dd, 1H, J=8. 3,8. 7 Hz), 4.36 (q, 1H, J=7.1 Hz), 1.40 (t, 3H, J=14.2 Hz).

Step 3. 4-[4-Amino-5-(2-chloro-6-fluoro-benzoyl)-thiazol-2-ylamino]- benzoic Acid

Prepared in a manner similar to Step 2 of Method A and used without any further purification.

1H NMR (CD30D) : 8 8.06 (d, 2H, J=8.9 Hz), 7.82 (d, 2H, J=8.9 Hz), 7.52-7. 44 (m, 1H), 7.38 (d, 1H, J=8.1 Hz), 7.24 (dd, J=8.5, 8.5 Hz).

The title Example was prepared in a manner similar to step 3 in Method A, from 4- [4- amino-5- (2-chloro-6-fluoro-benzoyl)-thiazol-2-ylamino]-benzoic acid and (1-methyl- pyrrolidin-2S-yl) -methylamine (Sassaman, et al., Bioorg. Med Chem., 6,1759-1766 (1998)).

1H NMR (CD30D) : 8 7.87 (d, 2H, J=8. 8 Hz), 7.76 (d, 2H, J=8. 8 Hz), 7.52-7. 43 (m, 1H), 7.35 (d, 1H, J=8. 1 Hz), 7.21 (dd, 1H, J=7.9, 8.5 Hz), 3.71 (dd, 1H, J=4.0, 13.5 Hz), 3.18- 3.08 (m, 1H), 2.65-2. 56 (m, 1H), 2.50 (s, 3H), 2.36 (dd, 1H, J=9.0, 18.1 Hz), 2.08-1. 98 (m, 1H).

LC-MS (M+H+) : 488; (M-H-) : 486.

Anal. Calcd. for C23H23ClFNsO2S 0. 8H20*0. 06CH2CI2 : C, 54.58% ; H, 4.91% ; N, 13.80% ; S, 6.32% ; Cl, 7.82%. Found: C, 54.82% ; H, 4.97% ; N, 13.48% ; S, 6.07% ; Cl, 8.11%.

Example A72: 4-45-(2-Acetylamino-benzoyl)-4-amino-thiazol-2-ylamino}-N-(l -methyl- pyrrolidin-2S-ylmethyl)-benzamide Step 1. N-(2-Acetyl-phefiyl)-acetanaide

Acetic anhydride (10 ml) was added to a solution of 2'-aminoacetophenone (2.00 ml, 16.2 mmol) in acetic acid (10 ml) and heated at 70°C for a half-hour. Allowed to cool and quenched with ice water (150 ml). The resultant white solid was filtered, washed with ice- water, dried under high vacuum to give 2.75 g of solid which displayed an NMR spectrum identical to that described in Adam, et. al, J. Org. Chenu, 59,2733-2739 (1994) and was used without any further purification.

Step 2. N-(2- (2-Bromo-acetyl)-phenylJ-acetarraide Made in a manner similar to that for 2-bromo-2', 6'-difluoro-acetophenone in Method A, to provide an NMR which matched that described in Alkhathlan et. al, Heterocycles, 48, 641-656 (1998) and used without any further purification.

Step 3. 4- (5- (2-Acetylamino-benzoyl)-4-amirao-thiazol-2-ylamifaoJ-benzoic Acid Ethyl Ester Prepared as described in Step 1 in Method A. 4-Ethoxycarbonylphenyl isothiocyanate and N- [2- (2-bromo-acetyl)-phenyl]-acetamide provided a yellow solid in 100% yield, which was used without any further purification.

1H NMR (DMSO-d6): 8 11.12 (s, 1H), 9.89 (s, 1H), 8.26 (br, 2H), 8.01 (d, 1H, J=8.2 Hz), 7.99 (d, 2H, J=8.8 Hz), 7.77 (d, 2H, J=8.8 Hz), 7.58 (dd, 1H, J=1. 2,7. 6 Hz), 7.49 (dt, 1H, J=1.2, 8.2 Hz), 7.18 (t, 1H, J=7.6 Hz), 4.30 (q, 2H, J=7. 1 Hz), 2.03 (s, 3H), 1.32 (t, 3H, J=7.1 Hz).

ESIMS (M-H+) : 423 Step 4. 4-[5-(2-Acetylamino-benzoyl)-4-amino-thiazol-2-ylamino]-benz oic acid

Prepared as described in Step 2 in Method A in 74% yield.

1H NMR (DMSO-d6) : 8 12.66 (br, 1H), 11.05 (s, 1H), 8.23 (br, 2H), 7.98 (d, 1H, J=8. 2 Hz), 7.89 (d, 2H, J=8.6Hz), 7.71 (d, 2H, J=8.6 Hz), 7.54 (d, 1H, J=7.6 Hz), 7.40 (t, 1H, J=7. 6 Hz), 7.19 (t, 1H, J=7.6 Hz), 1.99 (s, 3H).

ESIMS (M-H+) : 395.

The title compound was prepared in a manner analogous to Step 3 in Method A.

1H NMR (DMSO-d6): 8 11.02 (br, 1H), 9.97 (s, 1H), 8.31 (s, 1H), 8.29 (br, 2H), 8.08 (d, 1H, J=8.7 Hz), 7.89 (d, 2H, J=8.4Hz), 7.74 (d, 2H, J=8.4 Hz), 7.63 (d, 1H, J=7.5 Hz), 7.48 (t, 1H, J=7.5 Hz), 7.22 (t, 1H, J=7.5 Hz), 3.49 (m, 1H), 3.19 (m, 1H), 3.00 (m, 1H), 2.41 (m, 1H), 2.37 (s, 3H), 2.20 (m, 1H), 2.09 (s, 3H), 1.89 (m, 1H).

ESIMS (M+H+) : 529.

Anal. Calcd. for C25H2sN603S'0. 5 H20: C, 58.52% ; H, 6.23% ; N, 15.75% ; S, 6.01%. Found : C, 58.35% ; H, 5. 89% ; N, 15. 79% ; S, 6.03%.

Example A73: 4-{4-Amino-5-(2-methanesulfonyl-benzoyl)-thiazol-2-ylamino}- N-(l- methyl-pyrrolidin-2S-ylmethyl) -benzamide Trifluoroacetic Acid Salt Step 1. 1- (2-Methanesulfoiiyl-pliettyl)-ethanoize

Prepared as described in Binder et al, Arch. Phare. (Weinheim Ger.), 313,587-602 (1980), and used without any further purification.

1H NMR (CDC13) : 8 8.09 (dd, 1H, J=1.2, 7.8 Hz), 7.68 (m, 1H) 7.62 (m, 1H) 7.45 (dd, 1H, J=1.3, 7.4 Hz), 3.24 (s, 3H), 2.65 (s, 3H).

ESIMS (M+H+) : 199.

Step 2. 2-bromo-1-(2-methanesulfonyl-phenyl)-ethanone Prepared in a manner similar to that for 2-bromo-2', 6'-difluoro-acetophenone in Method A and used without any further purification.

1H NMR (CDC13) : 6 8.07 (dd, 1H, J=1.4, 7.7 Hz), 7.72 (m, 1H) 7.68 (m, 1H) 7.53 (dd, 1H, J=1.4, 7.1 Hz), 4.50 (s, 2H), 3.17 (s, 3H).

Step 3. 4-[4-Amino-5-(2-methanesulfonyl-benzoyl)-thiazol-2-ylamino]- benzoic Acid Ethyl Ester Prepared as described for Step 1 in Method A, from 4-ethoxycarbonylphenyl- isothiocyanate and 2-bromo-1-(2-methanesulfonyl-phenyl)-ethanone to provide a yellow solid in 95% yield, which was used without any further purification.

1H NMR (DMSO-d6) : 8 11.09 (s, 1H), 8.08 (br, 2H), 8. 01 (d, 1H, J=7.0 Hz), 7.93 (d, 2H, J=8.7 Hz), 7.81 (dd, 1H, J=7.0, 7.3 Hz), 7.73 (d, 2H, J=8.7 Hz), 7.66 (dd 1H, J=7.0, 7.3 Hz), 4.29 (q, 2H, J=7.1 Hz), 3.37 (s, 3H), 1.31 (t, 3H, J=7.1 Hz).

ESIMS (M-H+) : 444.

Step 4. 4-[4-Amino-5-(2-methanesulfonyl-benzoyl)-thiazol-2-ylamino]- benzoic Acid

Prepared as described in Step 2 of Method A to afford a yellow solid in 87% yield, which was used without any further purification.

1H NMR (DMSO-d6): 8 12.52 (br, 1H), 11.09 (s, 1H), 8.09 (br, 2H), 8.01 (d, 1H, J=7.4 Hz), 7.91 (d, 2H, J=8.7Hz), 7.81 (dd, 1H, J=7.3, 7.4 Hz), 7.73 (dd, 1H, J=7.3, 7.4 Hz), 7.71 (d, 2H, J=7.3, 7.4 Hz), 7.64 (d, 1H, J=7.3 Hz), 3.37 (s, 3H).

ESIMS (M-H+) : 416.

The title compound was prepared in a manner analogous to Step 3 in Method A, from 4- [4- amino-5- (2-methanesulfonyl-benzoyl)-thiazol-2-ylamino]-benzoic acid and (1-methyl- pyrrolidin-2S-yl)-methylamine (Sassaman, et al. , Bioorg. Med. Chem., 6,1759-1766 (1998) ), and purified via preparative HPLC.

1H NMR (DMSO-d6): 8 11.03 (s, 1H), 9.36 (br, 1H), 8.71 (dd, 1H, J=5.3, 5.7 Hz), 8.07 (br, 2H), 8.01 (d, 1H, J=7.6 Hz), 7.87 (d, 2H, J=8. 7Hz), 7.81 (dd, 1H, J=7.2, 7.6 Hz), 7.74 (d, 1H, J=7.2, 7.6 Hz), 7.69 (d, 2H, J=8.7 Hz), 7.64 (d, 1H, J=7.2 Hz), 3.37 (s, 3H), 3.10 (m, 1H), 2.94 (d, 2H, J=4.7), 2.15 (m, 1H), 1.19 (m, 3H).

ESIMS (M-H+) : 512.

Anal. Calcd. for C24H27NsO4S2 1. 0 H2O 1. 2 TFA: C, 46.15% ; H, 4.43% ; N, 10.12% ; S, 9.26%. Found: C, 46.31% ; H, 4.41% ; N, 10.39% ; S, 9.48%.

