MXPA06005844A - Quinazolinone compounds as anticancer agents - Google Patents

Abstract

Quinazolinone compounds, pharmaceutically acceptable salts, and prodrugs thereof;compositions that include a pharmaceutically acceptable carrier and one or more of the quinazolinone compounds, either alone or in combination with at least one additional therapeutic agent. Methods of using the quinazolinone compounds, either alone or in combination with at least one additional therapeutic agent as KSP inhibitors, in the prophylaxis or treatment of proliferative diseases.

Description

COMPOUNDS OF QUINAZQLINONE AS ANTICANCER AGENTS FIELD OF THE INVENTION The present invention relates to novel quinazolinone compounds, their pharmaceutically acceptable salts, and prodrugs thereof; compositions of the new compounds, either alone or in combination with at least one additional therapeutic agent with a pharmaceutically acceptable carrier; and the uses of the novel compounds, either alone or in combination with at least one additional therapeutic agent, in the prophylaxis or treatment of proliferative diseases.

BACKGROUND OF THE INVENTION The kinesins are motor proteins that use adenosine triphosphate to bind to microtubules and generate mechanical strength. The kinesins are characterized by a motor domain that has approximately 350 residual amino acids. The crystalline structures of several kinesin engine domains have been resolved. Currently, approximately one hundred proteins related to kinesin (KRP) have been identified. The kinesins are involved in a variety of cellular biological processes, including transport of organelles and vesicles, and maintenance of the endoplasmic reticulum. Ref: 173090 Several KRPs interact with microtubules of the mitotic spindle or with chromosomes directly, and seem to play a central role during the mitotic stages of the cell cycle. These mitotic KRPs are of particular interest for the development of therapeutic agents for cancer. Spindle protein kinesin (KSP) (also known as Eg5, HsEg5, KNSL1, or KIFII) is one of several kinesin-like motor proteins that are located in the mitotic spindle and are known to be required for formation and / or function of the bipolar mitotic spindle. In 1995, depletion of KSP using an antibody directed against the C-terminus of KSP was shown to counteract HeLa cells in mitosis with arrays of monoastral microtubules (Blangy et al., Cell 83: 1159-1169, 1995). Mutations in the bi C and cut7 genes, which are considered homologs of the KSP, produce faults in the separation of the centrosome in Aspergillus nidulans (Enos, AP, and NR Morris, Cell 60: 1019-1027, 1990) and Schizosaccharomyces pombe (Hagan, I., and M. Yanagida, Nature 347: 563-566, 1990). Treatment of the cells with ATRA (all trans-retinoic acid), which reduces the expression of KSP at the protein level, or depletion of KSP using antisense oligonucleotides revealed significant inhibition in growth in DAN- pancreatic carcinoma cells. G indicating that KSP may be involved in the antiproliferative action of all trans-retinoic acid (Kaiser, A., et al., J., Biol. Chem. 274: 18925-18931, 1999) Interestingly, the protein Xenopus laevis-related kinase Aurora pEg2 was shown to associate and phosphorylate XlEg5 (Giet, R., et al., J. Biol. Chem. 274: 15005-15013, 1999) Potential substrates of Aurora-related kinases are of particular interest For the development of drugs or drugs for cancer, for example, Aurora 1 and 2 kinases are overexpressed on a protein and the level of RNA and genes are amplified in patients with colon cancer. cellular permeable kinase for the KSP, the "monastrol", showed to repress the cells with monopolar spindles without affecting the polymerization of microtubules as do conventional chemotherapeutic agents such as taxanes and vinca alkaloids (Mayer, T.U. , et al., Science 286: 971-974, 1999). Monastrol was identified as an inhibitor in sieves based on the phenotype and it was suggested that this compound could serve as a common thread for the development of anticancer drugs or drugs. Inhibition was determined not competitively with respect to adenosine triphosphate and is rapidly reversible (DeBonis, S., et al., Biochemistry 42: 338-349, 2003; Kapoor, TM, et al., J. Cell Biol. 150: 975-988, 2000).

Recently, other KSP kinesin inhibitors have been described. WO 02/057244 and WO 02/056880 describe phenothiazine compounds and triphenylmethane compounds, respectively, for treating proliferative diseases. WO 02/078639 discloses cyano-substituted dihydropyrimidine compounds for treating proliferative diseases. U.S. Patent No. 6,472,521 discloses oligonucleotides and oligonucleotide derivatives to inhibit the expression of human KSP. WO 01/98278, WO 01/30768 and WO 03/039460 describe quinazolinone compounds which are useful in the treatment of cell proliferative diseases associated with the activity of KSP. The compounds described in these references are 2- (2-aminomethyl) quinazolinone derivatives. The quinazolinone compounds described in WO 01/98278 and WO 01/30768 have 2-aminomethyl substituents which are substituents of amino, amides, or sulfonamide. The quinazolinone compounds described in WO 03/039460 have the amino group of the 2-aminomethyl substituent incorporated in a 5-12 membered nitrogen-containing heterocycle. WO 03/050064 discloses thieno-pyrimidinone compounds which are useful for treating cell proliferative diseases, for treating disorders associated with KSP activity, and for inhibiting KSP.

WO 03/103575 discloses fused, heterocyclic pyrimidinone derivatives which are inhibitors of mitotic KSP and which are useful in the treatment of cellular proliferative diseases. These derivatives are N-heterocyclic fused pyrimidinone derivatives. Representative derivatives that are described include pyrido [a, β-γ] pyrimidin-d-ones, pyrimido [a, ß-?] Pyrimidin-d-ones, pyrimido [a, ß-?] Pyridazin-d-ones and pteridin-4-ones.

SUMMARY OF THE INVENTION In one aspect of the present invention, novel quinazolinone compounds, their pharmaceutically acceptable salts and prodrugs thereof are provided. Quinazolinone compounds, pharmaceutically acceptable salts and prodrugs are inhibitors of KSP and are useful in the treatment of cell proliferation diseases. In one embodiment, the quinazolinone compounds have the formula (I): or a stereoisomer, tautomer, pharmaceutically acceptable salt, or prodrug thereof, wherein X is 0 or S; i is selected from the group consisting of (1 hydrogen, (2 substituted or unsubstituted alkyl, (3 substituted or unsubstituted alkenyl, (4 substituted or unsubstituted alkynyl, (5 substituted or unsubstituted aryl, (6 heteroaryl substituted or not substituted (substituted or unsubstituted heterocyclyl; (8 substituted or unsubstituted alkylsulfonyl; and (9 substituted or unsubstituted arylsulfonyl; R2 is selected from the group consisting of (1 hydrogen, (2 substituted or unsubstituted alkyl; substituted or unsubstituted; and (4 substituted or unsubstituted alkynyl; 3 is selected from the group consisting of (1 C02R? o, (2 CORio, (3 CONRuR12, (4 S (0) mR_3, and (5 S02NR14R? 5 or R2 and R3 taken together with the carbon atom to which they are attached form a 3- or 7-membered carbocyclic or heterocyclic ring, with the proviso that when R4 and R are taken together to form a 5-membered heterocyclic ring 12 members, R3 is CONR__R? 2 or R2 and R3 tom together with the carbon atom to which they are attached form a carbocyclic or heterocyclic ring of 3 to 7 members; R 4 is selected from the group consisting of (1 hydrogen, (2 substituted or unsubstituted alkyl, (3 substituted or unsubstituted alkenyl, (4 substituted or unsubstituted alkynyl, (5 substituted or unsubstituted aryl, (6 heteroaryl substituted or not substituted; and (7 substituted or unsubstituted heterocyclyl; R5 is selected from the group consisting of (i) hydrogen, (2 substituted or unsubstituted alkyl, (3 substituted or unsubstituted alkoxy, (4 substituted or unsubstituted aryl; substituted or unsubstituted; (6 substituted or unsubstituted heterocyclyl (7 COR17, (8 C02Ri8, (9 CONR? 9R20, and (10) S02R2 ?; or R and R5 are taken together with the nitrogen atom to which they are attached form a ring of heteroaryl or heterocyclyl, wherein the heteroaryl ring contains one or two heteroatoms in the ring, wherein the heterocyclyl ring contains one or two heteroatoms in the ring, and wherein the heteroaryl or heterocyclyl ring is optionally substituted with a halogen, alkyl, hydroxy, amino, cyano, alkylamino, dialkylamino, alkyl aminoalkyl, dialkylaminoalkyl, alkoxy, aryl, aryloxy, heteroaryl, arylalkyl, heterocyclyl, aminocarbonyl, carbonylamino, alkylcarbonyl, alkylcarboxy, alkylaminocarbonyl, alkylcarbonylamino, carbocycle, or heteroaryl alkyl; that when R4 and R5 taken together with the nitrogen atom to which they are attached form a 5-membered heterocyclic ring, the γ-cyclic ring is not an 2,4-dioxo-3-oxazolidinyl ring, a 2,5-dioxo-1-imidazolidinyl ring or a 2,4,5-trioxo-1-imidazolidinyl ring; R6, R7, R8 and R_ are independently selected from the group consisting of (1) hydrogen, (2) halogen, (3) hydroxy, (4) nitro, (5) amino, (6) cyano, (7) alkoxy, (8) alkylthio, (9) methylenedioxy, (10) haloalkoxy, (11) C02R? O, (12) COR10, (13) ORio, ((1144)) CONRuR? 2, (15) substituted or unsubstituted alkyl, (16) substituted or unsubstituted aryl, (17) substituted or unsubstituted heteroaryl, (18) substituted or unsubstituted alkylamino, ((1199)) substituted or unsubstituted dialkylamino, (20) substituted or unsubstituted alkylsulfonyl, (21) unsubstituted or substituted arylsulfonyl, (22) substituted or unsubstituted alkylcarboxy, (23) substituted or unsubstituted carboxamido, ((2244)) substituted or unsubstituted carboxyamino, (25) substituted or unsubstituted aminocarboxy, (26) substituted or substituted aminocarbonyl or unsubstituted; and (27) substituted or unsubstituted alkylsulfonamido; Rio R-n, R-? 2, R13, R_, Ris, R-17, Rie, 19, R2o and R_? are independently selected from the group consisting of (1) hydrogen, (2) substituted or unsubstituted alkyl; (3) substituted or unsubstituted alkenyl; (4) substituted or unsubstituted alkynyl; (5) substituted or unsubstituted aryl; (6) substituted or unsubstituted heteroaryl; and (7) substituted or unsubstituted heterocyclyl; or Rn and R12, R_ and R__, or R? 9 and R20 taken together form a carbocyclic or heterocyclic ring of 3 to 7 members; and m = 0, 1 or 2. In another aspect, the present invention provides methods for treating proliferative diseases in a human subject, or animal in need of such treatment, comprising administering to the subject an effective amount of an effective compound of formula (I) to reduce or prevent cell proliferation in the subject. In another aspect of the present invention, methods for treating proliferative diseases in a human or animal subject in need of such treatment comprises administering to the subject an amount of a compound of formula (I) effective to reduce or prevent cell proliferation in the subject in combination with at least one additional agent for the treatment of cancer. In other aspects, the present invention provides therapeutic compositions, comprising at least one compound of formula (I) in combination with one or more additional agents for the treatment of cancer, as are commonly employed in cancer therapy. The compounds of the invention are useful in the treatment of cancers, including, for example, lung and bronchi; prostate; mom; pancreas; colon and rectum; thyroid; stomach; liver and intrahepatic bile duct; Kidney kidney and pelvis; urinary bladder; uterine body; uterine cervix; ovary; multiple myeloma; esophagus; acute myelogenous leukemia; chronic myelogenous leukemia; lymphocytic leukemia; myeloid leukemia; brain; oral cavity and pharynx; larynx; small intestine; Non-Hodgkin's lymphoma; melanoma; and adenoma of the villous colon. The invention further provides compositions, equipment, methods of use, and methods of manufacture as described in the detailed description of the invention.

DETAILED DESCRIPTION OF THE PREFERRED MODALITY In one aspect of the present invention, novel quinazolinone compounds, their pharmaceutically acceptable salts and prodrugs or prodrugs thereof are provided. Quinazolinone compounds, pharmaceutically acceptable salts and prodrugs are inhibitors of KSP and are useful in the treatment of cell proliferation diseases.

The quinazolinone compounds have the formula (I): or a stereoisomer, tautomer, pharmaceutically acceptable salt, or prodrug thereof, wherein X is O or S; Ri is selected from the group consisting of (1 hydrogen, (2 substituted or unsubstituted alkyl, (3 substituted or unsubstituted alkenyl, (4 substituted or unsubstituted alkynyl, (5 substituted or unsubstituted aryl, (6 heteroaryl substituted or not substituted (substituted or unsubstituted heterocyclyl; (8 substituted or unsubstituted alkylsulfonyl; and (9 substituted or unsubstituted arylsulfonyl; R2 is selected from the group consisting of (1 hydrogen, (2 substituted or unsubstituted alkyl; substituted or unsubstituted; and (4) substituted or unsubstituted alkynyl; R3 is selected from the group consisting of (1) C02R? o, (2) CORio, (3) CONR? R? 2, (4) S (0) mR_3, and (5) S02NR? 4R? 5; or R2 and R3 taken together with the carbon atom to which they are attached form a carbocyclic or heterocyclic ring of 3 to 7 members; with the proviso that when R4 and R5 are taken together to form a heterocyclic ring of 5 to 12 members, R3 and s C0 RnR? 2 or R2 and R3 taken together with the carbon atom to which they are attached form a carbocyclic or heterocyclic ring of 3 to 7 members; R 4 is selected from the group consisting of (1) hydrogen, (2) substituted or unsubstituted alkyl; (3) substituted or unsubstituted alkenyl; (4) substituted or unsubstituted alkynyl; (5) substituted or unsubstituted aryl; (6) substituted or unsubstituted heteroaryl; and (7) substituted or unsubstituted heterocyclyl; R5 is selected from the group consisting of (1) hydrogen, (2) substituted or unsubstituted alkyl; (3) substituted or unsubstituted alkoxy; (4) substituted or unsubstituted aryl; (5) substituted or unsubstituted heteroaryl; (6) substituted or unsubstituted heterocyclyl; (7) COR? 7, (8) C02R? 8, (9) CONR? 9R20, and (10) S02R2?; or R4 and R5 are taken together with the nitrogen atom to which they are attached form a heteroaryl or heterocyclyl ring, wherein the heteroaryl ring contains one or two heteroatoms in the ring, wherein the heterocyclyl ring contains one or two heteroatoms in the ring. the ring, and wherein the heteroaryl or heterocyclyl ring is optionally substituted with a halogen, alkyl, hydroxy, amino, cyano, alkylamino, dialkylamino, alkyl aminoalkyl, dialkylaminoalkyl, alkoxy, aryl, aryloxy, heteroaryl, arylalkyl, heterocycle, aminocarbonyl group, carbo-n-amino, alkylcarbonyl, alkylcarboxy, alkylaminocarbonyl, alkylcarbonylamino, carbocycle, or heteroarylalkyl; with the proviso that when R and R5 taken together with the nitrogen atom to which they are attached form a 5-membered heterocyclic ring, the heterocyclic ring is not a 2,4-dioxo-3-oxazolidinyl ring, a ring of 2,5-dioxo-l-imidazolidinyl or a 2,4,5-trioxo-l-imidazolidinyl ring; R6, R7, Rs and R9 are independently selected from the group consisting of (1) hydrogen, (2) halogen, (3) hydroxy, (4) nitro, (5) amino, (6) cyano, ((77)) alkoxy, (8) alkylthio, (9) methylenedioxy, (10) haloalkoxy, (11) C02R? o, ((1122)) COR10, (14) CONR11R12, (15) substituted or unsubstituted alkyl, (16) substituted aryl or unsubstituted, ((1177)) substituted or unsubstituted heteroaryl, (18) substituted or unsubstituted alkylamino, (19) substituted or unsubstituted dialkylamino, (20) substituted or unsubstituted alkylsulfonyl, (21) substituted or unsubstituted arylsulfonyl , ((2222)) substituted or unsubstituted alkylcarboxy, (23) substituted or unsubstituted carboxamido, (24) substituted or unsubstituted carboxyamino, (25) substituted or unsubstituted aminocarboxi, (26) substituted or unsubstituted aminocarbonyl, and ( 27) substituted or unsubstituted alkylsulfonamido; Rio, Rn, R? 2, R13, 14, Ris, 17 Laugh, Ris, R20 and R_? are independently selected from the group consisting of (1) hydrogen, (2) substituted or unsubstituted alkyl; (3) substituted or unsubstituted alkenyl; (4) substituted or unsubstituted alkynyl; (5) substituted or unsubstituted aryl; (6) substituted or unsubstituted heteroaryl; and (7) substituted or unsubstituted heterocyclyl; or R11 and R_2, R_4 and R? 5, or R19 and R20 taken together form a carbocyclic or heterocyclic ring of 3 to 7 members; and m = 0, 1 or 2. In one embodiment, X is O. In one embodiment, Rx is arylalkyl. In one embodiment, the arylalkyl is benzyl or substituted benzyl. In one embodiment, Ri is benzyl substituted with halo. In one embodiment, Ri is 3-chlorobenzyl. In one embodiment, Rx is 3-fluorobenzyl. In one embodiment, Rx is 3-methoxybenzyl. In one embodiment, Rx is 3-trifluoromethylbenzyl. In one embodiment, Rx is 3-trifluoromethoxybenzyl.

In one embodiment, Rx is 3,5-dimethylbenzyl. In one embodiment, Ri is 2-naphthylmethyl. In one embodiment, R2 is hydrogen and R3 is CO2R? 0. In one modality, Rio is. I rent. In one embodiment, R2 is hydrogen and R3 is CONRnR? 2.

In one embodiment, n and R12 are alkyl. In one embodiment, Rlx and R12 are methyl. In one embodiment, Ru and R12 taken together with the nitrogen atom to which they are attached form a heterocyclic ring of 3 to 7 members. In one embodiment, R is alkyl substituted with amino. In one embodiment, R 4 is 3-aminopropyl. In one embodiment, R5 is hydrogen, alkyl, aryl or COR? 7. In one embodiment, Ri7 is aryl, arylalkyl, aryl substituted with alkyl or aryl substituted with halogen. In an R6 mode, Re and R9 are hydrogen. In one embodiment, R7 is a halogen. For the compounds of formula (I), the representative substituted alkyl groups include the arylalkyl, heteroarylalkyl, heterocyclylalkyl, amino alkyl, alkylaminoalkyl, dialkylaminoalkyl and sulfonamido alkyl groups. Representative substituted aryl groups include sulfonamidoaryl groups. Representative substituted heteroaryl groups include alkylheteroaryl groups. In other aspects, the present invention provides methods for the manufacture of compounds of formula (I). Methods for making representative compounds of the invention are described in Examples 1 and 2. It was further contemplated that, in addition to the compounds of formula (I), the intermediates and their corresponding synthesis methods are included within the scope of the invention. Representative compounds of the invention are illustrated in Table 1 in Example 3. In other aspects, the present invention provides compositions that include the KSP inhibitors described herein, and methods that utilize the KSP inhibitors described herein. In one aspect, the present invention provides pharmaceutical compositions comprising at least one quinazolinone compound (e.g., a compound of formula (I)) together with a pharmaceutically acceptable carrier suitable for administration to a human or animal subject, either alone or or together with other anticancer agents. A number of anticancer agents suitable for use as combined therapeutic agents were contemplated for use in the compositions and methods of the present invention. Suitable anticancer agents to be used in combination with the compounds of the invention include agents that induce apoptosis; polynucleotides (e.g., ribozymes); polypeptides (e.g., enzymes); drugs or drugs; biological mimetics, alkaloids; alkylating agents; antitumor antibiotics; antimetabolites; hormones; platinum compounds; monoclonal antibodies conjugated with drugs or anticancer drugs, toxins and / or radionuclides; biological response modifiers (e.g., interferons [e.g., INF-a] and interleukins [e.g., IL-2]); adoptive immunotherapeutic agents; hematopoietic growth factors; agents that induce the differentiation of tumor cells (e.g., all-trans-retinoic acid); reagents for gene therapy; antisense and nucleotide therapy reagents; tumor vaccines; inhibitors of angiogenesis; and similar. Numerous other examples of chemotherapeutic compounds and anti-cancer therapies suitable for the co-administration of the described compounds of formula (I) are known to those skilled in the art. In certain embodiments, the anticancer agents to be used in combination with the compounds of the present invention comprise agents that induce or stimulate apoptosis. Agents that induce apoptosis include, but are not limited to radiation; kinase inhibitors (e.g. Epidermal Growth Factor Receptor Kinase Inhibitor [EGFR], Vascular Growth Factor Receptor Kinase Inhibitor [VGFR], Fibroblast Growth Factor Receptor Kinase Inhibitor [FGFR] , Kinase Inhibitor of the Platelet-derived Growth Factor Receptor [PGFR] I, and Bcr-Abl Kinase Inhibitors such as STI-571, Gleevec, and Glivec]); antisense molecules; antibodies [for example Herceptin and Rituxan]; anti-estrogens [eg, raloxifene and tamoxifen]; anti-androgens [eg, flutamide, bicalutamide, finasteride, amino-glutetamide, Ketoconazole, and corticosteroids]; cyclooxygenase-2 inhibitors (COX-2) [eg Celecoxib, meloxicam, NS-398, and drugs or nonsteroidal anti-inflammatory drugs (NSAIDs)]; and chemotherapeutic drugs for cancer [eg, irinotecan (Camptosar), CPT-11, fludarabine (Fludara), dacarbazine (DTIC), dexamethasone, mitoxantrone, Mylotarg, VP-16, cisplatin, 5-FU, Doxrubicin, TAXOTERE or TAXOL]; cell signaling molecules; ceramides and cytokines; staurosprine; and similar. In other aspects, the invention provides methods for using the compounds described herein. For example, the compounds described herein can be used in the treatment of cancer. The compounds described herein can also be used in the manufacture of a medicament for the treatment of cancer. In one embodiment, the present invention provides methods for treating human subjects or animals suffering from a cell proliferative disease, such as cancer. The present invention provides methods for treating a human or animal subject in need of such treatment, comprising administering to the subject a therapeutically effective amount of a quinazolinone compound (e.g., a compound of formula (I)), either alone or in combination with other anticancer agents. In another embodiment, the present invention provides methods for treating a cell proliferative disease in a human or animal subject in need of such treatments, comprising, administering to the subject an amount of a quinazolinone compound (e.g., a compound of formula (I )) effective to reduce or prevent cell proliferation or tumor growth in the subject. In another embodiment, the present invention provides methods for treating a cell proliferative disease in a human or animal subject in need of such treatment comprising administering to the subject an amount of a quinazolinone compound (e.g., a compound of formula (I)) effective to reduce or prevent cell proliferation in the subject in combination with at least one additional agent for the treatment of cancer. The present invention provides compounds that are inhibitors of KSP. Inhibitors are useful in pharmaceutical compositions for human or veterinary use, where the inhibition of KSP is indicated, for example, in the treatment of cell proliferative diseases such as tumor growth and / or cancer cells mediated by KSP In particular, the compounds are useful in the treatment of human or animal (e.g., murine) cancers, including, for example, lung and bronchus; prostate; mom; pancreas; colon and rectum; thyroid; stomach; liver and hepatic bile duct; Kidney kidney and pelvis; urinary bladder; uterine body; uterine cervix; ovary; multiple myeloma; esophagus; acute myelogenous leukemia; chronic myelogenous leukemia; lymphocytic leukemia; myeloid leukemia; brain; oral cavity and pharynx; larynx; small intestine; lymphoma; melanoma; and adenoma of the villous colon. In another embodiment, the invention provides methods for treating a disorder mediated by KSP. In one method, an effective amount of a quinazolinone compound is administered to a patient (e.g., a human or animal subject) who needs it to mediate (or modulate) the activity of KSP. A representative assay for determining the inhibitory activity of KSP is described in Example 4. The following definitions are provided to better understand the invention. > As used herein, the term "quinazolinone" refers to a quinazolinone compound having a carbonyl or thiocarbonyl group at the 4-position. "Alkyl" refers to alkyl groups that do not contain heteroatoms. Thus the phrase includes straight chain alkyl groups such as methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, nonyl, decyl, undecyl, and the like. The phrase also includes branched chain isomers of straight chain alkyl groups, including but not limited to the following, which are provided by way of example: -CH (CH3) 2, -CH (CH3) (CH2CH3) - CH (CH2CH3) 2, -C (CH3) 3, -CH2CH (CH3) 2, -CH2CH (CH3) (CH2CH3), -CH2C (CH3) 3, -CH2C (CH2CH3) 3, -CH (CH_) -CH (CH3) (CH2CH3), -CH2CH2CH (CH3) 2, -CH2CH2CH (CH3) (CH2CH3), -CH2CH2CH (CH2CH3) 2, -CH2CH2C (CH3) 3, -CH2CH2C (CH2CH3) 3, -CH (CH3) CH2-CH (CH3) 2, -CH (CH3) CH (CH3) CH (CH3) 2, -CH (CH2CH3) CH (CH3) ) CH (CH3) (CH2CH3), and others. The phrase also includes cyclic alkyl groups such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl and those rings substituted with straight or branched chain alkyl groups as defined above. Thus the phrase "alkyl groups" includes primary alkyl groups, secondary alkyl groups, and tertiary alkyl groups. Preferred alkyl groups include straight or branched chain alkyl groups and cyclic alkyl groups having from 1 to 12 carbon atoms. "Alkylene" refers to the same residues noted above for "alkyl", but which have two attachment points. Exemplary alkylene groups include ethylene (-CH2CH2_), propylene (-CH2CH2CH2-), dimethylpropylene (-CH2C (CH3) 2CH2-), and cyclohexylpropylene (-CH2CH2CH (CSH_3) -). "Alkenyl" refers to straight chain, branched or cyclic radicals having one or more carbon-carbon double bonds and from 2 to about 20 carbon atoms. Preferred alkenyl groups include straight-chain and branched alkenyl groups and cyclic alkenyl groups having from 2 to 12 carbon atoms. "Alkynyl" refers to straight-chain, branched or cyclic radicals having one or more triple carbon-carbon bonds and from 2 to about 20 carbon atoms. Preferred alkynyl groups include straight chain or branched alkynyl groups having from 2 to 12 carbon atoms. The alkyl, alkenyl and alkynyl groups may be substituted. "Substituted alkyl" refers to an alkyl group as defined above, in which one or more bonds to a carbon or hydrogen are replaced by a bond with atoms other than hydrogen and carbon such as, but not limited to, an halogen such as F, Cl, Br and I; an oxygen atom in groups such as hydroxyl groups, alkoxy groups, aryloxy groups and ester groups; a sulfur atom in groups such as thiol groups, alkyl and aryl sulfide groups, sulfone groups, sulfonyl groups and sulfoxide groups; a nitrogen atom in groups such as amines, amides, alkylamines, dialkylamines, arylamines, alkylaryl amines, diarylamines, N-oxides, imides and enamines; a silicon atom in groups such as trialkylsilyl groups, dialkylarylsilyl groups, alkyldiarylsilyl groups and triarylsilyl groups; and other heteroatoms in several other groups. Substituted alkyl groups also include groups in which one or more bonds to a carbon or hydrogen atom is replaced by a higher order bond (eg, a double or triple bond) to a heteroatom such as oxygen in oxo, carbonyl groups , carboxyl and ester; nitrogen in groups such as imines, oximes, hydrazones and nitriles. The substituted alkyl groups further include alkyl groups in which one or more bonds to carbon or hydrogen atoms are replaced by a bond to an aryl, heteroaryl, heterocyclyl or cycloalkyl group. Preferred substituted alkyl groups include, among others, alkyl groups in which one or more bonds to a carbon or hydrogen atom are replaced by one or more bonds to a fluorine, chlorine or bromine group. Another preferred substituted alkyl group is the trifluoromethyl group and other alkyl groups containing the trifluoromethyl group. Other preferred substituted alkyl groups include those in which one or more bonds to a carbon or hydrogen atom are replaced by a bond to an oxygen atom so that the substituted alkyl group contains a hydroxyl, alkoxy or aryloxy group. Other preferred substituted alkyl groups include alkyl groups having an unsubstituted or substituted amine or alkylamine group, dialkylamine, arylamine, (alkyl) (aryl) amine, diarylamine, heterocyclylamine diheterocyclylamine, (alkyl) (heterocyclyl) amine, or (aryl) (heterocyclyl) amine. Still further preferred substituted alkyl groups include those in which one or more bonds to a carbon or hydrogen atom is replaced by a bond to an aryl, heteroaryl, heterocyclyl or cycloalkyl group. Examples of substituted alkyl are: - (CH2) 3NH2, - (CH2) 3NH (CH3), - (CH2) 3NH (CH3) 2, - -CH2C (= CH2) CH2NH2, -CH2C (= 0) CH2NH2, - CH2S (= 0) 2CH3, -CH20CH2NH2, -C02H. Examples of substituted alkyl substituents are: -CH3, -C2H5, -CH20H, -OH, 0CH3, -0C2H5, -0CF3, -0C (= 0) CH3, -0C (= 0) NH2, -0C (= 0 ) N (CH3) 2, -CN, -N02, -C (= 0) CH3, -C02H, -C02CH3, -C0NH2, -NH2, -N (CH3) 2, -NHS02CH3, -NHC0CH3, -NHC (= 0) 0CH3, -NHSO-2CH3, -S02CH3, -S02NH2, Halo. "Substituted alkenyl" has the same meaning with respect to the alkenyl groups that the substituted alkyl groups had with respect to the unsubstituted alkyl groups. A substituted alkenyl group includes alkenyl groups in which an atom other than carbon or hydrogen is bonded to a double bond of carbon to another carbon and those in which one of the atoms other than carbon or hydrogen is attached to carbon not involved in a double bond to another carbon.