Example A74 : 4-{4-Amino-5-(2, 6-difluoro-benzoyl)-thiazol-2-ylamino}-N-(1, 2-dimethyl- pyrrolidin-2S-ylmethyl) -benzamide Trifluoroacetic Acid Salt

The starting materials were prepared as follows: Step 1. 2S-Metltyl-pyrrolidifae-1, 2-dicarboxylicAcid 1-tert-ButylEster

To a solution of 2S-methyl-pyrrolidine-2-carboxylic acid hydrobromide (1. 50 g, 11.6 mmol; Bachem) in a mixture of H20 (15 ml) and dioxane (15 ml) was added Et3N (3.6 ml, 26 mmol) and di-tert-butyl dicarbonate (5.57 g, 25.5 mmol). The resultant solution stirred for 5 h, diluted with H2O (50 ml), washed with Et2O (50 ml), acidified to pH 2 with

10% HC1, and extracted with 10% MeOH/CHC13 (2 X 100 ml). The combined organic layers were dried over Na2S04, filtered, and concentrated in vacuo to afford 1.1 g of white powder in 64% yield, which displayed an tH NMR that matched previously reported (Khalil, et al., Tetrahedron Lett., 37,3441-3444 (1996) ) and was used without any further purification.

2S-Carbamoyl-2-methyl-pyrrolidinel-carboxylicAcid tert-ButylEster

To a solution of 2S-methyl-pyrrolidine-1, 2-dicarboxylic acid 1-tert-butyl ester (1.00 g, 6.74 mmol) in CH2C12 (20 ml) was sequentially added 1, 1'-carbonyldiimidazole (1.20 g, 7.42 mmol) and N-hydroxysuccinimide (0.930 g, 8.08 mmol). The resultant solution was stirred for 4 h, concentrated in vacuo, diluted with dioxane, and treated with 58% NH40H (5 ml). After 2 days, diluted with EtOAc (100 ml). The organic layer was washed with H20 (50 ml) and sat. NaHCO3 (50 ml), dried over Na2S04, filtered, and concentrated to afford a white solid in 27% yield, which was used without further purification.

1H NMR (CD30D) : # 3.72-3. 62 (m, 1H), 3. 58-3. 52 (m, 1H), 2.32-2. 23 (m, 1H), 1.60 (s, 3H), 1.53 (s, 9H).

C-(1, 2S-Dimethyl-pyrrolidin-2-yl)-methylami7Ze

Prepared in a manner similar to Step 2 in Example A39 and used without any further purification.

1H NMR (CD30D) : 8 2.78 (s, 2H), 2.50 (s, 3H), 1.25 (s, 3H).

The title compound was prepared in a manner similar to Step 3 in Method A, from 4- [4- amino-5- (2, 6-difluoro-benzoyl)-thiazol-2-ylamino]-benzoic acid (3) and C- (1, 2S-dimethyl- pyrrolidin-2-yl) -methylamine and purified via preparative HPLC.

1H NMR (CD30D) : 5 7.68 (d, 2H, J=8. 7 Hz), 7.45 (dd, 2H, J=1. 9,8. 7 Hz), 6.97 (dd, 2H, J=7.7, 8.1 Hz), 4.00 (d, 0.7H, J=15.1 Hz), 3.48 (d, 1.3H, J=15.2 Hz), 2.98 (s, 2. 1H), 2.68 (s, 0.9H), 1. 54 (s, 0. 8H), 1.40 (s, 2.2H).

LC-MS (M+H+) : 486 ; (M-H-): 484. Anal. Calcd. for C24H2sF2N502S1. 7TFA: C, 48.44% ; H, 3.96% ; N, 10.31% ; S, 4.72%.

Found: C, 48.57% ; H, 4.11% ; N, 10.39% ; S, 4.82%.

Example A75: 4- [4-Amino-5- (2, 6-difluoro-benzoyl)-thiazol-2-ylamino]-N- (l-methyl- azetidin-3-ylmethyl)-benzamide

The starting materials were prepared as follows: Step 1. Azetidine-1, 3-dicarboxylic Acid Mono tert-ButylEster Prepared in a manner analogous to Step 1 in Example A74 for 2S-methyl- pyrrolidine-1, 2-dicarboxylic acid 1-tert-butyl ester, from azetidine-3-carboxylic acid and used without further purification.

1H NMR (CI) 30D) : S 4.18-4. 00 (m, 4H), 3.42-3. 38 (m, 1H), 1. 48 (s, 9H).

Step 2. 3-Carbamoyl-azetidine-1-carboxylic Acid tert-Butyl Ester Prepared in a manner analogous to Step 2 in Example A74 for 2S-carbamoyl-2- methyl-pyrrolidine-1-carboxylic acid tert-butyl ester, from azetidine-1, 3-dicarboxylic acid mono tert-butyl ester and used without further purification.

1H NMR (CD30D) : 8 4.09-3. 92 (m, 4H), 1.45 (s, 9H).

The title compound was prepared from 3-carbamoyl-azetidine-1-carboxylic acid tert-butyl ester after 1) reduction in a manner similar to similar to Step 2 in Example A39 and 2) subsequent coupling with 4- [4-amino-5- (2, 6-difluoro-benzoyl) -thiazol-2-ylamino]-benzoic acid (3) in a manner similar to Step 3 in Method A.

1H NMR (CD30D) : eS 7.82 (d, 2H, J=8. 8 Hz), 7. 74 (d, 2H, J=8.8 Hz), 7.52-7. 42 (m, 1H), 7.06 (dd, 2H, J=7.7, 8.1 Hz), 3.52 (dd, 4H, J=6.8, 12.7 Hz), 3.10 (dd, 2H, J=7.1, 8.1 Hz), 2.84-2. 74 (m, 1H), 2.36 (s, 1H).

LC-MS (M+H+) : 458.

Anal. Calcd. for C22H2lF2N502S1. OH200. 3CHC13 : C, 52. 38% ; H, 4.59% ; N, 13.70% ; S, 6.27%. Found: C, 52.74% ; H, 4.85% ; N, 13.58% ; S, 6.06%.

Example A76: 4- [4-Amino-5- (2, 6-difluoro-benzoyl)-thiazol-2-ylamino]-N- (2-methyl-2- aza-bicyclo [2.2. 1] hept-3-endo-ylmethyl)-benzamide The starting materials were prepared as follows: Step 1. 3-endo-2-(tert-Butoxycarbonyl)-2-azabicyclo[2.2.1]hept-5-ene -3-carboxylic Acid Ethyl Ester.

Prepared in a manner similar to Step 1 in Example A74, from 3-endo-2-azabicyclo- [2. 2.1] hept-5-ene-3-carboxylic acid ethyl ester (Hursthouse, et al, J. Chem. Soc. Perkin Trans. 1, 2419-2425 (1995) ), and used without further purification.

1H NMR (CDC13) : 6 6.58 (bs, 1H), 6.10 (bs, 1H), 4.90 (bs, 1H), 4.32 (bs, 1H), 4.20-4. 08 (q, 2H, J=9.0 Hz), 3. 48 (bs, 1H), 1.45 (s, 9H), 1.25 (t, 3H, J=9.0 Hz).

Step 2. 3-endo-2- (tert-Butoxycarbonyl)-2-azabicyclo [2. 2. IJheptane-3-carboxylic Acid.

According to the conditions described in Hursthouse, et al, J. Chem. Soc. Perkin Trans. 1, 2419-2425 (1995), to a solution of 3-endo-2- (tert-butoxycarbonyl)-2- azabicyclo [2.2. 1] hept-5-ene-3-carboxylic acid ethyl ester (3.74 g, 14.0 mmol) in MeOH (13.8 ml) at 0°C was added 2.5 N NaOH (5.9 ml). Allowed to warm to ambient

temperature. After 2 days, the MeOH was removed under reduced pressure, the concentrate was washed with EtOAc (2 x 20 ml ; discarded), adjusted to pH3 with 10% citric acid, and extracted with EtOAc (2 x 30 ml). The acidic extracts were dried over Na2SO4 and concentrated in vacuo to give 2.04 g of a viscous oil in 61% yield, which was used without any further purification.

'H NMR (CDC13) : 6 6.42 (bs, 2H), 4.88 (bs, 1H), 4.38 (d, 1H, J= 3.0 Hz), 3.62 (bd, 1H), 1.72 (dd, 2H, J=9.0, 9.0 Hz), 1.52 (s, 9H).

Anal. Calcd. for Ci2Hl7N04 : C, 60.24% ; H, 7.16% ; N, 5.85. Found: C, 59.80% ; H, 7.22% ; N, 5.76. <BR> <BR> <P>Step 3. 3-endo-2- (tert-Butoxycarbonyl)-2-azabicyclo [2. 2. 1] heptane-3-carboxylicAcid

According to the conditions carefully defined in Alonso, et al, J. Org. Chenet., 64, 2276-2280 (1999), a mixture of 3-endo-2- (tert-butoxycarbonyl)-2-azabicyclo [2.2. 1] hept-5- ene-3-carboxylic acid (1.00 g, 4.20 mmol) in ethanol (100 ml) and 10% Pd/C (100 mg) stirred under a balloon of hydrogen for 3.5 h at ambient temperature. The catalyst was filtered off and filtrate concentrated in vacuo to give 988 mg of a solid in 99% yield, which was used without any further purification.

1H NMR (CD30D) : 8 4.36-4. 26 (m, 1H), 4.18 (d, 1H, J=3.7 Hz), 2.80 (bs, 1H), 1.84-1. 50 (m, 6H), 1.47 (s, 3H), 1.42 (s, 6H).

Step 4. 3-endo-Carbamoyl-2-aza-bicyclo [2. 2. 1 Jheptane-2-carboxylic Acid tert-Butyl Ester

Prepared in manner analogous to Step 2 in Example A74 for 2S-carbamoyl 2- methyl-pyrrolidine-1-carboxylic acid tert-butyl ester, from 2-aza-bicyclo [2.2. 1] heptane- 2,3-endo-dicarboxylic acid 2-tert-butyl ester. Used without any further purification.

1H NMR (CD30D) : 8 4.38 (bs, 1H), 4.10 (d, 1H, J=3.8 Hz), 2.80 (bs, 1H), 1. 45 (s, 9H).

The title compound was prepared in a manner similar to that of Example A75, originating from 3-endo-carbamoyl-2-aza-bicyclo [2.2. 1] heptane-2-carboxylic acid tert-butyl ester.

1H NMR (CD30D) : 8 7.76 (d, 2H, J=8.5 Hz), 7.54 (d, 2H, J=8.7 Hz), 7.08 (dd, 2H, J=7.6, 8.1 Hz), 2.55 (s, 3H).

LC-MS (M+H+) : 498; (M-H-): 496.

Anal. Calcd. for C25H25F2Ns02S. 1. 3H20. 0. 1CHCl3 : C, 56.57% ; H, 5.24% ; N, 13.14% ; S, 6.02%. Found: C, 56. 97%; H, 5.31% ; N, 13.07% ; S, 5.65%.

Example A77 : 4-{[4-Amino-5-(2, 6-difluorobenzoyl)-1, 3-thiazol-2-yl] amino}-N-{[1- (dimethylamino) cyclopentyl] methyl}benzamide The title compound was prepared in a manner similar to Step 3 in Method A; from coupling 4- [4-amino-5- (2, 6-difluoro-benzoyl)-thiazol-2-ylamino]-benzoic acid (3) and 1- (aminomethyl)- N, N-dimethylcyclopentanamine (Yang et al., Eur. J. Med. Chem. 31,231-239 (1996) ) to afford a yellow amorphous powder in 62% yield.