"Substituted alkynyl" has the same meaning with respect to the alkynyl groups that the substituted alkyl groups had with respect to the unsubstituted alkyl groups. A substituted alkynyl group includes alkynyl groups in which an atom other than carbon or hydrogen is bonded to a triple bond of carbon to another carbon and those in which an atom other than carbon and hydrogen is attached to a carbon that is not involved in a triple bond to another carbon. "Alkoxy" refers to RO- where R is alkyl. Representative examples of alkoxy groups include methoxy, ethoxy, t-butoxy, trifluoromethoxy and the like. "Halogen" or "halo" refers to the chloro, bromo, fluoro and iodo groups. The term "haloalkyl" refers to an alkyl radical substituted with one or more halogen atoms. The term "haloalkoxy" refers to an alkoxy radical substituted with one or more halogen atoms. "Amino" refers here to the group -NH2. The term "alkylamino" refers herein to the group -NRR 'wherein R is alkyl and R' is hydrogen or alkyl. The term "arylamino" refers herein to the group -NRR 'where R is aryl and R' is hydrogen, alkyl or aryl. The term "aralkylamino" refers herein to the group -NRR 'wherein R is aralkyl and R' is hydrogen, alkyl, aryl or aralkyl. "Alkoxyalkyl" refers to the group -alk? -0-alk2 where alqx is alkyl or alkenyl, and alk2 is alkyl or alkenyl. The term "aryloxyalkyl" refers to the group -alkyl O-aryl. The term "" aralkoxyalkyl "refers to the alkylenyl-O-aralkyl group." Alkoxyalkylamino "refers herein to the group -NR- (alkoxyalkyl), where R is typically hydrogen, aralkyl or alkyl." Aminocarbonyl "refers herein to the group - C (0) -NH2.

"Substituted aminocarbonyl" refers herein to the group -C (0) -NRR 'where R is alkyl and R' is hydrogen or alkyl. The term "arylaminocarbonyl" refers herein to the group -C (0) -NRR 'wherein R is aryl and R' is hydrogen, alkyl or aryl.

"Aralkylaminocarbonyl" refers herein to the group -C (O) -NRR 'where R is aralkyl and R' is hydrogen, alkyl, aryl or aralkyl. "Aminosulf onyl" refers to the group -S (O) 2-NH2 here. "Substituted aminosulfonyl" refers herein to the group -S (0) 2NRR 'where R is alkyl and R' is hydrogen or alkyl. The term "aralkylaminosulfonylaryl" refers to the group -aryl-S (O) 2-NH-aralkyl. "Carbonyl" refers to the divalent group -C (0) -. "Carbonyloxy" refers generally to the group -C (0) -0. These groups include esters, -C (0) -0-R, where R is alkyl, cycloalkium, aryl or aralkyl. The term "carbonyloxycycloalkyl" generally refers here to both a "carbonyloxycarbocycloalkyl" and a "carbonyloxy heterocycloalkyl," that is, wherein R is an alkyl or heterocycloalkyl carbocycle, respectively. The term "arylcarbonyloxy" refers herein to the group -C (0) -O) -aryl, wherein the aryl is a mono- or polycyclic carbocycloaryl or heterocycloaryl. The term "aralkylcarbonyloxy" refers to the group -C (0) -0-aralkyl. "Sulfonyl" refers to the group -S02- here. "Alkylsulfonyl" refers to a substituted sulfonyl of the structure -S02R- in which R is alkyl The alkylsulfonyl groups used in the compounds of the invention are typically alkylsulfonyl groups having from 1 to 6 carbon atoms in their structure in this way , typical alkylsulfonyl groups employed in the compounds of the present invention include, for example, methylsulfonyl (ie, where R is methyl), ethylsulfonyl (ie, where R is ethyl), propylsulfonyl (ie, where R is propyl) and the like The term "arylsulfonyl" refers here to the group -S02-aryl. The term "aralkylsulfonyl" refers here to the group -S02-aralkyl. The term "sulfonamido" refers herein to -S02NH2"Carbonilamino" refers to the divalent group -NH- C (O) - in which the hydrogen atom of the amide nitrogen of the carbonylamino group can be replaced by an alkyl group, aryl or aralkyl. These groups include portions such as carbamate esters (-NH-C (0) -0-R) and amides -NH-C (0) -R, where R is a straight or branched chain alkyl, cycloalkyl, or aryl or aralkyl . The term "alkylcarbonylamino" refers to alkylcarbonylamino where R is alkyl having from 1 to 6 carbon atoms in its structure. The term "arylcarbonylamino" refers to the group -NH-C (0) -R where R is an aryl. Similarly, the term "aralkylcarbonylamino" refers to carbonylamino where R is aralkyl. "Guanidino" or guanidyl "refers to portions derived from guanidine, HN-C (= NH) -NH2, Those portions or portions include those attached to the nitrogen atom containing the formal double bond (" position 2 of guanidine, " for example, diaminomethyleneamino, (H2N) -C (= NH-)) and those attached to any of the nitrogen atoms that contain a formal single bond (the "1" and / or "3" positions of guanidine, for example , H2N-C (= NH) -NH-)). The hydrogen atoms of any of the nitrogens can be replaced with a suitable substituent, such as alkyl, aryl or aralkyl. "Amidino" refers to the portions RC (= N) -NR'- (the radical being in the nitrogen "N1") and R (NR ') C = N (the radical being in the nitrogen "N2"), where R and R 'can be hydrogen, alkyl, aryl or aralkyl. "Cycloalkyl" refers to a mono- or polycyclic, heterocyclic or carbocyclic alkyl substituent. Typical cycloalkyl substituents have from 3 to 8 atoms in their structure (ie ring) in which each atom of the structure is carbon or a heteroatom. The term "heterocycloalkyl" refers herein to cycloalkyl substituents having from 1 to 5, and more typically from 1 to 4 heteroatoms in the ring structure. Suitable heteroatoms employed in the compounds of the present invention are nitrogen, oxygen and sulfur. Representative heterocycloalkyl moieties include, for example, morpholino, piperazinyl, piperadinyl and the like. The carbocycloalkyl groups are cycloalkyl groups in which all the ring atoms are carbon. When used in connection with cycloalkyl substituents, the term "polycyclic" refers herein to fused and unfused cyclic alkyl structures. "Substituted heterocycle", "heterocyclic group", "heterocycle" or "heterocyclyl", as used herein refers to any 3 or 4 membered ring having a heteroatom selected from nitrogen, oxygen and sulfur or a ring of 5 or 6 members containing 1 to 3 heteroatoms selected from the group consisting of nitrogen, oxygen or sulfur; where the five-membered ring has 0-2 double bonds and the 6-membered ring has 0-3 double bonds; wherein the nitrogen and sulfur atom may optionally be oxidized; wherein the nitrogen and sulfur heteroatoms may optionally be quaternized; and including any bicyclic group in which any of the above heterocyclic rings is fused to a benzene ring or other 5 or 6 membered heterocyclic ring independently defined above. The term "heterocycle" thus denotes rings in which nitrogen is the heteroatom as well as partially or fully saturated rings. Preferred heterocycles include, for example, diazapinyl, pyrryl, pyrrolinyl, pyrrolidinyl, pyrazolyl, pyrazolinyl, pyrazolidinyl, imidazolyl, imidazolinyl, imidazolidinyl, pyridyl, piperidinyl, pyrazinyl, piperazinyl, N-methyl piperazinyl, azetidinyl, N-methyl azetidinyl, pyrimidinyl, pyridazinyl, oxazolyl, oxazolidinyl, isoxazolyl, isoazolidinilo, morpholinyl, thiazolyl, thiazolidinyl, isothiazolyl, isothiazolidinyl, indlilo, quinolinyl, isoquinolinyl, benzimidazolyl, benzothiazolyl, benzoxazolyl, furyl, thienyl, triazolyl and benzothienyl. The heterocyclic moieties can not be substituted or monosubstituted or disubstituted with various substituents independently selected from hydroxy, halo, oxo (C = 0) alkylimino (RN =, wherein R is an alkyl or alkoxy group), amino, alkylamino, dialkylamino, acylamino alkyl , alkoxy, thioalkoxy, polyalkoxy, alkyl, cycloalkyl or haloalkyl. The heterocyclic groups can be linked in various positions as will be apparent to those skilled in the techniques of organic chemistry in medicine in conjunction with the description herein. where R is H or a heterocyclic substituent, as described herein. Representative heterocycles include, for example, imidazolyl, pyridyl, piperazinyl, acetydinyl, thiazolyl, furanyl, triazolyl benzimidazolyl, benzothiazolyl, benzoxazolyl, quinolinyl, isoquinolinyl, quinazo-linyl, quinoxalinyl, phthalazinyl, indolyl, napthpyridinyl, indazolyl and quinolininyl.

"Aryl" refers to optionally substituted monocyclic and polycyclic aromatic groups having from 3 to 14 carbon atoms or heteroatoms, and includes carbocyclic aryl groups and heterocyclic aryl groups. The carbocyclic aryl groups are aryl groups in which all the ring atoms in the aromatic aryl are carbon atoms. The term "heteroaryl" refers herein to aryl groups having 1 to 4 heteroatoms as ring atoms in an aromatic ring with the remainder of the ring atoms being carbon atoms. When used in connection with aryl substituents, the term "polycyclic aryl" refers herein to fused or unfused cyclic structures in which at least one cyclic structure is aromatic, such as, for example, benzodioxozolo (which has a fused heterocyclic structure). to a phenyl group, i.e., naphthyl, and the like.

Examples employed as substituents in the compounds of the present invention include phenyl, pyrididyl, pyrimidinyl, thiazolyl, indolyl, imidazolyl, oxadiazolyl, tetrazolyl, pyrazinyl, triazolyl, thiophenyl, furanyl, quinolinyl, purinyl, naphthyl, benzothiazolyl, benzo-pyridyl, and benzimidazolyl and the like. "Aralkyl or" arylalkyl "refers to an alkyl group substituted with an aryl group Typically, the aralkyl groups used in compounds of the present invention have from 1 to 6 carbon atoms incorporated within the alkyl portion of the aralkyl group. Suitable aralkyl groups used in the compounds of the present invention include, for example, benzyl, picolyl, and the like Representative heteroaryl groups include, for example, those shown below.These heteroaryl groups may be further substituted and may be attached at various positions as It will be evident to those who have experience in the techniques of organic chemistry and medicine in conjunction with the description of the present.

Representative heteroaryls include, for example, imidazolyl, pyridyl, thiazolyl, triazolyl benzimidazolyl, benzothiazolyl and benzoxazolyl. "Biaryl" refers to a group or substituent to which two aryl groups joined, which did not condense with each other. Exemplary biaryl compounds include, for example, phenylbenzenes, diphenyldiazene, 4-methylthio-1-phenylbenzene, phenoxybenzene, (2-phenylethynyl) benzene, diphenyl ketone, (4-phenylbuta-1,3-diinyl) benzene, phenylbenzylamine, ( phenylmethoxy) benzene, and the like. Optionally preferred biaryl groups include: 2 (phenylamino) -N- [4- (2-phenylethynyl) -phenyl] acetamide, 1,4-diphenylbenzene, N- [4- (2-phenylethynyl) phenyl] -2- [benzyl] -amino] -acetamide, 2-amino-N- [4- (2-phenylethynyl) phenyl] propanamide, 2-amino-N- [4- (2-phenyl-ethynyl) phenyl] acetamide, 2- (cyclopropylamino) - N- [4- (2-phenyl-ethynyl) -phenyl] -acetamide, 2- (ethylamino) -N- [4- (2-phenylethynyl) phenyl] acetamide, 2- [(2-methyl-propyl) amino] - N- [4- (2-phenyl-ethynyl) phenyl] acetamide, 5-phenyl-2H-benzo- [d] 1,3-dioxolene, 2-chloro-l-methoxy-4-phenylbenzene, 2- [(imidazolylmethyl ) -amino] -N- [4- (2-phenylethynyl) phenyl] acetamide, 4-phenyl-1-phenoxybenzene, N - (2-amino-ethyl) - [4- (2-phenylethynyl) phenyl] carboxamide, 2 -. { [(4-fluorophenyl) methyl] -amino} -N- [4- (2-phenylethynyl) phenyl] acetamide, 2-. { [(4-methylphenyl) methyl] amino} -N- [4- (2-phenyl-ethynyl) phenyl] acetamide, 4-phenyl-1- (trifluoromethyl) benzene, l-butyl-4-phenyl-benzene, 2- (cyclohexylamino) -N- [4- ( 2-phenylethynyl) phenyl] acetamide, 2- (ethyl-methyl-amino) -N- [4- (2-phenylethynyl) phenyl] acetamide, 2- (butylamino) -N- [4- (2-phenyl-ethynyl) -phenyl] -acetamide, N- [4- (2-phenylethynyl) phenyl] 2- (4-pyridylamino) -acetamide, N- [ 4- (2-phenyl ethynyl) phenyl] -2- (quinuclidin-3-ylamino) acetamide, N- [4- (2-phenylethynyl) phenyl] pyrrolidin-2-ylcarboxamide, 2-amino-3-methyl-N- [4- (2-phenyl-ethynyl] -phenyl] butanamide, 4- (4-phenylbuta-l, 3-diinyl) phenylamine, 2- (dimethylamino) -N- [4- (4-phenylbuta- 1, 3-diinyl) phenyl] acetamide, 2- (ethylamino) -N- [4- (4-phenylbuta-1,3-diinyl) -phenyl] acetamide, 4-ethyl-1-phenylbenzene, 1- [4- (2-phenyl-ethynyl) -phenyl] -ethan-1-one, N- (l-carbamoyl-2-hydroxypropyl) [4- (4-phenylbuta-l, 3-diinyl) -phenyl] -carboxamide, N- [4- (2-phenylethynyl) phenyl] -propanamide, 4-methoxy-phenyl phenyl ketone, phenyl-N-benzamide, (tet-butoxy) -N- [(4-phenylphenyl) -methyl] -carboxamide, 2- (3-phenyl-phenoxy) ethanhydroxamic acid, 3-phenylphenyl propanoate, 1- (4-ethoxyphenyl) -4-methoxybenzene and [ 4- (2-phenyl ethynyl) phenyl] -pyrrole. "Heteroarylaryl" refers to a biaryl group wherein one of the aryl groups is a heteroaryl group. Exemplary heteroarylaryl groups include, for example, 2-phenylpyridine, phenylpyrrole, 3- (2-phenylethynyl) pyridine, phenyl pyrazole, 5- (2-phenyl-ethynyl) -1,3-dihydropyrimidine-2,4-dione, 4- phenyl-1,2,3-thiadiazole, 2- (2-phenyl-ethynyl) pyrazine, 2-phenyl thiophene, f-nilimidazole, 3- (2-piperazinyl-phenyl) -furan, 3- (2,4-dichlorophenyl) -4 -methylpyrrole and the like. Preferred optionally substituted heteroarylaryl groups include: 5- (2-phenylethynyl) pyrimidin-2-ylamine, l-methoxy-4- (2-thienyl) benzene, l-methoxy-3- (2-thienyl) benzene, 5-methyl -2-phenyl-pyridine, 5-methyl-3-phenylisoxazole, 2- [3- (trifluoromethyl) phenyl] furan, 3-fluoro-5- (2-furyl) -2-methoxy-1-prop-2- enylbenzene, (hydroxyimino) (5-phenyl (2-thienyl)) -methane, 5- [(4-methylpiperazinyl) methyl] -2-phenylthiophene, 2- (4-ethylphenyl) -thiophene, 4-methyl-thio-1 - (2-thienyl) benzene, 2- (3-nitrophenyl) thiophene, (tert-butoxy) Nf (5-phenyl- (3-pyridyl)) methyl] carboxamide, hydroxy-N- [(5-phenyl) -3- pyridyl)) methyl] -amide, 2- (phenyl-methyl-thio) pyridine, and benzylimidazole. "Heteroaryl heteroaryl" refers to a biaryl group wherein both of the aryl groups are heteroaryl groups. Heteroarylheteroaryl groups include, for example, 3-pyridylimidazole, 2-imidazolylpyrazine, and the like. Optionally preferred heteroaryl heteroaryl groups include: 2- (4-piperazinyl-3-pyridyl) furan, diethyl- (3-pyrazin-2-yl (4-pyridyl)) amine, and dimethyl. { 2- [2- (5-Methylpiracin-2-yl) ethynyl] (4-pyridyl)} amine. "Optionally substituted" or "substituted" refers to the replacement of hydrogen with a monovalent or divalent radical. Suitable substituent groups include, for example, hydroxyl, nitro, amino, imino, cyano, halo, thio, sulfonyl, thioamido, amidino, imidino, oxo, oxamidino, methoxamidino, imidino, guanidino, sulfonamido, carboxyl, formyl, alkyl, haloalkyl. , alkylamino, haloalkylamino, alkoxy, haloalkoxy, alkoxy-alkyl, alkylcarbonyl, aminocarbonyl, arylcarbonyl, aralkylcarbonyl, heteroarylcarbonyl, heteroaralkylcarbonyl, alkylthio, aminoalkyl, cyanoalkyl, aryl and the like. The substituent group can itself be substituted. The group substituted on the substituent group can be carboxyl, halo, nitro, amino, cyano, hydroxyl, alkyl, alkoxy, aminocarbonyl, -SR, thioamido, -S03H, -S02R, or cycloalkyl, where R is typically hydrogen, hydroxyl or alkyl . When the substituted substituent includes a straight chain group, substitution may occur within the chain (e.g., 2-hydroxypropyl, 2-aminobutyl, and the like) or in the terminal part of the chain (e.g., 2-hydroxyethyl, 3-cyanopropyl and the like). Substituted substituents may be straight chain, branched and cyclic arrays of covalently attached carbon or heteroatoms. "Carboxy protecting group" refers to a carbonyl group which has been esterified with one of the commonly used carboxylic acid protecting ester groups used to block or protect the carboxylic acid function while carrying out other functional sites of the carboxylic acid. compound. In addition, a carboxy protecting group can be attached to a solid carrier, whereby the compound remains connected to the solid carrier as a carboxylate until it is cleaved by hydrolytic methods to release the corresponding free acid. Representative carboxy protecting groups include, for example, alkyl esters, secondary amides and the like. Certain of the compounds of the invention comprise asymmetrically substituted carbon atoms. Those asymmetrically substituted carbon acids can result in compounds of the invention comprising mixtures of stereoisomers of a particular asymmetrically substituted carbon atom or a single stereoisomer. As a result, racemic mixtures, mixtures of diastereomers, as well as individual diastereomers of the compounds of the invention are included in the present invention. The terms "S" and "R" configuration, as used herein, are as defined by IUPAC 1974"RECOMMENDATIONS FOR SECTION E, FUNDAMENTAL STEREOCHEMISTRY," Puré Appl. Chem. 45: 13-30, 1976. The terms y are used for ring positions of cyclic compounds. The a side of the reference plane is that side on which the preferred substituent is located in the position with the least number. Those substituents that are on the opposite side of the reference plane are assigned the descriptor ß. It should be noted that this use differs from that of cyclic stereos, in which "a" means "below the plane" and does not denote an absolute configuration. The terms "configuration" and "β" as used herein, are as defined by "Chemical Abstracts Index Guide", Appendix IV, paragraph 203, 1987. As used herein, the term "pharmaceutically acceptable salts" refers to acid or metal salts non-toxic alkaline earth metals of the compounds of formula (I) These salts can be prepared in itself during the isolation and final configuration of the compounds of formula (I), or separately by reacting the basic or acid functions with a suitable organic or inorganic acid or base, respectively. Representative salts include, but are not limited to, the following: acetate, adipate, alginate, citrate, aspartate, benzoate, benzene sulfonate, bisulfate, butyrate, camphorrate, camphorsulfonate, digluconate, cyclopentanpropionate, dodecylisulfate, ethane sulfonate, glucoheptanoate, glycerophosphate , semisulfate, heptanoate, hexanoate, fumarate, hydrochloride, hydrobromide, iodohydrate, 2-hydroxyethanesulfonate, lactate, maleate, methanesulfonate, nicotinate, 2-naphthalenesulfonate, oxalate, pamoate, pectinate, persulfate, 3-phenylpropionate, picrate, pivalate, propionate, succinate , sulfate, tartrate, thiocyanate, p-toluenesulfonate and undecanoate. Also, groups containing basic nitrogen can be quaternized as agents, alkyl halides, such as methyl, ethyl, propyl and butyl chloride, bromides and iodides; dialkyl sulfates such as dimethyl, diethyl, dibutyl and diamyl sulfates, long chain halides such as decyl, lauryl, myristyl and stearyl chlorides, bromides and iodides, aralkyl halides such as benzyl and phenethyl bromides, and others. Therefore, water-dispersible or oil-soluble products are obtained. Examples of acids which can be used to form pharmaceutically acceptable acid addition salts include inorganic acids such as hydrochloric acid, sulfuric acid and phosphoric acid and organic acids such as oxalic acid, maleic acid, methanesulfonic acid, succinic acid and citric acid. The basic addition salts can be prepared in itself during the final isolation and purification of the compounds of formula (I), or separately by reacting carboxylic acid portions with a suitable base such as the hydroxide, carbonate or bicarbonate of a cation of pharmaceutically acceptable metal or with ammonia, or a primary, secondary or tertiary organic amine. The pharmaceutically acceptable salts include, but are not limited to, cations based on alkali and alkaline earth metals, such as sodium, lithium, potassium, calcium, magnesium, aluminum salts and the like, as well as non-toxic ammonium, quaternary ammonium and amine cations. , including but not limited to ammonium, tetramethylammonium, tetraethyl ammonium, methylamine, diethylamine, trimethylamine, triethylamine, ethylamine and the like. Other representative organic amines useful for the formation of base addition salts include diethylamine, ethylenediamine, ethanolamine, diethanolamine, piperazine and the like. The term "pharmaceutically acceptable prodrugs or prodrugs" as used herein refers to those prodrugs or prodrugs of the compounds of the present invention which are, within the scope of good medical judgment, suitable for use in contact with the tissues of humans and humans. lower animals without undue toxicity, irritation, allergic response, and the like, commensurate with a reasonable benefit / risk ratio, and effective for their intended use, as well as the zwitterionic forms, where possible, of the compounds of the invention. The term "prodrug or prodrug" refers to compounds that are rapidly transformed in vivo to produce the parent compound of the above formula, for example, by hydrolysis in the blood. A full discussion is provided in Higuchi, T., and V. Stella, "Pro-drugs as Novel Delivery Systems," A. C. Symposium Series 14 and in "Bioreversible Carriers in Drug Design", in Edward B. Roche (ed.), American Pharmaceutical Association, Pergamon Press, 1987, both of which are incorporated herein by reference.