1H NMR (DMSO-d6): 6 10.71 (bs, 1H), 8.01 (bs, 2H), 7.94 (bs, 1H), 7.79 (d, 2H, J=8.7 Hz), 7.64 (d, 2H, J=8.7 Hz), 7.54 (ddd, 1H, J=6.4, 8.4, 15.1 Hz), 7.20 (t, 2H, J=7. 7 Hz), 3.38 (d, 2H, J=5.8 Hz), 2.26 (s, 6H), 1.57 (bs, 8H).

LCESIMS (M+HF) : 500.15.

Anal. Calcd. for C25H27F2N5O2S#0. 41 H20 : C, 59.23% ; H, 5.53% ; N, 13. 81% ; S, 6.33%.

Found: C, 59.50% ; H, 5.37% ; N, 13.41% ; S, 5.96%.

Example A78: 4-{[4-Amino-5-(2, 6-difluorobenzoyl)-1, 3-thiazol-2-yl] amino}-N-{[1- (dimethylamino) cyclobutyl] methyl} benzamide

The title compound was prepared in a manner similar to Step 3 in Method A; from coupling 4- [4-amino-5- (2, 6-difluoro-benzoyl)-thiazol-2-ylamino]-benzoic acid (3) and 1- (aminomethyl)- N, N-dimethylcyclobutanamine (Yang et al., Eur. J. Med. Chem. 31,231-239 (1996) ) to afford a yellow amorphous powder in 61% yield.

1H NMR (DMSO-d6): # 11.05 (bs, 1H), 8.17 (bs, 1H), 7.73 (s, 3H), 7.82 (d, 2H, J=8.7 Hz), 7.64 (d, 2H, J=8.7 Hz), 7.54 (ddd, 1H, J=6.6, 8.3, 15.1 Hz), 7.20 (t, 2H, J=8.1 Hz), 3.49 (d, 2H, J=6.0 Hz), 2. 19 (s, 6H), 1.85-1. 95 (m, 4H), 1.62 (quintet, 2H, J=7.3 Hz).

LCESIMS (M+H) : 486.20.

Anal. Calcd. for C23H2sF2NsO2S F 0. 3 H20 : C, 58.71% ; H, 5.26% ; N, 14.26% ; S, 6.53%.

Found: C, 58. 99% ; H, 5.41% ; N, 14.20% ; S, 6.49%.

Method B cl. 0 0 0 s 0 Br NH2 \ CI CI, t_Bu0 O I C clA cl t-BuO N NH2 NCS CI r CI 5 Step 1 6 Step 2 0 z I O R. N/N NH2 TFA Ho N NN2 R-NHZ O H py$op CI/CI CI/CI step 4 Step 3 Clto Step 4 i) Step 3

Step 1. 4-Isothiocyanato-benzoic Acid tert-Butyl Ester (0 t-Butyl 4-aminobenzoate (2.39 g, 12.3 mmol ; Fluka) was dissolved in CH2C12 (100 ml), and cooled to 0°C. Thiophosgene (1.87 ml, 24.7 mmol) was added dropwise over 15 minutes. The resultant solution was allowed to warm to room temperature and stirred for 3 hours. The reaction mixture was diluted with CH2C12 (200 ml), washed with saturated aqueous NaHCO3 solution, brine, and dried over MgS04, filtered and concentrated to a syrup. Chromatography on silica (hexane/ethyl acetate =3/1) afforded 2.52 g of desired product as a yellow solid in 86 % yield, which was used without further purification.

IH NMR (CDC13) : 8 7.98 (d, 2H, J=8.8 Hz), 7.22 (d, 2H, J=8.8Hz), 1.60 (s, 9H).

IR (KBr): 2226 cm-1.

Step 2. 4-4-Amino-5- (2, 6-dichlorobenzoyl)-thiazol-2-ylaminoJ-berazoic Acid tert-Butyl Ester (7) The title compound was prepared from 4-isothiocyanato-benzoic acid tert-butyl ester (6) and 2-bromo-2', 6'-dichloro-acetophenone in a manner similar to Step 1 in Method A and used without further purification.

'H NMR (DMSO-d6) : S 11. 18 (bs, 1H), 8. 20 (br, 1H), 7.90 (d, 2H, J=8.8 Hz), 7.72 (d, 2H, J=8.8 Hz), 7.54 (m, 1H), 7.20 (t, 2H, J=8.7 Hz), 1.52 (s, 9H).

Step 3. 4-[4-Amino-5-(2,6-dichloro-benzoyl)-thiazol-2-ylamino]-benzo ic Acid (8) To a solution of 4- [4-amino-5- (2, 6-difluoro-benzoyl)-thiazol-2-ylamino]-benzoic acid tert- butyl ester (7, 1.25 g, 2.9 mmol) in CH2C12 (14 ml), trifluoroacetic acid (6 ml) was added. The reaction solution was stirred for 1 hour. Solvent was evaporated and a solution of resultant residue in ethyl acetate was washed with brine, dried with MgS04, filtered and concentrated to afford 0.98 g of desired product as a light yellow solid in 90% yield, which was used without further purification.

1H NMR (DMSO-d6) : 8 11.18 (bs, 1H), 8.20 (br, 1H), 7.90 (d, 2H, J=8.8 Hz), 7.72 (d, 2H, J=8.8 Hz), 7.54 (m, 1H), 7.20 (t, 2H, J=8.7 Hz).

Step 4. The following Examples B1 to B5 were prepared from 4- [4-amino-5- (2, 6-dichloro- benzoyl)-thiazol-2-ylamino]-benzoic acid (t and corresponding amines (R-NH2) in a manner similar to Step 3 in Method A.

Example Bl : 4- [4-Amino-5- (2, 6-dichloro-benzoyl)-thiazol-2-ylamino]-N-carbamoylmethyl- benzamide.

1H NMR (DMSO-d6) : 811. 02 (s, 1H), 8. 58 (t, 1H, J=5.9 Hz), 8.18 (bs, 2H), 7.88 (d, 2H, J=8. 8 Hz), 7.67 (d, 2H, J=8.8 Hz), 7.58-7. 45 (m, 3H), 7.35 (br, 1H), 7.02 (br, 1H), 3.80 (d, 2H, J=5.9 Hz).

HRFABMS : Calcd for C19H15Cl2N5O3SNa (M+Na+) : 486.0170. Found: 486.0183.

Example B2: 4- [4-Amino-5- (2, 6-dichloro-benzoyl)-thiazol-2-ylamino]-N- (2-hydroxy-ethyl)- benzamide.

'H NMR (DMSO-d6) : 8 11.02 (s, 1H), 8. 35 (t, 1H, J=5.5 Hz), 8.20 (bs, 2H), 7.88 (d, 2H, J=8.7 Hz), 7.67 (d, 2H, J=8. 7 Hz), 7.59-7. 42 (m, 3H), 4.71 (t, 1H, J=5.6 Hz), 3.56-3. 45 (m, 2H), 3.34- 3.25 (m, 2H).

HRFABMS : Calcd for C19H16C12N4O3SNa (M+Na+) : 473.0218. Found: 473.0229.

Example B3: 4- [4-Amino-5- (2, 6-dichloro-benzoyl)-thiazol-2-ylamino]-N- (2, 3-dihydroxy-propyl) - benzamide 1H NMR (DMSO-d6) : 8 10.95 (s, 1H), 8.25 (t, 1H, J=5.5 Hz), 8. 18 (bs, 2H), 7.82 (d, 2H, J=8.7 Hz), 7.58 (d, 2H, J=8.7 Hz), 7.52-7. 38 (m, 3H), 4.78 (d, 1H, J=6.0 Hz), 4.49 (t, 1H, J=6.0 Hz), 3.58 (m, 1H), 3. 39-3. 21 (m, 3H), 3.14 (m, 2H).

HRFABMS : Calcd for C20H18Cl2N4O4SNa (M+Na+) : 503.0324. Found: 503.0336.

Example B4: 4- [4-Amino-5- (2, 6-dichloro-benzoyl)-thiazol-2-ylamino]-N- (2-dimethylamino- ethyl)-benzamide.

'H NMR (DMSO-d6): 6 11. 00 (s, 1H), 8.31 (br, 1H), 8. 18 (bs, 1H), 7.82 (d, 2H, J=8. 8 Hz), 7.65 (d, 2H, J=8. 8 Hz), 7.59-7. 43 (m, 3H), 3.35 (t, 2H, J=6.9 Hz), 2.44 (t, 2H, J=6. 9 Hz), 2.20 (s, 6H).

HRFABMS : Calcd for C2lH2lClzNsOzSNa (M+Na+) : 500.0691. Found: 500.0671.

Example B5 : 4- [4-Amino-5- (2, 6-dichloro-benzoyl)-thiazol-2-ylamino]-N- [2- (2-hydroxy-ethoxy)- ethyl]-benzamide.

1H NMR (DMSO-d6) : 8 11. 20 (s, 1H), 8.60 (br, 1H), 8.35 (bs, 2H), 8.04 (d, 2H, J=8. 8 Hz), 7.85 (d, 2H, J=8.8 Hz), 7.75-7. 64 (m, 3H), 4.79 (t, 1H, J=2.7 Hz), 3.77-3. 57 (m, 8H).

HRFABMS : Calcd for C2lH2lCl2N502SNa (M+Na+) : 517.0480. Found: 517.0488.

Method C F 0 6r CI ci S Cl O HOOC NH2 oh Cl) (CI HOOCuts F tNlStO O NH, NCS H2NCN/DBU F F Step l Step 2 12 v P O Cl o a R NHz PyBop H F H F r Step 3 13. I Step 1. 2-Chloro-4-isothiocyanato-benzoic Acid ( The title compound was prepared from 4-amino-2-chloro-benzoic acid in a manner similar to that of Step 1 in Method B, and used without further purification.

1H NMR (DMSO-d6) : # 7.62 (s, 1H, J=8.4 Hz), 7.47 (d, 1H, J=2.0 Hz), 7.23 (dd, 1H, J=2.0, 8.4 Hz).

Step 2. 4-[4-Amino-5-(2,6-difluorobenzoyl)-thiazol-2-ylamino}-2-chlo ro-benzoic Acid (12) The title compound was prepared from 2-chloro-4-isothiocyanato-benzoic acid (11 and 2- bromo-2', 6'-difluoro-acetophenone in a manner similar to Step 1 in Method A to give a yellow solid in 45% yield.

Step 3. Example Cl : 4- [4-Amino-5- (2, 6-difluoro-benzoyl)-thiazol-2-ylamino]-2-chloro-N- (2- dimethylamino-ethyl)-benzamide.

The title compound was prepared from 4- {4-amino-5- (2, 6-difluoro-benzoyl) -thiazol-2- ylamino}-2-chloro-benzoic acid (12 and N, N-dimethyl-ethylene-diamine in a manner similar to Step 3 in Method A.