The term "cancer" refers to cancerous diseases that can be beneficially treated by the inhibition of KSP, including, for example, solid cancers, such as carcinomas (eg, from the lungs, pancreas, thyroid, bladder or colon); myeloid disorders (e.g., myeloid leukemia); and adenomas (for example, villous adenoma). Cancer is a proliferative disease. The compounds of the invention are useful in vi tro or in vivo to inhibit the growth of cancer cells. The compounds can be used alone or in compositions together with a pharmaceutically acceptable excipient carrier. Suitable pharmaceutically acceptable carriers or excipients include, for example, processing sources and modifiers and enhancers of drug or drug release, such as, for example, calcium phosphate, magnesium stearate, talc, monosaccharides, disaccharides, starch, gelatin, cellulose, methyl cellulose, sodium carboxymethyl cellulose, hydroxypropyl-β-cyclodextrin, polyvinyl pyrrolidone, low melting point waxes, ion exchange resins, and the like, as well as combinations of any two or more thereof. Other suitable pharmaceutically acceptable excipients are described in "Remington's Pharmaceutical Sciences", Mack Pub. Co., New Jersey, 1991, incorporated herein by reference.

The effective amounts of the compounds of the invention will generally include any amount sufficient to detectably inhibit KSP activity by any of the assays described herein, by other assays of KSP activity known to those skilled in the art, or by Detection of an inhibition or alleviation of cancer symptoms. The amount of the active ingredient that can be combined with carrier materials to produce a single dosage form will vary depending on the host treated and the particular mode of administration. It will be understood, however, that the specific dose level for any particular patient will depend on a variety of factors, including the activity of the specific compound employed, age, body weight, general health, sex, diet, time of administration, route of administration, rate of excretion, combination of drugs or drugs, and the severity of the particular disease that is under therapy. The therapeutically effective amount for a given situation can easily be determined by routine experimentation and is well within the skills and judgment of expert clinicians. For purposes of the present invention, a therapeutically effective dose will generally be a total daily dose administered to a host with a single dose or the doses may be divided in amounts, for example, from 0.001 to 1000 mg / kg of body weight daily and, more preferably from 1.0 to 30 mg / kg of body weight daily. The unit dosage compositions may contain such amounts of submultiples thereof to produce the daily dose. The compounds of the present invention may be administered orally, parenterally, sublingually, by aerosolization or inhalation spray, rectally, or typically in unit dosage formulations containing conventional, non-toxic pharmaceutically acceptable carriers or excipients, adjuvants and vehicles, as appropriate. want. Topical administration may also involve the use of transdermal administration as transdermal patches or iontophoresis devices. Parenteral term as used herein includes subcutaneous injections, intravenous, intramuscular, intrasternal injection, or infusion techniques. Injectable preparations, for example, sterile injectable aqueous or oleaginous suspensions can be formulated according to the known art using suitable dispersing or wetting agents and suspending agents. The sterile injectable preparation can also be a sterile injectable solution or suspension in a non-toxic pharmaceutically acceptable diluent or solvent, for example, as a solution in 1,3-propanediol. Among the vehicles and acceptable solvents that can be used are water, Ringer's solution and isotonic sodium chloride solution. In addition, fixed, sterile oils are conventionally employed as a solvent or suspending medium. For this purpose, any soft fixed oil including synthetic mono- or diglycerides can be used. In addition, fatty acids such as oleic acid find use in the preparation of injectables. Suppositories for rectal administration of the drug or drug can be prepared by mixing a drug or drug with a suitable non-irritating excipient such as cocoa butter and polyethylene glycols, which are solid at ordinary temperatures but liquid at rectal temperature and therefore they will melt in the rectum and release the drug. Solid dosage forms for oral administration can be in capsules, tablets, pills, powders and granules. In those solid dosage forms, the active compound can be mixed with at least one inert diluent such as sucrose, lactose or starch. These dosage forms may also comprise, as is normal in practice, additional substances other than inert diluents, for example, lubricating agents such as magnesium stearate. In the case of capsules, tablets and pills, the dosage forms may also comprise buffering agents. Tablets and pills can also be • prepared additionally with enteric coatings. Liquid dosage forms for oral administration may include pharmaceutically acceptable emulsions, solutions, suspensions, syrups and elixirs containing inert diluents commonly used in the art, such as water. These compositions may also comprise adjuvants, such as wetting agents, emulsifying agents, and suspending agents, cyclodextrins and sweeteners, flavors, and perfuming agents. The compounds of the present invention can also be administered in the form of liposomes. As is known in the art, liposomes are generally derivatives of phospholipids or other lipid substances. The liposomes are formed by mono or multilamellar hydrated liquid crystals that are dispersed in an aqueous medium. Any non-toxic, physiologically acceptable and metabolizable lipid capable of forming liposomes can be used. The compositions herein in liposome form may contain, in addition to a compound of the present invention, stabilizers, preservatives, excipients and the like. The preferred lipids are phospholipids and phosphatidylcholine (lecithins), both natural and synthetic. Methods for forming liposomes are known in the art. See, for example, Prescott (ed.), "Methods in Cell Biology," "Volume XIV, Academic Press, New York, 1976, p.33 et seq. Although the compounds of the invention can be administered as the sole agent. Active pharmaceutical agents can also be used in combination with one or more other agents used in the treatment of cancer Representative agents useful in combination with the compounds of the invention for the treatment of cancer include, for example, irinotecan, topotecan, gemcitabine , gleevec, herceptin, 5-fluorouracil, leucovorin, carboplatin, cisplatin, taxanes, tezacitabine, cyclophosphamide, vinca alkaloids, and atinib, anthracyclines, rituximab, trastuzumab, topoisomerase I inhibitors, as well as other chemotherapeutic agents for cancer. prior to being employed in combination with the compounds in the invention will be used in therapeutic amounts as indicated in the Physicians' Desk Reference (PDR) 47t h Edition (1993), which is incorporated herein by reference, or in therapeutically useful amounts as is known to one skilled in the art. The compounds of the invention and the other anticancer agents can be administered at the maximum recommended chemical dose or at lower doses. The dosage levels of the active compounds in the compositions of the invention can be varied to obtain a desired therapeutic response depending on the route of administration, the severity and the response of the patient. The combination can be administered as separate compositions or as a single dosage form containing both agents. When administered as a combination, the therapeutic agents can be formulated as separate compositions, which leave at the same time or different times, or the therapeutic agents, can be given as a single composition. Antiestrogens, such as tamoxifen, inhibit the growth of breast cancer through the induction of cell cycle disruption, which requires the action of the cell cycle inhibitor p27Kip. Recently, it has been demonstrated that the activation of the Ras-Raf-MAP kinase pathway alters the phosphorylation state of p27Kip, so that its inhibitory activity in the attenuation of attenuated cell cycles, thus contributing to antiestrogen resistance ( Donovan, et al, J. Biol. Chem. 276: 40888,2001). According to the report by Donovan et al., Inhibition of MAPK signaling through treatment with MEK inhibitor changed the phosphorylation status of p27 in breast cancer cell lines refractory to hormones and thus restored sensitivity to the hormones. In consecuense, in one aspect, the compounds of formula (I) can be used in the treatment of hormone-dependent cancers, such as breast and prostate cancers, to reverse the hormone resistance commonly observed in those cancers with conventional anticancer agents. In haematological cancers, such as chronic myelogenous leukemia (CML), chromosomal translocation is responsible for the constitutively activated BCR-ABI tyrosine kinase. Affected patients respond to gleevec, a small molecule tyrosine kinase inhibitor, as a result of the inhibition of Abl kinase activity. However, many patients with advanced disease respond to the level initially, but subsequently relapse due to mutations that confer resistance in the Abl kinase domain. In vitro studies have shown that BCR-Avl uses the Raf kinase pathway to produce its effects. In addition, the inhibition of more than one kinase in the same pathway provides additional protection against mutations that confer resistance. Accordingly, in another aspect of the invention, the compounds of formula (I) are used in combination with at least one additional agent, such as gleevec, in the treatment of hematologic cancers, such as chronic myelogenous leukemia (CML), to reverse or prevent resistance to at least one additional agent. In another aspect of the invention, kits are provided that include one or more compounds of the invention. Representative kits include a compound of formula (I) and a package insert or other label that includes indications for treating a cell proliferative disease by administering a KSP inhibitory amount of the compound. The present invention will be more readily understood with reference to the following examples, which were provided by way of illustration and are not intended to be limiting of the present invention.