IH NMR (CD30D) : 8 7.99 (d, 1H, J=1. 9 Hz), 7.58-7. 43 (m, 3H), 7.06 (t, 2H, J=7.8 Hz), 3.53 (t, 2H, J=6.9 Hz), 2.66 (t, 2H, J=6. 8 Hz), 2.39 (s, 6H).

FABMS (MH+) : 480; (M-H-) : 478.

Method D F 0 O OH S o OH tBr O OH NHZ Ph0 I CIC'PhQ I \ F Ph0 \ NH2 NCS H2NCN/DBU H 14 Step 1 15 Step 2 16 F, I F 0 OH R-NH2, OH R./NHZ ------'N-s-"Y° Step 3 H F, F 17 Step 1. 2-Hydroxy-4-isothiocyanatob-benzoic Acid Phenyl Ester (15) The title compound was prepared from 4-amino-2-hydroxy-benzoic acid phenyl ester (14 in a manner similar to Step 1 in Method B, and used without further purification.

'H NMR (CDC13) : 8 10.64 (s, 1H), 8.04 (s, 1H, J=8. 5Hz), 7.46 (m, 2H), 7.32 (m, 1H), 7.20 (m, 2H), 6.84 (m, 2H).

Step 2. 4-{4-Amino-5-(2, 6-difluoro-benzoyl)-thiazol-2-ylaminod-2-hydroXy-benzoicAcid Phenyl Ester (16) The title compound was prepared from 2-hydroxy-4-isothiocyanato-benzoic acid phenyl ester (15 and 2-bromo-2', 6'-difluoro-acetophenone in a manner similar to Step 1 in Method A, and used without further purification. lH NMR (CD30D) : 8 8.04 (s, 1H, J=8.5 Hz), 7.46 (m, 2H), 7.32 (m, 1H), 7.25 (m, 2H), 7.10 (m, 3H), 6.76 (m, 2H).

Step 3. Example Dl : 4- [4-Amino-5- (2, 6-difluoro-benzoyl)-thiazol-2-ylamino]-2-hydroxy-N- (2- phenylamino-ethyl)-benzamide

A solution of 4- [4-amino-5- (2, 6-difluoro-benzoyl)-thiazol-2-ylamino]-2-hydroxy-benzoic acid phenyl ester (16) and N-phenyl-ethylene-diamine (5 eq) in DMF was heated at 70°C for 1 hour. DMF was removed under reduced pressure and the solution of resultant residue in ethyl acetate was washed with saturated aqueous NaHCO3 solution, brine, dried with MgS04, filtered and concentrated. The product was purified by HPLC.

1H NMR (DMSO-d6) : # 12.94 (s, 1H), 10.99 (s, 1H), 8.81 (br, 1H), 8.22 (bs, 2H), 7. 85 (d, 2H, J=8.8 Hz), 7.57 (m, 1H), 7.31 (s, 1H), 7.21 (t, 2H, J=7.9 Hz), 7.09 (t, 2H, J=7.8 Hz), 6.98 (d, 1H, J=8.5 Hz), 6.62 (d, 2H, J=7.8 Hz), 6.53 (t, 1H, J=3.5 Hz), 5.73 (br, 1H), 3.45 (m, 2H), 3.22 (m, 2H).

HRFABMS : Calcd. For C25H21F2N5O3S (M+H+) : 510.1411. Found : 510.1422.

Example D2: 4- [4-Amino-5- (2, 6-difluoro-benzoyl)-thiazol-2-ylamino]-N- (2-dimethylamino-lRS- methyl-ethyl)-2-hydroxy-benzamide

The title compound was prepared from 4-{4-amino-5-[1-(2, 6-difluoro-phenyl) -methanoyl]- thiazol-2-ylamino}-2-hydroxy-benzoic acid phenyl ester (16) and NINl-dimethyl-propane-1, 2- diamine in a manner similar to Step 3 in Method D for Example D1.

1H NMR (CD30D) : 8 7.77 (d, 1H, J=8.7 Hz), 7.47 (m, 1H), 7.31 (d, 1H, J=2.1 Hz), 7.09 (t, 2H, J=10.9 Hz), 6. 97 (dd, 1H, J=2.1, 8.7 Hz), 4.36 (m, 1H), 2.81 (m, 1H), 2.50 (m, 1H), 2.42 (s, 6H), 1.25 (d, 3H, J=8.7 Hz).

HRFABMS : Calcd. For C25H2lF2N503S (M+H+) : 476.1568. Found: 476.1564.

Method E oQ I ° ° o N----NH, I H2 N NO, Pd/C--N-- ; : aNH, F 0 p 1g Step 19 Step 2 20 F O \ B NH2 N I \ I N'N \ O CI CI N NCS I HzNCN/DBU O H O F/F Step 3 21 Step 4 22

Step 1. 2-(2-Dimethylamino-ethyl)-5-nitro-isoindole-1,3-dione (19) A reaction solution of 4-nitro-phthalic anhydride (18; 0.96g, 5 mmol) and N, N-dimethyl- ethylenediamine (0.5 g, 5.5 mmol) in toluene (50 ml) was refluxed for four hours. The reaction solution was diluted with ethyl acetate and washed with 0.1 N NaOH, brine, dried with MgS04, filtered and concentrated to give 0.7 g of desired product in 53% yield, which was used without further purification.

1H NMR (CDCl3) : 8 8.66 (d, 1H, J=1.6 Hz), 8.58 (dd, 1H, J=1. 6, 6.7 Hz), 8.02 (d, 1H, J=6.7 Hz), 3.88 (t, 2H, J=7.2 Hz), 2.64 (t, 2H, J=7. Z Hz), 2.28 (s, 6H).

Step 2. 5-Amino-2-(2-dimethylamino-ethyl)-isoindole-1, 3-dione (_t A solution of 2- (2-dimethylamino-ethyl)-5-nitro-isoindole-1, 3-dione (19 ; 0.70 g, 2.6 mmol) in methanol (150 ml) and concentrated HC1 (2 ml) was hydrogenated on 10% Pd/C (0.5 g) at 20 psi for 2 hours. The catalyst was filtered off and the filtrate was concentrated to give the desired product as a hydrochloride salt, which was used without further purification.

Step 3. 2-(2-Dimethylamino-ethyl)-5-isothiocyanato-isoindole-1,3-dio ne(21) The title compound was prepared from 5-amino-2- (2-dimethylamino-ethyl)-isoindole-1, 3- dione (IOD in a manner similar to Step 1 in Method B, and used without further purification.

Step 4. This step is carried out in a manner similar to Step 1 in Method A.

Example El : 5- [4-Amino-5- (2, 6-difluoro-benzoyl)-thiazol-2-ylamino]-2- (2-dimethylamino-ethyl)- isoindole-1, 3-dione

The title compound was prepared from 2- (2-dimethylamino-ethyl)-5-isothiocyanato- isoindole-1, 3-dione (21) and 2-bromo-2', 6'-difluoro-acetophenone in a manner similar to Step 1 in Method A. lH NMR (CDC13) : 8 7.86 (s, 1H), 7.68 (q, 2H, J=5.0 Hz), 7.34 (m, 1H), 6.90 (t, 2H, J=8.7 Hz), 3.88 (t, 2H, J=5.2 Hz), 2.64 (t, 2H, J=5.2 Hz), 2.28 (s, 6H).

HRFABMS : Calcd for C23H19F2N5O3S (M+H+) : 472.1255. Found: 472.1244.

Method F F o s O NH \ cya \-eo w NS o I"H t-BO /t-BuONCS FIZNCN/DBU O F/F nu2 0 23 Step 1 o 24 Step2 25 U NH2 /N z N H j !--------'0"FJL. P TFA I I Q FGF PyBop 27 Step 3 26 Step 4 Step 1. 3-Isothiocyanato-benzoic Acid tert-Butyl Ester (2 The title compound was prepared from t-butyl-3-amino-benzoate (23) in a manner similar to Step 1 in Method B, and used without further purification.

1H NMR (DMSO-d6) : 8 8.08 (s, 1H), 7.94 (d, 1H, J=7.7 Hz), 7.60 (d, 1H, J=8.5 Hz), 7.52 (m, 1H), 1.55 (s, 9H).

Step 2. 3-[4-Amino-5-(2,6-difluoro-benzoyl)-thiazol-2-ylamin]}-benzo ic Acid tert-butyl Ester (25) The title compound was prepared from t-butyl-3-isothiocyanato-benzoate (24) and 2- bromo-2', 6'-difluoro-acetophenone in a manner similar to Step 1 in Method A, and used without further purification.

1H NMR (DMSO-d6) : 8 11.02 (s, 1H), 8.15 (br, 2H), 8.08 (s, 1H), 7.94 (d, 1H, J=7.7 Hz), 7.60 (d, 1H, J=8.5 Hz), 7.52 (m, 3H), 7.20 (t, 2H, J=8.7 Hz), 1.55 (s, 9H).

Step 3. 3- (4-Afnino-5- (2, 6-difluoro-benzoyl)-thiazol-2-ylaminoJ-benzoicAcid (26

The title compound was prepared from 3- [4-amino-5- (2, 6-difluoro-benzoyl)-thiazol-2- ylamino] -benzoic acid tert-butyl ester (25) in a manner similar to Step 3 in Method B, and used without further purification.

1H NMR (DMSO-d6) : 8 13.00 (br, 1H), 11.02 (s, 1H), 8. 15 (br, 2H), 8.08 (s, 1H), 7.94 (d, 1H, J=7.7 Hz), 7.60 (d, 1H, J=8. 5 Hz), 7.52 (m, 3H), 7.20 (t, 2H, J=8.7 Hz).

Step 4. This step was carried out in a manner similar to Step 3 in Method A.

Exainple Fl : 3- [4-Amino-5- (2, 6-difluoro-benzoyl)-thiazol-2-ylamino]-N- (2-methylamino-ethyl)- benzamide The title compound was prepared from 3- [4-amino-5- (2, 6-difluoro-benzoyl) -thiazol-2- ylamino] -benzoic acid 26 and N', Nl-dimethyl-ethylenediamine in a manner similar to Step 3 in Method A.

1H NMR (DMSO-d6) : 810. 98 (s, 1H), 8.48 (br, 1H), 8.21 (bs, 2H), 7.92-7. 81 (m, 2H), 7.58-7. 42 (m, 3H), 7.21 (t, 2H, J=7. 9 Hz), 3.43 (m, 2H), 2.65 (m, 2H), 2.38 (s, 6H).

HRFABMS : Calcd for C2lH2iF2NsO2S (M+HF) : 446.1462. Found: 446.1473.

Examples Gl-G396 All compounds from Example Gl to G396, formulae of which are shown in Table 2 below, were combinatorially synthesized by the general method described as Step 3 in Method A from 4- [4-amino-5- (2, 6-difluoro-benzoyl) -thiazol-2-ylamino] -benzoic acid 3 and corresponding amines (R-NH2), except a stock solution of (3) in 5% DIEA/DMF was distributed into 96 deep-well plates such that each well contained 10 umol of material. Then, 10, mol of corresponding amine and 10 umol of HATU [0- (7-azabenzotriazol-1-yl)- N, N, N', N'-tetramethyluronium hexafluoro-phosphate] in DMF were added into individual wells of each plate. The reaction mixture was shaken at room temperature for 16 hours. The reaction solvent was removed and the resultant combinatorial compounds were submitted for bioassays without further purification.

BIOCHEMICAL AND BIOLOGICAL EVALUATION: Cyclin-dependent kinase activity was measured by quantifying the enzyme-catalyzed, time- dependent incorporation of radioactive phosphate from [32P]ATP or [32P]ATP into a protein substrate. Unless noted otherwise, assays were performed in 96-well plates in a total volume of 50 RL, in the presence of 10 mM HEPES (N- [2-hydroxyethyl] piperazine-N'- [2-ethanesulfonic acid] ) (pH 7.4), 10 mM MgCl2, 25 aM adenosine triphosphate (ATP), 1 mg/mL ovalbumin, 5 llg/mL leupeptin, 1 mM dithiothreitol, 10 mM p-glycerophosphate, 0.1 mM sodium vanadate, 1 mM sodium fluoride, 2.5 mM ethylene glycol-bis(ß-aminoethyl ether)-N,N,N'N'-tetraacetic acid (EGTA), 2% (v/v) dimethylsulfoxide, and 0.03 - 0.4 µCi [32/33A]ATP per reaction. Reactions were initiated with enzyme, incubated at 30°C, and terminated after 20 minutes by the addition of ethylenediaminetetraacetic acid (EDTA) to 250 mM. The phosphorylated substrate was then captured on a nitrocellulose or phosphocellulose membrane using a 96-well filtration manifold, and unincorporated radioactivity was removed by repeated washing with 0.85% phosphoric acid.

Radioactivity was quantified by exposing the dried membranes to a phosphorimager.

Compounds from combinatorial libraries were screened from 96-well plates for % inhibition of CDK activity at 30 nM theoretical compound concentration. Inhibition was measured relative to control wells that contained all reaction components including 2% (v/v) DMSO but no compound, after subtraction of background radioactivity measured in the absence of enzyme.

Apparent Ki values of discrete compounds were measured by assaying enzyme activity in the presence of different inhibitor compound concentrations and subtracting the background radioactivity measured in the absence of enzyme. The kinetic parameters (kcat, Km for ATP) were measured for each enzyme under the usual assay conditions by determining the dependence of initial rates on ATP concentration. Inhibition data were fit to an equation for competitive inhibition using Kaleidagraph (Synergy Software), or were fit to an equation for competitive tight- binding inhibition using the software KineTic (BioKin, Ltd.).

Inhibition of CDK4/Cyclin D Retinoblastoma Kinase Activity : A complex of human CDK4 and genetically truncated (1-264) cyclin D3 was purified using traditional biochemical chromatographic techniques from insect cells that had been co-infected with the corresponding baculovirus expression vectors (see e. g. , Meijer and Kim,"Chemical Inhibitors of Cyclin-Depe7çdent Kinases,"Methods in Enzymol., 283 (1997), pp. 113-128. ). The enzyme complex (5 nM) was assayed with 0.3-0. 5 llg of purified recombinant retinoblastoma protein fragment (Rb) as a substrate. The engineered Rb fragment (residues 386-928 of the native retinoblastoma protein; 62.3 kDa) contains the majority of the phosphorylation sites found in the

native 106-kDa protein, as well as a tag of six histidine residues for ease of purification.

Phosphorylated Rb substrate was captured by microfiltration on a nitrocellulose membrane and quantified using a phosphorimager as described above. For measurement of tight-binding inhibitors, the assay duration was extended to 60 minutes, during which the time-dependence of product formation was linear and initial rate conditions were met. Ki values were measured as described above and shown in Table 1. Percent inhibition was calculated as described above and shown in Table 2.

Inhibition of CDK2/Cyclin A Retinoblastoma Kinase Activity : CDK2 was purified using published methodology (Rosenblatt et al.,"Purificatio7 and Crystallization ofHurnan Cycliya-dependeratKinase 2, "J. Mol. Biol. , 230, 1993, pp. 1317-1319) from insect cells that had been infected with a baculovirus expression vector. Cyclin A was purified from E. coli cells expressing full-length recombinant cyclin A, and a truncated cyclin A construct was generated by limited proteolysis and purified as described previously (Jeffrey et al., "Mechanism of CDKActivation Revealed by the Structure of a Cyclin A-CDK2 Complex,"Nature, 376 (1995), pp. 313-320). A complex of CDK2 and proteolyzed cyclin A was prepared and purified by gel filtration. The substrate for this assay was the same Rb substrate fragment used for the CDK4 assays, and the methodology of the CDK2/delta cyclin A and the CDK4/delta cyclin D3 assays was essentially the same, except that CDK2 was present at 10 nM or 19 nM. The duration of the assay was 60 or 75 minutes, during which the time-dependence of product formation was linear and initial rate conditions were met. Ki values were measured as described above and shown in Table 1. And, the percent inhibition was calculated as described above and shown in Table 2.

Inhibition ofCDKl (cdc2)/Cyclin B Histone Hl Kinase Activity : The complex of human CDK1 (cdc2) and cyclin B was purchased from New England Biolabs (Beverly, MA). Alternatively, a CDKl/glutathione-S-transferase-cyclin B1 complex was purified using glutathione affinity chromatography from insect cells that had been co-infected with the corresponding baculovirus expression vectors. The assay was executed as described above at 30°C using 2.5 units of cdc2/cyclin B, 10 llg Histone Hl protein, and 0.1-0. 3 pCi [32/33pATP per assay. Phosphorylated histone substrate was captured by microfiltration on a phosphocellulose P81 membrane and quantified using a phosphorimager as described above. Ki values were measured using the described curve-fitting programs. The results are shown in Table 3.

Inhibition of phosphorvlated FGF receptor and LCK Tyrosine Kinase Activity : Cloning, expression and purification of the cytosolic domain of FGFRl tyrosine kinase (amino acids 456-766) containing three amino acid substitutions (L457V, C488A, and C584S) were conducted as previously described (Mohammadi, M. , Schlessinger, J. , & Hubbard, S. R. Cell, 86, (1996) 577-587). This domain was expressed in Sf9 insect cells using a baculovirus expression vector, and protein was purified using conventional techniques. The LCK tyrosine kinase was expressed in insect cells as an N-terminal deletion starting from amino acid 223 to the end of the protein at amino acid 509. The N-terminus of the protein also had two amino acid substitutions, P223M and C 224D. Kinases were purified using conventional chromatographic methods.

Tyrosine kinase activity was measured using a coupled, continuous spectrophotometric assay, in which production of phosphorylated poly (Glu, Tyr; 4: 1) substrate and ADP is coupled to the pyruvate kinase-catalyzed transfer of a phosphate from phosphoenolpyruvate to ADP, with generation of pyruvate and regeneration of ATP. Pyruvate production is in turn coupled to the lactate dehydrogenase-catalyzed reduction of pyruvate to form lactate, with concomitant conversion of NADH to NAD+. Loss of NADH is monitored by measuring absorbance at 340 nm (see e. g. , Technikova-Dobrova et al.,"Spectrophotometric Determination of Functional Characteristics of Protein Kinases with Coupled Enzymatic Assay,"FEBS Letters, 292 (1991), pp.

69-72). Enzyme activity was measured in the presence of 200 mM HEPES (pH 7.5), 2 mM phosphoenolpyruvate, 0. 3 mM NADH, 20 mM MgCl2, 100 ßM ATP, 5 mM DTT, 5.1 or 25 mM poly (Glu, Tyr) 4: 1 for P-FGF or P-LCK assays, respectively, and 15 units/mL each of pyruvate kinase and lactate dehydrogenase. Phosphorylated FGF receptor kinase was present at 100 nM and phosphorylated LCK kinase was present at 50 nM. Assays were performed under initial rate conditions at 37°C, and rates were corrected for any background rate measured in the absence of enzyme. Percent inhibition was calculated relative to control enzyme assayed in the presence of 2% (v/v) DMSO. The results are shown in Table 1.

Inhibition of Cell Growth: Assessment ofCvtotoxicity : Inhibition of cell growth was measured using the tetrazolium salt assay, which is based on the ability of viable cells to reduce 3- (4, 5-dimethylthiazol-2-yl) -2, 5- [2H]-diphenyltetrazolium bromide (MTT) to formazan (Mossman, Journal of Immunological Methods, 65, (1983), pp. 55- 58). The water-insoluble purple formazan product was then detected spectrophotometrically. The HCT-116 cell line was used as a representative cancer cell line and grown in 96-well plates. Cells were plated in McCoy's 5A Medium at a volume of 135 Ill/well. Plates were incubated for four hours before addition of inhibitor compounds. Different concentrations of inhibitor compounds were added in 0.5% (v/v) dimethylsulfoxide (15 uL/well), and cells were incubated at 37°C (5%

CO2) for three to five days. At the end of the incubation, MTT was added to a final concentration of 0.2 mg/mL, and cells were incubated for 4 hours more at 37°C. After centrifugation of the plates and removal of medium, the absorbance of the formazan (solubilized in dimethylsulfoxide) was measured at 540 nm. The concentration of inhibitor compound causing 50% (IC5o) or 90% (IC9o) inhibition of growth was determined from the linear portion of a semi-log plot of inhibitor concentration versus percent inhibition. All results were compared to control cells treated only with 0.5% (v/v) dimethylsulfoxide. The ICso and IC90 of the A-F compounds are shown in Table 1. Percent inhibitions at 0.25 uM or 0. 1 uM of G compounds were calculated and shown in Table 2.

For the compounds shown in Tables 1 and 2, the group of-N (H)- and methyl (-CH3) of the formulae are sometimes shown as"-N-"and"-"for the simplicity, respectively, and the compounds in the form of salts are shown in their free base forms. For both Tables 1 and 2,"NT" indicates not tested. In Table 2, the""refers to the point of attachment of the Formula (I) attached to the group R.