EXAMPLES Referring to the following examples, the compounds of the present invention were synthesized using the methods described herein, or other methods, which are well known in the art. The compounds and / or intermediates were characterized by high performance liquid chromatography (CIAD) using a Waters Millenium chromatography system with a 2690 separation module (Milford, MA). The analytical columns were the Alti to C-18 in reverse phase, 4.6 x 250 mm from Altech (Deerfield, IL). An elution gradient was used, typically starting with 5% acetonitrile / with 95% water and progressing to 100% acetonitrile over a period of 40 minutes. All solvents had 0.1% trifluoroacetic acid (TFA). The compounds were detected by ultraviolet (UV) light absorption at either 220 or 254 mm. The solvents of the (CLAD) were Burdick and Jackson (Muskegan, MI) or Fisher Scientific (Pittsburg, PA). In some cases, the purity was evaluated by thin-layer chromatography (TLC) using silica gel plates supported on plastic glass, such as, for example, flexible sheets of Baker-Flex 1B2-F Silica Gel. The results of the CCF were easily detected visually under ultraviolet light, or using the well-known iodine vapor or other different staining techniques. The mass spectrometric analysis was performed in one of two LCMS instruments: a Waters System (Alliance HT and a mass spectrometer Micromass ZQ; Column: Eclipse XDB-C18, 2.1 x 50 mm, solvent system: 5-95% ( or 35-95%, or 65-95% or 95-95%) acetonitrile in water with 0.05% TFA, flow rate of 0.8 mL / min, molecular weight range of 500-1500, cone voltage 20 V; column temperature of 40 ° C) or a Hewlett Packard System (LAB 1100 series; Column: Eclipse XDB-C18.2.1 x 50 mm; solvent system: 1-95% acetonitrile in water with 0.05% TFA; flow rate 0.4 mL / min, molecular weight range 150-850, cone voltage 50V, column temperature 30 ° C). All masses were reported as those of the protonated original ions. The GCMS analysis is performed on a Hewlett Packard instrument (gas chromatograph of the HP6890 Series with a selective mass detector 5973, injection volume, 1 μL, initial column temperature: 50 ° C, final column temperature: 250 ° C, rise time: 20 minutes, gas flow rate: 1 mL / min, column: 5% phenyl methyl siloxane, Model No. HP 190915-443, dimensions: 30. Om x 25m x 0.25m). Nuclear magnetic resonance (NMR) analysis was performed on one of the compounds with a Varnish NMR of 300 MHz (Palo Alto, CA). The spectral reference was TMS or the known chemical deviation of the solvent. Some samples of compounds have left elevated temperatures (for example, 75 ° C) to promote the increase of the solubility of the sample. The purity of some of the compounds of the invention was evaluated by elemental analysis (Desert Analytics, Tucson, AZ) Melting points were determined on a Mel-Temp apparatus at Laboratorio Devices (Holliston, MA). The preparative separations were carried out using an Instant 40 and KP-Sil, 60A chromatography system (Biotage, Charlottesville, VA), or by flash chromatography using silica gel packing material (230-400 mesh) or by CLAD using a column phase C-18. The typical solvents used by the Instantaneous 40 Biotage system and flash chromatography were dichloromethane, methanol, ethyl acetate, hexane, acetone, aqueous hydroxyamine, and triethylamine. The typical solvents used for the reverse phase CLAD were in various concentrations of acetonitrile and water with 0.1% trifluoroacetic acid. The following are abbreviations used in the examples: AcOH: Acetic acid ac: Aqueous ATP: Adenosine triphosphate 9-BBN 9-Borabicyclo [3.3.1] nonane Boc: tert-butoxycarbonyl Celite DAP or Dap filter agent: Diaminopropionate DCM: Dichloromethane DEAD : Diethyl Azodicarboxylate DIEA: Diisopropylethyl ina DMAP 4-Dimethylareneopyridine DME: 1, 2-Dimethoxyethane DMF: N, N-Dimethylformamide DMSO: Dimethyl sulfoxide DPPA: Diphenyl phosphoryl azide Et3N: Triethylamine EDC: N- (3-Dimethylaminopropyl) -N'-ethylcarbodiimide EDCI: 1- (3-Dimethylaminopropyl) 3-ethylcarbodiimide EtOAc : Ethyl acetate EtOH: Ethanol Fmoc: 9-Fluorenylmethoxycarbonyl Gly-OH Glycine HATU: O- (7- Azabenzotriazol-1-yl) -N, N, N'N'- tetramethyluronium hexafluorophosphate HBTU: 2- (lH hexafluorophosphate - Benziotrazole-1-yl) -1,1,3,3-tetramethyluronium Hex: Hexane HOBt: Butyl alcohol HOBT: 1-Hydroxybenzotriazole CLAP: High-pressure liquid chromatography NIS N-Yodosuccinimide C5o value: The concentration of an inhibitor which produces a 50% reduction in a measured activity iPrOH: Isopropanol LC / MS: Liquid chromatography / mass spectrometry PPh3: Triphenylphosphine PTFE: Polytetrafluoroethylene CLAP-FI: High pressure liquid chromatography in inverted phase TA: Ambient temperature Sat Saturated TEA: Triethylamine TFA: Trifluoroacetic acid THF: Tetrahydrofuran Thr: Threonine CCF: Thin layer chromatography Trt-Br: Ter-butyl bromide The nomenclature for the exemplary compounds was provided using the ACD Ñame program version 5.7 (November 14, 2001) available from Advanced Chemistry Development, Inc. Some of the compounds and initial materials were named using the standard IUPAC nomenclature. It should be understood that the organic compounds according to the invention may exhibit the phenomenon of tautomerism. Since the chemical structures within this specification may represent only one of the possible tautomeric forms, it should be understood that the invention encompasses any tautomeric form of the drawn structure. It should be understood that the invention is not limited to the embodiments set forth herein as an illustration, but encompasses all those forms thereof falling within the scope of the foregoing description.

Example 1 Synthesis of N- (3-aminopropyl) -N- [1- (3-benzyl-7-chloro-4-oxo-3,4-dihydroquinazolin-2-yl) -2- (dimethylamino) -2-oxoethyl ] -4- Methylbenzaptide Step 1: 3-benzyl-7-chloro-2-methylquinazolin-4 (3H) -one 2-Amino-4-chlorobenzoic acid (250 mg, 1 eq.) And N-benzylacetamide (261 mg, 1.2 eq.) Were dissolved in phosphorus oxychloride (2 ml). The reaction was placed in the microwave for 10 minutes at 150 ° C. The reaction was extinguished by pouring the mixture into ice. The crude product was extracted into ethyl acetate. The ethyl acetate layer was washed with water, 10% aqueous sodium hydroxide, dried over magnesium sulfate, filtered and concentrated to yield 3-benzyl-7-chloro-2-methylquinazolin-4 (3H) -on? like an orange solid.

Step 2: 2- (3-benzyl-7-chloro-4-oxo-3,4-dihydro-quinazolin-2-yl) '- N, N-dimethyl-acetamide. 3-Benzyl-7-chloro-2-methylquinazolin-4- (3H) -one (2 g, 1 eq.) Was dissolved in tetrahydrofuran (20 mL). The solution was cooled to -78 ° C for 15 minutes. Lithium hexamethyl disilazide (LHMDS) was slowly added and the mixture was stirred at -78 ° C for 45 minutes. Dimethylcarbamyl chloride was added and the mixture was stirred at -78 ° C for 1 h. The reaction was allowed to warm to room temperature and was stirred for 3 h. The solvent was evaporated and the resulting solid was dissolved in ethyl acetate. The ethyl acetate layer was washed with water, saturated sodium bicarbonate, saturated sodium chloride, dried over magnesium sulfate, filtered and concentrated. The crude product was purified by flash chromatography to give 2- (3-benzyl-7-chloro-4-oxo-3,4-dihydroquinazolin-2-yl) -N, N-dimethyl acetamide (1.2 g) as a solid.

Step 3: 2- (3-benzyl-7-chloro-4-oxo-3,4-dihydroquina-zolin-2-yl) -2-bromo-N, N-dimethylacetamide. To a mixture of 2- (3-benzyl-7-chloro-4-oxo-3,4-dihydroquinazolin-2-yl) -N, N-dimethylacetamide (1.1 g, 1 eq.) And sodium acetate (761 mg) , 3 eq.) In acetic acid (15 mL), bromine (158 ul, 1 eq.) Was added and the reaction was stirred at room temperature for 4 h. Water was added and the product was extracted into ethyl acetate. The ethyl acetate layer was washed several times with water, saturated sodium bicarbonate, saturated sodium chloride, dried over magnesium sulfate, filtered and concentrated to give 2- (3-benzyl-7-chloro-4-oxo-3). , 4-dihydroquinazolin-2-yl) -2-bromo-N, N-dimethylacetamide (1.44 g) as a yellow solid.

Step 4: 3- { [1- (3-benzyl-7-chloro-4-oxo-3,4-dihydro-quinazolin-2-yl) -2- (dimethylamino) -2-oxoethyl] amino} propylcarba tert-butyl matte. oc To a solution of 2- (3-benzyl-7-chloro-4-oxo-3,4-dihydroquinazolin-2-yl) -2-bromo-N, N-dimethylacetamide (1.4 g, 1 eq.) In N, N-dimethylformamide (10 ml), N-Boc-1,3-diaminopropane (2.8 g, 5 eq.) Was added. The reaction was stirred at room temperature for 4 h and then heated to 40 ° C. The mixture was stirred at 40 ° C overnight. Water and ethyl acetate were added to the mixture. The organic layer was washed with saturated sodium bicarbonate, saturated sodium chloride, dried over magnesium sulfate, filtered and concentrated. The crude product was purified by flash chromatography to give 3-. { [1- (3-benzyl-7-chloro-4-oxo-3,4-dihydroquinazolin-2-yl) -2- (dimethylamino) -2-oxoethyl] amino} tert-butyl propylcarbamate (1 g) as a pale yellow solid. Step 5: 3- [[1- (3-benzyl-7-chloro-4-oxo-3,4-dihydro-quinazolin-2-yl) -2- (dimethylamino) -2-oxoethyl] (4-methylbenzoyl) amino ] tert-butyl propylcarbamate.

To a solution of 3-. { [1- (3-benzyl-7-chloro-4-oxo-3,4-dihydroquinazolin-2-yl) -2- (dimethylamino) -2-oxoethyl] amino} tert-butyl polycarbamate (500 mg, 1 eq.) in methyl chloride (5 ml), 4-methyl benzoyl chloride (380 ul, 3 eq.) and triethylamine (660 ul, 5 eq.) were added. The reaction mixture was stirred at room temperature overnight. The solvent was evaporated and the crude product was dissolved in ethyl acetate. The ethyl acetate layer was washed with water, saturated sodium carbonate, saturated sodium chloride, dried over magnesium sulfate, filtered and evaporated to give 3- [[1- (3-benzyl-7-chloro-4-oxo Crude tert-butyl -3,4-dihydroquinazolin-2-yl) -2- (dimethylamino) -2-oxoethyl] (4-methylbenzoyl) amino] propyl carbamate.

Step 6: N- (3-aminopropyl) -N- [1- (3-benzyl-7-chloro-4-oxo-3,4-dihydro-quinazolin-2-yl) -2- (dimethylamino) -2- oxoethyl] -4-methylbenzamide.

To a solution of 3- [[1- (3-benzyl-7-chloro-4-oxo-3,4-dihydroquinazolin-2-yl) -2- (dimethylamino) 2-oxoethyl (4-methyl benzoyl) amino] tert-butyl propylcarbamate (500 mg), 20% solution of trifluoroacetic acid in methylene chloride was added at room temperature. The mixture was dried at room temperature overnight. The solvent was removed under reduced pressure. The crude product was purified by flash chromatography to give N- (3-aminopropyl) -N- [1- (3-benzyl-7-chloro-4-oxo-3,4-dihydroquinazo-lin-2-yl) -2 - (dimethylamino) -2-oxoethyl] -4-methylbenzamide (336 mg) as a white solid.

Example 2 Synthesis of N- (3-aminopropyl) -N- [1- [7-chloro-3- (3-methylbenzyl) -4-oxo-3,4-dihydroquinazolin-2-yl] -2- (diemti lamino ) -2-oxoethyl] -4-p.ethylbenzamide Step 1: 2- (7-chloro-4-oxo-3,4-dihydroquinazolin-2-yl) -N, N-dimethylacetamide.

CA a mixture of 2-amino-4-chloro methyl benzoate (5 g, 1 eq.) And N, N-dimethylamino acetamide (3.63 g, 1.2 eq.), A solution of 4M HCl in dioxane (40 ml. ). The reaction was stirred at room temperature overnight. The dioxane was removed under reduced pressure and the resulting solid residue was triturated with cold water. The aqueous solution was basified with 10% ammonium hydroxide. The precipitate was collected, washed with more cold water, washed with ether and dried to give 2- (7-chloro-4-oxo-3,4-dihydroquinazolin-2-yl) -N, N-dimethylacetamide 7.4 g (96%) ) as a white solid.

Step 2: 2-bromo-2- (7-chloro-4-oxo-3,4-dihydroquina-zolin-2-yl) -N, N-dimethylacetamide.

To a mixture of 2- (7-chloro-4-oxo-3,4-dihydro quinazolin-2-yl) -N, N-dimethylacetamide and sodium acetate (930 mg, 3 eq.) In acetic acid (15 ml) ), bromine (190 ul, 1 eq.) was added. The reaction mixture was stirred at room temperature overnight. Water was added and the product was extracted into ethyl acetate. The ethyl acetate layer was washed several times with water, sodium bicarbonate saturated with saturated sodium chloride, dried over magnesium sulfate, filtered and concentrated to give 2-bromo-2- (7-chloro-4-OXO-3). , 4-dihydroquinazolin-2-yl) -N, N-dimethylacetamide (0.95 g) as a brown solid.

Step 3: 3- { [1- (7-chloro-4-oxo-3,4-dihydroquinazolin-2-yl) -2- (dimethylamino) -2-oxoethyl] amino} tert -butyl propylcarbamate.

To a solution of 2-bromo-2- (7-chloro-4-oxo-3,4-dihydroquinazolin-2-yl) -N, N-dimethylacetamide (950 mg, 1 eq.) In N, N-dimethylformamide ( 10 ml), N-Boc-1,3-diaminopropane (2.4 g, 5 eq.) Was added. The reaction was stirred at 60 ° C for 30 minutes. Water and ethyl acetate were added. The ethyl acetate layer was washed with saturated sodium bicarbonate, saturated sodium chloride, dried over magnesium sulfate, filtered and concentrated to give 3-. { [1- (7-Chloro-4-oxo-3,4-dihydroquinazolin-2-yl) -2- (dimethylamino) -2-oxoethyl] amino-propylcarbamate of tert-butyl (1.2 g) as a pale orange solid.

Step 4: 4-methylbenzoate of 2- [1- [. { 3- [(tert-butoxycarbonyl) amino] propyl} (4-methylbenzoyl) amino] -2- (dimethylamino) -2-oxoethyl] -7-chloro-3,4-dihydroquinazolin-4-yl.