Table 1 T-JfT CDK2 CDK4 HCT-116, ' P-FGF P-LCK 116 Example STRUCTURE Ki Ki IC50 IC90 % % Inhibition Inhibition Inhibition Inhibition M M M at 1 at 1 M Al N 0. 14 0. 027 0. 75 1. 5 NT NT A2 C N4 0. 0032 0. 008 0. 14 0. 61 8 4 F/1 S 1' 4 1N A3 CHiNAt 0. 17 0. 021 0. 75 2. 1 7 5 I He N A4"^ C 0. 23 0. 016 0. 19 0. 23 NT NT r n fa A5 Nti 0. 072 0. 066 1. 2 3. 1 5 3 F \, A6 0. 0075 0. 015 0. 22 0. 6 NT NT . _. YY A7 « eN4t 0 061 0. 026 0. 41 NT NT \ AS 0. 054 0. 005 0. 74 1. 7 NT NT A9 0. 027 0. 012 0. 14 0. 4 5 5 , CDK2 CDK4 HCT HCT P-FGF P-LCK 116 Example STRUCTURE Ki Ki IC50 IC90 Inhibition Inhibition M M at 1 M at 1 t A10 0. 29 0. 049 1. 6 3. 5 NT NT C. T N All 0. 082 0. 014 0. 17 0. 31 9 6 All'ji A12 0. 091 0. 02 0. 13 0. 28 NT NT H, c H, c Ct fTfl A13 tN<t, 0. 079 0. 009 0. 21 0. 43 NT NT F F HO \ I A14 NA \$ 0. 06 0. 014 0. 042 0. 11 0 0 \ n y ( A15 0. 15 0. 007 0. 09 0. 2 0 0 F NC F e I A16 X 0. 068 0. 025 0. 17 0. 3 NT NT A16 A17 tNX \t 0. 051 0. 026 0. 1 0. 21 0 0 fui hICN NFIa A18 \-0. 19 0. 006 0. 92 2. 1 NT NT ; nu '-) j, Fuzz A20 aNt $ 0. 162 0. 032 0. 076 0. 18 0 0 CDK2 CDK4 HCT-116 HCT-P-FGF P-LCK 116 Example STRUCTURE Ki Ki IC50 IC90 % Inhibition Inhibition Inhibition Inhibition M M M at 1 M at 1 A21 0. 105 0. 105 0. 1 0. 21 0 0 '%- qj ! A22 0. 006 0. 005 0. 17 0. 42 NT NT A23 4 Nt Nt 0. 13 0. 008 0. 1 0. 21 NT NT mi, A24 X R1S 0. 1 0. 094 0. 16 0. 24 NT NT ' A25 0. 062 0. 013 0. 094 0. 21 0 0. r. A26 NAt O. 0 79 0. 02 0. 17 0. 38 NT NT A27 0. 066 0. 041 NT NT NT NT F/ N \ O A28 0. 025 0. 076 0. 06 0. 17 0 0 zu M) 9 ! M J) Jtn, A29 N 0. 052 0. 026 0. 22 0. 53 NT NT NU, F NHi A30 0. 069 0. 007 0. 09 0. 23 NT NT F q ; P A31 0. 049 0. 007 0. 03 0. 07 0 0 A31, F TJT' CDK2 CDK4 HCT-1 l6 HCT P-FGF P-LCK 116 Example STRUCTURE Ki Ki IC50 IC90 % % Inhibition Inhibition Inhibition Inhibition N, M M M at 1 at 1 A32 H, c-NO N<N 0. 077 0. 006 0. 28 0. 68 NT NT F i Hz A33 0. 091 0. 01 2. 2 4. 8 NT NT F, H O 0. 099 0. 01 0. 14 0. 29 NT NT F L., o A35 CNNt X 0. 054 0. 006 0. 12 0. 26 NT NT Clt A36'"1Cj- (/ 0. 223 0. 044 0. 78 1. 3 NT NT Ton I" \ O A37 0. 111 0. 053 0. 3 0. 73 NT NT A38 0. 14 0. 024 0. 1 0. 23 NT NT H, C A39 NAt 0. 16 0. 011 0. 17 0. 36 NT NT if 'lof H A40 0. 094 0. 009 0. 04 0. 085 NT NT Ike j. AX w 0. 23 0. 035 0. 18 0. 31 NT NT HI A42 0. 165 0. 023 0. 15 0. 37 NT NT TTT CDK2 CDK4 HCT-116 HCT-P-FGF P-LCK Example STRUCTURE Ki Ki IC50 IC90 % % Inhibition Inhibition E. M M at 1 M at 1 A43, cl 0. 109 0. 013 0. 58 1. 9 NT NT HnH Nie A44 C XNAX 0. 12 0. 01 0. 13 0. 31 NT NT <QJL. A45 NA5A0 0. 048 0. 007 0. 086 0. 21 NT NT F F \ 1 N Hx A46 Nt F 0. 22 0. 015 0. 086 0. 21 NT NT Yl A47 0. 055 0. 005 0. 58 1. 4 NT NT Fez N N A48 9 NA5A0 0. 055 0. 005 0. 58 1. 4 NT NT F v S N A49 nit 0. 26 0. 011 0. 32 0. 63 NT NT F J N A 50 % t N v X 0. 02 0. 015 0. 17 0. 3 NT NT N S i A51 0. 11 0. 007 0. 09 0. 22 NT NT a A52 0. 17 0. 009 0. 13 0. 27 NT NT TT/*'qr CDK2 CDK4 HCT-116, ' P-FGF P-LCK 116 Example STRUCTURE 1 Ii IC50 IC90 % % Inhibition Inhibition Inhibition Inhibition (iM jiM) JLM) J. M atljiM atlM M M M at 1 M at 1 M N 0. 12 0. 004 0. 15 0. 3 NT NT A53 N NON N A54 H3 N S F 0. 052 0. 009 0. 6 1. 9 NT NT F/\. A55 zu NT NU O A56 nul 0. 067 0. 008 4. 5 >5 NT NT H A % A57 JUNIF 0. 054 0. 01 3. 8 >5 NT NT F v I H. O A58 3. 4 1 NT NT NT NT H2 \ 0 0. 097 2. 9 >5 NT NT N A60 C / NHx 0. 091 0. 031 0. 2 0. 5 NT NT -0 NH2 H3-H3Ci 3°/° A61 s 2 W HN 0. 0375 0. 232 0. 22 0. 52 NT NT 2 CI Nez NUI A62 ScHNt 0. 0028 0. 120 0. 044 0. 11 NT NT H H v H H TTT' CDK2 CDK4 HCT-116 HCT-P-FGF P-LCK 1 1 116 Example STRUCTURE Ki Ki IC50 IC90 % % Inhibition Inhibition Inhibition Inhibition go zum uM atl M atl M O Hz A63 0. 0153 0. 018 1. 6 3. 8 NT NT Ho Hic H2 A64 N D HA 0. 019 0. 022 >5 >5 NT NT ex NHZ A65 AH) 4N t 0 16 0. 057 >0. 5 >0. 5 NT NT o Hz A66 N N ° F 0. 018 0. 35 0. 12 0. 23 NT NT N S "\=/ H NU 0 A67 N F 0. 013 0. 088 0. 077 0. 17 NT NT C"s Q BOF H A68 « N 0. 00 85 0. 045 0. 075 0. 19 NT NT N"'" ( Nez o N F 0. 0146 0. 234 2. 1 4. 8 NT NT C' % 0 : D NNz A70 N0 NNH, 0. 0061 0. 128 0. 023 0. 051 NT NT CH3 H H3C/ NHZ A71 ¢CHt) > 0. 0056 0. 082 0. 034 0. 075 NT NT Oui A72 NH 0% 9 0% 9 >0. 5 >0. 5 NT NT 0 NH, A73 1. 2 36 >5 >5 NT NT J ! S. o H t-rT CDK2 CDK4 HCT-116 HCT-P-FGF P-LCK 116 Example STRUCTURE Ki Ki IC50 IC90 % % Inhibition Inhibition pu uM ELM at 1 Zum at 1 b Hz A74 mu 0. 0098 0. 38 1. 9 4. 1 NT NT CH H i H 1 NS V'CHa H p NHz A75 0 NH 073 0. 051 1. 9 5 NT NT / . N H H F I HIC NH A76 ICH30 N 0 0. 015 0. 12 1. 1 2. 3 NT NT N --s H"N F A//H3 NH2 0 A77 HDC_d_N% N, AF 0. 084 0. 0052 0. 12 0. 22 NT NT \ N F dz A78 PH3 0. 11 0. 0082 0. 13 0. 28 NT NT a HC-N N) Bl N"N I//g O CI Bu 0 0. 065 0. 017 18 25 NT NT a \ HoN NFii B2 ° 0. 096 0. 018 3. 6 8. 3 NT NT a HO N \ OH I/N/ 0 B3 0. 066 0. 008 18 25 NT NT f" vCnNN I \ O B4 N a s a 0. 22 0. 008 0. 52 1. 3 NT NT HON \ o B5 Nat 0. 15 0. 059 NT NT NT NT J1 T CDK2 CDK4 HCT-116, ' P-FOF P-LCK 116 Example STRUCTURE Ki Ki IC50 IC90 % % Inhibition Inhibition Inhibition Inhibition M M at 1 M at 1 tint SCiNN \ N O C'"pl)- 0-17 0. 027 0. 21 0. 52 NT NT I \ \ O 0. 0094 0. 017 1 3. 7 NT NT Fizz /N N/I/' O D2 0. 051 0. 025 0. 58 1. 7 NT NT i W o E 'c N p p 0. 4 0. 24 #N/A #N/A NT NT' H, FiaC tJ I ^ \ Fi O F ""SF V F 0. 27 0. 14 1. 8 3. 8 NT NT

Table 2 CDK2 CDK4 HCT-116 HCT-116 Ex. R % Inhibition % Inhibition % Inhibition % Inhibition at 0. 03 at 0. 03 at 0. 25 . M at 0. 1 Glu k-3-10 56 NT CANA G2 - 9 8 51 NT Hz HgC" G3 - 1 4 50 NT G4 HIC - 7 4 53 NT OH Gus - -23-3 47 NT . G6 o .-1 10 47 NT NH G7 4 5 80 NT CDK2 CDK4 HCT-116 HCT-116 Ex. R Inhibition % Inhibition % Inhibition % Inhibition at 0. 03 at 0. 03 at 0. 25 at 0. 1 G8 &-1-5 50 NT I G9 H c -' - 1 2 46 NT G10 - 4-2 51 NT oh Gill - 12 6 49 NT CH, CHa G12 HO NC-14 10 48 NT Ho Y G13-16 0 44 NT 0'CH G14 OH 9 26 50 NT G15 I--12 4 46 NT CHEZ G16-7 1 50 NT \ G17 H3. 2 7 45 nit OH G18 0 - 10 4 41 NT CH G19 4 41 NT Te-7 4 43 NT kH3 CDK2 CDK4 HCT-116 HCT-116 Ex. R % Inhibition % Inhibition % Inhibition % Inhibition at 0. 03 M at 0. 03 M at 0. 25 at 0. 1 . M G20 10 9 50 NT kN CH3 </ G21 hic 3 14 46 NT SH2 G22 XX 2-3 50 NT zip F I G23 8 7 63 NT H, C G24 7 11 58 NT H, C G25-16 10 52 NT OH OH G26 s J 3 13 53 NT G27 H. C bu2-6 4 60 NT CH, HaC s G28 < 19 66 NT G29 HC 4 32 55 NT H3C N G30 s 5 5 82 NT , +- CDK2 CDK4 HCT-116 HCT-116 Ex. R % Inhibition % Inhibition % Inhibition % Inhibition at 0. 03 pM at 0. 03 M at 0. 25 at 0. 1 KIT G31 ly 4 4 75 NT G32 G32 1, 8 27 55 NT G33 G33 \-3 10 54 NT G34 p 8 9 53 NT \o G35 HC,, N 5 8 53 NT CH G36 - 4 6 62 NT O ^'3 H. C\ G37 iN""' 11 25 65 NT G38 ci G38" 3 7 65 NT H, C G39 i'-4-1 65 NT G40 4 18 61 NT G41 0 11 10 50 NT G42 0 G42 0 10 7 54 NT 3 CDK2 CDK4 HCT-116 HCT-116 Ex. R % Inhibition % Inhibition % Inhibition % Inhibition at0. 03 at0. 03 at0. 25 atO. I M G43 H2N) (C S 12 62 NT 0 H, C I H3C/I G44 8 14 72 NT I G45 O\CH3 16 16 89 NT f G46 X 4 11 58 NT /\Nz G47 \ X-15 6 53 NT G48 1 3 50 NT G49 HO/ IN" G49 HO 7 4 57 NT o, G50 9 10 61 NT ° 3 Ns G51 6XH 9-1 89 NT .- G52 0S° 10 5 65 NT O G53 d-17 6 89 NT . G54 HC-0 8 9 86 NT CDK2 CDK4 HCT-116 HCT-116 Ex. R % Inhibition % Inhibition % Inhibition % Inhibition at 0. 03 M at 0. 03 M at 0. 25 at 0. 1 M G55 HO < 22 16 57 NT G56 G56 HO 24 10 59 NT HO G57 cr 3 H C SN s, 17 19 51 NT CH3, Hz G58 19 17 53 NT H, C/I G59 ! L 25 3 53 NT G60 II. 12 18 66 NT G61 i 19 19 58 NT G62 7 22 50 NT 0 G63 HO 4 7 54 NT Ho H3Clli 5 17 57 NT G64 CH3 3 G65 ^,,. IJ HaC N 12 17 58 NT o 0 O l/ G66 CH3 < 26 14 60 NT CH3 CDK2 CDK4 HCT-116 HCT-116 Ex. R % Inhibition % Inhibition % Inhibition % Inhibition at 0. 03 M at 0. 03 M at 0. 25 at 0. 1 M G68 F 25 12 82 NT G68 6 3 59 NT F G69 7 3 70 nit G70 G70 - 4 10 53 NT I H G71 3 16 59 NT if G72 2 12 54 NT CHEZ G73 19 18 56 NT CH, 0 G74 Ha/ !)] 23 18 78 NT G75 G75 G76 ß 21 15 64 NT Mu G76a G76 7 7 61 NT G77 G77 H, C 9 6 51 NT ° G78 r i 11 13 58 NT CDK2 CDK4 HCT-116 HCT-116 Ex. R % Inhibition % Inhibition % Inhibition % Inhibition at 0. 03 at 0. 03 M at 0. 25 M at 0. 1 G79' 2 10 51 NT i G80 3 7 36 NT CHg G81 e 15 19 58 NT N G82 O pH2 24 15 48 NT Gaz N 16 7 64 NT ci G84 9 3 63 NT G85 G85 7 6 56 NT y G86. a-3 10 0 73 39 H3C'o G87-40 13 78 54 Ctt G88 ¢4-23 6 49 24 CH G89 H3C\H\N-20-4 59 30 CH3 G90-30 2 54 24 Hz CDK2 CDK4 HCT-116 HCT-116 Ex. R % Inhibition % Inhibition % Inhibition % Inhibition at 0. 03 M at 0. 03 M at 0. 25 M at 0. 1 G91 19 9 68 34 G92 H3C of z H3C ACH3-7 10 98 85 C G93 IH3-4 11 58 26 G94 N G94 H3 HO 10 4 80 38 . G95 i 12 18 63 32 G96 CH3 CN- H3C-N G97 H3C 1J ! 2 11 56 28 CH3 G98 H3C \) 1-24 11 60 22 CH3 I G99 H3CzN/+N-16 23 62 24 G100 y 13 22 89 27 N _ G101 ßa 11 19 46 10 H 0 H3C H3 G102 Ho-3 is 55 18 CDK2 CDK4 HCT-116 HCT-116 Ex. R % Inhibition % Inhibition % Inhibition % Inhibition at 0. 03 at 0. 03 at 0. 25 at 0. 1 CH Gt03 H3C'° aN'-2 5 59 21 3 HO G104 8 14 91 38 Y G105 3 9 67 24 GI06 7 7 61 0 CHIA CH3 G107 H3CHw'-5 12 59 5 HC"N . Gros-5 12 60 0 H, C CH, G109 CH3 6 22 54 0 HO\ In HA Hic CH3 H3C G111 t, 15 20 52 0 Cl, '3 - 11 13 57 6 G112o HIC ,/ G113 51 43 80 26 G114 H, C--'O 3 11 48 0 CDK2 CDK4 HCT-116 HCT-116 Ex. R % Inhibition % Inhibition % Inhibition % Inhibition at 0. 03 M at 0. 03 M at 0. 25 M at 0. 1 M G115 O ; t 27 24 88 30 0 G116 7 24 46 0 G117 jazz 13 55 6 o' H. C G118 11 21 48 5 H3C V J G119 CHa 11 31 64 0 CL, G120 zu IS 14 23 54 0 o G121 S9N'13 20 55 0 o 0 o fHv G122 OC l5 15 59 0 G123 zu - 5 12 50 4 G124 10 17 64 0 G125 CH3 CH3 3 9 59 13 G126 H3C, f N/3 7 53 O H3C G126 Hic 3 7 53 0 CH CDK2 CDK4 HCT-116 HCT-116 Ex. R % Inhibition % Inhibition % Inhibition % Inhibition at 0. 03 at 0. 03 at 0. 25 at 0. 1 M H, C'-'-"-'N G127 L 10 29 61 0 G128 C 15 41 78 23 G129 0 H3C,, 0 / YYI G130 0 1 11 77 0 G131 6 16 58 0 G132 G132 F 1'9 27 52 0 0 3 G133 <-6 13 47 0 i G134 60 38 89 1 G135 CIH3 2 25 56 0 H3C G136 - 4 12 49 0 G137 2 25 59 0 0 O G138 7 17 65 0 CDK2 CDK4 HCT-116 HCT-116 Ex. R % Inhibition % Inhibition % Inhibition % Inhibition at 0. 03 pM at 0. 03 at 0. 25 M at 0. 1 M G139 6 17 56 0 G140 G140, 15 19 54 0 G141 CjHs JL JL 0 11 50 0 Hic G142 11 20 46 0 CH 3 G143 2 27 65 0 G144 0 11 57 0 G145 H, C 10""N 19 18 68 0 0 G146 % 6 7 52 1 G147 10 35 65 0 CH, G148 CH3 3 5 14 48 0 G149 iH3 H, C N 23 36 82 10 3 G150 H3 H, NaN 15 25 57 0 \)- CDK2 CDK4 HCT-116 HCT-116 Ex. R % Inhibition % Inhibition % Inhibition % Inhibition at 0. 03 M at 0. 03 at 0. 25 M at 0. 1 M G151 a 16 7 94 27 HAC H, C s G152 Ho 16 7 53 5 G153 G153 0 18 15 66 0 J) N G154 10 34 91 17 G155 G155 32 38 67 0 . HO, G156 N3 HO 24 24 61 0 ho G157 aH3 18 30 87 0 HaC "N i G158 e o\N 22 40 73 0 CHs G159 HC'o 6 5 74 0 Oh Gaz if 24 6 87 0 Ho G161 13 7 57 0 H ; C sN So sH3 H, G162 25 20 84 3 i CDK2 CDK4 HCT-116 HCT-116 Ex. R % Inhibition % Inhibition % Inhibition % Inhibition at 0. 03 M at 0. 03 M at 0. 25 at 0. 1 CH G163 Hic 16 21 67 0 "3-"' G164 H3C'N'13 19 59 O 3 G165 H3CSDN'.'22 61 O G166 22 4 90 8 G167 CH G167 cH3 C tN 19 29 53 26 i HsC "N i G168 CH3 4 17 52 25 CHg G169 H3C 38 49 71 32 b G170 26 32 78 44 G171 4 16 47 30 Ho G172. 36 54 61 37 tO _ G173 14 21 54 18 G174 1 0 15 56 28 OH CDK2 CDK4 HCT-116 HCT-116 Ex. R % Inhibition % Inhibition % Inhibition % Inhibition at0. 03 at0. 03 M at0. 25 M at0. 1 M Gaz CHs HO 15 31 47 11 G176 22 21 62 32 r G177 <~, 10 23 45 24 N G178 mN/20 54 83 43 N4' G179-5 10 42 21 0 G180 22 29 68 25 G181 30 36 75 28 113C'N G182 iXzHa-2 6 52 23 Il wCH3 H3 G183 23 38 48 11 Ho G184 34 36 58 17 1 G185 7 20 49 10 G186 G186 HaC 4 7 30 51 14 3 CDK2 CDK4 HCT-116 HCT-116 Ex. R % Inhibition % Inhibition % Inhibition % Inhibition at 0. 03 M at 0. 03 at 0. 25 M at 0. 1 G187 - 2 12 48 16 G188 29 39 51 17 G189 10 18 56 13 G190 5 4 55 9 ONH, G191 14 15 51 3 H3C CH3 G192 H, c"N 8 23 49 13 o G193 19 26 56 17 G194 1 19 49 20 G195 ! L 20 26 47 17 G196 ci G196 c. 7 13 48 13 Cri H 14 9 61 26 G197 G198 O ho 19 42 44 9 HO CDK2 CDK4 HCT-116 HCT-116 Ex. R % Inhibition % Inhibition % Inhibition % Inhibition at 0. 03 M at 0. 03 at 0. 25 M at 0. 1 M G199 o °V\ 18 22 52 12 o HaC // i G200 15 23 50 19 G201 oN 26 43 Zip G202 5 25 48 20 HO G203 Q 7 20 53 18 G204 H, c 6 10 49 19 H3r'/ G205 I 1 7 52 12 G206 13 19 58 13 F G207 15 15 66 15 Jn F r G208 F 36 36 56 11 F H3C/ G209 lr 9 16 50 9 jY G210 13 20 45 15 zu CDK2 CDK4 HCT-116 HCT-116 Ex. R % Inhibition % Inhibition % Inhibition % Inhibition at0. 03 at0. 