To a solution 3-. { [1- (7-chloro-4-oxo-3, -dihydroquinazolin-2-yl) -2- (dimethylamino) -2-oxoethyl] amino} pro-pylcarbate tert-butyl ether (1.2 g, 1 eq.) and methylene chloride (920 ml) at 0 ° C, 4-methyl benzoyl chloride (1.1 ml, 3 eq.) and triethylamine (1.9 ml) were added. , 5 eq.). The reaction was allowed to warm to room temperature and was stirred at room temperature overnight. The solvent was evaporated and the crude product was dissolved in ethyl acetate. The ethyl acetate layer was washed with water, saturated sodium carbonate, saturated sodium chloride, dried over magnesium sulfate, filtered and evaporated to give 4-methylbenzoate of 2- [1- [. { 3- [(tert-butoxycarbonyl) amino] propyl} (4-methylbenzoyl) amino] -2- (dimethylamino) -2-oxoethyl] -7-chloro-3,4-dihydroquinazolin-4-yl (2.3 g) as a brown solid.

Step 5: 3- [[1- (7-Chloro-4-oxo-3,4-dihydroquinazolin-2-yl) -2- (dimethylamino) 2-oxoethyl] (4-methylbenzoyl) amino] propyl carbamate tert-butyl.

To a solution of 4-methylbenzoate 2- [l- [. { 3- [(tert-butoxycarbonyl) amino] propyl} (4-methylbenzoyl) amino] -2- (dimethylamino) -2-oxoethyl] -7-chloro-3-4-dihydroquinazolin-4-yl in a 1: 1 mixture of tetrahydrofuran and water (20 ml), hydroxide was added of lithium (284 mg, 2 eq.) at room temperature. The mixture was stirred at room temperature for 3 h. The reaction mixture was acidified with 1M aqueous hydrogen chloride to pH 6-7 and subsequently extracted into methylene chloride. The organic layer was washed with more water, dried over magnesium sulfate, filtered and concentrated. The product was purified by flash chromatography to give 3- [[1- (7-chloro-4-oxo-3,4-dihydro-quinazolin-2-yl) -2- (dimethylamino) -2-oxoethyl] (4-methylbenzoyl) ) -amino] -tert-butyl propylcarbamate (257 mg) as a yellow solid.

Step 6: 3- [[1- [7-chloro-3- (3-methylbenzyl) -4-oxo-3, 4-Dihydro-quinazolin-2-yl] 2- (dimethylamino) -2-oxoethyl] (4-methylbenzoyl) amino] propyl-carbamic acid tert-butyl ester.

To a solution of 3 - [[1- (7-chloro-4-oxo-3,4-dihydroquinazolin-2-yl) 2- (dimethylamino) -2-oxoethyl (4-methylbenzoyl) amino] propylcarbamate ter -butyl (29 mg, 1 eq.) in dimethyl formamide (1 ml), 3-methylbenzyl bromide (8 μl, 1.2 eq.) and potassium carbonate (22 mg, 3 eq.) were added. The reaction mixture was stirred at room temperature overnight. Water was added and the material was extracted into ethyl acetate. The ethyl acetate layer was washed with water, saturated sodium carbonate, saturated sodium chloride, dried over magnesium sulfate, filtered and evaporated. The product was purified by flash chromatography to give 3- [[1- [7-chloro-3- (3-methylbenzyl) -4-oxo-3,4-dihydroquina-zolin-2-yl] -2- (dimethylamino) 2-Oxoethyl] (4-methylbenzoyl) amino] propylcarbamate tert-butyl. Step 7: N- (3-aminopropyl) -N- [1- [7-chloro-3- (3-methylbenzyl) 4-oxo-3,4-dihydroquinazolin-2-yl] -2 (dimethylamino) -2- oxoethyl] -4-methylbenzamide.

To a solution of 3- [[1- [7-chloro-3- (3-methylbenzyl) -4-OXO-3,4-dihydroquinazolin-2-yl] -2- (dimethylamino) -2-oxoethyl] (4 -methylbenzoyl) amino] propyl carbamate from tert-butyl, a 20% solution of trifluoroacetic acid in methylene chloride was added at room temperature. The reaction was stirred at room temperature for 2 h. The solvent was removed under reduced pressure. The crude product was purified by reverse phase CLAP to give N- (3-aminopropyl) -N- [1- [7-chloro-3- (3-methylbenzyl) -4-oxo-3,4-dihi-droquinazolin- 2-yl] -2- (dimethylamino) -2-oxoethyl] -4-methylbenzamide (9 mg) as TFA salt.

EXAMPLE 3 Representative Quinazolinone Compounds Representative quinazolinone compounds of the invention are shown in Table 1. In Table 1, MH + refers to the molecular ion observed by mass spectrometry.

Table Quinazolinone Compounds Representative fifteen twenty twenty twenty twenty 10 fifteen twenty 10 fifteen twenty 19 654.0 N- (3-aminopropyl) -N- [1- (3-benzyl-7-chloro-4-oxo-3,4-dihydroquinazolin-2-yl) -2-morpholin-4-yl-2- oxoethyl) -4- bromobenzamide 20 609.5 N- (3-aminopropyl) -N- [1- (3-benzyl-7-chloro-4-oxo-3,4-dihydroquinazolin-2-yl) -2-morpholine- 4-yl-2-oxoethyl] -4-chlorobenzamide twenty 10 fifteen twenty twenty twenty twenty 10 fifteen twenty twenty twenty Using the procedure described in Example 4, it was demonstrated that the above compounds have a KSP inhibitory activity at an IC5u of less than about 50 μM. Certain of the compounds have a CIS0 of less than about 1 μM, and certain other compounds have an IC50 of less than about 100 nM.

Example 4 Assay to Determine KSP Activity In this example, a representative in vitro assay for determining KSP activity is described. Purified microtubules from bovine brain were purchased from Cytoskeleton Inc. The motor domain of the human KSP (Eg5, KNSL1) was cloned and purified to a purity greater than 95%. The Biomol Green was purchased from Affinity Research Products Ltd. The microtubules and the KSP motor protein were diluted in assay buffer (20 mM Tris-HCl, pH 7.5, MgCl2 ImM, 10 mM DTT and 0.25 mg / ml BSA) a concentration of 35 μg / ml for microtubules and 45 nM for KSP. The microtubule / KSP mixture was then preincubated at 37 ° C for 10 min to promote the binding of KPS to the microtubules. ATP was also diluted to a concentration of 300 μM in the same assay buffer. To each well of the resulting plate (384-well plate) containing 1.25 uL of the compounds in DMSO or DMSO only, 25 uL of ATP solution. To begin the reaction, 25 uL of microtubule / KSP solution was added to the ATP / compound mixture. Plates were incubated at room temperature for 1 hr. At the end of the incubation period, 65 uL of Biomol Green was added to each well. The plates were incubated for 5-10 min and then the absorbance at 630 nm was determined. The Green Biomol reagent is a malachite green based on a dye that detects the release of inorganic phosphate. The revealed color signal was read using a Victor II reader. The concentration of each compound for 50% inhibition (CI5o) was calculated by non-linear regression using the data analysis program XLFit for Excel or Prism by GraphPad Software Inc. Although the preferred embodiment of the invention has been illustrated and described, it will be appreciated that various changes may be made here without departing from the spirit and scope of the invention. It is noted that in relation to this date, the best method known by the applicant to carry out the aforementioned invention, is the conventional one for the manufacture of the objects to which it relates.

Claims (41)

1. CLAIMS Having described the invention as above, the content of the following claims is claimed as property. 1. A compound, characterized in that it has the formula: or a stereoisomer, tautomer, pharmaceutically acceptable salt, or prodrug thereof, wherein X is 0 or S; Ri is selected from the group consisting of (1 hydrogen, (2-substituted or unsubstituted alkyl, (3-substituted or unsubstituted alkenyl, (4-substituted or unsubstituted alkynyl, (5-substituted or unsubstituted aryl; unsubstituted, (7 substituted or unsubstituted heterocyclyl, (8 substituted or unsubstituted alkylsulfonyl, and (9 substituted or unsubstituted arylsulfonyl; R2 is selected from the group consisting of (1) hydrogen, (2) substituted or unsubstituted alkyl; (3) substituted or unsubstituted alkenyl, and (4) substituted or unsubstituted alkynyl, R3 is selected from the group consisting of (1) C02R? O, (2) CORio, (3) CONR? R? 2, ( 4) S (0) mR? 3, and (5) - S02NR? 4R_5; or R2 and R3 taken together with the carbon atom to which they are attached form a carbocyclic or heterocyclic ring of 3 to 7 members; that when R4 and R5 are taken together to form a heterocyclic ring of 5 to 12 members, R 3 is CONRnR? _ Or R2 and R3 taken together with the carbon atom to which they are attached form a carbocyclic or heterocyclic ring of 3 to 7 members; R 4 is selected from the group consisting of (1) hydrogen, (2) substituted or unsubstituted alkyl; (3) substituted or unsubstituted alkenyl; (4) substituted or unsubstituted alkynyl; (5) substituted or unsubstituted aryl; (6) substituted or unsubstituted heteroaryl, and (7) substituted or unsubstituted heterocyclyl; R5 is selected from the group consisting of (1) hydrogen, (2) substituted or unsubstituted alkyl; (3) substituted or unsubstituted alkoxy; (4) substituted or unsubstituted aryl; (5) substituted or unsubstituted heteroaryl; (6) substituted or unsubstituted heterocyclyl; (7) COR? 7, (8) C02R? 8, (9) CONR? 9R20, and (10) S02R2 ?; or R4 and R5 are taken together with the nitrogen atom to which they are attached form a heteroaryl or heterocyclyl ring, wherein the heteroaryl ring contains one or two heteroatoms in the ring, wherein the heterocyclyl ring contains one or two heteroatoms in the ring. the ring, and wherein the heteroaryl or heterocyclyl ring is optionally substituted with a halogen, alkyl, hydroxy, amino, cyano, alkylamino, dialkylamino, alkyl aminoalkyl, dialkylaminoalkyl, alkoxy, aryl, aryloxy, heteroaryl, arylalkyl, heterocycle, aminocarbonyl group, carbonylamino, alkylcarbonyl, alkylcarboxy, alkylaminocarbonyl alkylcarbonylamino, carbocycle, or heteroarylalkyl; with the proviso that when R4 and R5 taken together with the nitrogen atom to which they are attached form a 5-membered heterocyclic ring, the heterocyclic ring is not a 2,4,4-dioxo-3-oxazolidinyl ring, a ring of 2,5-dioxo-l-imidazolidinyl or a 2,4,5-trioxo-l-imidazolidinyl ring; Rs, R7, R8 and R9 are independently selected from the group consisting of (1) hydrogen, (2) halogen, (3) hydroxy, ((44)) nitro, (5) amino, (6) cyano, (7) alkoxy, (8) alkylthio, ((99)) methylenedioxy, (10) haloalkoxy, (11) C02R? o, (12) CORio, (13) ORio, ((1144)) CONR ?? R? 2, (15) ) substituted or unsubstituted alkyl, (16) substituted or unsubstituted aryl, (17) substituted or unsubstituted heteroaryl, (18) substituted or unsubstituted alkylamino, ((1199)) substituted or unsubstituted dialkylamino, (20) substituted alkylsulfonyl or unsubstituted, (21) substituted or unsubstituted arylsulfonyl, (22) substituted or unsubstituted alkylcarboxy, (23) substituted or unsubstituted carboxamido, (24) substituted or unsubstituted carboxyamino, (25) substituted or unsubstituted aminocarboxy, ( 26) substituted or unsubstituted aminocarbonyl, and (27) substituted or unsubstituted alkylsulfonamido; Rio Rii R12, R_3, R_, 15, R_7, Ris, R19, R2o and R_? are independently selected from the group consisting of (1) hydrogen, (2) substituted or unsubstituted alkyl; (3) substituted or unsubstituted alkenyl; (4) substituted or unsubstituted alkynyl; (5) substituted or unsubstituted aryl; (6) substituted or unsubstituted heteroaryl; and (7) substituted or unsubstituted heterocyclyl; or n Y R12, R_ and Ris, or R? 9 and R20 taken together form a carbocyclic or heterocyclic ring of 3 to 7 members; and m = 0, 1 or
2. 2. The compound according to claim 1, characterized in that the substituted alkyl comprises arylalkyl, heteroarylalkyl, heterocyclylalkyl, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl or sulfonamidoalkyl.
3. 3. The compound according to claim 1, characterized in that X is O.
4. 4. The compound according to claim 1, characterized in that Rx is substituted or unsubstituted arylalkyl.
5. 5. The compound according to claim 4, characterized in that Rx is benzyl.
6. 6. The compound according to claim 4, characterized in that Ri is substituted benzyl.
7. 7. The compound according to claim 6, characterized in that Ri is benzyl substituted with halogen.
8. 8. The compound of ccoonnffoorrmmiiddaadd with claim 7, characterized in that Ries 3-chlorobenzyl.
9. 9. The compound according to claim 7, characterized in that Ries 3-fluorobenzyl.
10. 10. The compound according to claim 7, characterized in that Ries 3-methoxybenzyl.
11. 11. The compound according to claim 7, characterized in that Ri is 3-trifluoro methylbenzyl.
12. 12. The compound according to claim 7, characterized in that Rx is 3-trifluoro methoxybenzyl.
13. 13. The compound according to claim 6, characterized in that Rx is 3,5-dimethylbenzyl.
14. 14. The compound according to claim 1, characterized in that Rx is 2-naphthylmethyl.
15. 15. The compound according to claim 1, characterized in that R2 is hydrogen and R3 is COR? 0.
16. 16. The compound according to claim 15, characterized in that RXo is alkyl.
17. 17. The compound according to claim 1, characterized in that R2 is hydrogen and R3 is CONRnR12.
18. 18. The compound according to claim 17, characterized in that ü and Ra2 are alkyl.
19. 19. The compound according to claim 18, characterized in that Ruy R_2 are methyl.
20. 20. The compound according to claim 17, characterized in that Ru and R_2 taken together with the nitrogen atom to which they are attached form a heterocyclic ring of 3 to 7 members.
21. 21. The compound according to claim 1, characterized in that R4 is alkyl substituted with amino.
22. 22. The compound according to claim 21, characterized in that R4 is 3-aminopropyl.
23. 23. The compound according to claim 1, characterized in that R5 is hydrogen, alkyl, aryl, or COR? 7.
24. 24. The compound according to claim 23, characterized in that R5 is C0R? 7.
25. 25. The compound according to claim 24, characterized in that R17 is aryl, arylalkyl, aryl substituted with alkyl or aryl substituted with halogen.
26. 26. The compound according to claim 25, characterized in that the aryl is phenyl.
27. 27. The compound according to claim 1, characterized in that Rs, Rs and R9 are hydrogen.
28. 28. The compound according to claim 1, characterized in that R7 is halogen.
29. 29. The compound according to claim 1, characterized in that it is selected from the group consisting of: (3-benzyl-7-chloro-4-oxo-3,4-dihydroquinazolin-2-yl) . { (4-bromobenzoyl) [3- (dimethylamino) propyl] amino} ethyl acetate; [(3-Aminopropyl) (4-methylbenzoyl) amino] (3-benzyl-7-chloro-4-oxo-3,4-dihydroquinazolin-2-yl) ethyl acetate; (3-benzyl-7-chloro-4-oxo-3,4-dihydroquinazolin-2-yl) [[3- (dimethylamino) propyl] (4-methylbenzoyl) amino] isopropyl acetate; [(3-aminopropyl) (4-bromobenzoyl) amino] (3-benzyl-7-chloro-4-oxo-3,4-dihydroquinazolin-2-yl) isopropyl acetate; [(3-aminopropyl) (4-methylbenzoyl) amino] (3-benzyl-7-chloro-4-oxo-3,4-dihydroquinazolin-2-yl) isopropyl acetate; N- (3-aminopropyl) -N- [1- (3-benzyl-7-chloro-4-oxo-3,4-dihydroquinazolin-2-yl) -2- (diethylamino) -2-oxoethyl] -4- Bromo-benzamide; N- (3-aminopropyl) -N- [1- (3-benzyl-7-chloro-4-oxo-3,4-dihydroquinazolin-2-yl) -2- (diethylamino) -2-oxoethyl] -4- methylbenzamide; N- (3-aminopropyl) -N- [1- (3-benzyl-7-chloro-4-oxo-3,4-dihydroquinazolin-2-yl) -2-oxo-2-pyrrolidin-1-ylethyl] - 4-bromo-benzamide; N- (3-Aminopropyl) -N- [1- (3-benzyl-7-chloro-4-oxo-3,4-dihydroquinazolin-2-yl) -2-oxo-2-pyrrolidin-1-ylethyl] - 4-chloro-benzamide; N- (3-aminopropyl) -N- [1- (3-benzyl-7-chloro-4-oxo-3,4-dihydroquinazolin-2-yl) -2-morpholin-4-yl-2-oxoethyl] - 4-bromo-benzamide; N- (3-Aminopropyl) -N- [1- (3-benzyl-7-chloro-4-oxo-3,4-dihydroquinazolin-2-yl) -2-morpholin-4-yl-2-oxoethyl] - 4-chloro-benzamide; N- (3-aminopropyl) -N- [1- (3-benzyl-7-chloro-4-oxo-3,4-dihydroquinazolin-2-yl) -2- (dimethylamino) -2-oxoethyl] -4- Bromo-benzamide; N- (3-aminopropyl) -N- [1- (3-benzyl-7-chloro-4-oxo-3,4-dihydroquinazolin-2-yl) -2- (dimethylamino) -2-oxoethyl] -4- chloro-benzamide; N- (3-aminopropyl) -N- [1- (3-benzyl-7-chloro-4-oxo-3,4-dihydroquinazolin-2-yl) -2-oxo-2-pyrrolidin-1-ylethyl] - 4-methyl-benzamide; N- (3-aminopropyl) -N- [1- (3-benzyl-7-chloro-4-oxo-3,4-dihydroquinazolin-2-yl) -2- (dimethylamino) -2-oxoethyl] -4- methyl-benzamide; N- (3-Aminopropyl) -N- [1- [7-chloro-3- (3-chlorobenzyl) -4-OXO-3,4-dihydroquinazolin-2-yl] -2- (dimethylamino) -2-oxo -ethyl] -4-methylbenzamide; N- (3-aminopropyl) -N- [1- [7-chloro-3- (3-fluorobenzyl) -4-OXO-3,4-dihydroquinazolin-2-yl] -2- (dimethylamino) -2-oxo -ethyl] -4-methylbenzamide; N- (3-Aminopropyl) -N- [1- [7-chloro-3- (3-methylbenzyl) -4-oxo-3,4-dihydroquinazolin-2-yl] -2- (dimethylamino) -2-oxoe -ethyl] -4-methylbenzamide; N- (3-aminopropyl) N- [1-. { 7-Chloro-4-oxo-3- [4- (trifluoromethoxy) benzyl] -3,4-dihydroquinazolin-2-yl} -2- (dimethylamino) -2-oxoethyl] -4-methylbenzamide; N- (3-Aminopropyl) -N- [1- [7-chloro-3- (4-chlorobenzyl) -4-oxo-3,4-dihydroquinazolin-2-yl] -2- (dimethylamino) -2-oxo -ethyl] -4-methylbenzamide; N- (3-aminopropyl) -N- [1- [7-chloro-3- (3-methoxybenzyl) -4-oxo-3,4-dihydroquinazolin-2-yl] -2- (dimethylamino) -2-oxoe -ethyl] -4-methylbenzamide; N- (3-Aminopropyl) -N- [1- [7-chloro-3- (2-naphthylmethyl) -4-oxo-3,4-dihydroquinazolin-2-yl] -2- (dimethylamino) -2-oxo -ethyl] -4-methylbenzamide; N- (3-Aminopropyl) N- [1- [7-chloro-4-oxo-3- [3- (trif? Uo-romethyl) benzyl] -3,4-dihydroquinazolin-2-yl} -2- (dimethylamino) -2-oxoethyl] -4-methylbenzamide; N- (3-Aminopropyl) N- [1- [7-chloro-4-oxo-3- [3- (trifluo-romethoxy) benzyl] -3,4-dihydroquinazolin-2-yl} -2- (dimethylamino) -2-oxoethyl] -4-methylbenzamide; N- (3-aminopropyl) -N- [1- [7-chloro-3- (3-hydroxy-benzyl) -4-oxo-3,4-dihydroquinazolin-2-yl] 2- (dimethylamino) -2- oxoethyl] -4-methylbenzamide; N- (3-aminopropyl) -N- [1- [7-chloro-3- (3,5-dimethylbenzyl) -4-OXO-3,4-dihydroquinazolin-2-yl] -2- (dimethylamino) -2-oxoethyl] -4-methylbenzamide; N- (3-aminopropyl) -N- [1- [3- (1,1'-biphenyl-3-ylmethyl) -7-chloro-4-oxo-3,4-dihydroquinazolin-2-yl] -2- (dimethylamino) -2-oxoethyl] -4-methylbenzamide; N- (3-Aminopropyl) -N- [1- [7-chloro-3- (3-cyanobenzyl) -4-OXO-3,4-dihydroquinazolin-2-yl] -2- (dimethylamino) -2-oxo -ethyl] -4-methylbenzamide; N- (3-Aminopropyl) -N- [1- [7-chloro-3- (3-nitrobenzyl) -4-oxo-3,4-dihydroquinazolin-2-yl] -2- (dimethylamino) -2-oxo -ethyl] -4-methylbenzamide; N- (3-Aminopropyl) -N- [1- [7-chloro-3- (3,4-dichloro-benzyl) -4-oxo-3,4-dihydroquinazolin-2-yl] -2- (dimethylamino) -2-oxoethyl] -4-methylbenzamide; N- (3-aminopropyl) -N- [1- (3-benzyl-7-chloro-4-oxo-3,4-dihydroquinazolin-2-yl) -2- [ethyl (methyl) amino] -2-oxoethyl } -4-methylbenzamide; N- (3-aminopropyl) N-. { l- [7-Chloro-3 (3, 5-dimethyl-benzyl) -4-oxo-3,4-dihydroquinazolin-2-yl] -2- [ethyl (methyl) -amino] -2-oxo ethyl} -4-methylbenzamide; N- (3-aminopropyl) -N-. { l- [7-Chloro-3- (3, 5-dimethyl-benzyl) -4-oxo-3,4-dihydroquinazolin-2-yl] -2- [ethyl (methyl) -amino] -2 -oxoethyl} -4-methylbenzamide; N- (3-aminopropyl) -N-. { l- [7-Chloro-3- (3-methoxybenzyl) -4-OXO-3,4-dihydroquinazolin-2-yl] -2- [ethyl (methyl) amino] -2-oxo-ethyl} -4-methylbenzamide; N- (3-aminopropyl) -N- [1- [7-chloro-3- (3,5-difluorobenzyl) -4-OXO-3,4-dihydroquinazolin-2-yl] -2- (dimethylamino) -2-oxo-ethyl] -4-methylbenzamide; N- (3-aminopropyl) -N- [1-. { 7-Chloro-3- [(6-chloropyridin-2-yl) methyl] -4-oxo-3,4-dihydroquinazolin-2-yl} 2- (dimethylamino) -2-oxoethyl] -4-methylbenzamide; N- (3-aminopropyl) -N- [1-. { 7-Chloro-3- [(2-chloropyridin-4-yl) methyl] 4-oxo-3,4-dihydroquinazolin-2-yl} -2- (dimethylamino) 2-oxoethyl] -4-methylbenzamide; and N- (3-aminopropyl) -N- [1- [7-chloro-4-oxo-3- (quinolin- '2-ylmethyl) -3,4-dihydroquinazolin-2-yl] -2- (dimethylamino) -2-oxoethyl] -4-methylbenzamide.
30. 30. A composition characterized in that it comprises a pharmaceutically acceptable carrier and an amount of a compound according to claim 1, effective to inhibit the activity of KSP in a human or animal subject when administered thereto.
31. 31. The composition according to claim 30, characterized in that it also comprises at least one additional agent for the treatment of cancer.
32. 32. The composition according to claim 31, characterized in that at least one additional agent for the treatment of cancer is selected from irinotecan, topotecan, gemcitabine, gleevec, herceptin, 5-fluorouracil, leucovorin, carboplatin, cisplatin, taxanes, tezacitabine, cyclophosphamide, vinca alkaloids, imatinib, anthracyclines, rituximab and trastuzumab.
33. 33. Use of a compound according to claim 1 for preparing a medicament for treating a ction by modulating the activity of the KSP protein in a human or animal subject in need of such treatment.
34. 34. Use according to claim 33, wherein the compound has an IC50 value of less than about 50 μM in a cell proliferation assay.
35. 35. Use according to claim 33, wherein the ction is cancer.
36. 36. Use of a composition comprising an amount of a compound according to claim 1 effective to make a medicament for inhibiting the activity of KSP in a human or animal subject.
37. 37. Use of a composition comprising an amount of a compound according to claim 1, effective to make a medicament for inhibiting the activity of KSP and treating a carcinogenic disorder in a human or animal subject.
38. 38. Use according to claim 37, which further comprises administering to the human or animal subject at least one additional agent for the treatment of cancer.
39. 39. Use according to claim 38, wherein at least one additional agent for the treatment of cancer is selected from irinotecan, topotecan, gemcitabine, gleevec, herceptin, 5-fluoro uracil, leucovorin, carboplatin, cisplatin, taxanes, tezacitabine, cyclophosphamide, vinca alkaloids, imatinib, anthracyclines, rituximab and trastuzumab.
40. 40. The compound according to claim 1, for use in the treatment of cancer.
41. 41. The use of a compound according to claim 1 in the manufacture of a medicament for the treatment of cancer.