03 at0. 25 at0. 1 M G211 ci 23 23 45 13 . a ! N G212 H3C sb <, 16 20 53 17 G213o uN-1 9 49 16 N G214 11 16 52 15 H, C 10 G215 HC 18 27 73 22 I, G216 cl 29 36 54 16 i G217 17 34 51 8 G218 CH3 8 19 52 11 3 G219 H2C wN'10 13 52 8 zu G220 ° ! fl 10 12 54 18 Heb s F G221 9 29 34 74 20 HO, G222 30 27 61 8 CDK2 CDK4 HCT-116 HCT-116 Ex. R % Inhibition % Inhibition % Inhibition % Inhibition at 0. 03 at 0. 03 at 0. 25 at 0. 1 M G223 ho a 14 19 50 14 CHEZ G224° HC--'N 16 28 53 10 . Ha G225 Hou i t CH3 36 41 51 0 G226 H H, C 48 44 56 15 G227 28 17 84 17 N G228 cll 38 36 75 24 G229 0 G229 N4o ' G230 F X aq 8 20 52 19 F G231 15 30 55 6 0 0ICN' G232 iH3 9 19 53 9 CHg G233 10 21 48 16 OH G234 Hp 10 G234 35 39 63 20 ou 3 CDK2 CDK4 HCT-116 HCT-116 Ex. R % Inhibition % Inhibition % Inhibition % Inhibition at 0. 03 M at 0. 03 M at 0. 25 M at 0. 1 G235 i 14 14 51 10 G236 jfj"39 36 66 16 G237/9 12 49 20 Foc Y) G238 H3coo N IS 26 58 22 G239 3 H3 H3C wN AN'15 27 50 21 G240 11 27 52 15 N3 bu G241 H, C 22 29 57 28 H, C o G242 o 43 49 69 34 0 0 G243 18 11 40 31 H G244 35 27 67 30 G245 (J 36 34 55 18 G246 G246 32 35 62 20 / CDK2 CDK4 HCT-116 HCT-116 Ex. R % Inhibition % Inhibition % Inhibition % Inhibition at 0. 03 at 0. 03 at 0. 25 at 0. 1 M CH3 G247 H3C 41 17 23 54 12 3 G248 Hp 8 17 55 13 CH, G249 39 40 80 37 G250 39 39 72 31 Hic G251 HC 10 11 48 16 G252 F G252 F 29 31 67 33 / G253 G253 16 26 62 19 HIC G254 H, C o 28 20 75 35 CHEZ CH, G255 H3C'S/ H, ! j !-25 0 63 25 G256 HO-12 11 49 19 G257 4C-43 2 51 33 HO G258 25 20 84 41 ci' CDK2 CDK4 HCT-116 HCT-116 Ex. R % Inhibition % Inhibition % Inhibition % Inhibition at0. 03 at0. 03 at0. 25 M at0. 1 M H, C cl G259 <-30-20 46 21 G260-27 1 59 30 Nez G261 F 30 27 69 26 F F G262 HP 10 1 28 59 24 ou G263 hic G263 H3c 2 24 54 26 6H, OH G264 HO-9 13 53 22 G265 4'-24 1 48 21 G266 ci 0 7 30 28 14ph G267 Hop-23-14 44 24 G268 NI, -11 2 63 26 G269 F 6 2 65 19 I G270 H3C XC 26 17 45 15 CH, CDK2 CDK4 HCT-116 HCT-116 Ex. R % Inhibition % Inhibition % Inhibition % Inhibition at 0. 03 at 0. 03 M at 0. 25 M at 0. 1 G271 32 27 49 8 0 HzC, G272-20 0 47 10 CH, dz G273 - 33'-2 45 17 CHEZ G274 HO-4 5 47 15 Gaz 27 19 63 25 HaG) CI G276 F 2-2 58 25 I G277 S 8 26 56 11 i G278 25 27 76 6 G279 F G279 l A9-2 17 = HO-2 17 52 2 OH G280 H3 - 7 9 70 7 G281 cri G2 63 6 G282." H. cl aH-14 6 56 1 H CDK2 CDK4 HCT-116 HCT-116 Ex. R % Inhibition % Inhibition % Inhibition % Inhibition at0. 03 M at0. 03 M at0. 25 at0. 1 M G283 - 6 10 75 16 H, C/ aC G284 H. 0-30-12 69 4 F G285 0 13 is 60 1 'L G286 ci 23 25 60 10 r G287 -8 7 32 9 G288 ! 10 11 60 16 R F G289 r-6 9 62 7 G290 G290 - 12-2 39 2 3 G291 6 14 53 5 F F f G292 FF>2-31-15 60 0 G293 F F Ft 23 32 56 10 F I G294 30 29 74 15 CH, CDK2 CDK4 HCT-116 HCT-116 Ex. R % Inhibition % Inhibition % Inhibition % Inhibition at 0. 03 M at 0. 03 zum at 0. 25 at 0. 1 ICH3 G295 °r !) 8 22 78 10 N, c - w. G296 N~ 0 22 43 0 zu G297 cN9 ) 3 8 45 0 Ho \ i G298 H C N _9 30 46 0 CH, CH3 G299 a-11-7 49 10 Tu G300 - 18-10 70 18 F G301 13 25 79 18 F G302, I G302 17 29 63 17 F F 3 G303 6'-""N'2 45 72 18 G304 Ni 0 20 54 15 I G305-6 11 81 29 Hic G306 17 0 44 9 CDK2 CDK4 HCT-116 HCT-116 Ex. R % Inhibition % Inhibition % Inhibition % Inhibition at0. 03 at0. 03 at0. 25 at0. 1 G307 CH'3 12 54 8 3 G308 Ct-23 5 60 5 G309 G308 j" G309' : 7 30 65 5 CL, G310 5 10 53 14 . G311 G311. - 1 46 43 5 N G312 Cl---io 5 58 8 . / G313 <'11 12 57 10 G314 Hop - 7 0 47 9 G315 G315 . cl,-1 11 50 7 CHUS G316-2 11 56 1 G317 F G317 F 27 33 87 27 F H G318 tH-14 1 48 16 "11-I CDK2 CDK4 HCT-116 HCT-116 Ex. R % Inhibition % Inhibition % Inhibition % Inhibition at0. 03 M at0. 03 M at0. 25 M at0. 1 G319 >,-5 14 54 17 G320 G320 - 15 5 46 12 X G321 N 1 19 51 11 G322 G322 Hp. ")-12 4 50 13 I G323 ao _14 7 72 14 A ' G324 28 26 60 5 ci G325 fN 13 23 51 6 G326 G326 12 22 13 11 G327 H-7 11 55 8 Ho N HO/ G328 19 29 89 33 G329 10 19 56 9 ho G330-1 12 55 2 CDK2 CDK4 HCT-116 HCT-116 Ex. R % Inhibition % Inhibition % Inhibition % Inhibition at 0. 03 M at 0. 03 M at 0. 25 RM at 0. 1 jim G331 f 1 37 93 54 H3c soN N' G332 17 14 66 21 .. ° 3 G333 CHg r - 16-5 51 4 Hic G334 - 2 8 41 6 HO"M r G335 2 21 42 3 G336 36 36 51 12 i ci G337 7 11 52 13 , G338 ho 31 27 54 18 HP °) N G339 6 34 48 9 OH G340-12 9 40 28 OH G341 °'YY- 93 23 G342-10 13 55 20 CDK2 CDK4 HCT-116 HCT-116 Ex. R % Inhibition % Inhibition % Inhibition % Inhibition at 0. 03 jim at0. 03 M at0. 25 at0. 1 G343 NC 1 12 71 27 Nj G344 H3co) N I ° 1 25 18 50 24 CHEZ G345 HaC b v r 6 36 22 . G346 HO G346 ho 'N G347n" G347 H, C 13 15 53 21 F-'N G348 - 21 14 51 23 H3C CH3 G349-6 11 48 31 F G350 4 9 41 24 . G351 HO 0-1 62 24 Hop G350 Nz 4 0 64 24 0 G352 H3CouN. 5 G353 35 46 55 0 >' F G354 0 9 3 60 31 YS< CH, CDK2 CDK4 HCT-116 HCT-116 Ex. R % Inhibition % Inhibition % Inhibition % Inhibition at0. 03 at0. 03 at0. 25 at0. 1 M zu G355) 29 13 54 28 / f G356 H, Ci-16 5 50 27 en, G357 Hp _14 17 88 17 H, C G358 HO,-5 7 55 21 H G359-7-5 69 25 G360 HC 31 9 73 18 G361-3-1 48 26 F . G362 12 6 57 9 H3C'N' HaC// i G363 S 27 16 63 24 N G364-12 9 40 20 aa G365 8 22 93 34 G366 1 9 55 26 CDK2 CDK4 HCT-116 HCT-116 Ex. R % Inhibition % Inhibition % Inhibition % Inhibition at 0. 03 M at 0. 03 M at 0. 25 M at 0. 1 M Y G367 ° 38 15 71 22 F F G368 F 3-3 50 25 G369 26 8 36 21 ON G370 O A. 22 17 52 19 3 Guv F a-11 7 53 27 G372 -21 6 51 19 Cl G373 H3C44-7 10 48 31 0 G374 Hp-10 13 41 21 CH, G375 10-3 62 26 G376 G376 HO 20-6 64 27 G377 F 10-1 55 25 F H G378 i'40 8 60 27 CDK2 CDK4 HCT-116 HCT-116 Ex. R % Inhibition % Inhibition % Inhibition % Inhibition at0. Ho at0. 03 M at0. 25 M at0. l G379 ho 13 8 54 31 I G380 G380-19 7 50 26 cl, G381 5 38 88 43 I G382 HC N _-,, N-17 8 47 17 chez CH3 G383 SsX 15-10 51 33 G384 X 45 23 84 38 2 Ho G385 bu3 1-1 50 28 CH, N G386 19 12 51 28 HS, KC G387 10 11 52 32 '6 G388 ru 3 3 8 45 9 i G389 H3Cu,-12 4 61 11 CHEZ G390 - 14 2 40 10 Ho CDK2 CDK4 HCT-116 HCT-116 Ex. R % Inhibition % Inhibition % Inhibition % Inhibition at0. 03 M at0. 03 M at0. 25 at0. 1 Y G391 Jk 1-7 50 11 H3C w0 <N/ G392 o) 12-2 49 8 CH3 0 G393 H, C 8 0 46 8 HO G394 Cl C 35 11 73 14 cl G395 rN 17 15 48 19 U/ G396 H - 6 9 67 14 H, G Table 3 Example Structure Ki CDK1/B (, uM) A14 0 NH, F 0. 042 N NH 0. 068 0 A20,, o', p-0. 15 HER NEZ Nez NN \ 1/S \ NHZ A21 0 N F 0. 12 N F H F =jC'"H" NH A31 e N ° F 0. 082 H v I N H3 H F "" 0 0. 044 C Hc 'fy. 7 A44 o NHZ '7 H3C NI1 \ F . /G, H3C NHJS F CHa s

The examples above illustrate compounds according to Formula (I) and assays that may readily be performed to determine their activity levels against the various enzymes and for cell growth inhibition. It will be apparent that such assays or other suitable assays known in the art may be used to select an inhibitor having a desired level of activity against a selected target.

While the invention has been illustrated by reference to specific and preferred embodiments, the invention is intended not to be limited by the foregoing description, but to be defined by the appended claims and their equivalents.